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

Abstract

The metal‐free reaction of terminal arylacetylenes with α,α‐dichloroaldimines in 1,1,1,3,3,3‐hexafluoro‐2‐propanol as the sole solvent results in the rapid and selective formation of γ,γ‐dichloro‐β‐amino ketones. In this solvent the expected dichlorinated 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 α′‐H at the nitrogen substituent), while electron‐deficient acetylenes only reacted with N‐tert‐butylaldimines (no α′‐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 β‐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.magnified image

Gold‐Catalyzed One‐Pot Cycloisomerization/Nucleophilic Addition/Rearrangement of Acenaphthylene Carbaldehyde Derivatives

“…To deepen our studies around the rearrangement part (Scheme 5), we performed control tests, to show the necessity of the gold complex associated with HFIP to perform efficiently the rearrangement. [16] Indeed we confirmed the orthogonal aspect of the tandem reaction, and the impact of gold on the C!O rearrangement. After 45 minutes, whereas no rearrangement occurred in the presence of gold, almost all the starting material was consumed in the presence of Considering these studies, we may propose that the presence of HFIP with the assistance of gold would promote the opening of the benzoisochromene, leading to the enol carbocation C. After a protonation and CÀ C rotation, the last elemental step on D would lead to the 6-enolendo-exo-trig product 2 a.…”

HFIP in Organic Synthesis

“…An unexpected reaction of terminal arylacetylenes with various N -alkyl-α,α-dichloroaldimines in HFIP selectively yielded γ,γ-dichloro-β-amino ketones instead of the expected dichlorinated propargylamines or allylic amines (Scheme ). Electron-rich acetylenes were the preferred substrates and the electron-withdrawing dichloromethylene moiety on the aldimines was needed as an activating group. The authors proposed that HFIP initially functions as a Brønsted acid to protonate the imine, activating it toward a rate-determining addition reaction with arylacetylenes.…”

Fluorinated Alcohols: Magic Reaction Medium and Promoters for Organic Synthesis

“…In 2016, Tehrani and co-workers described an approach to construct chlorinated β-amino ketones 115 via an unexpected reaction of imines 113 with arylacetylenes 114 in HFIP (Scheme 35). [61] Assisted by the protonation of HFIP, the reactive imino carbon of the imines can be attacked by electron-rich arylacetylenes. As illustrated in Scheme 35, the author gave a mechanism involved two intermediates.…”