FIELD OF THE INVENTION

The present invention relates to a method of converting an alcohol into a corresponding halide. Further, the present invention relates to a method of converting an alcohol into a corresponding substitution product, wherein this method comprises as a step thereof the method of converting an alcohol into a corresponding halide.

BACKGROUND OF THE INVENTION

Substitution reactions of hydroxyl groups of alcohols with nucleophiles to give, for example, halides are a fundamental transformation of organic chemistry. In most cases direct substitution of a hydroxyl group of an alcohol by a nucleophile is not possible, since the hydroxyl group is a poor leaving group. Hence, this chemical transformation lacks a thermodynamic driving force, and in addition a high activation energy has to be provided as the activation barrier is comparably high.

Therefore, known methods for carrying out a reaction in which the hydroxyl group of an alcohol is substituted by a halogen atom use reagents which activate the hydroxyl group of the starting material and bind the water liberated during the substitution reaction. While by using reagents for activation of the hydroxyl group the required amount of activation energy is decreased, binding of the water increases the thermodynamic driving force. A known method for the substitution of a hydroxyl group by a chlorine atom, which utilizes these effects, is the Appel reaction (see, for example, Appel, R.; Kleinstuck, R. Chem. Ber. 1974, 107, 5-12). In the Appel reaction an alcohol is reacted with carbon tetrachloride and triphenylphosphane in order to give the corresponding chloride, wherein the hydroxyl group of the alcohol is replaced by a chlorine atome. However, as a drawback, the Appel reaction requires the use of stoichiometric amounts of triphenylposhane (and highly carcinogenic tetrachloromethane), which in the course of the reaction is converted into triphenylphosphane oxide and therefore produce a high weight amount of waste product.

Further methods known from the prior art for replacing the hydroxyl group of an alcohol by a chlorine atom employ acid chlorides such as thionyl chloride or phosgene as chlorination agent in the presence of Ν,Ν-dimethylformamide (see, for example, DE 1 133 716 and DE 2 653 150 C2). In these methods, Ν,Ν-dimethylformamide is employed in catalytic amounts. However, thionyl chloride is a highly toxic and corrosive liquid, which during the process is converted into toxic sulphur dioxide. Phosgene is also a highly toxic reagent. With both reagents hydrogenchloride, a strong acid, is additionally formed as stoichiometric byproduct. Thus undesired side reactions with functional groups present in the substrate may occur. In addition, hydrochloric acid may cause corrosion of reactor materials containing metal, which provides a further limitation for the application in industrial processes. Consequently, special measures need to be taken in order to minimize hazards arising from the use of such reagents. Further known methods use [l,3,5]triazine or pivaloyl chloride as the chlorination agent in the conversion of alcohols to the corresponding chlorides in the presence of N,N-Dimethylformamide (see L. De Luca, G. Giacomelli, A. Porcheddu, Org. Lett. 2002, 4, 553-555, and A. Dubey, A. K. Upadhyay, P. Kumar, Tetrahedron Lett. 2010, 51, 744-746). However, in these procedures N,N- dimethylformamide is used in excess amounts as solvent and has to be treated with the reagent prior to the addition of the alcohol substrate.

The method of Dubey et al. uses a pre-formed complex of Ν,Ν-dimethylformamide and pivaloyl chloride for converting alcohols in to the corresponding chlorides (see A. Dubey, A. K. Upadhyay, P. Kumar, Tetrahedron Letters 2010, 51, 744-746). In this regard, the alcohols are treated with a pre- formed complex of Ν,Ν-dimethylformamide and pivaloyl chloride.

A method published by Kimura et al. (see. Y. Kimura, D. Matsuura, T. Hanawa, Y. Kobayashi, Tetrahedron Letters 2012, 53, 1116-1118) relates to a preparation method for the Vilsmeier reagent and related imidoyl chlorides. The Vilsmeier reagent is used for the transformation of alcohols into chlorides.

In sum, there is a need to provide new methods of converting an alcohol in a corresponding halide which are broadly applicable, can be easily performed and take into account the drawbacks of the prior art.

SUMMARY OF THE INVENTION

This need is addressed by the present invention as defined in the appended claims, described in the description, and illustrated in the Examples. The present invention relates to a method of converting an alcohol into a corresponding halide, the method comprising:

Reacting the alcohol with an optionally substituted aromatic carboxylic acid halide in presence of an N-substituted formamide to replace a hydroxyl group of the alcohol by a halogen atom.

In embodiments the aromatic carboxylic acid halide is an aromatic carboxylic acid chloride or an aromatic carboxylic acid bromide.

In preferred embodiments the aromatic carboxylic acid halide is an optionally substituted benzoic acid halide.

In some embodiments of the method of converting an alcohol into a corresponding halide the N- substituted formamide is an N-monosubstituted formamide or an Ν,Ν-disubstituted formamide. In some embodiments the alcohol is a primary, secondary or tertiary alcohol. In some embodiments the alcohol is an optionally substituted alkyl alcohol. In some embodiments the alcohol is an optionally substituted allylic alcohol. In some embodiments the alcohol is an optionally substituted propargylic alcohol. In some embodiments the alcohol is an optionally substituted benzylic alcohol. In some embodiments the alcohol is an optionally substituted a-hydroxy carboxylic acid ester. In some embodiments the alcohol is an optically active alcohol.

In some embodiments, the conversion of the alcohol into the corresponding halide is carried out in a solvent. In other embodiments the conversion of the alcohol into the corresponding halide is carried out under solvent-free conditions.

The present invention also relates to a method of converting an alcohol into a corresponding substitution product, the method comprising:

(a) performing any one of the methods of converting an alcohol into the corresponding halide described herein; and

(b) reacting the corresponding halide with a nucleophile to convert the halide into the nucleophilic substitution product.

In some embodiments of the method of converting an alcohol into a corresponding substitution product steps (a) and (b) are performed in a one-pot procedure without isolation of the halide. In some embodiments of the method of converting an alcohol into a corresponding substitution product the nucleophile is selected from the group consisting of C nucleophiles, N nucleophiles, O nucleophiles, and S nucleophiles. DETAILED DESCRIPTION OF THE INVENTION

It was an object of the present invention to provide new methods of converting an alcohol into a corresponding halide which are broadly applicable and can be easily performed.

Thus, the present invention relates to a method of converting an alcohol into a corresponding halide, the method comprising:

Reacting the alcohol with an optionally substituted aromatic carboxylic acid halide in presence of an N-substituted formamide to replace a hydroxyl group of the alcohol by a halogen atom.

In the methods of converting an alcohol into a corresponding halide described herein the hydroxyl group of the alcohol is replaced by a halogen atom which derives from the optionally substituted aromatic carboxylic acid halide. In other words, the halogen atom which replaces the hydroxyl group of the alcohol is provided by the optionally substituted aromatic carboxylic acid halide. The term "aromatic carboxylic acid halide" as used herein in general refers to a compound having a halogenocarbonyl group linked to an aromatic nucleus, such as, for example, a benzene or a naphthalene nucleus. The term "optionally substituted aromatic carboxylic acid halide" in general encompasses an optionally substituted aromatic carboxylic acid fluoride, an optionally substituted aromatic carboxylic acid chloride, an optionally substituted aromatic carboxylic acid bromide, and an optionally substituted aromatic carboxylic acid iodide. The term "optionally substituted" as used in context with the aromatic carboxylic acid halide indicates that the aromatic carboxylic acid halide may be unsubstituted or substituted. In some embodiments of the methods of converting an alcohol into a corresponding halide described herein the optionally substituted aromatic carboxylic acid halide is an optionally substituted aromatic carboxylic acid chloride or an optionally substituted aromatic carboxylic acid bromide. Preferably, the optionally substituted aromatic carboxylic acid halide is an optionally substituted aromatic carboxylic acid chloride.

The present inventor has found a method of converting an alcohol into a corresponding halide which has a broad scope and is applicable to a great variety of alcohols. In particular, the inventor has found out that by using an optionally substituted aromatic carboxylic acid halide and an N- substituted formamide alcohol substrates having a great structural variety can be converted into the corresponding halide. Starting from an alcohol, this reaction in general provides the halogenated product in satisfactory to high yield and selectivity. On the other hand, an ester formed as a byproduct from the alcohol used as starting material in a reaction with the aromatic carboxylic acid halide is in general formed in low to minimum amounts only. The method disclosed herein further tolerates a large variety of functional groups present in the starting materials. Furthermore, the method of converting an alcohol into a corresponding halide allows for an ecologically beneficial synthesis of chlorinated compounds since the amount of waste products can be kept low compared to known methods. In this respect, it is in general sufficient to employ the N-substituted formamide in catalytic amounts. In addition, the method of the invention can be performed under solvent-free conditions. As a further advantageous consequence, the method of converting an alcohol into a corresponding halide is easily scalable. Hence, the conversions described herein can be up-scaled, and the methods described herein can be applied in syntheses on larger scale.

As has been found out by the inventor, the presence of the N-substituted formamide in the conversion of an alcohol into a corresponding halide described herein is required in order to perform such conversion successfully. In case that the N-substituted formamide is absent, as shown by numerous examples the alcohol directly reacts with the aromatic carboxylic acid halide to form an ester, and only low to minimum amounts of the desired conversion product in which the hydroxyl group of the alcohol is replaced by the halogen atom are obtained. Without wishing to be bound by any theory, it can be therefore assumed that the N-substituted formamide catalyzes the desired conversion of the alcohol into the corresponding halide.

As described herein, the methods of converting an alcohol into a corresponding halide comprise reacting the alcohol with an optionally substituted aromatic carboxylic acid halide in the presence of an N-substituted formamide to replace a hydroxyl group of the alcohol by a halogen atom. Accordingly, in the methods described herein the aromatic carboxylic acid halide is reacted with the alcohol in the presence of the N-substituted formamide to give the corresponding halide. In particular, in order to undergo reaction, the alcohol may be contacted with the aromatic carboxylic acid halide. In particular, the alcohol may be contacted with the aromatic carboxylic acid halide in the presence of the N-substituted formamide. Since the alcohol and the aromatic carboxylic acid halide are reacted with each other in the presence of the N-substituted formamide, in embodiments of the methods described herein a conversion of the alcohol to the corresponding halide employing a preformed halogenation reagent, such as, for example, a pre-formed complex obtained from a formamide and a carboxylic acid halide, or a pre-formed Vilsmeier reagent, may be avoided. In this regard, the term "pre-formed halogenation reagent" in particular denotes a halogenation reagent, which is pre-formed by reacting a formamide with a carboxylic acid halide prior to contacting the obtained reagent with the alcohol to be converted. Thus, since in the methods described herein the aromatic carboxylic acid halide and the alcohol are reacted with each other in the presence of the N- substituted formamide, in embodiments an additional step of pre-forming a halogenation reagent, in particular by reacting a formamide with a carboxylic acid halide, may be avoided. Accordingly, the methods described herein allow for carrying out the conversion of an alcohol into the corresponding halide in an efficient manner.

Throughout this whole specification, whenever a compound, a group, a radical, and the like is denoted as "optionally substituted", this means that said compound, group, radical, and the like may either be unsubstituted, or that said compound, group, radical, and the like may be substituted with one or more substituents.

In preferred embodiments of the methods of converting an alcohol into a corresponding halide disclosed herein above or below the optionally substituted aromatic carboxylic acid halide is an optionally substituted benzoic acid halide. With this regard, the term "optionally substituted benzoic acid halide" encompasses an optionally substituted benzoic acid fluoride, an optionally substituted benzoic acid chloride, an optionally substituted benzoic acid bromide and an optionally substituted benzoic acid iodide. In any embodiment in which reference to an "optionally substituted benzoic acid halide" is made the term "optionally substituted" denotes that the benzoic acid halide may be unsubstituted or may be substituted with one or more substituents independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl optionally substituted alkoxy, optionally substituted alkanoyloxy, optionally substituted alkylamino, optionally substituted alkanoylamino, optionally substituted alkanoyl, carboxyl, optionally substituted alkoxycarbonyl, carbamoyl, optionally substituted N-alkylcarbamoyl, optionally substituted Ν,Ν-dialkylcarbamoyl, optionally substituted thioalkoxy, optionally substituted alkylsulfonyl, and optionally substituted alkylsulfoxyl.

The possible meaning of some substituents disclosed within the context of the "optionally substituted benzoic acid halide" is defined in the following. Examples for a "halogen" are a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. The term "optionally substituted aryl" may refer to an aromatic hydrocarbon radical having six to ten ring atoms, and includes fused and non-fused aryl rings. Preferably, the aromatic hydrocarbon radical has six ring atoms, i.e. preferably the aromatic hydrocarbon radical is a phenyl radical. As denoted by the term "optionally substituted", the aryl group may be unsubstituted or substituted. Substituents of the aryl group may be, for example, H, halogen, N0 ₂ , CN, NMe ₂ , OMe, and the like. The term "optionally substituted heteroaryl" may refer to aromatic radicals containing from five to ten skeletal ring atoms, preferably from five to seven skeletal ring atoms, more preferably five or six skeletal ring atoms, where one or more of the ring atoms is a heteroatom independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon and selenium, preferably selected from oxygen, nitrogen and sulfur, but not limited to these atoms. The term "heteroaryl" may include heteroaryl radicals having one or two heteroatoms. "Heteroaryl" may also include fused and non-fused heteroaryls having from five to ten skeletal ring atoms. As denoted by the term "optionally substituted", the heteroaryl group may be unsubstituted or substituted. Substituents of the heteroaryl group may be, for example, H, halogen, N0 ₂ , CN, NMe ₂ , OMe, and the like. The term "optionally substituted alkyl" may refer to a linear or branched C1-C10, preferably to a linear or branched C1-C6, more preferably to a linear or branched C1-C4, most preferably to a linear or branched C1-C3 saturated hydrocarbon radical. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and the like. As denoted by the term "optionally substituted", the alkyl group may be unsubstituted or substituted. Substituents of the alkyl group may be, for example, H, halogen, N0 ₂ , CN, NMe ₂ , OMe, and the like. The term "optionally substituted alkenyl" may refer to a linear or branched C2-C10, preferably to a linear or branched C2-C6, more preferably to a linear or branched C2-C4, most preferably to a linear or branched C2-C3 radical having one or more carbon-carbon double bond(s). The group may be either in the cis or trans and E or Z, respectively, configuration about the double bond(s), and should be understood to include both isomers. Non-limiting examples include ethenyl (- CH=CH ₂ ), 1-propenyl (-CH ₂ CH=CH ₂ ), isopropenyl [-C(CH ₃ )=CH ₂ ], butenyl, 1,3-butadienyl and the like. As denoted by the term "optionally substituted", the alkenyl group may be unsubstituted or substituted. Substituents of the alkenyl group may be, for example, H, halogen, N0 ₂ , CN, NMe ₂ , OMe, and the like. The term "optionally substituted alkynyl" may refer to a linear or branched C2-C10, preferably to a linear or branched C2-C6, more preferably to a linear or branched C2-C4, most preferably to a linear or branched C2-C3 hydrocarbon radical having one or more carbon-carbon triple bond(s). Non-limiting examples include ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. As denoted by the term "optionally substituted", the alkynyl group may be unsubstituted or substituted. Substituents of the alkynyl group may be, for example, H, halogen, N0 ₂ , CN, NMe ₂ , OMe, and the like. The term "optionally substituted alkoxy" may refer to an alkyl ether radical, O-alkyl, wherein the alkyl group is a linear or branched C1-C10, preferably a linear or branched C1-C6, more preferably a linear or branched C1-C4, most preferably a linear or branched C1-C3 saturated hydrocarbon radical. Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like. As denoted by the term "optionally substituted", the alkoxy group may be unsubstituted or substituted. Substituents of the alkoxy group may be, for example, H, halogen, N0 ₂ , CN, NMe ₂ , OMe, and the like. The term "optionally substituted alkanoyloxy" may refer to an alkanoyloxy group -0(CO)Alk, wherein the alkyl portion Alk of the alkanoyloxy group is a linear or branched C1-C10, preferably a linear or branched C1-C6, more preferably a linear or branched C1-C4, most preferably a linear or branched C1-C3 saturated hydrocarbon radical. As denoted by the term "optionally substituted", the alkanoyloxy group may be unsubstituted or substituted. Substituents of the alkanoyloxy group may be, for example, H, halogen, N0 ₂ , CN, NMe ₂ , OMe, and the like. The term "optionally substituted alkylamino" may refer to a monoalkylamino group, i.e. an amino group in which one hydrogen atom is replaced by an alkyl group, group or a dialkylamino group, i.e. an amino group in which two hydrogen atoms are replaced by an alkyl group. The alkyl group of both a monoalkylamino group and a dialkylamino group may be a linear or branched C1-C10, preferably a linear or branched C1-C6, more preferably a linear or branched C1-C4, most preferably a linear or branched C1-C3 saturated hydrocarbon radical. In case of a dialkylamino group, the two alkyl groups may be selected independently from each other. Examples for a monoalkylamino group are methylamino, ethylamino, n-propylamino, iso-propylamino, and the like. Examples for a dialkylamino group are dimethylamino, diethylamino, di-n-propylamino, di-iso-propylamino, and the like. As denoted by the term "optionally substituted", the alkylamino group may be unsubstituted or substituted. Substituents of the monoalkylamino and the dialkylamino group may be, for example, H, halogen, N0 ₂ , CN, NMe ₂ , OMe, and the like. The term "optionally substituted alkanoylamino" may refer to a group -NH(CO)Alk, wherein the alkyl portion Alk of the alkanoylamino group is a linear or branched C1-C10, preferably a linear or branched C1-C6, more preferably a linear or branched C1-C4, most preferably a linear or branched C1-C3 saturated hydrocarbon radical. As denoted by the term "optionally substituted", the alkanoylamino group may be unsubstituted or substituted. Substituents of the alkanoylamino group may be, for example, H, halogen, N0 ₂ , CN, NMe ₂ , OMe, and the like. The term "optionally substituted alkanoyi" may refer to a group -(CO)Alk, wherein the alkyl portion Alk of the alkanoyi group is a linear or branched C1-C10, preferably a linear or branched C1-C6, more preferably a linear or branched C1-C4, most preferably a linear or branched C1-C3 saturated hydrocarbon radical. As denoted by the term "optionally substituted", the alkanoyi group may be unsubstituted or substituted. Substituents of the alkanoyi group may be, for example, H, halogen, N0 ₂ , CN, NMe ₂ , OMe, and the like. The term "optionally substituted alkoxycarbonyl" may refer to an alkoxycarbonyl group -(CO)OAIk, wherein the alkyl portion Alk of the alkoxycarbonyl group is a linear or branched C1-C10, preferably a linear or branched C1-C6, more preferably a linear or branched Cl- C4, most preferably a linear or branched C1-C3 saturated hydrocarbon radical. As denoted by the term "optionally substituted", the alkoxycarbonyl group may be unsubstituted or substituted. Substituents of the alkoxycarbonyl group may be, for example, H, halogen, N0 ₂ , CN, NMe ₂ , OMe, and the like. The term "optionally substituted N-alkylcarbamoyl" may refer to an N-alkylcarbamoyl group -(CO)NHAIk, wherein the alkyl portion Alk of the N-alkylcarbamoyl group group is a linear or branched Cl-ClO, preferably a linear or branched C1-C6, more preferably a linear or branched C1-C4, most preferably a linear or branched C1-C3 saturated hydrocarbon radical. As denoted by the term "optionally substituted", the N-alkylcarbamoyl group may be unsubstituted or substituted. Substituents of the N-alkylcarbamoyl group may be, for example, H, halogen, N0 ₂ , CN, NMe ₂ , OMe, and the like. The term "optionally substituted Ν,Ν-dialkylcarbamoyl" may refer to an N,N- dialkylcarbamoyl group -(CO)N(Alk) ₂ , wherein the alkyl portions Alk of the N,N-dialkylcarbamoyl group group are a linear or branched Cl-ClO, preferably a linear or branched C1-C6, more preferably a linear or branched C1-C4, most preferably a linear or branched C1-C3 saturated hydrocarbon radical. The two alkyl portions Alk of (Alk) ₂ may be the same or may be selected independently from each other. As denoted by the term "optionally substituted", the Ν,Ν-dialkylcarbamoyl group may be unsubstituted or substituted. Substituents of the Ν,Ν-dialkylcarbamoyl group group may be, for example, H, halogen, N0 ₂ , CN, NMe ₂ , OMe, and the like. The term "optionally substituted thioalkoxy" may refer to an alkyl thioether radical, S-alkyl, wherein the alkyl group is a linear or branched Cl-ClO, preferably a linear or branched C1-C6, more preferably a linear or branched C1-C4, most preferably a linear or branched C1-C3 saturated hydrocarbon radical. Non-limiting examples of thioalkoxy groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, and the like. As denoted by the term "optionally substituted", the thioalkoxy group may be unsubstituted or substituted. Substituents of the thioalkoxy group may be, for example, H, halogen, N0 ₂ , CN, NMe ₂ , OMe, and the like. The term "optionally substituted alkylsulfonyl" may refer to an alkylsulfonyl group -(S0 ₂ )Alk, wherein the alkyl portion Alk of the alkylsulfonyl group is a linear or branched Cl-ClO, preferably a linear or branched C1-C6, more preferably a linear or branched Cl- C4, most preferably a linear or branched C1-C3 saturated hydrocarbon radical. As denoted by the term "optionally substituted", the alkylsulfonyl group may be unsubstituted or substituted. Substituents of the alkylsulfonyl group may be, for example, H, halogen, N0 ₂ , CN, NMe ₂ , OMe, and the like. The term "optionally substituted alkylsulfoxyl" may refer to an alkylsulfoxyl group -(SO)Alk, wherein the alkyl portion Alk of the alkylsulfoxyl group is a linear or branched Cl-ClO, preferably a linear or branched C1-C6, more preferably a linear or branched C1-C4, most preferably a linear or branched C1-C3 saturated hydrocarbon radical. As denoted by the term "optionally substituted", the alkylsulfoxyl group may be unsubstituted or substituted. Substituents of the alkylsulfoxyl group may be, for example, H, halogen, N0 ₂ , CN, NMe ₂ , OMe, and the like. The definitions of the substituents provided in this paragraph may be also applied to the following specific embodiments which make reference to an optionally substituted benzoic acid halide. In particular, these definitions may be applied to the radical of the specific embodiments set forth in the following which make reference to an optionally substituted benzoic acid halide having formula (I). Also, the definitions of the substituents provided in this paragraph may be applied to an "optionally substituted naphtalene carboxylic acid halide", an "optionally substituted 1-naphthalene carboxylic acid halide" or an "optionally substituted 2-naphthalene carboxylic acid halide" as set forth herein further below.

In some embodiments the optionally substituted benzoic acid halide has the formula (I):

wherein R is each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl optionally substituted alkoxy, optionally substituted alkanoyloxy, optionally substituted alkylamino, optionally substituted alkanoylamino, optionally substituted alkanoyl, carboxyl, optionally substituted alkoxycarbonyl, carbamoyl, optionally substituted N-alkylcarbamoyl, optionally substituted N,N-dialkylcarbamoyl, optionally substituted thioalkoxy, optionally substituted alkylsulfonyl, and optionally substituted alkylsulfoxyl;

wherein n is an integer of from 0 to 5, preferably of from 0 to 3, more preferably of from 0 to 2 and most preferably of from 0 to 1; and

wherein X is a halogen atom, preferably a chlorine atom or a bromine atom, more preferably a chlorine atom. In case that X of formula (I) is a chlorine atom, the hydroxyl group of the alcohol is replaced by a chlorine atom. In case that X is a bromine atom, the hydroxyl group of the alcohol is replaced by a bromine atom.

In some embodiments of the methods of converting an alcohol into a corresponding halide disclosed herein, in the optionally substituted benzoic acid halide of formula (I) the radical R is each independently selected from the group consisting of hydrogen, halogen, nitro, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkanoyloxy, optionally substituted alkylamino, optionally substituted alkanoylamino; wherein n is an integer of from 0 to 5, preferably of from 0 to 3, more preferably of from 0 to 2 and most preferably of from 0 to 1;

and wherein X is a halogen atom, preferably a chlorine atom or a bromine atom, more preferably a chlorine atom.

In a preferred embodiment of the methods of converting an alcohol into a corresponding halide disclosed herein, in the optionally substituted benzoic acid halide of formula (I) the radical is each independently selected from the group consisting of hydrogen, halogen, nitro, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted alkylamino;

wherein n is an integer from 0 to 5, preferably of from 0 to 3, more preferably of from 0 to 2 and most preferably of from 0 to 1; and

wherein X is a halogen atom, preferably a chlorine atom or a bromine atom, more preferably a chlorine atom. In a further preferred embodiment of the methods of converting an alcohol into a corresponding halide disclosed herein, in the optionally substituted benzoic acid halide of formula (I) the radical R is each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, nitro, methyl, methoxy, and Ν,Ν-dimethyl amino;

wherein n is an integer from 0 to 5, preferably of from 0 to 3, more preferably of from 0 to 2 and most preferably of from 0 to 1; and

wherein X is a halogen atom, preferably a chlorine atom or a bromine atom, more preferably a chlorine atom.

In some embodiments of the methods of converting an alcohol into a corresponding halide disclosed herein, in the optionally substituted benzoic acid halide of formula (I) n is 1 or 2. In case that n is 2, R may be each the same.

As noted above, preferably in any one of the compounds of formula (I) disclosed herein in context with the methods of converting an alcohol into a corresponding halide, X is a chlorine atom. Accordingly, in some preferred embodiments the compound of formula (I) represents an optionally substituted benzoyl chloride.

In some embodiments the compound of formula (I) is selected from the group consisting of:

that any one of these aforementioned compounds is used, the N-substituted formamide may be selected from the group consisting of N-methylformamide, Ν,Ν-dimethylformamide, N- formylpyrrolidine, and any combination thereof.

In some referred embodiments the compound of formula (I) is selected from the group consisting of

provided high yields in the methods of converting an alcohol into a corresponding halide and have provided the chlorinated product with a particularly high selectivity. In non-limiting embodiments, in case that any one of these aforementioned compounds is used, the N-substituted formamide may be selected from the group consisting of N-methylformamide, Ν,Ν-dimethylformamide, N- formylpyrrolidine, and any combination thereof.

In some preferred embodiments the compound of formula (I) is selected from the group consisting of _t and any combination thereof. In non-limiting embodiments, in case that any one of these aforementioned compounds is used, the N-substituted formamide may be selected from the group consisting of N-methylformamide, N,N- dimethylformamide, N-formylpyrrolidine, and any combination thereof.

In a preferred embodiment the compound of formula (I) is This compound is 2- fluorobenzoyl chloride and, in particular, it has been found that this compound is useful in the conversion of optically active, i.e. enantioenriched, chiral alpha-hydroxyesters to the corresponding chlorides. With this regard, in case that 2-fluorobenzoyl chloride is used, the corresponding a- chlorohydroxyesters are obtained in a particularly high enantiomeric purity. In a non-limiting embodiment, in case that 2-fluorobenzoyl chloride is used, the N-substituted formamide may be selected from the group consisting of N-methylformamide, Ν,Ν-dimethylformamide, N- formylpyrrolidine, and any combination thereof.

In a preferred embodiment the compound of formula (I) is . This compound is 4- methoxybenzoyl chloride and provides excellent yields of the chlorinated product in case that the alcohol to be converted into the corresponding chloride is an aliphatic alcohol. In a non-limiting embodiment, in case that 4-methoxybenzoyl chloride is used, the N-substituted formamide may be selected from the group consisting of N-methylformamide, Ν,Ν-dimethylformamide, N- formylpyrrolidine, and any combination thereof.

In a preferred embodiment the compound of formula (I) is . This compound is benzoyl chloride and provides excellent yield and selectivity for the chlorinated product in the methods of converting an alcohol into a corresponding chloride with a great variety of alcohols. Furthermore, benzoyl chloride is readily available and minimizes the weight amount of waste since benzoyl chloride does not bear any further substituents. As a further advantage, benzoyl chloride is rather stable towards hydrolysis, and therefore the methods of converting an alcohol into the corresponding chloride described herein may be performed without special measures for excluding moisture, such as, for example, moisture from air, from the process in case that benzoyl chloride is used. In a non-limiting embodiment, in case that benzoyl chloride is used, the N-substituted formamide may be selected from the group consisting of N-methylformamide, N,N- dimethylformamide, N-formylpyrrolidine, and any combination thereof.

In another embodiment the compound of formula (I) is j _n j _s compound is benzoyl bromide and may be used in case that the hydroxyl group of the alcohol is replaced by a bromine atom. In a non-limiting embodiment, in case that benzoyl bromide is used, the N-substituted formamide may be selected from the group consisting of N-methylformamide, N,N- dimethylformamide, N-formylpyrrolidine, and any combination thereof.

In some embodiments of the methods of converting an alcohol into a corresponding halide the optionally substituted benzoic acid halide has the formula (II):

wherein n is 2 or 3. Using a benzoyl chloride derivative of formula (II), which has more than one acid chloride moieties, allows for utilizing substoichiometric amounts of the reagent and therefore further diminishes the amount of waste obtained in the conversion. In some embodiments the optionally

substituted benzoic acid halide is selected from the group consisting of

, and any combination thereof. In one embodiment the optionally substituted benzoic acid halide is . This compound is isopthaloyl chloride and provides particularly high yields in the conversion of an alcohol into the corresponding chloride in case that it is employed in substoichiometric amounts. In non-limiting embodiments, in case that any one of these aforementioned compounds is used, the N-substituted formamide may be selected from the group consisting of N-methylformamide, N,N- dimethylformamide, N-formylpyrrolidine, and any combination thereof.

In some embodiments the aromatic carboxylic acid halide is an optionally substituted naphthalene carboxylic acid halide. With this regard, the term "optionally substituted naphthalene carboxylic acid halide" encompasses an optionally substituted naphthalene carboxylic acid fluoride, an optionally substituted naphthalene carboxylic acid chloride, an optionally substituted naphthalene carboxylic acid bromide and an optionally substituted naphthalene carboxylic acid iodide. In particular, the optionally substituted naphthalene carboxylic acid halide may be an optionally substituted naphthalene carboxylic acid chloride or an optionally substituted naphthalene carboxylic acid bromide. In some embodiments of the methods of converting an alcohol into a corresponding halide described herein the optionally substituted naphthalene carboxylic acid halide is an optionally substituted 1-naphthalene carboxylic acid halide. In particular, the optionally substituted 1- naphthalene carboxylic acid halide may be an optionally substituted 1-naphthalene carboxylic acid chloride or an optionally substituted 1-naphthalene carboxylic acid bromide. In some embodiments the optionally substituted naphthalene carboxylic acid halide is an optionally substituted 2- naphthalene carboxylic acid halide. In particular, the optionally substituted 2-naphthalene carboxylic acid halide may be an optionally substituted 2-naphthalene carboxylic acid chloride or an optionally substituted 2-naphthalene carboxylic acid bromide. In any embodiment in which reference to an "optionally substituted naphtalene carboxylic acid halide", an "optionally substituted 1-naphthalene carboxylic acid halide" or an "optionally substituted 2-naphthalene carboxylic acid halide" is made the term "optionally substituted" denotes that the naphthalene carboxylic acid halide may be unsubstituted or may be substituted with one or more substituents independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkanoyloxy, optionally substituted alkylamino, optionally substituted alkanoylamino, optionally substituted alkanoyl, carboxyl, optionally substituted alkoxycarbonyl, carbamoyl, optionally substituted N-alkylcarbamoyl, optionally substituted N,N-dialkylcarbamoyl, optionally substituted thioalkoxy, optionally substituted alkylsulfonyl, and optionally substituted alkylsulfoxyl. The naphthalene carboxylic acid halide may be unsubstituted or may carry 1, 2, 3, 4, 5, 6, or 7 of the aforementioned substituents. More preferably, the naphthalene carboxylic acid halide is unsubstituted or carries 1, 2, or 3 of these substituents. Non-limiting Examples for substituents of the naphthalene carboxylic acid are H, CH ₃ , halogen, N0 ₂ , CN, NMe ₂ , OMe, and the like. The possible meanings of the substituents disclosed herein with regard to an "optionally substituted naphtalene carboxylic acid halide", an "optionally substituted 1-naphthalene carboxylic acid halide" or an "optionally substituted 2-naphthalene carboxylic acid halide" are the same as set out herein above with regard to the "optionally substituted benzoic acid halide".

The inventor has found out that a great variety of N-substituted formamides can be employed in the methods of converting an alcohol into a corresponding halide described herein. In general, the term "N-substituted formamide" as used with regard to any one of the methods for converting an alcohol into the corresponding halide described herein denotes a compound which has the formula (III):

wherein Rl and R2 are not both hydrogen. In this respect, at most one out of Rl and R2 may be hydrogen.

In embodiments the N-substituted formamide employed in the methods disclosed herein is an N- monosubstituted formamide or an Ν,Ν-disubstituted formamide. In case of an N-monosubstituted formamide one of Rl and R2 is hydrogen, and the other of Rl and R2 is not hydrogen. In case of an Ν,Ν-disubstituted formamide both Rl and R2 are not hydrogen and may be the same or different from each other.

In some embodiments the N-substituted formamide has the formula (III):

wherein Rl and R2 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted aralkyl. The possible meaning of some substituents disclosed above and below for Rl and R2 within the context of an N-substituted formamide having the formula (III) is defined in the following. The term "optionally substituted alkyl" may refer to a linear or branched C1-C6, preferably to a linear or branched C1-C4, more preferably to a linear or branched C1-C3, most preferably to a linear or branched C1-C2 saturated hydrocarbon radical. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and the like. As denoted by the term "optionally substituted", the alkyl group may be unsubstituted or substituted. Substituents of the alkyl group may be, for example, H, halogen, N0 ₂ , CN, NMe ₂ , OMe, and the like. The term "optionally substituted cycloalkyl" may refer to a saturated hydrocarbon ring containing from three to ten ring carbon atoms, preferably from four to seven ring carbon atoms, and more preferbly five or six ring carbon atoms. As denoted by the term "optionally substituted", the cycloalkyl group may be unsubstituted or substituted. Substituents of the cycloalkyl group may be, for example, H, halogen, a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n- butyl, sec-butyl, tert-butyl, and the like, N0 ₂ , CN, NMe ₂ , OMe, and the like. The term "optionally substituted aryl" may refer to an aromatic hydrocarbon radical having six to ten ring atoms, and includes fused and non-fused aryl rings. For example, "aryl" may be a phenyl or naphthyl radical. Preferably, "aryl" is a phenyl radical. As denoted by the term "optionally substituted", the aryl group may be unsubstituted or substituted. Substituents of the aryl group may be, for example, H, halogen, a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n- butyl, sec-butyl, tert-butyl, and the like, N0 ₂ , CN, NMe ₂ , OMe, and the like. A non-limiting example for an optionally substituted aryl group is an optionally substituted phenyl group. The term "optionally substituted phenyl" when used herein whithin the context of formula (III) may denote an unsubstituted or substituted phenyl group. Substituents of the phenyl group may be, for example, H, halogen, a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso- propyl, n-butyl, sec-butyl, tert-butyl, and the like, N0 ₂ , CN, NMe ₂ , OMe, and the like. The term "optionally substituted heteroaryl" may refer to aromatic radicals containing from five to ten skeletal ring atoms, preferably from five to seven skeletal ring atoms, more preferably five or six skeletal ring atoms, where one or more of the ring atoms is a heteroatom independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon and selenium, preferably selected from oxygen, nitrogen and sulfur, but not limited to these atoms. The term "heteroaryl" may include heteroaryl radicals having one or two heteroatoms. "Heteroaryl" may also include fused and non-fused heteroaryls having from five to ten skeletal ring atoms. As denoted by the term "optionally substituted", the heteroaryl group may be unsubstituted or substituted. Substituents of the heteroaryl group may be, for example, H, halogen, a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso- propyl, n-butyl, sec-butyl, tert-butyl, and the like, N0 ₂ , CN, NMe ₂ , OMe, and the like. The term "optionally substituted aralkyl" may refer to a group -Alk-Ar, wherein the alkyl portion Alk is a linear or branched C1-C6, preferably a linear or branched C1-C4, more preferably a linear or branched Cl- C3, most preferably a linear or branched C1-C2 saturated hydrocarbon radical. Examples for the alkyl portion Alk include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert- butyl, and the like. The aryl portion Ar of the aralkyl group may be an aromatic hydrocarbon radical having six to ten ring atoms, and includes fused and non-fused aryl rings. For example, the aryl portion may be a phenyl or naphthyl radical. Preferably, the aryl portion Ar is a phenyl radical. Non- limiting examples for the aralkyl group are benzyl, phenylethyl, phenyl-n-propyl, and the like. As denoted by the term "optionally substituted", the aralkyl group may be unsusbtituted or substituted. Substituents of the aralkyl group may be, for example, H, halogen, a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, and the like, N0 ₂ , CN, NMe ₂ , OMe, and the like. The substituents may be attached to the alkyl portion and/or the aryl portion of the aralkyl group. Preferably, the substituents are attached to the aryl portion, and the alkyl portion is unsubstituted. A non-limiting example for an optionally substituted aralkyl group is an optionally substituted benzyl group. When used herein within the context of formula (III), the term "optionally substituted benzyl" may denote an unsubstituted or substituted benzyl group. Substituents of the benzyl group may be, for example, H, halogen, a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, and the like, N0 ₂ , CN, NMe ₂ , OMe, and the like. The substituents may be attached to the phenyl portion and/or the CH ₂ portion of the benzyl group. Preferably, in case that the benzyl group is substituted, the phenyl portion of the benzyl group is substituted and the CH ₂ portion of the benzyl group is unsubstituted.

In some embodiments the N-substituted formamide has the formula (III), wherein l and R2 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted aralkyl.

In some embodiments the N-substituted formamide has the formula (III), wherein Rl and R2 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted phenyl and optionally substituted benzyl. In some embodiments the N-substituted formamide has the formula (III), wherein Rl and R2 are the same.

In some embodiments the N-substituted formamide has the formula (III), wherein Rl and R2 are each independently selected from the group consisting of hydrogen and optionally substituted alkyl. Thus, in one embodiment Rl may be hydrogen and R2 may be optionally substituted alkyl. In this embodiment R2 may be, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl or tert- butyl. In another embodiment both Rl and R2 may be optionally substituted alkyl. In case that both Rl and R2 are optionally substituted alkyl, one or both of Rl and R2 may be, for example, methyl, ethyl, n-propyl or n-butyl.

In some embodiments the N-substituted formamide has the formula (III), wherein Rl is selected from the group consisting of hydrogen and optionally substituted alkyl; and wherein R2 is selected from the group consisting of optionally substituted phenyl and optionally substituted benzyl. In some embodiments the N-substituted formamide has the formula (III), wherein Rl is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl and n-butyl; and wherein R2 is selected from the group consisting of optionally substituted phenyl and optionally substituted benzyl. Preferably, in these embodiments Rl is selected from the group consisting of hydrogen, methyl or ethyl. More preferably, Rl is hydrogen or methyl.

In one embodiment the N-substituted formamide has the formula (III), wherein Rl and R2 are both optionally substituted benzyl.

In some embodiments the N-substituted formamide has the formula (III), wherein Rl and R2 are each optionally substituted alkyl; and wherein Rl and R2 are joined together to form a three- to eight-membered ring. Said ring may optionally comprise 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, silicon, phosphorus, and any combination thereof. Preferably, the optional heteroatoms are selected from the group consisting of nitrogen, oxygen, sulfur, and any combination thereof. Preferably, Rl and R2 are joined together to form a four- to seven- membered ring, more preferably to form a five- or six-membered ring.

In some embodiments of the method of converting an alcohol into a corresponding halide disclosed

herein the N-substituted formamide is selected from the group consisting of

and any combination thereof.

In some embodiments the N-substituted formamide is selected from the group consisting of

O and

In some referred embodiments the N-substituted formamide is selected from the group consisting

combination thereof. These N-substituted formamides have been found out to provide high yields in the methods of converting an alcohol into a corresponding halide with a particularly high selectivity for the halogenated product.

In further preferred embodiments the N-substituted formamide is selected from , O O

^{N Me} 2 , H NHMe , and any combination thereof.

In a preferred embodiment the N-substituted formamide is . In an embodiment, this compound N-formyl pyrrolidine may be used as the N-substituted formamide in case that benzoyl chloride, 4-methoxybenzoyl chloride and 2-fluoro benzoyl chloride, respectively, is used as the aromatic carboxylic acid halide. It has been found that N-formylpyrrolidine exhibits a high catalytic activity in the methods of converting an alcohol into the corresponding halide described herein and therefore allows for particularly low catalyst loadings compared to other N-substituted formamides without compromising yield and selectivity for the halogenated product. In addition, it has been found that N-formyl pyrrolidine is particularly preferred in case that the alcohol to be converted into the corresponding halide is an optically active alcohol, i.e. an enantioenriched chiral alcohol. With this regard, in case that N-formyl pyrrolidine is used as the N-substituted formamide, the corresponding halides can be obtained in a particularly high enantiomeric urity.

In a preferred embodiment the N-substituted formamide is . In an embodiment th compound Ν,Ν-dimethyl formamide may be used as the N-substituted formamide in case that benzoyl chloride is used as the aromatic carboxylic acid halide. Ν,Ν-dimethylformamide is readily available and provides high yield and selectivity for the halogenated product when employed in the methods of converting an alcohol into a corresponding halide described herein. As a further advantage, in the methods described herein Ν,Ν-dimethyl formamide can be used in catalytic amounts. However, it is also possible to use excess Ν,Ν-dimethyl formamide as solvent in the methods of converting an alcohol to a corresponding halide described herein.

O

In a preferred embodiment the N-substituted formamide is H X NHMe . in an embodiment this compound N-methyl formamide may be used as the N-substituted formamide in case that benzoyl chloride is used as the aromatic carboxylic acid halide. N-methyl formamide also provides high yield and selectivity for the halogenated product when employed in the methods for converting an alcohol into the corresponding halide described herein. As an additional advantage, N-methyl formamide is the N-substituted formamide having the lowest molecular mass and is therefore particularly useful in case that the conversion of an alcohol into the corresponding halide is performed in a large scale. In this context, due to the low molecular mass in a large scale synthesis the weight amount of waste can be efficiently lowered.

The alcohol employed in the methods of converting an alcohol into a corresponding halide described herein is not particularly limited, and virtually any alcohol can be used. As shown in the Examples, a great variety of structurally different alcohols can be converted into the corresponding halides using the methods disclosed herein. For the purposes of the present invention and in accordance with the view of a person skilled in the art an alcohol is regarded as a compound in which a hydroxyl group is bound to a saturated carbon atom. On the other hand, a compound in which a hydroxyl group is bonded to an unsaturated carbon atom, such as an aromatic or an olefinic carbon atom, is in general not regarded as an alcohol. For example, in accordance with this definition phenol or an enol is not regarded as an alcohol. In some embodiments the alcohol is a primary, a secondary or a tertiary alcohol.

In some embodiments the alcohol has the formula (IV):

wherein R3, R4 and R5 are each independently selected from the group consisting of hydrogen, deuterium, carboxylic acid ester, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, optionally substituted heteroalkenyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkenyl, optionally substituted alkynyl, optionally substituted heteroalkynyl, optionally substituted cycloalkynyl, optionally substituted heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted aralkenyl, optionally substituted heteroaralkenyl, optionally substituted aralkinyl, and optionally substituted heteroaralkinyl.

The general meaning of some substituents disclosed for R3, R4 and R5 within the context of the alcohol having the formula (IV) is defined in the following. The term "optionally substituted alkyl" may refer to a linear or branched C1-C30, preferably to a linear or branched C1-C20, more preferably to a linear or branched C1-C15, still more, preferably to a linear or branched C1-C10, and most preferably to a linear or branched C1-C5 saturated hydrocarbon radical. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, decyl, dodecyl, and the like. As denoted by the term "optionally substituted", the alkyl group may be unsubstituted or substituted. Substituents of the alkyl group may be, for example, H, halogen, a nitrogen containing group such as, for example, N0 ₂ , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe ₂ and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond and the like. The term "optionally substituted heteroalkyl" may refer to a linear or branched saturated hydrocarbon-containing radical comprising 1 to 30, preferably 1 to 20, more preferably 1 to 15, still more preferably 1 to 10 and most preferably 1 to 5 chain atoms, wherein one or more of the chain atoms is a heteroatom independently selected from oxygen, nitrogen, sulfur, selenium, phosphorus and silicon, but not limited to these atoms. A non-limiting example for heteroalkyl may be an oligoethyleneglycol radical. As denoted by the term "optionally substituted", the heteroalkyi group may be unsubstuted or substituted. Substituents of the heteroalkyi group may be, for example, H, halogen, a nitrogen containing group, such as, for example, N0 ₂ , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe ₂ and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond and the like. The term "optionally substituted cycloalkyi" may refer to a saturated hydrocarbon ring having from three to fifteen ring carbon atoms, preferably from four to ten ring carbon atoms, more pfererably from five to seven ring carbon atoms, and most preferably five or six ring carbon atoms. As denoted by the term "optionally substituted", the cycloalkyi group may be unsubstituted or substituted. Substituents of the cycloalkyi group may be, for example, H, halogen, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl and the like, a nitrogen containing group, such as, for example, N0 ₂ , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe ₂ and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond and the like. The term "optionally substituted heterocycloalkyl" may refer to a cyclic hydrocarbon radical having from three to fifteen ring atoms, preferably from four to ten ring atoms, more pfererably from five to seven ring atoms, and most preferably five or six ring atoms, wherein one or more of the ring atoms is a heteroatom independently selected from oxygen, nitrogen, sulfur, selenium, phosphorus and silicon, but not limited to these atoms. As denoted by the term "optionally substituted", the heterocycloalkyl group may be unsubstituted or substituted. Substituents of the heterocycloalkyl group may be, for example, H, halogen, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n- butyl, sec-butyl, tert-butyl and the like, a nitrogen containing group, such as, for example, N0 ₂ , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe ₂ and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond and the like. The term "optionally substituted alkenyl" may refer to a linear or branched C2-C30, preferably to a linear or branched C2-C20, more preferably to a linear or branched C2-C15, still more preferably to a linear or branched C2-C10, most preferably to a linear or branched C2-C5 radical having one or more carbon-carbon double bond(s). The group may be either in the cis or trans configuration about the double bond(s), and should be understood to include both isomers. Non-limiting examples include ethenyl (-CH=CH ₂ ), 1-propenyl (- CH ₂ CH=CH ₂ ), isopropenyl [-C(CH ₃ )=CH ₂ ], butenyl, 1,3-butadienyl and the like. As denoted by the term "optionally substituted", the alkenyl group may be unsubstituted or substituted. Substituents of the alkenyl group may be, for example, H, halogen, a nitrogen containing group, such as, for example, N0 ₂ , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe ₂ and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon triple bond and the like. The term "optionally substituted heteroalkenyl" may refer to a linear or branched hydrocarbon-containing radical comprising 1 to 30, preferably 1 to 20, more preferably 1 to 15, still more preferably 1 to 10 and most preferably 1 to 5 chain atoms, wherein one or more of the chain atoms is a heteroatom independently selected from oxygen, nitrogen, sulfur, selenium, phosphorus and silicon, but not limited to these atoms, and wherein the radical has one or more carbon-carbon double bond. The group may be either in the cis or trans configuration about the double bond(s), and should be understood to include both isomers. As denoted by the term "optionally substituted", the heteroalkenyl group may be unsubstituted or substituted. Substituents of the heteroalkenyl group may be, for example, H, halogen, a nitrogen containing group, such as, for example, N0 ₂ , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe ₂ and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon- carbon triple bond and the like. The term "optionally substituted cycloalkenyl" may refer to an olefinic unsaturated hydrocarbon ring having from three to fifteen ring carbon atoms, preferably from four to ten ring carbon atoms, more pfererably from five to seven ring carbon atoms, and most preferably five or six ring carbon atoms, wherein the hydrocarbon ring has one or more carbon- carbon double bond. As denoted by the term "optionally substituted", the cycloalkenyl group may be unsubstituted or substituted. Substituents of the cycloalkenyl group may be, for example, H, halogen, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl and the like, a nitrogen containing group, such as, for example, N0 ₂ , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe ₂ and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond and the like. The term "optionally substituted heterocycloalkenyl" may refer to an olefinic unsaturated cyclic radical having from three to fifteen ring atoms, preferably from four to ten ring atoms, more pfererably from five to seven ring atoms, and most preferably five or six ring atoms, wherein one or more of the ring atoms is a heteroatom independently selected from oxygen, nitrogen, sulfur, selenium, phosphorus and silicon, but not limited to these atoms, and wherein the ring has one or more carbon-carbon double bond(s). As denoted by the term "optionally substituted", the heterocycloalkenyl group may be unsubstituted or substituted. Substituents of the heterocycloalkenyl group may be, for example, H, halogen, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n- butyl, sec-butyl, tert-butyl and the like, a nitrogen containing group, such as, for example, N0 ₂ , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe ₂ and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, and the like. The term "optionally substituted alkynyl" may refer to a linear or branched C2-C30, preferably to a linear or branched C2-C20, more preferably to a linear or branched C2-C15, still more preferably to a linear or branched C2-C10, most preferably to a linear or branched C2-C5 radical having one or more carbon-carbon triple bond(s). Non-limiting examples include ethynyl, 1-propynyl, 1-butynyl, 1,3-butadiynyl and the like. As denoted by the term "optionally substituted", the alkynyl group may be unsubstituted or substituted. Substituents of the alkynyl group may be, for example, H, halogen, a nitrogen containing group, such as, for example, N0 ₂ , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe ₂ and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, and the like. The term "optionally substituted heteroalkynyl" may refer to a linear or branched hydrocarbon-containing radical comprising 1 to 30, preferably 1 to 20, more preferably 1 to 15, still more preferably 1 to 10 and most preferably 1 to 5 chain atoms, wherein one or more of the chain atoms is a heteroatom independently selected from oxygen, nitrogen, sulfur, selenium, phosphorus and silicon, but not limited to these atoms, and wherein the radical has one or more carbon-carbon triple bond(s). As denoted by the term "optionally substituted", the heteroalkynyl group may be unsubstituted or substituted. Substituents of the heteroalkynyl group may be, for example, H, halogen, a nitrogen containing group, such as, for example, N0 ₂ , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe ₂ and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond and the like. The term "optionally substituted cycloalkynyl" may refer to an acetylenic unsaturated hydrocarbon ring having from eight to fifteen ring carbon atoms, preferably from ten to fifteen ring carbon atoms, wherein the hydrocarbon ring has one or more carbon-carbon triple bond. As denoted by the term "optionally substituted", the cycloalkynyl group may be unsubstituted or substituted. Substituents of the cycloalkynyl group may be, for example, H, halogen, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl and the like, a nitrogen containing group, such as, for example, N0 ₂ , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe ₂ and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, and the like. The term "optionally substituted heterocycloalkynyl" may refer to an acetylenic unsaturated cyclic radical having from eight to fifteen ring atoms, preferably from ten to fifteen ring atoms, wherein one or more of the ring atoms is a heteroatom independently selected from oxygen, nitrogen, sulfur, selenium, phosphorus and silicon, but not limited to these atoms, and wherein the ring has one or more carbon-carbon triple bond(s). As denoted by the term "optionally substituted", the heterocycloalkynyl group may be unsubstituted or substituted. Substituents of the heterocycloalkynyl group may be, for example, H, halogen, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n- butyl, sec-butyl, tert-butyl and the like, a nitrogen containing group, such as, for example, N0 ₂ , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe ₂ and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, and the like. The term "optionally substituted aryl" may refer to an aromatic hydrocarbon radical having six to ten ring atoms, and includes fused and non-fused aryl rings. For example, the aryl group may be a phenyl or naphthyl radical. Preferably, the aryl group is a phenyl radical. As denoted by the term "optionally substituted", the aryl group may be unsubstituted or substituted. Substituents of the aryl group may be, for example, H, halogen, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl and the like, a nitrogen containing group, such as, for example, N0 ₂ , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe ₂ and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, and the like. The term "optionally substituted heteroaryl" may refer to aromatic radicals containing from five to ten skeletal ring atoms, preferably from five to seven skeletal ring atoms, more preferably five or six skeletal ring atoms, where one or more of the ring atoms is a heteroatom independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon and selenium, but not limited to these atoms. "Heteroaryl" may also include fused and non-fused heteroaryls having from five to ten skeletal ring atoms. As denoted by the term "optionally substituted", the heteroaryl group may be unsubstituted or substituted. Substituents of the heteroaryl group may be, for example, H, halogen, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl and the like, a nitrogen containing group, such as, for example, N0 ₂ , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe ₂ and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, and the like. The term "optionally substituted aralkyl" may refer to a group -Alk-Ar, wherein the alkyl portion Alk is a linear or branched C1-C10, preferably a linear or branched C1-C6, more preferably a linear or branched Cl- C4, still more preferably a linear or branched C1-C3, most preferably a linear or branched C1-C2 saturated hydrocarbon radical. Examples for the alkyl portion include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like. The aryl portion Ar of the aralkyl group may be an aromatic hydrocarbon radical having six to ten ring atoms, and includes fused and non-fused aryl rings. For example, the aryl portion may be a phenyl or naphthyl radical. Preferably, the aryl portion is a phenyl radical. Non-limiting examples for the aralkyl group are benzyl, phenylethyl, phenyl-n-propyl, and the like. As denoted by the term "optionally substituted", the aralkyl group may be unsubstituted or substituted. Substituents of the aralkyl group may be, for example, H, halogen, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl and the like, a nitrogen containing group, such as, for example, N0 ₂ , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe ₂ and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, and the like. The substituents may be attached to the alkyl portion and/or the aryl portion of the aralkyl group. The term "optionally substituted heteroaralkyl" may refer to a group - Alk-HAr, wherein the alkyl portion Alk is a linear or branched C1-C10, preferably a linear or branched C1-C6, more preferably a linear or branched C1-C4, still more preferably a linear or branched C1-C3, most preferably a linear or branched C1-C2 saturated hydrocarbon radical. Examples for the alkyl portion include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert- butyl, pentyl, hexyl, and the like. The heteroaryl portion HAr of the heteroaralkyl group may refer to aromatic radicals containing from five to ten skeletal ring atoms, preferably from five to seven skeletal ring atoms, more preferably five or six skeletal ring atoms, where one or more of the ring atoms is a heteroatom indenpendently selected from oxygen, nitrogen, sulfur, phosphorus, silicon and selenium, but not limited to these atoms. The heteroaryl portion may also include fused and non-fused heteroaryls having from five to ten skeletal ring atoms. As denoted by the term "optionally substituted", the heteroaralkyl group may be unsubstituted or substituted. Substituents of the heteroaralkyl group may be, for example, H, halogen, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec- butyl, tert-butyl and the like, a nitrogen containing group, such as, for example, N0 ₂ , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe ₂ and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, and the like. The substituents may be attached to the alkyl portion and/or the heteroaryl portion of the heteroaralkyl group. The term "optionally substituted aralkenyl" may refer to a group -Alkenyl-Ar, wherein the alkenyl portion Alkenyl is a linear or branched C2-C10, preferably to a linear or branched C2-C6, more preferably to a linear or branched C2-C4, most preferably to a linear or branched C2-C3 radical having one or more carbon- carbon double bond(s). The group may be either in the cis or trans configuration about the double bond(s), and should be understood to include both isomers. Examples for the alkenyl portion include, but are not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like. The aryl portion Ar of the aralkyl group may be an aromatic hydrocarbon radical having six to ten ring atoms, and includes fused and non-fused aryl rings. For example, the aryl portion may be a phenyl or naphthyl radical. Preferably, the aryl portion is a phenyl radical. As denoted by the term "optionally substituted", the aralkenyl group may be unsubstituted or substituted. Substituents of the aralkenyl group may be, for example, H, halogen, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert- butyl and the like, a nitrogen containing group, such as, for example, N0 ₂ , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe ₂ and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, and the like. The substituents may be attached to the alkenyl portion and/or the aryl portion of the aralkenyl group. The term "optionally substituted heteroaralkenyl" may refer to a group -Alkenyl-HAr, wherein the alkenyl portion Alkenyl is a linear or branched C2-C10, preferably to a linear or branched C2-C6, more preferably to a linear or branched C2-C4, most preferably to a linear or branched C2-C3 radical having one or more carbon- carbon double bonds. The group may be either in the cis or trans configuration about the double bond(s), and should be understood to include both isomers. Examples for the alkenyl portion include, but are not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like. The heteroaryl portion HAr of the heteroaralkenyl group may refer to aromatic radicals containing from five to ten skeletal ring atoms, preferably from five to seven skeletal ring atoms, more preferably five or six skeletal ring atoms, where one or more of the ring atoms is a heteroatom indenpendently selected from oxygen, nitrogen, sulfur, phosphorus, silicon and selenium, but not limited to these atoms. The heteroaryl portion may also include fused and non-fused heteroaryls having from five to ten skeletal ring atoms. As denoted by the term "optionally substituted", the heteroaralkenyl group may be unsusbtituted or substituted. Substituents of the heteroaralkenyl group may be, for example, H, halogen, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl and the like, a nitrogen containing group, such as, for example, N0 ₂ , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe ₂ and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, and the like. The substituents may be attached to the alkenyl portion and/or the heteroaryl portion of the heteroaralkenyl group. The term "optionally substituted aralkynyl" may refer to a group - Alkynyl-Ar, wherein the alkynyl portion Alkynyl is a linear or branched C2-C10, preferably to a linear or branched C2-C6, more preferably to a linear or branched C2-C4, most preferably to a linear or branched C2-C3 radical having one or more carbon-carbon triple bond(s). Examples for the alkynyl portion include, but are not limited to ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. The aryl portion Ar of the aralkynyl group may be an aromatic hydrocarbon radical having six to ten ring atoms, and includes fused and non-fused aryl rings. For example, the aryl portion may be a phenyl or naphthyl radical. Preferably, the aryl portion is a phenyl radical. As denoted by the term "optionally substituted", the aralkynyl group may be unsubstituted or substituted. Substituents of the aralkynyl group may be, for example, H, halogen, a linear or branched C1-C6, a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl and the like, a nitrogen containing group, such as, for example, N0 ₂ , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe ₂ and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, and the like. The substituents may be attached to the alkynyl portion and/or the aryl portion of the aralkynyl group. The term "optionally substituted heteroaralkynyl" may refer to a group -Alkynyl-HAr, wherein the alkynyl portion Alkynyl is a linear or branched C2-C10, preferably to a linear or branched C2-C6, more preferably to a linear or branched C2-C4, most preferably to a linear or branched C2-C3 radical having one or more carbon-carbon triple bond(s). Examples for the alkynyl portion include, but are not limited to ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. The heteroaryl portion HAr of the heteroaralkynyl group may refer to aromatic radicals containing from five to ten skeletal ring atoms, preferably from five to seven skeletal ring atoms, more preferably five or six skeletal ring atoms, where one or more of the ring atoms is a heteroatom independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon and selenium, but not limited to these atoms. The heteroaryl portion may also include fused and non-fused heteroaryls having from five to ten skeletal ring atoms. As denoted by the term "optionally substituted", the heteroaralkynyl group may be unsubstituted or substituted. Substituents of the heteroaralkynyl group may be, for example, H, halogen, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert- butyl and the like, a nitrogen containing group, such as, for example, N0 ₂ , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe ₂ and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, and the like. The substituents may be attached to the alkynyl portion and/or the heteroaryl portion of the heteroaralkynyl group.

In some embodiments the alcohol has the formula (IV), wherein R3, R4 and R5 are each independently selected from the group consisting of hydrogen, carboxylic acid ester, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted aralkyl.

As noted above, the optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroalkenyl, optionally substituted heterocycloalkenyl, optionally substituted heteroalkynyl, optionally substituted heterocycloalkynyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkinyl may comprise one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, sulfur, selenium, phosphorus, silicon, and any combination thereof. Preferably, the one or more heteroatoms are selected from the group consisting of nitrogen, oxygen, sulfur, and any combination thereof.

In some embodiments the alcohol has the formula (IV), wherein one of R3, R4 and R5 is hydrogen. The two other radicals out of R3, R4 and R5, respectively, may be, in particular, independently selected from the radicals disclosed herein above with regard to formula (IV) and are each not hydrogen. The alcohols of these embodiments are therefore secondary alcohols.

In some embodiments the alcohol has the formula (IV), wherein two of R3, R4 and R5 are hydrogen. The one other radical out of R3, R4 and R5, respectively, may be, in particular, selected from the radicals disclosed herein above with regard to formula (IV) and is not hydrogen. The alcohols of these embodiments are therefore primary alcohols.

In some embodiments the alcohol has the formula (IV), wherein one of 3, R4 and R5 is selected from the group consisting of methyl, ethyl and propyl. "Propyl" may be n-propyl or iso-propyl. Preferably, the one of R3, R4 and R5 is methyl. In any case, the two other radicals out of R3, R4 and R5, respectively, may be, in particular, selected from the radicals disclosed herein above with regard to formula (IV) and are not hydrogen. The alcohols of these embodiments are therefore tertiary alcohols.

