β-芳基乙胺的合成汇总
β-芳基乙胺骨架是药物分子和天然产物中常见的结构 ，含有这种骨架的分子在缓解疼痛、治疗神经系统疾病和阿片类药物成瘾等方面具有引人瞩目的生理活性，这使得构建 β-芳基乙胺骨架也成了合成化学家关注的课题。β-芳基乙胺是有机合成中非常重要的中间体，下面小编汇总一下常见的合成方法。
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一、通过芳醛和硝基烷烃通过Henry反应构建α,β-不饱和硝基化合物，然后还原直接得到β-芳基乙胺。【硝基还原制备胺】
还原相关条件：LiAlH4【Journal of Organic Chemistry, 2006, vol. 71, # 25, p. 9440 - 9448；Synthetic Communications, 2019, vol. 49, # 22, p. 3218 - 3225】，锌粉【Synlett, 2014, 25, 2891 - 2894】，硼氢化钠【Tetrahedron, 2016, 72，6099 - 6106】，氢气钯碳【Tetrahedron Letters, 2012, 53, 7125 - 7127】。
二、通过苄基卤代烃和氰化物反应制备得到α-芳基乙腈，然后还原腈制备得到β-芳基乙胺。
反应实例
1、Reney Ni 催化加氢还原腈基示例
A mixture of the material (413 mg, 1.51 mmol), Raney nickel (413 mg) and ammonia (0.9 g) in methanol (20 mL) was hydrogenated under 340 KPa (50 psi) hydrogen overnight at room temperature. The mixture was filtered and the filtrate was concentrat- ed in vacuo. The residue was partitioned between ethyl acetate (50 mL) and water (40 mL) and the ethyl acetate extract was washed with brine (30 mL), dried (sodium sulfate) and concentrated in vacuo. The residue (400 mg) was purified by column chromatography on silica gel (100 g), eluting with 85: 15 ethyl acetate/methanol to yield the title compound as an oil (321 mg, 77% yield).
2 、Reney Ni-NH2-NH2 催化加氢还原腈基示例
The starting material (1.39 g, 3.1 mmol) was dissolved in ethanol and warmed to 55 °C before it was treated with Raney-nickel (1 mL slurry in water) followed by addition of hydrazine monohydrate (1.5 mL). The resulting mixture was allowed to stir at 55°C for 30 min or until the evolution of gas had stopped. The cooled reaction mixture was filtered through diatomaceous earth, rinsed with methanol and dichloro- methane. The filtrate was diluted with saturated sodium bicarbonate (50 ML) and extracted with dichloromethane (50 mL×3). The combined organic layers were dried with sodium sulfate and concentrated. Chromatography with NH4OH: MeOH: EtOAc (5:10:85) afforded the product (1.30 g, 93%yield).
3、 PtO2 催化加氢还原腈基示例
The material (3 g, 13 mmol) was dissolved in methanol (35 mL) and concentrated HCl (4.4mL). This solution was combined with 10 percent PtO2 (0.1 g) and hydrogenated under 50 psi for 2 hours. The methanol was removed under reduced pressure and the residue was diluted with 35 mL of ice cold water and 2.5 mL of 50 percent NaOH. The product was extracted with CH2Cl2, dried with MgSO4 and evaporated to an oil. This oil was purified by Prep 500 chromatography (10 percent MeOH/DCM) to yield 2.5 g of an oil. The salicylate was precipitated from an ether solution to give 3.3 g of product. m.p. 160°C.
4、 LAH 还原腈基示例
2-bromophenylacetonitrile (10.0 g, 51.0 mmol) were dissolved in ether (80 mL) and the solution was added dropwise to lithium aluminium hydride (5.81 g, 153 mol) in ether (230mL). The mixture was heated under reflux for three hours, while stirring, and, after cooling, 80 mL of potassium hydroxide solution (10 wt. percent) were slowly added dropwise, with vigorous stirring. After stirring overnight, the supernatant was decanted off, the residue was rinsed twice with 100 mL of ether each time, the combined organic phases were dried over anhydrous magnesium sulfate and filtered and the filtrate was concentrated on a rotary evaporator (500~10 mbar). 9.48 g of 2-(2-bromo-phenyl)-ethylamine (93% yield) were obtained in this manner.
5 、BH3 还原腈基示例
The material (1.0 g, 3.7 mmol) was dissolved in anhydrous THF (10 mL). BH3.THF (10mL, 1.0 M solution in THF, 10 mmol) is added. The reaction mixture is maintained under reflux for 3 hours before being cooled to room temperature. An aqueous solution (12 mL) trifluoroacetic acid (50 percent) was added dropwise. The mixture was heated under reflux for 1 hour. The solvents and the trifluoroacetic acid are eva- porated. The residue is redissolved in 20 ml of THF and evaporated to dryness. A crude solid product is obtained which contains essentially the desired product and is used directly in the following acetylation step.
