Background of invention

A/-arylations of aliphatic amines are important chemical transformations as the resulting aniline derivatives have found broad applications as pharmaceuticals, materials for organic electronics and dyes for industrial and research applications. Pyrazine and morpholine derivatives are of special interest, as these are found in a range of top selling pharmaceuticals.

A range of transition metal-catalyzed reactions has been developed for the formal halide to nitrogen substitution on aryl halides. Most renowned are the Ullmann and Buchwald-Hartwig couplings employing copper and palladium catalysis respectively. These results notwithstanding, the employment of transition metals as catalysts has several drawbacks in industrial applications, especially due to high costs, oxygen sensitivity, challenging purifications and toxic metal contaminants being present in the final products. To overcome these shortcomings, catalyst-free S _N Ar reactions on highly activated halide-substituted benzene derivatives have been applied. However, the scope of this approach has so far been limited as strongly electron-withdrawing groups, such as nitro or cyano substituents, have been considered essential for reactivity. Thus, leading text books in organic chemistry describes: a) "Without electron-attracting groups present, nucleophilic aromatic substitution occurs only under extreme reaction conditions" F. A. Carey, R. J. Sundberg in Advanced Organic Chemistry: Part A: Structure and

Mechanisms; 4th ed. Springer Science and Business Media, New York, 2000. b) "To summarize: Any anion-stabilizing (electron-withdrawing) group ortho or para to a potential leaving group can be used to make nucleophilic aromatic substitution possible." J. Clayden, N. Greeves, S. Warren, P. Wothers in Organic Chemistry; Oxford University Press, New York, 2001 .

WO 2014/191548 discloses a synthetic process for the production of 1 - (2-((2,4-dimethyl-phenyl)sulfonyl)phenyl)piperazine by arylation in the presence of Cs ₂ C0 ₃ . The process however requires incubation at elevated temperature for more than 14 days.

Summary of invention

The present invention provides catalyst free N-arylation of amines. The methods are very effective, and can typically results in high yields.

Thus, the invention provides methods for preparing an arylated amine, said method comprising the steps of

a. Providing a nucleophile, wherein said nucleophile comprises an -NH- or an -NH ₂ group directly linked to only non-aromatic carbon atoms or a salt of said nucleophile;

b. Providing an electrophile, wherein said electrophile is aryl substituted with at least two substituents, wherein the first substituent is halogen and the second substituent and any further optional substituent(s) are selected from the group consisting of halogen, aryl, substituted aryl, alkenyl, substituted alkenyl, heteroalkenyl, alkyl, substituted alkyl, heteroalkyl, alkoxy, substituted alkoxy, amino, substituted amino, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, heteroaryl, and phosphinyl, with the proviso that said aryl is substituted with at the most 4 halogens;

c. Providing a base, wherein the corresponding acid has a pKa above 32 in

DMSO and/or a pKa above 26 in THF;

d. Providing an organic solvent that only contain protons with a pKa above

32 in DMSO.

e. Reacting said nucleophile with said electrophile in said organic solvent in the presence of the base, thereby obtaining an arylated amine consisting of said aryl, wherein the first substituent is substituted by said amine; f. Optionally purifiying the arylated amine.

Description of Drawings

Figure 1 : Examples of pharmaceuticals containing an A/-arylated secondary amine.

Figure 2 shows the yield of catalyst-free A/-arylation of morpholine using various different polyfluorinated benzene derivatives.

Figure 3 shows the yield of catalyst-free A/-arylation of various amines. General reaction conditions used in is: Amine (1 .0 eq.), LiHMDS (1 .0M in THF, 1 .5 eq.) and benzene derivative (1 .5 eq.) were mixed and heated. Compounds 3r, 3s, 3t, 3ad, 3ae, 3af, and 3ag were synthesized by slightly modified procedures.

Detailed description of the invention Definitions The term "alkane" refers to saturated linear or branched carbohydrides of the general formula C _n H _2n+ 2-

The term "alkenyl" as used herein refers to a substituent derived from an alkene by removal of one -H. An alkene may be any acyclic carbonhydride comprising at least one double bond. Frequently, alkenyl will have the general formula -C _n H _2n -i .

The term "alkyl" refers to a substituent derived from an alkane by removal of one -H.

The term "alkynyl" as used herein refers to a substituent derived from an alkyne by removal of one -H. An alkyne may be any acyclic carbonhydride comprising at least one triple bond. Frequently, alkynyl will have the general formula -C _n H ₂ n-3. "amino" as used herein refers to a substituent of the general formula . The waved line indicates the point of attachment of the substituent. Amino may thus for example be -NH ₂ or -NH-.

The term "arene" as used herein refers to aromatic mono- or polycyclic carbonhydrides.

The term "aromatic" refers to a chemical substituent characterised by the following:

• contains a delocalized conjugated π system, most commonly an arrangement of alternating single and double bonds

• has a coplanar structure, with all the contributing atoms in the same plan

• the contributing atoms are arranged in one or more rings

• it contains a number of π delocalized electrons that is even, but not a multiple of

The term "aromatic carbon atom" as used herein refers to a carbon atom, which contributes to an aromatic moiety. Consequently a "non-aromatic carbon atom" is a carbon atom which is not an integral part of an aromatic moiety. Accordingly, a non- aromatic carbon atom may optionally be linked to an aromatic moiety by a covalent bond. By way of examples, all carbon atoms of a phenyl group are considered

"aromatic carbon atoms", however the carbon atoms of an alkyl group covalently linked to phenyl are considered "non-aromatic carbon atoms".

The term "aryl" as used herein refers to a substituent derived from an arene by removal of one -H from a C in the ring. Examples of useful aryls to be used with the present invention comprise phenyl, napthyl, anthracenyl, phenanthrenyl, and pyrenyl.

The term halogen as used herein refers to a substituent selected from the group consisting of -F, -CI, -Br and -I.

The term "heteroalkenyl" refers to an alkenyl group, of which one or more carbon has been replaced by a heteroatom selected from S, O and N. The term "heteroalkyi" refers to a straight- or branched-chain alkyl group, of which one or more carbon has been replaced by a heteroatom selected from S, O and N.

Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, and alkyl sulfides.

The term "heteroaryl" as used herein refers to a substituent derived from an heteroarene by removal of one -H from an atom in the ring structure of said heteroarene. Heteroarenes are mono- or polycyclic aromatic compounds comprising one or more heteroatoms in the ring structure. Said heteroatoms are preferably selected from the group consisting of S, N and O. Non limiting examples of useful heteroaryls to be used with the present invention comprise azolyl, pyridinyl, pyrimidinyl, furanyl, and thiophenyl.

The term "non-aromatic heterocycle" refers to a mono- or polycyclic compound, which is not aromatic, and which comprises one or more heteroatom in the ring structure. Said heteroatoms are preferably selected from the group consisting of S, N and O. Examples of non-aromatic heterocycle includes but are not limited to pyrrolidine, piperidine, piperazine, morpholine, and thiomorpholine. phosphinyl" as used herein refers to a substituent of the general structure The waved line indicates the point of attachment of the substituent. Thus, phosphinyl may be -PH ₃ .

The term pKa as used herein refers to the negative logarithmic of the dissociation constant K _a for an acid in a given solvent: p _a = -Logi ₀ K _a.

K _a , also called the acidity constant, is defined as:

for the reaction:

HA + S ^ A ^"' -f- SET wherein S is the solvent and HA is an acid that dissociates into A-, known as the conjugate base of the acid, and a hydrogen ion which combines with a solvent molecule. When the concentration of solvent molecules can be taken to be constant,

The term "substituted" as used herein in relation to chemical compounds refers to hydrogen group(s) being substituted with another moiety. Thus, "substituted with X" as used herein in relation to chemical compounds refers to hydrogen group(s) being substituted with X. Similarly, "substituted X" refers to X, wherein one hydrogen group has been substituted with another moiety. By way of example "substituted alkyl" refers to alkyl-R, wherein R is any moiety but -H.

The term "substituent" as used herein in relation to chemical compounds refers to an atom or group of atoms substituted in place of a hydrogen atom. The term "strongly electron withdrawing substituents" as used herein refers to substituents with a Hammet meta substituent constant above 0.5, as described in Hanhsch 1991 , and/or substituents having a double bond to oxygen of the linking atom.

The term "thioalkyl" as used herein refers to a substituent of the general formula -S- alkyl.

The term "thioaryl" as used herein refers to a substituent of the general formula -S-aryl.

The term "transition metal catalyst" refers to a compound capable of catalysing a chemical reaction, wherein said compound comprises a transition element or an ion of a transition element. A transition element is an element whose atom has an incomplete d sub-shell, or which can give rise to cations with an incomplete d sub-shell.

Method for preparing an arylated amine

The present invention provides methods for preparing arylated amines. In particular, the methods of the present invention can be performed even in the absence of a transition metal catalyst. The methods of the invention may comprise the steps of a. Providing a nucleophile comprising an -NH- or and -NH ₂ group, wherein the nucleophile for example may be any of the nucleophiles described herein below in the section "Nucleophile";

b. Providing an electrophile comprising an aryl substituted with at least one halogen and optionally further substituents, wherein the electrophile for example may be any of the electrophiles described herein below in the section "Electrophile",

c. Providing a base, which for example may be any of the bases described herein below in the section "Base"

d. Providing an organic solvent, wherein the solvent for example may be the solvent described herein below in the section "Solvent"; e. reacting said nucleophile with said electrophile in said organic solvent in the presence of the base, there by obtaining an arylated amine consisting of said aryl, wherein the halogen is substituted by said amine, f. Optionally purifying the arylated amine.

The steps a., b., c. and d. may be performed in any suitable order. In one embodiment step e) comprises the sub-steps of

i) Reacting said nucleophile with said base,

ii) Reacting the product of sub-step i) with said electrophile,

wherein sub-steps i) and ii) are performed in the indicated order. This may in particular be the case in embodiments of the invention, where a strong base is used, e.g. a base, wherein the corresponding acid has a pKa above 45, such as above 49.

In case the nucleophile provided in a) comprises more than one -NH- and/or -NH ₂ group, the amino group mentioned in a) is the amine acting as nucleophile in reaction to obtain the arylated amine.

