Carboxy indole

Almotriptan has also been synthesized via decarboxylation of the carboxylic acid intermediate 65, but a detailed preparation of 65 was not provided in the patent literature (Scheme 22)." The patent indicates that the carboxy indole 65 was prepared according to the method of Gonzalez.°° Thus, (2-oxo-tetrahydro-3-furanyl)-glyoxylic acid ethyl ester (62) was heated in aqueous H2SO4 to give 2-oxo-5-hydroxypentanoic acid in situ, which was treated with hydrazine 59 to produce hydrazone 63. Fischer cyclization of 63 using HCl gas in DMF gave the lactone 64, which was converted to carboxylic acid 65. Decarboxylation of 65 was catalyzed by cuprous oxide in quinoline at 190 °C to afford almotriptan (5)." ... 

Dagegen fiihrt die Reduktion der freien 2-Hydroximino-3-(2-nitro-phenyl)-propan-saure liber Platin oder Palladium (20°/lbar) zu einem Gemisch aus 1 -Hydroxy-2-carb-oxy-indol und 2-Carboxy-indol im Verhaltnis 3 2 mit einer Gesamtausbeute von 87% d.Th.2. 

Several protecting groups similar in structure to Boc, other A -(carboxy)indoles andiV-(carbamoyl)indoles, have been investigated in C2-lithiation reactions. Examples of the protecting groups, bases, and electrophiles that have been used appear below (Table 9). 

Table 9 C2-lithiation of iV-(carboxy)indoles and 7/-(carbamoyl)indoles...

Methylthiophene is metallated in the 5-position whereas 3-methoxy-, 3-methylthio-, 3-carboxy- and 3-bromo-thiophenes are metallated in the 2-position (80TL5051). Lithiation of tricarbonyl(i7 -N-protected indole)chromium complexes occurs initially at C-2. If this position is trimethylsilylated, subsequent lithiation is at C-7 with minor amounts at C-4 (81CC1260). Tricarbonyl(Tj -l-triisopropylsilylindole)chromium(0) is selectively lithiated at C-4 by n-butyllithium-TMEDA. This offers an attractive intermediate for the preparation of 4-substituted indoles by reaction with electrophiles and deprotection by irradiation (82CC467). 

Ethyl tram-5 a,9 a-dihydro-1 H- -benzazepine-1 -carboxy late (2), a photorearrangement product of ethyl 3,3a,7a,7b-tetrahydro-l//-cycIobut[6]indole-3-carboxylate (1), on treatment with tet-rachloro-l,2-benzoquinone in benzene undergoes oxidation to the l//-l-benzazepine 3.109... 

Contrary to an alkoxy benzene scaffold, secondary amides were generated via novel aldehyde linker 43 based upon an indole scaffold (Scheme 15) [52]. The indole resin was prepared from indole-3-carboxy-aldehyde in two steps and reacted with amines under reductive conditions to generate resin-bound secondary amines. Treatment of the resin with... 

The functional groups of the enzyme involved in the chemical bonding are the TV-terminal and s-amino groups (from lysine) as well as the carboxy-(aspartic or glutamic acid), sulfhydryl- (cysteine), hydroxyl- (serine, threonine), indole (tryptophan), imidazole (hystidine) and phenolic (tyrosine) functions. 

This indole synthesis has been extended to P-tetrahydrocarbolines (300) [371], azaketotetrahydrocarbazoles [372], carbolines, carbazoles, and pyrido[l,2-a]benzimidazoles [373]. Examples of the former two reaction types are illustrated. An early Heck cyclization of 2-carboxy-2 -iododiphenylamine to 1-carbazolecarboxylie acid (73% yield) [374] has been generally overlooked by subsequent investigators. 

Carboxy substituted diazepines 226 and 229 react with phenyl isocyanate to afford pyrimido diones 227 and 230, correspondingly (Scheme 48, Section 3.1.1.3 (1993JHC897)). N-Hydroxymethylation on an indole ring annulated to benzaze-pinone, as well as formation of the corresponding carbamate and urea, has been described (2004MI1076). 

Carboxy-2-pyridylthio)propionic acids, prepared by the reaction of 2-mercatopyridin-3-carboxylic acid with 3-bromopropionic acid in aqueous KOH, undergo cyclization upon treatment with anhydrous sodium acetate and acetic anhydride to afford 2,3-dihydrothiopyrano[2,3-3]pyridin-4(4//)-ones. These products undergo further reaction with phenylhydrazine to give the phenylhydrazone (isolated) and then Fischer indole cyclization to give novel 5/7,1177-pyrido[2, 3 2,3]thiopyrano[4,3-3]indoles <2000JHC379>. 

Carboxy 7 chloro-2 (ethoxycarbonyl)indole-3-propanoic acid. 68... 

A limited number of reports of indoles arising from o-bromoaniline and enolates have appeared (equation 107) (80JOC1546,8lT(S9)393). The final cyclization step is of the condensation type already recognized in several other procedures. The inertness of unactivated halobenzenes, such as o-bromoaniline, requires an alternative to direct aromatic nucleophilic substitution and those cases where success has been reported depend upon photoinitiated substitution by an electron transfer process. The scope of this method remains to be explored but it appears that alkyl, alkoxy and carboxy groups can be tolerated on the aromatic ring. When the enolates are derived from an unsymmetrical ketone in which one group is methyl, there appears to be a preference for exclusive involvement of the less substituted enolate, leading to 2-alkylindoles. 

The carboxylic acid family of substituents is most often introduced at the stage of ring synthesis for both pyrroles and indoles. Many of the cyclizative condensation routes to pyrroles in fact rely on the presence of ester substituents. Indoles with 2-carboxy substituents are easily available from the adaptation of the Fisher synthesis, which provides the arylhy-... 

The magnesium bromide salt of indole gives the 3-carboxy derivatives in about 30% yield on reaction with carbon dioxide (56JCS2853). Ethyl indole-3-carboxylate can be obtained directly, but in modest yield, using ethyl chloroformate (62JOC496, 6602805). Indole-2-carboxylic acid derivatives can be obtained via the benzenesulfonyl-protected 2-lithio derivative (equation 181) (73JOC3324). 

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