von Braun酰胺降解反應

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N-烷基苯甲酰胺(N,N-二烷基苯甲酰胺或不含α-H的酰胺)和五鹵化磷加熱得到腈和鹵代烷烴的反應，被稱為von Braun酰胺降解反應。此反應最早由von Pechmann在1895年首先報道，后來von Braun在上世紀初對此反應進行系統的研究，因此此反應被命名為von Braun酰胺降解反應（和另外一個相區別）。此反應的底物通常是芳基甲酸的酰胺和不含α-H的酰胺，因為不含α-H的酰胺可能通過Bedoukian鹵代生成α-鹵代酰胺。電子效應和空間位阻都會影響此反應的產率。非芐基的N-烷基酰胺通過形成腈正離子中間體（nitrilium ion，Ritter中間體），接著鹵離子親核進攻中間體的α N -碳，得到腈，此反應相當于的逆反應。伯酰胺脫水制備腈相對容易【】，條件溫和， [Et3N+SO2N-COOMe]，三氟醋酸酐(TFAA)－三乙胺，(COCl)2-NEt3-DMSO，三聚氯氰等條件可以在低溫和幾乎中性的條件下反應 ，因此此反應合成價值較低，可以用于分析副反應，特別是對于，和等涉及 腈正離子中間體 的反應。但【】效果還是很好的。

反應機理

酰胺通過五氯化磷脫水得到亞胺酰氯中間體，消除一個Cl離子生成腈正離子，Cl-親核進攻αN-碳得到腈和鹵代烴。

反應實例

【J. Am. Chem. Soc., 1962, 84, 769】

【J. Am. Chem. Soc., 1949, 71, 2808】

A solution of 1.240 mmol ofN-tert-butyl-4-(6,7-dihydro-5H-[2]pyridin-7-yl)benzamide and 1.0 ml of thionylchloride in 30 ml of chloroform is stirred under reflux for 6 hours. The reaction mixture is cooled to roomtemperature and evaporated. The residueis taken up in dichloromethane and mixed with saturated aqueous sodiumbicarbonate solution. The organic phaseis separated and the aqueous phase is extracted with dichloromethane (2x). The combined organic phases are dried withsodium sulphate and concentrated. Theresidue is dissolved in diethyl ether and the title compound is converted intothe hydrochloride salt by adding ethereal HCI solution (2N). The solid is stirred in diethyl ether/acetone(1: 1), filtered and dried. The titlecompound is obtained as a dark grey solid. Rf (free base) = 0.36 (EtOAc)

【Reference: WO2005/118540 】

A 5 L round bottom flask was charged with N,N'-di-tert-butyl-5-(2,3-difluoro-6-nitro-phenoxy)-isophthalamide (21; 564 g) and 1.3 L ofphosphorus oxychloride. The mixture washeated to between 90 deg C. ~ 100.deg. C. for 2 h, after which approximately1/2 of the POCl3was removed by distillation. Toluene was added (1 L) and additional liquidwas distilled. After cooling the mixtureovernight, a crude was obtained by filtration. Additional material was obtained by recovery from the mother liquid. The combined solids were stirred in MeOH (0.7L) for between 1 and 3 h, filtered and dried in a vacuum oven between 50~80 degC.at 25 Torr with a nitrogen bleed to afford 339 g of 22 (90percent theory).

【Reference: US2005/234236】

At ice-water bath, oxalyl chloride (0.345 ml) wasadded dropwise to a solution of 1.0 g of ethyl1-{4-[2-(t-butylaminocarbonyl)phenyl]phenyl}methyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate in 10 ml of methylene chloride. The mixture was stirred at the sametemperature for 2 hours. The reactionmixture was diluted with an aqueous solution of sodium hydrogencarbonate andethyl acetate, and the ethyl acetate layer was separated, dried over anhydrousmagnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by silica gel columnchromatography, using 1:1 EtOAc/hex (v/v) as the eluent, to give 0.69 g of thetitle compound as crystals.

【Reference: US5616599】

參考資料

Comprehensive Organic Name Reactions and Reagents, by Zerong Wang，2900-2903.

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