Indoles 1-hydroxy

One of the virtues of the Fischer indole synthesis is that it can frequently be used to prepare indoles having functionalized substituents. This versatility extends beyond the range of very stable substituents such as alkoxy and halogens and includes esters, amides and hydroxy substituents. Table 7.3 gives some examples. These include cases of introduction of 3-acetic acid, 3-acetamide, 3-(2-aminoethyl)- and 3-(2-hydroxyethyl)- side-chains, all of which are of special importance in the preparation of biologically active indole derivatives. Entry 11 is an efficient synthesis of the non-steroidal anti-inflammatory drug indomethacin. A noteworthy feature of the reaction is the... 

Pyridazinones may undergo ring contraction to pyrroles, pyrazoles and indoles, the process being induced either by an acid or base. The structure of the final product is strongly dependent on the reaction conditions. For example, 4,5-dichloro-l-phenylpyridazin-6(lFT)-one rearranges thermally to 4-chloro-l-phenylpyrazole-5-carboxylic acid (12S), while in aqueous base the corresponding 4-hydroxy acid (126) is formed (Scheme 40). 

Indole, 3-hydroxymethyl-2-phenyl-stability, 4, 272 Indole, I-hydroxy-2-phenyl-synthesis, 4, 363 Indole, 2-iodo-synthesis, 4, 216 Indole, 3-iodo-reaetions, 4, 307 synthesis, 4, 216 Indole, 2-iodo-l-methyl-reaetions, 4, 307 Indole, 2-lithio-synthesis, 4, 308 Indole, 3-lithio-synthesis, 4, 308 Indole, 2-mereapto-tautomerism, 4, 38, 199 Indole, 3-mercapto-tautomerism, 4, 38, 199 Indole, 3-methoxy-synthesis, 4, 367 Indole, 5-methoxy-oxidation, 4, 248 Indole, 7-methoxy-2,3-dimethyl-aeetylation, 4, 219 benzoylation, 4, 219 Indole, 5-methoxy-l-methyl-reduetion, 4, 256 Indole, 5-methoxy-l-methyl-3-(2-dimethylaminoethyl)-reaetions... 

Indole-2-carboxylic acid, 5-bromo-l-hydroxy-tautomerism, 4, 197-198 Indolecarboxylic acid chloride synthesis, 4, 288... 

A wide vanety of nucleophiles, such as 1-alkylpyrroles, furans, thiophenls [51], phenols [52], anilmes [55, 54], indoles [55], CH-acidic compounds [56, 57], as well as organolithium [56], Gngnard [57, 59], organocadmiura, and organozmc compounds [56], undergo C-hydroxyalkylation with trifluoropynivates to yield derivatives of a-trifluoromethyi a-hydroxy acids. 

Carboxyphenyl-(2-methyl-3-indoleninjdidene)methanol (303) was said to be formed by the action of phthalic anhydride on 2-methyl-indole magnesium bromide. Skatole magnesium bromide, on the other hand, apparently gave 2-carboxyphenyl-(3-methyl-2-indole-ninylidene)methanol (304) and 3-hydroxy-3-(3-methyl-l-indolyl)-phthalide (305) on treatment with 1 mole of phthalic anhydride. The derivative 305 was easily hydrolyzed in alkali, giving skatole and phthalic acid, and was thus formulated as a 1-skatolyl derivative. ... 

IV. Chemical Reactions of 1-Hydroxy-, 1-Alkoxy-, and l-(Q -D-Glucopyranosyl)indoles. . 109... 

On the other hand, an electron-donating substituent destabilizes the 1-hydroxy-indole structure, often to the extent that it cannot be isolated. Even in such a case, alkylation of the 1-hydroxy group greatly improves the stability. Among alkylations, methylation is the best choice. This fact explains why every isolated natural product has a 1-methoxyindole structure (91YGK205, 99H1157). 

Hydroxy- and 1-alkoxyindoles undergo characteristic reactions depending on their structures, reagents, and reaction conditions. At the beginning of this section, preparations of 1-alkoxyindoles and l-(Q -D-glucopyranosyl)indoles are discussed. 

The reaction of Ab-acetyl-1 -hydroxytryptamine (39) with mesyl chloride (MsCl) in THF in the presence of EtsN provides 1-acetyl-1,2,3,8-tetrahydropyrrolo[2,3-(j] indole (49a, 35%) (70JA343), Ab-acetyl-6-mesyloxytryptamine (50a, 4%), Ab-acetyl-2,3-dihydro-2-oxotryptamine (51a, 5%), l-acetyl-3a-(4-chlorobutoxy)-l,2,3,3a,8,8a-hexahydropyrrolo[2,3-(j]indole (52a, 7%), and Ab-acetyltryptamine (53a, 2%) as shown in Scheme 6 (2000H483). In the same reaction with MsCl, l-hydroxy-Ab-methoxycarbonyltryptamine (34) produces 50b (7%), 51b (34%), and 52b (9%), while the formation of 49b is not observed at all. In the case of Ab-trifluoroacetyl-l-hydroxytryptamine (48), 49c (45%), 50c (8%), 51c (4%), and 52c (6%) are produced. These data suggest that the yield of 49 increases, whereas the yield of 51 decreases in the order of electron-withdrawing ability of Ab substituents (COOMe < COMe < COCF3). Stability of 49 seems to govern the quantity of 51, which is probably formed by hydrolysis of 49. 

Treatment of 1-hydroxy-iVb-trifluoroacetyltryptamine (48), which is readily available in three steps from tryptamine (259, Scheme 40), with MsCl in THF in the presence of indole (3 mol eq) and EtsN produces l-trifluoroacetyl-1,2,3,8-tetrahydropyrrolo[2,3-(j]indole (49c, 25%), l-trifluoroacetyl-3a-(4-chlorobutoxy)-l,2,3,3a,8,8a-hexahydropyrrolo[2,3-(j]indole (52c, 6%), iVb-trifluoroacetyl-6-mesyloxytryptamine (50c, 8%), 3a-(indol-2-yl)- (260, 5%), and 3a-(indol-3-yl)-l-trifluoroacetyl-l,2,3,3a,8,8a-hexahydropyrrolo[2,3-(j]indole (261, 12%). In this reaction, solvent plays an important role. Among the tested solvents such as benzene, CHCI3, 1,2-dichloroethane, THF, DMF, CH3CN, and iV-methylformamide, CHCI3 is found to be the solvent of choice to provide a 21% yield of 261. The use of excess indole (10 mol eq) further raises the yield to 30%. 

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