Organophotoredox Hydrodefluorination of Trifluoromethylarenes with Translational Applicability to Drug Discovery

Abstract

Molecular editing such as insertion, deletion, and single atom exchange in highly functionalized compounds is an aspirational goal for all chemists. Here, we disclose a photoredox protocol for the replacement of a single fluorine atom with hydrogen in electron-deficient trifluoromethylarenes including complex drug molecules. A robustness screening experiment shows that this reductive defluorination tolerates a range of functional groups and heterocycles commonly found in bioactive molecules. Preliminary studies allude to a catalytic cycle whereby the excited state of the organophotocatalyst is reductively quenched by the hydrogen atom donor, and returned in its original oxidation state by the trifluoromethylarene.

Organic thermally activated delayed fluorescence (TADF) compounds used in photocatalysis

“…162). 352 The proposed mechanism, shown in Fig. 163, suggests the thiolate anion generated by deprotonation of 4-hydroxythiophenol (4-HTP) under basic conditions, is capable of reductively quenching the excited PC.…”

C-F bond activation under transition-metal-free conditions

“…Subsequently, Gouverneur and co-workers' research [57] on selective mono-HDF of trifluoromethylarenes with electron-withdrawing groups (EWG) further significantly expanded the application scope (Scheme 16). Functionalities on the aromatic ring, including cyano (71, 72), fluorine (72), ester (73), unprotected sulfonamide (74), were tolerated.…”

Late-stage difluoromethylation: concepts, developments and perspective

“…Approaches towards RCF 2 H based on carbon-fluorine bond formation or hydrodefluorination are not described in this review. [26][27][28][29][30] 1.1 Properties of the CF 2 H group…”