Rosenmund-von Braun腈化反应

芳基卤化物和过量的氰化亚铜在高沸点极性溶剂（如DMF，NMP, 硝基苯和吡啶）中回流反应得到芳基腈类化合物的反应。此反应通常需要较高温度进行（150℃以上），三级胺和吡啶对此反应有促进作用，硫酸铜也可以催化此反应。1914年，德国化学家 Karl Wilhelm Rosenmund 与其博士学生 Erich Struck 发现催化量氰化亚铜存在下，芳卤可以与氰化钾在醇水混合溶液中反应，产生相应的芳香羧酸。不久后，Rosenmund 提出芳腈是上述反应的中间体。后来，Alfred Pongratz和 Julius von Braun分别对反应作了一些改进，将反应温度提高，并使反应在无水溶剂条件下进行。此后又出现了其他一些改进法，例如用离子液体作为反应介质等。

反应机理

首先芳基卤化物和氰化亚铜进行氧化加成得到Cu(III)中间体。紧接着还原消除得到产物：

此反应中过量的氰化亚铜和极性高沸点溶剂纯化起来都比较困难。另外，很高的反应温度，对底物的官能团的耐受度要求也很高。利用碱金属氰化物或氰化试剂（如氰醇）在催化量的碘化亚铜和碱金属碘化物存在下，可以和芳基溴化物在较温和的条件下进行催化氰化反应。

芳基碘化物，氰化钠和碘化亚铜发生此反应，其机理应该和Ullmann-type reaction的机理类似：

芳基溴化物的反应可以加入碱金属碘化物，可以进行反应平衡转化为高活性芳基碘化物：

H.-J. Christeau 报道了利用丙酮氰醇进行氰化的反应(Chem. Eur. J.,2005, 11, 2483).

反应实例

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)】

【J. Am. Chem. Soc.,2003, 125, 2890-2891】

At room temperature, 120 mg CuCN (1.3 mmol) was added to a stirred

solution of 150 mg (3R)-6-bromo-7-naphthalen-1-ylmethyl-5-oxo-8-phenyl-2,3-dihydro-5H-thiazolo[3,2-α]pyridine-3-carboxylic acid methyl ester (0.30 mmol) in 1.0 mL NMP.The mixture was heated at 220◦C for 20 min under microwave irradiation, and the solvent

was then removed by lyophilization from deionized water. The residue was thoroughly extracted with CH2Cl2, dried, and concentrated. Silica gel column chromatography using heptane/EtOAc (1:1) as the eluent afforded 110mg(3R)-6-cyano-7-naphthalen-1-ylmethyl-

5-oxo-8-phenyl-2,3-dihydro-5H-thiazolo[3,2-α]pyridine-3-carboxylic acid methyl ester as a white foam, in a yield of 82%.

【J. Org. Chem.,2004, 69, 7830】

相关改进：

芳香卤代烃与KCN或Zn(CN)2在钯催化剂（Pd(PPh3)4,Pd(OAc)2/PPh3, Pd2dba3）作用下可以实现氰基取代反应，Ni(CN)2 or NaCN/NiBr2也可以进行类似反应。DMF或NMP为常用溶剂。

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)】

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-pyrrolidinone (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.

【Patent; Wallace, Eli; Publ.: US2005/54701 A1 (2005/03/10),Appl: US2004-929295 (2004/08/30)】

In a 10-mL glass tube were placed 0.171 g 4-bromotoluene (1.0 mmol), 110 mg Ni(CN)2·4H2O (0.6 mmol), 1.0 mL NMP, and a magnetic stir bar. The vessel was sealed with a septum and placed into the microwave cavity, and irradiated at 200◦C for 10 min. After allowing the mixture to cool to room temperature, the reaction mixture was transferred to a separating funnel, and the tube was washed with water and then with ether. All washings were added to the separating funnel then another 20 mL water and Et2O each were added, and the organic layer was separated. The aqueous layer was further extracted with Et2O, and the combined organic layers were washed with water (3×40 mL) to remove remaining NMP. The organic layer was dried over MgSO4 and concentrated to afford 99% of 4-methyl benzonitrile.

【J. Org. Chem.,2003, 68, 9122】

相关文献

1 Rosenmund KW， Chem Ber.，1916, 52, 1749

2 Braun JV， Liebigs Ann.，1931, 488, 111

3R Bunnett JF， Chem Rev.，1951, 49, 392

4 Allen RE， J Am Chem Soc.，1958, 80, 591

5 Freedman L， J Org Chem.，1961, 26, 2522

6 Newmann MS， J Org Chem.，1961, 26, 2525

7 Ren XR ，Tet Lett.，2002, 43, 387

8 Santagostino M， Tet Lett.，2005, 46, 1815

9 Minacheva LK， Russ J Coord Chem.，2005, 31, 671

相关资料：

一、Organic Chemistry Portal：https://www.organic-chemistry.org/namedreactions/rosenmund-von-braun-reaction.shtm

二、Comprehensive Organic Name Reactions and Reagents，Rosenmund-von Braun Synthesis，2425-2408.

三、Organic Syntheses Based On Name Reactions, 3RdEd, A. Hassner, Page 407.