6- Hydroxy-5-methoxyindole

In the assay described by Smit et al. (1990), 5,6-dihydroxyindole-2-carboxylic acid was the substrate. Two products are formed, 5-hydroxy-6-methoxyindole-2-carboxylic add and 6-hydroxy-5-methoxyindole-2-carbox-ylic add. 

The position of the sugar residue in the dihydroindole portion can be determined by methylation of the pigment with diazomethane and subsequent alkaline degradation of the resulting neobetanin derivative. In the case of 5-0-glycosides, 5-hydroxy-6-methoxyindole-2-carboxylic acid is obtained, whereas the 6-O-glyco-sides yield 6-hydroxy-5-methoxyindole-2-carboxylic acid (47,48). The indole carboxylic acids are easily identified by TIjC. 

Phenolic oxidative coupling. Oxidation of the phenolic amine (1) with 4.1 molar equivalents of ferric chloride hexahydrate gives 5-hydroxy-6-methoxyindole (2) in 10.6% yield. The amino nitrogen can also be substituted by an alkyl group.1... 

This procedure, with slight modifications, was extended to the synthesis of 5-hydroxy-6-methoxyindole 21, 6-hydroxy-5-methoxyindole 22 and their O-acetates (87JHC941). The synthesis of 4-methyl-, 7-methyl- and 4,7-dimethyl-5,6-dihydroxy-tryptamines from substituted benzaldehydes via the corresponding indoles has also been reported (85JMC1273). 

A soln. of K-nitrosodisulfonate and NaHCOg added simultaneously with ethyl acetate to a stirred aq. soln. of methyl 3-hydroxy-4-methoxyphenylalaninate, and the product isolated after 0.5 hr. from the 2-phase system methyl 5-hydroxy-6-methoxyindole-2-carboxylate. Y 68%. M. E. Wilcox et ah, Helv. 4-8, 252 (1965). 

B. 1-Hydroxy- and 1-Methoxyindoles Cairying an Electi on-Withdrawing Group... 

On the other hand, an electron-donating substituent destabilizes the 1-hydroxy-indole structure, often to the extent that it cannot be isolated. Even in such a case, alkylation of the 1-hydroxy group greatly improves the stability. Among alkylations, methylation is the best choice. This fact explains why every isolated natural product has a 1-methoxyindole structure (91YGK205, 99H1157). 

Many early claims of having prepared simple 1-hydroxyindoles have proved to be unfounded, although the unusually stable l-hydroxy-2-phenylindole was obtained in 1895.1-Hydroxyindole itself polymerizes on attempted isolation, while O-acylation, O-alkylation, or the presence of substituents greatly stabilizes the molecule. One 1-hydroxyindole antibiotic has been identified and is the only 1-hydroxyindole derivative isolated from natural sources so far. In contrast, a substantial number of 1-methoxyindoles occurs in various plants, and some of these may inhibit tumor formation in mammals. The biochemistry of these compounds, which include 1-methoxy-indoles, -indolines and -2-oxindoles, has not been widely investigated and could be a very fruitful area for new research which might well lead to novel medicinal agents and other useful compounds. 

The l3C-NMR spectra for several indoles and 1-hydroxy-, 1-acetoxy-, and 1-methoxyindoles have been very carefully measured, and selected data is presented in Table V. In the oxygenated compounds, which have quite similar spectra, the 3-carbon atom moves significantly upheld, as does the 7-carbon atom, but to a smaller extent. Detailed correlations between the various substituents and the chemical shifts and coupling... 

Hydrolysis of 1-acetoxy- or l-hydroxy-3-cyanoindole (115) by hydrogen peroxide or 1 M sodium hydroxide gave the corresponding amide, while QM sodium hydroxide gave the 3-carboxylic acid which decomposed rapidly at room temperature with diazomethane, the last compound gave the stable methyl l-methoxyindole-3-carboxylate [78JCS(P1)1117]. 1-... 

Proton chemical shifts of 1-hydroxyindole have been assigned unambiguously (Table 2) based on NOE effects measured in the NOESY spectrum of the closely related 1-methoxyindole <1997H(44)157>. The H-4 in 1-hydroxy-indole is relatively deshielded S 7.56) and H-3 is the most shielded proton of the series 6 6.31), while the OH proton resonates at S 5.56. 

Other evaluated serological markers from the melanogenesis pathway include the phaeomelanin metabohte S-S-CD (see Ref. 5 for an review of 5-S-CD in melanoma with 2648 samples taken from 218 patients) and to a lesser extent the eumelanin metabohte 6-hydroxy-5-methoxyindole-2-carboxyhc acid. Since 5-S-CD is very sensitive to light and oxidation, analysis requires immediate centrifugation, freezing of the samples after blood collection and exclusion of light and air-oxygen. 

Monoterpene Bases.—Yohimbine-Corynantheine (and Related Oxindoles)-Pier aline Group. It is well known that 3,4-dehydroyohimbane (35a) is reduced by zinc-acetic acid to a mixture of yohimbane (35c) and i/ -yohimbane (35d) however, when 10-methoxy-3,4-dehydroyohimbane (35b) was similarly treated, a 2,3,4,7-tetrahydro-derivative (17 % yield) was formed as well as the corresponding 10-methoxy-yohimbanes. It was shown that this did not arise by further reduction of either of the methoxy-yohimbanes and no explanation is yet available for this interesting difference. Reserpine, a 6-methoxyindole, underwent C(3)-N(4) bond fission on reaction with zinc-acetic acid, as did indoles with no ring A methoxy-group. Cleavage of the C(3)-N(4) bond with the formation of N(4)-cyano-C(3)-alkoxy- or hydroxy-seco-derivatives was observed when yohimbine, i/ -yohimbine, and methyl reserpate were subjected to von Braun degradation conditions in alcohol or aqueous solution. 

Hydroxy- and 1-alkoxyindoles are being developed for various synthetic purposes for example lithiation of 1-methoxyindole takes place at C-2 and thus substituents can be introduced. More importantly, various nucleophilic substitutions, with departure of the 1-substituent take place. One of the reactions below shows the introduction of a hydroxy group onto the indole 5-position by an acid-catalysed reaction of a 1-hydroxyindole. 1-Methoxy groups allow nucleophilic attack on the heterocyclic ring, as illustrated by the second example. ... 

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... 

Utilizing the unique features of 1-hydroxy- and 1-methoxyindoles, three kinds of useful routes for preparing 3a-alkoxy-l,2,3,3a,8,8a-hexahydro-pyrrolo[2,3-fo]indoles have been developed [30]. 

Nucleophilic substitution reactions are rarely observed in indole chemistry [32]. We have disclosed that 1-hydroxy- and 1-methoxyindoles can undergo nucleophiUc substitution reactions that are impossible in the corresponding indole compounds [1-8]. 

Methoxyindole-3-carbaldehyde (10a) undergoes nucleophilic substitution reactions in sharp contrast with indole-3-carbaldehyde that does not react with nucleophiles under forcing reaction conditions. The most reactive reactant among the thus-far obtained l-hydroxy and 1-methoxy derivatives is l-methoxy-6-nitroindole-3-carbaldehyde (10b) as shown in Fig. 2. So, the nudeophihc substitution reactions of 10b in DMF are examined for the synthesis of new 2,3,6-trisubstituted indoles. The representative results are shown in Scheme 14 [13]. 

C11H11NO3, 5-Methoxyindole-3-acetic acid, 41B, 322 C11H12N2, 6-Dimethylamino-5-aza-azulene, 34B, 149 C11H12N2O3, 5-Hydroxy-DL-tryptophan, 39B, 197... 

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