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

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

Kim Søholm Halskov  1 , Howard S Roth  1 , Jonathan A Ellman  1
Affiliations

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

Kim Søholm Halskov et al. Angew Chem Int Ed Engl. .

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.

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Figures

Figure 1
Figure 1
Synthesis of fused [5,6]-bicyclic nitrogen heterocycles via Rh(III)-catalyzed C-H functionalization.
Figure 2
Figure 2
Reaction of donor/acceptor diazoketone allowing for divergent product formation. [a]After 16 h, added AcOH (5 mL) and stirred at 100 °C for 24 h.
Scheme 1
Scheme 1
a) Mechanism of Rh(III)-catalyzed coupling of alkenyl azoles with alkynes. b) Mechanism of Rh(III)-catalyzed coupling of alkenyl azoles with diazoketones.
Scheme 2
Scheme 2
Synthesis of potential drug candidate 12 utilizing developed methodology.
See this image and copyright information in PMC

References

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