Demethylation of ethers

In general, tetrazolium salts are stable in mineral acids. This stability has allowed a number of synthetic transformations such as ester and amide hydrolysis and demethylation of ethers etc.209-212 This is not the case with tetrazolium salts containing a heterocyclic substituent in the 3-position. They tend to decompose in mineral acid to the corresponding tetrazoles.230 Tetrazolyl-substituted tetrazoliums (146) and mesoionic tetrazoles, e.g., 145, are unaffected by acids.228,232... 

Demethylation of ethers. Primary and secondary alkyl methyl ethers and aryl methyl ethers are cleaved to alcohols by BF3 etherate in several thiols (ethanethiol is particularly effective). The reaction occurs at room temperature, but requires 1-12 days. Retention of stereochemistry is observed. ... 

The method is not restricted to group V derivatives and can easily be applied to oxygen esters and ethers. The use of various nucleophiles in this type of reaction has been discussed. The main advantage of this technique for the demethylation of ethers with ethanethiolate in a solvent such as DMF is that a relatively low temperature is required and the group R may be acid sensitive. ... 

Likewise alkyl amines, 0-dealkylation (demethylation) of ethers are commonly observed for P-450 catalyzed oxidation [225, 242, 243]. Para-nitroanisole and 7-ethoxycoumarin are the typical substrates for the 0-dealkylation catalyzed by P-450 [242,... 

Halide ions may attack 5-substituted thiiranium ions at three sites the sulfur atom (Section 5.06.3.4.5), a ring carbon atom or an 5-alkyl carbon atom. In the highly sterically hindered salt (46) attack occurs only on sulfur (Scheme 62) or the S-methyl group (Scheme 89). The demethylation of (46) by bromide and chloride ion is the only example of attack on the carbon atom of the sulfur substituent in any thiiranium salt (78CC630). Iodide and fluoride ion (the latter in the presence of a crown ether) prefer to attack the sulfur atom of (46). cis-l-Methyl-2,3-di-t-butylthiiranium fluorosulfonate, despite being somewhat hindered, nevertheless is attacked at a ring carbon atom by chloride and bromide ions. The trans isomer could not be prepared its behavior to nucleophiles is therefore unknown (74JA3146). 

Treatment of that intermediate with aluminum chloride leads to selective demethylation of that ether para to the carbonyl group (23). Cyclization by means of tosic acid gives the dihydronaphthalene nucleus (24). Alkylation of the phenol with N-(2-chloroethyl)pyrrolidine affords nafoxidine (25). ... 

Xn. Demethylation of Aryl Methyl Ethers by Boron Tribromide... 

DEMETHYLATION OF METHYL ARYL ETHERS 4-ETHOXY-3-HYDROX YBEN Z ALDEHYDE... 

The present procedure illustrates the facile demethylation of methyl aryl ethers by lithium diphenylphosphide.3 This reaction is specific for methyl ethers and may be carried out in the presence of ethyl ethers in high yield.4 Use of excess reagent allows cleavage in the presence of enolizable ketones.5 In the present case, the cleavage may be performed without protection of the aldehyde, but two equivalents of reagent are required, and the yield is reduced to ca. 60%. 

The exact time and temperature required for complete reaction must be determined for each individual compound. It has been observed that nucleophilic demethylation of methyl o-alkoxyaryl ethers is accelerated relative to anisole [Benzene, methoxy-],6 and this reaction is no exception. Lithium diphenylphosphide cleavage of anisole is complete in about 4 hours in refluxing tetrahydrofuran, whereas the present reaction is complete within 2 hours at 25°. 

Encouraged by the short synthesis of K vitamins, the chromium-mediated benzannulation was extended to the synthesis of vitamin E 68 [59]. The problem of imperfect regioselectivity of alkyne incorporation - which did not hamper the approach to vitamin K due to the final oxidation to the quinone - was tackled by demethylation of both regioisomeric hydroquinone monomethyl ethers 67 to give the unprotected hydroquinone. Subsequent ring closure yielded a-tocopherol (vitamin E) 68 (Scheme 39). 

Selective demethylation of (63) to the phenolic ether (64) has been achieved by the use of lithium diphenylphosphide. ... 

Aryl methyl ethers. A great deal of attention has been directed to the demethylation of aryl methyl ethers on account of interest in the degradation of lignin and related compounds by both aerobic and anaerobic organisms. 

In this series, too, replacement of the N-methyl by a group such as cyclopropylmethyl leads to a compound with reduced abuse potential by virtue of mixed agonist-antagonist action. To accomplish this, reduction of 24 followed by reaction with tertiary butylmagnesium chloride gives the tertiary carbinol 27. The N-methyl group is then removed by the classic von Braun procedure. Thus, reaction with cyanogen bromide leads to the N-cyano derivative (28) hydrolysis affords the secondary amine 29. (One of the more efficient demethylation procedures, such as reaction with ethyl chloroformate would presumably be used today.) Acylation with cyclopropylcarbonyl chloride then leads to the amide 30. Reduction with lithium aluminum hydride (31) followed by demethylation of the phenolic ether affords buprenorphine (32).9... 

Demethylation of a phenolic ether by hydriodic acid, 22, 91 Desiccator, vacuum, dumb-bell type, 23,105... 

Primary alkyl phenols have been prepared by the reduction of acyl phenols 1 by the demethylation of the corresponding ethers 12 by the diazotization of the corresponding amines 3 and by the alkali fusion of sulfonates.4 Alkyl resorcinols have been prepared by the reduction of acyl resorcinols.1 5 6 Alkyl chlororesorcinols have been prepared from the corresponding acyl chlororesorcinols by reduction.7... 

Olivetol. (5-Alkyl Resourcinol) BER 69, 1644 (1936). Mix 25 g of ethyl-3,4,5-trimethoxy benzoyl acetate and 2.0 g of clean sodium in 100 ml ethanol and warm to react. Add 2 g n-propyl iodide (this may be replaced with n-amyl iodide) and heat on a steam bath for 12 hours, then neutralize and remove the ethanol by distillation. Extract the residue with ether, dry, and evaporate in vacuo to get 30 g of the alkyl acetate. Heat 22 g of this acetate in 5% KOH ethanolic solution for 1 hour at 50° and let stand to precipitate 14 g of 3,4,5-trimethoxyvalerophenone. Mix 11 g of the above product with 60 g of sodium in 600 ml ethanol. Warm and after dissolving the sodium add 2 liters of water. M e acidic with HCl acid and remove the ethanol by distillation. Extract with ether, dry, and evaporate the ether in vacuo to get if. g olivetol dimethyl ether. To demethylate this ether add it to 70 ml of hydrogen iodide and heat to boiling and reflux for two hours. Distill and keep the fraction at 160°-170° with 3-4 mm of vacuum applied to the distillation set-up. Yield about 6 g. 

Dithioacetals derived from heteropine 177 smoothly react with methylene iodide in the presence of a zinc-copper couple in refluxing ether to give the corresponding fused thiophenes 178. The suggested mechanism involves formation of an ylide which undergoes intramolecular aldol-type condensation assisted by coordination of zinc with a carbonyl followed by demethylation of the S-methylthiophenium species (Scheme 35 (1989TL3093)). 

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