Indoles carboxylate formation

As Table 8 illustrates, the venerable Japp-Klingemann variation of the Fischer indolization continues to attract interest. Entry 1 features a three-component Japp-Klingemann indolization involving diazonium salts, acid chlorides, and amines or alcohols and involving the intermediacy of a-hydrazono carboxylic acid esters and amides prior to indole ring formation [385]. Entry 2 describes a preparation of 5-indolyl-Mannich bases and, hence, an expedient source of 5-(chloromethyl)indoles (acetyl... 

Flash vacuum pyrolysis of 2-methoxycarbonylpyrrole (11) gives the ketene (12), characterized by IR absorption at 2110 cm. On warming to -100 to -90 °C the dimer (13) is formed (82CC360). Flash vacuum pyrolysis of indole-2-carboxylic acid (14) results in loss of water and the formation of a ketene (15) showing absorption at 2106 cm (82CC360). 

As foretold in the introduction, ring formation via attack on a double bond in the endo-trig mode is not well exemplified. The palladium(II) catalyzed oxidative cyclization of o-aminostyrenes to indoles has been described (78JA5800). The treatment of o-methyl-selenocinnamates with bromine in pyridine gives excellent yields of benzoselenophene-2-carboxylates (Scheme 10a) (77BSF157). The base promoted conversion of dienoic thioamides to 2-aminothiophenes is another synthetically useful example of this type (Scheme 10b) (73RTC1331). 

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). 

Novel l//-imidazo[l,2-a]indole-3-carboxylates 47 were prepared <96SC745>. Thermolyses of halogenated 4,5-dicyanoimidazole derivatives 48 (X = H, Y = F, Cl X = 1, Y = Cl, Br, I) at 100-290 °C led to formation of perhaps the ultimate fused-ring imidazole, hexacaib(Hiitrilelris(iinidazo)triazene (HTT) <96JOC6666>. 

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. 

Ethyl 3-azido-l-methyl-177-indole-2-carboxylate 361 is prepared in 70% yield by diazotization of amine 360 followed by substitution of the created diazonium group with sodium azide. In cycloadditions with nitrile anions, azide 361 forms triazole intermediates 362. However, under the reaction conditions, cyclocondensation of the amino and ethoxycarbonyl groups in 362 results in formation of an additional ring. This domino process provides efficiently 4/7-indolo[2,3-i ]l,2,3-triazolo[l,5- ]pyrimidines 363 in 70-80% yield (Scheme 57) <2006TL2187>. 

Alternatively, diazotization of ethyl indole-2-carboxylate (179) leads to formation of 2-carboethoxy-3-diazo-3H-indole (180) which undergoes rhodium-catalyzed alcohol O-H insertion reactions leading to 3-alkoxyindoles 181 <00TL6905>. 

Diels-Alder reaction of 3-vinylindole 131 with aryne in the presence of air gives, besides primary Diels-Alder product 132, the methyl 12-methyl-12H-[3]-benzoxepino[l,2-l7]indole-5-carboxylate 135. This can be explained by the formation of 1,2-dioxetane 133, its cyclo reversion and final intramolecular cyclization of dienol 134 or its tautomers (Scheme 26 (1996JCS(P1)1767)). 

The susceptibility of the indole ring towards electrophilic attack has also been exploited by Merour in the annulation of a coumarin unit to the indole ring. The heating of the o-bromophenyl ester of indole-2-carboxylic acid in the presence of a palladium-triphenylphosphine catalyst led to the formation of the tetracyclic product in 66% yield (4.32.)40... 

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