[3+2] Cycloaddition Route to Spirooxindoles

Significance

Spirocyclic oxindoles are found in various biologically active compounds (see Review below). Within this family, the 3,3′-cyclopropyl spirooxindoles are of particular interest since they have found utility as HIV-1 non-nucleoside ­reverse transcriptase inhibitors (NNRTi), kinase ­inhibitors, and arginine vasopressin inhibitors. ­Recently, Carreira and co-workers have demonstrated that the highly active compound 2,2,2-trifluorodiazoethane (CF₃CHN₂) can be prepared in situ and used in transition-metal-promoted cyclopropanations of terminal olefins and alkynes to ­provide CF ₃ -containing cyclopropanes (Angew. Chem. Int. Ed. 2011, 50, 1101 and references cited therein). However, to date the use of the reagent with electron-deficient alkenes has not been exploited.

Review

G. S. Singh, Z. Y. Desta Chem. Rev. 2012, 112, 6104–6155.

Comment

The current work demonstrates a ­metal-free [3+2] cycloaddition of CF₃CHN₂ with alkylenyloxindole A followed by a ring contraction to give densely functionalized CF₃-3,3′-cyclopyropyl spirooxindoles in high yields and stereoselectivities. CF₃CH₂NH₂·HCl/NaNO₂ is generated in PhMe–H₂O, followed by addition of the alkylenyl­oxindole A at 0 °C. After 36 hours, to allow formation of the cycloaddition product B, the mixture is heated to reflux to effect ring contraction and afford the final product. In addition, intermediate B can be utilized to form a CF₃-containing spiropyrazoline oxindole by treatment with DABCO to effect a 1,3-H shift to C. The CF₃-containing ring systems described can be anticipated to offer many opportunities in the future for drug discovery programs.