Alcohols activated DMSO

The initiating step in these reactions is the attachment of a group to the sulfoxide oxygen to produce an activated intermediate (5). Suitable groups are proton, acyl, alkyl, or almost any of the groups that also initiate the oxidations of alcohols with DMSO (40,48). In a reaction, eg, the one between DMSO and acetic anhydride, the second step is removal of a proton from an a-carbon to give an yUde (6). Release of an acetate ion generates the sulfur-stabilized carbonium ion (7), and the addition of acetate ion to the carbonium ion (7) results in the product (eq. 15) ... 

AtCCD7 (Schwartz et al. 2004). Organic solvent addition (dioxane, DMSO, methanol or acetone) improved activity under low concentrations (Mathieu et al. 2007). Short chain aliphatic alcohols activated the enzymes although the reason for this activation is unclear (probably due to influences on substrate accessibility or micellar structure). An increase in activity was observed for all aliphatic alcohols tested, although the optimal concentration lessened with increasing log P values (Schilling etal. 2007). 

An interesting consequence of the fast formation of the chromic ester is that, sometimes, chromium-based oxidants counter-intuitively are able to oxidize quicker alcohols possessing a greater steric hindrance, as the initially fonned chromic ester releases greater tension on evolving to a carbonyl. Thus, axial alcohols are oxidized quicker than equatorial ones with chromic acid.6 The reverse—a somehow expected behavior—is observed, for example in oxidations with activated DMSO.7... 

The activated DMSO 9 can also suffer an elimination, resulting in the highly reactive H2C=S(+)-CH3 species that can react with the alcohol, yielding a methylthiomethyl ether 13 as a side compound. Fortunately, this elimination demands a higher temperature than the normal temperature of oxidation, and a proper control of the temperature minimizes the formation of the methylthiomethyl ether side compound. 

Corey and Kim described an oxidation,6a in which activated DMSO is not generated by activation of DMSO, but by oxidation of dimethyl sulfide. Although, they described only the use of chlorine and /V-chlorosuccinimidc as dimethyl sulfide oxidants, we propose that the name Corey-Kim oxidations be applied to alcohol oxidations, in which activated DMSO is generated by oxidation of dimethyl sulfide, regardless of the oxidant employed. 

Sometimes, small amounts of methylthiomethyl ethers of primary or secondary alcohols are isolated. As these ethers originate from H2C=S(+)-Me, formed by decomposition of activated DMSO that needs relatively high temperature, it is expected that lowering the reaction temperature would minimize the formation of these side compounds.48... 

The oxidation of the primary alcohol leads to an aldehyde that is isolated as an aminal. Minor amounts of a methylthiomethyl ether are isolated, resulting from the reaction of the alcohol with CH2=S(+)-Me that is formed by thermal decomposition of activated DMSO. Interestingly, a Swern oxidation fails to deliver the desire product, because it causes the chlorination of the indole. 

The less hindered primary alcohol reacts selectively with activated DMSO, resulting in the formation of an intermediate alkoxydimethylsulfonium salt. This intermediate, instead of evolving as usual to an aldehyde, produces a cyclic ether by an intramolecular displacement, in which DMSO acts as a good-leaving group. 

The use of trifluoroacetic anhydride for the activation of DMSO in the oxidation of alcohols was first attempted by Albright and Goldman in 196 5.119,120 According to these authors, who tried the reaction at room temperature, trifluoroacetic anhydride is not effective in the activation of DMSO. Later, Swern et al. made a detailed study of the interaction of DMSO with TFAA,121 and proved that the resulting activated DMSO is stable at low temperature and can be used in the oxidation of alcohols. In... 

This form of activated DMSO is stable below —30°C, but suffer a Pummerer rearrangement above this temperature, resulting in the formation of methylthio-methyl trifluoroacetate (23). In fact, compound 23 reacts with alcohols in the presence of an amine, resulting in a very quick trifluoroacetylation. However, this trifluoroacetylation pathway is not operative in a properly perfonned Omura-Sharma-Swem oxidation, because alcohols are previously transfonned in afkoxy-dimethylsulfonium salts 24. 

Interestingly, although trifluoroacetic anhydride reacts very quickly with alcohols, the reaction with DMSO is even quicker. Therefore, the formation of the activated DMSO species 22 can be made in the presence of the alcohol, resulting in little erosion of the oxidation yield. 

Interesting modifications of the standard Procedure A include, allowing a prolonged reaction—till 90 min—of activated DMSO 22 with the alcohol at low temperature, in order to make sure the complete formation of the alkoxysulfonium intermediate 24,126 and performing the final steps at ca. — 78°C127 or 0°C128 rather than at room temperature. 

Quite remarkably, although TFAA-activated DMSO is decomposed above —30°C, there is one published report of successful oxidation, in which TFAA is added over a solution of DMSO and the alcohol, kept at —20°C.125 This oxidation succeeds apparently, because at this temperature, TFAA-activated DMSO suffers decomposition slower than conversion into an alkoxysulfonium salt by attack of the alcohol. 

