Recent Breakthroughs in Cyclizations of Ortho-Quinone Methides

Ortho-quinone methides (o-QMs) constitute a class of highly reactive and versatile intermediates in organic synthesis, characterized by a unique polarized electronic structure that combines an electron-deficient quinoid ring with an exocyclic electrophilic methylene or alkylidene unit. This distinctive feature renders powerful C4 synthons capable of participating in a wide range of higher-order cyclization reactions. In particular, [4 + n] cyclizations involving o-QMs (e.g., [4 + 1], [4 + 2], and [4 + 3]) have emerged as effective strategies for the rapid construction of structurally complex carbocyclic and heterocyclic frameworks, many of which serve as privileged scaffolds in natural products and functional materials. This review provides a comprehensive overview of recent advances in this rapidly developing field, with a systematic discussion of reaction design, mechanistic insights, and synthetic applications across various [4 + n] cyclization modes. Furthermore, current challenges are critically evaluated, and future opportunities are proposed, particularly in the development of novel catalytic systems, asymmetric variants, and innovative o-QM precursors. Overall, this review aims to offer researchers a clear understanding of the state of the art in o-QM chemistry and to inspire further innovation in this dynamic area of organic synthesis.