Hofmann降解是將伯酰胺通過氧化降解成少一個碳原子的伯胺, 其機理如下：
最早期的Hofmann降解是使用NaOH水溶液和Br2來實施的。這個條件比較劇烈，后續(xù)有許多改進的方法陸續(xù)被報道，主要是通過改進氧化劑和堿。如Keillor等人1997年報道了用NBS做氧化劑，DBU做堿，甲醇中回流25分鐘就得到了甲氧羰基保護的胺（JOC, 1997, 62, 7495-7496）.
2.1 經(jīng)典的Br2-NaOH體系Hofmann 降解示例
Sodium hydroxide (3.48 kg, 87.0 mol) was dissolved in water (22 L), and the solution was cooled to 0°C. Bromine (0.63 L, 11.8 mol) was added over 30 min while the temperature was maintained at 0-10°C. In a second vessel, (R)-tosylasparagine (2.86 kg, 9.48 mol) was added in portions to a solution of NaOH (0.8 kg, 20.0 mol) in water (7.2 L) kept cold at 0-10°C. The solution was cooled to 0°C, and the sodium hypobromite solution was added over 10 min while maintaining a temperature <10°C. After the addition, the resulting yellow solution was aged for 15 min at 10-15°C, and then heated to 40°C within 30 min. Heating was suspended and the reaction temperature was allowed to increase to 50°C over 20 min due to the exothermic reaction. When the internal temperature dropped to 45°C, the reaction solution was heated to 70°C over 20 min and kept at 70°C for 10 min. HPLC analysis measured a 90% solution yield of compound 2. The reaction was cooled to 10-15°C, and with vigorous stirring the pH of the mixture was adjusted to 7 by the addition of concentrated hydrochloric acid (4 L), whereupon the product precipitated. The mixture was stirred for 20 min at 15°C, and the product was filtered. The cake was slurry washed with water (2-8 L) and then displacement washed with water (8 L). The product was dried with a nitrogen stream at 20°C affording (2R)-3-amino tosylaminoalanine (1.67 kg, 70%).
Reference: JOC, 1998, 63, 9533-9534.
2.2 NBS作氧化劑用于Hofmann 降解示例
p-Methoxybenzamide (76 mg, 0.5 mmol), NBS (90 mg, 0.5 mmol), and DBU (230 uL) in methanol (5 mL) were heated at reflux for 15 min, at which point more NBS (90 mg, 0.5 mmol) was added. The reaction was allowed to continue for another 10 min. Methanol was then removed by rotary evaporation, and the residue was dissolved in 50 mL of EtOAc. The EtOAc solution was washed with 5% HCl and saturated NaHCO3 and was then dried over MgSO4. The product, methyl (p-methoxyphenyl) carbamate, was purified by flash column chromatography (silica gel, eluant 5% EtOAc in CH2Cl2) to give a white solid (86 mg, 95%),
Reference: JOC, 1997, 62, 7495-7496.
2.3 PhI(OCOCH3)作氧化劑用于Hofmann 降解示例
A slurry of N-benzyloxycarbonyl-L-asparagine (140 g, 0.53 mol), ethyl acetate(680 mL), acetonitrile (680 mL), water (340 mL), and Iodobenzene I,I-diacetate (200 g, 0.62 mol) was cooled and stirred at 16°C for 30min. the temperature was allowed to reach to 20°C, and the reaction was stirred until completion (4h). The mixture was cooled to 5°C, and the product was filtered, washed with ethyl acetate (100 mL), and dried in vacuo at 50°C to afford the target compound (100 g, 79%) 1HNMR: zsf0303 73， TLC:(Chloroform/Methanol/acetic acid 5:3:1)
Preparation of Iodobenzene I,I-diacetate
To a flask was charged with iodobenzene (20.4 g, 0.10 mol) and immersed in a water bath maintained at 30°C. Commercial 40% peracetic acid (31 mL., 0.24 mole) was added dropwise to the well-stirred iodobenzene over a period of 30–40 minutes. After further 20 minutes at a bath temperature of 30°C, a homogeneous yellow solution was formed. Crystallization of iodosobenzene diacetate may begin during this period. The beaker is chilled in an ice bath for 1 hour. The crystalline diacetate was collected on a Büchner funnel and washed with cold water (3*20 mL). After drying for 30 minutes on the funnel with suction, the diacetate was dried overnight in a vacuum desiccator containing anhydrous calcium chloride to provide the diacetate (26.7–29.3 g. 83–91%).
2.4 NaClO作氧化劑用于Hofmann 降解示例 (JACS,1958,965)
A mixture of indazole (4 g, 0.02 mole) and sodium hydroxide (4 g, 0.1 mole) in 30 ml of icewater containing 1.5 g. (0.02 mole) of chlorine was stirred at room temperature for 2 hours. Then the reaction was warmed on a steam-bath for 1 hour during which time the solution was effected. The solution was extracted four times with 50 ml. of ethyl acetate, and the extracts were dried with anhydrous magnesium sulfate. Ether containing hydrogen chloride was added, and the mixture was allowed to stand for several days. The solid was collected recrystallized from ethyl alcohol to give the target compound (3 g, 64% yield)
Reference: JACS, 1958, 965
2.5 PhI(OCF3)2 (BTI)作氧化劑用于Hofmann 降解示例
A 500-mL, round-bottomed flask is equipped with a magnetic stirring bar and covered with aluminum foil. To the flask was added a solution of BTI (16.13 g, 37.5 mmol) in 37.5 mL of acetonitrile, and the resulting solution was diluted with 37.5 mL of distilled deionized water. Cyclobutanecarboxamide (2.48 g, 25 mmol) was added; the amide quickly dissolves. Stirring was continued for 4 hr, and the acetonitrile was removed with a rotary evaporator. The aqueous layer was stirred with 250 mL of diethyl ether; to the stirring mixture was added 50 mL of concd hydrochloric acid. The mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with ether (2*150 mL). The organic fractions were combined and extracted with 75 mL of 2 N hydrochloric acid. The aqueous fractions are combined and concentrated with a rotary evaporator using a vacuum pump. Benzene (50 mL) was added to the residue and the solution was concentrated with the rotary evaporator, again using a vacuum pump. Addition of benzene and concentration was repeated five more times. The crude solid was dried under reduced pressure over sulfuric acid overnight. To the product was added 5 mL of absolute ethanol and 35 mL of anhydrous ether, and the solution was heated at reflux on a steam bath. Ethanol was added slowly to the mixture, with swirling, until all the material was dissolved; the solution was cooled to room temperature. Anhydrous ether was added slowly until crystallization just begins. The flask was placed in the freezer and the product was allowed to crystallize. Filtration of the product and drying overnight under reduced pressure over phosphorus pentoxide to provide cyclobutylamine hydrochloride (1.86–2.06 g, 69–77%).
Reference: Organic Syntheses, Coll. Vol. 8, p.132; Vol. 66, p.132
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