Methoxymethylation of Alcohols

Methoxymethylation of alcohols is generally achieved through alkylation with chloromethyl methyl ether. The procedure described here for the preparation of Bu3SnCH20CH20CH3 avoids the use of the highly toxic chloromethyl ether by employing an acid-catalyzed acetal exchange reaction with dimethoxymethane for the... 

K. Luji, S. Nakano, and E. Lujita, An improved method for methoxymethylation of alcohols under mild acidic conditions, Synthesis (1975) 216-211. 

Methoxymethyl ethers. Methoxymethylation of alcohols can be carried out in high yield by reaction with methylal at 25° in chloroform catalyzed by phosphorus pentoxide. These ethers are preferable to tetrahydropyranyl ethers... 

Niknam, K., Zolfigol, M.A., Khorramabadi-Zad, A., Zare, R. and Shayegh, M. 2006. Silica sulfuric acid as an efficient and recyclable catalyst for the methoxymethylation of alcohols under solvent-free conditions. Catal. Commun. 7(7) 494—498. 

The use of polymer-supported bismuth catalysts for organic synthesis is highly attractive since this approach combines the advantages of the relative nontoxicity of bismuth salts with their easy separation and recyclability after reaction [131]. For example, microencapsulated Bi(0Tf)3 xH20 in polystyrene has been successfully reported for the methoxymethylation of alcohols, allylation of aldehydes, Michael-type and aldol reactions as well as Baeyer-Villiger oxidations [132]. 

Bismuth triflate also catalyzes methoxymethylation of alcohols, and carboxylic acids with dimethoxymethane in acetonitrile under reflux conditions (Equation (8.13)). This reaction affords corresponding ethers and carboxylic esters in good to excellent yields for a variety of structurally divergent substrates. Following this route a wide range of methoxymethyl ethers can be produced from corresponding alcohols and carboxylic acids in good yields and shorter reaction times, and under mild conditions [32]. 

Methoxymethylation of alcohols under mildly acidic conditions. 

Again, the activity of Nafion-H in the above protection processes (transformation of alcohols to THP ethers672 and methoxymethyl ethers679) is lower, and consequently, longer reaction times and elevated temperatures are required to achieve yields comparable to those over Nafion nanocomposites. Obviously, this is due to the low specific surface area and low accessibility of the active sites of Nafion-H as compared with Nafion SAC-13. 

This procedure consists of the synthesis of a precursor, methoxymethyl vinyl ether, an a-hydroxy enol ether, and the intramolecular hydrosilylatlon of the latter followed by oxidative cleavage of the silicon-carbon bonds. The first step, methoxymethylation of 2-bromoethanol, is based on Fujita s method.7 The second and third steps are modifications of results reported by McDougal and his co-workers. Dehydrobromination of 2-bromoethyl methoxymethyl ether to methoxymethyl vinyl ether was achieved most efficiently with potassium hydroxide pellets -9 rather than with potassium tert-butoxide as originally reported for dehydrobromination of the tetrahydropyranyl analog.10 Potassium tert-butoxide was effective for the dehydrobromination, but formed an adduct of tert-butyl alcohol with the vinyl ether as a by-product in substantial amounts. Methoxymethyl vinyl ether is lithiated efficiently with sec-butyllithium in THF and, somewhat less efficiently, with n-butyllithium in tetrahydrofuran. Since lithiation of simple vinyl ethers such as ethyl vinyl ether requires tert-butyllithium,11 metalation may be assisted by the methoxymethoxy group in the present case. 

Hatakeyama [6] reduced the number of alcohol groups by approximately 50% in perfluoro terpmonomer resists to modify surface adhesion and transparency by postreacting with methoxymethyl chloride. 

The ability of DAST (1) to replace hydroxy groups of alcohols with fluorine was discovered by Middleton. Many dialkylaminosulfur trifluorides, differing from DAST (1) only by the amino substituent, as well as bis(dialkylamino)sulfur difluorides have been prepared (for a recent review, see ref 38). but none has become as popular as DAST. This is due to the fact that DAST was the first to be commercially available, although its high cost may be prohibitive for industrial applications in most cases. Recently, a homochiral aminofluoro-A -sulfanc, [(5)-2-(methoxymethyl)pyrrolidin-l-yl]sulfur trifluoride, was synthesized. In the reaction of this DAST analog with racemic silylated alcohols, only low to moderate enantiomeric excesses of fluorinated products have been observed. ... 

Cs-X has also been used to promote the selective O-methylation of phenol with dimethyl carbonate. 2 N-Monomethylaniline was obtained in 93% yield by reacting aniline with dimethyl carbonate over a K-Y catalyst at 180°C (Eqn. 22.46). 3 The reaction of alcohols with chloromethyl ether over Na-Y gave the resulting methoxymethyl ethers in 70%-90% yields (Eqn. 22.47). 4... 

Methoxymethyl ethers. Etherification of alcohols is readily achieved by refluxing them with graphite in methylal. 

Methoxymethyl ethers. Etherification of alcohols with this reagent is mediated by AgOTf-NaOAc. This method is suitable for derivatizing acid-sensitive alcohols. Primary, secondary, and tertiary alcohols react at comparable rates, phenols slower. 

Intermolecular reaction of 1,2-ethanedithiol with methoxymethyl-amino alcohols led to the selective formation of new N-hydroxyalkyl-1,5,3-... 

Recently, Sc(OTf)3 has been widely used in many protection reactions such as methoxymethylation [69], tetrahydropyranylation [70], O-glycosidation [71], acylation [72, 73], esterification of alcohols [74], and thioglycosidation of glycols [75]. Scandium salts such as Sc(OTf)3 and SCCI3 were also found to be efficient and recyclable catalysts for conversion of carbonyl compounds to 1,3-oxathiolanes, 1,3-dithiolanes, and 1,3-dithianes [76, 77]. By employing this protocol, chemose-lective oxathioactalization of aldehydes in the presence of ketones was achieved (Scheme 12.34) [78]. 

The cleavage of ethers was carried out in acetic anhydride to promote subsequent acetylation giving the corresponding acetate derivatives in good yields (Scheme 16.47) [54]. Under mild condition, cyclopentenone skeleton or diene moiety survived [55, 56]. This method was applied to cleave methoxymethyl-O (MEM-O) ether bond in a total synthesis (Scheme 16.48) [57] FeCls (5 mol%) in acetic acid or in acetic acid-CH2Cl2 also provides a simple protocol for acetylation of alcohols, ethers, and ketals to the corresponding acetates in very high yields [58]. 

For the preparation of allyl, t-butyl, methoxymethyl, tetrahydropyranyl and triphenyl methyl ethers see section 45A (Protection of Alcohols and Phenols)... 

Ethyldiisopropylamine Protection of alcohol groups as methoxymethyl ethers... 

Silyl ether protected alcohols (eq 5) have been converted directly into the corresponding bromides with PhaP and CBr4. The reaction works best if 1.5 equiv of acetone are added. Tetrahy-dropyranyl ether protected alcohols have also been directly transformed into the bromides using this reagent combination. The reaction has been reported to proceed with inversion of configuration (eq 6). If unsaturation is appropriately placed within a tetrahydropyranyl (eq 7) or a methoxymethyl (eq 8) protected alcohol, cyclization occurs to afford tetrahydropyrans. The conversion of an alcohol to the bromide without complications with a methoxymethyl protected alcohol in the molecule is possible (eq 9).i ... 

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