One-pot multicomponent green Hantzsch synthesis of 1,2-dihydropyridine derivatives with antiproliferative activity

Giovanna Bosica; Kaylie Demanuele; José M Padrón; Adrián Puerta

doi:10.3762/bjoc.16.235

One-pot multicomponent green Hantzsch synthesis of 1,2-dihydropyridine derivatives with antiproliferative activity

Beilstein J Org Chem. 2020 Nov 24:16:2862-2869. doi: 10.3762/bjoc.16.235. eCollection 2020.

Authors

Giovanna Bosica¹, Kaylie Demanuele¹, José M Padrón², Adrián Puerta²

Affiliations

¹ Department of Chemistry, University of Malta, Msida, MSD 2080 Malta.
² BioLab, Instituto Universitario de Bio-Orgánica "Antonio González" (IUBO-AG), Universidad de La Laguna, c/Astrofísico Francisco Sánchez 2, 38206 La Laguna, Spain.

Abstract

A rapid route for obtaining unsymmetrical 1,2-dihydropyridines (1,2-DHPs) as opposed to 1,4-dihydropyridines (1,4-DHPs) has been achieved via a one-pot multicomponent Hantzsch reaction. A benign protocol has been developed for the preparation of various 1,2-dihydropyridine derivatives using heterogenized phosphotungstic acid on alumina support (40 wt %). High yields of over 75% have been accomplished in just 2-3.5 h after screening several heterogeneous catalysts and investigating the optimal reaction conditions. The catalyst chosen has passed the heterogeneity test and was shown to have the potential of being reused for up to 8 consecutive cycles before having a significant loss in activity. In addition, aromatic aldehydes gave the aforementioned regioisomer while the classical 1,4-DHPs were obtained when carrying out the reaction using aliphatic aldehydes. The preliminary study of the antiproliferative activity against human solid tumor cells demonstrated that 1,2-DHPs could inhibit cancer cell growth in the low micromolar range.

Keywords: 1,2-dihydropyridines; antiproliferative activity; green Hantzsch synthesis; heterogeneous catalysis; one-pot multicomponent reaction.

Grants and funding

The authors thank the University of Malta and the ENDEAVOUR Scholarship Scheme (Malta), part-financed by the European Union–European Social Fund (ESF) under the Operational Programme II–Cohesion Policy 2014-2020, “Investing in human capital to create more opportunities and promote the well-being of society” for financial and technical support. A. P. and J. M. P. thank the Spanish Government for financial support through project PGC2018-094503-B-C22 (MCIU/AEI/FEDER, UE). A. P. thanks the EU Social Fund (FSE) and the Canary Islands ACIISI for a predoctoral grant TESIS2020010055.