Facile ecofriendly one pot synthesis of heterocyclic priviledged medicinal scaffolds via biginelli reaction using retrievable nickel nanoparticles as catalyst

Article abstract of DOI:10.4067/s0717-97072018000203974

An efficient and greener synthesis of a series of dihydropyrimidone (DHPMs)/ dihydropyrimithione (DHPMTs) derivatives were accomplished via three component one pot condensation between quinoline aldehyde (2-hydroxy-4-formyl quinoline/2-formyl-4-methoxy quinoline), β - keto ester (ethyl acetoacetate / methyl acetoacetate) and urea/ thiourea using nickel(II) exchanged zeolite [Ni(II)Y] (NiNPs). The NiNPs were characterized by Infrared spectroscopy, Powder X ray diffraction patterns, Electronic microscopy studies- Scanning Electron Microscopy (FESEM) and Transmission Electron Microscopy (TEM). After the course of the reaction, the NiNPs were recovered and reused without any apparent loss of activity. The newly synthesized compounds were screened for antimicrobial activity against two human bacterial pathogens, the Gram-positive Methicillin resistant Staphylococcus aureus (MRSA) and the Gram-negative Pseudomonas aeruginosa (MTCC 201) and a human yeast pathogen, Fluconazole resistant Candida albicans (FRCA). The synthesised compounds were also evaluated for their antioxidant activity and the compounds show significant scavenging activity compared to aspartic acid.

