# Patent

## Title
Process for preparing aryl- and heteroarylacetic acid derivatives

## Abstract

The invention relates to a process for preparing aryl- and heteroarylacetic acids and derivatives thereof by reaction of aryl or heteroaryl halides with malonic diesters in the presence of a palladium catalyst, of one or more bases and optionally of a phase transfer catalyst. This process enables the preparation of a multitude of functionalized aryl- and heteroarylacetic acids and derivatives thereof, especially also the preparation of arylacetic acids with sterically demanding substituents.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a §371 National Stage Application of PCT/EP2012/053233, filed Feb. 27, 2012, which claims priority to European Application No. 11156559.4, filed Mar. 2, 2011, and U.S. Provisional Application No. 61/448,379, filed Mar. 2, 2011.


BACKGROUND OF THE INVENTION
Field of the Invention
The invention relates to a process for preparing aryl- and heteroarylacetic acids and derivatives thereof by reaction of aryl or heteroaryl halides with malonic diesters in the presence of a palladium catalyst, of one or more bases and optionally of a phase transfer catalyst. This process enables the preparation of a multitude of functionalized aryl- and heteroarylacetic acids and derivatives thereof, especially also the preparation of arylacetic acids with sterically demanding substituents.
Typically, phenylacetic acid derivatives are prepared in multistage syntheses, most of which have low group tolerance. The preparation can be effected, for example, proceeding from acetophenones by a Willgerodt-Kindler reaction (see, for example, H. E. Zaugg et al., J. Amer. Chem. Soc. 70 (1948) 3224-8). In this method, however, large amounts of sulphur-containing wastes arise. Moreover, volatile sulphur compounds with a high level of odour nuisance can occur.
A further method for preparing arylacetic acids proceeds from benzyl bromides or chlorides. Sodium cyanide, for example, is used to prepare the corresponding nitriles therefrom, and these are subsequently hydrolysed. The benzyl bromides or chlorides required can be obtained, for example, by bromo- or chloromethylation of the corresponding aromatics. However, a disadvantage here is that the occurrence of highly carcinogenic compounds such as bis(chloromethyl)ether or bis(bromomethyl)ether cannot be ruled out, and so a high degree of safety measures has to be implemented in industry. Moreover, the halomethylation of substituted aromatics in many cases leads to isomer mixtures.
The carbonylation of benzyl halides in the presence of alcohols likewise gives phenylacetic esters. The already mentioned limited availability of benzyl halides and the need to use toxic CO gas, in some cases even under elevated pressure, are further disadvantages of this process.
There has also already been a disclosure of ketalizing α-chloroacetophenones and then subjecting the ketals to a rearrangement reaction (C. Giordano et al., Angew. Chem. 96 (1984) 413-9). The α-chloroacetophenones are obtained either by chlorination of acetophenones or directly by a Friedel-Crafts acylation of the aromatic in question with chloroacetyl chloride. This again gives rise to the disadvantage that the Friedel-Crafts acylations of substituted aromatics frequently proceed unselectively.
A further known method for preparing phenylacetic acids consists in diazotizing a corresponding aniline in the first step, reacting the resulting diazonium compound with vinylidene chloride in the second step, and then reacting the trichloro- or bromodichloroethyl compound thus obtained with water or alcohols in the third step to give the arylacetic acid or esters thereof (see, for example, V. M. Naidan and A. V. Dombrovskii, Zhumal Obshchei Khimii 34 (1984) 1469-73; EP-A-835243). This reaction, however, generally affords good yields only with those anilines which bear electron-withdrawing radicals on the aromatic and in which the amino group is not sterically blocked.
Additionally known is the reaction of bromobenzenes with chloroacetic acid derivatives in the presence of stoichiometric amounts of silver or copper at 180-200° C. Disadvantages of this process are the high temperature, which rules out use in the case of thermally sensitive compounds, the low yield and the use of stoichiometric amounts of metals which are costly and difficult to work up.
The reaction of aryl-Grignard compounds with α-haloacetic acid derivatives likewise leads to phenylacetic acid derivatives. A disadvantage, however, is the extremely limited tolerance of functional groups, which results from the use of highly reactive Grignard compounds which are difficult to handle.
Alternatives to the processes mentioned which have also been described are cross-couplings of aryl halides with Reformatsky reagents, tin enolates, copper enolates and other enolates, or ketene acetals (see, for example, J. Am. Chem. Soc. 1959, 81, 1627-1630; J. Organomet. Chem. 1979, 177, 273-281; Synth. Comm. 1987, 17, 1389-1402; Bull. Chem. Soc. Jpn. 1985, 58, 3383-3384; J. Org. Chem. 1993, 58, 7606-7607; J. Chem. Soc. Perkin 1 1993, 2433-2440; J. Am. Chem. Soc. 1975, 97, 2507-2517; J. Am. Chem. Soc. 1977, 99, 4833-4835; J. Am. Chem. Soc. 1999, 121, 1473-78; J. Org. Chem. 1991, 56, 261-263, Heterocycles 1993, 36, 2509-2512, Tetrahedron Lett. 1998, 39, 8807-8810). However, the applicability of these processes is limited. For instance, Reformatsky reagents and ketene acetals are difficult to prepare and handle. The use of tin compounds is disadvantageous for toxicological reasons, and the use of stoichiometric amounts of copper causes considerable costs in disposal. The use of enolates is generally possible only when no further enolizable groups are present in the molecule. For example, ketones are therefore ruled out as substrates for such processes. Some electrochemical processes are likewise known (Synthesis 1990, 369-381; J. Org. Chem. 1996, 61, 1748-1755), but these processes are disadvantageous due to the complex reaction regime and the low space-time yields.
Likewise already known is a method for preparing phenylacetic acid derivatives by a palladium-catalysed coupling reaction between arylboronic acids and ethyl bromoacetate (Chem. Commun. 2001, 660-70; DE-A-10111262). However, this process requires the preparation of the boronic acids, typically from the corresponding aryl or heteroaryl halides. Moreover, it has not been possible to date to use this preparation of sterically demanding, for example 2,6-disubstituted, phenylacetic acid derivatives. Chem. Commun. 2001, 660-70 states that sterically hindered arylboronic acids can also be converted efficiently under the conditions described therein. However, the examples contain only 2-tolylboronic acid as a sterically hindered substrate. Arylboronic acids with greater steric hindrance, for example 2,6-dialkylphenylboronic acids, are not described.
A further known method is that of the palladium- or copper-catalysed coupling reaction of aryl halides with malonic esters or β-keto esters, followed by a thermally induced dealkoxycarbonylation or retro-Claisen condensation. This involved reacting aryl iodides and activated aryl bromides with diethyl malonate in the presence of a palladium catalyst and 10 equivalents of very expensive caesium carbonate, and reaction times of up to 76 hours were needed (Chem. Commun. 2001, 2704-2705). Higher yields with shorter reaction times are possible, but these require the use of very specific N-heterocyclic carbene ligands which can be prepared only with difficulty; in addition, the expensive caesium carbonate is used here too (Tetrahedron Lett. 2004, 45, 5823-5825). The palladium- or copper-catalysed arylation of acetoacetic esters, followed by an in situ deacetylation, ultimately only has a narrow range of application; moreover, the deacetylation is frequently incomplete, which results in unsatisfactory yields of arylacetic esters (Tetrahedron Lett. 2004, 45, 4261-4264; Tetrahedron Lett. 2007, 48, 3289-3293).
All methods which have become known to date for preparing phenylacetic acid derivatives, more particularly also those with sterically demanding substitution, accordingly have shortcomings and disadvantages, some of them considerable, which complicate the use thereof. Since phenylacetic acids in general, and among them specifically also those with sterically demanding substitution, are important precursors, for example for active ingredients in crop protection, there is a need for a technically simple and highly efficient method for preparing such compounds.
Surprisingly, a process for preparing aryl- and heteroarylacetic acids and derivatives thereof from aryl and heteroaryl halides and malonic esters has now been found, which is characterized in that the reaction is performed in the presence of a palladium catalyst, a phosphine, and

