Brønsted acid-catalyzed synthesis of trifluoromethylated azulenes via cyclization of 1-phenyl-2-CF3-1,3-enynes

Abstract

Azulene and its derivatives are important scaffolds with broad applications. The introduction of a trifluoromethyl group is an efficient way to enhance the activity and physicochemical properties of drugs and other functional molecules. However, existing methods for the synthesis of trifluoromethyl azulenes often require harsh conditions or suffer from low yield. Herein, we report a simple, Brønsted acid-catalyzed, intramolecular annulation of 1-phenyl-2-CF₃-1,3-enynes for the efficient construction of valuable trifluoromethyl-substituted azulenes. A variety of trifluoromethylated azulenes bearing diverse functional groups, including alkyl, alkoxy, phenyl, and halogen substituents, were synthesized in moderate to good yields under mild conditions. Distinct from other approaches, this  method features a metal-free protocol, mild conditions, a one-step procedure, and perfect atom economy. Mechanistic studies involving deuterium-labeling experiments and DFT calculations elucidated the reaction mechanism, which involves triple-bond protonation, ring expansion, and deprotonation.