A facile ionic liquid-accelerated, four-component cascade reaction protocol for the regioselective synthesis of biologically interesting ferrocene engrafted spiropyrrolidine hybrid heterocycles

1 Introduction

The construction of structurally diverse and pharmaceutically important heterocyclic hybrids from commercially available simple starting materials while combining propitious economic and environmental aspects constitutes a pronounced challenge in drug discovery especially in the area of combinatorial and diverse oriented synthesis (Cerulli et al., 2012; Sore et al., 2010). Among them, multi-component reactions (MCRs) were the preferred synthetic methods that creates several bonds in a single operation and affords notable benefits such as atom economy, tractability, simple operation, facile mechanization, less number of workup steps and easy extraction and purification methods, makes the conversions more environmental friendly (Ganem, 2009; Domling, 2006; Li and Chen, 2006) that enabled to obtain structurally interesting spirohybrid heterocycles without isolating intermediates (Sumesh et al., 2018).

Spiropyrrolidine heterocyclic motifs have attracted the attention of synthetic and medicinal chemists due to their stimulating biological properties (Trost and Brennan, 2009; Zhou et al., 2010) and these structural motifs are embodied in several natural alkaloids. For instance, (i) spirotryprostatine A and B, (Cui et al., 1996) were active against mammalian cell cycle at the G2/M phase (ii) horsfiline has utilized as a native medicine (Jossang et al., 1991) (iii) Mitraphylline was found to be inhibitor of human brain cancer cell lines, neuroblastoma SKN-BE(2) and malignant glioma GAMG (Prado et al., 2007). Apart from natural origin, many other synthetic spiropyrrolidine analogs have been reported to display anticancer (Yu et al., 2015), antimicrobial (Bhaskar et al., 2012), antimycobacterial (Rajesh et al., 2011), anti-inflammatory, analgesic (Rajanarendar et al., 2013), local anesthetics (Kornet and Thio, 1976) and AChE inhibition activities (Arumugam et al., 2019). Ferrocene is another important organometallic scaffold owing to their synthetic versatility, thermal and photochemical stability and potential biological properties. Ferrocene grafted organic molecules displays anti-cancer and antimalarial properties (Biot et al., 1997; Domarie et al., 1998; Motohashi et al., 1990; Allardyce et al., 2005). Many more ferrocene-based heterocycles possess antimicrobial properties (Fang et al., 2003a; Fang et al., 2003b; Jin et al., 2005).

Based on the above biological precedents, we reasoned the combination of spiropyrrolidine and ferrocene motifs in a single molecule would be of paramount interest in drug discovery. As a extension of our previous research interest in multicomponent cycloaddition strategy, we describe in this article the synthesis of these spirocycloadducts by employing a four-component sequence possessing 1,3-dipolar cycloaddition as crucial step (Gothelf and Jorgensen, 1998; Harju and Yli-Kauhaluoma, 2005). It is pertinent to note that the [3 + 2] cycloaddition involving a combination of ninhydrin and o-phenylenediamine along with L-phenylalanine to create 1,3-dipole comprising indenoquinoxaline unit, respectively, are relatively less explored in literature.

