Ethers, methylthiomethyl

Methylthiomethyl ethers are quite stable to acidic conditions. Most ethers and 1,3-dithianes are stable to the neutral mercuric chloride used to remove the MTM group. One problem with the MTM group is that it is sometimes difficult to introduce. 

HgCl2, CH3CN-H2O, reflux, 10 h, 90-95% yield. Aiyl methylthiomethyl ethers are stable to the conditions used to hydrolyze primary alkyl MTM ethers (e.g., HgCl2/CH3CN-H20, 25°, 6 h). They are moderately stable to acidic conditions (95% recovered from HOAC/THF-H2O, 25°, 4 h). 

CH3CN H20 (4 1), HgCl2, 24 h, 90-94% yield. The methylthiomethyl ether group can be removed in the presence of the phenylthiomethyl ether. ... 

An authentic sample from Aldrich Chemical Company, Inc., had m.p. 45-50°. The product is analyzed by gas chromatography at 80° on F M Research chromatograph model 1810 with 3% OV-17 column, which indicates the contamination of the product by 4-ferf-butylcyclohexanol (<2%) and 4-fert-butylcyclohexyl-methyl methylthiomethyl ether (<2%).3 The submitters reported a yield of 6.0 g. (96%) of purity greater than 96%. 

Succinimide (8) 2,5-Pyrrolidinedione (9) (123-56-8) rert-Butylcyclohexylmethyl methylthiomethyl ether Cyclohexane, l-fert-butyl-4-(methylthiomethoxymethyl)- (8) Cyclohexane, 1-(l,l-dimethylethyl)-4-(methylthiomethoxymethyl)- (9) (-)... 

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. 

Using solvents of low polarity also minimizes the fonnation of methylthiomethyl ethers.6 That is why, oxidations with activated DMSO are normally carried out in CH2CI2, a solvent of low polarity possessing good solubilizing power. 

Very occasionally, solvents other than benzene, such as toluene,23 CH2CI224 or DME,25 have been used. It must be mentioned that the use of polar solvents tends to promote the formation of methylthiomethyl ethers in oxidations with activated DM SO.26 So far, pyridinium trifluoroacetate27 is the acid most commonly used, while phosphoric28 and dichloroacetic acid18 are being used less often. Acids rarely used include pyridinium tosylate,29 pyridinium phosphate30 and pyridinium chloride,31 which are normally employed in the presence of excess of pyridine. 

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 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. 

Very rarely, some quantity of methylthiomethyl ether is formed.93 It must be mentioned that the formation of methylthiomethyl ethers in oxidation with activated DMSO can be minimized by the use of low polarity solvents.117... 

This is a rare example, in which formation of a methylthiomethyl ether is reported during a... 

For an example of isolation of a methylthiomethyl ether in a Parikh-Doering oxidation see Takano, S. Sato, N. Akiyama, M. Ogasawaia, K. Heterocycles 1985,23, 2859. 

Additionally, it must be mentioned that the formation of methylthio-methyl ethers in oxidations with activated DMSO is minimized by the use of solvents of low polarity.123 Hence, the routine use of CH2CI2—which possesses a good balance of solubilizing power versus low polarity—is practiced in Omura-Sharma-Swern and MofTatt oxidations. The formation of side compounds—both trifluoroacetates and methylthiomethyl ethers—is decreased by using more diluted reaction conditions under Procedure C, while concentration has little effect on the yield in oxidations performed under Procedure A.124... 

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. 

As in other Moffatt oxidations, a Corey-Kim oxidation may produce minor amounts of methylthiomethyl ethers. These can be minimized by using a solvent of low polarity, like toluene.248a Nonetheless, very often dichloromethane is used, because of its better solubilizing power. Almost always triethylamine is used as base. 

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... 

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