芳腈化合物在有機合成中占據非常重要的地位，尤其是在染料，除草劑，農用化學品，藥物及自然產品中應用非常廣泛。傳統方法合成芳腈化合物主要通過苯胺的重氮化接著Sandmeyer反應制得，對不是復雜的苯腈可由甲苯類化合物在NH3作用下直接氧化制備。但這些方法有較大局限性：反應條件較劇烈，底物要比較簡單取代基較少，毒性很大。以下介紹的是實驗室常用方法。
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1?芳香鹵代烴與氰化亞酮作用可用來制備相應芳腈化合物
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)
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2 芳香鹵代烴與KCN或?Zn(CN)2在鈀催化劑作用下可以實現氰基取代反應。這類反應常用的催化劑及配體有：Pd(PPh3)4,Pd(OAc)2/PPh3, Pd2dba3等。DMF或NMP為常用溶劑。
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實例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)
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實例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)
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3?Cu催化下芳香鹵代烴或（TfO-）和K4[Fe(CN)6]反應氰基取代
最近，Thornds Schdreind,Alexander zapf 報道了一種在Cu催化下芳香鹵代烴或（TfO-）和K4[Fe(CN)6]反應高收率生成氰基化合物的方法。作者經過一系列實驗，使用不同的銅催化劑，以及不同的配體與溶劑，從而得到了最好的實驗條件。即：Cu(BF4)2.6H2O為催化劑，DMEDA為配體，DMAc為溶劑。
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
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4 微波反應芳鹵氰基化
在7.1反應實例中，這些直接取代大多用高溫反應，最近有人開發了使用微波反應做這一取代。
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 肟脫水生成腈
芳香或烷基的醛可以通過轉變成肟脫水成相應的腈.
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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