Diastereoselective Radical Aminoacylation of Olefins through N-Heterocyclic Carbene Catalysis

Abstract

There have been significant advancements in radical-mediated reactions through covalent-based organocatalysis. Here, we present the generation of iminyl and amidyl radicals via N-heterocyclic carbene (NHC) catalysis, enabling diastereoselective aminoacylation of trisubstituted alkenes. Different from photoredox catalysis, single electron transfer from the deprotonated Breslow intermediate to O-aryl hydroxylamine generates an NHC-bound ketyl radical, which undergoes diastereocontrolled cross-coupling with the prochiral C-centered radical. This operationally simple method provides a straightforward access to a variety of pyrroline and oxazolidinone heterocycles with vicinal stereocenters (77 examples, up to >19:1 d.r.). Electrochemical studies of the acyl thiazolium salts support our reaction design and highlight the reducing ability of Breslow-type derivatives. A detailed computational analysis of this organocatalytic system suggests that radical−radical coupling is the rate-determining step, in which π−π stacking interaction between the radical intermediates subtly controls the diastereoselectivity.

Radical acylation: concepts, synthetic applications and directions

“…More recently, Zhao's group developed NHC-catalyzed radical diastereoselective iminoacylation and amidoacylation of trisubstituted alkenes, providing ready access to functionalized pyrrolines (Scheme 31). 57 With NHC-1 (20 mol%) as cata-lyst, NO 2 -substituted oximes tethered to an alkenyl group and aldehydes in DMSO at 60 °C with Cs 2 CO 3 (1.5 equiv.) as base diastereoselectively delivered the corresponding substituted pyrroline in satisfactory yields.…”

Synthesis of 2-pyrrolidinone derivativesviaN-heterocyclic carbene catalyzed radical tandem cyclization/coupling reactions

“…4). 11 Notably, the radical trapping product 5 and selenide product 6 were isolated in 35% yield and 21% yield. This showed the formation of the ketyl radical and the 2-pyrrolidone-based benzyl radical intermediates unambiguously during this transformation.…”

Iminoacylation of Alkenes via Photoredox N-Heterocyclic Carbene Catalysis

“…Reactions of N-centered radicals for the synthesis of N-containing compounds, especially N-heterocyclic molecules, are of great importance but far less developed in NHC catalysis. During the preparation of this manuscript, Houk and Zhao et al reported the NHC-catalyzed aminoacylation of alkenes tethered with O -aryl oxime . Inspired by the efficient generation of iminyl radicals from readily available α-imino-oxy acids and our ongoing interests in alkene 1,2-difunctionalizations and NHC catalysis via radicals, , we envisioned that the reaction of alkene-tethered α-imino-oxy acids, with acyl imidazoles under photoredox NHC catalysis, might be feasible to deliver the corresponding N-heterocyclic molecules via the N-radical and ketyl radical (Scheme c).…”

“…During the preparation of this manuscript, Houk and Zhao et al reported the NHC-catalyzed aminoacylation of alkenes tethered with O-aryl oxime. 20 Inspired by the efficient generation of iminyl radicals from readily available α-imino-oxy acids 21 and our ongoing interests in alkene 1,2-difunctionalizations 22 and NHC catalysis via radicals, 10a,23 we envisioned that the reaction of alkene-tethered α-imino-oxy acids, with acyl imidazoles under photoredox NHC catalysis, might be feasible to deliver the corresponding N-heterocyclic molecules via the N-radical and ketyl radical (Scheme 1c). The alkene-tethered α-imino-oxy acids could be easily prepared via condensation of the corresponding enones with α-amino-oxy acid.…”