A new DMAP-catalyzed and microwave-assisted approach for introducing heteroarylamino substituents at position-4 of the quinazoline ring |
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Authors: | Armand Gellis Charline Kieffer Nicolas Primas Gilles Lanzada Michel Giorgi Pierre Verhaeghe Patrice Vanelle |
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Affiliation: | 1. Aix-Marseille Université, CNRS, ICR, UMR 7273, Laboratoire de Pharmacochimie Radicalaire, Faculté de Pharmacie, 27 Bd Jean Moulin—CS30064, 13385 Marseille cedex 05, France;2. Aix-Marseille Université, CNRS, Spectropole FR 1739, 13397 Marseille cedex 20, France;3. Université Paul Sabatier, Faculté des Sciences Pharmaceutiques, Laboratoire de Chimie de Coordination UPR 8241 CNRS, 205 Route de Narbonne, 31400 Toulouse, France |
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Abstract: | We report herein a new methodology for synthesizing quinazoline derivatives bearing a heteroarylamino moiety at position-4 of the quinazoline ring. As an alternative to the Buchwald–Hartwig cross-coupling reaction, which appears, until now, as the only efficient way to react 4-chloroquinazolines with numerous amino nitrogen-containing heterocycles displaying poor nucleophilicity, we developed a DMAP-catalyzed reaction involving microwave irradiation. Optimization of the reaction conditions led to the use of 30 mol % of DMAP in toluene, using a monomode microwave reactor and sealed vials. Moreover, the SNAr reaction intermediate salt was isolated and fully characterized. Finally, the procedure was extended to two different 2-substituted-quinazoline series and also to various anilines, demonstrating that this approach was a general efficient way to access to such 4-substituted quinazoline scaffolds of high pharmaceutical interest. |
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Keywords: | Quinazoline ring Pharmaceutical chemistry Heteroaryl moiety DMAP Microwave |
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