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.

An intermolecular, photocatalytic dicarbofunctionalization (DCF) of olefins enabled by the merger of Giese-type addition with Ni/photoredox dual catalysis has been realized. Capitalizing on the rapid addition of 3° radicals to alkenes and their reluctance toward single electron metalation to Ni complexes, regioselective alkylation and arylation of olefins is possible. This dual catalytic method not only permits elaborate species to be assembled from commodity materials, but also allows quaternary and tertiary centers to be installed in a singular, chemoselective olefin difunctionalization. This multicomponent process occurs under exceptionally mild conditions, compatible with a diverse range of functional groups and synthetic handles such as pinacolboronate esters. This technology was directly applied to the synthesis of an intermediate to a preclinical candidate (TK-666) and its derivatives.

Alkenes, ethers, and alcohols account for a significant percentage of bulk reagents available to the chemistry community. The petrochemical, pharmaceutical, and agrochemical industries each consume gigagrams of these materials as fuels and solvents each year. However, the utilization of such materials as building blocks for the construction of complex small molecules is limited by the necessity of prefunctionalization to achieve chemoselective reactivity. Herein, we report the implementation of efficient, sustainable, diaryl ketone hydrogen-atom transfer (HAT) catalysis to activate native C−H bonds for multicomponent dicarbofunctionalization of alkenes. The ability to forge new carbon−carbon bonds between reagents typically viewed as commodity solvents provides a new, more atom-economic outlook for organic synthesis. Through detailed experimental and computational investigation, the critical effect of hydrogen bonding on the reactivity of this transformation was uncovered.

A mild, metal-free, regioselective carbofluorination of dehydroalanine derivatives has been developed. Alkyl radicals resulting from visible-light photoredox catalysis engage in a radical conjugate addition to dehydroalanine, with subsequent fluorination of the newly generated radical to afford an α-fluoro-α-amino acid. By using a highly oxidizing organic photocatalyst, this process incorporates non-stabilized primary, secondary, and tertiary alkyl radicals derived from commercially available alkyltrifluoroborates to furnish a wide range of fluorinated unnatural amino acids.

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