In-water facile synthesis of poly-substituted 6-arylamino pyridines and 2-pyrrolidone derivatives using tetragonal nano-ZrO₂ as reusable catalyst

Abstract

Here, we report a facile synthetic protocol to access a series of ethyl 5-cyano-2-methyl-4-aryl-6-(arylamino)nicotinates and ethyl 4-hydroxy-2-(4-nitroaryl)-5-oxo-1-aryl-2,5-dihydro-1H-pyrrole-3-carboxylates using tetragonal nano-ZrO₂ as reusable catalyst. It was observed that the ZrO₂ nanoparticles were stable during reaction and apparently no leaching of Zr-content occurred when the catalyst was recycled eight times.

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Poly-substituted pyridine moieties have emerged as one of the favoured medicinal scaffolds as they have found wide pharmaceutical applications and constitute a core entity in various natural products.^1a–c These moieties also act as anti-prions,^2a anti-hepatitis B virus,^2b anti-bacterial,^2c and anti-cancer^2d agents. In addition, these pyridine scaffolds have revealed potential drug action against Parkinson's disease, hypoxia, asthma, kidney disease, epilepsy, cancer, and Creutzfeldt–Jakob disease.³ As a consequence, a number of methods have been developed for constructing functionalized pyridine derivatives.^4,5 Among others, recently, one-pot multicomponent reactions (MCRs) have emerged as effective tools for the synthesis of these moieties from the perspective of green synthesis.^4,5 This is because the MCRs offer rapid and direct access to a combinatorial library of highly convergent and functionalized bioactive organic scaffolds, e.g. pyridine derivatives, without producing unwanted by-products.^6–8 Poly-substituted pyridines of general structure (A) (Fig. 1) were obtained via one-pot reactions of aldehyde, two molecules of malononitrile and nucleophile, NuH (Nu = S, O, NH) through a nucleophilic addition/intramolecular cyclization process.⁹ On the other hand, pyridines of diverse functionality of general structure (B) (Fig. 1) have recently been synthesized by the reactions of aldehyde, ethyl acetoacetate, malononitrile and a nucleophile (RXH; X = O, NH). Among these, the synthesis of pyridines (B) (Fig. 1) has rarely been reported and only two methods are present in the literature.^10,11 He et al. have furnished a new method to access poly-substituted pyridine derivatives via nucleophilic addition/intermolecular cyclization catalysed by FeCl₃ in ethanol medium.¹⁰ Reddy et al. have employed SnCl₂·2H₂O for the same reaction.¹¹ Nevertheless, both the protocols were associated with long reaction time (6–10 h), and produced moderate to good yields (45–90%), and the catalysts were not reusable.

Fig. 1 Bio-active poly-substituted pyridines and 2-pyrrolidinone scaffolds.

Functionalized 2-pyrrolidinone derivatives are of enormous significance as these moieties exhibit several important biological and pharmacological activities like anti-cancer,¹² anti-tumour,¹³ HIV-1 integrase inhibitor,¹⁴ anti-microbial,¹⁵ anti-bacterial¹⁶ and anti-inflammatory.¹⁷ Over the years, several reports have been published for the synthesis of these important compounds.¹⁸ Recently, Ahankar et al. have reported a new protocol leading to 2-pyrrolidinones (Fig. 1C) via three-component condensation of aryl aldehyde, aryl amine and diethyl acetylenedicarboxylate catalysed by citric acid in ethanol under ultrasonic irradiation.^19a As a part of our continuous interest in nano-catalysis,²⁰ we have explored the excellent catalytic activity of ZrO₂ nanoparticles (NPs) in MCRs.^20g,i Here, a facile green protocol for the synthesis of poly-substituted pyridines (B) and 2-pyrrolidinone derivatives (C) by using reusable t-ZrO₂ NPs in aqueous ethanol (Scheme 1) is reported.

Scheme 1 Tetragonal nano-ZrO₂-catalysed synthesis of functionalized pyridine and 2-pyrrolidinone derivatives.

Results & discussion

Primarily, tetragonal nano-ZrO₂ was prepared via a sol–gel method involving the condensation of ZrO₂Cl₂·8H₂O under basic conditions followed by the calcination of powder at 500 °C following our previously reported protocol^20g (see ESI 1† for details). The formation of nano-ZrO₂ with pure tetragonal phase was evident from the powder X-ray diffraction (XRD) and transmission electron microscopy (TEM) studies.

