Mitsunobu反应

由于微信更改了订阅号的推送规则，很多朋友不能快速找到我们，其实我们每天都在推送！您可以将有机合成设置为星标（点击右上方“...", 设为星标），就能在微信订阅号中快速找到我们，查看每天订阅。

反应机理

反应应用

一、醇的翻转

【J. Org. Chem. 1996, 61, 2544】

Tsunoda等发现，对于位阻较大的醇，TMAD(N, N, N’, N’-tetramethyl- azodicarboxamide) 和三丁基膦的体系效果比较好。

【Tetrahedron. Letter 1995, 36, 2529】。

【J. Am. Chem. Soc. 2000, 122, 4583-4592】

二、Mitsunobu醚化反应

在Mitsunobu 反应中，羟基也可以作为亲核试剂参与SN2取代，结果是生成醚。但通常只限于酚羟基和pKa<13的羟基，否则反应不能进行。

A solution of benzyl alcohol (0.200 g, 1.85 mmol), 4-hydroxybenzaldehyde (0.226 g, 1.85 mmol), and PPh3(0.582 g, 2.22 mmol) was stirred in dry THF (20 mL) at 0 °C under a nitrogen atmosphere. To this mixture was added dropwise DIAD (0.44 mL, 2.22 mmol) over a period of 5 min, and the reaction was monitored by TLC. After complete disappearance of starting material (1 h), the solvent was evaporated under reduced pressure and the resulting oil purified by flash column chromatography (hexane/AcOEt, 8/2). Phenyl ether (0.297 g, 76%) was finally obtained as a white powder after precipitation from CH2Cl2/petroleum ether.

【J. Org. Lett. 2004, 6, 397】

三、Mitsunobu氮取代反应

【Synlett. 1997, 529】

【Tetrahedron 2003, 59, 8571–8587】

【Tetrahedron 1994, 50, 9757】

【J. Am. Chem. Soc. 2001, 123, 9465-9467】

 To a cooled solution (-5^oC)of DIAD (7.9 g, 93 mmol) in THF (5 mL) was added the substituted alchol (7.06g, 18.7 mmol) and PPh₃ (10.3 g, 39.1 mmol). After 15 min, diphenylphosphorazidate (DPPA, 12.86 g, 46.77mmol) was added and the reaction mixturewas allowed to warm to room temperature. After stirring overnight, the solventwas removed in vacuo to give a yellow oil. The crude material was purified byflash column chromatograghy (2:1,PE/Tol) to give the desired product (7.28 g,91%) as a colorless oil. 

  The de-protection andhydrogenation were routine operations.

【J. Org. Chem. 1998, 63, 4898.】

四、Mitsunobu硫代反应

【Tetrahedron. Lett. 1981, 22, 3119】

  芳香类硫醇化合物都有足够的活性参与这种反应。

【J. Am. Chem. Soc. 2001, 123, 12426-12427】

To a solution of 2-[(R)—N-(tert-butyloxycarbonyl)amino]-1-propanol(15 g, 85.6 mmol) in THF (200 mL) was added 2-mercaptobenzothiazole (14.3 g,85.6 mmol) and PPh3 (24.7 g, 94.2 mmol). After stirring for 0.25 h asolution of DEAD (14.8 mL, 94.2 mmol) in dry THF (100 mL) was added dropwiseover 0.5 h. The reaction mixture was stirred for 1 h at 20oC and filtered. Thefiltrate was evaporated and stirred with EA (100 mL), and the product wascollected by filtration (20.66 g, 74%). 

【J. Med. Chem. 1999, 42, 3463.】

五、Mitsunobu卤代反应

在Mitsunobu 反应中，用卤原子取代羟基生成卤代物也有报导，但其应用还不多见。Falck 等报导了通过Mitsunobu 过程合成一系列的卤代烃，除了氟代的产率不高以外，氯代，溴代和碘代的产率都不错。

