Selective demethylation

Another important use of BCl is as a Ftiedel-Crafts catalyst ia various polymerisation, alkylation, and acylation reactions, and ia other organic syntheses (see Friedel-Crafts reaction). Examples include conversion of cyclophosphasenes to polymers (81,82) polymerisation of olefins such as ethylene (75,83—88) graft polymerisation of vinyl chloride and isobutylene (89) stereospecific polymerisation of propylene (90) copolymerisation of isobutylene and styrene (91,92), and other unsaturated aromatics with maleic anhydride (93) polymerisation of norhornene (94), butadiene (95) preparation of electrically conducting epoxy resins (96), and polymers containing B and N (97) and selective demethylation of methoxy groups ortho to OH groups (98). 

As described earlier one of the possible products from the AFO reaction is dihydroxyflavonols. Simpson and coworkers took advantage of this outcome in their synthesis of the flavonol rhamnocitrin (23). Chalcone 24 was subjected to the typical AFO conditions to deliver dihydroxyflavonol 25. The isolated product was further subjected to hydrogen peroxide to afford flavonol 25a in 30% yield. However, treatment of 25 with bismuth acetate, generated in situ from bismuth carbonate and acetic acid, gave 25a in 77% yield for a respectable 52% overall yield over two steps. 25a was then selectively demethylated with anilinium chloride to deliver rhamnocitrin (23). 

In the example below, Bhardwaj and coworkers synthesized tetramethoxyflavone 36 this flavonol was believed to be the structure of a compound isolated from Artemisia annua Methyl ketone 37 and aldehyde 38 were smoothly condensed to afford chalcone 39 in 73% yield. 39 was then converted to 40 under slightly modified AFO conditions in low yield. Selective demethylation of 40 gave 36. However, spectral data and melting point data of 36 did not match up with the compound isolated from the plant. Hence, the original structure was misassigned and was not flavonol 36. 

Demethylation of trequinsin (3) with a 65 35 mixture of AcOH and 48% HBr at 115 °C for 3 h gave mainly 10-hydroxyl derivatives 148 (R = r = H), which was accompanied by traces of its 9-hydroxyl and 9,10-dihydroxy derivatives. In boiling 48% HBr for 2 h its 9,10-dihydroxy derivative formed in 63% yield (98IJC(B)1). 9-Methoxy group of 3 and that of its 2-[(2,6-dimethyl-4-carboxyphenyl)imino] derivative 178 (R = COOH) was selectively demethylated by the treatment with 60% NaOH and EtSH in HMPA. Treatment of 3 with pyridine HCl in boiling pyridine for 20 min afforded its 9,10-dihydroxy-3-desmethyl derivative in 65% yield. 4 -Hydroxymethyl... 

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). ... 

Asymmetric syntheses of warfarin <96TL8321> and the axially chiral bicoumarin, isokotanin A <96TL3015> have been reported. The former is based on a Rh-catalysed asymmetric hydrogenation of a 3-(a,P-unsaturated ketone) substituted coumarin, whilst the key steps of the latter are an asymmetric Ullmann coupling and a selective demethylation. The stereochemistry of the fused dihydrocoumarin resulting from Li/NHs reduction of... 

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

Ethylisoeugenol and ethoxyanisole can be selectively demethylated or deethylated by use of potassium t-butoxide in the presence of 18-crown-6 (Eq. 56) [79]. 

Methylation of carbazole phenolic oxygen has been achieved using dimethyl sulfate without reaction at nitrogen. Demethylation of carbazole methyl ethers has been achieved with hydrobromic acid-acetic acid, boron trichloride,and pyridine hydrochloride. Selective demethylation of methoxyl ortho to an aldehydo function has been achieved using boron trifluoride. ° ° Partial demethylation of 1-methoxy-3-formylcarbazole occurred during Wolff-Kischner reduction." ... 

Horie, T. et al., Studies of the selective 0-alkylation and dealkylation of flavonoids. X. Selective demethylation of 7-OH-3,5,8-triOMe flavones with anhydrous aluminium halide in acetonitrile or ether, J. Org. Chem., 52, 4702, 1987. 

