Studies On Controllable Huisgen Cycloaddition And Its Mechanism

1,2,3-Triazole is a well-known pharmacophore possessing a wide spectrum of interesting biological activities. Due to its unique biological activity, it is widely used for structural modification of peptides, DNAs and carbohydrates. 1,2,3-Triazole was mostly prepare by the Huisgen reaction, a thermal 1,3-dipolar cycloaddition of azides and alkynes, however with low regioselectivities for even terminal alkynes. The Cu-catalyzed variant of this transformation(Cu AAC), first reported in 2002, marked the emergence of “click chemistry”. With the recent advances in N-hetereocyclic carbene(NHC) chemistry, a few Cu-NHC complexes have been reported to catalyze azide cycloaddition to terminal alkynes. While the Cu AAC of terminal alkynes enjoys excellent regioselectivity for 1,4-disubstituted product, unsymmetric internal alkynes remain difficult substrates due to low reactivity and problematic regioselectivity control.We investigated herein the Huisgen reaction of internal alkynes under both microwave irradiation and Cu-NHC catalysis. The substrates, a series of azide substituted alkynes, were based on easily accessible chiral propargylic amines. It was demonstrated that the reactivity is dictated by the conditions: microwave promoted intramolecular cycloaddition, affording 1,4,5-trisubstituted triazoles, while Cu-NHC complexes catalyzed intermolecular cycloaddition in an unexpected desilylative fashion, leading to 1,4-disubstituted triazoles. Only [1+1] intermolecular reaction products were obtained in the latter case, and no intramolecular reaction product or higher oligomers was isolated. It is worth noting that this is the first direct Cu AAC of 1-silyl alkynes without the need of a prior de-silylation step or reagent. To elucidate this de-silylation, a series of control experiments were performed, and it was proved that the anchimeric effect of the amide carbonyl is crucial.This work is an interesting addition to Click Chemistry and promotes the diversity-oriented synthesis of propargylic amines.