Nucleophiles, other than alcohols, can react with the TFAA-activated DMSO molecule—F3CC02-S(+)Me2—, indoles being particularly prone to do so. 

Few oxidation methods have enjoyed the almost immediate success of the Swern procedure for the oxidation of alcohols. Since the publication of three foundational papers161 in 1978-79, Swern has become the de facto oxidation method by default whenever activated DMSO is desired. It offers the advantage of quite consistent good yields in many substrates, with an operation performed under very low temperature and mild conditions. Swern s procedure consists of the oxidation of an alcohol using DMSO, activated by reaction with oxalyl chloride. According to Swern, oxalyl chloride is the most effective activator of DMSO examined by his group.162 It must be mentioned that Swern s research team is probably the one that has tried the highest number of DMSO activators for the oxidation of alcohols. 

During a Swern oxidation, after the formation of the activated DMSO molecule 30, the alcohol is added at low temperature. The alcohol reacts very quickly with activated DMSO, resulting in the formation of an alkoxydi-methylsulfonium chloride (32). 

According to the standard protocol (procedure A) as described by Swern et at., the alcohol is allowed to react with activated DMSO for 15 min at low temperature (normally —78 to —50°C). This is followed by the addition of triethylamine, which reacts with the activated alcohol, while the reaction is left to reach room temperature. This standard protocol, involving the generation of activated DMSO in CH2C12 at low temperature (ca. -60°C), followed by activation of the alcohol for 15 min, addition of triethylamine and after 5 min allowing the reaction to heat up slowly to room temperature, is found suitable for most substrates. However, some variations have been introduced to suit the oxidation of diverse alcohols. 

Interestingly, oxalyl chloride reacts quicker with DMSO than alcohols. Therefore, although not common,164 it is possible to generate an activated alcohol by the addition of oxalyl chloride over a mixture of alcohol and DMSO. 

For experimental convenience, it may be advisable to carry out the reaction at a maximum temperature. As the activated DMSO molecule— compound 30—decomposes above -20°C, it is not possible to use a temperature much higher than this one. On the other hand, the stability of the activated alcohol species 32, being very diverse depending on the concrete... 

As activated DMSO and activated alcohols have a certain acidity, a prolonged alcohol activation before the addition of base may cause decomposition of very acid-sensitive functionalities. 

Triethylamine must be added immediately after mixing the alcohol and activated DMSO, in order to avoid the aeid-catalyzed cleavage of a very sensitive acetal. 

Tertiary alcohols react with activated DMSO, yielding an activated alcohol, that, as it lacks an a-hydrogen, is not able to evolve to a carbonyl compound. Nevertheless, when a (3-hydrogen is present, elimination to an alkene can occur under the action of a base.219... 

The desired oxidation of the alcohol was accompanied by a-chlorination of the cyclohexanone. The chlorination could be avoided by using a stoichiometric amount of activated DMSO, or by activating the DMSO with acetic anhydride. 

Sometimes, the transformation of allylic alcohols into chlorides, by the action of activated DMSO, is so quick that it competes with a normal oxidation.234... 

The surplus activated DMSO, which remains unreacted after the activation of the alcohol during a Swern oxidation, decomposes on heating, generating the highly reactive species H2C=S(+)-Me (page 97). This species can react with tertiary alcohols present in the molecule, resulting in the formation of a methylthiomethyl ether.237... 

This is a rare case of methylthiomethylation of a primary alcohol during a Swern oxidation. A primary neopentilic alcohol, quite resistant to reaction, was treated under Swern conditions at the temperature of - 10°C. At this temperature, a substantial decomposition of activated DMSO occurred during the activation of the alcohol, resulting in the formation of H2C=S(+)-Me that produced the generation of the methylthiomethyl ether side compound. 

This is a rare case in which a 1,5-diol is transformed into a lactone by a Swern oxidation. The oxidation of the primary alcohol into an aldehyde is followed by the formation of a lactol by attack of the tertiary alcohol. At this point, in spite of the presence of Et3N, enough activated DMSO is present for the activation of the hydroxy group in the lactol and... 

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. 

Similar to other Moffatt oxidations, the Corey-Kim method results sometimes in the generation of methylthiomethyl ethers by reaction of alcohols with H2C=S(+)-Me, resulting from decomposition of activated DMSO.259... 

Other Alcohol Oxidations Using Activated DMSO... 

Almost any electrophile, able to react with DMSO, can generate an active DMSO species that can be used for the oxidation of alcohols. Dozens of such activators have been described in the literature as shown in Table 2.2. Many of these activators have been the subject of very superficial analyses and, therefore, their potential for Moffatt oxidation of alcohols is not known in detail. Some of these activators particularly... 

Some standard alcohol oxidants that may not have been originally devised for selective oxidations are able, in favourable substrates, to oxidize secondary alcohols in the presence of primary ones.1 Thus, cases are known in which Corey-Kim oxidation,2 TFAA-activated DMSO,lb Collins reagent2 or PDClb show a certain preference for the oxidation of secondary alcohols. 

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