Innovative Efficient Method for the Synthesis of 1,4-Dihydropyridines

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An innovative efficient method for the synthesis of 1,4dihydropyridines using Y2O3 loaded on ZrO2 as catalyst Sebenzile Shabalala, Suresh Maddila, Werner E. Van Zyl, and Sreekantha Babu Jonnalagadda Ind. Eng. Chem. Res., Just Accepted Manuscript • DOI: 10.1021/acs.iecr.7b02579 • Publication Date (Web): 18 Sep 2017 Downloaded from http://pubs.acs.org on September 19, 2017

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Industrial & Engineering Chemistry Research

An innovative efficient method for the synthesis of 1,4-dihydropyridines using Y2O3 loaded on ZrO2 as catalyst Sebenzile Shabalala, Suresh Maddila, Werner E. van Zyl and Sreekantha B Jonnalagadda* *School of Chemistry & Physics, University of KwaZulu-Natal, Westville Campus, Chiltern Hills, Durban-4000, South Africa. *Corresponding Author: Prof. Sreekantha B. Jonnalagadda School of Chemistry & Physics, University of KwaZulu-Natal, Durban 4000, South Africa. Tel.: +27 31 2607325, Fax: +27 31 2603091 E-mail address: [email protected]

Abstract In this study a highly efficient protocol is reported to synthesize 1,4-dihydropyridine derivatives using 2.5% Y2O3/ZrO2 as heterogeneous catalyst. The one-pot four component reaction

involves

substituted

aldehyde,

malononitrile,

4-bromoaniline

and

dimethylacetylenedicarboxylate in green solvent ethanol. The new catalyst material is characterized by powder X-ray diffraction, TEM, SEM and nitrogen adsorption/desorption analysis techniques. The key benefits of this novel approach are easy work-up, green solvent, short reaction times (< 20 min), energy efficient reaction conditions and no chromatographic separation techniques plus excellent yields (88-95%). Keywords: Multicomponent reaction, Heterogeneous catalysis, Pyridines, Sustainability, Efficient protocol, Y2O3/ZrO3.

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Introduction Green chemistry refers to design of chemical reactions and products that minimize or eliminate the use or generation of hazardous compounds.1 It is basically concerned with the efficient use resources, averting of the use of toxic and/or hazardous reagents and solvents in the manufacture and application of chemical compounds.2 It is focused on the use of green principles in organic synthesis and on the industrial scale processes in chemical industry in general and pharmaceutical industry in particular,3 with objective to develop the optimal methods to minimize energy consumption for the production of desired products.4,5 Multicomponent reaction (MCR) use several reactant molecule to form a product.5 It is one of the most important protocol in organic synthesis and medicinal chemistry.6 The benefits of one-pot reactions are rapid access to diverse highly functionalized organic molecules with efficiency, and cost effectiveness.7 MCR approach is of central current interest in the construction of combinatorial libraries and optimization in drug discovery process.8 MCRs are the cornerstone in the diversity oriented construction of molecular complexity due to the ability to incorporate in a fast and efficient manner.9,10 These are highly selective, simply operated under mild conditions, high atom economy, high yields, simple workup and mainly no use of chromatography.11,12 Heterogeneous catalysis plays an important role in both the research laboratory and in the chemical and pharmaceutical industries.13 These are the key technology used in varies catalytic fields.14 They generate high purity products without any need to purify the obtained products and also it can be separated easily from the product.15,16 Their cost is low, wide availability, environmental friendly and reusable.17 They exhibit very high activity and selectivity for a large

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range of reactions.18 Hence, there is always demand for good recyclable heterogeneous catalyst with high selectivity and good activity.17-19 Zirconium oxide (ZrO2) has received great attention both as catalyst and catalyst support,20 owing to its amphoteric nature, which means it has the presence of both acidic and basic sites and can act as bi-functional catalytic material.21 It’s high specific surface area, better flexibility, active metal centers and thermal stability, make it appropriate over wide-ranging temperatures.22 Rare-earth elements, including yttrium possess large surface area and stable at high temperatures making ideal as catalyst materials.23 The combination of zirconia with yttrium shows even better properties than individual components.24 The exceptional activity of the mixed oxides is described by ultrahigh vacuum surface experiments.23-25 The structure of yttrium doped zirconia strengthens the interaction between these two components, thus enhancing its catalytic activity because of its dispersion on zirconia. Literature reports various methodologies for the synthesis of different heterocyclic compounds with unique biological properties.26 Such methods constitute the largest of the classic division of organic chemistry in terms of number of new compounds synthesized.27 Many of the new molecules played important part in the discovery of new drugs and bioactive compounds, including anti-tumor, anti-bacteria and ant-virulence agents.28 Several naturally occurring organic compounds with nitrogen containing heterocyclic moieties are reported to exhibit remarkable biological activities.29 Pyridines and their derivatives are useful structural motifs have interesting biological and pharmaceutical properties.30 Generally, these derivatives are used as antimicrobial,31 anticancer,32 antioxidant,33 antimalarial,34 anti-inflammatory,35 anti-HIV36 and anti-ulcer activity.37 Owing to their viable and scientific relevance, several procedures have been reported in literature for synthesis of various dihydropyridine derivatives. The Hantzsch

