A Modular Approach for the Palladium-Catalyzed Synthesis of Bis-heterocyclic Spirocycles

• Published in: Organic letters 2022-01, Vol.24 (1), p.95-99
• Main Authors: Marchese, Austin D, Durant, Andrew G, Lautens, Mark
• Format: Article
• Language: English
• ISSN: 1523-7060; 1523-7052
• DOI: 10.1021/acs.orglett.1c03682

A simple and modular approach toward bis-heterocyclic spirocycles using palladium catalysis is reported. The enclosed methodology leverages a Mizoroki–Heck-type reaction to generate a neopentylpalladium species. This species can undergo intramolecular C–H activation on a wide array of (hetero)­aryl C–H bonds, generating a variety of [4.4] and [4.5] bis-heterocyclic spirocycles in up to 95% yield. A diverse range of bis-heterocyclic spirocycles were possible, with 24 examples and 18 different combinations of heterocycles were synthesized. Biologically relevant aza-heterocycles such as purine, pyrazole, (benz)­imidazole, (aza)­indole, and pyridine were readily incorporated into the spirocyclic core. The reaction was readily scalable to 1 mmol using a lower catalyst loading and number of base equivalents, and the product was purified without the use flash column chromatography.