Metallaphotoredox Difluoromethylation of Aryl Bromides

Abstract

Herein, we report a convenient and broadly applicable strategy for the difluoromethylation of aryl bromides by metallaphotoredox catalysis. Bromodifluoromethane, a simple and commercially available alkyl halide, is harnessed as an effective source of difluoromethyl radical by silyl‐radical‐mediated halogen abstraction. The merger of this fluoroalkyl electrophile activation pathway with a dual nickel/photoredox catalytic platform enables the difluoromethylation of a diverse array of aryl and heteroaryl bromides under mild conditions. The utility of this procedure is showcased in the late‐stage functionalization of several drug analogues.

Hydrodifluoromethylation of Alkenes with Difluoroacetic Acid

“…[4] Furthermore,t he exothermic decomposition of these reagents at elevated temperature or in contact with water presents safety concerns,e specially for large-scale synthesis. [5] In response to these challenges,l atestage difluoromethylation reactions of (hetero)arenes [6] and new transformations,such as the hydrodifluoromethylation of alkene starting materials,h ave been developed. In 2015, Dolbier and co-workers disclosed an elegant photocatalytic hydrodifluoromethylation of electron-deficient alkenes.…”

Nickel-catalyzed oxidative fluoroalkylation of aryl halides via paired electrolysis

“…1B, left). 11,12 However, the use of instable organometallic reagents, the stoichiometric reductants, 6,9,14,15 and gaseous uorine sources 16 could not be avoided. The readily accessible and operationally simple oxidative di uoromethylating reagents are promising candidate to address the above issues.…”

Copper-Catalyzed Difluoromethylation of Alkyl Halides Enabled by Aryl Radical Activation of Carbon–Halogen Bonds

“…60 One of the most straightforward approaches to the synthesis of CF2H-containing compounds is the direct difluoromethylation of the corresponding organohalides. Although transition metal catalysis has received great success in the difluoromethylation of aryl halides, [61][62][63][64][65][66][67][68][69] the analogous reaction with unactivated alkyl halides remains a formidable challenge. 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.…”