# US 5,352,820 A · Expedient route to aryl propenoic esters

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- Number: US 5,352,820 A
- Document ID: US5352820A
- Status: Granted
- Kind: A
- Application number: 08/083,817
- Filed: 1993-06-28
- Granted: 1994-10-04
- Earliest claimed: 1993-06-28
- Inventors: Jeremy I. Levin
- Web page: https://patentgrep.com/patent/US5352820A

## CPC

- C07C 67/343: by increase in the number of carbon atoms
- C07C 201/12: by reactions not involving the formation of nitro groups
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The invention is an expedient route to synthesizing substituted or unsubstituted aryl-2-propenoic esters. The substituted or unsubstituted aryl-2-propenoic esters are useful in preparing optically active substituted or unsubstituted 2-arylpropanoic acids known to be active anti-inflammatory agents.

## Claims

### Claim 1

The process for making a substituted or unsubstituted aryl-2-propenoic ester of formula I: ##STR9## wherein Ar is ##STR10## Z is NH, O or S; X and X' are independently hydrogen, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, (C.sub.1 -C.sub.4)alkanoyl, (C.sub.1 -C.sub.4)alkoxycarbonyl, trifluoromethyl, nitro, bromine, chlorine, fluorine, phenyl, substituted phenyl wherein the substitution is hydrogen, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, (C.sub.1 -C.sub.4)alkanoyl, (C.sub.1 -C.sub.4)alkoxycarbonyl, trifluoromethyl, nitro, bromine, chlorine or fluorine, thiophene, pyridine or furan; and R is (C.sub.1 -C.sub.4)alkyl;
which comprises:
reacting a substituted or unsubstituted aryl iodide of the formula:
Ar--.vertline.
wherein Ar is as defined hereinabove;
with an .alpha.-stannyl acrylate ester of the formula: ##STR11## wherein R is as defined hereinabove and R.sup.1 is (C.sub.1 -C.sub.4)alkyl;
in the presence of palladium(0) or palladium(II), and copper(I or II) catalyst, in a polar-aprotic solvent at room temperature for from 1 to 100 hours and recovering the substituted or unsubstituted aryl-2-propenoic ester so produced.

### Claim 2

The process for making substituted or unsubstituted aryl-2-propenoic esters of formula I, ##STR12## wherein Ar is ##STR13## Z is NH, O or S; X and X' are independently hydrogen, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, (C.sub.1 -C.sub.4)alkanoyl, (C.sub.1 -C.sub.4)alkoxycarbonyl, trifluoromethyl, nitro, bromine, chlorine, fluorine, phenyl, substituted phenyl wherein the substitution is hydrogen, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, (C.sub.1 -C.sub.4)alkanoyl, (C.sub.1 -C.sub.4)alkoxycarbonyl, trifluoromethyl, nitro, bromine, chlorine or fluorine, thiophene, pyridine or furan; and R is (C.sub.1 -C.sub.4)alkyl;
which comprises:
reacting a substituted or unsubstituted aryl triflate of the formula; ##STR14## with an .alpha.-stannyl acrylate ester of the formula: ##STR15## wherein R is as defined hereinabove and R.sup.1 is (C.sub.1 -C.sub.4)alkyl;
in the presence of palladium(0) or palladium(II), copper(I or II), and lithium chloride catalyst, in a polar-aprotic solvent at room temperature for from 1 to 100 hours and recovering substituted or unsubstituted aryl-2-propenoic esters so produced.

### Claim 3 (depends on 1)

The process for making compounds according to claim 1, wherein Ar is ##STR16## Z is NH, O or S; X is hydrogen and X' is hydrogen, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, (C.sub.1 -C.sub.4)alkanoyl, (C.sub.1 -C.sub.4)alkoxycarbonyl, trifluoromethyl, nitro, bromine, chlorine or fluorine.

### Claim 4 (depends on 3)

The process for making compound according to claim 3, wherein Ar is phenyl, X is hydrogen and X' is hydrogen, methyl, methoxy, acyl, methoxycarbonyl, trifluoromethyl, nitro or bromo.

### Claim 5 (depends on 2)

The process for making compounds according to claim 2, wherein Ar is ##STR17## Z is NH, O, or S; X is hydrogen, and X' is hydrogen, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, (C.sub.1 -C.sub.4)alkanoyl, (C.sub.1 -C.sub.4)alkoxycarbonyl, trifluoromethyl, nitro, bromine, chlorine or fluorine.

### Claim 6 (depends on 5)

The process for making compounds according to claim 5, wherein Ar is ##STR18## X is hydrogen and X' is hydrogen, methyl, methoxy, acyl, methoxycarbonyl, trifluoromethyl, nitro or bromo.

### Claim 7 (depends on 1)

The process of claim 1, wherein the polar-aprotic solvent is dimethylformamide, N-methyl-pyrrolidinone, or dimethylacetamide.

### Claim 8 (depends on 7)

The process of claim 7, wherein the polar-aprotic solvent is dimethylformamide.

### Claim 9 (depends on 1)

The process of claim 1, wherein the range of molar ratio of substituted or unsubstituted aryl iodide to .alpha.-stannyl acrylate ester is 1:0.5 to 1:10.

### Claim 10 (depends on 7)

The process of claim 7, wherein the molar ratio of substituted or unsubstituted aryl iodide to .alpha.-stannyl acrylate ester is 1:2.5.

