The installation of gem-difluoromethylene groups into organic structures remains a daunting synthetic challenge despite their attractive structural, physical, and biochemical properties. A very efficient retrosynthetic approach would be the functionalization of a single C−F bond from a trifluoromethyl group. Recent advances in this line of attack have enabled the C−F activation of trifluoromethylarenes, but limit the accessible motifs to only benzylic gem-difluorinated scaffolds. In contrast, the C−F activation of trifluoroacetates would enable their use as a bifunctional gem-difluoromethylene synthon. Herein, we report a photochemically mediated method for the defluorinative alkylation of a commodity feedstock: ethyl trifluoroacetate. A novel mechanistic approach was identified using our previously developed diaryl ketone HAT catalyst to enable the hydroalkylation of a diverse suite of alkenes. Furthermore, electrochemical studies revealed that more challenging radical precursors, namely trifluoroacetamides, could also be functionalized via synergistic Lewis acid/photochemical activation. Finally, this method enabled a concise synthetic approach to novel gem-difluoro analogs of FDA-approved pharmaceutical compounds.

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An aryl disulfide mediated C−F bond activation of the trifluoromethyl group to generate valuable gem-difluoroalkylindoles is described. This method relies on readily available commodity reagents under mild reaction conditions and represents the first transition-metal-free redox-neutral C−F bond activation strategy. The reaction employs various substituted indoles and αfluoro-substituted esters. Further, this mode of C−F activation was also amenable to the activation of trifluoromethylated arenes for the preparation of bis-benzylic gem-difluoromethylenes between indole and arene substructures, providing access to a unique chemical space.T he incorporation of fluorine into organic molecules is well-known to alter chemical properties, including stability, reactivity, acidity, and conformational bias. 1−3 Therefore, substantial efforts have been invested in incorporating these motifs into organic frameworks. 1,2,4,5 For example, over 50% of new agrochemicals introduced on the market from 1998 to 2020 contained at least one C−F bond, 6 and over 40% of new small molecule drugs in 2018 and 2019 were fluorinated compounds. 7 Another important class of pharmaceutically relevant motifs are indoles, 8,9 as they are among the most prevalent substructures in biologically active small-molecule drugs. 10,11 Consequently, the ability to incorporate fluorine onto indoles is of high interest and has been pursued in both academic and industrial laboratories. 12 Specifically, the gem-difluoromethylene motif is an attractive bioisostere for common organic functional groups such as alcohols, amines, and ketones, and is known to improve biological properties while providing greater chemical stability. 13,14 Early efforts on the synthesis of gem-difluoromethylated indoles relied on the use of transition-metal-mediated or -catalyzed reactions (Scheme 1A). These methods require the use of catalytic Pd, 15 Ni, 16 or Cu 17,18 under elevated temperatures. Further, these methods make use of either the activated ethyl (iodo-or bromo)difluoroacetate precursor. Another report of a Rh-catalyzed method exists. 19 However, this approach requires the use of a difluorovinyl precursor at elevated temperatures. More recently, light-induced methods for the preparation of difluoromethylene-containing indoles have appeared in the literature as an alternative (Scheme 1B). These methods used an iridium, 20,21 ruthenium, 22,23 or a triphenylphosphine photocatalyst. 24 However, these lightinduced methods again relied on the use of activated, noncommodity reagents, and do not provide access to a large pool of available substrates. Thus, the ability to install the gem-difluoroalkyl group onto indoles with a more diverse