Dimethyl sulfoxide reaction with oxalyl chloride

One drawback of these reactions is the formation of volatile, odorous dimethyl sulfide. Various solutions to this problem have been reported, such as the use of dodecyl methyl sulfoxide (Ci2H25SOMe) with oxalyl chloride followed by triethy-lamine. The by-product dodecyl methyl sulfide is non-volatile and yields are only slightly reduced in comparison with the use of dimethyl sulfoxide. 

As an alternative to chromium-based oxidants, chemists have developed other reagents for oxidizing alcohols, several of which are based on chlorodimethylsulfonium ion [(CH3)2SC1 ]. Most commonly, chlorodimethylsulfonium ion is generated under the reaction conditions by the reaction of dimethyl sulfoxide with oxalyl chloride. 

The ionic species 5, as well as 6, represent the so-called activated dimethyl sulfoxide. Variants using reagents other than oxalyl chloride for the activation of DMSO are known. In the reaction with an alcohol 1, species 5, as well as 6, leads to the formation of a sulfonium salt 7 ... 

Quebrachitol was converted into iL-c/j/roinositol (105). Exhaustive O-isopropylidenation of 105 with 2,2-dimethoxypropane, selective removal of the 3,4-0-protective group, and preferential 3-0-benzylation gave compound 106. Oxidation of 106 with dimethyl sulfoxide-oxalyl chloride provided the inosose 107. Wittig reaction of 107 with methyl(triphenyl)phos-phonium bromide and butyllithium, and subsequent hydroboration and oxidation furnished compound 108. A series of reactions, namely, protection of the primary hydroxyl group, 0-debenzylation, formation of A-methyl dithiocarbonate, deoxygenation with tributyltin hydride, and removal of the protective groups, converted 108 into 7. 

The reaction of the aldehyde 174, prepared from D-glucose diethyl dithio-acetal by way of compounds 172 and 173, with lithium dimethyl methyl-phosphonate gave the adduct 175. Conversion of 175 into compound 176, followed by oxidation with dimethyl sulfoxide-oxalyl chloride, provided diketone 177. Cyclization of 177 with ethyldiisopropylamine gave the enone 178, which furnished compounds 179 and 180 on sodium borohydride reduction. 0-Desilylation, catalytic hydrogenation, 0-debenzyIation, and acetylation converted 179 into the pentaacetate 93 and 5a-carba-a-L-ido-pyranose pentaacetate (181). 

Formyl derivative 362 was prepared when 9-hydroxymethylpyrido-pyrimidin-4-one 361 in dichloromethane was added to a cooled mixture of oxalyl chloride and dimethyl sulfoxide at - 50°C/ - 60°C in the presence of triethylamine. 9-Formyl derivative 362 was oxidized with silver nitrate in aqueous ethanol, and after 15 minutes of stirring the reaction mixture was treated with aqueous potassium nitrate for 2 hours at ambient temperature to give pyrido[ 1,2-a]pyrimidine-9-carboxylic acid 363 (91EUP453042). 

Also, psudo-P-D-mannopyranose (115) has been synthesized from 99 by the following reactions [28], Halogenation of 99 with triphenylphosphine, imidazole and iodine gave 1 L-4-0-benzyl-3-deoxy-3-iodo-1,2 5,6-di-0-isopropylidene-a//o-inositol (106), m.p. 77.4 °C, [oc]p° —30.1° (chloroform). Treatment of 106 with lithium aluminium hydride-resulted in a formation of two endocyclic olefins (107) and (108) in an approximately 1 2 ratio. Oxidation of 108with dimethyl sulfoxide and oxalyl chloride gave the enone (109) as a syrup, [a] 0 —68.11° (chloroform). Stereoselective... 

Another method of aetivation is known as the Swern oxidation. Under these conditions a reactive dimethylchlorosulfonium chloride is formed from the reaction of dimethyl sulfoxide and oxalyl chloride (Scheme 2.28b). This then reacts with an alcohol to give an alkoxysulfonium salt. In the presence of a base (triethylamine) this salt fragments with the formation of a carbonyl compound (Scheme 2.28c). 

