5,6-Dihydroxyindole

Since the oxidative polymerization of phenols is the industrial process used to produce poly(phenyleneoxide)s (Scheme 4), the application of polymer catalysts may well be of interest. Furthermore, enzymic, oxidative polymerization of phenols is an important pathway in biosynthesis. For example, black pigment of animal kingdom "melanin" is the polymeric product of 2,6-dihydroxyindole which is the oxidative product of tyrosine, catalyzed by copper enzyme "tyrosinase". In plants "lignin" is the natural polymer of phenols, such as coniferyl alcohol 2 and sinapyl alcohol 3. Tyrosinase contains four Cu ions in cataly-tically active site which are considered to act cooperatively. These Cu ions are presumed to be surrounded by the non-polar apoprotein, and their reactivities in substitution and redox reactions are controlled by the environmental protein. 

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). 

Such results seem to be rather indicative of the opportunity to exploit TD-DFT and the PBEO functional in predicting spectroscopic properties of mixtures containing the three tautomers 1-Q, 1-QM, and 1-QI in aqueous solution. This approach should be very useful for future experimental mechanistic investigations clarifying the complex mechanisms of dihydroxyindole oxidation. 

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]. 

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. 

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... 

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