Methylthiomethyl ethers, formation

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. 

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. 

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... 

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. 

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... 

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... 

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... 

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. 

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]. 

Alcohol oxidations using acid anhydrides, such as acetic anhydride and benzoic anhydride, and phosphorus pentoxide with DMSO, have also been found to proceed in mild conditions to give the corresponding carbonyl compounds in good yields.27-29 The method is general and is especially useful for sterically hindered hydroxyl groups however, the reactions often suffer from concomitant formation of methylthiomethyl ether by-products. 

Formation of methylthiomethyl ethers is often observed in oxidation of alcohols by dimethyl sulfoxide-acetic anhydride. Suggest a mechanism that would account for the formation of these by-products. 

The effects of changes in the nature of the aikoxy group (equation 3) are evident in Table 2. High levels of asymmetric induction are achieved by the use of a-substituents such as methoxymethyl ether, benzyl ether, and methylthiomethyl (MTM) ether. The sterically demanding tetrahydropyranyl ether substituent, however, interferes with chelate formation, and its use generates poor selectivities. 

Like organosilyl cations stabilized by two 2-(methoxymethyl)phenyl ligands [4], 11 reacts with pyridine with transfer of a methyl group and formation of a cyclic silyl ether 17. In contrast to organosilyl cations chelated by two 2-(methylthiomethyl)phenyl ligands, a displacement of the intramolecular donors by pyridine is not possible in 12 (Scheme 3). 

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. 

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