Dihydroxyindoles

This chapter aims at filling this gap. It is aimed at covering the chemistry of 

6- dihydroxyindoles up to the end of 2004, and exemplifies in its authorship the long tradition of the Neapolitan and English schools of organic chemistry in the field. The focus is naturally on the 5,6-dihydroxyindoles (e.g. 1 and 2), bnt other indoles are also considered because of their structural analogy and conceptual relevance. These include 2,3-dihydro-5,6-dihydroxyindoles, 2,3-dihydroindole-5,6-diones (usually referred to as aminochromes) and l//-indole-5,6-diones. Quite unprecedented is the latter section, which represents the first systematic review of the chemistry of l//-indole-5,6-diones, a class of compounds that until a few years ago belonged to the realm more of conjectures than of direct experimental evidence. Whenever appropriate, an historical perspective of the field will be presented, with the dual scope of keeping due records of the early papers that laid the foundations of 

6-dihydroxyindoles, including the parent system 1, are usually white-to-grey crystalline solids that melt with extensive decomposition and darkening. They are soluble in alcoholic solvents and acetone, less in acetonitrile, ethyl acetate, dimethyl sulphoxide (DMSO), tetrahydrofuran (THF), and water, and only sparingly soluble in hydrocarbons, e.g. benzene and light petroleum. A detailed physicochemical characterization of compound 1 was described by Murphy and Schultz (85JOC5873) (85JOC2790). The values for the first and second ionizations of indole 1 were determined as 8.9 and 10.2, respectively. 5,6-Dihydroxy-1-methylindole 3 has values of 8.4 and 10.7 in water. 

A characteristic subgroup of 5,6-dihydroxyindoles is represented by the 3,5,6-trihydroxyindoles (e.g. 4b), also known as 5,6-dihydroxyindoxyls or lutins , which exist almost exclusively in the 3-keto form (i.e. 4a). These are crystalline solids which form deep-yellow solutions in water and exhibit a typical intense green fluorescence that has provided the basis of several tests for catecholamines in biological fluids (59CR181). When pure, both anhydrous 3,5,6-trihydroxy-1-methylindole 4 

The UV spectral data of several 5,6-dihydroxyindoles are summarized in Table 1. 

10-Tetrahydroindeno[l,26]indole has been shown to inhibit hpid peroxidation and is thought to act as a free radical scavenger (Shertzer and Sainsbury 1991). In Jurkat T cells treated with the cytotoxic agents camptothecin, actinomycin D and ultraviolet irradiation, 4b,5,9b,10-tetrahydroindeno [1,2 b] indole was found to inhibit the morphological features of apoptosis (Devitt et al. 1999). In UV-irradiated cells, 4b,5,9b,10-tetrahydroindeno[l,2b] indole partly inhibited O2 production. 4b,5,9b,10-Tetrahydroindeno[ 1,2 b] indole was unable to inhibit mitochondrial depolarisation in UV, camptothecin or anti-Fas-treated cells. 

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Melanin Drying. One development (ca 1993) in hair coloring involves the formation of pigments within the hair that are very similar to natural melanin. Thus either catalytic or air oxidation of 5,6-dihydroxyindole [3131-52-0] can be effectively used to permanently dye hair within a short time (38). The formed color can, if required, be further modulated with dilute H2O2 or can be even totally removed from hair by this oxidant. 

Eumelanins — These melanins are considered polymers derived from tyrosine derivatives, mainly 5,6-dihydroxyindole-2-carboxylic acid (DHCIA) and dihidrox-yindole (DHl), with high degrees of cross-linking. In vivo eumelanins are associated with proteins and with metals, most frequently copper, zinc, or iron. 

Melanin biosynthesis in animals is a complex process starting with the L-tyrosine amino acid. In the first step, L-tyrosine is converted first into DOPA and then into dopaquinone, a process catalyzed by tyrosinase. In the biosynthesis of eumelanins, dopaquinone undergoes a cyclization to form dopachrome and subsequently a tau-tomerization into 5,6-dihydroxyindole-2-carboxylic acid (DHICA). DHICA is further oxidized to indole-5,6-quinone2-carboxylic acid, the precnrsor of DHICA eumelanins. Tyrosinase-related proteins TRP-2 and TRP-1, respectively, are responsible for the last two steps, and they are under the control of the tyrosinase promoter. 

Pezzella, A. et al., An integrated approach to the structure of sepia melanin evidence for a high proportion of degraded 5,6-dihydroxyindole-2-carboxylic acid units in the pigment backbone, Tetrahedron, 53, 8281, 1997. 

