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Straightforward Synthesis of 6-Aryl-2-azido-4-(trifluoromethyl)­pyrimidines and Their Regioselective Copper-Catalyzed Click Cycloaddition to 6-Aryl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)-4-(trifluoromethyl)pyrimidines

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Abstract

A straightforward one-pot synthesis of 6-aryl-2-azido-4-(trifluoromethyl)pyrimidine derivatives 3 by the [3+3] cyclocondensation of 1,1,1-trifluoro-4-methoxybut-3-en-2-ones [1, F3CC(O)CH=C(R1)OMe, where R1 = Ph (a), 3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalen-2-yl (b), 4-PhC6H4 (c), 4-FC6H4 (d), furan-2-yl (e), thiophen-2-yl (f)] with 2-aminotetrazole monohydrate (2) under basic conditions is described. Tetrazolo[1,5-a]pyrimidine is the most probable intermediate product in the reaction, though it has not been identified. Copper-catalyzed click reaction of 3 with phenylacetylene (4) afforded 6-aryl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)-4-(trifluoromethyl)pyrimidines 5. All products were characterized using multinuclear 1H, 13C, and 19F NMR, IR spectroscopy, and electrospray ionization high-resolution mass spectrometry (HRMS). The structures of 2-azido-4-phenyl-6-(trifluoromethyl)pyrimidine (3a), 6-(furan-2-yl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)-4-(trifluoromethyl)pyrimidine (5e), and 2-(4-phenyl-1H-1,2,3-triazol-1-yl)-6-(thiophen-2-yl)-4-(trifluoro­methyl)pyrimidine (5f) have been determined using single-crystal X-ray diffraction.

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Funding

The authors are grateful for financial support from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Researcher grant 310209/2019-6) and Programa de Apoio à Pós-graduação CAPES (PROAP/CAPES/PPGQTA-FURG). Fellowships from CAPES (M.A. Delevati, F.P. Ludwig) are also acknowledged.

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Authors and Affiliations

  1. Escola de Química e Alimentos, Universidade Federal do Rio Grande, 96203-900, Rio Grande, Brazil

    F. P. Ludwig, M. A. Delevati, J. R. M. Vicenti, D. C. Flores & A. F. C. Flores

  2. Departamento de Química, Universidade Federal de Santa Maria, 97105-900, Santa Maria, Brazil

    R. Cargnelutti & R. Cervo

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  1. F. P. Ludwig
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Correspondence to A. F. C. Flores.

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Ludwig, F.P., Delevati, M.A., Cargnelutti, R. et al. Straightforward Synthesis of 6-Aryl-2-azido-4-(trifluoromethyl)­pyrimidines and Their Regioselective Copper-Catalyzed Click Cycloaddition to 6-Aryl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)-4-(trifluoromethyl)pyrimidines. Russ J Org Chem 59, 164–173 (2023). https://doi.org/10.1134/S1070428023010189

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