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

Sep 18, 2017 - In this study a highly efficient protocol is reported to synthesize 1,4-dihydropyridine derivatives using 2.5% Y2O3/ZrO2 as heterogeneo...
0 downloads 6 Views 1MB Size
Subscriber access provided by FLORIDA ATLANTIC UNIV

Article

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

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Industrial & Engineering Chemistry Research is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 28

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

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.

1

ACS Paragon Plus Environment

Industrial & Engineering Chemistry Research

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

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

2

ACS Paragon Plus Environment

Page 2 of 28

Page 3 of 28

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

Industrial & Engineering Chemistry Research

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

3

ACS Paragon Plus Environment

Industrial & Engineering Chemistry Research

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

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

4

ACS Paragon Plus Environment

Page 4 of 28

Page 5 of 28

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

Industrial & Engineering Chemistry Research

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

ACS Paragon Plus Environment

Industrial & Engineering Chemistry Research

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

Page 6 of 28

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);

13

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);

13

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;

6

ACS Paragon Plus Environment

Page 7 of 28

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

Industrial & Engineering Chemistry Research

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.

7

ACS Paragon Plus Environment

Industrial & Engineering Chemistry Research

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

Page 8 of 28

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.

8

ACS Paragon Plus Environment

Page 9 of 28

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

Industrial & Engineering Chemistry Research

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

9

ACS Paragon Plus Environment

Industrial & Engineering Chemistry Research

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

Page 10 of 28

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

ACS Paragon Plus Environment

Page 11 of 28

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

Industrial & Engineering Chemistry Research

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

ACS Paragon Plus Environment

Industrial & Engineering Chemistry Research

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)

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

Page 12 of 28

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-

12

ACS Paragon Plus Environment

Page 13 of 28

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

Industrial & Engineering Chemistry Research

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

ACS Paragon Plus Environment

Time (h) 12 12 12 12 12 12

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

Industrial & Engineering Chemistry Research

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,

Page 14 of 28

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

ACS Paragon Plus Environment

Page 15 of 28

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

Industrial & Engineering Chemistry Research

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.

15

ACS Paragon Plus Environment

Industrial & Engineering Chemistry Research

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

Page 16 of 28

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

ACS Paragon Plus Environment

Page 17 of 28

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

Industrial & Engineering Chemistry Research

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

ACS Paragon Plus Environment

Industrial & Engineering Chemistry Research

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

18

ACS Paragon Plus Environment

Page 18 of 28

Page 19 of 28

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

Industrial & Engineering Chemistry Research

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.

References (1)

Anastas, P.; Eghbali, N. Green chemistry: Principles and practice. Chem. Soc. Rev., 2010, 39, 301–312.

(2)

Sheldon, R. A. Green chemistry, catalysis and valorization of waste biomass, J. Mol. Catal. A: Chem. 2016, 422, 3–12.

(3)

Anastas, P. T.; Kirchhoff, M. M. Origins, current status, and future challenges of green chemistry. Acc. Chem. Res. 2002, 35, 686–694.

(4)

Maddila, S. N.; Maddila, S.; Gangu, K. K.; van Zyl, W. E., Jonnalagadda, S. B. Sm2O3/Fluoroapatite as a reusable catalyst for the facile, green, one-pot synthesis of triazolidine-3-thione derivatives under aqueous conditions. J. Flu. Chem. 2017, 195, 79– 84.

(5)

Maddila, S.; Gangu, K. K.; Maddila, S. N.; Jonnalagadda, S.B. A facile, efficient and sustainable Chitosan/CaHAp catalyst and one-pot synthesis of novel 2,6-diamino-pyran3,5-dicarbonitriles. Mol. Diversity. 2017, 21, 247–255.

(6)

Slobbe, P.; Ruijter, E.; Orru, R. V. Recent applications of multicomponent reactions in medicinal chemistry. Med. Chem. Commun. 2012, 3, 1189–1218.

19

ACS Paragon Plus Environment

Industrial & Engineering Chemistry Research

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)

Page 20 of 28

Gangu, K. K.; Maddila, S.; Maddila, S. N.; Jonnalagadda, S. B. Novel iron doped calcium oxalates as promising heterogeneous catalysts for one-pot multi-component synthesis of pyranopyrazoles. RSC Adv. 2016, 6, 58226–58235.

