Disclosed herein is an efficient strategy for the synthesis of 2,4,5-trisubstituted pyridines via CuI/NBS-catalyzed formal intermolecular [2+2+2] cycloaddition of easily available primary amines and nonactivated terminal alkynes. Moreover, this given reaction features a new mode of cycloaddition with high regio- and chemoselectivity, good atom- and step-economy, broad substrate scope, and wide functional group compatibility. Further mechanism studies indicate that this transformation starts with oxidative alkynylation of the amine to form a propargylamine intermediate, followed by radical addition to the alkyne and intramolecular cycloaddition, delivering the pharmacologically interesting multisubstituted pyridines.