The maiin domain of oxidation with dimethyl sulfoxide is the conver-sionofprimary alcoholsinto aldehydes andofsecondaryalcoholsintoketones. These reactions are accomplished under very mild conditions, sometimes at temperatures well below 0 °C. The reactions require the presence of acid catalysts such as acetic anhydride [713, 1008, 1009], trifluoroacetic acid [1010], trifluoroacetic anhydride [1011, 1012, 1013], trifluorometh-anesulfonic acid [1014], phosphoric acid [1015, 1016], phosphorus pentox-ide [1006, 1017], hydrobromic acid [1001], sulfur trioxide [1018], chlorine [1019, 1020], A -bromosuccinimide [997], carbonyl chloride (phosgene) [1021], and oxalyl chloride (the Swem oxidation) [1022, 1023, 1024], Dimethyl sulfoxide also converts sufficiently reactive halogen derivatives. into aldehydes or ketones [998, 999] and epoxides to a-hydroxy ketones at -78 °C [1014]. 

In more recent works, the use of dicyclohexylcarbodiimide has been abandoned because the reaction works satisfactorily with acid catalysts alone, followed by bases such as triethylamine or diisopropylethylamine, which gives, sometimes, even better yields than triethylamine [1012,1023. Several activators are being used, and the best seems to be oxalyl chloride (theSwern oxidation) [1023,1149]. Other activators are mentioned in the section Oxidation of Primary Alcohols to Aldehydes. The advantages of oxidations with dimethyl sulfoxide lie in the mildness of the reagent and in the low temperatures, sometimes -45 °C [1020] or -60 °C [1023], at which the reactions are run. 

Protection of aldoses at the non-anomeric positions makes it possible to use many of the common procedures in organic chemistry for oxidizing lactols as shown with mannofura-nose 1 and glucopyranose 3 (O Table 1). The reactions can be divided into three main categories oxidations mediated by activated dimethyl sulfoxide (DMSO), oxidations with chromi-um(VI) oxides, and oxidations catalyzed by ruthenium oxides. The DMSO-mediated oxidations of alcohols can be promoted by several activators [27]. With the partially protected aldoses the activation has mainly been achieved with acetic anhydride and oxalyl chloride. Competing /3-elimination does usually not occur unless the eliminating group is an ester, e. g., an acetate or a benzoate [27]. 

C. 9-Thiabicyclo[3.3.1]nonane-2,6-dione(3). (CautionI Oxalyl chloride and dimethyl sulfoxide are reported to react explosively at room temperature. Preparation C should be carried out in a well-ventilated hood since a co-product of the reaction is dimethyl sulfide). To a 1-L, three-necked flask equipped with a magnetic stirring bar, low temperature thermometer, dropping funnel protected from moisture by a drying... 

The additional carbon atom required for building the five-membered ring D is then added by means of methyl-magnesium bromide (16-4). The ester at future C15 is reduced to a carbinol by reaction with lithium aluminum hydride. Swern oxidation (dimethyl sulfoxide and oxalyl chloride) next serves to oxidize each of the two resulting hydroxyl groups to carbonyl functions (16-5). Dieckmann-like base-catalyzed condensation then closes the five-membered ring... 

The mechanism of the Swem oxidation has been studied in depth and the formation of an initial adduct 7 from the reaction between dimethyl sulfoxide and oxalyl chloride which then collapses to give a dimethylchlorosulfonium species 8 is clearly indicated by mechanistic studies.3,8 Reaction of 8 with an alcohol then produces the alkyoxysulfonium ion 9 which upon treatment with an amine base gives the ylide 10. Subsequent proton extraction gives the carbonyl product 2 with the release of dimethyl sulfide. 

Step 1 The alcohol reacts with the active oxidizing agent, chlorodimethylsulfonium ion, previously generated by the reaction between dimethyl sulfoxide and oxalyl chloride. The oxygen of the alcohol displaces chloride from sulfur. 