    
    
        A) an inorganic base and a phase transfer catalyst
        or
        B) a mixture of inorganic bases,

the coupling reaction being followed by a dealkoxycarbonylation in situ.

    
    


The discovery in process step A) that the addition of a phase transfer catalyst positively influences the selectivity of the reaction was unforeseeable and makes the discovery of this process particularly surprising. The use of the phase transfer catalyst makes it possible for the first time to shift selectivity and yield significantly in favour of the desired product. This makes the process much more economically viable than the processes known according to the prior art.
The discovery in process step B) that the use of a mixture of inorganic bases positively influences the conversion was unforeseeable and makes the discovery of this process particularly surprising. The use of a mixture of inorganic bases makes it possible for the first time to obtain the desired products in high selectivity and yield. This makes the process much more economically viable than the processes known according to the prior art.
The process according to the invention for preparing aryl- and heteroarylcarbonyl compounds is characterized in that aryl- or heteroaryl halides of the formula (I)

Ar—Hal  (I)

in which

    
    
        Hal is chlorine, bromine or iodine and
        Ar is the
    
    






group,

where

    
    
        R1, R2, R3, R4 and R5 are the same or different and are each independently hydrogen, amino, cyano, nitro, halogen, optionally halogen-substituted C1-C6-alkyl, C1-C6-thioalkyl, thiophenyl, C1-C6-alkoxy, C6-C10-aryloxy, phenyl, —CO—C6-C10-aryl, —CO—C1-C3-alkyl, —COO—C1-C6-alkyl or —COO—C6-C10-aryl,
        the Ar radical may additionally also be a heteroaromatic radical such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-thienyl or 3-thienyl or
        the Ar radical may also be 1- or 2-naphthyl,

are reacted with malonic esters of the formula (II)

    
    






in which

    
    
        R6 and R7 are each independently optionally substituted C1-C8-alkyl, phenyl, aryl, or NR8R9,
        where R8 and R9 are the same or different and are each independently C1-C4-alkyl, or phenyl optionally substituted by optionally fluorine- or chlorine-substituted C1-C3-alkyl, by nitro, cyano or di-C1-C3-alkylamino, or together with the nitrogen atom to which they are bonded are a saturated or unsaturated, substituted or unsubstituted cycle,

in the presence of a palladium catalyst, of a phosphine ligand and

        A) of an inorganic base and of a phase transfer catalyst
        or
        B) a mixture of inorganic bases,

optionally using an organic solvent

to give α-arylmethylcarbonyl compounds of the formula (III)

    
    






in which Ar and the R6 and R7 radicals are each as defined above.

This forms 2-arylmalonic diesters of the formula (IV) as intermediates, but they are not isolated.
This reaction is accordingly illustrated by the following reaction equation:




Preferred substituents or ranges of the radicals given in the formulae mentioned above and below are illustrated hereinafter:

    
    
        Ar is preferably 1- or 2-naphthyl, 3-thienyl or the
    
    






group, where

    
    
        R1, R2, R3, R4 and R5 are the same or different and are preferably each independently hydrogen, amino, cyano, nitro, fluorine, optionally fluorine-substituted C1-C4-alkyl, C1-C4-thioalkyl, thiophenyl, C1-C4 alkoxy, C6-C10-aryloxy, phenyl, —CO—C6-C8-aryl, —CO—C1-C3-alkyl, —COO—C1-C4-alkyl or —COO—C6-C8-aryl,
        Hal is preferably chlorine, bromine or iodine,
        R6 and R7 are the same or different and are preferably each independently C1-C4-alkyl.
        Ar is more preferably 1- or 2-naphthyl, 3-thienyl or the
    
    






group, where

    
    
