Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 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.

PubMed Disclaimer

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

Similar articles

See all similar articles

Cited by

References

    1. Erian A.W., Sherif S.M., Gaber H.M. The chemistry of α-haloketones and their utility in heterocyclic synthesis. Molecules. 2003;8:793–865. doi: 10.3390/81100793. - DOI
    1. Chupakhin E., Babich O., Prosekov A., Asyakina L., Krasavin M. Spirocyclic motifs in natural products. Molecules. 2019;24:4165. doi: 10.3390/molecules24224165. - DOI - PMC - PubMed
    1. Smith L.K., Baxendale I.R. Total syntheses of natural products containing spirocarbocycles. Org. Biomol. Chem. 2015;13:9907–9933. doi: 10.1039/C5OB01524C. - DOI - PubMed
    1. Laviós A., Sanz-Marco A., Vila C., Blay G., Pedro J.R. Asymmetric Organocatalytic Synthesis of aza-Spirocyclic Compounds from Isothiocyanates and Isocyanides. Eur. J. Org. Chem. 2021;2021:2268–2284. doi: 10.1002/ejoc.202100232. - DOI
    1. Khanna P., Panda S.S., Khanna L., Jain S.C. Aqua Mediated Synthesis of Spirocyclic Compounds. Mini-Rev. Org. Chem. 2014;11:73–86. doi: 10.2174/1570193X1101140402101831. - DOI

LinkOut - more resources