Selective demethylation of 2,4-dimethoxyquinolines occurs on heating with hydrogen chloride in ether, normally giving 4-methoxyquinol-2-ones, e.g. Scheme 103 <73JCS(Pl)94). If, however, alkali is used and an electron-withdrawing 3-substituent is present, as in (118), then the demethylation occurs at position 4 (Scheme 103) <8iiJC(B)543). 

C11H14O2, Mr 178.23, exists in cis (mp 35-36 °C) and in Irans mp 86°C) forms. The trans isomer has a sweet vanilla-like odor. Propenylguethol can be prepared from isosafrole by reaction with methyl magnesium chloride or by ethylation of isoeugenol followed by selective demethylation with alkali [169]. 

The initial acylation is followed by selective demethylation at the most electron-rich ortho ether function of the benzophenone (73JCS(P1)1329). Cyclization to the xanthone is achieved in almost quantitative yield on boiling the benzophenone with aqueous alkali or with aqueous piperidine. Coupled with the selective demethylation of polymethoxybenzo-phenones or xanthones which is possible under acidic or basic conditions, this method provides an attractive and efficient synthesis of naturally occurring xanthones. 

The above reactions in this section have been examples of addition alone or addition followed by elimination. Ligand reactions involving nucleophilic substitution are also known and these are of the dealkylation type. Lewis acids such as aluminum chloride or tin(IV) chloride have been used for many years in the selective demethylation of aromatic methyl ethers, where chelation is involved (Scheme 27). Similar cleavage of thioethers, specially using mercury(II) salts, is commonly used to remove thioacetal functions masking ketones (equation 27).104 In some cases, reactions of metal ions with thioether ligands result in isolation of complexes of the dealkylated organic moiety (equations 28 and 29).105-107... 

SCHEME 4. Selective demethylation of readily available aldehyde 4... 

Boron heterocycles. A novel synthesis of the natural chalcone aurentiacin (3) involves the reaction of 2,4,6-trimethoxytoluene (1) with cinnamic acid and BF3 etherate at 80° to form the novel heterocycle 2, which is hydrolyzed to 3. The formation of 2 involves a selective demethylation, since the reaction of 4 with 2-phenylpropionic acid and BF3 followed by hydrolysis gives 5, isomeric with dihydro-3. 

Ester hydrolysis.1 Pyridinium chloride selectively demethylates methyl esters of o-substituted aromatic carboxylic acids. 

The Ru(II)/ROOH system can also be used to oxidize tertiary amines. The intermediate iminium ion is formed, as described earlier for secondary amines, and can be trapped by nucleophiles. Thus, the ruthenium-catalysed oxidation of tertiary amines with hydrogen peroxide in methanol can be performed to give the corresponding a-methoxyamines with high efficiency as illustrated in Fig. 24 [ 137]. Another example is the selective demethylation of tertiary amines in methanol with a combination of Ru(II) and H202, followed by hydrolysis of the intermediate a-methoxylated amines. For example, the methoxylation of N,N-dimethyl-p-toluidine followed by treatment with 2 N HC1 solution gave N-methyl-p-toluidine in 75% yield (Eq. 35) [137]. 

Microbiological transformation of laudanosine by the micro-organism Cunninghamella blakesleeana is accomplished by selective demethylation, to give i/f-codamine (19).29 Isoquinoline alkaloids that can be selectively halogenated can readily be converted into hydroxy-compounds by lithiation of the bromo-... 

Demethylation. AICI,-NaI (1 1) in acetonitrile selectively demethylates aliphatic methyl ethers at room temperature in the presence of aromatic methyl ethers. Acetals are also cleaved, but esters and lactones are not affected. The methyl ether of a primary alcohol is cleaved somewhat more readily than the methyl ether of a secondary alcohol. ... 

Selective demethylation of methoxyarenes. Boron trichloride is generally useful for selective cleavage of the more hindered methoxy group of polymethoxybenzenes and of peri-methoxynaphthalenes. 

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