A Novel Synthesis of Highly Functionalized Pyridines by a One-Pot, Three-Component Tandem Reaction of Aldehydes, Malononitrile and N-Alkyl-2-cyanoacetamides under Microwave Irradiation

Abstract

A convenient, fast and environmentally benign procedure for the synthesis of a new series of highly functionalized N-alkylated pyridines as privileged medicinal scaffolds was developed via a unique three-component reaction of easily available aromatic as well as heteroaromatic aldehydes, N-alkyl-2-cyanoacetamides and malononitrile in EtOH in the presence of K2CO3 as a base promoter under microwave irradiation. The presented tandem process is presumed to proceed via Knoevenagel condensation, Michael addition, intramolecular cyclization, autoxidation and subsequent aromatization. Particularly valuable features of this protocol, including high product yields, mild conditions, atom-efficiency, simple execution, short reaction times and easy purification make it a highly efficient and promising synthetic strategy to prepare substituted pyridine nuclei. The proposed mechanism of this novel one-pot reaction and structure elucidation of the products are discussed.

Utilization of 5‐Chloro‐2‐(cyanoacetamido)pyridines in the Synthesis of Biologically Active Heterocyclic Hybrids

“…The nucleophilic position C‐2 is more reactive than NH, while the electrophilic site C‐3 is more reactive than position C‐1. Cyanoacetamides (Figure ) are highly reactive polyfunctional substrates for preparing of structurally diverse five and six membered heterocycles including pyrazoles, thiazoles, thiophenes, and pyridines . The latter heterocycles that contain one or two heteroatoms have attracted researchers due to their wide range of biological activities .…”

Synthesis and Antibacterial Evaluation of Some New Thiazole‐Based Polyheterocyclic Ring Systems

“…N ‐Thiazol‐2‐yl cyanoacetamide ( R = 2‐thiazolyl) allows introduction of an additional diversity nucleophilic point into the molecule via nitrogen atom of thiazole. Cyanoacetamides derivatives have been utilized as highly reactive polyfunctional precursors for the construction of various 5‐membered and 6‐membered rings such as pyrrole , pyrazole , thiazole , thiophene , pyridine , pyrimidine , isoquinoline derivatives , and fused heterocycles .…”

An Efficient Ultrasound Promoted Three‐Component and Regioselective Synthesis of Indenoquinoxaline Compounds Containing Pyrrolopyrimidine Skeleton

“…The term MCRs (multicomponent reactions) offers an efficient and one‐pot pathway to construct densely functionalized targets from simple and readily available substrates. The MCRs also have the benefits including high atom economy, high chemical yields, selectivity, and flexibility . Furthermore, MCRs are of notable significance in chemical, medicinal and pharmaceutical laboratories and have been known as one of the most powerful synthetic tools due to high efficiency in the construction of heterocyclic frameworks with high molecular complexity and diversity ,…”