(8)

Weber, L. Multi-component reactions and evolutionary chemistry. Drug Discovery Today. 2002, 7, 143–147.

(9)

Ganem, B., Strategies for innovation in multicomponent reaction design. Acc. Chem. Res. 2009, 42(3), 463–472.

(10)

Marsault, E.; Peterson, M. L. Macrocycles are great cycles: Applications, opportunities, and challenges of synthetic macrocycles in drug discovery. J. Med. Chem. 2011, 54 (7), 1961–2004.

(11)

Maddila, S. N.; Maddila, S.; Van Zyl, W. E.; Jonnalagadda, S. B. Swift and green protocol for one-pot synthesis of pyrano[2,3-c]pyrazole-3-carboxylates with RuCaHAp as catalyst. Curr. Org. Chem. 2016, 20(20), 2125-2133.

(12)

Gangu, K. K.; Maddila, S.; Maddila, S. N.; Jonnalagadda, S. B. Nanostructured Samarium doped fluorapatites and their catalytic activity towards synthesis of 1,2,4triazole moiety. Molecules. 2016, 21, 1281–1296.

(13)

Elwahy, A. H. M.; Shaaban, M. R. Synthesis of heterocycles and fused heterocycles catalyzed by nanomaterials. RSC Adv. 2015, 5, 75659–75710.

(14)

Chughtai, A. H.; Ahmad, N.; Younus, H.A.; Laypkov, A.; Verpoort, F. Metal–organic frameworks:

versatile

heterogeneous

catalysts

for

efficient

catalytic

organic

transformations. Chem. Soc. Rev. 2015, 44, 6804–6849. (15)

Dhakshinamoorthy, A.; Asiri, A. M.; Garcia, H. Metal–organic frameworks catalyzed C– C and C–heteroatom coupling reactions. Chem. Soc. Rev. 2015, 44, 1922–1947.

20

ACS Paragon Plus Environment

Page 21 of 28

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

Industrial & Engineering Chemistry Research

(16)

Gawande, M. B.; Branco, P.S.; Varma, R. S. Nano-magnetite (Fe3O4) as a support for recyclable catalysts in the development of sustainable methodologies. Chem. Soc. Rev. 2013, 42, 3371–3393.

(17)

Maddila, S. N.; Maddila, S.; Van Zyl, W. E.; Jonnalagadda, S. B. One-pot synthesis of pyranopyrazoles using Ru-hydroxyapatite as reusable catalyst- a green approach. Curr. Org. Syn. 2016, 13(6), 893–900.

(18)

Maddila, S. N.; Maddila, S.; Van Zyl, W. E.; Jonnalagadda, S. B. Ce-V/SiO2 catalyzed aascade for C-C and C-O bond activation: Green one-pot synthesis of 2-amino-3-cyano4H-pyrans. ChemistryOpen. 2016, 5, 38–42.

(19)

Maddila, S.; Rana, S.; Pagadala, R.; Jonnalagadda, S. B. Mg-V/CO3 Hydrotalcite: An efficient and reusable catalyst for one-pot synthesis of multisubstituted pyridines. Res. Chem. Intermed. 2015, 41, 8269–8278.

(20)

(a) Chorghade, R.; Battilocchio, C.; Hawkins, J. M.; Ley, S. V. Sustainable flow oppenauer oxidation of secondary benzylic alcohols with a heterogeneous zirconia catalyst. Org. Lett. 2013, 15, 5698–5701; (b) Patil, M. K.; Prasad, A. N.; Reddy, B. M. Zirconia-based solid acids: Green and heterogeneous catalysts for organic synthesis. Curr. Org. Chem. 2011, 15, 3961-3985; (c) Reddy, B. M.; Sreekanth, P. M.; Lakshmanan, P. Sulfated zirconia as an efficient catalyst for organic synthesis and transformation reactions. J. Mol. Catal. A: Chem. 2005, 237, 93-100; (d) Reddy, B. M.; Patil, M. K.; Reddy, B. T. An efficient protocol for Aza-Michael addition reactions under solvent-free condition employing sulfated zirconia catalyst. Catal. Lett. 2008, 126, 413– 418.

