Regioselective synthesis of spiroxindolopyrrolidine: a one step cycloaddition reaction twists inherent optical and fluorescence property of ferrocene–anthracene dyad

Abstract

We report a regioselective synthesis of spiroxindole using a 1,3-dipolar cycloaddition reaction (1,3-DC). The ferrocene–anthracene (Fc–An) dyad is used as the dipolarophilic partner. After the introduction of oxindole by cycloaddition, the fluorescence of anthracene is surprisingly enhanced. Using ¹H NMR, we have observed an unusual up field shift of the ferrocene aromatic protons from δ 4.2 to δ 2.87, which reveals an interaction between the ferrocene and anthracene π systems. These novel interactions are observed only after the regioselective cycloaddition on the Fc–An core. Our results shows that cycloaddition can alter the inherent optical and fluorescence properties of the Fc–An dyad system.

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In this communication, we describe the interaction of ferrocene, a redox-active electron donor, with anthracene, an electron accepting analyte of interest, with concomitant change in the properties of the resulting “Donor–Acceptor” (D–A) system. Among both academic and industrial researchers, “D–A” systems are primary models for the investigation of electron transfer,¹ dye-sensitized solar cells,^2–4 nonlinear optics,^5–7 and organic memory devices.⁸ The design and synthesis of novel molecules with the ability to form a unique and effective “D–A” system remains a challenge to the scientific community.⁹ Non-covalent interactions, such as hydrogen bonding, π–π, cation–π, and X–H⋯π (where X = N, O, C), among others, are important for investigating the structures and properties of molecular assemblies in biology, chemistry, and material science.¹⁰ Our work is intended to provide a synthesis of novel and potentially useful molecules and to fine-tune their non-covalent donor and acceptor interactions. These interactions control the design of molecular devices and regulate the self-assembly of natural and artificial systems.^11–13 Herein, we present a ferrocene–anthracene (Fc–An) dyad 1, which has attracted research in recent years, due to its intriguing properties and broad applicability in fluorosensing,^14–17 energy transfer,¹⁸ binding to DNA by intercalation,¹⁹ donor–π–donor molecular hybrids,²⁰ electroactive pH and sulfide and anionic sensing.^21,22 With a view to study the scope of the donor–acceptor Fc–An molecular system and in light of the considerable interest engendered by the spiro-oxindole ring system,^23–34 we were interested in the synthesis of novel ferrocene based spiro-oxindolopyrrolidines. Our synthetic design involves fine-tuning of D–A interactions for the Fc–An π system through bond and space interaction. We could accomplish this by regioselective cycloaddition on the Fc–An core. The spirocycloadduct (1-N-methyl-spiro-[2,3′]-oxindole-3-ferrocenoyl-4-anthracenyl pyrrolidine) 4, containing the Fc–An core, was obtained by a [3 + 2] cycloaddition reaction of 1-ferrocenyl-3-anthracenylprop-2-ene-1-one 1 with an azomethine ylide generated from isatin 2 and sarcosine 3 in refluxing toluene (Scheme 1).

Scheme 1 Synthesis of spiroxindolopyrrolidine.

Azomethine ylide was generated in situ by the decarboxylative condensation of the diketone, isatin 2, with the secondary amino acid, sarcosine 3. The generation of a non-stabilised azomethine ylide involves the initial formation of an iminium carboxylate betaine, followed by decarboxylation. The mechanism for the formation of the azomethine ylide and its mode of attack on the dipolarophile, Fc–An dyad is shown below (Scheme 2).

Scheme 2 The mechanism for the formation of spiroxindolopyrrolidine.

A structural elucidation was made on the basis of spectroscopic data and single crystal X-ray diffraction analysis. The observed ¹H NMR signals for cycloadduct 4 gave enough evidence for intramolecular interactions. The ¹H NMR spectrum for dyad 1, showed a singlet at δ 4.29 ppm, which was accounted for by the unsubstituted ferrocene cyclopentadienyl (Cp) ring (Fig. 1a). Surprisingly, after the incorporation of the oxindole moiety in dyad 1, the cycloadduct 4a showed a significant change in the spectral pattern of the ferrocene unit. The Cp protons shifted upfield from δ 4.29 ppm to the aliphatic region at δ 2.87 (Fig. 1b). To the best of our knowledge, there is no such report in the literature, and very few reports are available for even minor up field shifts.¹⁶ The most likely explanation for the up field shift is a change in the dihedral angle between the enone and the anthracene ring upon cycloaddition.

Fig. 1 Upfield shift of ferrocene Cp protons in ¹H NMR spectra of (a) dyad 1 and (b) cycloadduct 4a.

The benefit of introducing this spiro-oxindole compound is that it twists the linear dyad and induces non-covalent interactions between ferrocene and anthracene, which leads to significant changes in the NMR pattern of the ferrocene unit. The cycloaddition product 4a is conformationally locked and makes ferrocene and anthracene moieties proximal to each other. Similar results were obtained for other derivatives of the cycloadduct (4b–4d). Through NMR analysis, we have observed that upon cycloaddition, the anthracene moiety and ferrocene Cp rings were orthogonally disposed. Anthracene's electron cloud shielded the protons of Cp, resulting in an upfield shift in their NMR signals. This speculation was confirmed by the X-ray crystal structure of 4d, as shown in Fig. 2.