The diffraction peaks at 2θ = 30.85, 51.20 and 59.50 in the powder XRD pattern (Fig. 2) of nano-ZrO₂ are assigned to the {101}, {112} and {211} reflection planes and are in good agreement with pure tetragonal phase (JCPDS card no. 79-1771). The lattice fringes with lattice spacing 0.292 nm are associated with the {111} plane of t-ZrO₂ (JCPDS card no. 17-0923), which also confirms the presence of a single tetragonal phase. The diffraction peaks, angles and the lattice spacing resemble previously reported data.^20g,21 Peaks related to cubic or monoclinic phase are not detected in the powder XRD pattern. The broadening of diffraction peaks was due to the formation of small t-ZrO₂ particles. The average particle size of the as-prepared NPs was evaluated to be 14 nm from the powder XRD pattern using the Scherrer formula.²²

Fig. 2 Powder X-ray diffraction pattern of nano t-ZrO₂.

The TEM study revealed the formation of spherical ZrO₂ NPs (Fig. 3a and b). The magnified high resolution TEM (HRTEM) image in Fig. 3c shows the lattice fringes with lattice spacing 0.292 nm associated with the {111} plane of t-ZrO₂ (JCPDS card no. 17-0923), which also confirms the presence of single tetragonal phase.^21b The selected electron diffraction (SAED) pattern (Fig. 3d) exposes the existence of t-ZrO₂ NPs.^21b Energy-dispersive X-ray analysis (EDX) through HRTEM shows that no impurity is present in the sample (Fig. 3e). The average size of the t-ZrO₂ NPs was measured to be 13.6 nm from size distribution study (Fig. 3f) by HRTEM over 100 grains.

Fig. 3 (a) HRTEM image. (b) Magnified HRTEM image. (c) Showing lattice fringes with lattice spacing. (d) SAED pattern. (e) HRTEM-EDX. (f) Size distribution by HRTEM of t-ZrO₂ NPs.

Next, the catalytic activity of as-prepared t-ZrO₂ NPs was investigated in a four-component reaction for the synthesis of poly-substituted pyridines (B, Fig. 1). When a mixture of benzaldehyde (1 mmol), malononitrile (1 mmol), aniline (1 mmol), ethyl acetoacetate (1 mmol) and t-ZrO₂ NPs (12 mg, 10 mol%) was heated at 80 °C in ethanol (4 ml), a moderate yield of ethyl 5-cyano-2-methyl-4-phenyl-6-(phenylamino)nicotinate (75%) was obtained after 2 h (entry 2, Table 1). To optimize the reaction conditions, we performed several reactions. The reaction did not run in absence of the catalyst (entry 1, Table 1). The rate of reaction was accelerated markedly in ethanol–water (1 : 1) mixture and produced an excellent yield (91%) of product (1a) in 2 h (entry 3, Table 1). However, at room temperature the same reaction produced only 40% desired product even after 4 h (entry 4, Table 1). The ZrO₂ NPs were found to be less active in organic solvents like toluene, tetrahydrofuran (THF) and dimethyl formamide (DMF) (entries 5–7, Table 1). Next, investigating the effect of phase of ZrO₂ on the reactivity, we observed that the t-ZrO₂ NPs were superior to monoclinic (m-ZrO₂) and cubic (c-ZrO₂) ones (entries 8 and 9 Table 1). In addition, the t-ZrO₂ NPs were able to produce better yields of product 1a (Table 2) than other oxide NPs such as Fe₃O₄, SiO₂, CuO, NiO and ZnO (entries 10–14, Table 1). When only 5 mol% catalyst was used, the yield was decreased to 80% (entry 15, Table 1). Thus, the reaction using 10 mol% of t-ZrO₂ NPs in ethanol–water (1 : 1) mixture at 80 °C was considered to have the optimized reaction conditions for the synthesis of poly-substituted pyridine derivatives.

Table 1 Optimization of reaction conditions for the synthesis of poly-substituted pyridine derivatives^a

Entry	Catalyst	Solvent/cond.	Time (h)	Yield^b (%)
a Reaction conditions: benzaldehyde (1 mmol), malononitrile (1 mmol), aniline (1 mmol), ethyl acetoacetate (1 mmol), catalyst (10 mol%), solvent (5 ml) with continuous stirring.b Isolated yield.c 5 mol% catalyst was used. RT means room temperature.
1	No catalyst	EtOH/80 °C	4	—
2	t-ZrO2 NPs	EtOH/80 °C	2	75
3	t-ZrO2 NPs	EtOH–H2O (1 : 1)/80 °C	2	91
4	t-ZrO2 NPs	EtOH–H2O (1 : 1)/RT	4	40
5	t-ZrO2 NPs	Toluene/80 °C	2	68
6	t-ZrO2 NPs	THF/80 °C	2	59
7	t-ZrO2 NPs	DMF/80 °C	2	60
8	Bulk-ZrO2	EtOH–H2O (1 : 1)/80 °C	2	53
9	m-ZrO2 NPs	EtOH–H2O (1 : 1)/80 °C	2	61
10	Fe3O4 NPs	EtOH–H2O (1 : 1)/80 °C	2	79
11	SiO2 NPs	EtOH–H2O (1 : 1)/80 °C	2	52
12	CuO NPs	EtOH–H2O (1 : 1)/80 °C	2	71
13	NiO NPs	EtOH–H2O (1 : 1)/80 °C	2	62
14	ZnO NPs	EtOH–H2O (1 : 1)/80 °C	2	67
15	t-ZrO2 NPs	EtOH–H2O (1 : 1)/80 °C	2	80^c

