Ene–azide chemistry in the synthesis of 1,2,3-triazoline/triazole and the corresponding mechanistic aspects

Abstract

Alkenes and azides have been proven to be significant synthons in organic chemistry for the preparation of diverse medicinally valued nitrogen-containing heterocycles. The ene–azide cycloaddition reaction appears as an alternative to azide–alkyne cycloaddition for the synthesis of 1,2,3-triazole building blocks. This review surveys 1,2,3-triazole/triazoline synthesis, focusing on non-click techniques, and explores ene–azide cycloaddition reactions, detailing alkene structure/electronic effects and challenges associated with triazoline instability. Strategies for stable triazoline/triazole synthesis using activated/strained alkenes, effects of reaction conditions, and inter/intramolecular reactions are examined. Alternative triazole routes are also explored. Mechanistic aspects including triazoline transformations are discussed with illustrative examples. Metal-catalyzed/free methods including applications of carbohydrate chemistry are presented. This review discloses various approaches for the functionalization and conjugation of diverse natural products, medicinally significant scaffolds, and other organic molecules, bearing olefinic functional groups with the required scaffolds. This review could guide synthetic and medicinal chemists to design and develop novel and efficient drug candidates using ene–azide chemistry.