        R1, R2, R3, R4 and R5 are the same or different and are more preferably each independently hydrogen, amino, cyano, nitro, fluorine, methyl, methylthio, ethyl, i-propyl, n-propyl, CF3, C2F5, C3F7, methoxy, ethoxy, phenyl, —CO-phenyl, —CO-methyl, —CO-ethyl, —COO-methyl, —COO-ethyl or —COO-phenyl,
        Hal is more preferably chlorine, bromine or iodine,
        R6 and R7 are more preferably each independently methyl or ethyl, with emphasis for ethyl.
        Ar is most preferably 1-naphthyl, 2-naphthyl, phenyl, 4-N,N-dimethylaminophenyl, 4-methylthiophenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 2-ethylphenyl, 4-ethoxycarbonylphenyl, 3-thienyl.
        Ar is also most preferably 2,6-dimethylphenyl, 2,4,6-trimethylphenyl, 4-cyanophenyl, 4-cyano-2-methylphenyl, 3-cyanophenyl, 4-ethoxycarbonylphenyl, 4-trifluoromethylphenyl, 4-acetylphenyl, 4-nitrophenyl, 4-benzoylphenyl.
    
    


The abovementioned general or preferred radical definitions or illustrations can be combined with one another as desired, i.e. including combinations between the respective ranges and preferred ranges. They apply both to the end products and correspondingly to the intermediates.
The aryl halides of the formula (I) are known in principle or can be prepared by known methods.
The compounds of the formula (II) are known in principle or can be prepared by known methods.
The bases used in process step A) of the invention are inorganic bases such as alkali metal or alkaline earth metal hydroxides, carbonates, bicarbonates, oxides, phosphates, hydrogenphosphates, fluorides or hydrogenfluorides. Preference is given to using alkali metal and alkaline earth metal phosphates, carbonates or fluorides, and particular preference to using sodium phosphate and potassium phosphate. Emphasis is given to potassium phosphate.
The bases used in process step B) of the invention are mixtures of inorganic bases such as alkali metal or alkaline earth metal hydroxides, carbonates, bicarbonates, oxides, phosphates, hydrogenphosphates, fluorides or hydrogenfluorides, for example lithium hydroxide, sodium hydroxide, potassium hydroxide, caesium hydroxide, magnesium hydroxide, rubidium hydroxide, calcium hydroxide or barium hydroxide, lithium oxide, sodium oxide, potassium oxide, caesium oxide, magnesium oxide, rubidium oxide, calcium oxide or barium oxide, lithium phosphate, sodium phosphate, potassium phosphate, caesium phosphate, magnesium phosphate, rubidium phosphate, calcium phosphate or barium phosphate, lithium hydrogenphosphate, sodium hydrogenphosphate, potassium hydrogenphosphate, caesium hydrogenphosphate, magnesium hydrogenphosphate, rubidium hydrogenphosphate, calcium hydrogenphosphate or barium hydrogenphosphate, lithium fluoride, sodium fluoride, potassium fluoride, caesium fluoride, magnesium fluoride, rubidium fluoride, calcium fluoride or barium fluoride, lithium hydrogenfluoride, sodium hydrogenfluoride, potassium hydrogenfluoride, caesium hydrogenfluoride, magnesium hydrogenfluoride, rubidium hydrogenfluoride, calcium hydrogenfluoride or barium hydrogenfluoride, and lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, rubidium carbonate, calcium carbonate or barium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, rubidium bicarbonate, calcium bicarbonate or barium bicarbonate. Preference is given to using mixtures of alkali metal and alkaline earth metal phosphates, carbonates or bicarbonates, and particular preference to using mixtures of sodium carbonates and potassium carbonates and sodium bicarbonates and potassium bicarbonates. Emphasis is given to the mixture of potassium carbonate and potassium bicarbonate. The mixtures of the inorganic bases may contain different molar ratios of the individual bases. In general, molar ratios between 0.1 and 10 are used. Preference is given to working with molar ratios of 0.5 to 5.
In the process according to the invention, 1 to 10 equivalents of the respective base are used. Preference is given to using 1.2-5 equivalents of the base.
The palladium catalysts used in the process according to the invention are palladium(II) salts, for instance palladium chloride, bromide, iodide, acetate or acetylacetonate, which may optionally be stabilized by further ligands, for example alkyl nitriles, or Pd(0) species such as palladium on activated carbon, Pd(PPh3)4, bis(dibenzylideneacetone)palladium or tris(dibenzylideneacetone)dipalladium. Preference is given to bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)dipalladium, palladium chloride, palladium bromide and palladium acetate; emphasis is given to bis(dibenzylideneacetone)palladium and palladium acetate.
The amount of palladium catalyst used in the process according to the invention is 0.001 to 5 mole percent, based on aryl halide used. Preferably, 0.005 to 3 mole percent is used, more preferably 0.01 to 1 mole percent.
The phosphine ligands used in the process according to the invention are PR10R11R12 ligands where the R10, R11 and R12 radicals are each hydrogen, linear and branched C1-C8-alkyl, vinyl, aryl or heteroaryl from the group of pyridine, pyrimidine, pyrrole, thiophene or furan, which may in turn be substituted by further substituents from the group of linear and branched C1-C8-alkyl or C6-C10-aryl, linear and branched C1-C8-alkyloxy or C1-C10-aryloxy, halogenated linear and branched C1-C8-alkyl or halogenated C6-C10-aryl, linear and branched C1-C8-alkyl or C6-C10-aryloxycarbonyl, linear and branched C1-C8-alkylamino, linear and branched C1-C8-dialkylamino, C1-C8-arylamino, C1-C8-diarylamino, formyl, hydroxyl, carboxyl, cyano, and halogens such as F, Cl, Br and I, obtained in situ.
Preferred phosphine ligands are trialkylphosphines such as triethylphosphine, tri-n-butylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, tris(1-adamantyl)phosphine, n-butyldi(1-adamantyl)phosphine (cataCXium® A), benzyldi(1-adamantyl)phosphine (cataCXium® ABn), 2-(di-tert-butylphosphino)biphenyl (JohnPhos), 2-(dicyclohexylphosphino)-2′-(N,N-dimethylamino)biphenyl (DavePhos) and 2-(dicyclohexylphosphino)-2′,6′-dimethoxy-1,1′-biphenyl (SPhos). Particular preference is given to tri-tert-butylphosphine.
Tri-tert-butylphosphine can be used as the free phosphine or in the form of the HBF4 adduct.
As an alternative to this, it is also possible to use defined palladium complexes which have been obtained from the abovementioned ligands in one or more process steps.
In the process according to the invention, 1-20 molar equivalents of phosphine are used, based on the amount of palladium used. Preferably, 1-4 molar equivalents are used.
In process step A) of the invention, a phase transfer catalyst from the group of the quaternary ammonium salts, the quaternary phosphonium salts or the crown ethers is used.
The phase transfer catalysts from the group of the quaternary ammonium salts or of the quaternary phosphonium salts preferably have the formula (V)