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Table 2 Tetragonal nano-ZrO₂-catalysed synthesis of poly-functionalized pyridine derivatives^a

a Reaction conditions: aldehyde (1 mmol), malononitrile (1 mmol), amine (1 mmol), ethyl acetoacetate (1 mmol), ZrO2 NPs (10 mol%), ethanol–H2O (1 : 1) (5 ml) with continuous stirring at 80 °C for 2 h.

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Next, utilizing these optimized conditions and the general experimental procedure (see ESI 2† for detail experimental procedure), we examined the scope of the methodology for the synthesis of pyridine derivatives. We observed that the t-ZrO₂ NPs were able to furnish excellent yields (85–94%) of ethyl 5-cyano-2-methyl-4-aryl-6-(arylamino)nicotinates (1a–o, Table 2) by the condensation/cyclization of a variety of substituted aryl aldehydes and aryl amines with malononitrile and ethyl acetoacetate within a practical time period of 2 h. The results are summarized in Table 2. Aryl aldehydes containing both electron-donating (e.g. –OH, –OMe, –CH₃, –Cl, –Br etc.) and electron-withdrawing (e.g. –NO₂) groups participated smoothly in the reaction without any electronic effect, while in the case of aryl amines, the presence of electron-donating groups (e.g. –OMe, –CH₃, –Cl, –Br) increased the product yield but an electron-withdrawing group (e.g. –NO₂) in the aryl amine decreased the reaction rate as well as the product yield. The observations are listed in Table 2.

All the prepared pyridine derivatives are solid and were purified by recrystallization from hot ethanol. Thus, the present protocol does not require column chromatography. The compounds were identified by melting point determination followed by nuclear magnetic resonance (¹H NMR and ¹³C NMR) spectroscopic studies. The NMR spectra are provided in ESI 5.†

To show the advantages of the present protocol, a comparison of present and previously reported methods is given in Table 3, which reveals the efficacy of the t-ZrO₂ catalyst over the reported FeCl₃ and SnCl₂ catalysts in terms of yields, reaction times and recyclability.

Table 3 Comparative study of the present and reported methods

Sl no.	Catalyst	Reaction conditions	Yield (%)	Time (h)	Reusable?
a Present work.
1	t-ZrO2 NPs^a	EtOH–H2O (1 : 1)/80 °C	85–94	2	Yes
2	FeCl3 (ref. 10)	EtOH/70 °C	45–86	6	No
3	SnCl2·2H2O (ref. 11)	H2O/60 °C	82–90	7–10	No

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The t-ZrO₂ NPs showed better activity than others examined here. This is possibly due to the Lewis acid–base character and active surface of the material. The Lewis acid–base nature of ZrO₂ is well known in the literature^20g,23 and is due to the presence of active hydroxyl, oxide and Zr⁴⁺. In our previous reports, we have already proved the Lewis acid–base nature of the t-ZrO₂ NPs.^20g Here also, we studied the IR-based adsorption studies and we observed that both phenol and pyridine were adsorbed on the surface of the ZrO₂ NPs, which clearly signifies the presence of acidic and basic sites (Fig. S2 and S3 in ESI-5†). It has also been reported that t-ZrO₂ NPs contain more acidic and basic sites than c-ZrO₂ and are more active.^20g,23 In addition, we observed that in aqueous ethanol medium ZrO₂ NPs showed basic character (pH = 8.1).

Next, we investigated the reusability of t-ZrO₂ nano-catalyst for the synthesis of ethyl 5-cyano-2-methyl-4-phenyl-6-(phenylamino)nicotinate (1a, Table 2) as a model reaction. After reaction, t-ZrO₂ NPs were separated from the reaction mixture by centrifugation, washed successively with ethanol and water, dried and reused for the subsequent run. We observed that tetragonal phase catalyst remained intact after the eighth cycle (confirmed by powder XRD; see Fig. S1, ESI-4†), with minimal loss (∼9%) in yield of isolated product at the eighth run (Fig. 4a). The TEM image of the reused t-ZrO₂ NPs (Fig. 4b) indicates that the spherical morphology of particles remained intact even after the eighth cycle. The slight decrease in yield may possibly be due to loss of surface hydroxyl groups,^20g decrease of oxygen vacancies²⁰ⁱ or agglomeration of the nanoparticles.

Fig. 4 (a) Reusability of t-ZrO₂ NPs for the synthesis of pyridine derivative (1a, Table 1) and (b) HRTEM image of t-ZrO₂ NPs after the eighth reuse.