As mentioned above one advantage of the methods according to the present invention is that the methods can be performed in the absence of a transition metal catalyst. Thus, it is preferred that step e. is performed in the absence of a transition metal catalyst. In some embodiments, it may be preferred that the methods are performed in the absence of any transition metals, and in particular that step e. is performed in the absence of any transition metals. In particular, it may be preferred that the methods are performed in the absence of cupper, palladium and nickel, and in particular that step e. is performed in the absence of any cupper, palladium and nickel. Thus, the reaction, and in particular step e. is preferably performed in the absence of cupper, palladium and nickel in any oxidation state and any form. Reacting said nucleophile with said electrophile may be done at any useful

temperature. Thus, step e. may be performed at any useful temperature. One advantage of the methods of the invention is that the methods generally can be performed at temperatures, which are easy to handle, even in large scare. Thus, reacting said nucleophile with said electrophile may be performed at a temperature of at the most 120 °C, such as at the most 1 10 °C. Frequently even lower temperatures can be applied.

Reacting said nucleophile with said electrophile may be done for a time sufficient to allow the reaction. Thus, step e. may be performed for sufficient time to allow the reaction. One advantage of the methods of the invention is that generally a relative short time is required for the reactions. Thus, said nucleophile may typically be allowed to react with said electrophile for at the most one week. Frequently, the reaction may be even faster, thus in some embodiments of the invention, said nucleophile may be allowed to react with said electrophile for at the most 900 min, such as for at the most 720 min, such as for the mostl 80 min, for example for in the range of 5 to 900 min or in the range of 5 to 720 min.

Nucleophile The methods of the invention involve reacting a nucleophile and an electrophile. The nucleophile useful with the present invention must comprise an -NH- or and -NH ₂ group. In general, said nucleophile comprises an -NH- or an -NH ₂ group directly linked to only non-aromatic carbon atoms. Thus, in one embodiment the nucleophile contains an -NH- group, which is covalently linked to two non-aromatic carbon atoms. Said non-aromatic carbon atoms may for example be a carbon atom of an alkyl or of an alkyl substituted with one or more substituents. It follows that the nucleophile thus may be a secondary amine. In another embodiment, said nucleophile comprises an -NH ₂ group, which is covalently linked to a non-aromatic carbon atom. For example said nucleophile may be alkyl-NH ₂ or alkyl-NH ₂ , wherein said alkyl is substituted with one or more substituents. It follows that the nucleophile may be a primary amine.

In one embodiment, the nucleophile may be a compound of the formula I: (I), wherein

R _a and R _b individually are selected from the group consisting of -H and alkyl, wherein said alkyl optionally may be substituted with aryl or substituted aryl with the proviso that only one of R _a and R _b may be -H; or

R _a and R _b together forms a non-aromatic heterocycle, which optionally may comprise one or more heteroatoms, wherein said heterocycle optionally may be substituted.

Thus, in one embodiment R _a may be selected from the group consisting of -H, Ci- ₅₀ - alkyl, Ci-i ₀ -alkyl-aryl. For example, R _a may be selected from the group consisting of -H, d- ₁₀ -alkyl and Ci-i ₀ -alkyl-phenyl. In particular, R _a may be selected from the group consisting of -H, Ci_ ₅ -alkyl and-CH ₂ -phenyl.

In one embodiment R _b may be selected from the group consisting of Ci- ₅₀ -alkyl, CM ₀ - alkyl-aryl. For example, R _b may be selected from the group consisting of d- ₁₀ -alkyl and Ci-io-alkyl-phenyl. In particular, R _b may be selected from the group consisting of C ₁ -5- alkyl and-CH ₂ -phenyl.

The nucleophile may also be a compound of formula I, wherein R _a and R _b together forms a non-aromatic heterocycle, which optionally may comprise one or more heteroatoms, and which may be substituted.

Thus, it is comprised in the invention that the nucleophile may be 4 to 10 membered non-aromatic heterocycle comprising at least one N atom. For example, the

nucleophile may be a 4 to 10 membered non-aromatic heterocycle comprising 1 or 2 heteroatoms, wherein at least one is an N atom. Said 4 to 10 membered non-aromatic heterocycle may for example be a monocyclic or a bicyclic non-aromatic heterocycle. Said 4 to 10 membered non-aromatic heterocycle comprising at least one N atom may optionally be substituted with one or more substituents, e.g. with one or more substituents selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl. For example, said 4 to 10 membered non-aromatic heterocycle may be substituted with one or more substituents selected from the group consisting of Ci-e-alkyl and aryl. For example said 4 to 10 membered non-aromatic heterocycle may be substituted with one substituent selected from the group consisting of phenyl and Ci-3-alkyl, e.g. methyl.

It is also comprised within the invention that the nucleophile may be a 4 to 8 membered non-aromatic heterocycle comprising at least one N atom. Thus, the nucleophile may be a 4 to 8 membered non-aromatic heterocycle comprising only 1 heteroatom, wherein said heteroatom is an N atom. The term "comprising only 1 heteroatom" as used herein refers to that the ring of said heterocycle consists of carbon atoms and said one heteroatom. Said carbon atoms may optionally be substituted. Thus, said 4 to 8 membered non-aromatic heterocycle comprising at least one N atom may optionally be substituted with one or more substituents, e.g. with one or more substituents selected from the group consisting of aryl, substituted aryl, heteroaryl, substistuted heteroaryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl. For example, said 4 to 8 membered non-aromatic heterocycle may be substituted with one or more substituents selected from the group consisting of Ci _-6 - alkyl and aryl. For example said 4 to 8 membered non-aromatic heterocycle may be substituted with one substituent selected from the group consisting of phenyl and C _1-3 - alkyl, e.g. methyl. Said non-aromatic heterocycle may for example be selected from the group consisting of piperazine, morpholine, tetrahydroisoquinoline, dioxa-azaspiro- decane, piperidine, and thiomorpholine.

In one embodiment of the invention the nucleophile is a compound of the formula II

wherein X is NR _C , NH, O or S. R _c may for example be aryl, substituted aryl, heteroaryl, substistuted heteroaryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, 3 to 8 membered cycloalkyi or 3-8 membered nonaromatic heterocycle. For example, R _c may be selected from the group consisting of aryl, d-10-alkyl, C ₂ -i ₀ -alkenyl, C ₂ -i o-alkynyl and 3-8 membered nonaromatic heterocycle. For example, R _c may be selected from the group consisting of phenyl, and C _1-10 -alkyl.

In one embodiment the nucleophile is selected from the group consisting of: pyrrolidine, N-methylpiperazine, 1 -methylpiperazine, 1 ,4-dioxa-8-azaspiro[4.5]decane, piperidine, piperazine, morpholine, thiomorpholine, 1 -phenylpiperazine, N-ethylbutan-1 -amine, 1 ,2,3,4-tetrahydroisoquinoline, dibenzylamine, N-methyl-benzylamine and

benzylamine.

In one preferred embodiment the nucleophile is selected from the group consisting of N-methylpiperazine, piperazine, morpholine and 1 ,2,3,4-tetrahydroisoquinoline. In one preferred embodiment the nucleophile is selected from the group consisting of N- methylpiperazine, piperazine and morpholine.

The nucleophile may also be salts of any of the aforementioned nucleophiles. For example, the nucleophile may be a salt of any of the aforementioned nucleophiles with various inorganic or organic acids. In embodiments of the invention, where the arylated amine is for pharmaceutical use, said salt may be a pharmaceutically acceptable salt. Electrophile

The methods of the invention involve reacting a nucleophile and an electrophile. The electrophile useful with the present invention comprises or consists of an aryl substituted with at least one halogen and optionally further substituents. Preferably, the electrophile is aryl substituted with at least two substituents, wherein the first substituent is halogen and the second substituent is selected from the group of substituents consisting of halogen, aryl, substituted aryl, alkenyl, substituted alkenyl, heteroalkenyl, alkyl, substituted alkyl, heteroalkyl, alkoxy, substituted alkoxy, amino, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, heteroaryl, and phosphinyl, with the proviso that said aryl is substituted with at the most 4 halogens. In addition to said first and second substituents, said aryl may be substituted with one or more additional substituents, which preferably are selected from the same group of substituents as the second substituents. In one embodiment, the second substituent may also be selected from the group of substituents consisting of halogen, aryl, substituted aryl, alkyi, substituted alkyi, alkoxy, substituted alkoxy, amino, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, heteroaryl, and phosphinyl, with the proviso that said aryl is substituted with at the most 4 halogens.

The aryl may be any aryl, for example the aryl may be selected from the group consisting phenyl and naphtalenyl. In preferred embodiments of the invention the aryl is phenyl. Thus, the electrophile may be aryl (e.g. phenyl) substituted with halogen (e.g. - F) and a 2 ^nd substituent. The electrophile may be aryl (e.g. phenyl) substituted with halogen (e.g. -F) and a 2 ^nd and a 3 ^rd substituent. The electrophile may be aryl (e.g. phenyl) substituted with halogen (e.g. -F) and a 2 ^nd , a 3 ^rd and a 4 ^th substituent. The electrophile may be aryl (e.g. phenyl) substituted with halogen (e.g. -F) and a 2 ^nd , a 3 ^rd , a 4 ^th and a 5 ^th substituent. The electrophile may be aryl (e.g. phenyl) substituted with halogen (e.g. -F) and a 2 ^nd , a 3 ^rd , a 4 ^th , a 5 ^th , and a 6 ^th substituent. Said 2 ^nd , 3 ^rd , 4 ^th , 5 ^th and 6 ^th substituent may for example be any of the substituents described herein below in this section.

In one embodiment, the electrophile may be a chloro- or fluorobenzene derivative without strongly electron withdrawing substituents.

The electrophile may also be a weakly or non-electron deficient chloro- or

fluorobenzene derivative.

The electrophile may also be phenyl substituted with only 2 halogens and optionally a 3 ^rd , 4 ^th , 5 ^th and/or 6 ^th substituent. Thus, in such embodiment the phenyl is covalently linked to exactly two halogens. Said halogen may in particular be -F. In addition, said phenyl may be substituted with a 3 ^rd , 4 ^th , 5 ^th and/or 6 ^th substituent, which is not halogen. The 3 ^rd , 4 ^th , 5 ^th and/or 6 ^th substituent may be any of the substituents described herein below in this section. The electrophile may also be phenyl substituted with only 1 -F and optionally a 2 , 3 , 4 ^th , 5 ^th and/or 6 ^th substituent. Thus, in such embodiment the phenyl is covalently linked to exactly one -F. In addition, said phenyl may be substituted with a 2 ^nd , 3 ^rd , 4 ^th , 5 ^th and/or 6 ^th substituent, which is not -F, and preferably not halogen. The 2 ^nd , 3 ^rd , 4 ^th , 5 ^th and/or 6 ^th substituent may be any of the substituents described herein below in this section.

