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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, 15:32 and posted on 06.06.2019, 16:01 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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