Recent Advances in Catalytic Asymmetric Aza‐Michael Addition Triggered Cascade Reactions

Abstract

As an important branch of the Michael addition reaction, the aza‐Michael addition cascade reaction has been developed rapidly in recent years. This is because the reaction serves as an important method for effectively constructing functionalized C−N bonds, which can be widely used in the synthesis of chiral drugs and their intermediates and natural products. Given the importance of this topic, this review highlights the recent developments of aza‐Michael addition triggered cascade reactions in asymmetric synthesis, including aza‐Michael/Michael, aza‐Michael/Aldol, aza‐Michael/Henry, aza‐Michael/hemiacetal, aza‐Michael/Mannich, aza‐Michael/alkylation, aza‐Michael/cyclization, aza‐Michael/ring‐opening, aza‐Michael‐IED/HAD, aza‐Michael/INCR, and aza‐Michael/1,6‐conjugate addition reactions. In this paper, the reaction mechanism and derivatization experiments of different reactions are timely introduced to provide a more comprehensive theoretical basis for subsequent studies.

Recent developments in enantioselective nickel(ii)-catalyzed conjugate additions

“…43 Since the first metal-catalyzed domino Michael/aldol reaction reported by Noyori et al in 1996, 44 there have been numerous examples of domino reactions based on Michael additions. 45 Among recent examples involving nickel catalysts, the first example of enantioselective domino sulfa-Michael/aldol reaction between methyleneindolinones and thiosalicylaldehydes was described by Arai Scheme 24 Tandem double Michael reaction of nitrostyrenes with γ,δ-unsaturated β-ketoesters.…”

Pull‐Pull Alkenes in the Aza‐Michael Reaction

“…Finally, last but not least, the polyfunctional alkenes are versatile and valuable building blocks in the synthesis of multifunctional molecules which are often relevant to synthetic and pharmaceutical chemistry. Among the nucleophilic conjugate addition reactions the addition of nitrogen nucleophiles (so‐called aza‐Michael reaction) holds a special place [1–6] . It is a simplest and shortest pathway to β‐amino ketones, β‐amino acids and their derivatives which are ubiquitous motifs in natural products and constitute an important class of building blocks in organic synthesis.…”

“…Among the nucleophilic conjugate addition reactions the addition of nitrogen nucleophiles (so-called aza-Michael reaction) holds a special place. [1][2][3][4][5][6] It is a simplest and shortest pathway to β-amino ketones, β-amino acids and their derivatives which are ubiquitous motifs in natural products and constitute an important class of building blocks in organic synthesis. This reaction exhibits a great versatility and atom economy.…”

Isothiourea-catalyzed formal enantioselective conjugate addition of benzophenone imines to β-fluorinated α,β-unsaturated esters

“…Over the last two decades, several enantioselective organocatalytic approaches to amine conjugate addition have been introduced. To date, these successful approaches rely upon enals, 3 enones, 4 N -acyl pyrazoles, 5 and nitro-olefins 6 as Michael acceptors, with the use of bifunctional thiourea 4 a ,5 b ,7,8 a – c , e or squaramide 4,5 c ,8 a , b , e organocatalysts, or Lewis basic pyrrolidines 3,8 commonplace. Catalytic enantioselective amine conjugate additions to α,β-unsaturated esters are rare, reflecting the recognized recalcitrance of α,β-unsaturated esters as Michael acceptors (Scheme 1b).…”