Pd(II)-catalyzed enantioselective C—H arylation of free carboxylic acids

Patent metadata

Field	Value
Publication number	US-11021427-B2
Application number	US-201915733763-A
Country	US
Kind code	B2
Filing date	Apr 17, 2019
Priority date	Apr 19, 2018
Publication date	Jun 1, 2021
Grant date	Jun 1, 2021

Abstract

The invention includes procedures for stereoselective β-acylation of carboxylic acids having a β-carbon atom. For example, stereoselective acylation procedures include the following reactions: (I)

First claim

What is claimed is:

1. A method of stereoselective arylation of a β-carbon atom of a cyclopropanecarboxylic acid having a β-hydrogen atom, the cyclopropropanecarboxylic acid having either an α-substituent or having no α-substituent, comprising contacting the cyclopropanecarboxylic acid and an aryl iodide in the presence of a catalytic quantity of a Pd(II) salt, a molar equivalent or more on an Ag(I) basis of an Ag(I) salt, and a molar equivalent or more of a base, in 1,1,1,3,3,3-hexafluoroisopropanol solvent, in the presence of an single enantiomer, either (R) or (S), of an acetyl-protected aminoethyl amine (APAA) ligand of formula

wherein Ac is acetyl, each R is independently selected methyl or ethyl, or the two R groups together with the nitrogen atom to which they are bonded form a 4- to 6-membered heterocyclyl ring; and wherein R 1 is an unsubstituted or substituted benzyl group, or wherein R 1 is a (C 3 -C 4 )-alkyl group;
to stereoselectively provide a β-aryl-cyclopropanecarboxylic acid, wherein the arylated β-carbon atom of the β-aryl-cyclopropanecarboxylic acid product, when no α-substituent is present is of an (R) or (S) single enantiomeric configuration, respectively, and when an α-substituent is present is of an (S) or (R) single enantiomeric configuration, respectively; the aryl group introduced being disposed cis to the carboxylic acid group of the cyclopropanecarboxylic acid.

2. The method of claim 1 wherein the APAA ligand is of formula

3. The method of claim 1 wherein the Pd(II) salt is Pd(OAc) 2 .

4. The method of claim 1 wherein the carbonate base is Na 2 CO 3 , or wherein the Ag(I) salt is Ag 2 CO 3 , or both.

5. The method of claim 1 wherein the Pd(II) salt is present at about 10 mole %, the ligand is present at about 20 mole %, or both.

6. A method of stereoselective arylation of a β-carbon atom of 2-phthalimidoisobutryic acid, comprising contacting the 2-phthalimidoisobutryic acid and an aryl iodide in the presence of a catalytic quantity of a Pd(II) salt, a molar equivalent or more on an Ag(I) basis of an Ag(I) salt, and a molar equivalent or more of a base, in 1,1,1,3,3,3-hexafluoroisopropanol solvent, in the presence of an single enantiomer, either (R) or (S), of an acetyl-protected aminoethyl amine (APAA) ligand of formula

wherein Ac is acetyl, each R is independently selected methyl or ethyl, or the two R groups together with the nitrogen atom to which they are bonded form a 4- to 6-membered heterocyclyl ring; and wherein R 1 is an unsubstituted or substituted benzyl group, or wherein R 1 is a (C 3 -C 4 )-alkyl group;
to stereoselectively provide a β-aryl-2-phthalimidoisobutryic acid, wherein the β-aryl-2-phthalimidoisobutryic acid product is of an (R) or (S) single enantiomeric configuration, respectively.

7. The method of claim 6 wherein the APAA ligand is of formula

8. The method of claim 6 wherein the Pd(II) salt is Pd(OAc) 2 .

9. The method of claim 6 wherein the carbonate base is Na 2 CO 3 , or wherein the Ag(I) salt is Ag 2 CO 3 , or both.

10. The method of claim 6 wherein the Pd(II) salt is present at about 10 mole %, the ligand is present at about 20 mole %, or both.

Assignees

• Scripps Research Inst

Inventors

• Yu Jin-Quan
• Shen Pengxiang

Classifications

• C07C67/343 Primary

  by increase in the number of carbon atoms · CPC title

• C07D209/48

  with oxygen atoms in positions 1 and 3, e.g. phthalimide · CPC title

• C07C51/353 Primary

  by isomerisation; by change of size of the carbon skeleton · CPC title

• C07F9/4071

  the ester moiety containing a substituent or a structure which is considered as characteristic · CPC title

• C07D307/54

  Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title