Hydroxyindole

Peroxide oxidation of Af-phenylsulfonylindole-3-boronic acid gives A -phenylsulfonylindoxyl, which can be converted into the triflate of the 3-hydroxyindole tautomer. The same A -protected indoxyl can be prepared by ring synthesis, as shown below. 

Isatin is a stable, bright orange solid that is commercially available in large quantities. Because it readily undergoes clean aromatic substitution reactions at C-5, iV-alkylation via an anion, and ketonic reactions at the C-3-carbonyl group, for example enolate addition, it is a very useful intermediate for the synthesis of indoles and other heterocycles. 

Conversion of isatins into oxindoles can be achieved by catalytic reduction in acid, or by the Wolff-Kischner process.3-Substituted indoles result from Grignard addition at the ketone carbonyl, followed by lithium aluminium hydride reduction of the residual amide, then dehydration. The reaction of isatin with triphenylphosphine provides an easy synthesis of 3-(triphenylphosphorylidene)oxindole, a Wittig reagent.  

A process that produces pyrroles, from ketones and hydroxyproline, works well with isatins.  

1-Hydroxyindole can be prepared in solution, but attempted purihcation leads to dimerisation via its nitrone tautomer however, 0-alkyl-derivatives can be formed easily and are stable.  

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Reactions of quinones with enamino ketones have not been reported, but ethyl (S-anilinocrotonate (94), an enamino ester, has been shown to condense (71) with p-benzoquinone to give l-phenyl-2-methyl-3-carbethoxy-5-hydroxyindole (95). 

The procedure was largely ignored until the 1950s when interest in melanin-related substances and recognition of serotonin as a 5-hydroxy derivative stimulated exploration of the scope of the reaction. Nowadays, the Nenitzescu reaction is one of the most efficient processes for the preparation of 5-hydroxyindoles. 

At least two pathways have been proposed for the Nenitzescu reaction. The mechanism outlined below is generally accepted." Illustrated here is the indolization of the 1,4-benzoquinone (4) with ethyl 3-aminocrotonate (5). The mechanism consists of four stages (I) Michael addition of the carbon terminal of the enamine 5 to quinone 4 (II) Oxidation of the resulting hydroquinone 10 to the quinone 11 either by the starting quinone 4 or the quinonimmonium intermediate 13, which is generated at a later stage (HI) Cyclization of the quinone adduct 11, if in the cw-configuration, to the carbinolamine 12 or quinonimmonium intermediate 13 (IV) Reduction of the intermediates 12 or 13 to the 5-hydroxyindole 6 by the initial hydroquinone adduct 7 (or 8, 9,10). 

Condensation of the TV-substituted p-aminocrotonic acid ester 15 with p-benzoquinone (4) has been successfully carried out to furnish the 5-hydroxyindole 29 when the substituent R on the nitrogen of the aminocrotonic acid ester was methyl, ethyl, -propyl, isopropyl, or -butyl, -hexyl, p-cyanoethyl, p-hydroxyethyl, carbethoxymethyl, benzyl, phenyl, o-tolyl, dimethylaminopropyl, y-hydroxypropyl etc ... 

Additional variations of the enamine moiety that have been satisfactorily condensed with a p-benzoquinone (4) to form 5-hydroxyindole 31 are given in the following table. 

The choice of experimental conditions exerts a major influence on the course of Nenitzescu procedure and thereby determines the structure of the major product. The mechanism demonstrated to be operative for the method can be employed to understand the genesis of certain anomalous products and suggests ways to avoid them, thus increasing the efficiency of the synthesis of 5-hydroxyindoles. 

The best yields of 5-hydroxyindoles are obtained when equimolar amounts of the quinone and enamine are used. An excess of enamine gives rise to non-indolic products derived from reaction of two enamine units and one quinone unit or the product which results from the initial Michael addition of the enamine to the quinone. Use of excess quinone has been reported less frequently, but limited studies indicate no advantage. When 2,5-dichloro-l,4-benzoquinone (32) was treated with a 50% excess of ethyl 3-... 

The Nenitzescu process is presumed to involve an internal oxidation-reduction sequence. Since electron transfer processes, characterized by deep burgundy colored reaction mixtures, may be an important mechanistic aspect, the outcome should be sensitive to the reaction medium. Many solvents have been employed in the Nenitzescu reaction including acetone, methanol, ethanol, benzene, methylene chloride, chloroform, and ethylene chloride however, acetic acid and nitromethane are the most effective solvents for the process. The utility of acetic acid is likely the result of its ability to isomerize the olefinic intermediate (9) to the isomeric (10) capable of providing 5-hydroxyindole derivatives. The reaction of benzoquinone 4 with ethyl 3-aminocinnamate 35 illustrates this effect. ... 

Preparation of ethyl 2,6-dimethyl-5-hydroxyindole-3-carboxylate(50) and ethyl 2,7-dimethyl-5-hydroxyindole-3-carboxylate(51). ... 

Arbidol (ethyl 6-bromo-4-dimethylaminomethyl-5-hydroxyindole-3-carbox-ylate), anew immunomodulator 99KFZ(3)3. 

