Site-selective remote C(sp3)–H heteroarylation of amides via organic photoredox catalysis

Abstract

Radical translocation processes triggered by nitrogen-centered radicals (NCRs), such as 1,5-hydrogen atom transfers (1,5-HAT), demonstrated by the well-established Hofmann-Löffler-Freytag (HLF) reaction, provide an attractive approach for the controllable and selective functionalization of remote inert C(sp3)–H bonds. Here we report an amidyl radical-triggered site-selective remote C(sp3)–H heteroarylation of amides under organic photoredox conditions. This approach provides a mild and highly regioselective reaction affording remote C(sp3)–H heteroarylated amides at room temperature under transition-metal free, weakly basic, and redox-neutral conditions. Non-prefunctionalized heteroarenes, such as purines, thiazolopyridines, benzoxazole, benzothiazoles, benzothiophene, benzofuran, thiazoles and quinoxalines, can be alkylated directly. Sequential and orthogonal C–H functionalization of different heteroarenes by taking advantage pH value or polarity of radicals has also been achieved. DFT calculations explain and can predict the site-selectivity and reactivity of this reaction. This strategy expands the scope of the Minisci reaction and serves as its alternative and potential complement.

Photoinduced and Palladium-Catalyzed Remote Desaturation of Amide Derivatives

“…We recently became interested in remote C­(sp3)–H functionalization mediated by nitrogen-centered radicals ( N -radicals) under photoredox conditions. , The success of these reactions depends on the generation of N -radicals from hydroxylamine derivatives and subsequent radical translocation giving the alkyl radicals. Inspired by these N -radical-mediated remote C­(sp3)–H functionalizations, as well as the aforementioned HAT-mediated desaturation, we would like to report a photoinduced and Pd-catalyzed remote desaturation of amide derivatives mediated by N -radicals giving unsaturated amides (Figure d).…”

“…Based on the aforementioned mechanistic studies and relevant literatures − a proposed mechanism for this reaction is presented in Figure . Initially, the Pd(0) complex is excited by visible light, which is quenched by an O -acyl hydroxamide 1a .…”

Visible Light‐induced Functionalization of C−H Bonds: Opening of New Avenues in Organic Synthesis

“…In 2019, the Yu group demonstrated N-centered radical triggered unconventional remote C(sp 3 )À H functionalization of aliphatic amides (29) via 1,5-HAT process to derive heteroarylated amides (30) under photoredox conditions (Scheme 13). [54] The proposed mechanism involves the formation of amidyl radical from hydroxamide via single-electron reduction assisted by photoexcited 3CzClIPN* along with the generation of carboxylate anion and 3CzClIPN + . 1,5-HAT from carbon to nitrogen then generates a carbon-centered radical from carbon to nitrogen which subsequently delivers the desired product upon the loss of hydrogen atom in the presence of a base.…”

Radical Functionalization of Remote C(sp 3 )–H Bonds Mediated by Unprotected Alcohols and Amides

“…63 Late-stage modification of amide-based bioactive molecules opens an efficient arena for drug screening. Inspired by the pioneering Hofmann-Löffler-Freytag (HLF) reaction that enables pyrrolidine formation via remote C(sp 3 )-H functionalization of aliphatic amines (Scheme 9), 3 recently many research groups, for example, Li, 64,65 Cook, 66 Muñiz, 67 Studer, 68,69 Yu, 70,71 Zhu, 72,73 Nagib, 74 Roizen, 75 Wang, 76 Leonori, 77 Hong, 78 Liu, 79 and Yang 80 et al, have made new breakthroughs in amidyl radical-mediated remote C(sp 3 )-H functionalization. Notably, Liu et al 81 achieved the copper-catalyzed regio-and enantio-selective Sonogashira-type oxidative cross-coupling of C(sp 3 )-H bonds with alkynes by using N-fluoroamides as amidyl radical precursors.…”