Defluoroalkylation of Trifluoromethylarenes with Hydrazones: Rapid Access to Benzylic Difluoroarylethylamines

Abstract

Here, we report an efficient and modular approach toward the formation of difluorinated arylethylamines from simple aldehyde-derived N,N-dialkylhydrazones and trifluoromethylarenes (CF 3 -arenes). This method relies on selective C−F bond cleavage via reduction of the CF 3 -arene. We show that a diverse set of CF 3 -arenes and CF 3 -heteroarenes react smoothly with a range of aryl and alkyl hydrazones. The β-difluorobenzylic hydrazine product can be selectively cleaved to form the corresponding benzylic difluoroarylethylamines.

Recent Advance in the C−F Bond Functionalization of Trifluoromethyl Aromatic and Carbonyl Compounds

“…Based on the previous research, an efficient and modular approach toward the formation of β ‐difluorobenzylic hydrazines from simple aldehyde‐derived N,N ‐dialkyl hydrazones and inexpensive trifluoromethylarenes was developed by Jui and Blakey in 2023 (Scheme 8V) [29] . In contrast to the previously proposed mechanism, this reaction was facilitated by CO 2 ⋅ − reduction and HAT pathway, operating through an efficient radical chain mechanism.…”

Photoinduced Dehalocyclization to Access Oxindoles Using Formate as a Reductant

“…Due to its negative reduction potential, CO 2 •− ( E 1/2 ° = −2.2 V vs SCE) has been used to activate a wide range of challenging chemical bonds ( e.g ., aryl chlorides, aryl bromides, benzyl C‐F, etc .) through single electron transfer (SET) process, [ 37‐43 ] facilitating radical generation. Considering the property of CO 2 •− and continuing our interest in photoredox chemistry, [ 44‐47 ] we envisioned that ortho ‐ bromophenylacrylamide A could be reduced by CO 2 •− through a single electron reduction process to yield the intermediate aryl radical B , accompanied by the production of CO 2 .…”

Recent Advances in Reactions Involving Carbon Dioxide Radical Anion

“…Recently, Blakey's group further expanded the alkene substrate scope to hydrazones, leading to benzylic difluoroarylethylamines in good results (Scheme 7). 23 In the same year, Shang and co-workers further modified the conditions of defluoroalkylation and hydrodefluorination of trifluoromethyls, which could be available in the absence of an external photocatalyst with 4-methoxythiophenol S6 as both a HAT catalyst and a strongly reducing electron-donating redox catalyst (Scheme 8). 11 Trifluoroacetates, trifluoroacetamides, •− , which could also reduce ArS • to regenerate ArS − to complete the photoredox cycle.…”