O,S,Se-containing Biginelli products based on cyclic β-ketosulfone and their postfunctionalization

Abstract

A one-pot three-component Biginelli synthesis of dihydropyrimidinones/thiones/selenones via acetic acid or solvent-free Yb(OTf)₃-catalyzed tandem reaction of β-ketosulfone (dihydro-2H-thiopyran-3(4H)-one-1,1-dioxide), an appropriate urea, and arylaldehyde has been developed. The reaction proceeds with high chemo- and regioselectivity to give diverse DHPMs in reasonable yields up to 95%. Moreover, an SO₂-containing analogue of anticancer drug-candidate enastron (SO₂ vs C=O) was obtained by using the here reported method in gram scale. We also demonstrate the reactivity of the Biginelli product in various directions - synthesis of condensed thiazoles and tetrazoles. In silico assessment of ADMET parameters shows that most compounds meet the lead-likeness requirements. The biological profiles of new compounds demonstrate high probability levels of activity against the following pathogens/diseases: Candida albicans, Alphis gossypii, Tripomastigote Chagas, Tcruzi amastigota, Tcruzi epimastigota, Leishmania amazonensis, and Dengue larvicida.

Keywords: dihydropyrimidinone/thione/selenone; green chemistry; in silico biological profile; multicomponent reaction (MCR); thiopyrandioxide.

Scheme 1

The general Biginelli reaction (A) and examples of DHMP (B) and thiopyran-1,1-dioxide (C) containing drugs.

Figure 1

Number of aryl-substituted Biginelli-type products and publications as analyzed by Reaxys database. The search was performed using depicted substructures “on all atoms” (May 2024).

Scheme 2

Scope of the obtained Biginelli products 2a–q.

Scheme 3

Synthesis of SO₂-containing enastron analogue 2r.

Scheme 4

Postmodification of the Biginelli product 2a.

Figure 2

Distribution of compounds 2a–r, 3–7 (log P (y)–MW (x)) through LLAMA software. The chemical structure of a representative compound 2m is shown.