Demethylation aromatic methyl ethers

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... 

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. ... 

Yet another metabolite of aflatoxin Bj(i) is derived through the demethylation of the aromatic methyl ether. The resultant compound was isolated, and christened aflatoxin Pj83> 84. The structure was determined to be that depicted in (18). 

Of several reagents for ring opening or dealkylation of ethers, the AlX3-EtSH (X = Cl or Br) system is particularly useful for the demethylation of aliphatic and aromatic methyl ethers and the demethylenation of methylenedioxy-compounds. ... 

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... 

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]. 

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