Radical hydrodifluoromethylation of unsaturated C−C bonds via an electroreductively triggered two-pronged approach

Abstract

Due to its superior ability in controlling pharmaceutical activity, the installation of difluoromethyl (CF2H) functionality into organic molecules has been an area of intensive research. In this context, difluoromethylation of C−C π bonds mediated by a CF2H radical have been pursued as a central strategy to grant access to difluoromethylated hydrocarbons. However, early precedents necessitate the generation of oxidative chemical species that can limit the generality and utility of the reaction. We report here the successful implementation of radical hydrodifluoromethylation of unsaturated C−C bonds via an electroreductively triggered two-pronged approach. Preliminary mechanistic investigations suggest that the key distinction of the present strategy originates from the reconciliation of multiple redox processes under highly reducing electrochemical conditions. The reaction conditions can be chosen based on the electronic properties of the alkenes of interest, highlighting the hydrodifluoromethylation of both unactivated and activated alkenes. Notably, the reaction delivers geminal (bis)difluoromethylated products from alkynes in a single step by consecutive hydrodifluoromethylation, granting access to an underutilized 1,1,3,3-tetrafluoropropan-2-yl functional group. The late-stage hydrodifluoromethylation of densely functionalized pharmaceutical agents is also presented.

A guide to organic electroreduction using sacrificial anodes

“…In 2022, Kim, Lee, Kwak and co-workers developed an electroreductive hydrodifluoromethylation of unsaturated C–C bonds in the presence of commercially available CF 2 H sources (Scheme 29). 61 The use of a sacrificial Zn anode enabled the reductive cleavage of the C–S bond to generate a CF 2 H radical. The low oxidation potential of Zn [Eox(Zn 0 /Zn 2+ ) = 0.01 V vs. Fc/Fc + ] could also suppress the undesired oxidation of a carbon-centered radical to carbocation.…”

Tetrafluoroisopropylation of alkenes and alkynes enabled by photocatalytic consecutive difluoromethylation with CF2HSO2Na

“…1b ) 15 , however, the use of highly volatile 1,1,3,3-tetrafluoroacetone (CF 2 HCOCF 2 H) has hindered its application. An alternative procedure relied on the electroreductive double hydrodifluoromethylation of terminal aryl alkynes with Hu reagent, 2-PySO 2 CF 2 H, which suffers from low yields and limited substrate scope 16 . Therefore, the development of efficient and general protocols for accessing tetrafluoroisopropylated compounds is still highly desirable.…”

Difluoromethylation–Carboxylation and −Deuteration of Alkenes Triggered by Electroreduction of Difluoromethyltriphenylphosphonium Bromide

“…Organic electrosynthesis is acknowledged as an environmentally benign synthetic tactic owing to the use of electrons as mass-free oxidants and reductants, rather than the conventional redox reagents, and this strategy is also applied to the electrochemical difluoromethylation, including electrooxidative and electroreductive difluoromethylation. Compared with the extensive research on the electrooxidative difluoromethylation reaction, electroreductive difluoromethylation is rarely reported. As a supplement to electrooxidative difluoromethylation, electroreductive difluoromethylation can further enrich the reaction types and extend the product range.…”