Furochromone-isatin conjugates via an uncatalyzed diastereoselective [4 + 1] cycloaddition/tautomerization/Friedel-Crafts hydroxyalkylation domino reaction

doi:10.1016/j.tet.2016.12.010

Tetrahedron

Volume 73, Issue 3, 19 January 2017, Pages 262-271

https://doi.org/10.1016/j.tet.2016.12.010 Get rights and content

Abstract

A series of diverse polycyclic heterocycles containing 3-hydroxyoxindole, and alkyliminofurochromone fused rings have been synthesized through the uncatalyzed Friedel-Crafts hydroxyalkylation of 3-(alkylamino)-9H-furo [3,4-b]chromen-9-ones generated in situ by the [4 + 1] cycloaddition/tautomerization of alkyl isocyanides and 3-formylchromones with isatin derivatives. The method is simple and provides a new class of pharmacologically important furochromone-isatin conjugates in moderate to good yields. The products bearing two contiguous stereogenic centers and one stereogenic group were obtained in excellent diastereoselectivities.

Graphical abstract

Introduction

Chiral 3-functionalized 3-hydroxy-2-oxindoles are attractive synthetic targets because of their prevalence in numerous natural products, such as convolutamydines (A and E), donaxaridine, maremycin B, dioxibrassinines, arundaphine, 3′-hydroxyglucoisatisin, TMC-95A, etc. showing a wide spectrum of biological activities (Fig. 1).¹ Structure-activity relationship studies have shown that the biological and pharmacological activities of these compounds are greatly affected both by the configuration of the C-3 carbinol carbon and its substituent pattern.²

On the other hand, it should be noted that the chromone and its derivatives are an important class of oxygen-containing heterocyclic compounds, which is a common and integral feature of a variety of natural products such as flavonoid family and medicinal agents.³ These heterocycles show a variety of pharmacological properties, and change of their structure offers a high degree of diversity that has proven useful in the search for new therapeutic agents. Chromone derivatives are abundant in nature and exhibit a wide range of pharmacological activity like anti-bacterial, anti-fungal,4, 5 anti-cancer,⁶ anti-oxidant,⁷ anti-HIV,⁸ anti-ulcers,⁹ immunostimulators,¹⁰ biocidal,¹¹ wound healing,¹² anti-inflammatory,¹³ and immune-stimulatory.¹⁴ Many chromone derivatives are also photoactive and can be used easily in various photoinduced reactions affording diverse heterocyclic compounds.¹⁵ Chromone derivatives are also active at benzodiazepine receptors.¹⁶

A variety of isocyanide-based multicomponent reactions involving various electrophiles, such as 3-formylchromones,17, 18, 19, 20, 21 ninhydrin,¹⁹ alloxan,²⁰ and azodicarboxylates²¹ have been reported. Recently, the cascade transformation of 3-formylchromones and alkyl isocyanides to furnish (1Z)-3-(alkylimino)-1-[(chromone-3-yl)methylene]-1,3-dihydro-9H-furo [3,4-b]chromen-9-ones have been reported by our group (Scheme 1).^17b This pseudo three-component tandem reaction involved two equivalents of 3-formylchromones and one equivalent of an alkyl isocyanide. In order to study whether the second equivalent of 3-formylchromone can be replaced with another carbonyl compound of higher electrophilicity than that of the 3-formylchromone, we herein disclose reactions using isatin derivatives as highly active electrophiles. Isatins are well-known biological manifolds with a reactive keto-carbonyl group that readily undergoes condensations, resulting in C-3 functionalized oxindole derivatives.

Section snippets

Results and discussion

Owing to the significance of 3-substituted-3-hydroxy-2-oxindoles and intense research activity of medicinal chemists in the construction of small bioactive chemical entities, we envisioned the combination of both chromone and oxindole motif with a hydroxyl-bearing C-3 substitution to generate biologically attractive architectures. To the best of our knowledge, no method for the synthesis of alkyliminofurochromone-substituted 3-hydroxy-2-oxindoles has been reported.

On the basis of our previous

Conclusions

In conclusion, we have developed a simple and efficient method that allows the preparation of furochromone-isatin conjugates that have potential interest as pharmacological agents to prevent oxidative cellular damage. This new multicomponent reaction takes place through a novel tandem process involving a [4 + 1] cycloaddition of isocyanides followed by electrophilic hydroxyalkylation of an aminofurochromone intermediate.

General

Melting points were measured on a Büchi 535 apparatus and are uncorrected. Elemental analyses were performed using an Elementar Vario EL III instrument. FT-IR Spectra were recorded on a Bruker Equinox-55 spectrometer. ¹H and ¹³C NMR spectra were recorded on a Bruker DRX-400 Avance spectrometer at 400.13 and 100.77 MHz, respectively, with CDCl₃ or DMSO-d₆ as solvents and calibrated using residual undeuterated solvent as an internal reference. Chemical shifts are reported in parts per million

Acknowledgements

The authors thank the Kharazmi University research council for financial support of this research.

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Furochromone-isatin conjugates via an uncatalyzed diastereoselective [4 + 1] cycloaddition/tautomerization/Friedel-Crafts hydroxyalkylation domino reaction

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Conclusions

General

Acknowledgements

Phytochemistry

Res Commun Chem Pathol Pharmacol

J Biosci

Holzforschung

Phytomedicine

Tetrahedron Lett

Curr Bioact Compd

Nat Prod Rep

Eur J Org Chem

J Antibiot

J Org Chem

RSC Adv

Eur J Med Chem

J Am Chem Soc