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Swern氧化反应

利⽤草酰氯，DMSO和三⼄胺将醇氧化为相应的羰基化合物的反应。在1976年，swern 等发现-50℃下在⼆氯甲烷中⽤三氟⼄酸酐处理DMSO可以得到三氟⼄酰氧⼆甲硫鎓三氟⼄酸盐，这种盐加⼊三⼄胺后可以迅速氧化伯醇和仲醇得到相应的醛酮。1978年，进⽽发现草酰氯是⽐三氟⼄酸酐更有效的活化试剂。其实早在上世纪60年代早就类似反应被发现， Pfitzner-Moffatt氧化反应（DCC/DMSO)，Albright- Goldman氧化反应（Ac2O/DMSO), Parikh–Doering氧化 (Py-SO3/DMSO)，这些反应都⽤到DMSO作为活化试剂，但草酰氯的氧化体系副反应较少。最初⽤TFAA的⽅法活性⾮常⾼，但副反应也较多。反应后试剂产⽣的副产物沸点低，容易除去，常⽤于⼤量合成醛，但是，反应会⽣成化学当量的⼆甲硫醚，有恶臭的⽓味。

反应特点和注意事项

1、在没有溶剂存在时，DMSO和TFAA，草酰氯反应⾮常剧烈，可能会爆炸，因此常加⼊⼆氯甲烷作为溶剂，此外THF、⼄醚也能使⽤；

2、如上⾯机理所⽰，TFAA活化时，最初中间体在超过-30℃时不稳定，重排为氯甲基甲硫醚；

3、⽽草酰氯作为活化剂时，最初中间体的稳定温度是低于-60℃，因此反应常常在-78℃下反应；

4、经典的操作步骤：在低温下，先⽤TFAA或草酰氯活化DMSO，然后缓慢加⼊醇，再加⼊三级胺反应后，缓慢升⾄室温；

5、加⼊三级胺，如DIPEA, TEA，可以有效的促进烷氧基硫盐的分解；

6、反应底物的位阻不会影响氧化的效率；

7、⽤TFAA做活化剂时，常常会有醇的三氟⼄酸酯副产物，⽽草酰氯没有；

8、对于⼀些含有对酸敏感基团的底物，加⼊醇后要尽快加⼊三级胺；

9、为防⽌⽣成的羰基化合物发⽣α-差向异构或双键迁移，要避免⽤三⼄胺，⽽⽤DIPEA或N-甲基啉等⼤位阻的碱，在低温下淬灭。10、除⾮有特别要求，⼀般都是以底物：⼄⼆酰氯：DMSO：三⼄胺 = 1:2:3:6的摩尔⽐作为标准配⽐来进⾏反应。11、DMSO产⽣的恶臭⽓味，全部操作都要在通风橱内，使⽤后的玻璃仪器⽤次氯酸⽔溶液浸泡，能除去恶臭的⽓味。

反应操作步骤

摄像机三脚架General Procedure for Oxidation of Alcohols Using Swern Oxidation:

绿隔热玻璃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.

反应机理

DMSO与草酰氯反应，⽣成氯锍盐中间体作为氧化活性剂，这⼀试剂对⽔敏感，且温度超过-60°C迅速分解，所以，此反应必须在低温（-78°C）及⽆⽔条件下进⾏。另外，有毒⽓体CO和恶臭⽓味的Me2S的⽣成，反应须在通风橱⾥进⾏，这样，此反应的缺点是其操作较复杂。

DMSO/TFAA活化机理

DMSO/草酰氯活化机理

副反应中最常见的是甲硫甲基醚化（MTM化）。温度⾼时反应中的氯锍盐发⽣ Pummerer 异构的产物与醇反应，⽣成MTM保护产物。

反应实例

【 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）冷却到-78°C ，滴加DMSO（3.3 mL, 21 mmol）的⼆氯甲烷溶液（32 mL）。迅速有⼤量⽓体产⽣，5分钟后加⼊醇（4.0 g, 20 mmol）的⼆氯甲烷（26 mL）溶液，-78°C搅拌15分钟。然后⼀次性加⼊三⼄胺（14 .0 mL， 100 mmol）, -78 °C下搅拌10分钟后，缓缓升⾄室温，⽤⼆氯甲烷稀释后，饱和氯化铵⽔溶液、⾷盐⽔洗涤（2次），⽆⽔硫酸镁⼲燥，过滤，滤液在通风橱内减压蒸馏（有恶臭⽓味），flash柱⾊谱（⽯油醚/⼄酸⼄酯 = 9：1）纯化精制得到⽬标产物醛为⽆⾊液体（3.88 g，96%）。