21

ACS Paragon Plus Environment

Industrial & Engineering Chemistry Research

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

(21)

Page 22 of 28

Borges, M. E.; Diaz, L. Recent developments on heterogeneous catalysts for biodiesel production by oil esterification and transesterification reactions: A review. Renewable and Sustain. Ener. Rev. 2012, 16, 2839–2849.

(22)

Morris, W.; Volosskiy, B.; Demir, S.; Gandara, F.; McGrier, F. L.; Furukawa, H.; Cascio, D.; Stoddart, J. F.; Yaghi, O. M. Synthesis, structure, and metalation of two new highly porous zirconium metal–organic frameworks. Inorg. Chem. 2012, 51(12), 6443–6445.

(23)

Mamak, M.; Coombs, N.; Ozin, G. Self-assembling solid oxide fuel cell materials:  mesoporous yttria-zirconia and metal-yttria-zirconia solid solutions. J. Am. Chem. Soc. 2000, 122(37), 8932–8939.

(24)

Chane-Ching, J-Y.; Cobo, F.; Aubert, D.; Harvey, H. G.; Airiau, M.; Corma, A. A general method for the synthesis of nanostructured large-surface-area materials through the self-assembly of functionalized nanoparticles. Chem. A Euro. J. 2005, 11, 979–987.

(25)

Craciun, R.; Nentwick, B.; Hadjiivanov, K.; Knözinger, M. Structure and redox properties of MnOx/Yttrium-stabilized zirconia (YSZ) catalyst and its used in CO and CH4 oxidation. Appl. Catal. A: Gen. 2003, 243, 67–79.

(26)

Zheng, Y. G.; Su, J.; Gao, C. Y.; Jiang, P.; An, L.; Xue, Y. S.; Gao, J.; Liu, Y. Design, synthesis, and biological evaluation of novel 4-anilinoquinazoline derivatives bearing amino acid moiety as potential EGFR kinase inhibitors. Eur. J. Med. Chem. 2017, 130, 393–405.

(27)

Maddila, S.; Naicker, K.; Gorle, S.; Rana, S.; Kotaiah, Y.; Maddila, S. N.; Singh, M.; Singh, P.; Jonnalagadda, S. B. New pyrano[2,3-d:6,5-d']dipyrimidine derivatives Synthesis, in vitro cytotoxicity activity and computational studies. Anti-Cancer Agents in Med. Chem. 2016, 16(8), 1031–1037.

22

ACS Paragon Plus Environment

Page 23 of 28

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

Industrial & Engineering Chemistry Research

(28)

Maddila, S.; Pagadala, R.; Jonnalagadda, S. B. 1,2,4-Triazoles:A review of synthetic approaches and the biological activity. Lett. Org. Chem. 2013, 10(10), 693–714.

(29)

Akhtar, J.; Khan, A. A.; Ali, Z.; Haider, R.; Shahar, Y. M. Structure-activity relationship (SAR) study and design strategies of nitrogen-containing heterocyclic moieties for their anticancer activities. Eur. J. Med. Chem. 2017, 125, 143–189.

(30)

Delgado, O.; Delgado, F.; Vega, J. A.; Trabanco, A.A. N-bridged 5,6-bicyclic pyridines: Recent applications in central nervous system disorders. Eur. J. Med. Chem. 2015, 97, 719–723.

(31)

Nkosi, S.M.; Anand, K.; Anandakumar, S.; Singh, S.; Chuturgoon, A. A.; Gengan, R. M. Design, synthesis, anticancer, antimicrobial activities and molecular docking studies of novel quinoline bearing dihydropyridines. J. Photochem. Photobiol. B. 2016, 165, 266– 276.

(32)

Dam, J.; Ismail, Z.; Kurebwa, T.; Gangat, N.; Harmse, L.; Marques, H. M.; Lemmerer, A.; Bode, M. L.; de Koning, C. B. Synthesis of copper and zinc 2-(pyridin-2yl)imidazo[1,2-a]pyridine complexes and their potential anticancer activity. Eur. J. Med. Chem. 2017, 126, 353–368.

