The Chemistry of the Aminochromes. Part Viii: The Preparation and Properties of 4- And 7-Methyladrenochrome

Abstract

Two new catecholamines, 2-and 5-methyladrenaline, have been prepared from 3-methylcatechol and they gave 4-and 7-methyladrenochrome, respectively, on oxidation. 7-Iodo-4-methyladrenochrome was obtained on oxidation of 2-methyladrenaline with potassium iodate; however, an iodoaminochrorne could not be obtained in a similar manner from 5-methyladrenaline. T h e expected 5,6-dihydroxyindole derivatives were obtained on reduction of these aminochromes.I t has been known for many years that the oxidation of adrenaline with potassium iodate leads to the forination of deep-violet products (1, 2). The compound responsible for the violet color was first isolated in 1937 by Richter and Blaschko who described it as 3-hydroxy-2-iodo-l-methylindoline-5,6-quo (i.e. 2-iodoadrenochrome) (3). However, it has recently been shown that iodination actually occurs in the 7-position of the adrenochrome nucleus and it was further demonstrated that iodinatioil (and bromination) invariably occurs in the 7-position and not the 2-position in the aminochrome lnolecule (4).As part of a research prograin into the chemistry of the aminochromes, that is being carried out in these laboratories, it was decided to prepare 2-and 5-inethyladrenaline (I and I1 respectively) and t o investigate the effects of the methyl substitution of the aromatic ring on the oxidation of these hitherto unknown catecholamines with several different oxidizing agents.I t was possible t o prepare I and I1 by procedures similar to that originally described by Stolz for the preparation of adrenaline (5). w-Chloro-3,4-dihydroxy-2-methylacetophenone (111) was prepared froin 3-inethylcatechol (IV) by a Friedel-Crafts condensation with chloracetyl chloride in the presence of aluminium chloride in carbon disulfide solution. Methylation of the phenolic hydroxy groups of I11 gave w-chloro-3,4-dimethoxy-2-methylacetophenone (V), a compound that had previously been described in the literature (6), proving that the chloroacetyl residue had entered the aromatic ring of IV in the position ortho to the inethyl group. The n.m.r. spectrum of I11 in hexadeuteroacetone showed two well separated doublets centered a t 6 7.38 and 6 6.92 with a coupling constant of ca. 8.5 c.p.s., indicating the presence of two ortho aromatic hydrogens in the molecule and confirming the position of the chloroacetyl residue. w-NIethylamino-3,4-dihydroxy-2-methylacetophenone (VI) was prepared by treating I11 with methanolic methylainine a t room temperature (cf. ref. 7). Treatment of I11 with sodium iodide in acetone gave 3,4-dihydroxy-w-iodo-2-lnethylacetophenone (cf. ref. 6). Preliminary experiments indicated that there was no advantage in using the w-iodo derivative t o prepare VI. 2-Methyladrenaline (I) was obtained in good yield by catalytic hydrogenation of VI. The hydrochloride of I was hygroscopic, but the acid oxalate salt of I was not and was readily purified by recrystallization from aqueous ethanol.

Chemistry of the aminochromes. Part XI. Studies on 2-methylaminochromes

“…chrome (6) have recently been reported by the authors (5). This paper reports some of the results of a general extension of this research to aminochromes alkylated in the 2-position; in particular to 2-methyladrenochrome (7) and 2-methyl-1-ethylnoradrenochronle (8) and their 7-iodo derivatives 9 and 10.…”

Synthesis of the Indole Ring

“…N-Substituted indoles can be formed under similar conditions (78 Oxidation of G15 by silver oxide or ferricyanide gives G16, which can be reduced (and dehydrated) to G17 by ascorbic acid. The pattern of the cyclization parallels that of G13 -> G14 but the product G16, presumably because of the resonance stabilization present in the vinylogous amide group, does not tautomerize directly to an indole (98). Treatment of the ethyl ester of tyrosine with iV-bromosuccinimide gives ethyl 5,7-dibromo-6-hydroxyindole-2-carboxylate (278).…”