ALKALINE-EARTH-METAL SALT

Technical Field

[0001] The present invention relates to a method for performing Claisen

rearrangement reaction of allyl aryl ethers in the presence of at least one alkaline-earth-metal salt catalyst, and further to a method for performing such reaction to give rise in the para somer product selectivity.

Background Art

[0002] The Claisen rearrangement, the first recorded example of [3,3]-sigmatropic rearrangement, is a powerful tool for selective formation of new carbon- carbon bonds. Since its discovery in 1912, many efforts have been made to accelerate this thermal reaction by catalysts. However, the catalytic effects on the rearrangement are usually not great. Moreover, most reported methods predominantly generated the ortf?o- somer product and rarely gave a fair selectivity in the para somer product (normally 20% yield or lower), while the latter is generally considered more valuable in industrial application.

[0003] In 1991 , H. TAKATOSHI, et al. Studies on the Claisen Rearrangement.

Part 7. J. Chem. Research (S). 1991 , p.172-173.compared the catalytic effect of certain alkaline-earth-metal salts on the Claisen rearrangement of various allyl aryl ethers. In their study, a group of alkaline-earth-metal acetate and chloride salts were tested and only some of them showed detectable catalytic effect in ( -allyloxyphenol rearrangement. For other allyl aryl ethers used (including ( -allyloxyltoluene, ( -allyloxyanisole and p- allyloxyphenol), none of these alkaline-earth-metal salts were effective in accelerating their Claisen rearrangement.

[0004] In 2000, G.V.M.SHARMA, et al. Alternative Lewis Acids to Effect Claisen Rearrangement. Synlett. 2000, no.5, p.615-618. selected lanthanide triflate as an alternative catalyst to effect Claisen rearrangement of several allyl aryl ethers. While the lanthanide triflate catalyst helped provide a satisfactory product yield for the tested allyl aryl ethers, the reaction was necessarily carried out in an organic solvent medium (CH3CN), and notably needed prolonged reaction times (40-72 hours). Years later, B. SREEDHAR, et al. Bismuth (III) Triflate: Novel and Efficient Catalyst for Claisen and Fries Rearrangements of Allyl Ethers and Phenyl Esters.

Synthetic Communications. 2004, vol.34, no.8, p.1433-1440. examined the effect of bismuth triflate catalyst on the Claisen rearrangement of allyl phenyl ethers, and found that efficient rearrangement only took place in the acetonitrile solvent at reflux temperature, and other solvents such as methanol or benzene caused sluggish reaction. The dependence on this particular volatile organic solvent in a Claisen rearrangement reaction is problematic, as this reaction normally requires a high reaction temperature of 200°C or higher and could easily poses an environmental risk with the use of volatile organic solvents.

[0005] Instead of using organic solvents, F.ZULFIQAR, et al. Lewis acid- catalysed sequential reaction in ionic liquids. Green Chemistry. 2000, vol.2, p.296-297.reportedClaisen rearrangement of allyl phenyl ether using a catalytic system combining an ionic liquid and an anhydrous scandium trifluoromethanesulfonate salt. Similarly, Y.-L. LIN, et al. Microwave- accelerated Claisen rearrangement in bicyclic imidazolium [b-3C-im][NTf2] ionic liquid. Tetrahedron. 2007, vol.63, p.10949-10957.employed a magnesium chloride salt in a bicyclic imidazolium-based ionic liquid, [b-3C- im][NTf2], to carry out Claisen rearrangement of several allyl aryl ethers. The optimal para: ortho selectivity reported in Y.-L. LIN's study is 1 :2.4, slightly higher than the average parase\ec \\ achieved by the earlier Claisen rearrangement methods.

[0006] Although the use of ionic liquids may possess certain advantages

compared to standard organic solvents, their post-reaction recycling often remains burdensome.

[0007] P. WIPF, et al. Water-accelerated Claisen Rearrangement.

Adv.Synth.Catal.. 2002, vol.344, no.3+4, p.434-440. introduced an alternative combination of catalytic system for Claisen rearrangement, which used a mixture of water and Μβ3ΑΙ to give a detectable increase for para-C\a\sen derivatives in the product, reaching an optimal para: ortho selectivity of 1 :1.7. However, this parase\ec.wAy improvement was only realized in extremely low-temperature reaction systems (-78°C or -20°C), while bringing the reaction to room temperature jeopardized the para- selectivity and greatly prolonged the reaction time.

