Design and application of intramolecular vinylogous Michael reaction for the construction of 2-alkenyl indoles

A base-mediated transformation based on a designed intramolecular vinylogous Michael addition (intra-VMA) is presented to access 3-substituted 2-alkenyl indole derivatives. The reaction represents the first example of the intra-VMA for the construction of indoles. A one-pot N-allylation of ortho-tosylamidocinnamates/congeners with γ-bromocrotonates followed by intra-VMA has been described to provide access to a diverse range of 2-alkenyl indole derivatives in reasonable to high yields. The synthetic value of the developed intra-VMA has been demonstrated by gram-scale synthesis of a representative indole derivative and also by the formal synthesis of MK-7246: a Merck's clinical CRTH2 antagonist.