Isatin

Isalin. Six hundred grams of concentrated sulfuric acid (sp. gr. 1.84) is wanned to 50° in a i-l. round-bottom flask 

For purification, 200 g. of the crude product is suspended in 1 1. of hot water and treated with a solution of 88 g. of sodium hydroxide in 200 cc. of water. The solution is stirred mechanically and the isatin passes into solution. Dilute hydrochloric acid is then added, with stirring, until a slight precipitate appears. This requires about 290-300 cc. of an acid made by diluting one volume of concentrated hydrochloric acid (sp. gr. 1.19) with two volumes of water (Note 8). The mixture is then filtered at once, the precipitate is rejected, and the filtrate is made acid to Congo red paper with hydrochloric acid. The solution is then cooled rapidly and the isatin which separates is filtered with suction and dried in the air. The pure product thus obtained weighs 150-170 g. (Notes 9 and xo) and melts at 197-200° (corr.) 

Isatin may also be crystallized from three times its weight of glacial acetic acid. In this case it is obtained in large brown-red crystals which melt at 196-197°. 

Several runs were made in which the amounts of water and sodium sulfate were varied over a considerable range and this concentration was found to give the best yield of product of 

Redistilled aniline boiling over a two-degree range was used in these experiments. The ordinary pure grade gives slightly lower yields. 

---

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 —... 

Supplement 1953 3103-3241 Carbonyl compounds a-Pyrrolidone, 236. Tropinone, 259. Succinimide, 369. Isatin, 432. Phthalimide, 458. 

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). 

Thiosemicarba2ones have long been used as antiviral agents, principally against pox vimses of the vaccinia family. One compound of this series, the isatin derivative (6) C HgN OS, has been used prophylacticaHy to prevent outbreaks of smallpox in humans (10) and to inhibit the protein synthesis in poxvims-infected cells. The molecular mechanics relating to this property are still not known (11), though the binding of a metal ion may be a key factor... 

Methisa2one [1910-68-5] C qH qN OS (l-methyl-3-thiosemicarba2one of 2-oxoindole, (7), one of the more active in the isatin-3-thiosernicarba2one [487-16-1] series, has been used in the treatment and prevention of smallpox and vaccinia infections that develop as complications of smallpox vaccination... 

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). 

Ring formation by intramolecular acylation is exemplified by the isatin syntheses shown in Schemes 37c and 37d (75AHC(18)l). 

PFITZINGER Quinoline synthesis QumoHne-4-cartx)xyHc acids from isatin and a-methylene carbonyl compounds. 

Isatin (indoIe-2,3-dione) [91-56-5] M 147.1, m 201-203 , 205°, pK >12 (acidic NH). Crystd from amyl alcohol and sublimed at 180°/lmm. In aq NaOH the ring opens to yield sodium o-ami nobenzoy 1 formate. 

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. 

Commercial isatin from Eastman Kodak or Matheson, Coleman and Bell has been used, but poorer yields are obtained (about 10% less) than when purified material is employed. Purification by reprecipitation or by recrystallization from glacial acetic acid is equally satisfactory. 

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,... 

The Doebner reaction can provide the 4-carboxyl quinoline when the Pfitzinger reaction does not." Pfiztinger reaction of pinnacolone with isatin did not provide the desired quinoline. Doebner reaction of aniline with acetaldehyde and pyruvic acid did furnish the quinoline, albeit in only 8% yield. 

The Pfitzinger reaction describes the condensation of an o-aminophenylglyoxylic acid 16 (which can be generated in situ from an isatin IS) with 2 results in a quinoline-4-carboxylic acid (17), which is the subject of its own chapter in this book. ... 

The Pfitzinger reaction entails the synthesis of quinoline-4-carboxylic acids 2 via condensation of isatic acids formed from isatins 1 and a-methylene carbonyl compounds in the presence of strong aqueous bases. Subsequent decarboxylation can afford the corresponding quinolines. " ... 

---