Rosen Alexander, Lindsay Kara, Quillen Andrew, Nguyen Quynh, Neiser Matthew, Ramirez Stephen, Costan Stefana, Johnson Nathan, Do Thuy Donna, Ma Lili
Department of Chemistry & Biochemistry, Northern Kentucky University.
Department of Chemistry & Biochemistry, Northern Kentucky University;
J Vis Exp. 2020 Feb 16(156). doi: 10.3791/60441.
Heteroarylation introduces heteroaryl fragments to organic molecules. Despite the numerous available reactions reported for arylation via transition metal catalysis, the literature on direct heteroarylation is scarce. The presence of heteroatoms such as nitrogen, sulfur and oxygen often make heteroarylation a challenging research field due to catalyst poisoning, product decomposition and the rest. This protocol details a highly efficient direct α-C(sp3) heteroarylation of ketones under microwave irradiation. Key factors for successful heteroarylation include the use of XPhos Palladacycle Gen. 4 Catalyst, excess base to suppress side reactions and the high temperature and pressure achieved in a sealed reaction vial under microwave irradiation. The heteroarylation compounds prepared by this method were fully characterized by proton nuclear magnetic resonance spectroscopy (H NMR), carbon nuclear magnetic resonance spectroscopy (C NMR) and high-resolution mass spectrometry (HRMS). This methodology has several advantages over literature precedents including broad substrate scope, rapid reaction time, greener procedure and operational simplicity by eliminating the preparation of intermediates such as silyl enol ether. Possible applications for this protocol include, but are not limited to, diversity-oriented synthesis for the discovery of biologically active small molecules, domino synthesis for the preparation of natural products and ligand development for new transition metal catalytic systems.
杂芳基化反应是将杂芳基片段引入有机分子的过程。尽管通过过渡金属催化进行芳基化反应已有大量报道，但关于直接杂芳基化反应的文献却很少。由于氮、硫和氧等杂原子的存在，杂芳基化反应往往是一个具有挑战性的研究领域，这是由催化剂中毒、产物分解等问题导致的。本实验方案详细介绍了在微波辐射下酮类化合物高效的直接α-C(sp³)杂芳基化反应。成功实现杂芳基化反应的关键因素包括使用第四代XPhos钯环催化剂、过量碱以抑制副反应，以及在密封反应瓶中微波辐射下实现的高温高压条件。通过该方法制备的杂芳基化化合物通过质子核磁共振光谱（¹H NMR）、碳核磁共振光谱（¹³C NMR）和高分辨率质谱（HRMS）进行了全面表征。该方法相对于文献先例具有几个优点，包括底物范围广、反应时间短、更环保的操作流程以及通过省去硅烯醇醚等中间体的制备而实现的操作简便性。该实验方案的可能应用包括但不限于：用于发现生物活性小分子的多样化导向合成、用于制备天然产物的多米诺合成以及用于新型过渡金属催化体系的配体开发。
