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EXPANDING THE CHEMICAL SPACE OF 3(5)-FUNCTIONALIZED 1,2,4-TRIAZOLES

Dmytro M. Khomenko, Roman O. Doroshchuk, Yulia M. Ohorodnik, Hanna V. Ivanova, Borys V. Zakharchenko, Ilona V. Raspertova, Oleksandr V. Vaschenko, Alexey V. Dobrydnev, Oleksandr O. Grygorenko, Rostyslav D. Lampeka
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Abstract


An efficient approach to the gram-scale synthesis of 3(5)-substituted, 1,3- and 1,5-disubstituted 1,2,4-triazole-derived building blocks is described. The key synthetic precursors – 1,2,4-triazole-3(5)-carboxylates (20 examples, 35–89% yield) were prepared from readily available acyl hydrazides and ethyl 2-ethoxy-2-iminoacetate hydrochloride. Further transformations were performed following the convergent synthetic strategy and allowed the preparation of 1,3- and 1,5-disubstituted 1,2,4-triazole-derived esters (16 examples, 25–75% yield), 3(5)-substituted, 1,3- and 1,5-disubstituted carboxylate salts (18 examples, 78–93% yield), amides (5 examples, 82–93% yield), nitriles (5 examples, 30–85% yield), hydrazides (6 examples, 84–89% yield), and hydroxamic acids (3 examples, 73–78% yield). Considering wide applications of the 1,2,4-triazole motif in medicinal chemistry, these compounds are valuable building blocks for leadoriented synthesis; they have also great potential for coordination chemistry.An efficient approach to the gram-scale synthesis of 5(3)-substituted, 1,3- and 1,5-disubstituted 3(5)-functionalized-1,2,4-triazole-derived building blocks is described. The key synthetic precursors – 1,2,4-triazole-3(5)-carboxylates (20 examples; 35–89% yield) were prepared from readily available acyl hydrazides and ethyl 2-ethoxy-2-iminoacetate hydrochloride. Further transformations were performed following the convergent synthetic strategy and allowed for the preparation of 1,3- and 1,5-disubstituted 1,2,4-triazole-derived esters (16 examples; 25–75% yield); 5(3)-substituted, 1,3- and 1,5-disubstituted carboxylate salts (18 examples; 78–93% yield), amides (5 examples; 82–93% yield), nitriles (5 examples; 30–85% yield), hydrazides (6 examples; 84–89% yield), and hydroxamic acids (3 examples; 73–78% yield). Considering wide applications of the 1,2,4-triazole motif in medicinal chemistry, these compounds are valuable building blocks for lead-oriented synthesis; they have also great potential for coordination chemistry.

Keywords


acyl hydrazides; 1,2,4-triazoles; alkylation; cyclization; functional groups; regioisomers

Full Text: PDF Supplementary File(s): Supporting information (12MB)


 

 

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