Oxidation of isatins

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). 

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... 

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... 

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>. 

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... 

The oxidation of isatin using either hydrogen peroxide185,186 or chromic anhydride yields isatoic anhydride187 (Scheme 39) ... 

The oxidation of isatin with wetachloroperbenzoic acid yields l,4-benzoxazine-2,3 (4H)-dione, which was subsequently converted to blepharin, a glycoside obtained from Blepharis edulis Pers. whose seeds are used in rejuvenescent therapy in Ayurvedic medicine224. This oxidation can also be performed with potassium persulfate in sulfuric acid225,226 (Scheme 49). 

Kolbe2 in his last papers described a compound with the same formula, formed by oxidation of isatin (3) with Cr03, and called it isatoic acid. Meyer3 proved the identity of both compounds, and Niementowski and Rozanski4 were the first to establish the correct formula (1) when they found a new synthesis from anthranilic acid (4) and ethyl chloroformate. 

Oxidation of isatin in glacial acetic acid with Cr03 or peroxy carboxylic acids2,28-32 (see Scheme 1). 

Mandelaldehyde, PhCH(OH)CHO, can be condensed with 7V-phenyl-ethanolamine under acid catalysis to afford the 5,6-dihydro-1,4-oxazine (393) (80%) none of the isomeric oxazolidine is formed.""" Oxidation of isatins with peroxodisulphate gives excellent yields of 2,3-dioxo-benzo[Z>]-l,4-oxazines (394), in contrast to the formation of isatoic anhydrides by oxidation with a peroxide." Benzo[f>]-l,4-oxazines that are functionalized with methylene at position 2, i.e. (395), are obtained in good yields by the mercuric-oxide-promoted cyclization of o-(propargylamino)phenols." ... 

This compound has been known since 1892 and was previously synthesized in 1915 by oxidation of isatin with neutral potassium permanganate 134). Bird 135) has synthesized 53 from 0-methylisatin and o-aminobenzaldehyde. The isatin-a-(2-formylanil) 54 (appears to exist predominantly as 55) was converted to 53 by oxidation with CrO. The reaction of 7 l-sodioi satin with o-nitrobenzoyl chloride gave l-(2 -nitrobenzoyl)isatin, and its reduction afforded 53 (756). Bergman et al. 126,153) have developed a simple method heating of isatin, isatoic anhydride, and diisopropyl carbodiimide in pyridine with A-meth-ylpiperidine as catalyst afforded 53 in high yield. For information on other... 

Kolbe discovered nitroethane, C2H6NO2, independently of Victor Meyer (see p. 808). His last research, on isatic acid (indigotic acid) formed by the oxidation of isatin, was published in the year of his death. ... 

Vinyl carbanions derived from acrylic esters and their jS-phenyl derivatives react with several carbon electrophiles to give a-substituted and a,/8-disub-stituted derivatives. While /8>alkyl substituted acrylates have been shown to dimerize in the presence of potassium catalyst at 110 C. Three simple unsaturated esters undergo palladium(0)-catalysed codimerization with methylenecyc-lopropane to furnish methylenecyclopentanecarboxylic esters in reasonable yield. An efficient procedure for the oxidation of isatins to anthranilic acid esters has appeared. Methyl 2,4,6-tri-isopropylbenzoate forms a dipole-stabilized carbanion on reaction with Bu Li, which then reacts with carbon electrophiles [e.g. E = Bui, (CH3)2C0, or CH3CHO] to give a range of ester derivatives in good yield (Scheme 52). ... 

Anthranilic acids are useful reagents in synthetic chemistry, and two new and convenient syntheses have appeared. In one, carbonylation of bromoacetanilides utilizes palladium catalysis, and in the other, oxidation of isatins with hydrogen peroxide in the presence of sodium methoxide provides a ready source of anthranilic esters. 

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). 

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 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... 

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... 

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... 

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],... 

Oxidation of indigo results in dehydroindigo (4). Oxidation with permanganate or chromate splits the molecule, forming isatin (5). Oxidation and reduction of the indigo system are accompanied by corresponding changes in the spectroscopic properties (see Section 2.4). 

There are also examples of the use of compounds that are converted into diketones under the conditions of the Pfitzinger reaction and then react with isatins. Thus, the diacid 56 (yield 58%) was obtained from 2-hydroxy-3-butanone and isatin 7 in the presence of potassium hydroxide in water [26], while the dicarboxylic acids 58 were synthesized from 3-chloro-2-butanone and isatins 57 [44], The initial chloro ketone is clearly saponified to 2-hydroxy-3-butanone under the reaction conditions. As in the reaction with isatin 7, the product is then oxidized to 2,3-butanedione, which reacts with two molecules of isatin. 

Structures 64 and 65 were proposed in [7] for the product from the condensation of isatin 7 with acetoacetic acid (a P-keto acid). The first must clearly be preferred, since the CH2 group must be more active than CH3 under the conditions of the Pfitzinger reaction. Actually in [21] the structure of the product 64 was proved by its oxidation to the tricarboxylic acid 66, which was also synthesized from the keto dicarboxylic acid 67 and isatin 7. 

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