Four-Component Fusion Protocol with NiO/ZrO2 as a Robust Recyclable Catalyst for Novel 1,4-Dihydropyridines.

Nickel oxide loaded on zirconia (NiO/ZrO2) as an expedient catalyst is reported for the synthesis of 18 unsymmetrical 1,4-dihydropyridine derivatives. The Lewis acidic nature of the catalyst proved an excellent choice for the one-pot, four-component fusion reaction with excellent yields of 89-98% and a completion time of 20-45 min. Mechanistic studies show that enamine and imine functionalities are the two possible pathways for the formation of 1,4-dihydropyridines with high selectivity. Crystal structures of two novel compounds (5a, 5c) were reported. The catalyst demonstrated reusability up to six cycles. The reaction at room temperature and ethanol as a solvent make this protocol green and economical.

Introduction

Catalysts play a crucial role in facilitating product selectivity and decreasing the activation energy of the reactions.[1] Although homogeneous catalysts show better efficiency in chemo- and regioselectivity and their reaction mechanisms are better understood, their recovery from the reaction mixture is often difficult and involves several neutralization procedures.[2] To overcome these drawbacks, heterogeneous catalysts are more chosen in organic synthesis. Because of their surface-to-volume ratio, the amount of heterogeneous catalyst required for the transformation is reduced, enabling the transformation to become both efficient and economical, and it is easy to separate from the reaction medium.[3] In this context, mixed class="Chemical">metal oxides as heterogeneous catalysts contributed significantly to organic synthesis because of their tuneable characteristics of the versatile surface sites.[4] The synergy between active class="Chemical">pan class="Chemical">metal and support typically dictates the catalytic properties of the material.[5] In this context, nickel has been used both as a homogeneous and heterogeneous catalyst in many organic transformations like C–C bond formations, reductive eliminations including C–N and C–O bond formation reactions, and cross-coupling reactions.[6] Zirconia has attracted more interest than other support materials because of its higher tolerance toward corrosion and high temperatures,[7] as demonstrated by the use of ZrO2 in the heat shield of space shuttles. Moreover, zirconia gained importance as a catalyst due to its surface properties by possessing both acidic and basic sites. The surface properties can be modified by loading/doping with suitable metals.[8,9] Based on these advantages, we prepared materials with different loadings of Ni on ZrO2 support and investigated their efficacy as a reusable catalyst for selective organic transformation. Previous reports demonstrated the use of NiO/ZrO2 as a catalyst for simple conversions such as oxidative dehydrogenation[10] and C–S cross-coupling reactions.[11] This is the first report of using NiO/ZrO2 as a catalyst in a multicomponent, one-pot reaction system.

Multicomclass="Chemical">ponent reactions (MCRs) are imclass="Chemical">pan class="Chemical">portant synthetic tools with the ability to craft complex organic molecules with high atom economy. An MCR is an ecofriendly means to synthesize libraries of biologically important scaffolds.[12] Among the heterocyclic compounds, N-heterocyclic scaffolds in general acquired more prominence in the medicinal and pharmaceutical chemistry. In particular, 1,4-dihydropyridines (1,4-DHPs) are scaffolds of biological importance[13] as antimicrobial,[14] antitubercular,[15] anticancer,[16] anticoagulant,[17] neuroprotector,[18] antioxidant,[19] L/T-type calcium channel blocking,[20] AChE inhibiting,[21] and bone anabolic agents.[22] 1,4-DHPs were first reported by Hantzsch in 1882 via the multicomponent reaction of aromatic aldehyde, β-ketoester, and ammonia as nitrogen sources.[23] Well-known commercial drugs like felodipine, diludine, and nifedipine constitute 1,4-DHPs as the core moiety (Figure ).

Figure 1

Structures of commercially available 1,4-dihydropyridine drugs.

Structures of commercially available pan class="Chemical">1,4-dihydropyridine drugs.

