Multifaceted Domino Knoevenagel‐Cyclization Reactions; Four Movements for 2H‐Chromenes and Chromans

Abstract Domino Knoevenagel‐cyclization reactions of 2H‐chromene and chroman derivatives containing o‐formylaryl amine or ether side‐chain was carried out to produce four series of chiral condensed heterocycles representing four novel skeletons and exhibiting antiproliferative activity. The cyclization step occurred with four different mechanisms: a concerted intramolecular hetero Diels‐Alder reaction (IMHDA), a stepwise polar [2+2] cycloaddition, a [1,5]‐hydride shift‐6‐endo cyclization or a multi‐step nitro hetero Diels‐Alder‐ring‐opening‐Cadogan‐type cyclization sequence. The latter reaction provided a new route to hydroxyindoles by an inverse Cadogan‐type cyclization, in which the nitro group is deoxygenated by a nitro IMHDA‐ring‐opening sequence. The cyclization mechanisms and their stereoselectivity were studied by DFT calculations, based on which we proposed a mechanism for the multi‐step cyclization to hydroxyindoles and explained the observed diastereoselectivity.