Synthetic and mechanistic study of the acid-promoted aromatisation of the Diels–Alder adduct: 6,7-dimethoxy-1-(4-pyridyl)-1,4-epoxytetrahydronaphthalene-2,3-dicarboxylate

Abstract

A synthetic study of a 1-arylnaphthalene lignan having a heteroaryl group, such as the pyridyl group, at the C(1) position was conducted in detail. The Diels–Alder reaction of 1-pyridylisobenzofuran precursor 1 with dimethyl maleate or dimethyl fumarate gave desired 1,4-epoxides 2–5 in good yields as mixtures of exo and endo diastereoisomers. Intensive investigation of the following acid-promoted aromatisation using a Lewis acid or a Brønsted acid as a reaction promoter revealed that BF3·Et2O was the most suitable acid for this step. Examination of the reaction rates in aromatisation of 1,4-epoxides 2–5 provided information for the elaboration of reaction mechanisms in these reactions. Both the neighbouring-group effect of the 2-methoxycarbonyl substituent stabilising the benzyl cation intermediate and the longer length of the C(1)–O bond in 1,4-epoxide in 2-endo form 3 (or 5) than that of the C(4)–O bond presumably contribute to enhancing the reaction rate, and aromatisation of the 2-endo form would be greatly favoured over that of the 2-exo form.