Dimethyl Sulfoxide-Oxalyl Chloride1

(DMSO)

[67-68-5]  · C2H6OS  · Dimethyl Sulfoxide-Oxalyl Chloride  · (MW 78.13) ((COCl)2)

[79-37-8]  · C2Cl2O2  · Dimethyl Sulfoxide-Oxalyl Chloride  · (MW 126.93)

(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 minimal amounts of byproduct methylthiomethyl ethers)

Alternate Name: Swern reagent.

Physical Data: DMSO: mp 18.4 °C; bp 189 °C; d 1.101 g cm-3. (COCl)2: bp 63-64 °C/763 mmHg; d 1.455 g cm-3.

Solubility: DMSO: sol H2O, alcohol, acetone, THF, CH2Cl2. (COCl)2: reacts H2O; sol CH2Cl2, THF.

Form Supplied in: colorless liquids; widely available, including anhydrous grades of 99%+ DMSO packed under N2, and 2M (COCl)2 in CH2Cl2 under N2.

Preparative Method: the active reagent, Me2+SCl, is formed rapidly from DMSO-(COCl)2 at -78 °C in CH2Cl2.

Purification: DMSO: distillation from calcium hydride at 56-57 °C/5 mmHg2a or 83-85 °C/17 mmHg;2b storage over 3Å molecular sieves. (COCl)2: distillation under N2.

Handling, Storage, and Precautions: Dimethyl Sulfoxide is readily absorbed through the skin and should always be handled with gloves in a fume hood; its reactions 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;2c Oxalyl Chloride is corrosive and moisture-sensitive, and is said to react explosively with DMSO at rt.

DMSO-oxalyl chloride is the most widely used of the DMSO-based reagents 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.3 The active reagent (1) is generated in situ at low temperature by the addition of DMSO to (COCl)2 in a solvent such as CH2Cl2, ether, or THF (eq 1). 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).

In a typical procedure using Triethylamine as base, DMSO (2.4 equiv) is added to (COCl)2 (1.2 equiv) in CH2Cl2 cooled to -50 to -60 °C, and then geraniol (5) (1.0 equiv) is added, followed by Et3N (5 equiv). Washing and distillation give geranial (6) in 94% yield (eq 4).4a The sensitive alcohol (7) is oxidized to the aldehyde (8) in 83% yield, with less than 8% racemization (eq 5).4b The use of Diisopropylethylamine (DIPEA) as the base helps prevent epimerization (eq 6).4c This procedure has been applied on a 1 mol scale in a conversion that gave only a 40% yield with Chromium(VI) Oxide and H2SO4 (eq 7).4d

Diols are efficiently oxidized by this procedure (eqs 8 and 9),4e,f and selectivity for oxidation of less crowded hydroxy groups can be achieved (eq 10).4g,h Isolation of the ketoaldehyde (10) from oxidation of (9) proved difficult, so oxidation using the stronger base 1,8-Diazabicyclo[5.4.0]undec-7-ene was employed to give (11) directly from (9) (eq 11).4i Aryl dimethanols are oxidized to ortho-phthalaldehydes.4j

DMSO activated by (COCl)2 without the addition of base has also been used for the conversion of b-triketides such as (12) to g-pyrones (13) (eq 12).5 A mechanism was proposed in which DMSO was regenerated (eq 13). In the presence of Et3N the formation of (14) (30%) along with (13) (33%) was attributed to the intermediate (15) (eq 14).5

Examples of oxidation of alcohols to carbonyl compounds by DMSO-(COCl)2 followed by in situ reaction of the product with another reagent include the use of alkynyllithiums (eq 15),6a Wittig reagents (eq 16),6b and Mannich reagents (eq 17).6c Extraction of the crude product followed by reaction with Hydroxylamine gives oximes (eq 18),6d and oxidation in the presence of MeOH gave an ester (eq 19).6e

The sequence of eqs 20 and 21 illustrates the use of consecutive Swern oxidations and further conversions.6f Reaction of trimethylsilylallyl alcohol on a 0.3 mol scale gave the ketone in 78% yield (eq 22).6g

Trimethylsilyl and triethylsilyl ethers are oxidized to carbonyl products by DMSO-(COCl)2, but t-butyldimethylsilyl, t-butyldiphenylsilyl, and t-butoxydiphenylsilyl ethers are not (eq 23).7a-d Chloride attack on silicon is thought to assist the reaction.7b Primary triethylsilyl ethers are selectively oxidized by DMSO-(COCl)2 in the presence of tertiary triethylsilyl ethers (eq 24).7e This subject has been reviewed.7f

Elimination can occur from the carbonyl products resulting from oxidation of sensitive substrates (eq 25).8

Allylic alcohols can be converted to chlorides by treatment with DMSO-(COCl)2 without the use of added base, presumably by chloride displacement of DMSO from the alkoxysulfonium ion (eq 26).9a,b DMSO-(COCl)2 also acts as an electrophilic chlorinating reagent toward ketones (eq 27).9c Oxidation to the nonchlorinated ketone was achieved with Dimethyl Sulfoxide-Acetic Anhydride.9c

Oxidation of diaziridines with DMSO-(COCl)2 gives diazirines (eq 28),10a and dibenzylamine gives partial conversion to an imine (eq 29).10b

A related reagent for the activation of DMSO for oxidation of alcohols is Phenyl Dichlorophosphate (PhOP(O)Cl2),11a-c which is more effective than DMSO-(COCl)2 in the oxidation of benzyl alcohol (eq 30).11a Cyanuric chloride also activates DMSO for oxidation of alcohols.11d

Related Reagents.

N-Chlorosuccinimide-Dimethyl Sulfide; Chromic Acid; Dimethyl Sulfide-Chlorine; Dimethyl Sulfoxide-Acetic Anhydride; Dimethyl Sulfoxide-Dicyclohexylcarbodiimide; Dimethyl Sulfoxide-Iodine; Dimethyl Sulfoxide-Methanesulfonic Anhydride; Dimethyl Sulfoxide-Phosphorus Pentoxide; Dimethyl Sulfoxide-Sulfur Trioxide/Pyridine; Dimethyl Sulfoxide-Trifluoroacetic Anhydride; 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.


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Thomas T. Tidwell

University of Toronto, Ontario, Canada



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