Fig. 2 Perspective view of the molecule 4d (benzyl derivative) showing the thermal ellipsoids at 30% probability level.

In the crystal structure of dyad 1,³⁵ a torsion angle of 177.5 (3)° for [C11–C12–C13–C14] has been reported. This angle is not favorable for the interaction between anthracene and ferrocene. However, incorporation of oxindole into dyad 1 via the cycloaddition reaction changed the torsion angle to 78.7 (4)° for [C11–C12–C13–C31]. This change in angle induced bending of the dyad and increased the proximity of the two moieties Fc and An. As a result, the influence of anthracene on the ferrocene Cp ring was strong in the cycloadduct. The Cp of ferrocene ring and anthracene were almost orthogonal to each other; consequently, the H6 and H7 protons of the Cp ring were located within the electron cloud of anthracene, which resulted in an appreciable intramolecular C–H⋯π interaction. In addition, the amide carbonyl had intra-molecular interaction with the H2 proton of the substituted Cp of the ferrocene moiety. The ORTEP diagrams and atom numbering schemes for C₄₄H₃₆FeN₂O₂·CHCl₃ (benzyl derivative of 4) are shown in Fig. 2.

The C–H⋯π intra and inter molecular interactions are observed (Fig. 3). For detailed crystallographic data,³⁶ see Table 1 in ESI.†

Fig. 3 The intra and inter molecular C–H π interactions.

The UV-visible absorption and steady-state fluorescence spectra of dyad 1 and cycloadduct 4a in acetonitrile solutions were obtained (see ESI†). The UV-vis spectrum of 4a significantly differed from that of 1 in peak appearance. The absorption spectrum of 1 showed two main peaks at 389 and 494 nm that were responsible for π–π* and CT bands, whereas these bands were shifted toward shorter wavelengths for 4a due to the loss of conjugation. Furthermore, the band at 456 nm in the visible region was assigned to CT-like transitions from the ferrocene d to the anthracene π* orbitals. The peak positions and the wavelengths for the absorption, emission and fluorescence decay profiles are listed in Table 1.

Table 1 Photophysical parameters for dyad 1 and cycloadduct 4a

Compound	Absorbance λmax/nm		Emission λmax	Fluorescence lifetime τ (ns)			Relative amplitude
	π–π*	CT		τ1	τ2	τ3	B1	B2	B3
Dyad 1	389	494	455	0.65	1.2	6.17	9.01	65.14	25.85
Cycloadduct 4a	369	456	430	—	1.31	6.12	—	11.27	88.73

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Triple-exponential fluorescence decays were observed in time-resolved measurements. In dyad 1, the 455 nm fluorescence profiles were best fitted by lifetimes of 0.65 ns, 1.2 ns and 6.17 ns. Herein, the presence of a short-lived component τ₁ (0.65 ns) confirmed intramolecular fluorescence quenching in dyad 1, through bond interaction (TBI). These lifetime profiles significantly changed after cycloaddition in compound 1. The short-lived component τ₁ was not observed in compound 4a at 430 nm excitation. Furthermore, the loss of conjugation affected quenching of anthracene through bond interaction (TBI), and the two moieties were found to be spatially proximal to each other. This life time fluorescence data showed that the electron transfer in dyad 1 occurred via TBI, having only 25.85% of the long lived component τ₃. After cycloaddition, the relative amplitude of τ₃ (long lived component 6.1 ns) was 88.73%. Hence, it was understood that the regioselective cycloaddition reaction was the reason for enhancement of anthracene fluorescence.

In conclusion, our results provide important new insights into how the optical and fluorescence properties of the Fc–An dyad change after regioselective cycloaddition. Moreover, our findings will be useful for future studies in constructing a library of molecules related to the fluorophore (anthracene) tethered spiroxindole for the effective development of anticancer agents, as well as live cell imaging studies for IDO over expressed cancer cells.

Acknowledgements

P. S. thanks the CSIR for financial support in the form of SRF. R. R. thanks the DST and the DST-FIST, New Delhi, for financial support and the UGC for BSRF Fellowship. Authors thank Prof. P. Ramamurthy, National Centre for Ultrafast Processes, University of Madras, Taramani Campus, Chennai 600 113, India for Fluorescence Lifetime studies.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available: Experimental details, NMR spectrum, UV-vis, fluorescence spectrum, life-time studies and crystallographic studies. CCDC 1002132. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra22482b

‡ P. Saravanan – Synthesis, spectral studies and manuscript writing. E-mail: E-mail: saran2k5@gmail.com. S. Sundaramoorthy – Crystallography studies.

§ Post-doctoral Fellow, Indian Council of Medical Research, Chennai-600031, India.

¶ Teaching Fellow, Dept. of Physics, Anna University, Guindy, Chennai, India.

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