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synthesis is one of the distinguished techniques for the preparation of 1,4-dihydropyridines.38,39 Some of such processes have reported the use of TMSI,40 PEG-600,41 Et3N,42 I2,43, etc., as catalysts. Many of those reactions demand expensive reagents, tedious handling procedures, high temperatures and harsh reaction conditions, while the others suffer with low yields and timeconsuming reactions. Consequently, new concords with better features for the synthesis of 1,4dihydropyridine derivatives is paramount. An encouraged by a promising results in evolving synthetic methodologies for varied heterocyclic molecules.44-49 Recently, we have designated various procedures for synthesis of various biological interesting heterocyclic protocols.50-54 In this communication, in continued with pursuit for development of efficient catalyst materials, we report a heterogeneous catalyst, yttrium loaded on zirconia (Y2O3/ZrO2) and its characterization. In addition, we examined its activity for the synthesis of series of novel functionalized 1,4-dihydropyridine derivatives using one-pot four-component reaction at room temperature with ethanol as solvent. To the best of our knowledge, this is the first application of this type of heterogeneous catalyst in one-pot reactions and for the synthesis of 1,4-dihydropyridine scaffolds.

Experimental section Catalyst preparation A wet-impregnation process was used to prepare a series of loaded catalysts Y2O3/ZrO2 of weight percentage (1%, 2.5% & 5 wt%). The heterogeneous catalyst was achieved from mixture of zirconia (ZrO2, 2 g, Catalyst support, Alfa Aesar) and an appropriate wt% amount of yittrium carbonate [Y2(CO3)3 · 6H2O (Alfa Aesar)] in (60 mL) dissolved in distillated water. The mixture was stirred at room temperature for 6 h after which the resulting slurry was filtered under vacuum. Further, it was dried in an oven at 120–130 °C for 6 h and calcined in the

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presence of air, at 450 °C for 5 h to acquire of corresponding Y2O3/ZrO2 catalysts. The instrumentation details are provided in supplementary information file (S1). General synthesis of functionalized 1,4-dihydropyridine-2,3-dicarboxylates (5a-l) Substituted

benzaldehyde

(1

mmol),

dimethylacetylenedicarboxylate

(1

mmol),

malononitrile (1.1 mmol), 4-bromoanaline (1 mmol) and Y2O3/ZrO2 (30 mg) in 10 mL ethanol was taken a round-bottom flask and stirred at room temperature. TLC plate was used to check the progress of the reaction and completion. As the solid product formed and it was then collected by filtration, washed with ethyl acetate. It was further recrystallized to purify the crude product (Scheme 1). The obtained products were further confirmed with 1H NMR, 13C NMR, 15N NMR and HR-MS and also related spectra details are assimilated to the supplementary information file (S2). R

NC

2

O

CN COOMe

CHO

CN

Y2O3/ZrO2

+

EtOH/RT, 20 min

MeO MeO

NH2

N

NH2

COOMe

1a-j R

O

3

Cl Br

Br

5a-j

4

Scheme 1: Synthesis of novel 1,4-dihydropyridine derivatives 5



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Physical characterization data Dimethyl 6-amino-1-(4-bromophenyll)-5-cyano-4-(2-methoxyphenyl)-1,4-dihydropyridine-2,3dicarboxylate (5a): 1H NMR (400 MHz, DMSO-d6) δ 3.39 (s, 3H, OCH3), 3.47 (s, 3H, OCH3 ), 3.81 (s, 3H, OCH3), 4.88 (s, 1H, CH), 5.53 (s, 2H, NH2), 7.01 (t, J = 8.00 Hz, 2H, ArH), 7.15 (dd, J = 7.52, 1.44 Hz, 1H, ArH), 7.20 (d, J = 8.60 Hz, 3H, ArH), 7.68 (d, J = 8.60 Hz, 2H, ArH);

