Multicomponent, one-pot and expeditious synthesis of highly substituted new spiro[indolo-3,10′-indeno[1,2-b]quinolin]-2,4,11′-triones under micellar catalytic effect of CTAB in water

Abstract

A convenient multicomponent reaction strategy for the synthesis of highly substituted new spiro[indolo-3,10′-indeno[1,2-b]quinolin]-2,4,11′-triones has been developed under CTAB/H₂O system (easily recovered and recycled) to provide spiro products with excellent yields. The most exciting feature of this methodology is its mechanism involving the unusual ring opening of an isatin moiety followed by recyclisation.

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It is believed that heterocyclic spiro compounds occupy a key position in current organic synthesis because of their significant biological activities.¹ Amongst these skeletons, a unique class of indane-fused quinoline compounds is well known in medicinal chemistry as anti-malarials,² anti-bacterials,³ anti-cancer⁴ and anti-mycobacterials.^5–7 In addition, these compounds are also effective for inhibition of Mycobacterium tuberculosis.⁸ The spiro compounds, which are produced from isatin, are important pharmacophores, displaying excellent biological activities such as analgesic, fungicidal, antidepressant, antitumor and antibiotic activities.^9,10 Similarly, substituted quinolines are not only very useful in the pharmaceutical industry, but also demonstrate a wide range of biological potencies including antiasthmatic, anti-inflammatory and antimalarial activities.¹¹ Moreover, recently isatin and its derivatives have become the most useful synthetic skeletons for the synthesis of a large number of spirocyclic compounds like cyclopentyl-fused spiro[dihydropyridine-oxindoles] on the basis of MCR because of its high atom economy, operational simplicity and efficiency.¹² Also in the past few years, many diverse methods have been reported, including metal-based and organocatalytic¹³ for the synthesis of spiro compounds. Undoubtedly, each of the developed strategies belongs to a different class of spirocycle, which are biologically active. Regarding those utilities, we developed a new method in order to endow spirocyclic compounds with structural diversity. To carry out the synthesis under green chemical conditions, we had to avoid the use of volatile and poisonous organic solvents. On the Earth, water is the most plentiful solvent to use that is safe, inexpensive, nontoxic, inflammable and environmentally friendly.¹⁴ Moreover, the high cohesive energy density,¹⁵ stabilization of the transition state through H-bonding¹⁶ and hydrophobic nature¹⁷ of water molecules make it a more effective green reaction medium than any organic solvent. Therefore, water can be safely used as an ideal green solvent for the synthesis of our target organic compounds. Furthermore, reactions carried out under a multicomponent fashion show massive advantages in terms of time, yield and reproducibility¹⁸ over diverse synthesis. It is more helpful to amplify the efficacy, atom economy, selectivity and complexity in a particular synthesis for a modern chemist. In the presence of micellar medium, the solubility of the organic molecule in water increases, along with the hydrophobic property because of its salt-effect.¹⁹ Taking into account the effect of all these advantages, we developed a new method for the above mentioned synthesis of spiro[indolo-3,10′-indeno[1,2-b]quinolin]-2,4,11′-triones using the micellar catalytic effect of cetyltrimethylammonium bromide (CTAB) in water employing a multicomponent protocol.

There are several advantages of this particular catalytic system, for the improvement of the reaction rate and various reaction conditions (like temperature, pressure etc.) to reduce the use of costly anhydrous or aprotic hazardous organic solvents.²⁰ In our present study, we found that the three-component reaction of enaminones of dimedone, indane-1,3-dione and isatin in water using the micellar catalytic effect of cetyltrimethylammonium bromide (CTAB) resulted in highly substituted spiro[indolo-3,10′-indeno[1,2-b]quinolin]-2,4,11′-triones in excellent yields (Scheme 1). In order to explore the generality of this multicomponent cyclisation reaction, the reactivity of the other cyclic 1,3-diketones and 5-substituted isatins were also investigated in water under reflux.

Scheme 1 Synthesis of spiro[indolo-3,10′-indeno[1,2-b]quinolin]-2,4,11′-triones (4).

Scheme 2 Probable mechanism for the construction of spiro[indolo-3,10′-indeno[1,2-b]quinolin]-2,4,11′-triones via cyclisation.

Next, attention was turned to evaluate the generality of the three-component reaction of enaminones, isatin and indane-1,3-dione. Under similar conditions, various enaminones and isatins with different substituents at the 5-position were allowed to react with indane-1,3-dione in water in the presence of CTAB under reflux for 5 hours (approximately) to afford the corresponding spiro[indolo-3,10′-indeno[1,2-b]quinolin]-2,4,11′-triones (4aa–4hc, Scheme 3) in excellent yields.

Scheme 3 Structures of the synthesised spiro compounds.

