Organocatalyzed Enantioselective Michael Addition of 2‐Hydroxypyridines and α,β‐Unsaturated 1,4‐Dicarbonyl Compounds

Abstract

The framework of 2-pyridones is prevalent in biologically and medicinally important molecules. Here we report that chiral N-substituted 2-pyridones were prepared by enantioselective, organocatalytic aza-Michael additions of halogenated 2-hydroxypyridines (pyridin-2(1H)-ones) to α,β-unsaturated-1,4-dketones or 1,4-ketoesters. The reactions were optimized by the choice of solvents and systematic screening of Cinchona alkaloid-based bifunctional catalysts to achieve excellent yields and enantioselectivities (up to 98% yield and > 99% ee). Density functional theory calculations provided rationales for the observed enantioselectivity. Formal synthesis of a human rhinovirus protease inhibitor was achieved using the chiral Michael adduct generated by this method.

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

“…However, for others, the yields ranged from 50–98% with good to excellent enantioselectivity (47–98% ee). The observed results were rationalized with density functional theory calculations ( Table 8 ) [ 42 ].…”

Organocatalyzed C−N bond‐forming Reactions for the Synthesis of Amines and Amides

“…The absolute configuration of the product was determined by the X-ray crystallographic method, which was further strengthened by DFT analysis and favored the generation of R configurated product (Scheme 11). [17] In 2018, Peddinti and Bhagat developed an organocatalyzed N2-selective aza-Michael addition of triazoles 69 to cyclic enones 68. For this purpose, they have utilized thiourea based organocatalyst XI, which was developed by Chen and coworkers (2004) for the asymmetric Michael addition of aryl thiols to α,β-unsaturated carbonyl compounds.…”

Recent Advances in Organocatalytic Asymmetric Michael Addition Reactions to α, β‐Unsaturated Nitroolefins

“…Decades-long, asymmetric organocatalytic transformations have witnessed historic advancements to attain enantiomerenriched products without purification of the intermediates and protection or deprotection manipulation. [1][2][3][4][5][6][7][8][9][10][11] Along with, the organocatalysis [12][13][14] has prodigiously modified the outline of many asymmetric reactions such as Diels-Alder reaction, [15] aldol reaction, [16][17] Mannich reaction, [18] Michael addition reactions, [19] hetero-Michael addition reactions, [20] Shi Epoxidation [21] and organocatalytic transfer hydrogenation. [22] Among all these above organocatalytic reactions, Michael addition reactions are quite significant in the field of modern organic synthesis since these reactions produce the key precursors of natural products by constructing carbon-carbon and carbon-heteroatom bonds.…”