Difluoromethylation of Alkyl Bromides and Iodides with TMSCF₂H

Abstract

We describe, for the first time, two protocols for direct difluoromethylation of unactivated alkyl bromides and iodides. Reactions of alkyl iodides with TMSCF 2 H were mediated by a copper catalyst using CsF as the activator, while reactions of less reactive alkyl bromides required a combination of palladium and a stoichiometric amount of CuI as the catalysts. Preliminary mechanistic studies of the synergistic Pd/Cu-catalyzed difluoromethylation of alkyl bromides suggest that it proceeds likely via a Pd(I)/Pd(III) catalytic cycle.

Late-stage difluoromethylation: concepts, developments and perspective

“…In 2021, Shen and co-workers described the direct difluoromethylation of unactivated alkyl bromides, iodides, tosylates and mesylates (Scheme 38). 156 The authors illustrated that alkyl iodides, tosylates, and mesylates readily reacted with TMSCF 2 H and CsF as activator under copper catalysis. Alkyl bromides required a combination of stoichiometric CuI and catalytic amounts of Pd(dba) 2 .…”

Palladium‐catalyzed difluoromethylation and difluoroalkylation reactions: An overview

“…Zhao et al [ 43 ] proposed a method for the difluoromethylation of alkyl iodides and bromides. Cu catalyst was utilized in the case of alkyl iodides, and both Pd and Cu catalysts were utilized with alkyl bromides.…”

Copper‐Catalyzed Difluoromethylation of Alkyl Iodides Enabled by Aryl Radical Activation of Carbon–Iodine Bonds

“…Prakash has reported a nucleophilic substitution approach to the conversion of primary alkyl halides to their corresponding difluoromethyl phenyl sulfones, which were then transformed to the alkyl difluoromethanes using the sodium/mercury amalgam reduction [22] . Very recently, the Shen group has reported an elegant Pd‐catalyzed approach for the difluoromethylation of primary alkyl halides with TMSCF 2 H as the CF 2 H source along with stoichiometric copper iodide [23] . Nonetheless, the limitation to primary alkyl halides and the use of large quantity of copper salts might dampen the synthetic utilities of these methods.…”