β,β,β‐Trichloroethyl‐NH‐Enamine as Viable System for 5‐Endo‐trig Radical Cyclization via Multifaceted Cu^I−Cu^II Redox Catalysis: Single Step Synthesis of Multi‐Functionalized NH‐Pyrroles

Abstract

Here we report a mild and regioselective copper-catalyzed direct synthesis of multi-substituted and functionalized NH-pyrroles in high yields from diverse β,β,β-trichloroethyl-NH-enamines via a novel 5-endo-trig radical cyclization mode, previously known to be unviable in the enamine system. An approach to transform a geometrically 'disfavored to favored' 5-endo-trig radical cyclization mode in NH-enamine systems via multifaceted Cu I À Cu II redox catalysis generating radicals, preventing dehalogenative reduction of radical precursors and dehydrohalogenating the 5-endo-trig cyclized products have been demonstrated experimentally. With wider substrate scope, this method incorporates halo-, NH-and carbonyl functionalities besides alkyl, aryl and heteroaryl substituents in the pyrrole unit easily. These difficult to prepare 3-halo-NH-pyrroles are potential sources for natural products, agrochemicals, pharmaceuticals and organometallic chemistry. Scheme 1. a) Viable 5-endo-trig radical cyclizations in N-substituted enamide, b) unviable 5-endo-trig radical cyclizations in Nsubstituted enamine and c) transformation of unviable to viable mode in present work. UPDATES asc.wiley-vch.de Scheme 2. Synthesis of 3-chloro-NH-pyrroles 21 by Cu(I)/PMDETA-catalyzed 5-endo-trig radical cyclization-aromatization of NHenamines 20.Scheme 4. Study of the conformational role of substituents and functionalities of NH-enamines in the 5-endo-trig radical cyclization process.

Synthesis of Chlorinated, Heteroatom‐Rich and Differently Fused Tricyclic β‐Lactams by Cu(I)‐Catalyzed Halogen Atom Transfer Radical Cyclization

“…Therefore, a certain minimum concentration of catalyst and better solubility of catalyst in the reaction medium is required for producing free radical species for initiating the cyclization reaction. When 10 mol% of CuCl and PMDETA was used the reaction did not start because of the lower solubility of catalyst and minimum required concentration of radical species may not have been formed to initiate the cyclization reaction . Further stirring of reaction mixture for long hours resulted in decomposition of catalyst.…”

“…When 10 mol% of CuCl and PMDETA was used the reaction did not start because of the lower solubility of catalyst and minimum required concentration of radical species may not have been formed to initiate the cyclization reaction. [35] Further stirring of reaction mixture for long hours resulted in decomposition of catalyst. The staring material 11 a was recovered to the extent of 76% (entry 3).Therefore, reaction conditions in entry 2 were considered as optimal for efficient synthesis of the tricyclic β-lactam 12 a.…”

Recent Advancements in Pyrrole Synthesis

“…Substituted alkenes, including those of ,-unsaturated and allylic systems, are readily employed as starting materials to access pyrrole scaffolds. 25,26 For instance, Xu and…”

Recent Advances for the Synthesis of N‐Unsubstituted Pyrroles

“…Cu‐catalyzed transformation of β,β , β ‐trichloroethyl‐NH‐enamines 93 through a novel 5‐ endo‐trig radical cyclization mode was performed as a mild and regioselective protocol by Xu et al [31] . Variously polysubstituted‐ and functionalized 3‐halo‐NH‐pyrroles 96 were obtained in good yields (Scheme 30).…”

“…Cu-catalyzed transformation of β,β,β-trichloroethyl-NH-enamines 93 through a novel 5-endo-trig radical cyclization mode was performed as a mild and regioselective protocol by Xu et al [31] Variously polysubstituted-and functionalized 3-halo-NH-pyrroles 96 were obtained in good yields (Scheme 30). This transformation of NH-enamine system occurs as a result of the multifaceted redox catalysis of Cu I -Cu II with the formation of pyrrolidine radicals.…”