A DFT Study on the Binuclear Copper(I)‐Catalyzed Synthesis Mechanism of 1,2,3‐Triazolo[1,5‐c]Pyrimidine via Interrupted Click and Ketenimine Rearrangement

Abstract

In this paper, the mechanism of the full catalytic cycle for binuclear Cu(I)‐catalyzed sulfonyl azide‐alkyne cycloaddition reaction for the synthesis of triazolopyrimidines was rationalized by density functional theoretical (DFT) calculations. The computed reaction route consists of: (a) formation of dicopper intermediates, including C−H activation of terminal alkyne, 3+2 ring cycloaddition and ring‐reducing reaction and transmetalation, (b) interrupted CuAAC reaction, including di‐copper catalyzed ring‐opening of 2H‐azirines and C−C bond formation to generate the copper‐triazoles and ‐ketenimines, (c) two‐step C−N cross‐coupling and following (d) multi‐step hydrogen transfer by the hydrogen bonding chain of water to promote the C−N formation and another C−N cleavage through the removal of p‐tolyl sulfonamides. Our DFT results indicate that the multi‐step hydrogen transfer process is the rate‐determining step along the potential energy surface profile. The explicit water model was used for systematic determination of barrier for C−C cross‐coupling, C−N bond formation and cleavage, and p‐tolylsulfonamide removal. A critical insight in the interrupted CuAAC reaction was proposed. Further prediction interprets H2O hydrogen bond chain plays an important role in C−N bond formation and cleavage, and the removal of p‐tolylsulfonamide. This may have fundamental guidance on the design of 1, 5‐herterocyclic functionalized triazolopyrimidines via interrupted CuAAC rearrangement reaction, as well as hydrogen bond chain of water.