The Swern Oxidation

The Swern oxidation was also employed by Davis and McCoull [251 for the synthesis of 2iT-azirinephosphonates 27 and 28 from the corresponding aziridines 26 (Scheme 14). Interestingly, in this case a mixture of the regioiso-meric azirines is obtained, whereby the proton abstraction adjacent to the phos-... 

Preparatively useful procedures based on acetic anhydride,25 trifluoroacetic anhydride,26 and oxalyl chloride27 have been developed. The last method, known as the Swern oxidation, is currently the most popular. 

Acyl nitroso compounds (3, Scheme 7.2) contain a nitroso group (-N=0) directly attached to a carbonyl carbon. Oxidation of an N-acyl hydroxylamine derivative provides the most direct method for the preparation of acyl C-nitroso compounds [10]. Treatment of hydroxamic acids, N-hydroxy carbamates or N-hydroxyureas with sodium periodate or tetra-alkyl ammonium periodate salts results in the formation of the corresponding acyl nitroso species (Scheme 7.2) [11-14]. Other oxidants including the Dess-Martin periodinane and both ruthenium (II) and iridium (I) based species efficiently convert N-acyl hydroxylamines to the corresponding acyl nitroso compounds [15-18]. The Swern oxidation also provides a useful alternative procedure for the oxidative preparation of acyl nitroso species [19]. Horseradish peroxidase (HRP) catalyzed oxidation of N-hydroxyurea with hydrogen peroxide forms an acyl nitroso species, which can be trapped with 1, 3-cyclohexanone, giving evidence of the formation of these species with enzymatic oxidants [20]. 

Oxalyl chloride (98%) was purchased from Aldrich Chemical Company, Inc., and used without further purification. Amounts of reagents for the Swern oxidation have been optimized as reported. Alternative amounts reduce both yield and % ee. 

The Swern oxidation is a preparatively important reaction which allows for the oxidation of primary and secondary alcohols 1 to aldehydes and ketones 2, respectively, under mild conditions, using activated dimethyl sulfoxide (DMSO) as the oxidizing agent. 

Further oxidation of an aldehyde prodnct to the corresponding carboxylic acid does not take place. Moreover, the Swern oxidation reaction does not reqnire the nse of toxic and pollntant chromium reagents. The activated DMSO species, however, are stable only at low temperatnre, which might in some cases be a drawback of this method. 

All of the usual chromium-based oxidation reagents that have been used for the oxidation of cyclobutanols to cyclobutanones, for example, chromium(VI) oxide (Jones reagent),302 pyri-dinium chlorochromate,304 pyridinium dichromate,307 and chromium(YI) oxide/pyridine (Collins),303 are reported to do so without any serious problems. Alternatively, tetrapropylam-monium perruthenate in the presence of A-methylmorpholine A -oxide. oxalyl chloride in the presence of triethylamine in dimethyl sulfoxide (Swern),158,309,310 or phenyl dichlorophos-phate in the presence of triethylamine and dimethyl sulfoxide in dichloromethane (Pfitzner-Moffatt),308 can be used. The Pfitzner-Moffatt oxidation procedure is found to be more convenient than the Swern oxidation procedure, especially with respect to the strict temperature control that is necessary to achieve good yields in the latter, e.g. oxidation of 1 to give 2.308... 

Triflouroacetic anhydride was used before oxalyl chloride and is also known as the Swern Oxidation. Acetic anhydride can also be used. (Albright-Goldman Oxidation)... 

No yield provided however, it was reported that this process was not as effective as the Swern Oxidation. 

The Parikh-Doering oxidation is conveniently carried out at room temperature or moderately cool temperature. The activator—SO3 Py— generates side compounds that are very easily removed during the workup. In variance with other oxidations involving activating DMSO, the Parikh-Doering oxidation rarely delivers substantial amounts of methylthiomethyl ether side compounds.93 Unlike the Swern oxidation, no chlorinated side compounds are possible. 

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. 

The Swern oxidation shows a great regioselectivity for the oxidation of alcohols, in the presence of other functionalities with a high sensitivity for oxidants. For example, sulfides, thioacetals, disulfides (see page 146) and even selenides200 resist the action of Swern oxidation. 

The Swern oxidation of homoallylic alcohols leads to a (3,y-unsaturated carbonyl compound, which sometimes suffers an in situ base-induced isomerization of the alkene into conjugation with the carbonyl group.239... 

Although the Corey-Kim oxidation is not used as often as the Swern oxidation—probably because of the bad odour of dimethyl sulfide—it offers the advantage of allowing an operation above -25°C. Typically, NCS (A-chlorosuccinimide) and Me2S are mixed in toluene at 0°C, resulting in the formation of a precipitate of activated DMSO. The reaction mixture is cooled to ca. —25°C and the alcohol is added for activation. This is followed by addition of Et3N and allowing the reaction to reach room temperature. 

The activation of DMSO by electrophilic reagents such as oxallyl chloride or trifluoroacetic anhydride (TFAA) (among many others) produces an oxidant capable of oxidizing primary alcohols to aldehydes in high yields. This oxidation is called the Swern oxidation and yields the aldehyde (oxidized product) by reductive elimination of dimethylsulfide (reduced product) and proceeds under mild, slightly basic conditions. It is a second widely used and effective oxidative method for the production of aldehydes from primary alcohols. 

The Swern oxidation of isopropenyl-substituted cyclopropylcarbinols (Scheme 26) results in ring expansion to respective methyldihydrooxepines <1997BCJ2215>. The experimental parameters of the hetero-Cope... 

