4-Hydroxyindole, reaction with

Ring closures which depend on the conversion of the heteroatom into an electrophile are mostly associated with the formation of thiophene, selenophene and tellurophene rings and some illustrative examples are shown in Scheme 17. The last example which concerns the conversion of reaction with isocyanides is of particular interest since it appears to entail the attack of an electrophilic nitrogen species on the aryl ring. 

Methylation of 1-hydroxyindoles can be achieved readily by the reaction with diazomethane, Mel, orMc2S04 in the presence of an appropriate base, as described in previous reviews (79MI1, 90AHC105, 91YGK205, 99H1157). Alkylation and acylation also work well with alkyl halides, acyl halides, acid anhydrides, and acids in the presence of acid activators such as DCC and so on. 

Hidai and co-workers found that 3-vinylindole 326 undergoes cyclocarbonylation to afford 1-acetoxycarbazole 327 [425]. The reaction of indole with allene and CO in the presence of catalytic Pd(0) leads to Af-acylation (328) in good yield [426], An analogous reaction with 5-hydroxyindole affords N- and O-acylation products (47% yield). 

The synthesis of 7-methoxyindole was accomplished starting from 1-acetylindoline (34). Regioselec-tive intr uction of iodine was achieved using thallium trifluoroacetate, then potassium iodide. Deacetylation and oxidation to the indole (35), followed by reaction with sodium methoxide in DMF, gave the 7-methoxyindole (36) in 48% overall yield (Scheme 13). More recently, Somei et al have reported that treating the intermediate thallium species with copper(II) sulfate pentahydrate gives directly the l-acetyl-2,3-dihydro-7-hydroxyindole (37) in 42% yield (Scheme 14). It remains to be seen whether this is a general process. 

A useful preparative application of enolate oxidation was presented by Torii in the context of a facile synthesis of 4-hydroxyindole 59 [145]. Similar to Schafer s work [114], the anion of 1,3-cyclohexadione was added anodically to ethyl vinyl ether providing products 56 and 57 in 65%. The mixture of both can be transformed by reaction with (NH4)2C03 in methanol into 58 that is finally converted to 59. 

Hydroxyindole certainly contribntes in the tautomeric equilibrium with the carbonyl form, though it is the minor component. Indoxyl, 10.46, ° is more acidic than oxindole, the anion produced is ambident reactions with electrophiles at both oxygen and carbon are known. ... 

A hemiquinone intermediate rather than an o-quinone resulted from the oxidation of methyl 6-hydroxyindole-2-carboxylate in dimethoxyethane with activated manganese dioxide. By reaction with benzylamine in dimethoxyethane solution the intermediate formed methyl 2-phenylpyrrolo[2,3,e]-benzo-xazole-5-carboxylate in 61% yield (ref.61). 

Some final examples of the Makosza indole synthesis are tabulated in Table 2. Volovenko and colleague report a simple synthesis of 3-substituted-2-amino-5-nitroindoles (entry 1), which were transformed into pyrimido[l,2-fl] indoles upon reaction with p-dicarbonyl compounds [26]. A conventional VNS method was used by Lerman and colleagues to craft 6- and 7-hydroxyindoles via sacrificial chlorine atoms that serve to increase the electrophilicity of the benzene ring toward cyanomethylation. Subsequent transfer hydrogenation (Pd/C/HCO NH ) gives the respective hydroxyindoles (entries 2, 3) [27], The preparation of 3,6-dimethyl-5-methoxyindole by Skibo and coworkers (entry 4) was the starting point in a synthesis... 

In the reactions of 2a and 2b with diene 7 in EAN and [HMIMJpFJ (60°C, 24 h), all they provided normal DA products 19 (Figure 4) and its isomer l-tosyl-6-hydroxyindole 26, respectively, with moderate yield (ca 50%). The products in the reactions with diene 7 resulted from the aromatization of the nitro-adducts promoted by the loss of the nitro and methoxyl groups as nitrous acid and methanol, respectively. Again, the intermediate that suffered nitrous acid extrusion and retained the methoxy group was not detected in any case. In these reactions the regioselectivity was controlled by the nitro and the methoxy group of the diene. 

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). 

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