Of isatins

Commercial benzene may contain thiophene C H S, b.p. 84°, which cannot be separated by distillation or by fractional crystallisation. The presence of thiophene may be detected by shaking 3 ml. of benzene with a solution of 10 mg. of isatin in 10 ml. of concentrated sulphuric acid and allowing the mixture to stand for a short time a bluish-green colouration is produced if thiophene is present. The thiophene may be removed from benzene by any of the following methods —... 

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). 

B. 3-Hydroxycinchoninic acid. A 3-1., four-necked flask (Note 1) is equipped with a sealed mechanical stirrer, gas inlet tube, gas outlet consisting of a 1-mm. capillary (Note 7), and thermometer. The flask is charged with a freshly prepared solution containing 448 g. (8 moles) of reagent grade (85% minimum assay) potassium hydroxide and 900 ml. of water. The solution (hot from dissolution of potassium hydroxide) is stirred and 147 g. (1 mole) of isatin (Note 8) is introduced. The solid quickly dissolves to give an orange-yellow solution. 

The procedure described for the preparation of 3-hydroxycin-choninic acid is adapted from that reported. This synthesis is successful when bromopyruvic acid or its ethyl ester is substituted for chloropyruvic acid. The reaction of isatin with chloropyruvic acid to produce 3-hydroxycinchoninic acid has been reported however, no details or physical properties were given. This method offers a decided advantage over the method involving diazotization of the difficultly accessible 3-aminocinchoninic acid. ... 

Properties.—Mobile, colourless liquid m. p. 5 4 b. p. So 4 sp. gr. o 874 at 20°. Coal-tar benzene usually contains a little thiophene, C4H4S, which may be detected by dissolving a few crystals of isatin (see p. 229) in concentrated sulphuiicacid and shaking up with the benzene. If thiophene is present, a blue colour is produced (indophenin reaction). 

Isatin. -The formation of isatin fiom indigo may be represented as follows —... 

The constitution of isatin has been determined by its synthesis from ii-nitrophenylglyo.xylic acid,... 

In 1886 Pfltzinger reported a formal extension of the known Friedlander protocol for the synthesis of quinolic acids. This new protocol relied on the use of isatin which is much more stable than the ort/io-aminoaryl intermediates that are required in the Friedlander quinoline synthesis. In this early paper, Pfitzinger reports that upon heating of isatin 3 in the presence of aqueous sodium hydroxide, the former is. hydrolyzed to the isatic acid 4 which then in the presence of acetone reacts to give aniluvitonic acid 6. ... 

In 1903 Walther and co-workers recognized that imino-nitriles show parallel reactivity to that for the corresponding ketones in the presence of isatin under Pfitzinger conditions/... 

Buu-Hoi has shown that n-alkyl methyl ketones excluding ethyl methyl ketone, yield primarily 2-monosubstituted cinchoninic acids. It has been demonstrated that the products of the condensation of isatin with aryloxyketones are the corresponding 3-aryloxy-4-quinoline carboxylic acids rather than the isomeric 2-aryloxymethylcinchoninic acids.In the case of simple a-alkoxyketones such as 1-alkoxyethyl methylketones, the preferred products are the 2-alkoxyalkylcinchoninic... 

Condensation of Isatin 3 with Ethyl Methyl Ketone 39/... 

A mixture of 60 g (0.408 mol) of isatin, 200 mL of 34% potassium hydroxide in diluted alcohol solution, 88 g (1.22 mol) of ethyl methyl ketone and 375 mL of water were stirred and heated under reflux for 72 hours. About 125 mL of liquid was removed by distillation the residue was made slightly acidic and filtered. The filtrate was made strongly acidic to precipitate the reaction product, which was collected by filtration, washed, dried, weighed 70 g (85% yield). 

The Pfitzinger reaction consisting in the alkaline condensation of isatin or 6-bromoisatin with ketones has been applied extensively by Buu-Hoi et af.211.279.310.316,525,553 Cagniant, to acetylthio-... 

Monosubstituted hydrazones of isatin can exist in at least three tautomeric forms 124-126. According to spectroscopic data, only hydrazone 124 is present in solution (81JOC2764). 

Preliminary studies with a thio derivative of isatin (indole-2-thione-3-phenylhydrazone) also showed the hydrazone structure to be the favored tautomeric form (81JOC2764). 