The R13, R14, R15 and R16 radicals are the same or different and are each independently C1-C28-alkyl, optionally branched C1-C28-alkyl, C6-C10-aryl, or benzyl.
A is N or P.
The X radical is halogen, hydrogensulphate, sulphate, dihydrogenphosphate, hydrogenphosphate, phosphate or acetate.
Preferably, X is bromine, chlorine, fluorine, hydrogensulphate, sulphate, phosphate and acetate.
Examples of such phase transfer catalysts include tetrabutylammonium fluoride, chloride, bromide, iodide and acetate, tetraethylammonium iodide, benzyltriethylammonium bromide, dodecyltrimethylammonium bromide and methyltridecylammonium chloride (Aliquat 336).
The phase transfer catalysts from the group of the crown ethers have the formula (VI)




in which n is a number from 4 to 8

and the

    
    
        R17 to R20 radicals are each independently hydrogen, C1-C4-alkyl or phenyl, where two adjacent R radicals may also in each case together form a cyclic radical such as cyclopentyl, cyclohexyl or 1,2-phenylene.
    
    


Examples of typical crown ethers of the formula (VI) include:
benzo-15-crown-5, 15-crown-5, 18-crown-6, dibenzo-18-crown-6, dibenzo-24-crown-8 and dicyclohexano-18-crown-6.
Preference is given to using 18-crown-6, dibenzo-18-crown-6 and dibenzo-24-crown-8.
Particular preference is given to 18-crown-6.
The amount of phase transfer catalyst in the process according to the invention is from 1 to 100 mole percent, based on aryl halide of the formula (I). Preference is given to amounts from 25 to 75 mole percent.
The process according to the invention is performed at temperatures of 0° C. to 220° C., preferably at 50° C. to 200° C. and more preferably at 100° C. to 180° C.
The process according to the invention can be performed in the presence of a solvent or using an excess of malonic ester of the formula (II). Preference is given to working in the presence of an excess of malonic ester of the formula (II).
The excess of malonic ester of the formula (II) is from 2 to 20 molar equivalents, based on the aryl halide of the formula (I). Preference is given to working with excesses of 3 to 10 molar equivalents.
The process according to the invention is typically performed at standard pressure, but can also be performed at reduced or elevated pressure.
To isolate the aryl- and heteroarylacetic acids and derivatives thereof prepared in accordance with the invention, the reaction mixture, after the reaction has ended, is worked up, preferably by distillation and/or by extraction or chromatographic methods.
The process according to the invention is illustrated by the examples which follow, without being restricted thereto.