The oxidative polymerization of 5,6-dihydroxyindole (1) and related tyrosine-derived metabolites is a central, most elusive process in the biosynthesis of eumelanins, which are the characteristic pigments responsible for the dark color of human skin, hair, and eyes. Despite the intense experimental research for more than a century,36 the eumelanin structure remains uncharacterized because of the lack of defined physicochemical properties and the low solubility, which often prevents successful investigations by modem spectroscopic techniques. The starting step of the oxidative process is a one-electron oxidation of 5,6-dihydroxyindole generating the semiquinone 1-SQ (Scheme 2.7). 

Pezzella, A. Panzella, L. Crescenzi, O. Napolitano, A. Navaratman, S. Edge, R. Land, E. J. Barone, V. d lschia, M. Short-lived quinonoid species from 5,6-dihydroxyindole dimers en route to eumelanin polymers integrated chemical, pulse radiolytic, and quantum mechanical investigation. J. Am. Chem. Soc. 2006, 128, 15490-15498. 

Il ichev, Y. V. Simon, J. D. Building blocks of eumelanin relative stability and excitation energies of tautomers of 5,6-dihydroxyindole and 5,6-indolequinone. J. Phys. Chem. B 2003, 107, 7162-7171. 

Figure 1. The biosynthetic pathway from tyrosine to melanin (according to Hearing and Tsukamoto, 1991 Tsukamoto et al., 1992). Tyrosinase catalyzes three different reactions in this pathway (1, 2, 3). The reaction catalyzed by the product of TRP-2, DOPAchrome tautomerase, is indicated by 4. DOPA = 3,4-dihydroxyphenylalanine DHICA = 5,6-dihydroxyin-dole-2-carboxylic acid DHI = 5,6-dihydroxyindole.

LOX-hydrogen peroxide system catalyzed the conversion of 5,6-dihydroxyindole and 5,6-dihydroxyindole-2-carboxylic acid, which are important intermediates of melanogenesis, into melanin pigments [47]. 

Oxidative polymerization of phenol derivatives is also important pathway in vivo, and one example is the formation of melanin from tyrosine catalyzed by the Cu enzyme, tyrosinase. The pathway from tyrosine to melanin is described by Raper (7) and Mason (8) as Scheme 8 the oxygenation of tyrosine to 4-(3,4-dihydro-xyphenyl)-L-alanin (dopa), its subsequent oxidation to dopaqui-none, its oxidative cyclization to dopachrome and succeeding decarboxylation to 5,6-dihydroxyindole, and the oxidative coupling of the products leads to the melanin polymer. The oxidation of dopa to melanin was attempted here by using Cu as the catalyst. 

A. Pezzella, D. Vogna and G. Prota, Synthesis of optically active tetrameric intermediates by oxidation of the melanogenic procursor 5,6-dihydroxyindole-2-carboxilic acid under bio-mimetic conditions. Tetrahedron Assymetry 14 (2003) 1133-1140. 

The structurally related diindolocarbazoles are produced as a mixture of isomers in moderate yields by the ammonium persulfate-mediated oxidation of 5,6-dihydroxyindoles in aqueous acidic media <1998JOC7002>. 

Freshly prepared solutions of pure samples of the aminochromes should not exhibit any fluorescence. However, the ease with which they are converted into highly fluorescent 5,6-dihydroxyindoxyls (see Section IV, B) and 5,6-dihydroxyindoles (see Sections IV, B and IV, C) might lead to some confusion, since solutions of aminochromes contaminated with such compounds would undoubtedly fluoresce (cf. ref. 112). 

In 1927 Raper showed that the red pigment obtained on oxidation of DOPA [i.e. 2,3-dihydroindole-5,6-quinone-2-carboxylic acid, dopachrome (4)] rearranged spontaneously by an autoreduction process in vacuo to 5,6-dihydroxyindole (29).72 The rearrangement process could be accelerated by the action of alkali or sulfur dioxide.72 In the latter case, decarboxylation did not accompany the rearrangement and the colorless derivative was 5,6-dihydroxyindole-2-carboxylic acid (17).72 Compounds 17 and 29 were isolated as their dimethyl ethers, (30A) and (30B).72 Immediate decolorization of epinochrome (27) solutions on addition of alkali was reported a few years later.134... 

Subsequent investigations have shown that Raper s suggestion that dopachrome (4) and related aminochromes decompose by an internal oxidation-reduction process forming 5,6-dihydroxyindoles was essentially correct.73,118,120,184-137 The 5,6-dihydroxyindoles obtained from aminochromes such as dopachrome (4) and epino-chrome (27) (i.e. with no substitution in the 3-position) show only a relatively weak blue to blue-mauve fluorescence.118,120 The intense yellow-green fluorescence shown by the rearrangement products of aminochromes with a 3-hydroxyl group is due to the formation of... 