Said 2 ^nd , 3 ^rd , 4 ^,n , 5 ^,n and 6 ^,n substituent may be individually selected from the group of

F-, F ₃ C, R _j S-, and

wherein R _d , R _e , R _f , R _g , R _h , R,, R _j , R _k and R, individually are selected from the group consisting of -H, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl. The waved line indicates the point of attachment of the substituent.

Said 2 ^nd , 3 ^rd , ^th , 5 ^th and 6 ^th substituent may be individually selected from the group

consisting of Azolyl-, CI-, F-, and R _j S-,

wherein R _d , R _e , R _f , R _g , R _h , Ri and R _j individually are selected from the group consisting of -H, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl. The waved line indicates the point of attachment of the substituent.

Said 2 ^nd , 3 ^rd , 4 ^th , 5 ^th and 6 ^th substituent may be individually selected from the group

consisting of R _g O-, CI-, F-, and R _j S-,

wherein R _g , R _h , R, and R _j individually are selected from the group consisting of -H, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl. The waved line indicates the point of attachment of the substiuent.

Said 2 ^nd , 3 ^rd , 4 ^th , 5 ^th and 6 ^th substituent may be individually selected selected from the group consisting of CI-, F-, and R _j S-,

wherein R is selected from the group consisting of -H, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl. In one embodiment electrophile is aryl (e.g. phenyl) substituted with 2 to 4 substituents, wherein all of said substituents are halogen.

The first substituent may be halogen. Preferably, said halogen is selected from the group consisting of -F, -CI and -Br, more said first substituent is selected from the group consisting of -F and -CI, for example the first substituent is -F.

In embodiments of the invention, wherein one or more of the 2 ^nd , 3 ^rd , 4 ^th , 5 ^th and 6 ^th substituents are halogen, then said halogen may be any halogen, preferably said halogen is selected from the group consisting of -F, -CI and -Br, more preferably said halogen is selected from the group consisting of -F and -CI.

In one embodiment of the invention the electrophile is aryl (e.g. phenyl) substituted with one or more substituents, where all of said substituents are selected from the group consisting of -F and -CI.

In embodiments of the invention, wherein one or more of R _d , R _e , Rf, R _g , Rh, R,, R _j , Rk and R| is aryl, said aryl may be selected from the group consisting of phenyl, napthyl, indenyl, and fluorenyl, in particular said aryl may be phenyl. In embodiments of the invention, wherein one or more of R _d , R _e , Rf, R _g , Rh, R,, R _j , Rk and R| is substituted aryl, said substituted aryl may be selected from the group consisting of phenyl, napthyl, indenyl, and fluorenyl substituted with one or more selected from the group consisting of -OH, aryl, d-e-alkyl, C ₂ -6-alkenyl and C ₂ -6-alkynyl, in particular said substituted aryl may be phenyl substituted with one or more selected from the group consisting of phenyl, -OH, d-e-alkyl, C ₂ - ₆ -alkenyl and C ₂ - ₆ -alkynyl. In embodiments of the invention, wherein one or more of R _d , R _e , R _f , R _g , R _h , Ri, Rj, R _k and Ri is heteroaryl, said heteroaryl may individually for example be selected from the group consisting of tetrazolyl, imidazolyl, anthracenyl, phenanthrenyl, fluorenyl, pentalenyl, azulenyl, biphenylenyl, furanyl, triazolyl, pyranyl, thiadiazinyl,

benzothiophenyl, dihydro-benzo[b]thiophenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, benzisoxazolyl, quinolinyl, isoquinolinyl, phteridinyl, azepinyl, diazepinyl, imidazolyl, thiazolyl, quinolyl, carbazolyl, pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl,

tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrolopyrimidinyl, azaindolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, tetrazolyl, pyrazolinyl, and pyrazolidinyl.

In embodiments of the invention, wherein one or more of R _d , R _e , R _f , R _g , R _h , Ri, Rj, R _k and Ri is substituted heteroaryl, said substituted heteroaryl may individually for example be any of the aforementioned heteroaryl substituted with one or more selected from the group consisting of -OH, aryl, d-e-alkyl, C ₂ -6-alkenyl and C ₂ -6-alkynyl, in particular substituted with one or more selected from the group consisting of phenyl, - OH, d-e-alkyl, C ₂ -6-alkenyl and C ₂ -6-alkynyl. In embodiments of the invention, wherein one or more of R _d , R _e , R _f , R _g , R _h , R,, R _j , R _k and R| is alkyl, said alkyl may individually for example be C _{1 -10} -alkyl, such as C _{1 -6} -alkyl, for example C _{1 -3} -alkyl.

In embodiments of the invention, wherein one or more of R _d , R _e , R _f , R _g , R _h , R,, R _j , R _k and R, is substituted alkyl, said alkyl may individually for example be C _{1 -10} -alkyl, C _{1 -6} - alkyl or C _{1 -3} -alkyl.

In embodiments of the invention, wherein R _d , R _e , R _f , R _g , R _h , R,, R _j , R _k and/or R| is alkyl, said alkyl may for example be Ci-i ₀ -alkyl, such as d-e-alkyl, for example d_ ₃ -alkyl, substituted with one or more selected from the group consisting of -OH and aryl, in particular substituted with one or more selected from the group consisting of phenyl and -OH.

In embodiments of the invention, wherein one or more of R _d , R _e , R _f , R _g , R _h , Ri, Rj, R _k and R| is substituted alkenyl, said alkenyl may individually for example be C ₂ -i ₀ -alkenyl, C ₂ - ₆ -alkenyl or C ₂ - ₃ -alkenyl.

In embodiments of the invention, wherein R _d , R _e , R _f , R _g , R _h , R,, R _j , R _k and/or R| is alkenyl, said alkenyl may for example be C ₂ . ₁₀ -alkenyl, such as C ₂ . ₆ -alkenyl, for example C ₂ . ₃ -alkenyl, substituted with one or more selected from the group consisting of -OH and aryl, in particular substituted with one or more selected from the group consisting of phenyl and -OH.

In embodiments of the invention, wherein one or more of R _d , R _e , R _f , R _g , R _h , R,, R _j , R _k and R| is substituted alkynyl, said alkynyl may individually for example be C ₂ -i ₀ -alkynyl, C ₂ - ₆ -alkynyl or C ₂ - ₃ -alkynyl.

In embodiments of the invention, wherein R _d , R _e , R _f , R _g , R _h , R,, R _j , R _k and/or R| is alkynyl, said alkynyl may for example be C ₂ -i ₀ -alkynyl, such as C ₂ - ₆ -alkynyl, for example C ₂ - ₃ -alkynyl, substituted with one or more selected from the group consisting of -OH and aryl, in particular substituted with one or more selected from the group consisting of phenyl and -OH.

In one embodiment, said 2 ^nd , 3 ^rd , 4 ^th , 5 ^th and 6 ^th substituent may be individually selected from the group of consisting of -NH-alkenyl, -S-alkenyl, -O-alkenyl, -NH-(CH) _n -NH, -O- (CH) _n -NH, -S-(CH) _n -NH, -NH-N-(CH) _n -CH ₂ , -NH-N=NH, -NH-(CH ₂ ) _n -CH ₃ ,-(CH ₂ ) _n -NH- (CH ₂ ) _m -CH ₃ , wherein n and m are individually 0 or an integer.

In particular, one substituent may be fused directly with the arene. In other

embodiments, the substituent is not fused with the arene.

Two of said 2 ^nd , 3 ^rd , 4 ^th , 5 ^th and 6 ^th substituents may be fused and thereby forming a ring. Preferably, such fused substituents form a ring selected from the group consisting of pyrrole, furan, thiophene, pyrazole, oxazole, thiazole, imidazole, 1 ,2,3-triazole, 3,4- dihydro-pyrrole, and 2,3-dihydro-pyrrole rings. In one embodiment, the electrophile is an indole substituted with at least one halogen on the arene. In another embodiment, the electrophile is a benzofuran substituted with at least one halogen on the arene. In yet another embodiment, the electrophile is a benzothiophene substituted with at least one halogen on the arene. In yet another embodiment, the electrophile is an indazole substituted with at least one halogen on the arene. In yet another embodiment, the electrophile is a benzoxazole substituted with at least one halogen on the arene. In yet another embodiment, the electrophile is a benzothiazole substituted with at least one halogen on the arene. In yet another embodiment, the electrophile is a benzimidazole substituted with at least one halogen on the arene. In yet another embodiment, the electrophile is a benzotriazole substituted with at least one halogen on the arene. In yet another embodiment, the electrophile is an isoindoline substituted with at least one halogen on the arene. In yet another embodiment, the electrophile is an indoline substituted with at least one halogen on the arene. In embodiments of the invention, the electrophile is selected from the group consisting of indole, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, indazole, benzotriazole, isoindoline and indoline (shown below), substituted with at least one halogen on the benzene moiety and optionally further substituents. In the cases where a secondary amine is present in the ring fused with the aryl, said secondary amine is preferably first transformed into a tertiary amine, such as being alkylated, alkenylated or arylated.

The electrophile may for example be selected from the group consisting of the following compounds, wherein said compounds are substituted with at least one halogen on the

wherein R _p is selected from the group consisting of hydrogen, alkyl, alkenyl, carbamate, sulfone, benzyl, acetyl, benzoyl, carbobenzyloxy, p-methoxybenzyl carbonyl, tert-butyloxycarbonyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, p- methoxyphenyl, tosyl, and trichloroethyl chloroformate. In some embodiments, R _p is not hydrogen.

In other embodiments, none of the said 2 ^nd , 3 ^rd , 4 ^th , 5 ^th and 6 ^th substituents are fused with each other. In one embodiment the electrophile is phenyl substituted with first substituent selected from the group consisting of -F and -CI, and with a 2 ^nd substituent selected from the group consisting of -F, -CI, C^-alkoxy, C^-alkyl, thioaryl and phenyl, wherein said thioaryl may be substituted with up to 3 C^-alky!. In one embodiment the electrophile is phenyl substituted with first substituent selected from the group consisting of -F, -CI, Ci-3-alkoxy, d-3-alkyl, thioaryl and phenyl, wherein said thioaryl may be substituted with up to 3 d-3-alkyl.

