Activating pyrimidines by pre-distortion for the general synthesis of 7-aza-indazoles from 2-hydrazonylpyrimidines via intramolecular Diels-Alder reactions

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LE FOULER, Vincent Le, CHEN, Yu, GANDON, Vincent, BIZET, Vincent, SALOME, Christophe, FESSARD, Thomas, LIU, Fang, HOUK, Kendall N. et BLANCHARD, Nicolas, 2019. Activating pyrimidines by pre-distortion for the general synthesis of 7-aza-indazoles from 2-hydrazonylpyrimidines via intramolecular Diels-Alder reactions. [en ligne]. 6 septembre 2019. Vol. 141, pp. 15901-15909. [Consultésans date]. DOI 10.1021/jacs.9b07037. Consulté de : https://pubs.acs.org/doi/10.1021/jacs.9b07037
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Auteurs Vincent Le Fouler
Yu Chen
Vincent Gandon
Vincent Bizet
Christophe Salome
Thomas Fessard
Fang Liu
Kendall Houk
Nicolas Blanchard
Unité de recherche du site Laboratoire d'Innovation Moléculaire et Applications - LIMA - UMR7042
Langue

en
Volume

141
Page de début

15901
Page de fin

15909
Date de première publication

2019-09-06
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-hydrazonylpyrimidines, easily obtained in two steps from Show morePyrimidines 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-hydrazonylpyrimidines, 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 cycloaddition strategy. 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. Show less
DOI 10.1021/jacs.9b07037
URL éditeur https://pubs.acs.org/doi/10.1021/jacs.9b07037
Titre abrégé de la source

Journal of American Chemical Society
Type de publication

journal article
Type de publication

ACL
Domaine

Aucun
Unité de recherche extérieure au site

State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China
Institut de Chimie Moléculaire et des Matériaux d’Orsay, CNRS UMR 8182, Université Paris-Sud, Université Paris-Saclay, Bâtiment 420, 91405 Orsay cedex, France
SpiroChem AG Rosental Area, WRO-1047-3, Mattenstrasse 24, 4058 Basel, Switzerland
College of Sciences, Nanjing Agricultural University, Nanjing 210095, China
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
Audience

Non spécifiée
URL https://univoak.eu/islandora/object/islandora:96422