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

Angew Chem Int Ed Engl. 2017 Jul 24;56(31):9183-9187. doi: 10.1002/anie.201703967. Epub 2017 Jul 5.

Abstract

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.

Keywords: C−H activation; cyclization; homogeneous catalysis; nitrogen heterocycles; rhodium.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkynes / chemistry
  • Azoles / chemistry*
  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry*
  • Carbon / chemistry
  • Catalysis
  • Coordination Complexes / chemistry
  • Cyclization
  • Hydrogen / chemistry
  • Isomerism
  • Nitrogen / chemistry*
  • Rhodium / chemistry*

Substances

  • Alkynes
  • Azoles
  • Bridged Bicyclo Compounds, Heterocyclic
  • Coordination Complexes
  • Carbon
  • Hydrogen
  • Rhodium
  • Nitrogen