Visible-Light-Induced C–F Bond Activation for the Difluoroalkylation of Indoles

Abstract

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

Trifunctionalization of Cinnamyl Alcohols Provides Access to Brominated α,α-Difluoro-γ-lactones via a Photoinduced Radical–Polar–Radical Mechanism

“…Pursuing our interest in the functionalization of organic motifs with the gem -difluoro functional group (CF 2 R), herein we report a photochemical trifunctionalization method for the synthesis of α,α-difluoro-β-(bromo­((hetero)­aryl)­methyl)-γ-lactones from cinnamyl alcohols as feedstocks via well-orchestrated Giese addition/lactonization/XAT processes in a single flask (Scheme ). To the best of our knowledge, the construction of such brominated α,α-difluoro-γ-lactones through the sequential formation of C–CF 2 , C–O, and C–Br bonds has never been previously explored.…”

Photocatalyzed C–F Bond Heteroarylation of Trifluoromethyl­arenes with Heteroarenes: Two Roles of Bu3SnI as Fluoride Ion Scavenger and Activator for Photocatalyst

“…The late-stage C-F bond transformation is one of the most important issues in the development of F-containing drugs and agrochemicals. We demonstrated the heteroarylation of a C-F bond in bicalutamide (8), which is an antiandrogen used to treat prostate cancer. 17 The structure of 8 includes various functionalities such as CN and OH groups, amide and sulfone moieties, and C(sp 2 )-F bonds; however, a C-F bond of the CF3 group was selectively transformed to a pyrrolyl group (Scheme 5).…”

Difluoroalkylation of Anilines via Photoinduced Methods

“…Many arene difluoroalkylation reports utilize transition-metal (TM) catalysts, such as Ni or Pd from both C–H or C–Y substitution (Scheme , top, Y = B­(OH) 2 , I, Br). Also, photoinduced methods , provide access to the difluoroalkylated arenes through simple photocatalysts or by synergistic transition-metal and photocatalyst dual catalysis. For example, Molander explored the installation of the gem -difluoro group using boronic acids via Ir/Cu combination.…”