Oxidation of indoles to oxindoles

The conversion of indoles to oxindoles can be achieved in several ways. Reaction of indoles with a halogenaling agent such as NCS, NBS or pyridin-ium bromide perbromide in hydroxylic solvents leads to oxindoles[l]. The reaction proceeds by nucleophilic addition to a 3-haloindolenium intermediate. 

Use of an excess of the halogenating agent results in halogenation at the 3-position of the oxindole[3,4]. The halogenation and hydrolysis can be carried out as two separate steps. One optimized procedure of this type used NCS as the halogenating agent and it was found that 70% phosphoric acid in 2-mcthoxycthanol was the most effective medium for hydrolysis[2]. If the halogenation is carried out in pyridine, the intermediate is trapped as an 

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A -(indol-2-yl)pyridinium salt which can subsequently be hydrolysed to an oxindole[5]. 

The oxidation of 3-substituted indole to oxindoles can also be done with a mixture of DMSO and cone, hydrochloric acid[6-9]. This reaction probably involves a mechanism similar to the halogenation with a protonated DMSO molecule serving as the electrophile[10]. 

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The highest space-time yield (120 g 1. 1 d 1) was achieved in a continuously operated enzyme membrane reactor for the chloroperoxidase-catalyzed oxidation of indole to oxindole with H202 in aqueous t-BuOH, whereas a fed-batch reactor obtained the highest total turnover number (TTN 860 000) (Seelbach, 1997). 

Corbett MD, Chipko BR (1979) Peroxide oxidation of indole to oxindole by chloroper-oxidase catalysis. Biochem J 183 269-276... 

Batch reactors based on peroxidases are mainly applied for degradation purposes (see Chap. 8). LiP, manganese peroxidase (MnP), HRP, SBP, and CPO were used for the oxidation of phenolic compounds [3, 6, 7, 9, 20, 38, 74, 75, 95], decoloriza-tion of dye-containing effluents [5, 22], and pulp biobleaching [59]. In the field of synthesis, CPO is the most versatile and promising of the peroxidases (see Chap. 6). It was applied in discontinuous operation for epoxidations [78,79], enantioselective oxidations of alcohols to aldehydes [14,48], halogenations [77,80], hydroxylations, and oxidation of indole to oxindole, which is an important drug precursor [96]. 

In an approach to the core of iV-methylwelwitindolinone C isothiocyanate, the Garg group employed a diastereoselective oxidation of indole 202 using NBS, and then ethanolic HCl to access the oxindole subunit of 203 [119]. The C7 ring juncture of the bicycUc core was set using an indolyne cyclization strategy... 

Oxidation of indoles. Tryptophan and related 3-substiluted indoles are oxidized to oxindoles in high yield by DMSO and cone. HCl (equation 1). This reaction can be used for modification of tryptophan-containing peptides and proteins. ... 

Hartwig has reported an intramolecular/intermolecular process affording the 3-aryloxindoles 105 (Scheme 32).115 The intermolecular arylation of acetanilide derivative 104 is slower than the intramolecular arylation to form the oxindole. Thus, the overall transformation starts with cyclization followed by intermolecular arylation of indole. In order to slow down the intermolecular process and speed up the intramolecular reaction, chloroarene and bromine-substituted acetanilide precursors are used according to their respective reactivity with palladium(O) in the oxidative addition process. 

The mechanism of metabolic degradation of indol-3-ylacetic acid (39) is a matter of debate. A possible route demonstrated in vitro includes oxidative decarboxylation to skatolyl hydroperoxide (40), catalyzed by horseradish peroxidase isoenzyme C (HRP-C), followed by rearrangement to 3-(hydroxymethyl)oxindole (41), as shown in equation 12 . 

The final, critical oxidative spirocyclization of the 2,3-disubstituted indole to the spiro oxindole was effected by treatment of 124 with tert-butyl hypochlorite in pyridine to provide the labile 125 [Fig. (34)]. The Pinacol-type rearrangement was conducted by treating compound 125 with p-toluenesulfonic acid in THF/water. It is assumed that the chlorination of 124 proceeds from the least hindered face of the indole, to give the a-chloroindolene 125. The hydration of the imine functionality must also occur from the same a-face that is syn to the relatively large chlorine atom furnishing the syn-chlorohydrin 126, that subsequently rearranges stereospecifically to the desired spiro oxindole 127. 

Reductive cyclization of o-nitrophenylacetic acids is a very general method of oxindole synthesis (see Section 3.06.2.1.1 for the application of this method to indoles in general). The main problem is efficient construction of the desired phenylacetic acid. One method involves base-catalyzed condensation of substituted nitrotoluenes with diethyl oxalate followed by oxidation of the 3-arylpyruvate (equation 200) (63CB253). Nucleophilic substitution of o-nitrophenyl trifluoromethanesulfonate esters, which are readily prepared from phenols, by dimethyl malonate provides another route (equation 201) (79TL2857). 

Quite early in the chemical studies of Wieland and King, evidence accumulated that the calabash curare alkaloids are indole derivatives, and with present knowledge it is possible to correlate the UV-spectra of many of them with one or another of the following related chromo-phores formally derived from the indole nucleus by oxidation, reduction, and substitution, or combinations of these processes. They are the indoline (II), 2-hydroxyindoline and the derived ethers (III), iV-hydroxy-alkylindoline and its ethers (IV), 2-methyleneindoline or 1-vinylindoline (Va or Vb, respectively), indole (VI), oxindole or 1-acylindoline (Vila or Vllb, respectively), -indoxyl (VIII), and /J-carbolinium (IX) systems it is not possible to distinguish with certainty by spectroscopic methods between the chromophores III and IV, between Va and Vb, or between Vila and Vllb. 

The Martinet procedure for the synthesis of indole-2,3-diones involves the reaction of an aminoaromatic compound and either an oxomalonate ester or its hydrate in the presence of an acid to yield a 3-(3-hydroxy-2-oxindole)carboxylic acid derivative which after oxidative decarboxylation yields the respective isatin. This method was applied with success for the synthesis of 5,6-dimethoxyisatin from 4-aminoveratrole whereas the use of 2,4-dimethoxyaniline was less successful40 (Scheme 9). 

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