Atherton-Todd反應

亞磷酸二酯在溫和的堿性條件下與四氯化碳的作用，把P-H鍵轉換成P-Cl鍵，制備得到氯磷酸二酯的反應稱為Atherton-Todd反應。由于 氯磷酸二 酯活性太高很難分離，一般情況下會 接著和醇或胺反應合成磷酸酯或磷酰胺。

該反應是1945年F. R. Atherton, H. T. Openshawand, and A. R. Todd等人的一個偶然發現。實際上，他們原本的目的是想要在二芐基磷酸酯的四氯化碳溶液中加入氨水溶液來精制化合物。但是他們驚奇的發現，最后生成了 O,O -dibenzyl phosphoramidate的固體。
【Atherton, F. R. et al. J. Chem. Soc. 1945 , 660. DOI:10.1039/jr9450000660】

利用堿水溶液和相轉移催化劑可以明顯改善效果，可以用于制備各種磷酸混酯和磷酰胺。【(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. 】

反應機理

堿先拔掉亞磷酸二酯的氫，形成的亞磷酸二酯負離子進攻四氯化碳得到產物。

文獻報道還有另外一種機理，利用叔胺做堿時，在反應引發階段胺并不是拔氫而是先烷基化。【Phosphorus, Sulfur & Silicon and Related Elements, 1993, 83, 157】

反應實例

【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】

苯酚類化合物通過Atherton-Todd反應，得到芳基磷酸酯，再與硼酸在Ni催化下進行偶聯反應得到聯苯的一個實例。

【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】

相關文獻

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

參考文獻

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

二、化學空間：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