N-methyl-2-pyrrolidone → 2-(2-Chlorophenylamino)-5-cyano-3,4-difluorobenzoic acid methyl ester

Participants

Reaction Steps

A mixture of 5-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (14) (3.01 g, 7.99 mmol), 1,1′-bis(diphenylphosphino) ferrocene (dppf) (93 mg, 0.162 mmol), Pd2dba3 (73 mg, 0.080 mmol) and Zn(CN)2 (573 mg, 4.78 mmol) in 1-methyl-2-pyrrolidinone (NMP: 4.5 mL) was heated in a sealed tube reactor. After 20 hours, the reaction mixture was cooled to room temperature, quenched by the addition of 8 mL 4:1:4 (volume) mixture of saturated NH4Cl, concentrated NH4OH and water, and extracted with a mixture of EtOAc:THF. The combined organic extracts were washed with 4:1:4 (volume) mixture of saturated NH4Cl, concentrated NH4OH and water, and brine. The organic layer was dried (MgSO4) and concentrated. Purification by flash column chromatography using the Biotage system (twice: 100% hexanes to 35% CH2Cl2 in hexanes, then 30% CH2Cl2 in hexanes) provided 1.33 g (52%) of the desired product (15).

Provenance & Evidence