Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, U.K.
Medicinal Science & Technology, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, U.K.
J Org Chem. 2021 Feb 19;86(4):3583-3604. doi: 10.1021/acs.joc.0c02958. Epub 2021 Jan 29.
Substituted arylethylamines represent a key structural motif in natural, pharmaceutical, and agrochemical compounds. Access to such scaffolds has been the subject of long-standing synthetic interest. Herein, we report the synthesis of such scaffolds a palladium-catalyzed C(sp)-C(sp) coupling between (chloromethyl)aryls and air-/moisture-stable ,-dialkylaminomethyltrifluoroborate salts. Rapid hit identification was achieved using microscale high-throughput experimentation and was followed by millimolar-scale reaction parameter optimization. A range of structurally and electronically varied arylethylamine products were obtained in moderate to excellent yields (27-96%, >60 examples). The reaction mechanism is proposed to proceed formation of a trialkylbenzylammonium species prior to oxidative addition.
取代的芳基乙胺是天然、药物和农用化学品化合物中的关键结构基序。获得此类支架一直是长期合成研究的主题。在此，我们报告了此类支架的合成方法，即在钯催化下，(氯甲基)芳基与空气/水分稳定的，-二烷基氨甲基三氟硼酸盐盐之间进行 C(sp)-C(sp)偶联。使用微量高通量实验实现了快速命中鉴定，然后进行了毫摩尔规模的反应参数优化。在中等至优异的收率（27-96％，> 60 个实例）下获得了一系列结构和电子变化的芳基乙胺产物。该反应机制被提议通过三烷基苄基铵物种的形成来进行，然后进行氧化加成。
