Sequential One-Pot CuAAC Synthesis and Structural Characterization of Novel Tryptanthrin-Based 1,2,3-Triazole Hybrids

Abstract

Tryptanthrin is a naturally occurring indoloquinazoline alkaloid which has emerged as an attractive scaffold for the development of structurally diverse heterocyclic compounds because of its rigid fused-ring framework and ease of chemical functionalization. In the present study, an efficient sequential one-pot synthetic methodology was developed for the preparation of a series of novel tryptanthrin-based 1,2,3-triazole hybrids via copper-catalyzed azide alkyne cycloaddition (CuAAC). The synthetic strategy involved the preparation of propargylated tryptanthrin intermediates, followed by in situ generation of aryl azides from substituted anilines through diazotization using tert-butyl nitrite and sodium azide. Subsequent CuAAC under optimized reaction conditions afforded sixteen structurally diverse triazole derivatives in good to excellent isolated yields (75–91%) with excellent regioselectivity. The sequential one-pot protocol eliminated the need for isolation and handling of potentially hazardous organic azides, thereby improving operational safety, reducing purification steps, and enhancing overall synthetic efficiency. The developed methodology exhibited broad substrate tolerance toward both electron-donating and electron-withdrawing aromatic substituents, demonstrating its versatility for the rapid synthesis of molecularly diverse analogues. The structures of the synthesized compounds were comprehensively established by FTIR, ¹H and ¹³C NMR spectroscopy, electrospray ionization mass spectrometry, elemental analysis, and melting point determination. The present work provides a practical, regioselective, and scalable synthetic approach for the construction of tryptanthrin-based 1,2,3-triazole hybrids and highlights the utility of sequential one-pot CuAAC chemistry for the efficient synthesis of natural product-inspired heterocyclic libraries.