In some embodiments the alcohol has the formula (IV), wherein two of R3, R4 and R5 are selected from the group consisting of methyl, ethyl and propyl. "Propyl" may be n-propyl or iso-propyl. Preferably, two of R3, R4 and R5 are methyl. The one other radical out of R3, R4 and R5, respectively, may be, in particular, selected from the radicals disclosed herein above with regard to formula (IV) and is not hydrogen. The alcohols of these embodiments are therefore secondary alcohols.

In some embodiments the alcohol has the formula (IV), wherein one of R3, R4 and R5 is methyl or ethyl and one of R3, R4 and R5 is hydrogen. The one other radical out of R3, R4 and R5, respectively, may be, in particular, selected from the radicals disclosed herein above with regard to formula (IV) and is not hydrogen. The alcohols of these embodiments are thereforesecondary alcohols.

In some embodiments of the methods of converting an alcohol into the corresponding halide described herein the alcohol is an optionally substituted alkyl alcohol. An alkyl alcohol can be also regarded as an aliphatic alcohol, i.e. an alcohol, wherein the hydroxyl group is bonded to a saturated carbon atom. In particular, the alkyl alcohol may be a linear or branched C2-C20 alkyl alcohol, prepferably a linear or branched C2-C15 alkyl alcohol, more preferably a linear or branched C2 to CIO alkyl alcohol and most preferably a linear or branched C2-C4 alkyl alcohol. As denoted by the term "optionally substituted", the alkyl alcohol may be unsubstituted or substituted. Substituents of the alkyl alcohol may be, for example, H, halogen, a nitrogen containing group, such as, for example, N0 ₂ , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe ₂ and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, a group comprising an aryl group or a heteroaryl group, and the like. Since the alkyl alcohol may be substituted with a group containing a carbon-carbon double bond, the alkyl alcohol may be a homoallylic alcohol. In some embodiments of the methods the alkyl alcohol has the formula (V): m (V),

wherein m is an integer of from 0 to 18, preferably of from 2 to 16, more preferably of from 4 to 14, even more preferably of from 6 to 12, and most preferably of from 8 to 10.

In some embodiments the optionally substituted alkyl alcohol is selected from the group consisting

In some embodiments the optionally substituted alkyl alcohol is selected from the group consisting

alcohol

In some embodiments of the methods of converting an alcohol into the corresponding halide described herein the alcohol is an optionally substituted allylic alcohol. An allylic alcohol as referred to herein comprises the basic structure HO-CH ₂ -CH=CH ₂ . As denoted by the term "optionally substituted", the allylic alcohol may be unsubstituted or substituted. Substituents of the allylic alcohol may be, for example, H, halogen, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert- butyl, pentyl, hexyl, and the like, a nitrogen containing group, such as, for example, N0 ₂ , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe ₂ and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, a group containing an aryl group or a heteroaryl group, and the like.

In some embodiments the optionally substituted allylic alcohol is selected from the group consisting

In preferred embodiments the optionally substituted allylic alcohol is selected from the group

consisting of

In some preferred embodiments the optionally substituted allylic alcohol is

In some embodiments of the methods of converting an alcohol into the corresponding halide described herein the alcohol is an optionally substituted propargylic alcohol. A propargylic alcohol as

'OH

referred to herein comprises the basic structure . As denoted by the term "optionally substituted", the propargylic alcohol may be unsubstituted or substituted. Substituents of the propargylic alcohol may be, for example, H, halogen, a linear or branched C1-C6, preferably C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like, a nitrogen containing group, such as, for example, N0 ₂ , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe ₂ and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, a group containing an aryl group or a heteroaryl group, and the like.

In some embodiments the optionally substituted propargylic alcohol is selected from the group

consisting of , and

In a preferred embodiment the optionally substituted propargylic alcohol is

In some embodiments of the methods of converting an alcohol into the corresponding halide described herein the alcohol is an optionally substituted benzylic alcohol. A benzylic alcohol as referred to herein comprises the basic structure . As denoted by the term "optionally substituted", the benzylic alcohol may be unsubstituted or substituted. Substituents of the benzylic alcohol may be, for example, H, halogen, a carboxylic acid ester, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like, a nitrogen containing group, such as, for example, N0 ₂ , CN, a protected or substituted amino group, such as, for example, NHBoc, NHCbz, NHAIIoc, NHFmoc, NHPiv, NMe ₂ and the like, a protected or substituted hydroxyl group, such as, for example, an ether group, in particular such as OMe, OBn or a silyl ether, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, a group containing an aryl group or a heteroaryl group, and the like. The substituents may be, for example to the CH ₂ portion and/or the penyl ring of the benzylic alcohol having the basic structure

In some embodiments the optionally substituted benzylic alcohol is selected from the group

In some embodiments the optionally substituted benzylic alcohol is selected from the group

In some embodiments the o tionally substituted benzylic alcohol is selected from the group

In preferred embodiments the optionally substituted benzylic alcohol

In some embodiments of the methods of converting an alcohol into the corresponding halide described herein the alcohol is an optionally substituted a-hydroxy carboxylic acid ester. As denoted by the term "optionally substituted", the a-hydroxy carboxylic acid ester may be unsubstituted substituted or substituted. Substituents of the α-hydroxy carboxylic acid ester may be, for example, H, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, a group containing an aryl group such as, for example, a phenyl group or a phenyl group substituted with a hydrogen, a group containing a heteroaryl group, and the like. The part of the carboxylic acid ester group which formally derives from the alcohol may be, for example, a linear or branched C1-C6, preferably a linear or branched C1-C4 alkyl group, such as, for example, methyl, ethyl, n-propyl, iso- propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like, a group containing a carbon-carbon double bond, a group containing a carbon-carbon triple bond, a group containing an aryl group such as, for example, a benzyl group, a group containing a heteroaryl group, and the like. In some embodiments the optionally substituted a-hydroxy carboxylic acid ester is selected from the

OH OH OH

group consisting of "ΒυΟ^^ΟΗ ^ Et0 ₂ C^ Bn0 ₂ C^ Me0 ₂ C^Ph _{# and}

In a preferred embodiment the optionally substituted a-hydroxy carboxylic acid ester is

In some embodiments of the methods of converting an alcohol into the corresponding halide described herein the alcohol is an optically active alcohol. An optically active alcohol as referred to herein may also be denoted as a chiral alcohol, i.e. an alcohol having a stereogenic center. In particular, the "term optically active alcohol" denotes an enantioenriched chiral alcohol. In this context, "enantioenriched" is to be understood that in a sample of the alcohol one enantiomer, i.e. the major enantiomer, is present in a major amount, while the other enantiomer, i.e. the minor enantiomer, is present in a minor amount. Hence, in an enantioenriched alcohol the ratio of enantiomers deviates from a racemic sample in which both enantiomers are present in a 50:50 ratio. The major enantiomer is present in an amount of more than 50 %, and the minor enantiomer is present in an amount of less than 50 %, each based on 100 % of both enantiomers. For example, the major amount may be present in the sample in 60 %, 70 %, 80 %, 90 % or even 95 % based on 100 % of both enantiomers. In these cases, the ratio of the major enantiomer to the minor enantiomer, in other words the enantiomeric ratio, is 60:40, 70:30, 80:20, 90:10 and 95:5. The inventor has found out that in case that an enantioenriched alcohol is used in the method of converting an alcohol into the corresponding halide described herein, the enantiomeric ratio of the alcohol employed is substantially maintained in the obtained corresponding halide. Hence, in case that an enantioenriched alcohol having a high enantiomeric purity is used as starting material, such high enantiomeric purity is advantageously also found in the corresponding halide obtained as product. Therefore, the methods of converting an alcohol into the corresponding halide disclosed herein permit to synthesize halides having a high enantiomeric purity. With this regard, particularly good enantiomeric purities of the corresponding halide are achieved in case that N-formylpyrrolidine is used as the N-substituted formamide. Further, it has turned out that, in case that the alcohol is an a- hydroxy ester, using 2-fluorobenzoyl chloride provides a particularly high enantiomeric purity of the corresponding chlorides. It has been found out that in general the conversion of the alcohol into the corresponding halide proceeds with inversion of the configuration at the stereogenic center. In an embodiment the optically active alcohol is enantioenriched 1-phenyl ethanol. In an embodiment the optically active alcohol is enantioenriched 4-phenyl-2-butanol. In an embodiment the optically active alcohol is enantioenriched ethyl 2-hydroxypropanoate. In an embodiment the optically active alcohol is enantioenriched benzyl 2-hydroxypropanoate. In an embodiment the optically active alcohol is enantioenriched methyl 2-hydroxy-2-phenylethanoate. The enantiomer present in major amount in the enantioenriched alcohol may be the ( ) enantiomer or the (S) enantiomer. In the methods of converting an alcohol into the corresponding halide described herein the N- substituted formamide may be used in catalytic amounts, substoichiometric amounts, stoichiometric amounts and overstoichiometric amounts. With this regard, the terms "catalytic", "substoichiometric", "stoichiometric" and "overstoichiometric" are used to denote the molar ratio of the N-substituted formamide to the hydroxyl groups of the alcohol to be converted into the corresponding halide. Hence, in case that the N-substituted formamide is used in a stoichiometric amount, the molar ratio of the N-substituted formamide to the hydroxyl groups is 1:1. In case that the N-substituted formamide is used in catalytic or substoichiometric amounts, the molar ratio of the N-substituted formamide to the hydroxyl groups is less than 1, such as, e.g. 0.8, 0.5, 0.2 or 0.1. In case that the N-substituted formamide is used in overstoichiometric amounts, the molar ratio of the N-substituted formamide to the hydroxyl groups is, for example, 1.1.

In some embodiments the N-substituted formamide is used in an amount of from 0,05 to 120 mol-%, preferably of from 0.1 to 80 mol-%, more preferably of from 0.5 to 70 mol-%, even more preferably of from 0.8 to 60 mol-%, still more preferably of from 1 to 50 mol-%, still more preferably of from 3 to 40 mol-%, still more preferably of from 5 to 30 mol-% and most preferably of from 10 to 20 mol-% based on 100 mol-% of the hydroxyl groups to be converted into the corresponding halide. In further exemplary embodiments the N-substituted formamide may be used in an amount of from 1 to 40 mol-%, 5 to 60 mol-%, 5 to 20 mol-%, 10 to 20 mol-% and 20 to 60 mol-% based on 100 mol-% of the hydroxyl groups to be converted into the corresponding halide. As used herein with regard to the amount of the N-substituted foramide, the term "mol-%" denotes the amount of the N-substituted formamide relative to a reference value of 100 mol-% of the hydroxyl groups to be converted into the corresponding halide. With this regard, as an example, "20 mol-% of the N-substituted formamide" means that in case that 100 mmol of the hydroxyl groups are present, the amount of the N-substituted formamide is 20 mmol. Hence, in another representation which is fully equivalent with the aforementioned indications of mol-%, the amount of the N-substituted formamide may be expressed as the molar ratio of the N-substituted formamide to the hydroxyl groups to be converted into the corresponding halide. With this regard, in the methods of converting an alcohol into the corresponding halide described herein the N-substituted formamide may be used in a molar ratio of the N-substituted formamide to the hydroxyl groups to be converted into the corresponding halide of from 0.0005 to 1.2, preferably of from 0.001 to 0.8, more preferably of from 0.005 to 0.7, even more preferably of from 0.008 to 0.6, still more preferably of from 0.01 to 0.5, still more preferably of from 0.03 to 0.4, still more preferably of from 0.05 to 0.3 and most preferably of from 0.1 to 0.2. In further exemplary embodiments the N-substituted formamide may be used in a molar ratio of the N-substituted formamide to the hydroxyl groups to be converted into the corresponding halide of from 0.01 to 0.4, 0.05 to 0.6, 0.05 to 0.2, 0.1 to 0.2 and 0.2 to 0.6. From the viewpoint of minimizing the waste, as an advantage catalytic or substoichiometric amounts of the N-substituted formamide are in general sufficient to perform the methods of converting an alcohol into the corresponding halide described herein. The minimum amount of the N-substituted formamide required for carrying out the methods described herein can be readily determined by a person skilled in the art using routine experimentation.

In some embodiments the conversion of the alcohol into the corresponding halide is carried out in a solvent. In some embodiments the solvent is selected from the group consisting of N,N- dimethylformamide, dioxane, dichloromethane, tetrahydrofuran, acetone, diethylether, 1,2- dichloroethane, acetonitrile, chloroform, 1,2-dimethoxyethane, methyl-ieri-butyl ether, ethyl acetate, cyclohexane, toluene, and 2-methyl tetrahydrofuran, and any combination thereof. With this regard, in case that Ν,Ν-dimethylformamide is used as the solvent, it also acts as a catalyst for the conversion. In preferred embodiments the solvent is selected from the group consisting of N,N- dimethylformamide, dioxane, dichloromethane, tetrahydrofuran, acetone, 2- Methyltetrahydrofurane, diethylether, 1,2-dichloroethane, methyl-ieri-butyl ether, acetonitrile, chloroform, and 1,2-dimethoxyethane, and any combination thereof. It has been found that in these solvents the conversion of the alcohol into the corresponding halide results in a high yield and selectivity for the halogenated product.

In particularly preferred embodiments the solvent is selected from the group consisting of dioxane, methyl-ieri-butyl ether, acetone, and any combination thereof. Accordingly, in a preferred embodiment the solvent is dioxane. It has been found that by using dioxane as the solvent a particularly high selectivity for the halogenated product is achieved.

In a preferred embodiment the solvent is methyl-terf-butyl ether. Methyl-tert-butyl ether is an ecologically beneficial solvent and provides a high selectivity for the halogenated product. Furthermore, methyl-tert-butyl ether allows for a high enantiomeric purity in case that an optically active, enantioenriched alcohol is used as substrate for the conversion.

In a preferred embodiment the solvent is acetone. With this regard, acetone is a solvent which is particularly environmentally beneficial and is therefore preferred from an ecological point of view.

On the other hand, in the methods of converting an alcohol into a corresponding halide described herein the conversion of the alcohol into the corresponding halide can be carried out under solvent- free conditions. Employing solvent-free conditions is particularly preferred from the viewpoint of reducing waste and performing the methods of converting an alcohol into the corresponding halide as an economically as well as ecologically beneficial process. As used herein, the term "solvent-free conditions" does not exclude that the reaction is performed in the presence of an N-substituted formamide which may be also used as a solvent, such as, for example, N,N-dimethylformamide. However, in case that the method is carried out under solvent-free conditions, the N-substituted formamide is preferably used in substoichiometric or catalytic amounts. Also preferably, under solvent-free conditions the molar ratio of the N-substituted formamide to the hydroxyl groups of the alcohol to be converted into the corresponding halide is not more than 1.2:1.

In general, for carrying out the methods of converting an alcohol into a corresponding halide the alcohol to be converted, optionally a solvent, the N-substituted formamide and the optionally substituted aromatic carboxylic acid halide are added to a reaction vessel, and the resulting mixture is reacted for an appropriate time at an appropriate temperature. In particular, the acohol, the N- substituted formamide and the optionally substituted aromatic carboxylic acid halide may be added contemporaneously. Appropriate conditions for the temperature and the time can be readily selected by a person skilled in the art. Preferably, the reaction mixture is stirred during the conversion of the alcohol into the halide. In embodiments of the methods described herein a step of pre-forming a halogenation reagent may be avoided, as the aromatic carboxylic acid and the alcohol react with each other in the presence of the N-substituted formamide to convert the alcohol into the corresponding halide. Accordingly, in some embodiments the methods may be performed without employing a pre-formed halogenation reagent such as, for example, a reagent pre-formed from an N- substituted formamide and a carboxylic acid halide, and/or a Vilsmeier reagent.

The temperature at which the methods of converting an alcohol into the corresponding halide described herein are performed is not particularly limited. For example, the conversion of the alcohol into the corresponding halide is carried out at a temperature of from 0°C to 120°C, preferably of from 2°C to 100°C, more preferably of from 5°C to 80°C, even more preferably of from 10°C to 60°C, still more preferably of from 15°C to 40 °C, and most preferably of from 20°C to 25°C. Similarly, the reaction time is not particularly limited. For example, the conversion of the alcohol into the corresponding halide is carried out for a time of from 0.5 hours to 48 hours, preferably of from 1 hour to 24 hours, more preferably of from 2 hours to 20 hours, and most preferably of from 5 hours to 12 hours. The corresponding halide obtained from the alcohol by any one of the methods described herein may be isolated from the reaction mixture. Any suitable isolation technique may be used. As an example, the isolation may comprise work-up of the reaction mixture and/or purification of the corresponding halide. For example, the work-up may be carried out as aqueous work-up. Purification of the corresponding halide may be carried out using chromatography or distillation.

In some embodiments the methods of converting an alcohol into a corresponding halide described herein may comprise that an alcohol is reacted with an optionally substituted aromatic carboxylic acid chloride in presence of an N-substituted formamide and a bromide salt. In this regard, the inventor has found that when reacting an alcohol with an optionally substituted aromatic carboxylic acid chloride in the presence of an N-substituted formamide and in the presence of a bromide salt, the alcohol can be efficiently converted into the corresponding bromide by replacing the hydroxyl group of the alcohol by a bromine atom. Accordingly, in some embodiments the present invention also relates to a method of converting an alcohol into a corresponding halide, the method comprising:

reacting an alcohol with an optionally substituted aromatic carboxylic acid chloride in presence of an N-substituted formamide and a bromide salt to replace a hydroxyl group of the alcohol by a bromine atom. I n general, any alcohol described herein in the context of the methods of converting an alcohol into the corresponding halide may be used. I n some embodiments, the alcohol is an optionally substituted benzylic alcohol. I n some embodiments the alcohol is an optionally substituted alkyl alcohol. I n general, any optionally substituted carboxylic acid chloride described herein in the context of converting an alcohol into the corresponding halide in presence of an N-substituted formamide may be used. In some embodiments benzoyl chloride is used as the carboxylic acid chloride. I n some embodiments 2,6-dichlorobenzoyl chloride is used as the aromatic carboxylic acid chloride. I n general, any N-substituted formamide described herein in the context of the methods of converting an alcohol into the corresponding halide may be used. I n some embodiments N- formylpyrrolidine, Ν,Ν-dimethylformamide and/or N-methyl formamide is used as the N- substituted formamide. Preferably, N-formylpyrrolidine is used. The bromide salt used in these embodiments is not particularly limited. For example, in some embodiments an alkali metal bromide salt is used. The alkali metal bromide salt may be, for example, selected from the group consisting of lithium bromide, sodium bromide, potassium bromide and any combination thereof. For example, sodium bromide may be used as the bromide salt.

In some embodiments the methods of converting an alcohol into a corresponding halide described herein may comprise that an alcohol is reacted with an optionally substituted aromatic carboxylic acid chloride in presence of an N-substituted formamide and an iodide salt. In this regard, the inventor has found that when reacting an alcohol with an optionally substituted aromatic carboxylic acid chloride in the presence of an N-substituted formamide and in the presence of an iodide salt, the alcohol can be efficiently converted into the corresponding iodide by replacing the hydroxyl group of the alcohol by an iodine atom. Accordingly, in some embodiments the present invention also relates to a method of converting an alcohol into a corresponding halide, the method comprising:

reacting an alcohol with an optionally substituted aromatic carboxylic acid chloride in presence of an N-substituted formamide and an iodide salt to replace a hydroxyl group of the alcohol by an iodine atom. In general, any alcohol described herein in the context of the methods of converting an alcohol into the corresponding halide may be used. In some embodiments, the alcohol is an optionally substituted benzylic alcohol. In some embodiments the alcohol is an optionally substituted alkyl alcohol. In general, any optionally substituted carboxylic acid chloride described herein in the context of converting an alcohol into the corresponding halide in presence of an N-substituted formamide may be used. In some embodiments benzoyl chloride is used as the carboxylic acid chloride. In some embodiments 2,6-dichlorobenzoyl chloride is used as the aromatic carboxylic acid chloride. In general, any N-substituted formamide described herein in the context of the methods of converting an alcohol into the corresponding halide may be used. In some embodiments N-formylpyrrolidine, Ν,Ν-dimethylformamide and/or N-methyl formamide is used as the N-substituted formamide. Preferably, N-formylpyrrolidine is used. The iodide salt used in these embodiments is not particularly limited. For example, in some embodiments an alkali metal iodide salt is used. The alkali metal iodide salt may be, for example, selected from the group consisting of lithium iodide, sodium iodide, potassium iodide and any combination thereof. For example, sodium iodide may be used as the iodide salt.

The present invention also relates to a halide obtainable or being obtained from an alcohol by any one of the methods of converting an alcohol into a corresponding halide disclosed herein. The present invention further relates to a method of converting an alcohol into a corresponding substitution product, the method comprising:

(a) performing any one of the methods of converting an alcohol into the corresponding halide described herein; and

(b) reacting the corresponding halide with a nucleophile to convert the halide into the nucleophilic substitution product.

In step (a) of the method of converting an alcohol into a corresponding substitution product the alcohol is converted into the corresponding halide in accordance with any one the methods described herein above. In step (b) the corresponding halide is then reacted with a nucleophile. In step (b) the halide undergoes a nucleophilic substitution reaction with the nucleophile which converts the halide into the corresponding nucleophilic substitution product.

After the conversion of step (a) and before step (b) the corresponding halide may be isolated from the reaction mixture. However, in a particularly preferred embodiment of the method of converting an alcohol into a corresponding substitution product steps (a) and (b) are performed in a one-pot procedure without isolation of the halide. With this regard, as encompassed by the term "one-pot procedure" the halide obtained in step (a) is not isolated from the reaction mixture, and in step (b) the nucleophile is combined directly with the reaction mixture obtained in step (a), which comprises the halide. Thus, in step (b) the halide is preferably added to the same reaction vessel in which the conversion of step (a) is performed. Performing steps (a) and (b) in a one-pot procedure saves an isolation step, which may include work-up of the reaction mixture and/or purification of the halide, and is thus advantageous from an economical and ecological point of view. In some embodiments of the method of converting an alcohol into a corresponding substitution product the nucleophile is selected from the group consisting of C nucleophiles, N nucleophiles, O nucleophiles, and S nucleophiles.

In some embodiments the C nucleophile is a cyanide or an enolate. In particular, the C nucleophile

O O

may be or MeO OMe . As used herein, the term "CN " denotes the cyanide ion.

In some embodiments the N nucleophile is selected from the group consisting of an amine, an amide

or an azide. In particular, the N nucleophile may be selected from the group consisting of _/

In preferred embodiments the N-nucleophile e term "N ₃ ^~ " denotes the azide ion. In some

e mbodiments the N nucleophile is

In some embodiments of the method of converting an alcohol into a corresponding substitution product the O nucleophile is a compound having a hydroxyl group or a deprotonated hydroxyl group. For example, the compound having a hydroxyl group may be an alcohol. The compound having a deprotonated hydroxyl group may be, for example, an alcoholate. The O-nucleophile may be also an

Ph— OH

aromatic hydroxyl compound, such as, for example, or a deprotonated aromatic hydroxyl compound.

In some embodiments the S nucleophile is a thiol or a thiolate. For example, the S nucleophile is In some embodiments of the method of converting an alcohol into a corresponding substitution

³ . In preferred embodiments the alcohol reacted in step (a) and the nucleophile reacted in step (b) are:

method of converting an alcohol into a corresponding substitution product described herein leads to the compound clopidogrel having the formula:

which is an important antiplatelet drug.

In some embodiments the alcohol reacted in step (a) and the nucleophile reacted in step (b) are

In step (a) of the methods of converting an alcohol into a corresponding substitution product any solvent or solvent mixture as described herein above with regard to the methods of converting an alcohol into the corresponding halide may be used. In an embodiment step (a) is performed using dioxane as solvent. For example, dioxane can be used in case that steps (a) and (b) are performed in a one-pot procedure without isolation of the halide. Accordingly, dioxane may be also used as solvent in step (b). In addition, it is possible to combine a further solvent in step (b) such as, for example, acetonitrile or methanol. Hence, in an embodiment step (b) may be performed using a mixture of dioxane and acetonitrile. In another embodiment step (b) may be performed using a mixture of dioxane and methanol.

In an embodiment of the methods of converting an alcohol into a corresponding substitution product described herein step (a) is performed using benzoyl chloride as the aromatic carboxylic acid halide as the N-substituted formamide. As noted above, N-formyl pyrrolidine can be employed in catalytic amounts and allows for particularly low catalyst loadings compared to other N- substituted formamides described herein. As also noted above, benzoyl chloride provides good results with a great variety of alcohols, is readily available and minimizes the amount of waste since it does not bear any further substituents.

Step (b) of any one of the methods of converting an alcohol into a corresponding substitution product described herein may be performed in the presence of a base. Using a base in step (b) has turned out to be particularly useful in case that the nucleophile comprises a protic functional group which can be deprotonated by a base. Without wishing to be bound by any theory it is assumed that deprotonation of the nucleophile increases nucleophilicity and therefore reactivity in step (b) of the methods of converting an alcohol into a corresponding substitution product. Suitable bases which can be used in step (b) of the methods described herein are, for example, alkali carbonates or tertiary amines, such as triethyl amine. Accordingly, in an embodiment the base may be potassium carbonate.

The temperature at which step (b) of the methods of converting an alcohol into the corresponding substitution product described herein is performed is not particularly limited. A suitable reaction temperature can be appropriately selected by a person skilled in the art. For example, step (b) is performed at a temperature of from 0°C to 120°C, preferably of from 2°C to 100°C, more preferably of from 5°C to 80°C, even more preferably of from 10°C to 60°C, still more preferably of from 15°C to 40 °C, and most preferably of from 20°C to 25°C. Similarly, the reaction time of step (b) is not particularly limited and can be appropriately selected by a skilled person. For example, step (b) is carried out for a time of from 0.5 hours to 48 hours, preferably of from 1 hour to 24 hours, more preferably of from 2 hours to 20 hours, and most preferably of from 2 hours to 12 hours. The present invention also relates to a substitution product obtainable or being obtained from an alcohol by any one of the methods of converting an alcohol into a corresponding substitution product disclosed herein.

It must be noted that as used herein, the singular forms "a", "an", and "the", include plural references unless the context clearly indicates otherwise. Thus, for example, reference to "a reagent" includes one or more of such different reagents and reference to "the method" includes reference to equivalent steps and methods known to those of ordinary skill in the art that could be modified or substituted for the methods described herein. All publications and patents cited in this disclosure are incorporated by reference in their entirety. To the extent the material incorporated by reference contradicts or is inconsistent with this specification, the specification will supersede any such material.

Unless otherwise indicated, the term "at least" preceding a series of elements is to be understood to refer to every element in the series. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the present invention.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integer or step. When used herein the term "comprising" can be substituted with the term "containing" or sometimes when used herein with the term "having". When used herein "consisting of" excludes any element, step, or ingredient not specified in the claim element. When used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. In each instance herein any of the terms "comprising", "consisting essentially of" and "consisting of" may be replaced with either of the other two terms.

Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

EXAMPLES

The following Examples further illustrate the invention. These Examples should however not be construed as to limit the scope of this invention. The Examples are included for purposes of illustration and the present invention is limited only by the claims.

1. General Part

Unless otherwise stated all ^X H and ¹³ C NM spectra were recorded at room temperature on a Bruker Avance II 400 spectrometer. Chemical shifts (δ) are reported in parts per million (ppm) from tetramethylsilane (TMS) using the residual solvent resonance ( ¹³ C-NMR) or TMS ( ¹ H-NMR) as the internal standard (CDCI ₃ : 7.26 ppm for ¹ H NMR, 77.0 ppm for ¹³ C NMR). Multiplicities are abbreviated as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet). High resolution Mass spectra were recorded on a MAT 95Q spectrometer (CI) of Finnigan. Optical rotations were determined on a Perkin Elmer polarimeter 341. Melting points (uncorrected) were determined on a MEL-TEMP II machine of Laboratory Devices Inc.

Analytical TLC was carried out using precoated silica gel plates (Fluka TLC plates silica gel 60 F254 on PET-foils).TLC plates were visualized under UV irradiation (254 nm) or with KMn0 ₄ ^" (3 g KMn0 ₄ and 20 g K ₂ C0 ₃ in 300 mL water) and Ce(S0 ₄ ) ₂ /PMA (= jDoly molybdic acid, 10 g Ce(S0 ₄ ) ₂ ^" x 4 H ₂ 0, 25 g PMA, 80 mL 95% H ₂ S0 ₄ , 920 mL water) stain solutions. Flash column chromatographic purifications of alkyl chlorides were performed with ultra pure silica gel from Acros (40-60 μιτι, 60 A, product no. 360050010), all other compounds were purified with technical grade silica gel M60 from Macherey- Nagel (40-63 μιτι, 60 A).

Gas chromatography (GC) was conducted on a GC-2010 from Shimadzu with a CP-Chirasil-DX CB column (length 25 m, diameter 0.25 mm, 0.25 μιτι layer thickness) from Agilent Technologies and nitrogen as carrier gas. Compounds were either detected by an FID or a GCMS-QP2010 Plus mass detector from Shimadzu. High pressure liquid chromatography (HPLC) was conducted on a D-7000 machine from Merck-Hitachi with a Chiracel OD-H column of Daicel Industries (length 250 mm, diameter 4.6 mm). Visualisation was realized by a diode array UV detector (wavelength 190-300 nm).

All water sensitive reactions were carried out in heat gun dried glassware under a nitrogen atmosphere. Chemicals were purchased from Sigma-Aldrich, Acros, TCI chemicals, Carbolution and Alfa Aesar and used without further purification. Petrolether (bp. 40-60 °C, technical grade) was distilled prior usage; all other solvents were utilized without further purification. THF was distilled over Na/benzophenone; all other dry solvents were purchased from Acros. 2. General Procedures

2.1 Catalyzed Chlorinations

2.1.1 General Procedure I: Determination of Yield through NMR-Standard

A 4 mL glas vial with a stir bar was charged successively with the alcohol 1 (1.0 equiv, 0.2-1 mmol) and the catalyst, in particular the N-substituted formamide, either in pure form or as a 1 N solution in the solvent (In order to improve the accuracy of the determination of the catalyst loading for instance from DMF and FPyr were prepared 1 N stock solutions in the solvent and added via an Eppendorf pipette to the reaction vessel) and the mixture was diluted with the solvent to the desired concentration. In the following, the acid chloride was added via an Eppendorf pipette (Due to the high viscosity of for instance some starting materials 1 the amount of 1, the catalyst and reagent was additionally checked by weighing (in the reaction vial). at ambient temperature and the reaction mixture was stirred for the time period t at the reaction temperature T.

After cooling down to ambient temperature, the reaction mixture was diluted with Et ₂ 0 (1 mL) and saturated NaHC0 ₃ -solution (aq., 2 mL) was added carefully dropwise. After C0 ₂ -evolution had ceased (5 min stirring at rt) the mixture was taken up with a 20 mL syringe and diluted with Et ₂ 0 (3 mL). The phases were separated, the organic phase was dried over MgS0 ₄ , concentrated and dried under reduced pressure. Depending on the volatility of the chloride 2 the crude product was dried either at 50 mbar for 2 min (chlorides 2 < 8 C-atoms), for 5 min (chlorides 2 9-10 C-atoms) or 2 min at 20 mbar (chlorides 2 >10 C-atoms). Finally, the crude product was dissolved with an exactly weight amount of naphthalene or dodecane (20-50 mg) in CDCI ₃ (ca. 0.5 mL) and ca. 50 μί were transferred to an NM - tube and diluted with 0.5 mL of CDCI ₃ .

Work up with DMF as solvent: The reaction mixture was quenched through the dropwise addition of saturated NaHC0 ₃ -solution (aq., 2 mL), diluted with Et ₂ 0 (6 mL) the organic phase was washed with further NaHC0 ₃ solution (2 mL) and 1 N HCI solution (aq., 2 x 2 mL) to remove DMF completely (as judged by ¹ H-NMR of the crude material). Next the organic phase was dried over MgS0 ₄ , concentrated under reduced pressure and dried as described above.

Solvent-free Chlorinations were conducted with 1.00 mmol (1.0 equiv) of the starting material 1. In chlorinations of enantioenriched alcohols 1 (0.30 mmol, 1.0 equiv) for work up the reaction mixture was initially treated with 1,2-ethanolamine (13 μί, 0.21 mmol, 0.7 equiv) and then the work up was continued as described above. Ethanolamine quenched corrosive BzCI (see General Procedure II) in order not to harm the chiral GC-column during analysis to determine the er.

2.1.2 General Procedure II: Synthesis of Chlorides 2 on a small scale

A. Reaction

1 :8-1 :20) crude product in H ₂ 0-phase

A. Reaction: T = rt

A 4 mL glas vial with a stir bar was charged successively with the alcohol 1 (1.0 equiv, 1.00-2.00 mmol), dry solvent (mostly 1,4-dioxane, 1-2 mL, 2 M) and N-substituted formamide 2 (either dry DMF or formylpyrrolidine, 1-40 mol%), cooled to 0 °C (in a alumina carousel in an ice bath) and the acid chloride (BzCI or 2-FBzCI, 1.2-1.5 equiv) was added (Liquid starting materials, the formmide catalysts and reagents were added via Eppendorf pipette. Due to the high viscosity of for instance some starting materials 1 the amount of substance was additionally controlled by weighing (in the reaction vial). Next, the reaction vial was sealed with a screw cap, the mixture was allowed to stir for 0.25 h at 0 °C and than at room temperature (= T) until TLC control showed full consumption of the starting material 1 (for the time period t < 24 h).

A. Reaction: T = 40-80 °C

Same procedure as above except that the acid chloride was added at ambient temperature, and the reaction vial was immediately placed in an alumina carousel preheated to the temperature T.

B. Work up

In order to quench the excess of BzCI (which was elsewise coeluted with the nonpolar products 2 during chromatography) the reaction solution was treated at ambient temperature with ethanolamine (0.6 equiv with 1.2 equiv BzCI and 1.1 equiv with 1.5 equiv BzCI, respectively) under vigorous stirring and the resulting suspension was stirred for further 15-30 min (Full consumption of the remaining acid chloride was scured by TLC. BzCI (r _f = 0.41 in Et ₂ 0//iPen 1:99) and 2-FBzCI are UV- active, but cannot be visualized on TLC by KMn0 ₄ - or PMA/Ce(IV)-stain. If the acid chloride was not quenched completely, further 0.5 equiv of ethanolamine were added). Next, the heterogeneous mixture was transferred with Et ₂ 0 (6 mL) to 10 mL flask (including the stir bar), cooled to 0 °C and under vigorous stirring saturated NaHC0 ₃ (aq., 2 mL) and water (1 mL, to dissolve NaOBz completely) were added accompanied by a weak C0 ₂ -evolution. After 5 min stirring at 0 °C, the mixture was taken up with a 20 mL syringe, the phases were separated and the organic phase was washed with further NaHC0 ₃ -solution (1 x 2 mL) remaining in the syringe (In order to avoid leaking the needle of the syringe was sealed with a rubber plug during mixing of the phases). The organic phase was dried over MgS0 ₄ , concentrated and dried under reduced pressure at the rotatory evaporator. Depending on the volatility of the chloride 2 the crude product was dried either at 50 mbar for 2 min (chlorides 2 < 8 C-atoms), for 5 min (chlorides 2 9-10 C-atoms) or 2 min at 20 mbar (chlorides 2 >10 C-atoms). The conversion and ratio of the chloride 2 to the ester 3 were determined by ¹ H-NM (ca. 5 mg of the crude product) (Residual dioxane (50-100 mol%) was separated automatically by the chromatographic purification from the volatile chlorides 2).

C. Chromatography

In the following, the crude product was purified by column chromatography on silica gel (ultra pure, ratio 8-40:1 referred to the weight of the crude product, amount of Si0 ₂ dependent on the separation difficulty) (Small amounts of silica gel are utmost important to avoid significant decomposition of the chlorides 2. In particular chlorides 2 bearing electronrich π-systems in a-position are sensitive to decomposition. For instance, para-methoxybenzyl chloride and diphenylmethyl chloride showed multiple spots on TLC, although ¹ H-NMR of the isolated chlorides indicated purities > 95%) with Et ₂ 0//iPen mixtures as eluent system (In order to apply the crude product to column chromatography remaining in a 10 mL flask it was diluted with the eluent (ca. 0.5 mL), the flask was closed with a stopper (to avoid solvent evaporation) and the mixture was gently warmed in a water bath (40 °C) usally resulting in a milky emulsion (most likely the ester 3 precipitated). Adsorption on silica gel and isolute, respectively, of the crude material usually lead to significantly decreased yields). Thereby 2-3 mL fractions were collected with the product 2 usually starting to be eluted from the second to fourth fraction (no prefraction collected) (For chromatographic purification eluent mixtures with r _f (2) = 0.5-0.7 were choosen to minimize contact time of 2 with silica gel decreasing decomposition). Visualisation on TLC was usually achieved with PMA/Ce(IV)-stain and under UV light, if π-systems were present (KMn0 ₄ -stain in most cases was inappropriate). After concentration in vacuo (see above for pressure and time) (In particular with volatile chlorides 2 (< 10 C-atoms) care has to be taken: After chromatography the product containing fractions were transferred to an appropriate sized flask with nPen (to remove Et ₂ 0) and the solvent was removed under reduced pressure (700-800 mbar). Next, the residue was transferred with further nPen to a 10 mL flask and the solvent was removed in vacuo completely) the chlorides 2 were obtained as colorless, thin oils (or in some cases as solids) in >95% purity according to H-NMR and GC-MS.

All reactions were optimized regarding reaction temperature T, N-substituted formamide (catalyst) and acid chloride loading to achieve full conversion of the starting material 1 in less then 24 h (= t).

2.1.3 General Procedure III: Synthesis of Chlorides on a large scale

D. Purification

A. Reaction

2 + DMF ^■ * DMF o washing with water in H ₂ 0-phase

(no organic solvent)

C. Distillation

H X NR ₂

(5-60 mol%)

OH C. Distillation

BzCI (0.95-1.05 equiv) ^{Cl OBz} + 1 equiv BzOH CI

A A , + . A , + traces HCI

R solvent (2 M) or solvent-free R ' R R ^{" ^} R^ + <5 mol% BzCI A R

1 T t 3 (<20 mol%)

> 95% purity then Evaporation solvent reaction mixture

and T t ^'

B. Work up C. Distillation

BzONa

+ NaCI 2 + 3 + <5 mol% BzCI washing with Na ₂ C0 ₃ (aq.)

+ HCONR ₂ crude product in H ₂ 0-phase

A. Reaction: solvent, T = rt

A 250-1000 mL round bottom flask containing a strong stir bar was charged with the alcohol 1 (200-500 mmol, 1.0 equiv), the N-substituted formamide catalyst (FPyr, DMF or MF, 5-20 mol%) and the reagent grade solvent (e.g. MTBE, 2-MeTHF, Et ₂ 0, acetone, 2 M). The resulting solution was cooled in an ice bath and benzoyl chloride (0.95-1.1 equiv) (In order to avoid codistillation (with the product 2) of an excess of BzCI during purification a minimum amount of BzCI was utilized. To improve accuracy both the amount of starting material 1 and benzoyl chloride 2 was determined by their mass (Am = ±0.02 g) and not their volume. Due to the very small excess of BzCI utilized the reaction has to be driven to full conversion by evaporation of the solvent and further stirring at ambient temperature. In order to reduce the waste amount (improve the E-factor) we desisted from quenching the excess of BzCI with ethanolamine as described in general procedure II. As in the chlorination of 4-Methoxybenzyl alcohol bis[4-methoxybenzyl]ether formed following the equasion R-CI + R-OH -> R ₂ 0 + HCI 0.95 equiv of BzCI were sufficient enough to give full conversion) was added dropwise within 15-60 min via a dropping funnel. After 15 min of stirring at 0 °C, the cooling bath was removed and the mixture was stirred overnight (t < 14 h) at room temperature (= T). In order to accelerate the reaction ( ^X H-NMR of a small aliquot (5-10 mg) of the reaction mixture after evaporation of the solvent indicated 70-95% conversion), the solvent was evaporated under reduced pressure at the rotatory evaporator (In the case ot MTBE the distilled solvent was reused for the work up) and the residue was dried for 5 min at 150 mbar, whereby benzoic acid precipitated. Next, the resulting suspension was stirred at ambient temperature (If reaction control via ¹ H-NM showed less BzCI (charateristic t at 7.69 ppm) than remaining starting material 1 further BzCI was added at ambient temperature (in 0.01 equiv excess referred to residual 1)) (= T) until reaction control via TLC or ¹ H-NMR (For reaction control by ¹ H-NMR a small aliquot of the reaction mixture (5- 10 mg) was simply dissolved in CDCI ₃ ) indicated full conversion (t ^' = 4-12 h).

A. Reaction: solvent, T = 40-80 °C

As described above except that benzoyl chloride was added at 80 °C in 1-2 h and then the reaction solution was stirred at 80 °C until reaction control through TLC or ¹ H-NMR (For ¹ H-NMR a small aliquot of the reaction mixture (ca. 100 μί) was concentrated under reduced pressure (-> 50 mbar) and dissolved in CDCI ₃ (ca. 0.5 mL)) indicated full conversion of 1 (t = 1-2 h). After cooling down to ambient temperature either a work up was conducted as described below (->B) or the solvent was evaporated under reduced pressure and the crude reaction mixture was subjected to distillation (-^C). Considering the volatility of the products 2 during evaporation of the solvent the residue was dried for 5 min either at 150 mbar (chlorides 2 < 8 C-Atoms) or 50 mbar (chlorides 2 > 8 C-Atoms).

A. Reaction: solvent-free, T = rt

A 100-1000 mL round bottom flask containing a strong stir bar was charged with the alcohol 1 (200-2000 mmol, 1.0 equiv), the N-substituted formamide catalyst (DMF, FPyr or FPip, 10-60 mol%). The reaction mixture was next cooled in an ice bath and benzoyl chloride (0.95-1.05 equiv) (In order to avoid codistillation (with the product 2) of an excess of BzCI during purification a minimum amount of BzCI was utilized. To improve accuracy both the amount of starting material 1 and benzoyl chloride 2 was determined by their mass (Am = ±0.02 g) and not their volume. Due to the very small excess of BzCI utilized the reaction has to be driven to full conversion by evaporation of the solvent and further stirring at ambient temperature. In order to reduce the waste amount (improve the E-factor) we desisted from quenching the excess of BzCI with ethanolamine as described in general procedure II. As in the chlorination of 4-Methoxybenzyl alcohol bis[4-methoxybenzyl]ether formed following the equasion R-CI + R-OH -> R ₂ 0 + HCI 0.95 equiv of BzCI were sufficient enough to give full conversion) was added slowly dropwise within 1-2 h via a dropping funnel. After 15 min of stirring at 0 °C, the cooling bath was removed and the mixture was stirred (t < 24 h) at room temperature (= T) until reaction control via TLC or ¹ H-NMR (For reaction control by ¹ H-NMR a small aliquot of the reaction mixture (5-10 mg) was simply dissolved in CDCI ₃ ) showed full conversion, whereby benzoic acid precipitated.

A. Reaction: solvent-free, T = 80-100 °C

^J As described above except that the benzoyl chloride was added at the temperature T and the reaction mixture was stirred at the temperature T until reaction control indicated full conversion (t < 24 h). B. Work up

' For some substrates 1 an aqueous work up had to be performed, either because the catalyst and traces of benzoic acid were codistilled (e.g. 4-methoxybenzyl chloride) or the product decomposed (with geraniol and nerol), when distilled straightforward form the crude reaction mixture. Therefore the reaction mixture was diluted with MTBE or Et ₂ 0 (0.5 mL/1 mmol of 1), cooled in an ice bath and under vigorous stirring sat. Na ₂ C0 ₃ solution in water (0.3 mL/1 mmol of 1) was added dropwise via a dropping funnel in 5-10 min accompanied by a weak C0 ₂ -evolution. Next, the heterogeneous mixture was transferred to an extraction funnel (500-1000 mL) and the reaction flask was rinsed with water/ether (0.1 ml/1 mmol each, two portions). The mixture was further diluted with a minimum amount of water to dissolve the precipitate (NaOBz) completely (0.2-0.5 mL/1 mmol of 1) (pH = 7-8 of the aqueous phase. Total ratio of volume aqeous phase to amount of starting material 1 was thus 0.8-1.2 mL/mmol) the organic phase was washed with further Na ₂ C0 ₃ solution (0.2 mL/1 mmol) (If NaOBz precipitated during washing, water was added to dissolve all solids (0.05- 0.1 mL/1 mmol of 1). pH > 10 of aqueous washing phase) dried over MgS0 ₄ , concentrated under reduced pressure and dried for 5 min either at 150 mbar (chlorides 2 < 8 C-Atoms) or 50 mbar (chlorides 2 > 8 C-Atoms).

C. Distillation

Depending on the substrate the chloride 2 was separated by fractioned distillation either from the reaction mixture (after evaporation of solvent) or after work up (as described above). Volatile chlorides 2 (< 5 C-Atoms) where distilled through a Claisen distillation bridge with a 20 cm cooling pathway and the collecting flask was additionally cooled in an ice bath. Thereby distillation was either conducted at 1 atm (chlorides 2 with 3 C-Atoms) or under reduced pressure (150- 500 mbar), which was applied through a membrane pump. Especially with allylic chlorides (e.g. crotyl and prenyl chloride) attention was paid to adjust the pressure that way that the boiling point is < 60 °C. This avoided HCI-elimination (to give the corresponding olefins), and isomerisation from the linear to the branched chloride.

For less volatile chlorides 2 (> 7 C-Atoms and ethyl-2-chloro propionate and 3-chloropropionitrile) distillations were conducted in high vacuum, whereby the pressure (The pressure was measured between the vacuum pump and the cooling trap of the nitrogen/vacuum line and can therefore be slightly lower than the actual pressure in the distillation apparatus) was adjusted by a an„artificial leak" produced through a needle valve to the environment. In particular with sensitive chlorides (e.g. geranyl and neryl chloride £ Z-2 ₄ ) the pressure has to be adjusted in order to reach boiling points < 60 °C to avoid decomposition. Due to the low boiling point the collecting flask was consequently cooled in an ice bath. Depending on the separation difficulty the distillation was either conducted with a simple micro distillation apparatus or an additional Vigreux column (and micro distillation apparatus) (If the crude reaction mixture was directly submitted to distillation under reduced pressure (without work up) the joint between reaction flask and distillation apparatus got stucked by cristallized benzoic acid (mp. 125 °C). Heating via heat gun (to melt BzOH) allowed to separate both glas pieces easily). DMF was at least partially codistilled for chlorides > 5 C-atoms and removed from the distillate through washing as described below (-> D).

D. Purification

^J To remove DMF and acid traces the neat distillate was washed with water (3-4 times, 0.05-0.1 mL water/1 mmol 1) and finally either with mixtures of sat., aq., Na ₂ C0 ₃ -solution and water or brine depending on the density of the chloride (On a 200 mmol scale the washing was conducted in a 60 mL syringe). Drying over MgS0 ₄ then provided the pure chloride 2.

2.2 One-pot Chlorination and Nucleophilic Substitution

2.2.1 General Procedure IV: One-pot Chlorination and subsequent Trapping with a Nucleophile

H-Nu (1 .3-3.3 equiv)

l%)

1 :5 (0.3 M) T ₂ t ₂

H-Nu = H-NR ₂ , H-NHR, H-OAr, HSR, H-CH(C0 ₂ R) ₂

According to general procedure II (chapter 2.1.2) a 4 mL glas vial was charged with the alcohol (1 mmol, 1.0 equiv), formyl pyrrolidine (10-20 mol%) and dioxane (0.5 mL, 2 M). The mixture was allowed to react with the acid chloride (BzCI or 2-FBzCI, 1.2 mmol, 1.2 equiv) at the temperature Ti until TLC control revealed full consumption of the starting material 1 (ti < 24 h). After cooling down to ambient temperature the mixture was diluted with acetonitrile (reagent grade, 2 mL, dioxane/MeCN 1:4, 0.4 M), freshly mortared, fine-powdered K ₂ C0 ₃ (318 mg, 2.3 mmol, 2.3 equiv) and the nucleophile (H-Nu, 1.3-5.0 equiv) were added successively. For less reactive substrates and nucleophiles additionally TBAI (38 mg, 0.1 mmol, 10 mol%) was added to accelerate the reaction. Next, the reaction mixture was stirred at the temperature T ₂ (in an alumina carousel) for 24 h (= t ₂ ).

After cooling down to room temperature the heterogeneous mixture was dissolved in water (4 mL) and diethylether (3 mL) and the organic phase was separated (The work up was conducted in a 20 mL syringe rather then an extraction funnel). Subsequently, the aqueous phase (pH > 10) was extracted with further diethylether (2 x 3 mL), the combined organic phases were washed with brine (3 mL), dried over MgS0 ₄ , concentrated under reduced pressure and dried at 20 mbar for 5 min. Chromatographic purification on silica gel with Et ₂ 0//iPen mixtures then provided the pure products 4. Thereby, amines were adsorbed on silica gel (mass of crude product/Si0 ₂ 1:2-1:2.5) through dissolution in DCM (ca. 5 mL), addition of silica gel and concentration. Chromatography with Et ₂ 0/NEt ₃ //iPen (up to 5 vol% of NEt ₃ ) allowed the polar amines 4 to be eluted cleanly minimizing diffusion. Importantly, the silica gel column had to be prepared with the same eluent mixture without NEt ₃ in prior.

MNu = KCN, NaN ₃

As described above, except that after chlorination (1 -> 2) the reaction mixture was diluted with MeOH (reagent grade, 2.5 mL, dioxane/MeOH 1:5, 0.33 M), K ₂ C0 ₃ (180 mg, 1.3 mmol, 1.3 equiv), TBAI (37 mg, 0.10 mmol, 10 mol%) and the salt MNu (1.5-2.0 mmol, 1.5-2.0 equiv) were added. Volatile azides 4 were dried at 50 mbar for 5 min (after work up and chromatography).

3. Comparison of the current method with literature methods

Two representative examples as shown in Table 3 and 4 were chosen to compare the environmental impact of the present catalyzed method with concurring literature methods. Two widely spread green chemistry metrics were chosen for evaluation. At first the concept of atom economy (= AE) introduced by Trost, which basically reflects the amount of atoms transferred from the starting materials and reagents to the product and is thus ideally 100% ((a) Trost, B. M. Science 1991, 254, 1471-1477. (b) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259-281. (c) Trost, B. M. Acc. Chem. Res. 2002, 35, 695-705):

AE = M(product)/(M(starting materials) + M(reagents)

with M = molecular mass However, the AE does not consider the stoichiometry of reagents and starting materials, isolated yield of the product and solvents utilized in a process. These additional contributions are taken into account by the Economy factor (E-factor) created by Sheldon ((a) Sheldon, . A. Chem. Ind. 1992, 903-906. (b) Sheldon, R. A. Green Chem. 2007, 9, 1273-1283). E-factor =∑m(waste)/m(product) = (∑m(raw materials) - m(product)/m(product) with m = mass

The mass of raw materials implies the mass of starting materials, catalysts and solvents (except of water) and therefore gives a more exact picture of the amount of waste formed (environmental impact) of a given process. Ideally, the E-factor of a process is 0 (no waste is generated).

According to the principles of green chemistry ((a) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice, Oxford University Press, New York, 1998. Anastas, P.; Eghbali, N. Chem.Soc.Rev. 2010, 39, 301-312. (c) Sheldon, . A. Chem. Soc. Rev., 2012, 41, 1437-1451) beside prevention of waste (AE and E-factor) the hazards originating form the raw materials and waste have to be considered. Thus hazardous, unsafe reagents, byproducts and solvents should be avoided.

In comparison with literature processes to prepare geranyl chloride E-2 ₄ from geraniol E-l ₄ (entry 3- 6) the current method (entry 1-2) is by far superior regarding atom economy and E-factor (Table 3). For the calculation of the E-factors, solvents and auxiliary reagents for the work up were not considered, as the work up procedures of most literature protocols might have not been optimized towards sustainability. Nevertheless, even accounting the work up the E-factor of the present process to prepare chloride E-2 ₄ is still in a range < 5 suitable for bulk production. Indeed, the E- factors (considering the work up) for the solvent free synthesis of E-2 ₄ and the preparation in MTBE are similar, because also under solvent free conditions a work up has to be performed in order to avoid decomposition of the product during subsequent distillation.

While the reported methods utilize undesirable solvents (CCI ₄ , HMPTA, DCM) and toxic reagents (pyridine, SMe ₂ ), for the current method MTBE or even no solvent is applied. Additionally, innocuous benzoic acid, a legal food additive, is formed as sole byproduct.

Another important factor for a technical process is the scalability, which is roughly approximated by the utilized solvent volume (as the major component of a reaction mixture). Therefore the scalability is also closely related to the amount of waste formed (-> E-factor). The lower the amount of solvent/starting material 1 ratio, the smaller the reaction vessel/reactor can be chosen. Again, the present process needs clearly the lowest solvent amounts, indicating the best scalability.

Table 3. Comparison of E-factors for the chlorination of Geraniol E-l ₄ sorted by descending E-factor

Volume

solvent AE

entr yield 2 ₄ E- eferenc conditions / 1 mol [%]

y factor e

1 ¹

[L/mol]

MsCI (2.0 equiv), Py (2.0 equiv), n-pen

3 79 2 50 12.1 [3]*

(0.2 M)

4 PPh ₃ (1.3 equiv) in CCI ₄ (9.0 equiv), reflux 75-81 0.9 30 12.5 [4]*

MeLi (1.0 equiv), TsCI (1.05 equiv),

5 82-85 3.3 42 19 [5]* LiCI (0.99 equiv), HMPTA/Et ₂ 0 1:7 (0.3 M)

NCS (1.5 equiv), SMe ₂ (2.0 equiv),

6 74 1.7 49 20 [6]*

DCM (0.6 M), -50 to 0 °C

1. AE = Atom economy under consideration of the stoichiometry (= equiv) of the reactants. 2. E- factor including solvents and inorganic salts (1 equiv of Na ₂ C0 ₃ ) utilized during work up. BzCI = Benzoyl chloride, DCM = dichlormethane, MsCI = Methylsulfonyl chloride, Py = pyridine, TsCI = para- tolylsulfonyl chloride, HMPTA = hexamethylphosphoric acid triamide, NCS = /V-chlorosuccinimide. [3] Bunton, C. A.; Hachey, D. L; Leresc, J. -P. J. Org. Chem. 1976, 37, 4036-4038. [4] (a) Calzada, J. G.; Hooz, J.; Chan, K.-K.; Specian, A.; Bross, A. Org. Synth. 1974, 54, 63-68. (b) Hooz, J.; Gilani, S. S. H. Can. J. Chem. 1968, 46, 86-87. [5] (a) Stork, G.; Grieco, P. A.; Gregson, M.; Aristoff, P. A.; Ireland R. E. Org. Synth. 1974, 54, 68-70. (b) Stork, G.; Grieco, P. A.; Gregson, M. Tetrahedron Lett. 1969, 1393- 1395. [6] (a) Nowotny, S.; Tucker, C. E.; Jubert, C; Knochel, P. J. Org. Chem. 1995, 60, 2762-2772. (b) Woodside, A. B.; Huang, Z.; Poulter, C. D.; Seaton, P; White; J. D. Org. Synth. 1988, 66, 211-215. (b) Corey, E. J.; Kim, C. U.; Takeda, M. Tetrahedron Lett. 1972, 4339-4442.

* Comparative Example Noteworthy, in the literature-known chlorination methods given in Table 4 (entry 2, 3, 6-8, 10, 11) other more complex allylic substrates than cinnamyl alcohol (such as geraniol) are rare. Geraniol F-l ₄ occurs as substrate only in the TMSCI driven, Se0 ₂ catalyzed chlorination to give an undesired 50:50 mixture of regioisomers (reference of entry 3). Remarkably, thionyl chloride as one of the most simple chlorination reagents cannot convert geraniol F-l ₄ efficiently to geranyl chloride F-2 ₄ as demonstrated in the course of the development of the present method (due to the lack of literature references, see chapter 4.3).

As second (model) substrate for comparison with known processes simple benzylic alcohol li was selected, as it is a very common substrate (Table 4). Again the present method provides the best E- factor (entry 1) in comparison with various catalytic and non-catalytic literature chlorinations of li. In contrast to the chlorination of geraniol (Table 3) no work up is required, which results in an improved E-factor of 1.6 (for the solvent-free preparation) amenable to bulk production scale (compare Table 1). Nevertheless, also chlorination of li in MTBE shows a good E-factor of 4.8 (entry 4). Albeit the utilisation of isophthalic acid chloride improves the atom economy slightly (considering only 0.5 equiv are theoretically needed), overall more waste is produced due to the work up mandatory to separate the stoichiometric byproduct isophthalic acid (entry 5). Again for the literature protocols solvents and auxiliary reagents were not included in the calculation of the E-factor.

Table 4. Comparison of E-factors for the chlorination of benzylic alcohol li sorted by descending E- Factor catalyst of a

I lsophthCI ₂

Volume

work solvent/ AE E- entry conditions Reference up 1 mol li [%] factor

[L/mol]

BzCI (1.02 equiv), DMF {30 mol ) 82 ^; no 51 1.6 this work TMSCI (2.0 equiv), DMSO (26 mol%) 95 ¹ no 39 ² 1.9

TMSCI (1.95 equiv), Se0 ₂ (2 mol%),

95 ¹ no 0.05 39 ^z 3.2 [8P CCI ₄ (0.6 equiv), reflux

7 TCT (1.05 equiv), DMF/DCM 1:13 (0.35 M) 98 ¹ yes 2.9 43 32 [10]*

9 PivCI (1.5 equiv), DMF/DCM 1:5 (0.25 M) 80 ¹ yes 4 55 51 [12]*

(COCI) ₂ (1.0 equiv),

11 84 ⁵ yes 33.3 54 407 [14]* catalyst I (10 mol%), DCM (0.03 M)

1. Isolated yield. 2. Calculated considering 2.0 equiv of the reagent. 3. Calculated considering 0.5 equiv of the reagent. 4. E-factor including solvents and inorganic salts (1 equiv of Na ₂ C0 ₃ ) utilized during work up. 5. Yield determined by NM -Standard. TMSCI = trimethylchlorosilane, TCT = 2,4,6- trichloro-l,3,4-triazine, PivCI = pivaloyl chloride, PMP = ^ara-MethoxyjDhenyl. [7] Snyder, D. C. J. Org. Chem. 1995, 60, 2638-2639. [8] Lee, J. G.; Kang, K. K. J. Org. Chem. 1988, 53, 3634-3637. [9] Sun, L; Peng, G.; Niu, H.; Wang, Q.; Li, C. Synthesis 2008, 24, 3919-3924. [10] De Luca, L; Giacomelli, G.; Porcheddu, A. Org. Lett. 2002, 4, 553-555. [11] (a) Denton, R. M.; An, J.; Adeniran, B. Chem. Commun. 2010, 46, 3025-3027. (b) Denton, R. M.; An, J.; Adeniran, B.; Blake, A. J.; Lewis, W.; Poulton, A. M. J. Org. Chem. 2011, 76, 6749-6767. [12] Dubey, A.; Upadhyay, A. K.; Kumar, P. Tetrahedron Letters 2010, 51, 744-746. [13] Nguyen, T. V.; Bekensir, A. Org. Lett. 2014, 16, 1720-1723. [14] Vanos, C. M.; Lambert T. H. Angew. Chem. Int. Ed. 2011, 50, 12222-12226.

* Comparative Example.

Although for some literature processes the atom economy is slightly improved compared to the current method (51% -> 54-55%), more importantly the E-factor significantly declines to 50-407 (entries 8-11) due to large solvent amounts required for those chlorinations. In sharp contrast to most of the known chlorination methods (entry 7-11) the present chlorination process does not rely on undesired halogenated solvents (DCM, CHCI ₃ ) but can be conducted even in the absence of any solvent (entry 1).

Furthermore, the present method uses inexpensive benzoyl chloride, while literature protocols require more expensive reagents such as oxalyl chloride (entries 8, 10 and 11), pivaloyl chloride (entry 9) and TMSCI (2 equiv, entries 2, 3). Additionally, the catalysts of the present method show significantly lower molecular weights (< 100 g/mol) than those of reported ones (> 200 g/mol, entries 8, 10, 11) and are commercial available. Beside DMSO (entry 2) DMF is also one of the cheapest catalysts, as it is a commonly used organic solvent.