In 1882 Baeyer and Oekonomides advanced formula 72 (R = H) for isatin on chemical grounds, but shortly thereafter the dioxo structure 73 (R H) was proposed since the ultraviolet spectrum of isatin resembled that of the N—Me derivative (73, R Me) and not that of the O—Me derivative (72, R = Me). " It was later shown, despite a conflicting report, that the ultraviolet spectrum of isatin is very similar to the spectra of both the O— and N—Me deriva-tives - the early investigators had failed to take into consideration the facile decomposition of the O—Me derivative. Although isolation of the separate tautomers of isatin has been reported, - these claims were disproved. A first attempt to determine the position of the mobile hydrogen atom using X-ray crystallographic techniques was inconclusive, but later X-ray work," dipole moment data, and especially the infrared spectrum demonstrated the correctness of the... 

The reaction of isatin with tetraphosphorus decasulfidc gives a low yield of compound 1, whose structure was confirmed by X-ray analysis.415... 

Naphtho[2,l-6]furo[2,3-c][l,2,4]triazines 198 were prepared (88JHC-1117) by the reaction of 4-5-benzocoumaran-2,3-dione with thiosemicar-bazide to give 195, whose ethylation in the presence of sodium hydroxide gave 197 via 196. Reaction of 197 with aniline gave 198 via the first displacement of the ethylthio group whose product could be isolated with a shorter reaction time. On the other hand, the similar sequence of reactions on coumaran-2,3-diones differs markedly from that of 4,5-benzocoumaran-2,3-diones, where the cyclization of 195 to 198 could not be effected. The behavior of the later dione resembles that of isatin and thianaphthenequinone (Scheme 41). 

Meth-Cohn has developed an efficient one-pot synthesis of isatins 108 by the sequential treatment of iV-substituted formanilides 107 with oxalyl chloride, Hunig s base, and bromine... 

Silver salts may be unstable when heated. An explosion occurred while the silver salt of isatin was being dried under reduced pressure at ca. 100°. 

Virus replication comprises numerous biochemieal transformations that might provide suitable targets for antiviral therapy. The antiviral effect of thiosemicarbazones was first demonstrated by Hamre et al. [53, 54], who showed that p-aminobenzaldehyde-3-thiosemicarbazone and several of its derivatives were active against vaccinia virus in mice. These studies were extended to include thiosemicarbazones of isatin, benzene, thiophene, pyridine, and quinoline derivatives, which also showed activity against vaccinia-induced encephalitis. The nature of the aldehyde/ketone moiety was not as significant as the presence of the thiosemicarbazide side chain the latter was deemed essential for antiviral activity. 

The structure/activity relationships for the methisazone, 3a, derivatives against adenoviruses and poxviruses have been shown to be similar [78]. Pearson and Zimmerman [79] demonstrated that all three types of polioviruses are inhibited by 2-acetylpyridine JV-dibutylthiosemicarbazone, which is similar to 3a, by blocking viral RNA synthesis. A 3-substituted triazinoindole derivative of isatin was effective against several strains of rhinovirus in tissue culture the mechanism of action is unknown [80]. 

Bhargava109 has reported that no ac polarographic wave is obtained for the first step of the reduction, and for the second step of reduction, the ac wave is conspicuous only at low audio frequencies, indicating that both steps are very slow and irreversible. The diffusion coefficient of isatin in a buffer of pH 1.1 is reported to be 1.85 x 10-6cm2/s and the value of n for the second step is 2. 

The Pfitzinger reaction of isatins with a-methylene carbonyl compounds is widely used for the synthesis of substituted quinoline-4-carboxylic acids. Ivachtchenko and colleagues have recently reported on the Pfitzinger reaction in a series of 5-sulfa-moylisatins (Scheme 6.239) [422]. Treatment of 5-sulfamoylisatins with diethyl mal-... 

Spiro[3H-indole-3,5(4.H)-(l,2,4)triazoline]-2-one derivatives 204 have been obtained using microwave irradiation in the reaction between imines of isatin 203 and nitrile imines generated in situ from the corresponding hydrazonyl chlorides 199 (Scheme 9.63). The yields are in the range 85-95% and the reaction is complete within 5 min [110]. Similar reactions performed under thermal conditions were complete in 6-10 h and yields decreased to 20-30%. However, when the reaction was performed at ambient temperature, the products were obtained in excellent yields but only after a prolonged reaction time (30 h). 

Cyclocondensation of isatin hydrazones 620 with 621 in strong acid gave thiazolo[3, 4 2,3][l,2,4]triazino[5,6-6]indoles 622, which underwent conventional reaction with 2-methyl-3-ethylbenzothiazolium perchlorate 623 to form unsymmetrical cyanines 624 (83URP1054350 85KGS211). The spectral properties of a series of polymethine dyes were examined (88KGS1547). 

Reaction of isatin derivatives with 2,3-diaminoquinazoline in ethanolic KOH gave indolotriazinoquinazolinones 359 and triazinoquinazolinedi-ones 360, probably through a Schiff base intermediate. Such compounds showed a significant antibacterial activity [92IJC(B)105]. 

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