Amine-cation-driven heteroannulation of halomaleimides with C–N cleavage: metal-free access to heterobicyclic frameworks

Abstract

Maleimides and their derivatives are highly versatile scaffolds with broad applications in synthetic chemistry, medicinal chemistry, and materials science; however, methods to expand their structural diversity remain limited. Here, we present a so far undescribed, metal-free, and mild strategy for the rapid construction of functionalized maleimides from readily available dihalomaleimide derivatives. The reaction is initiated by tertiary amine-mediated formation of an ammonium cation, which directs heteroannulation to efficiently generate heterobicyclic scaffolds. This modular approach also enables the synthesis of 3,4-diamino-substituted maleimides, including challenging second halogen substitutions with weak nucleophiles. Mechanistic studies indicate that a quaternary enamine intermediate plays a central role in steering the transformation, providing broad functional group tolerance and synthetically useful yields. Overall, this strategy offers a versatile platform for accessing structurally diverse maleimides, unlocking new opportunities in bioconjugation, medicinal chemistry, and materials science.