In one embodiment the electrophile is selected from the group consisting of tetra- fluorobenzene, trifluorobenzene, difluorobenzene, fluoro-chlorobenzene, dichloro- fluorobenzene, trichlorobenzene, dichlorobenzene, chloro-difluorobenzene, methyl- difluorobenzene, methyl-chloro-fluorobenzene, methoxy-fluorobenzene, di-methyl- thiophenol-fluorobenzene, fluoro-1 , 1 '-biphenyl, N-benzyl-3,5-difluoro-N-methylaniline and bi-phenyl.

In one embodiment the electrophile is selected from 2,3-dichloro-fluorobenzene, 1 ,2,3- trichlorobenzene, 2-(4,2-di-methyl-thiophenol-yl)-fluorobenzene, and 2-(4,2-di-methyl- thiophenol-yl)-chlorobenzene. The electrophile may be a product of an organic synthesis and may thus be considered an intermediate. For example, the electrophile may be a product of a cross coupling reaction. Base

The methods of the present invention involve reacting a nucleophile and an electrophile in the presence of a base. Preferably said base is a base, wherein the corresponding acid has a pKa above 29, such as at least 30 in DMSO. It may also be preferred that said base has a pKa above 25, preferably at least 26 in THF. Thus, it is generally preferred that the base is not a weak base, for example the base is preferably not Cs ₂ C0 ₃ . In some embodiments of the invention the base may be a base, wherein the

corresponding acid has a pKa above 32 in DMSO. In some embodiments the base may be a base, wherein the corresponding acid has a pKa above 26 in THF.

In some embodiments of the invention it may be preferred that the base is not too strong. Thus, in some embodiments it is preferred that the base is a base, wherein the corresponding acid has a pKa in the range of 29 to 49, such as in the range of 29 to 45. In other embodiments the base is a base, wherein the corresponding acid has a pKa in the range of 32 to 49, such as in the range of 32 to 45. Aforementioned pKa is preferably determined in DMSO. pKa may be determined by any conventional method. pKa values in DMSO is preferably measured up to the value of 35, and values above 35 may be extrapolated as described in Bordwell, Acc. Chem. Res. 1988, 21 , 456-463.

The corresponding acid to butyllithium (BuLi) has a pKa 50, and may thus in some embodiments be less preferable. Thus, in some embodiments the base is a base, wherein the corresponding acid has a pKa above 29, for example above 32, with the proviso that the base is not BuLi.

In some embodiments, the base is a metal hydride, such as an alkali metal hydride. In some embodiments, the base is selected from the group consisting of lithium hydride, sodium hydride, potassium hydride, cesium hydride, magnesium hydride, calcium hydride, lithium aluminium hydride, sodium aluminium hydride, potassium aluminium hydride, lithium borohydride, sodium borohydride and potassium borohydride. In one embodiment the base is selected from the group consisting of lithium

bis(trimethylsilyl)amide (LiHMDS), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), lithium 2,2,6,6,-tertmethylpiperidide (LiTMP), and BuLi.

In some embodiments, the base is a non-nucleophilic base, i.e. a base only acting as a nucleophile in the removal of protons. Typical non-nucleophilic bases are sterically hindered and bulky, preventing them from attacking as nucleophiles. Hence, protons can attach to the basic center of the base but alkylation and complexation is inhibited. Examples of non-nucleophilic bases are lithium diisopropylamide (LDA), LiTMP and silicon-based amides such as LiHMDS, NaHMDS and KHMDS. Generally, non- nucleophilic bases are sterically hindered and bulky, and thus the base may be a base having a M _w of at least 120 g/mol, preferably of at least 130 g/mol, such as of at least 140 g/mol. More preferably the base has aforementioned Mw and aforementioned pKa. Thus, it may be preferred that the base has:

• a pKa above 29 in DMSO and/or a pKa in THF above 25; and a Mw of at least 120 g/mol or a M _w of at least 140 g/mol.

In other embodiments the base is selected from the group consisting of LiHMDS, NaHMDS, KHMDS and LiTMP.

Solvent

The methods of the present invention involve reacting a nucleophile and an electrophile in a solvent and in the presence of a base. The solvent may be any organic solvent.

In one embodiment the solvent may be chosen according to the base used in the particular reaction. Thus, the solvent may be an organic solvent, which is stable in the presence the base employed under the reaction conditions employed.

In addition, it is preferred that the solvent is a liquid at the reaction temperature.

It is preferred that the solvent is a solvent that only contain protons with a pKa above 35.1 in DMSO. In one embodiment the solvent is a solvent that only contains protons with a pKa above 32 in DMSO. In one embodiment the solvent is not DMSO. Thus, the solvent may be a solvent that only contains protons with a pKa above 32 in DMSO, with the proviso that the solvent is not DMSO.

In one embodiment the solvent is a solvent that does not contain any carbonyl groups. In one embodiment the solvent is a solvent that does not contain any sulfoxide groups.

The solvent may for example be selected from the group consisting of ethers, alkanes, benzene and substituted benzene. Ethers useful as solvent include any ether. In particular, the ether may be an ether, which only contain protons with a pKa above 32, for example above 35.1 in DMSO. It may further be preferred that the ether is a liquid at the reaction temperature. It may further be preferred that the ether does not contain any carbonyl groups. The ether may for example be selected from the group consisting of tetrahydrofuran (THF), dioxane, dimethoxyethane (DME), 2-methyl-tetrahydrofuran (2-Me-THF), and diethoxyethane.

Alkanes useful as solvent include any alkane. In particular, the alkane may be an alkane, which only contain protons with a pKa above 32, for example above 35.1 in DMSO. It may further be preferred that the alkane is a liquid at the reaction

temperature. It may further be preferred that the alkane does not contain any carbonyl groups. The alkane may be a linear, branched or cyclic alkane, e.g. a C ₄ - ₂ o linear, branched or cyclic alkane. For example, the alkane may be methylcyclohexane. Substituted benzenes useful as solvent include any substituted benzene. In particular, the substituted benzene may be a substituted benzene, which only contain protons with a pKa above 32, for example above 35.1 in DMSO. It may further be preferred that the substituted benzene is a liquid at the reaction temperature. It may further be preferred that the substituted benzene does not contain any carbonyl group. The substituted benzene is in general different from the electrophile used in the reaction. However in some embodiments, the electrophile may also be used as solvent. For example the substituted benzene may be substituted with one or more substituents selected from the group consisting of Ci- ₃ -alkyl. In addition or alternatively, the benzene may be substituted with up to 1 -CI.. The substituted benzene may for example be selected from the group consisting of toluene, xylene and chlorobenzene. Arylated amine

The arylated amine to be prepared by the methods according to the invention may be any of the electrophiles described herein above, wherein in place of the first substituent, the aryl of the electrophile is covalently N-linked to one of the nucleophiles described herein above.

In one embodiment of the invention the arylated amine is selected from the group of compounds shown in figure 2 as compounds 3c,3d, 3e, 3f, 3g, 3h, 3i, 3j, 3I and 3m.

In one embodiment of the invention the arylated amine is selected from the group of compounds shown in figure 3 as compounds 3n, 3o, 3p, 3q, 3r, 3s, 3t, 3u, 3v, 3w, 3x, 3y, 3z, 3aa, 3ab, 3ac, 3ad, 3ae, 3af and 3ag.

In one embodiment the arylated amine is selected from the group of compounds shown in figure 1 .

The arylated amine may be used in further organic synthesis, and thus in some embodiments the arylated amine may be an intermediate. Thus, the arylated amine may be a substrate for further functionalization e.g. through cross coupling reactions. In other embodiments the arylated amine may be a final product. The arylated amine may be purified by any conventional method including for example extraction, precipitation, crystallisation, distillation and/or chromatography.

Examples

The invention is further illustrated by the following examples, which however should not be construed as being limiting for the invention.

Example 1

In the following examples, N-arylation of amines was performed as follows unless otherwise specified: To a vial was added amine nucleophile (1 .0 mmol) and base. If nothing else is specified the base employed was LiHMDS (1 .0 M in THF, 1 .5 ml_). The vial was sealed and stirred at the designated temperature for 10 minutes. To this mixture was then added fluoro electrophile (1 .5 mmol) at room temperature. The reaction was stirred at the designated temperature until judged complete by HPLC. The reaction was then quenched by addition of solid NaHC0 ₃ and loaded directly onto a silica gel column. The product was purified by flash chromatography on silica gel using a suitable mixture of ethyl acetate and heptane as eluent. Example 2

N-arylation of compound 1 a (N-methylpiperazine) with compound 2 (1 ,3,5- trifluorobenzene) was performed using the following general reaction conditions: 1a (0.2 mmol) and the base (0.5 mmol) was mixed in solvent (0.5 mL) at room temperature. Different solvents, bases and temperatures were tested.

After 10 minutes 2 (0.6 mmol) was added and reaction heated to temperature and stirred for 12 h. Yields assessed by HPLC. The results are shown in table 1 below.

Temperature

12 h

Table 1

Yield 3a

Entry Base M„ Solvent Temperature

(g/mol) DMSO THF (%) ^a

A None - - - THF 50°C 0

B Cs ₂ C0 ₃ 325.82 _{** **} THF 50°C 0

C LiO'Bu 80.05 29 THF 50°C <5"

D LiHMDS 167.33 30 ^* " 26 THF 50°C >95

E ^* LiTMP 147.19 37 THF 90°C 42 (3b)

F LiHMDS 167.33 30 ^*** 26 DME 50°C 73 G □ HMDS 167.33 30 ^* " 26 2-Me-THF 50°C 51

a Evaluated by HPLC.

^* 1 -fluoro-3-methoxybenzene used instead of 1 ,3,5-trifluorobenzene.

^** pKa of Cs ₂ C0 ₃ is expected to be lower than 29 in DMSO and 25 in THF.

^*** pKa of LiHMDS has been reported to be 30 in DMSO (http://wjvw.d-bernier.fr/pKa.php)

The reaction was successfully performed using LiOtBu as base, but it was significantly less efficient than using some of the other bases.

Example 3

The scope of arylation reactions with respect to the f luorobenzenes in reaction with morpholine 1 b was investigated, and the results are provided in Figure 2.

