Swern氧化反應

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利用草酰氯，DMSO和三乙胺將醇氧化為相應的羰基化合物的反應。在1976年，swern 等發現-50℃下在二氯甲烷中用三氟乙酸酐處理DMSO可以得到三氟乙酰氧二甲硫鎓三氟乙酸鹽，這種鹽加入三乙胺后可以迅速氧化伯醇和仲醇得到相應的醛酮。1978年，進而發現草酰氯是比三氟乙酸酐更有效的活化試劑。其實早在上世紀60年代早就類似反應被發現，（DCC/DMSO)，（Ac2O/DMSO), (Py-SO3/DMSO)，這些反應都用到DMSO作為活化試劑，但草酰氯的氧化體系副反應較少。最初用TFAA的方法活性非常高，但副反應也較多。反應后試劑產生的副產物沸點低，容易除去，常用于大量合成醛，但是，反應會生成化學當量的二甲硫醚，有惡臭的氣味。

反應特點和注意事項

1、在沒有溶劑存在時，DMSO和TFAA，草酰氯反應非常劇烈，可能會爆炸，因此常加入二氯甲烷作為溶劑，此外THF、乙醚也能使用；2、如上面機理所示，TFAA活化時，最初中間體在超過-30℃時不穩定，重排為氯甲基甲硫醚；3、而草酰氯作為活化劑時，最初中間體的穩定溫度是低于-60℃，因此反應常常在-78℃下反應；4、經典的操作步驟：在低溫下，先用TFAA或草酰氯活化DMSO，然后緩慢加入醇，再加入三級胺反應后，緩慢升至室溫；5、加入三級胺，如DIPEA, TEA，可以有效的促進烷氧基硫鹽的分解；6、反應底物的位阻不會影響氧化的效率；7、用TFAA做活化劑時，常常會有醇的三氟乙酸酯副產物，而草酰氯沒有；8、對于一些含有對酸敏感基團的底物，加入醇后要盡快加入三級胺；9、為防止生成的羰基化合物發生α-差向異構或雙鍵遷移，要避免用三乙胺，而用DIPEA或N-甲基嗎啡啉等大位阻的堿，在低溫下淬滅。10、除非有特別要求，一般都是以底物：乙二酰氯：DMSO：三乙胺 = 1:2:3:6的摩爾比作為標準配比來進行反應。11、DMSO產生的惡臭氣味，全部操作都要在通風櫥內，使用后的玻璃儀器用次氯酸水溶液浸泡，能除去惡臭的氣味。

反應操作步驟

General Procedure for Oxidation of Alcohols Using Swern Oxidation:

From 2 to 11equiv., typically 2.2 equiv. of dry DMSO are slowly added over a cold stirredca. 0.2–0.9 M solution of 1.1–5 equiv., typically 1.1 equiv. of oxalyl chloridein dry DCM. After the evolution of gas ceased, ca. 1–20 min, a ca. 0.1–0.5 Msolution of 1 equiv. of the alcohol in dry DCM is slowly added to the resultingcold solution of activated DMSO. After 5 min to 2 h, typically 15 min, ca.1.2–16 equiv., typically 5 equiv. of Et3N are added. After 5 to 120min, typically 5 min, the reaction is left to reach room temperature.

The reaction isquenched by the addition of either water, a buffer phosphate solution at pH 7,or a slightly acidic aqueous solution, formed, for example, by ca. 10% ammoniumchloride, or 0.1–0.5 M sodium bisulfate. The organic phase is separated and theaqueous phase is washed with DCM. At this point, it may be helpful to add someDCM, or other organic solvent, like Et2O or EtOAc, in order tofacilitate the fractioning of phases. The collected organic phases may be optionally washed with water or brine. Theresulting organic solution is dried with Na2SO4 or MgSO4and concentrated, giving a residue that may need some purification.

In the oxidation of substrates with poor solubility in cold DCM, it may be advisable to increasesubstantially the quantity of DMSO, in order to dissolve the alcohol.

Non aqueous workup:

Normally, thework-up of Swern oxidations is carried out by a routine fractioning between an aqueous and an organic phase. Somealdehydes with a high tendency to exist as a hydrate—typically, aldehydespossessing an alkoxy group at the a position—are hydrated during the standardwork-up, resulting in a chemical species resistant to react with nucleophilesas aldehydes do. In such cases, it is advisable to perform a non-aqueouswork-up, in which an organic solvent(acetone, ether or EtOAc) is added, thesolids are filtered, the resulting solution is concentrated, and the residue ispurified with a silica column.

Modified Swern Reagent

The standard Swernoxidation employing DMSO results in the formation of dimethyl sulfide, which isa toxic volatile liquid (b.p. 38 C) with an unpleasant smell. This can beavoided by using other sulfoxides that generate sulfides lacking volatility.

