酰基疊氮加熱進行1,2-C-N遷移并放出氮氣，生成異氰酸酯的反應被稱為Curtius重排。反應中原位生成的異氰酸酯和各種親核試劑反應，可以得到氨基甲酸酯，脲等各種N-酰基衍生物。也可以直接水解得到伯胺。

酰氯被轉化為酰基疊氮，其加熱重排脫去一分子氮氣后得到相應的異氰酸酯，異氰酸酯水解或和其他親核試劑反應得到胺及相應的衍生物。 早期的合成方法都是將酸轉變為相應的酰氯，再生成酰基疊氮。 后來Shiori（ JACS，1972，94，6203 ）等人報道了DPPA和羧酸在室溫下很溫和的生成?；B氮，可一鍋法合成胺。若直接用過量的醇或直接用醇做溶劑可得到相應的胺的衍生物。如用芐醇可一步得到Cbz保護的胺; 用叔丁醇可一步得到Boc保護的胺?！尽?/p>

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

一般情況下，用此方法直接做胺并不是一個好的方法，特別是制備烷基胺，其主要有兩個原因：一是得到的胺特別是烷基胺不易純化；二是加水分解異氰酸酯時得到的胺會和未反應完全的異氰酸酯反應成脲，因此分解時要劇烈攪拌， 另外也有人使用稀酸水解異氰酸酯得到相應的胺的鹽酸鹽。

反應機理

熱重排機理：

光照條件下也可以重排，酰基疊氮在光照條件下先生成 氮賓，而后重排為異氰酸酯：

反應實例

【Eur. J. Org. Chem. 2003, 1704–1710】

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

Weinstock改進法

【 Org. Lett. 2006 , 8, 3995–3998】

【Synlett 2007, 235–238】

Lebel改進法【 Eur. J. Org. Chem. 2007 , 1064– 1068 】

?；B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和芐醇合成Cbz保護的胺示例

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保護的胺示例

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，需要大大過量，一般使用叔丁醇作溶劑進行反應，在研究過程中我們發現若在反應液中加入3-5當量的Boc2O可抑制副反應，提高反應產率。

【 J. Med. Chem. 2004, 47, 871 - 887 】

Theodor Curtius (1857-1928)生于德國杜伊斯堡。他在做化學研究之前是學音樂的，先后在跟隨Bunsen, Kolbe, von Baeye和Victor Meyer做化學研究，后來出任海德堡大學教授。他發現了重氮乙酸酯，肼，吡唑啉衍生物和很多氮雜環化合物。雖然是個化學家，他仍然進行音樂創作和音樂會歌唱。

相關文獻

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.; ?zer, M. S.; Cengiz, B.; ?ahin, E.; Balci, M. Tetrahedron 2013, 69, 395–409.

參考資料

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

二、藥明寶典。