Functionalized Diphenyl (2-Oxochroman-4-yl)phosphonates: Dual Synthetic Approaches, Mechanistic Insights, and Exploration of a Promising Anti-Lung Cancerous Molecule

Abstract

We herein disclose a dual synthetic approach involving room temperature and mechanochemical strategies for a new series of substituted diphenyl (2-oxochroman-4-yl)phosphonates. Both methods offer a practical and straightforward synthetic route for these biorelevant organophosphorus compounds. The salient features of both methods are metal-free synthesis, mild and energy-efficient reaction conditions, good yields with high chemo- and regioselectivity, the avoidance of column chromatographic purification, gram-scale synthetic applicability, and operational simplicity. The density functional theory study provides mechanistic insights into this transformation. Furthermore, biological studies of the synthesized organophosphorus compounds explored their possible anticancer profiles, and among the series, diphenyl (6-(tert-butyl)-2-oxochroman-4-yl)phosphonate (3c) exhibited anti-lung cancer activity in vitro. We herein emphasize that 3c might be considered for preclinical evaluation to establish its therapeutic relevance as an anticancer agent.

Keywords

Diphenyl (2-oxochroman-4-yl)phosphonates - Coumarin-3-carboxylic acids - Decarboxylative C-4 phosphorylation - DFT study - Anticancer activity

Supporting Information

General information, synthetic methods, physical, spectroscopic, and analytical data, scanned copies of respective ¹H NMR, ¹³C NMR, DEPT-135, ³¹P NMR, and 2D NMR (for one representative compound 3e) spectra for all the synthesized compounds 3a–3l, along with representative HRMS spectra for compounds 3a and 3c, are documented in the Supporting Information. Coordinates and other thermodynamic parameters of the optimized geometries obtained on the Potential Energy Surface (PES). Compound screening based on physicochemical and pharmacokinetic profiles, biological significance analysis of the identified gene set, simplified Molecular Input Line Entry Specification (SMILES) and chemical structure of the compound, physicochemical and pharmacokinetic properties of 3c and probable biological targets for compound 3c. (PDF)

Publikationsverlauf

Eingereicht: 08. August 2025

Angenommen nach Revision: 16. Oktober 2025

Accepted Manuscript online:
16. Oktober 2025

Artikel online veröffentlicht:
20. November 2025

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