Swern氧化反应

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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-甲基吗啡啉等大位阻的碱,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

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

Swern氧化反应   第1张

DMSO/草酰氯活化机理

Swern氧化反应   第2张

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】

Swern氧化反应   第3张

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

J. Org. Chem. 2000, 65, 3738 

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

Swern氧化反应   第4张

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

Swern氧化反应   第5张

【 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%)。

相关文献

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.; Usković, 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.

参考资料


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