2 Materials and methods

3 Results and discussion

The pre-requisite starting substrates, ferrocenyl chalcone 5a-h were prepared according to reported method (Mukhtari et al., 2014). The cycloaddition reaction of ferrocenyl chalcone with azomethine ylide derived from indenoquinoxalinone 3 and L-phenylalanine 4 under heating at 100 °C in 1-butyl-3-methylimidazoliumbromide ([bmim]Br) afforded new class of ferrocene engrafted spiropyrrolidine heterocycles in good to excellent yields (83–91%) (Scheme 1). Initially, the reaction was carried out with different solvents including methanol, ethanol, acetonitrile, 1,4-dioxane, mixture of solvents, methanol: acetonitrile (1:1, V/V) and methanol:1,4-dioxane (1:1, V/V) that afforded the cycloadduct in moderate yields as shown in Table 1. In order to enhance the yield, we attempted the reaction under the green synthetic protocol. The reaction was investigated with [bmim]Br as it possesses distinctive properties such as low vapor pressure, non-flammability, act as acidic or basic catalyst, recyclability and has more thermal stability. Thus, in a typical reaction, an equimolar amount of o-phenylenediamine 1, ninhydrin 2, L-phenylalanine 4 and ferrocenyl chalcone 5b were heated in [bmim]Br (Michael Rajesh et al., 2012) for 1 h which afforded 6b in excellent yields (Table 1, entry 7). With this optimized reaction conditions in hand and the structure established for 6b, the plausibility of all these ferrocenyl chalcones 5 towards multicomponent reaction with 1,3-dipole was explored.

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Scheme 1

Synthesis of spiropyrrolidino-indenoquioxaline engrafted ferrocene heterocyclic hybrids, 6a-h.

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The structure of spiropyrrolidine tethered ferrocene hybrid heterocycles was confirmed through spectroscopic data (vide Supplementary data). The structural elucidation of 6b (Fig. 1) is discussed as follows. In its ¹H NMR spectrum, the compound 6b showing a doublet at δ 5.06 (J = 9.5 Hz) due to H-3 of pyrrolidine ring hydrogen which showed H, H-COSY correlation with the triplet at δ 3.91 (J = 9.5 Hz), being assigned to H-4 pyrrolidine ring hydrogen. Further, H-3 shows HMBCs with spiro carbon C-2 and C-4 at δ 89.4 and δ 45.6, respectively. H-4 shows HMBCs (Fig. 2) with H-3, H-5 and H-6 at δ 66.2, 65.6 and δ 40.6, respectively. The multiplet at δ 4.34–4.38 is assigned to H-5 hydrogen which showed H, H-COSY correlation with two doublet of doublets at δ 3.38–3.47 and 2.92–2.96 assigned to 6-CH₂ hydrogens. The correlation of H-4 hydrogen with C-6 confirms the obtained regioisomer. Further, the structure of the compound 6a (CCDC deposition number. 1989690) was determined by single crystal X-ray diffraction analysis (Fig. 3).

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Fig. 1

Selected chemical shift of 6b.

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Fig. 2

Selected HBMCs of 6b.

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Fig. 3

ORTEP diagram of 6a.

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The mechanism for the construction of ferrocene grafted spiroheterocycles 6a-h is described in Scheme 2. Initially, o-phenylenediamine 1 reacts with ninhydrin 2 affording indenoquinoxalinone 3 by the elimination of water molecules via cyclocondensation which further reacts with the α-amino acid, L-phenylalanine 4 to form spiro-oxazolidinone intermediate 9 via 8 followed by generation of 1,3-dipole 10. Consequently, the 1,3-dipole 10 attacks the C⚌C bond of the ferrocenyl chalcone 5 regioselectively furnishing the spirocycloadduct 6 forming four contiguous setereocenter in a one-pot conversion, out of which one is quaternary carbon. The ionic liquid, [bmim]Br played an essential role in the cycloaddition sequence as described in Scheme 2 which is supported by our earlier report (Arumugam et al., 2019).

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Scheme 2

The mechanism for the formation of ferrocene grafted spiropyrrolidines, 6a-h.

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4 Conclusion

A small library of hitherto unexplored heterocycles comprising spiropyrrolidine, indenoquinoxaline and ferrocene structural sub-units has been accomplished in good to excellent yields using [bmim]Br mediated multicomponent cycloaddition approach. A relatively less explored non-stabilized 1,3-dipole, derived from indenoquinoxalinone and L-phenylanine was employed. The structure of synthesized spiropyrrolidine hybrids were assigned through ¹H, ¹³C, and 2D NMR spectroscopic analysis. The biological activity of synthesized compounds will be done in due course.