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C NMR (100 MHz, DMSO-d6): 31.92, 51.88, 52.50, 55.73, 59.64, 104.05, 111.74,

120.82, 123.27, 127.25, 128.24, 132.85, 134.82, 142.21, 150.96, 156.19, 163.14, 165.13; FT-IR: 3820, 2466, 1675, 1480, 1343, 1244, 1184, 1082; HRMS of

[C23H20BrN3O5 + H]+ (m/z):

498.0644; Calcd: 498.0665. Dimethyl 6-amino-1-(4-bromophenyll)-5-cyano-4-(4-methoxyphenyl)-1,4-dihydropyridine-2,3dicarboxylate (5b): 1H NMR (400 MHz, DMSO-d6) δ 3.42 (s, 3H, OCH3), 3.49 (s, 3H, OCH3 ), 3.83 (s, 3H, OCH3 ), 4.89 (s, 1H, CH), 5.58 (s, 2H, NH2), 6.96-7.04 (m, 2H, ArH), 7.15 (dd, J = 7.68, 1.26 Hz, 1H, ArH), 7.19-7.23 (m, 3H, ArH), 7.70 (d, J = 8.44 Hz, 2H, ArH);

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C NMR

(100 MHz, DMSO-d6): 31.92, 51.85, 55.74, 59.76, 104.05, 111.74, 120.78, 120.82, 123.17, 127.23, 128.14, 132.20, 132.62, 132.99, 134.46, 142.27, 150.95, 156.20, 165.08; FT-IR: 3866, 2342, 1644, 1586, 1573, 1288, 1134, 1054; HRMS of [C23H20BrN3O5 + H]+ (m/z): 498.0674; Calcd: 498.0665. Dimethyl

6-amino-1-(4-bromophenyl)-5-cyano-4-(2-chlorophenyl)-1,4-dihydropyridine-2,3-

dicarboxylate (5c): 1H NMR (400 MHz, DMSO-d6) δ 3.38 (s, 3H, OCH3), 3.52 (s, 3H, OCH3 ), 4.37 (s, 1H, CH), 5.67 (s, 2H, NH2), 6.90 (d, J = 1.44 Hz. 2H, ArH), 7.02-7.18 (m, 2H, ArH), 7.23 (d, J = 8.68 Hz, 2H, ArH), 7.69 (d, J = 8.64 Hz, 2H, ArH); 13C NMR (100 MHz, DMSOd6): 30.63, 45.72, 51.91, 52.46, 59.88, 104.78, 113.49, 114.04, 115.73, 117.21, 120.87, 123.31, 129.64, 131.27, 132.26, 132.62, 134.27, 141.34, 146.69, 148.02, 150.55, 157.66, 162.96, 165.04;

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FT-IR: 3844, 2466, 1456, 1367, 1422, 1210, 1108, 1088; HRMS of

[C22H17BrClN3O4 + H]+

(m/z): 502.0148; Calcd: 502.0169. Dimethyl

6-amino-1-(4-bromophenyll)-5-cyano-4-(4-bromophenyl)-1,4-dihydropyridine-2,3-

dicarboxylate (5d): 1H NMR (400 MHz, DMSO-d6) δ 3.39 (s, 3H, OCH3), 3.50 (s, 3H, OCH3 ), 4.78 (s, 1H, CH), 5.78 (s, 2H, NH2), 7.25-7.34 (m, 6H, ArH), 7.71 (d, J = 8.60 Hz, 2H, ArH); 13C NMR (100 MHz, DMSO-d6): 8.62, 30.64, 33.35, 45.75, 51.91, 52.48, 58.32, 102.81, 115.73, 115.78, 120.57, 123.40, 124.83, 129.04, 129.34, 131.83, 131.83, 131.96, 132.64, 134.62, 142.34, 150.89, 158.59, 161.04, 162.81, 164.79; FT-IR: 3829, 2480, 1505, 1450, 1399, 1394, 1224, 1100. Dimethyl

6-amino-1-(4-bromophenyll)-5-cyano-4-(4-chlorophenyl)-1,4-dihydropyridine-2,3-

dicarboxylate (5e): 1H NMR (400 MHz, DMSO-d6) δ 3.37 (s, 3H, OCH3), 3.51 (s, 3H, OCH3 ), 4.49 (s, 1H, CH), 5.75 (s, 2H, NH2), 7.25-7.31 (m, 4H, ArH), 7.43 (d, J = 8.44 Hz, 2H, ArH). 7.69 (d, J = 8.68 Hz, 2H, ArH);

