Methyl-5-hydroxyindole

Interesting derivatives of indole were described in [35]. When 3-ethoxy carbonyl-2-methyM-(trimethylammonium)methyl-5-hydroxyindole iodide [162, 163] is heated with an excess of trialkyl phosphite [64] (160-165°C, 30 min) 3-ethoxycarbonyl-2-methyl-4,5-(2-oxo-2-alkoxy-l,2-oxaphospholene-4,5)indoles 65... 

Nenitzescu, C. D. Derivatives of 2-methyl-5-hydroxyindole. Bull soc. chim. Romania 1929, 11, 37-43. 

Hydroxyindole (181) represents a well known example of a compound in which the hydroxyl group is to the ring heteroatom. The equilibrium mixture again contains mainly the carbonyl form (182), indoxyl. Deprotonation gives a reactive ambident anion which can be methylated either on oxygen or C-2 (Scheme 73). Indoxyl is easily oxidized to indigo (184), which may be formed by dimerization of the radical (183) produced by electron loss from the anion. 

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). 

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 ... 

Addition of the alcohol 42 to a solution of BF3 Et20/TMSCN in DCM provided the nitrile 43 in 83% yield. Hydrolysis of nitrile 43 then furnished amide 44 in 85% yield. Demethylation of the methoxyindole 44 with BBra in DCM provided the hydroxyindole 45 in 80% yield. This was followed by alkylation of 45 with the bromide 46 under phase transfer conditions to provide the phosphonate ester 47 and subsequent cleavage of the methyl ester by TMS-I furnished trimethylsilyl phosphonic acid 48, which upon alcoholic workup afforded LY311727. 

The values of the 1-hydroxy moiety of (5)-(- -)-iVb-acetyl- 1-hydroxytrypto-phan methyl ester (32), methyl l-hydroxyindole-3-butylate (33), iVb-methoxy-carbonyl-l-hydroxytryptamine (34), 1-hydroxymelatonm (19), l-hydroxy-6-nitroindole (35), and l-hydroxy-5-nitroindole (36) are determined to be 9.8, 8.4, 8.2, 8.1, 6.9, and 6.8, respectively (Fig. 2) (2000H1881). Thus, 1-hydroxyindoles are weak acids, stronger than phenol and weaker than succinimide. Therefore,... 

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. 

Edstrom has utilized the carbonylation variation to engineer new routes to 3-substituted 4-hydroxyindoles, indolequinones, and mitosene analogs [113, 114]. For example, triflate 155 is converted to methyl ester 156 in high yield [114]. Subsequent oxidation affords indole 157. 

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. 

The removal of the semicarbazide residue from aminochrome mono-semicarbazones by alkaline degradation has been reported.303 The resulting 6-hydroxyindole derivatives could be readily isolated as their methyl ethers.303... 

The products of the base-catalyzed Stobbe condensation of 3-formylindole and of 2-formylpyrroles undergo acid-catalyzed cyclization to yield l-hydroxycarbazole-3-carboxylic esters and 4-hydroxyindole-6-carboxylic esters, respectively (73JPR295, 74JPR386, 76JPR816). The analogous condensation of dimethyl homophthalate with 2-formyi-l-methylpyrrole and with 3-formylindole produces (443 Hetero= l-methyl-2-pyrrolyl, 3-indolyl), (444) and (445) under acidic conditions (76JHC83). 

The H-NMR spectra (Table I) show no evidence of tautomerism of 1-hydroxypyrroles to 2H- or 3//-pyrrole 1-oxides and are similar to those of corresponding pyrroles. The hydroxyl proton is not always seen, as in the case of 1-hydroxyindole, and is easily exchanged out by deuterium oxide. The H-NMR spectrum of 2-cyano-2-methyl-2//-pyrrole 1-oxide (2) in dimethyl sulfoxide (DMSO) was unambiguous (Table I), but in deuter-iochloroform, the 3- and 4-protons appeared at the same position. 

Heating the methyl 2-nitro-5-phenyl-2,4-pentadienoates (66) with f-butylisocyanide gave the corresponding 1-hydroxypyrroles (67) (83JOC3639), the mechanism probably being similar to that suggested for the formation of 1-hydroxyindole 49 (see Section lll.G). 

A microsomal O -methyltransI erase that methylates a number of alkyl-, methoxy-, and halophenols has been described from rabbit liver and lungs. These methylations are inhibited by SKF-525, A-ethyl-maleimide and /->-chloromercuribenzoate. A hydroxyin-dole O-methyItransferase, which methylates A -acetyl-serotonin to melatonin and, to a lesser extent, other 5-hydroxyindoles and 5,6-dihydroxyindoles, has been described from the pineal gland of mammals, birds, reptiles, amphibians, and fish. 

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