The first total synthesis of 87 was published in 1990 (90TL1523). 5-Hydroxyindole (88) was mesylated and then reduced with sodium cyanoborohydride to give an indoline which was brominated to afford the bromoindoline 89 in good yield (Scheme 33). Cross-coupling with ortho-formyl boronic acid under Suzuki conditions, followed by air oxidation of the resulting cyclized product, followed by reduction of the lactam formed with excess Red-Al gave the target compound 87. 

FIGURE 3-27 Three-dimensional chromatogram for oxidizable biological compounds at a multichannel amperometric detection system, consisting of an array of 16 carbon-paste electrodes held at different potentials. AA = ascorbic acid NE = norepinephrine DOPAC = 3,4-dihydroxyphenylacetic acid 5-HIAA = 5-hydroxyindole-3-acetic acid DA = dopamine HVA = homovanillic acid. (Reproduced with permission from reference 68.)... 

Multiple doses of MDMA or MDA resulted in a further decline in TPH activity (figure 4). In contrast to METH, however, neither MDA nor MDMA altered neostriatal TH activity. The decrease in TPH activity was accompanied by a dramatic decrease in 5-HT and 5-HIAA concentrations these changes in TPH activity and in 5-hydroxyindole content also occurred in other serotonergic terminal areas such as the hippocampus and cerebral cortex. Both neostriatal DA and homovanillic acid (HVA) were initially elevated 3 hours after a single dose of MDMA, but had returned to normal... 

Sanders-Bush, E. Bushing, J.A. and Sulser, F. Long-term effects of p-chloroamphetamine on tryptophan hydroxylase activity and on levels of 5-hydroxytryptamine and 5-hydroxyindole aeetie acid in brain. 

Fuller, R.W., and Snoddy, H.D. Long-term effects of 4-chloroamphetamine on brain 5-hydroxyindole metabolism in rats. Neuropharmacology 13 85-90, 1974. 

Figure 2 Selective electrochemical detection of a mixture on multielectrode amper-ometry. AA = Ascorbic acid, NE = norepinephrine, DOPAC = 3-4-dihydroxy-phenylacetic acid, E = epinephrine bitartrate, 5-HIAA = 5-hydroxyindole-3-acetic acid, HVA = homovanillic acid, TRP = tryptophan, 5-HT = 5-hydroxytryptamine, and 3-MT = 3-methoxytyramine (separated by RPLC). Detection was with a 4-electrode glassy carbon array, with electrode 1 at 500 m V) electrode 2 at 700 mV, electrode 3 at 900 mV, and electrode 4 at 1100 mV. Note that at electrode 1, HVA, TRP, and 3-MT are not seen. At electrode 2, only TRP is not seen. A standard calomel electrode was used as reference. (Reprinted with permission from Hoogvliet, J. C., Reijn, J. M., and van Bennekom, W. P., Anal. Chem., 63, 2418, 1991. 1991 Analytical Chemistry.)...

Houdouin, F., Cespuglio, R. 8r Jouvet, M. (1991). Effects induced by the electrical stimulation of the nucleus raphe dorsalis upon hypothalamic release of 5-hydroxyindole compounds and sleep parameters in the rat. Brain Res. 565, 48-56. 

Gong and co-workers employed an intermolecular Nenitzescu reaction, a type lice transformation, for the condensation of a P-amino-a,(3-unsaturated ester with 1,4-benzoquinone to afford a 5-hydroxyindole derivative <06BMC911>. 

Figure 9 Chromatogram of 5-hydroxyindoles derivatized with 6-AMP. Peaks (2.5 pmol each on column) 1 = 5-hydroxytryptophan 2 = serotonin 3 = 5-hydroxyindole-3-acetic acid. (From Ref. 50.)...

Ketcha and Wilson reported the solid-phase version of the classic Nenitzescu indole synthesis in a process involving initial acetoacetylation of ArgoPore-NH2 resin with diketene to afford a polymer bound acetoacetamide <00TL6253>. Formation of the corresponding enaminone 102 via condensation with primary amines in the presence of trimethylorthoformate followed by addition of 1,4-benzoquinones 103 leads to formation of polymer bound 5-hydroxyindole-3-carboxamides 104 which could be cleaved from the resin using TFA yielding the indoles 105. 

FIG. 1. Reversal by a 5-HT antagonist (methiothepin) of changes induced by LSD administration on indole levels in the whole brain of adult rats. LSD alone (2X1 mg/kg i.p. 120 and 100 min before death) induced a significant reduction of the 5-HIAA/5-HT ratio, indicating a marked decrease in 5-HT turnover. This effect was almost entirely suppressed by the combined treatment with the potent 5-HT antagonist methiothepin (20 mg/kg i.p. 110 min before death). Therefore, 5-hydroxyindole alterations due to LSD involve the direct stimulation of 5-HT receptors by the hallucinogen. Bar, mean SEM of six determinations. p < 0.05 when compared with saline-treated rats p < 0.05 when compared with rats treated with LSD alone. 

The possible effects of hallucinogens on central monoaminergic neurons were first explored by Freedman (34), who discovered that a single injection of LSD increases 5-HT levels in the rat brain, whereas its inactive congener BOL fails to affect brain 5-HT. Since this change is associated with a decrease in the concentration of the main metabolite of 5-HT, 5-hydroxyindole acetic acid (5-HIAA) (Fig. 1), Rosecrans et al. (98) postulated that LSD administration in... 

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