A visible-light mediated three-component radical process using dithiocarbamate anion catalysis

Abstract

A three-component radical process is reported that, by coupling alkyl chlorides, maleimides, and heteroaromatic fragments, installs multiple biologically relevant heterocycles within complex cascade products. This method, which generates radicals via an SN2-based photochemical catalytic mechanism, activates substrates incompatible with or inert to classical radical-generating strategies.

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“…Langlois' reagent was instead used to introduce the trifluoromethyl group (Scheme 68). 133 Maleimides proved to be suitable unsaturated radical acceptors, as demonstrated in a recent report from Cuadros, Horwitz et al 134 The reaction entailed the carbo-difunctionalization of the double bond by reaction with alkyl chlorides as the radical precursor and heterocycles (Scheme 69). The authors presented peculiar reactivity manifold based on the choice of dithiocarbamate (DTC) anion as the catalyst.…”

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“…For the reaction mechanism, the authors declared a radical pathway [55] radical-type reaction, which coupled with readily available alkyl chlorides 309, maleimides 310, and heteroaromatic fragments 311 to give complex products as well as chiral compounds with high diastereocontrol (Scheme 52a). [56] Additionally, following the similar mechanism involving the generation of radicals upon S N 2-based activation of alkyl halides and blue light irradiation using a nucleophilic organocatalyst, the α-alkylation of ketones could also be achieved from the corresponding silyl enol ethers 314 and alkyl radical precursors 313 (Scheme 52b). [57] Furthermore, co-catalyzed with a chiral amine catalyst 319, the stereoselective catalytic α-alkylation of ketones was developed, which further extended the synthetic utility of this strategy (Scheme 52c).…”

“…And the redox-neutral nature of this radical generation strategy made it compatible with a lot of redox-sensitive radical precursors and catalysts, which thus allowing the installation of multiple biologically relevant compounds and inspiring the design of other voltage-independent radical applications in organic synthesis. [58] Not just limited to the substrates amenable to generating alkyl radicals, [54,[56][57] very recently, Melchiorre group expanded their photochemical catalytic approach to the generation of acyl radicals and carbamoyl radicals via nucleophilic acyl substitution of acyl/carbamoyl chlorides for the subsequent CÀ C bond construction. [59] Using commercially available potassium ethyl xanthate 323 as the catalyst, both aryl and alkyl acyl chlorides 320 could couple with different electron-poor olefins 321 through a Giese addition process under the irradiation of blue LED and mild reaction conditions (Scheme 53a).…”

“…Based on their preliminary work, Melchiorre and co‐workers further realized a visible light mediated three‐component radical‐type reaction, which coupled with readily available alkyl chlorides 309 , maleimides 310 , and heteroaromatic fragments 311 to give complex products 312 as well as chiral compounds with high diastereocontrol (Scheme 52a) [56] . Additionally, following the similar mechanism involving the generation of radicals upon S N 2‐based activation of alkyl halides and blue light irradiation using a nucleophilic organocatalyst, the α‐alkylation of ketones could also be achieved from the corresponding silyl enol ethers 314 and alkyl radical precursors 313 (Scheme 52b) [57] .…”

“…Not just limited to the substrates amenable to generating alkyl radicals, [54,56–57] very recently, Melchiorre group expanded their photochemical catalytic approach to the generation of acyl radicals and carbamoyl radicals via nucleophilic acyl substitution of acyl/carbamoyl chlorides for the subsequent C−C bond construction [59] . Using commercially available potassium ethyl xanthate 323 as the catalyst, both aryl and alkyl acyl chlorides 320 could couple with different electron‐poor olefins 321 through a Giese addition process under the irradiation of blue LED and mild reaction conditions (Scheme 53a).…”