Acid-catalyzed intramolecular cyclization of alkyl beta-amino acrylates

Abstract

The acid-induced reaction of the amphiphilic β-amino acrylates (enamines) was thoroughly investigated in this work. The electron-deficient enamines have been widely used as the important intermediates for C-C formation in total synthesis. The structure of these enamines contains three conjugated functional groups exhibiting both nucleophilic and electrophilic properties. The simple Michael addition between aliphatic amines and ethyl propiolate in DCM was used to prepare ethyl β-amino acrylates to provide aliphatic enamines in quantitative yields. For aromatic enamines, addition of the copper(I) iodide at 60 ℃ was required to push the reaction forward. In the cyclization step, the unstable ethyl β-amino acrylates were immediately treated as a substrate in situ with acid in an optimized condition. Several acids and Lewis acid e.g. HCl, H₂SO₄, TFA, BF₃.OEt₂, AlCl₃, AlMe₂Cl and TiCl₄ were used in sub-stoichiometric amount. Along with the study of reaction under several acidic conditions, the novel synthetic methods for a couple sets of new compounds, oxazolidin-2-ones and 1,4-dihydropyridines were successfully developed. In details, a set of oxazolidin-2-ones were synthesized in very good yield by intramolecular cyclization for the case of Boc-enamides bearing dialkyl acetal moiety. On the other hand, 1,4-dihydropyridine containing various N-substituents were synthesized by treatment of β-amino acrylates with 0.2 - 0.5 equivalent of TiCl₄ under mild condition resulted in excellent yields. The cyclization reaction mechanism was proposed base on the separation of dimeric intermediate.