Full text of DOI:10.4067/s0717-97072018000203974

J. Chil. Chem. Soc., 63, Nº 2 (2018)
FACILE ECOFRIENDLY ONE POT SYNTHESIS OF HETEROCYCLIC PRIVILEDGED MEDICINAL
SCAFFOLDS VIA BIGINELLI REACTION USING RETRIEVABLE NICKEL NANOPARTICLES AS CATALYST
DHIVYA PAUL1, RAMANJANEYA REDDY GONTU2, SUBRAMANIAN PARAMESWARAN RAJENDRAN1*
1Department of Chemistry, School of Chemical Sciences, Bharathiar University, Coimbatore 641046, Tamil Nadu, India
2Department of Inorganic Chemistry, School of Chemical Sciences, University of Madras, Guindy Campus, Chennai 600025, Tamil Nadu, India
ABSTRACT
An efficient and greener synthesis of a series of dihydropyrimidone (DHPMs)/ dihydropyrimithione (DHPMTs) derivatives were accomplished via three
component one pot condensation between quinoline aldehyde (2-hydroxy-4-formyl quinoline/2-formyl-4-methoxy quinoline) , β – keto ester (ethyl acetoacetate /
methyl acetoacetate) and urea/ thiourea using nickel(II) exchanged zeolite [Ni(II)Y] (NiNPs). The NiNPs were characterized by Infrared spectroscopy, Powder X
ray diffraction patterns, Electronic microscopy studies- Scanning Electron Microscopy (FESEM) and Transmission Electron Microscopy (TEM). After the course
of the reaction, the NiNPs were recovered and reused without any apparent loss of activity. The newly synthesized compounds were screened for antimicrobial
activity against two human bacterial pathogens, the Gram-positive Methicillin resistant Staphylococcus aureus (MRSA) and the Gram-negative Pseudomonas
aeruginosa (MTCC 201) and a human yeast pathogen, Fluconazole resistant Candida albicans (FRCA). The synthesised compounds were also evaluated for their
antioxidant activity and the compounds show significant scavenging activity compared to aspartic acid.
Keywords: Nickel (II) exchanged zeolite [Ni(II)Y]; Biginelli reaction ; microwave irradiation; green condition; human pathogens; DPPH radical scavenging
activity.
easily recovered from the reaction mixture by simple filtration and can
be used after activation or without activation, thereby making the process
economically viable. Nano structured materials serve to be integral backbone
as heterogeneous catalysts for various organic transformations, especially
because they meet the goals of green chemistry. Transition metal nanoparticles
have gained tremendous importance due to their interesting electrical, optical,
magnetic, chemical properties and especially catalytic properties, which cannot
be achieved by their bulk counterparts 60, 61. Of late, there has been growing
interest in using nickel nanoparticles in organic synthesis owing to their easy
preparation, potent catalytic activity, possible process ability, high stability
and ease of recyclability compared to traditional Raney Nickel catalyst. Ni
nanoparticles have been used as catalyst for functional group transformations
like transfer hydrogenation of carbonyl compounds62-64, reductive amination
of aldehydes65, alkylation of ketones and indirect aza-wittig reaction with
alcohols66, oxidative coupling of thiols67, Hantzch condensation for polyhydro
quinoline derivatives68 and Knoevenagel condensation by PV- stabilized Ni (0)
nanoparticles by Polyol method69.
1. INTRODUCTION
The advent of multicomponent reactions has emerged out to be a powerful
tool in synthetic organic chemistry 1,2. They allow the assembly of complex
molecules in one pot, leading to a product that ideally contains all atoms of
the reactants. Biginelli reaction is one of the most essential multicomponent
reactions (MCRs). Discovered way back in 18933, this reaction results in the
condensation of three components: a urea, an aldehyde and a β-keto ester to
that subsequently forms 4-aryl-3,4-dihydropyrimidin-2(1H)-one(DHPM).
Dihydropyrimidinone/thiones annulated heterocyclic scaffolds represent
a privileged structural motif with a broad spectrum of significant biological
activities 4,5. A brief overview6 features on the stimulated resurgence on the
interest of dihydropyrimidones (DHPMs) ranging from their pharmacological
activities such as antimalarial7, antitubercular8, A2B adenosine receptor
antagonists9, anticancer10, antihypertensive11, anti-inflammatory12, calcium
channel modulators13, cardio vascular activity14, its wide presence in diverse
natural products15 and increasing applications in the development of materials
such as renewable polymers16, adhesives17, fabric dyes18 has been vastly
explored. The reaction mechanism was discussed in various experimental and
theoretical studies 19, 20. Recent times have witnessed the exploitation of Biginelli
reaction in asymmetric synthesis21, 22, solid phase synthesis for combinatorial
chemistry23, chemical biology24 and optical properties18. Literature review
reveals the versality of modifications on the combinatorial protocol of the
reactants, catalyst, solvents, temperature and reaction conditions in order to
increase the efficiency of the process. In the context, a large number of methods
for the synthesis of dihydropyrimidinone/thiones have already been reported in
the literature such as by using lanthanide triflate25, indium triflate26, iodine27,
strontium(II) triflate28, zirconium tetrachloride29, cobaltous chloride30, zinc
chloride31, copper(II)complex32, ferric chloride33, natural zeolite34, lanthanum
chloride35, lithium bromide36, 12-tungstophosphoric acid37, montmorillonite38,
diammonium hydrogen phosphate39, alumina supported MoO340, Nafion-
Ga41, phthalimide-N -sulfonic acid42, ZrOCl2/montmorillonite K1043, natural
phosphates44, metal phosphates45, doped hydroxyapatite46, fluorapatite47,
Microwave-accelerated chemical syntheses in solvents as well as under
solvent-free conditions have witnessed an explosive growth. The rapid one-
pot preparation of heterocyclic compounds from in situ generated reactive
intermediates and the general application to multi-component reactions, that
are adaptable for building a library of compounds has been accomplished
using this MW technique70. The salient features of microwave irradiation often
leads to shorter reaction times, increased yields, easier workup, matches with
green chemistry protocols and can enhance the region and stereo selectivity
of reactions. In fact, the high usefulness of microwave-assisted synthesis
encouraged us to increase the efficiency of several organic transformations
and synthesis. Microwave methods provide an efficient and safe technology
conforming to “green chemistry” requirements 71
.
Prompted by all these factors, the current strategy of the work is to discover
new and an inexpensive catalyst for the preparation of dihydropyrimidin-2-
(1H)-ones/thiones under neutral and mild condition is of prime importance.
Hence, we herein report the synthesis of dihydropyrimidone (DHPM)/
dihydropyrimithione (DHPMT) derivatives via three component one pot
condensation between quinoline aldehyde ( 2-hydroxy-4-formyl quinoline/
2-formyl-4-methoxy quinoline) , β – keto ester (ethyl acetoacetate /methyl
acetoacetate) and urea/ thiourea using nickel(II) exchanged zeolite [Ni(II)
Y] (NiNPs) in ethanol under microwave irradiation and to evaluate their
antimicrobial activity against two human bacterial pathogens, the Gram-
positive Methicillin resistant Staphylococcus aureus (MRSA) and the Gram-
negative Pseudomonas aeruginosa (MTCC 201) and a human yeast pathogen,
Fluconazole resistant Candida albicans (FRCA). The radical-scavenging
abilities of the obtained DHPMs/ DHPMTs were carried out by reacting with
2,2’-diphenyl-1-picrylhydrazyl radical (DPPH).
48
modified fluorapatite alone or doped with metal halides are also reported
as a catalyst in the Biginelli reaction. Bismuth containing compounds such as
bismuth triflate 49, bismuth chloride 50, bismuth subnitrate 51, bismuth nitrate
52, copper nanoparticles 53, nickel nanoparticles 54, nano-titanium dioxide
55
56
and hydrated stannous chloride have also been used as catalyst. Metal
cordordination complexes57 with catalytic functions and bronsted acidic ionic
liquids58 have successfully been employed to catalyse Biginelli reactions.
However in spite of the potential excellence, they still suffer a number
of limitations such as long reaction times, tedious work up, harsh reaction
conditions, expensive catalyst/ reagents and high catalytic load.
In recent years, the suscitate of heterogeneous catalysts has received
tremendous attention in different areas of organic synthesis59. Heterogeneous
catalysts surcease conventional homogeneous catalysts as they can be
3974
e-mail: dhivsanto@gmail.com , rajendransp@yahoo.co.in

