An Efficient Multicomponent Synthesis of Polysubstituted Pyrrolidines and Tetrahydropyrimidines Starting Directly from Nitro Compounds in Water¹

Abstract

A distinct approach for the synthesis of 1,3,3-trisubstituted 4,5-dioxopyrrolidines and 1,3,4,5-tetrasubstituted 1,2,3,6-tetrahydropyrimidines has been discovered, in the form of a threecomponent reaction of nitroarenes, formaldehyde, and dialkyl acetylenedicarboxylates using indium in dilute aqueous HCl at room temperature. The molar ratios of these substrates are 1:1:4 and 2:1:4 for the preparation of dioxopyrrolidines and tetrahydropyrimidines, respectively. The reactions involve the reduction of nitro compounds to amines, which are simultaneously attacked by dialkyl acetylenedicarboxylates and formaldehyde. The products are formed in good to high yields.Pyrrolidines and pyrimidines are considered as important biologically active heterocycles. The former exhibit anticancer, antibacterial, and antifungal properties 2 while the latter antiviral, anti-inflammatory, and muscarinic agonist activities. 3 Tetrahydropyrimidines are also responsible for salt and heat sensitivity of protein-DNA interactions. 4 Dioxopyrrolidines and tetrahydropyrimidines can be prepared by multicomponent reactions 5 of anilines, formaldehyde, and alkynoates, but the methods involving these reactions are limited. 6 Moreover, high temperature, long reaction time, and the exchange of the functional groups of the alkynoates with the solvents are the problems in different earlier methods. Another point to mention is that the 4,5-dioxopyrrolidine derivatives prepared by Cao et al. was initially considered 6a as 3,6-dihydro-1,3-oxazines and very recently their structures have been revised 6b through X-ray crystallographic analysis. Here, we report a distinct approach for the synthesis of 4,5-dioxopyrrolidine and tetrahydropyrimidine derivatives starting directly from the nitro compounds.In continuation of our work 7 on the development of useful synthetic methodologies using aqueous medium, we have discovered that 1,3,3-trisubstituted 4,5-dioxopyrrolidines and 1,3,4,5-tetrasubstituted 1,2,3,6-tetrahydropyrimidines can be synthesized efficiently through the threecomponent reactions of nitroarenes, dialkyl acetylenedicarboxylates, and formaldehyde using indium in dilute aqueous HCl at room temperature. 4,5-Dioxopyrrolidine derivatives were formed using a molar ratio of 1:1:4 of these substrates, while tetrahydropyrimidines were produced when this ratio was 2:1:4 (Scheme 1).

Catalyst-free multicomponent synthesis of novel adamantyl-containing tetrahydropyrimidine carboxylates

“…Our literature survey at this stage revealed that there are some reports [18][19][20][21][22] on the synthesis of tetrahydropyrimidine derivatives containing an ester group in position 5. Khan and coworkers reported [18] the synthesis of substituted tetrahydropyrimidine and bis-tetrahydropyrimidine derivatives in good-to-excellent yields involving the reaction of dimethyl acetylenedicarboxylate, amines/diamines, and formaldehyde in the presence of (HClO 4 -SiO 2 ) as catalyst.…”

“…It should be mentioned that the work reported by Khan et al used [20]. Also, Das et al described [21] a three-component reaction of nitroarenes, formaldehyde, and dialkylacetylenedicarboxylates for the synthesis of 1,3,4,5-tetrasubstituted 1,2,3,6-tetrahydropyrimidines using indium as catalyst in dilute aqueous HCl at room temperature. The authors further extended their work and reported a multicomponent synthesis of tetrahydropyrimidines employing iodine as catalyst [22].…”

An Efficient Phosphotungstic Acid Catalysed Synthesis of 4,5‐Dioxopyrrolidines and Study of the Mechanistic Effect of the Solvent on the Reaction

“…Previous work that were reported for the synthesis of dioxopyrrolidines, generally involved higher reaction temperature, longer time period or hazardous catalysts. In one of those examples, Das and his group synthesised dioxopyrrolidines using HCl as catalyst . In addition, in another report, they synthesized the same products using I 2 .…”

Aqueous phase synthesis of polysubstituted pyrimidines/pyrrolidines catalyzed by β-cyclodextrin

“…Das et. al. reported the synthesis of poly substituted pyrrolidines and tetra-hydropyrimidines involving indium as a catalyst in aqueous medium [17]. Zhu et.…”