【ASC】溫和，高效，芳胺的脫氨反應(yīng)！

《Salicylic Acid-Catalyzed One-Pot Hydrodeamination of Aromatic

Amines by tert-Butyl Nitrite in Tetrahydrofuran》

Adv. Synth. Catal. 2017, 359, 2857 – 2863

傳統(tǒng)脫氨基方法需分離不穩(wěn)定的重氮鹽，且常伴隨副反應(yīng)（如酚或醚的生成），電子供體取代基的底物反應(yīng)性低。西班牙阿利坎特大學(xué)有機(jī)合成研究所的 Diego Felipe-Blanco等人報道了一種 一鍋法芳胺脫氨氫化新方法。在10 mol%水楊酸催化下，四氫呋喃（THF）作為氫供體時，原位生成的芳香胺重氮鹽的氫脫氨反應(yīng)顯著加速。該反應(yīng)在20℃下高效進(jìn)行，適用于多種取代苯胺（包括10 mmol規(guī)模），無需其他添加劑。該方案還可用于某些芳香胺的選擇性氘代脫氨。控制實(shí)驗(yàn)明確表明，反應(yīng)機(jī)制涉及芳基自由基的生成。

實(shí)驗(yàn)條件優(yōu)化

以對甲氧基苯胺（1a）為模型底物，篩選添加劑。發(fā)現(xiàn)水楊酸（10 mol%）催化產(chǎn)率達(dá)100%（3 h，20℃），優(yōu)于抗壞血酸（96%）和沒食子酸（92%）。光照實(shí)驗(yàn)顯示反應(yīng)無需光誘導(dǎo)，O-乙酰水楊酸催化活性較低（41%），甲酯無活性。

底物擴(kuò)展

此方法官能團(tuán)耐受度高，包括醚、酯、酮、鹵素、硝基、氰基、三氟甲基等取代基，耐受游離羧酸（2b）和羥基（2c）。對于一些挑戰(zhàn)性底物效果也不錯，鄰羥基苯胺（因分子內(nèi)氫鍵抑制反應(yīng)）、碘代苯胺（2h、2u）仍獲中等至良好產(chǎn)率（51-81%）。克級規(guī)模實(shí)驗(yàn)，10 mmol底物1v成功轉(zhuǎn)化為2v（產(chǎn)率74%）。

氘代反應(yīng)

使用[D8]-THF，氘代率≥97%，產(chǎn)率42-81%。此方法避免競爭性氫轉(zhuǎn)移，實(shí)現(xiàn)高同位素純度。

機(jī)理研究

自由基證據(jù)：TEMPO捕獲實(shí)驗(yàn)（Scheme 3b）分離到自由基加合物3（56%產(chǎn)率）。碘轉(zhuǎn)移實(shí)驗(yàn)（Scheme 3c）生成4-溴碘苯（52%），證實(shí)芳基自由基參與。KIE實(shí)驗(yàn)（kH/kD=2.70）表明THF的H-攫取為決速步。

推測機(jī)理：水楊酸質(zhì)子化重氮鹽，生成芳基苯甲酸酯中間體（II），分解釋放N?并產(chǎn)生芳基自由基（III）。THF提供H/D，生成產(chǎn)物和α-四氫呋喃自由基（IV），后者通過鏈傳遞再生芳基自由基。

反應(yīng)操作

General Procedure for the hydrodeamination reaction (Table 2)

The corresponding aniline (0.30 mmol) and salicylic acid(4.14 mg, 0.03 mmol) were added to an oven dried Schlenck. The system was evacuated and filled with argon (three times) before dry THF (1 mL) was added, and the reaction mixture was stirred vigorously until a homogeneous solution was obtained (5 min aprox.). At this point, tert-butylnitrite (47 mL, 41.3 mg, 0.36 mmol) was added (the solution turned orange after some minutes) and the stirring was continued for 3 h, keeping the temperature at 20℃ with a water bath. At this time, water was added (2 mL) and the mixture was extracted with EtOAc (334 mL). The organic layers were collected, dried over anhydrous MgSO4 and filtered. To this solution was added phenanthrene (53.4 mg, 0.3 mmol) as the internal standard (IS). An aliquot of this solution was injected into a GC apparatus to determine the reaction yield. Substrates o-1d, o-1k, 1p, 1s, 1t, and 1u were subjected to this procedure at 5-mmol scale and 1v at 10-mmol scale, and the corresponding compounds 2 were isolated in pure form after column chromatography to determine the yields.

本文報道了一種水楊酸催化的溫和、高效脫氨氫化方法，適用于多種芳香胺及雜環(huán)胺，THF作為氫源，無需金屬或光誘導(dǎo)。該方法可擴(kuò)展至氘代反應(yīng)（使用[D8]-THF），氘代率>97%。機(jī)理研究表明芳基自由基為關(guān)鍵中間體，THF的H-攫取為決速步驟。水楊酸作為廉價、無毒的生物基催化劑，為芳基自由基化學(xué)提供了新思路。