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.

Ramadan Mekheimer,Hanadi Medrasi,Mariam Al-Sheikh,Najla Alsofyani

doi:10.3390/molecules23030619

Ramadan Mekheimer, Hanadi Medrasi + Show 2 more

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https://doi.org/10.3390/molecules23030619

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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.

Highlights

One-pot multi-component reactions (MCRs) in which three or more reactants are combined together in a single synthetic operation to create a highly complex molecule incorporating most atoms present in the starting materials have proven to be a very rapid, powerful and elegant synthetic procedure
Microwave-assisted organic chemistry (MAOC) is one of the high-speed techniques which has attracted a great attention in recent years
We report a general and efficient microwave-assisted one-pot three-component synthesis of a series of dense substituted N-alkylated 2-pyridones, utilizing malononitrile, a wide range of aromatic as well as heteroaromatic aldehydes and variety of

Summary

Introduction

One-pot multi-component reactions (MCRs) in which three or more reactants are combined together in a single synthetic operation to create a highly complex molecule incorporating most atoms present in the starting materials have proven to be a very rapid, powerful and elegant synthetic procedure. The MCRs strategy provides important advantages over conventional multistep synthesis because of its ease of execution, efficiency, simple procedures and equipment, flexibility, atom economic nature, high yields, productivity, convergence, and highly selectivity [1,2,3,4]. By reducing waste production, the number of operational steps, avoiding the complicated isolation and purification of intermediates, minimization of time, energy consumption, cost, solvents, reagents and expenditure of human labor, MCRs represent eco-friendly processes [5]. These advantages make MCRs well-suited for the easy construction of libraries of ‘drug-like’ molecules [6,7].

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