PREPARATION EXAMPLES
Example 1
ethyl 4-methylphenylacetate
A dry Schlenk vessel was initially charged with 171 mg [1 mmol] of 4-bromotoluene, 1056 mg [6.6 mmol] of diethyl malonate, 2.88 mg [0.005 mmol] of Pd(dba)2, 3.19 mg [0.011 mmol] of P(tert-Bu)3×HBF4, 594 mg [2.8 mmol] of dried K3PO4 and 132 mg [0.5 mmol] of 18-crown-6. The reaction vessel was three times evacuated and filled with nitrogen. This was followed by stirring at 160° C. until completion of conversion (8 to 12 hours). After cooling to room temperature, the reaction mixture was diluted with ethyl acetate. The resulting solution was washed successively with 20 ml each of water, saturated aq. NaHCO3 solution and saturated aq. NaCl solution, dried over MgSO4, filtered and concentrated under reduced pressure. Chromatographic purification using silica gel (hexane/ethyl acetate) gave ethyl 4-methylphenylacetate in a yield of 88% of theory.
1H NMR (400 MHz, CDCl3): δ=7.19 (d, J=8.0 Hz, 2H), 7.14 (d, J=8.0 Hz, 2H), 4.16 (q, J=8.0 Hz, 2H), 3.58 (s, 2H), 2.34 (s, 3H), 1.26 (t, J=8.0 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ=171.8, 136.6, 131.1, 129.2, 129.1, 60.8, 41.0, 21.0, 14.2. MS (70 eV), m/z (%): 178 (34) [M+], 106 (10), 105 (100). IR (NaCl): {tilde over (v)}=2980 (vs), 2927 (m), 1735 (vs), 1515 (m), 1446 (m), 1367 (m), 1301 (m), 1253 (m), 1152 (m), 1032 (m), 809 (m).
Example 2
ethyl 2-ethylphenylacetate
Analogously to Example 1, 185 mg [1 mmol] of 2-ethylbromobenzene were used to obtain 170 mg of the title compound (88% of theory).
1H NMR (400 MHz, CDCl3): δ=7.27-7.16 (m, 4H), 7.56 (t, J=8.0 Hz, 1H), 7.46 (t, J=8.0 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 4.17 (q, J=8.0 Hz, 2H), 3.68 (s, 2H), 2.70 (q, J=8.0 Hz, 2H), 1.29-1.23 (m, 6H). 13C NMR (101 MHz, CDCl3): δ=171.6, 142.5, 132.0, 130.3, 128.4, 127.4, 125.9, 60.7, 38.5, 25.7, 14.8, 14.1. MS (70 eV), m/z (%): 193 (4), 192 (24) [M+], 146 (29), 119 (100), 91 (54), 77 (21). IR (NaCl): {tilde over (v)}=2980 (vs), 2935 (m), 1734 (vs), 1615 (m), 1583 (w), 1513 (s), 1246 (s), 1032 (m), 821 (m).
Example 3
ethyl 3-methoxyphenylacetate
Analogously to Example 1,187 mg [1 mmol] of 3-bromoanisole were used to obtain 180 mg of the title compound (93% of theory).
1H NMR (400 MHz, CDCl3): δ=7.25 (t, J=8.0 Hz, 1H), 6.91-6.81 (m, 3H), 4.17 (q, J=8.0 Hz, 2H), 3.81 (s, 3H), 3.60 (s, 2H), 1.27 (t, J=8.0 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ=171.4, 159.6, 135.5, 129.4, 121.5, 114.8, 112.5, 60.8, 55.1, 41.4, 14.1. MS (70 eV), m/z (%): 195 (7), 194 (50) [M+], 121 (100), 91 (37), 78 (17), 77 (26). IR (NaCl): {tilde over (v)}=2979 (vs), 1731 (vs), 1601 (s), 1586 (m), 1492 (m), 1368 (m), 1262 (m), 1031 (m), 870 (m), 773 (m).
Example 4
ethyl 4-methylthiophenylacetate
Analogously to Example 1,203 mg [1 mmol] of 4-bromothioanisole were used to obtain 199 mg of the title compound (95% of theory).
1H NMR (400 MHz, CDCl3): δ=7.25-7.18 (m, 4H), 4.14 (q, J=8.0 Hz, 2H), 3.56 (s, 2H), 2.46 (s, 3H), 1.24 (t, J=8.0 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ=171.5, 137.1, 131.0, 129.7, 126.9, 60.7, 40.8, 16.0, 14.2. MS (70 eV), m/z (%): 211 (16), 210 (100) [M+], 137 (88), 121 (9). IR (KBr): {tilde over (v)}=1730 (vs), 1495 (m), 1469 (m), 1366 (m), 1225 (m), 1031 (m), 802 (s).
Example 5
ethyl 3-thienylacetate
Analogously to Example 1,163 mg [1 mmol] of 3-bromothiophene were used to obtain 160 mg of the title compound (94% of theory).
1H NMR (400 MHz, CDCl3): δ=7.29-7.26 (m, 1H), 7.14 (s, 1H), 7.04 (d, J=8.0 Hz, 1H), 4.16 (q, J=8.0 Hz, 2H), 3.64 (s, 2H), 1.26 (t, J=8.0 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ=170.1, 133.7, 128.5, 125.6, 122.7, 60.9, 35.9, 14.1. MS (70 eV), m/z (%): 171 (10), 170 (58) [M+], 98 (22), 97 (100). R (NaCl): {tilde over (v)}=2979 (s), 2937 (m), 1733 (vs), 1464 (m), 1369 (m), 1259 (m), 1206 (m), 1155 (m), 1028 (m).
Example 6
ethyl 4-methylphenylacetate
Analogously to Example 1,128 mg [1 mmol] of 4-chlorotoluene were used to obtain the title compound in a yield of 85% of theory.
Example 7
ethyl 4-methylphenylacetate
Analogously to Example 1,218 mg [1 mmol] of 4-iodotoluene were used to obtain the title compound in a yield of 91% of theory.
Example 8
ethyl 2-naphthylacetate
Analogously to Example 1,207 mg [1 mmol] of 2-bromonaphthalene were used to obtain 200 mg of the title compound (93% of theory).
1H NMR (400 MHz, CDCl3): δ=7.87-7.79 (m, 3H), 7.75 (s, 1H), 7.51-7.42 (m, 3H), 4.18 (q, J=8.0 Hz, 2H), 3.79 (s, 2H), 1.27 (t, J=8.0 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ=171.5, 133.4, 132.4, 131.6, 128.1, 127.9, 127.61, 127.58, 127.3, 126.0, 125.7, 60.9, 41.6, 14.2. MS (70 eV), m/z (%): 215 (10), 214 (57) [M+], 141 (100), 115 (31). IR (NaCl): {tilde over (v)}=2980 (vs), 2936 (m), 1734 (vs), 1601 (m), 1508 (m), 1368 (m), 1258 (m), 1159 (m), 1031 (s), 859 (m), 818 (m), 802 (m), 759 (m), 742 (m).
Example 9
ethyl 4-methylphenylacetate
A dry Schlenk vessel was initially charged with 171 mg [1 mmol] of 4-bromotoluene, 1056 mg [6.6 mmol] of diethyl malonate, 1.12 mg [0.005 mmol] of Pd(OAc)2, 3.19 mg [0.011 mmol] of P(tert-Bu)3×HBF4, 594 mg [2.8 mmol] of dried K3PO4 and 132 mg [0.5 mmol] of 18-crown-6. The reaction vessel was three times evacuated and filled with nitrogen. This was followed by stirring at 160° C. until completion of conversion (8 to 12 hours). After cooling to room temperature, the reaction mixture was diluted with ethyl acetate. The resulting solution was washed successively with 20 ml each of water, saturated aq. NaHCO3 solution and saturated aq. NaCl solution, dried over MgSO4, filtered and concentrated under reduced pressure. Chromatographic purification using silica gel (hexane/ethyl acetate) gave ethyl 4-methylphenylacetate in a yield of 75% of theory.
Example 10
ethyl 4-methylphenylacetate
A dry Schlenk vessel was initially charged with 171 mg [1 mmol] of 4-bromotoluene, 1056 mg [6.6 mmol] of diethyl malonate, 2.88 mg [0.005 mmol] of Pd(dba)2, 2.22 mg [0.011 mmol] of P(tert-Bu)3, 594 mg [2.8 mmol] of dried K3PO4 and 132 mg [0.5 mmol] of 18-crown-6. The reaction vessel was three times evacuated and filled with nitrogen. This was followed by stirring at 160° C. until completion of conversion (8 to 12 hours). After cooling to room temperature, the reaction mixture was diluted with ethyl acetate. The resulting solution was washed successively with 20 ml each of water, saturated aq. NaHCO3 solution and saturated aq. NaCl solution, dried over MgSO4, filtered and concentrated under reduced pressure. Chromatographic purification using silica gel (hexane/ethyl acetate) gave ethyl 4-methylphenylacetate in a yield of 76% of theory.
Example 11
ethyl 2,6-dimethylphenylacetate