Several neutral oxidation reactions do not involve chromium(VI), but readily convert an alcohol to a ketone or an aldehyde. One such reaction uses a reagent derived from the reaction of dimethyl sulfoxide (DMSO, 37) and oxalyl chloride (38 see Chapter 16, Section 16.7). When 2-butanol is mixed with these reagents at -60°C, dimethyl sulfide (MeSMe) is observed as a product and 2-butanone (43) is isolated in 78% yield. ... 

The main applications of oxalyl chloride, as described in Chapter 4, are the formation of aryl isocyanates and chloroformates (by reactions with amines and hydroxylic substrates, respectively), and the formation of acyl chlorides from carboxylic acids under very mild conditions. Oxalyl chloride reacts with amides to give acyl isocyanates, and it is used with dimethyl sulfoxide as a mild reagent for the oxidation of alcohols (Swern-type oxidation). It is also used with N,N-dimethylformamide as a mild reagent for chlorination and formylation. Oxalyl chloride is widely used in commercial formulations of speciality polymers, antioxidants, photographic chemicals, X-ray contrasting agents, and chemiluminescent materials. Other physical properties are presented in Chapter 3. 

Oxalyl chloride reacts with dimethyl sulfoxide at low temperatures to initially form adduct 1790a, which collapses to a dimethylchlorosulfonium species 1790b. Reaction of 1790b with an alcohol at 78 °C produces the alkoxysulfonium ion 1791, which is converted into the product by reaction with an amine base to give yhde 1792, which further reacts intramolecularly to give the carbonyl product. 

Typical procedure. Ethyl (E)-3-(trimethylsilyl) methacrylate 1867 [1388] To a stirred solution of oxalyl chloride (131 pL, 0.190 mg, 1.50 mmol) in dichloromethane (8.0 mL) at —78 °C was added dimethyl sulfoxide (121 pL, 0.133 mg, 1.70 mmol). After 10 min, a solution of (trimethylsilyl)methanol (104 mg, 1.00 mmol) in dichloromethane (2 mL) was added over 4 min, and, after 15 min, triethylamine (0.52 mL, 377 mg, 3.7 mmol) was added over 1 min. After 5 min at —78 °C, a solution of ethyl 2-(triphenylphosphoranylidene)propionate (690 mg, 1.9 mmol) in dichloromethane was added over 3 min. The reaction mixture was then allowed to warm to room temperature, diluted with diethyl ether (70 mL), and then washed with water (40 mL) and brine (40 mL). The organic phase was dried over magnesium sulfate and then concentrated under reduced pressure. Chromatography of the residue eluting with diethyl ether/petroleum ether, 3 97, afforded 101 mg (54%) of product 1867 as a colorless oil. 

The Swem oxidation oxidizes primary alcohols to aldehydes and secondary alcohols to ketones using dimethyl sulfoxide and oxalyl chloride, followed by reaction with triethylamine. The actual oxidizing agent is the dimethylchlorosulfonium ion, (CH3)2SC1. (To see how this compound is formed from the reactants, see Problem 77 in Chapter 17.) Propose a mechanism for the oxidation. (Hint the first step is an Sn2 reaction, the last step is an E2 reaction.)... 

A very useful group of procedures for oxidation of alcohols to ketones have been developed that involve dimethyl sulfoxide (DMSO) and any one of a number of electrophilic molecules, particularly dicyclohexylcarbodiimide, acetic anhydride, trifluoroacetic anhydride, oxalyl chloride, and sulfur trioxide. The initial work involved the DMSO-dicyclohexylcarbodiimide system.The utility of the method has been greatest in the oxidation of molecules that are highly sensitive to more powerful oxidants and therefore cannot tolerate alternative methods. The mechanism of the oxidation involves formation of intermediate A by nucleophilic attack of DMSO on the carbodiimide, followed by reaction of this species with the alcohol. A major part of the driving force for the reaction is derived from the conversion of the carbodiimide to a urea, with formation of an amide carbonyl. ... 

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