[0008] Accordingly, there is a need in the art for a catalytic Claisen

rearrangement reaction that proceeds quickly, does not rely on freezing equipment or any additional solvent, and can be used to give rise in para- isomer product selectivity.

Summary of invention

[0009] It is therefore a primary object of the invention to provide a novel Claisen rearrangement reaction that addresses the above-mentioned need in the art.

[0010] Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.

[001 1] In one embodiment, then, the present invention provides a process for carrying out a Claisen rearrangement reaction, comprising reacting an allyl aryl ether in the presence of a metal salt catalyst, wherein the metal salt catalyst is an alkaline-earth-metal triflate salt or an alkaline-earth-metal triflimide salt, wherein the alkaline-earth-metal is selected from a group consisting of magnesium (Mg), calcium (Ca), strontium (Sr), and barium (Ba).

[0012] The term "triflate salt" as used herein, and according to conventional

practice, refers to a salt containing at least one triflate anion of formula

CF3SO3-.

[0013] Specifically, the alkaline-earth-metal triflate salt used in the present

process may be represented by the formula M(OSO2CF3)2, wherein M represents an alkaline-earth-metal selected from the group consisting of Mg, Ca, Sr and Ba, and is preferably Ca or Ba. [0014] The term "triflimide salt" as used herein, and according to conventional practice, refers to a salt containing at least one triflimide anion of formula [(CF ₃ SO ₂ ) ₂ N]-.

[0015] Specifically, the alkaline-earth-metal triflimide salt used in the present process may be represented by the formula M[(CF3SO2)2N]2, wherein the definition of M is the same as above.

[0016] Optionally, the alkaline-earth-metal triflimide salt used in the present

process may have a ligand, such as a ligand selected from the group consisting of oxos, phosphines (e.g. triphenylphosphine), water, halides and pyridines.

[0017] The term "allyl aryl ether", as used herein, refers to an aromatic compound having at least one allyl group (i.e. -CH2-CH=CH2) attached to an aromatic ring via an oxygen atom, wherein the aromatic ring can optionally be fused or otherwise attached to other aromatic rings or aliphatic groups.

Examples of said aromatic ring include an aromatic hydrocarbon ring such as a benzene ring, a biphenyl ring, a naphthalene ring, a fluorene ring, an anthracene ring and a phenanthrene ring, and a heteroaromatic ring such as a thiophene ring, a pyrrole ring, a pyridine ring, a pyrimidine ring, a quinoline ring, an isoquinoline ring and a quinoxaline ring.

[0018] Preferably, the allyl aryl ether reactant in the invented process is selected from compounds of formula (I), as below.

(I)

wherein m is an integer between 1 and 5, preferably 1 , and each R is independently selected from the group consisting of hydrido, halo, hydroxyl, sulfhydryl, amino, substituted amino, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl.

[0019] In particularly preferred embodiment of the invention, the allyl aryl ether reactant is selected from the compounds of formula (II), as below.

(II)

wherein R' is selected from the group consisting of alkoxyl, alkyl, hydroxyl, and halogen, and is preferably selected from the group consisting of C1- C6 alkoxyl and C1-C6 alkyl.

[0020] Examples of particularly preferred allyl aryl ether reactants include, but are not limited to O-allyloxyanisole and 1-(allyloxy)-2-ethoxybenzene.

[0021] As used herein, the term "hydrido" denotes a single hydrogen atom. The terms "halo" and "halogen" are used in the conventional sense to refer to a chloro, bromo, fluoro or iodo substituent.

[0022] The term "hydroxyl" is used herein to refer to the group -OH, and the term "sulfhydryl" is used herein to refer to the -SH group.

[0023] The term "amino" is used herein to refer to the -NH2 group, while

"substituted amino" refers to— NZ ¹ Z ² groups, where each of Z ¹ and Z ² is independently selected from the group consisting of optionally substituted hydrocarbyl and heteroatom-containing hydrocarbyl, or wherein Z ¹ and Z ² are linked to form an optionally substituted hydrocarbylene or heteroatom- containing hydrocarbylene bridge.