A dry Schlenk vessel was initially charged with 185 mg [1 mmol] of 2,6-dimethylbromobenzene, 1056 mg [6.6 mmol] of diethyl malonate, 2.88 mg [0.005 mmol] of Pd(dba)2, 3.19 mg [0.011 mmol] of P(tert-Bu)3×HBF4, 207 mg [1.5 mmol] of dried K2CO3 and 150 mg [1.5 mmol] of KHCO3. The reaction vessel was three times evacuated and filled with nitrogen. This was followed by stirring at 160° C. until completion of conversion (8 hours). After cooling to room temperature, the reaction mixture was diluted with ethyl acetate. The resulting solution was washed successively with 20 ml each of water, saturated aq. NaHCO3 solution and saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated under reduced pressure. Chromatographic purification using silica gel (hexane/ethyl acetate) gave ethyl 2,6-dimethylphenylacetate in a yield of 81% of theory.
1H NMR (400 MHz, CDCl3): δ=7.11-7.03 (m, 3H), 4.16 (q, J=8.0 Hz, 2H), 3.70 (s, 2H), 2.35 (s, 6H), 1.26 (t, J=8.0 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ=171.2, 137.1, 131.7, 128.0, 126.9, 60.6, 35.4, 20.2, 14.1. MS (70 eV), m/z (%): 193 (9), 192 (37) [M+], 119 (100), 118 (51), 91 (27). IR (NaCl): {tilde over (v)}=2979 (vs), 1734 (vs), 1589 (m), 1472 (m), 1445 (m), 1327 (m), 1246 (m), 1152 (s), 1031 (s), 769 (m).
Example 12
ethyl 2,4,6-trimethylphenylacetate
Analogously to Example 11, 199 mg [1 mmol] of 2,4,6-trimethylbromobenzene were used to obtain 172 mg of the title compound (83% of theory).
1H NMR (400 MHz, CDCl3): δ=6.89 (s, 2H), 4.17 (q, J=8.0 Hz, 2H), 3.7 (s, 2H), 2.33 (s, 6H), 2.29 (s, 3H), 1.27 (t, J=8.0 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ=171.4, 136.9, 136.3, 128.8, 128.7, 60.6, 35.0, 20.8, 20.1, 14.1. MS (70 eV), m/z (%): 207 (7), 206 (42) [M+], 133 (100), 132 (39), 117 (12), 105 (15), 91 (14). IR (NaCl): {tilde over (v)}=2977 (vs), 2919 (vs), 1734 (vs), 1613 (s), 1580 (m), 1485 (m), 1445 (m), 1157 (m), 1030 (s), 850 (s), 783 (m).
Example 13
ethyl 4-cyano-2-methylphenylacetate
Analogously to Example 11, 196 mg [1 mmol] of 4-bromo-3-methylbenzonitrile were used to obtain 190 mg of the title compound (93% of theory).
1H NMR (400 MHz, CDCl3): δ=7.49-7.41 (m, 2H), 7.28 (d, J=8.0 Hz, 1H), 4.14 (q, J=8.0 Hz, 2H), 3.65 (s, 2H), 2.33 (s, 3H), 1.23 (t, J=8.0 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ=170.1, 138.3, 133.6, 130.9, 129.8, 118.8, 111.1, 61.2, 39.2, 19.4, 14.1. MS (70 eV), m/z (%): 204 (9), 203 (29) [M+], 157 (19), 131 (40), 130 (100), 129 (20), 104 (16), 103 (37), 102 (12), 77 (23). IR (NaCl): {tilde over (v)}=2981 (vs), 2935 (s), 2229 (vs), 1731 (vs), 1607 (m), 1569 (w), 1499 (m), 1367 (s), 1334 (s), 1256 (s), 1234 (s), 1216 (s), 1174 (s), 1162 (s), 1030 (s), 886 (w), 838 (w), 808 (w), 788 (w). Anal. calcd. for C12H13NO2: H, 6.45; C, 70.92; N, 6.89. found: H, 6.61; C, 79.63; N6.56.
Example 14
ethyl 4-benzoylphenylacetate
Analogously to Example 11, 261 mg [1 mmol] of 4-bromobenzophenone were used to obtain 255 mg of the title compound (95% of theory).
1H NMR (400 MHz, CDCl3): δ=7.77 (t, J=8.0 Hz, 4H), 7.56 (t, J=8.0 Hz, 1H), 7.46 (t, J=8.0 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 4.16 (q, J=8.0 Hz, 2H), 3.68 (s, 2H), 1.25 (t, J=8.0 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ=196.2, 170.8, 138.8, 137.5, 136.3, 132.3, 130.3, 129.9, 129.2, 128.2, 61.1, 41.3, 14.1. MS (70 eV), m/z (%): 269 (25), 268 (99) [M+], 196 (44), 195 (70), 192 (94), 168 (100), 105 (69), 89 (51), 77 (51). IR (KBr): {tilde over (v)}=2981 (vs), 2935 (m), 1734 (vs), 1654 (vs), 1607 (s), 1578 (m), 1446 (m), 1277 (m), 1150 (m), 1029 (m), 701 (s).
Example 15
ethyl 4-trifluoromethylphenylacetate
Analogously to Example 11, 223 mg [1 mmol] of 4-bromobenzotrifluoride were used to obtain 190 mg of the title compound (82% of theory).
1H NMR (400 MHz, CDCl3): δ=7.59 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 4.17 (q, J=8.0 Hz, 2H), 3.68 (s, 2H), 1.27 (t, J=8.0 Hz, 3H). 19F NMR (376 MHz, CDCl3): δ=62.6 (s, Ar—F). 13C NMR (101 MHz, CDCl3): δ=170.7, 138.1, 129.6, 129.4 (q, 2JC-F=32.3 Hz), 125.4 (q, 3JC-F=4.0 Hz), 124.1 (q, 1JC-F=272.7 Hz), 61.1, 41.0, 14.0. MS (70 eV), m/z (%): 233 (7), 232 (5) [M+], 213 (14), 204 (18), 160 (23), 159 (100). IR (KBr): {tilde over (v)}=2983 (vs), 2938 (s), 1735 (vs), 1619 (m), 1586 (w), 1420 (m), 1326 (vs), 1164 (s), 1124 (s), 1067 (s), 1020 (m), 823 (w).
Example 16
ethyl 4-trifluoromethylphenylacetate
Analogously to Example 15, 179 mg [1 mmol] of 4-chlorobenzotrifluoride were used to obtain 170 mg of the title compound (73% of theory).
Example 17
ethyl 4-acetylphenylacetate
Analogously to Example 11, 199 mg [1 mmol] of 4-bromoacetophenone were used to obtain 150 mg of the title compound (73% of theory).
1H NMR (400 MHz, CDCl3): δ=7.90 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 4.14 (q, J=8.0 Hz, 2H), 3.65 (s, 2H), 2.57 (s, 3H), 1.23 (t, J=8.0 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ=197.6, 170.7, 139.4, 135.9, 129.7, 128.5, 61.1, 41.3, 26.6, 14.1. MS (70 eV), m/z (%): 207 (10) [M+], 191 (100), 163 (21), 133 (20), 118 (10), 105 (35), 89 (21). IR (KBr): {tilde over (v)}=1735 (vs), 1683 (s), 1607 (m), 1472 (m), 1368 (m), 1269 (m), 1110 (m), 1031 (m), 957 (w).
Example 18
ethyl 4-acetylphenylacetate
Analogously to Example 17, 155 mg [1 mmol] of 4-chloroacetophenone were used to obtain 180 mg of the title compound (87% of theory).
Example 19
ethyl 4-nitrophenylacetate
Analogously to Example 11, 158 mg [1 mmol] of 4-chloronitrobenzene were used to obtain 147 mg of the title compound (70% of theory).
1H NMR (400 MHz, CDCl3): δ=8.18 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 4.16 (q, J=8.0 Hz, 2H), 3.17 (s, 2H), 1.25 (t, J=8.0 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ=170.1, 147.1, 141.4, 130.2, 123.7, 61.4, 41.0, 14.1. MS (70 eV), m/z (%): 210 (29), 209 (20) [M+], 137 (100), 136 (72), 107 (99), 106 (41), 91 (21), 89 (94), 78 (90). IR (KBr): {tilde over (v)}=2984 (m), 1734 (vs), 1604 (m), 1521 (s), 1348 (m), 1223 (m), 1174 (m), 1030 (m), 859 (m), 807 (m), 718 (m).
Example 20
ethyl 4-ethoxycarbonylphenylacetate
Analogously to Example 11, 185 mg [1 mmol] of ethyl 4-chlorobenzoate were used to obtain 208 mg of the title compound (88% of theory).
1H NMR (400 MHz, CDCl3): δ=8.01 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 4.37 (q, J=8.0 Hz, 2H), 4.16 (q, J=8.0 Hz, 2H), 3.67 (s, 2H), 1.39 (t, J=8.0 Hz, 3H), 1.25 (t, J=8.0 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ=170.8, 166.3, 139.1, 129.7, 129.2, 61.0, 60.9, 41.3, 14.3, 14.1. MS (70 eV), m/z (%): 237 (15), 236 (5) [M+], 208 (11), 191 (39), 180 (13), 163 (100), 149 (18), 136 (25), 135 (47), 119 (13), 118 (18), 107 (40), 91 (24), 90 (28), 89 (35), 77 (13). IR (NaCl): {tilde over (v)}=2983 (vs), 2938 (m), 1735 (vs), 1718 (vs), 1612 (m), 1368 (m), 1277 (s), 1106 (m), 1032 (s).

