Beiträge zur Chemie der 4-Hydroxyindol-Verbindungen 10. Mitteilung über synthetische indolverbindungen [1]

Catalytic hydrogenation of 4-benzyloxyindoles does not stop at the hydroxyindole stage, but slowly leads to the 4,5,6,7-tetrahydro-4-ox-indoles 3 . Some procedures for the selective preparation of 4-hydroxyindoles 2 are described. When 4-benzyloxy-3-(1-hydroxyimino-ethyl)-indole ( 4c ) is warmed with trifluoroacetic acid, cleavage of the ether results as well as partial benzylation of the free hydroxyindole in the position 5 ( 5a, 5b ); no Beckmann rearrangement is observed. Esters of 4-benzyloxy-indole-2-carboxylic acid are formylated with POCl₃/dimethylformamide in the 7-position to give 7a ; in the corresponding dimethylamide, on the other hand, the formyl group enters the 3-position to give 8 . Both 4- and 7-hydroxyindole are oxidized with Frémy's salt to the 4, 7-quinone 13 ; on reduction this yields 4, 7-dihydroxyindole 14 , which is tautomerized by base-catalysis to 5, 6-dihydro-4, 7-dioxo-indole 15 . The course of the etherification of 4-hydroxyindoles with epichlorohydrin and related compounds is described, and the resulting side-chains are characterized by their NMR. spectra.     

Synthesis of aminoindoles by the Bucherer reaction

The reaction of 5-hydroxyindoles with ammonia, alkylamines, or dialkylamines in the presence of sulfites leads to the corresponding 5-aminoindoles. Partial or complete elimination of the substituent is observed in the case of indoles that have an electron-acceptor substituent (COOC₂H₅, COCH₃).Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 786–789, June, 1979.     

Spectrofluorimetric determination of 5-hydroxyindoles with benzylamine or 3,4-dimethoxybenzylamine as a selective fluorogenic reagent.

A spectrofluorimetric method has been developed for the sensitive and selective determination of 5-hydroxyindoles; the method is based on the reaction of 5-hydroxyindoles in a weakly alkaline solution (pH 9.0) with aromatic methylamines in the presence of potassium hexacyanoferrate(III) and dimethyl sulphoxide; the compounds produced fluoresce intensely in an alkaline solution (pH 11-12). Of the eight aromatic methylamines tested, benzylamine and 3,4-dimethoxybenzylamine were found to be the most favourable fluorogenic reagents in terms of sensitivity and reactivity. The methods with benzylamine and 3,4-dimethoxybenzylamine permit the determination of 5-hydroxyindoles at concentrations as low as 22-72 pmol ml-1 and 1.0-2.4 nmol ml-1, respectively.     

Chemistry of indole

5-Methoxy-3-carbethoxyindoles are nitrated primarily in the 4 position. Replacement of the methoxy group by an acetoxy group leads to a change in orientation — only the 6 isomer is obtained. In the case of the similarly constructed 5-hydroxyindoles, monosubstitution cannot be accomplished under various conditions, and only the 4,6-dinitro derivative is formed. The synthesis of the corresponding amines by reduction of the nitro compounds is described.See [1] for communication XXXVIII.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1646–1653, December, 1973.     

Online photocatalytic device for highly selective pre-column fluorescence derivatization of 5-hydroxyindoles with benzylamine

A fluorimetric liquid chromatographic method for the determination of 5-hydroxyindoles based on the benzylamine derivatization process mediated through an online photocatalytic oxidation has been developed. In this study, we used a photocatalytic column comprising tefzel tubing packed with TiO₂-coated glass beads, as a pre-column derivatization reactor. The fluorescence derivatization of 5-hydroxyindoles using benzylamine proceeded during their passage through the reaction column under near-UV irradiation. The 5-hydroxyindole derivatives were separated continuously on a reversed-phase liquid chromatography within 50 min, using 100 mM acetate buffer (pH 4.6)-acetonitrile (72:28, v/v; isocratic elution) containing 3 mM sodium octanesulfonate; the samples were detected fluorimetrically at 465 nm upon excitation at 350 nm. The detection limits (signal-to-noise ratio = 3) of the 5-hydroxyindoles were in the range from 160 to 360 fmol per 5 μL injection. We have applied this method, which requires minimal sample pre-treatment, to the determination of 5-hydroxyindole-3-acetic acid in human urine.     

Some observations on the formation of 1-hydroxyindoles in the leimgruber-batcho indole synthesis

The factors influencing the formation of 1-hydroxyindoles in the catalytic hydrogenation of β-dimethylamino-2-nitrostyrenes (Leimgruber-Batcho indole synthesis) have been investigated. Significant amounts of 1-hydroxyindoles were obtained only when the β-dimethylamino-2-nitrostyrene was substituted with an electron-withdrawing group at the 5 or 6 position. The proportion of 1-hydroxyindole formed relative to the normal indole product was found to increase as both the amount of catalyst and hydrogen pressure were decreased.     