Albeit the TMSCI driven chlorinations given in entry 2 and 3 posses good E-factors, these methods showed a limited substrate scope. With DMSO as the catalyst only primary and tertiary alcohols could be converted to their corresponding chlorides (entry 2). Moreover, the substrate scope did not include any allylic alcohols and substrates with other functional groups than a phenyl moiety. Also in the presence of Se0 ₂ as catalyst allylic substrates are rare (entry 3), chlorination of geraniol resulted in 50:50 mixture of regioisomers. Only alkenes and phenyl groups were proven to be tolerated.

Direct comparison with chlorinations utilizing toxic phosgene and thionyl chloride catalyzed by either DMF ((a) Pasedach, H.; Fischer, . Verfahren zur Herstellung von Chlorkohlenwasserstoffen der Acetylenreihe. DE Patent 1,135,893, September 6th, 1962; (b) Ludsteck, D.; Neubauer, G.; Pasedach H.; Seefelder, M. Verfahren zur Herstellung von Di- und Polychlorverbindungen, DE Patent 1,133,716, July, 26th, 1962) or phosphane oxides ((a) Henkelmann, J.; Troetsch-Schaller, I.; Wettling, T.; Kahl, T.- M.; Hupfer, L; Franzischka, W.; Koehler, H. Process for the preparation of alkyl-, alkenyl and alkinyl chlorides., EP Patent 0,514,683 Bl, January 18th, 1995. (b) Rohde, T.; Hutenloch, O.; Osswald, F.; Wissel, K. Method for chlorinating alcohols. WO Patent 2007/028761 Al March 15th, 2007) is not possible, because benzylic alcohol li is not included as a substrate. As no solvent was utilized, E- factors should be < 5. Nevertheless, the substrate scopes in these patents is rather narrow, which might reflect a low functional group tolerance due to the harsh reaction conditions (generation of one equivalent of HCI).

An additional advantage of the present method is the excellent transfer of enantiopurity from chiral non racemic alcohols of type 1 to the corresponding chlorides 2 under inversion as exemplified with phenylethanol S-l ₃ (Table 5, entry 2). Regarding known methods the chlorination protocol of Lambert (oxalyl chloride in the presence of a cyclopropenone catalyst) provides phenylethyl chloride 2 ₃ in the highest enantiomeric ratio (98:2, entry 1) reported thus far.

With the above described exception the present method (BzCI, FPyr) gave chloride 2 ₃ in a superior enantiomeric ratio of 97.5:2.5 (entry 2) compared to various other methods including the waste intensive Appel reaction (entry 3) and methylsulfonyl chloride (entry 5) and thionyl chloride (entries 6 and 7) driven halogenations. As only very limited literature data was available for the chlorination of 1 ₃ under Appel conditions and with thionyl chloride optimisation towards these established methods were conducted throughout the current studies (entry 3 and 7 see chapter 4.2.2 and 4.2.3).

Table 5: Comparison of optical purity (er) of chloride 2 ₃ under various conditions

yield 2 ₃

entry Conditions er of 1 ₃ er of 2 ₃ Reference

>98:2

(COCI) ₂ (l.O equiv),

(>96.5% 98 ¹ 98:2 [38]* catalyst I (10 mol%), DCM (0.03 M)

ee)

NCS (1.3 equiv), PPh ₃ (1.4 equiv) see chapter

>99:1 77^ 94:6

DCM (0.3 M) 4.2.2* (COCI) ₂ (1.1 equiv),

>99:1 82 ¹ 90:10 [41]* catalyst II (20 mol%), DCM (0.04 M)

MsCI (1.1 equiv), Py (1.2 equiv),

5 >99:1 50 ¹ 89:19 [42]*

nPen (0.4 M)

6 SOCI ₂ (1.2 equiv), neat, 0 °C 99:1 93 ¹ 85:15 [49]*

SOCI ₂ (1.2 equiv), Py (1.5 equiv), DCM see chapter 7 >99:1 60 76:24

(0.3 M)

1. Isolated yield. 2. Yield determined with NM -standard. [38] Vanos, C. M.; Lambert T. H. Angew. Chem. Int. Ed. 2011, 50, 12222-12226. See supporting information. [41] Zhao, C; Toste, F. D.; Raymond, K. N.; Bergman, R. G. J. Am. Chem. Soc. 2014, 136, 14409-14412. [42] Tanaka, K.; Ajik, K. Org. Lett. 2005, 7, 1537-1539. [49] Delgado-Abad,T.; Martinez-Ferrer, T. J.; Caballero, A.; Olmos, A.; Mello, R.; Gonzalez-Nunez, M. E.; Perez, P. J.; Asensio, G. Angew. Chem. Int. Ed. 2013, 52, 13298- 13301.

* Comparative Example

4. Development of Formamide Catalyzed Chlorination of Alcohols

The current method converts alcohols 1 to chlorides 2, which in turn are transformed with nucleophiles H-Nu to condensation products 4. For a better transparency a systematic numbering system was introduced (Scheme 1). The capital number x therefore describes the key functional group: As already given compounds with the number 1 are starting alcohols, 2 alkyl chlorides and 4 amines, ethers, cyanides and azides, respectively, depending on the nucleophile. Sideproducts are assigned as follows: The number 3 corresponds to benzoate esters, 5 to alkenes (formally resulting from β-HCI elimination of chlorides 2), 6 to ethers (originating from condensations of chlorides 2 with alcohols 1), 7 to formyl esters and 9 to amines, which were twofold alkylated. Finally number 8 was correlated to alkyl bromides.

Y CI R

OH catalyst reagent CI H-Nu Nu

R^R ² conditions ' R^R ² R ¹ ^R ²

functional group

with

x = 1 , 2, 3, .

nucleophile

n = 1 , 2, 3,

carbon scaffold J m = a, b, c,

Scheme 1. Chlorinations of alcohols 1„ and further conversion with nucleophiles to compounds 4 _nm The first index n (= 1, 2, 3, ...) describes the carbon scaffold in the order of appearance. For instance n = 1 was assigned to a benzyl skeleton, n = 3 to a 1-phenylethyl backbone. Thus compound 3i corresponds to benzyl benzoate, 5 ₃ to phenylethene (styrene). The second index m (= a, b, c, ...) is allocated to the nucleophile introduced in the reaction step 2->4 in the order of appearance. For instance a was assigned to piperidine, c to azide. Therefore compound 4 _3a is N-(l- phenylethyl)piperidine 4 _ic accords to benzyl azide.

4.1 Chlorination of Benzylic and 4-tert-Butyl Benzylic Alcohol

For the development of the present method initially benzyl alcohol li was chosen as model substrate as illustrated in Scheme 2 due to its high reactivity (as a primary benzylic alcohol) and simple ¹ H-NM spectra (and of thereof derived products), which allowed a more accurate determination of the yields through NMR-standard than with more complex substrates.

'1 ,2

Scheme 2. Chlorination of the model substrates li and 1 ₂

As shown in the following chapters the desired chlorides 2 exclusively formed in the presence of a suitable catalyst. In the absence of any catalytic component only ester 3 and starting material 1 were isolated. Thus chlorides 2 must be formed through a catalytic pathway. The observation, that the ester 3 was obtained as the sole product in the absence of a catalytically active species, indicates that it resulted from a (presumably completely uncatalyzed) direct acylation of the starting material 1. Therefore the catalytic activity is displayed approximately by the ratio of the desired chloride and the undesired ester 2:3. All optimisations aimed on the improvement of this ratio.

Due to the volatility of benzylic alcohol li, the corresponding chloride 2i and the ester 3i the ratio 2:3 gave a more exact and reproducible impression of the catalytic capability than the yield of 2i.(To improve reproducability the isolated crude products were dried for exactly 2 min at 50 mbar at the rotarory evaporator. Additionally, the ratio 2:3 is not influenced by work up mistakes). Later during the current studies 4-ieri-butyl benzyl alcohol 1 ₂ was utilized as model substrate because it is less volatile and shows a comparable reactivity.

4.1.1 Screening of Carboxylic Acid Chlorides as Reagents

The development of the formamide catalyzed chlorination of alcohols 1 was commenced with a screening of various carboxylic acids as shown in Table 6. Thereby benzylic alcohol li was treated with the acid chloride reagent in the presence of DMF (N-substituted formamide, 30 mol%) as catalyst and CH ₂ CI ₂ as solvent (the reagent screen was conducted prior to the solvent optimisation).

It turned out quickly, that aromatic acid chlorides (entries 1-13) are superior to aliphatic (entries 14-

16), which mainly delivered the undesired esters of type 3i as major products. Thus acetyl chloride and pivaloyl chloride, which served as a reagent to prepare Vilsmeyer Haack type complexes for chlorinations l->2 (Dubey, A.; Upadhyay, A. K.; Kumar, P. Tetrahedron Letters 2010, 51, 744-746) are inappropriate reagents in case that DMF is used in catalytic amounts only. Table 6. Screening of carboxylic acid chlorides sorted by descending ratio 2:3 (30 mol% DMF in DCM)

carboxylic acid .

entry acronym yield yield 1 [%Y yield 3i [%Y ratio

ride

According to General Procedure I (see chapter 2.1.1) benzyl alcohol li (52 μί, 55 mg, 0.50 mmol, 1.0 equiv) was allowed to react with the carboxylic acid chloride (0.60 mmol, 1.2 equiv, see Table 6 for details) in the presence of DMF (11.6 μΐ, 11.0 mg, 0.15 mmol, 30 mol%) in dry DCM (0.5 mL, 1 M) for 12 h at room temperature.

If not otherwise mentioned conversion >98% according to ¹ H-NM of the crude product. 1. Yield determined by NMR-standard (naphthalene). 2. Ratio determined by ¹ H-NMR of the crude material. 3. 18% conversion. 4. Determination of yield not possible due to overlapping of multiplets of NMR- Standard with multiplets of other compounds. Bz = Benzoyl (Ph(C=0)), Piv = Pi aloyl (iBu(C=0)). * Comparative Example

Amongst the aroyl chlorides simple benzoyl chloride and ortho- and para-halogeno substituted derivatives displayed the best ratios of desired chloride 2 ₁ to undesired ester 3i (entry 2-4, 6, 8-9). Stronger electron withdrawing substituents such as a nitro group lead to a decreased ratio 2i:3i (entry 11). This might be rationalized by a higher reactivity of this acid chloride and hence lower selectivity in the direct acylation of the starting material li (giving 3i) and the catalyst (DMF), the initial step of the catalytic cycle proposed (leading to 2 ₂ ).

Owing to the excellent chloride to ester ratio 2:3 (97:3), atom economy (lowest molecular weight of all aroyl chlorides) and cost efficiency inexpensive benzoyl chloride seems to be an optimal reagent. Interestingly, in the absence of DMF the yields of chloride 2i was found to be < 5% for all carboxylic acid chlorides examined (Table 7), clearly demonstrating the catalytic role of DMF.

Table 7. Screening of carboxylic acid chlorides w/o catalyst (DMF) sorted in analogy to Table 6

CH ₂ CI ₂ (1 M)

12 h rt

entry carboxylic acid chloride yield li [%Ϋ yield 2ι [%Ϋ yield 3ι [%Ϋ conv. [%] ² ratio 2i:3i ²

1 2,4,6-CI ₃ BzCI 87 / / <2 <2:98 *

2 4-FBzCI 66 / 23 23 <2:98 *

3 2-FBzCI 67 / 14 18 <2:98 *

4 BzCI 69 / 29 32 <2:98 *

5 4-MeBzCI 53 <2 30 37 4:96 *

6 4-CIBzCI 60 4 27 33 12:88 *

7 4-(Me ₂ N)BzCI 51 2 42 46 3:97 *

9 2-CIBzCI 34 <2 37 95 5:95 *

10 4-MeOBzCI 3 / 86 97 <2:98 *

11 4-0 ₂ NBzCI 10 6 71 93 7:93 *

12 2-MeBzCI / / 90 >98 2:98 *

13 2-MeOBzCI / n.d. ³ n.d. ³ >98 8:92 *

14 PivCI / / 97 >98 <2:98 *

15 AcCI / / 74 >98 <2:98 *

17 2,4,6-Me ₃ BzCI / / 90 >98 <2:98 *

According to General Procedure I (see chapter 2.1.1) benzyl alcohol li (52 μί, 55 mg, 0.50 mmol, 1.0 equiv) was allowed to react with the carboxylic acid chloride (0.60 mmol, 1.2 equiv, see Table 7 for details) without DMF in dry DCM (0.5 mL, 1 M) for 12 h at room temperature. 1. Yield determined by NMR-standard (naphthalene). 2. Conversion and ratio determined by ¹ H-NMR of the crude material. 3. Determination of yield not possible due to overlapping of multiplets of NMR-Standard with multiplets of other compounds.

* Comparative Example.

In order to further optimize the reaction, chlorinations were repeated at a lower catalyst loading (10 mol% DMF) as displayed in Table 8 (entries 1, 3-7 and 13-14). Here the reactions were conducted in dioxane, because it emerged as optimal solvent from the solvent screen (see chapter 4.1.3). Additionally, several meia-substituted benzoyl and naphthoyi chlorides were included (entry 2, entries 8-12). Benzoyl chloride proved still to be the optimal reagent. Remarkably, in the absence of the catalyst (DMF) no chloride 2i formed at all (entry 5) in dioxane (with BzCI).

Table 8. Screening of carboxylic acid chlorides sorted by descending ratio 2:3 (10 mol% DMF in dioxane)

1 ₂ (R ^' fBu)

carboxylic acid

entry R ^' yield 1 [% yield 2 [% yield 3 [% conv. [%] ² ratio 2:3 ²

(3,5-Me ₂ BzCI)

3 H 4-MeBzCI 16 51 <2 78 96:4

4 H 4-FBzCI 8 65 3 89 95:5

5 H 2-FBzCI / 68 4 ≥98 94:6

6 H 4-CIBzCI 5 62 4 94 93:7

7 H 4-MeOBzCI 22 44 4 69 92:8

(3,5-(F ₃ C) ₂ BzCI)

13 tBu PivCI ³ 14 23 62 85 24:76 *

14 tBu AcCI ³ 6 6 88 94 6:94 *

15 H BzCI 66 iilii li 19 22 <2:98 *

According to General Procedure I (see chapter 2.1.1) benzyl alcohol li (52 μί, 55 mg, 0.50 mmol, 1.0 equiv) and 1 ₂ (89 μί, 83 mg, 0.50 mmol, 1.0 equiv), respectively, was allowed to react with the carboxylic acid chloride (0.6 mmol, 1.2 equiv, see Table 8 for details) in the presence of DMF (50 0L of a 1 N DMF solution in dry dioxane, 0.05 mmol, 10 mol%) in dry dioxane (0.45 mL, 1 M) for 20 h at room temperature. 1. Yield determined by NM -standard (naphthalene). 2. Conversion and ratio determined by ¹ H-NMR of the crude material. 3. Reaction time 24 h, 2 M in dioxane. 4. w/o DMF. * Comparative Example.

Due to its higher molecular weight and thus lower volatility, 4-ieri-butyl benzyl alcohol 2 ₂ was here partially chosen as model substrate. Moreover, various di- and tricarboxylic acid chlorides were tested as potential reagents to improve the atom economy for the chlorination 1 -> 2 utilizing substoichiometric reagent amounts (theoretically 0.5 equiv, Table 9).

Table 9. Screening of di- and tricarboxylic acid chlorides sorted by descending yield of 2 ₂ (10 mol% DMF in dioxane)

According to General Procedure I (see chapter 2.1.1) benzyl alcohol 1 ₂ (89 μί, 83 mg, 0.50 mmol, 1.0 equiv) was allowed to react with the di-/tricarboxylic acid chloride (0.35-1.2 equiv, see Table 9 for details) in the presence of DMF (50 μί of a I N DMF solution in dry dioxane, 0.05 mmol, 10 mol%) in dry dioxane (0.20 mL, 2 M) for 24 h at room temperature. 1. Yield determined by NM -standard (dodecane). 2. Conversion determined by ¹ H-NMR of the crude material.

Indeed only 0.6 equiv of isophthaloyl chloride were sufficient to reach full conversion within 24 h and deliver chloride 2 ₂ in 80% yield (entry 1). For two representative examples of chlorinations with 0.6 equiv of this acid chloride on a 200 mmol scale see chapter 4.4.2.1 and 4.4.4.1. 4.1.2 Screening of Potential Catalysts

A screening of various potential catalysts (10 mol%) identified Formylpyrrolidine (= FPyr), DMF and formyl piperidine (= FPip) as very powerful N-substituted formamides for the chlorination 1 -> 2 (entries 1-3 in Table 10). Noteworthy, when developing a substrate scope FPyr proved to be even superior to DMF (and FPip) for the chlorination of many less reactive alcohols.

Table 10. Screening of potential catalyst sorted by descending ratio 2:3

O

Y

3 ₂

yield 1 yield 2 yield 3 conv.

entry catalyst acronym t [h] ratio 2:3 ro/ il ro/ il ro/ il ro/ i2

O

u DBuF 24 8 82 9 92 90:10

H NnBu ₂

O

X _^

H N Ph DBnF 24 18 71 11 82 87:13

NMP

18 PivNMe, 20 68 / 32 32 <2:98

NMe ₂

19 no catalyst 20 73 / 27 27 <2:98

o

21 OPPh 24 42 / 50 54 <2:98

Ph' ±?Ph

22 OPPyr ₃ 24 66 / 27 30 <2:98

According to General Procedure I (see chapter 2.1.1) benzyl alcohol 1 ₂ (89 μί, 83 mg, 0.50 mmol, 1.0 equiv) was allowed to react with benzoyl chloride (70 μί, 85 mg, 0.60 mmol, 1.2 equiv) in the presence of the potential catalyst (0.05 mmol, 10 mol%, see Table 10 for details) in dry dioxane (0.20 mL, 2 M) for 20-24 h at room temperature. 1. Yield determined by NMR-standard (naphthalene or dodecane). 2. Conversion and ratio determined by ¹ H-NMR of the crude material. 3. Isolated yield on a 2 mmol scale. FPyr = l-Formylpyrollidine, FPip = 1-Formylpiperidine, BnF = Benzylformamide, iBuF = fe/t-Butylformamide, MF = Methylformamide, BnMF = Benzylmethylformamide, DBuF = Di-n- butylformamide, DBnF = Dibenzylformamide, PMPMF = (^ara-MethoxyjDhenyl) methylformamide, MPF = Methyl^henylformamide, DPF = Di^henylformamide, NMP = /\/-Methyl]Dyrrolidinone, F = Formamide.

* Comparative Example. /V-monosubstituted formamides are capable to yield 2 ₂ in an almost similar efficiency as N,N- disubstituted formamides such as DMF (entries 4-6). For a representative example of a chlorination in the presence of 10 mol% methylformamide (MF) on a 200 mmol scale see chapter 4.4.3.1. Notably, with a molecular weight of 59 g/mol MF is one of the smallest Lewis base catalyst to date. Interestingly, formal replacement of the formyl H-atom of DMF with a methyl group (resulting in dimethylacetamide) lead to a total loss of catalytic activity (yield of chloride 2 ₂ < 2%, entry 13). Also some other amides (including unsubstituted formamide) were not capable of catalyzing the chlorination l->2 (entry 14-18). Remarkably, in the absence of any catalyst no chloride 2 ₂ was formed at all. Importantly other Lewis bases effecting chlorinations of alcohols 2 with oxalyl chloride ((a) Denton, R. M.; An, J.; Adeniran, B. Chem. Commun. 2010, 46, 3025-3027. (b) Denton, R. M.; An, J.; Adeniran, B.; Blake, A. J.; Lewis, W.; Poulton, A. M. J. Org. Chem. 2011, 76, 6749-6767) (Nguyen, T. V.; Bekensir, A. Org. Lett. 2014, 16, 1720-1723) showed negligible activity in chlorinations with benzoyl chloride (entries 20-21). In the presence of ureas and pyridinones no formation of the desired product 2i was observed (Table 11).

Table 11. Screening of potential catalyst sorted by descending ratio 2:3

O

catalyst (30 mol%) O

2i

catalyst yield 1 yield 2 yield 3 conv.

entry catalyst ratio 2i:3i ²

acronym [% [%Ϋ [%Ϋ [%] ²

O

MeN X NMe DMPU 35 / 56 61 <2:98

A/-Methyl-2-pyridinone

According to General Procedure I (see chapter 2.1.1) benzyl alcohol 1 ₂ (89 μί, 83 mg, 0.50 mmol, 1.0 equiv), was allowed to react with benzoyl chloride (70 μί, 85 mg, 0.60 mmol, 1.2 equiv) in the presence of the potential catalyst (0.15 mmol, 30 mol%, see Table 11 for details) in dry DCM (0.5 mL, 1 M) for 12 h at room temperature.

1. Yield determined by NM -standard (naphthalene). 2. Conversion and ratio determined by ¹ H-NMR of the crude material. TMU = Tetramethylurea, DMPU = DimethyljDropylene urea.

* Comparative Example.

4.1.3 Solvent Screening

At a catalyst loading of 30 mol% (DMF) the chlorination li -> 2i worked well in broad range of solvents (Table 12). Of course in DMF as solvent (and catalyst) basically no ester side product 3i was detectable (entry 1). Remarkably, 30 mol% of DMF in dioxane have almost the same effect as DMF as solvent (ratio 2i/3i > 98:2, entry 2). In a range of other solvents still very good ratios 2/3 were attained (entry 3-9). Noteworthy, even acetone the 2nd most desired environmental friendly solvent in industrial processes (after water) (Alfonsi, K.; Colberg, J.; Dunn, P J.; Fevig, T.; Jennings, S.; Johnson, T. A.; Kleine, H. P.; Knight, C; Nagy, M. A.; Perry, D. A.; Stefaniak, M. Green Chem. 2008, 10, 31-36) provides chloride 2i in a good yield (entry 5). A representative example for chlorination in acetone on a 200 mmol scale is given in chapter 4.4.4.1.

Table 12: Screening of solvents sorted by descending ratio 2:3 (30 mol% DMF) entry solvent yield 2 ₁ [ ] ¹ yield 3 _! [%Ϋ ratio 2i:3

1 DMF 82 2 >98:2

2 dioxane 70 2 ≥98:2

3 DCM 71 2 97:3

4 THF 81 3 97:3

5 acetone 72 2 97:3

6 Et ₂ 0 58 2 97:3

7 CICH ₂ CH ₂ CI 80 4 96:4

8 MeCN 83 4 96:4

10 no solvent 83 7 92:8

According to General Procedure I (see chapter 2.1.1) benzyl alcohol li (52 μί, 55 mg, 0.50 mmol, l.O equiv) was allowed to react with benzoyl chloride (70 μί, 85 mg, 0.60 mmol, 1.2 equiv) in the presence of DMF (11.6 μί, 11.0 mg, 0.15 mmol, 30 mol%) in the indicated solvent (0.5 mL, 1 M, see Table 12 for details) for 12 h at room temperature. If not otherwise mentioned conversion >98% according to ¹ H-NM of the crude product. 1. Yield determined by NMR-standard (naphthalene). 2. Ratio determined by ¹ H-NMR of the crude material. 3. Chloroform stabilized with amylene. 4. Chloroform stabilized with ethanol. DME = 1,2-dimethoxy ethane.

Furthermore even in the absence of any solvent the chloride 2i was obtained in a good yield pointing towards the possibility of a solvent-free chlorination (entry 10). In order to further optimize the reaction, a second screening was conducted in the presence of 10 mol% DMF (Table 13). Here ethereal solvents and acetone emerged (entries 1-3) superior to halogenated counterparts (entry 4- 5). Table 13: Screening of solvents sorted by descending ratio 2:3 (10 mol% DMF) entry solvent yield l _! [ ] ¹ yield 1 \%f yield 3 _! [%Ϋ conv. [%] ² ratio 2i:3i ^'

1 dioxane 10 69 2 . .88 97:3

2 acetone 13 58 4 82 94:6

3 DME 15 54 4 80 93:7 4 CICH ₂ CH ₂ CI 13 61 9 84 86:14

5 DCM 13 54 16 85 77:23

According to General Procedure I (see chapter 2.1.1) benzyl alcohol li (52 μί, 55 mg, 0.50 mmol, l.O equiv) was allowed to react with benzoyl chloride (70 μί, 85 mg, 0.60 mmol, 1.2 equiv) in the presence of DMF (50 μί of a 1 N DMF solution in the solvent, 0.05 mmol, 10 mol%) in the indicated solvent (0.5 mL, 1 M, see Table 13 for details) for 24 h at room temperature.

1. Yield determined by NM -standard (naphthalene). 2. Ratio determined by ¹ H-NMR of the crude material.

4.1.4 Optimisation of Catalyst Loading and Concentration

As illustrated in Table 15 10 mol% catalyst loading emerged to be optimal (entry 5, Table 15). Higher DMF loadings did not improve the yield and ratio of chloride to ester 2i/3i significantly (entries 1-4). With lower amounts of DMF the ratio 2i/3i slowly declined and conversion reached within 24 h decreased clearly. However, even with only 3 mol% of DMF the chloride 2i is still formed as the major product. An example of an isolation of a benzylic chloride in 61% yield in synthesized in the presence of only 1 mol% of DMF is given in chapter 4.4.2.2.

Table 15: Optimisation of Catalyst Loading

\ 2 3

entry DMF loading [mol%] yield l _! [%Ϋ yield 2 ₁ [%Ϋ yield 3ι [%Ϋ conv. [%] ² ratio 2 _! :3i ²

1 40 ³ / 72 2 >98 >98:2

2 30 ³ / 70 2 >98 >98:2

3 20 / 75 2 >98 97:3

4 15 / 74 3 >98 97:3

5 10 / 72 3 >98 96:4

6 7.5 2 74 5 >98 94:6

7 5 8 67 6 90 93:7

8 4 13 62 6 84 91:9

9 3 18 53 8 77 87:13

According to General Procedure I (see chapter 2.1.1) benzyl alcohol li (52 μί, 55 mg, 0.50 mmol, l.O equiv) was allowed to react with benzoyl chloride (70 μί, 85 mg, 0.60 mmol, 1.2 equiv) in the presence of DMF (15-200 μί of a 1 N DM F solution in dioxane, see Table 15 for details) in dry dioxane (50-235 μί, 2 M) for 24 h at room temperature. 1. Yield determined by N M -standard (naphthalene). 2. Ratio determined by ¹ H-N MR of the crude material. 3. Reaction time 12 h.

Next, the chlorination l->2 was performed in different concentrations in dioxane (Table 16) resulting in a 2 M concentration to be optimal. Fortunately, this comparably high concentration is strongly beneficial in terms of sustainability (less waste) and scalability (less volume).

Table 16: Optimisation of Concentratic entry Concentration [mol/L] yield [%Ϋ yield 2 ₁ [%Ϋ yield 3 ₁ [%Ϋ conv. [%] ² ratio 2i:3i ²

1 no solvent ³ 5 40 48 >98 46:54

2 4 / 62 5 >98 93:7

3 2 72 3 ^■ ≥98 96:4

4 l ⁴ 7 71 3 92 96:4

5 0,5 25 49 4 68 94:6

6 0.25 61 20 2 27 94:6

7 0.25 ^s 32 42 2 59 95:5

According to General Procedure I (see chapter 2.1.1) benzyl alcohol li (52 μί, 55 mg, 0.50 mmol, 1.0 equiv) was allowed to react with benzoyl chloride (70 μί, 85 mg, 0.60 mmol, 1.2 equiv) in the presence of DMF (50 μί of a 1 N DMF solution in dioxane) in the desired amount of dry dioxane (see Table 16 for details) for 24 h at room temperature. 1. Yield determined by N MR-standard (naphthalene). 2. Ratio determined by ¹ H-N MR of the crude material. 3. Reaction time 10 h. 4. Reaction time 36 h. 5. Reaction time 72 h.

4.2 Chlorination of S-l-Phenylethanol

4.2.1 Formamide catalyzed Chlorination (This Work)

To probe the transfer of enantiopurity in chlorinations (l->2) enantioenriched phenylethanol 1 ₃ was chosen as model substrate, because as a secondary benzylic alcohol it is prone to undergo S _w l type substitutions under racemisation (Table 17). Either commercial samples of S-l ₃ (er > 99: 1) or batches obtained via kinetic enzymatic resolution with an er > 99:1 according to chiral H PLC and GC were utilized. Importantly, DMF as catalyst provided phenylethyl chloride R-2 ₃ in a diminished enantiomeric ratio (85:15) compared to N-formylpyrrolidine (90:10) under elsewise identical conditions (entry 1+2). In particular, N-formylpyrrolidine provided good results with regard to a high enantiomeric ratio (er) of the product R-2 ₃ .

Table 17. Screening of catalysts

O

I I

Y

(er = 99:1 )

2 conv. [%] ³ ratio 2 ₃ :3 ₃ ³

O

U 66 4 84:16 91 94:6

H^N' ^' Ph

According to General Procedure I (see chapter 2.1.1) phenylethanol S-l ₃ (36.3 μΐ, 24.0 mg, 0.30 mmol, 1.0 equiv, er > 99:1 according to chiral HPLC) was allowed to react with benzoyl chloride (63.9 μί, 52.8 mg, 0.45 mmol, 1.5 equiv) in the presence of the catalyst (see Table 17 for details) in dioxane (150 μί, 2 M) for 24 h at 40 °C. 1. Yield determined by N MR-standard (naphthalene or dodecane). 2. er determined by chiral GC from the crude material. 3. Ratio determined by ¹ H-N MR of the crude material.

To further improve the enantiomeric ratio (er) of the product 2 ₃ a solvent screening was conducted as shown in Table 18.

Table 18. Screening of Solvents at various Temperatures T

(er = 99: 1 )

entry Solvent T [°C] yield 1 ₃ [%Ϋ yield 2 ₃ [%Ϋ yield 3 ₃ [%Ϋ conv. er of 2 ₃ ³ ratio 2 ₃ :3 ₃ ² [%] ²

1 Et ₂ 0 40 / 73 <2 >98 94:6 97:3

2 MTBE / 78 <2 >98 94:6 >98:2

3 EtOAc / 73 <2 >98 92:8 97:3

4 cHex <2 66 3 97 92:8 96:4

5 dioxane <2 63 <2 97 90:10 >98:2

6 THF / 75 <2 >98 89:11 >98:2

7 DME / 76 <2 >98 89:11 97:3

8 toluene / 56 <2 >98 89:11 97:3

9 DCM / 70 4 >98 86:14 95:5

10 CICH ₂ CH ₂ CI <2 72 4 >98 85:15 94:6

11 acetone 4 70 4 94 77:23 95:5

12 Et _z O rt / 81 ≤2 _. . ≥98 96:4 ≥98:2

13 MTBE " ≤2 83 ≤2 >98 95:5 ≥98:2

14 2-MeTHF / 85 <2 >98 94:6 >98:2

15 DMF ⁴ 5 57 / 93 75:25 >98:2

16 Et ₂ 0 n.d. 75 ^s n.d. >98 93:7 97:3

17 MTBE (I M)* 0 °C to rt n.d. 81 ^s n.d. >98 97.5:2.5 >98:2

Entries 1-15: According to General Procedure I (see chapter 2.1.1) phenylethanol S-l ₃ (36.3 μί, 24.0 mg, 0.30 mmol, 1.0 equiv, er > 99:1 according to chiral HPLC) was allowed to react with benzoyl chloride (63.9 μί, 52.8 mg, 0.45 mmol, 1.5 equiv) in the presence of the FPyr (5.9 mg, 6.1 mg, 0.06 mmol, 0.2 equiv) in the solvent (150 μί, 2 M, see Table 18) for 24 h at the temperature T (see Table 18).

1. Yield determined by NMR-standard (naphthalene or dodecane). 2. Ratio determined by ¹ H-NMR of the crude material. 3. er determined by chiral GC from the crude material. 4. Reaction time 3 h, 1.2 equiv BzCI. 5. Isolated yield on a 2 mmol scale. 6. 1.5 equiv BzCI. 2-MeTHF = 2- Methyltetrahydrofurane

In a simple approximation the enantiomeric ratio of the product 2 ₃ correlates with the solvent polarity inversed proportional (entries 1-11). The er of 2 ₃ increased from DMF as solvent (entry 15) 75:25 in the order acetone, DCM, THF, dioxane, EtOAc, MTBE and Et ₂ 0 to 94:6. Less polar solvents such as toluene and cyclohexane again lead to diminished ratios of enantiomers (89:11 and 92:8, respectively).

Moreover, the higher activity of FPyr compared to DMF allowed to lower the reaction temperature from 40 °C to room temperature still giving full conversion within 24 h. Thus in ethereal solvents (Et ₂ 0, MTBE, 2-MeTHF) the enantiopurity of the product 2 ₃ was further improved to an enantiomeric ratio (er) of up to 96:4 (entries 12-14). In an up scaling from 0.3 to 1 mmol only a slightly decreased enantiomeric ratio (er) was observed (93:7, entry 16). At a lower concentration (1 M instead of 2 M) and by a careful temperature control (0 °C to rt) an even improved er of 97.5:2.5 in 2 mmol scale was achieved comprising one of the best results throughout the literature (see chapter 3).

4.2.2 Chlorination under Appel Conditions

As chlorination of enantioenriched phenylethanol 1 ₃ under Appel type conditions (phosphine + oxidizing agent) (Appel, .; Kleinstuck, R. Chem. Ber. 1974, 107, 5-12) has yet not been reported, we investigate in the transfer of enantiopurity from substrate S-l ₃ (er > 99:1) to chloride 2 ₃ under this conditions as depicted in Table 19 (for comparison with the present method). Interestingly, even under the neutral Appel conditions formation of styrene 5 ₃ and of the ether 6 ₃ as side products were observed as with the present method.

Table 19. Chlorination under Appel conditions

entry Cl-Y solvent t [h] yield 2 ₃ [% yield 2 ₃ [% conv. [%] ² er of 2 ₃ ³

2 DCM 24 7 60 89 92:8 *

*

6 DCM 2 / 74 >98 93:7 *

*

7 DCM 0.75 / 73 >98 93:7

8 this work: BzCI, FPyr (20 mol n.d. 81 ⁶ ≥98 97.5:2.5

According to General Procedure V (see chapter 4.4.1.1) phenylethanol S-l ₃ (0.3 mmol) was converted to the chloride S-2 ₃ . 1. Yield determined by NMR-standard (naphthalene). 2. Conversion was determined by ¹ H-NM of the crude material. 3. er determined by chiral GC from the crude material. 4. PPh ₃ and Cl-Y were allowed to react before the alcohol 1 ₃ was introduced. 5. Conditions: BzCI (1.5 equiv), FPyr (20 mol%) in MTBE (1 M), 24 h 0 °C to rt. 6. Isolated yield after chromatography on a 2 mmol scale.

* Comparative Example.

The Appel chlorinations l ₃ ->2 ₃ were conducted with PPh ₃ and either CCI ₄ or NCS as oxidizing agent. As solvents were chosen CH ₂ CI ₂ , THF and Et ₂ 0, which had proven to be the optimal solvent regarding optical purity of 2 ₃ with the present method (BzCI and FPyr, see chapter 4.2.1). With CCI ₄ an enantiomeric ratio (er) of 92:8 was achieved as best result in CH ₂ CI ₂ , which was cleanly reproducible (entries 1+2).

Moreover, improved enantiomeric ratios were observed with NCS in Et ₂ 0 (up to 94:6, entry 4), while in CH ₂ CI ₂ and THF similar optical purities were obtained than with CCI ₄ (entry 3 and 6). 6ln comparison with the present method (entry 8) the much more waste intensive Appel reaction provides access to chloride S-2 ₃ in a decreased enantiopurity.

4.2.3 Chlorinations with Thionyl chloride

Already in the mid of the last century the transfer of optical purity in the chorination of non racemic phenylethanol 1 ₃ with phosphoryl chloride (and pyridine) was examined showing a significant degree of racemization ((a) Gerrard, W. J. Chem. Soc. 1945, 106-112. (b) Burwell, R. L. Jr.; Shields, A. D.; Hart, H. J. Am. Chem. Soc, 1954, 66, 908-909). However, despite of rotatory degrees no further data regarding the enantiopurities of the product 2 ₃ is available from these sources. Moreover, an er of 85:15 for chloride 2 ₃ resulting from chlorination of 1 ₃ with thionyl chloride (in the absence of bases and solvents) as the sole example has been reported (Delgado-Abad,T.; Martinez-Ferrer, T. J.; Caballero, A.; Olmos, A.; Mello, R.; Gonzalez-Nunez, M. E.; Perez, P. J.; Asensio, G. Angew. Chem. Int. Ed. 2013, 52, 13298-13301). Due to this lack of literature data for comparison we performed an optimisation of thionyl chloride driven chlorinations of alcohol S-l ₃ (er > 99:1) as given in Table 20. Table 20. Chlorinations with Thionyl chloride ci' ^s ¾i

U J

S-I 3 R-2,

(er = 99:1)

entry solvent base T [°C] t [h] yield 2 ₃ [%Ϋ conversion ² [%] er of 2 ₃ ³

1 DCM Py rt 18 90 >98 60:40 *

2 Et ₂ G Py 40 24 60 98 76:24 *

3 CHCI3 Py 60 18 61 >98 55:45 *

4 Py / rt 5 10 13 58:42 *

5 Et ₂ 0 / 40 48 74 90 71:29 *

7 / / 0 0.33 93 n.d. 85:15 [49]*

8 this work: BzCI, FPyr (20 mol%)* 81 ⁵ ≥98 97.5:2.5

According to General Procedure VI (see chapter 4.4.1.2) phenylethanol S-l ₃ (0.3 mmol) was converted to the chloride S-2 ₃ . Yield determined by NMR-standard (naphthalene). 2. Enantiomeric ratio (er) determined by chiral GC from the crude material. 3. Conversion was determined by ¹ H-NMR of the crude material. 4. Detailed conditions: BzCI (1.5 equiv), FPyr (20 mol%) in MTBE (1 M), 24 h 0 °C to rt. 5. Isolated yield after chromatography on a 2 mmol scale. [49] Delgado-Abad,T.; Martinez- Ferrer, T. J.; Caballero, A.; Olmos, A.; Mello, R.; Gonzalez-Nunez, M. E.; Perez, P. J.; Asensio, G. Angew. Chem. Int. Ed. 2013, 52, 13298-13301.

* Comparative Example.

In accordance with the present method (see chapter 4.2.10) and the results obtained under Appel conditions (chapter 4.2.2) in diethylether better enantiomeric ratios of 2 ₃ were obtained than in DCM (in the presence of pyridine, entries 1 and 2). Also chloroform and pyridine (as solvent) proved to be detrimental (entries 3 and 4). Lower enantiopurities were observed in the absence of pyridine (entry 5). In conclusion, the present method (BzCI, FPyr, entry 8) provides chloride 2 ₃ in a clearly superior enantiomeric ratio (97.5:2.5) compared to chlorination with thionyl chloride regarding literature (85:15, entry 7) (Delgado-Abad,T.; Martinez-Ferrer, T. J.; Caballero, A.; Olmos, A.; Mello, R.; Gonzalez- Nunez, M. E.; Perez, P. J.; Asensio, G. Angew. Chem. Int. Ed. 2013, 52, 13298-13301) and our own results (76:24, entry 2; (for comparison with other methods see chapter 3). 4.3 Chlorination of Geraniol and Nerol with Thionyl chloride

It has been reported, that chlorinations of the natural abundant terpenoid alcohols geraniol F-l ₄ and nerol Z-l ₄ with thionyl chloride and PCI ₃ , respectively, result in complex mixtures of the linear allyl chlorides l-E- and /-Z-2 ₄ and their branched regioisomer 6-2 ₄ (Table 21) (Bunton, C. A.; Hachey, D. L; Leresc, J. -P. J. Org. Chem. 1976, 37, 4036-4038) ((a) Forster, M. O.; Cardwell, D. J. Chem. Soc. 1913, 1338-1346; (b) Barnar, D.; Bateman, L; Harding, J.; Koch, H. P.; Sheppard, N.; Sutherland, G. B. B. M. J. Chem. Soc. 1950, 915-925. (c) Barnar, D.; Bateman, L. J. Chem. Soc. 1950, 926-932). However, no quantitative data for the isomerisation with these standard reagents is available. For comparison with the present method an optimisation for the chlorination of both, geraniol and nerol, with thionyl chloride was performed as shown in Table 21 and 22.

Poor ratios of the linear and branched isomer //6-2 ₄ (38:62-62:38) and detrimental yields (63-69%) were obtained in the absence of a base either without solvent, in DCM or in Et ₂ 0 (Table 21, entries 1- 6). Thereby, the regioselectivity and yield were both virtually not influenced by performing no or an aqueous work up (compare entries 1/2, 3/4 and 5/6). Albeit the ratio of the regioisomers //6-2 ₄ was improved in the presence of a base (pyridine or NEt ₃ ) in DCM, the yield of 2 ₄ (mixture of isomers) declined even further to 58-62% (entries 7-8). Reaction in Et ₂ 0 in the presence of pyridine and NEt ₃ , respectively, resulted in almost no regioselectivity at all (entries 9-10). The present method (BzCI and 10mol% FPyr in MTBE, entry 12) allowed the synthesis of geranyl chloride /-/F-2 ₄ as a pure regio- (//6-2 ₄ > 98:2) and diastereomer on a 500 mmol scale in 83% yield (= 72 g of product). Hence it is by far superior to chlorinations of geraniol with thionyl chloride (optimized conditions entry 8 //6-2 ₄ = 81:19 and 58% yield for both isomers). Exactly the same yield for geranyl chloride was achieved with the present method on 1 mmol scale (yield determination via NMR-standard). This proves that the yields of thionyl chloride driven chlorinations l -^2 ₄ on a 1 mmol scale (entries 1-10) represent the maximal yield on a larger scale. As illustrated in chapter 3 other literature protocols for the preparation of geranyl chloride F-2 ₄ utilize much more complex/waste intensive and toxic reagent mixtures at comparable to even decreased yields.

Table 21. Chlorination of Geraniol F-l ₄ with Thionyl chloride

(Geraniol)

entry solvent base t [h] yield 2, ¹ [%] l/b-2, ²

1 neat ³ / 0 63 62:38 *

2 neat / 0 65 61:39 *

3 DCM (2 M) ³ / 0 69 54:46 *

4 DCM (2 M) / 0 66 54:46 *

5 Et ₂ 0 (2 M) ³ / 1 69 41:59 *

6 Et ₂ 0 (2 M) / 2 64 38:62 *

7 MTBE (2 M) / 2 61 37:63 *

8 DCM (1 M) Py 16 58 81:19 *

9 DCM (1 M) NEt ₃ 16 62 74:26 *

10 Et ₂ 0 (0.5 M) Py 24 55 48:52 *

11 Et ₂ 0 (0.5 M) ⁴ NEt ₃ 24 23 41:59 *

12 this method: BzCI, FPyr (10 mol%) ⁵ 83 >98:2

13 this method: BzCI, FPyr (10 mol ) In MTBE (2 Mf 83 (72 g >98:2

According to the general procedure VII (see chapter 4.4.1.3) geraniol E-l ₄ (1.00 mmol) was chlorinated with thionyl chloride. If not otherwise mentioned conversion >98% according to ¹ H-NMR of the crude product. 1. Yield determined by NMR-standard (dodecane). 2. Ratio //¾-2 ₄ was determined by ¹ H-NMR of the crude material. 3. No aqueous work up was performed. 4. 95% conversion. 5. Detailed conditions: BzCI (1.1 equiv), FPyr (10 mol%) in MTBE (2 M), 18 h 0 °C to rt. 6. Detailed conditions: BzCI (1.01 equiv), FPyr (10 mol%) in MTBE (2 M), 17 h 0 °C to rt. 7. Isolated yield after distillation.

* Comparative Example.

The results of the chlorinations of nerol Z-l ₄ with thionyl chloride are even inferior than those of geraniol E-l ₄ as demonstrated by Table 22. In the absence of pyridine moderate yields are observed (51-54%) in combination with virtually no regioselectivity (//¾-2 ₄ 49:51-58:42). In the presence of pyridine the ratio of regioisomers improved to (still poor values of) 73:27-77:23 but the yield of 2 ₄ dropped to 24-35% (entry 3-4). Again the present method allowed the synthesis of the desired chloride on a 500 mmol scale as a pure regio- and diastereomer in 79% yield (= 79%, entry 6). As described for the chlorination of geraniol, direct comparability of a 1 mmol to larger scales is evidenced by entry 5. Literature methods require again much more complex reagent mixtures and are inferior in isolated yield (entries 7-8). Table 22. Chlori

Z-1 ₄ /-Z-2 ₄ b-2

(Nerol)

yield 2, ¹ l/b- Z/E- entry solvent base t [h]

[%] 2 ₄ ² 2 ₄ ²

1 neat / o 54 58:42 >98:2 *

2 DCM (2 M) / o 51 49:51 >98:2 *

3 DCM (1 M) Py 17 24 73:27 76:24 *

4 DCM (1 M) Py 18 35 77:23 76:24 *

5 this method: BzCI, FPyr (10 mol%) ³ 74 >98:2 >98:2

6 this method: BzCI, FPyr (10 mol%) ⁴ 79 {S9 g >98:2 >98:2

Literature Conditions Reference

7 MsCI (2.0 equiv), Py (2.0 equiv) in n-pen (0.2 M) 40 ⁵ n.d. / [27]*

NCS (1.5 equiv), SMe ₂ (2.0 equiv) in DCM (0.6 M),

8 74 ⁵ / [30]*

-50 to 0 °C

According to the general procedure VII (see chapter 4.4.1.3) geraniol E-l ₄ (1.00 mmol) was chlorinated with thionyl chloride. Conversion >98% according to ¹ H-NMR of the crude product. 1. Yield determined by NMR-standard (dodecane). 2. Ratio //¾-2 ₄ was determined by ¹ H-NMR of the crude material. 3. Detailed conditions: BzCI (1.1 equiv), FPyr (10 mol%) in MTBE (2 M), 19 h 0 °C to rt 4. Detailed conditions: BzCI (1.01 equiv), FPyr (10 mol%) in MTBE (2 M), 17 h 0 °C to rt. 5. Isolated yield after distillation. [27] Bunton, C. A.; Hachey, D. L; Leresc, J. -P. J. Org. Chem. 1976, 37, 4036- 4038. [30] (a) Nowotny, S.; Tucker, C. E.; Jubert, C; Knochel, P. J. Org. Chem. 1995, 60, 2762-2772. (b) Woodside, A. B.; Huang, Z.; Poulter, C. D.; Seaton, P; White; J. D. Org. Synth. 1988, 66, 211-215. (b) Corey, E. J.; Kim, C. U.; Takeda, M. Tetrahedron Lett. 1972, 4339-4442.

* Comparative Example. 4.4 Synthesis of Chlorides

4.4.1 General Procedures for Reference Chlorination Methods

4.4.1.1 General Procedure V: Chlorination of 1-Phenylethanol under Appel conditions

iv)

Table 19: A 4 mL glas vial with stir bar was charged with the starting alcohol S-l ₃ (36.3 μί, 37.0 mg, 0.30 mmol, 1.0 equiv, er > 99:1 according to chiral H PLC), PPh ₃ (112 mg, 0.42 mmol, 1.4 equiv) and the dry solvent (1 mL, 0.3 M). To the resulting solution was added the oxidizing agent Cl-X, either CCI ₄ (44 μί, 0.45 mmol, 1.5 equiv) or NCS (53.7 mg, 0.390 mmol, 1.3 equiv), in one portion. While CCI ₄ was added at ambient temperature, NCS was added under cooling of the reaction solution in an ice bath. After 10 min of stirring the cooling bath was removed and the reaction mixture allowed to stir for the time t at ambient temperature.

Next, the reaction mixture was transferred to a one necked flask (25 mL) and under vigorous stirring nPen (10 mL) was added dropwise, whereby a solid precipitated (OPPh ₃ ). The mixture was stirred vigorously for 10 min in order to coagulate the precipitated phosphine oxide and filtered through a plug of wool. Both, the 4 mL reaction vial and the 25 mL flask were washed with nPen (2 x 2 mL), the collected filtrates were concentrated under reduced pressure and dried at 50 mbar for 2 min.

Entry 5 + 8 of Table 19: A solution of PPh ₃ (112 mg, 0.42 mmol, 1.4 equiv) in the solvent (0.7 mL) was cooled to 0 °C and the oxidizing agent Cl-X, either CCI ₄ (44 μΐ, 0.45 mmol, 1.5 equiv) or NCS (53.7 mg, 0.390 mmol, 1.3 equiv), was added in one portion. After stirring for 5 min at 0 C, the cooling bath was removed and the mixture allowed to stir for 1.5 h at ambient temperature. Then, the reaction solution was cooled to 0 °C, the substrate 1 ₃ (36.3 μί, 37.0 mg, 0.30 mmol, 1.0 equiv, er > 99: 1 according to chiral H PLC) was added dropwise as a solution in the solvent (0.3 mL, 1 M) and after 10 min the cooling bath was removed and the reaction mixture was stirred for the time period t at room temperature. The work-up was performed as described above. 4.4.1.2 General Procedure VI: Chlorination of 1-Phenylethanol with Thionyl chloride

O

cf ^S ci

S-1 ₃ R-2 ₃

(er = 99:1)

Table 20: A 4 mL glas vial with a stir bar was charged with the starting alcohol S-l ₃ (36.3 μί, 37.0 mg, 0.30 mmol, 1.0 equiv, er > 99:1 according to chiral HPLC), the base (pyridine: 37.1 μί, 36.3 mg, 0.45 mmol, 1.5 equiv) and the dry solvent (1 mL, 0.3 M). Under cooling in an ice bath thionyl chloride was added (28.7 μί, 0.39 mmol, 1.3 equiv) and in the following the reaction mixture was either allowed to stir at ambient temperature or heated to the temperature T for the time period t.

After cooling down to ambient temperature the mixture was diluted with Et ₂ 0 (2 mL) and sat. NaHC0 ₃ solution (aq., 2 mL) was added dropwise. After further dilution with diethyl ether (2 mL), the organic phase was washed with a second portion of NaHC0 ₃ solution (2 mL) and 1 N HCI solution (2 x 2 mL) (The work up was conducted with a 10 mL syringe instead of extraction funnel), dried over MgS0 ₄ , concentrated under reduced pressure and dried at 50 mbar for 2 min.

4.4.1.3 General Procedure VII: Chlorination of Geraniol and Nerol with Thionyl chloride

Table 21+22: A 4 mL glas vial was charged with the alcohol 1 ₄ (178 μί, 156 mg 1.00 mmol, 1.0 equiv), the base (either pyridine or triethylamine, 1.50 mmol, 1.5 equiv) and the solvent (0.5-2 mL, 0.5-2 M). The vial was closed with a screw cap with septa, the septa was punctured with a needle to allow pressure balance and cooled to 0 °C. Next, thionyl chloride (96 μί, 1.20 mmol, 1.2 equiv) was added dropwise by means of a syringe (S0 ₂ - and HCI-evolution), the mixture was stirred 15 min at 0 °C and for the time period t at ambient temperature.

Work up:

Table 21, entry 1: An exactly weighed amount of the NMR-standard (dodecane) was directly added to the reaction mixture. Table 21, entries 2, 4, 6, 7 and Table 22, entries 1-4: The reaction mixture was diluted with Et ₂ 0 (1 mL), cooled to 0 °C and sat. NaHC0 ₃ -solution (aq., 2 mL) was added dropwise. After C0 ₂ -evolution had ceased (10 min of stirring), the mixture was diluted with further Et ₂ 0 (3 mL), the organic phase was washed with further NaHC0 ₃ solution (2 mL) (The work up was conducted with a 20 mL syringe instead of extraction funnel), dried over MgS0 ₄ , concentrated under reduced pressure (-> 50 mbar) and dried at 50 mbar for 2 min.

Table 21, entry 3, 5: The reaction mixture was transferred to a 10 mL flask with DCM, concentrated under reduced pressure (-> 50 mbar) and dried at 50 mbar for 2 min.

Table 21 entries, 8-9: 1 N HCI solution (aq., 2 mL) and DCM (4 mL) were added to the reaction mixture, the organic phase was washed successively with further 1 N HCI solution (2 mL) and sat., aq. NaHC0 ₃ solution/water (1 mL/1 mL), dried over MgS0 ₄ , concentrated under reduced pressure (-> 50 mbar) and dried at 50 mbar for 2 min.

Table 21, entries 10+11: 1 N HCI solution (aq., 2 mL) and Et ₂ 0 (4 mL) were added to the reaction mixture, the organic phase was washed successively with further 1 N HCI solution (2 mL) and sat., aq. NaHC0 ₃ solution (2 mL), dried over MgS0 ₄ , concentrated under reduced pressure (-> 50 mbar) and dried at 50 mbar for 2 min.

4.4.2 Synthesis of Primary Benzylic Chlorides

The following scheme provides an overview over primary benzylic chlorides synthesized by formamide catalyzed chlorinations. Deviations from standard conditions are given in parenthesis:

Standard Conditions

in dioxane (2 M): BzCI (0.95-1.2 equiv), FPyr (10 mol%), <24 h rt * 200 mmol scale !

solvent-free: BzCI (0.95-1.03 equiv), DMF(30 mol%), <24 h rt

2i 2 ₂ 2 ₅

86% (in MTBE) ^* 90% (10 mol% DMF) 76% (in MTBE) ^*

82% (solvent-free) ^* 73% (5 mol% FPyr, in MTBE) ^*

2 ₇ 2 ₈ 2 ₉

85% °C) 92% (40 °C) 87% (40 °C)

88% 81 % Synthesis of Benzylic Chloride (2i)

1. Isolated yield. 2. Yield determined via NMR-Standard.

Under optimized conditions (10 mol% FPyr, MTBE) benzyl chloride (2i) was isolated in 86% yield on a 200 mmol scale (entry 1). In the absence of any solvent with 30 mol% of DMF the product 2i was still obtained in 82% yield (entry 2). With 2,4,6-trichlorobenzoyl chloride as reagent benzyl chloride 2i was attained in 81% yield (NMR-standard) at an increased reaction temperature of 80 °C (entry 4).

Entry 1: According to general procedure III (chapter 2.1.3) benzylic alcohol li (20.9 mL, 21.85 g, 200.0 mmol, 1.0 equiv) and FPyr (2.0 mL, 1.97 g, 20.0 mmol, 10 mol%) were dissolved in MTBE (200 mL, 2 M) in 250 mL flask and treated with BzCI (24.2 mL, 29.25 g, 206.0 mmol, 1.03 equiv) at 0 °C. After stirring overnight (12.5 h) at room temperature the reaction solution was concentrated under reduced pressure (reaction control via ¹ H-NMR indicated 95% conversion) and stirred further at ambient temperature until full conversion was achieved (4.5 h, 2i/3i 94:6). Next the chloride 2i was separated through distillation through a micro distillation apparatus without distillation dispenser at 10.0 mbar. Complete separation of the product was achieved by raising the oil bath temperature gradually from 110-160 °C (Thereby the boiling point raised up to 92 °C. At lower pressures a micro distillation bridge was not sufficient enough to condens the product completely). Finally, the chloride 2i was obtained as a colorless liquid with a bp. of 77-79 °C at 10 mbar in 86% yield (21.858 g, 172.7 mmol).

Entry 2: In agreement with general procedure III (chapter 2.1.3) benzylic alcohol li (200.0 mmol, 1.0 equiv) and DMF (4.7 mL, 60.0 mmol, 30 mol%) were combined with BzCI (24.0 mL, 28.97 g, 204.0 mmol, 1.02 equiv) at 0 °C in a 100 mL flask (addition time 1 h). After 2.5 h of stirring at ambient temperature ¹ H-NMR showed full conversion (2i/3i 91:9). The resulting suspension was subjected to distillation at reduced pressure as described for entry 1. As the collected distillate (26.214 g, colorless liquid, bp. 75-125 °C at 10 mbar) contained 30 mol% of DMF (referred to the product 2i) as visualized by ¹ H-NMR, washing with water (4 x 10 mL, 1 x 2 mL Na ₂ C0 ₃ /8 mL H ₂ 0) and drying over MgS0 ₄ provided the chloride 2i as a colorless liquid (20.858 g, 164.8 mmol, 82%). Importantly, due to its higher density the product 2i formed the lower phase during washing.

Entry 3: In alignment to general procedure III (chapter 2.1.3) benzylic alcohol li (200.0 mmol, 1.0 equiv) and FPyr (20.0 mmol, 10 mol%) were dissolved in MTBE (50 mL, 4 M) in a 500 mL flask. Isophthalic acid chloride was melted at 50 °C in a water bath (of a rotatory evaporator), weighed into to 250 mL flask (17.7 mL, 24.61 g, 120.0 mmol, 0.6 equiv) with the aid of a pipette preheated to 80 °C (in an oven) and dissolved in MTBE (50 mL, [li] = 2 M) under warming to 50 °C. This solution was added under cooling to 0 °C within 30 min to the solution of the substrate li. After 15 min of further stirring, the ice bath was removed and the reaction solution was allowed to stir for 24 h at ambient temperature, whereupon reaction control via ¹ H-NMR revealed full conversion (A small aliquot of the reaction suspension (ca. 100 μί) was concentrated under reduced pressure, diluted with CDCI ₃ (600 μί) and filtered through a small plug of wool). Thereby isophthalic acid started to precipitate after 2 h of stirring.

To separate isophthalic acid the reaction mixture was cooled in an ice bath and saturated, aqueous Na ₂ C0 ₃ solution (80 mL) was added dropwise accompanied by a week C0 ₂ evolution. The mixture was transferred to a 500 mL extraction funnel, the reaction flask was rinsed with MTBE and H ₂ 0 (2 x 20 mL/20 mL) and water (120 mL) was added to improve phase separation (pH of the aq. phase ca. 7). Then the organic phase was washed successively with water (40 mL) and Na ₂ C0 ₃ -solution (40 mL), whereby during Na ₂ C0 ₃ -washing water (40 mL) had to be added to improve the phase separation (pH of the aq. phase > 10). After drying of the organic phase over MgS0 ₄ , concentration under reduced pressure (->200 mbar) and drying at 200 mbar for 5 min crude chloride 2i was obtained as a pale yellow oil (27.23 g, 108%). After distillation as given for the chlorination in entry 1 the chloride 2i was isolated as a colorless liquid in 65% yield (16.387 g, 129.4 mmol) with a boiling point of 72-73 °C at 9 mbar. Thereby the oil bath temperature was raised gradually form 90 to 140 °C (Further heating to 160 °C did not improve the yield. ¹ H-NMR of the distillation residue showed remaining traces of the product 2i).

Entry 4: Following general procedure I (chapter 2.1.1) benzylic alcohol li (109 μί, 105 mg, 1.00 mmol, 1.0 equiv), DMF (7.7 μΐ, 7,3 mg, 0.100 mmol, 10 mol%), dioxane (250 μΐ, 4 M) and benzoyl chloride (176 μί, 274 mg, 1.20 mmol, 1.2 equiv) were combined at room temperature and heated to 80 °C for 20 h. Determination of the yield via naphthalene as NMR-standard gave 81% of chloride 2i(0.810 mmol; 2i/3i > 98:2, > 98% conversion).

M (C ₇ H ₇ CI) = 126.58 g/mol. 4.4.2.2 Synthesis of 4-ferf-Butylbenzyl Chloride (2 ₂ )

BzCi (1.5 equiv), DMF (5 mol%)

2 2 81% ^x dioxane (2 M), 0.5 h 0°C, 24 h rt

BzCi (1.5 equiv), DMF (2.5 mol%)

3 2 dioxane (2 M), 0.5 h 0°C, 24 h rt, 76% ^x

8 h 40 °C

BzCi (1.5 equiv), DMF (1 mol%)

4 2 dioxane (2 M), 0.5 h 0°C, 24 h rt 6 /0 ¹

48 h 40 °C

BzCi (1.2 equiv), w/o catalyst

5 0.5 <2% ² * dioxane (2 M), 0.5 h 0°C, 24 h rt

1. Isolated yield. 2. Yield determined via NM -Standard. * Comparative Example.

In the presence of 10 mol% of DMF benzylic chloride 2 ₂ resulted in 90% isolated yield (entry 1). Lowering the amount of catalyst to 5 and 2.5 mol%, respectively, provided chloride 2 ₂ in 81-76% yield (entry 2 + 3). Noteworthy, with only 1 mol% DMF the desired chloride 2 ₂ still remained the major product and could be isolated in 61% yield after 3 d of reaction time (entry 4). In the absence of DMF under elsewise identical conditions no chloride 2 ₂ was observed at all (entry 5).

Entry 1: Following general procedure II (chapter 2.1.2) 4-ieri-butyl benzyl alcohol 1 ₂ (361 μί, 335 mg, 2.00 mmol, 1.0 equiv), DMF (15.5 μΐ, 14.6 mg, 0.20 mmol, 10 mol%), dioxane (1 mL, 2 M) and BzCi (282 μΐ, 341 mg, 2.40 mmol) were combined at 0 °C and stirred for 0.5 h at 0 °C and 24 h at room temperature. ¹ H-NMR of the crude material (430 mg) indicated >98% conversion and a ratio of the chloride 2 ₂ to ester 3 ₂ of 96:4. Chromatographic purification (mass crude material/Si0 ₂ 1:13) furnished chloride 2 ₂ as a colorless oil in 90% yield (330 mg, 1.80 mmol).