## Claims

1. A process for preparing a compound of formula (III)



in which
Ar is a





group,
where
R1, R2, R3, R4 and R5 are the same or different and are each independently hydrogen, amino, cyano, nitro, halogen, optionally halogen-substituted C1-C6-alkyl, C1-C6-thioalkyl, thiophenyl, C1-C6-alkoxy, C6-C10-aryloxy, phenyl, —CO—C6-C10-aryl, —CO—C1-C3-alkyl, —COO—C1-C6-alkyl or —COO—C6-C10-aryl,
the Ar radical may additionally also be a heteroaromatic radical or
the Ar radical may also be 1- or 2-naphthyl,
and
R6 and R7 are each independently optionally substituted C1-C8-alkyl, phenyl, aryl, or NR8R9,
where R8 and R9 are the same or different and are each independently C1-C4-alkyl, or phenyl optionally substituted by optionally fluorine- or chlorine-substituted C1-C3-alkyl, by nitro, cyano or di-C1-C3-alkylamino, or together with the nitrogen atom to which they are bonded are a saturated or unsaturated, substituted or unsubstituted cycle,
wherein an aryl or heteroaryl halide of formula (I)


Ar-Hal  (I)


in which
Hal is chlorine, bromine or iodine and
Ar is as defined above,
is reacted with a malonic ester of formula (II)




in the presence of a palladium catalyst, of a phosphine ligand and
of an inorganic base and of a phase transfer catalyst
optionally using an organic solvent wherein the phase transfer catalyst comprises a quaternary ammonium salt or phosphonium salt of formula (V)




in which
R13, R14, R15 and R16 are the same or different and are each independently C1-C28-alkyl, optionally branched C1-C28-alkyl, C6-C10-aryl, or benzyl,
A is N or P and
X is halogen, hydrogensulphate, sulphate, dihydrogenphosphate, hydrogenphosphate, phosphate or acetate;
or a crown ether of formula (VI)




in which n is a number from 4 to 8
and the R17 to R20 radicals are each independently hydrogen, C1-C4-alkyl or phenyl, where two adjacent R17 to R20 radicals may also in each case together form a cyclic radical.

