Efficient, Green One-Pot Synthesis of Antimicrobial Agents: Functionalized DPTS Catalyst for the Preparation of 2-Amino-4-Aryl-5-Oxo-4H-Chromene-3-Carbonitriles, with Theoretical Calculations

Abstract

In the search for a new and effective synthetic approach to biologically chromene-derived compounds, a series of 2-amino-7, 7-dimethyl-5-oxo-4H-tetrahydrochromene-3-carbonitrile derivatives (4a-i) were synthesized. This synthesis involved the use of 4-(dimethylamino)pyridiniump-toluenesulfonate (DPTS) as a catalyst in an aqueous medium. Additionally, the relative stability between isomers was investigated using DFT/B3LYP calculations. The target compounds were synthesized through a multicomponent reaction of 5,5-dimethyl-1,3-cyclohexanedione (dimedone) 1, various arylaldehydes (2a-i), and malononitrile 3 in water and were recrystallized in ethanol. The reaction was promoted using DPTS, which is a low-toxic, inexpensive, commercially available, and easy-to-handle catalyst. The catalytic activity of DPTS was investigated in a condensation reaction conducted in an aqueous medium at room temperature. All synthesized compounds displayed considerable antimicrobial activities against human pathogenic bacteria and fungi. The developed synthetic protocol demonstrates energy efficiency, shorter reaction time, environmental friendliness, high product yields with purity, and scalability to gram-scale synthesis. DPTS proved to be a valuable contribution to the field of organocatalysis. The synthesized compounds were screened for in vitro antimicrobial activities, demonstrating varying potency against the microbial strains. Compound 4h exhibited the most potent activity with a zone of inhibition (ZOI) measuring 15 mm against E.coli. This was followed by compounds 4b, 4d, 4f, and 4g, which displayed a ZOI of 12 mm. Furthermore, the antifungal results revealed promising anticandidal activity for compounds 4b, 4e, and 4h, with a lower minimum inhibitory concentration (MIC) of 0.031 mg/ml. In addition, molecular electrostatic potential (MEP) mapping, reactivity indices such as electronegativity, electrophilic index, softness, and hardness, as well as frontier molecular orbitals (HOMO-LUMO), were used to provide further evidence regarding the stability and reactivity of the synthesized products.