Aromatic ethers, demethylation

P + GSH- CH2-2H 0.0157 Aromatic ether Demethylation followed by oxidation to quinone... 

Similarly, HF—SbF5-induced isomerization of androsta-4,6-diene-3,17-dione 230 has been studied in detail,840 which led to a new entry into the 9-methylsterane series 231. Also, methods have been developed for the synthesis of isosterane derivatives841 and other methyl-substituted estrane dione derivatives of unnatural configurations.842 HF SbF5 superacid medium is also capable of demethylating aromatic ethers. This reaction has been successfully employed in the synthesis of 11-deoxyanthracyclines 232 [Eq. (5.305)].843... 

When the thioacetal (128) was treated with allylmagnesium bromide and subsequently with BFs etherate, nucleophilic addition on the carbonyl carbon and a subsequent cationic cyclization took place the product (129) was obtained by aromatization with loss of methanethiol (Scheme 18) <84TL5095>. The reaction of (128) under the Simmons-Smith reaction conditions gave the thienothiepine derivative (130). The proposed mechanism for the formation of (130) involves a nucleophilic attack of the initially formed sulfonium ylide intermediate, intramolecular aldol type condensation, aromatization and demethylation (Scheme 19) <89TL3093>. 

Scheme 1 Demethylation of aromatic ethers by BCI3 in CH2CI2...

Ether groups in the benzene ring of quinazoline behave as in ethers of homocyclic aromatic compounds, e.g., they can be demethylated with anhydrous aluminum chloride. Allyl ethers also undergo a Claisen rearrangement/ ... 

The nature of the aromatic substituents is apparently not critical for SSRI activity, as indicated by the structure of duloxetine (23-5), where one ring is replaced by thiophene and the other by naphthalene. The synthesis starts as above by the formation of the Mannich base (23-1) from 1-acetyl thiophene with formaldehyde and dimethyl-amine. Treatment of that intermediate with the complex from lithium aluminum hydride and the 2R,3S entantiomer of dimethylamino-l,2-diphenyl-3-methyl-butane-2-ol gives the S isomer (23-2) in high enantiomeric excess. Treatment of the aUcoxide from (23-2) and sodium hydride with 1-fluoronaphthalene leads to the displacement of halogen and thus the formation of ether (23-2). The surplus methyl group is then removed by yet another variant of the von Braun reaction that avoids the use of a base for saponifying the intermediate urethane. Thus, reaction of (23-3) with trichloroethyl formate leads to the A -demethylated chlorinated urethane (23-4). Treatment of that intermediate with zinc leads to a loss of the carbamate and the formation of the free secondary amine duloxetine (23-5) [23]. 

Since arucadiol and miltirone both have an aromatic "B" ring, enone 64 served as a common intermediate for both of these quinone pigments. The aromatization of 64 was readily achieved using 2,3-dicyano-5,6-dichloro-l,4-quinone (DDQ) (Equation 5.2). With substrate 65 in hand, only demethylation of the ethers was required to complete a synthesis of arucadiol (58). This transformation was accomplished in nearly quantitative yield using boron tribromide. Our synthetic arcudiol was spectrally identical with the natural material. 

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... 

Other preliminary experiments on alkali lignin included oxidations by barium peroxide and alkali (5, 6), alkali fusion, and alkali fusions in the presence of calcium peroxide, sodium borate perhydrate, and monopersulfate compound. Ether extractives and water extractives were examined, but in all cases too many of the oxidation products obtained were new and unidentifiable, and it was impossible to evaluate the experiments adequately with the available techniques. Vanillic acid appeared to be the chief oxidation product under conditions which did not demethylate further or destroy the aromatic nature of the oxidation products. Some oxidation conditions yielded p-hydroxybenzyl moieties as products, and some gave no trace of these products whatever. More detailed studies of the ether-insoluble, water-soluble components of the several oxidation mixtures were postponed until adequate procedures were developed for analytical isolation and identification. 

Cleavage of alkyl ary ethers (4, 305). The most difficult step in a recent synthesis of aklavinone (3) is demethylation of 1 to 2. Lewis acid reagents (BBr3) were useless because of preferential attack of the allylic hydroxyl nucleophilic demethylation (LiSCH3) results in concomitant aromatization of ring A. Demethylation "with Lil buffered with benzoic acid in pyridine-collidine at 145° was successful and proceeded in 92% yield.4, Aklavinone is the aglycone of an antitumor anthracycline that is less toxic than adriamycin. 

Transformations of the dimeric alkaloid vinblastine (46) by Streptomyces species have been reported which involve N-demethylation (51), aromatic hydroxylation (55), and intramolecular ether formation (53). With Streptomyces albogriseolus, N-demethylation occurs in an undisclosed yield to produce 47 (51). The same organism in the hands of the same workers is also reported to lead to the formation of vinblastine ether (50) in low yield, along... 

Sterol biosynthesis inhibiting insecticides. The earliest examples of sterol biosynthesis inhibitors were triadimefon, imazalil, and triarimol. These compounds act by blocking the C14 alpha demethylation step in ergosterol biosynthesis [54], Further work in this area has resulted in numerous fungicides, a number of them containing aromatic fluorine, perfluoroalkyl ethers, and the trifluoromethylphenyl group (Fig. 11). In this section, we will discuss the trifluoromethylphenyl sterol biosynthesis inhibitors, such as triflumizole and fluotrimazole. 

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. ... 

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