Synthesis and Isomerization of Tetrahydro-4H-chromene Derivatives

Authors

• Ryan Jacob Burk, The University of Texas at Arlington
• Anasuya Ghorai, The University of Texas at Arlington
• James X. Mao, Texas A&M University
• Vo Quang Huy Phan, The University of Texas at Arlington
• H. V. Rasika Dias, The University of Texas at Arlington
• Miyase Gözde Gündüz, Hacettepe Üniversitesi
• Carl J. Lovely, Mississippi State University
• Daniel W. Armstrong, The University of Texas at Arlington

ORCID

Burk: https://orcid.org/0009-0003-4551-1349; Dias: https://orcid.org/0000-0002-2362-1331; Gündüz: https://orcid.org/0000-0002-2287-9509; Lovely: https://orcid.org/0000-0001-7012-2001; Armstrong: https://orcid.org/0000-0003-0501-6231

MSU Affiliation

College of Arts and Sciences; Department of Chemistry

Creation Date

2026-06-30

Abstract

One-pot multicomponent reactions (MCRs) are commonly used to synthesize heterocyclic compounds including tetrahydro-4H-chromene derivatives. Despite extensive research on 4H-chromene synthesis via MCR, the formation and characterization of structural isomers arising from diketones that lack a vertical plane of symmetry have been neglected. MCR routes to several 4H-chromene derivatives were examined with an emphasis on characterizing the isomeric products that have likely been overlooked in previous studies. We report the synthesis and characterization of chiral tetrahydro-4H-chromene derivatives as racemic mixtures of constitutional isomers. Experiments conducted under varying reaction conditions consistently produced comparable quantities of isomeric product pairs. Effective characterization required heteronuclear multiple bond correlation (HMBC) NMR and reaction monitoring by high performance liquid chromatography (HPLC). Additionally, it is demonstrated that these product pairs isomerize in aqueous environments, suggesting that similar isomerization may occur under physiological conditions. A kinetic analysis of the isomerization and a putative conversion mechanism are reported. Because isomeric pairs were consistently produced regardless of reaction conditions, previous studies likely generated similar pairs. The confirmation of isomeric counterparts of known 4H-chromene derivatives suggests more careful analysis is necessary in related MCRs where multiple reaction pathways exist.

Publication Date

9-26-2025

Publication Title

The Journal of Organic Chemistry

Publisher

SAGE Publications [Commercial Publisher]

First Page

14106

Last Page

14117

Rights

© 2025 The Authors

Recommended Citation

Burk, R. J., Ghorai, A., Mao, J. X., Phan, V. Q. H., Dias, H. V. R., Gündüz, M. G., Lovely, C. J., & Armstrong, D. W. (2025). Synthesis and Isomerization of Tetrahydro-4H-chromene Derivatives. The Journal of Organic Chemistry, 90(40), 14106–14117. https://doi.org/10.1021/acs.joc.5c01569