Ethyl indole-2-acetate

One route to o-nitrobenzyl ketones is by acylation of carbon nucleophiles by o-nitrophenylacetyl chloride. This reaction has been applied to such nucleophiles as diethyl malonatc[l], methyl acetoacetate[2], Meldrum s acid[3] and enamines[4]. The procedure given below for ethyl indole-2-acetate is a good example of this methodology. Acylation of u-nitrobenzyl anions, as illustrated by the reaction with diethyl oxalate in the classic Reissert procedure for preparing indolc-2-carboxylate esters[5], is another route to o-nitrobenzyl ketones. The o-nitrophenyl enamines generated in the first step of the Leimgruber-Batcho synthesis (see Section 2.1) are also potential substrates for C-acylation[6,7], Deformylation and reduction leads to 2-sub-stituted indoles. 

In an approach employing oxidative radical alkylation, the pyrrole 61 was converted to the corresponding pyrrol-2-acetic acid derivative 62 by treatment with the xanthate 63 in the presence of dilauroyl peroxide (DLP). This procedure was also useful for the alkylation of other heterocyclic systems (e,g, indole) producing ethyl indole-2-acetate <03CC2316>. Alternatively, pyrrole-2-acetic acids have been obtained by treatment of pyrrole with various substituted iodoacetic acids and Na2S203/n-Bu4NI with propylene oxide as the Hl-trap in... 

Ethyl indole-2-carboxylate Acetic acid Acetic anhydride Hydrogen... 

Indole synthesis. In the first step of the synthesis o-nitrotoluene is condensed with diethyl oxalate in the presence of potassium ethoxide, and the product is isolated as the deep purple potassium enolate. Hydrogenation in acetic acid reduces the nitro group and effects cyclization to ethyl indole-2-carboxylate. This on hydrolysis and decarboxylation affords indole. 

Heterocyclic Synthesis. - The reactions of phosphorus ylides with phenan-threne-9,10-quinone (113) have been used to prepare phenanthrene [9,10-x]-fused compounds with four, five, and six membered heterocyclic rings. (E)-4-carbethoxymethylene-l,2,3,4-tetrahydro-2-quinolones 114 have been obtained from the stereoselective reaction of 3-hydroxy-1,2,3,4-tetrahydroquinoline-2,4-diones and ethyl(triphenylphosphoranylidene)acetate. A -trifluoroacetylanilines 115 react with Ph3P=C02Et producing enamine derivatives 116 as a mixture of (E)- and (Z)-isomers. Enamines 116 are useful precursors for the synthesis of indoles and quinolones. 

Inhibition of Limonoid Biosynthesis by Auxins. Auxins are potent inhibitors of nomilin biosynthesis in citrus seedlings (31). For instance, up to 91% inhibition was observed when 10 ppm of indoleacetic acid was fed to the stem of a lemeon seedling two days prior to and two days following feeding of 25 pCi of 14-C acetate (Table 1). Other auxins tested include 1-naphthaleneacetic acid (NAA), indolepropionic acid, indolebutyric acid, 3-indole acetonitrile, ethyl indole-3-acetate, 3-indoleacrylic acid, 3-(2-hydroxyethyl)indole, indole-2-carboxylic acid and 2,3,4-trichlorophenoxyacetic acid. They were all very effective. 

C12H13N02 ethyl indole 3 yl acetate R-CN Lichrospher 5pim SDS 72 17 60 29 21... 

N-[2-( 1 -Methoxyindol-3-yl)ethyl]-1 -methoxyindole-3-acetamide (43a), its AT-methyl analog (43b), and Ar-[2-(l-methoxyindol-3-yl)ethyl]indole-3-acet-amide (51) are prepared by the following route (Scheme 8) [23]. 

Condensation of tryptamines (14,44) with indole-3-acetic acid (45) provides N-[2-(indol-3-yl)ethyl]indole-3-acetamides (46a, 81% 46b, 98%). Reduction of 46a with EtsSiH/TFA produces bis-2,3-dihydroindole derivative (47a, 90%), while the reduction with NaBHsCN gives rise to 47a (42%) and 48 (45%), a product reduced selectively at the tryptamine pyrrole part. 

Reduction of 46b with EtsSiH/TFA produces similarly N-methyl-bis-2,3-dihydroindole (47b, 85%). Employing the tungstate method, 47a,b and 48 are converted to N-[2-(l-hydroxyindol-3-yl)ethyl]-l-hydroxyindole-3-acet-amides (49a, 51% 49b, 39%) and N-[2-(l-hydroxyindol-3-yl)ethyl]indole-3-acetamide (50, 55%), respectively. Subsequent methylation of 49a,b and 50 affords 43a (91%), 43b (72%), and 51 (100%). 

