cooled to 0 deg C and 2.48 mL (54.02 mmol) ethanol and 9.21 g (82.2 mmol) potassium t-butoxide were added.

The mixture was heated at 60 deg C for 18 hours, cooled and

concentrated. The residue was taken up in ethyl acetate, washed with brine, dried over sodium sulfate and concentrated to give an oil. The oil was purified by chromatography on silica gel using hexane/ethyl acetate as eluent to afford 4.6 g (100percent) of oil. Reference: 72800; Patent; Pfizer Inc.; Publ.: US5373003 A1 (1994/12/13),

6. 用2,4,6-三异丙基磺酰肼-KCN将酮转化为氰基

NO2,4,6-triisopropylbenzenesulphonohydrazineKCNCNN

3-Quinuclidinone (24.2 g, 0.19 mol) and 2,4,6-triisopropylbenzenesulphonohydrazide (72 g, 0.24 mol) were stirred together in anhydrous MeOH (250 mL) for 3 h. Potassium cyanide (33.8 g, 0.51 mol) was added and the mixture was heated under reflux for 5 h. The residue after evaporation of the solvent was partitioned between water and CH2C12. The organic phase was dried and evaporated and the residue was fractionally distilled under reduced pressure to give 3-cyanoquinuclidine (32, 6.1 g). Reference: J. Med. Chem. 1990, 33, 1128-1138

7. 芳香卤代烃在金属催化作用下的腈化反应

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。

7.1a 芳香卤代烃与氰化亚酮作用可用来制备相应芳腈化合物

ClBrCuCNOOODMFOOOClCN

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About 14.7 g (0.05 mol) of 5-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 hours while stirring under nitrogen atmosphere. After cooling, the reaction mixture is stirred well with 250 ml of methylene chloride and 250 ml of 2N hydrochloric acid. The insoluble portions are filtered off with suction filtration and the layers are separated in a separating funnel. The methylene chloride solution is washed neutral with water and then concentrated by evaporation. The obtained residue was re-crystallized from methylene chloride/hexane to give pure 4-chloro-5-cyano-2-methoxybenzoic acid ethyl ester. Ref.: Frontpage/Claim: 59938; Patent; Ciba Geigy Corporation; Publ.: US4559349 A1 (1985/12/17), Appl.: US1984-586493 (1984/03/05)

7.1b 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

BrNNNOZn(CN)2OPd(PPh3)4NNCNNOO

In a similar fashion, a mixture of 3-(2-pyridyl)-5-(2-bromo-5-methoxyphenyl)-1,2,4- oxadiazole (33.2 mg, 0.1 mmol), zinc cyanide (17.6 mg, 0.15 mmol) and Pd(PPh3)4 (11.5 mg, 0.01 mmol) in N,N-dimethylformamide (1 ML) was heated under an argon atmosphere at 80 deg C for 16 hours. After cooling the reaction mixture was poured into water and the crude product was extracted with dichloromethane. Silica gel chromatography using 50 percent ethyl acetate in hexane afforded of 3-(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

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FFNHOOBrZn(CN)2Pd2dba3FNH

FCNClClOO

A mixture of 5-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, 0.162 mmol), 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 was cooled 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 washed with 4:1:4 (volume) mixture of saturated NH4Cl, concentrated NH4OH and water, and then brine. The organic layer was dried (MgSO4) and concentrated. Purification by flash column chromatography using the Biotage system (twice:100 percent hexanes to 35percent CH2Cl2 in hexanes, then 30 percent CH2Cl2 in hexanes) provided 1.33 g (52 percent) of the desired product. Ref: Patent; Wallace, Eli; Publ.: US2005/54701 A1 (2005/03/10), Appl: US2004-929295 (2004/08/30)

7.2 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。

BrF3CK4[Fe(CN)6]Cu(BF4)2.6H2OF3CCN

No condition details were available in this literature. The general reaction conditions that the author gave were: 2.0 mmol aryl halide, Cu(BF4)2.6H2O(0.1 eq), 20 mol% dry

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K4[Fe(CN)6], 2 mL DMAc, 20 mol% KI, 20 mol % Na2CO3, 100 mol % DMEDA. Reference: Tetrahedron Letters. 46 (2005) 2585-2588

7.3 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。

BrNZn(CN)2Pd(PPh3)4NCN

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 nitrogen and the screw cap tightened thoroughly before mixing with a Whirlimixer. The reaction mixture was exposed to microwave irradiation (60 W) for 2 min (for 2g 2.5 min). The reaction tube was allowed to reach room temperature before the reaction mixture was diluted in EtOAc (60 mL) and washed with water. The organic phase was dried and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to give the pure nitrile. Reference: : J. Org. Chem. 2000, 65, 7984-7989.

8. 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.

FFOHNHONOFthionyl chlorideOFFOHNNOFOOO

A solution of the powder (0.49 g) of diethyl 2-methyl-4-(2-trifluoromethylphenyl)-6- hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate and thionyl chloride (1.5 ml) in dry diethyl ether (1.5 ml) was stirred at room temperature for 30 minutes. After the resultant solution was evaporated to dryness, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give brown oil (0.39 g). The oil was

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purified by column chromatography on silica gel with eluent of 5:1 benzene:ethyl acetate and crystallized with n-hexane to give a yellow powder (50 mg). The powder was further recrystallized from diethyl 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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The End