Dimethyl Sulfoxide-Trifluoroacetic Anhydride1

(DMSO)

[67-68-5]  · C2H6OS  · Dimethyl Sulfoxide-Trifluoroacetic Anhydride  · (MW 78.13) (TFAA)

[407-25-0]  · C4F6O3  · Dimethyl Sulfoxide-Trifluoroacetic Anhydride  · (MW 210.03)

(oxidant for the conversion of primary and secondary alcohols to aldehydes and ketones, respectively; avoids overoxidation to carboxylic acids; suitable for large-scale oxidation; gives good yields with only small amounts of byproduct methylthiomethyl ethers but alcohols can be converted to trifluoroacetate esters, particularly at higher temperatures; also used for the conversion of primary amines to sulfilimines)

Alternate Name: Swern reagent.

Physical Data: DMSO: mp 18.4 °C; bp 189 °C d 1.101 g cm-3. TFAA: mp -65 °C; bp 39.5-40 °C; d 1.487 g cm-3.

Solubility: DMSO: sol H2O, alcohol, acetone, THF, CH2Cl2. TFAA: sol CH2Cl2, ether, THF. Drying: DMSO: distillation from CaH2 at 56-57 °C/5 mmHg2a or 83-85 °C/17 mmHg;2b storage over 3Å molecular sieves. TFAA: distillation.

Form Supplied in: colorless liquids; widely available, including anhydrous grades of DMSO packed under N2, and 99%+ TFAA.

Preparative Method: The active reagent Me2+SO2CCF3 is formed rapidly on the addition of TFAA to DMSO in CH2Cl2 at -78 °C, and is used in situ.

Handling, Storage, and Precautions: Dimethyl Sulfoxide is readily absorbed through the skin and should always be handled with gloves in a fume hood; reactions with DMSO form foul-smelling byproducts and should be carried out with good ventilation, and the waste byproducts and liquids used for washing should be treated with KMnO4 solution to oxidize volatile sulfur compounds; DMSO undergoes appreciable disproportionation to dimethyl sulfide (stench!) and dimethyl sulfone above 90 °C on distillation at atmospheric pressure;2c Trifluoroacetic Anhydride is toxic, corrosive, and water-sensitive, and reacts violently with DMSO at rt.

DMSO-TFAA is commonly used for the oxidation of primary and secondary alcohols to aldehydes and ketones, respectively, and usually gives excellent yields with short reaction times and minimal formation of byproducts. The active reagent (1) is generated in situ at low temperature by the addition of TFAA to DMSO in a solvent such as CH2Cl2 (eq 1).3a-c Addition of the alcohol to (1) gives the alkoxysulfonium ion (2) (eq 2), which on addition of an amine base is deprotonated to (3); the latter forms the carbonyl product (4) by intramolecular proton abstraction (eq 3). Trifluoroacetates are sometimes byproducts in these reactions, but the use of Trichloroacetic Anhydride instead of TFAA prevents this problem.3d

The examples shown in eq 44a and eq 54b illustrate the preparation of ketones in good yield with this reagent, while eq 6,4c eq 7,4d and eq 84e show the oxidation of diols. The example of eq 6 gave only a 25% yield with Oxalyl Chloride activation.4c In the reaction of eq 8, ring opening and elimination of HBr also occurs.4e The addition of 2-propanol has been used to quench excess oxidant in this procedure.4f

The title reagent can react with electron-rich aromatic compounds to give aryldimethylsulfonium salts (eq 9).5a DMSO and Trifluoroacetic Acid (TFA) oxidize sulfides to disulfides, and the activation of the DMSO in this case was proposed to occur by protonation of the DMSO (eq 10).5b Oxidations with DMSO-TFAA followed by Triethylamine can result in formation of the byproduct (5), which is suggested to arise by a single electron transfer process (eq 11).4c Activation of DMSO by TFAA for oxidation of a dithiane avoids the problem of dithiane monosulfoxide formation encountered with (COCl)2 activation.5c Sulfilimines are formed by reaction of DMSO-TFAA with primary amines (eq 12).1e,5d

Related Reagents.

N-Chlorosuccinimide-Dimethyl Sulfide; Chromic Acid; Dimethyl Sulfide-Chlorine; Dimethyl Sulfoxide-Acetic Anhydride; Dimethyl Sulfoxide-Dicyclohexylcarbodiimide; Dimethyl Sulfoxide-Oxalyl Chloride; Dimethyl Sulfoxide-Phosphorus Pentoxide; Dimethyl Sulfoxide-Sulfur Trioxide/Pyridine; Dimethyl Sulfoxide-Triphosgene; Manganese Dioxide; Pyridinium Chlorochromate; Pyridinium Dichromate; Ruthenium(VIII) Oxide; Silver(I) Carbonate; 1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one.


1. (a) Tidwell, T. T. OR 1990, 39, 297. (b) Tidwell, T. T. S 1990, 857. (c) Lee, T. V. COS 1991, 7, 291. (d) Haines, A. H. Methods for the Oxidation of Organic Compounds; Academic: London, 1988. (e) Hudlicky, M. Oxidations in Organic Chemistry; ACS: Washington, 1990. (f) Mancuso, A. J.; Swern, D. S 1981, 165. (g) Moffatt, J. G. In Oxidation; Augustine, R. L.; Trecker, D. J., Eds.; Dekker: New York, 1971; Vol. 2, Chapter 1.
2. (a) Iwai, I.; Ide, J. OSC 1988, 6, 531. (b) Insalaco, M. A.; Tarbell, D. S. OSC 1988, 6, 207. (c) Corey, E. J.; Chaykovsky, M. OSC 1973, 5, 755.
3. (a) Omura, K.; Swern, D. T 1978, 34, 1651. (b) Omura, K.; Sharma, A. K.; Swern, D. JOC 1976, 41, 957. (c) Huang, S.-L.; Omura, K.; Swern, D. JOC 1976, 41, 3329. (d) Corey, E. J.; Danheiser, R. L.; Chandrasekaran, S.; Siret, P.; Keck, G. E.; Gras, J.-L. JACS 1978, 100, 8031.
4. (a) Roush, W. R.; Gillis, H. R.; Ko, A. I. JACS 1982, 104, 2269. (b) Chamberlin, A. R.; Chung, J. Y. L. JOC 1985, 50, 4425. (c) Amon, C. M.; Banwell, M. G.; Gravatt, G. L. JOC 1987, 52, 4851. (d) Ley, S. V.; Mahon, M. TL 1981, 22, 3909. (e) Banwell, M. G.; Onrust, R. TL 1985, 26, 4543. (f) Barrett, A. G. M.; Barta, T. E.; Flygare, J. A.; Sabat, M.; Spilling, C. D. JOC 1990, 55, 2409.
5. (a) Hartke, K.; Teuber, D.; Gerber, H.-D. T 1988, 44, 3261. (b) Otaka, A.; Koide, T.; Shide, A.; Fujii, N. TL 1991, 32, 1223. (c) Braish, T. F.; Saddler, J. C.; Fuchs, P. L. JOC 1988, 53, 3647. (d) Hyde, C. B.; Welham, K. J.; Mascagni, P. JCS(P2) 1989, 2011.

Thomas T. Tidwell

University of Toronto, Ontario Canada



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