Activating Pyrimidines by Pre-distortion for the General Synthesis of 7-Aza-indazoles from 2-Hydrazonylpyrimidines via Intramolecular Diels–Alder Reactions - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Journal of the American Chemical Society Année : 2019

Activating Pyrimidines by Pre-distortion for the General Synthesis of 7-Aza-indazoles from 2-Hydrazonylpyrimidines via Intramolecular Diels–Alder Reactions

Résumé

Pyrimidines are almost unreactive partners in Diels-Alder cycloadditions with alkenes and alkynes, and only reactions under drastic conditions have previously been reported. We describe how 2-hydrazonylpy-rimidines, easily obtained in two steps from commercially available 2-halopyrimidines can be exceptionally activated by trifluoroacetylation. This allows a Diels-Alder cycloaddition under very mild reaction 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. A straightforward synthesis of a key intermediate of Bayer's Vericiguat illustrates the potential of this cycload-dition strategy. Quantum mechanical calculations show how the simple N-trifluoromethylation of 2-hydra-zonylpyrimidines distorts the substrate into a transition state-like geometry that readily undergoes the intramolec-ular Diels-Alder cycloaddition.

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Chimie
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Dates et versions

hal-02323378 , version 1 (06-11-2020)

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Vincent Le Fouler, Yu Chen, Vincent Gandon, Vincent Bizet, Christophe Salomé, et al.. Activating Pyrimidines by Pre-distortion for the General Synthesis of 7-Aza-indazoles from 2-Hydrazonylpyrimidines via Intramolecular Diels–Alder Reactions. Journal of the American Chemical Society, 2019, 141 (40), pp.15901-15909. ⟨10.1021/jacs.9b07037⟩. ⟨hal-02323378⟩
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