Polyfluorinated benzene derivates perform well in these reactions as seen from the formation of products 3c-3m, which was isolated in yields up to 93%. Important notions about these reactions are the ability to achieve mono-substitution in the presence of additional fluorine atoms as well as the high degree of regioselectivity. For example, product 3c is formed as a single regioisomer even though the starting 1 ,2,3,5- tetrafluorobenzene contains no less than three distinct fluorine atoms. Difluorinated benzenes can also be employed as electrophiles in the reactions as illustrated by the formation of 3f and 3g isolated in 81 % and 86% yield, respectively.

The general reaction conditions used in this example: Morpholine 1 b (1 .0 mmol), LiHMDS (1 .0M in THF, 1 .5 mL) and fluorobenzene derivative (1 .5 mmol) was mixed and heated. Details regarding the individual reactions are given below. The structure of the compounds is provided in figure 2.

Compound 3c, 4-(2,3,5-trifluorophenyl)morpholine:

Synthesized from 1 ,2,3,5-tetrafluorobenzene according to the general procedure. After 3 hours at room temperature the compound 3c was isolated in 70% yield as an off-white solid. ¹ H NMR (CDCI ₃ ) δ ppm 6.58 - 6.48 (m, 1 H), 6.41 (ddt, J= 1 1 .2, 5.6, 2.6 Hz, 1 H), 3.90 - 3.81 (m, 4H), 3.12 - 3.07 (m, 4H). ¹³ C NMR (CDCI ₃ ) δ ppm 157.9 (ddd, J= 243.5, 13.4, 3.3 Hz), 151 .3 (ddd, J= 247.4, 15.3, 13.5 Hz), 142.1 (ddd, J= 10.5, 6.8, 3.5 Hz), 140.5 (ddd, J= 242.9, 14.1 , 4.6 Hz), 100.7 (dt, J= 26.1 , 2.4 Hz), 97.7 (dd, J = 27.7, 21 .9 Hz), 66.7, 50.5 (d, J = 3.8 Hz). Compound 3d, 4-(2,5-difluorophenyl)morpholine:

Synthesized from 1 ,2,4-trifluorobenzene according to the general procedure.

After 14 hours at 50°C the compound 3d was isolated in 73% yield as a yellowish solid. ¹ H NMR (CDCI ₃ ) δ ppm 6.96 (ddd, J= 12.1 , 8.7, 5.2 Hz, 1 H), 6.73 - 6.44 (m, 2H), 3.95 - 3.73 (m, 4H), 3.16 - 2.89 (m, 4H). ¹³ C NMR (CDCI ₃ ) δ ppm 159.1 (dd, J= 241 .9, 2.2 Hz), 151 .6 (dd, J = 241 .2, 2.9 Hz), 141 .0 (dd, J= 10.5, 8.8 Hz), 1 16.5 (dd, J= 23.6, 10.0 Hz), 107.9 (dd, J= 23.9, 8.3 Hz), 105.8 (dd, J = 26.3, 3.5 Hz), 66.8, 50.5 (d, J = 3.8 Hz). Compound 3e, 4-(3,5-difluorophenyl)morpholine:

Synthesized from 1 ,3,5-trifluorobenzene according to the general procedure.

After 14 hours at 50°C the compound 3e was isolated in 76% yield as a yellowish solid.

¹ H NMR (CDCI ₃ ) δ ppm 6.39 - 6.32 (m, 2H), 6.28 (tt, J= 8.8, 2.2 Hz, 1 H), 3.86 - 3.79

(m, 4H), 3.16 - 3.1 1 (m, 4H). ¹³ C NMR (CDCI ₃ ) δ ppm 164.0 (dd, J= 244.4, 15.8 Hz), 153.3 (t, J = 12.2 Hz), 98.3 - 97.0 (m), 94.5 (t, J = 26.1 Hz), 66.5, 48.3.

Compound 3f, 4-(2-fluorophenyl)morpholine:

Synthesized from 1 ,2-difluorobenzene according to the general procedure.

After 2.5 hours at 100°C the compound 3f was isolated in 81 % yield as a dark yellow oil. ¹ H NMR (CDCI ₃ ) δ ppm 7.10 - 7.00 (m, 2H), 6.98 - 6.91 (m, 2H), 3.89 - 3.83 (m,

4H), 3.10 - 3.06 (m, 4H). ¹³ C NMR (CDCI ₃ ) δ ppm 155.7 (d, J= 246.1 Hz), 139.9 (d, J = 8.4 Hz), 124.4 (d, J = 3.6 Hz), 122.6 (d, J= 8.1 Hz), 1 18.6 (d, J = 2.9 Hz), 1 16.1 (d, J = 20.6 Hz), 67.0, 50.9 (d, J = 3.4 Hz). Compound 3g, 4-(3-fluorophenyl)morpholine:

Synthesized from 1 ,3-difluorobenzene according to the general procedure.

After 2.5 hours at 100°C the compound 3g was isolated in 86% yield as a dark yellow oil. ¹ H NMR (CDCI ₃ ) δ ppm 7.21 (td, J= 8.2, 6.9 Hz, 1 H), 6.67 (dd, J= 8.3, 2.2 Hz, 1 H), 6.61 - 6.53 (m, 2H), 3.88 - 3.81 (m, 4H), 3.19 - 3.12 (m, 4H). ¹³ C NMR (CDCI ₃ ) δ ppm 163.8 (d, J= 243.4 Hz), 152.9 (d, J = 9.8 Hz), 130.1 (d, J = 10.0 Hz), 1 10.7 (d, J = 2.5 Hz), 106.2 (d, J = 21 .4 Hz), 102.4 (d, J = 25.1 Hz), 66.7, 48.8.

Compound 3h, 4-(2-chlorophenyl)morpholine:

Synthesized from 1 -chloro-2-fluorobenzene according to the general procedure. After 1.5 hours at 100°C the compound 3h was isolated in 72% yield as a yellow oil. ¹ H NMR (CDCI ₃ ) 6ppm 7.37 (dd, J= 7.9, 1.5 Hz, 1H), 7.24 (td, J= 7.7, 1.6 Hz, 1H), 7.04 (dd, J = 8.1, 1.5 Hz, 1H), 6.99 (td, J= 7.7, 1.6 Hz, 1H), 3.88 (t, J= 4.6 Hz, 4H), 3.06 (t, J = 4.6 Hz, 4H). ¹³ C NMR (CDCI ₃ ) δ ppm 149.0, 130.7, 128.8, 127.6, 123.9, 120.2, 67.1,51.6.

Compound 3i, 4-(4-chlorophenyl)morpholine:

Synthesized from 1-chloro-4-fluorobenzene according to the general procedure.

After 14 hours at 80°C the compound 3i was isolated in 53% yield as a white solid. ¹ H NMR (CDCI ₃ ) δ ppm 7.25 - 7.15 (m, 2H), 6.86 - 6.80 (m, 2H), 3.87 - 3.82 (m, 4H), 3.14-3.07 (m, 4H). ¹³ C NMR (CDCI ₃ ) δ ppm 149.9, 129.0, 124.9, 116.9,66.8, 49.3.

Compound 3j, 4-(2-chloro-5-methylphenyl)morpholine:

Synthesized from 1-chloro-2-fluoro-4-methylbenzene according to the general procedure.

After 14 hours at 90°C the compound 3j was isolated in 77% yield as a clear oil. ¹ H NMR (CDCI ₃ ) δ ppm 7.23 (d, J = 8.0 Hz, 1 H), 6.84 (d, J = 2.0 Hz, 1 H), 6.82 - 6.77 (m, 1H), 3.97 - 3.72 (m, 4H), 3.13 - 2.93 (m, 4H), 2.32 (s, 3H). ¹³ C NMR (CDCI ₃ ) δ ppm 148.6, 137.5, 130.3, 125.5, 124.5, 120.9, 67.1, 51.6, 21.1.

Compound 3I, 4-(3-methoxyphenyl)morpholine:

Synthesized from 1-fluoro-3-methoxybenzene according to the general procedure. After 14 hours at 90°C the compound 3I was isolated in 93% yield as a bright yellow oil. ¹ H NMR (CDCI ₃ ) δ ppm 7.24 - 7.16 (m, 1 H), 6.54 (ddd, J= 8.3, 2.3, 0.9 Hz, 1 H), 6.48 - 6.42 (m, 2H), 3.88 - 3.82 (m, 4H), 3.80 (s, 3H), 3.19 - 3.11 (m, 4H). ¹³ C NMR (CDCI ₃ ) δρρηι 160.6, 152.6, 129.8, 108.4, 104.6, 102.1, 66.8, 55.1, 49.2.

Compound 3m, 4-([1,1'-biphenyl]-4-yl)morpholine:

Synthesized from 4-fluoro-1 ,1 '-biphenyl according to the general procedure.

After 14 hours at 100°C the compound 3m was isolated in 65% yield as a yellowish solid. ¹ H NMR (CDCI ₃ ) δ ppm 7.62 - 7.51 (m, 4H), 7.45 - 7.39 (m, 2H), 7.33 - 7.28 (m, 1H), 7.02-6.97 (m, 2H), 3.93-3.85 (m, 4H), 3.26-3.18 (m, 4H). ¹³ C NMR (CDCI ₃ ) δ ppm 150.5, 140.8, 132.6, 128.7, 127.8, 126.5, 126.5, 115.7, 66.9,49.2. The reactions proved to be selective to fluorine substitution over chlorine-substitution in derivatives containing both, leading to e.g. 3h-3j. Such structural motifs are in themselves important for the pharmaceutical industry (see examples of

pharmaceutically important compounds in figure 1 ), while the chlorine substituent may also provide a site for further functionalization e.g. through cross coupling reactions. It should be stressed that the benzyne mechanism is ruled out for the here presented reactions as no or negligible regioisomers are observed in NMR spectra of the crude reaction mixtures.

Of special interests were the findings that no additional halogen substituents were required and that even electron-rich fluorobenzene derivatives are feasible reaction partners. Simply adding LiHMDS in THF and fluorobenzene to a vial containing morpholine 1 b provides product 3k in 82% yield. Employing 3-fluoroanisole under similar conditions forms the product 3I, which can be isolated in 93% yield. Formation of product 3I from morpholine have previously (Desmartes 2002, Katoka 2002, Maes 2004, Urgaonkar 2004, Lerma 2005, Shen 2008, Otsuka 2010, Guo 2010, Lu 201 1 , Jacobsen 2016) been accomplished by employing, nickel, copper, palladium or ruthenium catalysis utilizing 3-halogen-substituted anisole derivatives. Product 3m further illustrates the complementary properties of these reactions to cross coupling reactions. This product may be synthesized by a cross coupling reaction of 4-chloro- fluorobenzene and phenyl boronic acid followed by the here presented catalyst-free reaction with morpholine, or in the vice versa reaction order through initial generation of 3i followed by a cross coupling reaction.

