Divergent Synthesis of Cyclobutyl and Biscyclobutenyl Amines via Lewis Acid-Catalyzed Reaction of Bicyclo[1.1.0]butanes with Triazinanes

In this study, we describe a Lewis acid-catalyzed divergent synthesis of cyclobutyl and biscyclobutenyl amines by exploiting the distinct reactivity exhibited by bicyclo[1.1.0]butane (BCB) ketones and esters with triazinanes. The cycloaddition of BCB ketones with triazinanes yields 2,4-diazabicyclo[4.1.1]octanes (aza-BCOs) under B(C6F5)3 catalysis. A direct acidic treatment of the resulting aza-BCOs efficiently cleaves the aminal moiety, leading to a series of medicinally intriguing cis-cyclobutyl diamines. This "cycloaddition/ring-opening" process can be conducted in either a stepwise or one-pot manner. In contrast, the reaction of BCB esters with triazinanes produces a range of beautiful butterfly-shaped biscyclobutenyl amines under In(OTf)3 catalysis. Both reactions feature simple operation, mild reaction conditions, and a broad substrate scope. Mechanistic studies reveal that the distinct reaction pathways originate from the different activation modes of BCBs by Lewis acid, the reaction of BCB ketones with triazinanes follows a stepwise (2+2+3) rather than (4+3) cycloaddition, and the reaction of BCB esters with triazinanes involves a Leitch’s carbocation intermediate. We believe that our findings will promote the exploration of BCB chemistry to access more synthetically challenging cyclobutane frameworks.