2. The process for preparing a compound of formula (III) according to claim 1, where
Ar is 1- or 2-naphthyl, 3-thienyl or a





group,
where
R1, R2, R3, R4 and R5 are the same or different and are each independently hydrogen, amino, cyano, nitro, fluorine, optionally fluorine-substituted C1-C4-alkyl, C1-C4-thioalkyl, thiophenyl, C1-C4-alkoxy, C6-C10-aryloxy, phenyl, —CO—C6-C8-aryl, —CO—C1-C3-alkyl, —COO—C1-C4-alkyl or —COO—C6-C8-aryl,
Hal is chlorine, bromine or iodine,
R6 and R7 are the same or different and are each independently C1-C4-alkyl.

3. The process for preparing a compound of formula (III) according to claim 1, where
Ar is 1- or 2-naphthyl, 3-thienyl or a





group,
where
R1, R2, R3, R4 and R5 are the same or different and are each independently hydrogen, amino, cyano, nitro, fluorine, methyl, methylthio, ethyl, i-propyl, n-propyl, CF3, C2F5, C3F7, methoxy, ethoxy, phenyl, —CO-phenyl, —CO-methyl, —CO-ethyl, —COO-methyl, —COO-ethyl or —COO-phenyl,
Hal is chlorine, bromine or iodine,
R6 and R7 are each independently methyl or ethyl.

4. The process for preparing a compound of formula (III) according to claim 1, where
Ar is 1-naphthyl, 2-naphthyl, phenyl, 4-N,N-dimethylaminophenyl, 4-methylthiophenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 2-ethylphenyl, 4-ethoxycarbonylphenyl, 3-thienyl.

5. The process for preparing a compound of formula (III) according to claim 1, where
Ar is 2,6-dimethylphenyl, 2,4,6-trimethylphenyl, 4-cyanophenyl, 4-cyano-2-methylphenyl, 3-cyanophenyl, 4-ethoxycarbonylphenyl, 4-trifluoromethylphenyl, 4-acetylphenyl, 4-nitrophenyl, 4-benzoylphenyl.

6. The process for preparing a compound of formula (III) according to claim 1, where
R6 and R7 are each ethyl.

7. The process for preparing a compound of formula (III) according to claim 1, wherein the palladium catalyst used is bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)dipalladium or palladium acetate.

8. The process for preparing a compound of formula (III) according to claim 1, wherein the phosphine ligand used is tri-tert-butylphosphine, tricyclohexylphosphine, tris(1-adamantyl)phosphine, n-butyldi(1-adamantyl)phosphine, benzyldi(1-adamantyl)phosphine, 2-(di-tert-butylphosphino)biphenyl or 2-(dicyclohexylphosphino)-2′-(N,N-dimethylamino.

9. The process for preparing a compound of formula (III) according to claim 1, wherein the phosphine ligand used is tri(tert-butyl)phosphine.

10. The process for preparing a compound of formula (III) according to claim 1, wherein the base used is potassium phosphate.

11. The process for preparing a compound of formula (III) according to claim 1, wherein the base used comprises a mixture of potassium carbonate and potassium bicarbonate.

12. The process for preparing a compound of formula (III) according to claim 1, wherein the phase transfer catalyst used comprises a quaternary ammonium salt or phosphonium salt of formula (V)



in which
R13, R14, R15 and R16 are the same or different and are each independently C1-C28-alkyl, optionally branched C1-C28-alkyl, C6-C10-aryl, or benzyl,
A is N or P and
X is halogen, hydrogensulphate, sulphate, dihydrogenphosphate, hydrogenphosphate, phosphate or acetate.

13. The process for preparing a compound of formula (III) according to claim 1, wherein the phase transfer catalyst used comprises a crown ether of formula (VI)



in which n is a number from 4 to 8
and the R17 to R20 radicals are each independently hydrogen, C1-C4-alkyl or phenyl, where two adjacent R17 to R20 radicals may also in each case together form a cyclic radical.

14. The process for preparing a compound of formula (III) according to claim 1, wherein the phase transfer catalyst used is 18-crown-6.

15. The process for preparing a compound of formula (III) according to claim 1, wherein a malonic ester of formula (II) is used as a solvent in excess.

16. The process for preparing a compound of formula (III) according to claim 1, wherein a temperature of from 100 to 180° C. is employed.

17. The process for preparing a compound of formula (III) according to claim 1, wherein the phase transfer catalyst used comprises a crown ether of formula (VI)



in which n is a number from 4 to 8
and the R17 to R20 radicals are each independently hydrogen, C1-C4-alkyl or phenyl, where two adjacent R17 to R20 radicals may also in each case together form a cyclic radical comprising cyclopentyl, cyclohexyl or 1,2-phenylene.

18. The process for preparing a compound of formula (III) according to claim 1,
where Ar is a





group,
where
R1, R2, R3, R4 and R5 are the same or different and are each independently hydrogen, amino, cyano, nitro, halogen, optionally halogen-substituted C1-C6-alkyl, C1-C6-thioalkyl, thiophenyl, C1-C6-alkoxy, C1-C10-aryloxy, phenyl, —CO—C6-C10-aryl, —CO—C1-C3-alkyl, —COO—C1-C6-alkyl or —COO—C6-C10-aryl.