Entry 2: According to general procedure II (chapter 2.1.2) 4-ieri-butyl benzyl alcohol 1 ₂ (2.00 mmol, 1.0 equiv), a 1 N solution of DMF in dioxane (100 μί, 0.10 mmol, 5 mol%), dioxane (0.9 mL, 2 M) and BzCi (352 μί, 426 mg, 3.00 mmol, 1.5 equiv) were combined at 0 °C and stirred for 0.5 h at 0 °C and 24 h at room temperature. ¹ H-NMR of the crude material (476 mg) showed >98% conversion and a ratio 2 ₂ to 3 ₂ of 93:7. Chromatographic purification (mass crude material/Si0 ₂ 1:10) delivered chloride 2 ₂ as a colorless oil in 81% yield (297 mg, 1.62 mmol). Entry 3: In agreement with general procedure II (chapter 2.1.2) 4-ieri-butyl benzyl alcohol 1 ₂ (2.00 mmol, l.O equiv), a I N solution of DMF in dioxane (50 μί, 0.050 mmol, 2.5 mol%), dioxane (0.95 mL, 2 M) and BzCI (3.00 mmol, 1.5 equiv) were combined at 0 °C and stirred for 0.5 h at 0 °C and 24 h at room temperature. As TLC control still showed traces of the starting material 1 ₂ , the reaction mixture was heated to 40 °C for 8 h. ¹ H-NMR of the crude material (502 mg) indicated 95% conversion and a ratio 2 ₂ to 3 ₂ of 88:12. Chromatographic purification (mass crude material/Si0 ₂ 1:10) provided chloride 2 ₂ as a colorless oil in 76% yield (278 mg, 1.52 mmol).

Entry 4: According to general procedure II (chapter 2.1.2) 4-ieri-butyl benzyl alcohol 1 ₂ (2.00 mmol, 1.0 equiv), a 1 N solution of DMF in dioxane (20 μί, 0.010 mmol, 1 mol%), dioxane (0.98 mL, 2 M) and BzCI (3.00 mmol, 1.5 equiv) were combined at 0 °C and stirred for 0.5 h at 0 °C and 24 h at room temperature. As TLC control still showed traces of the starting material 1 ₂ , the reaction mixture was heated to 40 °C for 48 h. ¹ H-NMR of the crude material (529 mg) indicated full conversion and a ratio 2 ₂ /3 ₂ of 69:31. Chromatographic purification (mass crude material/Si0 ₂ 1:15) delivered chloride 2 ₂ as a colorless oil in 61% yield (224 mg, 1.23 mmol).

Entry 5: According to general procedure I (chapter 2.1.1) a solution of 4-ieri-butyl benzyl alcohol 1 ₂ (89.4 μΐ, 83.0 mg, 0.50 mmol, l.O equiv) in dioxane (0.25 mL, 2 M) was treated with BzCI (70.4 μΐ, 85.2 mg, 0.60 mmol, 1.2 equiv) and stirred for 24 h at room temperature. ¹ H-NMR of the crude material with naphthalene as NMR-standard showed starting material 1 ₂ in 76% and ester 3 ₂ in 24% yield (-> 24% conversion). The chloride 2 ₂ was not detectable (<2% yield, 2 ₂ /3 ₂ <2:98).

M (C _n H ₁₅ CI) = 182.70 g/mol; r _f (Si0 ₂ , Et ₂ 0//iPen 1:99) = 0.56.

4.4.2.3 Synthesis of 4-Methoxybenzyl chloride (2 ₅ )

1. Isolated yield. 2. Yield determined via NMR-Standard.

* Comparative Example. Only 0.95 equiv of BzCI proved to be sufficient to achieve full conversion of 4-methoxybenzyl alcohol 1 ₅ due to formation of ether 6 ₅ as sideproduct. With 10 mol% FPyr the electronrich benzyl chloride 2 ₅ was isolated in 76% yield on a 200 mmol scale (entry 1). Decreasing the catalyst loading to 5 mol% FPyr still allowed the isolation of chloride 2 ₅ in 73% yield (entry 2). Also under solvent-free conditions only 10 mol% of FPyr were required to obtain the desired product in 72% yield (entry 3). On a smaller (0.5 mmol) scale the yield for the chlorination l ₅ ->2 ₅ was determined via NMR-standard to be 89% (entry). The difference in yield compared to the 400-fold upscaled chlorinations in entry 1-3 can thus be explained by hydrolysis of the product 2 ₅ during work up and the separation of the resulting starting material 1 ₅ during distillation. In the absence of any catalyst still 45% of chloride 2 ₅ were attained (entry 5). Here chlorination might proceed through initial esterification to give 3 ₅ and subsequent S _w l-type chlorination with HCI.

Entry 1: According to general procedure III (chapter 2.1.3) 4-methoxybenzylic alcohol 1 ₅ (25.3 mL, 28.20 g, 200.0 mmol, 1.0 equiv), FPyr (2.0 mL, 1.97 g, 20.0 mmol, 10 mol%), MTBE (100 mL, 2 M) and BzCI (22.3 mL, 26.98 g, 190.0 mmol, 0.95 equiv) (Utilizing larger amounts of BzCI the excess reagent (BzCI) remained in the crude product and was partially codistilled with the product 2 ₅ during purification, which resulted in diminished yields) were combined at 0 °C in a 500 mL flask. After stirring overnight (13 h) the clear reaction solution was concentrated under reduced pressure (97% conversion according to ¹ H-NMR) (70 mL of MTBE were reisolated and subsequently used for the work up). The resulting suspension was stirred for further 4 h, whereupon reaction control via ^Χ Η- NMR showed full conversion.

In order to reduce hydrolysis of the chloride 2 ₅ the reaction mixture was dissolved in MTBE (200 mL, 1 mL/1 mmol of 1 ₅ ) cooled in an ice bath and 60 mL of saturated, aqueous Na ₂ C0 ₃ -solution were added dropwise within 5 min. Immediately the mixture was transferred to a 500 mL extraction funnel and diluted with water (140 mL, ratio total volume of aq. phase to amount of starting material 1 ₅ 1 mL/1 mmol) to dissolve precipitated NaOBz. The aqueous phase was separated (pH = 7-8) and the organic phase was washed with further Na ₂ C0 ₃ -solution/water (30 mL/30 mL, pH = 9-10) to separate BzOH completely. Drying over MgS0 ₄ , concentration under reduced pressure and drying at 50 mbar for 5 min delivered the crude chloride 2 ₅ as a pale yellow oil (32.35 g, 103%) (While reaction control through ¹ H-NMR prior to work up showed a conversion of >98% and a ratio 2 ₅ /3 ₅ >98:2, traces of the starting alcohol 1 ₅ were visible in the ¹ H-NMR of the crude material (corresponding to 97% conversion) resulting necessarily from hydrolysis. The ratio 2 ₅ /3 ₅ decreased to 96:4. The reaction control also displayed 8 mol% of the ether 6 ₅ (refered to 2 ₅ ) originating from condensation of the starting alcohol 1 ₅ and the chloride 2 ₅ (or an activated iminium intermediate). This observation rationalized why substiochiometric amounts of BzCI (0.95 equiv) were sufficient to effect full conversion) (Isolation of chloride 2 ₅ required a work up. During distillation of the crude reaction mixture FPyr and traces of BzOH were codistillid. Both could be separate by washing the neat distillate with water. However, the washing with water resulted inevitable in partial hydrolysis of chloride 2 ₅ to the parent alcohol 1 ₅ ).

Next distillation through a micro distillation apparatus without dispenser (Distillation through a 15 cm Vigreux column lead to significantly diminished yields. Due to the relatively high viscosity of the chloride 2 ₅ large amounts remained in the distillation apparatus) at O.l mbar delivered the chloride 2 ₅ ( 23.945 g, 152.9 mmol, 76%, bp. 70-72 °C) as a colorless oil. To maintain a continuous distillation the oil bath temperature was slowly raised from 110-130 °C. Further heating to 160 °C provided a fraction of the chloride 2 ₅ (611 mg) with a bp. of 73-85 °C containing 3 mol% of alcohol 1 ₅ and benzoic acid.

Entry 2: As described in general procedure III (chapter 2.1.3) 4-methoxybenzylic alcohol (200.0 mmol, 1.0 equiv), FPyr (1.0 mL, 0.98 g, 10.0 mmol, 5 mol%), MTBE (100 mL, 2 M) and BzCI (190.0 mmol, 0.95 equiv) were combined at 0 °C in a 500 mL flask. After stirring overnight (12.5 h) the clear reaction solution was concentrated under reduced pressure (97% conversion according to ¹ H-NM ). The resulting suspension was stirred for further 3.5 h, whereupon reaction control via ¹ H-NMR showed full conversion. Work up and distillation as described above (entry 1) provided the chloride 2 ₅ (22.820 g, 145.7 mmol, bp. 73-74 °C at 0.12 mbar) in 73%yield as a colorless oil.

Entry 3: As described in general procedure III (chapter 2.1.3) 4-methoxybenzylic alcohol (200.0 mmol, 1.0 equiv), FPyr (20.0 mmol, 19 mol%) and BzCI (21.8 mL, 26.41 g, 186.0 mmol, 0.93 equiv) were combined at 0 °C in a 500 mL flask within 30 min. After stirring at ambient temperature for 20 min BzOH started to precipitate accompanied by a slightly exothermic reaction. ¹ H-NMR after 3.5 h of stirring proved full conversion. Then (after 4 h of stirring) work up and distillation as described above (entry 1) provided the chloride 2 ₅ ( 22.466 g, 143.5 mmol, bp. 72-74 °C at 0.10 mbar) in 72%yield as a colorless oil.

Entry 4: In alignment to general procedure I (chapter 2.1.1) 4-methoxybenzylic alcohol (63.3 μί, 70.5 mg, 0.50 mmol, 1.0 equiv), a I N solution of DMF in dioxane (50 μί, 0.05 mmol, 10 mol%), dioxane (0.20 mL, 2 M) and benzoyl chloride (70.4 μί, 85.2 mg, 0.60 mmol, 1.2 equiv) were combined and stirred for 24 h at room temperature. ¹ H-NMR of the crude material with naphthalene as standard displayed chloride 2 ₅ in 89% yield alongside with 2% of the ester 3 ₅ at full conversion giving a ratio 2 ₅ /3 ₅ of 96:4.

Entry 5: Following general procedure I (chapter 2.1.1) 4-methoxybenzylic alcohol (0.50 mmol, 1.0 equiv), dioxane (0.25 mL, 2 M) and benzoyl chloride (70.4 μί, 85.2 mg, 0.60 mmol, 1.2 equiv) were combined and stirred for 24 h at room temperature. ¹ H-NM of the crude material with naphthalene as standard displayed chloride 2 ₅ in 45% yield alongside with 34% of the ester 3 ₅ and 17% of starting material correlating to 84% conversion and a ratio 2 ₅ /3 ₅ of 56:44.

M (CgHgCIO) = 152.61 g/mol.

4.4.2.4 Synthesis of 4-Chlorobenzyl chloride (2 ₆ )

According to general procedure II (chapter 2.1.2) a solution of 4-chlorobenzylic alcohol 1 ₆ (282 mg, 2.00 mmol, l.O equiv), FPyr (19.7 μΐ, 20.4 mg, 0.20 mmol, 10 mol%) in dioxane (1 mL, 2 M) was treated with benzoyl chloride (282 μί,

2 ₆ 10 341 mg, 2.40 mmol, 1.2 equiv) at 0 °C and the resulting mixture was stirred for

24 h at ambient temperature. ¹ H-NMR of the crude material (350 mg) displayed full conversion and a ratio chloride 2 ₆ to ester 3 ₆ of 97:3. After chromatographic purification (mass of crude material/Si0 ₂ 1:15) with Et ₂ 0//iPen 5:95 the chloride 2 ₆ was isolated in 82% yield (264 mg, 1.64 mmol) as a colorless oil. ¹ H- and ¹³ C-NMR-data was identical with the literature (Hu, Y. Lu, M.; Ge, Q.; Wang, P.; Zhang, S.; Lu, T. J. Chil. Chem. Soc. 2010, 55, 97-102).

M (C ₇ H ₆ CI ₂ ) = 161.03 g/mol; r _f (Si0 ₂ , Et ₂ 0//iPen 95:5) = 0.60; ¹ H-NMR (400 MHz, CDCI ₃ ): δ [ppm] = 7.35-7.30 (m, 4 H, H-3, H-4), 4.55 (s, 2 H, H-l); ¹³ C-NMR (100 MHz, CDCI ₃ ) δ [ppm] = 136.0 (C-2), 134.3 (C-5), 129.9 (C-3), 128.9 (C-4), 45.4 (C-l); GC-MS (El, 70 eV): m/z [u] = 162 (82, [M+H] ⁺ ), 161 (29, [M] ⁺ ), 125 (100, [M-CI] ⁺ ), 99 (68), 89 (95), 75 (31), 73 (40), 63 (89), 51 (36); HR-MS (CI, [C ₇ H ₇ CI ₂ ] ⁺ ) m/z calc. 159.9847 u found 159.9849 u.

4.4.2.5 Synthesis of 4-Fluorobenzyl chloride (2 ₇ )

Following general procedure II (chapter 2.1.2) a solution 4-fluorobenzylic alcohol

1 ₇ (219 μί, 253 mg, 2.00 mmol, l.O equiv), FPyr (19.7 μί, 20.4 mg, 0.20 mmol, 10 mol%) in dioxane (1 mL, 2 M) was allowed to react with benzoyl chloride

(282 μί, 341 mg, 2.40 mmol, 1.2 equiv) for 24 h at 40 °C. ^X H-NMR of the crude material (350 mg) showed full conversion and a ratio chloride 2 ₇ to ester 3 ₇ of

97:3. Chromatographic purification (mass of crude material/Si0 ₂ 1:14) with Et ₂ 0//iPen 5:95 delivered chloride 2 ₆ in 74% yield (214 mg, 1.48 mmol) as a colorless oil. ^X H- and ¹³ C-NMR-data was identical with the literature (Klimesova, V.; Koci, J.; Waisser, K.; Kaustova, J.; Mollmann, U. Eur. J. Med. Chem. 2009, 44, 2286-2293).

M (C ₇ H ₆ CIF) = 144.573 g/mol; r _f (Si0 ₂ , Et ₂ 0//iPen 95:5) = 0.52; ¹ H-NMR (400 MHz, CDCI ₃ ): δ [ppm] = 7.36 (dd, 2 H, H-3, J = 8.4 Hz, 5.6 Hz), 7.04 (dd, 2 H, H-4, J = 8.4, 8.4 Hz), 4.56 (s, 2 H, H-l); ¹³ C-NMR (100 MHz, CDCI3) δ [ppm] = 162.6 (d, C-5, J = 243 Hz), 133.4 (C-2), 130.5 (d, C-3, J = 8.6 Hz), 115.7 (d, C-4, J = 22 Hz), 45.5 (C-l); GC-MS (El, 70 eV) m/z [u] = 145 (77, [M+H] ⁺ ), 144 (100, [M] ⁺ ), 127 (1, [M- F] ⁺ ), 109 (100, [M-CI] ⁺ ), 89 (36), 83 (100), 63 (53), 57 (76), 51 (29).

Synthesis of 4-Nitrobenzyl chloride (2 ₈ )

2 8 BzCi (1.5 equiv), DMF (10 mol%)

2 2 93% ^x

dioxane (2 M), 0.25 h 0 °, 24 h 40 °C

BzCi (1.5 equiv), no catalyst

3 0.5 <2% ² *

dioxane (2 M), 0.25 h 0 °, 24 h 40 °C

1. Isolated yield. 2. Yield determined via NM -Standard.

* Comparative Example

With 10 mol FPyr and DMF, respectively, electron deficient nitrobenzyl chloride 2 ₈ was isolated in basically the same yield (92-93%, entry 1+2). However, with FPyr the amount of BzCi could be reduced from 1.5 to 1.2 equiv. Furthermore, without a catalyst no chloride 2 ₈ was observed at all (entry 3).

Entry 1: In alignment to general procedure II (chapter 2.1.2) 4-nitrobenzyl alcohol 1 ₈ (309 mg, 2.00 mmol, 1.0 equiv) was allowed to react with benzoyl chloride (282 μί, 341 mg, 1.20 mmol, 1.0 equiv) in the presence of FPyr (19.7 μί, 20.4 mg, 0.20 mmol, 10 mol%), in dioxane (1 mL, 2 M) at 40 °C for 24 h. ¹ H-NMR of the crude product (456 mg) showed full conversion and a ratio 2 ₈ /3 ₈ of 97:3. Next, the crude material was dissolved in Et ₂ 0 (ca. 5 mL), silica gel was added (mass crude material/Si0 ₂ 1:2) and the mixture was concentrated under reduced pressure. Chromatographic purification (mass crude material/Si0 ₂ 1:13) with DCM/nPen 4:6 and drying for 20 min at 20 mbar gave the chloride 2 ₈ as a colorless solid in yield of 92% (317 mg, 1.85 mmol).

Entry 2: According to general procedure II (chapter 2.1.2) 4-nitrobenzyl alcohol 1 ₈ (2.00 mmol, 1.0 equiv), DMF (15.5 μί, 14.6 mg, 0.20 mmol, 10 mol%), dioxane (1 mL, 2 M) and BzCi (352 μί, 426 mg, 3.00 mmol, 1.5 equiv) were combined and stirred for 24 h at 40 °C. Purification as described above (mass crude material/Si0 ₂ 1:13) delivered the product 2 ₉ as a colorless solid (319 mg, 1.86 mmol, 93%).

Entry 3: As described in general procedure I (chapter 2.1.1), a solution of 4-nitrobenzyl alcohol 1 ₈ (77 mg, 0.50 mmol, 1.0 equiv) in dioxane (0.25 mL, 2 M) was treated with BzCi (88.0 μΐ, 106.5 mg, 0.75 mmol, 1.5 equiv) and stirred for 24 h at 40 °C. ^X H-NMR of the crude material with naphthalene as standard indicated the ester 3 ₈ in 18% and starting material in 76% yield correlating to 19% conversion. Only very small traces of the chloride 2 ₈ were visible (< 2% yield) resulting in a ratio 2 ₈ /3 ₈ of < 2:98.

M (C ₇ H ₆ CIN0 ₂ ) = 171.58 g/mol; r _f (Si0 ₂ , DCM/nPen 4:6) = 0.36. 4.4.2.7 Synthesis of 4-(Trifluoromethyl)benzyl chloride (2 ₉ )

According to general procedure II (chapter 2.1.2) 4-(trifluoromethyl)benzyl alcohol 1 ₉ (353 mg, 2.00 mmol, l.O equiv), FPyr (19.7 μΐ, 20.4 mg, 0.20 mmol, 10 mol%), dioxane (1 mL, 2 M) and benzoyl chloride (282 μΐ, 341 mg, 2.40 mmol, 1.2 equiv) were combined and stirred for 24 h at ambient temperature. After quenching with ethanolamine the reaction mixture was diluted with DCM (4 mL), saturated, aqueous NaHC0 ₃ -soution (2 mL) and water (2 mL). The aqueous phase was extracted with further DCM (2 x 2 mL) and the collected organic phases were dried over MgS0 ₄ and concentrated under reduced pressure to give the crude chloride 2 ₉ (490 mg, conversion > 98%, 2 ₉ /3 ₉ 97:3). Chromatographic purification (mass of crude material/Si0 ₂ 1:12) provided the product 2 ₉ as a colorless oil in 85% yield (331 mg, 1.71 mmol). ¹ H- and ¹³ C-NM -data was identical with the literature (Klimesova, V.; Koci, J.; Waisser, K.; Kaustova, J.; Mollmann, U. Eur. J. Med. Chem. 2009, 44, 2286-2293).

M (CgH ₆ CIF ₃ ) = 194.58 g/mol; r _f (Si0 ₂ , Et ₂ 0//iPen 5:95) = 0.53; ¹ H-NMR (400 MHz, CDCI ₃ ): δ [ppm] = 7.63 (d, 2 H, H-4, J = 8.4 Hz), 7.51 (dd, 2 H, H-3, J = 8.4 Hz), 4.62 (s, 2 H, H-l); ¹³ C-NMR (100 MHz, CDCI3): δ [ppm] = 141.3 (C-2), 130.6 (q, C-5, = 31 Hz), 128.8 (C-3), 125.7 (q, C-4, J = 3.7 Hz), 124.0 (q, C-6, J = 273 Hz) 45.1 (C-l); GC-MS (El, 70 eV) m/z [u] = 194 (35, [M] ⁺ ), 175 (13, [M-F] ⁺ ), 159 (100, [M- Cl] ⁺ ), 139 (8), 125 (22, [M-CF ₃ ] ⁺ ), 109 (51), 89 (16), 69 (5, [CF ₃ ] ⁺ ), 63 (13), 51 (7).

4.4.2.8 Synthesis of 2,4,6-Trimethylbenzyl chloride (2 ₁₀ )

As described in general procedure II (chapter 2.1.2) 2,4,6-trimethylbenzyl alcohol 1 ₉ (300 mg, 2.00 mmol, l.O equiv), FPyr (19.7 μΐ, 20.4 mg, 0.20 mmol, 10 mol%), dioxane (1 mL, 2 M) and benzoyl chloride (282 μΐ, 341 mg,

2.40 mmol, 1.2 equiv) were combined and stirred for 24 h at room temperature. ^X H-NMR of the crude material (460 mg) proved full conversion and a ratio of the chloride 2 ₁₀ to the ester 3i ₀ of 97:3. After chromatographic purification (mass of crude material/Si0 ₂ 1:15) with Et ₂ 0//iPen 1:99 the product 2 ₉ was obtained as a colorless solid in 84% yield (282 mg, 1.67 mmol). ^X H- and ¹³ C-NMR-data was identical with the literature (Klimesova, V.; Koci, J.; Waisser, K.; Kaustova, J.; Mollmann, U. Eur. J. Med. Chem. 2009, 44, 2286-2293).

M (C ₁₀ H ₁₃ CI) = 168.66 g/mol; r _f (Si0 ₂ , Et ₂ 0//iPen 1:99) = 0.57; mp. = 34-36 °C; ¹ H-NMR (400 MHz, CDCI3): δ [ppm] = 6.87 (s, 2 H, H-4), 4.65 (s, 2 H, H-l), 2.39 (s, 6 H, H-l ^' ), 2.26 (s, 3 H, H-2 ^' ); ¹³ C-NMR (100 MHz, CDCI3): δ [ppm] = 138.5 (C-5), 137.4 (C-3), 131.1 (C-2), 129.2 (d, C-4), 41.2 (C-l), 21.0 (C- 1 ^' ), 19.2 (C-2 ^' ); GC-MS (El, 70 eV): m/z [u] = 168 (70, [M] ⁺ ), 153 (2, [M-CH ₃ ] ⁺ ), 133 (100, [M-CI] ⁺ ), 115 (49), 105 (56, [PhMe ₂ ] ⁺ ), 91 (74, [Bn] ⁺ ), 77 (35, [Bn] ⁺ ), 65 (29, [Cp] ⁺ ), 51 (33); HR-MS (CI, [C ₁₀ H ₁₃ CI ³⁵ ] ⁺ ) m/z calc. 168.0700 u foundl68.0703 u.

4.4.2.9 Synthesis of l-(ieri-Butoxycarbonyl)-3-(chloromethyl)indole (2 _n )

According to general procedure I I (chapter 2.1.1) to a solution of l-(tert- Butoxycarbonyl)-3-(hydroxymethyl)indole (In, 373 mg, 1.51 mmol, l.O equiv), FPyr (15.0 μΐ, 15.6 mg, 0.150 mmol, 10 mol%) in dioxane (1 mL, 2 M) was added benzoyl chloride (216 μί, 261 mg, 1.84 mmol, 1.2 equiv) at 0 °C. After 15 min of stirring, the cooling bath was removed and the reaction

solution was allowed to stir for 24 h at room temperature. ¹ H-N M of the crude material (447 mg, brownish solid) showed > 98% conversion and a ratio 2n/3 of >98:2. Next the crude product was dissolved in a minimum amount of toluene (0.5 mL) at 40 °C in a water bath (The crude material is virtually insoluble in the eluent. Adsorption on silica gel or isolute prior to chromatography results in diminished yields and low purities). This solution was applied to column chromatography on silica gel (mass crude material/Si0 ₂ 1:9) with Et ₂ 0//iPen 10:90. After concentration with chloroform (2 x 2 mL) and drying for 20 min at 20 mbar the chloride 2 _U was isolated as colorless solid in 81% yield (326 mg, 1.227 mmol).

M (C ₁₄ H ₁₆ CIN0 ₂ ) = 265.74 g/mol; HR-MS (CI, [C ₁₄ H ₁₆ N0 ₂ CI ³⁵ ] ⁺ ) calc. 265.0870 u found 265.0836 u, ([C ₁₄ H ₁₅ N0 ₂ CI] ⁺ ) calc. 264.0786 u found 264.0821 u.

4.4.3 Synthesis of Primary Allylic and Propargylic Chlorides

The following scheme provides an igure overview over primary allylic and propargylic chlorides synthesized by formamide catalyzed chlorinations. Deviations from standard conditions are given in parenthesis.

Standard Conditions

in dioxane (2 M): BzCI (1 .00-1 .2 equiv), FPyr (10 mol%), <24 h rt >200 mmol scale ' solvent-free: BzCI (1 .00-1 .1 equiv), DMF (30 mol%), <24 h rt

, ,

Ph CI

'17

2l3 82% (solvent-free, l/b >98:2)

85% (10 mol% DMF) .4.3.1 Synthesis of Z-l-(benzyloxy)-4-chloro-2-butene (2 ₁₂ )

dioxane (2 M), 0.5 h 0 °, 23 h rt

1. Isolated yield The reactive allylic alcohol 1 ₁₂ (Z-4-(benzyloxy)-2-buten-l-ol) was chlorinated with BzCI in the presence of both 10 mol% FPyr and DM F, respectively, in virtually the same efficiency (entries 1+2).

Entry 1: As given in general procedure I I (chapter 2.1.2) Z-4-(benzyloxy)-2-buten-l-ol (1 ₁₂ , 357 mg, 2.00 mmol, 1.0 equiv), FPyr (19.7 μΐ, 20.4 mg, 0.20 mmol, 10 mol%), dioxane (1 mL, 2 M) and benzoyl chloride (282 μί, 341 mg, 2.40 mmol, 1.2 equiv) were combined at 0 °C and than allowed to react for 24 h at room temperature. ¹ H-N M of the crude material (520 mg) showed full conversion and an chloride 2 ₁₂ to ester 3 _i2 ratio of 95:5. GC-MS showed no other compound with the same mass and fragmentation pattern than chloride 2 ₁₂ (Z/E≥ 98:2, ratio linear to branched isomer of 2 ₁₂ l/b≥ 98:2). Chromatographic purification (mass crude material/Si0 ₂ 1:16) with Et ₂ 0//iPen 10:90 provided the product 2i ₂ as a colorless oil in 71% yield (279 mg, 1.41 mmol).

Entry 2: As described in general procedure I I (chapter 2.1.2) Z-4-(benzyloxy)-2-buten-l-ol (1 ₁₂ , 2.00 mmol, 1.0 equiv), DMF (15.5 μΐ, 14.6 mg, 0.20 mmol, 10 mol%), dioxane (1 mL, 2 M) and 2- fluorobenzoyl chloride (297 μί, 392 mg, 2.40 mmol, 1.2 equiv) were combined at 0 °C and than allowed to react for 23 h at room temperature. ¹ H-N MR of the crude material (560 mg) showed full conversion and an chloride 2 ₁₂ to ester 3 _i2 ratio of 92:8. GC-MS showed no other compound with the same mass and fragmentation pattern than chloride 2 ₁₂ (Z/E≥ 98:2, ratio linear to branched isomer of 2i2 l/b≥ 98:2). Chromatographic purification (mass crude material/Si0 ₂ 1:10) with Et ₂ 0//iPen 1:9 provided the product 2i ₂ as a colorless oil in 71% yield (279 mg, 1.41 mmol).

M (C _n H ₁₃ CIO) = 196.67 g/mol; r _f (Si0 ₂ , Et ₂ 0//iPen 10:90) = 0.43.

4.4.3.2 Synthesis of E-l-Chloro-3,7-dimethyl-2,6-octadien (Geranyl Chloride E-2 ₄ )

scale l/b yield entry conditions

[mmol] crude/isolated ³ 2i

BzCi (1.01 equiv), FPyr (10 mol%), MTBE (2 M),

1 500 97:3/>98:2 83% ^x

1.25 h 0 °, 16 h rt

BzCi (1.2 equiv), FPyr (5 mol%), MTBE (2 M),

2 200 96:4/>98:2 79% ^x

0.75 h 0 °, 18 h rt

BzCi (1.01 equiv), MF (10 mol%), MTBE (2 M),

3 200 97:3/>98:2 81% ^x

2 h 0 °, 20 h rt

BzCi (1.01 equiv), DMF (10 mol%), MTBE (2 M),

4 200 96:4/97:3 76% ^x

1 h 0 °, 21 h rt

BzCi (1.01 equiv), DM F (30 mol%), solvent-free,

5 200 96:4/>98:2 75% ^x

2.25 h 0 °, 3 h rt

BzCi (1.1 equiv), FPyr (10 mol%), MTBE (2 M), >98 0.25 h 0 °, 18 h rt

1. Isolated yield 2. Yield determined via NM -Standard. 3. Determined by H-NMR.

On a 500 mmol scale chlorination of geraniol E-l ₄ with BzCI in the presence of 10 mol% in MTBE furnished 72 g of geranyl chloride E-2 ₄ as a virtually pure regioisomer (entry 1). Furthermore, cutting the catalyst amount down to 5 mol% still afforded chloride E-2 ₄ in 79% isolated yield (entry 2). Also with 10 mol% MF and DMF, respectively, the chloride E-2 ₄ was attained in good yields (76-81%) on a representative 200 mmol scale. In the absence of any solvent the desired product E-2 ₄ was still provided in 75% yield, although an aqueous work up was mandatory to circumvent decomposition (entry 5). Finally, also on a smaller (1 mmol) scale the yield determined by NMR-standard stayed the same as in the 500 fold

upscaled example (entry 6, compare with entry 1).

6-2 ₄

Entry 1: According to general procedure III (chapter 2.1.3) £-3,7-dimethyl-2,6-octadien-l-ol (geraniol E-l ₄ , 89 mL, 77.90 g, 500 mmol, l.O equiv) and FPyr (4.9 mL; 5.11 g, 50.0 mmol, 10 mol%) were dissolved in MTBE (250 mL, 2 M) in a 1 L one necked flask with a strong stir bar. Next the reaction solution was cooled in an ice bath and benzoyl chloride (59 mL, 71.70 g, 505 mmol, 1.01 equiv) was added dropwise via a dropping funnel within 45 min. After further 30 min of stirring the cooling bath was removed and the reaction solution was allowed to stir overnight (14 h). Then the resulting pale yellow reaction suspension was concentrated under reduced pressure (190 mL of MTBE were reisolated and utilized for the work up) and dried at 150 mbar for 10 min. ¹ H-NMR of a small aliquot of the reaction mixture (ca. 10 mg) showed 97% conversion. After 2 h of further stirring at ambient temperature reaction control through ¹ H-NMR indicated full conversion.

In the following the reaction mixture was diluted with MTBE (250 mL, MTBE/amount of starting material 1 0.5 mL/1 mmol), cooled to 0 °C and saturated, aqueous Na ₂ C0 ₃ -solution (150 mL, 0.3 mL/1 mmol of 1) was added dropwise within 15 min, whereby a weak C0 ₂ -evolution occured. The heterogeneous mixture was transferred to a 1 L extraction funnel and the reaction flask was rinsed with water (2 x 100 mL, 0.4 mL/1 mmol). To dissolve precipitated NaOBz the mixture was diluted with further water (250 mL, volume of the total aqueous phase 1.2 mL/1 mmol of 1, pH = 7-8). Afterwards the organic phase was washed with Na ₂ C0 ₃ -solution/water (1 x 100 mL/50 mL, 0.3 mL/1 mmol, pH = 9-10), dried over MgS0 ₄ , concentrated under reduced pressure and dried at 50 mbar for 10 min to yield the crude chloride 2 ₄ as a pale yellow oil (92.29 g). ¹ H-NMR proved full conversion, a chloride /-E-2 ₄ to ester 3 ₄ ratio of 95:5 and a regioisomer ratio /-/6-2 ₄ of 97:3. Fractioned distillation through a micro distillation apparatus with a NS 29 cooling finger with Vigreux column (10 cm pathway, NS 29, vacuum-mantled and metal-coated) at 0.15 mbar delivered initially a prefraction with a bp. of 53-57 °C (5.26 g, 30.5 mmol, 6%, colorless oil, oil bath temperature 85 °C) consisting of chloride F-2 ₄ in a regioisomer ratio of 90: 10 l/b an small traces of BzCI (< 2 mol% referred to F-2 ₄ ) (Distillation of the reaction mixture (without work up) resulted in decomposition of the chloride /Γ-2 ₄ ). Gradually raising the oil bath temperature from 85 to 120 °C then provided the chloride /-F-2 ₄ as a colorless liquid with a bp. 56-58 °C (71.64 g, 414.8 mmol, 83%). Both ¹ H-N M and GC-MS proved a regioisomeric ratio /-/6-2 ₄ >98:2. Further increasing the oil bath temperature to up to 150 °C lead to the collection of a small fraction with a bp. of 59-62 °C (492 mg) containing the product 2 ₄ in a depleted ratio of isomers (94:6 l/b). Importantly, the collecting flasks were cooled in an ice bath. As no distillation dispenser was utilized, the collecting flasks were exchanged under interruption of heating and vacuum.

Entry 2: As described in general procedure I II (chapter 2.1.3) geraniol F-l ₄ (35.5 mL, 31.16 g, 200 mmol, 1.0 equiv) and FPyr (1.02 mL, 0.98 g, 10.0 mmol, 5 mol%), MTBE (100 mL, 2 M) and benzoyl chloride (24.2 mL, 29.25 g, 206 mmol, 1.03 equiv) were combined in a 500 mL flask at 0 C. After stirring overnight (14 h), the yellow reaction solution was concentrated under reduced pressure (95% conversion according to ¹ H-NM R) and the resulting suspension was stirred for 4 h at room temperature to achieve full conversion. After aqueous work up ¹ H-N MR of the crude material (37.16 g, pale yellow oil) showed a chloride /-/F-2 ₄ to ester 3 ₄ ratio of 92:8 and a regioisomer ratio I- /6-2 ₄ of 96:4. Fractioned distillation at 0.10 mbar through a micro distillation apparatus with Vigreux column (14 cm pathway, NS 14.5) provided the chloride F-2 ₄ as a colorless liquid in 79% yield with a bp. 40-42 °C and ratio //¾-2 ₄ of >98:2 as indicated by ¹ H-N MR (27.44 g, 158.9 mmol).

Entry 3: As described in general procedure I II (chapter 2.1.3) a solution of geraniol F-l ₄ (200 mmol, 1.0 equiv) and methylformamide (MF, 1.18 mL, 1.19 g, 20.0 mmol, 10 mol%) in MTBE (100 mL, 2 M) was treated with benzoyl chloride (23.8 mL, 28.82 g, 203 mmol, 1.015 equiv) at 0 °C. After stirring for 1.5 h at 0 °C and overnight at room temperature (16 h), the pale yellow reaction suspension was concentrated (95% conversion according to ¹ H-NM R) and allowed to reacted for 3.5 h at ambient temperature, whereupon reaction control ( ¹ H-N MR) proved full conversion. Fractioned distillation of the crude material (37.20 g, F-2 ₄ /F-3 ₄ 93:7, //6-2 ₄ 97:3) after work up at 0.18 mbar through a micro distillation apparatus with Vigreux column (14 cm pathway, NS 14.5) delivered the chloride /-/F-2 ₄ as a virtually pure regioisomer (l/b >98:2, 27.96 g, 161.9 mmol, 81%) with a bp. of 60-62 °C.

Entry 4: As given in general procedure I II (chapter 2.1.3) geraniol F-l ₄ (200 mmol, 1.0 equiv) was allowed to react with benzoyl chloride (23.9 mL, 28.97 g, 204 mmol, 1.02 equiv) in the presence of DMF (1.55 mL, 1.46 g, 20.0 mmol, 10 mol%) in MTBE (100 mL, 2 M) overnight (13.5 h). The resulting yellow reaction solution was concentrated under reduced pressure (93% conversion as indicated by ¹ H-NM ) and stirred for 7 h at ambient temperature. After work up ¹ H-NMR of the crude material (37.59 g, E-2 ₄ /E-3 ₄ 89:11, //¾-2 ₄ 96:4) proved full conversion. In the following fraction distillation at 0.16 mbar through a micro distillation apparatus with Vigreux column (14 cm pathway, NS 14.5) allowed to isolate the desired product E-2 ₄ in 76% yield as a colorless liquid with a bp. of 56-58 °C (26.35 g, 152.7 mmol, //¾-2 ₄ 97:3).

Entry 5: According to general procedure III (chapter 2.1.3) in a 250 mL flask to a mixture of geraniol E-l ₄ (200 mmol, l.O equiv) and DMF (60.0 mmol, 30 mol%) was added benzoyl chloride (28.4 mL, 23.47 g, 200 mmol, l.O equiv) slowly within 1.75 h under ice bath cooling, whereby after 1.5 h benzoic acid started to precipitate. After further 30 min of stirring, the cooling bath was removed and reaction suspension was allowed to stir for 3 h at ambient temperature. Monitoring by ¹ H-NMR showed 97% conversion after 1 h of stirring at room temperature and full consumption of the starting material 1 ₄ after 2.5 h. Work up provided the crude chloride 2 ₄ (36.12 g) as yellow oil with a ratios E-2 ₄ /E-3 ₄ 91:9 and //¾-2 ₄ 96:4 as judged by ¹ H-NMR. Fractioned distillation through a micro distillation apparatus with Vigreux column (14 cm pathway, NS 14.5) lead to the isolation of the desired product E-2 ₄ in 71% yield (24.42 g, 141.4 mmol, l/b≥ 98:2) as a colorless liquid with a bp. of 69-71 °C at 0.4 mbar. Additionally a prefraction was collected (1.247 g, 7.22 mmol, 4%) with a bp. of 67-69 °C and a ratio of regioisomers of 78:22 appearing as colorless a oil.

Entry 6: Following general procedure I (chapter 2.1.1) geraniol E-l ₄ (178 μί, 156 mg, 1.00 mmol, l.O equiv), FPyr (9.8 μΐ, 10.2 mg, 0.10 mmol, 10 mol%), MTBE (0.5 mL, 2 M) and BzCI (129 μΐ, 156 mg, 1.10 mmol, 1.1 equiv) were combined and stirred for 18 h at ambient temperature. ¹ H-NMR of the crude product with naphthalene showed chloride E-2 ₄ in 83% yield and a ratio of regioisomers //¾-2 ₄ of >98:2.

M (C ₁₀ H ₁₇ CI) = 172.70 g/mol

4.4.3.3 Synthesis of Z-l-Chloro-3,7-dimethyl-2,6-octadien (Neryl Chloride Z-2 ₄ )

scale l/b yield entry conditions

[mmol] crude/isolated ³ 2i

BzCi (1.01 equiv), FPyr (10 mol%), MTBE (2 M),

97:3/>98:2 79% ^x

1.25 h 0 °, 17 h rt

BzCi (1.1 equiv), FPyr (10 mol%), MTBE (2 M),

>98:2 74% ² 0.25 h 0 °, 17 h rt

1. Isolated yield 2. Yield determined via NMR-Standard. 3. Determined by ¹ H-NMR. Entry 1: According to general procedure III (chapter 2.1.3) Z-3,7-dimethyl-2,6-

4 octadien-l-ol (nerol Z-l ₄ , 90 mL, 78.70 g, 500 mmol, l.O equiv) and FPyr (4.9 mL; 5 5.11 g, 50.0 mmol, 10 mol%) were dissolved in MTBE (250 mL, 2 M) in a 1 L one necked flask with a strong stir bar. Next the reaction solution was cooled in an ice

bath and benzoyl chloride (59 mL, 71.70 g, 505 mmol, 1.01 equiv) was added l-Z-2,

dropwise via a dropping funnel within 45 min. After further 30 min of stirring the cooling bath was removed and the reaction solution was allowed to stir overnight (13 h). Then the resulting yellow reaction suspension was concentrated under reduced pressure (180 mL of MTBE were reisolated and utilized for the work up) and dried at 150 mbar for 5 min. ¹ H-NM of a small aliquot of the reaction mixture

(ca. 10 mg) showed 95% conversion. After 5 h of further stirring at ambient

6-2 ₄

temperature reaction control through ¹ H-NMR indicated full consumption of the starting alcohol Z-l ₄ . In the following the reaction mixture was diluted with MTBE (250 mL, MTBE/amount of starting material 1 0.5 mL/1 mmol), cooled to 0 °C and saturated, aqueous Na ₂ C0 ₃ -solution (150 mL, 0.3 mL/1 mmol of 1) was added dropwise within 15 min, whereby a weak C0 ₂ -evolution occured. The heterogeneous mixture was transferred to a 1 L extraction funnel and the reaction flask was rinsed with water (2 x 100 mL, 0.4 mL/1 mmol). To dissolve precipitated NaOBz the mixture was diluted with further water (150 mL, volume of the total aqueous phase = 1 mL/1 mmol of 1, pH = 7). Next the organic phase was washed with Na ₂ C0 ₃ -solution/water (1 x 100 mL, 0.2 mL/1 mmol, pH >10), dried over MgS0 ₄ , concentrated under reduced pressure and dried at 50 mbar for 10 min to yield the crude chloride 2 ₄ as a yellow oil (91.77 g). ¹ H-NMR proved full conversion, a chloride /-Z-2 ₄ to ester Z- 3 ₄ ratio of 95:5 and a regioisomer ratio /-/6-2 ₄ of 97:3.

Fractioned distillation through a micro distillation apparatus with a NS 29 cooling finger with Vigreux column (10 cm pathway, NS 29, vacuum-mantled and metal-coated) at 0.10 mbar delivered initially a prefraction with a bp. 41-52 °C (6.91 g, 40.0 mmol, 8%, colorless oil, oil bath temperature 85 °C) consisting of chloride Z-2 ₄ in a regioisomer ratio of 89:11 l/b. Gradually raising the oil bath temperature from 85 to 110 °C then delivered the chloride /-Z-2 ₄ as a colorless liquid with a bp. of 52- 54 °C (68.00 g, 393.7 mmol, 79%). Both ¹ H-NMR and GC-MS indicated a regioisomeric ratio /-/¾-2 ₄ >98:2. Further increasing the oil bath temperature to up to 130 °C lead to the collection of a small fraction with a bp. of ca. 52 °C (1.47 g, no continuous distillation) containing the product 2 ₄ as a pure regioisomer (>98:2 l/b) and most likely the formyl ester of nerol Z-7 ₄ (2 mol% referred to Z-2 ₄ ). Importantly, the collecting flasks were cooled in an ice bath. As no distillation dispenser was utilized, the collecting flasks were exchanged under interruption of heating and vacuum.

Entry 2: As described general procedure I (chapter 2.1.1) nerol Z-l ₄ (180 μί, 157 mg, 1.00 mmol, l.O equiv), FPyr (9.8 μΐ, 10.2 mg, 0.10 mmol, 10 mol%), MTBE (0.5 mL, 2 M) and BzCI (129 μί,

156 mg, 1.10 mmol, 1.1 equiv) were combined and stirred for 18 h at ambient temperature. ¹ H-NM of the crude product with naphthalene showed chloride Z-2 ₄ in 74% yield and a ratio of regioisomers

//¾-2 ₄ of >98:2.

M (C ₁₀ H ₁₇ CI) = 172.70 g/mol

4.4.3.4 Synthesis of E/Z-l-Chloro-3,7-dimethyl-2,6-octadien (E/Z-2 ₄ )

According to general procedure III (chapter 2.1.3) in a 250 mL flask to a mixture of Linalool 6-l ₄ (rac-3,7-dimethyl-l,6-octadien-3-ol, 36.6 mL, 31.48 g, 200 mmol, l.O equiv) and DMF (4.6 mL, 4.39 g, 60.0 mmol, 30 mol%) was added benzoyl chloride (23.7 mL, 28.68 g, 200 mmol, 1.01 equiv) within 10 min under cooling to

/-E/Z-2 ₄

0 °C. After further 15 min of stirring, the cooling bath was removed and reaction suspension was allowed to stir for 15 h at ambient temperature, whereupon reaction control via ¹ H-NMR revealed a conversion of 68%. Thus the reaction suspension was stirred for further 12 h at 40 °C. Monitoring by ¹ H-NMR showed 90% conversion after 6 h of stirring at room temperature and > 96% after 11.5 h. In the following the brownish reaction suspension was diluted with MTBE (100 mL, MTBE/amount of starting material 1 0.5 mL/1 mmol), cooled to 0 °C and saturated, aqueous Na ₂ C0 ₃ -solution (60 mL, 0.3 mL/1 mmol of 1) was added dropwise within 5 min, whereby a weak C0 ₂ -evolution occured. The heterogeneous mixture was transferred to a 0.5 L extraction funnel and the reaction flask was rinsed with water (2 x 50 mL, 0.5 mL/1 mmol). To dissolve precipitated NaOBz the mixture was diluted with further water (40 mL, volume of the total aqueous phase 1 mL/1 mmol of 1, pH = 7-8). Afterwards the organic phase was washed with Na ₂ C0 ₃ -solution (1 x 40 mL, 0.2 mL/1 mmol, pH > 10), dried over MgS0 ₄ , concentrated under reduced pressure and dried at 50 mbar for 10 min to yield the crude chloride 2 ₄ as a brown yellow oil (37.64 g). ¹ H-NMR showed a regioisomer ratio /-/6-2 ₄ of 91:9 and a diastereomeric ratio /-E/Z-2 ₄ of 60:40.

Fractioned distillation through a micro distillation apparatus with Vigreux column (14 cm pathway, NS 14.5) lead to the isolation of the the chloride 2 ₄ in 67% yield (23.08 g, 133.9 mmol, l/b≥ 98:2) as a colorless liquid with a bp. of 49-50 °C at 0.11 mbar. ¹ H-NMR indicated a regioisomer ratio /-/6-2 ₄ of 96:4 and a diastereomeric ratio /-E/Z-2 ₄ of 58:42. Additionally a prefraction was collected (5.594 g) with a bp. of 29-54 °C at 0.14 mbar consisting of mycrene, benzoyl chloride, starting alcohol 6-l ₄ and the chloride /-/¾-2 ₄ in a ratio of 63:37.

4.4.3.5 Synthesis of f-l-Chloro-2-methyl-3-phenyl-2-propene (2 ₁₃ )

5 3 1 5 According to general procedure I I (chapter 2.1.2) £-2-methyl-3-phenyl-2- I j I propen-l-ol (li ₃ , 302 μί, 302 mg, 2.00 mmol, l.O equiv), DMF (15.5 μί,

^ 14.6 mg, 0.20 mmol, 10 mol%), dioxane (1 mL, 2 M) and benzoyl chloride

^E'2is (282 μί, 341 mg, 2.40 mmol, 1.2 equiv) were combined at 0 °C and than allowed to react for 24 h at room temperature. The crude material (445 mg) was next subjected to chromatographic purification (mass of crude material/Si0 ₂ 1:10) with Et ₂ 0//iPen 1:99 gave the allyl chloride E-2 ₁₃ as a colorless oil in 85% yield (285 mg, 1.71 mmol).

M (C ₁₀ H _U CI) = 166.64 g/mol; r _f (Si0 ₂ , Et ₂ 0//iPen 1:99) = 0.41 + 0.00 (+ 0.14 weak).

Synthesis of f-l-Chloro-3-phenyl-2-propene (Cinnamyl Chloride 2 ₁₄ )

BzCi (1.2 equiv), FPyr (20 mol%), dioxane

3 2 62%

(2 M), 0.25 h 0 °, 23 h rt, from 6-l ₁₄

1. Isolated yield 2. Yield determined via N M -Standard.

* Comparative Example

Cinnamyl chloride 2 _i4 was isolated in 94% yield with DMF in catalytic quantities (entry 1), while without any catalyst only small traces of this chloride were observed (9% according to N MR- standard, entry 2). However, also the regioisomeric starting material 6-li ₄ gave the linear chloride 2 _i4 in an S _w 2 ^' -substitution in 62% yield with 20 mol% FPyr (entry 3).

Entry 1: According to general procedure I I (chapter 2.1.2) f-3-phenyl-2-propen-l-ol (cinnamyl alcohol /-li ₄ , 263 μί, 274 mg, 2.00 mmol, 1.0 equiv) was allowed to react with benzoyl chloride (282 μί, 341 mg, 2.40 mmol, 1.2 equiv) in the presence of DM F (15.5 μί, 14.6 mg, 0.20 mmol, 10 mol%) in dioxane (1 mL, 2 M) for 23 h at room temperature. As indicated by ¹ H-N MR of the crude material (460 mg) full conversion and a chloride 2 _i4 to ester 3 _i4 ratio of 96:4 were reached. In the following chromatographic purification (mass of crude material/Si0 ₂ 1:10) with Et ₂ 0//iPen 2:98 gave the allyl chloride 2 _i4 as a colorless oil in 94% yield (286 mg, 1.87 mmol).

Entry 2: Following general procedure I (chapter 2.1.1) cinnamyl alcohol /-li ₄ (66 μί, 69 mg, 0.50 mmol, l.O equiv), dioxane (0.25 mL, 2 M) and benzoyl chloride (70.4 μί, 85.2 mg, 0.60 mmol, 1.2 equiv) were combined and stirred for 24 h at room temperature. ¹ H-NM of the crude material with naphthalene as standard proved chloride 2 _i4 in 9% yield alongside with 30% of the ester 3 _i4 and 41% of starting material correlating to 84% conversion and a ratio 2i ₄ /3i ₄ of 23:77.

from Entry 3: As described in general procedure II (chapter 2.1.2) l-phenyl-2-propen-l-ol b- i ₁₄ (268 mg, 2.00 mmol, 1.0 equiv), FPyr (39.3 μΐ, 40.9 mg, 0.40 mmol, 1.0 equiv) and BzCI (282 μί, 341 mg, 2.40 mmol, 1.2 equiv) were combined and allowed to react for 6-li 24 h at ambient temperature. Chromatographic purification of the crude material

(459 mg) on silica gel (mass crude material/Si0 ₂ 1:12) with Et ₂ 0//iPen 2:98 delivered the chloride 2 _i4 as a colorless oil (189.2 mg, 1.24 mmol, 62%).

M (C ₉ H ₉ CI) = 152.62 g/mol; r _f (Si0 ₂ , Et ₂ 0//iPen 2:98) = 0.42.

4.4.3.7 Synthesis of E-l-Chloro-2-octene (2i ₅ )

d entry

BzCi (1.2 equiv), DMF (10 mol%), dioxane (2 M),

1 2 >98/<2/<2 74% ^x

0.25 h 0 °, 24 h rt

BzCi (1.2 equiv), no catalyst, dioxane (2 M), 24 h

2 0.5 n.d. 5% ² * rt

BzCi (1.2 equiv), DMF (20 mol%), dioxane (2 M),

3 2 73/6/21 73%

24 h 80 °C, from b-l ₁₆

1. Isolated yield 2. Yield determined via NMR-Standard. 3. Determined by ¹ H-NMR.

* Comparative Example.

-E-2 ₁₅

l-Z-2, The linear trans-configured ally alcohol li ₅ (f-2-octen-l-ol) was transformed cleanly without isomerisation to the volatile chloride I-E-2 _1S in 74% (entry 1).

Without DM F in substoichiometric quantities the desired product was only formed in small traces (5%, entry 2). The corresponding branched starting alcohol

5 6-li5 (rac-l-octen-3-ol) however resulted (in the presence of 10 mol% DMF in a mixture of chlorides favouring the linear isomer l-2 ₁₆ (entry 3).

Entry 1: According to general procedure I I (chapter 2.1.2) f-2-ecten-l-ol [I-E-1 _1S , 308 μί, 262 mg, 2.00 mmol, 1.0 equiv) was converted with benzoyl chloride (282 μί, 341 mg, 2.40 mmol, 1.2 equiv) in the presence of DMF (15.5 μί, 14.6 mg, 0.20 mmol, 10 mol%) in dioxane (1 mL, 2 M) for 24 h at room temperature to the chloride 2 ₁₅ . ¹ H-N M of the crude material (360 mg) showed full conversion and a chloride 2 ₁₅ to ester 3i ₅ ratio of 94:6. Then chromatographic purification (mass of crude material/Si0 ₂ 1:10) with nPen provided the allyl chloride 2 ₁₅ as a colorless oil in 74% yield (216 mg, 1.47 mmol).

Entry 2: As described in general procedure I (chapter 2.1.1) the alcohol l-E-l ₁₅ (77 μί, 65 mg, 0.50 mmol, 1.0 equiv), dioxane (0.25 mL, 2 M) and benzoyl chloride (70.4 μί, 85.2 mg, 0.60 mmol, 1.2 equiv) were combined and stirred for 24 h at room temperature. ¹ H-N MR of the crude material with naphthalene as standard proved chloride 2 ₁₅ in 6% yield alongside with 38% of the ester 3i ₅ and 36% of starting material correlating to 56% conversion and a ratio 2 ₁₅ /3i ₅ of 11:89.

Entry 3: Following general procedure I I (chapter 2.1.2) l-octen-3-ol (6-li ₅ , 312 μί, 262 mg, 2.00 mmol, 1.0 equiv) was reacted with benzoyl chloride (282 μί, 341 mg, 2.40 mmol, 1.2 equiv) in the presence of DMF ( 15.5 μί, 14.6 mg, 0.20 mmol, 10 mol%) in fc ^"1 " dioxane (1 mL, 2 M) for 24 h at 80 °C. ¹ H-N MR of the crude material (360 mg) showed full conversion. Next chromatographic purification (mass of crude material/Si0 ₂ 1:12) with nPen provided the product 2 ₁₅ as a colorless oil in 73% yield (215 mg, 1.46 mmol). ¹ H-N MR showed a ratio of the isomeric chlorides l-E-2 ₁₅ / l-Z-2 ₁₅ / b-2 ₁₅ of 73:6:21 corresponding to at E/Z ratio of 92:8. The existence of these three isomers was proven additionally by GC-MS indicating three compounds with identical mass and similar fragmentation patterns in a ratio of 70:7:23.

M (C ₈ H ₁₅ CI) = 146.66 g/mol; r _f (Si0 ₂ , nPen) = 0.50.

4.4.3.8 Synthesis of Allyl Chloride (2 ₁₆ )

According to general procedure II I (chapter 2.1.3) a 100 mL flask with a strong stir bar

was charged with allyl alcohol li ₆ (13.8 mL, 11.73 g, 200 mmol, 1.0 equiv) and DMF 2

¹⁶ (4.6 mL, 4.39 g, 60.0 mmol, 30 mol%). The reaction solution was cooled in an ice bath and benzoyl chloride (24.6 mL, 29.82 g, 210 mmol, 1.05 equiv) was added slowly through a dropping funnel within 1.5 h. Then the cooling bath was removed and the mixture was allowed to stir for 4 h at room temperature, whereby benzoic acid started to precipitate (after 1 h). ¹ H-NM after 3.5 h of stirring at ambient temperature proved full consumption of the starting material li ₆ . The white reaction suspension was next subjected to distillation at 1 atm through a Claisen distillation bridge with a 20 cm water cooler to yield allyl chloride 2 ₁₆ as a colorless liquid with bp. of 41-42 °C (12.45 g, 162.3 mmol, 82%). Thereby the distillation apparatus was equipped with a KOH-drying tube and the collecting flask was cooled in an ice bath. To achieve complete separation of the product 2 ₁₆ from the reaction mixture the oil bath temperature had to be raised from 90 to 180 °C.

4.4.3.9 Synthesis of l-Chloro-2-butene (Crotyl chloride 2 ₁₇ )

3 1 According to general procedure III (chapter 2.1.3) a 100 mL flask with a strong stir bar was charged with 2-buten-l-ol (crotyl alcohol 1 ₁₇ 13.8 mL, 11.73 g, 200 mmol, 1.0 equiv, E/Z-l ₁₇ 96:4 according to ¹ H-NMR) and DMF (4.6 mL, 4.39 g, 60.0 mmol, 5 30 mol%). The reaction solution was cooled in an ice bath and benzoyl chloride (25.8 mL, 31.24 g, 220 mmol, 1.1 equiv) was added slowly through a dropping

funnel within 1 h. After 1 h of further stirring (after 15 min BzOH began to l-Z-2 n

crystallize) the cooling bath was removed and the mixture was allowed to stir for 1 h at room temperature, whereupon ¹ H-NMR showed full conversion of the

20 starting material li ₆ and a chloride 2 ₁₇ to ester 3 _i7 ratio of 88:12. In the following b-2 n fractioned distillation at 300 mbar (Distillation at 1 atm lead to significant formation of the regioisomer b-2 ₁₇ due to the higher temperature necessary for distillation (l/b-2 ₁₇ 94:6) (applied via a membrane pump) through a Claisen distillation bridge with a 20 cm water cooler delivered crotyl chloride 2 ₁₇ as a colorless liquid with bp. of 44-48 °C (13.96 g, 154.1 mmol, 77%, oil bath temperature 80-120 °C). ¹ H-NMR indicated a E/Z-2 ₁₇ ratio of 95:5 and not even a trace of the regioisomer b-2 ₁₇ (l/b ≤ 98:2). Increasing the oil bath temperature to up to 140 °C lead to the isolation of further product 2 ₁₇ in 5% yield as a colorless oil (834 mg, 9.3 mmol, no constant boiling point, E/Z-2 ₁₇ 94:6, l/b-2 ₁₇ (l/b≤ 98:2). Importantly the collecting flasks were cooled in an ice bath. M (C ₄ H ₇ CI) = 90.55 g/mol.

4.4.3.10 Synthesis of l-Chloro-3-methyl-2-butene (Prenyl chloride 2 ₁₈ )

scale yield entry conditions l/b-2 ₁₈ ³

[mmol]

BzCi (1.03 equiv), DMF (30 mol%), solvent- 1 500 95:5 ⁴ /93:7 ⁵ 70% ^x

free, 2.5 h 0 °, 3 h rt BzCi (1.05 equiv), FPip (20 mol%), solvent-

200 92:8 ⁴ /94:6 ⁵ 67% ^x

free, 3 h 0 °, 1.5 h rt

BzCI (1.03 equiv), DM F (30 mol%), solvent-

1000 83:17/>98:2 ⁶ 79% ^x

free, 2 h 0 °, 15 h rt, from 6-li ₈

BzCI (1.03 equiv), no catalyst, solvent-free, 7 h

87:13 9% ² 40 °C, from 6-l ₁₈

1. Isolated yield 2. Yield determined via N MR-Standard. 3. Determined by ¹ H-N MR. 4. Before distillation. 5. After distillation. 6. After a 2nd distillation.

* Comparative Example.

1 ^' On a 500 mmol scale prenol -li ₈ (3-methyl-2-butenol) was converted to prenyl

3l 1

^^V^CI chloride 2 ₁₈ as a 93:7 mixture of //b-regioisomers in 70% yield (entry 1). FPip 2

(20 mol%) allowed the synthesis of prenyl chloride 2 _1S in a similar efficiency (entry

/-2 ₁₈

5 2), but was not partially codistilled with the product. Thus the distillate had not to be washed with water as for entry 1. On a 1000 mmol scale the inexpensive tertiary alcohol 6-li ₈ (cheaper than prenol /-li ₈ !) was effectively isomerized to give prenyl chloride 2 _1S (l/b 83:17) in 79% yield (entry 3). A second distillation allowed an enrichment of the desired regioisomer to a ratio >98:2. In the absence of a formamide catalyst the desired chloride 2 _1S was only obtained in traces (9%, entry

4).