Due to the vast biological and synthetic imclass="Chemical">portance of 1,4-DHclass="Chemical">pan class="Chemical">P derivatives, several protocols have been reported via a one-pot strategy and employing different catalysts like nano-tungsten trioxide-supported sulfonic acid (n-WSA),[24] sulfated boric acid nanoparticles,[25] chitosan-supported copper(II) sulfate,[26] Fe3O4@SiO2@Si-(CH2)3@melamine-picolineimine@SO3H,[27] sulfated polyborate,[28] Fe3O4/KCC-1/BPAT,[29] chitosan-supported vanadium oxo,[30] magnetic guanidinylated chitosan,[31] nano-ZrO2-SO3H (n-ZrSA),[32] Gd(OTf)3,[33] nicotinic acid,[34] γ-Fe2O3/Cu@cellulose,[35] SBA-15@AMPD-Co,[36] sulfamic acid,[19] Fe3O4@D-NH-(CH2)4-SO3H,[37] Cu-adenine@boehmite,[38] hydromagnesite,[39] Cu(OTf)2,[40] ascorbic acid,[41] NS-C4(DABCO-SO3H)2·4Cl,[42] CBr4,[43] and aminated CNTs.[14] Many of these methods either suffer from usage of reflux conditions, lower yields, or long reaction times.

We reclass="Chemical">port for the first time class="Chemical">pan class="Chemical">NiO/ZrO2 as a reusable catalyst in a one-pot four-component fusion reaction for the synthesis of novel 1,4-dihydropyridine derivatives at room temperature. We also report significant advances into the proposed mechanism based on the reaction intermediates, including a single-crystal structure.

Results and Discussion

X-ray Diffraction (XRD) Analysis

Figure shows the X-ray diffraction pattern of 2.5 wt % class="Chemical">NiO–class="Chemical">pan class="Chemical">ZrO2 and the diffraction peaks (2 theta) from 0 to 80°. The major diffraction peaks at 2θ of 24.5, 27.8, 31.3, 35.4, 40.5, 50.3, 54.4, 55.6, 57.8, 59.9, 65.4, and 71.2° for ZrO2 are correlated with the international standard file (JCPDS 37-1484). The NiO peaks are displayed in the XRD diffractogram at 2θ = 37.2, 45.3, 62.8, 71.3, and 75.5° were further matched with the standard file (JCPDS 47-1049). The diffraction pattern revealed the polycrystalline nature of the prepared catalytic material.

Figure 2

Powder X-ray diffractogram of 2.5% NiO–ZrO2 catalyst.

class="Chemical">Powder X-ray diffractogram of 2.5% class="Chemical">pan class="Chemical">NiO–ZrO2 catalyst.

Transmission Electron Microscopy (TEM) Analysis

The TEM investigation was performed to explore the catalyst morphology. Figure illustrates a distinctive TEM image class="Chemical">NiO/ZrO2 (2.5 wt %). The image indicated an irregular cubic morclass="Chemical">phology with nominal agglomeration of class="Chemical">pan class="Chemical">NiO. It was further observed that the black irregular-shaped nickel oxide particles are evenly distributed on the surface of oval-shaped zirconia particles, which may improve catalytic activity.

Figure 3

TEM micrograph of 2.5% NiO–ZrO2 catalyst.

TEM micrograph of 2.5% pan class="Chemical">NiO–class="Chemical">pan class="Chemical">ZrO2 catalyst.

Scanning Electron Microscope (SEM) Analysis

The surface morphology of 2.5 wt % class="Chemical">NiO/ZrO2 was assessed by SEM, which is shown in Figure . Figure a shows the irregular-round class="Chemical">particles aggregated on the surface of class="Chemical">pan class="Chemical">ZrO2. The surface was further analyzed by mapping and energy-dispersive X-ray spectroscopy (EDS) (Figure b,c), which show the even distribution of Ni on the surface of zirconia.

Figure 4

(a) SEM micrograph, (b) mapping, and (c) EDS spectra of 2.5% NiO/ZrO2 catalyst.

(a) SEM micrograph, (b) mapping, and (c) EDS spectra of 2.5% pan class="Chemical">NiO/ZrO2 catalyst.

Brunauer–Emmett–Teller Surface Area Analysis

The 2.5 wt % class="Chemical">NiO/ZrO2 class="Chemical">pan class="Chemical">N2 adsorption–desorption isotherm illustrated in Figure shows a type-IV adsorption isotherm with a hysteresis loop of H2, which is a characteristic of a mesoporous material (p/po range of 0.67–0.98). The surface area is 76.35 m2 g–1 with a pore volume of 0.29 cm3 g–1 and a pore size 12.14 nm.

