One-Step Synthesis of Heterocyclic Privileged Medicinal Scaffolds by a Multicomponent Reaction of Malononitrile with Aldehydes and Thiols

Abstract

Heterocyclic privileged medicinal scaffolds involving pyridine, 1,4-dihydropyridine, chromeno[2,3-b]pyridine, and dihydro-1,4-dithiepine frameworks are prepared via a single-step multicomponent reaction of structurally diverse aldehydes with various thiols and malononitrile. Mechanistic studies of the synthetic pathway leading to pyridines reveal that 1,4-dihydropyridines undergo oxidation by the intermediate Knoevenagel adducts rather than by air oxygen. The use of o,o'-disubstituted aromatic aldehydes leads to the corresponding 1,4-dihydropyridines, whereas salicylic aldehydes result in chromeno[2,3-b]pyridines. Reactions of ethanedithiol as a thiol component produce dimeric pyridines with sterically unencumbered aldehydes, while o,o'-disubstituted aromatic aldehydes give dihydro-1,4-dithiepines. Thus, depending on the aldehyde and thiol types, diverse libraries of medicinally relevant compounds can be prepared by a simple one-step process involving no chromatography.

O-iodoxybenzoic acid in water: optimized green alternative for multicomponent one-pot synthesis of 2-amino-3,5-dicarbonitrile-6-thiopyridines

“…The products are accomplished in good to excellent yields and their physical and spectral data are in agreement with literature reports. 12,14,21 Indeed, the method has the ability to tolerate functional groups such as methoxy, nitro, halides, etc.…”

“…11 In view of their high significance, many methodologies have been developed for the construction of the pyridine skeleton. Various basic catalysts like piperidine, Et 12 and TBAH (tetrabutylammonium hydroxide) 12 have also been used for this reaction. Sridhar et al 13 showed that this reaction can be carried out using Lewis acid catalyst (ZnCl 2 ), which shows better results than base catalyzed reactions.…”

Microwave Promoted Sodium Acetate Catalyzed One Pot Synthesis of Highly Functionalized Pyridine Derivatives

“…Generally, this condensation has been carried out under basic conditions using various bases such as, Et 3 N, DABCO, piperidine 10 , morpholine, thiomorpholine, pyrrolidine, N,N-DIPEA, pyridine, 2,4,6-collidine, DMAP, aniline, Nmethylaniline, N,N-dimethylaniline and N,N-diethylaniline 10 13 . However, most of these methods suffer by the formation of inevitable side products, which results in lower yield of desired product with long reaction time.…”

A Rapid, Convient and Diversified-Multicomponent Synthesis and Characterization of Pyrano[2,3-<i>b</i>]Indoles

“…MCRs comply with the principles of green chemistry in terms of economy of steps as well as many of the rigid criteria of an ideal organic synthesis. These reactions are effective in construction highly functionalized small organic molecules from readily available starting materials in a single step with natural flexibility for creating molecular complexity and diversity coupled with minimization of time, labor, cost and waste production [3][4][5][6] . The pyran nucleus is a fertile source of biologically important molecules.…”