Recent advances in organocatalytic asymmetric aza-Michael reactions of amines and amides

Abstract

Nitrogen-containing scaffolds are ubiquitous in nature and constitute an important class of building blocks in organic synthesis. The asymmetric aza-Michael reaction (aza-MR) alone or in tandem with other organic reaction(s) is an important synthetic tool to form new C–N bond(s) leading to developing new libraries of diverse types of bioactive nitrogen compounds. The synthesis and application of a variety of organocatalysts for accomplishing highly useful organic syntheses without causing environmental pollution in compliance with ‘Green Chemistry” has been a landmark development in the recent past. Application of many of these organocatalysts has been extended to asymmetric aza-MR during the last two decades. The present article overviews the literature published during the last 10 years concerning the asymmetric aza-MR of amines and amides catalysed by organocatalysts. Both types of the organocatalysts, i.e., those acting through non-covalent interactions and those working through covalent bond formation have been applied for the asymmetric aza-MR. Thus, the review includes the examples wherein cinchona alkaloids, squaramides, chiral amines, phase-transfer catalysts and chiral bifunctional thioureas have been used, which activate the substrates through hydrogen bond formation. Most of these reactions are accompanied by high yields and enantiomeric excesses. On the other hand, N-heterocyclic carbenes and chiral pyrrolidine derivatives acting through covalent bond formation such as the iminium ions with the substrates have also been included. Wherever possible, a comparison has been made between the efficacies of various organocatalysts in asymmetric aza-MR.

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.…”

Enantioselective synthesis of isoxazole-containing spirooxindole tetrahydroquinolines via squaramide-catalysed cascade reactions

“…Aza-Michael addition triggered cascade reactions serve as an important method for effectively constructing nitrogen-containing heterocyclic compound. 6 In the past decade, N -tosyl aminomethyl enones or enoates, 5 a ,7 2-aminophenyl α,β-unsaturated ketones or esters 4 a ,8 have been successfully proved to be effective tandem reaction reagents, and 2-aminophenyl α,β-unsaturated ketones or esters could often successfully construct tetrahydroquinoline framework through the cascade reaction. As an essential branch of heterocyclic structures, tetrahydroquinoline derivatives are proverbially present in a variety of natural products and pharmaceuticals.…”

Asymmetric Phase-Transfer Catalytic aza-Michael Addition to Cyclic Enone: Highly Enantioselective and Diastereoselective Synthesis of Cyclic 1,3-Aminoalcohols

“…Among nitrogen-containing compounds, the β-amino carbonyl structure is present in various natural products that exhibit important biological activities and can be converted into various synthetic intermediates, such as β-amino alcohol, β-amino acid, and 1,3-diamine by chemical conversion . Regarding the synthesis of chiral β-amino carbonyl compounds, enantioselective aza-Michael reaction is a representative synthetic method that stereoselectively introduces amines at the β-position of carboxylic acid derivatives, ketones, and aldehydes . In previous studies, aza-Michael reactions used various nitrogen nucleophiles such as aliphatic/aromatic amines, alkoxyamines, aldoximes, hydrazoic acid, and azide anion .…”