13

C NMR (100 MHz, DMSO-d6): 18.31, 38.08, 51.98, 52.54,

56.08, 59.27, 104.31, 115.86, 120.69, 123.49, 128.61, 128.76, 131.64, 132.27, 132.68, 134.43, 141.36, 144.19, 150.64, 162.84, 164.91; FT-IR: 3822, 2455, 1688, 1544, 1520, 1422, 1065, 1006; HRMS of [C22H17BrClN3O4 + H]+ (m/z): 502.2573; Calcd: 502.2559. Dimethyl

6-amino-1-(4-bromophenyll)-5-cyano-4-(2-fluorophenyl)-1,4-dihydropyridine-2,3-

dicarboxylate (5f): 1H NMR (400 MHz, DMSO-d6) δ 3.39 (s, 3H, OCH3), 3.53 (s, 3H, OCH3 ), 4.51 (s, 1H, CH), 5.78 (s, 2H, NH2), 7.18-7.34 (m, 6H, ArH), 7.70 (d, J = 8.64 Hz, 2H, ArH); 13

C NMR (100 MHz, DMSO-d6): 37.97, 51.93, 52.49, 59.64, 104.56, 115.39, 115.60, 120.73,

123.39, 128.57, 128.66, 132.34, 132.62, 134.62, 141.48, 150.57, 159.94, 162.35, 162.85, 164.93; FT-IR: 3798, 2455, 1644, 1424, 1398, 1255, 1248, 1097; HRMS of [C22H17BrFN3O4 + H]+ (m/z): 486.0483; Calcd: 486.0465.

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Dimethyl 6-amino-1-(4-bromophenyll)-5-cyano-4-(2,5-dimethoxyphenyl)-1,4-dihydropyridine2,3-dicarboxylate (5g): 1H NMR (400 MHz, DMSO-d6) δ 3.42 (s, 3H, OCH3), 3.49 (s, 3H, OCH3), 3.70 (s, 3H, OCH3 ), 3.78 (s, 3H, OCH3), 4.84 (s, 1H, CH), 5.61 (s, 2H, NH2), 6.68 (d, J = 3.18 Hz, 1H, ArH), 6.80 (dd, J = 8.68, 3.08 Hz, 1H, ArH), 6.98 (d, J = 8.92 Hz, 1H, ArH), 7.16 (d, J = 8.71 Hz, 2H, ArH), 7.71 (d, J = 9.04 Hz, 2H, ArH); 13C NMR (100 MHz, DMSOd6): 13.37, 30.63, 32.26, 45.77, 51.87, 52.51, 55.17, 56.43, 59.63, 62.59, 103.84, 111.80, 113.01, 113.70, 120.67, 121.46, 123.18, 132.07, 132.68, 134.18, 134.95, 142.37, 150.48, 150.95, 153.34, 163.08, 165.01; FT-IR: 3809, 2480, 1405, 1350, 1273, 1194, 1044, 1002; HRMS of [C24H22BrN3O6 + H]+ (m/z): 528.0775; Calcd: 528.0770. Dimethyl

6-amino-1-(4-bromophenyll)-5-cyano-4-(4-fluorophenyl)-1,4-dihydropyridine-2,3-

dicarboxylate (5h): 1H NMR (400 MHz, DMSO-d6) δ 3.39 (s, 3H, OCH3), 3.53 (s, 3H, OCH3 ), 4.36 (s, 1H, CH), 5.68 (s, 2H, NH2), 6.76 (d, J = 8 48 Hz, 6H, ArH), 7.08 (d, J = 8.48 Hz, 2H, ArH), 7.24 (d, J = 8.60 Hz, 2H, ArH), 7.69 (d, J = 8.64 Hz, 2H, ArH);

13

C NMR (100 MHz,

DMSO-d6): 8.79, 37.67, 45.67, 51.84, 52.43, 60.32, 105.28, 115.41, 120.97, 123.26, 127.78, 131.27, 132.27, 132.60, 134.84, 135.82, 140.88, 150.39, 156.35, 163.02, 165.16; FT-IR: 3811, 2462, 1605, 1520, 1313, 1294, 1224, 1034. Dimethyl

