Two-Carbon Ring Expansion of Cyclobutanols to Cyclohexenones Enabled by Indole Radical Cation Intermediate: Development and Application to a Total Synthesis of Uleine

A single-electron transfer (SET) oxidation of indole or benzo[b]thiophene to a radical cation reverses the intrinsic polarity of these pi-excessive bicyclic heteroarenes. Here we report an oxidative two-carbon homologation of cyclobutanols to cyclohexenones under a visible-light photoredox catalysis. 1-(Indol-2-yl)cyclobutan-1-ols are converted to 2,3,4,9-tetrahydro-1H-carbazol-1-ones, important structural motifs found in alkaloids and pharmaceuticals, with a broad substrate scope. A mechanistic study suggests that the reaction is initiated by an SET from an indole to an excited acridinium salt to generate the radical cation, which is followed by two consecutive 1,2-alkyl migrations and a rearomatization. Benzo[b]thiophene-substituted cyclobutanols are similarly converted to 2,3-dihydrodibenzo[b,d]thiophen-4(1H)-ones. A total synthesis of (+/-)-uleine featuring this ring-expansion process is documented.

Automated summary

In this study, a visible-light photoredox catalysis is used to achieve an oxidative two-carbon homologation of cyclobutanols to cyclohexenones. The reaction involves the conversion of 1-(indol-2-yl)cyclobutan-1-ols to 2,3,4,9-tetrahydro-1H-carbazol-1-ones, which are important structural motifs found in alkaloids and pharmaceuticals. Mechanistic studies reveal that the reaction is initiated by a single-electron transfer from an indole to an excited acridinium salt, followed by consecutive 1,2-alkyl migrations and rearomatization.