Indolines and Isoindolines

Partly reduced counterparts of the indole nucleus provide the basis for several agents with varied biological activities. A pair of closely related A-phenyl derivatives have both shown antidepressant activity in test systems. The apparent preference for the monomethyl amine suggests that these act by the same mechanism as the classical tricyclic antidepressants, where the secondary amine is the more active species. The first step in the preparation of the common intermediate (27-3) to these compounds consists of acylation of diphenylamine (27-1) with chloroacetyl chloride. 

FIVE-MEMBERED HETEROCYCLES FUSED TO A BENZENE RING 

Cyclization of the product (27-2) under Friedel-Crafts conditions gives the desired indolinone (27-3). Reaction of the carbanion obtained on treatment of that with 3-chloropropyldimethylamine then gives the alkylation product (27-4). It should be noted that, in spite of this extra step, the scheme is greatly simplified by starting with the very readily available tertiary amine. The superfluous methyl group is then removed by reaction of (27-4) with ethyl chloroformate in the current version of the Von Braun reaction. There is thus obtained amedalin (27-5). Reduction of the amine by any of several methods, for example diborane, leads to the antidepressant daledalin (27-6) [28]. 

An indolone comprises a prominent moiety in the dopamine D2 selective antipsychotic agent ziprasidone (32-8). Reduction of the ketonoid carbonyl group on the indoxyl (32-1) under Wolff-Kischner conditions affords the indolone (32-2). Acylation of the product with chloroacetyl chloride in the presence of aluminum chloride then affords the reactive chloroacetyl derivative (32-3). In a convergent sequence, reaction of isothiazolone (32-4) with phosphorus oxychloride leads to 

The low level of research that continued on thaUdomide, in spite of its ill repute, unexpectedly showed that the compound affected immune function. The dmg was, for example, recently approved by the FDA for treatment of comphcations from leprosy it has also been investigated as an adjunct for treating some malignancies. 

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SCHEME 1730 Synthesis of indolines and isoindolines via the metathesis cascade. (Adapted with permission from Ref. [10]. Copyright (2009) American Chemical Society). 

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