Example 4

The methods are useful for arylation of a range of secondary amines as seen in figure 3. Both cyclic and acyclic secondary amines can be functionalized as illustrated by formation of products 3n-3ag in high yields. Thus, most of these compounds were obtained with a 75-80% yield. Moreover, pyrazine and 1 -methylpyrazine can be employed as nucleophiles and the resultant products 3q and 3r isolated in 62 and 72% yield, respectively. As seen in figure 1 both mono- and diarylated pyrazines are common substructures in pharmaceutical substances. Interestingly, by simply increasing the amount of base and electrophile, the reaction switched from mono- to bis-substitution on pyrazine to afford 3r or 3s respectively.

General reaction conditions used in this example: Amine (1 .0 mmol), LiHMDS (1 .OM in THF, 1 .5 mmol) and benzene derivative (1 .5 mmol) was mixed and heated.

The structure or the compounds is provided in figure 3.

Compound 3n, 1 -(3-fluorophenyl)pyrrolidine:

Synthesized from pyrrolidine and 1 ,3-difluorobenzene according to the general procedure.

After 3 hours at 80°C the compound 3n was isolated in 80% yield yellow oil. ¹ H NMR (CDCI ₃ ) δ ppm 7.14 (td, J= 8.2, 6.9 Hz, 1 H), 6.39 - 6.28 (m, 2H), 6.24 (dt, J = 12.4, 2.4 Hz, 1 H), 3.30 - 3.21 (m, 4H), 2.08 - 1 .97 (m, 4H). ¹³ C NMR (CDCI ₃ ) δ ppm 164.1 (d, J = 241 .6 Hz), 149.5 (d, J = 1 1 .0 Hz), 130.0 (d, J = 10.5 Hz), 107.3 (d, J= 2.1 Hz), 101 .7 (d, J = 21 .7 Hz), 98.4 (d, J = 25.4 Hz), 47.7, 25.4.

Compound 3o, N-benzyl-3,5-difluoro-N-methylaniline:

Synthesized from N-methyl-benzylamine and 1 ,3,5-trifluorobenzene according to the general procedure. After 14 hours at 50°C the compound 3o was isolated in 79% yield as a dark yellow oil. ¹ H NMR (CDCI ₃ ) δ ppm 7.36 - 7.32 (m, 2H), 7.30 - 7.23 (m, 1 H), 7.22 - 7.14 (m, 2H), 6.28 - 6.17 (m, 2H), 6.14 (tt, J= 9.1 , 2.2 Hz, 1 H), 4.52 (s, 2H), 3.03 (s, 3H). ¹³ C NMR (CDCI ₃ ) δ ppm 164.2 (dd, J= 242.9, 16.3 Hz), 151 .6 (t, J = 13.2 Hz), 137.7, 128.7, 127.2, 126.4, 95.2 - 94.6 (m), 91 .4 (t, J= 26.3 Hz), 56.2, 38.7.

Compound 3p, N-benzyl-3-methoxy-N-methylaniline:

Synthesized from N-methyl-benzylamine and 1 -fluoro-3-methoxybenzene according to the general procedure. After 14 hours at 90°C the compound 3p was isolated in 75% yield as a clear oil. ¹ H NMR (CDCI ₃ ) δ ppm 7.38 - 7.31 (m, 2H), 7.31 - 7.22 (m, 3H), 7.16 (td, J = 8.1 , 2.0 Hz, 1 H), 6.46 - 6.38 (m, 1 H), 6.37 - 6.31 (m, 2H), 4.56 (s, 2H), 3.80 (s, 3H), 3.04 (s, 3H). ¹³ C NMR (CDCI ₃ ) δ ppm 160.7, 151 .1 , 138.9, 129.8, 128.5, 126.8, 126.7, 105.5, 101 .3, 98.9, 56.5, 55.0, 38.5.

Compound 3q, 1 -(2-fluorophenyl)-4-methylpiperazine: Synthesized from N-methyl-piperazine and 1 ,2-difluorobenzene according to the general procedure. After 3 hours at 80°C the reaction was quenched by the addition of HCI (0.01 M in H ₂ 0), the solvent evaporated and the compound redissolved in

CH ₃ CN:H ₂ 0 (1 :1 ). The compound 3q was isolated as the HCI salt by VLC on C18 gel (0 to 50% CH ₃ CN in 0.01 M HCI) in 62% yield as light brown solid. ¹ H NMR (DMSO-d ₆ ) δ ppm 1 1 .37 (s, 1 H), 7.24 - 6.95 (m, 4H), 3.51 - 3.40 (m, 4H), 3.25 - 3.12 (m, 4H), 2.78 (d, J= 4.8 Hz, 3H). ¹³ C NMR (DMSO-d ₆ ) δ ppm 154.84 (d, J= 244.3 Hz), 138.29 (d, J= 8.6 Hz), 124.97 (d, J= 3.4 Hz), 123.40 (d, J = 7.9 Hz), 1 19.63 (d, J= 2.6 Hz), 1 16.14 (d, J= 20.3 Hz), 52.27, 47.00 (d, J= 3.4 Hz), 41 .98.

Compound 3r, 1 -(3-methoxyphenyl)piperazine:

Synthesized according to a modified procedure. Piperazine (3.0 mmol), LiHMDS (1 .0M in THF, 1 .5 mmol) and 1 -fluoro-3-methoxybenzene (1 .0 mmol) was mixed and heated. After 3 hours at 80°C the reaction was quenched by the addition of HCI (0.01 M in H ₂ 0), the solvent evaporated and the compound redissolved in CH ₃ CN:H ₂ 0 (1 :1 ). The compound 3r was isolated as the HCI salt by VLC on C18 gel (0 to 50% CH ₃ CN in 0.01 M HCI) in 72% yield as light brown solid. ¹ H NMR (DMSO-d ₆ ) δ ppm 9.19 (s, 2H), 7.15 (t, J = 8.2 Hz, 1 H), 6.56 (dd, J = 8.2, 2.3 Hz, 1 H), 6.51 (t, J = 2.4 Hz, 1 H), 6.45 (dd, J = 8.1 , 2.3 Hz, 1 H), 3.72 (s, 3H), 3.43 - 3.25 (m, 4H), 3.27 - 3.07 (m, 4H). ¹³ C NMR (DMSO-d ₆ ) δ ppm 160.23, 150.94, 129.91 , 108.65, 105.77, 102.45, 55.01 , 45.60, 42.29.

Compound 3s, 1 ,4-bis(3-fluorophenyl)piperazine:

Synthesized according to a modified procedure. Piperazine (1 .0 mmol), LiHMDS (1 .0M in THF, 3.0 mmol) and 1 ,3-difluorobenzene (3.0 mmol) was mixed and heated.

After 3 hours at 80°C the compound 3s was isolated in 72% yield as a bright yellow solid. ¹ H NMR (CDCI ₃ ) δ ppm 7.23 (td, J= 8.2, 6.9 Hz, 2H), 6.73 (ddd, J= 8.4, 2.4, 0.8 Hz, 2H), 6.64 (dt, J= 12.2, 2.4 Hz, 2H), 6.57 (tdd, J = 8.2, 2.4, 0.8 Hz, 2H), 3.34 (s, 8H). ¹³ C NMR (CDCI ₃ ) δ ppm 163.8 (d, J= 243.6 Hz), 152.7 (d, J = 9.8 Hz), 130.2 (d, J = 9.9 Hz), 1 1 1 .4 (d, J = 2.6 Hz), 106.3 (d, J = 21 .4 Hz), 103.0 (d, J= 25.0 Hz), 48.7.

Compound 3t, 1 -(2,3-dichlorophenyl)piperazine:

Synthesized according to a modified procedure. Piperazine (3.0 mmol), LiHMDS (1 .0M in THF, 3.0 mmol) and 2,3-dichlorofluorobenzene (1 .0 mmol) was mixed and heated. After 12 hours at 50°C the reaction was quenched by the addition of HCI (0.01 M in H ₂ 0), the solvent evaporated and the compound redissolved in CH ₃ CN:H ₂ 0 (1 :1 ). The compound 3t was isolated as the HCI salt by VLC on C18 gel (0 to 50% CH3CN in 0.01 M HCI) in 66% yield as white solid.

Employing 1 ,2,3-trichlorobenzene as electrophile instead of 2,3-dichlorofluorobenzene the same product was obtained in 51 % yield after 22 hours at 65°C. ¹ H NMR (DMSO- d ₆ ) δ ppm 9.50 (s, 2H), 7.42 - 7.30 (m, 2H), 7.20 (dd, J= 7.2, 2.3 Hz, 1 H), 3.22 (s, 8H). ¹³ C NMR (DMSO-d ₆ ) δ ppm 150.00, 132.69, 128.62, 126.15, 125.20, 1 19.82, 47.78, 42.98.

Compound 3u, 8-(3-methoxyphenyl)-1 ,4-dioxa-8-azaspiro[4.5]decane:

Synthesized from 1 ,4-dioxa-8-azaspiro[4.5]decane and 1 -fluoro-3-methoxybenzene according to the general procedure. After 14 hours at 90°C the compound 3u was isolated in 90% yield as a yellow oil. ¹ H NMR (CDCI ₃ ) 6 ppm 7.16 (t, J = 8.2 Hz, 1 H), 6.56 (ddd, J= 8.2, 2.4, 0.8 Hz, 1 H), 6.49 (t, J = 2.4 Hz, 1 H), 6.40 (ddd, J= 8.1 , 2.4, 0.8 Hz, 1 H), 3.98 (s, 4H), 3.79 (s, 3H), 3.39 - 3.27 (m, 4H), 1 .88 - 1 .77 (m, 4H). ¹³ C NMR (CDCI ₃ ) δ ppm 160.50, 152.19, 129.66, 109.24, 107.1 1 , 104.04, 102.81 , 64.23, 55.05, 47.51 , 34.40. Compound 3v, 1 -(3,5-difluorophenyl)piperidine:

Synthesized from piperidine and 1 ,3,5-trifluorobenzene according to the general procedure. After 14 hours at 50°C the compound 3v was isolated in 61 % yield as a clear oil. ¹ H NMR (CDCI ₃ ) δ ppm 6.46 - 6.27 (m, 2H), 6.19 (tt, J = 8.9, 2.2 Hz, 1 H), 3.23 - 3.04 (m, 4H), 1 .72 - 1 .47 (m, 6H). ¹³ C NMR (CDCI ₃ ) δ ppm 164.03 (dd, J= 243.2, 16.1 Hz), 153.65 (t, J = 12.4 Hz), 98.96 - 96.87 (m), 93.12 (t, J= 26.2 Hz), 49.40, 25.32, 24.18.

