芳腈化合物在有机合成中占据非常重要的地位，尤其是在染料，除草剂，农用化学品，药物及自然产品中应用非常广泛。传统方法合成芳腈化合物主要通过苯胺的重氮化接着Sandmeyer反应制得，对不是复杂的苯腈可由甲苯类化合物在NH3作用下直接氧化制备。但这些方法有较大局限性：反应条件较剧烈，底物要比较简单取代基较少，毒性很大。以下介绍的是实验室常用方法。
1 芳香卤代烃与氰化亚酮作用可用来制备相应芳腈化合物
About 14.7 g (0.05 mol) of5-bromo-4-chloro-2-methoxybenzoic acid ethyl ester, 5.4 g (0.06 mol) of copper (I)cyanide and 8 ml of dimethylformamide are heated at 190 deg for three hourswhile stirring under nitrogen atmosphere. After cooling, the reaction mixture is stirred well with 250 ml ofmethylene chloride and 250 ml of 2N hydrochloric acid. The insoluble portions are filtered off withsuction filtration and the layers are separated in a separating funnel. The methylene chloride solution is washedneutral with water and then concentrated by evaporation. The obtained residue was re-crystallized frommethylene chloride/hexane to give pure 4-chloro-5-cyano-2-methoxybenzoic acidethyl ester.
Ref.:Frontpage/Claim: 59938; Patent; CibaGeigy Corporation; Publ.: US4559349 A1 (1985/12/17), Appl.: US1984-586493 (1984/03/05)
2 芳香卤代烃与KCN或 Zn(CN)2在钯催化剂作用下可以实现氰基取代反应。这类反应常用的催化剂及配体有：Pd(PPh3)4,Pd(OAc)2/PPh3, Pd2dba3等。DMF或NMP为常用溶剂。
实例1
In a similar fashion, a mixture of3-(2-pyridyl)-5-(2-bromo-5-methoxyphenyl)-1,2,4-
oxadiazole (33.2 mg, 0.1 mmol), zinccyanide (17.6 mg, 0.15 mmol) and Pd(PPh3)4 (11.5 mg, 0.01 mmol) inN,N-dimethylformamide (1 ML) was heated under an argon atmosphere at 80 deg Cfor 16 hours. After cooling the reactionmixture was poured into water and the crude product was extracted withdichloromethane. Silica gelchromatography using 50 percent ethyl acetate in hexane afforded of3-(2-pyridyl)-5-(2-cyano-5-methoxyphenyl)-1,2,4-
oxadiazole.
Ref.: Patent;Wagenen, Bradford Van; Publ.: US2003/55085 A1 (2003/03/20), Appl.: US2002-76618 (2002/02/19)
实例2
A mixture of5-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (14)(3.01 g, 7.99 mmol), 1,1′-bis(diphenylphosphino) ferrocene (dppf) (93 mg, 0.162mmol), Pd2dba3 (73 mg, 0.080 mmol) and Zn(CN)2 (573 mg, 4.78 mmol) in 1-methyl-2-pyrrolidin
one (NMP: 4.5 ml) was heated in a sealed tube reactor. After 20 hours the reaction mixture wascooled to room temperature, quenched by the addition of 8 ml 4:1:4 (volume)mixture of saturated NH4Cl, concentrated NH4OH and water. The solution was extracted with a mixture of EtOAc/THF. The combined organic extracts were washedwith 4:1:4 (volume) mixture of saturated NH4Cl, concentrated NH4OH and water,and then brine. The organic layer wasdried (MgSO4)and concentrated. Purification by flashcolumn chromatography using the Biotage system (twice:100 percent hexanes to35percent CH2Cl2 in hexanes, then 30 percent CH2Cl2 in hexanes) provided 1.33 g (52 percent) ofthe desired product.
Ref: Patent; Wallace, Eli; Publ.: US2005/54701 A1 (2005/03/10),Appl: US2004-929295 (2004/08/30)
3 Cu催化下芳香卤代烃或（TfO-）和K4[Fe(CN)6]反应氰基取代
最近，Thornds Schdreind,Alexander zapf 报道了一种在Cu催化下芳香卤代烃或（TfO-）和K4[Fe(CN)6]反应高收率生成氰基化合物的方法。作者经过一系列实验，使用不同的铜催化剂，以及不同的配体与溶剂，从而得到了最好的实验条件。即：Cu(BF4)2.6H2O为催化剂，DMEDA为配体，DMAc为溶剂。
No condition details were available in this literature. The general reaction conditions that theauthor gave were: 2.0 mmol aryl halide, Cu(BF4)2.6H2O(0.1eq), 20 mol% dry K4[Fe(CN)6], 2 mL DMAc, 20 mol% KI, 20mol % Na2CO3, 100 mol % DMEDA.
Reference: Tetrahedron Letters. 46 (2005) 2585-2588
4 微波反应芳卤氰基化
在7.1反应实例中，这些直接取代大多用高温反应，最近有人开发了使用微波反应做这一取代。
A dried heavy-walled pyrex tube was charged with organo-bromide(0.2 mmol), Zn(CN)2 (23.5 mg, 0.2 mmol) and Pd(PPh3)4(6.9 mg, 6.0 ímol) in DMF (1 ml). The reaction mixture was flushed with nitrogenand the screw cap tightened thoroughly before mixing with a Whirlimixer. The reaction mixture was exposed to microwaveirradiation (60 W) for 2 min (for 2g 2.5 min). The reaction tube was allowed to reach roomtemperature before the reaction mixture was diluted in EtOAc (60 mL) and washedwith water. The organic phase was dried andthe solvent was removed under reduced pressure. The crude product was purified by columnchromatography to give the pure nitrile.
Reference:: J. Org. Chem. 2000, 65, 7984-7989.
5 肟脱水生成腈
芳香或烷基的醛可以通过转变成肟脱水成相应的腈.
Asolution of the powder (0.49 g) of diethyl 2-methyl-4-(2-trifluoromethylphenyl)-6-
hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylateand thionyl chloride (1.5 ml) in dry diethyl ether (1.5 ml) was stirred at roomtemperature for 30 minutes. After theresultant solution was evaporated to dryness, water was added to the residueand the mixture was extracted with ethyl acetate. The extract was washed with water, dried overmagnesium sulfate and concentrated under reduced pressure to give brown oil(0.39 g). The oil was purified by columnchromatography on silica gel with eluent of 5:1 benzene:ethyl acetate andcrystallized with n-hexane to give a yellow powder (50 mg). The powder was further recrystallized fromdiethyl ether / n-hexane to give crystals of diethyl 2-methyl-4-
(2-trifluoromethyl-phenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate.
Reference: Chem Pharm Bull. 1991,89-3201.
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