Indole- 3-carboxylates, synthesis

Stanovnik, B., Tisler, M. and Carlock, J.T. (1976) Heterocycles, CLIX. A novel synthesis of alkyl indole-3-carboxylates. Synthesis, (11), 754—755. 

Yamazaki, Kondo and coworkers [78] reported on a combination of a Heck reaction and an animation on solid phase for the synthesis of indole carboxylate 6/1-148, employing an acetylated immobilized enamide 6/1-145 and a bifunctionalized... 

In a similar heterocyclic quinodimethane ring construction strategy, the hexacyclic adducts (64) were isolated in good yield upon condensation of appropriately functionalized indole imines with ( )-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid chloride (Equation (35)) (88JA2242). In a demonstration of the utility of this new method for indole alkaloid synthesis, further transformations conducted on compound (64 R = R2 = H, R3 = Et) were shown to lead to ( —)-16-methoxy-tabersonine. 

Hudzinski, P, Evrard, D. A., Bloomquist, W. E., Lacefield, W. B. Indazoles as indole bioisosteres synthesis and evaluation of the tro-panyl ester and amide of indazole-3-carboxylate as antagonists to the serotonin 5HT3 receptor. J. Med. Chem. 1987, 30, 1535—1537. 

A combination of a Mizoroki-Heck reaction and a C—N coupling on solid phase was reported by Yamazaki et al. [105] in the synthesis of indole carboxylate 197 employing immobilized A-acetyldehydroalanine (194) and a bifunctionalized arene 195. In these transformations, 196 is the intermediate. The best results were obtained with o-dibromoarenes such as 195b and 195d using the Pd2(dba)3/P-r-Bu3/Cy2NMe catalytic system developed by Littke and Fu [106]. The protocol was also extended to the synthesis of isoquinolines [107] (Scheme 8.50). 

The limitation of the previous methodology to indole-2-carboxylates somewhat diminishes the synthetic value of this approach. The same group recently provided a possible solution to this problem by developing a very efficient complementary approach toward the indole ring synthesis, where aryl azides were employed as electrophilic nitrogen sources. In this way, orfho-vinyl-substituted aryl azides 208,... 

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. 

The main example of a category I indole synthesis is the Hemetsberger procedure for preparation of indole-2-carboxylate esters from ot-azidocinna-mates[l]. The procedure involves condensation of an aromatic aldehyde with an azidoacetate ester, followed by thermolysis of the resulting a-azidocinna-mate. The conditions used for the base-catalysed condensation are critical since the azidoacetate enolate can decompose by elimination of nitrogen. Conditions developed by Moody usually give good yields[2]. This involves slow addition of the aldehyde and 3-5 equiv. of the azide to a cold solution of sodium ethoxide. While the thermolysis might be viewed as a nitrene insertion reaction, it has been demonstrated that azirine intermediates can be isolated at intermediate temperatures[3]. 

Lewis acids such as zinc triflate[16] and BF3[17] have been used to effect the reaction of indole with jV-proiected aziridine-2-carboxylate esters. These alkylations by aziridines constitute a potential method for the enantioselective introduction of tryptophan side-chains in a single step. (See Chapter 13 for other methods of synthesis of tryptophans.)... 

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

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). 

It has been said that the above procedure cannot be applied to the synthesis of the corresponding nitro derivative, 8-nitro[l,2,4]triazino[5,6-b]indole-3-thione. Thus, heating 5-nitroisatin-3-thiosemicarbazone in aqueous potassium carbonate gave after acidification a mixture of oxotria-zinethione 137 and 5-nitroindazole 3-carboxylic acid (90ZOR1327). 

A type Ilac synthesis of functionalized pyrroles was developed that adapted the Larock indole synthesis <06OL5837>. For example, treatment of iodoacrylate 19 and trimethylsilylphenylacetylene 20 with palladium acetate led to the formation of pyrrole-2-carboxylate 21 with excellent regioselectivity. 19 was prepared by iodinating (N-iodosuccinimide) the corresponding commercially available dehydroamino ester. 

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