Process for preparing substituted biphenyls

Patent metadata

Field	Value
Publication number	US-10683256-B2
Application number	US-201616326940-A
Country	US
Kind code	B2
Filing date	Aug 22, 2016
Priority date	Aug 22, 2016
Publication date	Jun 16, 2020
Grant date	Jun 16, 2020

Abstract

The present invention relates to a process for preparing substituted biphenyls via Suzuki coupling using specific phosphorus ligands and a solvent mixture containing water, a non-polar organic solvent and a polar aprotic co-solvent.

First claim

The invention claimed is:

1. A process for preparing substituted biphenyls of the formula I

in which the substituents are each defined as follows:
R 1 is nitro, amino, C 1 -C 4 -alkylamino, —N(H)PG, —NH—CO—R′, —N═CR′R″ or a moiety of the formula Q 1 , Q 2 or Q 3

with
PG being a protective group;
R′ and R″ being independently of each other and independently of each occurrence C 1 -C 4 -alkyl or phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy;
R 4 being methyl, optionally substituted by 1, 2 or 3 fluorine atoms; and
# being the attachment point to the remainder of the molecule;

R 2 is selected from the group consisting of cyano, nitro, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 3 -C 10 -cycloalkyl which may carry 1, 2, 3 or 4 C 1 -C 4 -alkyl substituents; C 3 -C 10 -halocycloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -alkylcarbonyl; C 1 -C 6 -haloalkylcarbonyl; C 1 -C 6 -alkoxycarbonyl; C 1 -C 6 -haloalkoxycarbonyl; aryl; aryl-C 1 -C 4 -alkyl; arylcarbonyl; aryl-C 1 -C 4 -alkylcarbonyl; aryloxycarbonyl; aryl-C 1 -C 4 -alkoxycarbonyl, wherein aryl in the six last-mentioned radicals may carry 1, 2, 3 or 4 substituents selected from halogen, cyano, nitro, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy; aminocarbonyl, C 1 -C 4 -alkylaminocarbonyl, and di-(C 1 -C 4 -alkyl)-aminocarbonyl;
n is 0, 1, 2 or 3, where, in case that n=2 or 3, the R 2 radicals may have identical or different definitions; and
R 3 is hydrogen, cyano, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl or C 1 -C 4 -alkoxy;
which comprises reacting a compound of the formula II

in which Hal is chlorine or bromine and R 1 and R 3 are each as defined above,
in the presence of a base and of a palladium catalyst which comprises a palladium source and a phosphorus ligand of the formula III

in which
R 5 is C 1 -C 6 -alkyl, trifluoromethyl, C 6 -C 10 -aryl or 5- to 10-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N and O as ring members;
R 6 , R 7 , R 8 are each independently selected from the group consisting of hydrogen, trifluoromethyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl, 5- to 11-membered saturated, partially unsaturated or maximally unsaturated heterocyclyl containing 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from the group consisting of N, O, NO and SO 2 as ring members, C 6 -C 10 -aryl and NR 16 R 17 , wherein the above C 3 -C 10 -cycloalkyl, 5- to 11-membered heterocyclyl and C 6 -C 10 -aryl groups are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy and trifluoromethyl; or
R 6 and R 7 , or R 7 and R 8 , together with the carbon atoms they are bound to, form a 5- or 6-membered partially unsaturated or maximally unsaturated carbocyclic or heterocyclic ring, where the heterocyclic ring contains 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from N, O, NO and SO 2 as ring members; where the carbocyclic or heterocyclic ring may carry one or more substituents selected from the group consisting of trifluoromethyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl, 5- to 11-membered saturated, partially unsaturated or maximally unsaturated heterocyclyl containing 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from N, O, NO and SO 2 as ring members, C 6 -C 10 -aryl and NR 16 R 17 , wherein the above C 3 -C 10 -cycloalkyl, 5- to 11-membered heterocyclyl and C 6 -C 10 -aryl groups are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy and trifluoromethyl;
R 9 , R 10 are each independently selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, 3- to 6-membered saturated, partially unsaturated or maximally unsaturated heterocyclyl containing 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from the group consisting of N, O, NO and SO 2 as ring members, C 6 -C 10 -aryl and Si(R 16 ) 3 , wherein the above C 3 -C 6 -cycloalkyl, 3- to 6-membered heterocyclyl and C 6 -C 10 -aryl groups are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy and trifluoromethyl;
R 11 , R 12 , R 13 , R 14 , R 15 are each independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 -alkyl, trifluoromethyl, C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl, 5- to 11-membered saturated, partially unsaturated or maximally unsaturated heterocyclyl containing 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from the group consisting of N, O, NO and SO 2 as ring members, C 6 -C 10 -aryl, NR 16 R 17 , —Si(R 16 ) 3 and —SR 16 , wherein the above C 3 -C 10 -cycloalkyl, 5- to 11-membered heterocyclyl and C 6 -C 10 -aryl groups are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy and trifluoromethyl;
or

any two adjacent instances of R 11 , R 12 , R 13 , R 14 , R 15 , together with the carbon atoms to which they are bound, form a five- or six-membered partially unsaturated or maximally unsaturated carbocyclic or heterocyclic ring, where the heterocyclic ring contains 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from N, O, NO and SO 2 as ring members; where the carbocyclic or heterocyclic ring may carry one or more substituents selected from the group consisting of trifluoromethyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl, C 6 -C 10 -aryl, 5- to 11-membered saturated, partially unsaturated or maximally unsaturated heterocyclyl containing 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from the group consisting of N, O, NO and SO 2 as ring members, and NR 16 R 17 , wherein the above C 3 -C 10 -cycloalkyl, 5- to 11-membered heterocyclyl and C 6 -C 10 -aryl groups are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy and trifluoromethyl;
R 16 , R 17 are each independently selected from the group consisting of hydrogen, trifluoromethyl, C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, saturated, partially unsaturated or maximally unsaturated 5- to 11-membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from the group consisting of N, O, NO and SO 2 as ring members, C 6 -C 10 -aryl, wherein the above C 3 -C 10 -cycloalkyl, 5- to 11-membered heterocyclyl and C 6 -C 10 -aryl groups are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy and trifluoromethyl;
in a solvent mixture of water, a non-polar organic solvent and a polar aprotic co-solvent,
with an organoboron compound of the formula IV

wherein R 2 and n are as defined above and the compound of formula IV is selected from the group con

Assignees

• Basf Se

Inventors

• Xu Xiaoming
• Huang Chao
• Frassetto Timo

Classifications

• C07F9/65683

  the ring phosphorus atom being part of a phosphine · CPC title

• C07C205/12 Primary

  the six-membered aromatic ring or a condensed ring system containing that ring being substituted by halogen atoms · CPC title

• C07C201/12 Primary

  by reactions not involving the formation of nitro groups · CPC title

• C07B37/04

  Substitution · CPC title

• B01J2531/824

  Palladium · CPC title