A dearomative [3,3′]‐sigmatropic rearrangement that converts N‐alkenylbenzisoxazolines into spirocyclic pyrroline cyclohexadienones has been developed by using the dipolar cycloaddition of an N‐alkenylnitrone and an aryne to access these unusual transient rearrangement precursors. This cascade reaction affords spirocyclic pyrrolines that are inaccessible through dipolar cycloadditions of exocyclic cyclohexenones and provides a fundamentally new approach to novel spirocyclic pyrroline and pyrrolidine motifs that are common scaffolds in biologically‐active molecules. Diastereoselective functionalization processes have also been explored to demonstrate the divergent synthetic utility of the unsaturated spirocyclic products.
The synthesis of 1-pyrrolines from N-alkenylnitrones and alkynes has been explored as ar etrosynthetic alternative to traditional approaches.T hese cascade reactions are formal [4 + 1] cycloadditions that proceed through ap roposed dipolar cycloaddition and N-alkenylisoxazoline [3,3']sigmatropic rearrangement. Av ariety of cyclic alkynes and terminal alkynes have been shown to undergo the transformation with N-alkenylnitrones under mild conditions to provide the corresponding spirocyclic and densely substituted 1-pyrrolines with high regio-and diastereoselectivity.M echanistic studies provide insight into the balance of steric and electronic effects that promote the cascade process and control the diastereo-and regioisomeric preferences of the 1-pyrroline products.D iastereoselective derivatization of the 1-pyrrolines prepared by the cascade reaction demonstrate the divergent synthetic utility of the new method.Scheme 1. N-Alkenylisoxazoline approach to 1-pyrroline synthesis.LG = leaving group. EWG = electron-withdrawing group.
The synthesis of 1-pyrrolines from N-alkenylnitrones and alkynes has been explored as ar etrosynthetic alternative to traditional approaches.T hese cascade reactions are formal [4 + 1] cycloadditions that proceed through ap roposed dipolar cycloaddition and N-alkenylisoxazoline [3,3']sigmatropic rearrangement. Av ariety of cyclic alkynes and terminal alkynes have been shown to undergo the transformation with N-alkenylnitrones under mild conditions to provide the corresponding spirocyclic and densely substituted 1-pyrrolines with high regio-and diastereoselectivity.M echanistic studies provide insight into the balance of steric and electronic effects that promote the cascade process and control the diastereo-and regioisomeric preferences of the 1-pyrroline products.D iastereoselective derivatization of the 1-pyrrolines prepared by the cascade reaction demonstrate the divergent synthetic utility of the new method.Scheme 1. N-Alkenylisoxazoline approach to 1-pyrroline synthesis.LG = leaving group. EWG = electron-withdrawing group.
A dearomative [3,3′]‐sigmatropic rearrangement that converts N‐alkenylbenzisoxazolines into spirocyclic pyrroline cyclohexadienones has been developed by using the dipolar cycloaddition of an N‐alkenylnitrone and an aryne to access these unusual transient rearrangement precursors. This cascade reaction affords spirocyclic pyrrolines that are inaccessible through dipolar cycloadditions of exocyclic cyclohexenones and provides a fundamentally new approach to novel spirocyclic pyrroline and pyrrolidine motifs that are common scaffolds in biologically‐active molecules. Diastereoselective functionalization processes have also been explored to demonstrate the divergent synthetic utility of the unsaturated spirocyclic products.
The roles of substituent and solvent effects in promoting the 4π-electrocyclization of N-alkenylnitrones to give azetidine nitrones have been investigated by experimental examination of relative rates, activation energies, and linear free energy relationships. These transformations are synthetically important because they favor formation of a strained heterocyclic ring with imbedded functionality and stereochemical information for versatile derivatization. Mechanistic investigations, including Hammett studies, solvent-dependent Eyring studies, and solvent isotope effects, provide insight into the steric and electronic factors that control these electrocyclizations and identify trends that can be used to advance this approach towards the rapid synthesis of complex azetidines.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.