Compound 3w, 1 -(3-methoxyphenyl)-4-phenylpiperazine:

Synthesized from 1 -phenylpiperazine and 1 -fluoro-3-methoxybenzene according to the general procedure. After 14 hours at 90°C the compound 3w was isolated in 73% yield as an off-white solid. ¹ H NMR (CDCI ₃ ) δ ppm 7.34 - 7.27 (m, 2H), 7.22 (t, J = 8.2 Hz, 1 H), 7.02 - 6.97 (m, 2H), 6.91 (tt, J= 7.3, 1 .1 Hz, 1 H), 6.62 (ddd, J = 8.3, 2.4, 0.8 Hz, 1 H), 6.54 (t, J= 2.4 Hz, 1 H), 6.47 (ddd, J= 8.2, 2.4, 0.8 Hz, 1 H), 3.82 (s, 3H), 3.35 (s, 8H). ¹³ C NMR (CDCI ₃ ) δ ppm 160.60, 152.60, 151 .19, 129.83, 129.15, 120.03, 1 16.30, 109.04, 104.72, 102.74, 55.19, 49.34.

Compound 3x, 1 -(2-chlorophenyl)-4-phenylpiperazine:

Synthesized from 1 -phenylpiperazine and 1 -chloro-2-fluorobenzene according to the general procedure. After 2.5 hours at 100°C the compound 3x was isolated in 50% yield as a white solid. ¹ H NMR (CDCI ₃ ) δ ppm 7.41 (dd, J= 8.0, 1 .5 Hz, 1 H), 7.35 - 7.29 (m, 2H), 7.29 - 7.22 (m, 1 H), 7.1 1 (dd, J= 8.0, 1 .6 Hz, 1 H), 7.05 - 6.98 (m, 3H), 6.91 (ddt, J = 8.4, 7.3, 1 .1 Hz, 1 H), 3.41 - 3.36 (m, 4H), 3.26 - 3.21 (m, 4H). ¹³ C NMR (CDCI ₃ ) 6 ppm 151 .35, 149.12, 130.68, 129.12, 128.84, 127.60, 123.84, 120.35, 1 19.85, 1 16.21 , 51 .30, 49.49.

Compound 3y, N-butyl-N-ethyl-3-methoxyaniline:

Synthesized from N-ethylbutan-1 -amine and 1 -fluoro-3-methoxybenzene according to the general procedure. After 14 hours at 90°C the compound 3y was isolated in 82% yield as a clear oil. ¹ H NMR (CDCI ₃ ) δ ppm 7.17 (td, J= 8.5, 1 .0 Hz, 1 H), 6.40 - 6.31 (m, 1 H), 6.33 - 6.19 (m, 2H), 3.40 (q, J= 7.1 Hz, 2H), 3.34 - 3.24 (m, 2H), 1 .69 - 1 .57 (m, 2H), 1 .45 - 1 .36 (m, 2H), 1 .20 (t, J= 6.9 Hz, 3H), 1 .02 (t, J= 7.4 Hz, 3H). ¹³ C NMR (CDCI ₃ ) δ ppm 160.86, 149.36, 129.80, 105.01 , 99.78, 98.32, 55.02, 50.20, 44.96, 29.71 , 20.35, 13.99, 12.32.

Compound 3z, 8-(3,5-difluorophenyl)-1 ,4-dioxa-8-azaspiro[4.5]decane:

Synthesized from 1 ,4-dioxa-8-azaspiro[4.5]decane and 1 ,3,5-trifluorobenzene according to the general procedure. After 14 hours at 50°C the compound 3z was isolated in 76% yield as an yellow oil. ¹ H NMR (CDCI ₃ ) δ ppm 6.43 - 6.30 (m, 2H), 6.25

- 6.12 (m, 1 H), 3.98 (s, 4H), 3.41 - 3.25 (m, 4H), 1 .84 - 1 .69 (m, 4H). ¹³ C NMR (CDCI ₃ ) δ ppm 164.02 (dd, J= 243.7, 16.1 Hz), 152.48 (t, J= 12.4 Hz), 106.89, 99.15 - 97.06 (m), 93.50 (t, J= 26.2 Hz), 64.36, 46.59, 34.08. Compound 3aa, 2-(2-chlorophenyl)-1 ,2,3,4-tetrahydroisoquinoline:

Synthesized from 1 ,2,3,4-tetrahydroisoquinoline and 1 -chloro-2-fluorobenzene according to the general procedure. After 2.5 hours at 100°C the compound 3aa was isolated in 74% yield as an yellow oil. ¹ H NMR (CDCI ₃ ) δ ppm 7.59 - 7.38 (m, 1 H), 7.38

- 7.14 (m, 6H), 7.12 - 6.87 (m, 1 H), 4.34 (s, 2H), 3.47 (t, J= 5.8 Hz, 2H), 3.10 (t, J = 5.9 Hz, 2H). ¹³ C NMR (CDCI ₃ ) δ ppm 149.17, 134.75, 134.57, 130.76, 129.04, 128.88, 127.56, 126.43, 126.36, 125.84, 123.64, 120.69, 53.32, 49.99, 29.16.

Compound 3ab, N-butyl-N-ethyl-3,5-difluoroaniline:

Synthesized from N-ethylbutan-1 -amine and 1 ,3,5-trifluorobenzene according to the general procedure. After 14 hours at 50°C the compound 3ab was isolated in 41 % yield as a clear oil. ¹ H NMR (CDCI ₃ ) δ ppm 6.19 - 5.98 (m, 3H), 3.32 (q, J= 7.1 Hz, 2H), 3.25 - 3.14 (m, 2H), 1 .63 - 1 .49 (m, 2H), 1 .42 - 1 .31 (m, 2H), 1 .15 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.3 Hz, 3H). ¹³ C NMR (CDCI ₃ ) δ ppm 164.41 (dd, J= 241 .7, 16.7 Hz), 149.98 (t, J = 13.3 Hz), 94.43 - 93.37 (m), 90.09 (t, J= 26.5 Hz), 50.28, 45.12, 29.46, 20.26, 13.92, 12.08.

Compound 3ac, N,N-dibenzyl-3-methoxyaniline:

Synthesized from dibenzylamine and 1 -fluoro-3-methoxybenzene according to the general procedure. After 14 hours at 90°C the compound 3ac was isolated in 89% yield as a clear oil. ¹ H NMR (CDCI ₃ ) δ ppm 7.40 - 7.32 (m, 4H), 7.32 - 7.20 (m, 6H), 7.1 1 (td, J= 8.2, 1 .4 Hz, 1 H), 6.41 (ddd, J= 8.4, 2.3, 1 .2 Hz, 1 H), 6.36 - 6.28 (m, 2H), 4.67 (s, 4H), 3.76 - 3.68 (m, 3H). ¹³ C NMR (CDCI ₃ ) δ ppm 160.73, 150.59, 138.50, 129.86, 128.60, 126.85, 126.61 , 105.61 , 101 .49, 99.07, 54.99, 54.20.

Compound 3ad, N-benzyl-2-chloroaniline:

Synthesized by a modified procedure. Benzyl amine (2.5 mmol), LiHMDS (1 .0M in THF, 2.5 mmol) and 2-chlorofluorobenzene (0.5 mmol) were mixed and heated. After 3 hours at 100°C the compound 3ad was isolated in 42% yield as a clear oil. ¹ H NMR (CDCI ₃ ) δ ppm 7.26 - 7.21 (m, 4H), 7.20 - 7.15 (m, 2H), 6.98 (td, J= 7.8, 1 .5 Hz, 1 H), 6.56 - 6.49 (m, 2H), 4.64 (d, J= 5.7 Hz, 1 H), 4.29 (d, J = 5.7 Hz, 2H). ¹³ C NMR (CDCI ₃ ) 6 ppm 143.82, 138.71 , 129.07, 128.68, 127.76, 127.31 , 127.23, 1 19.07, 1 17.38, 1 1 1 .47, 47.81 . Compound 3ae, N-benzyl-3,5-difluoroaniline:

Synthesized by a modified procedure. Benzyl amine (2.5 mmol), LiHMDS (1 .0M in THF, 2.5 mmol) and 1 ,3,5-trifluorobenzene (0.5 mmol) were mixed and heated. After 14 hours at 50°C the compound 3ae was isolated in 41 % yield as an yellow oil. ¹ H NMR (CDCI ₃ ) δ ppm 7.42 - 7.27 (m, 5H), 6.21 - 6.08 (m, 3H), 4.30 (s, 2H), 4.28 (s, 1 H). ¹³ C NMR (CDCI ₃ ) δ 164.16 (dd, J= 244.2, 16.0 Hz), 150.28 (t, J= 13.3 Hz), 138.23, 128.82, 127.61 , 127.42, 96.68 - 94.46 (m), 92.60 (t, J= 26.1 Hz), 48.08.

Compound 3af, 4-(4-methylpiperazin-1 -yl)benzothiophene-2-carboxylic acid:

Synthesized by a modified procedure. N-methyl-piperazine (0.2 mmol), 4-fluoro-1 - benzothiophene-2-carboxylic acid (0.1 mmol) and LiHMDS (1 .0 M in THF, 0.25 mmol) were mixed and heated. After 14 hours at 65°C the reaction was quenched by the addition of HCI (1 .0 M in H ₂ 0), the solvent evaporated and the compound redissolved in CH ₃ CN:H ₂ 0 (1 :1 ). The compound 3af was isolated as the HCI salt by

chromatography on C18 gel (0 to 50% CH ₃ CN in 0.01 M HCI) in 31 % yield as white solid.

