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. 2017 Oct 25;139(42):14833-14836.
doi: 10.1021/jacs.7b07518. Epub 2017 Oct 12.

Understanding and Interrupting the Fischer Azaindolization Reaction

Bryan J Simmons  1 , Marie Hoffmann  1 , Pier Alexandre Champagne  1 , Elias Picazo  1 , Katsuya Yamakawa  1 , Lucas A Morrill  1 , K N Houk  1 , Neil K Garg  1
Affiliations

Understanding and Interrupting the Fischer Azaindolization Reaction

Bryan J Simmons et al. J Am Chem Soc. .

Abstract

Experimental and computational studies pertaining to the Fischer azaindolization reaction are reported. These studies explain why pyridylhydrazines are poorly reactive in Fischer indolization reactions, in addition to the origin of hydrazine substituent effects. Additionally, an interrupted variant of Fischer azaindolization methodology is disclosed, which provides a synthetic entryway into fused azaindoline scaffolds.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Azaindole drug Zelboraf (1), indoline-containing natural product aspidophylline A (2), and interrupted Fischer azaindolization methodology.
Figure 2
Figure 2
Comparative calculations of the [3,3]-sigmatropic rearrangement transition states as a function of the arylhydrazine component.
Figure 3
Figure 3
Calculations suggest that an unfavorable equilibrium between 10 and 11 leads to challenging Fischer azaindolization of 3-pyridylhydrazones.
Figure 4
Figure 4
Synthesis of aza-analogues.
See this image and copyright information in PMC

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