Copper-Catalyzed 1,2-Difunctionalization Trifluoromethylamidation of Alkynes Assisted by a Coordinating Group

Abstract

The radical 1,2-difunctionalization reaction of alkynes has evolved into a versatile approach to multisubstituted alkylenes. However, robust catalytic strategies to perform carboamination are lacking, despite the ubiquity of resulting enamines in natural molecules, bioactive and pharmaceutical compounds. Herein, we show that a bidentate coordinating group judiciously installed on amines could act as an efficient tool for enabling radical trifluoromethylamidation of alkynes. This strategy exhibits a broad substrate scope with good functional group compatibility and is amenable for late-stage functionalization of natural compounds and biologically relevant motifs, allowing a straightforward synthesis of a large library of CF3-containing enamides, the high-value pharmacophores, in a single step from readily accessible amides, Langlois’ reagent, and alkynes. The current methodology can also be successfully extended to difluoromethylamidation of alkynes. Additionally, various mechanistic experiments, such as competition experiments, H/D isotopic exchanging experiments, radical trap experiments, Hammett studies, and kinetic studies, have been performed for a better understanding of the reaction mechanism.

Photocatalytic Cyclization Cascades by Radical Relay toward Pyrrolo[1,2-a]indoles: Synthesis, Mechanism, and Application

“…Considering the biological and functional activities of organic compounds significantly influenced by the trifluoromethyl group, various methodologies for the preparation of trifluoromethylated organic compounds have been developed in the past decades. − Notably, Langlois’ reagent (CF 3 SO 2 Na) has generally been used in the field of radical chemistry, probably due to its high stability, commercial availability, and lower-cost. − Prompted by these related publications and our previous work, − we envisioned that a series of trifluoromethylated pyrrolo­[1,2- a ]­indoles could be prepared from the oxidative cyclization cascade of unactivated N -alkene-linked indoles with CF 3 SO 2 Na by a photocatalytic trifluoromethyl radical relay (Scheme ). Hopefully, this paper was also highlighted by gaining insights into reaction mechanisms through DFT-based calculation and application exploration in living-cell imaging.…”

Coordinating activation strategy enables 1,2-alkylamidation of alkynes

“…In order to achieve this challenging catalytic process, we considered installing a 2-pyridylacyl group 9 on the amine to serve as the coordinating group. We surmised that the metallacycle species, a coordination product formed from the reaction of the metal catalyst with a substrate bearing a bidentate auxiliary, could efficiently catch the vinyl radical intermediate, thus providing a straightforward strategy for the realization of difunctionalization carboamidation of alkynes.…”

Visible Light-Induced Copper-Catalyzed Regio- and Stereoselective Difluoroalkylthiocyanation of Alkynes

“…Later, the perfluoroalkylcyanation of arylacetylenes with R f I and TMSCN was reported by Bao in the presence of a copper catalyst and stoichiometric peroxide (Scheme b, ii) . Very recently, Li successfully introduced a CF 3 group and a coordinating group-tethered amide moiety into alkynes through a copper-catalyzed oxidant-promoted procedure (Scheme b, iii), and the group of Shi and Gao achieved fluoroalkylphosphorothiolation of terminal alkynes under cooper catalysis or iridium-photoredox/copper dual catalysis (Scheme b, iv) . In addition, the Reiser group demonstrated the effectiveness of copper-phenanthroline complexes as photoredox catalysts and made great contributions in the transformation of C–C multiple bonds .…”