Facile Assembly of Functionalizable Conjugated Dienes via Skeletal Editing of Alkynyl Diazoketones Enabled by a Traceless 2-Pyridyloxy Group

Abstract

Herein, we report an efficient and practical strategy for the facile assembly of functionalizable conjugated dienes through skeletal editing of alkynyl diazoketones enabled by a traceless 2-pyridyloxy group. Conjugated dienes are important structural motifs and versatile synthetic building blocks, yet the stereodefined preparation of highly substituted dienes bearing a readily transformable functional handle remains challenging. In this protocol, alkynyl diazoketones react with 2-pyridone-derived N,N-acetals under mild Lewis-acid-promoted conditions to furnish polysubstituted conjugated dienes with useful chemo-, regio-, and stereoselectivity. The readily available 2-pyridyloxy moiety plays a dual role: it facilitates the multiple rearrangement sequence and remains in the products as a versatile handle for further diversification. The reaction exhibits broad substrate scope, tolerating alkynyl diazoketones bearing electron-donating and electron-withdrawing aryl substituents, heteroaryl and alkyl groups, and terminal alkynes, as well as N,N-acetals derived from substituted pyridones, pyrimidines, and various secondary amines. In addition, a convenient one-pot three-component protocol can be performed directly from an acetal amine, 2-pyridinone, and an alkynyl diazoketone without isolation of the intermediate N,N-acetal. The synthetic practicality of the method is further demonstrated by gram-scale preparation and diverse downstream transformations of the resulting dienes. In particular, the 2-pyridyloxy group can be replaced by sulfur, aryl, and alkenyl substituents through substitution or cross-coupling reactions, can enable installation of a complex cholesterol-derived fragment, and can also be removed reductively. The structure of representative product 3a was confirmed by single-crystal X-ray diffraction, supporting the proposed connectivity and nitrogen-initiated reaction pathway. Mechanistically, the transformation is proposed to proceed through Wolff rearrangement of the alkynyl diazoketone to an alkynyl ketene, nitrogen-initiated nucleophilic addition of the N,N-acetal, subsequent 1,5-migration to an allenamide intermediate, and a final [3,3]-sigmatropic rearrangement to generate the conjugated diene framework. Overall, this strategy provides a modular, scalable, and practical platform for accessing structurally diverse and readily functionalizable conjugated dienes.