Highly Stereoselective Reaction of Bicyclo[1.1.0]butanes and Isatins

Abstract Bicyclo[1.1.0]butanes (BCBs) have emerged as versatile strained building blocks for constructing stereodefined cyclic scaffolds. However, the Lewis-acid-catalyzed reaction of BCBs and ketones remains elusive, hampered by the poor electrophilicity and substantial steric hindrance of the ketonic carbonyl group. The La(OTf)3-catalyzed reaction of BCBs and isatins achieved highly stereoselective synthesis of 3-(cyclobuten-3-yl)-3-hydroxyindolin-2-ones in up to 97% yield with excellent diastereoselectivity (dr of >20:1). Control experiments and density functional theory calculations corroborate the reaction as a Baylis–Hillman-type ring-opening activation strategy with isatin derivatives as representative cyclic ketones, revealing that the amidic carbonyl moiety of isatins stabilizes the key carbocation intermediates, which is the primary origin of the observed high diastereoselectivity. Notably, partial products precipitate spontaneously and can be isolated via simple filtration without tedious column chromatography, facilitating scale-up preparation. This protocol provides an efficient avenue to functionalized heterocyclic scaffolds and expands the synthetic utility of BCBs.