6-amino-1-(4-bromophenyll)-5-cyano-4-(2-ethylphenyl)-1,4-dihydropyridine-2,3-

dicarboxylate (5i): 1H NMR (400 MHz, DMSO-d6) δ 1.06 (t, J = 6.96 Hz, 3H, CH3), 3.39 (s, 3H, OCH3), 3.53 (s, 3H, OCH3 ), 3.67 (s, 2H, CH2), 4.50 (s, 1H, CH), 5.81 (s, 2H, NH2), 7.25-7.29 (m, 4H, ArH), 7.59 (d, J = 8.40 Hz, 2H, ArH), 7.70 (d, J = 8.64 Hz, 2H, ArH); 13C NMR (100 MHz, DMSO-d6): 18.48, 30.61, 38.24, 45.79, 51.94, 52.50, 55.00, 56.03, 59.24, 104.18, 120.66, 123.45, 128.98, 131.68, 132.35, 132.63, 134.55, 141.68, 144.71, 150.65, 162.79, 164.86; FT-IR: 3869, 2477, 1466, 1480, 1312, 1244, 1145, 1066.

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Dimethyl

6-amino-1-(4-bromophenyll)-5-cyano-4-(2-bromophenyl)-1,4-dihydropyridine-2,3-

dicarboxylate (5j): 1H NMR (400 MHz, DMSO-d6) δ 3.37 (s, 3H, OCH3), 3.51 (s, 3H, OCH3 ), 4.48 (s, 1H, CH), 5.76 (s, 2H, NH2), 7.24 (t, J = 8.92 Hz, 4H, ArH), 7.55 (d, J = 8.24 Hz, 2H, ArH), 7.68 (d, J = 8.59 Hz, 2H, ArH);

13

C NMR (100 MHz, DMSO-d6): 18.34, 51.98, 52.53,

56.07, 59.19, 89.74, 104.22, 115.84, 120.12, 120.68, 123.48, 128.99, 131.69, 132.28, 132.67, 134.44, 141.59, 144.63, 150.64, 162.82, 164.89; FT-IR: 3866, 2324, 1420, 1344, 1234, 1122, 1066, 1024; HRMS of [C22H16Br2N3O4 + 2H]+ (m/z): 547.9636; Calcd: 547.9644.

Results and discussion SEM analysis The Y2O3/ZrO2 and bare ZrO2 material morphology was observed using SEM micrographs (Fig. 1a & 1b). The Y2O3/ZrO2 catalyst particles agglomerates have no specific/particular shape uniformity. The dispersal size of the agglomerate particles is in a nanometric scale as can be seen. It represents that the agglomeration state of the zirconia units with yttria owing to its homogenous dispersion and also they are very crystalline and homogeneous materials. This implies that even the active sites are dominant leading to the catalysts to be more effective. TEM analysis The method used in this study to determine the size and size distribution of particle of interest is TEM. Figure 2(a-d) shows the pattern and size distribution of (a) Bare ZrO2, (b) 1% Y2O3/ZrO2, (c) 2.5% Y2O3/ZrO2, (d) 5% Y2O3/ZrO2. From this images the bare ZrO2 is an indistinct shape. After yttria amendment on the zirconia surface, the morphology changes it can be perceived that dark spots are dispersed on the interface and surface of the big amorphous particles. It basically shows clusters in an oval shape of about from 8 to 12 nm. This is shown in

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some part of the given image bearing in mind that in most part, it is just the combination/mixture of both Y2O3/ZrO2.

Fig. 1a

Fig. 1b

Figure 1: SEM micrograph of (a) Bare ZrO2 and (b) 2.5% Y2O3/ZrO2 catalyst

Figure 2: TEM micrograph of (a) Bare ZrO2, (b) 1% Y2O3/ZrO2, (c) 2.5% Y2O3/ZrO2, (d) 5% Y2O3/ZrO2 10


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Powder X-ray Diffraction The crystallinity of the synthesized catalyst materials was examined by powdered X-ray diffraction analysis. The P-XRD pattern of (a) pure ZrO2 and 2.5% Y2O3/ZrO2 is shown in the Figure. 3. Yttrium oxide is temperature dependent therefore it is calcined at higher temperature of 450 °C so that oxide can be obtained. It confirms diffraction peaks 2θ values at 28.4°, 32.6°, 49.7°, 56.2°, 62.1°, 70.0° and 79.2° are assigned to Y2O3. Their higher intensity confirms that indeed they are yttrium oxide without any water remaining after calcinations. The obtained XRD peaks are in correspondence with the standard Y2O3 [(JCPDS) 25-1200]. In addition, the zirconia sample showed diffraction patterns at 2θ angles of 23.9°, 28.8°, 33.9°, 33.6°, 44.1°, 53.4° and 60.1° that corresponds to ZrO2 (JCPDS file No. 01-089-9066). The average crystallite size of the sample was calculated using with Scherrer equation. It was about 9.3 nm, based on the maximum intensity diffraction peaks of Y2O3/ZrO2 catalyst. 1000

