Ethers methylthiomethyl, alcohol

Methylthiomethyl ethers. Methylthiomethyl ethers have been obtained as by-products in the oxidation of alcohols with DMSO-AC2O (2,163). If HOAc is deliberately added, these ethers can become major products, even in the oxidation of sec- and ter/-alcohols, in addition to primary alcohols. This method is superior to that of Corey and Bock, which is only suitable in the case of primary alcohols (6, 109-110). 

Full details have now appeared of the general method for formation of methylthiomethyl (MTM) ethers from alcohols by treatment with DMSO in acetic anhydride containing acetic acid. These authors also report their mild cleavage method of methyl iodide in moist acetone the use of volatile reagents is advantageous as it allows easier product isolation than the previous Ag and Hg procedures. 

The methylthiomethyl (MTM) group is a related alcohol-protecting group. There are several methods for introducing the MTM group. Alkylation of an alcoholate by methylthiomethyl chloride is efficient if catalyzed by iodide ion.9 Alcohols are also converted to MTM ethers by reaction with dimethyl sulfoxide in the presence of acetic acid and acetic anhydride10 or with benzoyl peroxide and dimethyl sulfide.11 The latter two methods involve the generation of the methylthiomethylium ion by ionization of an acyloxysulfonium ion (Pummerer reaction). 

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. 

Normally, tertiary alcohols do not interfere with the oxidation of primary or secondary alcohols, although the use of a liberal quantity of reagent can lead to the formation of the methylthiomethyl ether of the tertiary alcohol, accompanying a normal oxidation of a primary or secondary alcohol.47... 

The use of a liberal quantity of reagent leads to the desired oxidation of the secondary alcohol, being accompanied by the formation of a methylthiomethyl ether on the tertiary alcohol. 

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. 

In 1965, Albright and Goldman3 demonstrated that alcohols are oxidized to aldehydes and ketones by the action of a mixture of DMSO and acetic anhydride at room temperature. Two years later,56 they presented a full paper, in which optimized conditions for this oxidation were established using yohimbine (16) as a model substrate. Thus, it was found that treatment of yohimbine with a mixture of DMSO and AC2O produces the desired oxidation to yohim-binone (17), accompanied by formation of the methylthiomethyl ether 18. 

Oxidation of the more sterically hindered axial alcohol is slower, but produces a better yield of the corresponding ketone. The less hindered equatorial alcohol produces a substantial quantity of methylthiomethyl ether. 

As mentioned earlier, the most common side reaction during oxidations with the Albright-Goldman protocol is the formation of methylthiomethyl ethers.71 The other common side reaction is the acetylation of the alcohol. These side reactions can be minimized by limiting the amount of Ac20 to about 5 equivalents56 or even less,59 or by lowering the temperature to ca. 5°C.57... 

The formation of methylthiomethyl ethers is minimized in solvents of low polarity and hindered alcohols... 

Alcohol Procedure Carbonyl (%) Trifluoroacetate ester (%) Methylthiomethyl ether (%)... 

The action of the amine over the alkoxysulfonium intermediate— ROS(+)Me2—can produce either the desired oxidation, or the generation of H2C=S(+)-Me. This compound can react with alcohols, resulting in the formation of methylthiomethyl ethers, R-0-CH2-S-Me. It can also react with other nucleophilic sites, resulting in the introduction of a methylthiomethyl group. Unhindered alcohols are particularly prone to the generation of methylthiomethyl ethers, whose formation can be difficult to avoid by adjusting reaction conditions. Nevertheless, like other Molfatt oxidations, it... 

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. 

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... 

Methylthiomethyl (MTM) ethers. These ethers (h, 109-lltY) ear he prepared by reaction of alcohols with dimethyl sulfide (8 equiv.) and dibenzoyl peroxide (4 equiv.) in CH3CN at 0° (75-90% yield). Excess dimethyl sulfide is required since some of the sulfide is oxidized to dimethyl sulfoxide. 

Cleavage of methyl ethers. Alkyl methyl ethers are converted into acetates in high yield on contact with these two reagents. Both alkyl and aryl methylthiomethyl ethers are cleaved in 60-70% yield by this system. Tertiary alcohols can be acetylated by this reaction (two examples, 90% yield)... 

Protection of tertiary alcohols,2 Methylthiomethyl (MTM) ethers have the advantage that they can be prepared from tertiary alcohols (7,135), but the disadvantage that they are prone to oxidation. They can be converted into 2-methoxyethoxymethyl (MEM) ethers, methoxy methyl (MOM) ethers, or ethoxy methyl (EOM) ethers by reaction with... 

Methylthiomethyl ethers (6, 109-110). Alcohols can be converted into these ethers in 40-95% yield by reaction with DMSO, acetic anhydride, and acetic acid at room temperature. (Higher temperatures favor oxidation of the alcohol to the ketone.) This reaction is applicable to primary, secondary, tertiary, and hindered alcohols. 

Protection of alcohols. Primary and secondary alcohols are converted into the 2-tetrahydrothienyl (THT) ethers by acid-catalyzed exchange with 1. The ethers can be cleaved quantitatively by HgCU in aqueous acetonitrile in fact the THT group is cleaved faster than the methylthiomethyl group (6, 302). 

Methylthiomethyl ethers. MTM ethers of a wide range of alcohols can be prepared in 60-80% yield by reaction of primary or secondary alcohols with chloromethyl methyl sulfide and silver nitrate in the presence of triethylamine (benzene, 20-80°). ... 

The new oxidation process has one important limitation. Allylic or benzylic alcohols are not oxidized but instead replacement of hydroxyl by chlorine is observed. Still another reaction may occur in polar media thus, methylthiomethyl ether formation becomes pronounced when methylene chloride-dimethyl sulfoxide is used as solvent. 

Trifluoroacetic anhydride (TFAA) is also a very potent activator for DMSO and concomitant trifluoroacetylation of the starting alcohol is usually not observed [27]. Both the Swem and the TFAA procedure are carried out at low temperature to prevent undesired side reactions, particularly formation of the methylthiomethyl ether. Before these two methods became developed, acetic anhydride was often used for DMSO activation. Flowever, the oxidation under these conditions is slower and the methylthiomethyl ether byproduct is often observed [27]. 

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