Figure 5

N2 adsorption–desorption isotherms of 2.5% NiO/ZrO2 catalyst.

pan class="Chemical">N2 adsorclass="Chemical">ption–desorclass="Chemical">ption isotherms of 2.5% class="Chemical">pan class="Chemical">NiO/ZrO2 catalyst.

Pyridine IR

The nature of the surface active sites was examined by class="Chemical">ex-Pyridine IR.[44] class="Chemical">pan class="Chemical">Pyridine is widely used as a probe to characterize the surface acidity of the materials. Pyridine as a base interacts with Brønsted acid sites and through H+ transfer lead to the formation of pyridinium ion. Pyridine can act as a Lewis base, and it is capable to donate a pair of electrons toward the electrophilic Lewis acidic sites. Such characteristic bands are perceived in the range of 1550–1400 cm–1. Based on this, the characteristic peak at 1448 cm–1 corresponds to the Lewis acidic sites with bands at 1481 and 1531 cm–1 that correspond to the Lewis + Brønsted and Brønsted acidic sites, respectively. Figure confirms that the catalyst possesses prominent Lewis acidic sites, which could facilitate its catalytic activity.

Figure 6

Pyridine FT-IR spectra of 2.5% NiO/ZrO2 catalyst. L = Lewis acidic sites; B + L = Brønsted and Lewis acidic sites; B = Brønsted acidic sites.

pan class="Chemical">Pyridine FT-IR sclass="Chemical">pectra of 2.5% class="Chemical">pan class="Chemical">NiO/ZrO2 catalyst. L = Lewis acidic sites; B + L = Brønsted and Lewis acidic sites; B = Brønsted acidic sites.

Reaction Optimization

The catalytic efficiency of prepared class="Chemical">NiO/ZrO2 toward the title multicomclass="Chemical">pan class="Chemical">ponent reaction was evaluated. The reaction was performed by taking four components, 2,3,4-OMe benzaldehyde (1a), ethyl acetoacetate (2) cyclohexanone (3), and ammonium acetate (4) in the same molar ratio (Scheme ). In separate studies, the effects of various catalysts, the amount of catalyst, and role of solvents were examined. Initially, the reaction was studied under neat conditions at room temperature and reflux up to 8 h. Only a trace amount of product was obtained. Next, the effect of different homogeneous catalysts and organic or inorganic bases such as triethyl amine (TEA), pyridine, DABCO, NaOH, and K2CO3 were explored on the title reaction at room temperature (RT) conditions (5–7 h) and low yields were observed (Table , entries 3–7). For comparison, further studies conducted with acidic catalysts AcOH, FeCl3, PTSA, and TFA gave moderate yields in 4–6 h (Table , entries 8−11). Different heterogeneous metal oxides like SiO2, ZrO2, and Al2O3 (normally used as support materials) were explored under the same reaction conditions. SiO2 gave 53% yield, Al2O3 gave 60% in 3.5–4 h time, ZrO2 gave a higher yield of 68% in 2 h time, and NiO gave 65% in 2.5 h time (Table , entries 12–15). Considering the interesting results from NiO and ZrO2, to identify the efficient catalyst, the scope of various ZrO2-based mixed oxide catalysts, 2.5 wt % CuO/ZrO2, CeO2/ZrO2, and NiO/ZrO2 (Table , entries 16–18) were investigated. An impressive yield of 98% was observed with 2.5% NiO/ZrO2 in a relatively short time of 20 min compared to 73% in 60 min with 2.5% CuO/ZrO2 (Table , entry 16) and 81% yield in 45 min (Table , entry 17) with 2.5% CeO2/ZrO2. While using 1% NiO/ZrO2 catalyst yielded 91% product in 30 min under similar conditions (Table , entry 19), 5% NiO/ZrO2 led to a slight decreased yield (94%) in 25 min (Table , entry 20). Therefore, 2.5% NiO/ZrO2 was the preferred catalyst for further studies. The higher catalytic activity may be due to the even distribution of the active material on the surface of the support and availability of more optimally active NiO sites in combination with ZrO2, which help in speeding up the rate of reaction selectively compared to 1 and 5% catalyst. For the 1% NiO/ZrO2 catalyst loading, the particles are small and have a high surface area but less number of active sites compared to the 2.5% NiO/ZrO2, whereas for 5% NiO/ZrO2 loading, the nickel particles are visibly larger and hence have a smaller surface area, thus slightly lower yield when compared to the 2.5% NiO/ZrO2. Hence, 2.5% NiO/ZrO2 acts as a good promoter for the present transformation.