6 、NaBH4 还原腈基示例
Sodium borohydride (2.2 g, 58.2 mmol) are suspended in dry THF (50 mL) and cooled to ca.0°C under moisture exclusion. The material (6.7 g, 23.1 mmol) are added and the mixture is subsequently cooled to -5°C to -10°C and added dropwise to (1.5 mL, 26.7 mmol) 95% sulfuric acid (vigorous foaming). The suspension is left to stand for two days at RT without further cooling. Under renewed cooling to ca. 0°C, 40 mL of 2 M sodium hydroxide solution is added dropwise. The aqueous phase is extracted with 30 mL of THF and thereafter the combined organic phases are washed twice, each with 30 mL of saturated NaCl solution, dried over sodium sulfate and the solution is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH/NH4OH (90/10/1). Yield: 3.9 g (57% yield).
还原相关条件：氢气钯碳【Tetrahedron Letters, 1995, vol. 36, # 14, p. 2497 - 2500】，LiAlH4/AlCl3【Journal of Medicinal Chemistry, 1993, 36， 2868 - 2877】，硼氢化锂【Journal of Organic Chemistry, 2009, vol. 74, # 5, p. 1964 - 1970】，Raney Ni【US2008/280991, 2008, A1】，硼氢化钠/氯化钴【US2006/14830, 2006, A1】
近期马大为院士团队报道了铜催化下，利用草酰胺作为配体高效实现卤代芳烃与氰乙酸乙酯的高效偶联反应，实现了重要合成砌块芳基乙腈的便利合成。
【Angewandte Chemie International Edition, 2021, 60, 7082-7086 】
三、通过Knoevenagel缩合反应, Wittig反应, Horner-Wadsworth-Emmons反应，Heck反应，Suzuki–Miyaura反应，烯烃交叉复分解反应制备β-芳基丙烯酸衍生物，还原制备β-芳基丙酰胺，然后Hofmann重排得到β-芳基乙胺。
1881年，A.W Hofmann发现利用溴和钠（或氢氧化钾）处理乙酰胺可以得到N-溴代乙酰胺。接着碱性条件下脱质子，加热，N-溴代乙酰胺在无水条件下重排为甲基异氰酸酯，在水中则生成甲胺。
伯酰胺通过次卤化物处理（或氧化）经过异氰酸酯中间体生成少一个碳的伯胺的反应，被称为Hofmann重排反应或Hofmann降解反应。最早期的Hofmann重排是使用KOH水溶液和Br2来实施的。这个条件比较剧烈，后续有许多改进的方法，主要是通过氧化剂和碱来实现的。如Keillor等人1997年报道了用NBS做氧化剂，DBU做碱，甲醇中回流25分钟就得到了甲氧羰基保护的胺（JOC, 1997, 62, 7495-7496）。在四乙酸铅或高价碘(PIDA, PIFA, PhI(OH)OTs)氧化条件下，可以在酸性条件下进行Hofmann重排。酰胺α-碳如果有手性，重排后构型保持。α,β-不饱和酰胺或α-羟基酰胺进行Hofmann重排会生成醛酮。
反应机理
【Knoevenagel缩合反应】【Wittig反应】【Horner-Wadsworth-Emmons反应】【Heck反应】【Suzuki–Miyaura反应】【烯烃交叉复分解反应】【Hofmann重排】
另外还可以对于一些富电子的芳环可以和丙烯腈通过Friedel-Crafts烷基化反应先生成芳基丙腈，然后水解为酰胺【腈水解制备酰胺】，再进行Hofmann重排得到β-芳基乙胺类化合物。
腈加水可以分解为伯酰胺。由于伯酰胺会继续水解为羧酸，一般要控制水解的条件。目前有许多方法报道，有时需要根据底物的特性选择酸性，碱性或中性的水解条件。作为中性的条件，也有文献报道使用镍或钯催化剂的方法。
在酸性条件下与饱和碳相连的氰基，可以在酸中很方便的水解转化为酰胺，并在条件较为剧烈时，很容易进一步水解成酸。但乙烯基或芳基腈的水解条件则要求剧烈得多，一般需要强酸条件，而且一般不会进一步水解。
在碱性条件下，利用过氧化氢氧化的方法可在室温下短时间内水解腈为伯酰胺，这是一个较为可靠的方法。利用NaOH(aq.)-CH2Cl2 相转移催化体系，DMSO-K2CO3 体系，可以用于各种腈水解为伯酰胺。
1、盐酸水解腈为伯酰胺示例（Organic Syntheses, Coll. Vol. 1963, 4, 760）
In a 3-l. three-necked round-bottomed flask equipped with glass joints are placed 200 g. (1.71moles) of benzyl cyanide and 800 ml. of 35% hydrochloric acid. The flask is fitted with a reflux condenser, a thermometer, and an efficient mechanical stirrer. At a bath temperature of about 40° the mixture is stirred vigorously. Within a period of 20–40 minutes the benzyl cyanide goes into solution. During this time, the temperature of the reaction mixture risesabout 10° above that of the bath. The homogeneous solution is kept in the bath with, or without, stirring for an additional 20–30 minutes. The warm water in the bath is replaced by tap water at about 15–20°, and the thermometer is replaced by a dropping funnel from which
800 ml. of cold distilled water is added with stirring. After the addition of about 100–150ml., crystals begin to separate. When the total amount of water has been added, the mixture is cooled externally with ice water for about 30 minutes. The cooled mixture is filtered by suction. Crude phenylacetamide remains on the filter and is washed with two 100-ml. portions of water. The crystals are then dried at 50–80°. The yield of crude phenylacetamide is 190–200 g. (82–86%).
