除了利用DPPA和活性醇反应制备叠氮化物，现在又有了新方法！

利用DPPA通过Mitsunobu反应取代羟基合成叠氮化物的文章（点击：），但Mitsunobu反应会生成大量的副产物，不易纯化。下面介绍一种可以得到相同产物的方法，利用DPPA和DBU，可以取代羟基得到构型翻转的叠氮化物，此反应生成副产物磷酸二苯酯和DBU盐都可以用水洗掉，可以很好的避免消除产物。但此反应，只对于活性醇（苄醇或羧酸α位羟基）效果较好。

近期，上海有机化学研究所有机氟化学重点实验室胡金波课题组利用前期自主研发的一种新型氟化试剂-N-对甲苯磺酰-4-氯苯氨亚基替磺酰氟（简称SulfoxFluor；见Chem. Eur. J. 2019, 25, 7259，专利号 ZL201710007613.1）进行脱氧叠氮化反应。【】

他们引入NaN3作为亲核性高于氟负离子的亲核试剂，替代F离子对醇羟基进行取代的反应，成功实现了SulfoxFluor促进的对醇的直接脱氧叠氮化反应，论文发表在最近的《自然·通讯》上(Nat. Commun. 2022, 13, 2752. DOI：10.1038/s41467-022-30132-x)。相比于之前已报道的对醇的脱氧叠氮化方法，该方法反应条件更温和、底物适用范围更广，官能团耐受性更优秀，对结构复杂的含醇羟基分子进行后期修饰方面比其他方法有很大的优势。

反应机理

一、DPPA脱氧叠氮化机理：在DBU碱性条件下醇和DPPA反应得到磷酸酯，取代下来的DBU叠氮盐对磷酸酯进行SN2反应，构型翻转。

二、SulfoxFluor脱氧叠氮化机理：

General Procedure: A mixture of the alcohol (10 mmol) and diphenylphosphoryl azide (3.3 g, 12 mmol) were dissolved in dry solvent (18 ml). To the mixture at 0°C, under N2 was added neat l,8-diazabicyclo[5.4.0]undec-7-ene (1.8 ml, 12 mmol). The reaction was warmed to room temperature and stirred until complete. The resulting two phase mixture was washed with H2O (2 x 10 ml) and 5% HC1 (10 ml). The organic phase was concentrated in vacuo and purified by silica gel chromatography using 95:5

(v:v) hexane: ethyl acetate.

(S)-(+)-ethyl lactate (2.54 g, 21.5 mmol) and DPPA (7 g, 25.4 mmol) were reacted with DBU (3.1 ml, 20.7 mmol) in THF (35 ml) at 20°C for 48 h. The batch was diluted with 5:1 hexane:ethyl acetate (120 ml) and washed with H2 O (2 x 40 ml) and 5% HC1 (40 ml). The yield by HPLC assay was 87%. HPLC conditions [CH3CN:H2 0 gradient elution from 50:50 to 70:30 in 15 min,

flow =1.5 ml/min, U.V.detection at 210 nm] tR 4„5 min. The batch was concentrated and distilled to afford 2.2 gm (72%) of the volatile azide.

参考文献

J. Org. Chem., 1993, 58 (22), pp 5886–5888

其他应用

DPPA为缩合剂合成酰胺示例

To solution of this free amine 30 (0.270 g, 0.96 mmol) was added DMF (5 mL),(2-phthalimidoethoxy)acetic acid 29 (0.237 g, 0.96 mmol), DPPA (0.25 mL, 1.15mmol) and Et3N (0.29 mL, 2.11 mmol) at 0℃ while stirring. The ice bath was removed after two hours and the reaction was stirred at R.T. overnight. EtOAc (70 mL) was added and the solution wasextracted successively with 10% citric acid, H2O, saturated NaHCO3solution, H2O, and saturated NaCl solution (20 mL each), dried(anhydrous MgSO4) and finnaly evaporated in vacuo. The oily residue was purified by columnchromatography on silica gel, eluting with 7:1 CHCl3-MeOH to givethe desired product 31 as a white solid. Yield: 81% (two steps)。