Synthesis of 1,3-disubstituted-2-amino-5-hydroxyindoles by reductive aromatization

Reductive aromatization and demethylation of 1,3-disubstituted-2-amino-5-oxo-7a-methyl-5,7a-dihydroindoles with zinc, pyridine and a trace of water yields 1,3-disubstituted-2-amino-5-hydroxyindoles. Simple derivatives of the 5-hydroxy substituent are described.     

Simultaneous liquid chromatographic measurement of melatonin and related indoles through post-column electrochemical demethylation and fluorescence derivatization.

In this paper we describe a highly sensitive and selective liquid chromatographic method for the determination of 5-methoxyindoles (5-methoxyindole-3-acetic acid, 5-methoxytryptamine, 5-methoxytryptophol, and melatonin) using a post-column technique involving electrolytic demethylation followed by fluorescence derivatization with benzylamine. We separated these compounds within 30 min by reversed-phase liquid chromatography using acetate buffer (pH 6.5)-acetonitrile-methanol [8:1:1 (v/v); isocratic elution] and then demethylated them, using a commercial coulometric system, to give the corresponding 5-hydroxyindoles. Next, we converted the 5-hydroxyindole products into fluorescent derivatives by their reactions with benzylamine in the presence of potassium hexacyanoferrate(III). We detected the derivatives spectrofluorometrically at 480 nm upon excitation at 345 nm. The detection limits (signal-to-noise ratio = 3) of the 5-methoxyindoles were in the range from 12 to 93 fmol per 20-microL injection.     

Synthesis of alkylamine derivatives of 1-aryl-5-hydroxyindole

Condensing substituted l-aryl-5-hydroxyindoles with bisdimethylaminomethane, or sodium-alcohol reduction of l-aryl-2-methyl-3-acetyl-5-methoxyindoles gives 4-dimethylaminomethyl and 3-alkylamino derivatives of 1-aryl-5-hydroxy (methoxy) indole, isolated as the hydrochlorides.     

Synthesis of aldehydes and nitriles in the 5-hydroxyindole series

A preparative method for the synthesis of previously inaccessible 3-formyl-5-hydroxyindole derivatives by Vilsmeier formylation of 5-acetoxyindoles is proposed. 5-Hydroxyindole-3-carboxylic acid nitriles and their 4-dimethylamino-methyl derivatives were obtained from 3-formyl-5-hydroxyindoles through their oximes.     

General synthesis of mono-, di-, and tri-acetylated indoles from indolin-2-ones

Having developed the one-pot triacetylation of indolin-3-ones, we have now devised a simple two-step reaction sequences to produce di- and mono-acetylated indoles from indolin-2-ones. The indolin-2-ones were first subjected to acetylation in the presence of acetic anhydride and a catalytic amount of N,N-dimethylaminopyridine to give 2-acetoxy-1,3-diacetylindoles. Subsequently, an enzyme-assisted deacetylation resulted in the chemoselective deprotection of the acetoxy group to produce 1,3-diacetyl-2-hydroxyindoles. However, a chemical deacetylation of 2-acetoxy-1,3-diacetylinoles under mild basic or acidic conditions resulted in the formation of 3-acetyl-2-hydroxyindoles.     

A rapid method for simultaneous estimation of 5-hydroxy-3-indole acetic acid (5HIAA) and 5-hydroxytryptamine (5HT) in rat brain

The authors describe a method to separate 5-hydroxy-3-indole acetic acid (5HIAA) from 5-hydroxyindole derivatives by means of a batch procedure using Dowex 50 WX 12 resins. These compounds were assayed by the Maickel and Miller procedure, and 5-hydroxytryptamine (5HT) was then calculated as the difference between total 5-hydroxyindoles and 5HIAA. This procedure allows a rapid assay of 5HT and 5HIAA in about 60 mg of rat cerebral tissue, but it may not be used when large amounts of 5-hydroxytryptophan are present.     

Ring closure reactions with nitriles. III. Formation of 2-amino- and 2-oxo-3-hydroxyindoles from the reaction of 2′-aroylacylanilides with cyanide

Treatment of 2′-aroylhaloacylanilides with potassium cyanide produced quinazolines, carbostyrils, and 3-hydroxyindoles. From the reaction of 2′-aroyl-2,2-dichloroacetanilides with cyanide, good yields of 2-amino-3-hydroxyindoles were obtained and their reactions were studied.     

The role of a Lewis acid in the Nenitzescu indole synthesis

A highly efficient Lewis acid-catalyzed method for the Nenitzescu synthesis of 5-hydroxyindoles with a range of substituents at N-1 and C-3 and symmetric 5,5′-dihydroxydiindoles has been developed. The amount of the catalyst (10-100 mol %) required depended on the nature of the enaminone component. It has been shown that Lewis acid plays a role in enaminone component activation through an enamine-ZnC1₂ complex followed by its deprotonation.     