Scheme 1

Optimization Reaction Conditions for 5a Synthesis

Table 1

Effect of Different Catalysts on the Synthesis of 5aa

entry	catalyst	solvent	condition	time (h)	yield (%)b
1	–	–	RT	8	12
2	–	–	reflux	8	17
3	TEAc	EtOH	RT	5.0	30
4	pyridinec	EtOH	RT	7.0	27
5	DABCOc	EtOH	RT	5.0	25
6	NaOHc	EtOH	RT	6.0	33
7	K2CO3c	EtOH	RT	6.0	29
8	AcOHc	EtOH	RT	5.5	36
9	FeCl3c	EtOH	RT	5.0	38
10	PTSAc	EtOH	RT	6.0	45
11	TFAc	EtOH	RT	4.0	40
12	SiO2d	EtOH	RT	4.0	53
13	ZrO2d	EtOH	RT	2.0	68
14	Al2O3d	EtOH	RT	3.5	60
15	NiOd	EtOH	RT	2.5	65
16	2.5% CuO/ZrO2e	EtOH	RT	1.0	73
17	2.5% CeO2/ZrO2e	EtOH	RT	0.75	81
18	2.5% NiO/ZrO2e	EtOH	RT	0.33	98
19	1% NiO/ZrO2e	EtOH	RT	0.50	91
20	5% NiO/ZrO2e	EtOH	RT	0.41	94

Reaction conditions: 2,3,4-trimethoxybenzaldehyde (1 mmol) (1), ethyl acetoacetate (1 mmol) (2), 1,3-cyclohexadione (1 mmol) (3), and ammonium acetate (1 mmol) (4); 5 mL of solvent; and stirring at RT.

Isolated yields.

100 mg of catalyst.

60 mg of catalyst.

30 mg of catalyst.

No catalyst.

Reaction conditions: class="Chemical">2,3,4-trimethoxybenzaldehyde (1 mmol) (1), ethyl acetoclass="Chemical">pan class="Chemical">acetate (1 mmol) (2), 1,3-cyclohexadione (1 mmol) (3), and ammonium acetate (1 mmol) (4); 5 mL of solvent; and stirring at RT.

To further optimize the conditions, we examined the role of the solvent in the organic conversion employing different nonclass="Chemical">polar and class="Chemical">pan class="Chemical">polar solvents (Table ). In the presence of nonpolar solvents like n-hexane and toluene at RT, no product was identified even after 4 h possibly due to the poor solubility of the reactants. Among the polar solvents such as DMF, THF, MeCN, EtOH, and MeOH, the highest yields were observed with EtOH.

Table 2

Role of Different Solvent in the Synthesis of 5aa

entry	solventb	time (h)	yield (%)
1	n-hexane	4.0	–
2	toluene	4.0	–
3	DMF	1.3	19
4	THF	1.1	24
5	MeCN	1.0	31
6	CH3OH	0.75	76
7	C2H5OH	0.33	98

Reaction conditions: 2,3,4-trimethoxybenzaldehyde (1 mmol) (1), ethyl acetoacetate (1 mmol) (2), 1,3-cyclohexanedione (1 mmol) (3), and ammonium acetate (1 mmol) (4); 5 mL of solvent; and stirring at RT.

DMF, dimethyl formamide; THF, tetrahydrofuran; MeCN, acetonitrile; CH3OH, methanol; C2H5OH, ethanol.

No product.

Reaction conditions: class="Chemical">2,3,4-trimethoxybenzaldehyde (1 mmol) (1), class="Chemical">pan class="Chemical">ethyl acetoacetate (1 mmol) (2), 1,3-cyclohexanedione (1 mmol) (3), and ammonium acetate (1 mmol) (4); 5 mL of solvent; and stirring at RT.

class="Chemical">DMF, class="Chemical">pan class="Chemical">dimethyl formamide; THF, tetrahydrofuran; MeCN, acetonitrile; CH3OH, methanol; C2H5OH, ethanol.

