Green chemistry oriented multi-component strategy to hybrid heterocycles

Abstract

An oxindole decorated 4H-chromene scaffold has been synthesized in water under catalyst-free reaction conditions at ambient temperature in good yields with moderate to high diastereoselectivities by implementing an ingenious methodology by integrating the guiding principles of Diversity Oriented Synthesis (DOS) and green chemistry.

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Synthetic organic chemistry plays a vital role in medicinal chemistry for identifying new drugs.¹ The paucity of potential bioactive scaffolds in modern drug discovery, has challenged synthetic organic chemists to evolve new strategies to synthesize a collection of natural-product-like and non-natural bioactive small molecules.² Diversity Oriented Synthesis³ (DOS), a splendid area of research in organic synthesis with its sub-disciplines privileged sub-structure based Diversity Oriented Synthesis⁴ (pDOS) and biology oriented synthesis⁵ (BIOS) has provided sophisticated ideologies to access bioactive small molecules. In addition, synthetic organic chemists have to abide by the stringent criteria of an ideal organic synthesis.⁶ Multi-Component Reactions⁷ (MCRs) in water can be visualized as an “elegant greener approach” and also as cutting-edge research to achieve diverse and complex small organic molecules from simple educts so as to quickly populate the chemical space.

Chromene is one of the privileged pharmacophores⁸ in medicinal chemistry, which is capable of interacting with a variety of cellular targets and thus possessing a wide range of biological activities⁹ such as antitumor, antivascular, antimicrobial, antioxidant, antifungal, antiviral, anticancer, anti-HIV, antitubercular and anti-inflammatory activity. In recent decades, chromene derivatives have become attractive motifs as potential anti-cancer agents.¹⁰ Oxindole is an another important heterocyclic ring systems found most frequently in small molecule drugs¹¹ and oxindole appended with heterocyclic motifs are ubiquitous in natural products and synthetic bioactive small molecules (Fig. 1).¹² Therefore, a hybrid heterocyclic framework consisting of both 4H-chromene and oxindole might possess properties of both and enhance the activity. Synthesizing hybrid heterocyclic frameworks with 4H-chromene and investigating their potential utility as anti-cancer drugs continues to be an active area of research.

Fig. 1 Medicinally privileged 4H-chromene and oxindole scaffolds.

To the best of our knowledge only a few reports are available in the literature¹³ for the synthesis of 4-heterocycle decorated 4H-chromenes-3-carbonitrile derivatives, many of which significantly drift away from green chemistry limitations such as avoidance of organic solvents, harsh reaction conditions, expensive catalysts and prolonged reaction times etc. Performing organic reactions in water, in addition to its eco-benefits, often imparts a remarkable effect on the reactivity and selectivity of organic reactions.¹⁴

We are actively engaged in developing multi-component reaction protocols in water with a specific focus of intensifying MCRs in water by integrating the strategies of DOS like Single Reactant Replacement¹⁵ (SRR) strategy and BIOS to access biologically relevant small molecules.

In the continued endeavour of our research group to access novel small organic molecules by amalgamating the guiding principles of DOS and green chemistry, a catalyst-free synthesis of 4-pyrazolyl substituted 4H-chromene derivatives¹⁶ in water at ambient temperature was achieved as an improvement of our work on accessing 4-azolidinonyl substituted 4H-chromene derivatives in a single operation incorporating stereochemical diversity, we hereby report an efficient and eco-friendly reaction protocol to access this hybrid heterocycle (Scheme 1). A catalyst-free three-component reaction between salicylaldehyde (1), oxindole (2) and malononitrile (3) was performed in water at ambient temperature for 4 h. The product that formed in the reaction was filtered and then washed with ethyl acetate/hexane mixture (2 : 8 ratio), which was characterised by IR, ¹H, ¹³C NMR and mass spectral analysis without any further purification. Two methyne protons are observed in ¹H NMR spectrum. The coupling constant (J = 2.0–2.8 Hz) of the two vicinal methyne protons (C2 and C3 protons of oxindole and chromene respectively) indicated that the two hydrogens on the chiral carbons have adopted gauche conformation.¹⁷ Surprisingly, both diastereomers of S₁ (S_1a and S_1b) had crystallized together.¹⁸ Single crystal X-ray diffraction analysis of both S_1a and S_1b showed that the two hydrogens on C2 and C3 of oxindole and chromene respectively had adopted a gauche conformation (Fig. 3). All these analytical data were supported to an unambiguous confirmation of the product 2-amino-4-(2-oxoindolin-3-yl)-4H-chromene-3-carbonitrile with two contiguous stereocenter. The diastereomers could be separated by simple recrystallization at room temperature, which is shown in Fig. 2.