The rearrangement of the aminochromes to 5,6-dihydroxyindoles or 5,6-dihydroxyindoxyls is catalyzed by zinc salts (and less readily... 

Dihydroxyindoles also form complexes readily with sodium bisulfite,118,123, 156 and the presence of the 5,6-dihydroxy -A-methyl-indole-sodium bisulfite addition complex among the products obtained... 

Zinc and dilute acetic acid reduce aminochromes in solution very rapidly giving the expected 5,6-dihydroxyindole in high yield.148,1B1,1BB The reduction reaction apparently takes precedence... 

Reduction of the 7-iodoaminochromes70 with zinc and dilute acid was usually accompanied by virtually complete elimination of the iodine atom,109,155 except in the case of 7-iodonoradrenochrome (42), where, although the main product was 5,6-dihydroxyindole (29), traces of 5,6-dihydroxy-7-iodoindole (56) were also detected.156 Only partial debromination was observed when 7-bromoadrenochrome (57) was reduced with this system 7-bromo-5,6-dihydroxy-.V-methylindole (58) and 5,6-dihydroxy-iV-methylindole (28) were both obtained in significant quantities.155... 

Reduction of the 7-iodo- and 7-bromo-aminochromes with this reagent gives more complex mixtures of products. The reduction process is accompanied by a considerable amount of dehalogenation in each case, and both the expected halogeno-5,6-dihydroxyindole and the corresponding 5,6-dihydroxyindoles are produced.155 Traces of products, similar to the unidentified fluorescent product obtained from adrenochrome, were usually also detected chromatographically, together with several minor unidentified products.155... 

The n.m.r. spectra of several 5,6-dihydroxyindoles (and their diacetyl derivatives) obtained by reduction of different non-halo-genated aminochromes were compared with those obtained from the appropriate 5,6-dihydroxy-(or 5,6-diacetoxy)-iodoindoles produced by reduction of the corresponding iodoaminochromes. The n.m.r. data clearly demonstrated the presence of a- and /3-protons in the indole nuclei (except in the case of the products derived from 2-methylnoradrenochrome and the corresponding iodoaminochrome,... 

Dihydroxyindole and 5,6-dihydroxyindole-2-carboxylic acid were shown to form after the red pigment stage that occurred during the conversion of DOPA into a melanin, by Raper, who isolated these compounds as their dimethyl ethers.72 The presence of 5,6-dihydroxyindoles in solutions of DOPA, dopamine, and noradrenaline which are undergoing oxidation has subsequently been confirmed by paper and thin-layer chromatography.118,120,222 5,6-Dihydroxyin-dole and 5,6-dihydroxyindole-2-carboxylic acid have recently been isolated from the alkali fusion products of sepiomelanin, indicating... 

It is interesting to note that there are several references in the patent literature to the use of 5,6-dihydroxyindoles in hair dyeing preparations.226-228... 

Assay procedures for dopamine which are superficially similar to the lutin procedure described above have been reported recently.266-268 The chemistry of the production of the fluorophore from dopamine is, however, somewhat different since the fluorophore is not a 5,6-dihydroxyindoxyl, it is incorrect to refer to the trihy-droxyindole fluorophore of dopamine (cf. ref. 252). Oxidation of the extracted catecholamine is usually carried out with iodine,266-268 presumably with the formation of 7-iodonorepinochrome. The aminochrome is subsequently rearranged to 5,6-dihydroxyindole (it is probable that deiodination accompanies the rearrangement in this case) by a solution of sodium sulfite in aqueous alkali the solution is acidified before measuring the fluorescence of the product (which is said to form relatively slowly and to be very stable).266-268 Irradiation of the reaction mixture with ultraviolet light accelerates the maximal development of fluorescence.266 Since acidification will produce sodium bisulfite in the reaction mixture, it is probable that the fluorophore is a 5,6-dihydroxyindole-sodium bisulfite addition complex. Complexes of this type are known to be both fluorescent and relatively stable in dilute acid solution.118 123,156 265 They also form relatively slowly.255... 

Harley-Mason has shown that 5,6-dihydroxyindole (29) can also be obtained from /9-(2,4,5-trihydroxyphenyl)ethylamine (101). Oxidation of 101 with potassium ferricyanide, buffered with sodium bicarbonate, gives a deep red solution [presumably containing norepinochrome (106)] from which 29 was obtained, after the solution had been allowed to stand under hydrogen for 24 hours.281... 

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