Methylthiomethyl acetate

A 1,3-dithiane is stable to the conditions (HgCl2, CaC03, CH3CN-H2O, 25°, 1-2 h) used to cleave a methylthiomethyl (MTM) ether (i.e., a mono-thio acetal). ... 

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). 

Potassium nitrosodisulfonate, 258 Trimethylsilyl chlorochromate, 327 By hydrolysis of acetals or thioacetals Amberlyst ion-exchange resin, 152 Methylthiomethyl p-tolyl sulfone, 192 By isomerization of allylic alcohols N-Lithioethylenediamine, 157 By oxidation of aromatic side chains Trimethylsilyl chlorochromate, 327 From oxidative cleavage of alkenes [Bis(salicylidene-7-iminopropyl)-methylamine]cobalt(II)... 

Methylthiomethyl p-tolyl sulfone, 192 Potassium ruthenate, 259 Trimethylsilyl chlorochromate, 327 a-Substituted ketones (see also Halo carbonyl compounds, Hydroxy aldehydes and ketones) a-Acetoxy ketones Benzeneselenenyl chloride-Silver acetate, 27... 

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. 

Like their 5,5-acetal counterparts, the 0,5-acetals can be hydrolysed after 5-alkylation [Scheme 2.99]197 or mercury(Il) catalysis [Scheme 2.100].lw In the latter case, the selective destruction of the methylthiomethyl ether (see section 4.6) in the presence of a dithiane bears witness to the enhanced lability of 0,5-acetals, Under similar conditions an 0.5-acetal can be cleaved in the presence of a dioxolane.199 For a comprehensive list of reagents and conditions for cleaving 0,5-acetals, the interested reader should consult the review by Wimmer. ... 

Methylthiomethyl ethers are comparable in stability to alkoxymethyl ethers towards strongly basic conditions or mild acid. For example, methylthiomethyl ethers survive aqueous acetic acid under conditions that hydrolyse TBS ethers, dioxolanes or tetrahydropyranyl protectors. They can be removed under rather specific and mild conditions that do not affect most acetal-type protectors such as MEM. MOM. etc. (see above). The presence of the sulfur makes this group liable to oxidation by strong oxidants such as peracids. Cr(VI), and N-bromo-succinimide, and it will poison Pd catalysts. The methylthiomethyl group was First introduced by Corey and co-workers586 and its virtues exploited by them in a synthesis of the antibiotics Erythronolide587 588 and Brefeldin.589... 

Methylthiomethyl ethers, like most 0,5-acetals, are stable to aqueous acid, but they can be removed under essentially neutral conditions in the presence of heavy metal catalysts with a high affinity for sulfur such as mercury(Il) or silver ), Typically, the substrate is treated with mercury(II) chloride in acetoni-trile-H20 (4 1) at room temperature or slightly above.586 With acid-sensitive... 

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)... 

The methylthiomethyl ether (MTMOR) Tertiary hydroxyl groups, which are susceptible to acid-catalyzed dehydration, can be easily protected as MTM ethers and recovered in good yield. The MTM ether of a hydroxyl group can be formed either by a typical Williamson ether synthesis or on reaction with dimethylsulfoxide (DMSO) and acetic anhydride (AC2O). In the latter case, the reaction proceeds with the Pummerer rearrangement " (Scheme 1.25). 

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. 

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]. 

Appropriate alkyl iodides or bromides were reacted with 57 and 2-epi-Sl in the presence of Ag20 in CH3CN with yields ranging from 36 to 77% (74, Scheme 10) [34, 51]. However, with these conditions preparation of branched alkyl ethers was unsuccessful [51]. Reacting 57 with chloromethyl methyl ether, diisopropylethy-lamine, and catalytic DMAP in CH2CI2 afforded 75 in a 72% yield and was the first 1 derivative reported to have increased affinity at the KOP receptor relative to 1. [41, 52]. Based on the successful increase in affinity of derivative 75, additional simple alkoxymethyl ethers were obtained using appropriate alkyoxymethyl chloride with diisopropylethylamine in DMF (76-78). However, more complex alkoxymethyl derivatives were synthesized from the common methylthiomethyl ether intermediate (79), which was obtained from reaction of 57 with acetic acid, acetic anhydride, and dimethylsulfoxide (DMSO) [52]. Compound 79 was then... 

The reaction of thiols with alkyl halides produces sulfides, which are converted into sulfonium halides in the presence of excess alkyl halides.2680 Dimethyl sulfoxide (42) and acetic anhydride (41) react with starch365 to cause oxidation at the C-3 and C-6 positions, and methylthiomethyl ethers are formed at 0-6, according to the following reaction (43-46) ... 

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. 

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