∗♦ ♦

1000

ZrO2

900

900

800

800 Intensity (a.u.)

Intensity (a.u.)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


700 600 500 400

♦ Z rO

♦

700 600

∗

500

♦

♦

∗ ♦ ∗ ♦

400

♦

∗

♦

300

300

♦

∗

200

200

2

∗ Y 2O 3

∗∗

100

100 10

20

30

40

50

60

70

80

10

90

2 Theta (Degree)

20

30

40 50 60 70 2 Theta (DEGREE)

80

Figure 3. Powder XRD spectra of Bare TiO2 and 2.5% Y2O3/ZrO2 catalyst BET surface area analysis Figure 4 depicts N2 adsorption/desorption isotherms. This basically illustrates the pore size distribution of 2.5% Y2O3/ZrO2 catalyst. The pore size distribution assign a mesoporous

11



pore size of 98.12 Å texture for the sample, and the isotherms P/Po range was found to be 0.680.83. The surface area was given to be 68 m2 g−1 with a pore volume of 0.312 cm3 g−1. As seen from the figure, this 2.5% Y2O3/ZrO2 catalyst describes type-IV adsorption isotherms which signifies a mesoporous materials. 160 140 120

Adsorption Desorption

3

Volume adsorbed (cm /g STD)

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100 80 60 40 20 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Relative Pressure (P/Po)

Figure 4. N2 adsorption & desorption isotherms of a 2.5% Y2O3/ZrO2 catalyst Optimization The model reaction was conducted by a one-pot, four-component reaction of 2methoxybenzaldehyde (1 mmol), dimethylacetylenedicarboxylate (1 mmol), malononitrile (1 mmol), and dimethylaniline (1 mmol) in 10 ml ethanol. Different reaction conditions were tested on this model reaction. A variety of catalyst and solvent were assessed at the different temperature conditions. Initially, in the absence of any catalyst and any solvent, even after 12 h stirring of the reaction mixture, no product was observed both at RT and reflux conditions (Table 1, entries 1 & 2). Then, the reaction was tried in ethanol in absence of any catalyst at both conditions and no product was formed (Table 1, entries 3 & 4). Thereafter, a different catalysts were used, starting with acidic catalysts such as acetic acid (AcOH), FeCl3 and H3BO3 to assess the efficiency of the catalyst. No product was observed at RT in all the runs (Table 1, entries 5-

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7). A trace amount of product was obtained by using ionic liquids like DABCO or (Bmim)BF4 as a catalysts after 8 h reaction (Table 1, entries 8 & 9). When the reaction was attempted using with different basic catalysts, such as KOH, Na2CO3, pyridine and TEA in ethanol at RT, the yield was low (Table 1, entry 10 & 13). Further, the pure heterogeneous oxide catalysts like alumina (Al2O3), silica (SiO2) and zirconia (ZrO2) were examined, and those oxides proved effective giving the desired product in 52-69% yield at RT after 3 h (Table 1, entries 14-16). Among the chosen pure oxide catalysts, zirconia gave relatively higher yield (Table 1, entries 16). Hence, using zirconia as support bimetallic mixed oxides 2.5% CeO2/ZrO2, MnO2/ZrO2, and Y2O3/ZrO2 were prepared and efficiency was tested to enhance the catalytic activity. Impressive yields (82-95%) were obtained by using the mixed oxide catalysts within 20 min reaction time in ethanol and at RT (Table 1, entry 17-19). As the condensation catalyzed by metallic yttria, one important key for the excellent catalytic activity is the large accessible Y2O3 surface area, because a higher Y2O3 surface area can supply more catalytically active sites for well higher product yields. The other mixed metal oxides such as CeO2/ZrO2 and MnO2/ZrO2 catalysts with the less surface area exhibits moderate catalytic performance with less stability. Among the three catalysts investigated, Y2O3/ZrO2 showed significant results, which gave the target functionalized 1,4-dihydropyridines in 95% yield selectively in 20 min reaction time under RT. Table 1: Optimal conditions for the synthesis of model reaction by 2.5% Y2O3/ZrO2 catalysta Entry 1 2 3 4 5 6