Inspired by the above synthetic results, next we extended the scope of t-ZrO₂ NP-catalysed MCRs in the synthesis of bio-active 2-pyrrolidinone moieties by the reactions of aryl aldehyde, aryl amine and diethyl acetylenedicarboxylate. Thus, when a mixture of benzaldehyde (1 mmol), aniline (1 mmol) and diethyl acetylenedicarboxylate (1 mmol) was stirred at room temperature in the presence of 10 mol% t-ZrO₂ in ethanol–water (1 : 1), followed by extraction and recrystallization, we obtained 92% yield of product, identified as ethyl 4-hydroxy-2-(4-nitrophenyl)-5-oxo-1-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylate (2a, Table 4). In a simple experimental procedure using t-ZrO₂ NPs, we have synthesized a variety of 2-pyrrolidone derivatives (2a-I, Table 4).

Table 4 Nano t-ZrO₂-catalysed synthesis of 2-pyrrolidinone derivatives^a

a Reaction conditions: aryl aldehyde (1 mmol), aryl amine (1 mmol), diethyl acetylenedicarboxylate (1 mmol), ZrO2 NPs (10 mol%), ethanol–H2O (1 : 1) (5 ml), with continuous stirring at room temperature.

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The detailed experimental procedure for the above syntheses is provided in ESI-3.† These reactions were very fast (5–12 min.) and high yielding (87–95%). Moreover, this protocol does not require any external energy source such as ultrasonic irradiation.

A comparative study for the synthesis of 2-pyrrolidinone moieties, presented in Table 5, clearly indicates that the present method using t-ZrO₂ NPs is a better alternative to the existing protocols.¹⁹

Table 5 Comparative study of present vs. previously reported methodology for the synthesis of 2-pyrrolidinones

Sl no.	Catalyst	Reaction conditions	Yield (%)	Time	Re-usable?
a Present work.
1	t-ZrO2 NPs^a	EtOH–H2O (1 : 1)/RT	87–95	5–12 min	Yes
2	Citric acid^19a	EtOH/ultra sound	80–92	10–50 min	No
3	PTSA^19b	EtOH/RT	52–76	48 h	No
4	Catalyst free^19c	EtOH–H2O (1 : 1)/RT	80–87	15–24 h	—

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Finally, a leaching study by hot filtration test was executed to examine the stability of t-ZrO₂ in the synthesis of ethyl 5-cyano-2-methyl-4-phenyl-6-(phenylamino)nicotinate (1a, Table 2). The catalyst was removed from the reaction mixture after 45 minutes by ultracentrifugation under hot conditions and the remaining filtrate was further stirred for up to 2 h under similar conditions. It was observed that a negligible amount (16%) of desired product (1a, Table 1) was formed after removal of the catalyst at 45 minutes, without further improvement of yield. The results are depicted in Fig. 5, and prove that the t-ZrO₂ NPs were highly stable during reaction and apparently no leaching of Zr-content occurred.

Fig. 5 Catalyst leaching study by hot filtration test performed with: (a) complete run (green line) and (b) catalyst removed after 45 min (red line). For the synthesis of pyridine derivative 1a (Table 2).

Conclusions

In conclusion, we have demonstrated a simple and efficient method for the synthesis of ethyl 5-cyano-2-methyl-4-aryl-6-(arylamino)nicotinate and ethyl 4-hydroxy-2-(4-nitroaryl)-5-oxo-1-aryl-2,5-dihydro-1H-pyrrole-3-carboxylate using t-ZrO₂ NPs. All the reactions listed in Tables 2 and 4 are very clean and high yielding (85–94%). Moreover, a significant acceleration of reaction rate (2 h) was observed for the synthesis of pyridines (1a–o, Table 2) compared with reported methods (6–10 h).^10,11 The comparative results of present and previously reported methods for the synthesis of pyridines (B, Fig. 1) and 2-pyrrolidones (C, Fig. 1) presented in Tables 3 and 5 demonstrate a significant improvement in terms of reaction time, yields and greenness. Additionally, use of mild t-ZrO₂ NPs as catalyst, ethanol–water mixture as solvent, simple isolation and purification of products without using column chromatography, and recycling of catalyst make the present synthetic methodology more convenient and environmentally friendly in nature.

Acknowledgements

We are pleased to acknowledge the funding agency Department of Science and Technology, New Delhi, Govt of India (No.·SB/FT/CS-023/2012). AS and SP also thank Guru Ghasidas Vishwavidyalaya for their fellowship. Special thanks to Prof. B. C. Ranu and his group for their help in NMR studies.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Details of experimental procedure for preparation of catalysts and synthesis of poly functionalized pyridine and 2-pyrrolidinone derivatives, NMR copy of the representative compounds. See DOI: 10.1039/c6ra24367c

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