4,4 -Dimethoxydiphenyl ether

A second degradative approach was more informative, for the products obtained accounted for all thirty-seven carbon atoms of the alkaloid. Permanganate oxidation of 0,0-dimethylliensinine (LXIV) afforded p-methoxybenzoic acid, l-oxo-2-methyl-6,7-dimethoxy-1,2,3,4-tetra-hydroisoquinoline, and a compound (O-methylliensinic acid) which was found to have structure LXX, mainly by degradation to 4,5,5 -tri-carboxy-2,2 -dimethoxydiphenyl ether. Similarly the permanganate oxidation of 0,0-diethylliensinine (LXV) yielded p-ethoxybenzoic acid and the acid LXXI (0-ethylliensinic acid). The above data revealed the constitution of the alkaloid to be as indicated in formula LXIII. 

Two years later King (77) repeated the work on the oxidative degradation of bebeerine, and from the mixture of degradation products, in addition to the tricarboxylic acid (LIV) which the previous workers isolated and identified, he isolated an unknown isomeric tricarboxylic acid. Although he did not synthesize this acid he assigned to it the structure LXV on the basis that on decarboxylation it yielded 2,2 -dimethoxydiphenyl ether. Consequently, King proposed the structure LXVI in which the phenolic groups are methylated for bebeerine dimethyl ether. 

At the same time an important paper (67) appeared in which essentially the same conclusions with regard to the structure of bebeerine were arrived at by a different route. Faltis, Kadiera, and Doblhammer (67) treated the inactive a, a -dimethylbebeerine methine, obtained by a one-stage Hofmann degradation of bebeerine dimethyl ether, with ozone and obtained a mixture of two dimethylamino dialdehydes. These were not isolated but were converted to the chloromethylate derivatives, oxidized with potassium permanganate to the acids, and boiled with dilute alkah to decompose the quaternary bases. Besides trimethylamine, a mixture of two vinyl carboxylic acids were obtained. One of these proved to be 4, 6-dicarboxy-2,3-dimethoxy-5-vinyldiphenyl ether (LIX). The other vinyl carboxylic acid, which was readily separated from LIX by virtue of its low solubility, was first decarboxylated by heating with quinoline and naturkupfer C and then oxidized with potassium permanganate in acetone. This yielded 4-carboxy-2,2 -dimethoxydiphenyl ether (LXIII), the structure of which was proved by direct comparison with the synthetic compound prepared by the Ullmann condensation of o-bromoanisole and vanillic acid. 

The correctness of the assumption that the parent vinyl carboxylic acid of LXIII must have the structure LXIV was shown by the oxidation of LXIV to 4,5,5 -tricarboxy-2,2 -dimethoxydiphenyl ether (LXV) and comparison with the compound synthesized by the Ullmann condensation of 4-iodo-5-methoxyphthalic acid with isovanillic acid (69) or by the condensation of 3-methyl-4-acetyl-6-methoxyphenol with 3-bromoanisic acid followed by oxidation (69). The natural LXV and the synthetic compound were identical in all respects. When the three degradation products, LXIV, LIX and trimethylamine, were pieced together the structure LXVI for bebeerine was arrived at, the positions of the phenolic groups being assigned arbitrarily. 

Further elucidation of the structure of insularinic acid came when it (LXXII) was heated at 130-145° in a sealed bomb with hydrogen bromide for one and one-half hours. The resulting product (LXIXVIII) on catalytic reduction followed by methylation with diazomethane and saponification yielded 4,5 -dicarboxy-2 -methyl-2,3-dimethoxydiphenyl ether (LXXIX). This was synthesized from the potassium salt of methyl 4-hydroxy-3-methylbenzoate and methyl 3-bromo-4,5-dimethoxybenzoate by the Ullmann condensation. 

Me ether [76652-99-8]. 2 3,4 5-Tetrabromo-2,6 -dimethoxydiphenyl ether Ci4HioBr403 M 545.847 Constit. of Phyllospongia foliascens. Mp 86-88°. 

In an analogous reaction, where anisole (0.5 mole), chloromethyl ether (0.1 mole), and REX catalyst (2 gm) were stirred for 14 hours at room temperature, a 28% yield of a mixture of 2,2 -dimethoxydiphenyl-methane, 2,4 -dimethoxydiphenylmethane, and 4,4 -dimethoxydi-phenylmethane in the ratio of 1 5.7 5.4 was obtained. No 1 1 adduct (chloromethyl- or methoxymethylanisole) was observed. The lower reaction temperatures required with anisole reflect the activating effect of an electron-donating substituent in electrophilic aromatic substitution. 

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