Next, the required amount of catalyst for the reaction was optimized. Results are summarized in Table and show that the yields of products increased with the increase in amount of catalyst from 10 to 30 mg. There was no increase in the yield with >30 mg. To broaden the viability and scope of the method, 18 substituted class="Chemical">1,4-dihydropyridines were synthesised emclass="Chemical">ploying the oclass="Chemical">ptimized conditions, of which 12 were novel derivatives. All of the 18 derivatives gave excellent yields in a relatively short time of ≈45 min, and the results are summarized in Figure . The structures of all synthesized comclass="Chemical">pan class="Chemical">pounds were confirmed by 1H NMR, 13C NMR, and 15N spectroscopy and high-resolution mass spectrometry (HRMS) analyses. The single-crystal X-ray structures of 5a and 5c are shown in Figures and 9, respectively. Table shows the crystal data, and further information is incorporated in the Supporting Information (page S3).

Table 3

Optimization of the Amount of 2.5% NiO/ZrO2 Catalyst for the Synthesis of 5aa

entry	catalyst (mg)	time (h)	yield (%)
1	10	0.83	74
2	20	0.5	85
3	30	0.33	98
4	40	0.33	98
5	50	0.33	97
6	60	0.33	97

Reaction conditions: 2,3,4-trimethoxybenzaldehyde (1 mmol) (1), ethyl acetoacetate (1 mmol) (2), 1,3-cyclohexadione (1 mmol) (3), and ammonium acetate (1 mmol) (4); 5 mL of EtOH; and stirring at RT.

Figure 7

Library synthesis of novel unsymmetrical 1,4-dihydropyridine derivatives. Reaction conditions: substituted aldehydes (1 mmol) (1), ethyl acetoacetate (1 mmol) (2), 1,3-cyclohexadione/5,5-dimethyl-1,3-cyclohexanedione (1 mmol) (3), and ammonium acetate (1 mmol) (4); 5 mL of ethanol; 2.5% NiO/ZrO2 (30 mg) catalyst; and stirring at RT; melting point (m.p.) in °C.

Figure 8

Single-crystal X-ray structure of 5a.

Figure 9

Single-crystal X-ray structure of 5c.

Table 4

Single-Crystal Data of 5a and 5c

identification code	5a	5c
empirical formula	C22H27NO6	C20H23NO3
formula weight	401.44	325.39
temperature (K)	100.0	100.0
crystal system	orthorhombic	triclinic
space group	Pna21	P-1
a (Å)	14.6836(6)	7.29920(10)
b (Å)	8.4477(3)	9.58180(10)
c (Å)	15.5290(6)	12.3976(2)
α (°)	90	83.9450(10)
β (°)	90	86.8650(10)
γ (°)	90	71.9730(10)
volume (Å3)	1926.26(13)	819.69(2)
Z	4	2
ρcalc (g/cm3)	1.384	1.318
μ (mm–1)	0.101	0.088
F(000)	856.0	348.0
crystal size (mm3)	0.38 × 0.24 × 0.16	0.31 × 0.23 × 0.12
radiation	Mo Kα (λ = 0.71073)	Mo Kα (λ = 0.71073)
2Θ range for data collection (°)	5.246–56.7	3.304–57.038
index ranges	–19 ≤ h ≤ 15, −11 ≤ k ≤ 11, −20 ≤ l ≤ 20	–9 ≤ h ≤ 9, −12 ≤ k ≤ 12, −16 ≤ l ≤ 16
reflections collected	13 133	26 777
independent reflections	4622 [Rint = 0.0196, Rsigma = 0.0237]	4083 [Rint = 0.0179, Rsigma = 0.0131]
data/restraints/parameters	4622/1/267	4083/0/220
goodness-of-fit on F2	1.024	1.048
final R indexes [I ≥ 2σ(I)]	R1 = 0.0312, wR2 = 0.0772	R1 = 0.0365, wR2 = 0.0972
final R indexes [all data]	R1 = 0.0345, wR2 = 0.0796	R1 = 0.0408, wR2 = 0.1008
largest diff. peak/hole (e Å–3)	0.29/–0.21	0.40/–0.19

