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Energizing Listless Pyrimidines by Pre-Distortion for the General Synthesis of 7-Aza-Indazoles from 2-Hydrazonylpyrimidines via Intramolecular Diels-Alder Reactions

preprint
submitted on 05.06.2019 and posted on 06.06.2019 by Vincent Le Fouler, yu Chen, Vincent Gandon, Vincent Bizet, Christophe Salomé, Thomas Fessard, Fang Liu, K. N. Houk, Nicolas Blanchard

Pyrimidines are almost unreactive partners in Diels-Alder cycloadditions with alkenes and alkynes, and usually only reactions under drastic conditions were historically reported. We describe how 2-hydrazonylpyrimidines, easily obtained in two steps from commercially available 2-halopyrimidines can be exceptionally activated by trifluoro acetylation. This allows a Diels-Alder cycloaddition under very mild conditions, leading to a large diversity of aza-indazoles, a ubiquitous scaffold in medicinal chemistry. This reaction is general, scalable and has an excellent functional group tolerance. Quantum mechanical calculations show how the simple N-trifluoromethylation of 2-hydrazonylpyrimidines distorts the substrate into a transition state-like geometry that readily undergoes the intramolecular Diels-Alder cycloaddition.

Funding

Universite de Haute-Alsace

Universite de Strasbourg

CNRS

Ecole Polytechnique

US National Science Foundation CHE-1764328

History

Email Address of Submitting Author

n.blanchard@unistra.fr

Institution

CNRS UMR 7042

Country

France

ORCID For Submitting Author

0000-0002-3097-0548

Declaration of Conflict of Interest

VLF, YC, VG, VB, FL, KNH and NB declare no competing interests. CS and TF are Team Leader and CEO (respectively) of Spirochem, a Swiss CRO company selling the building blocks leading to compounds 45-48.

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