A novel process using N-benzylhydroxylamine hydrochloride as a “C1N1 synthon” in [2 + 2 + 1] cyclization for the construction of 1,2,5-trisubstituted imidazoles has been described for the first time. The key to realizing this process lies on capturing arylamines by in situ generated novel acyl ketonitrone intermediates. Subsequent tautomerization activates the α–C(sp3)−H of N-benzylhydroxylamines, thus breaks through its inherent reaction mode and achieves N, α–C site-selective cyclization. Furthermore, this method enables scale-up synthesis and late-stage modification of complex molecules.