Indole derivatives 3- carboxylation

In some instances, ring contraction is accompanied by cyclization to indole derivatives. For example, l-aryl-6-oxo-l,4,5,6-tetrahydropyridazines with a carboxyl or methyl group at position 3 give indoles when treated with an ethanolic solution saturated with hydrogen chloride or in the presence of BF3 etherate. 

Rauwolscine gives colour reactions like those of yohimbine and the absorption curves of the hydrochlorides of the two alkaloids are very similar. Heated to 300°/5 mm. rauwolscinic acid forms barman (p. 490) and 3-ethylindole and on fusion with potassium hydroxide decomposes into indole-2-carboxylic acid, isophthalic acid, barman and an unidentified indole derivative. Rauwolscine itself on distillation with zinc dust produces barman, 2-methylindole (scatole) and tsoquinoline. It is suggested that the alkaloid has the skeletal strueture suggested by Seholz (formula XIV, p. 508) for yohimbine, the positions of the hydroxyl and earbomethoxy grouf s being still imdetermined. 

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). 

The first characterized derivative substituted in the benzene rings, namely 105c, arose ftom eleciropolymerized indole-5-carboxylic acid, and could be isolated... 

Thus, novel 2-substituted methyl 2,3-dihydro-l-methyl-3-oxo-5//-pyrido[4,3-/j] indole-4-carboxylates are available. Since the methyl group at the 1 position is expected to react with various reagents, many 1-substituted derivatives could be produced. 

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>. 

The carboxylafion of indole into indole-3-carboxylate was observed by the purified indole-3-carboxylate decarboxylase as well as by the whole cells. For the carboxylafion reaction, temperatures over 30°C were not appropriate. The activities at 10, 20, and 30°C were about the same. The activity was maximal at pH 8.0 (Tris-HCl buffer, 100 mM). As shown in Fig. 10, the resting cells of A. nicotianae F11612 also catalyzed the carboxylafion of indole efficiently in the reaction mixture containing 20 mM indole, 3M KHCO3, 100mM potassium phosphate buffer (pH 6.0) in a tightly closed reaction vessel. By 6h, 6.81 mM indole-3-carboxylic acid accumulated in the reaction mixture with a molar conversion yield of 34%. Compared to the carhoxylation of pyrrole by pyrrole-2-carboxylate decarboxylase, the lower value compared might derive from the lower solubility of indole in the reaction mixture. 

Combination of MCR with the Pictet-Spengler cyclization also leads to different types of scaffolds with ketopiperazine fused ring systems. Tetrahydro-jS-carboline scaffold 221 was prepared in a convergent, two-step procedure [67]. An array of indole derivatives was prepared by the reaction of tryptophan derivative 222, aldehyde 223, carboxylic acid 224, and bifunctional amine 214 (Scheme 40). 

Benzoic acid and naphthoic acid are formed by the oxidative carbonylation by use of Pd(OAc)2 in AcOH. /-Bu02H and allyl chloride are used as reoxidants. Addition of phenanthroline gives a favorable effect[360]. Furan and thiophene are also carbonylated selectively at the 2-position[361,3621. Indole-3-carboxylic acid is prepared by the carboxylation of 1-acetylindole using Pd(OAc)2 and peroxodisulfate (Na2S20s)[362a]. Benzoic acid derivatives are obtained by the reaction of benzene derivatives with sodium palladium mal-onate in refluxing AcOH[363],... 

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. 

In certain cases copper catalyzed processes might also be used for the N-alkynylation of azoles. Methyl indole-3-carboxylate was coupled with 1-bromo-2-triisopropylsilyl-acetylene in the presence of a copper-phenantroline catalyst to give the desired 1-ethynylindole derivative in excellent yield (6.74.),105... 

The presence of an electron-withdrawing substituent on the five-membered ring of the indole system generally deactivates that ring to electrophilic attack by both elemental bromine and A-bromosuccinimide. Thus, ethyl indole-3-carboxylate and 3-formylindole are brominated on the benzenoid ring (72HC(25-2)127,79HC(25-3)357). The 2-carboxylic ester, however, yields the 3,5-dibromo derivative. 

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). 

The magnesium bromide salt of indole gives the 3-carboxy derivatives in about 30% yield on reaction with carbon dioxide (56JCS2853). Ethyl indole-3-carboxylate can be obtained directly, but in modest yield, using ethyl chloroformate (62JOC496, 6602805). Indole-2-carboxylic acid derivatives can be obtained via the benzenesulfonyl-protected 2-lithio derivative (equation 181) (73JOC3324). 

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