Laboratoire de Chimie Moléculaire UMR 7509, Université de Strasbourg, CNRS , Strasbourg F-67000, France.
Medicinal Chemistry, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche, Ltd. , Grenzacherstrasse 124, Basel CH-4070, Switzerland.
J Org Chem. 2017 Feb 3;82(3):1726-1742. doi: 10.1021/acs.joc.6b02986. Epub 2017 Jan 20.
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.
4-氨基吡啶是一般化学工业的重要骨架，从生命科学到催化。我们在此报告了一系列结构多样的多环稠合和螺-4-氨基吡啶，它们仅通过三步就可从商业可得的嘧啶制备得到。这个短序列的关键步骤是嘧啶和炔酰胺之间的[4+2]/逆-[4+2]环加成，这构成了炔酰胺作为富电子双烯体在[4+2]环加成反应中的第一个例子。此外，通过在过热的甲苯中连续进行 ihDA/rDA 反应，克服了 MW 反应的有限可扩展性，与分批模式相比，产量显著增加。最后，密度泛函理论研究揭示了 ihDA/rDA 序列不同步骤的能量和几何要求。