¹ H NMR (500 MHz, DMSO-d6) δ 13.53 (s, 1 H), 10.74 (s, 1 H), 8.04 (s, 1 H), 7.73 (d, J = 8.2 Hz, 1 H), 7.46 (t, J = 7.9 Hz, 1 H), 7.05 (d, J= 7.6 Hz, 1 H), 3.60 - 3.48 (m, 4H), 3.42 - 3.31 (m, 2H), 3.24 - 3.12 (m, 2H), 2.86 (d, J= 4.7 Hz, 3H). ¹³ C NMR (126 MHz, DMSO) δ 163.4, 148.1 , 142.9, 133.7, 132.9, 128.0, 127.5, 1 18.0, 1 13.6, 52.7, 48.9, 42.1 .

Compound 3ag, 1 -methyl-6-(4-phenylpiperazin-1 -yl)-indole:

Synthesized by a modified procedure. 1 -Phenylpiperazine (0.2 mmol), 6-fluoro-1 - methyl-indole (0.1 mmol) and LiHMDS (1 .0 M in THF, 0.2 mmol) were mixed and heated. After 14 hours at 90°C in a sealed tube the reaction was quenched by the addition of HCI (1 .0 M in H ₂ 0), the solvent evaporated and the compound redissolved in CH ₃ CN:H ₂ 0 (1 :1 ). The compound 3ag was isolated as the HCI salt by

chromatography on C18 gel (0 to 50% CH ₃ CN in 0.01 M HCI) in 53% yield as white solid.

¹ H NMR (500 MHz, DMSO-d6) δ 8.07 (s, 1 H), 7.70 (d, J= 8.5 Hz, 1 H), 7.65 - 7.54 (m, 1 H), 7.51 (d, J= 3.1 Hz, 1 H), 7.40 - 7.24 (m, 3H), 7.18 - 7.07 (m, 2H), 6.98 - 6.90 (m, 1 H), 6.52 (d, J= 3.2 Hz, 1 H), 3.91 - 3.67 (m, 1 1 H). ¹³ C NMR (126 MHz, DMSO) δ 149.3, 135.8, 132.0, 129.2, 129.1 , 121 .3, 120.2, 1 16.3, 1 16.1 , 1 12.2, 103.0, 100.7, 54.5, 46.5, 32.7. Example 5

Compound 4, N-benzyl-3-fluoro-N-methyl-5-morpholinoaniline:

N-benzyl-3,5-difluoro-N-methylaniline (3o) (0.5 mmol), morpholine (1 .0 mmol) and LiHMDS (1 .OM in THF, 1 .0 mmol) were mixed and heated. After 24 hours at 100°C the compound 4 was isolated in 62% yield as a bright yellow oil. ¹ H NMR (CDCI ₃ ) δ ppm 7.37 - 7.29 (m, 2H), 7.29 - 7.19 (m, 3H), 6.06 - 5.97 (m, 3H), 4.52 (s, 2H), 3.85 - 3.78 (m, 4H), 3.13 - 3.07 (m, 4H), 3.02 (s, 3H). ¹³ C NMR (CDCI ₃ ) δ ppm 164.9 (d, J= 238.5 Hz), 153.4 (d, J= 12.5 Hz), 151 .6 (d, J= 13.2 Hz), 138.5, 128.6, 127.0, 126.6, 95.0 (d, J = 1 .7 Hz), 91 .8 (d, J= 18.1 Hz), 91 .6 (d, J= 17.3 Hz), 66.8, 56.5, 49.2, 38.7.

A two steps reaction applying first a weaker nucleophile followed by an amine nucleophile also proved viable (scheme 2). Applying imidazole as the weak azole nucleophile followed by addition of morpholine provided derivative 7, which is a substructure in metabotropic glutamate 5 receptor antagonists with nanomolar activity. Thiophenol also proved highly applicable in this approach, illustrated by the synthesis of recently marketed pharmaceutical antidepressant Vortioxetine 9 from 1 ,2- difluorobenzene. This should be compared to the present industrial production process, which utilizes two subsequent cross-coupling reactions on 2-bromo-iodobenzene.

140 °C 8 ₈₀ o _C 9 (Vortioxetine)

87% yield 53% yield

Scheme 2: Disubstitution on fluorobenzenes. DMA = dimethylacetamide.

Compound 6, 1-(3,5-difluorophenyl)-1 H-imidazole:

To a vial was added imidazole (1.0 mmol), 1 ,3,5-trifluorobenzene (2.0 mmol), Cs ₂ C0 ₃ (3.0 mmol) and dimethylacetamide (2.0 mL). The vial was sealed and stirred at 120 °C for 12 hours. The reaction was quenched with water and brine and then extracted into Et ₂ 0. After evaporation, the product 6 was purified by chromatography on silica gel (EtOAC), and isolated in 75% yield as a white solid. ¹ H NMR (CDCI ₃ ) δ ppm 7.90 (t, J = 1.1 Hz, 1H), 7.27 (t, J= 1.4 Hz, 1H), 7.23 (t, J= 1.2 Hz, 1H), 7.01 -6.93 (m, 2H), 6.83 (tt, J=8.7, 2.3 Hz, 1H). ¹³ C NMR (CDCI ₃ ) δ ppm 163.6 (dd, J= 250.7, 14.1 Hz), 139.2 (t, J= 12.2 Hz), 135.3, 130.99, 117.8, 105.5-104.1 (m), 102.9 (t, J=25.3 Hz).

Compound 7, 4-(3-fluoro-5-(1H-imidazol-1-yl)phenyl)morpholine:

Morpholine (0.5 mmol), 1 -(3, 5-difluorophenyl)-1 H-imidazole (6) (0.6 mmol) and

□HMDS (1.0M in THF, 1.2 mmol) were mixed and heated. After 2 hours at 80°C the compound 7 was isolated by flash chromatography (5% EtOH in EtOAc) in 71% yield as a yellowish solid. ¹ H NMR (CDCI ₃ ) δ ppm 7.82 (t, J= 1.2 Hz, 1 H), 7.23 (t, J= 1.4 Hz, 1H), 7.18 (d, J= 1.2 Hz, 1H), 6.63 (d, J=2.2 Hz, 1H), 6.60-6.51 (m, 2H), 3.91 -3.81 (m, 4H), 3.26-3.15 (m, 4H). ¹³ C NMR (CDCI ₃ ) δ ppm 164.2 (d, J= 245.0 Hz), 153.5 (d, J = 11.4 Hz), 139.2 (d, J= 13.0 Hz), 135.6, 130.5, 118.3, 103.7 (d, J= 2.5 Hz), 100.8 (d, J= 25.4 Hz), 99.9 (d, J= 25.6 Hz), 66.5, 48.3. Compound 8, 2-(2,4-di-methyl-thiophenol-yl)-fluorobenzene:

To a vial was added 2,4-dimethylthiophenol (1 .0 mmol), 1 ,2-difluorobenzene (2.0 mmol), Cs ₂ C0 ₃ (2.5 mmol) and dimethylacetamide (2.0 ml_). The vial was sealed and stirred at 140 °C for 4 hours. The reaction was quenched with water and brine and then extracted into Et ₂ 0. After evaporation, the product 8 was purified by VLC on silica gel, and isolated in 87% yield as a clear oil. ¹ H NMR (CDCI ₃ ) δ ppm 7.28 (d, J= 7.8 Hz, 1 H), 7.19 - 7.09 (m, 2H), 7.09 - 7.03 (m, 1 H), 7.02 - 6.95 (m, 2H), 6.87 (td, J= 7.7, 1 .7 Hz, 1 H), 2.37 (s, 3H), 2.34 (s, 3H). ¹³ C NMR (CDCI ₃ ) δ ppm 160.0 (d, J= 245.2 Hz), 141 .0, 138.9, 134.4, 131 .7, 130.2 (d, J= 1 .9 Hz), 127.7, 127.6, 127.5 (d, J= 7.5 Hz), 124.6 (d, J = 3.5 Hz), 124.4, 1 15.5 (d, J = 21 .8 Hz), 21 .1 , 20.5.

Compound 9, 1 -[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]piperazine:

Piperazine (1 .25 mmol), 2-(2,4-di-methyl-thiophenol-yl)-fluorobenzene (8) (0.25 mmol) and LiHMDS (1 .0 M in THF, 1 .0 mmol) were mixed and heated in a sealed vial. After 2 hours at 80°C the reaction was quenched by the addition of HCI (0.01 M in H ₂ 0), the solvent evaporated and the compound redissolved in CH ₃ CN:H ₂ 0 (1 :1 ). The compound 9 was isolated as the HCI salt by VLC on C18 gel (0 to 50% CH ₃ CN in 0.01 M HCI) in 53% yield as white solid. ¹ H NMR (DMSO-d ₆ ) δ ppm 9.41 (s, 2H), 7.33 (d, J = 7.8 Hz, 1 H), 7.24 (d, J = 1 .9 Hz, 1 H), 7.16 - 7.07 (m, 3H), 6.96 (ddd, J = 7.9, 5.9, 2.7 Hz, 1 H), 6.44 - 6.39 (m, 1 H), 3.21 (s, 8H), 2.32 (s, 3H), 2.24 (s, 3H). ¹³ C NMR (DMSO-d ₆ ) δ 147.8, 141 .6, 139.3, 135.7, 133.3, 131 .7, 128.1 , 126.8, 126.0, 125.8, 125.1 , 120.2, 48.1 , 43.3, 20.7, 20.1 .

The invention provides a novel method for the amination of unactivated fluorobenzene derivatives. A key factor for reactivity is the applied base's ability to sufficiently deprotonate the amine nucleophile under the applied reaction conditions without simultaneously degrading the fluorobenzene electrophile. For secondary aliphatic amines the reactions proceed readily by addition of a simple base such as LiHMDS, and thus circumvent the need for transition metals. The reactions proceed with great regio- and chemoselectivity and are compatible with a broad range of additional substituents including alkyl, aryl, alkoxy, amine, azolyl, thioethers, fluorine and chlorine. The versatility of these new reactions was illustrated by the synthesis of a variety of anilinesincluding the antidepressant Vortioxetine. References Hansch et al. Chem. Rev. 1991 , 91 , 165-195

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Jacobsen, C. B.; Meldal, M.; Diness, F.Chemistry - A European Journal, 2016, accepted, DOI: 10.1002/chem.201604098