2 、浓硫酸水解不饱和腈为伯酰胺示例（Org. Syn., Coll. Vol. 1973,5, 73; 1955,3, 66,88）
To 106 g of 84 % sulfuric acid, was added 50 g of acrylonitrile. After stirring for 30 min at r.t., the resulting mixture was heated to 95 ℃, and stirred for 2 h. After cooling, the solid was collected by suction, and the filter cake was transferred into a beaker. To the ice-cooled solid, was added aq. ammonia with the speed that keep the temperature less than 50℃. The precipitated ammonium sulphate was filtered off, and the filtrate was cooled. The precipitate was collected by filtration, and the filter cake was washed by water, dried in vacuum to give
the desired product.
3、 H2O2-K2CO3-DMSO 体系水解腈为伯酰胺示例（Synthesis 1989, 949）
To a stirred solution of 4-chlorobenzonitrile (1.37 g, 0.01 mol) in DMSO (3 ml), cooled in a ice bath, was added 30% H2O2 (1.2 ml) and K2CO3, the reaction was allowed to warm up to r.t. (strong exothermic effect was observed). After 5 min., distilled water (50 ml) was added, cooling applied, and the product was collected by filtration, yield 85%.
4、NaOH(aq.)-CH2Cl2 相转移催化体系水解腈为伯酰胺（Synthesis, 1980, 243）
To a magnetically stirred dichloromethane solution (1.5 ml) of o-tolunitrile (0.5 g, 4.27 mmol) cooled in an ice bath, are added 30% hydrogen peroxide (2.0 ml), tetrabutylammonium hydrogen sulfate (0.290 g, 0.85 mmol), and a 20% aqueous solution of sodium hydroxide (1.6 ml). The reaction mixture is allowed to warm up to r.t. and maintained under stirring. After 1.6 h,dichloromethane is added, the organic layer is separated, washed with brine, and dried with sodium sulphate. The solvent is removed under reduced pressure to leave a white solid from
which pure o-toluamide is obtained by chromatography on silica gel. Yield 0.485 g (97%).
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1877年, C. Friedel和J.M. Crafts想利用氯戊烷和碘在金属铝催化下的苯溶液中制备碘戊烷，结果没有得到碘戊烷却得到了戊基苯。经过系统的研究，他们发表了Lewis酸催化的芳环烷基化或酰基化的50多篇论文。
在Lewis酸催化下，利用烷基卤代物，烯烃，炔烃或醇在芳环上引入烷基的反应被称为Friedel-Crafts烷基化反应。常用的Lewis酸有：AlCl3，BeCl2, CdCl2, BF3, BBr3, GaCl3, AlBr3, FeCl3, TiCl4, SnCl4, SbCl5, 三卤代镧系金属盐和烷基卤化铝 (AlRX2)。其中烷基卤代物的FC反应中最常用的就是AlCl3和BF3。
反应机理
亲电取代反应。
四、通过芳基卤代物制备格氏试剂【Grignard反应（格氏反应）】然后和环氧乙烷反应得到2-芳基乙醇，卤化后通过Gabriel反应得到β-芳基乙胺。
邻苯二甲酰亚胺钾盐是一种-NH2合成子，它可通过和烷基卤代烃反应制备伯胺。烷基化后，邻苯二甲酰亚胺没有亲核性，不能继续反应，产物通过碱或者肼裂解得到伯胺产物和环状副产物。邻苯二甲酰亚胺作为酸和醇进行Mitsunobu反应在有机合成中有很好的应用。
反应机理
邻苯二甲酰亚胺的活泼氢显酸性。
最后一步也可以和叠氮化钠反应得到叠氮化物，让后还原得到芳基乙胺【叠氮还原制备胺】。
五、其他方法
金属介导的氮亲核试剂加成到活性烯烃，随后通过还原-消除形成芳基-碳键。
【Synthesis., 2012, 44, 351】
刘国生研究员等人报道了铜催化苯乙烯的磺酰胺-芳基化反应。
【J. Am. Chem. Soc., 2017, 139, 6811-6814】
美国密歇根大学的Corey R. J. Stephenson教授团队受到自由基Smiles-Truce重排反应的启发，设计了芳基磺酰胺作为氨基芳基化双官能化试剂，在光催化下富电子烯烃发生氨基芳基化反应，由此高效得到一系列2,2-二芳基乙胺。
【Science, 2018, 361, 1369】
剑桥大学Matthew J. Gaunt教授课题组利用光与过渡金属的双催化模式，实现了烯烃、芳基亲电试剂、氮亲核试剂的多组分偶联，一步合成结构和功能多样的β-芳基叠氮化物。【Nature：一步合成β-芳基乙胺骨架】
【Nature, 2021, DOI: 10.1038/s41586-021-03980-8】