Electrochemical Trifluoromethoxylation of (Hetero)aromatics with a Trifluoromethyl Source and Oxygen

Abstract

Trifluoromethoxylated aromatics (ArOCF3) are valuable structural motifs in the area of drug discovery due to the enhancement of their desired physicochemical properties upon the introduction of the trifluoromethoxy group (CF3O). Although significant progress has been made recently in the introduction of CF3O group into aromatics, current methods either require the use of expensive trifluoromethoxylation reagents or require harsh reaction conditions. We present a conceptually new and operationally simple protocol for the direct C−H trifluoromethoxylation of (hetero)aromatics by the combination of the readily available trifluoromethylating reagent and oxygen under electrochemical reaction conditions. This reaction proceeds through the initial generation of CF3 radical followed by conversion to CF3O radical, addition to (hetero)aromatics and rearomatization. The utility of this electrochemical trifluoromethoxylation is illustrated by the direct incorporation of CF3O group into a variety of (hetero)aromatics as well as bio‐relevant molecules.

Visible-Light-Induced DDQ-Catalyzed Fluorocarbamoylation Using CF3SO2Na and Oxygen

“…Instead, a trace amount of TEMPO−CF 3 was only detected by GC-MS, which suggests that a redox process between CF 3 SO 2 Na and DDQ under visible-light irradiation is involved in this transformation. 22 Considering these experimental results and related information from the previous literatures, 21,23 we proposed a plausible mechanism as described in Scheme 5. First, the excited DDQ induced by visible-light irradiation can oxidize CF 3 SO 2 Na to produce the CF 3 SO 2 radical, which is transformed to the CF 3 radical by releasing SO 2 .…”

“…First, the excited DDQ induced by visible-light irradiation can oxidize CF 3 SO 2 Na to produce the CF 3 SO 2 radical, which is transformed to the CF 3 radical by releasing SO 2 . 15 The CF 3 radical is reacted with oxygen to generate the CF 3 OO radical, 23 which is converted to trifluoromethyl hydroperoxide (CF 3 OOH) through proton transfer and reoxidation of the semiquinone radical anion to DDQ. Finally, the decomposition of CF 3 OOH provides carbonyl difluoride, which is subsequently reacted with amines to afford carbamoyl fluorides.…”

New synthetic approaches toward OCF3-containing compounds

“…In 2021, the Qing group was inspired by pioneering progress in the synthesis of oxygen-containing compounds using molecular oxygen as an oxygen source and reported a novel protocol (Scheme 5). 22 To avoid complex and expensive reagents and pre-functionalized substrates, readily available trifluoromethylating reagent 17 and oxygen were chosen as the OCF 3 sources to react with (hetero)aromatics or bio-relevant molecules. This atom-economical approach was compatible with a variety of commercially available drugs, for instance, Trancopal (neural system drug 18f , 50%) and Letrozole (anti-cancer drug 18g , 69%).…”