Synthesis of [5,6]‐Bicyclic Heterocycles with a Ring‐Junction Nitrogen Atom: Rhodium(III)‐Catalyzed C−H Functionalization of Alkenyl Azoles

• Published in: Angewandte Chemie International Edition 2017-07, Vol.56 (31), p.9183-9187
• Main Authors: Halskov, Kim Søholm, Roth, Howard S., Ellman, Jonathan A.
• Format: Article
• Language: English
• Subjects: Alkynes; Azoles; Chemical reactions; Coupling; cyclization; C−H activation; Heterocyclic compounds; homogeneous catalysis; Nitrogen; Nitrogen atoms; nitrogen heterocycles; Pyrazoles; Rhodium; Synthesis; Triazoles
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201703967

The first syntheses of privileged [5,6]‐bicyclic heterocycles, with ring‐junction nitrogen atoms, by transition metal catalyzed C−H functionalization of C‐alkenyl azoles is disclosed. Several reactions are applied to alkenyl imidazoles, pyrazoles, and triazoles to provide products with nitrogen incorporated at different sites. Alkyne and diazoketone coupling partners give azolopyridines with various substitution patterns. In addition, 1,4,2‐dioxazolone coupling partners yield azolopyrimidines. Furthermore, the mechanisms for the reactions are discussed and the utility of the developed approach is demonstrated by iterative application of C−H functionalization for the rapid synthesis of a patented drug candidate. Ride that bicycle: A wide range of [5,6]‐bicyclic heterocycles with a ring‐junction nitrogen atom were accessed by the title reaction. Alkenyl imidazoles, pyrazoles, and triazoles as C−H activation substrates, in combination with either alkynes, diazoketones, or 1,4,2‐dioxazolones as reaction partners, allow formation of this privileged class of heterocycles with rich diversity in substitution patterns and nitrogen‐atom incorporation.