(33)

Santana, W. E.; Nunez, C. V.; Moya, H. D. Antioxidant activity and polyphenol content of some brazilian medicinal plants exploiting the formation of the Fe(II)/2,2'-bipyridine complexes. Nat. Prod. Commun. 2015, 10(11), 1821–1824.

(34)

Ribeiro-Viana, R. M.; Butera, A. P.; Santos, E. S.; Tischer, C. A.; Alves, R. B.; Pereira de, F. R.; Guimaraes, L.; Varotti, F. P.; Viana, G. H.; Nascimento, C. S. Revealing the binding process of new 3-alkylpyridine marine alkaloid analogue antimalarials and the

23

ACS Paragon Plus Environment

Industrial & Engineering Chemistry Research

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

Page 24 of 28

heme group: an experimental and theoretical investigation. J. Chem. Inf. Model. 2016, 56(3), 571–579. (35)

Kirwen, E. M.; Batra, T.; Karthikeyan, C.; Deora, G. S.; Rathore, V.; Mulakayala, C.; Mulakayala, N.; Nusbaum, N. C.; Chen, J.; Amawi, H.; McIntosh, K.; Shivnath, N.; Chowarsia, D.; Sharma, N.; Arshad, Md.; Trivedi, P.; Tiwari, A. K. 2,3-Diaryl-3Himidazo[4,5-b]pyridine derivatives as potential anticancer and anti-inflammatory agents. Acta Pharmaceu. Sinica B. 2017, 7(1), 73-79.

(36)

Yang, J.; Chen, W.; Kang, D.; Lu, X.; Li, X.; Liu, Z.; Huang, B.; Daelemans, D.; Pannecouque, C.; De Clercq, E.; Zhan, P.; Liu, X. Design, synthesis and anti-HIV evaluation of novel diarylpyridine derivatives targeting the entrance channel of NNRTI binding pocket. Eur. J. Med. Chem. 2016, 109, 294-304.

(37)

El-Sayed, N. N. E.; Abdelaziz, M. A.; Wardakhan, W. A.; Mohareb, R. M. The Knoevenagel reaction of cyanoacetylhydrazine with pregnenolone: Synthesis of thiophene, thieno[2,3-d]pyrimidine, 1,2,4-triazole, pyran and pyridine derivatives with anti-inflammatory and anti-ulcer activities. Steroids. 2016, 107, 98-111.

(38)

Rekunge, D. S.; Khatri, C. K.; Chaturbhuj, G. U. Sulfated polyborate: An efficient and reusable catalyst for one pot synthesis of Hantzsch 1,4-dihydropyridines derivatives using ammonium carbonate under solvent free conditions. Tetrahed. Lett. 2017, 58(12), 12401244.

(39)

Zhong, Q.; Fan, Q.; Yan, H. Synthesis of 2,3-dihydropyrroles by photo rearrangement of Hantzsch 1,4-dihydropyridines with high diastereoselectivity. Tetrahed. Lett. 2017, 58(13), 1292-1295.

24

ACS Paragon Plus Environment

Page 25 of 28

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

Industrial & Engineering Chemistry Research

(40)

Sabitha, G.; Reddy, G. S. K. K.; Reddy, Ch. S.; Yadav, J. S. A novel TMSI-mediated synthesis of Hantzsch 1,4-dihydropyridines at ambient temperature. Tetrahed. Lett. 2003, 44, 4129–4131.

(41)

Pal, S.; Singh, V.; Das, P.; Choudhury, L. H. PEG-mediated one-pot multicomponent reactions for the efficient synthesis of functionalized dihydropyridines and their functional group dependent DNA cleavage activity. Bioorg. Chem. 2013, 48, 8-15.

(42)

Sun, J.; Xia, E. Y; Wu, Q.; Yan, C. G. Synthesis of polysubstituted dihydropyridines by four-component reactions of aromatic aldehydes, malononitrile, arylamines, and acetylenedicarboxylate. Org. Lett. 2010, 12, 3678–3681.

