Buchwald-Hartwig Mono-N-arylation of 2,6-Dihaloisonicotinic Acid Derivatives: A Convenient Desymmetrization Method

Abstract

A method for the Buchwald-Hartwig mono-N-arylation of aniline with methyl 2,6-dichloroisonicotinate using Pd(OAc)2, XPhos, and t-BuONa is reported. Use of m-anisidine under the same conditions resulted in the amidation of the methyl ester. Mono-N-arylation of m-anisidine with 2,6-dichloro-N,N-diisopropylisonicotinamide and 2,6-dibromo-N,N-diisopropylisonicotinamide, however, was successfully achieved using Pd(OAc)(2),/XPhos/t-BuONa or Pd(OAc)(2)/(+/-)-BINAP/K(2)CO(3), respectively. The present study demonstrates the sensitivity of this cross-coupling method to both the steric and electronic nature of the coupling partners.