Indole-2-carboxylic acids, formation

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). 

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). 

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... 

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). 

The synthesis of the heteroarylcarboxylic acid chlorides is fraught with difficulties. When isolated, the acid chlorides are generally unstable and readily produce bisheteroaryl ketones (see Section 3.05.1.2.9). Using standard preparative procedures the increase in the acidity of the reaction medium can cause polymerization, whilst the addition of a base can result in the formation of compounds of the type (403) and (404). Attempts to prepare indole-2 -carboxylic acid chloride using thionyl chloride result in the isolation of sulfur-containing derivatives, which arise from electrophilic attack at the 3-position (64JOC178). 

A number of interesting photocyclizations have been reported in aromatic nitro compounds. The first authenticated example is probably that of Tanasescu392 who showed that photolysis of 2-nitrocinnamic acid (370) led to the formation of 3-hydroxy-3/7-indole-2-carboxylic acid 1-oxide (371). Although the mechanism of... 

Reaction of Jt-excessive heterocycles (e.g. thiophene, indole), enol ethers (e.g. dihydropyran) and enol acetates, and carboxylic acids with chlorosulfonyl isocyanate leads in generally excellent yields to A-chlorosulfonylamides. These intermediates are converted into the corresponding nitriles by heating in DMF, although the yields can be somewhat variable. A recent reinvestigation of the N-chlorosulfonylamide to nitrile conversion revealed that treatment of the amides with one equivalent of triethylamine led to formation of the nitriles in excellent yield. Clearly, the mechanisms of the DMF and the EtsN induced transformations are different. 

Many compounds will undergo dimerization reactions those containing thiols (e.g., disulfide formation) olefins, alcohols, and carboxylic acids (or other carbonyl chemistry e.g., aldol condensation reactions). Indoles have been shown to dimerize under acidic conditions. The dimerization is presumed to occur as shown in Figure 120 via protonation at C3 and nucleophilic attack of a second indole on C2. Phenols have been shown to dimerize under free radical initiated oxidative conditions, usually to ortho phenols. Nalidixic acid API undergoes dimerization under thermolysis conditions to decarboxylate and produce a dimeric structure (Fig. 121) (172). 

Scheme 20 Formation of 2,3-dimethylindole and decarboxylation of indole-2-carboxylic acid in water [77]...

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