Synthesis of Derivatives of 2-(Indol-1-yl)propionic Acids (original) (raw)

Simple synthesis of methyl 1-(1,1-dimethyl-prop-2-en-1-yl)-1h-indole-3-carboxylate

Chemistry of Heterocyclic Compounds, 2008

Although few in number, indole derivatives containing a 1,1-dimethylpropen-2-yl (isopropenyl) fragment on the nitrogen atom are extremely interesting from the viewpoint of the medicinal chemistry of a class of naturally occurring compounds showing diverse biological properties. Some of these show anticancer, antifungal, antibiotic, anti-inflammatory, and antiviral activity [1-4]. The simplest member of the N-isopropenyl indole alkaloids is methyl 1-(1,1-dimethylprop-2-en-1-yl)-1H-indole-3-carboxylate (1) which is isolated from the Aporpium caryae basidiomycetes fungus and shows clear antifungal activity [4]. Compound 1 also serves as the synthetic precursor of other biologically active, naturally occurring indole derivatives i.e. methyl 1-(2,3-dihydroxy-1,1,-dimethylprop-2-en-1-yl)-and 1-(1,1-dimethyl-2,3-epoxyprop-2-en-1-yl)-1H-indole-3-carboxylates. Despite the relative structural simplicity of compound 1 its synthesis is not a trivial problem in view of the impossibility of directly introducing an isopropenyl substituent at position 1 of the indole. Up to this time the preparation of this compound involved two "indirect" synthetic strategies. The first of these consists of five stages (overall yield 60%) and is based on initial preparation of an N-isopropenylindoline, oxidation to the corresponding indole, and the introduction of a methoxycarbonyl group at position 3 in the final synthetic step [1, 2]. The second strategy consists of seven stages (overall yield 22%) and includes the preliminary transformation of an N-(1-ethoxycarbonyl)ethyl substituent in the N-indole to N-isopropenyl and then the introduction of the methoxycarbonyl substituent at position 3 [3]. We propose a novel, simple, and efficient method for the synthesis of compound 1 based on the use of the method reported recently by us to prepare N-substituted 1H-indole-3-carboxylic acids via a copper (I) iodide-catalyzed intramolecular Ullman reaction [5]. Refluxing equimolar solutions of methyl α-formyl-(o-bromophenyl)acetate (2) and the commercially available 1-methylbutyn-3-yl-2-amine in methanol gave the enamine 3 needed for cyclization and used in the following step without further purification. We have previously shown that cyclization of enamines prepared from α-branched primary aliphatic amines under standard conditions (CuI (5 mol %), K 3 PO 4 (2 equiv.), 80ºC) occurs slowly, full conversion of starting enamine needing a prolonged reaction time (10-20 h) and the indole yield did not exceed 50% [5]. An analogous situation has been seen in the cyclization of enamine 3, the yield of the N-isopropenyl indole 4 not exceeding 36% under these conditions. Increasing the reaction temperature to 140ºC caused only a minor increase in the yield to 50%.

Synthesis, characterization and biological activity of indole-2-carboxylic acid derivatives

International Journal of Pharmaceutical Chemistry, 2015

Synthesis of indole-2-carboxylic acid derivatives has attracted considerable attention in view of therapeutic applications. In the presented research work, a series of 3-[ N , N -Dialkylamine(oxo)acetyl]-1-propyl-1 H -indole-2-carboxylic acids was synthesized from 1-Propyl-1H-indole-2-carboxylic acid. The synthesis was carried out by treating 1-Propyl-1H-indole-2-carboxylic acid with oxalyl chloride in dry dichloromethane and condensation of different secondary amines with 1-propyl-1 H -indole-2-carbohydrazide forms the titled compounds (OND 1 OND 10). All the synthesized compounds have been characterized by using elemental analysis, FT-IR, 1 H NMR, 13 C NMR spectroscopy and further supported by mass spectroscopy. Purity of all the compounds has been checked on thin layer chromatographic plate and HPLC technique. All the synthesized compounds were screened for their antibacterial activities against Staphylococcus aureus, Staphylococcus pyogenus, Escherichia coli and Pseudomonas aeru...

New 3H-Indole Synthesis by Fischer’s Method. Part I.

Methyl indolenines (4a-c) and (5a-c) were prepared in high yield by a Fischer indole synthesis reaction of o,m-tolylhydrazine hydrochlorides (1a-b) with isopropyl methyl ketone (2) and 2-methylcyclohexanone (3) in acetic acid at room temperature. o,p-Nitrophenylhydrazines (1c-d) were reacted with 2-methylcyclohexanone (3) in acetic acid at reflux to give nitroindolenines (5d-e), while the attempted reactions of o,pnitrohydrazines with isopropyl methyl ketone (2) in acetic acid were not successful. Compounds (1c-d) were reacted with isopropyl methyl ketone (2) in acetic acid/HCl to give 2,3,3-trimethyl-5-nitro-indolenine (4e) and 2,3,3-trimethyl-7-nitroindolenine (4d).