Multikilogram-Scale Synthesis of a Biphenyl Carboxylic Acid Derivative Using a Pd/C-Mediated Suzuki Coupling Approach

Abstract

Reaction of 4-bromo-3-methylaniline with 4-chlorobutyryl chloride/TEA and subsequent treatment of the resulting secondary amide intermediate with KOt-Bu gives 1-(4-bromo-3-methylphenyl)pyrrolidin-2-one in 65% yield. This procedure has been optimised (74−76% overall yield) and has been carried out on 41 molar scale. In a variation of this process, we have employed NaOH as the ring-closing base under phase-transfer conditions. NaOH is added to a mixture of 4-bromo-3-methylaniline, 4-chlorobutyryl chloride, and catalytic TBAC in THF/H2O. A further 2 equiv of aqueous NaOH is added, and the mixture is heated at 40−45 °C, providing access to cyclised product in an improved 86% yield. 1-(4-Bromo-3-methylphenyl)pyrrolidin-2-one is subsequently coupled with 4-carboxyphenylboronic acid under standard Suzuki coupling conditions [Pd(PPh3)4, Na2CO3, DME/H2O] to give 2‘-methyl-4‘-(2-oxo-1-pyrrolidinyl)biphenyl-4-carboxylic acid in 64% yield, contaminated with 40−80 ppm of residual Pd. In a modification of this process, we have used Pd/C as the catalyst. Reaction in MeOH/H2O gives an improved yield of the biphenylcarboxylic acid with residual Pd levels of <6 ppm. This process has been carried out on 24 molar scale. The synthesis of the arylpyrrolidinone and subsequent Suzuki coupling have been combined into a one-pot procedure, providing access to 2‘-methyl-4‘-(2-oxo-1-pyrrolidinyl)biphenyl-4-carboxylic acid in 82% overall yield from 4-bromo-3-methylaniline.