Selective Synthesis of Azoloyl NH-1,2,3-Triazoles and Azolyl Diazoketones: Experimental and Computational Insights

Yuri M Shafran; Aqeel A Hussein; Nikolai A Beliaev; Vadim A Shevyrin; Sergey Shityakov; Tetyana V Beryozkina; Vasiliy A Bakulev

doi:10.1021/acsomega.1c05898

Selective Synthesis of Azoloyl NH-1,2,3-Triazoles and Azolyl Diazoketones: Experimental and Computational Insights

ACS Omega. 2022 Feb 2;7(6):5008-5031. doi: 10.1021/acsomega.1c05898. eCollection 2022 Feb 15.

Authors

Yuri M Shafran¹, Aqeel A Hussein², Nikolai A Beliaev¹, Vadim A Shevyrin¹, Sergey Shityakov³, Tetyana V Beryozkina¹, Vasiliy A Bakulev¹

Affiliations

¹ Technology for Organic Synthesis Department, Ural Federal University, 19 Mira Street, Ekaterinburg 620002, Russia.
² Department of Pharmacy, College of Medicine, Komar University of Science and Technology, Sulaymaniyah 46002, Kurdistan Region, Iraq.
³ Laboratory of Chemoinformatics, Infochemistry Scientific Center, ITMO University, 9 Lomonosova Street, Saint-Petersburg 191002, Russia.

Abstract

Here, we report that the reaction of enaminones, from a class of azole series, with sulfonyl azides leads to a difficult-to-separate mixture of two pairs of compounds: (1) 4-azoloyl-NH-1,2,3-triazoles with sulfonamides and (2) azolyl diazoketones with N-sulfonamidines, as a result of the implementation of two competing reactions. On one hand, the electron-donating methyl or methoxy group in the aryl para-position of arylsulfonyl azides favors the production of NH-1,2,3-triazoles together with sulfonamides. On the other hand, the use of highly electrophilic 4-nitrophenylsulfonyl azide promotes the formation of diazoketones and sulfonamidines. It is shown that the direction of each reaction is not only controlled by the nature of the initial enaminones and sulfonyl azides but also depends on the tested solvent. The problem of removing sulfonamides and amidines from the desired products was solved for the first time using new water-soluble enaminones. Based on the experimental and computational studies, the factors contributing to the selective course of alternative reactions were identified, and methods for the synthesis of azoloyl-NH-1,2,3-triazoles and azolyl diazoketones were developed. Density functional theory (DFT) results have shown that the 1,3-dipolar cycloaddition is totally driven toward one single regioisomer with a high asynchronous bond formation, and the introduction of an electron-deficient group in sulfonyl azides induces faster cycloaddition. Additionally, DFT calculations were used to gain further mechanistic insights on the reaction studied here.