The most exciting feature of this protocol is its mechanism that we have postulated here involving the unusual ring opening of an isatin moiety. At first, the nucleophilic addition reaction occurs between the enaminone (3) with the more electrophilic carbonyl centre of isatin (2) in ecofriendly water medium to give an imine species (5) that tautomerizes to yield 6 (Scheme 2). This intermediate (6) undergoes intramolecular cyclisation to form the intermediate (7), which is immediately converted to a more reactive and unstable intermediate (8) via ring-opening of indoline-2,3-dione. After that, due to the high reactivity, intermediate (8) instantly undergoes further nucleophilic addition with the other molecule of indane-1,3-dione (1) to produce another imine intermediate (9), which tautomerizes to yield (10). Finally, the intramolecular cyclisation of (10) results in the ultimate spiro compound (4) via tautomerization of (11). The most observable feature is the formation of a more essential intermediate (8), because it is the key intermediate for the final product. We were not able to isolate this intermediate due to its low stability, and because of this, it immediately reacts with the more reactive indane-1,3-dione. In order to obtain evidence for the formation of the intermediate (8), we isolated a very small amount of another product (12) via simple dehydration of intermediate (8), which proves that the intermediate (8) must be formed in the reaction medium. For proof, NMR data of the product (12, 4acSA and 4aiSA) are given in ESI 2.†

To carry out our investigation under green conditions, we conducted this multicyclization reaction with indane-1,3-dione 1a, unsubstituted isatin 2a and 5,5-dimethyl-3-phenylamino-cyclohex-2-enone 3a in water. When these three components were mixed in a ratio of 1 : 1 : 1 and subjected to reflux in ecofriendly water medium in the presence of CTAB (15 mol%) at 100 °C, an intermolecular spirocyclic product, 6,6-dimethyl-1-phenyl-5,6,7,5′-tetrahydro-1H-spiro[indolo-3,10′-indeno[1,2-b]quinolin]-2,4,11′-trione 4aa (Scheme 3), was obtained in 90% yield. This initial observation prompted us to further optimize the reaction conditions. Interestingly, in consideration of surfactants, we observed that when the reaction was carried out without any surfactant, no product was obtained (Table 1, entry 1). Although TTAB and TEBA afforded a slightly better yield, the yield was less than that of CTAB (Table 1, entries 2, 3, 7), because all of these phase transfer catalysts form the cationic micelle, which is the most significant feature of this reaction. In the presence of surfactant CTAB (a cationic one), it forms micelles, which work both by solubilization due to a hydrophobic effect and by counter ion binding due to electrostatic forces (the presence of the positive polar head group of CTAB interacts with carbonyl groups and increases the electrophilic nature of carbonyl carbon of the reactants). However, in case of SDS, the yield was remarkably lower (Table 1, entries 4, 5), due to the formation of an anionic micelle, which is less effective for this reaction, even when the reaction was carried out for several hours. Therefore, CTAB was our obvious choice of surfactant.

Table 1 Optimization of reaction conditions for the formation of spiro derivatives^a

Entry	Surfactant (mol%)	Solvent	Temp (°C)/time (h)	Yield^b 4aa (%)
a Reaction conditions: indane-1,3-dione (1a, 1 mmol), isatin (2a, 1 mmol), enaminone (3a, 1 mmol), different catalysts, different solvents, different temperatures, different times.b Isolated yields.
1	None (—)	H2O	100, 20	—
2	TTAB (15)	H2O	100, 5	65
3	TEBA (15)	H2O	100, 10	55
4	SDS (15)	H2O	100, 5	30
5	SDS (15)	H2O	100, 10	50
6	CTAB (15)	H2O	100, 3	75
7	CTAB (15)	H2O	100, 5	90
8	CTAB (15)	H2O	70, 15	60
9	CTAB (20)	H2O	100, 5	85
10	CTAB (15)	DCM	30–35, 5	40
11	CTAB (15)	MeOH	50–60, 5	65
12	CTAB (15)	EtOH	70–80, 5	75
13	CTAB (15)	ACN	70–80, 5	79
14	CTAB (15)	Toluene	100–110, 5	60
15	CTAB (15)	DMSO	120–130, 5	55
16	CTAB (15)	DMF	120–130, 5	65

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Again, temperature played a significant role since there was only a 60% yield at 70 °C compared to the 90% yield at 100 °C (Table 1, entries 6 and 7). Various solvents, such as DCM, MeOH, EtOH, ACN, toluene, DMSO and DMF, were thus employed as reaction media. Although the reaction was investigated with moderate yield in high boiling point organic solvents (such as toluene, DMSO, DMF, etc.), the isolated yields were comparatively low (Table 1, entries 14, 15, 16). On the other hand, the reaction in low boiling point solvents (DCM, MeOH) afforded poor yields of 4aa (Table 1, entries 10, 11). Applying similar conditions, better yields were obtained in the case of EtOH and acetonitrile (Table 1, entries 12, 13).