Library synthesis of novel unsymmetrical class="Chemical">1,4-dihydropyridine derivatives. Reaction conditions: substituted class="Chemical">pan class="Chemical">aldehydes (1 mmol) (1), ethyl acetoacetate (1 mmol) (2), 1,3-cyclohexadione/5,5-dimethyl-1,3-cyclohexanedione (1 mmol) (3), and ammonium acetate (1 mmol) (4); 5 mL of ethanol; 2.5% NiO/ZrO2 (30 mg) catalyst; and stirring at RT; melting point (m.p.) in °C.

Reaction conditions: class="Chemical">2,3,4-trimethoxybenzaldehyde (1 mmol) (1), class="Chemical">pan class="Chemical">ethyl acetoacetate (1 mmol) (2), 1,3-cyclohexadione (1 mmol) (3), and ammonium acetate (1 mmol) (4); 5 mL of EtOH; and stirring at RT.

The heteronuclear multiple bond correlation (HMBC) interactions of trial reaction 5a are shown in Figure . In the class="Chemical">1H NMR sclass="Chemical">pectra, the distinguishing singlet class="Chemical">peaks at δ = 2.18, 3.67, 3.70, 3.77, 4.98, and 8.99 indicate the class="Chemical">presence of −CH3, −OCH3, −CH, and −NH class="Chemical">protons. The selected HMBC interactions of 5a are a definite class="Chemical">proof for the class="Chemical">product formation. The −CH class="Chemical">proton in the class="Chemical">pan class="Chemical">1,4-dihydropyridine ring was assigned to the peak at δ = 4.98, and it further interacted with carbon atoms at δ = 18.04, 103.90, 110.54, 124.53, 133.18, 151.41, 167.28, and 194.25. The singlet peak at δ = 8.99 was attributed to the −NH proton in the dihydropyridine ring, which further interacts with the carbon atoms at δ = 18.04, 26.29, 110.54, 103.90, 143.42, 167.28, and 194.25. The HRMS showed the m/z = 400.1770 [C22H27NO6-H+], which corresponds well with the theoretical value for 5a.

Figure 10

13C chemical shifts and selected HMBC interactions of −CH and −NH protons of 5a.

pan class="Chemical">13C chemical shifts and selected HMBC interactions of −CH and −NH class="Chemical">protons of 5a.

Insight into the Mechanism

To examine the mechanism of the present reaction, an attempt was made to identify the reaction intermediates by analyzing the reaction mixture after 10 min (Figure ). Characterization relied on liquid chromatography–mass spectrometry (LC–MS) studies and was based on peaks identified at 112 and 130 corresclass="Chemical">ponding to the class="Chemical">presence of class="Chemical">pan class="Chemical">enamine, the peak at 309 corresponding to imine, and the peak at 291 to the existence of a Knoevenagel condensation transient intermediate. Based on experimental observations, the generation of the final product is proposed to occur through two pathways: (i) by enamine and (ii) by imine, which is supported by the literature reports.[45,46] In the proposed scheme, the key intermediates in the reaction are designated as (6), (7), (8), and (9). It is assumed that for the formation of a knoevenagel intermediate[47] between 2,3,4-OMe benzaldehyde (1) and 1,3-cyclohexanedione (2), Lewis acidic sites present on the surface plays a key role, which can activate the carbonyl group of aldehyde and make it electrophilic to form an intermediate (a) and then react with nucleophilic 1,3-cyclohexanedione (2), which further will dissociate from the catalyst surface by taking a proton from the solvent ethanol to give the intermediate (b) and to give (6) upon further dehydration. Similarly, (7) is also formed by the same procedure with the reaction of ethyl acetoacetate through the intermediate (c). Furthermore, ammonium acetate (4) acts as a nitrogen source to further dissociate to ammonia (4a). The enamine intermediates (8) and (9) are formed by the reaction of ammonia (4a) with (2) and (3) on the catalyst surface. Enamine (8) possibly reacts with (7) and undergoes Michael addition to give the key structure (11). The ring closure of (11) leads to the formation intermediate (12), which undergoes dehydration, finally yielding the stable product, 5a. Similarly, the enamine (9) upon reaction with (6) gives (13) via Michael addition and subsequent ring closure generates intermediate (14), which upon dehydration offers 5a. The enamine (9) reacts with (1) to give an imine intermediate (10), which further reacts with (2) to give (13). Further ring closure provides the intermediate (14) followed by dehydration, which gives 5a (Scheme ). The comparative catalytic efficiency of the 2.5% NiO/ZrO2 with other reported catalysts is given in Table .

