Arylation of enelactams using TIPSOTf: reaction scope and mechanistic insight

A novel method for the inter- and intramolecular arylation of enelactams (3,4-dihydropyridin-2-ones), up to 99% yield, triggered by triisopropylsilyltrifluoromethanesulfonate (TIPSOTf) is proposed. It offers high synthetic usefulness, especially for the synthesis of polycyclic systems obtained from conformationally rigid delta-enelactams, for which the use of the conventional method, involving cyclization by treatment with TfOH, failed. Multinuclear (H-1, C-13, F-19 and Si-29) NMR spectroscopy applied for the reaction monitoring as well as DOSY NMR experiment permitted identification of the intermediates and proposition of the reaction mechanism. In the process of checking the scope of the method application, condensed and bridged polycyclic piperidin-2-ones, including a derivative of alangiifoliumine A, were obtained. The inhibition of malignant melanoma A375 cell proliferation by some benzoquinolizidine derivatives (up to IC50 = 5.3 +/- 0.4 mu M) was evidenced.

Automated summary

A novel method for the arylation of enelactams using TIPSOTf as the catalyst, with high yield up to 99%, has been proposed. The reaction mechanism and intermediates were identified using multinuclear NMR spectroscopy, and the method showed potential for synthesizing polycyclic systems. The inhibition of melanoma cell proliferation by some benzoquinolizidine derivatives was also demonstrated.