A General Protocol for C−H Difluoromethylation of Carbon Acids with TMSCF₂Br

Abstract

An efficient method for the selective C‐difluoromethylation of carbon acids with the reagent TMSCF2Br has been developed. A variety of structurally diverse sp3‐ and sp‐hybridized carbon nucleophiles, including esters, amides, fluorenes, terminal alkynes, β‐ketoesters, malonates, and other activated C−H nucleophiles, could be efficiently and selectively transformed into the corresponding C‐difluoromethylated products under mild conditions. This protocol is also effective for the late‐stage difluoromethylation of pharmaceutically relevant molecules and can be readily scaled up. Moreover, ambident substrates with more than one reactive site towards difluorocarbene can be difluoromethylated orthogonally using TMSCF2Br.

Photoredox-catalyzed silyldifluoromethylation of silyl enol ethers

“…Recently, (bromodifluoromethyl)trimethylsilane (1) which can be readily obtained from the Ruppert-Prakash reagent [14,15], has been introduced as a reagent for the synthesis of various difluorinated compounds [16][17][18]. This silane is very sensitive to Lewis bases and accordingly it was used as a precursor of difluorocarbene, which can react with enol ethers [19,20] (Scheme 1).…”

Late-stage difluoromethylation: concepts, developments and perspective

“…In 2019, Hu and co-workers demonstrated that commercially available TMSCF 2 Br was an efficient reagent for the C-difluoromethylation of a range of C(sp 3 ) and C(sp) nucleophiles, such as esters, amides, fluorenes, terminal alkynes, malonates, b-ketoesters and other activated C-H nucleophiles (Scheme 29C). 129 For this protocol, the authors also propose a difluorocarbene mechanism.…”

“…In 2019, Hu and co-workers reported the use of commercially available TMSCF 2 Br as a difluoromethylation reagent for a selection of electron-rich and electron-neutral alkynes under ambient conditions (Scheme 62). 129 Heterocycles such as dibenzothiophene and benzofuran are compatible under the optimised reaction conditions. The authors suggested that a difluorocarbene mechanism is operating.…”

Pd‐Catalyzed Transfer of Difluorocarbene for Three Component Cross‐Coupling†

“…[ 4 ] Hu disclosed an efficient C—H difluoromethylation by using TMSCF 2 Br, a reagent developed by them recently, [ 5 ] as a difluorocarbene source. [ 6 ] Difluorocarbene can also act as a dipolar CF 2 unit for consecutive bond‐forming reactions, [ 7 ] which were described by Dilman. [ 8 ] Outstanding accomplishments have been achieved in the chemistry of difluorocarbene.…”