Recent Developments in Azide‐Free Synthesis of 1,2,3‐Triazoles

Abstract

1,2,3‐Triazoles, as one of the most significant nitrogen‐containing heterocycles due to their extensive use in biology, material science and organic synthesis, have aroused great interest. 1,2,3‐Triazoles are commonly synthesized by metal‐catalyzed azide–alkyne cycloaddition and organocatalytic azide–carbonyl cycloaddition, which indispensably employ the toxic and potentially explosive azides. The azide‐free synthetic approaches provide a powerful and straightforward alternative to the assembly of diverse 1,2,3‐triazoles without the use of azides. In this review, we summarize the recent development of the construction of 1,2,3‐triazoles under azide‐free conditions.

Base‐Promoted Regiospecific Synthesis of Fully Substituted 1,2,3‐Triazoles and 1,5‐Disubstituted 1,2,3‐Triazoles

“…The combined organic layers were dried over Na 2 SO 4 . Removal of the solvent gave a residue, which was purified by a column chromatography (silica gel, PE/EtOAc=6/1) to afford 4 aa as white solid [24] . 1 H NMR (400 MHz, CDCl 3 ) δ 7.84 (s, 1H), 7.42–7.29 (m, 8H), 7.20 (d, J =8.0 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 137.6, 136.4, 133.2, 129.2 (2 C), 129.1 (2 C), 128.7 (2 C), 128.4 (2 C), 126.6, 125.0 (2 C).…”

“…[18] Although these transition-metal-catalyzed strategies have shown high efficiency and regioselectivity, the contamination of heavy metals limits their potential application in the life science and pharmaceutical industry. [19] Recently, several metal-free or metal-and azide-free strategies including organocatalytic azide-carbonyl cycloaddition (scheme 1b), [20][21] the condensation of azides with phosphonium ylides, [22] TsOHcatalyzed nitroolefin-azide cycloaddition [23] and the cyclization reactions of hydrazones with primary amines [24] have also been explored for the preparation of regiospecific 1,2,3-triazoles. Representatively, Cui group and Wan group reported the cycloaddition of enaminones with sulfonylazides to provide 1,5disubstituted 1,2,3-triazoles and 1,4-disubstituted 1,2,3-triazoles under metal-free conditions, respectively (Scheme 1c).…”

Diazocarbonyl and Related Compounds in the Synthesis of Azoles

“…Additionally, RuAAC also works well with internal alkynes providing fully substituted triazoles, although in this case, regioselectivity cannot always be reliably controlled [ 163 ]. In contrast with this method, a number of azide-free methodologies for regiospecific synthesis of variously substituted 1,2,3-triazoles have been developed [ 164 , 165 ], including the «diazo» approach, specifically, the Wolff cyclocondensation. Moreover, for the latter reaction, common Lewis acids are used and often no transition metal catalyst is needed.…”

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

“…Furthermore, there is a persistent need for further diversification of 1,2,3‐triazoles in the framework of the various applications. As a result, a vast number of inventive organocatalytic pathways have been developed throughout the past decade [26–31] . The majority are cycloaddition reactions with azides and enolizable ketones, aldehydes, or functionalized olefins, and offer regiospecific access to a variety of substitution patterns, including ring‐fused derivatives [26–28,30] .…”

“…At the same time, the development of metal‐ and azide‐free methods gained considerable attention, with the latter due to the potentially hazardous nature of the azido substrates. Azide‐free methods involve cyclization reactions with N ‐tosylhydrazones and have been well summarized in separate review articles [29,31] …”