Figure 11

LC–MS spectra of the reaction mixture with compound 5a.

Scheme 2

Formation of Unsymmetrical 1,4-DHPs 5a in the Presence of NiO/ZrO2 Catalyst

Table 5

Comparison of Present Work with Previous Reports

catalystref	solvent	reaction condition	time	yield (%)
sulfamic acid[19]	MeOH	reflux	24 h	47–92
γ-Fe2O3/Cu@cellulose[35]	solvent-free	RT	9–30 min	80–98
SBA-15@AMPD-Co[36]	solvent-free	100 °C	35–90 min	90–97
Fe3O4@D-NH-(CH2)4-SO3H[37]	EtOH	reflux	40 min	86–90
Cu-Adenine@boehmite[38]	EtOH	reflux	20–120 min	89–97
nano-tungsten trioxide-supported sulfonic acid (n-WSA)[24]	solvent-free	100 °C	10–25 min	86–98
sulfated boric acid nanoparticles[25]	EtOH	60 °C	20–60 min	86–98
chitosan-supported copper(II) sulfate (CSCS)[26]	EtOH	reflux	20–87 min	80–97
Fe3O4@SiO2@Si-(CH2)3@melamine-picolineimine@SO3H[27]	solvent-free	60 °C	4–11 min	48–90
sulfated polyborate[28]	solvent-free	90 °C	15–35 min	85–95
Fe3O4/KCC-1/BPAT[29]	water	reflux	4 h	79–88
chitosan-supported vanadium oxo[30]	solvent-free	85 °C	20–55 min	81–94
magnetic guanidinylated chitosan[31]	EtOH	reflux	15 min	82–89
nano-ZrO2-SO3H (n-ZrSA)[32]	solvent-free	80 °C	35–65 min	84–93
Gd(OTf)3[33]	EtOH	RT	5–6 h	82–89
nicotinic acid[34]	solvent-free	80 °C	2–7 min	87–96
hydromagnesite[39]	water	90 °C	20–45 min	80–98
Cu(OTf)2[40]	EtOH	100 °C	15 min	81–98
ascorbic acid[41]	solvent-free	80 °C	1.5–4.5 h	70–96
NS-C4(DABCO-SO3H)2·4Cl[42]	solvent-free	100 °C	8–50 min	80–100
CBr4[43]	EtOH	RT	3–6 h	70–98
aminated CNTs[14]	EtOH	reflux	3–6 h	80–96
2.5% NiO/ZrO2 (present work)	EtOH	RT	20–45 min	89–98

LC–MS spectra of the reaction mixture with compan class="Chemical">pound 5a.

Moreover, green metrics calculations for a series of synthesized class="Chemical">1,4-dihydropyridine derivatives were class="Chemical">performed (Table S1, class="Chemical">page S50). For the class="Chemical">proclass="Chemical">pan class="Chemical">posed method, the calculated atom economy and atom efficiency ranges from 74.1 to 83.2%, which are below 100% due to the loss of three H2O molecules and one acetate ion as byproducts, and E factors ranging from 0.26 to 0.44 g/g are also validated and indicate the good green credential of the present protocol. The other green metrics are shown in Table S1, page S50 (Supporting Information).

