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. 2023 Jan 24;24(3):2307.
doi: 10.3390/ijms24032307.

Aqua/Mechanochemical Mediated Synthesis of Novel Spiro [Indole-Pyrrolidine] Derivatives

Sodeeq Aderotimi Salami  1 , Vincent J Smith  1 , Rui Werner Maçedo Krause  1
Affiliations

Aqua/Mechanochemical Mediated Synthesis of Novel Spiro [Indole-Pyrrolidine] Derivatives

Sodeeq Aderotimi Salami et al. Int J Mol Sci. .

Abstract

Spirocyclic scaffolds are found in many pharmacologically active natural and synthetic compounds. From time to time, efforts have been made to develop new or better processes for the synthesis of spirocyclic compounds. Spiro [Indole-pyrrolidine] Derivatives are readily synthesized in high to excellent yields by the Michael condensation of 3-dicyanomethylene-2H-indol-2-ones (produced via the Knoevenagel condensation of indole-2,3-dione with malononitrile) with isothiocyanate derivatives under aqueous and mechanochemical conditions. The advantages of this protocol are that the reactions are solvent-free, occur at ambient temperature, require short reaction times, have experimental simplicity, and produce excellent yields. These environmentally friendly reaction media are useful alternatives to volatile organic solvents.

Keywords: 3-dicyanomethylene-2H-indole-2-ones; aqueous media; indole-2,3-diones; isothiocyanates; mechanochemistry; spiro [indole–pyrrolidine.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Selected examples of natural products and compounds of pharmaceutical interest which contain spiro rings.
Figure 2
Figure 2
Selected natural and bioactive compounds featuring a spirooxindole motif.
Scheme 1
Scheme 1
Synthesis of spiroindole–pyrrolidine derivative in aqueous media.
Figure 3
Figure 3
Variation of isothiocyanate moieties in the synthesis of spiroindoline pyrrolidine under aqua condition.
Scheme 2
Scheme 2
Synthesis of 3-dicyanomethylene-2H-indol-2-ones (3a) under mechanochemical activation without any additive.
Scheme 3
Scheme 3
Synthesis of spiroindole–pyrrolidine derivative (5a) under mechanochemical activation.
Scheme 4
Scheme 4
Unsuccessful one step synthesis of spiroindole–pyrrolidine derivative (5a) under mechanochemical activation.
Figure 4
Figure 4
Synthesis of spiroindole–pyrrolidine derivative (5i) using 5-bromo isatin (1b) under mechanochemical activation.
Figure 5
Figure 5
Variation of isothiocyanate moieties in the synthesis of spiroindole pyrrolidine under aqua condition.
Figure 5
Figure 5
Variation of isothiocyanate moieties in the synthesis of spiroindole pyrrolidine under aqua condition.
See this image and copyright information in PMC

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