Oxalyl chloride, and DMSO

One example is Swern oxidation, which uses oxalyl chloride and DMSO and is particularly suitable for the selective oxidation of alcohols to aldehydes or ketones. The disadvantages of this oxidation method are the need for low temperatures, the smell of the dimethyl sulfide formed and the possible oxidation of other heteroatoms. Dess-Martin periodinane (DMP, 5) or iodoxybenzoic acid (IBX, 6) are also common oxidizing agents. The main advantage of these two methods is the short reaction time at room temperature. However, typical problems are the low solubility of IBX and the formation of byproducts. In this context, Finney et al. have reported an interesting procedure avoiding these problems by a variation of the temperature IBX is sufficiently soluble in solvents such as ethyl acetate or dichloromethane at elevated temperatures, whereas it is insoluble in these solvents at room temperature. Because of this, the remaining IBX as well as the IBX-derived byproducts can be separated from the reaction mixture by simple filtration. These reisolated IBX byproducts can then be reoxidized and reused. 

Swern oxidations have been performed using the PEG2000 bound sulfoxide 34 as a dimethylsulfoxide (DMSO) substitute (reaction 13).49-50 Several alcohols were efficiently oxidized to their aldehydes or ketones using this reagent, oxalyl chloride, and triethylamine. Precipitation of the polymer with cold diethyl ether and filtration through a pad of silica afforded the desired oxidized products in very good yields and purities. The reduced sulfide polymer could be reoxidized to sulfoxide 34 with sodium metaperiodate and used again in reactions with no appreciable loss in oxidation capacity. 

Another total synthesis of sufentanil has been described the cyclization of 2-(2-thienyl)ethylamine with allyl-trimethylsilane and formaldehyde gives 4-hydroxy-1-[2-(2-thienyl)ethyl]piperidine, which is oxidized with oxalyl chloride in DMSO/dichloromethane to 1-[2-(2-thienyl) ethyl]piperidin-4-one. The epoxidation of this compound by means of trimethylsulfonium iodide and the sodium salt of DMSO yields the spiro-epoxide, which is opened with... 

Ihis mild procedure utilizes DMSO as the oxidizing agent DMSO initially reacts with oxalyl chloride, and subsequent elimination of carbon dioxide, carbon monoxide, and chloride results in the acti... 

The decomposition of acid-sensitive substrates during Swern oxidations can also be explained by the presence of adventitious hydrogen chloride. This can be avoided by the use of freshly distilled oxalyl chloride and carefully dried DMSO.174... 

As traces of HC1 promoted the decomposition of the starting compound, adventitious HC1 had to be carefully excluded during the Swern oxidation, by using freshly distilled oxalyl chloride and carefully dried DMSO. 

Protecting groups that are cleaved by an oxidant, like p-methoxyben-zyl201 and dimethoxybenzyl202 ethers or p-methoxybenzylidene203 and dimethoxybenzylidene204 acetals, resist the action of oxalyl chloride-activated DMSO. 

The protected methyl glycoside 3 is converted to the corresponding aldehyde by Swern oxidation using oxalyl chloride activated DMSO. Further reaction with triethyl phosphonoacetate and sodium hydride -known as the Horner-Wadsworth-Emmons reaction - provides selectively the trans et /Tun saturated ester 4 in 72 % yield. This valuable alternative to the Wittig olefination protocol uses phosphonate esters as substrates which are readily available from alkyl halides and trialkyl phosphites via the Arbuzov rearrangement.9 co2Et Reaction of the phosphonate with a suitable base gives the... 

In this subsection we want to consider oxidations that employ dimethyl sulfoxide (DMSO) as the oxidizing reagent. These oxidations, which almost always are carried out in the presence of first oxalyl chloride and then NEt3, are referred to as Swern-oxidations. The mechanism of this reaction is known in detail (Figure 17.13). In the prelude, the O atom of DMSO acts as... 

In the Swern oxidation, the reaction of oxalyl chloride with DMSO may generate chlorodimethylsulfonium chloride (A), which reacts with the alcohol to give alkoxysulfonium ion intermediate B. The base, typically triethylamine, deprotonates the alkoxysulfonium ion B to give the sulfur ylide C, which decomposes to give DMS and the desired aldehyde or ketone (Scheme 7.7). The temperature of this reaction is kept near —60 to -78°C. 

In a typical example, 10 mmol of an alcohol, 11 mmol of oxalyl chloride, and 24 mmol of DMSO in 40 mL of dichloromethane react at -60 °C. The mixture is then made alkaline with 50 mmol of triethylamine [1023] (equation 262). In other instances, the molar ratios of the alcohol to DMSO and to the activator (benzoic anhydride) were 1 47 and 1 17, respectively with phosphorus pentoxide as the activator, the respective molar ratios were 1 47 and 1 1 [1009], and with pyridine-sulfur trioxide, they were 1 70 and 1 3 [1018]. Dichloromethane and toluene [1012] are the best solvents. 