Entry 1: According to general procedure I II (chapter 2.1.3) a 250 mL flask with a strong stir bar was charged with 3-methyl-2-buten-l-ol (prenol l-l ₁₈ , 51.3 mL, 43.50 g, 500 mmol, 1.0 equiv) and DMF (11.6 mL, 4.39 g, 60.0 mmol, 30 mol%). Then the mixture was cooled in an ice bath and benzoyl chloride (60.4 mL, 73.13 g, 515 mmol, 1.03 equiv) was added with the aid of a dropping funnel throughout 2.5 h, whereby BzOH began to precipitate after 1.5 h. After 0.5 h of further stirring the ice bath was removed and the reaction suspension was stirred for 3 h at room temperature. ¹ H-NMR of a small aliquot of the reaction mixture (ca. 10 mg) proved full consumption of starting material 1 _1S , a chloride I-2 _1S to ester 3 _i8 ratio of 92:8 and a regioisomer ratio l/b-2 _is of 95:5. Next distillation at lOO mbar (applied via a membrane pump) through a Claisen distillation bridge with a 20 cm water cooler delivered prenyl chloride 2 _1S as a colorless emulsion with a bp. of 37-42 °C (39.12 g, oil bath temperature 95-120 °C) and residual trace amounts of DMF according to ¹ H-N MR. Noteworthy, the collecting flask was cooled in an ice bath. To remove DMF and acid traces the mixture was washed in a 100 mL extraction funnel with brine/water (10/10 mL), water (20 mL) and finally brine/saturated, aqueous NaHC0 ₃ solution (10/10 mL). After drying over MgS0 ₄ prenyl chloride 2 _1S was isolated as a colorless oil in 70% yield (36.80 g, 351.80 mmol) and a regioisomer ratio l/b-2 _is of 93:7 as judged by ¹ H-NMR.

Entry 2: Following general procedure III (chapter 2.1.3) to a mixture of alcohol -li ₈ (20.5 mL, 17.40 g, 200 mmol, 1.0 equiv) and /V-formyl piperidine (4.5 mL, 4.57 g, 40 mmol, 20 mol%) was added benzoyl chloride (24.6 mL, 29.82 g, 210 mmol, 1.05 equiv) at 0 °C within 1.5 h. After further 1.5 h of stirring the ice bath was removed and the reaction suspension was stirred for 1.5 h at ambient temperature to reach full conversion. Additionally ¹ H-NMR showed a ratio of the chloride I-2 _1S to the ester /-3i ₈ of 87:13 and a regioisomer ratio l/b-2 _ls of 92:8. Distillation at 150 mbar then provided the chloride 2 _1S with a bp. of 38-48 °C in a yield of 68% (14.09 g, 134.7 mmol, 67%) as a colorless liquid without codistillation of the catalyst (l/b-2 ₁₈ 94:6).

Entry 3: According to general procedure III (chapter 2.1.3) a one-necked 0.5 L flask with a strong stir bar was charged with 2-methyl-3-buten-2-ol (6-li ₈ , 106.6 mL, 87.9 g, 1000 mmol, 1.0 equiv) and DMF (23.2 mL, 21.9 g, 300 mmol, 30 mol%). The reaction solution was cooled in an ice bath and benzoyl chloride (121 mL, 146.3 g, 1030 mmol, 1.03 equiv) was added dropwise within 1.75 h via a dropping funnel. The clear reaction solution was stirred for further 15 min at 0 °C, the cooling bath was removed, the dropping funnel was replaced by an internal thermometer with quick-fit and the reaction mixture was allowed to stir at ambient temperature. After 2 h the internal temperature had raised to 50 °C. Thus the reaction mixture was cooled for 5 min in an ice bath to decrease the internal temperature to 20 °C accompanied by precipitation of benzoic acid. As reaction control indicated 72% conversion only ( ¹ H-NMR) the reaction suspension was allowed to stir overnight (13 h), whereupon ¹ H-NMR proved full consumption of the starting material li ₈ and a regioisomeric ratio of 83:17.

Distillation at 100 mbar (membrane pump) through a Claisen bridge with a 20 cm water cooler lead to the isolation of a distillate (85.52 g) with a bp. of 26-48 °C appearing as a colorless emulsion (oil bath temperature 80-100 °C). To remove residual DMF the neat distillate was washed in a 250 mL extraction funnel with brine/water (10/20 mL), water (30 mL) and a mixture of saturated, aqueous NaHC0 ₃ -solution and brine (10/20 mL) and dried over MgS0 ₄ to yield the desired chloride 2 _1S as a colorless oil (82.39 g, 787.6 mmol, 79%, l/b-2 ₁₈ 83:17).

In order to separate the regioisomers the mixture was subjected to fractioned distillation at 400 mbar (membrane pump) through a Vigreux column (10 cm pathway, NS 29, vacuum mantled, metal coated) with a micro distillation apparatus with NS 29 cooling finger. Initially a fraction with the bp. of 41-79 °C was collected consisting out of a 56:44 mixture of the regioisomers l/b-2 _is (14.83 g, oil bath temperature 90-115 °C). Further increasing the oil bath temperature to up to 140 °C delivered prenyl chloride I-2 _1S as a virtually pure regioisomer (l/b ≥ 98:2) in 58% yield (60.53 g, 578.7 mmol) appearing as a colorless liquid. A second fractioned distillation of the first fraction at 400 mbar through a Vigreux column (14 cm pathway, NS 14.5) provided a second batch of prenyl chloride 2 ₁₈ with bp. of 83-84 °C (6.482 g, 62.0 mmol, 6%, l/b≥ 98:2). Alongside a fraction with the bp. of 51-54 °C was collected containing mainly the branched chloride b-2 _is (4.78 g, 45.7 mmol, 5%, l/b 3:97)

Entry 4: In alignment to general procedure I (chapter 2.1.1) the tertiary alcohol 6-li ₈ (107 μί, 88 mg, 1 mmol, 1.0 equiv) and benzoyl chloride (129 μί, 156 mg, 1.10 mmol, 1.1 equiv) were combined and stirred for 7 h at 40 °C. ¹ H-N MR of the reaction mixture (no work up !) with naphthalene as standard showed chloride 2 _i4 in 9% yield (l/b-2 _is = 87:13) alongside with 72% of starting material 6-li ₈ correlating to 13% conversion.

4.4.3.11 Synthesis of l-Chloro-2-decyne (2 ₁₉ )

According to general procedure I I (chapter 2.1.2) 2-octyn-l-ol (li ₉ , 373 μί,

318 mg, 2.00 mmol, 1.0 equiv) was treated with benzoyl chloride (282 μί, 341 mg, 2.40 mmol, 1.2 equiv) in the presence of DMF (15.5 μί, 14.6 mg, 0.20 mmol, 10 mol%) in dioxane (1 mL, 2 M) and allowed to react for 22.5 h at

2 ₁₉ room temperature. ¹ H-N MR of the crude material (463 mg) showed full conversion and a chloride 2 ₁₅ to ester 3i ₅ ratio of > 98:2. Next chromatographic purification (mass of crude material/Si0 ₂ 1:11) with nPen provided the propargylic chloride 2 ₁ as a colorless oil in 80% yield (277 mg, 1.60 mmol).

M (C ₁₀ H ₁₇ CI) = 172.70 g/mol; r _f (Si0 ₂ , nPen) = 0.56.

4.4.3.12 Synthesis of l-Chloro-2-propine (propargyl chloride 2 ₂₀ )

l 25 According to general procedure I II (chapter 2.1.3) to a mixture of propargyl alcohol li ₆ 3 ^^ "C\ (11.9 mL, 11.33 g, 200 mmol, 1.0 equiv) and DMF (4.6 mL, 4.39 g, 60.0 mmol,

2 ₂₀ 30 mol%) in a 100 mL flask with a strong stir bar was added at 0 °C benzoyl chloride

(24.6 mL, 29.82 g, 210 mmol, 1.05 equiv) through a dropping funnel within 1 h, whereby benzoic acid started to precipitate quickly. After stirring for further 15 min the cooling bath was removed and the reaction mixture was allowed to stir overnight (13 h), where after ¹ H-N MR indicated full conversion and a ratio 2 ₂ o/3 ₂ o of 90:10 ( ¹ H-N MR after 4 h revealed 85% conversion only). In the following the resulting brown suspension was subjected to distillation at 1 atm through a Claisen distillation bridge with a 20 cm water cooler to yield propargyl chloride 2 ₂ o as a colorless liquid with a bp. of 50-54 °C (11.11 g, 149.0 mmol, 75%). Thereby the distillation apparatus was equipped with a KOH-drying tube and the collecting flask was cooled in an ice bath. To effect complete separation of the product 2 ₁₆ from the reaction mixture the oil bath temperature had to be raised from 100 to 180 °C during distillation.

M (C3H3CI) = 75.51 g/mol.

4.4.4 Synthesis of Secondary Benzylic, Allylic and Propargylic Chlorides

The following scheme provides an overview over secondary benzylic, allylic and propargylic chlorides synthesized by formamide catalyzed chlorinations. Deviations from standard conditions are given in parenthesis:

Standard Conditions

in dioxane (2 M): BzCI (1 .2 equiv), FPyr (20 mol%), <24 h rt 200 mmol scale solvent-free: BzCI (1.00-1.05 equiv), DMF (30 mol%), <24 h rt

rac-2 ₃ 2 ₂₁ 89% (R = Et) 2 ₂₅ 2 ₂₇

90% (in MTBE)* 2 ₂₂ 79% (R = ;Pr, 50 ' 75% (10 mol% FPyr) 77% (b/l 97:3)

86% (in acetone) ^*

84% (10 mol% FPyr, in MTBE)

70% (solvent-free) ^* Ar .

CI 2 ₂₃ 81 % (R 2 ₂ 6 ' ₂ 8

2 ₂₄ 80% (R = 1 -Naph) 90% (10 mol% FPyr, 80 °C) 77% (40 °C)

PrT ^

R-2 _Z from S-1 ₃

81 % (in MTBE, er = 97.5:2.5)

4.4.4.1 Synthesis of roc-l-Chloro-l-phenylethane (rac-2 ₃ )

BzCi (1.02 equiv), FPyr (20 mol%), 2-MeTHF (2 M),

200 89% ¹

0.75 h 0 °, 16 h rt

BzCi (1.01 equiv), FPyr (20 mol%), acetone (2 M),

200 86% ¹

0.75 h 0 °, 17 h rt

BzCi (1.00 equiv), FPyr (10 mol%), Et ₂ 0 (2 M),

200 84%

0.75 h 0 °, 16 h rt, 6 h 60 °C

IsophthaloylC (0.6 equiv), FPyr (20 mol%), MTBE

5 200 81%

(2 M), 0.5 h 0 °, 24 h rt

6 200 BzCi (1.00 equiv), DMF (30 mol%), solvent-free 70% ^x (2 M), 1.25 h 0 °, 8 h rt

BzCi (1.2 equiv), no catalyst, dioxane (2 M), 24 h

7 0.5 <2% ² *

0 °, 40 °C

1. Isolated yield 2. Yield determined via NM -Standard.

* Comparative Example.

With 20 mol% FPyr in MTBE racemic phenylethyl chloride 2 ₂ was isolated in 90% yield through straightforward distillation from the reaction mixture (entry 1). Instead of in MTBE this chlorination could also be conducted in 2-MeTHF and even more environmentally-friendly acetone to furnish chloride 2 ₃ in 86-89% yield (entry 2+3). The catalyst loading could be reduced to 10 mol% FPyr, too, affording heating to 60 °C to achieve full conversion (entry 4). M oreover, instead of BzCI 0.6 equiv of isophthaloyl chloride were sufficient enough, to reach full consumption of the starting material 1 ₃ and deliver the desired chloride in 81% yield (entry 5). Finally, in a solvent-free version in the presence of 30 mol% DMF the benzyl chloride 2 ₃ was attained in a yield of 70% (entry 6). Here the yield is slightly decreased, because DMF, which had been codistilled with the product, had to be removed by washing of the distillate with water. Meaningfully, all reactions presented in entry 1-6 were conducted on a reasonable 200 mmol scale. Indeed not even a trace of phenylethyl chloride 2ι _¾ was detected in the absence of a catalyst (entry 7). Entry 1: According to general procedure III (chapter 2.1.3) a 250 mL flask with a strong stir bar was charged with racemic 1-phenylethanol (rac-l ₃ , 24.7 mL, 24.93 g, 200 mmol, 1.0 equiv), FPyr (3.9 mL, 4.09 g, 40.0 mmol, 20 mol%) and MTBE (100 mL, 2 M). The resulting mixture was cooled in an ice bath and benzoyl chloride (23.8 mL; 28.82 g, 203 mmol, 1.015 equiv) (Utilisation of benzoyl chloride in exact stoichiometric amounts was crucial, as an excess of BzCI was codistilled with the product 2 ₃ . In case of residual BzCI in the distillate, quenching with ethanolamine (2.5 equiv of BzCI amount) and washing with water as described in entry 2 provided the pure chloride 2 ₃ ) was added within 0.5 h. After 0.5 h of further stirring the cooling bath was removed and the reaction solution was stirred overnight (12 h). Then the mixture was concentrated under reduced pressure, dried for 5 min at 150 mbar and stirred for further 9 h at room temperature accompanied by the precipitation of BzOH. Monitoring of the reaction progress via ¹ H-NMR showed a conversion of 86% after concentration, 97% after 6 h and >98% after 9 h of further stirring and a ratio of the chloride 2 ₃ to the ester 3 ₃ of 97:3.

Straightforward distillation at 0.8 mbar (Distillation at higher pressures (e.g. 4 mbar) lead to formation of styrene 5 ₃ as byproduct through thermal HCI-elimination) through a micro distillation apparatus without dispenser provided the chloride 2 ₃ with a bp. of 53-62 °C as a colorless liquid in 90% yield (25.272, 180 mmol). In order to completely separate the product from the reaction mixture the oil bath temperature had to be increased from 85 to 140 °C. To prevent evaporation of the distillate the collecting flask was cooled in an ice bath.

Entry 2: According to general procedure III (chapter 2.1.3) 1-phenylethanol (rac-l ₃ , 200 mmol, 1.0 equiv), FPyr (40.0 mmol, 20 mol%), 2-MeTHF (100 mL, 2 M) and benzoyl chloride (23.9 mL; 28.97 g, 203 mmol, 1.015 equiv) were combined. After stirring overnight (15 h), concentration under reduced pressure ( ¹ H-NM revealed 90% conversion) and stirring for further 5 h at room temperature full consumption of the starting alcohol 1 ₃ was indicated by ¹ H-NMR (2 ₃ /3 ₃ >98:2). The resulting suspension was subjected to fractioned distillation at 0.9 mbar through a micro distillation apparatus without dispenser. With a bp. of 52-57 °C the chloride 2 ₃ was isolated as a colorless oil in a yield of 89% (24.924 g, 177.3 mmol; oil bath temperature 85-150 °C). Beside a small prefraction (476 mg) with a bp. of 32-25 °C was collected containing the product 2 ₃ and traces of styrene and 2- MeTHF.

As ¹ H-NMR of the distillate showed traces of BzCI and FPyr at the detection limit of the NMR (<2 mol% -> <4 mmol), the neat distillate was cooled in an ice bath and 2-ethanolamine (310 μί, 5.00 mmol) was added under vigorous stirring accompanied by a solid precipiate. After 10 min of stirring at 0 °C, the mixture was washed in a 60 mL syringe with water (2 x 20 mL, lower phase organic!) and saturated, aqueous NaHC0 ₃ -solution/brine (lO mL/lO mL, upper layer organic!) and dried over MgS0 ₄ to finally yield the chloride 2 ₃ as a colorless oil (22.67 g, 161.2 mmol, 81%).

Entry 3: According to general procedure III (chapter 2.1.3) a solution of 1-phenylethanol (rac-l ₃ , 200 mmol, 1.0 equiv), FPyr (40.0 mmol, 20 mol%) in acetone (reagent-grade, 100 mL, 2 M) was treated with benzoyl chloride (23.7 mL; 28.68 g, 202 mmol, 1.01 equiv) at 0 °C for 0.5 h. After stirring overnight (10 h), concentration under reduced pressure ( ¹ H-NMR showed 90% conversion) and stirring for further 7 h at room temperature full conversion was revealed by ¹ H-NMR (2 ₃ /3 ₃ 95:5). Fractioned distillation at 0.8 mbar provided the chloride 2 ₃ in a yield of 86% as a colorless liquid (24.10 g, 171.4 mmol) with a bp. of 51-57 °C (oil bath temperature 80-140 °C). Alongside a prefraction with a bp. of 45-50 °C was obtained consisting of the product 2 ₃ and styrene in a ratio of 81:19 (599 mg).

Entry 4: As described in general procedure III (chapter 2.1.3) to a solution of 1-phenylethanol (rac-l ₃ , 200 mmol, 1.0 equiv), FPyr (2.0 mL, 1.97 g, 40.0 mmol, 10 mol%) in Et ₂ 0 (MTBE had to be replaced in this case by Et ₂ 0 as it partially decomposed by heating to 60 °C. This in term lead to the consumption of BzCI. Thus full conversion was only achieved in the presence of an excess of BzCI leaving an excess of this reagent behind, which was not separable via distillation) (100 mL, 2 M) was added benzoyl chloride (23.5 mL; 28.40 g, 200 mmol, 1.0 equiv) at 0 °C within 20 min. After stirring overnight (12 h) the reaction solution was concentrated (73% conversion) and the resulting suspension was stirred for further 4.5 h at ambient temperature. As ¹ H-NM indicated incomplete consumption of the starting material (91% conversion), the reaction suspension was heated to 60 °C for 7 h finally reaching full conversion (2 ₃ /3 ₃ 95:5). Distillation at 0.9 mbar through a micro distillation apparatus without dispenser delivered the product 2 ₃ as a colorless oil in 84% yield (23.711 g, 168.6 mmol; oil bath temperature 80-140 °C, bp. 52-58 °C).

Entry 5: According to general procedure III (chapter 2.1.3) benzylic alcohol 1 ₃ (200.0 mmol, 1.0 equiv) and FPyr (3.9 mL, 4.09 g, 40.0 mmol, 20 mol%) were dissolved in MTBE (50 mL, 4 M) in a 500 mL flask. Isophthalic acid chloride was melted at 50 °C in a water bath (of a rotatory evaporator), weighed into to 250 mL flask (17.7 mL, 24.61 g, 120.0 mmol, 0.6 equiv) with the aid of a pipette preheated to 80 °C (in an oven) and dissolved in MTBE (50 mL, [1 ₃ ] = 2 M) under warming to 50 °C. This solution was added under cooling to 0 °C within 30 min to the solution of the substrate 1 ₃ . After 15 min of further stirring, the ice bath was removed and the reaction solution was allowed to stir for 24 h at ambient temperature, whereupon reaction control via ¹ H-NMR revealed full conversion (A small aliquot of the reaction suspension (ca. 100 μί) was concentrated under reduced pressure, diluted with CDCI ₃ (600 μί) and filtered through a small plug of wool). Thereby isophthalic acid started to precipitate after 1.5 h of stirring. To separate isophthalic acid the reaction mixture was cooled in an ice bath and saturated, aqueous Na ₂ C0 ₃ solution (80 mL) was added dropwise accompanied by a week C0 ₂ evolution (With isophthaloyl chloride a work up was mandatory to separate isophthalic acid, as concentration of the reaction mixture yielded a basically solid residue, which was impossible to stir and thus to distill). The mixture was transferred to a 500 mL extraction funnel and water (160 mL) was added to improve phase separation and dissolve all solids (pH of the aq. phase ca. 7). Then the organic phase was washed successively with water (40 mL) and Na ₂ C0 ₃ -solution (40 mL), whereby during Na ₂ C0 ₃ - washing water (40 mL) had to be added to improve the phase separation (pH of the aq. phase > 10). After drying of the organic phase over MgS0 ₄ , concentration under reduced pressure (->150 mbar) and drying at 150 mbar for 5 min crude chloride 2 ₃ was obtained as a colorless oil (30.54 g). Distillation at 0.9 mbar provided chloride 2 ₃ as a colorless liquid in 81% yield (22.67 g, 161.3 mmol) with a boiling point of 51-54 °C. Thereby the oil bath temperature was raised gradually form 80 to 90 °C.

Entry 6: As given in general procedure III (chapter 2.1.3) in a 250 mL flask a mixture of 1- phenylethanol (rac-l ₃ , 200 mmol, 1.0 equiv) and DMF (9.3 mL, 8.77 g, 60 mmol, 30 mol%) was treated with benzoyl chloride (23.5 mL; 28.40 g, 200 mmol, 1.0 equiv) at 0 °C within 1 h. After stirring for 15 min the cooling bath was removed and the reaction sol ution was stirred until reaction control via ¹ H-N M indicated full conversion (8 h, 2 ₃ /3 ₃ 96:4). The resulting suspension was subjected to distillation at l.O mbar through a micro distillation apparatus to give a colorless liquid (25.99 g, bp. 48-58 °C), which contained the chloride 2 ₃ alongside with 36 mol% of DMF and 3 mol% of BzCI (< 6.0 mmol) according to ¹ H-N MR. To remove the catalyst and the excess of reagent the neat distillate was cooled to 0 °C and under vigorous stirring 2-ethanolamine (850 μί, 13.7 mmol, 2.3 equiv of BzCI) was added. Then the mixture was washed and dried as described for entry 2, PH1024 to yield the product 2 ₃ as a colorless oil (19.62 g, 139.5 mmol, 70%).

Entry 7: In alignment to general procedure I (chapter 2.1.1) phenylethanol 1 ₃ (61 μί, 62 mg, 0.50 mmol, 1.0 equiv) and benzoyl chloride (70 μί, 85 mg, 0.60 mmol, 1.2 equiv) were combined and stirred for 24 h at 40 °C. ¹ H-N MR of the crude material with naphthalene as standard showed no trace of the chloride 2 ₃ (<2%). Instead starting material 1 ₃ (61% yield) and the ester 3 ₃ (6%) were detected.

M (CgHgCI) = 140.61 g/mol.

4.4.4.2 Synthesis of R-l-Chloro-l-phenylethane [R-2 ₃ )

9' scale

JL entry conditi

PIT ^ [mmol]

BzCi (1.5 equiv), FPyr (20 mol%), MTBE (1 M),

2 97.5:2.5 81% ^x

2 h 0 °C, 24 h rt

BzCi (1.2 equiv), FPyr (20 mol%), MTBE

2 97.0:3.0 84% ^x

(1.3 M), 2 h 0 °C, 24 h rt

Entry 1: As given in general procedure II (chapter 2.1.2) a solution of enantioenriched phenylethanol S-l ₃ (247 μΐ, 249 mg, 2.00 mmol, 1.0 equiv; er > 99.5:0.5 according to chiral H PLC and GC, see below), FPyr (39 μΐ, 41 mg, 0.40 mmol, 20 mol%) in MTBE (2 mL, 1 M) was cooled to 0 °C and treated dropwise with benzoyl chloride (350 μί, 3.00 mmol, 1.5 equiv) via syringe in 5 min. After 2 h of stirring at 0 °C the cooling bath was removed an the reaction mixture was allowed to stir for 24 h at room temperature. Next under at ambient temperature ethanolamine (244 μί, 4.00 mmol, 2.0 equiv) (In MTBE and Et ₂ 0 larger amounts of ethanol amine were required to quench the excess of BzCI as in dioxane. This might be related to the lower solu bility of ammonium salts (e.g. BzO ^{" +} H ₃ N EtOH) in the first two solvents) was added accompanied by the formation of a precipitate. After 0.5 h of stirring TLC control revealed full consumption of BzCI and the work up was continued as described in the general procedure I I, whereby in deviation the crude chloride 2 ₃ was dried at the rotatory evaporator at 100 mbar for 2 min. Chiral GC analysis of the crude material (325 mg) indicated an er of 97.5:2.5 (see below for gas chromatography). ¹ H-N M showed >98% conversion and a ratio 2 ₃ /3 ₃ of 97:3. Finally chromatographic purification (mass crude material/Si0 ₂ 1:8!) (To utilize small amounts of silica gel is utmost important, as larger amounts lead to an erosion of the enantiopurity. Indeed, stirring of an enantioentriched batch of R-2 ₃ (er = 91:9) as a solution in nPen with silica gel overnight lead to complete racemisation (beside a significant loss of material due to adsorption on Si0 ₂ was observed)) with Et ₂ 0//iPen 0.5:99.5 delivered the chloride R-2 ₃ as a colorless oil in 81% yield (226 mg, 1.61 mmol). GC-analysis revealed an er of 97.5:2.5.

Entry 2: According to general procedure I I (chapter 2.1.2) and as described for entry 1 alcohol S-l ₃ (2.00 mmol, l.O equiv), FPyr (0.40 mmol, 20 mol%), MTBE (1.5 mL, 1.3 M) and BzCI (280 μΐ, 2.40 mmol, 1.2 equiv) were combined at 0 °C and stirred of at this temperature for 2 h. After further 24 h of stirring at room temperature the reaction mixture was treated with 2-ethanol amine (184 μί, 3.00 mmol, 1.5 equiv). Past continuing the work up as given in general procedure I I chiral GC showed an er of 97.0:3.0 of the crude product (306 mg, >98% conversion, 2 ₃ /3 ₃ 97:3 according to N MR). Chromatographic purification (mass of crude material/Si0 ₂ 1:10) with Et ₂ 0//iPen 0.5:99.5 provided the chloride R-2 ₃ as a colorless oil in an enantiopurity er = 97.0:3.0 (chiral GC) and a yield of 84% (235 mg, 84%).

r _f (Si0 ₂ , Et ₂ 0//iPen 0.5:99.5) = 0.54 (+0.00); [ct] _D ²⁰ = +108.0 (c = 0.88 g/100 mL, CDCI ₃ ). The separation conditions for determination of the enantiomeric ratio through chiral gas chromatography with regard to 2 ₃ were: Column CP-Chirasil-Dex CB; Temperature program 90 °C for 30 min, gradient 20 °C/min to 200 °C, 200 °C for 10 min, column flow 1.5 mL/min, split ratio 50; temperature program PTC injector: gradient 50 °C/min from 30 to 250 °C, 20 min 250 °C. Samples of a concentration of 2 mg/1 mL DCM were injected (1 μί injection volume).

The separation conditions with regard to 1 ₃ were: Column CP-Chirasil-Dex CB; Temperature program 110 °C for 30 min, gradient 20 °C/min to 200 °C, 200 °C for 10 min, column flow 1.5 mL/min, split ratio 10; PTV injector temperature 250 °C. Samples of a concentration of 2 mg/1 mL DCM were injected (1 μί injection volume).

Synthesis of roc-l-Phenylpropanol (2 ₂ i)

(2 M), 24 h 40 °C

BzCi (1.5 equiv), no catalyst, dioxane (2 M),

0.5 <2% ²

24 h 40 °C

1. Isolated yield 2. Yield determined via NM -Standard.

* Comparative Example.

Racemic 1-phenylpropanol l _2i was cleanly converted to chlorophenylpropane 2 _2i in the presence of 20 mol% FPyr at room temperature (entry 1). To reach full conversion (of l ₂ i) with 20 mol% DMF required 1.5 equiv BzCi and heating to 40 °C (entry 2). However, with the more reactive 2- fluorobenzoyi chloride 10 mol% DMF were sufficient to achieve full consumption of the starting alcohol l ₂ i under elsewise identical conditions (entry 3). No chloride 2 _2i was formed at all in the absence of a catalyst (entry 4).

Entry 1: According to general procedure II (chapter 2.1.2) 1-phenyl propanol [rac-l ₂₁ , 278 μΐ, 275 mg, 2.00 mmol, 1.0 equiv), FPyr (39 μΐ, 41 mg, 0.40 mmol, 20 mol%), dioxane (1 mL, 2 M) and BzCi (282 μί, 341 mg, 2.40 mmol, 1.2 equiv) were combined and allowed to react for 24 h at room temperature. ^X H-NMR of the crude material (440 mg) revealed full conversion, a chloride 2 _2i to ester 3 ₂ i ratio of 97:3 and 4 mol% of the styrene derivative 5 _2i (referred to 2 _2i ). After chromatographic purification (mass crude material/Si0 ₂ 1:12) with Et ₂ 0//iPen 1:99 the chloride 2 _2i was isolated as a colorless oil (283 mg). Accounting 4 mol% residual olefine 5 _2i (r _f = 0.64 in Et ₂ 0//iPen 1:99) the product was obtained in a yield of 89% (1.78 mmol) (From (formal) HCI-elimination resulting olefinic sideproducts 5 were in general not completely separable via chromatography from the chlorides 2 owing to their very similar polarities (mass crude material/Si0 ₂ <1:20). Uitilisation of large silica gel amounts (mass crude material/Si0 ₂ » 1:20) and less polar eluent mixtures lead on the other hand to strongly depleted yields, as the products 2 decomposed massively. However, the alkenes of type 5 did not hemper the further conversion with nucleophiles as demonstrated in chapter 4.5. Elimination side products were also observed under Appel conditions and in chlorinations with SOCI ₂ ).

Entry 2: As given in general procedure II (chapter 2.1.2) a solution of the alcohol rac-l ₂ i (2.00 mmol, 1.0 equiv) and DMF (30.9 μΐ, 29.2 mg, 0.40 mmol, 20 mol%) in dioxane (1 mL, 2 M) was treated with BzCi (352 μί, 426 mg, 3.0 mmol, 1.5 equiv) and stirred for 24 h at 40 °C. ^X H-NMR of the crude material (320 mg) showed full conversion, a ratio 2 ₂ i/3 ₂ i of 96:4 and 5 mol% of the styrene derivative 5 ₂ i (referred to 2 _2i ). Chromatographic purification (mass crude material/Si0 ₂ 1:15) with Et ₂ 0//iPen 1:99 delivered the chloride 2 ₂₁ as a colorless oil (257 mg). Considering 3 mol% residual olefine 5 _2i the product was isolated in a yield of 81% (1.62 mmol).

Entry 3: As described in general proced ure II (chapter 2.1.2) to a solution of the alcohol roc-l ₂ i (2.00 mmol, 1.0 equiv) and DMF (15.5 μΐ, 14.6 mg, 0.20 mmol, 10 mol%) in dioxane (1 mL, 2 M) was added 2-FBzCI (372 μί, 490 mg, 3.0 mmol, 1.5 equiv) and stirred for 24 h at 40 °C. ¹ H-NM of the crude material (444 mg) proved full consumption of the starting material 1 ₂₁ , a ratio 2 ₂ i/3 ₂ i of 96:4 and 5 mol% of the styrene derivative 5 ₂ i (referred to 2 ₂₁ ). Chromatographic purification (mass crude material/Si0 ₂ 1:15) with Et ₂ 0//iPen 1:99 gave the chloride 2 ₂₁ as a colorless oil (268 mg). Considering 3 mol% residual olefine 5 _2i the product was isolated in a yield of 85% (1.69 mmol).

Entry 4: In alignment to general procedure I (chapter 2.1.1) the alcohol 1 ₂₁ (70 μί, 69 mg, 0.50 mmol, 1.0 equiv) was allowed to react for 24 h with benzoyl chloride (88 μί, 107 mg, 0.75 mmol, 1.5 equiv) in dioxane (250 μί, 2M) at 40 °C. ¹ H-NMR of the crude material with naphthalene as standard showed no trace of the chloride 2 ₂₁ (<2%). Instead starting material 1 ₂₁ (89%) and the ester 3 _2i (4%) were detected.

M (CgHuCI) = 154.63 g/mol; r _f (Si0 ₂ , Et ₂ 0//iPen 1:99) = 0.55.

4.4.4.4 Synthesis of rac-2-Methyl-l-phenylpropanol (2 ₂₂ )

According to general procedure II (chapter 2.1.2) 2-methyl-l-phenyl propanol (rac-l ₂₂ , 300 mg, 2.00 mmol, 1.0 equiv), FPyr (39 μΐ, 41 mg, 0.40 mmol, 20 mol%), dioxane (1 mL, 2 M) and BzCI (352 μΐ, 426 mg, 3.00 mmol, 1.5 equiv) were combined and stirred for 24 h at 50 °C. ¹ H-NMR of the crude product (490 mg) indicated full consumption of the starting alcohol 1 ₂₂ , a chloride 2 ₂₂ to ester 3 ₂₂ ratio of 92:8 and 6 mol% of the olefine 5 ₂₂ (referred to 2 ₂₂ ). After

chromatographic purification (mass crude material/Si0 ₂ 1:13) with Et ₂ 0//iPen

'22

25 1:99 the chloride 2 ₂₁ was isolated as a colorless oil (274 mg). Accounting 4 mol% residual olefi ne 5 ₂₂ (r - 0.70 in Et ₂ 0//iPen 1:99) the product was obtained in a yield of 79% (1.58 mmol).

M (C ₁₀ H ₁₃ CI) = 168.66 g/mol; r _f (Si0 ₂ , Et ₂ 0//iPen 1:99) = 0.63. 4.4.4.5 Synthesis of rac-2-(l-Chloroethyl)naphthalene (2 ₂₃ )

According to general procedure II (chapter 2.1.2) a solution of l-(2-naphthyl) ethanol {rac-l ₂₃ , 344 mg, 2.00 mmol, 1.0 equiv) and FPyr (39 μΐ, 41 mg, 0.40 mmol, 20 mol%) in dioxane (1 mL, 2 M) was treated with BzCI (282 μΐ,

341 mg, 2.40 mmol, 1.2 equiv) and the resulting mixture was stirred for 24 h at ambient temperature. ¹ H-NMR of the crude product (414 mg) indicated full conversion, a chloride 2 ₂₃ to ester 3 ₂ 3 ratio of 97:3 and 3 mol% of the 2-vinylnaphthalene 5 ₂ 3 (referred to 2 ₂ 3). Chromatographic purification (mass crude material/Si0 ₂ 1:13) with Et ₂ 0//iPen 1:99 delivered the chloride 2 ₂₃ after drying at 20 mbar for 20 min as a colorless solid (308 mg, 1.61 mmol, 81%). ¹ H-NM showed 2-vinylnaphthalene only in trace amounts (< 2 mol%). Importantly, for application to the silica gel column the crude chloride 2 ₂₃ was dissolved in a minimum amount of toluene (0.4 mL) at 40 °C.

M (C ₁₂ H _n CI) = 190.67 g/mol; mp. 59-61 °C; HR-MS (CI, [C ₁₂ H _n CI] ⁺ ) calc. 190.0549 u found 190.0552 u, ([C ₁₂ H ₁₀ CI] ⁺ ) calc. 189.0446 u found 189.0502 u. 4.4.4.6 Synthesis of roc-l-(l-Chloroethyl) naphthalene (2 ₂₄ )

According to general proced ure II (chapter 2.1.2) l-(l-naphthyl) ethanol (fGC-l ₂₄ , 344 mg, 2.00 mmol, 1.0 equiv) was converted with BzCI (282 μί, 341 mg, 2.40 mmol, 1.2 equiv) to the chloride 2 ₂₄ in the presence of FPyr (39 μί, 41 mg, 0.40 mmol, 20 mol%) in dioxane (1 mL, 2 M) through stirring for 24 h at ambient

15 temperature. ¹ H-NMR of the crude product (480 mg) proved full conversion, a chloride 2 ₂₄ to ester 3 ₂₄ ratio of >98:2 and 5 mol% of the 1-vinylnaphthalene (referred to 2 ₂₄ ). Chromatographic purification (mass crude material/Si0 ₂ 1:17) with Et ₂ 0//iPen 2:98 delivered the chloride 2 ₂₄ after drying at 20 mbar for 5 min as a colorless oil (303 mg, 1.60 mmol, 80%; fractions 6-13 with 2 mL per fraction). ¹ H-NMR showed 1-vinylnaphthalene (r _f = 0.74 in Et ₂ 0//iPen 5:95 only in trace amounts (< 2 mol%).

M (C ₁₂ H _U CI) = 190.67 g/mol; r _f (Si0 ₂ , Et ₂ 0//iPen 5:95) = 0.00 + 0.56 + 0.65.

Synthesis of roc- E-2-Chloro-4-phenyl-3-butene (2 ₂₅ )

1. Isolated yield 2. Yield determined via NMR-Standard.

* Comparative Example. With only 10 mol% of FPyr the vinylogous secondary benzyl chloride 2 ₂₅ was obtained in 75% isolated yield (entry 1). Compound 2 ₂₅ is very sensitive towards decomposition on silica gel, thus the yield determined with NMR-standard (without chromatographic purification) is significantly higher (84%, entry 2). Without a catalytic active species the yield depleted to 29% (entry 3).

Entry 1: According to general procedure II (chapter 2.1.2) f-4-phenyl-3-buten-2-ol (roc-l ₂₅ , 296 mg, 2.00 mmol, 1.0 equiv), FPyr (19.7 μΐ, 20.4 mg, 0.20 mmol, 10 mol%), dioxane (1 mL, 2 M) and BzCI (282 μί, 341 mg, 2.40 mmol, 1.2 equiv) were combined at 0 °C and subsequently stirred for 24 h at room temperature. Chloride 2 ₂₅ is sensitive towards hydrolysis. Therefore it is utmost important to first dilute the reaction mixture (after quenching with ethanolamine) with Et ₂ 0 and then to quench with aqueous, saturated NaHC0 ₃ -solution under cooling to 0 °C. ¹ H-NMR of the crude product (472 mg) proved full conversion, a chloride 2 _¾ to ester 3 ₂ 5 ratio of 96:4 and 6 mol% of the diene 5 _¾ (referred to 2 ₂₅ ). Rapid chromatographic purification (mass crude material/Si0 ₂ 1:7!) with Et ₂ 0//iPen 3:97 gave the chloride 2 ₂₅ as a colorless oil (263 mg; fractions 3-6 with 2 mL per fraction). As chloride 2 ₂₅ is very sensitive towards silica gel, utilisation of small amounts of Si0 ₂ and a high elution speed is important. Considering 7 mol% residual olefine 5 ₂₅ the desired vinylic chloride 2 ₂₅ was isolated in a yield of 75% (1.50 mmol).

Entry 2: Following general procedure I (chapter 2.1.1) the alcohol 1 ₂₅ (74 mg, 0.50 mmol, 1.0 equiv), FPyr (4.9 μΐ, 5.1 mg, 0.50 mmol, 10 mol%), dioxane (250 μΐ, 2M) and benzoyl chloride (70 μΐ, 85 mg, 0.60 mmol, 1.2 equiv) were combined and allowed to react for 24 h at ambient temperature. After work up as described in general procedure II (chapter 2.1.2) ¹ H-NMR of the crude product showed chloride 2 ₂₅ in 84% yield beside the diene 5 ₂₅ (3%) and traces of the ester 3 ₂₅ (<2%) referred to naphthalene as NMR-standard (> 98% conversion).

Entry 3: In accordance with general procedure I (chapter 2.1.1) the alcohol 1 ₂₅ (0.50 mmol, 1.0 equiv), dioxane (250 μί, 2M) and benzoyl chloride (0.60 mmol, 1.2 equiv) were combined and allowed to stir for 24 h at ambient temperature. After work up as described in general procedure II (chapter 2.1.2) ¹ H-NMR of the crude product with naphthalene as NMR-standard revealed chloride 2 ₂₅ in 29% yield beside the ester 3 ₂₅ (4%), starting material (22%) and another unidentified sideproduct.

M (C ₁₀ H _U CI) = 166.65 g/mol. 4.4.4.8 Synthesis of Chlorodiphenylmethane (2 ₂₆ )

BzCi (1.2 equiv), DMF (20 mol%), dioxane (2 M),

2 87% ^x

24 h 80 °C

BzCi (1.2 equiv), no catalyst, dioxane (2 M),

0.5 63%'

24 h 80 °C

1. Isolated yield 2. Yield determined via N M -Standard.

* Comparative Example.

Only 10 mol% FPyr were required to effect full conversion of diphenylmethanol 1 ₂₆ at 80 °C within 24 h and provide the secondary chloride 2 ₂₉ in 90% isolated yield (entry 1). In the presence of 20 mol% DMF the product 2 ₂₉ was formed in 87% yield (entry 2). As diphenylmethanol can form a strongly stabilized benzhydryl carbeniumion and thus reacts preferentially via an S _w l pathway, in the absence of a catalyst still 63% (N MR-yield) of the chloride 2 ₂₉ are obtained.

Entry 1: According to general procedure II (chapter 2.1.2) diphenylmethanol (1 ₂ 6, 372 mg, 2.00 mmol, 1.0 equiv), FPyr (19.7 μΐ, 20.4 mg, 0.20 mmol, 10 mol%), dioxane (1 mL, 2 M) and BzCi (282 μΐ, 341 mg, 2.40 mmol, 1.2 equiv) were combined and then heated to 80 °C for 24 h. ¹ H-N MR of the crude product (623 mg) revealed full conversion and a chloride 2 ₂ e to ester 3 ₂₆ ratio of 96:4. Rapid chromatographic purification (mass crude material/Si0 ₂ 1:9!) with Et ₂ 0//iPen 3:97 delivered the chloride 2 ₂₆ as a colorless liquid in 90% yield (366 mg, 1.81 mmol).

Entry 2: As given in general procedure II (chapter 2.1.2) diphenylmethanol (1 ₂₆ , 2.00 mmol, 1.0 equiv) was chlorinated with BzCi (2.40 mmol, 1.2 equiv) in the presence of DMF (30.9 μί, 29.2 mg, 0.40 mmol, 20 mol%) in dioxane (1 mL, 2 M) through heating to 80 °C for 24 h. ¹ H-NMR of the crude product (470 mg) indicated full conversion and a chloride 2 ₂₆ to ester 3 ₂₆ ratio of 97:3. Rapid chromatographic purification (mass crude material/Si0 ₂ 1:10) with Et ₂ 0//iPen 2:98 gave the chloride 2 ₂ 6 as a colorless liquid in 87% yield (353 mg, 1.74 mmol).

Entry 3: According to general procedure I (chapter 2.1.1) the alcohol 1 ₂ 6 (93 mg, 0.50 mmol, 1.0 equiv), dioxane (250 μί, 2M) and benzoyl chloride (70 μί, 85 mg, 0.60 mmol, 1.2 equiv) were combined and allowed stir for 24 h at 80 °C. Naphthalene as N M R-standard revealed the chloride 2 ₂₆ in 63% yield. Additionally ester 3 ₂₅ (10% yield) and starting material (6%) were observed.

M (CisHnCI) = 202.68 g/mol; r _f (Si0 ₂ , Et ₂ 0//iPen 3:97) = 0.46 + 0.00. 4.4.4.9 Synthesis of rcrc-3-Chloro-l-octyne (2 ₂₇ )

1-2

1. Isolated yield 2. Yield determined via N M -Standard.

* Comparative Example.

Chlorination of l-octyn-3-ol 2 ₂₇ at 50 °C with BzCI in the presence of 20 mol% FPyr delivered the chloride 2 ₂₇ as a 97:3 mixture of the propargyl 6-2 ₂₇ and the allenyl chloride /-2 ₂₇ (entry 1). Thus in contrast to secondary allyl alcohols secondary propargylic ones do give preferential the branched (propargylic) regioisomer. With DMF (20 mol%) as catalyst heating to 80 °C was required to completely consume the starting material 1 ₂₇ and in consequence a depleted regioselectivity occured (b/l-2 ₂₇ 90:10, entry 2). Importantly, in the absence of a catalyst no desired chloride 2 ₂₇ was formed at all. (entry 3).

Entry 1: According to general procedure I I (chapter 2.1.2) rac-l-octyn-3-ol {rac-l ₂₇ , 298 μΐ, 258 mg, 2.00 mmol, l.O equiv), FPyr (39 μΐ, 41 mg, 0.40 mmol, 20 mol%), dioxane (1 mL, 2 M) and BzCI (282 μΐ, 341 mg, 2.40 mmol, 1.2 equiv) were combined and then heated to 50 °C for 24 h. ¹ H-N MR of the crude product (411 mg) showed a conversion of >98%, a chloride 2 ₂₇ to ester 3 ₂₆ ratio of >98:2 and a ratio of the propargylic chloride/allenyl chloride b/l-2 ₂₇ of 94:6. After chromatographic purification (mass crude material/Si0 ₂ 1:10) with nPen the chloride 2 ₂₆ was isolated as a colorless liquid in 77% yield (222 mg, 1.54 mmol) and a ratio b/l-2 ₂₇ 97:3. Thereby the chlorides 2 ₂₇ were visualized on TLC with KMn0 ₄ -stain.

Entry 2: As described in general procedure I I (chapter 2.1.2) a solution of alcohol rac-l ₂₇ (2.00 mmol, 1.0 equiv) and DM F (30.9 μΐ, 29.2 mg, 0.40 mmol, 20 mol%) in dioxane (1 mL, 2 M) was treated with BzCI (352 μΐ, 426 mg, 3.00 mmol, 1.5 equiv) and then stirred for 24 h at 80 °C. ¹ H-N MR of the crude product (446 mg) revealed full consumption of the alcohol 1 ₂₇ , a chloride 2 ₂₇ /ester 3 ₂₆ ratio of 94:6 and a ratio b/l-2 ₂₇ of 89:11. After chromatographic purification (mass crude material/Si0 ₂ 1: 10) with nPen the chloride 2 ₂₆ was obtained as a colorless liquid in 73% yield (210 mg, 1.45 mmol) and a ratio b/l-2 ₂₇ 90:10.

Entry 3: Following general procedure I (chapter 2.1.1) the alcohol 1 ₂₇ (75 μί, 65 mg, 0.50 mmol, l.O equiv), dioxane (250 μί, 2M) and benzoyl chloride (70 μί, 85 mg, 0.60 mmol, 1.2 equiv) were combined and allowed stir for 24 h at 80 °C. ¹ H-NM with naphthalene as standard showed no trace chloride 2 ₂₆ (≤2% yield). Instead ester 3 ₂ 5 (30% yield) was formed and starting material 1 ₂₇ (36%) was reisolated.

M (C ₈ H ₁₃ CI) = 144.64 g/mol, r _f (Si0 ₂ , nPen) = 0.54 (b-2 ₂₇ ), 0.65 (l-2 ₂₇ ).

4.4.4.10 Synthesis of rac-l-Chloro-4-(ferf-butyldiphenylsiloxy)-l-phenyl butane (2 ₂₈ )

According to general procedure II (chapter 2.1.2) 4-{{tert- butyldiphenylsilyl)oxy)l-phenylbutan-l-ol (rac-l _2S , 179 mg, 0.442 mmol, l.OO equiv) was chlorinated in the presence of FPyr (9.0 μΐ, 9.4 mg, 0.092 mmol, 20 mol%) in dioxane (0.44 mL, 1 M)

15 with BzCI (81 μί, 98 mg, 0.666 mmol, 1.2 equiv) at 40 °C within

'28

24 h. Chromatographic purification of the crude material (195 mg, >98% conversion, 2 ₂₈ /3 ₂₈ >98:2) on silica gel (mass crude product/silica gel 1:25) with Et ₂ 0//iPen 3:97 delivered the

'28 chloride 2 ₂₈ as a colorless oil (150 mg). Considering 5 mol% residual olefine 5 ₂₈ ^H-NMR) the chloride 2 ₂₈ was obtained in 77% yield (0.338 mmol).

M (C ₂₆ H ₃ iCIOSi) = 423.07 g/mol; r _f (Si0 ₂ , Et ₂ 0//iPen 3:97) = 0.54; ¹ H-NMR (400 MHz, CDCI ₃ ) δ [ppm] = 7.65-7.62 (m, 4 H, H-6 ^' ), 7.44-7.27 (m, 10 H, 6-H, 7-H, 5 ^' -H, 6 ^' -H), 7.30 (m, 1 H, H-4 ^' ), 4.87 (dd, 1 H, H-l, J = 7.2, 7.2 Hz), 3.72-3.63 (m, 2 H, H-2), 2.27-2.13 (m, 2 H, H-2), 1.77-1.67 (m, 1 H, H-3 _a ), 1.63-1.53 (m, H-3 _b ), 1.04 (s, 9 H, H-10 ^' ); ¹³ C-NMR (100 MHz, CDCI ₃ ) δ [ppm] = 141.9 (C-l ^' ), 135.6 (C- 6 ^' ), 133.8 (C-5 ^' ), 129.6 (C-8 ^' ), 128.6 (C-2 ^' ), 128.2 (C-7 ^' ), 127.7 (C-4 ^' ), 127.0 (C-3 ^' ), 63.6 (C-4), 63.1 (C- 1), 36.4 (C-2), 29.9 (C-3), 26.9 (C-10 ^' ), 19.2 (s, C-9 ^' ); GC-MS (El, 70 eV) m/z [u] = 387 (3, [M-CI] ⁺ ), 355 (10), 281 (11), 221 (23), 207 (20), 199 (22, [HOSiPh ₂ ] ⁺ ), 147 (38, [M-HCI-TPS] ⁺ ), 125 (38, [BnCI] ⁺ ), 98 (9), 77 (9, [Ph] ⁺ ), 73 (100), 57 (21, [tBu] ⁺ ).

4.4.5 Synthesis of a-Chloro Esters

The following scheme provides an overview over a-chloro esters synthesized by formamide catalyzed chlorinations. Deviations from standard conditions are given in parenthesis: Standard Conditions

in dioxane (2 M): 2-FBzCI (1 .2-1 .5 equiv), FPyr (20 mol%), <24 h 80 °C 200 mmol scale solvent-free: BzCI (1 .2 equiv), DMF (30 mol%), <24 h 80 °C l

CI CI CI

I

nBu0 ₂ C^CI Et0 ₂ C ^ Bn0 ₂ C ^ Me0 ₂ C Ph

2 ₂ 9 f?-2 ₃₀ from S-2 ₃₀ R-2 ₃₁ from S-1 ₃₁ S-2 ₃₂ from R-2 ₃₂

75% (20 mol% DMF) 66% (solvent-free, 83% ( er = 98.5: 1 .5) 89% (er = 97.5:2.5) er = 97.5:2.5) ^*

4.4.5.1 Synthesis of n-Butyl 2-chloroethanoate (2 ₂₉ )

According to general procedure I I (chapter 2.1.2) n-butyl 2- hydroxyethanoate (l 267 μί/273 mg, 2.00 mmol, 1.0 equiv) was chlorinated with 2-fluorobenzoyl chloride (372 μί, 490 mg, 3.00 mmol,

1.5 equiv) in the presence of DMF (30.9 μί, 29.2 mg, 0.40 mmol, 20 mol%) in dioxane (1 mL, 2 M) in 16 h at 80 °C. Full conversion and a chloride 2 ₂₉ to ester 3 ₂₉ ratio of >98:2 were assigned by ¹ H-N MR of the crude material (443 mg). Finally chromatographic purification (mass of crude material/Si0 ₂ 1:12) with Et ₂ 0//iPen 5:95 provided the a-chloro ester 2 ₂₉ as a colorless oil in 75% yield (224 mg, 1.49 mmol).

M (C ₆ H _n CI0 ₂ ) = 150.60 g/mol; r _f (Si0 ₂ , Et ₂ 0//iPen 5:95) = 0.27.

4.4.5.2 Synthesis of R-Ethyl 2-chloroethanoate [R-2 ₃₀ )

Following general procedure I II (chapter 2.1.3) to a solution of S-ethyl 2- hydroxypropanoate (1 ₂₉ , ethyl lactate, 23.4 mL, 24.11 g, 200 mmol, 1.0 equiv) in

DMF (4.6 mL, 4.39 g, 60.0 mmol, 30 mol%) was added benzoyl chloride (28.2 g,

2

²⁹ 24.08 g, 60.0 mmol, 30 mol%) within 1.25 h under heating to 60 °C. After stirring

(er = 97.5:2.5)

overnight (12 h) reaction control via H-NMR revealed 86% conversion. Thus the reaction was heated to 80 °C, until full consumption of the starting material 1 ₂₉ was achieved as judged by N MR (7 h, 2 ₂₉ /3 ₂₉ 81:19). Next distillation at 70 mbar through a micro distillation apparatus without dispenser delivered a fraction with a bp. of 72-88 °C (21.74 g, colorless liquid, oil bath temperature 105-150 °C) containing 24 mol% of DMF (referred to the product 2 ₂₉ according to ^Χ Η- N MR). Therefore the neat distillate was washed in a 60 mL syringe with water (3 x 10 mL) and a mixture of water and saturated, aqueous Na ₂ C0 ₃ solution (9/1 mL), whereby the aqueous phase formed the upper layer due to the high density of the chloride 2 ₂₉ . Finally drying over MgS0 ₄ gave the chloride S-2 ₂₉ as a colorless liquid in 66% yield (17.93 g, 131.2 mmol) and an er of 97.5:2.5 according to chiral GC.

M (C ₅ H ₉ CI0 ₂ ) = 136.58 g/mol; [ct] _D ²⁰ = +17.2 (c = 1.68 g/100 mL, CHCI ₃ ). The separation conditions of the enantiomers of chloride 2 ₂ g through chiral gas chromatography were: Column CP-Chirasil-Dex CB; Temperature program 80 °C for 20 min, gradient 20 °C/min to 200 °C, 200 °C for 5 min, column flow l.O mL/min, split ratio 50; PTV injector temperature 250 °C. Samples of a concentration of 5 mg/1 mL DCM were injected (1 μί injection volume).

Synthesis of /?-Benzyl 2-chloropropanoate (R-2 ₃₁ )

R-2 ₃₁ 1 1 (20 mol%), dioxane (2 M), 12 h 98.5:1.5 80% ^χ

(er = 93.5:1.5) 80 °C

2-FBzCI (1.2 equiv), FPyr

2 0.3 (20 mol%), 2-MeTHF (2 M), 22 h 98.5:1.5 Ί /ο ¹

80 °C

BzCi (1.2 equiv), DMF (1 M), 26 h

3 0.3 90:10 77% ² rt

1. Isolated yield 2. Yield determined via N M -Standard. Under optimized conditions (20 mol% FPyr, 1.5 equiv 2-FBzCI, 80 °C) the chiral chloride R-2 ₃₁ was obtained in 80% isolated yield and an er of 98.5:1.5 (entry 1) from S-benzyl 2-hydroxypropionate (S- 1 ₃₁ ; er > 99:1 according to chiral H PLC). Dioxane could be replaced by the more environmentally friendly 2-MeTH F without effecting the enantiopurity (entry 2). However, in DMF as solvent a significantly depleted er (90:10) was observed (entry 3), although the reaction temperature could be lowered from 80 to 25 °C.

Entry 1: According to general procedure I I (chapter 2.1.2) S-benzyl 2-hydroxypropionate {S-l ₃₁ , containing 39 mol% residual BnOH from previous esterification, 220 mg, 1.00 mmol, l.O equiv; er > 99:1 according to chiral H PLC) was converted with 2-fluoro benzoyl chloride (186 μί, 245 mg, 1.50 mmol, 1.5 equiv) in the presence of FPyr (19.7 μί, 20.4 mg, 0.20 mmol, 20 mol%) in dioxane (0.5 mL, 2 M) at 80 C in 12 h to the chloride 2 ₃₁ . Chromatographic purification of the crude material (360 mg, 2 ₃ i/3 ₃ i 94:6) on silica gel (mass of crude material/Si0 ₂ 1:15) with Et ₂ 0//iPen 5:95 delivered the chloride R-2 ₃₁ as a colorless oil ( 160 mg, 0.804 mmol, 80%). Both GC analysis from the crude and isolated material revealed an er of 98.5:1.5. For chromatographic purification the crude product was dissolved DCM/nPen 15:85 (ca. 0.5 mL).

Entry 2: Following general procedure I (chapter 2.1.1) the chlorination of alcohol S-l ₃ i (containing 5 mol% of residual BnOH and 6 mol% of 3,6-dimethyldioxan-2,5-dione, 57 mg, 0.300 mmol, 1.0 equiv; er > 99:1 according to chiral H PLC) in the presence of FPyr (5.9 μί, 6.1 mg, 0.060 mmol, 20 mol%) in 2-MeTH F (150 μί, 2 M) with 2-FBzCI (45 μί, 59 mg, 0.360 mmol, 1.2 equiv) at 80 °C for 22 h provided chloride R-2 ₃₁ in 71% yield according to naphthalene as N M -standard and an er of 98.5:1.5 as indicated by chiral GC (2 ₃₁ /3 ₃₁ 94:6).

Entry 3: As described in procedure I (chapter 2.1.1) the alcohol S-l ₃ i (containing 5 mol% of residual BnOH and 6 mol% of 3,6-dimethyldioxan-2,5-dione, 57 mg, 0.300 mmol, 1.0 equiv; er > 99:1 according to chiral H PLC), DMF (300 μΐ, 1 M) and BzCI (42 μΐ, 59 mg, 0.360 mmol, 1.2 equiv) were combined at ambient temperature and stirred for 27 h at room temperature to reach full conversion.

According to naphthalene as N M R-standard the chloride R-2 ₃₁ was formed in 77% yield and an er of

90:10 (chiral GC) beside the ester 3 ₃₀ in 3% yield (2 ₃ i/3 ₃ i 97:3).

M (C ₁₀ H _n CIO ₂ ) = 198.95 g/mol; r _f (Si0 ₂ , Et ₂ 0//iPen 5:95) = 0.34; HR-MS (CI, PH6632, [C ₁₀ H _n O ₂ C ³⁵ ] ⁺ ) calc. 198.0448 u found 198.0425 u; [α] = +7.3 (c = 2.01 g/100 mL, CHCI ₃ ).

A racemic sample was subjected to gas chromatography (prepared as described above; concentration 2 mg/1 mL DCM, split ratio 20, injection volume 1 μί). The enantioenriched sample was subjected to gas chromatography (entry 1, concentration 1 mg/1 mL DCM, split ratio 15, injection volume 1 μί). The Separation conditions were: Column CP-Chirasil-Dex CB; Temperature program 120 °C for 30 min, gradient 20 °C/min to 200 °C, 200 °C for 10 min, column flow 1.0 mL/min; PTV injector temperature 250 °C. Samples of a concentration of 5 mg/1 mL DCM were injected (1 μί injection volume).

4.4.5.4 Synthesis of S-Methyl 2-Chloro-2-phenylethanoate (S-2 ₃₂ )

dioxane (2 M), 12 h 80 °C

S-2 ₃₂

2-FBzCI (1.5 equiv), FPyr (20 mol%),

(er = 97.5:2.5) 0.3 90:10 64%' dioxane (2 M), 2 d 80 °C

BzCi (1.2 equiv), FPyr (20 mol%),

0.5 96:4 77%' dioxane (2 M), 24 h 80 °C 4 0.5 BzCi (1.5 equiv), DMF (1 M), 24 h rt 71:29 71% ²

2-FBzCl (1.5 equiv), DMF

62% ^x

5 2 (20 mol%), dioxane (2 M), 36 h 50:50

(rac)

80 °C

1. Isolated yield 2. Yield determined via N M -Standard.

Under optimized conditions (20 mol% FPyr, 1.5 equiv 2-FBzCI, 80 °C) the a-chloro ester S-2 ₃₂ was obtained in 89% (isolated) yield and an enantiopurity of er = 97.5:2.5 (entry 1) from S-methyl 2- hydroxy-2-phenylethanoate (/?-l ₃₂ ; er > 99:1 according to chiral H PLC). As prolonged reaction time (12 h -> 2 d) lead to a decrease in the er (90: 10), most likely an enolisation process of the product is responsible for the partial racemisation (entry 2). Due to the slower conversion of alcohol 1 ₃₂ to chloride 2 ₃₂ (= increased reaction time) a slightly lower er (96:4) was observed with the less reactive BzCI (compared to 2-FBzCI, see entry 3). Utilizing DMF as solvent the enantiomeric ratio depletes even to 71:29 demonstrating the superiority of formamides in catalytic quantities (entry 4). With DMF (20 mol%) instead of FPyr, the reaction time was significantly prolonged (12 h->36 h) and as a consequence the yield deduced to 62% (with racemic starting material 1 ₃₂ ).

Entry 1: According to general procedure I I (chapter 2.1.2) S-methyl 2-hydroxy-2-phenylethanoate (/?- 1 ₃₂ , 168 mg, 1.00 mmol, 1.0 equiv; er > 99: 1 according to chiral H PLC), FPyr (19.7 μΐ, 20.4 mg, 0.20 mmol, 20 mol%), dioxane (0.5 mL, 2 M) and 2-fluoro benzoyl chloride (186 μΐ, 245 mg, 1.50 mmol, 1.5 equiv) were combined and allowed to react for 12 h at 80 C. Chromatographic purification of the crude material (350 mg, full conversion, 2 ₃₂ /3 ₃₂ 94:6) on silica gel (mass of crude material/Si0 ₂ 1:10) with Et ₂ 0//iPen 5:95 delivered the chloride S-2 ₃₂ as a colorless oil (159 mg, 0.892 mmol, 89%). Both GC analysis from the crude and isolated material showed an er of 97.5:2.5. For chromatographic purification the crude product was dissolved DCM/nPen 30:70 (ca. 0.5 mL).

Entry 2: Following general procedure I (chapter 2.1.1) the chlorination of alcohol R-l ₃₂ (50.4 mg, 0.300 mmol, 1.0 equiv; er > 99:1 according to chiral H PLC) in the presence of FPyr (5.9 μί, 6.1 mg, 0.060 mmol, 20 mol%) in dioxane (150 μΐ, 2 M) with 2-FBzCI (56 μΐ, 74 mg, 0.360 mmol, 1.5 equiv) at 80 °C for 2 d gave chloride S-2 ₃₂ in 64% yield according to naphthalene as N M R-standard and an er of 90:10 as indicated by chiral GC. Additionally the ester 3 ₃₂ was obtained in 3% yield (2 ₃₂ /3 ₃₂ 95:5), no starting material 1 ₃₂ was visible (>98% conversion).

