Synthesis of 1,3-Bis-trifluoromethylated (Hetero)cyclohexane-2-carboxylates from Alkylidenemalononitriles

Reported herein is a method for the syn-selective 1,3-bis-trifluoromethylation of (hetero)cycloalkylidenemalononitriles. The malononitrile-containing intermediate can be readily converted into carboxylates (and derivatives thereof) by oxidative decyanation. The products of this two-step sequence are 1,3-bis-trifluoromethylated physicochemically altered analogues of common (hetero)cyclohexane carboxylates. This study includes optimization of the bis-trifluoromethylation reaction, scope studies, synthesis of various new bis-trifluoromethylated (hetero)cycloalkane carboxylates, representative transformations relevant to pharmaceutical synthesis, mechanistic studies, and some computational analyses of the newly accessible scaffolds.