在药物化学中，N-芳基杂环芳胺是一类非常重要的骨架，特别是在小分子激酶抑制剂中（small-molecule kinase inhibitors (SMKIs)）。自从伊马替尼（Imatinib，也就是格列卫，Gleevec）在2001年被FDA批准为用于治疗用于治疗慢性粒细胞白血病(CML)急变期、加速期或α-干扰素治疗失败后的慢性期患者 ；不能手术切除或发生转移的恶性胃肠道间质肿瘤（GIST）患者以来，选择性激酶抑制剂的发展成为学术界和工业界的研究热点。

非常有意思的是，已经批准的药物中接近一半都含有N-芳基杂环芳胺结构。结构如下图所示。

通常情况下，N-芳基杂环芳胺是通过（杂）芳卤代物与芳胺通过取代或金属催化的偶联反应来实现，这些方法已经被用来合成部分SMKIs。在很多例子中，这两种方法都存在着一些绝限，要么底物范围受限，要么产率较低。因此，杂环芳胺与卤代芳烃的铜催化或钯催化的偶联反应，就变成了一类非常有吸引力的方法。然而这些偶联反应的背后充满着挑战：杂环芳胺的弱的亲核性和强的配位性。钯催化的方法在大位阻的膦配体的参与下可有效阻止杂环芳胺对钯的k2配位，可有效实现这一类反应。虽然说较便宜的铜催化也可实现该类转化，然后底物往往局限于溴代或碘代芳烃，有时往往需要较多的铜催化剂的参与。

正是在这样一个大背景下，来自中科院上海有机所的马大为研究员课题组最近几年成功发展了草酰胺类配体，可温和实现多种碳杂键的构建。这几天，该团队又为我们带来了草酰胺类配体参与的铜催化的杂环芳胺与芳基氯带，溴代，碘代芳烃的偶联反应，反应非常高效，通过一系列条件筛选，最终发现DBO效果最好。可以以最高90%的产率得到目标化合物3a，最佳反应条件是：5 mol % CuBr, 10 mol %L5, 130 °C。

作者将该催化体系用于各类杂环芳胺与氯带芳烃的偶联，普适性很好，产率基本上都在60%以上。

除了氯带芳烃，溴代和碘代芳烃效果也很好，产率最高可以达到94%。

The (hetero)aryl chlorides 2 (4.5 mmol), CuBr (0.15 mmol, 21.6 mg), t-BuONa (4.5 mmol, 432 mg), ligand L5 (0.3 mmol, 80.4 mg), heteroanilines 1(3.0 mmol) and freshly activated 4 Å MS (200-300 mg) were placed into a Schlenk tube (20 mL) with a magnetic stir bar. The reaction vessel was evacuated and backfilled with argon three times, then t-BuOH (3.0 mL) were added under a positive argon pressure (Note: for liquid substrates, they were added slowly under the ice bath after the tube was backfilled with argon). The reaction mixture was heated at 130 °C for 24 h under vigorous stirring. The cooled solution was acidified with 2 N HCl, then diluted with dichloromethane and washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel flash chromatography to afford the corresponding N-aryl heteroanilines.

The (hetero)aryl bromides or iodides 2 (3.0 mmol), CuI (0.03 or 0.06 mmol, 5.7 or 11.4 mg), t-BuOK (6.0 mmol, 672 mg), ligand L5 (0.06 or 0.12 mmol, 16.1 or 32.2 mg), heteroanilines 1 (3.6 mmol) and freshly activated 4 Å MS (200-300 mg) were S5 placed into a Schlenk tube (20 mL) with a magnetic stir bar. The reaction vessel was evacuated and backfilled with argon three times, then t-BuOH (3.0 mL) were added under a positive argon pressure (Note: for liquid substrates, they were added after the tube was backfilled with argon). The reaction mixture was heated at 80 or 100 °C for 24 h under vigorous stirring. The cooled solution was acidified with 2 N HCl, then diluted with dichloromethane and washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel flash chromatography to afford the corresponding N-aryl heteroanilines.

参考文献：Org. Lett.2019, 10.1021/acs.orglett.9b02509