Indole-2-carboxylic acid reduction

The Reissert procedure involves base-catalyzed condensation of an o-nitrotoluene derivative 1 with an ethyl oxalate (2) which is followed by reductive cyclization to an indole-2-carboxylic acid derivative 4, as illustrated below . ... 

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). 

Miki and Hachiken reported a total synthesis of murrayaquinone A (107) using 4-benzyl-l-ferf-butyldimethylsiloxy-4fT-furo[3,4-f>]indole (854) as an indolo-2,3-quinodimethane equivalent for the Diels-Alder reaction with methyl acrylate (624). 4-Benzyl-3,4-dihydro-lfT-furo[3,4-f>]indol-l-one (853), the precursor for the 4H-furo[3,4-f>]indole (854), was prepared in five steps and 30% overall yield starting from dimethyl indole-2,3-dicarboxylate (851). Alkaline hydrolysis of 851 followed by N-benzylation of the dicarboxylic acid with benzyl bromide and sodium hydride in DMF, and treatment of the corresponding l-benzylindole-2,3-dicarboxylic acid with trifluoroacetic anhydride (TFAA) gave the anhydride 852. Reduction of 852 with sodium borohydride, followed by lactonization of the intermediate 2-hydroxy-methylindole-3-carboxylic acid with l-methyl-2-chloropyridinium iodide, led to the lactone 853. The lactone 853 was transformed to 4-benzyl-l-ferf-butyldimethylsiloxy-4H-furo[3,4- 7]indole 854 by a base-induced silylation. Without isolation, the... 

The synthesis of a triptan with a chiral side chain begins by reduction of the carboxylic acid in chiral 4-nitrophenylalanine (15-1). The two-step procedure involves conversion of the acid to its ester by the acid chloride by successive reaction with thionyl chloride and then methanol. Treatment of the ester with sodium borohy-dride then afford the alanilol (15-2). Reaction of this last intermediate with phosgene closes the ring to afford the oxazolidone (15-3) the nitro group is then reduced to the aniline (15-4). The newly obtained amine is then converted to the hydrazine (15-5). Reaction of this product with the acetal from 3-chloropropionaldehyde followed by treatment of the hydrazone with acid affords the indole (15-6). The terminal halogen on the side chain is then replaced by an amine by successive displacement by means of sodium azide followed by catalytic reduction of the azide. The newly formed amine is then methylated by reductive alkylation with formaldehyde in the presence of sodium cyanoborohydride to afford zolmitriptan (15-7) [15]. 

Therefore better methods for the chiral reduction of indole-2-carboxylic acid derivatives would provide an elegant synthesis of this intermediate. A study by Kuwano and Kashiwabara of the reduction of indole derivatives into the corresponding indohnes found that a range of the more common ligand systems gave almost no enantioselectivity but the TRAP ligand gave the chiral indolines in up to 95 % ee for reduction of the methyl ester (B, R=Me, R =H). Further developments are awaited. 

For a review of the reduction of enamines and indoles with NaBH, and a carboxylic acid, see Gribble Nutaitis Org. Prep. Proced. Int. 1985, 17, 317-384. Enamines can also be reduced by formic acid sec Nilsson Carlson Acta Chem. Scand. Sect. B 1985, 39, 187. 

The Reimer-Tiemann reaction is not an effective route to formyl-pyrroles or -indoles (see Section 3.05.1.6) and the oxidation of alkyl and hydroxyalkyl derivatives of the heterocycles and the reduction of carboxylic acid derivatives are discussed in Sections 3.05.2.2 and 3.05.2.4, respectively. 

Halogenomethylpyrroles have been oxidized with lead(IV) salts or by chromium trioxide to yield the formylpyrroles, whilst catalytic hydrogenolysis or zinc-acetic acid reduction produces the 2-methylpyrroles (B-77MI30504). The methyl derivatives are also obtained by hydride reduction of trifluoromethyl-pyrroles and -indoles, and trifluoromethylindoles are converted into the carboxylic esters by ethanol under basic conditions (74JOC1836). 

Curtius rearrangement of the heteroaroyl azides, obtained from the reaction of the carboxylic acid chlorides with sodium azide, provides a route to the amino-pyrroles and -indoles (e.g. B-70MI30504, B-77MI30506, 78CPB1054), which, because of the ease of synthesis of the carboxylic acids, is frequently preferable to reduction of the nitro compounds. 

Indole-2-carboxylic acid, 3-(arylazo)-ethyl ester reduction, 4, 301... 

Nucleophilic substitution of chlorine is a key feature of a synthetic approach to a series of indole-6-carboxylic acids. For example, conversion of the starting nitrobenzene 392 using an SnAc reaction followed by reductive cyclization into the indole 393 was concluded by treatment with base to afford the final product 394 (Scheme 46) <2004SL883>. 

This ring closure takes place readily whenever the carbonyl and amino groups occur in the relative positions shown above. Reduction of o-nitro-phenylacetonitrile by stannous chloride produces indole rather than the corresponding amino aldehyde. The synthesis is most useful for the preparation of indole-2-carboxylic acid by reduction of o-nitrophenyl-pyruvic acid with ferrous sulfate and ammonia or with sodium hydrosulfite. The ethyl ester is obtained by a similar reduction with zinc and acetic acid or by catalytic hydrogenation of ethyl o-nitrophenyl-pyruvate over platinum oxide catalyst. ... 

The utility of sodium borohydride (and related metal hydrides) in carboxylic acid media in the reduction of indoles has been reviewed recently and several additional examples can be found cited in this review.There is increasing evidence to suggest that acyloxyborohydride species are the actual reducing agents that form under these conditions. ... 

For a review of the reduction of enamines and indoles with NaBH4 and a carboxylic acid, see Gribble,... 

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