4-Methoxybenzoic acid, demethylation

A conventional synthesis of tecleanthine (50) has been executed. Ullmann reaction of 2-amino-3-methoxybenzoic acid with 3-methoxy-4,5-methylene-dioxyiodobenzene gave the diphenylamine (49). Compound (49) was converted by cyclization (POCI3), hydrolysis (HCl), and methylation into tecleanthine (50). The Ullmann condensation was also used to prepare the natural acridones (48 R = R = R = R = OMe) and xanthoxoline (48 R = OH, R = R = R = H, iV-demethyl). The corresponding 9-thioketones were also synthesized. 

A few simple examples are the following. The interaction of o-amino-thiophenol and o-methoxybenzoic acid in polyphosphoric acid yields the expected benzothiazole (1 R= Me) at 160 °C, but results in the demethylated 2-(2-hydroxyphenyl)benzothiazole (1 R = H) at higher temperatures. Isatoic anhydride or the anhydride of an AW-(dicarboxy-... 

Preparationbyheatingamixtureof3-(3-chlorobenzoyl)-4-methoxybenzoic acid and pyridinium chloride at 200° for 20 h (65%) [923]. There are simultaneous demethylation and decarboxylation. 

Salicylic acid derivatives serve a similar purpose to 2-hydroxyacetophenones in a number of chromone syntheses, acting as a precursor of the 1,3-diketone fragment. For instance, a Claisen reaction between methyl 2-methoxybenzoate and acetone takes place in the presence of sodium to give the diketone. Demethylation occurs on reaction with hydriodic acid with concomitant ring closure to the chromone (00CB1998). The corresponding naphthol derivatives are a source of benzochromones (52JOC1419). 

Hydroxybenzo[6]thiophene has been isolated from coal tar.42 It may be prepared from 6-aminobenzo[fr]thiophene by standard procedures.241 6-Methoxybenzo[h]thiophene may be prepared by decarboxylation of the corresponding 2-carboxylic acid,341 and 6-ethoxybenzo[6]thiophene is obtained by reduction of 6-(ethoxy)-thioindoxyl (Section VI, 1,2). 6-Methoxy-5-methylbenzo[6]thiophene is obtained by cyclization of (3-methoxy-4-methylphenylthio)-acetaldehyde dimethyl acetal (Section IV,B).617 The product previously described542 as 6-hydroxy-3-phenylbenzo[6]thiophene has now been shown to be the 2-phenyl isomer.307 6-Methoxy-818 and 6-methoxy-5-methyl-benzo[6]thiophene617 are demethylated by pyridine hydrochloride. 

When a 2-alkylbenzo[b]thiophene undergoes Friedel-Crafts acylation with A1C13-cinnamoyl chloride, the resulting 3-ketone cyclizes spontaneously into the 4-position with loss of benzene to give the cyclic ketone 124.515 With 2-bromobenzo[b]thiophene, a similar reaction gives a mixture of 124 [R = Cl (sic)] and the 2-Br, 3-COCH2CHPh2 substituted benzo[f>]thiophene derivative with 2-methoxybenzo[h]thiophene, the ether is demethylated to give 124(R = OH).516 The formation of other cyclic ketones by intramolecular cyclization of carboxylic acids will be considered in Section IV,M. 

Another type of iron-containing monpoxygenase was flrst described by Bernhardt et al. ) and contains a two iron-two-acid-labile-sulfur cluster. It was isolated from bacteria and catalyzes the 0-demethylation of 4-methoxybenzoate The corresponding electron transport chain involves NADH, a flavoprotein and a second iron-sulfur protein It seems that many more bacterial monooxygenases belong to this type rather than to the heme-sulfur-containing category. 

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