An Enantioselective Biginelli Reaction Catalyzed by a Simple Chiral Secondary Amine and Achiral Brønsted Acid by a Dual‐Activation Route

Abstract

An enantioselective Biginelli reaction that proceeds by a dual-activation route has been developed by using a combined catalyst of a readily available trans-4-hydroxyproline-derived secondary amine and a Brønsted acid. Aromatic, heteroaromatic, and fused-ring aldehydes were found to be suitable substrates for this multicomponent reaction. The corresponding dihydropyrimidines were obtained in moderate-to-good yields with up to 98 % ee under mild conditions. Based on the experimental results and the observed absolute configurations of the products, a plausible transition state has been proposed to explain the origin of the activation and the asymmetric induction.

Novel supramolecular organocatalysts of hydroxyprolinamide based on calix[4]arene scaffold for the enantioselective Biginelli reaction

“…As a preliminary test, using the optimal conditions of catalyst 1 in Feng's work [28], organocatalysts based on calix [4]arene scaffold 2 were evaluated for their catalytic efficiencies in the enantioselective Biginelli reaction of benzaldehyde, ethyl acetoacetate, and urea. As shown in Table 1, compared to the results obtained from the reactions catalyzed by di-, tri-and tetra-hydroxyprolin-calix [4]areneamides 2b-2e with 10%-45% ee, mono-hydroxyprolinamide based on calix [4]arene 2a with 54% ee was evidently the best choice for the present reaction system in terms of enantioselectivity.…”

“…However, in the past decade, only the limited examples of the enantioselective Biginelli reaction have been reported [28][29][30][31][32][33][34][35][36][37]. Recently, Feng et al [28] used hydroxyprolinamide based on diamantane 1 (Scheme 1) as organocatalyst assisted by a Brønsted acid to smoothly catalyze asymmetric Biginelli reaction with up to 98% ee. Herein, more bulky, rigid, and tunable hydroxyprolinamide organocatalysts based on calix [4]arene scaffold 2 Scheme 1 Hydroxyprolinamide organocatalysts for enantioselective Biginelli reaction. (Scheme 1) were designed for the enantioselective Biginelli reaction.…”

Asymmetric Organocatalysis

“…An asymmetric Biginelli reaction catalyzed by combination of chiral secondary amine 78 and achiral Brønsted acid in the presence of catalytic amount of an organic amino salt as additive has been developed by Feng and co-workers (Scheme 22) [80]. Fairly good yields and high enantioselectivity were obtained for a wide range of substrates.…”

A Brønsted acid catalysed enantioselective Biginelli reaction

“…Yields and enantiomeric excesses of the pure (GC, GC-MS and NMR) isolated dihydropyrimidine-2-thiones 5 and dihydropyrimidine-2-ones 6 are reported in Table 3; yields of the pure (NMR) adducts 18 and 19 are reported in Table 4. Satisfactory microanalyses were obtained for new compounds 18d-f and 19a-d. Absolute configurations of the optically active 5a, 4 5b, 7b 6c 15 , 6d 16 and 6f 15 were determined on the basis of the measured specific rotations compared with literature values. All the other absolute configurations were assigned by analogy.…”