Catalyst ----AcOH FeCl3

Solvent --EtOH EtOH EtOH EtOH

Temperature RT Reflux RT Reflux RT RT

13


Time (h) 12 12 12 12 12 12

Yield (%)b -------


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

7 8 9 10 11 12 13 14 15 16 17 18 19 a

H3BO3 DABCO (Bmim)BF4 KOH Na2CO3 Pyridine TEA Al2O3 SiO2 ZrO2 2.5% CeO2/ZrO2 2.5% MnO2/ZrO2 2.5% Y2O3/ZrO2

EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH

All products were characterised by IR, 1H NMR,

RT RT RT RT RT RT RT RT RT RT RT RT RT 13

C NMR,

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12 8.0 8.0 7.0 7.5 8.0 7.0 5.5 4.5 3.5 1.5 2.0 0.30 15

-10 08 19 23 27 25 53 59 69 82 74 95

N NMR & HR-MS spectral

analysis. b Isolated yields. -- No reaction The effectiveness of the ideal solvent for this reaction was further investigated. The solvent optimization was performed to examine the scope to improve the yield of the desired products. This was done because the solvent has absolutely a major effect on the stability, solubility of the reactants and reaction mechanism. The title reaction was studied in the presence of non-polar solvents like DMF, acetonitrile, toluene and n-hexane (Table 2, entries 1-4), but yields were poor. The product yields were good to excellent, when the reaction carried out polar solvents such as ethanol, methanol and isopropyl alcohol respectively (Table 2, entries 5-7). Highest yield (95%) was afforded with ethanol as solvent, due to the hydrophobicity of the catalyst and organic reactant materials, ethanol might relatively promote their interactions with each other and final formation of the anticipated product.

14


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Table 2: Optimization of various solvent condition for the synthesis of functionalized 1,4dihydropyridines by 2.5% Y2O3/ZrO2 catalyst Entry 1 2 3 4 5 6 7

Solvent DMF acetonitrile toluene n-hexane MeOH EtOH isopropyl alcohol

Yield (%) 48 38 35 -76 95 67

The amount of catalyst needed is as much important as the catalyst itself. The optimum amount of catalyst was as investigated. In the absence of a catalyst, no product was formed (Table 3, entry 1). When, the amount of catalyst was increased from 10 to 30 mg, the yield of the product constantly increased from 74 to 95% (Table 3, entries 2-4). The further use of more than 30 mg of catalyst facilitated neither the yield nor the reaction time (Table 3, entries 5-7). The outcome of the results suggests that 30 mg of Y2O3/ZrO2 catalyst is most suitable for the chosen reaction conditions. To express the effectiveness and an excellence of the new synthetic procedure, reactions were studied using varied benzaldehyde derivatives substituted with different electronwithdrawing and electron-donating groups (Table 4, entries 1-10). All the ten reactions investigated gave well to excellent yields at a quick reactions. The structures of all the newly synthesized compounds characterized and positively confirmed employing 1H NMR, 15N NMR, 13

C NMR and HR-MS spectral analysis techniques.

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Table 3: Optimization of the amount of by 2.5% Y2O3/ZrO2 catalyst in the reaction Entry

Catalyst (mg)

Time (min)

Yield (%)

1 2 3 4 5 6 7

-10 20 30 40 50 60

120 45 30 15 15 15 15

-74 82 95 95 95 95

Table 4: Synthesis of functionalized 1,4-dihydropyridines catalyzed by 2.5%Y2O3/ZrO2 catalyst Entry

R

Product

1 2-OMe 5a 2 4-OMe 5b 3 2-Cl 5c 4 4-Br 5d 5 4-Cl 5e 6 4-F 5f 7 2,5-(OMe)2 5g 8 2-F 5h 9 4-Et 5i 10 2-Br 5j -- New compounds/no literature available.

