Atherton-Todd反应

亚磷酸二酯在温和的碱性条件下与四氯化碳的作用，把P-H键转换成P-Cl键，制备得到氯磷酸二酯的反应称为Atherton-Todd反应。由于 氯磷酸二 酯活性太高很难分离，一般情况下会 接着和醇或胺反应合成磷酸酯或磷酰胺。

该反应是1945年F. R. Atherton, H. T. Openshawand, and A. R. Todd等人的一个偶然发现。实际上，他们原本的目的是想要在二苄基磷酸酯的四氯化碳溶液中加入氨水溶液来精制化合物。但是他们惊奇的发现，最后生成了 O,O -dibenzyl phosphoramidate的固体。
【Atherton, F. R. et al. J. Chem. Soc. 1945 , 660. DOI:10.1039/jr9450000660】

利用碱水溶液和相转移催化剂可以明显改善效果，可以用于制备各种磷酸混酯和磷酰胺。【(a) Zwierzak, A., Synthesis, 1976, 305. (b) Zwierzak, A. and Sulewska, A., Synthesis, 1976, 835. (c) Zwierzak, A., Synthesis, 1975, 507. (d) Zwierzak, A. and Brylikowska, J., Synthesis, 1975, 712. (e) Zwierzak, A., Synthesis, 1975, 270. 】

反应机理

碱先拔掉亚磷酸二酯的氢，形成的亚磷酸二酯负离子进攻四氯化碳得到产物。

文献报道还有另外一种机理，利用叔胺做碱时，在反应引发阶段胺并不是拔氢而是先烷基化。【Phosphorus, Sulfur & Silicon and Related Elements, 1993, 83, 157】

反应实例

【Atherton, F. R.; Openshaw, H. T. and Todd, A. R., J. Chem. Soc., 1945, 660】

Diethyl N-phenylphosphoramide (4). To an ice cold stirred suspension of formylanilide 1 (605 mg,5 mmol) in CCl4 (25 mL) was added 30% NaOH (10 mL) and TEBAB (0.2 g). Diethyl phosphite 2(828 mg, 6 mmol) in CCl4 (5 mL) was added dropwise. After 1 h at 0 ℃ and 4 h at 20 ℃, the organic layer gave 4, after crystallization, 0.687 g (60%), mp 96–97 ℃.

【Lukanow LK, Synthesis, 1985, 671】

【J. Med. Chem., 2002, 45, 5797】

Diethyl phophoramide (5). Into vigorously stirred liquid NH3 (15–20 mL), 1.0 mmol of iodoform and 1.1 equiv of dialkyl phosphite 2 were added simultaneously at 33 C. After 5–10 min of stirring at 33 C, the cooling bath was removed and stirring was continued until NH3 was distilled off. The product was dissolved in dry chloroform and the mixture was filtered through Celite. After evaporation of the solvent, crystallization or distillation afforded 5 (83%).

【Mielniczak G, Syn Comm., 2003, 33, 3851】

苯酚类化合物通过Atherton-Todd反应，得到芳基磷酸酯，再与硼酸在Ni催化下进行偶联反应得到联苯的一个实例。

【Chen H, Huang Z, Hu X, Tang G, Xu P, Zhao Y, Cheng C-H. J. Org. Chem. 2011, 76, 2338. DOI: 10.1021/jo2000034】

相关文献

1 Atherton FR, Todd AR J Chem Soc 1945 660

2 Wadsworth WS J Am Chem Soc 1962 64 1316

3 Zwierzak A Synthesis 1982 922

4 Lukanow LK Synthesis 1985 671

5 Hovalla D Tet Lett 1992 33 2817

6 Garrigue B Syn Comm 1995 25 871

7 Liu LZ Org Prep Proc Int 1996 28 490

8 Zhao YF J Chem Res S 2003 262

9 Mielniczak G Syn Comm 2003 33 3851

10 Zhao YF Synlett 2005 1927

11 Ju Y Synthesis 2007 407

12 Donghi M Bioorg Med Chem Lett 2009 19 1392

13 Jaffrès, P.-A. et al, Beilstein J. Org. Chem. 2014, 10, 1166. DOI: 10.3762/bjoc.10.117

参考文献

一、Organic Syntheses Based On Name Reactions, 3RdEd, A. Hassner, 14.

二、化学空间：https://cn.chem-station.com/reactions/%e5%8f%96%e4%bb%a3%e5%8f%8d%e5%ba%94/2015/02/atherton-todd%e5%8f%8d%e5%ba%94atherton-todd-reaction.html

三、Comprehensive Organic Name Reactions and Reagents, by Zerong Wang，114-118