[0024] The term "hydrocarbyl" refers to univalent hydrocarbyl radicals containing 1 to about 30 carbon atoms, preferably 1 to about 24 carbon atoms, most preferably 1 to about 12 carbon atoms, including branched or unbranched, saturated or unsaturated species, such as alkyl groups, alkenyl groups, aryl groups, and the like. The term "lower hydrocarbyl" intends a

hydrocarbyl group of one to six carbon atoms, preferably one to four carbon atoms. The term "hydrocarbylene" intends a divalent hydrocarbyl moiety containing 1 to about 30 carbon atoms, preferably 1 to about 24 carbon atoms, most preferably 1 to about 12 carbon atoms, including branched or unbranched, saturated or unsaturated species, or the like. The term "lower hydrocarbylene" intends a hydrocarbylene group of one to six carbon atoms, preferably one to four carbon atoms. "Substituted hydrocarbyl" refers to hydrocarbyl substituted with one or more substituent groups, and the terms "heteroatom-containing hydrocarbyl" and

"heterohydrocarbyl" refer to hydrocarbyl in which at least one carbon atom is replaced with a heteroatom. Similarly, "substituted hydrocarbylene" refers to hydrocarbylene substituted with one or more substituent groups, and the terms "heteroatom-containing hydrocarbylene" and

"heterohydrocarbylene" refer to hydrocarbylene in which at least one carbon atom is replaced with a heteroatom.

[0025] The term "alkyl" as used herein refers to a branched or unbranched

saturated hydrocarbon group typically containing 1 to about 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and the like, as well as cycloalkyl groups such as cyclopentyl, cyclohexyl and the like. The term "lower alkyl" intends an alkyl group of one to six carbon atoms, preferably one to four carbon atoms. "Substituted alkyl" refers to alkyl substituted with one or more substituent groups, and the terms "heteroatom-containing alkyl" and "heteroalkyl" refer to alkyl in which at least one carbon atom is replaced with a heteroatom.

[0026] The term "alkenyl" as used herein refers to a branched or unbranched hydrocarbon group typically containing 2 to about 24 carbon atoms and at least one double bond, such as ethenyl, n-propenyl, isopropenyl, s- propenyl, 2-propenyl, n-butenyl, isobutenyl, octenyl, decenyl, and the like. The term "lower alkenyl" intends an alkenyl group of two to six carbon atoms, preferably two to four carbon atoms. "Substituted alkenyl" refers to alkenyl substituted with one or more substituent groups, and the terms "heteroatom-containing alkenyl" and "heteroalkenyl" refer to alkenyl in which at least one carbon atom is replaced with a heteroatom.

[0027] The term "aryl" as used herein, and unless otherwise specified, refers to an aromatic substituent containing a single aromatic ring or multiple aromatic rings that are fused together, linked covalently, or linked to a common group such as a methylene or ethylene moiety. The common linking group may also be a carbonyl as in benzophenone, an oxygen atom as in diphenylether, or a nitrogen atom as in diphenylamine.

Preferred aryl groups contain one aromatic ring or two fused or linked aromatic rings, e.g., phenyl, naphthyl, biphenyl, diphenylamine, benzophenone, and the like. In particular embodiments, aryl substituents have 1 to about 200 carbon atoms, typically 1 to about 50 carbon atoms, and preferably 1 to about 20 carbon atoms. "Substituted aryl" refers to an aryl moiety substituted with one or more substituent groups, and the terms "heteroatom-containing aryl" and "heteroaryl" refer to aryl in which at least one carbon atom is replaced with a heteroatom.

[0028] By "substituted" as in "substituted hydrocarbyl," "substituted

hydrocarbylene," "substituted alkyl," "substituted alkenyl" and the like, as alluded to in some of the aforementioned definitions, is meant that in the hydrocarbyl, hydrocarbylene, alkyl, alkenyl or other moiety, at least one hydrogen atom bound to a carbon atom is replaced with one or more substituents that are functional groups such as hydroxyl, alkoxy, thio, amino, halo, silyl, and the like. When the term "substituted" appears prior to a list of possible substituted groups, it is intended that the term apply to every member of that group. That is, the phrase "substituted alkyl, alkenyl and alkynyl" is to be interpreted as "substituted alkyl, substituted alkenyl and substituted alkynyl." Similarly, "optionally substituted alkyl, alkenyl and alkynyl" is to be interpreted as "optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl."