Yield (%)

m.p °C

Lit m.p °C

93 91 89 87 76 78 87 92 90 89

239-241 222-224 231-232 258-260 239-241 274-276 240-242 209–211 250–252 198-200

-----------

Conferring with our experimental results, a plausible reaction mechanism for the synthesis of 1,4-dihydropyridines using Y2O3/ZrO2 as catalyst is proposed in Scheme 2. It is proposed that in the first step, 2-arylidenemalononitrile (3) is obtained by a fast Knoevenagel condensation of malononitrile (1) with aldehyde (2) catalyzed by the active sites of Y2O3/ZrO2. The next step involves formation of a 1,3-dipole intermediate compound (6) by reaction of amine (5) with dimethylacetylenedicarboxylate (4) facilitated by the catalyst. In the third step, a Michael addition of 3 to 6 on the catalyst surface produces a reactive intermediate. Finally, an intramolecular cyclization the reactive intermediate affords the desired functionalized halo 1,4dihydropyridine derivatives. 16


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R

R

NC

CO2Me

NC Michael addition

C PhH3N

N

3

R

CO2Me

CN PhH3N

CO2Me

NC

CO2Me

N

6 H H

CO2Me

HO N

C

CN R

Knoevenagel Condensation

NC

C PhH3N

CN

CN

O

CO2Me

Catalyst Dehydration

NC

1

2

C

R

3

O MeO

R

R

O C

C

C

CO2Me

CO2Me

NC

N

C PhHN

CO2Me

OMe

4

Cyclization H2N

Ph

ArH3N

CO2Me

5

6

R

R

CO2Me

NC

H2N

N

5(a-j)

Ph

CO2Me

CO2Me

NC H HN

N

CO2Me

Ph

Scheme 2: Possible reaction mechanism Role of catalyst Encouraged by the above consequences, in this work, the efforts were made to prepare mixed metal oxides (Y2O3/ZrO2) and considered their catalytic performances in the condensation of 1,4-dihydropyridines at ambient conditions. The influence of the Y2O3 loading on the support its interaction, metal dispersion, surface activity and catalytic performance of the Y2O3/ZrO2

17



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

catalysts were evaluated by systematic analysis,. It was found that relatively higher yield (95%) was attained with 2.5% Y2O3/ZrO2. This could be accredited to synergistic effect between the catalytically active metallic yttria species and the strong zirconia basic sites on the surface, which mainly facilitated the condensation reaction. More notably, the catalyst exhibited sustainable catalytic performance up to 48 h without any deactivation. Further, the sturdiness of the catalyst was established by XRD, SEM, TEM along with BET characterization of the used samples, confirming no obvious changes in structure and morphology. Our results indicate that the Y2O3/ZrO2 materials have good potential as catalysts in development of new value added conversions. Reusability of the catalyst For the time and cost effectiveness, recyclable and reusability of the material is an esteemed benefit in heterogeneous catalytic processes. In this work, the reusability of Y2O3/ZrO2 in the synthesis of 1,4-dihydropyridines was examined under optimum reaction conditions. After accomplishment of the reaction, the reaction mixture was simply filtered under vacuum, washed with ethyl acetate and dried in a vacuum oven at 110 °C for 3 h. The flexibility of the recovered catalyst for reuse was evaluated in the subsequent reactions, where no leaching of yttria was perceived. It can be reused at least for six runs in successive reactions without significant loss in product yield.

Conclusion In summary, this study shows a highly efficient 2.5% Y2O3/ZrO2 heterogeneous catalyst, which is used in synthesis of ten novel 1,4-dihydropyridine derivatives under green solvent conditions in excellent yields (88-95%). This novel procedure offers numerous advantages such as simple workup, cleaner reactions, green solvent, reduced reaction times, high yields, reusable

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catalyst and an eco-friendly approach. We assume this approach will find widespread applications in the fields of medicinal, combinatorial and drug discovery syntheses.

Acknowledgements The authors are thankful to the National Research Foundation (NRF) of South Africa, and University of KwaZulu-Natal, Durban, for financial support and research facilities.

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An innovative efficient method for the synthesis of 1,4-dihydropyridines using Y2O3 loaded on ZrO2 as catalyst Sebenzile Shabalala, Suresh Maddila, Werner E. van Zyl and Sreekantha B Jonnalagadda* *School of Chemistry & Physics, University of KwaZulu-Natal, Westville Campus, Chiltern Hills, Durban-4000, South Africa. *Corresponding Author: Prof. Sreekantha B. Jonnalagadda School of Chemistry & Physics, University of KwaZulu-Natal, Durban 4000, South Africa. Tel.: +27 31 2607325, Fax: +27 31 2603091 E-mail address: [email protected] Graphical Abstract:


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Innovative Efficient Method for the Synthesis of 1,4-Dihydropyridines

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