### Claim 11 (depends on 1)

The process of claim 1, wherein the palladium catalysts are bis(triphenylphosphine)palladium(II) chloride, bis(benzonitrile)palladium(II) chloride, trans-benzyl(chloro)bis(triphenylphosphine)palladium(II) or tetrakis(triphenylphosphine)palladium(0).

### Claim 12 (depends on 11)

The process of claim 11, wherein the palladium(0) catalyst is terakis(triphenylphosphine)palladium(0).

### Claim 13 (depends on 1)

The process of claim 1, wherein the range of molar ratio of terakis(triphenylphosphine)palladium(0) is 1 to 15% of the substituted or unsubstituted aryl iodide.

### Claim 14 (depends on 13)

The process of claim 13, wherein the molar ratio of terakis(triphenylphosphine)palladium(0) is 10% of the substituted or unsubstituted aryl iodide.

### Claim 15 (depends on 1)

The process of claim 1, wherein the copper(I or II) catalyst is copper(I) iodide, copper(I) bromide, copper(I) cyanide, copper(I) bromide-dimethyl sulfide complex or copper(II) bromide.

### Claim 16 (depends on 15)

The process of claim 15, wherein the copper(I or II) catalyst is copper(I) iodide.

### Claim 17 (depends on 1)

The process of claim 1, wherein the range of molar ratio of copper(I) iodide catalyst is 10 to 150% of the substituted or unsubstituted aryl iodide.

### Claim 18 (depends on 17)

The process of claim 17 wherein the the molar ratio of copper(I) iodide is 75% of the substituted or unsubstituted aryl iodide.

### Claim 19 (depends on 2)

The process of claim 2, wherein the polar-aprotic solvent is dimethylformamide, N-methylpyrrolidinone, or dimethylacetamide,

### Claim 20 (depends on 19)

The process of claim 19, wherein the polar-aprotic solvent is dimethylformamide.

### Claim 21 (depends on 2)

The process of claim 2, wherein the range of molar ratio of substituted or unsubstituted aryl triflate to .alpha.-stannyl acrylate ester is 1:0.5 to 1:10.

### Claim 22 (depends on 21)

The process of claim 21 wherein the molar ratio of substituted or unsubstituted aryl triflate to .alpha.-stannyl acrylate ester is 1:2.5.

### Claim 23 (depends on 2)

The process of claim 2, wherein the palladium catalyst is bis(triphenylphosphine)palladium(II) chloride, bis(benzonitrile)palladium(II) chloride, trans-benzyl(chloro)bis(triphenylphosphine)palladium(II) or tetrakis(triphenylphosphine)palladium(0).

### Claim 24 (depends on 23)

The process of claim 23, wherein the palladium(0) catalyst is terakis(triphenylphosphine)palladium(0).

### Claim 25 (depends on 2)

The process of claim 2, wherein the range of molar ratio of terakis(triphenylphosphine)palladium(0) is 1 to 15% of the substituted or unsubstituted aryl triflate.

### Claim 26 (depends on 25)

The process of claim 25, wherein the molar ratio of terakis(triphenylphosphine)palladium(0) is 10% of the substituted or unsubstituted aryl triflate.

### Claim 27 (depends on 2)

The process of claim 2, wherein the copper(I or II) catalyst is copper(I) iodide, copper(I) bromide, copper(I) cyanide, copper(I) bromide-dimethyl sulfide complex or copper(II) bromide.

### Claim 28 (depends on 27)

The process of claim 27, wherein the copper(I or II) catalyst is copper(I) iodide.

### Claim 29 (depends on 2)

The process of claim 2, wherein the molar ratio of copper(I) iodide catalyst is 10-150% of the substituted or unsubstituted aryl triflate.

### Claim 30 (depends on 29)

The process of claim 29 wherein the the molar ratio of copper(I) iodide is 75% of the substituted or unsubstituted aryl triflate.

### Claim 31 (depends on 2)

The process of claim 2, wherein the molar ratio of lithium chloride is 3 times the substituted or unsubstituted aryl triflate.

### Claim 32 (depends on 1)

The process of claim 1, wherein .alpha.-Methylene-4-nitrobenzeneacetic acid methyl ester is produced.

### Claim 33 (depends on 1)

The process of claim 1, wherein .alpha.-Methylene-4-(trifluoromethyl)benzeneacetic acid methyl ester is produced.

### Claim 34 (depends on 1)

The process of claim 1, wherein 4-Acetyl-.alpha.-methylenebenzeneacetic acid methyl ester is produced.

### Claim 35 (depends on 1)

The process of claim 1, wherein 4-(Methoxycarbonyl)-.alpha.-methylenebenzeneacetic acid methyl ester is produced.

### Claim 36 (depends on 1)

The process of claim 1, wherein .alpha.-Methylenebenzeneacetic acid methyl ester is produced.

### Claim 37 (depends on 1)

The process of claim 1, wherein 4-Methyl-.alpha.-methylenebenzeneacetic acid methyl ester is produced.

### Claim 38 (depends on 1)

The process of claim 1, wherein 4-Bromo-.alpha.-methylenebenzeneacetic acid methyl ester is produced.

### Claim 39 (depends on 1)

The process of claim 1, wherein p-Methoxyatropic acid methyl ester is produced.

### Claim 40 (depends on 2)

The process of claim 2, wherein 6-Methoxy-.alpha.-methylene-2-naphthaleneacetic acid methyl ester is produced.