A DFT Study On 2H-Azirine Interrupted Copper(?)-Catalyzed Click Rearrangent Mechanism

Cu(?)-catalyzed azide-alkyne click reaction(CuAAC)due to its reliability,specificity and biocompatibility has become a prime example of click chemistry and has been widely used in medicine chemistry,material science,organic synthesis,polymer chemistry,and other fields.Recently,the "one pot" reaction of azides,alkynes and heterocyclic compounds catalyzed by Cu(I)has attracted much attention because it is an effective method for synthesis of new medicine and bioactive multifunctional compounds.The reaction mechanism is generally regarded that first disubstituted 1,2,3-triazole intermediates were generated by metal catalyzed cycloaddition of azides and alkynes,and then following selective C-E coupling reactions.At present,due to the limitation of experiment methods,the fundamental intermediates involved in Cu(I)click rearrangement reaction is to study furtter,more resonable and detail mechanism is to be perfect.In this paper,density functional theoretical(DFT)calculation was applied to investigate the mechanism of Cu(I)catalytic synthesis of 1,2,3-triazole[1,5-c]pyrimidine from azide,terminal alkyne and 2H-azirine.The main results and conclusion are as follows:(1)Initially,the[1,2,3]triazole[1,5-c]pyrimidine and[(IMes)Cu-(C6F5)]were optimized using three B3LYP,M06-2X and M06-L functionals with different basis sets.By comparing the calculated with the XRD experimental structural parameters,the optimium methods were determined.M06-L functionals was applied.The pseudo-potential basis sets SDD were used for the Cu(?),and the 6-311G**basis for other elements involving dispersion functions.Considering the economic and the accurate calculation,the ONIOM method was adopted by QM(M06-L-D3/6-311+G**/SDD):MM(PM6).(2)2H-azirine activated 5-dicopper(?)-1,2,3-triazole intermediates to inhibit the common CuAAC reaction,which lead to the cyclization of 5-dicopper(?)-1,2,3-triazole intermediates,further carrying out C-C coupling.Thus 2H-azirine interrupted 5-dicopper(?)-1,2,3-triazole to finish the CuAAC reaction with a potential barrier of?15 kcal/mol.The wave function analysis shows that the dicopper(?)intermediate effectively reduces the stability of 2H-azirine to easily lead to the ring-opening reaction,and then react to the four-memberred heterocyclic compound by the metal ligand exchange,which pushes the following C-C coupling reaction between 2H-azirine and 5-dicopper(?)-1,2,3-triazole.(3)The C-N coupling/rearrangement reactions were promoted due to the hydrogen bonding chain of H2O.The multi-step hydrogen transfer process pushed the removal of p-toluenesulfonamides and C-N coupling reaction.Hydrogen bonding chain reduced the potential barrier on the multi-step hydrogen transfer.