Isatin and its derivatives: a survey of recent syntheses, reactions, and applications

Abstract

Isatin (1H-indole-2,3-dione) and its derivatives represent an important class of heterocyclic compounds that can be used as precursors for drug synthesis. Since its discovery, a lot of research work has been done regarding the synthesis, chemical properties, and biological and industrial applications of isatin. In this review, we have reported several novel methods for the synthesis of N-, C2-, and C3-substituted and spiro derivatives of isatin. The isatin moiety also shows important chemical reactions such as oxidation, ring expansion, Friedel-Crafts reaction and aldol condensation. These reactions, in turn, produce several biologically viable compounds like 2-oxindoles, tryptanthrin, indirubins, and many more. We have also summarized some recently reported biological activities exhibited by isatin derivatives, like anti-cancer, anti-bacterial, anti-diabetic and others. Special attention has been paid to their anti-cancer activity, and various anti-cancer targets such as histone deacetylase, carbonic anhydrase, tyrosine kinase, and tubulin have been discussed in detail. Other applications of isatin derivatives, such as in the dye industry and in corrosion prevention, have also been discussed.

Fig. 1. Structure of isatin (1H-indole-2,3-dione).

Fig. 2. The various substitutions possible on the isatin scaffold.

Scheme 1. Synthesis of N-alkylated/arylated isatin derivatives from 2-amino acetophenones.

Scheme 2. Formation of N-alkylated isatins via photocatalytic aerobic oxidation of indoles.

Scheme 3. Direct amidation of 2′-aminophenylacetylene, 2′-aminostyrenes, and 2′-amino-β-ketoesters (in open air, 100 °C, DMSO) to form isatins.

Scheme 4. Synthetic routes to 2-hydroxy-2-substituted-indol-3-ones.

Scheme 5. Synthesis of pseudoindoxyls via intramolecular oxygenation of alkynes using a Cu/B2pin2 system.

Scheme 6. Synthesis of (E)-oxindolylidene acetates via a Pd-catalyzed Heck and alkoxycarbonylation reaction.

Scheme 7. Synthesis of F-18 labeled C-3-substituted thiosemicarbazone derivatives of isatin.

Scheme 8. Synthesis of a spiro compound under microwave irradiation in aqueous medium.

Scheme 9. One-pot multicomponent synthesis of regioselective spirooxindoles.

Scheme 10. Synthesis of spiro[oxindole-isoxazolidine] via 1,3-dipolar cycloaddition of reactants.

Scheme 11. Synthesis of meisoindigo in different yields by using different starting reactants.

Scheme 12. Synthesis of the 5,7-dibromoisatin derivative.

Scheme 13. Synthesis of C-5-substituted isatin derivatives from substituted anilines; further reaction also produces hybrids of these derivatives.

Scheme 14. Organoselenium-catalyzed oxidation of isatin to isatoic anhydride.

Scheme 15. Cu-Catalyzed aerobic oxidation of isatins to tryptanthrin derivatives.

Scheme 16. Formation of isoxazoloquinolines through one-pot synthesis.

Scheme 17. Synthesis of dibenzo[b,d]azepin-6-one scaffold via the two-carbon ring expansion of isatin.

Scheme 18. Friedel–Crafts alkylation of isatins with pyrroles to give oxindoles.

Scheme 19. Friedel–Crafts alkylation of isatins with indoles to give 2-oxindoles.

Scheme 20. Alleno-aldol condensation of isatins with allenic esters to give carbinol allenoates.

Scheme 21. Cross aldol reaction of isatins with acetaldehyde.

Scheme 22. Vinylogous aldol reaction of isatins with α-substituted α,β-unsaturated aldehydes.

Scheme 23. Alkylation of isatin in the presence of a base.

Scheme 24. Dimerization of isatin to produce indirubin.

Scheme 25. 1,3-Dipolar/inverse dipolar cycloaddition reaction of isatin with ethyl isocyanoacetate.

Varun

Sonam

Rita Kakkar