Rhodium-Catalyzed Cycloaddition of Bicyclo[1.1.0]butanes with N,N’-Cyclic Azomethine Imines: En Route to Fused Diaza-3D Scaffolds

The construction of aza-3D frameworks has emerged as a pivotal strategy in drug discovery, owing to their ability to mimic heteroarene bioisosteres. In this study, we introduce a novel strategy that employs an octahedral rhodium complex as an efficient Lewis acid catalyst for the cycloaddition reaction between bicyclo[1.1.0]butanes and N,N’-cyclic azomethine imines, yielding versatile azabicyclo[3.1.1]heptane derivatives. The reaction proceeds smoothly with a broad substrate scope, achieving yields of up to 98% in 27 examples. The synthetic feasibility of this cycloaddition reaction was demonstrated through a scaled-up reaction using only 2 mol% catalyst loading, followed by further transformations of the cyclized BCHeps product. Control experiment together with DFT caculations illustrated the detailed reaction pathway. Additionally, we have developed an enantioselective version of this reaction using a chiral-at-Rhodium catalyst (up to 91% ee).