In the first step Crimmins and co-workers used the Swern oxidation protocol to provide a ketone as prochiral, sp2-center. 

Fig. 17.13. Mechanism of the Swern oxidation of alcohols. The actual reagent is an "activated DMSO" (compound B or D), which reacts with an alcohol with formation of A or C, respectively. Dissociation leads to the sulfonium salt E, which is then converted into the sulfonium ylide F after NEt3 addition and raising the temperature from -60 to -45 °C. /3-Elimination via a cyclic transition state generates the carbonyl compound and dimethyl sulfide from F.

Ube Industries LtdinYamaguchi, Japan, and Kyoto University investigated the Swern oxidation for pharmaceutical intermediates [57,58]. In this reaction, alcohols are oxidized to carbonyl compounds using dimethyl sulfoxide. The reaction variant using dimethyl sulfoxide activated by trifluoroacetic anhydride (shown below) has found industrial application, but is limited to low-temperature operation (—50 °C or below) to avoid decomposition of an intermediate. 

The Swern oxidation uses dimethyl sulfoxide (DMSO) as the oxidizing agent to convert alcohols to ketones and aldehydes. DMSO and oxalyl chloride are added to the alcohol at low temperature, followed by a hindered base such as triethylamine. The reactive species (CH3)2SC1, formed in the solution, is thought to act as the oxidant in the Swem oxidation. Secondary alcohols are oxidized to ketones, and primary alcohols are oxidized only as far as the aldehyde. The by-products of this reaction are all volatile and are easily separated from the organic products. 

In Chapter 24 we mentioned the Swern oxidation briefly as an excellent method of converting alcohols to aldehydes. We said there that we would discuss this interesting reaction later and now is the time. The mechanism is related to the reactions that we have been discussing and it is relevant that the Swern oxidation is particularly effective at forming enals from allylic alcohols, the Swern oxidation... 

In our procedure methyl ester 3 is obtained by the McKillop method.2 Conditions and yields of steps A and B are essentially identical to those reported by McKillop. The reduction of crude 3 with lithium aluminum hydride (step C) to the alcohol 4 was essentially quantitative. Also this isolated compound did not require any purification for use in the next oxidation step (D). This was carried out by the Swern oxidation method12 using DMSO and (COCI)2 in the presence of a base. This crucial operation where Roush obtained considerable racemization of the resulting amino aldehyde 5, was carried out in the presence of diisopropylethylamine13 (Hunig s base). This simple yet important modification provided 5 in good yield (79-85% from 1) and enantiomeric purity (96-98%) comparable to that reported by Garner. 

A common synthetic route of dihydrooxepins is based on the interconversions between cA-Z-vinylcyclopropanecarbox-aldehyde 269 and 2,5-dihydrooxepin 270 <1969JA2813> and m-l,2-divinyloxirane 271 and 4,5-dihydrooxepin 272 (Scheme 143) <1963JOC1383, 1999J(P1)605>. For example, the Swern oxidation of isopropenyl-substituted cyclo-propylcarbinols 273 (Scheme 144) results in ring expansion to respective methyldihydrooxepins via the intermediate vinylcyclopropanecarboxaldehyde 274 . 

But the Pfitzner-Moffatt oxidation is not in much use because the Swern oxidation gives better yield and fewer side products. For example, methyl 12-hydroxydodecanoate (7.11) on treatment with DMSO and oxalyl chloride [(COCl)2] in CF12C12 followed by treatment with triethylamine yields 87% methyl 12-oxododecanoate (7.12). 

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. 

The disadvantage of the Swern oxidation is the formation of side products from the Pum-merer rearrangement (see section 1.6.1, Scheme 1.26). To avoid the side reactions in the Swern oxidation, the temperature is kept at -78°C, but when trifluoroacetic anhydride instead of oxalyl chloride is used the reaction can be warmed to -30° C. The use of diisopropylamine as a base stops side reactions. 

The variation of the Swern oxidation is the Corey-Kim oxidation Treatment of DMS (Me2S) with CI2 or N-chlorosuccinimide (NCS) forms dimethylchlorosulfonium ion (A), which reacts with alcohol to form sulfoxonium complex B. Treatment of sulfoxo-nium complex B with a base Et3N gives the corresponding aldehyde or ketone via ylide C (Scheme 7.8). 

Similarly, when dodecyl methyl sulfoxide (C12H25SOCH3) is used in the Swern oxidation, the odourless Dod-S-Me by-product instead of foul-smelling DMS is formed. 

A chiral phosphonate-substituted azirine was prepared and its Diels-Alder reactions studied <20020L655>. Azirine 105 is prepared by the Swern oxidation of the corresponding aziridine as shown in Scheme 18. The Diels-Alder reaction of azirine 105 with Danishefsky s diene provides aziridine 106 in excellent yield as a single diastereomer. Note that the reaction time for azirines such as used by Gilchrist is only 15 min as compared to 8h with the phosphonate substituted azirines suggesting that the carboxylate-substituted azirines are much more reactive than the phosphonate-substituted azirines <19978271, 2001J(P1)2969, 2005S555>. 

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). 

Nucleophilic Attack at Halogen. This field of activity continues to be dominated by applications of well-known phosphine-positive halogen combinations. Alcohols can be oxidised to the related aldehydes and ketones under mild conditions by the DMSO-Ph3PX2 system, which provides an alternative to the Swern oxidation." The triphenylphosphine-iodine system has been... 

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