Methyl-5-hydroxyindole derivative

The removal of the semicarbazide residue from aminochrome mono-semicarbazones by alkaline degradation has been reported.303 The resulting 6-hydroxyindole derivatives could be readily isolated as their methyl ethers.303... 

The UV-spectrum of mitragynine differs notably from the spectra of the other Mitragyna alkaloids. Whereas the absorption of the latter indicate the presence of oxindole nuclei, the spectrum of mitragynine shows a greater resemblance to that of the ajmalicine group of alkaloids (5). The presence of an indole nucleus is also suspected from its color reactions (2) and confirmed by the isolation of indole derivatives (so far unidentified) and 5-methoxy-9-methylharman (I) from the products of zinc dust distillation (6). The identification by synthesis (51) of this degradation product is of some interest, since the alkaloid itself does not apparently contain an iV-methyl group. Moreover, this was the first demonstration of the occurrence of a 4-hydroxyindole derivative in nature. 

Nevertheless, there are several other oxidation (dehydrogenation) routes to indoles from indolines. In a series of papers, Somei and colleagues used sodium tungstate to synthesize A-hydroxyindole derivatives from the corresponding indolines (Scheme 11, equations 1 and 2) [64, 103-107]. The simple l-hydroxy-6-nitroindole [106] and 4-, 6-, and 7-ethoxy-l-methoxyindoles were synthesized in similar fashion [107]. Pedras and coworkers employed the Somei method to prepare the natural phytoalexin methyl l-methoxyindole-3-carboxylate [108], and McNab and... 

As for the introduction of a secondary alkyl moiety to the 1-hydroxy oxygen, the usual alkyl halide method has given poor results. However, employing preformed cesium salt of 1-hydroxyindoles in DMF, this difficulty has been overcome (Scheme 9) [24]. Thus, the reaction of Nb-methoxycarbonyl-1-hydroxytryptamine (52) with methyl 2-bromopropionate, 2-bromopropane, cyclohexyl bromide, and 1-phenethylbromide gives birth to the corresponding l-(l-methoxycarbonyl)ethoxy (53a, 88%), l-(2-propyl)oxy (53b, 87%), 1-cyclohexyloxy (53c, 19%), and l-(l-methyl)benzyloxy derivatives (53d, 80%), respectively. l-t-Butyldimethylsilyloxy-M)-methoxycarbonyl-tryptamine (54) can be obtained by the conventional f-butyldimethylsilyl chloride and imidazole method [24]. 

Gronowitz adapted this technology to one-pot syntheses of indole-3-acetic acids and indole-3-pyruvic acid oxime ethers from A-BOC protected o-iodoanilines [328, 329]. Rawal employed the Pd-catalyzed cyclization of A-(o-bromoallyl)anilines to afford 4- and 6-hydroxyindoles, and a 4,6-dihydroxyindole [330], and Yang and co-workers have used a similar cyclization to prepare 8-carbolines 287 and 288 as illustrated by the two examples shown [331]. The apparent extraneous methyl group in 288 is derived from triethylamine. 

Interesting derivatives of indole were described in [35]. When 3-ethoxy carbonyl-2-methyM-(trimethylammonium)methyl-5-hydroxyindole iodide [162, 163] is heated with an excess of trialkyl phosphite [64] (160-165°C, 30 min) 3-ethoxycarbonyl-2-methyl-4,5-(2-oxo-2-alkoxy-l,2-oxaphospholene-4,5)indoles 65... 

The reactions of the methyl furo[2,3-6]pyrrole-5-carboxylate (153) or its 6-methyl derivative (154) with DMAD proceed via [4 -I- 2] cycloaddition at the a,a -positions of the furan ring, giving cycloadducts which by subsequent 1,5-sigmatropic rearrangement give trimethyl 5-hydroxyindole-2,6,7-tricarboxylate (155) or its 1-methyl derivative (156) <94UP 70i-0i>. 

Of much interest is the recent discovery of substances closely related to the harmala alkaloids in animals. One of these is adrenoglomerulotropine, a hormone of the pineal body, the chemical identity of which has been indicated as 2,3,4,9-tetrahydro-6-methoxy-i-methyl-iH-pyrido (3,4,6) indole. This substance is identical to 6-methoxyletrahydroharman which has been shown to be formed in vivo from 5-methoxy tryptamine and acetaldehyde. 6-methoxytetrahydroharman is an isomer of tetrahydro-harmine, one of the alkaloids in Banisteriopsis, and in the African Leptactinia densillora. One more substance, 6-methoxyharmalan, has been shown to derive, at least in vitro, from melatonin, which results from the methylation of acetylserotonin. The enzyme which makes this possible, hydroxyindole O-methyl transferase, has only been found in the pineal body. (Naranjo, in Efron et al. 

