Isatin ring synthesis

Sandmeyer s valuable isatin synthesis involves the removal of sulphur from diphenylthiourea (I) (p. 169) with basic lead carbonate. Hydrogen cyanide is combined with the reactive diphenylcarbodiimide (II) so obtained, and the nitrile (III) produced is converted by means of hydrogen sulphide into tbe thioamide (IV). Concentrated sulphuric acid brings about ring closure and the product is the a-anil of isatin (V). Then, by hydrolysis with dilute sulphuric acid, aniline is removed ... 

The alkaline hydrolysis of isatin is the first step of a method for the construction of the indazolic ring system354. This method has been applied to the synthesis of serotonin... 

Isatin, due to its cis a-dicarbonyl moiety, is a potentially good substrate for the synthesis of metal complexes, either alone or with other ligands. Their derivatives, mostly those substituted at C-3, such as isatin-3-hydrazones and isatin-3-imines bearing an extra heteroaromatic ring are also generally employed as ligands. In this manner, Schiff bases... 

Indoles yield 3-chloroquinolines by addition of dichlorocarbene and HCl elimination (see p 101). A number of ring enlargement reactions of isatins into quinolines are known (as example, see the Pfitzinger synthesis, p 328, and [107/108]). 

Baeyer confirmed his results by the total synthesis of oxindole, isatin and indole. Nitration ofphenylacetic acid, isolation of the o-nitro isomer, and reduction of the latter followed by ring closure gave oxindole. Reaction with nitrous acid ( .e. potassium nitrate and sulfuric acid) gave isatin oxime, from which by reduction, dehydrogenation with iron(lll) chloride and final hydrolysis, isatin itself was obtained. 

Perhaps the greatest value of the Sandmeyer synthesis is the preparation of isatin scaffolds for the generation of compounds of medicinal interest. The ambiphilic nature of isatin allows it to undergo ring forming reactions to produce a variety of heterocyclic systems. Reaction of isatin 33 with substituted isatoicanhydrides 34 to form indoloquinazoline 35,serves as an example. 

Indole-fused pyran-4-ones are prepared in one-pot two-step synthesis. In the first there is the acylation of 1-substituted 3-acetyl-lH-indol-2-ols with acid chlorides using triethylamine as base, in dichloromethane at room temperature. The second consists in the 4ff-pyran-4-one ring formation firom the in situ-obtained 3-acetyl-2-acyloxy-lF/-indole derivatives (13S1235).A highly diastereo- and enantioselective organocatalytic formal hDA reaction of enones with isatins occurs in the presence of amine 34, acid 35, and thiourea 36 to produce spirooxindole tetrahydro-4ff-pyran-4-ones (Scheme 59) (13CEJ6213). 

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