Entry 3: As described in general procedure I (chapter 2.1.1) the alcohol R-l ₃₂ (89 mg, 0.500 mmol, 1.0 equiv; er > 99:1 according to chiral H PLC) was subjected to chlorination with BzCI (70 μί, 85 mg, 0.600 mmol, 1.2 equiv) in the presence of FPyr (9.8 μί, 10.2 mg, 0.10 mmol, 20 mol%) in dioxane (250 μΐ, 2 M) at 80 °C for 24 h. As demonstrated by naphthalene as N M R-standard the product S-2 ₃₂ was provided in 77% yield with an er of 96:4 (chiral GC). Moreover the ester 3 ₃₂ was observed in 4% yield (2 ₃₂ /3 ₃ 2 95:5) alongside with the starting material 1 ₃₂ in 9% yield (90% conversion).

Entry 4: As given in procedure I (chapter 2.1.1) the alcohol S-l ₃ i (50.4 mg, 0.300 mmol, 1.0 equiv; er > 99:1 according to chiral H PLC), DMF (300 μΐ, 1 M) and BzCI (52.8 μΐ, 63.9 mg, 0.360 mmol, 1.2 equiv) were combined and stirred for 24 h at room temperature to reach full conversion. According to naphthalene as N M -standard the chloride S-2 ₃₂ was obtained in 71% yield and an er of 71:29 (chiral GC) beside the ester 3 ₃₂ in 2% yield (2 ₃₂ /3 ₃₂ 97:3).

Entry 5: According to general procedure I I (chapter 2.1.2) racemic methyl mandelate (roc-l ₃₂ , 336 mg, 2.00 mmol, 1.0 equiv), DMF (30.9 μΐ, 29.2 mg, 0.40 mmol, 20 mol%), dioxane (1 mL, 2 M) and 2-fluoro benzoyl chloride (372 μί, 490 mg, 3.00 mmol, 1.5 equiv) were combined and allowed to react for 36 h at 80 C. Chromatographic purification of the crude material (540 mg, 2 ₃₂ /3 ₃₂ 86:14) on silica gel (mass of crude material/Si0 ₂ 1:9) with Et ₂ 0//iPen 5:95 gave rise of the chloride rac-2 ₃₂ as a colorless oil (227 mg, 1.23 mmol, 62%).

M (C ₉ H ₉ CI0 ₂ ) = 184.62 g/mol; r _f (Si0 ₂ , Et ₂ 0//iPen 5:95) = 0.37; [ct] _D ²⁰ = +134.1 (c = 1.48 g/100 mL,

The separation conditions for the enantiomers of chloride 2 ₃₂ through chiral gas chromatography were: Column CP-Chirasil-Dex CB; Temperature program 115 °C for 30 min, gradient 20 °C/min to 200 °C, 200 °C for 10 min, column flow l.O mL/min, split ratio 10; PTV injector temperature 250 °C. Samples of a concentration of 1 mg/1 mL DCM were injected (1 μί injection volume).

4.4.6 Synthesis of Primary Aliphatic Chlorides

The following scheme provides an overview over primary aliphatic chlorides synthesized by formamide catalyzed chlorinations. Deviations from standard conditions are given in parenthesis:

Standard Conditions

in dioxane (1 M): BzCI (1 .03-1 .2 equiv), FPyr (20 mol%), <24 h 80 °C >200 mmol scale solvent-free: BzCI (1 .00-1 .1 equiv), DMF (60 mol%), <24 h 80 °C

*

2 ₃₄ 2 ₃₇

82% (40 mol% DMF) H

81 % (solvent-free) ^*

83% (30mol% FPyr, PG XI solvent-free) ^* CI 2 ₄₁ 69% (PG = Alloc)

2 ₄₂ 70% (PG = Cbz)

'38

2 ₄₃ 82% (PG = Fmoc)

67% (140 g, solvent-free)

2 ₄₄ 75% (PG = Piv)

2 ₃₅

236 239 75% (40 mol% FPyr,

78% (40 mol% DMF) 65% (solvent-free) solvent-free) ^* .6.1 Synthesis of 1-chlorododecane (2 ₃₃ )

5 0.5 BzCi (1.2 equiv), DMF (1 M), 20 h rt 91% ²

BzCi (1.2 equiv), DMF (110 mol%),

6 0.5 86% ² dioxane (2 M), 20 h rt

BzCi (1.2 equiv), DMF (30 mol%),

7 0.5 40% ² dioxane (2 M), 20 h rt

8 0.5 BzCi (1.2 equiv), no catalyst, <2% dioxane (1 M), 2 h 80°C

1. Isolated yield 2. Yield determined via NM -Standard.

* Comparative Example.

Under optimized conditions (20 mol% FPyr, 80 °C) 1-chlorododecane (2 ₃₃ ) was isolated in 84% yield (entry 1). However, even in the presence of the twofold amount of DMF (40 mol%) the chloride 233 was only obtained in 71% yield (entry 2). With less reactive (but also much more expensive) 2,4,6- trichlorobenzoyi chloride and 2,6-dichlorobenzoyl chloride ester formation could be suppressed virtually completely (2 ₃₃ /333 >98:2), albeit at the cost of an increased reaction time (24 h, entries 3+4). Both in DMF as solvent and in the presence of stoichiometric amounts of DMF (in dioxane) the reaction temperature could be lowered from 80 to 25 °C (entries 5+6). Finally in the absence of a formamide catalyst no chloride 2 ₃₃ formed at all (entry 8, reaction conditions 80 °C for 2 h).

Entry 1: According to general procedure II (chapter 2.1.2) to a solution of 1-dodecanol (1 ₃₃ 496 μί, 414 mg, 2.00 mmol, 1.00 equiv) (The alcohol 1 ₃₃ was melted in prior in a water bath at 40 °C) and FPyr (39 μΐ, 41 mg, 0.40 mmol, 20 mol%) in dioxane (2 mL, 1 M) was added BzCI (280 μΐ, 2.40 mmol, 1.2 equiv) within 20 min at 80 °C with the aid of a syringe pump and stirred for 2 h at 80 °C. ¹ H-NMR of the crude product (512 mg) revealed full conversion and a chloride 2 ₃₃ to ester 3 ₃₃ ratio of 87:13. Finally chromatographic purification on silica gel (mass of crude material/Si0 ₂ 1:10) with nPen delivered the alkyl chloride 2 ₃₃ as a colorless oil in 84% yield (346 mg, 1.69 mmol).

Entry 2: Following general procedure II (chapter 2.1.2) dodecanol 1 ₃₃ (2.00 mmol, 1.0 equiv), DMF (62 μΐ, 59 mg, 0.80 mmol, 40 mol%), dioxane (1 mL, 2 M) and benzoyl chloride (282 μΐ, 341 mg, 2.40 mmol, 1.2 equiv) were combined at ambient temperature and allowed to react at 80 °C for 2 h. ¹ H-NMR of crude material (460 mg) proved full consumption of the starting alcohol 1 ₃₃ and a ratio of 233/333 of 79:21. Next chromatographic purification (mass crude material/Si0 ₂ 1:15) gave the product 2 ₃₃ as a colorless oil in 71% yield (292.1 mg, 1.43 mmol).

Entry 3: As described in general procedure I (chapter 2.1.1) dodecanol 1 ₃₃ (112 μί, 94 mg, 0.50 mmol, 1.0 equiv) were allowed to react with 2,4,6-CI ₃ BzCI (88 μΐ, 137 mg, 0.55 mmol, 1.1 equiv) at 80 °C for 24 h in the presence of DMF (75 μΐ of a I N DMF-solution in dioxane, 0.75 mmol, 15 mol%) in dioxane (50 μί, in total 4 M). ^-NMR of the crude material in the presence of naphthalene as NMR- standard showed a yield of chloride 2 ₃₃ of 86%. Additionally, 4% of dodecyl formiate had formed. Neither starting material 1 ₃₃ nor ester 2 ₃₃ were detected.

Entry 4: According to general procedure I (chapter 2.1.1) dodecanol 1 ₃₃ (0.50 mmol, 1.0 equiv), DMF (75 μΐ of a 1 N DMF-solution in dioxane, 0.75 mmol, 15 mol%), dioxane (50 μΐ, in total 4 M) and 2,6- CI ₂ BzCI (78 μί, 116 mg, 0.55 mmol, 1.1 equiv) were combined at ambient temperature and allowed to stir at 80 °C for 24 h ¹ H-N MR of the crude product with naphthalene as standard uncovered a yield of chloride 2 ₃₃ of 90%. Moreover, 4% of dodecyl formiate had formed. Neither starting material 1 ₃₃ nor ester 2 ₃₃ were observed.

Entry 5: As given in general procedure I (chapter 2.1.1) dodecanol 1 ₃₃ (0.50 mmol, 1.0 equiv), DMF (0.5 mL, 1 M) and benzoyl chloride (70 μί, 85 mg, 0.60 mmol, 1.2 equiv) were combined at ambient temperature and allowed to stir for 20 h. ¹ H-N MR of the crude product with naphthalene as standard revealed full conversion and chloride 2 ₃₃ in 91% and ester 3 ₃₃ in 3% yield (2 ₃₃ /3 ₃₃ 97:3).

Entry 6: According to general procedure I (chapter 2.1.1) dodecanol 1 ₃₃ (0.50 mmol, 1.0 equiv), DM F (43 μί, 40 mg, 0.55 mmol, 1.1 equiv), dioxane (0.25 mL, 2 M) and benzoyl chloride (0.60 mmol, 1.2 equiv) were combined and allowed to stir for 20 h at ambient temperature. ¹ H-N MR of the crude product with naphthalene as standard indicated full conversion and chloride 2 ₃₃ in 86% and ester 3 ₃₃ in 13% yield (2 ₃₃ /3 ₃₃ 87:13).

Entry 7: According to general procedure I (chapter 2.1.1) dodecanol 1 ₃₃ (0.50 mmol, 1.0 equiv), DM F (11.6 μί, 11.0 mg, 0.15 mmol, 1.1 equiv), dioxane (2 M) and benzoyl chloride (0.60 mmol, 1.2 equiv) were combined and allowed to react for 20 h at room temperature. ¹ H-N MR of the crude product with naphthalene as standard indicated 97% conversion and chloride 2 ₃₃ in 40%, dodecyl formiate in 20% and ester 3 ₃₃ in 32% yield (2 ₃₃ /3 ₃₃ 54:46).

Entry 8: As stated in general procedure I (chapter 2.1.1) dodecanol 1 ₃₃ (0.50 mmol, 1.0 equiv) was allowed to react with benzoyl chloride (0.60 mmol, 1.2 equiv) in dioxane (2 M) in the absence of a formamide catalyst for 2 h at 80 °C. ¹ H-N MR of the crude product with naphthalene as standard showed no trace of the chloride 2 ₃₃ . Instead the ester 3 ₃₃ had formed in 59% yield beside the starting material 1 ₃₃ in 29% yield.

M (C ₁₂ H ₂₅ CI) = 208.78 g/mol r _f (Si0 ₂ , nPen) = 0.79.

4.4.6.2 Synthesis of 1-Chlorooctane (2 ₃₄ )

solvent-free, 2.5 h 80°C

1. Isolated yield 2. Yield determined via N MR-Standard. Under solvent-free conditions in the presence of 30 mol% FPyr octyl chloride 2 ₃₄ was isolated in 83% yield (entry 1). In 2-MeTHF as solvent 20 mol% FPyr were similarly efficiently, although the isolated yield was slightly lower (entry 2). This decrease in yield is mainly reasoned by partial codistillation of 2-MeTHF with product 2 ₃₄ during purification. Indeed, 60 mol% of DMF were required to obtain the chloride 2 ₃₄ in basically the same yield as with 30 mol% of FPyr in the absence of any solvent (compare entry 3 with 1). However, in the presence of 40 mol% of DMF the desired chloroalkane 2 ₃₄ was still formed in 70% isolated yield. Entry 1: According to general procedure III (chapter 2.1.3) a 100 mL flask with a strong stir bar was charged with 1-octanol (1 ₃₄ , 32.3 mL, 26.58 g, 200 mmol, l.O equiv) and FPyr (5.9 mL, 6.13 g, 60.0 mmol, 30 mol%) and heated to 80 °C. Then benzoyl chloride (24.2 mL, 29.25 g, 206 mmol, 1.03 equiv) was added through a dropping funnel within 2.25 h. After 0.5 h of further stirring at 80 °C reaction control by ^X H-NM revealed full conversion, a chloride 2 ₃₄ to benzoate 3 ₃₄ ratio of 89:11 and 6 mol% of octyl formiate 7 ₃₄ (referred to 2 ₃₄ ). After cooling down to room temperature the resulting suspension was subjected to distillation at 3.0 mbar through a micro distillation apparatus without dispenser, whereby the collecting flask was cooled in an ice bath. With a boiling range of 61-92 °C a colorless liquid with traces of a solid precipitate was collected (25.88 g, oil bath temperature 100- 150 °C). To remove residual benzoic acid the neat distillate was washed in a 60 mL syringe with water/brine (10 mL/5 mL), water (10 mL) and a mixture of saturated, aqueous Na ₂ C0 ₃ -solution/brine (5 mL/5 mL). Drying over MgS0 ₄ finally provided the chloride 2 ₃₄ as a colorless liquid (25.65 g). Considering 4 mol% of residual formiate 7 ₃₄ ( ¹ H-NMR) the chloroalkane 2 ₃₄ was obtained in 83% yield (165.5 mmol).

Entry 2: As described in general procedure III (chapter 2.1.3) to a solution of 1-octanol (1 ₃₄ , 200 mmol, 1.0 equiv) and FPyr (3.9 mL, 4.09 g, 40.0 mmol, 20 mol%) in 2-MeTHF (100 mL, 2 M, in a 250 mL flask) (In dioxane as solvent 1.1 equiv of BzCI were required to achieve full conversion. Due to codistillation of dioxane during purification chloride 2 ₃₄ was isolated in a diminished yield of 62% (PH1016). Also in MTBE 1.1 equiv of BzCI were necessary to drive the reaction towards full conversion. Additionally, chloride 2 ₃₄ was obtained in an depleted yield of 68% due to pronounced ester 3 ₃₄ formation (2 ₃₄ /3 ₃₄ 78:22)) was added benzoyl chloride (24.6 mL, 29.82 g, 210 mmol, 1.05 equiv) within 1.5 h at 80 C (without reflux condenser). After 2 h of further stirring at 80 °C ^X H- NMR proved full conversion (2 ₃₄ /3 ₃₄ 88:12, 4 mol% residual formiate 7 ₃₄ referred to 2 ₃₄ ). Past cooling down to room temperature the reaction mixture was concentrated under reduced pressure und dried at 50 mbar for 5 min. Distillation at 2.8 mbar as given for entry 1 delivered a prefraction with a boil ing area of 34-44 °C (1.118 g, oil bath temperature 80 °C) consisting of the chloride 23 ₄ and 14mol% 2-MeTHF. Further increasing the oil bath temperature to 100-150 °C then provided a fraction (24.20 g) with a boiling range of 63-85 °C. Finally washing and drying of this fraction as described for entry 1 gave chlorooctane 2 ₃₄ as a colorless liquid (22.67 g) in a yield of 75% (149.3 mmol) under consideration of 2mol% residual formiate 7 ₃₄ .

Entry 3: In accordance to general procedure III (chapter 2.1.3) 1-octanol (1 ₃₄ , 200 mmol, l.O equiv), DMF (9.3 mL, 120 mmol, 60 mol%) and benzoyl chloride (23.9 mL, 28.97 g, 204 mmol, 1.02 equiv) were combined at 80 °C within 2 h. ¹ H-NM after further 0.25 h of stirring at 80 °C showed full consumption of the starting material 1 ₃₄ , a ratio 2 ₃₄ /3 ₃₄ of 89:11 and 8 mol% of octyl formiate 7 ₃₄ (referred to 2 ₃₄ ). Distillation as described in entry 1 at 10 mbar next delivered a mixture of the chloride 2 ₃₄ and DMF with a boiling range of 57-90 °C as a colorless emulsion (34.60 g, oil bath temperature 95-160 °C). To remove DMF the neat distillate was washed in a 60 mL syringe with water/brine (15 mL/5 mL), water (20 mL) and a mixture of saturated, aqueous Na ₂ C0 ₃ -solution/brine (10 mL/5 mL) and dried over MgS0 ₄ to give the chloride 2 ₃₄ as a colorless liquid (24.92 g). Accounting 4 mol% of residual octyl formiate chlorooctane 2 ₃₄ was obtained in 80% yield (160.7 mmol).

Entry 4: In alignment to general procedure III (chapter 2.1.3) 1-octanol (1 ₃₄ , 200 mmol, l.O equiv), DMF (6.2 mL, 80 mmol, 40 mol%) and benzoyl chloride (1.02 equiv) were combined at 80 °C within 1.5 h. ¹ H-NMR after further 1 h of stirring at 80 °C showed full consumption of the starting material 1 ₃₄ , a ratio 2 ₃₄ /3 ₃₄ of 84:16 and 10 mol% of octyl formiate 7 ₃₄ (referred to 2 ₃₄ ). Distillation as described in entry 1 at 10 mbar gave a mixture of the chloride 2 ₃₄ and DMF with a boiling range of 61-95 °C as a colorless emulsion (29.14 g, oil bath temperature 100-160 °C). Next the neat distillate was washed as described in entry 3 and dried over MgS0 ₄ to result in the chloride 2 ₃₄ as a colorless liquid (24.28 g). Considering 4 mol% of residual octyl formiate the product 2 ₃₄ was isolated in a yield of 70% (140.8 mmol).

M (C ₈ H ₁₇ CI) = 148.67 g/mol

4.4.6.3 Synthesis of 1-Chlorobutane (2 ₃₅ )

7 ₃₅ full conversion, a chloride 2 ₃₅ to benzoate 3 ₃₅ ratio of 83:17 and 11 mol% of butyl formiate 7 ₃₅ (referred to 2 ₃₄ ). Fractioned distillation through a Claisen bridge with a 20 cm water cooler at 500 mbar delivered a major fraction with a bp. of 47-49 °C (12.14 g, oil bath temperature 95-130 °C) and a second fraction (3.55 g, oil bath temperature 140-170 °C) both as colorless liquids. ¹ H-NM showed 2 mol% residual formiate 7 ₃₅ in the first and 11 mol% in the second fraction. Thus chlorobutane 2 ₃₅ was obtained in 81% yield (162.5 mmol).

M (C ₄ H ₉ CI) = 92.57 g/mol

4.4.6.4 Synthesis of l-Chloro-2-phenylethane (2 ₃₆ )

dioxane (2 M), 2 h 80°C

1. Isolated yield 2. Yield determined via NMR-Standard.

While chlorination of 2-phenylethanol 1 ₃₆ with less reactive 4-methoxybenzoyl chloride provided chloride 2 ₃₆ in 78% yield (entry 1), with benzoyl chloride the yield depleted to 73% (entry 2).

Entry 1: According to general procedure II (chapter 2.1.2) 2-phenylethanol (1 ₃₆ , 247 μί, 252 mg, 2.00 mmol, 1.00 equiv), DMF (62 μΐ, 0.80 mmol, 59 mg, 40 mol%), dioxane (1 mL, 2 M) and 4- MeOBzCI (328 μί, 414 mg, 2.40 mmol, 1.2 equiv) were combined at ambient temperature and allowed to stir for 3 h at 80 °C. ¹ H-NMR of the crude product (440 mg) revealed full conversion and a chloride 2 ₃₆ to ester 3 ₃₆ ratio of 86:14. Finally chromatographic purification on silica gel (mass of crude material/Si0 ₂ 1:10) with Et ₂ 0//iPen 1:99 delivered the alkyl chloride 2 ₃₆ as a colorless oil in 78% yield (218 mg, 1.55 mmol).

Entry 2: Following general procedure II (chapter 2.1.2) 2-phenylethanol (1 ₃₆ 2.00 mmol, 1.00 equiv), DMF (0.80 mmol, 40 mol%), dioxane (1 mL, 2 M) and BzCI (282 μΐ, 341 mg, 2.40 mmol, 1.2 equiv) were combined at ambient temperature and allowed to react for 2 h at 80 °C. ¹ H-NMR of the crude material (400 mg) shoed complete consumption of the alcohol 1 ₃₆ and a ratio 2 ₃₆ /3 ₃₆ of 80:20. Then chromatographic purification on silica gel (mass of crude material/Si0 ₂ 1:10) with Et ₂ 0//iPen 1:99 gave the alkyl chloride 2 ₃₆ as a colorless oil in 73% yield (204 mg, 1.45 mmol).

M (CgHgCI) = 140.61 g/mol 4.4.6.5 Synthesis of roc-l-Chloro-3,7-dimethyl-6-octene (citronellyl chloride, 2 ₃₇ )

According to general procedure II (chapter 2.1.2) rac-3,7-dimethyl-6-octen-l-ol (1 ₃₇ , 247 μί, 252 mg, 2.00 mmol, 1.00 equiv, 95% purity), DMF (62 μί, 0.80 mmol, 59 mg, 40 mol%), dioxane (2 mL, 1 M) and 4-MeOBzCI (328 μΐ, 414 mg, m ^mo L 1-2 equiv) were combined at ambient temperature and allowed to stir

for 2 h at 80 °C. ¹ H-NM of the crude product (440 mg) revealed full conversion

2 ₃₇

and a chloride 2 ₃₇ to ester 3 ₃₇ ratio of 88:12. Finally chromatographic purification on silica gel (mass of crude material/Si0 ₂ 1:11) with Et ₂ 0//iPen 1:99 lead to the isolation of chloride 2 ₃₇ as a colorless oil in 82% yield (285 mg, 1.63 mmol).

M (C ₁₀ H ₁₉ CI) = 174.71 g/mol; r _f (Si0 ₂ , Et ₂ 0//iPen 1:99) = 0.55; HR-MS (CI, PH451, [C ₁₀ H ₁₉ CI ³⁵ ] ⁺ ) calc. 174.1175 u found 174.1134 u, ([C ₁₀ H ₁₇ CI ³⁵ ] ⁺ ) calc. 172.1019 found 172.1021 u.

4.4.6.6 Synthesis of l-Chloro-3-methyl-3-butene (2 ₃₈ )

According to general procedure III (chapter 2.1.3) a 1000 mL three necked 15 flask with a strong stir bar was charged with 3-methyl-3-buten-l-ol (1 ₃₈ ,

209 mL, 177.6 g, 2000 mmol, 1.0 equiv) and DMF (93 mL, 1200 mmol,

2

60 mol%) and equipped with a dropping funnel with pressure balance, reflux condenser and internal thermometer with quick fit. The mixture was heated to 80 °C and benzoyl chloride (240 mL, 2040 mmol, 1.02 equiv) was added

7 ₃₈ 20 through the dropping funnel within 5 h. During the addition of the acid chloride the internal temperature remained between 80-90 °C, no refluxing was observed. After 15 min of further stirring at 80 °C H-NMR of a small

aliquot of the reddish reaction solution (ca. 10 mg) revealed full conversion,

/-2 ₁₈

an ratio of the chloride 2 ₃₈ to the ester 3 ₃₈ of 90:10 and a ratio 2 ₃₈ /3 ₃₈ /7 ₃₈ //- 25 2 ₁₈ /2 ₅₄ of 73:8:5:4:10. After cooling down to room temperature, whereby benzoic acid precipitated, the dropping funnel was exchanged with a Claisen

2 ₅₄ distillation bridge with a 20 cm cooler, the reflux condenser and thermometer were replaced by glas stoppers. Next the pressure was lowered carefully (gas evolution) under vigorous stirring to 100 mbar (Distillation at 500 mbar effected partially isomerisation from homoallyalcohol 2 ₃₈ to the thermodynamic more stabile allyl alcohols l-/b-2 _is ) (applied by a membrane pump). Distillation delivered a turbid colorless liquid (149.77 g) with a boiling range from 42-65 °C (oil bath temperature 85-120 °C). Thereby the collecting flask was cooled in an ice bath. Residual DMF and benzoic acid were separated by washing of the neat distillate in a 250 mL extraction funnel successively with brine/water (40 mL/40 mL), water (2x40 mL) and a mixture of saturated, aqueous Na ₂ C0 ₃ -solution/brine (10 mL/30 mL). Then drying over MgS0 ₄ provided the chloride 2 ₃₈ as a colorless liquid (140.46 g, 134.3 mmol, 67%) in 90% purity. ¹ H-NM showed a ratio of 2 ₃₈ /73 ₈ //-2 ₁₈ /2 ₅ 4 90:4:4:2.

A second distillation at 500 mbar through a micro distillation apparatus with NS 29 cooling finger and with a Vigreux column (10 cm pathway, vacuum-mantled, metal-coated) delivered in the beginning a fraction (11.23 g) with a boiling range of 25-76 °C containing 2 ₃₈ //-2i ₈ /6-2i ₈ /isoprene in a ratio of 91:3:4:3 according to ¹ H-NMR (oil bath temperature 105-110 °C). Next a fraction with a bp. of 77- 81 °C was collected (113.76 g, 1088 mmol, 54%, colorless liquid) at an oil bath temperature of 110- 125 °C, which contained the desired chloride 2 ₃₈ and traces of prenyl chloride /-2i ₈ and its regioisomer 6-2i ₈ in a ratio of 95:4:1. Further increasing the oil bath temperature from 150 to 170 °C lead to the accumulation of a third fraction (7.83 g) with a boiling range of 85-103 °C, which composition was determined by ¹ H-NMR to be 2 ₃₈ /7 ₃₈ //-2i ₈ /2 ₅₄ 28:28:16:28.

In the following the first fraction (of the previous distillation) was subjected to a third (fractioned) distillation at 1 atm through a micro distillation apparatus with Vigreux column (14 cm pathway) to yield further homoallyl chloride 2 ₃₈ as a colorless oil with a bp. of 102-103 °C (7.96 g, 76.1 mmol, 4%, oil bath temperature 140-160 °C). ¹ H-NMR revealed a mixture of 2 ₃₈ / l-2 ₁₈ j b-2 ₁₈ 96:3:1. Thus the aliphatic chloride was isolated in total in a yield of 58% (121.72 g, 1164 mmol, 58%) in a purity of 95%.

M (C ₅ H ₉ CI) = 104.57 g/mol.

4.4.6.7 Synthesis of l-Chloro-2-ethylhexane (2 ₃₉ )

According to general procedure III (chapter 2.1.3) a 100 mL flask with a strong stir bar was charged with 2-ethyl-l-hexanol (1 ₃₉ , 32.2 mL, 26.30 g, 200 mmol, l.O equiv) and DMF (9.3 mL, 120.0 mmol, 60 mol%) and heated to 100 °C. Then benzoyl chloride (23.9 mL, 28.97 g, 204 mmol, 1.02 equiv) was added through a dropping funnel within 2 h. After 0.25 h of further stirring at 100 °C reaction control by ¹ H-NMR revealed full conversion, a chloride 2 ₃₉ to benzoate 3 ₃₉ ratio of 84:16 and 19 mol% formiate 7 ₃₉ (referred to 2 ₃₉ ). After cooling down to room temperature the resulting suspension was subjected to distillation at 10.0 mbar through a micro distillation apparatus without dispenser, whereby the collecting flask was cooled in an ice bath. With a boiling range of 58-78 °C a colorless liquid with traces of a solid precipitate was collected (29.31 g, oil bath temperature 90- 150 °C). To remove residual benzoic acid and DMF the neat distillate was washed in a 60 mL syringe with water/brine (10 mL/5 mL), water (15 mL) and a mixture of saturated, aqueous Na ₂ C0 ₃ - solution/brine (5 mL/10 mL). Drying over MgS0 ₄ finally gave the chloride 2 ₃₉ as a colorless liquid (21.48 g). Considering 11 mol% of residual formiate 7 ₃₉ ( ¹ H-N M ) the chloroalkane 2 ₃₉ was obtained in a yield of 65% (129.3 mmol).

M (C ₈ H ₁₇ CI) = 148.67 g/mol.

4.4.6.8 Synthesis of l-Chloro-2-methylpropane (2 ₄₀ )

Following general procedure I I I (chapter 2.1.3) a 100 mL flask was charged with

/ ^' so-butanol (1 ₄₀ , 18.7 mL, 14.97 g, 200 mL, l.O equiv) and DMF (7.7 mL,

100 mmol, 50 mol%) and heated to 100 C. In the following benzoyl chloride

10 (25.8 mL, 31.24 g, 220 mmol, 1.1 equiv) was added dropwise within 1.75 h. After

O

1 I I 0.5 h of further stirring at 80 °C reaction control by ¹ H-N MR revealed full 7 conversion, a chloride 2 ₄₀ to benzoate 3 ₄₀ ratio of 81:19 and 12 mol% of formiate

2 ^'

7 ₄₀ (referred to 2 ₄₀ ). Fractioned distillation through a Claisen bridge with a 20 cm ^ ⁴⁰ water cooler at 1 atm provided a fraction with a boiling range of 54-68 °C (11.76 g, colorless liquid, oil bath temperature 110-200 °C) consisting of the alkyl chloride 2 ₄₀ alongside with 8 mol% of the formyl ester 7 ₄₀ as shown by ¹ H-N MR. Thus chlorobutane 2 ₄₀ was obtained in 58% yield (116.3 mmol).

M (C ₄ H ₉ CI) = 92.57 g/mol. 4.4.6.9 Synthesis of l-(Allyloxycarbonylamino)-2-chloroethane(2 ₄₁ )

According to general procedure I I (chapter 2.1.2) 2- (Allyloxycarbonylamino)-l-ethanol (1 ₄₁ , 145 mg, 1.00 mmol, l.O equiv),

FPyr (19.7 μΐ, 20.4 mg, 0.20 mmol, 20 mol%), dioxane (1 mL, 1 M) and

2 ₄₁

benzoyl chloride (141 μί, 171 mg, 1.20 mmol, 1.2 equiv) were mixed at room temperature and then allowed to stir for 2 h at 80 °C. ¹ H-N MR of the crude material (193 mg) revealed full conversion and a chloride 2 _4i to ester 3 _4i ratio of 84:16. Chromatographic purification on silica gel (mass crude product/Si0 ₂ 1:40) with Et ₂ 0//iPen 30:70 delivered the chlorinated carbamate 2 _4i as a colorless oil (112 mg, 0.685 mmol, 69%).

M (C ₆ H ₁₀ CINO ₂ ) = 163.60 g/mol; r _f (Si0 ₂ , Et ₂ 0//iPen 30:70) = 0.22 (nPen/OEt ₂ 7:3); ¹ H-NMR (400 M Hz, CDCI3) δ [ppm] = 5.93 (ddt, 1H, H-2 ^' J = 17.2, 10.4, 5.6 Hz), 5.32 (ddt, 1H, H-3 ^' _& J = 17.2, 1.6, 1.6 Hz), 5.23 (ddt, 1 H, H-3 ^' _z , J = 10.4, 1.2, 1.2 Hz), 5.19 (bs, 1 H, NH), 4.58 (d, 2 H, H-l ^' , J = 5.6 Hz), 3.62 (t, 2H, H-l, J = 5.6 Hz), 3.53 (dt, 2 H, H-2, J = 5.6, 5.6 Hz); ¹³ C-NMR (100 MHz, CDCI ₃ ) δ [ppm] = 156.1 (C-3), 132.6 (C-2 ^' ), 117.9 (C-3 ^' ), 65.8 (C-l ^' ), 44.1 (C-2), 42.8 (C-l); GC-MS (El, 70 eV) m/z [u] = 163 (5, [M] ⁺ ), 128 (<1, [M-CI] ⁺ ), 114 (68, [M-CH ₂ CI] ⁺ ), 106 (12, [M-OAIIyl] ⁺ ), 86 (1, [AllylOCOH] ⁺ ), 70 (42), 63 (62, [C ₂ H ₄ CI] ⁺ ), 58 (100, [AllylOH] ⁺ ); HR-MS (CI, [C ₆ H _n N0 ₂ CI] ⁺ ) m/z calc. 164.0473 u found 164.0470 u. 4.4.6.10 Synthesis of l-(Benzyloxycarbonylamino)-2-chloroethane (2 ₄₂ )

Chloride 2 ₄₂ was prepared as described in general procedure I I

(chapter 2.1.2) from 2-(benzyloxycarbonylamino)-l-ethanol 1 ^■ ,42 (195 mg, 1.00 mmol, l.O equiv) with benzoyl chloride (141 μί,

171 mg, 1.20 mmol, 1.2 equiv) and FPyr (19.7 μί, 20.4 mg,

0.20 mmol, 20 mol%) in dioxane (1 mL, 1 M) at 80 °C for 2 h. ¹ H-N M of the crude material (253 mg) revealed full conversion and a chloride 2 ₄₂ to ester 3 ₄₂ ratio of 88:12. After chromatographic purification (mass of crude product/Si0 ₂ 1:40) with Et ₂ 0//iPen 30:70 the carbamate 2 ₄₂ was isolated as a colorless oil in 70% yield (150 mg, 0.702 mmol).

M (C ₁₀ H ₁₂ CINO ₂ ) = 213.66 g/mol; r _f = 0.18 (Si0 ₂ , Et ₂ 0//iPen 30:70); ¹ H-NMR (400 M Hz, CDCI ₃ ) δ [ppm] = 7.32-7.39 (m, 5H, H-3 ^' , H-4 ^' , H-5 ^' ), 5.17 (bs, 1H, N H), 5.12 (s, 2H, H-l ^' ), 3.62 (t, 2H, H-l, J = 5.2 Hz), 3.54 (dt, 2H, H-2, J = 5.2 Hz); ¹³ C-NMR (100 MHz, CDCI ₃ ) δ [ppm] = 156.2 (C-3), 136.3 (C-2 ^' ), 128.6 (C-4 ^' ), 128.3 (C-5 ^' ), 128.2 (C-3 ^' ), 67.0 (C-1 ^' ), 44.1 (C-2), 42.9 (C-1); GC-MS (El, 70 eV) m/z [u] = 213 (16, [M] ⁺ ), 164 (<1, [M-CH ₂ CI] ⁺ ), 152 (<1, [M-C ₂ H ₂ CI] ⁺ ), 109 (100, [BnOH ₂ ] ⁺ ), 91 (100, [Bn] ⁺ ), 79 (99, [CpCH ₂ ] ⁺ ), 77 (84, [Ph] ⁺ ), 65 (77, [Cp] ⁺ ), 63 (35, [C ₂ H ₄ CI] ⁺ ), 56 (61), 51 (43); HR-MS (CI, [C ₁₀ H ₁₃ NO ₂ CI] ⁺ ) m/z calc. 214.00629 u found 214.0635 u.

4.4.6.11 Synthesis of l-(Fluorenyloxycarbonylamino)-2-chloroethane (2 ₄₃ )

Chloride 2 ₄₂ was synthesized according to general procedure I I

(chapter 2.1.2) from 2-(fluorenyloxycarbonyl amino)-l-ethanol

1 ₄₃ (143 mg, 0.50 mmol, 1.0 equiv) with benzoyl chloride (70 μί,

85 mg, 0.60 mmol, 1.2 equiv) and FPyr (9.8 μί, 10.2 mg,

0.10 mmol, 20 mol%) in dioxane (0.5 mL, 1 M) at 80 °C for 2 h.

25 ^X H-N MR of the crude material (204 mg) proved full conversion and a chloride 2 ₄₃ to ester 3 ₄₃ ratio of 90:10. Chromatographic purification (mass of crude product/Si0 ₂ 1:60) with Et ₂ 0//iPen 30:70 provided the carbamate 2 ₄₃ as a colorless solid in 82% yield (123 mg, 0.409 mmol).

M (C ₁₇ H ₁₆ CIN0 ₂ ) = 301.770 g/mol; r _f (Si0 ₂ , Et ₂ 0//iPen 50:50) = 0.38; mp. = 106-109 °C; ¹ H-NMR (400 M Hz, CDCI3) δ [ppm] = 7.77 (d, 2H, H-7 ^' , J = 7.6 Hz), 7.59 (d, 2H, H-4 ^' , J = 7.6 Hz), 7.41 (dd, 2H, H-7 ^' , J = 7.6, 7.6 Hz), 7.32 (ddd, 2H, H-5 ^' , J = 7.6, 7.6, 1.2 Hz), 5.17 (bs, 1H, N H), 4.42 (d, 2H, H-l ^' , J = 6.8 Hz), 4.23 (t, 1H, H-2 ^' , J = 6.8 Hz), 3.62 (t, 2H, H-l, = 5.2 Hz), 3.35 (dt, 2H, H-2, = 5.6, 5.6 Hz); ¹³ C-NMR (100 MHz, CDCI3) δ [ppm] = 153.6 (C-3), 143.8 (C-3 ^' ), 141.4 (C-8 ^' ), 127.8 (C-6 ^' ), 127.1 (C-5 ^' ), 125.0 (C-4 ^' ), 120.0 (C-7 ^' ), 66.9 (C-1 ^' ), 47.2 (C-2 ^' ), 44.1 (C-2), 42.9 (C-1); GC-MS (El, 70 eV) m/z [u] = 302 (<1, [M+H] ⁺ ), 266 (<1, [M-CI] ⁺ ), 225 (<1, [FmocH+H] ⁺ ), 178 (100, [M-C0 ₂ -H ₂ N(CH ₂ ) ₂ OH] ⁺ ), 152 (19, [C ₁₂ H ₈ ] ⁺ ), 89 (25, [HCONH(CH ₂ ) ₂ OH] ⁺ ), 76 (37, [C ₆ H ₄ ] ⁺ ), 63 (10, [C ₂ H ₄ CI] ⁺ ); HR-MS (CI, [C ₁₇ H ₁₆ N0 ₂ CI] ⁺ ) calc. 301.0864 u found 301.0867 u.

4.4.6.12 Synthesis of l-(Pivaloylamino)-2-chloroethane (2 ₄₄ )

As given general procedure II (chapter 2.1.2) 2-(pivaloylamino)-l-ethanol 1 ₄₄ (73 mg, 0.50 mmol, l.O equiv), FPyr (9.8 μί, 10.2 mg, 0.10 mmol, 20 mol%),

dioxane (0.5 mL, 1 M) and benzoyl chloride (70 μί, 85 mg, 0.60 mmol,

2 ₄₄

1.2 equiv) were combined at room temperature and subsequently allowed to react at 80 °C for 2 h. Chromatographic purification (mass of crude product/Si0 ₂ 1:50) with Et ₂ 0//iPen 40:60 of the crude material (110 mg) provided the chloride 2 ₄₄ as a colorless solid in 75% yield (61 mg, 0.373 mmol).

M (C ₇ H ₁₄ CINO) = 163.65 g/mol; r _f (Si0 ₂ , Et ₂ 0//iPen 50:50) = 0.15; mp. = 55-57 °C; ¹ H-NMR (400 MHz, CDCI3) δ [ppm] = 6.07 (bs, 1H, NH), 3.57-3.65 (m, 4H, H-l, H-2), 1.22 (s, 9H, H-2 ^' ); ¹³ C-NMR (100 MHz, CDCI3) δ [ppm] = 178.8 (s, C-l ^' ), 44.3 (C-2), 41.2 (C-l), 38.8 (C-2 ^' ), 27.5 (C-3 ^' ); GC-MS (El, 70 eV) m/z [u] = 163 (20, [M] ⁺ ), 148 (8), 128 (6, [M-CI] ⁺ ), 112 (16), 108 (40), 106 (22, [M-iBu] ⁺ ), 85 (24, [Piv] ⁺ ), 69 (17), 63 (42, [C ₂ H ₄ CI] ⁺ ), 57 (100, [tBu] ⁺ ); HR-MS (CI, [C ₇ H ₁₅ NOCI] ⁺ ) m/z calc. 164.0837 u found 164.0835 u.

4.4.6.13 Synthesis of 3-Chloropropannitrile (2 ₄₅ )

1 2 3 ci ^entr y ^sca l ^e [mmol] conditions yield 2i

BzCi (1.03 equiv), FPyr (40 mol%),

1 200 75%'

solvent-free, 5.25 h 80°C

solvent-free, 5.5 h 70°C

BzCi (1.05 equiv), DMF (40 mol%),

3 200

solvent-free, 4.5 h 70°C

1. Isolated yield

Both FPyr and FPip (40 mol%) provided chloropropionitrile 2 ₄₅ in comparable yields of 71-75% under solvent-free conditions (entry 1+2). As DMF was codistilled with the product 2 ₄₅ and consequently had to be separated from the water soluble nitrile 2 ₄₅ by aqueous washing, in the presence of DMF (40 mol%) the isolated yield depleted to 47% (entry 3).

Entry 1: According to general procedure III (chapter 2.1.3) a 100 mL flask with strong stir bar was charged with 3-hydroxypropannitrile 1 ₄₅ (14.1 mL, 14.66 g, 200 mmol, l.O equiv) and FPyr (7.9 mL, 8.10 g, 80.0 mmol, 40mol%) and heated to 80 °C. Within 1.25 h benzoyl chloride (23.9 mL, 28.97 g, 204 mmol, 1.02 equiv) was added dropwise and the reaction mixture was stirred for further 4.25 h at 80 °C. After 4 h of stirring ¹ H-NM of a small aliquot of the reaction mixture (ca. 10 mg) showed full consumption of the starting material 1 ₄₅ and a chloride 2 ₄₅ to ester 3 ₄₅ ratio of 82:18. Then the reaction solution was allowed to cool down to ambient temperature accompanied by benzoic acid precipitating. Distillation at lO mbar through a micro distillation apparatus without dispenser delivered the chloride 2 ₄₅ as a colorless oil (13.75 g) with a boiling range of 66-80 °C (oil bath temperature 100-150 °C). As ¹ H-NMR showed 2 mol% formiate 7 ₄₅ (referred to 2 ₄₅ ), the desired chloroalkane 2 ₄₅ was obtained in 75% yield (150.2 mmol).

Entry 2: As described in general procedure III (chapter 2.1.3) to a mixture of alcohol 1 ₄₅ (200 mmol, 1.0 equiv) and FPip (8.9 mL, 9.14 g, 80 mmol, 40 mol%) was added BzCI (204 mmol, 1.02 equiv) throughout 2.25 h under heating to 70 °C. Reaching full conversion (as verified by ¹ H-NMR 2 ₄₅ /3 ₄₅ 76:24) required further 4 h of stirring at 70 °C. Distillation at lO mbar as described for entry 1 delivered the nitrile 2 ₄₅ as a colorless oil (12.78 g, 142.8 mmol, 71%) with a boiling range of 79- 117 °C.

Entry 3: Following general procedure III (chapter 2.1.3) a mixture of alcohol 1 ₄₅ (200 mmol, 1.0 equiv) and DMF (6.2 mL, 5.85 g, 80 mmol, 40 mol%) was treated dropwise with BzCI (24.2 mL, 29.25 g, 206 mmol, 1.03 equiv) within 2.5 h at 80 °C. After further 2.5 h of stirring at 80 °C full consumption of the starting material 1 ₄₅ was proven by ¹ H-NMR (2 ₄₅ /3 ₄₅ 76:24). Distillation at lO mbar as given in entry 1 then provided a colorless liquid (18.07 g) with a boiling range of 73-121 °C (oil bath temperature 105-170 °C) consisting of the chloride 2 ₄₅ and 50 mol% DMF. Considering residual DMF the chloride 2 ₄₅ was obtained in 72% yield (143.3 mmol). To remove DMF the neat distillate was washed in a 60 mL syringe successively with water (1 x 10 mL, 3 x 5 mL) and a mixture of saturated, aqueous Na ₂ C0 ₃ -solution and water (1/4 mL). Drying over MgS0 ₄ in the following delivered the aliphatic chloride 2 ₄₅ as a colorless liquid in 52% yield (9.29 g, 103.7 mmol).

4.4.7 Synthesis of Secondary and Tertiary Aliphatic Chlorides

The following scheme provides an overview over secondary and tertiary aliphatic chlorides synthesized by formamide catalyzed chlorinations. Deviations from standard conditions are given in parenthesis: Standard Conditions

in dioxane (1 M): BzCI (1 .03-1 .2 equiv), FPyr (20 mol%), <24 h 80 °C 200 mmol scale solvent-free: BzCI (1 .00-1 .05 equiv), DMF (60 mol%), <24 h 80 °C

4.4.7.1 Synthesis of roc-2-Chlorooctane (2 ₄₆ )

According to general procedure II (chapter 2.1.2) racemic 2-octanol (1 ₄₆ , 332 μί, 268 mg, 2.00 mmol, 1.0 equiv), DMF (62 μί, 0.80 mmol, 59 mg, 40 mol%), dioxane (1 mL, 2 M) and BzCI (282 μί, 341 mg, 2.40 mmol, 1.2 equiv) were combined at

ambient temperature and allowed to stir for 2 h at 80 °C. ¹ H-NM of the crude product (416 mg) revealed full conversion and a chloride 2 ₄₆ to ester 3 ₄₆ ratio of 81:19. Chromatographic purification on silica gel (mass of crude material/Si0 ₂ 1:14) with nPen delivered the chloride 2 ₄₆ as a colorless oil in 76% yield (227 mg, 1.53 mmol).

M (C ₈ H ₁₇ CI) = 148.67 g.

4.4.7.2 Synthesis of rac-2-Chlorobutane (2 ₄₇ )

CI According to general procedure III (chapter 2.1.3) a 100 mL flask with a strong stir

{ζ bar was charged with racemic 2-butanol (roc-2 ₄₇ , 18.5 mL, 14.97 g, 200 mmol, 2 ₄₇ 1.0 equiv) and DMF (9.3 mL, 8.77 g, 120 mmol, 60 mol%) and heated to 80 °C. Next benzoyl chloride (25.8 mL, 31.24 g, 220 mmol, 1.1 equiv) was added over 2.25 h. Then the reaction mixture was allowed to stir for further 1.5 h at 80 °C to reach full conversion, as proven by ¹ H-NMR. Additionally, the chloride 2 ₄₇ to ester 3 ₄₃ was

20 determined to be 92:8 and 6 mol% of formiate 7 ₄₇ (referred to 2 ₄₇ ) were observed.

7 ₄₇

After cooling down to ambient temperature the resulting suspension was subjected to distillation at 1 atm through a Claisen bridge with a 20 cm cooler providing a colorless liquid with a boiling rang of 55-62 °C (15.36 g, oil bath temperature 120-180 °C). Accounting 3 mol% of residual formyl ester 7 ₄₇ the chloride 2 ₄₇ was obtained in 80% yield (160.5 mmol). M (C ₄ H ₉ CI) = 92.57 g/mol

4.4.7.3 Synthesis of roc-2-Chloro-4-phenylbutane (2 ₄₈ )

According to general procedure II (chapter 2.1.2) to a solution of racemic 4- phenyl-2-butanol (313 μΐ, 304 mg, 2.00 mmol, 1.0 equiv) and FPyr (39 μΐ, 41 mg, 0.40 mmol, 20 mol%) in dioxane (2 mL, 1 M) was added benzoyl

248 chloride (280 μί, 2.40 mmol, 1.2 equiv) within 20 min via a syringe pump at

80 °C. The resulting mixture was then allowed to stir for 21 h at 80 °C. ¹ H-NM of the crude material (526 mg) revealed full consumption of the starting material roc-l ₄₈ and a chloride 2 ₄₈ to ester 3 ₄₈ ratio of 85:15. After chromatographic purification (mass crude product/Si0 ₂ 1:9) with Et ₂ 0//iPen 1:99 the chloride roc-2 ₄₈ was isolated as a colorless liquid in 81% yield (272 mg, 1.61 mmol).

M (C ₁₀ H ₁₃ CI) = 168.66 g/mol; r _f (Si0 ₂ , Et ₂ 0//iPen 1:99) = 0.66.

4.4.7.4 Synthesis of /?-2-Chloro-4-phenylbutane ( ?-2 ₄₈ )

4-MeOBzCi (1.2 equiv), FPyr (20 mol%),

2 1.0 99:1 75%' dioxane (1 M), 18 h 80 °C

4-MeOBzCI (1.2 equiv), FPyr (20 mol%),

3 0.3 99:1 83% ²

2-MeTHF (1 M), 24 h 80 °C

4 0.3 BzCi (1.2 equiv), DMF (1 M), 24 h 40 °C 98:2 76% ²

1. Isolated yield 2. Yield determined via NMR-Standard.

With BzCi as well as 4-MeOBzCI the chloride ?-2 ₄₈ was isolated in 75% yield and under full retention of the optical purity (er > 99.5:0.5; entries 1+2). Dioxane could be replaced with the more environmentally friendly solvent 2-MeTHF without effecting the enantiopurity of the product ?-2 ₄₈ (entry 3). Remarkably, with DMF as solvent a slightly but clearly depleted er (98:2) was observed.

Entry 1: According to general procedure II (chapter 2.1.2) to a solution of enantiopure S-4-Phenyl-2- butanol (S-2 ₄₈ 235 μΐ, 228 mg, 1.51 mmol, 1.0 equiv; er > 99.5:0.5 according to chiral HPLC) and FPyr (30 μΐ, 31 mg, 0.30 mmol, 20 mol%) in dioxane (1.5 mL, 1 M) was added benzoyl chloride (210 μΐ, 1.81 mmol, 1.2 equiv) within 15 min via a syringe pump at 80 °C. The resulting mixture was then allowed to stir for 14 h at 80 °C. ¹ H-NM of the crude material (396 mg) revealed full consumption of the starting material S-l ₄₈ and a chloride 2 ₄₈ to ester 3 ₄₈ ratio of 85:15. After chromatographic purification (mass crude product/Si0 ₂ 1:9) with Et ₂ 0//iPen 1:99 the chloride 2 ₄₈ was isolated as a colorless liquid in 75% yield (190 mg, 1.126 mmol). Chiral GC analysis from both the crude material and the isolated product revealed an enantiopurity of er 99.5:0.5.

Entry 2: As described in general procedure II (chapter 2.1.2) S-4-Phenyl-2-butanol (156 μί, 152 mg, 1.00 mmol, 1.0 equiv; er > 99.5:0.5 according to chiral HPLC) and FPyr (19.7 μΐ, 20.4 mg, 0.20 mmol, 20 mol%), dioxane (1 mL, 1 M) and 4-methoxybenzoyl chloride (164 μΐ, 208 mg, 1.20 mmol, 1.2 equiv) were combined at ambient temperature and then heated to 80 °C for 18 h. ¹ H-NMR of the crude material (267 mg) showed full conversion and a ratio 2 ₄₈ /3 ₄₈ of 86:14. Chromatographic purification (mass crude product/Si0 ₂ 1:10) with Et ₂ 0//iPen 1:99 delivered the chloride ?-2 ₄₈ as a colorless liquid in 75% yield (126 mg, 0.745 mmol). Chiral GC analysis from both the crude material and the isolated product revealed an enantiopurity of er > 99.5:0.5.

Entry 3: Following general proced ure I (chapter 2.1.1) the chloride ?-2 ₄₈ was prepared from alcohol S-l ₄₈ (47 μΐ, 46 mg, 0.300 mmol, 1.0 equiv; er > 99.5:0.5 according to chiral HPLC) with 4-MeOBzCI (49 μί, 62 mg, 0.360 mmol, 1.2 equiv) and FPyr (5.9 μΐ, 6.1 mg, 0.060 mmol, 20 mol%) in 2-MeTHF (0.3 mL, 1 M) at 80 °C for 24 h. ¹ H-NMR of the crude material with naphthalene as NMR-standard revealed chloride 2 ₄₈ in 83% beside the benzoate 3 ₄₈ in 12% (2 ₄₈ /3 ₄₈ 87:13) and formiate 7 ₃₈ in 5% yield. Chiral GC uncovered an er of > 99.5:0.5.

Entry 4: In analogy to general procedure I (chapter 2.1.1) to a solution of alcohol S-l ₄₈ (0.300 mmol, 1.0 equiv; er > 99.5:0.5 according to chiral HPLC) in DMF (300 μΐ, 1 M) was added at room temperature benzoyl chloride (42 μί, 51 mg, 0.360 mmol, 1.2 equiv). After stirring for 24 h at 40 °C and work up ¹ H-NMR with naphthalene as standard showed chloride 2 ₄₈ in a yield of 71% yield with traces of the benzoate 3 ₄₈ (< 2%). A er of ?-2 ₄₈ of 98:2 was determined by chiral GC.

[ct] _D ²⁰ (c = 1.18 g/100 mL, CHCI ₃ ) = -73.0.

The separation conditions for the enantiomers of chloride 2 ₄₈ through chiral gas chromatography were: Column CP-Chirasil-Dex CB; Temperature program 100 °C for 40 min, gradient 20 °C/min to 200 °C, 200 °C for 5 min, column flow 1.5 mL/min, split ratio 15; PTV injector temperature 250 °C. Samples of a concentration of 2 mg/1 mL DCM were injected (1 μί injection volume). 4.4.7.5 Synthesis of Cholesteryl chloride (2 ₄₉ )

80 °C

L ₄ 9

BzCl (1.2 equiv), FPyr

(20 mol%), dioxane (1 M), 14 h 59% ²

80 °C

1. Isolated yield 2. Yield determined via N M -Standard.

As crude chloride 2 ₄₉ had to be adsorbed on silica gel prior to chromatographic purification (due to its low solubility in the eluent), cholesteryl chloride 2 ₄₉ was isolated in a lower yield (46%, entry 1) than determined by N MR-standard from the crude material (59%, entry 2).

Entry 1: According to general procedure I I (chapter 2.1.2) to a solution of cholesterol 1 ₄₉ (387 mg, 1.00 mmol, 1.0 equiv) and FPyr (19.7 μΐ, 20.4 mg, 0.20 mmol, 20 mol%) in dioxane (1 mL, 1 M) was added benzoyl chloride (140 μί, 1.20 mmol, 1.2 equiv) via a syringe pump in 30 in at 80 °C. After stirring for 8 h at 80 °C and work up with DCM instead of Et ₂ 0 the crude material (571 mg, >98% conversion, 2 ₄₉ /3 ₄ 9 60:40 according to N MR) was adsorbed on silica gel (mass crude material/Si0 ₂ 1:2) through dissolution in DCM and concentration with Si0 ₂ under reduced pressure. Chromatographic purification (mass crude material/Si0 ₂ 1:4) with nPen delivered the chloride 2 ₄₉ as a colorless solid in 46% yield (186 mg, 0.459 mmol).

Entry 2: Following general procedure I (chapter 2.1.1) cholesterol 1 ₄₉ (193 mg, 0.50 mmol, 1.0 equiv), FPyr (9.8 μΐ, 10.2 mg, 0.100 mmol, 20 mol%), dioxane (0.5 mL, 1 M) and benzoyl chloride (70 μΐ, 85 mg, 0.60 mmol, 1.2 equiv) were combined at ambient temperature and allowed to react at 80 °C for 14 h. ¹ H-NMR of the crude material with naphthalene as standard revealed cholesteryl chloride 2 ₄₉ in 59% and benzoate 3 ₄₉ in 30% yield (2 ₄₉ /3 ₄₉ 67:33).

M (C ₂₇ H ₄₅ CI) = 405.10 g/mol; r _f (Si0 ₂ , nPen) = 0.48; HR-MS (CI, PH8632, [C ₂₇ H ₄₅ CI] ⁺ ) calc. 404.3210 u found 404.3216 u, ([C ₂₇ H ₄₆ CI] ⁺ ) calc. 405.3283 u found 405.3241 u. 4.4.7.6 Synthesis of 2-Chloro-2-methyl-l-phenylpropane (2 ₅₀ )

BzCI (1.05 equiv), no catalyst, solvent-free, 2 h

3 1 38% ² *

80 °C

SOCi ₂ (1.1 equiv), solvent-free, 0.25 h 0 °C, 1.5 h

4 1 78% ² * rt

1. Isolated yield 2. Yield determined via NMR-Standard.

* Comparative Examples.

After chlorination at 80 °C in the presence of 10 mol% of FPyr the tertiary chloride 2 ₅₀ was isolated in 71% yield (entry 1). The yield of 2 ₅₀ determined by an NMR-standard indeed was better (86%, entry 2), which is rationalized by the non-trivial separation of the product 2 ₅₀ and the olefinic sideproduct 5 ₅₀ through distillation. However, in the absence of any catalyst the alkyl chloride 2 ₅₀ was obtained in only 38% yield (entry 3). Noteworthy, chlorination with thionyl chloride provided the desired product 2 ₅₀ in a diminished yield of 78% (determined by NMR-standard, entry 4, compare with entry 2). Entry 1: According to general procedure III (chapter 2.1.3) a 250 mL flask with a strong stir bar was charged with 2-methyl-l-phenyl-2-propanol (1 ₅₀ , 31.5 mL, 30.66 g, 200 mmol, 1.0 equiv) and FPyr (2.0 mL, 2.04 g, 20.0 mmol, 10 mol%) and heated to 80 °C. Next benzoyl chloride (23.7 mL, 28.68 g, 202 mmol, 1.0 equiv) was added within 1.25 h. After 2 h of further stirring reaction control via ^Χ Η- NMR of a small aliquot of the reaction mixture (ca. 10 mg) revealed full conversion and 20 mol% of styrene derivative 5 ₅₀ (referred to chloride 2 ₅₀ ).

Then the yellow reaction solution was allowed to cool down to ambient temperature. The resulting suspension was dissolved in MTBE, cooled to 0 °C and saturated, aqueous NaHC0 ₃ solution (60 mL) was added within 5 min, whereby a C0 ₂ -evolution occured. Next the mixture was transferred to a 500 mL extraction funnel, the reaction flask was rinsed with water (2 x 40 mL) and the mixture was diluted with further water (40 mL, volume total aqueous phase 0.9 mL/1 mmol of 1 ₅₀ ) to dissolve NaOBz completely. The organic phase was washed successively with further NaHC0 ₃ -solution (40 mL) and water (40 mL), dried over MgS0 ₄ , concentrated under reduced pressure and dried at 50 mbar for 5 min to give the crude chloride 2 ₅₀ as colorless oil (34.72 g, 14 mol% elimination sideproduct 5 ₅₀ referred to 2 ₅₀ ) (Although the chloride 2 ₅₀ could be separated by distillation from the reaction mixture (without work up), FPyr codistilled (removed by work up) and the separation from the sideproduct 5 ₅₀ was poor).

Fractioned distillation at 5.0 mbar through a micro distillation apparatus with Vigreux column (14 cm pathway, NS14.5) afforded initially a prefraction with a boiling range of 85-92 °C (5.40 g, oil bath temperature 115-125 °C) comprising chloride 2 ₅₀ , 124 mol% alkene 5 ₅₀ and traces BzCI ( ¹ H-NM ). Next a second fraction was collected with a boiling point of 93-95 °C (4.68 g, oil bath temperature 125 °C), which contained the desired product 2 ₅₀ and 17 mol% olefine 5 ₅₀ . Finally with a boiling point of 95 °C the tertiary chloride 2 ₅₀ was isolated as a colorless oil in 63% yield (21.16 g, 125.5 mmol, oil bath temperature 125-140 °C). To improve the isolated yield the second fraction of the previous distillation was subjected to a second fraction distillation at 20 mbar (with the same setup as described above) to give further homobenzylic chloride 2 ₅₀ as a colorless liquid in a yield of 8% (2.593 g, 15.4 mmol) and a boiling point of 114-115 °C.

Entry 2: According to general procedure I (chapter 2.1.1) the alcohol 1 ₅₀ (157 μί, 153 mg, 1.00 mmol, l.O equiv), FPyr (9.8 μΐ, 10.2 mg, 0.10 mmol, 10 mol%) and benzoyl chloride (123 μΐ, 149 mg, 1.05 mmol, 1.05 equiv) were combined at ambient temperature and subsequently allowed to react at 80 °C for 2 h. Without work up ¹ H-NMR with naphthalene as standard revealed the chloride 2 ₅₀ in 86% and elimination sideproduct 5 ₅₀ in 13% yield.

Entry 3: As described for entry 2 chlorination was performed without FPyr to give 38% of chloride 2 ₅₀ , 30% of styrene derivative 5 ₅₀ and 27% starting material 1 ₅₀ .

Entry 4: A 4 mL vial with stir bar was charged with the alcohol 1 ₅₀ (1.00 mmol, 1.0 equiv), cooled in an ice bath and thionyl chloride (90 μί, 1.20 mmol, 1.2 equiv) was added dropwise under gas evolution. After 15 min of stirring the cooling bath was removed and the mixture was allowed to stir for 1.5 h at room temperature. Without work up ¹ H-NMR with naphthalene as standard showed 78% of chloride 2 ₅₀ and 18% of styrene derivative 5 ₅₀ .

