A general metal-free route towards the synthesis of 1,2,3-triazoles from readily available primary amines and ketones

Abstract

An unprecedented approach that enables the direct and selective preparation of 1,5-disubstituted 1,2,3-triazoles from abundantly available building blocks such as primary amines, enolizable ketones and 4-nitrophenyl azide as a renewable source of dinitrogen via an organocascade process has been developed. Furthermore, this efficient methodology also enables the synthesis of fully functionalized and fused N-substituted heterocycles.

Multi‐Gram Scale Synthesis of 1,2,3‐Triazolium Ionic Liquids and Assay of Their Resistance towards Bases

“…The formation of these two regioisomers was observed in both acetonitrile and solvent‐free conditions. The formation of only one product was described by Thomas et al when similar substrates were used . Based on their observations, the 4‐methyl‐5‐ethyl derivative is expected to be formed selectively.…”

“…Based on their observations, the 4‐methyl‐5‐ethyl derivative is expected to be formed selectively. The ratio of both products changed from 45:55 to 92:8 in favor of the expected regioisomer in solvent‐free conditions . Treating the 92:8 mixture with aminobenzoic acid in acetonitrile at 80 °C did not cause a change in the isomer ratio, implying that the observed 1,3‐“shift” occurs during the formation of the product, and is not an acid‐catalyzed rearrangement of the final product.…”

“…However, due to the lower cost of low molecular weight amines, this can be counteracted by the addition of a larger excess of the amine. Presumably, the poor solubility of the azidobenzoate salts of these amines reduces their availability to react with the ketone, which is the rate‐determining step in the mechanism of the triazolation described by Dehaen and coworkers . This strategy was effective for isobutylamine and other lower amines (Figure ).…”

“…In this paper, we present a new method for the synthesis of 1,2,3‐triazolium ionic liquids with high resistance towards bases. This pathway is inspired by a method described by Thomas and Dehaen in 2016, which affords trisubstituted 1,2,3‐triazoles from primary amines and ketones via an enamine intermediate , . The procedure is metal‐free and requires the synthesis of only one common organic azide, regardless of the compound of interest.…”

Metal‐Free Route for the Synthesis of 4‐Acyl‐1,2,3‐Triazoles from Readily Available Building Blocks

“…Very recently, our group designed two general and powerful strategies to synthesize triazole heterocycles . The first method involves an organocatalytic three‐component reaction for synthesizing fully functionalized triazoles from aldehydes, organic azides, and nitroalkanes,, whereas the second approach involves a metal‐free route towards the synthesis of fully functionalized or 1,5‐disubstituted 1,2,3‐triazoles from primary amines, ketones, and 4‐nitrophenyl azide as a renewable source of dinitrogen through an organocascade process …”