Excited-State Copper-Catalyzed [4 + 1] Annulation Reaction Enables Modular Synthesis of α,β-Unsaturated-γ-Lactams

Abstract

Synthesis of α,β-unsaturated-γ-lactams continue to attract attention due to the importance of this structural motif in organic chemistry. Herein, we report the development of a visiblelight-induced excited-state copper-catalyzed [4 + 1] annulation reaction for the preparation of a wide range of γ-H, −OH, and −OR-substituted α,β-unsaturated-γ-lactams using acrylamides as the 4-atom unit and aroyl chlorides as the 1-atom unit. This modular synthetic protocol features mild reaction conditions, broad substrate scope, and high functional group tolerance. The reaction is amenable to late-stage diversification of complex molecular architectures, including derivatives of marketed drugs. The products of the reaction can serve as versatile building blocks for further derivatization. Preliminary mechanistic studies suggest an inner-sphere catalytic cycle involving photoexcitation of the Cu(BINAP) catalyst, single-electron transfer, and capture of radical intermediates by copper species, followed by reductive elimination or protonation to give the desired γ-functionalized α,βunsaturated-γ-lactams.

Copper-catalyzed umpolung Sonogashira-type coupling of arene boronic acids under visible light

“…Based on the results of existing research in photoredox catalysis, 8,21 copper photocatalytic reaction, 22 as well as our results, we propose a plausible mechanism. Transmetallation of the aryl group from aryl boronic acid to the catalyst ( A ) generates aryl intermediate B , which then undergoes oxidative addition with ABX under light irradiation to produce copper ( iii ) intermediate C .…”

“…Based on the results of existing research in photoredox catalysis, 8,21 copper photocatalytic reaction, 22 In summary, a copper-catalyzed alkynyl Csp-Csp 2 coupling reaction of 1-alkynyl-1,2-benziodoxol-3(1H)-one with aryl or alkynyl boronic acid was developed under visible light irradiation. The reaction proceeded under extremely mild conditions with a broad substrate scope that tolerated various functional groups.…”

Synthesis of γ-Lactams from Acrylamides by Single-Carbon Atom Doping Annulation

“…A derivative of citronellal (i.e., 1l ) could also be converted into the corresponding γ-lactam 2l in 60% yield, with the other alkene moiety remaining intact. Compared with previously reported synthetic methods for producing α,β-unsaturated γ-lactams, SCAD annulation provides a highly straightforward strategy using readily available acrylamides and NHCs, thereby allowing for the facile access to elaborate γ-lactams, as demonstrated in Scheme …”

Cyclization of N-Boc-(E)-α,β-unsaturated γ-amino acid active esters into N-Boc-(Z)-α,β-unsaturated γ-lactams through E → Z isomerization

“…6 A variety of synthetic routes have been developed for N-aryl/alkylated α,β-unsaturated γ-lactam synthesis. 5,[7][8][9][10][11][12][13][14][15] Despite this wide range of applications of α,β-unsaturated γ-lactams, currently there are not many methods available for the synthesis of N-acylated α,β-unsaturated γ-lactams with broad side-chain specificity.…”

“…6 A variety of synthetic routes have been developed for N -aryl/alkylated α,β-unsaturated γ-lactam synthesis. 5,7–15 Despite this wide range of applications of α,β-unsaturated γ-lactams, currently there are not many methods available for the synthesis of N -acylated α,β-unsaturated γ-lactams with broad side-chain specificity. Here we are reporting a remarkable transformation of the pentafluorophenyl esters of N -protected ( E )-α,β-unsaturated γ-amino acids into N -protected ( Z )-α,β-unsaturated γ-lactams at room temperature in the presence of a weak base.…”