Synthesis of (1 H -1,2,3-Triazol-1-yl)acetic Acid Derivatives
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hesis of (1H-1,2,3-Triazol-1-yl)acetic Acid Derivatives N. T. Pokhodyloa, R. D. Savkaa, and M. D. Obushaka,* a
Ivan Franko National University of Lviv, Lviv, 79005 Ukraine *e-mail: [email protected]
Received April 5, 2020; revised April 13, 2020; accepted April 18, 2020
Abstract—A convenient synthetic approach to (1H-1,2,3-triazol-1-yl)acetic acid derivatives via the reaction of azidoacetamides with β-ketoesters and acetylacetone is proposed. Based on this strategy, 1,5-disubstituted 1,2,3-triazoles were prepared from available reagents under metal-free conditions. A one-pot protocol for the synthesis of (5-methyl-1H-1,2,3-triazol-1-yl)acetamides derived from N-substituted chloroacetamides is developed. Keywords: azides, 1,2,3-triazoles, Dimroth reaction, (1H-1,2,3-triazol-1-yl)acetic acids, 1,3-dicarbonyl compounds
DOI: 10.1134/S1070428020080138
The 1,2,3-triazole ring is a structural fragment, whose presence in compounds make them attractive for screening for biological activity, because it is an isostere of the amide bond, resistant to metabolic degradation, and can form hydrogen bonds, which is important for binding with biological targets [1]. The introduction of a carboxyl function in the 1,2,3-triazole ring favors creation of convenient structural blocks for the synthesis of combinatorial libraries. In particular, 1H-1,2,3triazole-4-carboxylic acid derivatives were used for the synthesis of compounds that exhibited antifungal activity [2–4], antimicrobial activity against the mycobacterium tuberculosis strain H37Rv [5], antiviral activity against replication of influenza A and herpes simplex virus type 1 (HSV-1) [6], as well as anticancer activity against various cancer cell lines [7–10]. (1H-1,2,3-Triazol-1-yl)acetic acids were used to synthesize compounds active against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci [11], antagonists of monoacylglycerol lipase [12], agonists and antagonists of sphingosine-1-phosphate receptors [13], inhibitors of stearoyl-coenzyme delta-9 [14], as well as anticancer and antiviral agents [16]. The synthesis and biological testing of a number of (1H-1,2,3-triazol-1-yl)acetic acid derivatives made possible their application as inhibitors of the HIV-1 capsid (HIV-1 CA) for the design of antiviral drugs on their basis [17]. (1H-1,2,3-Triazol-1-yl)acetic acids were most commonly prepared by the 1,3-dipolar cycloaddition reac-
tions of azides to terminal acetylenes. In the present work studied the use of Dimroth cyclocondesation of azidoacetic acid derivatives with dicarbonyl compounds for preparing compounds of this type. In case of success, such approach would allow introduction of a much wider range of substituents in the triazole ring of triazolylacetic acids. The reaction of 2-azidoacetamides 3a and 3b with 4-benzyl- and 4-phenoxyacetoacetic acids 2a, and 2b, prepared from the corresponding chlorides 1a and 1b by acylation of the Meldrumʼs acid was studied. It was found that the reaction in the presence of K2CO3 in DMSO in mild c
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