Curtius 重排

酰基叠氮加热进行1,2-C-N迁移并放出氮气，生成异氰酸酯的反应被称为Curtius重排。反应中原位生成的异氰酸酯和各种亲核试剂反应，可以得到氨基甲酸酯，脲等各种N-酰基衍生物。也可以直接水解得到伯胺。

酰氯被转化为酰基叠氮，其加热重排脱去一分子氮气后得到相应的异氰酸酯，异氰酸酯水解或和其他亲核试剂反应得到胺及相应的衍生物。 早期的合成方法都是将酸转变为相应的酰氯，再生成酰基叠氮。 后来Shiori（ JACS，1972，94，6203 ）等人报道了DPPA和羧酸在室温下很温和的生成酰基叠氮，可一锅法合成胺。若直接用过量的醇或直接用醇做溶剂可得到相应的胺的衍生物。如用苄醇可一步得到Cbz保护的胺; 用叔丁醇可一步得到Boc保护的胺。【】

【 J. Am. Chem. Soc. 2002 , 124, 9812–9824】

一般情况下，用此方法直接做胺并不是一个好的方法，特别是制备烷基胺，其主要有两个原因：一是得到的胺特别是烷基胺不易纯化；二是加水分解异氰酸酯时得到的胺会和未反应完全的异氰酸酯反应成脲，因此分解时要剧烈搅拌， 另外也有人使用稀酸水解异氰酸酯得到相应的胺的盐酸盐。

反应机理

热重排机理：

光照条件下也可以重排，酰基叠氮在光照条件下先生成 氮宾，而后重排为异氰酸酯：

反应实例

【Eur. J. Org. Chem. 2003, 1704–1710】

【 Tetrahedron Lett. 2004 , 45, 7455–7457】

Weinstock改进法

【 Org. Lett. 2006 , 8, 3995–3998】

【Synlett 2007, 235–238】

Lebel改进法【 Eur. J. Org. Chem. 2007 , 1064– 1068 】

酰基叠氮重排合成胺示例

2,6-difluoro-4-methoxyphenyl carboxylic acid (2.00 g, 10.6 mmol) was dissolved in thionyl chloride (16 mL). One drop of DMF was added and the mixture was heated to reflux for 2 h. The crude mixture was evaporated to dryness and the residue was dissolved in 5mL acetone. A solution of sodium azide (970 mg, 14.9 mmol) in water (2 mL ) was added dropwise at room temperature. After 30 min, water (10 mL) was added and the solution was extracted with toluene (50 mL). The organic layers were dried over sodium sulfate and heated to reflux for 30 min. Then 10 mL of a 45% sodium hydroxide solution was added and the mixture was heated for a further 30 min. The organic layer was separated, dried over sodium sulfate and evaporated. The residue was purified by column chromatography (dichloromethane) to yield 660 mg (39%) of the title compound.

【 Tetrahedron Lett. , 2004, 45 , 95 - 98 】

使用DPPA合成胺示例

2-benzyloxy-3-methoxy-4-nitroanilin acid (27.9 g, 91.8 mmol) was dissolved in THF (400 mL) and treated with Et3N (30 mL). Diphenylphosphoryl azide (26.5 g, 96.4 mmol) was added dropwise and the reaction mixture was stirred for 3 h at 25 oC. H2O (150 mL) was added and the reaction mixture was refluxed for 2 h. The solvent was removed in vacuo and the residue was treated with saturated aqueous K2CO3 (100 mL), diluted with H2O (500 mL), and extracted with EtOAc (2 × 500 mL). The combined organic extracts were washed with saturated aqueous NaCl (500 mL), dried (Na2SO4), and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 25% EtOAc−hexanes) to afford the title compound (19.5 g, 78%) as a yellow solid.

【 J. Am. Chem. Soc., 2004, 126, 8396 - 8398.】

使用DPPA和苄醇合成Cbz保护的胺示例

Under an argon atmosphere, a mixture of acid (200 mg, 0.59 mmol), diisopropyl ethylamine (0.36 mL, 2.0 mmol), diphenylphosphoryl azide (0.32 mL, 1.5 mmol) in toluene (25 mL) was heated at reflux for 3 h. After being cooled to room temperature, benzyl alcohol (0.2 mL, 2 mmol) was added, and the mixture was stirred for another 1h. After removing the solvent in vacuo, silica gel column chromatography gave the title compound (230 mg, 0.50 mmol, 85%).

【 J. Org. Chem. , 2001 , 6, 557 - 563】

使用DPPA和叔丁醇合成Boc保护的胺示例

Dry tert -butyl alcohol (123 mL), triethylamine (16.7 g, 0.65 mol), and DPPA (45.5 g, 0.165 mol) were added to a solution of 5-fluoro-1,3-benzodioxole-4-carboxylic acid (29 g, 0.157mol) in dioxane (430 mL) under nitrogen. The mixture was heated at 100 °C for 4.5 h. Upon cooling, the cloudy mixture was filtered. The filtrate was evaporated under vacuum, diluted in ethyl acetate, washed with a 5% aqueous citric acid, a 5% aqueous sodium bicarbonate, water, and brine, dried over magnesium sulfate, and concentrated under vacuum to provide desired compound (37.6 g, 93%).

由于叔丁醇的活性不高，需要大大过量，一般使用叔丁醇作溶剂进行反应，在研究过程中我们发现若在反应液中加入3-5当量的Boc2O可抑制副反应，提高反应产率。

【 J. Med. Chem. 2004, 47, 871 - 887 】

Theodor Curtius (1857-1928)生于德国杜伊斯堡。他在做化学研究之前是学音乐的，先后在跟随Bunsen, Kolbe, von Baeye和Victor Meyer做化学研究，后来出任海德堡大学教授。他发现了重氮乙酸酯，肼，吡唑啉衍生物和很多氮杂环化合物。虽然是个化学家，他仍然进行音乐创作和音乐会歌唱。

相关文献

1. Curtius, T. Ber. 1890, 23, 3033-3041.

2. Ng, F. W.; Lin, H.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 9812–9824.

3. van Well, R. M.; Overkleeft, H. S.; van Boom, J. H.; Coop, A.; Wang, J. B.; Wang, H.; van der Marel, G. A.; Overhand, M. Eur. J. Org. Chem. 2003, 1704–1710.

4. Dussault, P. H.; Xu, C. Tetrahedron Lett. 2004, 45, 7455–7457.

5. Holt, J.; Andreassen, T.; Bakke, J. M.; Fiksdahl, A. J. Heterocycl. Chem. 2005, 42, 259–264.

6. Crawley, S. L.; Funk, R. L. Org. Lett. 2006, 8, 3995–3998.

7. Tada, T.; Ishida, Y.; Saigo, K. Synlett 2007, 235–238.

8. Sawada, D.; Sasayama, S.; Takahashi, H.; Ikegami, S. Eur. J. Org. Chem. 2007, 1064– 1068.

9. Rojas, C. M. Curtius Rearrangements. In Name Reactions for Homologations-Part II; Li, J. J., Ed.; Wiley: Hoboken, NJ, 2009, pp 136-163. (Review).

10. Koza, G.; Keskin, S.; Özer, M. S.; Cengiz, B.; Şahin, E.; Balci, M. Tetrahedron 2013, 69, 395–409.

参考资料

一、Name Reactions （A Collection of Detailed Reaction Mechanisms）, Jie Jack Li, Curtius rearrangement，page 188-189.

二、药明宝典。