Nucleophile–nucleofuge duality of azide and arylthiolate groups in the synthesis of quinazoline and tetrazoloquinazoline derivatives?

Organic & Biomolecular Chemistry Pub Date: 2021-08-16 DOI: 10.1039/D1OB01315G

Abstract

5-Arylthio-tetrazolo[1,5-c]quinazolines (tautomers of 2-arylthio-4-azido-quinazolines) undergo facile nucleophilic aromatic substitution reactions with amines, alcohols and alkylthiols. This, combined with the recently reported arylsulfanyl group dance, provides straightforward access to 4-azido-2-N-, O-, S-substituted quinazolines and/or their tetrazolo tautomers from commercially available 2,4-dichloroquinazoline. The azidoazomethine-tetrazole tautomeric equilibrium and the electron-withdrawing character of the fused tetrazolo system plays a central role in the developed transformations. 5-Amino-substituted tetrazolo[1,5-c]quinazolines undergo media-controlled tautomeric equilibrium, which permits them to demonstrate the reactivity traditionally associated with the azido substituent. Furthermore, a method for 5-O-substitited tetrazolo[1,5-a]quinazolines from 2,4-diazidoquinazoline was developed during the structural elucidation of the substitution products. The developed methodology will facilitate medicinal chemistry investigations into quinazoline derivatives and the discovered fluorescent properties of some of the products (e.g., 4-(4-phenyl-1H-1,2,3-triazol-1-yl)-2-(4-methylpiperazin-1-yl)quinazoline: λem. = 461 nm, ΦDCM = 0.89) could serve as a starting point for their further applications in analytical and materials science.

Graphical abstract: Nucleophile–nucleofuge duality of azide and arylthiolate groups in the synthesis of quinazoline and tetrazoloquinazoline derivatives
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