Triazolization of Enolizable Ketones with Primary Amines: A General Strategy toward Multifunctional 1,2,3‐Triazoles

Abstract

The development of metal‐free syntheses toward 1,2,3‐triazoles has been a burgeoning research area throughout the past decade. Despite the numerous advances, the scarceness of methods for the preparation of 1,5‐disubstituted 1,2,3‐triazoles from readily available substrates remained a challenge that was addressed by our group in 2016. A metal‐free three‐component reaction, which we have dubbed the triazolization reaction, was established for the rapid synthesis of 1,5‐disubstituted, fully functionalized and NH‐1,2,3‐triazoles. This novel approach stands out because it utilizes widely available starting materials, namely primary amines and enolizable ketones. Furthermore, the broad substrate scope is a major advantage, and was further expanded by the number of modified protocols that have been reported. Triazolization products have successfully found utility as intermediates in various synthetic transformations, and were the subject of a few interesting biological activity studies.

4,5,6,7-Tetrahydroindol-4-Ones as a Valuable Starting Point for the Synthesis of Polyheterocyclic Structures

“…Very recently, our group reported the synthesis and spectroscopic properties of novel 1,2,3-triazole BOPAHY dyes and their corresponding triazolium salts ( Scheme 30 ) [ 84 ]. Thus, we started from N -tosyl-4,5,6,7-tetrahydroindol-4-one 118 and performed our in-house developed general metal-free triazolization reaction [ 85 , 86 , 87 , 88 , 89 ]. This route toward 1,2,3-triazoles starts from enolizable ketones, primary amines and 4-nitrophenyl azide as diazo-transfer agent.…”

Synthesis and Anti-HIV Activity of a Novel Series of Isoquinoline-Based CXCR4 Antagonists

“…In 2016, our group reported a metal-free three-component reaction for the synthesis of 1,5-disubstituted 1,2,3-triazoles [ 20 , 21 , 22 ], known as the “triazolization reaction of ketones”. In 2020, it was shown by our laboratory that the acid-mediated denitrogenative ring opening of triazoloisoquinolines furnished various 1-methyleneisoquinolines [ 23 ].…”

1-(4-Nitrophenyl)-1H-1,2,3-Triazole-4-carbaldehyde: Scalable Synthesis and Its Use in the Preparation of 1-Alkyl-4-Formyl-1,2,3-triazoles

“…Interestingly, a procedure was developed starting from FNPT 1a and primary amines that allowed for protein modification in excellent conversions without isolating the targeted aldehydes 7. Following our ongoing interest in the synthesis of 1,2,3-triazoles [36][37][38], we recognized the potential of this approach for the metal-free synthesis of 1-alkyl-4-formyl-As described by L'abbé, the equilibrium of the Cornforth rearrangement is shifted toward the triazole with the most electron-deficient substituent on the imine nitrogen. Fletcher et al, who further studied this rearrangement in 2018, observed the same trend [34].…”

“…Interestingly, a procedure was developed starting from FNPT 1a and primary amines that allowed for protein modification in excellent conversions without isolating the targeted aldehydes 7. Following our ongoing interest in the synthesis of 1,2,3-triazoles [36][37][38], we recognized the potential of this approach for the metal-free synthesis of 1-alkyl-4-formyl-1,2,3-triazoles 7. However, to the best of our knowledge, a metal-free and straightforward synthesis of FNPT 1a on a preparative scale was still lacking.…”