Metal-Free Synthesis of Chlorinated β-Amino Ketones via an Unexpected Reaction of Imines with Arylacetylenes in 1,1,1,3,3,3-Hexafluoro-2-propanol

The metal-free reaction of terminal arylacetylenes with alpha, alpha-dichloroaldimines in 1,1,1,3,3,3-hexafluoro-2-propanol as the sole solvent results in the rapid and selective formation of gamma, gamma-dichloro-beta-amino ketones. In this solvent the expected di-chlorinated propargylamines and/or allylic amines are not formed. The dichloromethylene moiety of the aldimine acts as an activating group and is essential to accomplish this transformation. Electron-rich acetylenes lead to the best results and work well with all imines (with or without alpha'-H at the nitrogen substituent), while electron-deficient acetylenes only reacted with N-tert-butylaldimines (no alpha'-H). The mechanistic pathway showed 1,1,1,3,3,3-hexafluoro-2-propanol to protonate the aldimine, which in the rate-determining step will react with the arylacetylene to form a resonance-stabilized allene cation, which is trapped by a HFIP molecule giving rise to an enol ether, which promptly hydrolyzes to furnish exclusively the beta-amino ketones. Using DFT techniques we found that the first C-C bond forming step is the rate-determining step and is associated with a barrier of about 21 kcal mol (1).