Isatins, oxidation

PUtzing erReaction. Quinoline-4-carboxyhc acids are easily prepared by the condensation of isatin [91-56-5] (16) with carbonyl compounds (50). The products may be decarboxylated to the corresponding quinolines. The reaction of isatin with cycHc ketones has been reported, eg, the addition of cyclohexanone gives the tricycHc intermediate (17) [38186-54-8] which upon oxidation produces quinoline-2,3,4-tricarboxyhc acid [16880-83-4] (51). 

Isatin (190) is a compound with interesting chemistry. It can be iV-acetylated with acetic anhydride, iV-methylated via its sodium or potassium salt and O-methylated via its silver salt. Oxidation of isatins with hydrogen peroxide in methanolic sodium methoxide yields methyl anthranilates (81AG(E)882>. In moist air, O-methylisatin (191) forms methylisatoid (192). Isatin forms normal carbonyl derivatives (193) with ketonic reagents such as hydroxylamine and phenylhydrazine and the reactive 3-carbonyl group also undergoes aldol condensation with active methylene compounds. Isatin forms a complex derivative, isamic acid (194), with ammonia (76JCS(P1)2004). 

Gopala Rao and Venkateswara Rao found that the oxidation of indigo to isatin by chromic acid is accelerated by the presence of oxalic acid, and at the same time the extent of the oxidation of oxalic acid by chromic acid is increased. This observation is an example of mutual induction. 

The degradation of indole-3-acetate has been examined in Bradyrhizobium japonicum and was initiated by oxidation to isatin that was hydrolyzed to 2-aminophenylglyoxylate and anthranilic acid (Figure 10.6) (Jensen et al. 1995). 

A more highly oxidized indole relative is isatin (47). The ketonic carbonyl group is nonenolizable and has interesting properties. In strong acid it... 

The best known oxidative transformation of indigo is that into isatin. This is a normal oxidation at a double bond ... 

Mercury Diphenyl Dimethylpyrone 1 5-Dibromopentane Diphenylnitrio Oxide Thioindigotin Thioindigo Scarlet Isatin (Sandmeyer s method)... 

Isatin, a cyclic a-ketoamide, when reacted with potassium peroxydisulfate in the presence of sulfuric acid gave regioselectively an oxidized product, i.e. 2,3-dioxo-l,4-benzoxazine in almost quantitative yield under mUd conditions (equation 16). In contrast, when isatin reacted with 30% H2O2 in the presence of acetic acid and H2SO4, isatoic anhydride was obtained (equation 16) . ... 

A major group of photochemical reduction reactions are oxidation-reduction processes. As typical examples, phenazine (CXXI) and alloxan (CXXIII) are reduced by ethanol to give dihydrophenazine (CXXIl)/ 2 and alloxantin (CXXIV).42 Isatin (CXXV) in the presence of ace-naphthene (CXXVI) is reduced to isatide (CXXVII).204 The photoreaction proceeds at the expense of the alcohol, or (CXXVI) acetaldehyde and acenaphthylene (CXXVIII), are formed as by-products respectively. The formation of CXXVII may be due to the interaction of CXXV with the intermediate oxindole (CXXIX). 

Oxidation of isatin. Two products are possible from Baeyer-Villiger oxidation of isatin (1). Oxidation with K2S208 in sulfuric acid gives only the 1,4-beiuoxazine 2, whereas oxidation with H202-H0Ac gives the anhydride (3) of isatoic acid.1 An earlier preparation of compounds of type 2 involves reaction of o-aminophenols and oxalyl chloride.2... 

A number of ring closures have been reported that lead to 2- or 3-substituted isatins. Thus, treatment of nitromalonbis-A-methylanilide with acid gives N-methylisatin-3-oxime.103 Reaction of 25 with cyclohexyl or Mnitylisocyanide gives 26, which was hydrolyzed by acid to 27.104 Heating of 28 gives, with oxidation, the isatin-2,3-dianil 29.105... 

Methoxy-2-methyl-l,4-dihydro-4-oxoquinoline was converted into 6-methoxyisatin by an oxidative ring opening followed by ring closure.1150, Oxidation of 4-methyl-A-(2,3-dimethylphenyl)-carbostyril with alkaline permanganate gave A7-(2, li-dimethy lpheny 1) isatin.7 4... 

