From Indole-2-Carboxylates

Indole-2-carboxylate (70) on Claisen condensation with butyro-lactones (71, 72) gave the lactones (73, 74) which on subsequent hydrolysis and decarboxylation gave the alcohols (75, 76). On oxidation with pyridiniumchlorochromate (PCC) the alcohols gave the aldehydes (77, 78) which on cyclisation with BF3-methanol gave 1-methoxycarbazole (74) derivatives. With 4-methylbutyrolactone (72) murrayafoline A (12) has been synthesised. 

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Pyrano[3,4-b]indol-3-ones are the most useful equivalents of the indol-2,3-quinodimethane synthon which are currently available for synthetic application. These compounds can be synthesized readily from indole-3-acetic acids and carboxylic anhydrides[5,6]. On heating with electrophilic alkenes or alkynes, adducts are formed which undergo decarboxylation to 1,2-dihydro-carbazoles or carbazoles, respectively. 

Beccalli et al. reported a synthesis of carbazomycin B (261) by a Diels-Alder cycloaddition using the 3-vinylindole 831 as diene, analogous to Pindur s synthesis of 4-deoxycarbazomycin B (619). The required 3-vinylindole, (Z)-ethyl 3-[(l-ethoxy-carbonyloxy-2-methoxy)ethenyl]-2-(ethoxy-carbonyloxy)indole-l-carboxylate (831), was synthesized starting from indol-2(3H)one (830) (620). The Diels-Alder reaction of the diene 831 with dimethyl acetylene dicarboxylate (DMAD) (535) gave the tetrasubstituted carbazole 832. Compound 832 was transformed to the acid 833 by alkaline hydrolysis. Finally, reduction of 833 with Red-Al afforded carbazomycin B (261) (621) (Scheme 5.99). 

Diacetylpyrrole is also formed (77JOC3952). The analogous reaction of indoles with carboxylic acids in the presence of trifluoroacetic anhydride and phosphoric acid also gives the 3-acylindoles (derived from the carboxylic acid) in high yield, but without the concomitant formation of the 3-trifluoroacetyl derivatives (80H(14)1939). 

Pyrrole- and indole-carboxylic acid chlorides react with dialkyl- and diaryl-cadmium to yield the ketones and it is noteworthy that the reaction of the anhydride of indole-2,3-dicarboxylic acid with diphenylcadmium produces 3-benzoylindole-2-carboxylic acid and not its isomer (53JCS1889). The ability of l-methylindole-2-carboxylic acid to react with nucleophiles is enhanced by conversion into the mixed anhydride with methanesulfonic acid. The mixed anhydride reacts with carbanions derived from diethyl malonate and from methyl acetate to yield the indolyl (3- keto esters (80TL1957). 

When intermediate 81 is formed from indole 80 and l,l -carbonyldiimidazole (GDI) using DMAP to promote indole nitrogen acylation in acetonitrile at reflux, it is reasonably stable, observed by TLC, but not isolated. Treatment of intermediate 81 in situ with amines, alcohols, or thiols afforded the desired derivatives 82. During the reaction of indoles with GDI, some carbonyl diindole 83 was formed. In many cases this material could be isolated and characterized. In an alternative approach, alcohols reacted with GDI stoichiometrically to form an unstable intermediate carbamate species 84, which could in turn be reacted with indoles to form the desired indole-1-carboxylates 82. This new methodology for the formation of compound 82 proved to be useful in one of the approaches for the synthesis of novel Serotonergics. 

An interesting transformation involving the indole nucleus was found from propargylic carboxylates to give tetracychc compounds with Au(I) (equation 85). This reaction proceeds by an allene-gold complex in equilibrium with the aUcenyl-gold species, which reacts intramolecularly with the indole to form the product. When the reaction of these substrates is performed with dichloro(pyridine-2-carboxylato)gold(III) or Pt(II) as catalysts, products in equation (86) are obtained instead. This new reactivity can be explained by a formal [3 + 2] cycloaddition of 1,3-dipole... 

Trifluoroacetyl-indoles, very simply obtained from indoles by electrophilic substitution, are useful stable equivalents of indol-3-yl-carboxylic acid chlorides, giving amides or acids in reactions with hthium amides or aqueous base respectively. The reactivity of the iV-hydrogen compounds is greater than of those with iV-alkyl, indicating the intermediacy of a ketene in the reactions of the former. ... 

A variety of methods have been developed for the selective installation of chirality at oxindole C3 that involve transfer of functionality from indole C2. The Vedejs group has prepared a small collection of chiral DMAP (4-(lV,A-dimethylamino) pyridine) derivatives bearing conformationally restricted side chains that have been employed as nucleophilic catalysts to direct the transfer of indolyl C2 acetate or carboxylate groups to oxindole C3 with excellent enantiofacial selectivity [15]. As illustrated in Scheme 1, indolyl acetate 1 was converted to the chiral oxindole 3 (94%, 91% ee) using DMAP catalyst 2, while the opposite sense of enantioselec-tivity was observed when indolyl carboxylate 4 was treated with DMAP catalyst 5 to afford 6 as the major oxindole adduct (99%, 94% ee). In addition to probing modifications of the DMAP side chains, it was demonstrated that the overall rate of the reaction catalyzed by DMAP 2 was decreased when the indolyl acetate 1 contained a branched isopropyl substituent at C3 however, good enantioselectivity was observed with the branching substituent (82%, 94% ee). It was also... 

Ligure 5.43 Impedance spectra of the cell Zn/IM ZnS04 (pH 5)/poly(indole-carboxylic acid) at various applied dc potentials in the frequency range of 10 mHz to 100 kHz, (Reproduced from Journal of Applied Polymer Science, 2005, 98, 917. Reprinted with permission of John Wiley Sons, Inc.)... 

However, these directing groups limit the utility of the method because of their irremovability. The authors succeeded in selectively synthesizing C2-alkenylated indoles from indole-3-carboxylic acids through the carboxyl-directed alkenyla-tion/decarboxylation sequence (Scheme 18.50) [49]. This reaction seems to proceed via coordination of a carboxylic oxygen to a Pd(II) species, directed palladation at the C2 position, alkene insertion, and -hydrogen elimination. After the C2-alkenylation, decarboxylation may occur smoothly to produce a 3-unsubstituted 2-alkenylindole derivative. 

Various intermediate products derived from tryptophane have been reported as occasional urinary constituents. These include indole aldehyde, indole acetic acid, scatoxyl, and indole carboxylic acid. Indole and scatole, themselves, are improbable urinary constituents. 

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]. 

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. 

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