Useful alternatives include: dodecyl methyl sulfoxide, 6-(methylsulfinyl)hexanoicacid, sulfoxides containing per-fluorated alkyl chains and sulfoxides bound topolymers, such as polystyrene or poly(ethylene)glycol.

反應機理

DMSO與草酰氯反應，生成氯锍鹽中間體作為氧化活性劑，這一試劑對水敏感，且溫度超過-60°C迅速分解，所以，此反應必須在低溫（-78°C）及無水條件下進行。另外，有毒氣體CO和惡臭氣味的Me2S的生成，反應須在通風櫥里進行，這樣，此反應的缺點是其操作較復雜。

DMSO/TFAA活化機理

DMSO/草酰氯活化機理

副反應中最常見的是甲硫甲基醚化（MTM化）。溫度高時反應中的氯锍鹽發生異構的產物與醇反應，生成MTM保護產物。

反應實例

【 J. Org. Chem.1988, 53, 2972-2979】

【 J. Org. Chem.1988, 53, 3647】

【 Tetrahedron Lett. 1988, 29, 49-52】

【 J. Org. Chem.1991, 56, 4714-4718】

【 J. Am. Chem. Soc.1999, 121, 866-867】

【 J. Org. Chem.2000, 65, 3738 】

【 J. Am. Chem. Soc.2001, 123, 3239-3242】

【 J. Am. Chem. Soc.2003, 125, 1843-1850】

【 J. Am. Chem. Soc.2003, 125, 5415-5421】

【 J. Org. Chem.2005, 70, 2097】

草酰氯（2.1 mL, 24 mmol）的二氯甲烷溶液（30 mL） 冷卻到-78°C ，滴加DMSO（3.3 mL, 21 mmol）的二氯甲烷溶液（32 mL）。迅速有大量氣體產生，5分鐘后加入醇 （4.0 g, 20 mmol）的二氯甲烷（26 mL）溶液，-78°C攪拌15分鐘。然后一次性加入三乙胺（14 .0 mL， 100 mmol）, -78 °C下攪拌10分鐘后，緩緩升至室溫，用二氯甲烷稀釋后，飽和氯化銨水溶液、食鹽水洗滌 （2次） ，無水硫酸鎂干燥，過濾，濾液在通風櫥內減壓蒸餾（有惡臭氣味），flash柱色譜（石油醚/乙酸乙酯 = 9： 1）純化精制得到目標產物醛為無色液體（3.88 g，96%）。

相關文獻

1. (a) Huang, S. L.; Omura, K.; Swern, D. J. Org. Chem. 1976, 41, 3329-3331. (b) Huang, S. L.; Omura, K.; Swern, D. Synthesis 1978, 4, 297-299. (c) Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43, 2480-2482. Daniel Swern was a professor at Temple University.

2. Ghera, E.; Ben-David, Y. J. Org. Chem. 1988, 53, 2972-2979.

3. Smith, A. B., III; Leenay, T. L.; Liu, H. J.; Nelson, L. A. K.; Ball, R. G. Tetrahedron Lett. 1988, 29, 49-52.

4. Tidwell, T. T. Org. React. 1990, 39, 297-572. (Review).

5. Chadka, N. K.; Batcho, A. D.; Tang P. C.; Courtney, L. F.; Cook C. M.; Wovliulich, P. M.; Uskovi?, M. R. J. Org. Chem. 1991, 56, 4714-4718.

6. Harris, J. M.; Liu, Y.; Chai, S.; Andrews, M. D.; Vederas, J. C. J. Org. Chem. 1998, 63, 2407-2409. (Odorless protocols).

7. Stork, G.; Niu, D.; Fujimoto, R. A.; Koft, E. R.; Bakovec, J. M.; Tata, J. R.; Dake, G. R. J. Am. Chem. Soc. 2001, 123, 3239-3242.

8. Nishide, K.; Ohsugi, S.-i.; Fudesaka, M.; Kodama, S.; Node, M. Tetrahedron Lett. 2002, 43, 5177-5179. (Another odorless protocols).

9. Ahmad, N. M. Swern Oxidation. In Name Reactions for Functional Group Transformations; Li, J. J., Ed.; Wiley: Hoboken, NJ, 2007, pp 291-308. (Review).

10. Lopez-Alvarado, P; Steinhoff, J; Miranda, S; Avendano, C; Menendez, J. C.Tetrahedron 2009, 65, 1660-1672.

11. Zanatta, N.; Aquino, E. da C.; da Silva, F. M.; Bonacorso, H. G.; Martins, M. A. P. Synthesis 2012, 44, 3477-3482.

參考資料

一、Name Reactions （A Collection of Detailed Reaction Mechanisms）, Jie Jack Li, Swern oxidation，page 595-596.

二、common oxidation reagents, Yue Xu, SundiaMeditech

三、StrategicApplications of Named Reactions in Organic Synthesis, László Kürti and Barbara Czakó, Swern oxidation, page 450-451.