Divergent Synthesis of Cyclobutyl and Biscyclobutenyl Amines via Lewis Acid-Catalyzed Reaction of Bicyclo1.1.0butanes 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 bicyclo1.1.0butane (BCB) ketones and esters with triazinanes. The cycloaddition of BCB ketones with triazinanes yields 2,4-diazabicyclo4.1.1octanes (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.