[CuI – TIBAL] – effective catalytic system for KA2 reaction to prepare tetrasubstituted propargylamine at room temperature

Three-component couplings of ketones, alkynes, and amines (KA2 reaction) are the most efficient method of forming tetrasubstituted propargylamine building blocks for rapid access to biologically active targets. Typically, the reaction is carried out at temperatures above 100 °C (or under microwave irradiation conditions) in the presence of copper catalysts in toluene or without solvent. The use of AuBr3 instead of copper salts allows the reaction temperature to be reduced to 60 °C. We have discovered for the first time that the CuI - TIBAL catalytic system (20 mol. %) makes it possible to carry out similar reactions in dichloromethane or dichloroethane in quantitative yield even at room temperature. Alkyl- and aryl-substituted terminal acetylenes (including diacetylenes), a number of secondary amines (piperidine, pyrrolidine, dibutylamine) and a number of ketones (cyclohexanone, cyclopentanone, acetone, 2-octanone, 3-nonanone) were involved in KA2 reaction. A solvent is an important factor in the reaction. The use of toluene and hexane leads to a negligible yield of tetrasubstituted propargylamines at room temperature. Thus, we found an activating effect of the TIBAL additive and dichloromethane on the KA2 reaction.