Metal‐Bearing and Trifluoromethyl‐Substituted Pyrimidines: Generation and Functionalization

Abstract5‐Pyrimidyllithium species are fairly stable when the metal is flanked by two electron‐withdrawing substituents such as trifluoromethyl and chlorine or bromine. Thus, the corresponding 5‐carboxylic acids are produced in high yields from 4,5‐dibromo‐6‐(trifluoromethyl)pyrimidine and 5‐bromo‐4‐chloro‐6‐(trifluoromethyl)pyrimidine upon halogen/metal permutation accomplished with isopropylmagnesium chloride or butyllithium followed by carboxylation. Satisfactory or excellent yields of 5‐carboxylic acids are equally obtained when 4‐chloro‐, 2,4‐dichloro‐ and 2,4‐dibromo‐6‐(trifluoromethyl)pyrimidine are deprotonated with lithium diisopropylamide before being allowed to react with dry ice. In contrast, consecutive treatment of 2‐bromo‐4‐(trifluoromethyl)pyrimidine and 2‐chloro‐5‐iodo‐4‐(trifluoromethyl)pyrimidine with butyllithium affords the expected carboxylic acids in only poor yields and not even trace amounts of acid were detected when 4‐bromo‐6‐(trifluoromethyl)pyrimidine served as the substrate. The formation of bipyrimidines, emerging from either one of two competing mechanistic pathways, is a permanently menacing side reaction. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)