M (C ₁₀ H ₁₃ CI) = 168.66 g/mol 4.4.8 Synthesis of Bromides

4.4.8.1 Synthesis of 4-ferf-butylbenzyl bromide (7 ₂ )

According to general procedure I (chapter 2.1.1) 4-tert-butylbenzyl alcohol (1 ₂ , 89 μΐ, 83 mg, 0.50 mmol, l.O equiv), a 1 N solution of DMF in dioxane (50 μΐ, 0.05 mmol, 10 mol%), dioxane (200 μΐ, 2 M) and benzoyl bromide

(73 μί, 115 mg, 0.60 mmol, 0.60 mmol) were combined at 0 °C and allowed

to stir for 2.5 h at 0 °C and 8 h at room temperature, where after TLC control revealed full conversion. Through ¹ H-NMR of the crude material with naphthalene as standard the bromide 8 ₂ was observed on 50% yield alongside 46% of the benzoate 3 ₂ (8 ₂ /3 ₂ 52:46).

M (C _n H ₁₅ Br) =227.14 g/mol

4.5 Synthesis of Amines, Ethers, Azides and Nitrils

The following scheme provides an overview synthesis of amines, ethers, azides and nitrils: OPh

63% (NEt ₃ instead of K ₂ C0 ₃ )

Clopidogrel (rac)

78% 4.5.1 Synthesis of Amines and Azides

4.5.1.1 Synthesis of A/-(4-ferf-butylbenzyl) piperidine (4 _2a )

scale yield entry conditions

1. BzCi (1.2 equiv), FPyr (10 mol%), dioxane (2 M) 24 h rt

1 1 2. H-Pip (1.5 equiv), K ₂ C0 ₃ (2.3 equiv), dioxane/MeCN 1:4 (0.4 M), 88% ^x

12 h rt

1. BzCi (1.2 equiv), FPyr (10 mol%), dioxane (2 M) 24 h rt

2 1 2. H-Pip (1.5 equiv), NEt ₃ (2.3 equiv), dioxane/MeCN 1:3 (0.5 M), 63% ^x

24 h rt

1. Isolated yield

While with K ₂ C0 ₃ as base the piperidine derivative 4 _2a was isolated in 88% yield (entry 1), NEt ₃ gave amine 4 _2a in a diminished yield of 63% (entry 2).

Entry 1: According to general procedure IV (chapter 2.2.1) -tert- butylbenzyl alcohol (1 ₂ , 179 μΐ, 166 mg, 1.00 mmol, 1.0 equiv), FPyr (9.8 μΐ, 10.2 mg, 0.10 mmol, 10 mol%), dioxane (0.5 mL, 2 M) and benzoyl chloride (141 μί, 170 mg, 1.20 mmol, 1.2 equiv) were combined and stirred for 24 h at room temperature. In the following the reaction mixture was diluted with MeCN (2 mL, dioxane/MeCN 1:4, 0.4 M), fine-powdered K ₂ C0 ₃ (320 mg, 2.30 mmol, 2.3 equiv) and piperidine (147 μί, 128 mg, 1.50 mmol, 1.5 equiv) were added. After 12 h of stirring at room temperature TLC control indicated full consumption of chloride 2 ₅₀ . Following work up chromatographic purification (mass of crude material/Si0 ₂ 1:32) of the crude product (266 mg) with Et ₂ 0/NEt ₃ //iPen 5:3:92 delivered the amine 4 _2a as a colorless oil in 88% yield (204 mg). Entry 2: Following general procedure IV (chapter 2.2.1) the benzylic alcohol 1 ₂ (1.00 mmol, 1.0 equiv) was chlorinated with benzoyl chloride (1.20 mmol, 1.2 equiv) in the presence of FPyr (0.10 mmol, 10 mol%) in dioxane (500 μί, 2 M). After 24 h of stirring at ambient temperature the reaction mixture was diluted with MeCN (1.5 mL, dioxane/MeCN 1:3, 0.5 M), NEt ₃ (320 μΐ, 2.30 mmol, 2.3 equiv) and piperidine was added (1.50 mmol, 1.5 equiv). The resulting reaction mixture was stirred for further 24 h at ambient temperature. Chromatographic purification of the crude material (247 mg) on silica gel (mass of crude material/Si0 ₂ 1:50) with Et ₂ 0/NEt ₃ //iPen 3:3:94 delivered the piperidine derivative 4 _2a as a colorless oil (145 mg, 0.625 mmol, 63%).

M (C ₁₆ H ₂₅ N) = 231.38 g/mol; HR-MS (CI, PH8052, [C ₁₆ H ₂₄ N] ⁺ ) calc. 230.1903 u found 230.1936 u; ([C ₁₆ H ₂₅ N] ⁺ ) calc. 231.1987 u found 231.1991 u; ([C ₁₆ H ₂₆ N] ⁺ ) calc. 232.2065 u found 232.2052 u.

4.5.1.2 Synthesis of (4-ferf-Butylbenzyl)cyclohexylamine (4 _2b )

According to general procedure IV (chapter 2.2.1) 4-ieri-butyl benzyl alcohol (1 ₂ , 179 μΐ, 166 mg, 1.00 mmol, l.O equiv), FPyr (9.8 μΐ, 10.2 mg, 0.10 mmol, 10 mol%), dioxane (0.5 mL, 2 M) and benzoyl chloride (141 μί, 170 mg, 1.20 mmol, 1.2 equiv) were combined and stirred for 24 h at room temperature. In the following the reaction mixture was diluted with MeCN (2 mL, dioxane/MeCN 1:4, 0.4 M) and K ₂ C0 ₃ (320 mg, 2.30 mmol, 2.3 equiv) and cyclohexylamine u (172 μί, 1.50 mmol, 1.5 equiv) were added. After stirring for 24 h at

92b 15 40 °C and work up ^-NM of the crude amine 4 _2b (285 mg) showed full conversion of the intermediate chloride 2 ₃ and a ratio of the secondary amine 4 _2b to the tertiary 9 _2b of 81:19. Next chromatographic purification on silica gel (mass of crude material/Si0 ₂ 1:30) with Et ₂ 0/NEt ₃ //iPen 10:3:87 provided the secondary amine 4 ₂ b as a colorless oil in 72% yield (183 mg, 0.719 mmol).

M (C ₁₇ H ₂₇ N) = 245.40 g/mol; HR-MS (CI, PH7942, [C ₁₇ H ₂₇ N] ⁺ ) calc. 245.2143 found 245.2144 u; [C ₁₇ H ₂₈ N] ⁺ ) calc. 246.2216 u found 246.2219 u.

4.5.1.3 Synthesis of 4-ferf-Butylbenzylazide (4 _2c )

scale yield entry conditions

1. BzCi (1.2 equiv), FPyr (10 mol%), dioxane (2 M) 24 h rt

2. NaN ₅ (1.5 equiv), K ₂ C0 ₃ (1.3 equiv), dioxane/MeOH 1:5 (0.3 M), 81% ^x 20 h 60 °C

1. BzCi (1.2 equiv), FPyr (10 mol%), dioxane (2 M) 24 h rt

2. NaN ₃ (1.5 equiv), TBAI (10 mol%) K ₂ C0 ₃ (1.3 equiv), 79% ^x dioxane/MeOH 1:5 (0.3 M), 20 h rt

1. Isolated yield Due to the improved solubility of NaN ₃ MeOH was preferred as solvent over MeCN for the synthesis of azides. Under optimized conditions the benzyl azide 4 _2c was obtained in 81% yield (entry 1). However, in the presence of catalytic

amounts of tetrabutylammonium iodide (TBAI) the temperature in the second step could be lowered from 60 °C to room temperature (entry 2).

Entry 1: According to general procedure IV (chapter 2.2.1) 4-ieri-butyl benzyl alcohol (1 ₂ , 179 μί, 166 mg, 1.00 mmol, 1.0 equiv), FPyr (9.8 μΐ, 10.2 mg, 0.10 mmol, 10 mol%), dioxane (0.5 mL, 2 M) and benzoyl chloride (141 μί, 170 mg, 1.20 mmol, 1.2 equiv) were combined and stirred for 24 h at room temperature. In the following the reaction mixture was diluted with MeOH (2.5 mL, dioxane/MeOH 1:5, 0.3 M) and K ₂ C0 ₃ (180 mg, 1.30 mmol, 1.3 equiv) and NaN ₃ (98 mg, 1.50 mmol, 1.5 equiv) were added. After stirring for 20 h at 60 °C and work up ¹ H-N M of the crude material (211 mg) showed full consumption of the intermediate chloride 2 ₂ and (beside 4 _2c ) traces from the starting alcohol 1 ₂ most likely resulting from hydrolysis of 2 ₂ during the second reaction step. Chromatographic purification on silica gel (mass of crude material/Si0 ₂ 1:38) with Et ₂ 0//iPen 1:99 finally delivered the azide 4 _2c as a colorless oil (153 mg, 0.806 mmol, 81%).

Entry 2: Azide 4 _2c was prepared as described for entry 1 with the exception that after chlorination (l ₂ ->2 ₂ ) TBAI (39 mg, 0.10 mmol, 10 mol%) was additionally added and the reaction suspension was allowed to stir at room temperature for 20 h. Chromatographic purification of the crude material (199 mg) on silica gel (mass of crude material/Si0 ₂ 1:40) with Et ₂ 0//iPen gave the azide 4 _2c as a colorless oil in 79% yield (150 mg, 0.792 mmol, 79%).

M (C _n H ₁₅ N ₃ ) = 189.26 g/mol.

4.5.1.4 Synthesis of rac-/V-(l-Phenylethyl) piperidine (rac-4 _2a )

7 ^' 25 According to general procedure IV (chapter 2.2.1) racemic 1-phenylethanol (rac- 1 ₃ , 126 μΐ, 125 mg, 1.00 mmol, 1.0 equiv), FPyr (19.7 μΐ, 20.4 mg, 0.20 mmol, 20 mol%), dioxane (0.5 mL, 2 M) and benzoyl chloride (141 μί, 170 mg,

1.20 mmol, 1.2 equiv) were combined and stirred for 24 h at room temperature. Then the reaction mixture was diluted with MeCN (2.0 mL, dioxane/MeCN 1:4, 2 ^a 30 0.4 M), K ₂ C0 ₃ (320 mg, 2.30 mmol, 2.3 equiv) and piperidine ( 147 μΐ, 1.50 mmol, 1.5 equiv) were added and the resulting reaction suspension was stirred for 24 h at 70 °C. After work up chromatographic purification on silica gel (mass of crude material/Si0 ₂ 1:24) with Et ₂ 0/N Et ₃ //iPen 3:3:94 of the crude product (242 mg) gave the piperidine derivative 4 _2c as a pale yellow oil (168 mg, 0.890 mmol, 89%).

M (C ₁₃ H ₁₉ N) = 189.30 g/mol; HR-MS (CI, PH8502, [C ₁₃ H ₁₉ N] ⁺ ) calc. 189.1517 u found 189.1515 u. 4.5.1.5 Synthesis S-/V-(1-Phenylethyl) piperidine (S-4 _2a )

In alignment to general procedure IV (chapter 2.2.1) in a Schlenk-tube enantioenriched S- 1-phenylethanol (S-l ₃ , 126 μί, 125 mg, 1.00 mmol, l.O equiv, er > 99.5:0.5 according to chiral GC and HPLC), FPyr (19.7 μί, 20.4 mg, 0.20 mmol, 20 mol%), Et ₂ 0 (1 mL, 1 M) and

5_4 ₂ benzoyl chloride (141 μί, 170 mg, 1.20 mmol, 1.2 equiv) were combined at 0 °C and stirred for 0.5 h at 0 °C and 24 h at room temperature. In the following the reaction mixture was concentrated under reduced pressure and dried for 2 min at 100 mbar to remove Et ₂ 0. The residue was diluted with MeCN (2.0 mL, dioxane/MeCN 1:4, 0.4 M), K ₂ C0 ₃ (320 mg, 2.30 mmol, 2.3 equiv) and piperidine (147 μί, 1.50 mmol, 1.5 equiv) were added and the resulting reaction suspension was stirred for 24 h at 70 °C. Finally chromatographic purification on silica gel (mass of crude material/Si0 ₂ 1:32) with Et ₂ 0/NEt ₃ //iPen 3:3:94 of the crude product (214 mg) provided the tertiary amine S-4 _2c as a colorless oil (155 mg, 0.816 mmol, 82%). Chiral GC-analysis from both the crude and the isolated material indicated an enantiomeric ratio (er) = 98.0:2.0.

The separation conditions for the enantiomers of amine 4 ₂ through chiral gas chromatography were: Column CP-Chirasil-Dex CB; Temperature program 100 °C for 40 min, gradient 20 °C/min to 200 °C, 200 °C for lOmin, column flow l.O mL/min, split ratio 20; PTV injector temperature 250 °C. Samples of a concentration of 1 mg/1 mL DCM were injected (1 0L injection volume).

4.5.1.6 Synthesis of roc-l-Phenylethyazide (rac-4 _3c )

According to general procedure IV (chapter 2.2.1) racemic 2-phenylethanol (1 ₃ , 125 μί, 126 mg, 1.00 mmol, l.O equiv), FPyr (19.7 μί, 20.4 mg, 0.10 mmol, io mol%), dioxane (0.5 mL, 2 M) and benzoyl chloride (141 μί, 170 mg, 1.20 mmol,

4 _3c 25 1.2 equiv) were combined and stirred for 24 h at room temperature. In the following the reaction mixture was diluted with MeOH (2.5 mL, dioxane/MeCN 1:5, 0.3 M) and K ₂ C0 ₃ (180 mg, 1.30 mmol, 1.3 equiv) and NaN ₃ (130 mg, 2.00 mmol, 2.0 equiv) were added. After stirring for 24 h at 60 °C and work up ¹ H-NMR of the crude material (228 mg) showed full conversion of the intermediate chloride 2 ₃ . Thereby the crude volatile azide 4 _3c was dried at 50 mbar for two minutes. Chromatographic purification on silica gel (mass of crude material/Si0 ₂ 1:40) with Et ₂ 0//iPen 1:99 finally delivered the volatile azide 4 _2c as a colorless oil (93.4 mg, 0.635 mmol, 64%).

M (C ₈ H ₉ N ₃ ) = 147.17 g/mol; HR-MS (CI, PH7832, [C ₈ H ₈ N ₃ ] ⁺ ) calc. 146.0713 u found 146.0732 u; ([C ₈ H ₉ N ₃ ] ⁺ ) calc. 147.0796 u found 147.0793 u. 4.5.1.7 Synthesis of roc-/V-Benzyl-/V-methyl-2,3-dihydro-lH-inden-l-amine

According to general procedure IV (chapter 2.2.1) racemic 2-indanol (rac- l ₅ i, 137 mg, 1.00 mmol, 1.0 equiv), FPyr (19.7 μί, 20.4 mg, 0.20 mmol,

20 mol%), dioxane (0.5 mL, 2 M) and benzoyl chloride (141 μί, 170 mg, 1.20 mmol, 1.2 equiv) were combined and stirred for 24 h at room temperature (The intermediate chloride 2 ₅ i could not be purified through

chromatography on silica gel due to decomposition. Chloride 2 _5ϊ quickly eliminated HCI to give indene in contact with Si0 ₂ ). Next the reaction mixture was diluted with MeCN (2.0 mL, dioxane/MeCN 1:4, 0.4 M), K ₂ C0 ₃ (320 mg, 2.30 mmol, 2.3 equiv) and /V-methylbenzylamine (201 μί, 1.50 mmol, 1.5 equiv) were added and the resulting suspension was stirred for 24 h at 50 °C to reach full conversion of the intermediate chloride 2 _5ϊ ( ¹ H-N M ). After chromatographic purification of the crude product (335 mg) on silica gel (mass of crude material/Si0 ₂ 1:30) with Et ₂ 0/N Et ₃ //iPen 3:3:94 the indene amine 4 ₅ ϋ was obtained as a colorless oil in 81% yield (193 mg, 0.812 mmol, 81%).

M (C ₁₇ H ₁₉ N) = 237.34 g/mol; HR-MS (CI, PH8382, [C ₁₇ H ₁₈ N] ⁺ ) calc. 236.1434 u found 236.1453 u; ([C ₁₇ H ₁₉ N] ⁺ ) calc. 237.1517 u found 237.1515 u.

4.5.1.8 Synthesis of rac-/V-Methyl-/V-phenyl-l,2,3,4-tetrahydronaphthalen-l-amine (rac-4 _52j )

According to general procedure IV (chapter 2.2.1) racemic 1,2,3,4- tetrahydro-l-naphthol (roc-l ₅₂ , 153 mg, 1.00 mmol, 1.0 equiv), FPyr (19.7 μί, 20.4 mg, 0.20 mmol, 20 mol%), dioxane (0.5 mL, 2 M) and benzoyl chloride (141 μί, 170 mg, 1.20 mmol, 1.2 equiv) were combined and stirred for 24 h

at room temperature (The intermediate chloride 2 ₅₂ could not be purified rac- '52j

through chromatography on silica gel due to decomposition. Chloride 2 ₅₂ quickly eliminated HCI to give dihydronaphthalene upon contact with Si0 ₂ ). Next the reaction mixture was diluted with MeCN (2.0 mL, dioxane/MeCN 1:4, 0.4 M), K ₂ C0 ₃ (320 mg, 2.30 mmol, 2.3 equiv) and /V-methylaniline (332 μί, 3.00 mmol, 3.0 equiv) were added and the resulting suspension was stirred for 24 h at 60 °C (At higher reaction temperatures formation of dihydronaphthalene in significant amounts occured. To reach full conversion (of the intermediate chloride 2 ₅₂ ) at 60 °C within 24 h 3.0 equiv of the nucleophile /V-methylaniline were required). After chromatographic purification of the crude product (502 mg) on silica gel (mass of crude material/Si0 ₂ 1:42) with Et ₂ 0/N Et ₃ //iPen 1:0.2:98.8 a yellow oil (176 mg) was isolated consisting of the aniline derivative 4 _52j and 2 mol% of the benzoate 3 ₅₂ (referred to 4 _52j ). To remove the ester the mixture was subjected to a second chromatographic purification on silica gel (mass of crude material/Si0 ₂ 1:40) with Et ₂ 0//iPen 2:98 to give the desired product roc-4 _52j as a yellow oil (174 mg, 0.731 mmol, 73%). M (C ₁₇ H ₁₉ N) = 237.34 g/mol; HR-MS (CI, PH8172, [C ₁₇ H ₂₅ N] ⁺ ) calc. 237.1517 u found 243.1516 u.

4.5.1.9 Synthesis of A/,/V-Diethyl geranyl amine (E-4 _4k )

scale yield entry conditions

[mmol] f-4 ₄ k

1. BzCi (1.2 equiv), FPyr (10 mol%), dioxane (2 M) 24 h rt

2. H-NEt ₂ (3.3 equiv), K ₂ C0 ₃ (2.3 equiv), dioxane/MeCN 1:4 75% (0.4 M), 24 h 40 °C

1. BzCi (1.2 equiv), FPyr (10 mol%), dioxane (2 M) 24 h rt

2. H-NEt, (5.0 equiv), K ₂ C0 ₃ (2.3 equiv), dioxane/MeCN 1:4 86% (0.4 M), 24 h 40 °C

1. Isolated yield

With 3.3 equiv of diethylamine the tertiary allylic amine E-4 _4k was obtained in 75% yield (entry 1). Increasing the amount of diethylamine to 5.0 equiv improved the yield to 86% (entry 2).

Entry 1: According to general procedure IV (chapter 2.2.1) geraniol E-l ₄ (179 μΐ, 159 mg, 1.00 mmol, 1.0 equiv), FPyr (9.8 μΐ, 10.2 mg, 0.10 mmol,

10 mol%), dioxane (0.5 mL, 2 M) and benzoyl chloride (141 μΐ, 170 mg, 1.20 mmol, 1.2 equiv) were combined and stirred for 24 h at room temperature. In the following MeCN (2.0 mL, dioxane/MeCN 1:4, 0.4 M), K ₂ C0 ₃ (320 mg, 2.30 mmol, 2.3 equiv) and diethylamine (348 μΐ, 3.30 mmol, 3.3 equiv) were added to the reaction mixture and the resulting suspension was stirred for 24 h at 40 °C. Chromatographic purification of the crude product (272 mg) on silica gel (mass of crude material/Si0 ₂ 1:35) with Et ₂ 0/NEt ₃ //iPen 10:3:87 diethylgeranyl amine E-4 _4k was isolated as a yellow

011 in 75% yield (157 mg, 0.748 mmol).

Entry 2: Following general procedure IV (chapter 2.2.1) geraniol E-l ₄ (1.00 mmol, 1.0 equiv) was allowed to react with benzoyl chloride (1.20 mmol, 1.2 equiv) in the presence of FPyr (0.10 mmol, 10 mol%) in dioxane (0.5 mL, 2 M) for 24 h at room temperature. Then MeCN (2.0 mL, dioxane/MeCN 1:4, 0.4 M), K ₂ C0 ₃ (320 mg, 2.30 mmol, 2.3 equiv) and diethylamine (530 μΐ, 5.00 mmol, 5.0 equiv) were added to the reaction mixture and the resulting suspension was stirred for 24 h at 40 °C. Chromatographic purification of the crude product (249 mg) on silica gel (mass of crude material/Si0 ₂ 1:35) with Et ₂ 0/NEt ₃ //iPen 5:3:92 gave diethylgeranyl amine E-4 _4k as a yellow oil in 86% yield (180 mg, 0.858 mmol).

M (C ₁₄ H ₂₇ N) = 209.37 g/mol 4.5.1.10 Synthesis of /V-Neryl-ephidrine (Z-4 _4! )

According to general procedure IV (chapter 2.2.1) nerol Z-l ₄ (179 μί, 159 mg, 1.00 mmol, 1.0 equiv), FPyr (9.8 μΐ, 10.2 mg, 0.10 mmol, 10 mol%), dioxane (0.5 mL, 2 M) and benzoyl chloride (141 μί, 170 mg, 1.20 mmol, 1.2 equiv) were combined and stirred for 23 h at

room temperature. Then the reaction solution was diluted with MeCN

Z-4 ₄

(2.0 mL, dioxane/MeCN 1:4, 0.4 M), K ₂ C0 ₃ (320 mg, 2.30 mmol, 2.3 equiv) and ephedrine (215 μί, 1.30 mmol, 1.3 equiv) were added and the resulting suspension was stirred for 11 h at ambient temperature and for 13 h at 40 °C. Finally after chromatographic purification of the crude material (413 mg) on silica gel (mass of crude material/Si0 ₂ 1:30) with Et ₂ 0/N Et ₃ //iPen 30:5:65 the allylated ephedrine analogue Z-4 _4! was isolated as a pale yellow oil in 59% yield (178 mg, 0.591 mmol).

M (C ₁₉ H ₂₉ NO) = 287.44 g/mol; HR-MS (CI, PH8392, [C ₂₀ H ₃ iNO] ⁺ ) calc. 302.2478 u found 302.2484 u.

4.5.1.11 Synthesis of l-(Diallylamino)-2-(l-naphthyl)ethane (rac-4 _24m )

According to general procedure IV (chapter 2.2.1) racemic 1-(1- naphthyl)-l-ethanol 1 ₂₄ (173 mg, 1.00 mmol, 1.0 equiv), FPyr (19.7 μΐ, 20.4 mg, 0.20 mmol, 20 mol%), dioxane (0.5 mL, 2 M) and 2- fluorobenzoyl chloride (149 μί, 196 mg, 1.20 mmol, 1.2 equiv) were combined and stirred for 24 h at room temperature. Thereafter to the rac-4 _24m reaction solution were added MeCN (2.0 mL, dioxane/MeCN 1:4, 0.4 M), K ₂ C0 ₃ (320 mg, 2.30 mmol, 2.3 equiv) and diallylamine (254 μΐ, 200 mg, 2.00 mmol, 2.0 equiv) and the resulting suspension was stirred for 16 h at 80 °C and for 8 h at 100 °C. ¹ H-N M of the crude material (342 mg) proved full conversion of the intermediate chloride 2 ₂ , an amine 4 _{2 m} to ester 3 ₂₄ ratio of 85:15 and 11 mol% of 1-vinylnaphthalene 5 ₂₄ (referred to 4 _24m ). The increased amounts of these two side products compared to the chlorination l ₂₄ ->2 ₂₄ (chapter 4.4.4.6) might be reasoned by esterification of the chloride 2 ₂₄ with 2-fluorobenzoic acid and K ₂ C0 ₃ induced HCI- elimination from chloride 2 ₂₄ (to give 1-vinylnaphthalene). Then chromatographic purification on silica gel (mass of crude material/Si0 ₂ 1:56) with Et ₂ 0/N Et ₃ //iPen 3:3:94 provided the amine 4 _24m as a pale yellow oil (163 mg, 0.647 mmol, 65%) in a purity of >95% according to ¹ H-N MR.

To remove small trace amounts of a residual impurity (< 5%, most likely bis[(l-naphthyl)-l- ethyl]ether 5 ₂₄ ) the isolated product was dissolved in 1 M H ₂ S0 ₄ solution in water (4 mL) and nPen (2 mL), the aqueous phase was washed with further nPen (2 mL), transferred to 10 mL flask with a stir bar, cooled in an ice bath and diluted with Et ₂ 0 (3 mL). Under stirring Na ₂ C0 ₃ (640 mg, 6.00 mmol) was added portionwise accompanied by a C0 ₂ -evolution. Then the mixture was diluted with water (5 mL) to dissolve precipitated Na ₂ S0 ₄ completely, the organic phase was separated and the aqueous phase (pH > 10) was extracted with further Et ₂ 0 (2 x 3 mL). The combined Et ₂ 0-phases were dried over MgS0 ₄ and concentrated to give the amine 4 _24m as a colorless oil (150 mg, 0.598 mmol, 60%).

M (C ₁₈ H ₂₁ N) = 251.37 g/mol; r _f (Si0 ₂ , Et ₂ 0//iPen 5:95) = 0.38 (tailing).

4.5.1.12 Synthesis of Dimethyldodecylamine (4 _33n )

scale yield entry conditions

[mmol] 4 _33n

1. BzCi (1.2 equiv), FPyr (20 mol%), dioxane (2 M) 2 h 80 °C

1 1 2. H NMe _; (2.0 equiv), TBAI (10 mol%), K ₂ C0 ₃ (2.3 equiv),

dioxane/MeCN 1:3 (0.5 M), 24 h 60 °C

1. BzCi (1.2 equiv), FPyr (20 mol%), dioxane (2 M) 2 h 70 °C

2 1 2. H-N e;, (3.0 equiv), K ₂ C0 ₃ (2.3 equiv), dioxane/MeCN 1:4 57% ^x

(0.4 M), 24 h 70 °C

1. Isolated yield

Albeit in the absence of TBAI the amine 4 _33m was obtained as the major product (entry 2), through the presence of catalytic amounts of TBAI (10 mol%) the yield was improved significantly (entry 1, 57->74%). Remarkably, a 40% solution of HNMe ₂ in water was utilized.

Entry 1: According to general procedure IV (chapter 2.2.1) 1-dodecanol 1 ₃₃ (215 μΐ, 186 mg, 1.00 mmol, 1.0 equiv), FPyr (19.7 μΐ, 20.4 mg, 0.20 mmol, 20 mol%), dioxane (0.5 mL, 2 M) and benzoyl chloride (141 μί, 170 mg, 1.20 mmol, 1.2 equiv) were combined at ambient temperature and allowed to react at 80 °C for 2 h. Afterwards to the reaction solution were added MeCN (1.5 mL, dioxane/MeCN 1:3, 0.5 M), K ₂ C0 ₃ (320 mg, 2.30 mmol, 2.3 equiv), TBAI (38 mg, 0.10 mmol, 10 mol%) and an 40% aqueous solution of dimethylamine in water (250 μί, 2.00 mmol, 2.0 equiv) and the resulting suspension was stirred for 24 h at 60 °C. Then chromatographic purification of the crude material (330 mg) on silica gel (mass of crude material/Si0 ₂ 1:30) with Et ₂ 0/NEt ₃ //iPen 20:5:75 delivered the amine 4 _33n as a pale yellow oil (157 mg, 0.736 mmol, 74%). Entry 2: Following general procedure IV (chapter 2.2.1) 1-dodeca nol 1 ₃₃ (1.00 mmol, 1.0 equiv), FPyr (0.20 mmol, 20 mol%), dioxane (0.5 mL, 2 M) and benzoyl chloride (1.20 mmol, 1.2 equiv) were combined at ambient temperature and allowed to react at 70 °C for 2 h. Then the reaction solution was diluted with MeCN (2 mL, dioxane/MeCN 1:4, 0.4 M), K ₂ C0 ₃ (320 mg, 2.30 mmol, 2.3 equiv) and an 40% aqueous solution of dimethylamine in water (380 μί, 3.00 mmol, 3.0 equiv) were added and the resulting suspension was stirred for 24 h at 70 °C. Finally chromatographic purification of the crude material (293 mg) on silica gel (mass of crude material/Si0 ₂ 1:32) with Et ₂ 0/N Et ₃ //iPen 20:3:77 delivered the amine 4 _33n as a colorless oil (122 mg, 0.571 mmol, 57%).

M (C ₁₄ H ₃ iN) = 213.40 g/mol; HR-MS (CI, PH8442, [C ₁₄ H ₃ iN] ⁺ ) calc. 213.2457 u found 213.2456 u; ([C ₁₄ H ₃₂ N] ⁺ ) calc. 214.2529 u found 214.2532. 4.5.1.13 Synthesis of roc-Methyl ((2-(thiophen-2-yl)ethyl)amino)-(2-chlorophenyl) ethanoate (roc-

4 _53o )

According to general procedure IV (chapter 2.2.1) racemic methyl l-(2- chlorophenyl)-l-hydroxyethanoate (100.3 mg, 0.50 mmol, 1.0 equiv), FPyr (9.8 μΐ, 10.2 mg, 0.10 mmol, 20 mol%), dioxane (0.25 mL, 2 M) and 2- fluorobenzoyl chloride (74 μί, 98 mg, 1.20 mmol, 1.2 equiv) (2- Fluorobenzoyl chloride was preferred over benzoyl chloride, because with the latter one larger amounts of the ester side product 3 ₅₃ were obtained rac-4 _53o during the second reaction step. As the ester is most likely formed through alkylation of the residual aromatic acid with intermediate chloride 2 ₅₃ , with less nucleophilic 2-fluorobenzoic acid (compared to benzoic acid) less ester 3 ₅₃ is obtained) were combined and stirred for 19 h at 80 °C. Then to the reaction solution were added MeCN (1.0 mL, dioxane/MeCN 1:4, 0.4 M),

K ₂ C0 ₃ (159 mg, 1.15 mmol, 2.3 equiv) and 2-(2-aminoethyl)thiophene

?53o

25 (79 μί, 0.65 mmol, 1.3 equiv) and the resulting suspension was stirred for 24 h at 60 °C. ¹ H-N M of the crude material (217 mg) proved full conversion of the intermediate chloride 2 ₅₃ , an amine 4 _53o to ester 3 ₅₃ ratio of 95:5 and a ratio of the desired secondary amine 4 _53o to its tertiary counterpart 9 _53o of > 98:2. Small traces of the staring alcohol 1 ₅₃ were additionally observed most likely resulting from hydrolysis of the intermediate chloride 1 ₅₃ through K ₂ C0 ₃ .

For purification the crude material was dissolved in Et ₂ 0//iPen (1.5/1.5 mL) and a 1 M H ₂ S0 ₄ solution in water (4 mL). The aqueous phase was washed with further nPen (2 x 2 mL), transferred to 10 mL flask with a stir bar, cooled in an ice bath and diluted with Et ₂ 0 (3 mL) to avoid hydrolysis of the ester function of 4 _53o . Under stirring Na ₂ C0 ₃ (1000 mg, 9.00 mmol) was added portionwise accompanied by a strong C0 ₂ -evolution. In the following the mixture was diluted with water (2 mL) to dissolve precipitated Na ₂ S0 ₄ completely, the organic phase was separated and the aqueous phase (pH > 10) was extracted with further Et ₂ 0 (2 x 3 mL). The combined Et ₂ 0-phases were dried over MgS0 ₄ and concentrated to deliver a 97:3 mixture of the amines 4 _53o and 9 ₅₃ as a yellow oil (146 mg) (Neutralisation of the collected nPen/Et ₂ 0 washing with aq. saturated Na ₂ C0 ₃ solution, drying over MgS0 ₄ and concentration under reduced pressure delivered a 27:46:27 mixture of the ester 3 ₅₃ . alcohol 1 ₅₃ and the desired amine 4 _53o (44.1 mg)). Then chromatographic purification on silica gel (mass of isolated material/Si0 ₂ 1:40) with Et ₂ 0/N Et ₃ //iPen 30:2:68 provided the amine 4s _3o as a pale yellow oil (109.0 mg, 0.352 mmol, 70%).

M (C ₁₅ H ₁₆ CIN0 ₂ S) = 309.81 g/mol; HR-MS (CI, PH9272, [C ₁₅ H ₁₇ N0 ₂ SCI] ⁺ ) calc : 310.0663 u found 310.0660 u.

4.5.1.14 Synthesis of Clopidogrel (roc-4 _53p )

According to general procedure IV (chapter 2.2.1) racemic methyl l-(2- chlorophenyl)-l-hydroxyethanoate (100.3 mg, 0.50 mmol, l.O equiv), FPyr (9.8 μΐ, 10.2 mg, 0.10 mmol, 20 mol%), dioxane (0.25 mL, 2 M) and 2- fluorobenzoyl chloride (74 μί, 98 mg, 1.20 mmol, 1.2 equiv) (2-Fluorobenzoyl chloride was preferred over benzoyl chloride, because with the latter one larger amounts of the ester side product 3 ₅₃ were obtained during the second roc-4 _53p reaction step. As the ester is most likely formed through alkylation of the residual aromatic acid with intermediate chloride 2 ₅₃ , with less nucleophilic 2- fluorobenzoic acid (compared to benzoic acid) less ester 3 ₅₃ is obtained) were combined and stirred for 17 h at 80 °C. Next the reaction solution was diluted with MeCN (1.0 mL, dioxane/MeCN 1:4, 0.4 M), K ₂ C0 ₃ (159 mg, 1.15 mmol, 2.3 equiv) and 4,5,6,7-tetrahydrothieno[3,2-c] pyridine (78 μΐ, 0.65 mmol, 1.3 equiv) and the resulting suspension was stirred for 24 h at 60 °C. ¹ H-N M of the crude material (229 mg) indicated full consumption of the intermediate chloride 2 ₅₃ and an amine 4 _53p to ester 3 ₅₃ ratio of 96:4. Small traces of the staring alcohol 1 ₅₃ were additionally observed most likely stemming from hydrolysis of the intermediate chloride 1 ₅₃ through K ₂ C0 ₃ .

For purification the crude material was dissolved in nPen (3 mL) and a 1 M H ₂ S0 ₄ solution in water (4 mL), the aqueous phase was washed with further nPen (2 x 2 mL), transferred to 10 mL flask with a stir bar, cooled in an ice bath and diluted with Et ₂ 0 (3 mL) to avoid hydrolysis of the ester function of 4 _53p . Under stirring Na ₂ C0 ₃ (1000 mg, 9.00 mmol) was added portionwise accompanied by a C0 ₂ - evolution. In the following the mixture was diluted with water (2 mL) to dissolve precipitated Na ₂ S0 ₄ completely, the organic phase was separated and the aqueous phase (pH > 10) was extracted with further Et ₂ 0 (2 x 3 mL). The combined Et ₂ 0-phases were dried over MgS0 ₄ and concentrated to deliver a 95:5 mixture of the amine 4 _53p and the starting alcohol 1 ₅₃ as a yellow oil (145 mg) (Neutralisation of the collected nPen/Et ₂ 0 washing with aq.,saturated Na ₂ C0 ₃ solution, drying over MgS0 ₄ and concentration under reduced pressure delivered a pale yellow oil (46.4 mg) showing small traces of the amine 4 _53p as indicated by ¹ H-NM ). Next chromatographic purification on silica gel (mass of isolated material/Si0 ₂ 1:30) with Et ₂ 0/NEt ₃ //iPen 20:1:79 and delivered the amine 4s _3P as a colorless oil (125.1 mg, 0.389 mmol, 78%).

M (C ₁₆ H ₁₆ CIN0 ₂ S) = 321.82 g/mol; HR-MS (CI, PH951, [C ₁₆ H ₁₇ N0 ₂ SCI] ⁺ ) calc: 322.0663 u found 322.0662 u.

4.5.2 Synthesis of Ethers

4.5.2.1 Synthesis of 4-ferf-Benzylphenylether (4 _2d )

scale yield entry conditions

1. BzCi (1.2 equiv), FPyr (20 mol%), dioxane (2 M) 2 h 80 °C

2. H-OPh (1.3 equiv), TBAI (10 mol%), K ₂ C0 ₃ (2.3 equiv), 71% dioxane/MeCN 1:3 (0.5 M), 24 h 50 °C

1. BzCi (1.2 equiv), FPyr (20 mol%), dioxane (2 M) 2 h 80 °C

2. H-OPh (1.3 equiv, K ₂ C0 ₃ (2.3 equiv), dioxane/MeCN 1:4 (0.4 M), 68%' 48 h 80 °C

In the presence of 10 mol% TBAI arylether 4 _2c i was obtained in 71% yield (entry 1). However, without TBAI the second alkylation step (2 ₂ ->4 _2d ) required two days of heating to 80 °C to achieve (almost) full conversion of intermediate chloride 2 ₂ , thus providing the

+2d desired ether 4 _2d in a yield of 68% (entry 2).

Entry 1: According to general procedure IV (chapter 2.2.1) 4-ieri-butyl benzyl alcohol 1 ₂ (179 μί, 166 mg, 1.00 mmol, 1.0 equiv), FPyr (9.8 μΐ, 10.2 mg, 0.10 mmol, 10 mol%), dioxane (0.5 mL, 2 M) and benzoyl chloride (141 μί, 170 mg, 1.20 mmol, 1.2 equiv) were combined and allowed to react at room temperature for 24 h. Thereafter the reaction solution was diluted with MeCN (1.5 mL, dioxane/MeCN 1:3, 0.5 M), K ₂ C0 ₃ (320 mg, 2.30 mmol, 2.3 equiv), TBAI (38 mg, 0.10 mmol, 10 mol%) and phenol (122 mg, 1.30 mmol, 1.3 equiv) were added and the resulting suspension was stirred for 24 h at 50 °C. ¹ H-NMR of the crude material (419 mg) revealed full conversion of the intermediate chloride 2 ₂ and a ether 4 _2d to ester 3 ₂ ratio of 76:24. In the following the crude material was adsorbed on silica gel (mass of crude product/Si0 ₂ 1:2) through dissolution in DCM, addition of Si0 ₂ and concentration under reduced pressure. This mixture was subjected to chromatographic purification on silica gel (mass of crude product/Si0 ₂ 1:30) with Et ₂ 0//iPen 2:98 to give the benzylphenylether 4 _2d as a colorless solid in 71% yield (171 mg, 0.709 mmol).

Entry 2: As described for entry 1 benzylalcohol 1 ₂ (1.00 mmol, 1.0 equiv) was chlorinated. Then to the reaction solution were added MeCN (2 mL, dioxane/MeCN 1:4, 0.5 M), K ₂ C0 ₃ (2.30 mmol, 2.3 equiv) and phenol (1.30 mmol, 1.3 equiv) and the resulting suspension was stirred for 48 h at 80 °C. ¹ H-NM of the crude mixture (361 mg) revealed an almost complete conversion (94%) of the intermediate chloride 2 ₂ and a ether 4 _2c i to ester 3 ₂ ratio of 76:24. In the following the crude material was adsorbed on silica gel (mass of crude product/Si0 ₂ 1:2) through dissolution in DCM, addition of silica gel and concentration under reduced pressure. This mixture was subjected to chromatographic purification on silica gel (gel (mass of crude product/Si0 ₂ 1:30) with Et ₂ 0//iPen 2:98 to give the benzylphenylether 4 _2d as a colorless solid in 68% yield (163 mg, 0.677 mmol).

M (C ₁₇ H ₂₀ O) = 240.34 g/mol.

4.5.2.2 Synthesis of 2-Phenyl-5-(Phenylethyl)tetrazole (4 _36h )

scale yield entry conditions

[mmol] 4 _33n

1. BzCi (1.2 equiv), FPyr (20 mol%), dioxane (2 M) 2 h 80 °C

1 1 2. H-SAr (1.3 equiv), TBAI (10 mol%), K ₂ C0 ₃ (2.3 equiv), 81% ^x dioxane/MeCN 1:3 (0.5 M), 24 h 60 °C

1. BzCi (1.2 equiv), FPyr (20 mol%), dioxane (2 M) 2.5 h 80 °C

2 1 2. H-SAr (1.3 equiv), K ₂ C0 ₃ (2.3 equiv), dioxane/MeCN 1:4 (0.4 M), 65% ^x

24 h 70 °C

1. Isolated yield

Again the presence of TBAI in catalytic amounts improved the yield in the synthesis of thioether 4 _36h significantly (65->81%; entries 1+2).

Entry 1: According to general procedure IV (chapter 2.2.1) 2- phenylethanol 1 ₃₆ (123 μΐ, 121 mg, 1.00 mmol, 1.0 equiv), FPyr (19.7 μΐ,

20.4 mg, 0.20 mmol, 20 mol%), dioxane (0.5 mL, 2 M) and benzoyl chloride (141 μί, 170 mg, 1.20 mmol, 1.2 equiv) were combined at ambient temperature and then heated to 80 °C for 2 h. Then the

^ <j^ _r reaction solution was diluted with MeCN (1.5 mL, dioxane/MeCN 1:3,

25 0.5 M), K ₂ C0 ₃ (320 mg, 2.30 mmol, 2.3 equiv), TBAI (38 mg, 0.10 mmol, 10 mol%) and the 5-thio-l-phenyltetrazol (232 mg, 1.30 mmol, 1.3 equiv) were added and the resulting suspension was stirred for 24 h at 60 °C. ¹ H-NMR of the crude material (375 mg) showed full conversion of the intermediate chloride 2 ₃₆ and a ether 4 _36h to ester 3 ₃₆ ratio of 87:13. In the following the crude material was adsorbed on silica gel (mass of crude product/Si0 ₂ 1:2) through dissolution in DCM, addition of Si0 _2# and concentration under reduced pressure. This mixture was subjected to chromatographic purification on silica gel (mass of crude product/Si0 ₂ 1:30) with Et ₂ 0/DCM//iPen 5:20:65. After drying in high vacuum under stirring for 1 h the thioether 4 _36h was isolated as a pale yellow oil in 81% yield (229 mg, 0.811 mmol).

Entry 2: As described for entry 1 phenylethanol 1 ₃₆ was chlorinated. The resulting reaction solution was then diluted with MeCN (2 mL, dioxane/MeCN 1:4, 0.4 M), K ₂ C0 ₃ (320 mg, 2.30 mmol, 2.3 equiv) and the 5-thio-l-phenyltetrazol (232 mg, 1.30 mmol, 1.3 equiv) were added and the reaction suspension was stirred for 24 h at 70 °C. ¹ H-NM of the crude reaction mixture revealed full consumption of the intermediate chloride 2 ₃₆ a ether 4 _36h to ester 3 ₃₆ ratio of 64:36. Purification of the crude product (296 mg) as described for entry 1 then delivered the tetrazol derivative 4 _36h as a pale yellow oil in 65% yield (184 mg, 0.651 mmol).

M (C ₁₅ H ₁₄ N4S) = 282.36 g/mol; r _f (Si0 ₂ , Et ₂ 0/DCM//iPen 10:20:70) = 0.43; HR-MS (CI, PH8332, [C ₁₅ H ₁₅ N4S] ⁺ ) calc. 283.1017 u found 283.1020 u.

4.5.2.3 Synthesis of 2-(4-ferf-Benzylthio)benzothiophene (4 _2g )

According to general procedure IV (chapter 2.2.1) -tert- butylbenzyl alcohol (1 ₂ , 179 μί, 166 mg, 1.00 mmol, 1.0 equiv), FPyr (9.8 μΐ, 10.2 mg, 0.10 mmol, 10 mol%), dioxane (0.5 mL, 2 M) and benzoyl chloride (141 μί, 170 mg, 1.20 mmol,

1.2 equiv) were combined and stirred for 24 h at room

+2g

temperature. In the following the reaction mixture was diluted with MeCN (2 mL, dioxane/MeCN 1:4, 0.4 M), fine-powdered K ₂ C0 ₃ (320 mg, 2.30 mmol, 2.3 equiv) and 2-thiobenzothiazol (217 mg, 1.30 mmol, 1.3 equiv) were added. After 20 h of stirring at room temperature TLC control indicated full consumption of chloride 2 ₂ . Then the crude material (435 mg) was adsorbed on silica gel (mass of crude product/Si0 ₂ 1:3) through dissolution in DCM, addition of silica gel and concentration under reduced pressure. This mixture was subjected to chromatographic purification on silica gel (mass of crude product/Si0 ₂ 1:15) with Et ₂ 0//iPen 4:96. After drying in high vacuum a colorless oil was isolated (300 mg) consisting of the thioether 4 _2g and the 4 mol% of the benzoate 3 ₂ according to ¹ H-NMR. Considering this residual impurity the thioether 4 _2g was obtained in a yield of 93% (0.925 mmol).M (C ₁₈ H ₁₉ NS ₂ ) = 313.48 g/mol; r _f (Si0 ₂ , Et ₂ 0//iPen) = 0.39 (5:95), 0.34 (4:96). 4.5.3 Synthesis of Cyanides and Malonic acid esters

4.5.3.1 Synthesis of 4-ferf-Butylbenzylnitrile (4 _2e )

scale yield entry conditions

1. BzCi (1.2 equiv), FPyr (10 mol%), dioxane (2 M) 24 h rt

1 2. KCN (2.0 equiv), TBAI (10 mol%), K ₂ C0 ₃ (2.3 equiv), 75% dioxane/MeOH 1:4 (0.4 M), 8 h rt, 16 h 40 °C

1. BzCI (1.2 equiv), FPyr (10 mol%), dioxane (2 M) 24 h rt

2. KCN (1.5 equiv), K ₂ C0 ₃ (2.3 equiv), dioxane/MeOH 1:4 (0.4 M),

24 h 40 °C

1. Isolated yield

Under optimized conditions nitrile 4 _2e was isolated in 75% yield (entry 1). Without TBAI (10 mol%) the cyano compound 4 _2e was obtained in a yield of 48% (entry 2).

t2e

Entry 1: According to general procedure IV (chapter 2.2.1) 4-ieri-butyl benzyl alcohol (1 ₂ , 179 μΐ, 166 mg, 1.00 mmol, l.O equiv), FPyr (9.8 μΐ, 10.2 mg, 0.10 mmol, 10 mol%), dioxane (0.5 mL, 2 M) and benzoyl chloride (141 μί, 170 mg, 1.20 mmol, 1.2 equiv) were combined and stirred for 24 h at room temperature. In the following the reaction mixture was diluted with MeOH (2 mL, dioxane/MeOH 1:4, 0.4 M) and K ₂ C0 ₃ (180 mg, 1.30 mmol, 1.3 equiv), TBAI (39 mg, 0.10 mmol, 10 mol%) and KCN (130 mg, 2.00 mmol, 2.0 equiv) were added. After stirring for 8 h at room temperature and at 40 °C for 16 h ¹ H-NM of the crude material (236 mg) showed 95% conversion of the intermediate chloride 2 ₂ and (beside 4 _2e ) traces from the starting alcohol 1 ₂ most likely resulting from hydrolysis of 2 ₂ during the second reaction step. Chromatographic purification on silica gel (mass of crude material/Si0 ₂ 1:35) with Et ₂ 0//iPen 15:85 finally delivered the cyanide 4 _2e as a colorless oil (130 mg, 0.752 mmol, 75%).

Entry 2: As described for entry 1 the benzylic alcohol 1 ₂ (1.00 mmol, l.O equiv) was chlorinated to alkyl chloride 2 ₂ . Then the reaction mixture was diluted with MeOH (2.9 mL, dioxane/MeOH 1:4, 0.4 M), K ₂ C0 ₃ (180 mg, 1.30 mmol, 1.3 equiv) and KCN (98 mg, 1.50 mmol, 1.5 equiv) were added and the resulting reaction suspension was stirred for 24 h at 40 °C. After chromatographic purification as given for entry 1 the cyanide 4 _2e was obtained as a colorless oil in 48% yield (83.9 mg, 0.484 mmol). M (C ₁₂ H ₁₅ N) = 173.25 g/mol; HR-MS (CI, PH8072, [C ₁₂ H ₁₅ N] ⁺ ) calc. 173.1204 u found 173.1183 u. 4.5.3.2 Synthesis of Dimethyl (4-ferf-butylbenzyl)malonate (4 _2f )

According to general procedure IV (chapter 2.2.1) 4-ieri-butyl benzyl alcohol (1 ₂ , 89 μΐ, 83 mg, 0.50 mmol, 1.0 equiv), FPyr (4.9 μΐ, 5.1 mg, 0.05 mmol, 10 mol%), dioxane (0.25 ml, 2 M) and benzoyl chloride (70 μί, 85 mg, 0.60 mmol, 1.2 equiv) were combined and stirred for

24 h at ambient temperature. Then to the reaction solution was added MeCN (l mL, dioxane/MeCN 1:4, 0.4 M), K ₂ C0 ₃ (159 mg, 1.15 mmol, 2.3 equiv) and (86 μΐ, 0.75 mmol, 1.5 equiv) and the resulting reaction mixture heated to 80 °C for 24 h. In deviation from the general procedure the reaction mixture was diluted with Et ₂ 0 (3 mL) and 1 N HCI solution in water (4 mL, C0 ₂ -evolution !), the aqueous phase was extracted with further Et ₂ 0 (2 x 3 mL), the combined organic phases were dried over MgS0 ₄ and concentrated under reduced pressure. ¹ H-NM with naphthalene as standard indicated malonate 4 _2f in 59% yield. Additionally, chloride 2 ₂ (9%) and benzoate 3 ₂ (21%) were detected.

M (C ₁₆ H ₂₂ 0 ₄ ) = 278.34 g/mol; HR-MS (CI, PH7796, [C ₁₆ H ₂₂ 0] ⁺ ) calc. 278.1518 u found 278.1523 u; ([C ₁₆ H ₂₂ 0] ⁺ ) calc. 279.1596 u found 279.1562 u.

4.6 Screening of Further Catalysts

The following scheme provides an overview over the screening of further catalysts for formamide

ratio 2:3

>80:20 Conditions

50:50-80:20 10 mol% catalyst

<50:50 dioxane (2 M), 24 h rt legend

catalyst H'j Ph h acronym 5%/15:85 yield 2/ratio 2:3

According to general procedure I (see chapter 2.1.1 herein above) 4-ieri-butyl benzyl alcohol 1 ₂ (0.50 mmol, 1.0 equiv) was allowed to react with benzoyl chloride (1.2 equiv) in the presence of a potential catalyst (10 mol%) in dioxane (2 M) for 20-24 h at room temperature. Yield of 2 was determined by NMR using internal standard (either naphthalene or dodecane depending of on the tested compound to avoid signal overlap in ¹ H-NMR) as described in chapter 2.1.1.

4.7 Synthesis of Further Chlorides General procedures I, II and III referred to in the following chapters 4.7.1 to 4.7.5 can be found in chapters 2.1.1, 2.1.2 and 2.1.3 herein above.

4.7.1 Synthesis of Further Primary Benzylic Chlorides

The following scheme provides an overview over further primary benzylic chlorides synthesized by formamide catalyzed chlorinations:

4.7.1.1 Synthesis of 4-(Methylthio)benzyl chloride (2 ₅₄ )

(4-Methylthio)benzyl alcohol (1 ₅₄ , 308 mg, 2.00 mmol, l.O equiv), FPyr (19.7 μί, 20.4 mg, 0.20 mmol, 10 mol%), dioxane (lmL) and BzCI (282 μί,

341 mg, 2.40 mmol, 1.2 equiv) were combined as described in general

2

procedure II. Chromatographic purification of the crude material (430 mg, conv. >98%, 2 ₅₄ /354 97:3) on silica gel (mass of crude material/Si0 ₂ 1:12) with Et ₂ 0//iPen 3:97 furnished the chloride 2 ₅₄ (270 mg, 1.56 mmol, 78%) as a colorless oil. To load the crude product onto the column, it was dissolved in the eluent (0.5 mL).

M (CgHgCIS) = 172.675 g/mol; HR-MS (CI, [C ₈ H ₉ CI ³⁵ S] ⁺ ) calc. 172.0108 u found 172.0123 u.

4.7.1.2 Synthesis of 4-(Methylsulfonyl)benzyl chloride (2 ₅₅ )

3 120 According to general procedure II 4-(Methylsulfonyl)benzyl alcohol (1 ₈ , 6 5JI I 186 mg, 1.00 mmol, 1.0 equiv) was allowed to react with 4-MeOBzCI (164 μί,

O O 207 mg, 1.20 mmol, 1.2 equiv) (here 4-MeOBzCI was utilized instead of BzCI, because the 4-methoxybenzoic acid ester of alcohol 1 ₅₅ was more simple to

255

separate through chromatography from the chloride 2 ₅₅ then the benzoic acid ester of 1 ₅₅ ) in presence of FPyr (9.8 μΐ, 10.2 mg, 0.10 mmol, 10 mol%) in dioxane (1 mL) for 12 h at ambient temperature and for 12 h at 40 °C. After work up with CH ₂ CI ₂ (instead of Et ₂ 0) the crude material (283 mg) was dissolved in Et ₂ 0 (0.5 mL) at 40 °C to load it onto a silica gel column. Chromatographic purification with silica gel (mass of crude product/Si0 ₂ 1:55) with Et ₂ 0//iPen 65:35 delivered the chloride 2 ₅₅ (181 mg), which contained 2 mol% 4-MeOBzOH according to ¹ H-N M . Dissolution in CH ₂ CI ₂ (6 mL), washing with sat. NaHC0 ₃ -solution (aq., 3 x 3 mL), drying over MgS0 ₄ and concentration in vacuo finally provided the sulfone 2 ₅₅ (175 mg, 0.854 mmol) as a colorless oil, which crystallized immediately upon scratching with a spatula, in 85% yield.

M (C ₈ H ₉ 0 ₂ SCI) = 204.674 g/mol; HR-MS (CI, [C ₈ H ₉ 0 ₂ SCI] ⁺ ) found 204.0006 u calc. 204.0013 u.

4.7.1.3 Synthesis of 3-(Tri-;so-propylsilyloxy)benzyl chloride (2 ₅₆ )

As described in general procedure I I a solution of 3-(tri-/ ^' so- propylsilyloxy)benzyl alcohol (1 ₅₆ , 280 mg, 1.00 mmol, 1.0 equiv) and FPyr (9.8 μΐ, 10.2 mg, 0.10 mmol, 10 mol%) in MTBE (500 μΐ) was cooled to 0 °C and BzCI (141 mg, 171 mg, 1.20 mmol, 1.2 equiv) added. Then the reaction mixture was allowed to stir for 15 min at 0 °C and 21 h at ambient temperature. In deviation from the general procedure the work up procedure was modified as follows: The reaction solution was diluted with CH ₂ CI ₂ (1 mL), cooled in an ice bath and treated with 2-ethanolamine (49 μί, 0.80 mmol, 0.8 equiv). After 5 min of stirring the ice bath was removed and the mixture was stirred for 30 min at room temperature. Then the heterogeneous mixture was diluted with Et ₂ 0 (5 mL) and aqueous 1 N NaOH-solution (3 mL), the organic phase was dried over MgS0 ₄ and concentrated under reduced pressure. In the following chromatographic purification of the crude material (306 mg, >98% conv., 2 ₅ β/3 ₅₆ 96:4 according to ¹ H-N MR) on silica gel (crude mass/Si0 ₂ 1:18) with CH ₂ CI ₂ //iPen 10:90 and drying at 20 mbar furnished chloride 2 ₅₆ as a pale yellow oil (256 mg, 0.856 mmol, 86%).

M (C ₁₆ H ₂₇ CIOSi) = 298.924 g/mol; HR-MS (CI, [C ₁₆ H ₂₇ CIOSi] ⁺ ) calc. 298.1520 u found 298.1533 u. 4.7.1.4 Synthesis of 3-(ferf-Butyldimethylsilyloxy)benzyl chloride (2 ₅₇ )

According to general procedure I I a solution of 3-(tert- butyldimethylsilyloxy)benzyl alcohol (1 ₅₇ , 238 mg, 1.00 mmol, 1.0 equiv) and FPyr (9.8 μΐ, 10.2 mg, 0.10 mmol, 10 mol%) in MTBE (500 μΐ) was cooled to 0 °C and treated with BzCI (141 mg, 171 mg, 1.20 mmol, 30 1.2 equiv). Next the reaction mixture was stirred for 15 min at 0 °C and for 21 h at ambient temperature. After a modified work up as described for the synthesis of chloride 2 ₅₆ (chapter 4.7.1.3) chromatographic purification of the crude product (272 mg, >98% conv., 2 ₅₇ /3 ₅₇ 96:4 according to ¹ H-N MR) on silica gel (crude mass/Si0 ₂ 1:21) with CH ₂ CI ₂ //iPen 20:80 and drying at 20 mbar furnished chloride 2 ₅₇ as a colorless oil (215 mg, 0.846 mmol, 84%). In order to load the crude material onto the column, it was diluted with CH ₂ CI ₂ (0.2 mL) and the eluent (0.4 mL). M (C ₁₃ H ₂₁ CIOSi) = 256.844 g/mol; HR-MS (CI, [C ₁₃ H ₂₁ CIOSi] ⁺ ) calc. 256.1050 u found 256.1044 u.

Synthesis of 3-(Triethylsilyloxy)benzyl chloride (2 ₅₈ )

As given in general procedure I I a solution of 3-(triethylsilyloxy)benzyl alcohol (1 ₅₈ , 238 mg, 1.00 mmol, l.O equiv) and FPyr (9.8 μΐ, 10.2 mg, 0.10 mmol, 10 mol%) in MTBE (500 μΐ) was cooled to 0 °C and treated

2 ₅₈ with BzCI (141 mg, 171 mg, 1.20 mmol, 1.2 equiv). In the following the reaction mixture was allowed to stir for 15 min at 0 °C and for 16 h at ambient temperature. After an alternated work up as given for the synthesis of chloride 2 ₅₆ (chapter 4.7.1.3) chromatographic purification of the crude product (253 mg, >98% conv., 2 ₅₈ /3 ₅ 8 96:4 according to ¹ H-N MR) on silica gel (crude mass/Si0 ₂ 1:23) with CH ₂ CI ₂ //iPen 25:75 and drying at 20 mbar provided the chloride 2 ₅₈ as a colorless oil (112 mg, 0.437 mmol, 44%).

M (C ₁₃ H ₂₁ CIOSi) = 256.844 g/mol; HR-MS (CI, [C ₁₃ H ₂₁ CIOSi] ⁺ ) calc. 256.1050 u found 256.1057 u.

4.7.1.6 Synthesis of 3-(ferf-Butoxycarbonyloxy)benzyl chloride (2 ₅₉ )

According to general procedure I I a solution of 3-(tert- ) and FPyr (9.8 μί, 10.2 mg, 0.10 mmol, 10 mol%) in MTBE (500 μί)

2 ₅₉ was cooled to 0 °C and treated with BzCI (141 mg, 171 mg, 1.20 mmol,

20 1.2 equiv). Then the reaction mixture was stirred for 15 min at 0 °C and for 20 h at ambient temperature. After a modified work up as described for the synthesis of chloride 2 ₅₆ (chapter 4.7.1.3) the crude chloride 2 ₅₉ (268 mg, >98% conv., 2 ₅ /3 ₅₉ 96:4 according to ¹ H-N MR) was dissolved in CH ₂ CI ₂ //iPen 50:50 (0.4 mL) and loaded onto a silica gel column (crude mass/Si0 ₂ 1:22). Finally, chromatographic purification with CH ₂ CI ₂ //iPen 50:50 and drying at 20 mbar gave chloride 2 ₅₉ as a colorless oil (212 mg, 0.875 mmol, 88%).

M (C ₁₂ H ₁₅ CI0 ₃ ) = 242.699 g/mol; HR-MS (CI, [C ₁₂ H ₁₆ CI0 ₃ ] ⁺ ) calc. 243.0782 u found 243.0739 u.