【Manna, S; Falck, J.R. Synth. Commun. 1985, 15, 663】

 Joulle 等报导脯胺酸衍生物在经过Mitsunobu过程后得到手性翻转的碘代产物。反应首先是生成一个甲醚中间体，然后在三苯膦的作用下发生碘代，同时手性翻转。

To a flame-driedround-bottomed flask eguipped with a magnetic stir bar and an addition funnelunder N₂ was added N-Boc-trans-4-hydroxy-L-proline methyl ester(19.29 g, 0.079 mol), triphenylphosphine (24.78 g, 0.094 mol) and anhydrous THF(2755 mL). The solution was cooled to 0^oC. Diethyl azodicarboxylate(DEAD, 14.9 mL, 0.094 mol) in anhydrous THF (15 mL) was added dropwise,followed by the addition of methyl iodide (5.88 mL, 0.094 mol). Upon additionof MeI, the solution turned from dark brown to bright yellow. The reactionmixture was allowed to warm to ambient temperature and stirred for 10 h. Thesolvent was removed under reduced pressure and the crude oil was purified bycolumn chromatograghy, eluting with 5% EA/PE to afford the desired product as awhite solid (26.22 g, 93.8%).

【Tetrahedron: Asymm. 1998, 9, 47】

六、其他

关环

【Tetrahedron: Asymmetry 2000, 11, 4407–4416】

碳碳键形成

【J. Am. Chem. Soc. 1996, 118, 2301-2302】

2019年《Science》上发表了一篇名为《Redox-neutral organocatalytic Mitsunobu reactions》文章，通讯作者是诺丁汉大学化学系Ross M. Denton教授，Ross M. Denton教授团队开发的是一种不涉及氧化还原反应的有机催化的Mitsunobu反应。他们利用一种二苯基苄基氧膦作为催化剂，在加热条件下就可以实现Mitsunobu反应，反应产生的唯一副产物就是水。经过验证基本上可以实现各种类型的Mitsunobu反应，构型反转也非常有效。甚至可以实现传统Mitsunobu反应不能实现的脂肪醇的自身成醚反应。

【Science 365, 910–914 (2019)；DOI: 10.1126/science.aax335】

【Tsunoda试剂活性逆天，二醇竟然可以发生Mitsunobu反应制备环醚！】

相关文献

1. (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380-2382. (b)Mitsunobu, O. Synthesis 1981, 1-28. (Review).

2. Smith, A. B., III; Hale, K. J.; Rivero, R. A. Tetrahedron Lett. 1986, 27, 5813-5816.

3. Kocieński, P. J.; Yeates, C.; Street, D. A.; Campbell, S. F. J. Chem. Soc., Perkin Trans. 1, 1987, 2183-2187.

4. Hughes, D. L. Org. React. 1992, 42, 335-656. (Review).

5. Hughes, D. L. Org. Prep. Proc. Int. 1996, 28, 127-164. (Review).

6. Vaccaro, W. D.; Sher, R.; Davis, H. R., Jr. Bioorg. Med. Chem. Lett. 1998, 8, 35–40.

7. Cevallos, A.; Rios, R.; Moyano, A.; Pericàs, M. A.; Riera, A. Tetrahedron: Asymmetry 2000, 11, 4407–4416.

8. Mukaiyama, T.; Shintou, T.; Fukumoto, K. J. Am. Chem. Soc. 2003, 125, 10538–10539.

9. Sumi, S.; Matsumoto, K.; Tokuyama, H.; Fukuyama, T. Tetrahedron 2003, 59, 8571–8587.

10. Christen, D. P. Mitsunobu reaction. In Name Reactions for Homologations-Part II; Li, J. J., Ed.; Wiley: Hoboken, NJ, 2009, pp 671-748. (Review).

11. Ganesan, M.; Salunke, R. V.; Singh, N.; Ramesh, N. G. Org. Biomol. Chem. 2013, 11, 559-611.

参考资料

一、维基百科（光延反应词条）

二、Strategic Applications of Named Reactions in Organic Synthesis, László Kürti and Barbara Czakó, Mitsunobu reaction, page 294.

三、药明康德宝典/Mitsunobu反应，谢军编著。

四、Name Reactions （A Collection of Detailed Reaction Mechanisms）, Jie Jack Li,  Mitsunobu reaction，page 407-408.

由于微信更改了订阅号的推送规则，很多朋友不能快速找到我们，其实我们每天都在推送！您可以将有机合成设置为星标（点击右上方“...", 设为星标），就能在微信订阅号中快速找到我们，查看每天订阅。