Reusability of the Catalyst

To examine the catalyst stability, recyclability experiments were conducted. After every run, the catalyst was recovered from the reaction mixture, washed with class="Chemical">ethanol, and dried at 120 °C for 2 h. For the first six cycles, the catalyst class="Chemical">proved efficient and the activity was retained with no loss. Afterward, the material catalytic activity decreased in the seventh cycle (Figure ). To examine the heterogeneity of the used 2.5% class="Chemical">pan class="Chemical">NiO/ZrO2 catalyst, a hot filtration method was employed for the synthesis of 5a. Ten minutes after the start of the reaction, the catalyst was removed from the reaction mixture through centrifugation and the remaining reaction mixture was kept under the same stirred condition to monitor the reaction progress. Even after 60 min, no reaction or increase in the product yield was observed (Figure ). From the above result, it shows that the catalyst leaching is very low. Furthermore, the catalyst after the reaction was analyzed by XRD and TEM incorporated (Figure S1). The XRD pattern of the reused material is much similar to that of the fresh one; furthermore, from the TEM image of the reused catalyst, there is as much similar to that of the fresh one, which indicates that there is no such erosion of the active material from the support, which shows the presence of the heterogeneous nature of material.

Figure 12

Recycling study of 2.5% NiO/ZrO2 catalyst for the synthesis of 1,4-dihydropyridine 5a.

Figure 13

Hot filtration test results of 2.5% NiO/ZrO2 catalyst for 5a. Reaction conditions: 2,3,4-trimethoxybenzaldehyde (1 mmol) (1), ethyl acetoacetate (1 mmol) (2), 1,3-cyclohexadione (1 mmol) (3), and ammonium acetate (1 mmol) (4); 5 mL of EtOH; and stirring at RT.

Recycling study of 2.5% pan class="Chemical">NiO/ZrO2 catalyst for the synthesis of class="Chemical">pan class="Chemical">1,4-dihydropyridine 5a.

Hot filtration test results of 2.5% class="Chemical">NiO/ZrO2 catalyst for 5a. Reaction conditions: class="Chemical">pan class="Chemical">2,3,4-trimethoxybenzaldehyde (1 mmol) (1), ethyl acetoacetate (1 mmol) (2), 1,3-cyclohexadione (1 mmol) (3), and ammonium acetate (1 mmol) (4); 5 mL of EtOH; and stirring at RT.

Conclusions

We introduced class="Chemical">NiO/ZrO2 as an efficient and cost-effective catalyst for the synthesis of 12 novel class="Chemical">pan class="Chemical">1,4-dihydropyridine derivatives in a four-component, one-pot strategy. This method proved effective toward the reaction of aromatic, heteroaromatic, and aliphatic aldehydes obtained with high yields. ESI-MS/MS studies are conducted, and insights into the mechanism of the reaction are proposed, which revealed that 1,4-DHPs mainly follow the enamine and imine pathways. We anticipate that this catalytic system will find further applications in both academic and industrial fields, and the prepared series of 1,4-DHPs may provide potential biological activity in the area of pharmaceutical sector.

Experimental Section

Catalyst Preparation

A series of class="Chemical">nickel oxide-loaded class="Chemical">pan class="Chemical">zirconia (NiO/ZrO2) catalysts with different weight percentages (1, 2.5, and 5 wt %) of Ni were prepared by the wet impregnation method. A mixture of zirconium oxide (ZrO2, 2 g, Alfa Aesar) and appropriate amount (wt %) of nickel sulfate (NiSO4·6H2O, Alfa Aesar) in 60 mL of deionized water was stirred for 7 h at room temperature. The resultant slurry was filtered under vacuum and dried at 100 °C for 6 h, followed by calcination at 450 °C for 6 h in the presence of air, to obtain different weight percents of NiO/ZrO2. Instrumentation details are included in the Supporting Information (page S2).

General Method for the Synthesis of Series of 1,4-Dihydropyridine Derivatives (5a–r)

For the synthesis of a series of class="Chemical">1,4-dihydropyridine derivatives, the reaction was class="Chemical">performed in a 25 mL round-bottom flask containing 5 mL of class="Chemical">pan class="Chemical">EtOH as a solvent. To these equimolar quantities of substituted aldehyde, ethyl acetoacetate, ammonium acetate, and 1,3-cyclohexadione, was added 30 mg of NiO/ZrO2 and stirred at room temperature (RT) (Scheme ). TLC was used to monitor the progress of the reaction at regular time intervals. After completion of the reaction, the catalyst was filtered by adding excess ethanol. The solvent was then evaporated, and the pure product was afforded by recrystallization from EtOH. The details and spectra are given in the Supplementary Information (pages S5–S12 and S13–S49).

Scheme 3

Synthesis of Novel 1,4-Dihydropyridines