Nenitzescu, C. D. Derivatives of 2-methyl-5-hydroxyindole. Bull soc. chim. Romania 1929, 11, 37-43. 

Fig. 17. GLC of a mixture of indole derivatives (1 /jg of each derivative injected). For conditions see text. IAN = indole-3-acetonitrile lAA-ME = methyl ester of in-dole-3-acetic acid lAA-EE = ethylindole 3-acetate ICA-ME = methyl ester of in-dole-3-carboxylio acid IPA-ME = methyl ester of indole-3-propionic acid IBA-ME = methyl ester of indole-3-butyrio acid 6-OH-IAA-ME = 5-hydroxyindole-3-acetic acid (methyl ester). Reproduced from Brook et al. (B22) with permission.

A characteristic feature of all these compounds, which are formally related to 3//-naphtho[2,l-h]pyran, is the presence of two absorption bands in the spectra of the open forms. The effect of the pyrrole ring in 7//-pyrano[3,2-e]indole is a small blue shift of the major absorption band to 428 nm (3,3-diphenyl-3/7-naphtho[2,l-6]pyran Xmax = 430 nm), but A-methylation leads to a red shift. The colourability of this band remains similar to that of the naphthopyran but the overall colour is influenced by the weaker band at ca. 520 nm. For example, the angular isomer derived from 5-hydroxyindole and l,l-dianisylprop-2-yn-l-ol... 

Acetylcholine is formed from choline (which is also an important constituent of phospholipids) and acetyl CoA under the catalytic influence of choline acetyl-ase. It is hydrolised by acetylcholinesterase or choline esterase. Two important steps in the formation of noradrenaline from tyr dopa decarboxylase and dopamine hydroxylase. Adrenaline is formed from noradrenaline by phenyl ethanolamine A -methyltransferase. Both noradrenaline and adrenaline are metabolised by catechol 0-methyl transferase or monoamine oxidase. Some later steps in their metabolism involve aldehyde dehydrogenase and alcohol dehydrogenase (aldehyde reductase), After hydroxylation to its 5-hydroxy derivative, tryptophan is converted by 5-hydroxytryptophan decarboxylase to 5-hydroxytryptamine (serotonin). The major routes of serotonin metabolism involve either monoamine oxidase or hydroxyindole 0-methyltransferase. Histamine is synthesised from histidine by histidine decarboxylase, and is metabolised by either diamine oxidase or histamine Af-methyltransferase. Gamma aminobutyric acid is formed by glutamate decarboxylase and metabolised by... 

Treatment of 3-(3 -methyl-2-oxobutyl>3-hydroxyindole with thionyl chloride gave, unexpectedly, the thiolan derivative (29), and reduction of tra f-4-phenyl-but-3-en-2-one with sulphurated sodium borohydride gave 3-acetyl-2,6-diphenyl-4-hydroxy-4-methylthian, of unknown configuration. The cis- and /runr-isomers of 2-mercaptothiolan-2,5-dicar-boxylic acid were formed by base-catalysed rearrangement of 1,2-dithian-3,6-dicarboxylic acid. Unexceptional methods were used to synthesize various thiosugar derivatives, and the synthesis of a-methylbiotin, a new natural product, by a modification of the Hofman-LaRoche method has been described. ... 

Indole derivatives. Better separations than in a single run have been obtained with hydroxyindoles using solvents C and D (Table 90) [14] various indole derivatives and their methyl esters in the solvents V and VI (Table 88) [19, 20], using double development and hydroxy-skatoles through four runs in chloroform-cyclohexane-diethylamine (50 + 40 + 10) [33]. 

The following solvent combinations, in order of use, have been so far proposed (Roman numerals refer to Tables 88/89, capital letters to Table 90) XIV -> XVI a [120] and V->IV [19] for separating simple indole derivatives, particularly from auxin metabolism (the second combination is suitable for the methyl esters of the acids also) XVII-> XIV [12], XV-> XVIa [9] isopropanol-25% ammonium hydroxide-water (80 + 4 + 8) IX [90] for separation of urine metabolites A B for hydroxyskatoles and C D for hydroxyindoles. 

A new route to 2-substituted indoles derived from 1-methoxyindole was recently described. Dimethyl sulfate proved to be the reagent of choice for the methylation of the unstable 1-hydroxyindole to give 1 -methoxyindole in 51 % yield (eq 10). The resulting methoxyindole undergoes 0-lithiation at the 2-posilion using n-Butyllithium, and can be trapped with appropriate electrophiles. It should be noted that methylation of 1-hydroxyindole using lodomethane afforded only very low yields of the desired methoxyindole. 

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