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1854年，Bechamp首先報道了利用鐵粉還原芳香硝基化合物合成芳香伯胺反應(yīng)，此反應(yīng)被稱為 Bechamp還原反應(yīng) 。制備芳胺 一般而言，最干凈和簡 便的還原方法就是通過Pd/C或Raney Ni加氫，但是當(dāng)分子內(nèi)存在對加氫敏感的官能團(tuán)， 如：鹵素（Cl, Br and I; F 對加氫不敏感），雙鍵，三鍵，氰基，羰基時，我們不得不采用其他方法 ， 最為經(jīng)典的要數(shù)鐵粉的還原。鐵粉還原一般在鹽類電解質(zhì)(如，氯化銨)或烯酸條件下進(jìn)行，此條件可以將芳香硝基，脂肪硝基，亞硝基和羥胺等基團(tuán)還原為氨基。鐵粉還原芳香硝基化合物時，芳基上有吸電子基團(tuán)時，有利于硝基獲得電子，反應(yīng)容易進(jìn)行。

常用的還原條件是： 一、鐵粉/HCl，THF體系或乙醇體系；二、鐵粉/AcOH； 另外常用的條件還有，鐵粉（5eq），氯化銨（10eq），在甲醇和水混合溶液（4：1）中回流，但此條件 很容易形成偶氮化合物，致使反應(yīng)變黑，氮?dú)獗Ｗo(hù)可以減少偶氮化合物的生成，上述兩種酸性條件很少生成偶氮類副產(chǎn)物。 此類反應(yīng)的后處理，一般情況下都是趁熱過濾，防止冷卻后，產(chǎn)品吸附到剩余的鐵粉和氧化鐵上。 強(qiáng)磁力攪拌投反應(yīng)時，一定要其他原料都加入反應(yīng)體系中后，最后在劇烈攪拌下慢慢加入鐵粉，如果開始就加入鐵粉，很可能會攪不動（機(jī)械攪拌可以忽略此步驟）。另外可以利用亞鐵鹽進(jìn)行還原，可以有效避免攪拌問題。

另外由于鐵粉反應(yīng)后氧化物的顏色較深，不好純化，有時會用鋅粉代替鐵粉進(jìn)行反應(yīng)，條件類似，鋅粉的另外一個優(yōu)點(diǎn)是利用磁力攪拌器就可以進(jìn)行較大量的反應(yīng)。

反應(yīng)機(jī)理

鐵粉還原為單電子轉(zhuǎn)移機(jī)理，反應(yīng)中需要轉(zhuǎn)移六個電子，理論上還原硝基至少需要3倍當(dāng)量鐵粉，實(shí)際反應(yīng)操作中一般加入4倍當(dāng)量以上鐵粉。

鐵鹽比較兩個常見的價態(tài)是+2價和+3價，反應(yīng)后鐵粉副產(chǎn)物是啥，小編認(rèn)為這和反應(yīng)中加入的鐵的當(dāng)量數(shù)有關(guān)。如果鐵粉過量很多，那主要副產(chǎn)物鐵鹽應(yīng)該是二價鐵，小編做反應(yīng)時發(fā)現(xiàn)鐵粉過量時，反應(yīng)體系如果隔絕空氣，體系是白色的，迅速趁熱過濾后，濾餅白色的鹽迅速變?yōu)楹稚�，這應(yīng)該是二價鐵鹽被空氣中氧氣氧化為三價鐵的現(xiàn)象。由于此反應(yīng)也可以利用二價鐵鹽做為還原劑，因此反應(yīng)中肯定是生成三價鐵鹽。如果鐵粉的當(dāng)量數(shù)較低時，考慮到非均相反應(yīng)，會導(dǎo)致鐵粉當(dāng)量數(shù)不足，二價鐵鹽會繼續(xù)參與反應(yīng)生成三價鐵鹽，那最后鐵粉的副產(chǎn)物應(yīng)該是二價鐵鹽和三價鐵鹽的混合物（當(dāng)然三價鐵也會和鐵粉反應(yīng)生成二價鐵）。 利用Fe/HCl，進(jìn)行此反應(yīng)時，小伙伴肯定有這種疑惑，鐵不是會和鹽酸反應(yīng)生成氫氣和FeCl2嗎？ 小編認(rèn)為可能最后主要其還原作用的恰恰是二價鐵，因此此體系小編建議鐵粉的當(dāng)量數(shù)要稍微大點(diǎn)。

如上圖機(jī)理中，反應(yīng)體系中除了產(chǎn)物還有亞硝基，然后芳香亞硝基化合物和羥胺，亞硝基化合物會和產(chǎn)物氨基生成偶氮化合物，羥胺和亞硝基化合物也反應(yīng)生成偶氮氧化物，這些偶氮化合物根據(jù)結(jié)構(gòu)可能會呈現(xiàn)橙色、紅色、深紅色乃至紅褐色，再加上一些其他雜質(zhì)，很容易呈現(xiàn)偏黑色。

反應(yīng)實(shí)例

To 300 mL EtOH was added 9.27 g 6-chloro-3-nitro-2-pyrrolopyridine (41 mmol), followed by 115.25 g FeSO4·7H2O(414 mmol), 0.5mL10NHCl, and 5mLwater. The mixture was heated at 80?C for 90 min, while a 30% ammonia solution was added in little fractions to maintain a basic pH. After cooling, EtOHwas evaporated under vacuum. The residuewas poured in 100 mL water and extracted with Et2O. After the usual treatment, the first amount of the product was obtained. The aqueous phase was alkalinized with ammonia solution and extracted with EtOAc. Finally, 4.59 g 3-amino-6-chloro-2-pyrrolopyridine was obtained as a beige powder, in a yield of 57%, m.p. 89?C (recrystallization from 80% Et2O and 20%n-hexane).

【J. Med. Chem., 1997, 40, 1808】

To mixture of 1.2 g iron (21.6 mmol), 0.25 mL 10 N HCl, 10 mL acetic acid, 10 mL ethanol and 5 mL water was added 1.0 g 2-nitro-5-(2-piperidin-1-ylethoxy)benzaldehyde (3.6 mmol). The mixture was refluxed for 15 min with stirring, and iron was removed by filtration. The product was worked up as usual.

【J. Med. Chem., 2002, 45, 5809】

To the starting material (3.1 g) was added acetic acid (24.4 mL) and then, reduced iron powder (9.15 g), and the mixture was stirred for 16 hours at room temperature. The mixture was filtered with Celite, and washed with ethyl acetate. The solvent was removed under reduced pressure, and water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 1.4 g of the desired product.

To 80 percent ethanol (5.0 mL), the starting material (300 mg, 1.76 mmol) and concentrated hydrochloric acid (0.45 ml, 5.28 mmol) were added to stir for 10 minutes at 20°C. Then, iron powder (500 mg, 8.95 mmol) was added to the mixture to further stirring for 1 hour at 20°C. Insoluble matters were filtered off and the filtrate was concentrated, adding 0.5N NaOH (10 mL) to the residue, filtering the solution to further remove insoluble matters, extracting the filtrate with chloroform, drying the extract over anhydrous sodium sulfate, concentrating the extract, and distilling the resulting crude product to afford 224 mg of the desired compound (91% yield).

參考資料

一、Comprehensive Organic Name Reactions and Reagents, by Zerong Wang，284-287.

二、藥明康德經(jīng)典化學(xué)合成反應(yīng)標(biāo)準(zhǔn)操作。