Exceptional, HFIP-Mediated Spiro-annulation Protocol to Access Spirocyclobutenes

Keywords

spiroannulation - spirocyclobutenes - HFIP - bicyclo[1.1.0]butanes

Significance

Spiro-annulation has emerged as a viable approach for bringing structural complexity into heterocyclic scaffolds used in medicinal and pharmaceutical chemistry research. The method often utilizes the strain imposed by one of the starting materials. In this regard, bicyclo[1.1.0]butanes (BCBs) remain a prominent carbocyclic precursor, with the central C–C bond can be easily activated via photocatalysis, acid catalysis, or transition-metal catalysis. In this study, BCB esters 1 were activated using HFIP to react with α-bromo hydroxamates 2 to furnish functionalized azaspiro[3.4]oct-1-ene-5,7-diones 3 via (3 + 2) annulation, rather than producing azabicyclo[3.1.1]heptan-3-ones 4 via the (3 + 3) annulation pathway.

 

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Comment

Various aryl substituents on BCB ester 1, as well as alkyl and aryl substituents the hydroxamate oxygen were both well tolerated, yielding moderate to good amounts of desired products 3. However, with a bulkier cyclohexyl substituent at the α-position in hydroxamate 2, a lower yield was obtained; more α-substituents could have increased diversity. In the authors’ suggested mechanism, BCB ester enolate nucleophilically attacks the in situ formed 1,3-bipolar azaoxyallyl cation, establishing a new C–C bond. Subsequent deprotonation and lactamization results in the formation of a spirocyclic product. Furthermore, it would be interesting to see how BCB esters react with other 1,3-dipolar molecules, thus expanding the scope of the method.

 

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Publikationsverlauf

Artikel online veröffentlicht:
23. September 2025