This is a good point to introduce some of the organic applications of higher-valent sulfur compounds. Dimethyl sulfoxide (DMSO) is well known in this regard it is not only an important polar, aprotic solvent but is also used to oxidize primary and secondary alcohols to the corresponding carbonyl compounds in a number of synthetic reactions, of which the Swern oxidation is the most important. The reagents used in the Swern oxidation are DMSO, oxalyl chloride, and an organic base such as triethylamine ... 

Introduction. The combination of DMSO, oxalyl chloride, and trlethylamlne (TEA) (Swem oxidation ) has been widely used for the oxidation of primary alcohols to aldehydes and secondary alcohols to ketones due to the mild reaction conditions and the tolerance of a broad range of functional groups (eq 1). However, the malodorous dlmethylsulfide (DMS) derived from DMSO makes the Swem oxidation unpleasant to conduct, especially on a large scale. Reagent 1 is designed as an alternative to DMSO by attaching a fluorous alkyl chain to one of the methyl groups. The introduction of the fluorous portion has two important consequences. 

One of the most used alcohol oxidations in organic synthesis is the Swern oxidation. A large number of variants exist for this reaction, but a common one involves DMSO, oxalyl chloride, and a base (pyridine, dimethylaminopy-ridine, and triethylamine are common). The currently accepted mechanism is shown below along with electron pushing for some steps. The first part of the mechanism involves activation of DMSO by reaction with oxalyl chloride. This is followed by nucleophilic attack of the alcohol on this activated species, creating an alkoxysulfonium intermediate. 

Oxidation of primary and secondary alcohols to aldehydes and ketones with DMSO, oxalyl chloride, and a base is knovm as Swem-oxidation. When using oxalyl chloride as the dehydration agent, the reaction must be kept colder than —60°C to avoid side reactions, such as Pummerer rearrangement. In contrast, when trifluoroacetic anhydride is used instead of oxalyl chloride, the reaction can be warmed to —30 °C without side reactions. Microflow systems offer a smart approach for controlling the 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. ... 

DMSO or other sulfoxides react with trimethylchlorosilanes (TCS) 14 or trimefhylsilyl bromide 16, via 789, to give the Sila-Pummerer product 1275. Rearrangement of 789 and further reaction with TCS 14 affords, with elimination of HMDSO 7 and via 1276 and 1277, methanesulfenyl chloride 1278, which is also accessible by chlorination of dimethyldisulfide, by treatment of DMSO with Me2SiCl2 48, with formation of silicon oil 56, or by reaction of DMSO with oxalyl chloride, whereupon CO and CO2 is evolved (cf also Section 8.2.2). On heating equimolar amounts of primary or secondary alcohols with DMSO and TCS 14 in benzene, formaldehyde acetals are formed in 76-96% yield [67]. Thus reaction of -butanol with DMSO and TCS 14 gives, via intermediate 1275 and the mixed acetal 1279, formaldehyde di-n-butyl acetal 1280 in 81% yield and methyl mercaptan (Scheme 8.26). Most importantly, use of DMSO-Dg furnishes acetals in which the 0,0 -methylene group is deuter-ated. Benzyl alcohol, however, affords, under these reaction conditions, 93% diben-zyl ether 1817 and no acetal [67]. 

Whereas the original Moffat-Pfitzner oxidation employs dicyclohexylcarbodiimide to convert DMSO into the reactive intermediate DMSO species 1297, which oxidizes primary or secondary alcohols via 1298 and 1299 to the carbonyl compounds and dicyclohexylurea [78-80], subsequent versions of the Moffat-Pfitzner oxidation used other reagents such as S03/pyridine [80a, 83] or oxalyl chloride [81-83] to avoid the formation of dicyclohexylurea, which is often difficult to remove. The so-called Swern oxidation, a version of the Moffat-Pfitzner oxidation employing DMSO/oxalyl chloride at -60°C in CH2CI2 and generating Me2SCl2 1277 with formation of CO/CO2, has become a standard reaction in preparative organic chemistry (Scheme 8.31). 

When there is no diluent, organic acid chlorides and metal halides react very violently with DMSO. This goes for acetyl chloride, benzenesulphonyl (C6H5SO2CI), cyanuryl chloride, phosphorus and phosphoryl trichlorides, tetrachlorosilane, sulphur, thionyl, and sulphuryl chlorides. With oxalyl chloride, the reaction is explosive at ambient temperature, but can be controlled at -60°C in a solution with dichloromethane. The dangerous reactions are thought to be... 

Several laboratories have reported that Swern oxidation of alcohols can be accompanied of a-chlorination of keto or (1-keto ester groups. Undesired electrophilic chlorination can be avoided by use of oxalyl chloride (1.05 equiv.) and DMSO (2.5 equiv.) in stoichiometric amounts or by use of acetic anhydride or trifluoroacetic anhydride in place of oxalyl chloride.1... 

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