A Metal‐Free Multicomponent Cascade Reaction for the Regiospecific Synthesis of 1,5‐Disubstituted 1,2,3‐Triazoles

Abstract

The thermal Huisgen 1,3-dipolar cycloaddition of organic azides and alkynes to build 1,2,3-triazoles usually requires elevated temperatures and provides a mixture of regioisomers. The copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) and ruthenium(II)-catalyzed azide–alkyne cycloaddition (RuAAC) have been developed as powerful strategies for the regiospecific assembly of 1,4-disubstituted 1,2,3-triazoles and 1,5-disubstituted 1,2,3-triazoles, respectively. These reliable processes have quickly found many applications in organic synthesis, chemical biology, and materials science. Nevertheless, the contamination of heavy metals limits their potential application in the pharmaceutical industry. Several metal-free methods, including the azide–enamine cycloaddition, the condensation of azides with phosphonium ylides, and the addition of acetylide species to azides, have also been developed for the regiospecific synthesis of 1,2,3-triazoles. Considerable drawbacks, however, exist with these processes, such as poor functional-group tolerance or requiring functionalized substrates. Westermann recently reported an improved Sakai reaction to synthesize 1,4-disubstituted triazoles from primary amines and a,a-dichlorotosylhydrazones (Scheme 1a). This procedure is limited to the synthesis of 1,4-disubstituted regioisomers. Therefore, a general and metal-free procedure to synthesize 1,5-disubstituted triazoles from readily available substrates under mild reaction conditions is still of considerable interest. Herein we report the synthesis of the 1,5disubstituted triazoles 5 from a three-component reaction of aliphatic amines (1), propynones (2), and TsN3 by a Michael addition/deacylative diazo transfer/cyclization sequence (Scheme 1b). Theoretically, the enaminone compounds 4 may exist as three tautomers: the iminoenol 4a, iminoketone 4b, and ketoenamine 4c. The a-diazo iminoketone 7 and 1-tosyl triazole 8 could be obtained from the Regitz diazo transfer of 4b and 1,3-dipolar cycloaddition of 4c with TsN3, respectively. We assumed that, in the presence of suitable bases, 4a might react with TsN3 to give the a-diazoimine intermediate 6, which could further cyclize to afford the triazole 5 (Scheme 2).