Methyl thiomethyl ethers

The cyclization of y -hydroxy ketones is useful for the formation of pyrans,306,403 both directly and via rearrangement, as illustrated in Eq. 231.153 As with their acyclic counterparts, these cyclizations also occur with the silyl ethers of the hydroxy ketones where Et3SiH/BiBr3 is used with the TBS and TES ethers.342,404 A methyl thiomethyl ether is also capable of undergoing the reductive cyclization 405 In like manner, 1,4-diols and e-hydroxy ketones provide oxepanes, with I ds Si H or PhMe2SiH/TMSOTf being especially effective (Eqs. 232 and 233).336,406 The trimethylsilyl ether of the alcohol also provides the oxepane.306... 

Reaction of cholesterol with the reagent gives as the major product the methyl thiomethyl ether.43d The Pfitzner-Moffatt reagent gives A1-cholestenone.43d... 

Protection of primary hydroxyl groups. Sodium alkoxides (from sodium hydride) react with iodomethyl methyl sulfide at 0° in DME to form methyl-thiomethyl ethers (MTM ethers) in yields usually >86%. These ethers are stable to bases and nucleophiles (NaH, RLi, NaOR) and fairly stable to acid. Thus acetonide and THP protecting groups can be cleaved more easUy by acid than the MTM ether function. 

Weakly acidic phenols that do not react with diazomethane can be methylated with sodium hydride and methyl iodide in THF at room temperature. The methoxymethyl ether moiety can be used to protect phenols. It is stable to alkali, Grignard reagents, lithium aluminum hydride, and catalytic hydrogenation, and is readily removed by mineral acid. Dimethoxymethane can be used in lieu of the carcinogenic chloromethyl methyl ether for this purpose. Alternatively, phenols may be protected as methyl thiomethyl ethers.The (9-acetylation of phenols in the presence of primary and secondary amines can be carried out with acetyl bromide and TFA. ... 

Hydrolysis of sulfonium salts serves as a useful protocol for removal of a protecting group or hydrolysis of a carboxylic acid derivative. For example, thioamides are converted into the corresponding methyl esters by methylation with methanolic methyl iodide followed by treatment with aqueous potassium carbonate (eq 25). Methyl thiomethyl ethers are readily hydrolyzed using an excess of methyl iodide in aqueous acetone (eq 26). Under similar reaction conditions, thioacetals are hydrolyzed to the corresponding carbonyl compounds (eq 21) ... 

In a study of SRN1 photoreactions of halothiophenes with phenylthiolates anions, phenylthiothiophene radical anions are formed and the yield of the expected phenylthiothiophene product is limited by the bond rupture in this intermediate the thiophenylthiolate anion is formed and detected as thiomethyl ether after quenching of the reaction by methyl iodide. By adding benzonitrile as an extra electron acceptor, the bond rupture may be controlled and the selectivity of the reaction has been improved in favour of the thiophenyl ether but at the expense of the overall reaction rate [118]. 

In comparison to some of the other activation methods however, the dimethyl sulfoxide-acetic anhydride procedure has certain disadvantages. The method often requires the use of long reaction times (1 24 h), which can result in many side reactions, especially with sensitive substrates. Notable in this respect is that it is not uncommon for this procedure to result in the formation of substantial yields of the thiomethyl ethers obtained from the Pummerer rearrangement product as described above. In fact upon attempted oxidation of cholesterol with this system, the major product obtained was the corresponding (methylthio)methyl ether. Acetates may also be formed if the alcohol is unhindered. For example the sugar derivative (9) reacts under these conditions to form an enol acetate (derived from the requir carbonyl compound) in 40% yield contaminated with 30% of the acetate (10 equation S). ... 

A mechanism suggested for Swern-Moffatt oxidation with TFAA is shown in Scheme 8.6. In the first step, DMSO reacts with TFAA to form cationic reactive species I, which is known to be stable only below —At higher temperatures, rearrangement of I takes place to give species II. The reaction of II with an alcohol IQ upon treatment with a base leads to formation of a major by-product, trifluoroacetic acid (TFA) ester VII. Therefore, the first step should be carried out below —50 °C. In the second step, reactive species I is allowed to react with an alcohol HI at or below —50°C to obtain intermediate IV. IV may also undergo the Pummerer rearrangement to give a methyl thiomethyl (MTM) ether VI upon treatment with a base. In the third step, IV is treated with a base (usually triethylamine) to obtain the desired carbonyl compound V and dimethyl sulfide. 

An alternative to SO2 expulsion is via the intermediate tetrathiacyclophane, generated by oxidative cyclization of a tetrathiol, which upon desulfurization afforded the dithiacyclophane <01JA4704>. Subsequent methylation with (MeO)2CHBF4, followed by the Stevens rearrangement gave the ring-contracted, Ws-thiomethyl ether that was S-methylated and subjected to a Hofmann elimination affording 3, which is in a 1 20 equilibrium with 4. 

C) Preparation of 2-Methyl-3-(2,2,2-Trifluoroethyl)Thiomethyl-6-Chloro-7-Sulfamyl-3,4-Dihydro-1,2,4-Benzothiadiazine-1,1-Dioxide To 4.6 g (0.015 mol) of 4-amino-2-chloro-5-(methylsulfamyl)benzenesulfonamide in 30 ml of the dimethyl ether of ethylene glycol is added 4.08 g (0.02 mol) of 2,2,2-trifluoroethylmercaptoacetaldehyde dimethylacetal followed by 1 ml of ethyl acetate saturated with hydrogen chloride gas. The resulting solution is refluxed for 1.5 hours, cooled and then slowly added to cold water dropwise with stirring. The crude product is filtered, dried and recrystallized from isopropanol (3.2 g), MP 202° to 202.5°C. A second recrystallization from isopropanol raised the MP to 202°... 

N-Methyl-N -benzyl thiourea may be obtained by the interaetion of benzylamine and methyl iso-thioeyanate, which on methylation yields a thioenol ether. Displaeement of the eorresponding thiomethyl group by methylamine via an addition elimination process affords bethanidine whieh on treatment with an aliquot of sulphuric acid gives the official product. 

Various ether derivatives of taxol have also been prepared. Simple C-7 silyl ethers have poor in vitro cytotoxicity (148 but other ether derivatives sometimes have improved activity. Thus treatment of 2 -protected taxol derivatives with chloromethyl methyl ether followed by deprotection yields the acetal derivative 4.1.1.19 (757), while treatment of baccatin III with dimethyl sulfide in the presence of benzoyl peroxide followed by coupling with side chain gives thiomethyl derivatives such as 4.1.1.20 (158). This latter compound has been selected for development by Bristol-Myers Squibb, and is currently in clinical trials (759). Other ethers such as the amino acid derivative 4.1.1.21 have also been prepared by treatment of 4.1.1.20 with chloroacetic acid, N-iodosuccinimide, and silver triflate followed by N-methylpiperazine (158). 

Related Reagents. Methoxy(phenylthio)(trimethylsilyl)-methane (7) is prepared by metalation-silylation of phenyl-thiomethyl methyl ether.[Methoxy(phenylthio)(trimethylsilyl)-methyl]lithium (8), prepared from (7) by metalation with s-butyllithium in the presence of TMEDA, undergoes clean and efficient Peterson alkenation with aldehydes to give ( )-ketene-0,5-acetals stereoselectively, which can then be hydrolyzed to thioesters (eq 10). ... 

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