(43)

Ko, S.; Sastry, M. N. V; Lin, C.; Ching-Fa, Y. Molecular iodine-catalyzed one-pot synthesis of 4-substituted-1,4-dihydropyridine derivatives via Hantzsch reaction, Tetrahed. Lett. 2005, 46, 5771-5774.

(44)

Gangu, K. K.; Maddila, S.; Jonnalagadda, S. B. Synthesis, structure and properties of new Mg(II)-metal-organic framework and its prowess as catalyst in the production of 4Hpyrans. ACS-Indu. & Eng. Chem. Res. 2017, 56, 2917–2924.

(45)

Shabalala, N.; Maddila, S.; Jonnalagadda, S. B. Catalyst-free, one-pot, four-component green

synthesis

of

functionalized

1-(2-fluorophenyl)-1,4-dihydropyridines

under

ultrasound irradiation. New J. Chem. 2016, 40, 5107-5112. (46)

Maddila, S.; Momin, M.; Lavanya, P.; Rao, C. V. An efficient and eco‐friendly synthesis of 6‐chloro‐8‐substituted‐9H-purines using cellulose sulfuric acid as a reusable catalyst under solvent‐free conditions. J. Saudi Chem. Soc. 2016, 20, 173-177.

25

ACS Paragon Plus Environment

Industrial & Engineering Chemistry Research

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

(47)

Maddila, S. N.; Maddila, S.; Van Zyl, W. E.; Jonnalagadda, S. B. Ce-V/SiO2 catalyzed aascade for C-C and C-O bond activation: Green one-pot synthesis of 2-amino-3-cyano4H-pyrans. ChemistryOpen. 2016, 5, 38–42.

(48)

Maddila, S.; Maddila, S. N.; Jonnalagadda, S. B.; Lavanya, P. Reusable Ce-V loaded alumina catalyst for multicomponent synthesis of substituted pyridines in green media. J. Heterocyc. Chem. 2016, 53, 658-664.

(49)

Maddila, S.; Lavanya, P.; Jonnalagadda, S. B. Cesium loaded on silica as an efficient and recyclable catalyst for the novel synthesis of selenophenes. Arab. J. Chem. 2016, 9(6), 891-897.

(50)

Maddila, S.; Gorle, S.; Seshadri, N.; Lavanya, P.; Jonnalagadda, S. B. Synthesis, antibacterial and antifungal activity of novel benzothiazole pyrimidine derivatives. Arab. J. Chem. 2016, 9, 681-687.

(51)

Maddila, S.; Gorle, S.; Singh, M.; Lavanya, P.; Jonnalagadda, S. B. Synthesis and antiinflammatory activity of fused 1,2,4-triazolo-[3,4-b][1,3,4] thiadiazole derivatives of phenothiazine. Lett. Drug Des. & Discov. 2013, 10(10), 977-983.

(52)

Maddila, S.; Pagadala, R.; Jonnalagadda, S. B. Synthesis and insecticidal activity of tetrazole linked triazole derivatives. J. Heterocyc. Chem. 2015, 52(2), 487-499.

(53)

Gorle, S.; Maddila, S.; Maddila, S. N.; Naicker, K.; Singh, M.; Singh, P.; Jonnalagadda, S. B. Synthesis, molecular docking study and in vitro anticancer activity of tetrazole linked benzochromene derivatives. Anti-Cancer Agents in Med. Chem. 2017, 17, 464470.

(54)

Maddila, S.; Naicker, K.; Momin, M.; Rana, S.; Gorle, S.; Maddila, S. N.; Kotaiah, Y.; Moganavelli, S.; Jonnalagadda, S. B. Novel 2-(1-(substitutedbenzyl)-1H-tetrazol-5-yl)-3-

26

ACS Paragon Plus Environment

Page 26 of 28

Page 27 of 28

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

Industrial & Engineering Chemistry Research

phenylacrylonitrile derivatives - Synthesis, in vitro antitumor activity and computational studies. Med. Chem. Res. 2016, 25, 283–291.

27

ACS Paragon Plus Environment

Industrial & Engineering Chemistry Research

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

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:

ACS Paragon Plus Environment

Page 28 of 28