4.7.1.7 Synthesis of 3-(2-(l,3-Dioxan-2-yl)ethyloxy)benzyl chloride (2 ₆₀ )

Following general procedure I I 4-methoxybenzoyl chloride (164 μί, 207 mg, 1.20 mmol 1.2 equiv) (instead of BzCI 4-MeOBzCI was utilized, as the 4-methoxybenzoic acid ester of alcohol l ₆ o (rf 2 ₆₀ = 0.16 in Et ₂ 0/CH ₂ CI ₂ 2:98) was more easy to separate through chromatography from the chloride 2 ₆ o than the benzoic acid ester of 1 ₆₀ (r _f = 0.25 in Et ₂ 0/CH ₂ CI ₂ 2:98)) was added at 0 °C to a solution of 3-(2-(l,3-dioxan-2- yl)ethyloxy)benzyl alcohol (1 ₆₀ , 238 mg, 1.00 mmol, 1.0 equiv) and FPyr (9.8 μΐ, 10.2 mg, 0.10 mmol, 10 mol%) in MTBE (500 μί). Then the reaction mixture was stirred for 15 min at 0 °C and for 20 h at ambient temperature. After a modified work up as described for the synthesis of chloride 2 ₅₆ (chapter 4.7.1.3) chromatographic purification of the crude product (264 mg, >98% conv., 2 ₆ o/3 ₆ o 94:6 according to ¹ H-N MR) on silica gel (crude mass/Si0 ₂ 1:28) with Et ₂ 0/CH ₂ CI ₂ 2:98 and drying at 20 mbar delivered chloride 2 ₆ o as a colorless oil (230 mg, 0.896 mmol, 90%).

M (C ₁₃ H ₁₇ CI0 ₃ ) = 256.725 g/mol; HR-MS (CI, [C ₁₃ H ₁₇ CI0 ₃ ] ⁺ ) calc. 256.0866 u found 256.0870 u.

4.7.1.8 Synthesis of 3-(Chloromethyl)phenyl 2-(tert-butoxycarbonylamino)acetate (2 ₆₁ )

According to general procedure I I a solution of 3-

(hydroxymethyl)phenyl-2-(tert-butoxycarbonyl )acetate (1 ₆₁ , 141 mg, 0.50 mmol, 1.0 equiv) and FPyr

(4.9 μί, 5.1 mg, 0.05 mmol, 10 mol%) in MTBE (250 μί) was

cooled in an ice bath and BzCI (70 mg, 85 mg, 0.60 mmol, 1.2 equiv) was added. Next the reaction mixture was stirred for 15 min at 0 °C and subsequently for 12.5 h at ambient temperature. After a modified work up as described for the synthesis of chloride 2 ₅₆ (chapter 4.7.1.3, instead of 49 μί ethanolamine 25 μί were utilized) chromatographic purification of the crude product (140.3 mg, >98% conv., 2 ₆₁ /3 ₆ i 97:43 according to ¹ H-N MR) on silica gel (crude mass/Si0 ₂ 1:24) with Et ₂ 0/CH ₂ CI ₂ 3:97 and drying at 20 mbar furnished chloride 2 ₆ i as a colorless oil (109 mg, 0.363 mmol, 73%).

M (C ₁₄ H ₁₈ CIN0 ₄ ) = 299.750 g/mol; HR-MS (CI, [C ₉ H ₁₀ CIO ₂ ] ⁺ ) calc. 199.0400 u found 199.0391 u.

4.7.1.9 Synthesis of ferf-Butyl 2-(3-(chloromethyl)phenyl)acetate (2 ₆₂ )

In accordance with general procedure I I a solution of ieri-butyl 2-(3- (hydroxymethyl)phenyl) acetate (1 ₆₂ , 238 mg, 1.00 mmol, 1.0 equiv) and FPyr (9.8 μί, 10.2 mg, 0.10 mmol, 10 mol%) in MTBE (500 μί)

was chilled to 0 °C and treated with BzCI (141 mg, 171 mg,

2 ₆₂

1.20 mmol, 1.2 equiv). Then the reaction mixture was stirred for 15 min at 0 °C and for 20.5 h at room temperature. After a modified work up as given in the synthesis of chloride 2 ₅₆ (chapter 4.7.1.3) chromatographic purification of the crude product (271 mg, >98% conv., 2 ₆₂ /3 ₆ 2 95:5 according to ¹ H-N MR) on silica gel (crude mass/Si0 ₂ 1:21) with CH ₂ CI ₂ //iPen 60:40 and drying at 20 mbar delivered chloride 2 ₆₂ as a colorless oil (221 mg, 0.860 mmol, 86%).

M (C ₁₃ H ₁₇ CI0 ₃ ) = 256.725 g/mol; HR-MS (CI, [C ₁₃ H ₁₇ CI0 ₃ ] ⁺ ) calc. 256.0866 u found 256.0859 u. 4.7.1.10 Synthesis of 4-Formylbenzyl chloride (2 ₆₃ )

As described in general procedure II a solution of 4-formyl benzyl alcohol (1 ₆ 3,

136.2 mg, 1.00 mmol, l.O equiv) and FPyr (9.8 μί, 10.2 mg, 0.10 mmol, 10 mol%) in dioxane (500 μΐ) was treated with BzCI (176 mg, 213 mg, 1.50 mmol, 1.5 equiv) and allowed to stir for 15 min at ambient temperature

and 24 h at 40 °C. After work up with CH ₂ CI ₂ (instead of Et ₂ 0) the crude material (223 mg, >98% conv., 2 ₆ 3/3 ₆ 3 97:3) was dissolved in toluene (0.5 mL) and loaded onto a silica gel column. Finally, chromatographic purification on silica gel (crude mass/Si0 ₂ 1:20) with Et ₂ 0/toluene 0.5:99.5, concentration with chloroform (3 x 2 mL) to remove residual toluene and drying at 20 mbar furnished chloride 2 ₆ 3 as a colorless solid (108.3 mg, 0.70 mmol, 70%).

M (C ₈ H ₇ CIO) = 154.594 g/mol; HR-MS (El, [C ₈ H ₇ 0] ⁺ ) calc. 119.0491 u found 119.0500 u.

4.7.2 Synthesis of Further Primary Allylic Chlorides

4.7.2.1 Improved Synthesis of f-l-Chloro-3,7-dimethyl-2,6-octadien (E-/-2 ₄ , Geranyl Chloride)

In alignment to general procedure III a 1 L flask with a strong stir bar was charged with geraniol (E-l ₄ , 178 mL, 155.8 g, 1000 mmol, l.O equiv) and DMF (23.2 mL; 21.9 g, 300.0 mmol, 30 mol%). Next the reaction funnel was cooled in an ice bath and benzoyl chloride (116 mL, 140.6 g, 990 mmol, 0.99 equiv) were slowly added within 1.5 h with the aid of a dropping funnel, whereby benzoic acid started to precipitate after 1.25 h. When BzOH started to precipitate the stirring speed was adjusted from 800 to 1400 rpm. After 1 h of further stirring the cooling bath was removed and the reaction suspension was allowed to stir for 2 h at ambient temperature. Monitoring by ¹ H-NM showed 97% conversion after 1 h of stirring

at room temperature and full consumption of the starting material 1 ₄ after 1.75 h.

6-2 ₄

25 In deviation from general procedure II the work up protocol was modified as follows: The reaction mixture was cooled in an ice bath and 4 N NaOH-solution (aq., 260 mL, 1040 mmol) was added through a dropping funnel within 15 min, whereby all solids dissolved (In a work up on the same scale utilizing sat. Na ₂ C0 ₃ -solution we experienced a rapid C0 ₂ -evolution upon shaking of the quenched reaction mixture in the extraction funnel. Therefore, NaOH-solution was preferred. In the ¹ H-NMR of the crude material very small traces of linalool (<2%, in comparison to the ¹ H-NMR spectra of commercial material) occurred, which were not present in the reaction control via ¹ H-NMR. Hence, hydrolysis was basically not observed). The quenched reaction mixture was transferred to a 1 L extraction funnel and the phases were separated without shaking of the funnel (pH of the separated aq. phase > 10). Next, the slightly turbid organic phase was washed with brine (30 mL), whereby EtOAc was added to improve phase separation, and dried over MgS0 ₄ (3.9 g). Filtration through a plug of wool provided the crude chloride 2 ₄ as a yellow oil (119.2 g, 115%). ¹ H- NM indicated a //6-ratio of 2 ₄ of 97:3 and a chloride to ester ratio 2 ₄ /3 ₄ of 91:9.

Fractioned distillation through a micro distillation apparatus with a NS 29 cooling finger with Vigreux column (19 cm pathway, NS 29, vacuum-mantled and metal-coated) at 0.11 mbar delivered initially a prefraction with a bp. of 45-56 °C (13.05 g, colorless oil, oil bath temperature 80 °C), which mainly consisted of linear chloride E-2 ₄ and its regioisomer linalyl chloride in ratio of 87:13 l/b and small traces of linalool (< 2 mol% referred to E-2 ₄ ) (to remove EtOAc initially the pressure was gradually lowered from 40 to 0.11 mbar with the aid of a needle valve and EtOAc was collected in a cooling trap cooled with nitrogen). A gradual raising the oil bath temperature from 80 to 120 °C then furnished the chloride /-E-2 ₄ as a colorless liquid with a bp. 56-58 °C (121.1 g, 701 mmol, 70%). Both ¹ H-NMR and GC-MS proved a regioisomeric ratio /-/6-2 ₄ >98:2. Further increasing the oil bath temperature to up to 150 °C lead to the collection of a small fraction with a bp. of 59-65 °C (2.109 g) containing the product 2 ₄ in purity of approximately 95% according to ¹ H-NMR. Importantly, the collecting flasks were cooled in an ice bath. A second distillation of the first fraction through a Vigreux column (14 cm pathway, NS 14.5) at 0.11 mbar delivered further geranyl chloride as a colorless thin oil with a bp. of 57-58 °C (8.714 g, 50.5 mmol, 6%, l/b >98:2). As no distillation dispenser was utilized, the collecting flasks were exchanged under interruption of heating and vacuum. 4.7.3 Synthesis of Further Primary Aliphatic Chlorides

The following scheme provides an overview over further primary benzylic chlorides synthesized by formamide catalyzed chlorinations:

2 ₆₄ 84% S-2 ₆₅ S-2 ₆₆ S-2 ₆₇ S-2 ₆₈

73% 70% 68% 83%

BzH

90% (in DMF) 88% (in DMF) 70% (w/o FPyr)

77% (in DMF)

Reaction Conditions

BzCI (1.2 equiv), FPyr (20 mol%) dioxane (1 M), 2.5-17 h 80 °C

Deviation from standard reaction conditions are given in parenthesis.

4.7.3.1 Synthesis of 3-(2-Chloroethyl)indole (2 ₆₄ )

According to general procedure II benzoyl chloride (282 μί, 341 mg,

2.40 mmol, 1.2 equiv) was added to a solution of 2-(3-indolyl)ethanol (322 mg, 2.00 mmol, 1.0 equiv) and FPyr (39.3 μΐ, 40.9 mg, 0.40 mmol, 20 mol%) in dioxane (2 mL, 1 M) at ambient temperature and the reaction 2β4 mixture was allowed to stir for 2.5 h at 80 °C. Work up with CH ₂ CI ₂ instead of

Et ₂ 0 provided the crude chloride 2 ₆₄ (472 mg, > 98% conv., 2 ₆₄ /364 85:15), which was dissolved in toluene (0.5 mL) and loaded onto a silica gel column (mass crude material/Si0 ₂ 1:13). Elution with toluene afforded the chloride 2 ₆₄ (302 mg, 1.68 mmol, 84%) as a pale yellow solid after concentration with chloroform (3 x 2 mL) in vacuo to remove remaining toluene and drying in high vacuum. 4.7.3.2 Synthesis of S-l-Chloro-2-(benzyloxycarbonylamino)-3-phenylpropane (S-2 ₆₅ )

BzCI (1.2 equiv), DMF (2 M), 18 h

78% ^a

S-2, 65 40 °C a. Isolated yield.

Entry 1: According to general procedure II benzoyl chloride (141 μί, 170 mg, 1.20 mmol, 1.2 equiv) was added to a solution of alaninol derivative 1 ₆₅ (285 mg, 1.00 mmol, 1.0 equiv) and FPyr (19.7 μί, 20.4 mg, 0.20 mmol, 20 mol%) in dioxane (1 mL, 1 M) at ambient temperature and then allowed to react at 80 °C for 8.5 h at 80 °C. Next, the crude material (353 mg, >98% conversion, 2 ₆₅ /3 ₆ 5 90:10 according to NMR) was dissolved under earful heating with a heat gun in toluene (0.5 mL) and loaded onto a silica gel column (mass crude material/Si0 ₂ 1:32). Elution with Et ₂ 0/toluene 3:97, concentration with chloroform (3 x 2 mL) to remove residual toluene and drying in high vacuum furnished the chloride 2 ₆₅ as a colorless solid in 73% yield (220.3 mg, 0.725 mmol).

Entry 2: In alignment to general procedure II a solution of the alcohol 1 ₆₅ (1.00 mmol, 1.0 equiv) in DMF (0.5 mL, 2 M) was combined with benzoyl chloride (1.2 equiv) at ambient temperature and the reaction solution was stirred for 18 h at 40 °C. Then, the crude product (297 mg, >98% conversion, 2 ₆ s/3 ₆₅ 96:4) was dissolved in toluene (0.5 mL) at 40 °C and loaded onto a silica gel column (mass crude material/Si0 ₂ 1:31). Elution with Et ₂ 0/toluene 3:97, concentration with chloroform (3 x 2 mL) and drying in high vacuum delivered the chloride 2 ₆₅ as a colorless oil in 78% yield (236 mg, 0.777 mmol, 78%).

M (C ₁₇ H ₁₈ CIN0 ₂ ) = 303.783 g/mol; HR-MS (CI, YK0033, [C ₁₇ H ₁₉ N0 ₂ CI ³⁵ ] ⁺ ) calc. 304.1104 u found 304.1107 u. [ct] _D ²⁰ = -23.3 (c = 0.56 g/100 mL, CHCI ₃ ).

4.7.3.3 Synthesis of S-l-Chloro-2-(allyloxycarbonylamino)-3-phenyl propane (2 ₆₆ )

3'

)

BzCi (1.2 equiv), DMF (2 M), 24 h

2 1 77% ^a

40 °C

a. Isolated yield.

Entry 1: According to general procedure II alaninol derivative 1 ₆ 6 (235 mg, 1.00 mmol, 1.0 equiv), FPyr (19.7 μΐ, 20.4 mg, 0.20 mmol, 20 mol%), dioxane (1 mL, 1 M) and benzoyl chloride (141 μΐ, 170 mg, 1.20 mmol, 1.2 equiv) were combined at ambient temperature and stirred for 16 h at 80 °C. After work up with CH ₂ CI ₂ instead of Et ₂ 0, the crude product (289 mg, >98% conversion, 2 ₆ 6/3 ₆ 6 89:11 according to ¹ H-NMR) was dissolved in toluene (0.5 mL) and loaded onto a silica gel column (mass crude material/Si0 ₂ 1:32). Elution with Et ₂ 0/toluene 3:97, concentration with chloroform (3 x 2 mL) to remove residual toluene and drying in high vacuum furnished the chloride 2 ₆ e as a pale yellow solid in 70% yield (178 mg, 0.700 mmol). Entry 2: As given in general procedure II a solution of the alcohol 1 ₆ 6 (1.00 mmol, 1.0 equiv) in DMF (0.5 mL, 2 M) was treated with benzoyl chloride (1.2 equiv) at ambient temperature and the reaction solution was stirred for 16 h at 40 °C. After work up with CH ₂ CI ₂ rather then Et ₂ 0 and in deviation from general procedure II additionally washing of the organic phase with water (2 x 3 mL) before MgS0 ₄ drying, the crude material (285 mg, 96% conversion, 2 ₆ 6/3 ₆ 6 96:4) was dissolved in toluene (0.5 mL) at 40 °C and loaded onto a silica gel column (mass crude material/Si0 ₂ 1:33). Elution with Et ₂ 0/toluene 3:97, concentration with chloroform (3 x 2 mL) and drying in high vacuum delivered the chloride 2 ₆ e as a colorless solid in 77% yield (196 mg, 0.773 mmol, 77%).

M (C ₁₃ H ₁₆ CIN0 ₂ ) = 253.725 g/mol; HR-MS (CI, [C ₁₃ H ₁₇ N0 ₂ CI] ⁺ ) calc. 254.0492 u found 254.0948 u; ([C ₁₃ H ₁₆ CI ³⁵ N0 ₂ ] ⁺ ) calc. 253.0864 u found 253.0870 u; [ct] _D ²⁰ = -13.6 (c = 0.99 g/100 mL, CHCI ₃ ).

4.7.3.4 Synthesis of S-l-Chloro-2-(trifluoroacetylamino)-3-phenyl propane (2 ₆₇ )

BzCi (1.2 equiv), DMF (2 M), 18 h 40 °C, 6 h

'67 2 1 90% ^a

60 °C

a. Isolated yield.

Entry 1: According to general procedure II the TFA-protected amino alcohol derivative 1 ₆₇ (247 mg, 1.00 mmol, 1.0 equiv) was allowed to react with benzoyl chloride (141 μί, 170 mg, 1.20 mmol, 1.2 equiv) in the presence of FPyr (19.7 μί, 20.4 mg, 0.20 mmol, 20 mol%) in dioxane (1 mL, 1 M) for 17 h at 80 °C. After work up with CH ₂ CI ₂ instead of Et ₂ 0, the crude chloride 2 ₆₇ (363 mg, > 98% conversion, 2 ₆₇ /3 ₆ 7 89:11 according to ¹ H-NM ) was dissolved in toluene (0.5 mL) and loaded onto a silica gel column (mass crude material/Si0 ₂ 1:30). Elution with Et ₂ 0/toluene 1:99, concentration with chloroform (3 x 2 mL) to remove residual toluene and drying in high vacuum provided the chloride 2 ₆₇ as a colorless solid (180 mg, 0.679 mmol, 68%).

Entry 2: As described in general procedure II a solution of the alcohol 1 ₆₇ (1.00 mmol, 1.0 equiv) in DMF (0.5 mL, 2 M) was treated with benzoyl chloride (1.2 equiv) at ambient temperature and the reaction solution was stirred for 18 h at 40 °C and for 6 h at 60 °C. After work up with CH ₂ CI ₂ rather then Et ₂ 0 and in deviation from general procedure II additionally washing of the organic phase with water (2 x 3 mL) before MgS0 ₄ drying, the crude material (342 mg, 96% conversion, 2 ₆₇ /3 ₆ 7 94:6) was dissolved in toluene (0.5 mL) and loaded onto a silica gel column (mass crude material/Si0 ₂ 1:33). Elution with Et ₂ 0/toluene 2:98, concentration with chloroform (3 x 2 mL) and drying in high vacuum delivered the chloride 2 ₆₇ as a colorless solid in 90% yield (239 mg, 0.901 mmol). M (CuHnCI FsNO) = 265.659 g/mol; HR-MS (CI, [C ₁₃ H ₁₆ CI ³⁵ F ₃ N0 ₂ ] ⁺ ) calc. 266.0554 u found 266.0564 u; [ct] _D ²⁰ = -2.0 (c = 1.14 g/100 mL, CHCI ₃ ).

4.7.3.5 Synthesis of S-l-Chloro-2-(4-tolylsulfonylamino)-3-phenyl propane (2 ₆₈ )

According to general procedure I I the tosyl-protected alaninol derivative l ₆ s (305 mg, 1.00 mmol, l.O equiv) was combined with FPyr (19.7 μΐ, 20.4 mg, 0.20 mmol, 20 mol%), dioxane (1 mL, 1 M) and benzoyl chloride (141 μί, 170 mg, 1.20 mmol, 1.2 equiv) at ambient temperature and allowed to react at 80 °C, until TLC

=■68 10 indicated full consumption of the starting material l ₆ s (16 h). After work up with CH ₂ CI ₂ instead of Et ₂ 0, the crude chloride 2 ₆ s (475 mg, > 98% conversion, 2 ₆₈ /3 ₆₈ 89: 11 according to ¹ H-N M ) was dissolved in Et ₂ 0/toluene 6:94 (0.5 mL) and loaded onto a silica gel column (mass crude material/Si0 ₂ 1:35). Elution with Et ₂ 0/toluene 6:94, concentration with chloroform (3 x 2 mL) under reduced pressure to remove residual toluene and drying in high vacuum gave the chloride 2 ₆ s as a colorless solid (269 mg, 0.829 mmol, 83%).

M (C ₁₆ H ₁₈ CIN0 ₂ S) = 323.838 g/mol; HR-MS (CI, [C ₁₆ H ₁₉ CI ³⁵ N0 ₂ S] ⁺ ) calc. 324.0820 u found 324.0780 u; [ct] _D ²⁰ = -17.8 (c = 1.04 g/100 mL, CHCI ₃ ).

4.7.3.6 Synthesis of 2-(Benzoylamino)-l-chloroethane (2 ₆₉ )

According to general procedure I I 4-methoxybenzoyl chloride (164 μί, 207 mg, 1.20 mmol, 1.2 equiv) (with 4-MeOBzCl as chlorination reagent the chromatographic separation of the ester side product of type 330 was

2 ^β 9 simplified compared to BzCl) was added at room temperature to a solution of A/-benzoyl-l-ethanol-2-amine (1 ₆ 9, 165.2 mg, 1.00 mmol, l.O equiv) and FPyr (19.7 μί, 20.4 mg, 0.20 mmol, 20 mol%) in dioxane (1 mL, 1 M) and the resulting mixture was stirred at 80 °C, until TLC indicated full consumption of the starting material 1 ₆ 9 (3.5 h). After work up with CH ₂ CI ₂ instead of Et ₂ 0, the crude product (267 mg, > 98% conversion, 2 ₆₉ /3 ₆ 9 87:13 according to ¹ H-NM R) was dissolved in CH ₂ CI ₂ (0.5 mL) at 40 °C and loaded onto a silica gel column (mass crude material/Si0 ₂ 1:31). Elution with Et ₂ 0//iPen 65:35 delivered the chloride 2 ₆ g as a colorless solid (139.6 mg, 0.762 mmol, 76%).

M (C ₉ H ₁₀ CI NO) = 183.635 g/mol. -l-Chloro-2-(2,2,2-trichloroethyloxycarbonylamino)-3-methyl butane (2 ₇₀ )

a. Isolated yield.

Entry lAccording to general procedure II the Troc-protected valinol derivative 1 ₇₀ (279 mg, 1.00 mmol, 1.0 equiv) was converted with benzoyl chloride (141 μί, 170 mg, 1.20 mmol, 1.2 equiv) in the presence of FPyr (19.7 μΐ, 20.4 mg, 0.20 mmol, 20 mol%) in dioxane (1 mL, 1 M) at 80 °C within 3.5 h into chloride 2 ₇₀ . In the following the crude product (322 mg, > 98% conversion, 2 ₇₀ /3 ₇₀ 89:11 according to ¹ H-NM ) was dissolved in toluene (0.5 mL) and loaded onto a silica gel column (mass crude material/Si0 ₂ 1:33). Elution with Et ₂ 0/toluene 0.5:99.5, concentration with chloroform (3 x 2 mL) to remove residual toluene and drying in high vacuum afforded chloride 2 ₇₀ as a colorless solid (220 mg, 0.736 mmol, 74%).

Entry 2ln accordance to general procedure II benzoyl chloride (1.2 equiv) was added to a solution of the substrate 1 ₇₀ (1.00 mmol, 1.0 equiv) in DMF (0.5 mL, 2 M) at ambient temperature and the reaction solution was stirred for 24 h at 40 °C. Next, the crude material (363 mg, > 98% conversion, 2 ₇ o/3 ₇ o 97:3) was dissolved in toluene (0.5 mL) and loaded onto a silica gel column (mass crude material/Si0 ₂ 1:30). Elution with toluene, concentration with chloroform (3 x 2 mL) and drying in high vacuum provided the product 2 ₇₀ as a pale yellow oil, which solidified upon storage in the fridge overnight, in 90% yield (268 mg, 0.902 mmol).

M (C ₈ H ₁₃ Cl ₄ N0 ₃ ) = 297.006 g/mol; HR-MS (CI, [C ₈ H ₁₄ (CI ³⁵ ) ₃ CI ³⁷ N0 ₂ ] ⁺ ) calc. 297.9749 u found 297.9749 u; [ct] _D ²⁰ = -40.2 (c = 1.12 g/100 mL, CHCI ₃ ). 4.7.3.8 Synthesis of 5-l-Chloro-2-(fluorenylmethoxycarbonylamino)-2-phenylethane (2 ₇₁ )

According to general procedure II a suspension of Fmoc- protected phenylglycinol (1 _71: 359 mg, 1.00 mmol, 1.0 equiv) in D F (0.5 mL, 2 M) was treated with benzoyl chloride (176 μί, 213 mg, 1.50 mmol, 1.5 equiv) and the reaction mixture was allowed to stir for 21 h at 60 °C, whereupon TLC indicated full conversion of the starting material 1 _Ί1 (r _f (Et ₂ 0) = 0.39). Work up

2

⁷¹ with CH ₂ CI ₂ instead of Et ₂ 0 and in deviation from general procedure II additionally washing of the organic phase with water (2 x 3 mL) before MgS0 ₄ drying delivered the crude chloride 2 ₇₁ (420 mg), which was dissolved under heating in a minimum amount of chloroform (1.5 mL) and loaded onto a silica gel column (mass crude product/Si0 ₂ 1:30). Elution with Et ₂ 0/toluene 4:96, concentration with chloroform (3 x 2 mL) to remove residual toluene and drying in high vacuum furnished chloride 2 ₇₁ as a colorless solid (296 mg, 0.783 mmol, 78%).

M (C ₂₃ H ₂₀ CINO ₂ ) = 377.863 g/mol; HR-MS (CI, [C ₂₃ H ₂₁ CI ³⁵ N0 ₂ ] ⁺ ) calc. 378.1255 u found 378.1260 u.

4.7.3.9 Synthesis of /?-Methyl 3-chloro-2-(benzyloxycarbonylamino) propanoate (2 ₇₂ )

dioxane (1 M), 16 h 80 °C

'72

BzCI (1.2 equiv), DMF (2 M), 15 min

2 1 88% ^a rt, 6.5 h 40 °C

a. Isolated yield.

Entry lAccording to general procedure II benzoyl chloride (176 μί, 213 mg, 1.50 mmol, 1.5 equiv) was added to a solution of Cbz-protected serine derivative 1 ₇₂ (253 mg, 1.00 mmol, 1.0 equiv) and FPyr (19.7 μί, 20.4 mg, 0.20 mmol, 20 mol%) in dioxane (0.5 mL, 2 M) at ambient temperature and the resulting reaction solution was heated to 80 °C for 16 h. After work up with CH ₂ CI ₂ instead of Et ₂ 0 the crude chloride 2 ₇₂ (356 mg, > 98% conversion, 2 ₇₂ /3 ₇₂ 90:10 according to ¹ H-NM ) was dissolved in Et ₂ 0/toluene 6:94 (0.5 mL) and loaded onto a silica gel column (mass crude material/Si0 ₂ 1:31). Elution with Et ₂ 0/toluene 6:94, concentration with chloroform (3 x 2 mL) to remove residual toluene and drying in high vacuum provided the product 2 ₇₂ as a colorless oil (230 mg, 0.847 mmol, 85%), which crystallized at ambient temperature.

Entry 2: In accordance to general procedure II substrate 1 ₇₂ (1.00 mmol, 1.0 equiv), DMF (0.5 mL, 2 M) and benzoyl chloride (141 μί, 170 mg, 1.20 mmol, 1.2 equiv) were combined at ambient temperature and the resulting reaction solution was stirred for 15 min at room temperature and for 6.5 h at 40 °C, whereupon TLC control revealed full consumption of the starting material. After work up with CH ₂ CI ₂ instead of Et ₂ 0 and in deviation from general procedure II additionally washing of the organic phase with water (2 x 3 mL) before MgS0 ₄ drying, the crude material (330 mg, > 98% conversion, 2 ₇₂ /3 ₇₂ 94:6) was dissolved in Et ₂ 0/toluene 6:94 (0.5 mL) and loaded onto a silica gel column (mass crude material/Si0 ₂ 1:30). Elution with Et ₂ 0/toluene 6:94, concentration with chloroform (3 x 2 mL) and drying in high vacuum gave the chloride 2 ₇₂ as a pale yellow oil, which solidified upon storage at room temperature, in 88% yield (237 mg, 0.876 mmol).

M (C ₁₂ H ₁₄ CIN0 ₄ ) = 271.700 g/mol; HR-MS (CI, [C ₁₂ H ₁₅ CI ³⁵ N0 ₄ ] ⁺ ) calc. 271.0606 u found 272.0692 u; [ct] _D ²⁰ = +42.0 (c = 1.63 g/100 mL, CHCI ₃ ). 4.7.3.10 Synthesis of S-2-(Chloromethyl)-l-formylpyrrolidine (2 ₇₃ )

2 0.3 BzCI (1.2 equiv), dioxane (1 M), 4 h 80 °C 70% ^b a. Isolated yield, b. Yield determined via internal NM -standard.

Interestingly, the chlorinated formamide 2 ₇₃ was also obtained as major product in the chlorination of the corresponding alcohol 1 ₇₃ in the absence of a formamide catalyst, which is most likely reasoned by a autocatalytic effect of substrate 1 ₇₃ (and product 2 ₇₃ ).

Entry 1: According to general procedure II benzoyl chloride (141 μί, 170 mg, 1.20 mmol, 1.2 equiv) prolinol derivative 1 ₇₃ (129.2 mg, 1.00 mmol, 1.0 equiv), FPyr (19.7 μΐ, 20.4 mg, 0.20 mmol, 20 mol%) and dioxane (1 mL, 1 M) were mixed at ambient temperature and the resulting reaction solution was subsequently stirred at 80 °C for 3.25 h, whereupon TLC control revealed of conversion of the alcohol 1 ₇₃ . After work up with CH ₂ CI ₂ instead of Et ₂ 0 the crude chloride 2 ₇₃ (188 mg, 2 ₇₃ /3 ₇₃ 93:7 according to ¹ H-NMR) was dissolved in EtOAc (0.5 mL) and loaded onto a silica gel column (mass crude material/Si0 ₂ 1:26). Elution with EtOAc, concentration with chloroform (3 x 2 mL) to remove residual EtOAc and drying under reduced pressure (20 mbar) furnished the chloride 2 ₇₃ as a pale yellow oil (121.1 mg, 0.820 mmol, 82%).

Entry 2: Following general procedure I the alcohol 1 ₇₃ (38.8 mg, 0.30 mmol, 1.0 equiv), dioxane (300 μί, 1 M) and benzoyl chloride (42 μί, 51 mg, 0.36 mmol, 1.2 equiv) were combined and allowed stir for 4 h at 80 °C (TLC indicated full conversion of 1 ₇₃ ). ¹ H-NMR with naphthalene as standard showed chloride 2 ₇₃ in 70% yield.

HR-MS (CI, [C ₆ H ₁₀ CI ³⁵ NO] ⁺ ) calc. 147.0451 u found 147.0457 u, ([C ₆ H _n CI ³⁵ NO] ⁺ ) calc. 148.0529 u found 148.0539 u.

4.7.3.11 Synthesis of 2-Chloroacetophenone (2 ₇₄ )

According to general procedure 2-hydroxyacetophenone (1 ₇₄ , 272 mg,

2.00 mmol, 1.0 equiv), FPyr (39 μί/41 mg, 0.40 mmol, 20 mol%), dioxane (1 mL, 2 M) and BzCI (282 μΐ, 341 mg, 2.40 mmol, 1.2 equiv) were combined at

274 ambient temperature and allowed to react for 4 h at 80 C. Work up provided crude chloride 2 ₇₄ (346 mg, >98% conv., 2 ₇₄ /3 ₇₄ 97:3) as a red oil, which was dissolved in toluene/nPen 60:40 (0.5 mL) and loaded onto a silica gel column (mass crude product/Si0 ₂ 1:21). Next, chromatographic purification with toluene/nPen 60:40, concentration with chloroform (3 x 2 mL) in vacuo to remove residual toluene furnished the chloride 2 ₇₄ as a pale yellow oil (260 mg, 1.684 mmol, 84%), which slowly crystallized to give a colorless solid.

4.7.3.12 Synthesis of rac-l-azido-2-chloro-l-phenyl ethane (rac-2 ₇₅ )

2 1 BzCI (1.2 equiv), DM F (2 M), 16 h 60 °C 77% ^a a. Isolated yield.

Entry 1: According to general procedure I I benzoyl chloride (176 μί, 213 mg, 1.50 mmol, 1.5 equiv) was added to a solution of 2-azido-2-phenyl-l-ethanol (1 ₇₅ , 163.2 mg, 1.00 mmol, 1.0 equiv) and FPyr (19.7 μί, 20.4 mg, 0.20 mmol, 20 mol%) in dioxane (1 mL, 1 M) at ambient temperature and the resulting reaction solution was heated to 80 °C for 8.5 h, whereupon TLC control indicated full conversion of the starting material. After work up the crude chloride 2 ₇₅ (226 mg, >98% conversion, 2 ₇₅ /3 ₇₅ 58:42 according to ¹ H-N M ) was dissolved in Et ₂ 0//iPen 2:98 (0.4 mL) and loaded onto a silica gel column (mass crude material/Si0 ₂ 1:14). Gradient elution with Et ₂ 0//iPen 2:98->5:95 and drying at 20 mbar for 5 min afforded the chloride 2 ₇₅ as a colorless oil (81.1 mg, 0.447 mmol, 45%) alongside with of (2-azido-2-phenyl-l-ethyl) benzoate in 25% yield (3 ₇₅ , colorless oil, 66.2 mg, 0.248 mmol). Entry 2: In accordance to general procedure I I substrate 1 ₇₅ (1.00 mmol, 1.0 equiv), DMF (0.5 mL, 2 M) and benzoyl chloride (141 μί, 170 mg, 1.20 mmol, 1.2 equiv) were combined at ambient temperature and the resulting reaction solution was allowed to stir at 60 °C until TLC control revealed full consumption of the starting material (16 h). After work up with CH ₂ CI ₂ instead of Et ₂ 0 and in deviation from general procedure I I additionally washing of the organic phase with water (2 x 3 mL) before MgS0 ₄ drying, the crude material (260 mg, >98% conversion, 2 ₇₅ /3 ₇₅ 94:6) was dissolved in Et ₂ 0//iPen 2:98 (0.4 mL) and loaded onto a silica gel column (mass crude material/Si0 ₂ 1:15). Elution with Et ₂ 0//iPen 2:98 and drying at 20 mbar for 5 min furnished the title compound in 77% yield as a colorless oil (140.3 mg, 0.773 mmol).

4.7.3.13 Synthesis of roc-4-(chloromethyl)-l,3-dioxolan-2-one (rac-2 ₇₆ )

According to general procedure I I rac-4-(hydroxymethyl)-l,3-dioxolan-2-one (rac-

1 ₇₆ , 262 mg, 2.00 mmol, 1.0 equiv), FPyr (39 μί/41 mg, 0.40 mmol, 20 mol%), dioxane (2 mL, 1 M) and BzCI (282 μί, 341 mg, 2.40 mmol, 1.2 equiv) were 2 ₇₆ combined at ambient temperature and allowed to react for 14.5 h at 80 C, whereupon TLC control proved full consumption of the alcohol 1 ₇₆ . Work up furnished crude chloride 2 ₇₆ (478 mg, >98% conv., 2 ₇₆ /3 ₇₆ 86:14) as a pale yellow oil, which was dissolved in Et ₂ 0/CH ₂ Cl2 0.5:99.5 (0.4 mL) and loaded onto a silica gel column (mass crude product/Si0 ₂ 1:30). In the following, chromatographic purification with Et ₂ 0/CH ₂ Cl2 0.5:99.5 afforded the chloride 2 ₇₆ as a colorless oil (215 mg, 1.57 mmol, 79%).

4.7.3.14 Synthesis of l-Chloro-3-(3-formylphenyloxy)propane (2 ₇₇ )

According to general procedure II rac-4-(hydroxymethyl)-l,3-dioxolan- 2-one (1 ₇₇ , 180 mg, 1.00 mmol, l.O equiv), FPyr (19.8 μί/20.4 mg, 0.40 mmol, 20 mol%), dioxane (1 mL, 1 M) and BzCI (141 μί, 171 mg,

2 ₇₇ 10 1.20 mmol, 1.2 equiv) were combined at ambient temperature and heated for 23 h to 80 C. Work up with 1 N NaOH-solution (aq.) instead of NaHC0 ₃ -solution gave crude chloride 2 ₇₇ (260 mg, >98% conv., 2 ₇₇ /3 ₇₇ 86:14) as a red oil, which was dissolved in CH ₂ CI ₂ //iPen 80:20 (0.4 mL) and loaded onto a silica gel column (mass crude product/Si0 ₂ 1:23). Afterwards chromatographic purification with CH ₂ CI ₂ //iPen 80:20 provided the chloride 2 ₇₇ as a pale yellow oil (133.3 mg, 0.671 mmol, 67%).

HR-MS (CI, [C ₁₀ H _n CI ³⁵ O ₂ ] ⁺ ) calc. 198.0448 u found 198.0455 u.

4.7.4 Synthesis of Further Secondary Benzylic Chlorides

4.7.4.1 Synthesis of roc-l-chloro-2,2-dimethyl-l-(thiophen-2-yl)propane (rac-2 ₇₈ )

As given in general procedure II 2,2-dimethyl-l-(2-thiophenyl)-l-propanol (1 ₇₈ , 170.1 mg, 1.00 mmol, 1.0 equiv) was allowed to react with BzCI (1.2 equiv) in the presence of FPyr (20 mol%) in dioxane (0.5 mL, 2 M) for 16 h at 40 °C and 8 h at

2 ₇₈ 60 °C. After work up with CH ₂ CI ₂ instead of Et ₂ 0, the crude chloride (259 mg, >

98% conv., 2 ₇₈ /3 ₇₈ 96:4) was diluted with nPen (0.3 mL) and Et ₂ 0 (0.2 mL) and loaded onto a silica gel column. Chromatographic purification (mass crude product/Si0 ₂ 1:14) with Et ₂ 0//iPen 2:98 finally furnished the chloride 2 ₇₈ as a colorless liquid (144.1 mg, 0.764 mmol, 76%). M (C ₉ H ₁₃ CIS) = 188.718 g/mol; HR-MS (CI, [C ₉ H ₁₃ SCI] ⁺ ) calc. 188.0421 u found 188.0423 u.

4.7.4.2 Synthesis of roc-l-Azido-2-chloro-2-phenylethane (2 ₇₉ )

According to general procedure II 2-azido-l-phenyl-l-ethanol (roc-l ₇₉ , 1 ⁶³ - ^{2 m} g _> 1.00 mmol, l.O equiv) was reacted with BzCI (176 μί, 213 mg, 1.50 mmol, 1.5 equiv) in the presence of FPyr (19.8 μί, 20.4 mg, 0.20 mmol, 2 ₇₉ 20 mol%) in dioxane (0.5 mL, 2 M) for 20 h at 40 °C and for 4 h at 60 °C. The crude chloride (293 mg, > 98% conv. according to ¹ H-NMR) was diluted with nPen (0.4 mL) and Et ₂ 0 (0.1 mL) and loaded onto a silica gel column (crude mass/Si0 ₂ 1:11). After chromatographic purification with Et ₂ 0/7jPen 2:98 the chloride 2 ₇₉ (155.2 mg, 0.855 mol, 86%) was obtained as a colorless oil.

M (CgHgCI Ns) = 181.622 g/mol; HR-MS (CI, [C ₇ H ₆ CI] ⁺ ) calc. 125.0158 u found 125.0180 u.

4.7.5 Synthesis of Further Secondary Aliphatic Chlorides

4.7.5.1 Synthesis of Cholesteryl chloride (2 ₄₉ )

BzCI (1.2 equiv),

2 0.5 DMF/CH ₂ CI ₂ 1:1 (1 M), 18 h 74% ^a

60 °C

a. Isolated yield.

Entry 1: According to general procedure II benzoyl chloride (141 μί, 170 mg, 1.20 mmol, 1.2 equiv) was added to a suspension of cholesterol 1 ₄₉ (387 mg, 1.00 mmol, 1.0 equiv) and FPyr (19.7 μί, 20.4 mg, 0.20 mmol, 20 mol%) in dioxane (1 mL, 1 M) at ambient temperature. After stirring for 8 h at 80 °C and work up with CH ₂ CI ₂ instead of Et ₂ 0 the crude material (592 mg, >98% conversion, 2 ₄₉ /3 ₄ 9 61:39 according to NM ) was dissolved under earful heating with a heat gun in cHex (0.5 mL) and loaded onto a silica gel column (mass crude material/Si0 ₂ 1:29). Elution with nPen afforded the chloride 2 ₄₉ as a colorless solid in 51% yield (206 mg, 0.509 mmol).

Entry 2: In alignment general procedure II a solution of cholesterol (1 ₄₉ , 387 mg, 1.00 mmol, 1.0 equiv) in DMF/CH ₂ CI ₂ 1:1 (1 mL, 1 M) (CH ₂ CI ₂ was used as co-solvent to keep the product 2 ₄₉ dissolved. Utilizing DMF as sole solvent the reaction mixture solidified even at 60 °C) was treated with benzoyl chloride (141 μί, 170 mg, 1.20 mmol, 1.2 equiv) at ambient temperature and heated to 60 °C for 18 h. After cooling down to ambient temperature ethanolamine (37μί, 0.60 mmol, 0.6 equiv) was added to the reaction mixture. After 30 min of stirring, the mixture was diluted with CH ₂ CI ₂ (7 mL), water (1 mL) and sat. NaHC0 ₃ solution (aq., 2 mL), the organic phase was washed successively with further NaHC0 ₃ -solution (1 x 3 mL), water (1 x 3 mL) and NaHC0 ₃ solution again (1 x 3 mL, to improve phase separation), dried over MgS0 ₄ and concentrated under reduced pressure. For chromatographic purification the crude material (458 mg, > 98% conv.) was dissolved under heating in cHex (0.5 mL) and loaded onto a silica gel column (mass crude product/Si0 ₂ 48:1). Elution with nPen furnished the chloride 2 ₄₉ as a colorless solid (299 mg, 0.739 mmol, 74%). 4.8 Synthesis of Further Amines

General procedure IV referred to in the following chapter 4.8.1.1 can be found in chapter 2.2.1 herein above.

Synthesis of S-(l-phenylethyl) (3,3-diphenylpropyl) amine (S-Fendiline, S-8 _2q )

According to general procedure IV S-l-phenylethanol (S-l _w , 126 μί, 125 mg, 1.00 mmol, 1.0 equiv, 99% ee according chiral GC), FPyr (19.7 μΐ, 20.4 mg, 0.20 mmol, 20 mol%), MTBE (0.5 mL, 2 M) and benzoyl chloride (141 μί, 170 mg, 1.20 mmol, 1.2 equiv) were combined at 0 °C and stirred for 30 min at 0 °C and for 24 h at room temperature. Then the reaction mixture was diluted with

MeCN (2.0 mL), K ₂ C0 ₃ (320 mg, 2.30 mmol, 2.3 equiv) and 3,3- diphenylpropane-l-amine (283 mg, 1.30 mmol, 1.3 equiv) were added and the resulting reaction suspension was stirred for 48 h at 100 °C. The work up was slightly modified compared to general procedure IV: Thus after cooling down to room temperature, the reaction mixture was diluted with Et ₂ 0 (4 mL) and water (4 mL). Subsequently, the aqueous phase was extracted with CH ₂ CI ₂ (2 x 3 mL), the combined organic phases were dried over MgS0 ₄ and concentrated in vacuo. Chromatographic purification on silica gel (mass of crude material/Si0 ₂ 1:30) with Et ₂ 0/NEt ₃ //iPen 25:4:69 of the crude product (459 mg) furnished the piperidine derivative S-8 _2q as a pale yellow oil (248 mg, 0.787 mmol, 79%). Comparison of the rotatory degree with literature values revealed an enantiopurity of > 95% ee.

M (C ₂₃ H ₂₅ N) = 315.451 g/mol; r _f (Si0 ₂ , Et ₂ 0) = 0.44 (tailing); HR-MS (CI, [C ₂₃ H ₂₆ N ⁺ ]) calc. 316.2060 u found 316.2039 u, ([C ₂₃ H ₂₅ N] ⁺ ) calc. 315.1987 u found 315.1978 u. [ct] _D ²⁰ = -46.7 (c = 1.10 g/100 mL, CHCI ₃ ), [ct] _D ²⁵ = -45.6 (c = 1.10 g/100 mL, CHCI ₃ ).

Lit-[ct] _D ²⁵ = +43.5 (c = 0.98 g/100 mL, CHCI ₃ for /?-8 _2q , 95% ee) (see Wakchaure, V. N.; Kaib, P. S. J.; Leutzsch, M.; List, B. Angew. Chem. Int. Ed. 2015, 54, 11852-11856).

4.9 Synthesis of Bromides and Iodides

4.9.1 General Procedure VIII: Bromination and lodination of Alcohols

Bromination: A 4 mL glas vial with a stir bar was charged successively with NaBr (1.3 equiv) the alcohol 1 (1.0 equiv, 0.5 mmol), FPyr (2.5-20 mol%) and acetone (250 μΐ, 2 M). Next, a 2 M solution of the acid chloride (either benzoyl or 2,6-dichlorobenzoyl chloride, 1.2-1.5 equiv) in acetone was added with the aid of a syringe pump over 30 min. Thereby the reaction mixture was cooled to 0 ^° C in the case of BzCI, while utilisation of 2,6-CI ₂ BzCI as reagent afforded addition under optimized conditions at 60-80 °C. Then the reaction suspension was allowed to stir at the temperature T (room temperature to 40 °C with BzCI, 60-80 °C with 2,6-CI ₂ BzCI) for the time period t = 7-20 h.

In the following the reaction mixture was diluted successively with Et ₂ 0 (6 mL) and 1 N NaOH-solution in water (3 mL), the organic phase was separated, dried over MgS0 ₄ and concentrated in vacuo. The crude bromide 8 was dissolved with an exactly weight amount of naphthalene or dodecane (20-50 mg) in CDCI ₃ (ca. 0.5 mL) and ca. 50 μί were transferred to an NMR- tube and diluted with CDCI ₃ (0.5 mL)

lodination: lodinations were conducted as described above in the case of bromination, whereby NaBr was replaced by Nal and the acid chloride was added neat at ambient temperature in one portion. During work up saturated Na ₂ S0 ₃ -solution in water (0.5 mL) was utilized to reduce iodine formed in the reaction.

4.9.2 Synthesis of Bromides 8

4.9.2.1 Synthesis of 4-ferf-Butylbenzyl chloride (8 ₂ )

(10 mol%), acetone (2-1 M), 0.5 h 0 °C, 20 h rt

a. Yield determined by internal NMR-standard.

Bromide 8 ₂ was prepared as described in general procedure VIII (chapter 4.9.1) utilizing 10 mol% of FPyr and BzCI (1.2 equiv, t = 20 h). According to internal NMR-standard the bromide 8 ₂ was formed in 78% yield beside traces of 4-ieri-butyl benzyl chloride (2 ₂ , <2%, ratio 8 ₂ /2 ₂ >98:2) and 4-tert- butyl benzyl benzoate (3 ₂ , ratio 8 ₂ +2 ₂ /3 ₂ 81:19) in 19% yield.

4.9.2.2 Synthesis of rad-Bromo-l-phenylethane (rac-8 ₃ )

a. Yield determined by internal NM -standard.

Bromide 8 ₃ was synthesized as given in general procedure VIII (chapter 4.9.1) employing 20 mol% of FPyr and BzCI (1.2 equiv, t = 20 h). As determined by internal NMR-standard the secondary bromide 8 ₃ was obtained in 77% yield beside 1-chloro-l-phenylethane (2 ₃ ) in 4% yield (ratio 8 ₃ /2 ₃ 95:5) and 1- phenylethyl benzoate (3 ₃ ) in 7% yield (ratio 8 ₃ +2 ₃ /3 ₃ 91:9).

Synthesis of 4-Methoxybenzyl bromide (8 ₅ )

a. Yield determined by internal NMR-standard.

Using 10 mol% of FPyr benzyl bromide 8 ₅ was prepared with BzCI (1.2 equiv) according to general procedure VIII (chapter 4.9.1, t = 20 h, T = rt) in 86% yield (internal standard). Moreover, 4- methoxybenzyl chloride 2 ₅ was obtained in 14% yield (ratio bromide 8 ₅ /chloride 2 ₅ 86:14) together with 4-methoxybenzyl benzoate 3 ₅ in 2% yield (ratio 8 ₅ +2 ₅ /3 ₅ 97:3).

4.9.2.4 Synthesis of Geranyl bromide (E-8 ₄ )

In the presence of 2.5 mol% FPyr allylic bromide 8 ₅ was synthesized with BzCI (1.2 equiv) according to general procedure VIII (chapter 4.9.1, t = 20 h) in 67% yield as shown by internal standard (ratio of linear and branched regioisomer of >98:2). Besides chloride 2 ₄ was obtained in 7% yield (ratio bromide 8 ₄ /chloride 2 ₄ 91:9) together with geranyl benzoate E-3 ₄ in 12% yield (ratio 8 ₄ +2 ₄ /3 ₄ 86:14). 4.9.2.5 Synthesis of Dodecyl bromide (8 ₃₃ )

2,6-CI ₂ BzCI (1.5 equiv), NaBr (1.3 equiv), acetone

2 0.5 <2% ^a *

(2-1 M), 20 h 60 °C

a. Yield determined by internal NM -standard. * Comparative Example

Entry 1: Bromide 8 ₃₃ was prepared with 2,6-CI ₂ BzCI (1.5 equiv) at 60 °C according to general procedure VIII (chapter 4.9.1, t = 20 h). Employing 20 mol% of FPyr dodecyl bromide (8 ₃₃ ) was obtained in 83% yield beside traces of dodecyl chloride (2 ₃₃ , <2%, ratio 833/233 >98:2), dodecyl formiate 4% and unreacted starting material 1 ₃₃ (8%).

Entry 2: According to general procedure VIII (chapter 4.9.1) treatment of dodecanol 1 ₃₃ with 2,6- CI ₂ BzCI (1.5 equiv) at 60 °C in the absence of FPyr gave dodecyl bromide 8 ₃₃ in trace quantities (<2%). Mostly unreacted starting material (94% yield) was observed alongside with traces of dodecyl 2,6- chlorobenzoate (<2%).

4.9.3 Synthesis of Iodides

4.9.3.1 Synthesis of 4-ferf-Butylbenzyl iodide (10 ₂ )

(10 mol%), acetone (2 M), 20 h 60 °C

10,

2,6-CI ₂ BzCI (1.2 equiv), Nai (1.3 equiv), FPyr

0.5 99% ^a

(10 mol%), solvent-free, 20 h 60 °C

a. Yield determined by internal NMR-standard.

Entry 1: Iodide 10 ₂ was prepared according to general procedure VIII (chapter 4.9.1, t = 20 h) with 2,6-CI ₂ BzCI (1.2 equiv) and 10 mol% FPyr at 60 °C in 88% yield. Moreover, traces of unreacted starting material (4%) and 4-ieri-butylenzyl 2,6-dichlorobenzoate (3%, ratio 10 ₂ /3 ₂ 97:3) were observed. Entry 2: Under solvent-free conditions iodide 10 ₂ was synthesized in alignment to general procedure VIII (chapter 4.9.1, t = 20 h) utilizing 2,6-CI ₂ BzCI (1.2 equiv) and 10 mol% FPyr at 60 °C in 99% yield. 4.9.3.2 Synthesis of roc-l-lodo-l-phenylethane (rac-10 ₃ )

BzCI (1.2 equiv), Nai (1.3 equiv), FPyr (20 mol%),

0.5 80% ^a

acetone (2 M), 7 h 40 °C

a. Yield determined by internal NM -standard.

Entry 1: According to general procedure VIII (chapter 4.9.1) iodide 10 ₃ was prepared in 73% yield utilizing 2,6-CI ₂ BzCI (1.2 equiv) and 10 mol% FPyr at 60 °C (t = 20 h). Alongside iodide 10 ₃ , 5% of 1- phenylethyl 2,6-dichlorobenzoate (10 ₃ /3 ₃ 93:7) and 9% of styrene were obtained. Entry 2: Following to general procedure VIII (chapter 4.9.1) 1-phenylethanol was transformed with BzCI (1.2 equiv) and FPyr (20 mol%) within 7 h at 40 °C to iodide 10 ₃ in 80% yield. Moreover, 2% of styrene and 17% of 1- phenylethyl benzoate were observed (10 ₃ /3 ₃ 83:17).

4.9.3.3 Synthesis of Dodecyl iodide (10 ₃₃ )

10 ₃₃ a. Yield determined by internal NMR-standard.

As described in general procedure VIII (chapter 4.9.1) dodecanol was converted to dodecyl iodide 10 ₃₃ with 2,6-CI ₂ BzCI (1.2 equiv) in the presence of 10 mol% FPyr at 80 °C within 20 h in 91% yield. Besides, 2% of starting material and 2% of dodecyl 2,6-dichlorobenzoate (10 ₃₃ /3 ₃₃ 98:2) was obtained.

4.10 Comparison of the Current Method with the Method of Dubey et al.

The inventor performed a comparison of the method of the present invention with the method of Dubey et al., published as A. Dubey, A.K. Upadhyay and P. Kumar, Pivaloyl chloride/DMF: a new reagent for conversion of alcohols into chlorides, Tetrahedron Letters vol. 51 (2010), pages 744-746. A result using pivaloyl chloride as reagent in a catalytic procedure has already been presented in Table 6, entry 14 in chapter 4.1.1 herein above. This result shows that, when catalytic amounts of the formamide are used, the use of pivaloyl chloride as chlorination agent provides the desired chlorination product in low yield only, since the main product formed is the undesired pivalate ester. The following table shows the result of the reworking of the method of Dubey et al. by the inventor (entry 1), the result when using pivaloyl chloride with catalytic amounts of a formamide (entry 2), and further examples of the current method using benzoyl chloride (entries 3 to 8) performed by the inventor.

conv. yield 2j yield 3i ratio

entry R (equiv) conditions Reference

[%Ϋ [%] ² [%] ²

1. PivCI, DMF 1 h rt 2.1j, DCM, 2 h rt

1 tBu (1.5) ≥98 50 17 75:25 / *

(= DMF/DCM 1:5, 0.2 M)

PivCI added to lj and DMF (30 mol%)

2 tBu (1.2) ≥98 9 85 10:90 / * in DCM (1 M), then 12 h rt

BzCI added to lj and DMF (30 mol%)

4 Ph (1.2) ≥98 70 ≤2 ≥98:2 / in dioxane (1 M), then 12 h rt

BzCI added to lj and DMF (30 mol%)

5 Ph (1.2) ≥98 71 2 97:3 / in DCM (1 M), then 12 h rt

BzCI added to lj and DMF (10 mol%)

6 Ph (1.2) ≥98 72 3 96:4 / in dioxane (2 M), then 20 h rt

BzCI added to lj and FPyr (10 mol%) 86^

7 Ph (1.03) ≥98 n.d. 94:6 / in MTBE (2 M) at 0 °C in 1 h, then 17 h rt (22 g)

BzCI added to lj and DMF (30 mol%) 82 ³

8 Ph (1.02) ≥98 n.d. 91:9 / at 0 °C in 1.5 h, then 2.5 h rt, solvent-free (21 g)

1. Conversion and ratio 2/3 were determined from ¹ H-NMR of the crude material. 2. Yield determined by internal NMR-

Standard if not otherwise stated. 3. Isolated yield.

Procedures to the entries of the table above as performed by the inventor:

Entry 1: According to Dubey et al. (see A. Dubey, A.K. Upadhyay and P. Kumar, Pivaloyl chloride/DMF: a new reagent for conversion of alcohols into chlorides, Tetrahedron Letters vol. 51 (2010), pages 744-746) PivCI (1.5 equiv) was added to dry DMF (0.4 mL, 2 M) at room temperature under an atmosphere of argon. After 1 h of stirring at ambient temperature, the reaction solution was diluted with dry DCM (2.3 mL, DMF/DCM 1:5, 0.2 M) and benzyl alcohol (0.53 mmol, 1.0 equiv) was added. Then the mixture was allowed to stir for 2 h at ambient temperature and was subsequently diluted with Et ₂ 0 (6 mL) and water (2 mL). The organic phase was successively washed with saturated, aqueous Na ₂ C0 ₃ -solution (1x2 mL), 1 N HCI- solution in water (1x2 mL) and brine (1x2 mL), dried over MgS0 ₄ and concentrated under reduced pressure.

Entry 2: According to general procedure I benzyl alcohol (0.50 mmol, 1.0 equiv) was allowed to react with PivCI (1.2 equiv) in DCM (0.5 mL, 1 M) in the presence of DMF (30 mol%) for 12 h at ambient temperature. Entry 3: According to general procedure I benzyl alcohol (0.50 mmol, 1.0 equiv) was transformed with BzCI (1.1 equiv) in DMF (0.5 mL, 1 M) into chloride 2j within 0.5 h at ambient temperature.

Entry 4: In accordance with general procedure I benzyl alcohol (0.50 mmol) was converted with BzCI (1.2 equiv) in the presence of DMF (30 mol%) in dioxane (0.5 mL, 1 M) within 12 h at room temperature to benzyl chloride.

Entry 5: As given in general procedure I BzCI (1.2 equiv) was added to a solution of benzyl alcohol (0.50 mmol, 1.0 equiv) and DMF (30 mol%) in DCM (0.5 mL, 1 M) and the resulting solution was allowed to stir for 12 h at ambient temperature. Entry 6: As described in general procedure I a solution of benzyl alcohol (0.50 mmol, 1.0 equiv) and DMF (10 mol%) was treated with BzCI (1.2 equiv) and allowed to stir for 20 h at room temperature.

Entry 7: See chapter 4.4.2.1, entry 1 herein above.

Entry 8: See chapter 4.4.2.1, entry 2 herein above.

The inventor reworked the procedure given in Dubey et al. using a pre-formed complex of N,N- dimethyl formamide (DMF) and pivaloyi chloride. In line with the conditions published by Dubey et al., pivaloyi chloride and excess DMF were stirred at room temperature for one hour; then the benzyl alcohol li was added to react the alcohol with the pre-formed complex of DM F and pivaloyi chloride (see above procedure to entry 1). By this, the inventor obtained a 75:25 mixture of chloride 2 _lt which corresponds to a yield of 50%, and pivalate ester 3i ( = tBu) under identical conditions as pu blished by Dubey et al., as shown in entry 1. Entry 2 of the above table shows that, when pivaloyi chloride is used with catalytic amounts of the formamide, a 10:90 mixure of chloride 2i and pivalate ester 3i (R = tBu) was obtained. Hence, using pivaloyi chloride with catalytic amounts of the formamide results in a poor selectivity and, consequently, in a poor yield of the desired benzyl chloride 2i. In contrast, entries 3 to 8 have been performed in accordance with the present invention using an aromatic carboxylic acid chloride as the chlorination agent. Considering entries 3 to 8, when using benzoyl chloride as the chlorination agent, under various reaction conditions higher selectivities and higher yields of the desired benzyl chloride 2i have been obtained compared to the method of Dubey et al. using a pre-formed complex of DMF and pivaloyi chloride.

4.11 Appendix

4.11.1 Abbreviations

2-FBzCI = 2-fluorobenzoyl chloride

2-MeTH F = 2-methyltetrahydrofurane

4-MeOBzCI = 4-methoxybenzoyl chloride

AE = atom economy

Alloc = Allyloxycarbonyl

aq. = aqueous

Boc = ieri-Butoxycarbonyl

bp. = boiling point br. = broad

BzCI = benzoyl chloride

Cbz = Carbonyloxybenzyl

CI = chemical ionization

conv. = conversion

d = doublet

DCE = 1,2-dichloroethane

DCM = dichlormethane

dioxane = 1,4-dioxane

DMA = A/,/V-dimethylacetamide

DME = 1,2-dimethoxyethane

DMF = dimethylformamide

ee = enantiomeric excess

E-factor = economy factor

El = electron ionization

equiv = equivalents

er = enantiomeric ratio

Fmoc = Fluorenyloxycarbonyl

FPip = 1-formylpiperidine

FPyr = 1-formylpyrrolidine

HMPTA = hexamethylphosphoric acid triamide lit. = literature

M = molar mass

MeCN = acetonitrile

MF = methylformamide

mp. = melting point

MsCI = Methylsulfonyl chloride

MTBE = methyl-ieri-butylether

n.d. = not determined

NCS = /V-chlorosuccinimide

NMM = /V-methylmorpholine

NM = nuclear magnetic resonance p = pentet

Piv = pivaloyl = ieri-butylcarbonyl

PivCI = pivaloyl chloride PE = petroleum ether

PMP = para-methoxyphenyl ppm = parts per million

Py = pyridine

q = quartet

r _f = retention factor

s = singlet

sat. = saturated

sept = septet

TBAI = tetrabutylammonium iodide

TCT = 2,4,6-trichloro-l,3,4-triazine

TFA = trifluoroacetyl

THF = tetrahydrofurane

TMS = tetramethylsilane

TMSCI = trimethylchlorosilane

TPS = ieri-butyldiphenylsilyl

Troc = 2,2,2-trichloroethyloxycarbonyl t = triplet

Ts = poro-tolylsulfonyl

TsCI = para-tolylsulfonyl chloride