With the optimal conditions in hand, we then carried out the investigation on the substrate scope of enaminones (3) and isatins (2). As pointed out in Scheme 3, various starting materials can be employed for this reaction that result in highly functionalized spiro derivatives that offer flexibility for structural modifications. For enaminone substrates, a variety of N-substituted aromatic rings bearing electron-donating groups (like CH₃, iPr, OMe etc.) (4ab–4ah) or -withdrawing (like Cl, Br, NO₂, COOH etc.) (4ai–4am) could all tolerate the reaction conditions. In addition, steric effects did not significantly affect the reaction. Using ortho CH₃ and ortho isopropyl phenyl enaminones, the corresponding products 4ab and 4af were generated in good yields. Notably, when N-aryl enaminones with two CH₃ groups at the 3 and 4 positions was employed, the respective product (4ae) was obtained in 92% yield. Not only the N-substituted aryl enaminones but also aliphatic enaminones reacted well (4an–4au). The above results indicated that both electron-withdrawing and electron-donating groups were suitable substrates, affording the corresponding products 4ab–4au in 75–96% yield. As an extension of the above study, mono or di substitutions at the 5 and 6 positions of enaminones (4ca–4cc and 4ba–4bb) and 5,5-unsubstituted enaminones (4da–4de) also delivered the corresponding products in good yield. Then, the influence of various substituents at C5 positions of the phenyl moiety of isatins on the reaction was also investigated. As shown in Scheme 3 (4ea–4hd), this protocol is amenable to a wide range of electronically different substituents at the C5 position of isatins, delivering structurally diverse spiro[indole-3,10′-indeno[1,2-b]quinolin]-2,4,11′-trione in excellent yields (86–95%). Furthermore, groups like bromide and chloride or even –NO₂ and –COOH were well tolerated. These functional groups provide ample opportunity for further functional group interconversions. The ready accessibility of starting materials and the broad compatibility of N-substituted enaminones make these reactions highly valuable for organic and biomedical fields. Furthermore, extension of this work is going on in our lab.

The reusability of the CTAB/H₂O system was evaluated with consideration of a reaction of 1a, 2a and 3a. At the end of the reaction (checked by TLC), a red coloured solid product was obtained, which was separated from the reaction mixture by filtration. After that, the filtrate was collected and reused in another cycle. It was found that 10 ml of 15 mol% aq. CTAB solution can be used for up to six cycles without any significant loss of activity (Table 2).

Table 2 Recycling of the CTAB/H₂O system involving the reaction of 1a, 2a and 3a (product 4aa)

Run	Volume of 15 mol aq. CTAB solution	Substrates used (mmol)	Time (h)	Yield (%)
1	10	1	5	90
2	9	1	5	86
3	8	1	5	84
4	7	0.5	5	80
5	6	0.5	5	75
6	4	0.25	5	72

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The structures of the above spiro[indolo-3,10′-indeno[1,2-b]quinolin]-2,4,11′-triones derivatives were fully characterized by ¹H, ¹³C NMR and IR spectroscopy. The structure of compounds 4al and 4bb (Fig. 1) were further confirmed by single crystal X-ray diffraction. The ORTEP diagrams of products 4bb and 4al are given below.

Fig. 1 ORTEP drawing of product 4bb (CCDC 984618†) and 4al (CCDC 984386†) in Scheme 3 showing the crystallographic numbering. In the case of 4al, a solvent molecule of DMSO-d₆ was removed from the crystal structure for the clarity of the target product.

In summary, we have reported for the first time a one-pot, three-component cyclization of enaminones, various 5-substituted isatins, and indane-1,3-dione and developed an efficient procedure for the synthesis of highly substituted spiro[indolo-3,10′-indeno[1,2-b]quinolin]-2,4,11′-triones in an aqueous micellar medium of CTAB. The most important advantages of this multicomponent cyclisation reaction are the wide scope of substrates, simple operation method, easy work-up procedures and short reaction times with good yields in the presence of environmentally friendly water as the medium.

Acknowledgements

One of the authors (AM) thanks the University Grants Commission (UGC), New Delhi, for his fellowship (JRF). We thank the CAS Instrumentation Facility, Department of Chemistry, University of Calcutta for spectral data.

References

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Footnote

† Electronic supplementary information (ESI) available: The experimental procedures for synthesis of spiro[indolo-3,10′-indeno[1,2-b]quinolin]-2,4,11′-triones and ¹H, ¹³C NMR spectra and IR analysis data of synthesised compounds are given. CCDC 984618 and 984386. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra04918g

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