title: Intramolecular Inverse Electron-Demand [4 + 2] Cycloadditions of Ynamides with Pyrimidines: Scope and Density Functional Theory Insights.
abstract: 4-Aminopyridines are valuable scaffolds for the chemical industry in general, from life sciences to catalysis. We report herein a collection of structurally diverse polycyclic fused and spiro-4-aminopyridines that are prepared in only three steps from commercially available pyrimidines. The key step of this short sequence is a [4 + 2]/retro-[4 + 2] cycloaddition between a pyrimidine and an ynamide, which constitutes the first examples of ynamides behaving as electron-rich dienophiles in [4 + 2] cycloaddition reactions. In addition, running the ihDA/rDA reaction in continuous mode in superheated toluene, to overcome the limited scalability of MW reactions, results in a notable production increase compared to batch mode. Finally, density functional theory investigations shed light on the energetic and geometric requirements of the different steps of the ihDA/rDA sequence.
authors.affiliation: Laboratoire de Chimie Moléculaire UMR 7509, Université de Strasbourg, CNRS , Strasbourg F-67000, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Duret
authors.affiliation: Laboratoire de Chimie Moléculaire UMR 7509, Université de Strasbourg, CNRS , Strasbourg F-67000, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Quinlan
authors.affiliation: Laboratoire de Chimie Moléculaire UMR 7509, Université de Strasbourg, CNRS , Strasbourg F-67000, France.
authors.forename: Boyang
authors.initials: B
authors.lastname: Yin
authors.affiliation: Medicinal Chemistry, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche, Ltd. , Grenzacherstrasse 124, Basel CH-4070, Switzerland.
authors.forename: Rainer E
authors.identifier: 0000-0001-7895-497X
authors.initials: RE
authors.lastname: Martin
authors.affiliation: Laboratoire de Chimie Moléculaire UMR 7509, Université de Strasbourg, CNRS , Strasbourg F-67000, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bisseret
authors.affiliation: Department of Chemistry, University of Basel , Spitalstrasse 51, Basel CH-4056, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Neuburger
authors.affiliation: Institut de Chimie Moléculaire et des Matériaux d'Orsay, CNRS UMR 8182, Université Paris-Sud, Université Paris-Saclay , bâtiment 420, Orsay cedex 91405, France.|Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Sud, Université Paris-Saclay , 1 av. de la Terrasse, Gif-sur-Yvette 91198, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Gandon
authors.affiliation: Laboratoire de Chimie Moléculaire UMR 7509, Université de Strasbourg, CNRS , Strasbourg F-67000, France.
authors.forename: Nicolas
authors.identifier: 0000-0002-3097-0548
authors.initials: N
authors.lastname: Blanchard