[0029] Particularly preferred examples of the metal salt catalyst used in the

invented process include, but not limited to, Ca(OSO2CF3)2,

Ba(OSO ₂ CF3)2,Ca[N(SO2CF3) ₂ ]2 and Ba[N(SO ₂ CF ₃ ) ₂ ]2.

[0030] The amount of the metal salt catalyst used in the reaction of the invented process is generally in the range of 0.1 mole % to 50 mole %, preferably 0.2 mole % to 10 mole %, and more preferably 0.5 mole % to 5

mole %, relative to the allyl aryl ether reactant.

[0031] The Claisen rearrangement reaction of the invented process may be

carried out in batch, semi-continuously or continuously; under inert, nonaqueous conditions; and may be run at atmospheric pressure or in a closed reactor under autogenous pressure.

[0032] The reaction temperature for the Claisen rearrangement reaction is

generally in the range of about -100°C to 300°C, preferably in the range of about 0°C to 250°C, more preferably in the range of about 100°C to 250°C. [0033] Advantageously, the process of the present invention may be carried out in the substantial absence of an additional solvent, which hereby means that no more than 10% by weight, based on the amount of the allyl aryl ether reactant, of materials which act as solvents/diluents and inert to the starting materials, catalyst and end products are present during the process. Suitably not more than 5% by weight, and preferably not more than 2% by weight, of additional solvent, based on the allyl aryl ether reactant, is used in the process.

[0034] If used, the additional solvent may be selected from the group consisting of water, polar organic solvents, dipolar aprotic organic solvents and ionic liquids.

[0035] Further advantageously, the process of the present invention may be

carried out in the complete absence of additional solvent, to avoid the negative environmental impact and the increased cost associated with the use of solvents (e.g. for separation of solvents from product and solvent disposal).

[0036] In one operation mode of carrying out the invented process, the allyl aryl ether reactant and the metal salt catalyst are placed in a reactor and then heated to a temperature in the range specified above.

[0037] Reaction time of the Claisen rearrangement reaction in the invented

process can vary considerably, depending on the specific reactant, reaction temperature and reaction pressure used. Preferred reaction time is between 10 seconds to 2 hours, and more preferably 30 seconds to 10 minutes, but longer reaction time is also possible.

[0038] Upon completion of reaction, the reaction mass is cooled, and the product is recovered using conventional separation means know in the art, e.g. by extraction, recrystallization, filtration, or other purification processes.

Conversion of the allyl aryl ether reactant can be readily determined using conventional analytic means such as ¹ H NMR spectrum.

[0039] Advantageously, the invented process is useful in conjunction with a

variety of allyl aryl ether reactants and, importantly, can be effectively carried out and give rise in para somer selectivity.

Description of embodiments [0040] The following examples are provided to illustrate preferred embodiments of the invention and are not intended to restrict the scope thereof. Other aspects, advantages and modifications within the scope of the invention will be apparent to those skilled in the art to which the invention pertains.

Examples

[0041] Example 1

To a 5ml_ Biotage® microwave vial fitted with a magnetic stirrer, was charged with calcium bis-triflimide (16 mg, 26.7 μιτιοΙ) and O-allylguaiacol (438 mg, 2.67 mmol). The vial was then sealed and the resultant homogeneous mixture was stirred for 2 minutes at the temperature of 200°C, under an autogenous pressure and a microwave irradiation generated by the Biotage® microwave instrument. After cooling to room temperature, the resulting reaction mixture was analysed by ¹ H NMR to determine the conversion ratio (100%) and isomeric composition (76% of ortho- eugenol and 24% of para- eugenol).

[0042] Example 2

To a 5ml_ Biotage® microwave vial fitted with a magnetic stirrer, was charged with calcium triflate (9 mg, 26.7 μιτιοΙ) and O-allylguaiacol (438 mg, 2.67 mmol). The vial was then sealed and the resultant homogenous mixture was stirred for 2 minutes at the temperature of 200°C, under an autogenous pressure and a microwave irradiation generated by the Biotage® microwave instrument. After cooling to room temperature, the resulting reaction mixture was analysed by ¹ H NMR to determine the conversion ratio (100%) and isomeric composition (76% of ortho- eugenol and 24% of para- eugenol).