Chromic acid oxidation of a variety of indoles has been used as a synthetic route to isatins.117-124 A variety of other oxidative methods... 

Dihalogenation of oxindole followed by alkaline hydrolysis of the 3,3-dihalooxindole has been applied to the synthesis of some isa-tins.66,126,136 137b A number of oxindoles have been treated with nitrous acid to give isatin-3-oximes.100,138 Reduction of the oximes to 3-aminooxindoles followed by ferric chloride oxidation gave isatins.100,138 When this sequence was applied to 7-azaoxindole, the azaisatin 33 was... 

The most frequently reported oxidation reaction of isatins is the oxidation with alkaline hydrogen peroxide to give anthranilic acids. This procedure has been both as a proof of structure of isatins and as a method of synthesis of anthranilic acids. The oxidation has been applied to alkyl 8"10 11 23 33>38-40>46 49>50>118halo n.18.35.36-38-40.47.10 .11 . 119,136,240 alkoxy,26,a8 39,47,75.io7,ii8,i36 trifluoromethyl,33,38,137 and nitro8,120,217 isatins. Use of N-substituted isatins led to N-substituted anthranilic acids.66,71,125,158,169,243 In the oxidation of 5-bromo-l-(y-carbethoxypropyl)-7-ethylisatin, 60 was isolated after treatment with ethanol and acid.11 Oxidation of isatin derivatives 61 led, after treatment with diazomethane, to the acridine derivatives 62.67 Application of this oxidation method to 7-hydroxyisatins gave rise to benzoxazo-lones (63).2,41... 

Catalytic hydrogenation of isatin and A-methylisatin gave oxindole and jV-methyloxindole,256 while similar reduction of 1-azidoacetylisatin gave 1-aminoacetyloxindole.165 Catalytic hydrogenation over platinum oxide of A-methylisatin and isatin-1-propionic acid gave 70.169 A... 

CHPh2, R" = H), which was oxidized by sodium dichromate-acetic acid to V-(diphenylmethyl)isatin.510... 

Isatoic anhydride (223 R = H) is easily prepared by passing phosgene into a solution of anthranilic acid in dilute hydrochloric acid (5SOSC(3)488), and clearly this approach can be used to form derivatives substituted in the benzene ring. There is an alternative approach, namely the Baeyer-Villiger oxidation of isatins with hydrogen peroxide in acetic acid (Scheme 100) < 0AG(E)222>. 

Isatin, and a number of derivatives, have been oxidized by lead dioxide to the radicals 210 and 211, which were not very stable but their ESR spectra were measured and analyzed (77G154). While isatin itself reacts with nucleophilic amines at position 3 (cf. 211), the corresponding radical... 

There are only two practical laboratory methods lor the production of isatin, viz. the oxidation of indigo,1 and the condensation of aniline, chloral hydrate, and hydroxylamine salts, followed by the action of sulfuric acid.2... 

The oxidation of glutamic acid to cyanopropionic acid with CAB in acid solution showed an inverse fractional dependence on acidity. Similarly in alkaline medium, the order in alkali is fractional inverse.143 Kinetics of ruthenium(III)-catalysed oxidation of diols with CAB have been obtained. The products arise due to a fission of the glycol bond.144 The oxidation of isatins with CAB, in alkaline solutions, showed a first-order dependence on CAB and isatin and fractional order in alkali. The rates correlate with the Hammett relationship, the reaction constant p being —0.31. The observed results have been explained by a plausible mechanism and the related rate law has been deduced.145 The oxidation of cysteine with CAB in sulfuric acid medium is first order in CAB and cysteine and the rate is decreased with an increase in the hydrogen ion concentration.146... 

Adolf von Baeyer reported the chemical structure of indigo in 1883, having already prepared the first synthetic indigo from isatin (2) in 1870. Until then, isa-tin had only been obtainable by oxidation of indigo. It was not until 1878 that von Baeyer first synthesized it from phenylacetic acid, making a complete synthesis of indigo possible [1],... 

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