Acetals of lactams and acid amides. 66. Synthesis and spectral studies of 4(and 6)-amino-5-hydroxyindole derivatives

A method has been developed for the selective N-alkylation of derivatives of 4-amino-5-hydroxy- and 6-amino-5-hydroxyindoles, based on the preliminary closure of the oxazolone ring by reaction with sodium cyanate and alkylation of the resulting oxazolo[4,5-e]- and oxazolo[5,4-f]-indole derivatives in an alkaline medium. The latter, on heating in an alkali, convert into 5-hydroxy-6-methylaminoindoles, while the former give substituted N-methyl-N-indolylurethanes under these conditions. The reaction of amino-hydroxyindoles with DMFA diethylacetal and certain reactions of the resulting amidines were studied.For communication 65, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 468–474, April, 1991.     

Nitroxide and anion radicals derived from isatogen and related indole derivatives

Neutral indolic nitroxides were obtained by oxidation of 1-hydroxyindoles with lead dioxide. Anion indolic nitroxides were obtained by reduction of indoline-N-oxides in DMSO/t-BuOK (reducing agent being the CH₃SOCH₂^? anion). In both cases an a^N of about 6 gauss was found. This value, which differs from values previously reported, is justified in the course of the work. Some other anion radicals derived from bi-indolic derivatives are also reported and their structures discussed on the basis of MO calculations or by comparison with analogous examples.     

Iridium-catalyzed C-H borylation-based synthesis of natural indolequinones

An iridium-catalyzed C-H borylation provides the key step in a short synthesis of two indolequinone natural products. This regioselective C-H functionalization strategy delivers 7-borylindoles that undergo facile oxidation-hydrolysis to 7-hydroxyindoles and subsequent oxidation to the desired indolequinones, thereby demonstrating a powerful application of the iridium-catalyzed C-H borylation reaction. A significant result has arisen from the iridium-catalyzed borylation of N-diethylhydrosilyl-6-methoxyindole; even in the presence of a substituent at C6, the N-hydrosilyl group still directs borylation exclusively into the more sterically hindered C7 position in preference to C2.     

Synthesis and aminomethylation of 6-hydroxyindoles

Condensation of p-benzoquinone with N-aryl--aminocrotonic esters was used to synthesize N-aryl-2-methyl-3-carbethoxy-6-hydroxyindoles, aminomethylation of which gave N-aryl-2-methyl-3-carbethoxy-6-hydroxy-7-dimethylaminomethylindolesTranslated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1354–1356, October, 1973.     

New synthetic technology for the construction of N-hydroxyindoles and synthesis of nocathiacin I model systems

A new synthetic method providing expedient access to a wide range of polyfunctionalized N-hydroxyindoles (IV) is reported. These unique constructs are assembled by nucleophilic additions to in situ generated α,β-unsaturated nitrones (III) through carbon-carbon and carbon-heteroatom bond formation. The new synthetic technology was applied to the synthesis of nocathiacin I (1) model systems (2 and 3a-c) containing the N-hydroxyindole structural motif.     

Position matters: competing O-H and N-H photodissociation pathways in hydroxy- and methoxy-substituted indoles

H (Rydberg) atom photofragment translational spectroscopy (HRA-PTS) and complete active space with second order perturbation theory (CASPT2) methods have been used to explore the competing N-H and O-H bond dissociation pathways of 4- and 5-hydroxyindoles (HI) and methoxyindoles (MI). When 4-HI was excited to bound (1)L(b) levels, (λ(phot) ≤ 284.893 nm) O-H bond fission was demonstrated by assignment of the structure within the resulting total kinetic energy release (TKER) spectra. By analogy with phenol, dissociation was deduced to occur by H atom tunnelling under the barrier associated with the lower diabats of the (1)L(b)/(1)πσ*((OH)) conical intersection (CI). No evidence was found for a significant N-H bond dissociation yield at these or shorter excitation wavelengths (284.893 ≥ λ(phot) ≥ 193.3 nm). Companion studies of 4-MI revealed different reaction dynamics. In this case, N-H bond fission is deduced to occur at λ(phot) ≤ 271.104 nm, by direct excitation to the (1)πσ*((NH)) state. Analysis of the measured TKER spectra implies a mechanism wherein, as in pyrrole, the (1)πσ*((NH)) state gains oscillator strength by intensity borrowing from nearby bound states with higher oscillator strengths. HRA-PTS studies of 5-HI, in contrast, showed no evidence for O-H bond dissociation when excited on (1)L(b) levels. The present CASPT2 calculations assist in rationalizing this observation: the area underneath the (1)L(b)/(1)πσ* CI diabats in 5-HI is ~60% greater than the corresponding area in 4-HI and O-H bond dissociation by tunnelling is thus much less probable. Only by reducing the wavelength to ≤ 255 nm were signs of N-H and/or O-H bond dissociation identified. By comparison with companion 5-MI studies, we deduce little O-H bond fission in 5-HI at λ(phot) > 235 nm and that N-H bond fission is the dominant source of H atoms in the wavelength region 255 > λ(phot) > 235 nm. The very different dissociation dynamics of 4- and 5-HI are traced to the position of the -OH substituent, and its effect on the overall electronic structure.