Method Two, Albertson et al. (48, 49). Hydrolysis of ethyl o-acet-amido-a-carbethoxy-j8-(3-indole)-propionate or ethyl-o-carbethoigr-ae-benzamido-j8-(3-indolyl)-propionate essentially by the procedure of Snyder and Smith (74) to give 35% over-all yield of tryptophan based on indole. Smith and Sogn (732) prepared ethyl a-carbetiioi -S-indole-propionate from ethyl o-ketocyclopentanone carboxylate (A) but no tryptophan could be synthesized sinCe they were not able to brominate (A). Similarly, Elks et al. (245) were unable to brominate ethyl (2-carbethoxy-3-indolylmethyl) malonate in the o-position although Maurer and Moser (562) stated that they had synthesized tryptophan by this procedure. 

Park YD, Rizzo TR, Peteanu LA, Levy DH (1986) Electronic spectroscopy of tryptophan analogs in supersonic jets - 3-indole acetic-acid, 3-indole propionic-acid, tryptamine, and N-acetyl tryptophan ethyl-ester. J Chem Phys 84(12) 6539-6549... 

Another category Ic indole synthesis involves cyclization of a-anilino aldehydes or ketones under the influence of protonic or Lewis acids. This corresponds to retro.synthetic path d in Scheme 4.1. Considerable work on such reactions was done in the early 1960s by Julia and co-workers. The most successful examples involved alkylation of anilines with y-haloacetoacetic esters or amides. For example, heating IV-substituted anilines with ethyl 4-bromoacetoacetate followed by cyclization w ith ZnClj gave indole-3-acetate esterfi]. Additional examples are given in Table 4.3. 

There are also palladium-catalysed procedures for allylation. Ethyl 3-bromo-l-(4-methylphenylsulfonyl)indole-2-carboxylate is allylated at C3 upon reaction with allyl acetate and hexabutylditin[27], Ihe reaction presumably Involves a ir-allyl-Pd intermediate formed from the allyl acetate, oxidative addition, transmetallation and cross coupling. 

In 1897, Reissert reported the synthesis of a variety of substituted indoles from o-nitrotoluene derivatives. Condensation of o-nitrotoluene (5) with diethyl oxalate (2) in the presense of sodium ethoxide afforded ethyl o-nitrophenylpyruvate (6). After hydrolysis of the ester, the free acid, o-nitrophenylpyruvic acid (7), was reduced with zinc in acetic acid to the intermediate, o-aminophenylpyruvic acid (8), which underwent cyclization with loss of water under the conditions of reduction to furnish the indole-2-carboxylic acid (9). When the indole-2-carboxylic acid (9) was heated above its melting point, carbon dioxide was evolved with concomitant formation of the indole (10). 

Acetylindole (213) was obtained by the action of ethyl acetate on indole magnesium iodide at low temperatures slightly higher yields were obtained when the reaction was carried out in anisole rather than in ether. Putochin subsequently observed that when the reaction was carried out in benzene at 85° both 213 and 3-acetylindole (109)... 

Recently two further examples of the 1-acetylation of indoles by this route have been observed by Heacock and Hutzinger. l-Acetyl-5-benzyloxyindole (216) and l-acetyl-5-benzyloxy-3-methylindole (217) were obtained by the action of ethyl acetate on the relevant indole Grignard reagents at low temperatures. ... 

Formylation of the V-allyl indole derivatives 311 (obtained by allylation of the indole 310) afforded l-allyl-7-formyl-indole 312. Subsequent condensation of 7-formyl indole derivatives 312 with ethyl acetate in presence of sodium ethoxide gave 313 (89S322). Reaction of 312 with N-methylhydroxylamine hydrochloride afforded the cycloadduct, tetracyclic... 

A similar synthesis starting with l-(2-nitrobenzyl)pyrrol-2-aldehyde used ethanol-ethyl acetate as solvent (62). Indoles are prepared in excellent yield by hydrogenation of o-nitrobenzyl ketones over Pd-on-C (i). Azaindoles are correspondingly prepared from nitropyridines (97). 

Aroylation of 3-arylhydrazonoisatin with aroyl chlorides gave 1043, which cyclized with ammonium acetate to give [1,2,4]triazino[5,6-A>]indole 1044 (92MI1). Derivatives of 1045 were prepared (92MI1). Cyclocondensation of 5-ethyl-3-hydrazino-5/f[l,2,4]triazino[5,6-b]indole 165 with succinic anhydride in acetic acid gave pyridazinedione derivative 1046 (90MI7) (Scheme 197). 

Dichlorophenoxy acetic acid (555ng) 12/ Indole-3-acetic acid ethyl ester (445ng)... 

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