Scheme 1 Catalyst-free synthesis of oxindolyl substituted 4H-chromene-3-carbonitrile.

Fig. 2 ¹H NMR (400 MHz, DMSO-d₆) spectrum of compounds S_4a and S_4b.

Fig. 3 ORTEP diagram of compounds S_1a, S_1b, S_4a and S_7a.

The scope of this tactics was further established with several substituted salicylaldehydes for appendage diversity of the scaffold, though the reaction rate, diastereomer ratio and yield of the product vary with the substituent (Chart 1). The diastereomer ratio for each product was calculated from signal at δ ∼ 3.9–4.3 ppm assignable to the hydrogens at the chiral centers.

Chart 1 2-Amino-4-(2-oxoindolin-3-yl)-4H-chromene-3-carbonitrile S₁–S₁₂ (ratio of diastereomers calculated by ¹H NMR of isolated product).

The oxindole substituted 4H-chromene hybrid is suggested to occur through (i) condensation of salicylaldehyde with malononitrile followed by intra molecular 6-exo-dig oxa-Thorpe–Ziegler cyclization on nitrile group, to afford 2-imino-3-cyano 2H-chromenes intermediate (4); followed by (ii) Michael addition of 4 with iminol form of oxindole (Scheme 2, path A). The product S₁ did not involve in the lactam–lactim tautomerism¹⁹ that reflect in the NMR and X-ray analysis.

Scheme 2 Plausible mechanistic pathway.

To verify the mechanism proposed for product formation, a two component reaction between 3-(2-hydroxybenzylidene)indolin-2-one (5) and malononitrile was performed in the optimized reaction condition, but the reaction did not yield oxindole substituted 4H-chromene hybrid (S₁) (Scheme 2, path B). Thus, there is a remarkable difference in the nature of products obtained when reactions are performed as conventional stepwise reaction and as a MCR.

Moreover, the nature of product obtained in the MCR and the major tautomer of the azolidinone in the hybrid heterocyclic scaffold is influenced by the nature of the azolidinone active methylene component. While azolidinone, which is more reactive than malononitrile would yield a single chiral center racemic product, a less reactive azolidinone yields a diastereomeric mixture with two contiguous chiral centers. Thus synthesis of 4-azolidinone substituted 4H-chromene hybrid by MCR cannot be considered as an appendage diversity reaction, but installing different biologically important motifs at 4-position of chromene necessitates independent investigations.

Conclusions

A hybrid heterocyclic scaffold, oxindole appended 4H-chromene-3-carbonitrile possessing two biologically active moieties with two contiguous stereo centers has been accessed in good yields by a catalyst-free three-component reaction in water at ambient temperature from simple educts. In addition to the efficiency and environmental benefits, this protocol has provided an insight in the scope of MCR in accessing novel scaffolds. Investigation on the effect of different heterocycles and factors contributing to the reaction to build novel 4-heterocycle substituted 4H-chromene are in progress.

Experimental

General procedure for the synthesis of oxindole decorated 4H-chromene scaffold

To a stirred aqueous mixture of oxindole 2 (3 mmol) respective 2-hydroxybenzaldehyde 1 (3 mmol) and malononitrile 3 (3 mmol) were added successively in 25 mL water at ambient temperature under an open atmosphere with vigorous stirring for 4 h. The precipitated solid was filtered, washed with water and then 5 mL of ethyl acetate/hexane mixture (2 : 8). The product S₁ obtained was pure by TLC and spectral techniques.

Acknowledgements

We thank CSIR (01(2500)/11/EMR-II) and DST (SR/S5/GC-22/2007), Government of India, for financial support, Central Instrumentation Facility (CIF), Pondicherry University, for high-resolution NMR and the Department of Chemistry (DST-FIST), Pondicherry University, for FT-IR and single crystal XRD.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: ¹H NMR and ¹³C NMR spectra for all reaction products are available. CCDC 1010756, 1010757 and 1010767. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra11543h

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