HFIP-mediated 2-aza-Cope rearrangement: metal-free synthesis of α-substituted homoallylamines at ambient temperature

An efficient metal-free strategy for the synthesis of alpha-substituted homoallylamine derivatives has been developed via a 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP)-promoted 2-aza-Cope rearrangement of aldimines, generated in situ by condensation of aldehydes with easily accessible 1,1-diphenylhomoallylamines. This reaction provides rapid access to alpha-substituted homoallylamines with excellent functional group tolerance and yields. The reaction takes place at room temperature and no chromatographic purification is required for product isolation. The synthetic utility of the current method is further demonstrated by the transformation of the obtained benzophenone ketimines into N-unprotected homoallylamines, an alpha-amino alcohol and an alpha-amino amide.

Automated summary

An efficient metal-free strategy has been developed for the synthesis of alpha-substituted homoallylamine derivatives via a 2-aza-Cope rearrangement promoted by HFIP. This method provides rapid access to the desired products with excellent functional group tolerance and high yields, without the need for chromatographic purification. The synthetic utility of this method is further demonstrated through the transformation of benzophenone ketimines into various compounds.