J. Chil. Chem. Soc., 63, Nº 2 (2018)
12.24%. Found: C 59.45, H 4.97, N 12.21%; IR (KBr, cm-1) : 3373 and 3273 (
stretching of N-H), 1682(C=O str) and 1194 (C=S str) ; 1H NMR ( 400MHz ,
CDCl3) δ ppm : 1.24 (t, 3H, -OCH2CH3), 1.60 (s, 3H, CH3), 3.65(m, 2H, - OCH2
), 4.92 (s, 1H, CH pyrimidone ring), 5.74 (s, 1H, NH ), 7.01 (s, 1H, NH), 11.62
(s, 1H, OH), 7.17 - 8.04 (m, 5H, Ar-H); 13C NMR (100MHz, CDCl3) δ ppm
: 16.21, 20.23, 57.58, 62.73, 97.54, 117.21, 118.96, 120.28, 122.85, 125.12,
130.24, 139.54, 147.67, 155.32, 164.06, 173.17, 182.42; ESI (M+) : m/z calcd
for C17H17N O3S: 343.10; found: 343.61
2. EXPERIMENTAL
2.1 Materials
All used materials were obtained from Sigma Aldrich and were used
without further purification.
2.2 Equipments
Melting points were determined on a Raga melting point apparatus melting
point apparatus in open capillary tubes and were not corrected. Microwave
reactions were carried on Biotage synthetic microwave oven. The H NMR
5-met3hoxycarbonyl-4(2’-hydroxyquinolin)-6-methyl-3,4-
dihydropyrimidin-2(1H)-thione (DHPMT2): Red solid; Yield : 77% ; m.p.
223-224º C ; Anal.Calcd. for C16H15N3O3S: C 58.34, H 4.59, N 12.76%. Found:
C 58.32, H 4.60, N 12.72%; IR (KBr, cm-1) : 3408 and 3267 ( stretching
1
and 13C NMR were recorded on Bruker AV-400 spectrometer chemical shifts
were recorded in ppm from internal tetra methyl silane standard and are
given in δ- units. The solvent for NMR spectra was deuteron- CCl unless
otherwise stated. Infrared spectra were taken on Shimadzu FT IR PC(4S) 8201
spectrometer instrument in potassium bromide pellets unless otherwise stated.
Mass spectra were obtained with a Thermo Scientific Mass spectrometer
detector and electrospray ionisation. All reactions were monitored by thin
layer chromatography (TLC) carried out on 0.2 mm silica gel 60 F (Merck)
plates using UV light (254 and 366 nm) for detection. Ethyl a2c5e4tate and
petroleum ether were used as developing solvents. Common reagents are either
commercially available and were used without further purification or prepared
by standard literature procedures.
1
of N-H), 1692 (C=O str), 1206 (C=S str) ; H NMR ( 400MHz , CDCl ) δ
ppm :2.42(s, 3H, CH3), 3.35(s, 3H, OCH3), 11.6(s, 1H, OH) 4.7 (s, 1H, 3CH
pyrimidone ring ), 5.8 (s, 1H, NH ), 6.37 (s, 1H, NH), 7.17-8.80 (m, 5H, Ar-H
); 13C NMR (100MHz, CDCl3) δ ppm : 18.03, 51.34, 53.12, 104.86, 110.62,
115.73, 122.18, 122.85, 123.67, 127.72, 129.08, 143.16, 147.81, 165.15,
178.09, 183.67; ESI (M+) : m/z calcd for C16H15N3O S: 329.08; found: 329.54
5 - e t h o x y c a r b o n y l - 4 ( 4 ’ - m e t h o x y q u3i n o l i n e ) - 6 - m e t h y l -
3,4dihydropyrimidin-2(1H)-one
(DHPM3): White solid; Yield: 62% ; m.p. 156-159º C ; Anal. Calcd. for
C18H19N3O4: C 63.33, H 5.61, N 12.31%. Found: C 63.32, H 5.63, N 12.28%;
IR (KBr, cm-1) : 3354 and 3296 ( stretching of N-H), 1684 and 1710 (C=O
2.3 Synthetic methodology
2.3.1 Synthesis of the nickel(II) exchanged zeolite [Ni(II)Y]
Following reported procedure72, 0.1 mmol of nickel(II)chloride was added
to the 50 mL aqueous solution of 1g NaY zeolite under stirring for 15 h at 100
°C. The resulting greenish solid was washed with 100 mL of hot distilled water
and dried at 120 °C for 6 h.
1
str) ; H NMR ( 400MHz , CDCl3) δ ppm : 1.25 (s, 3H, -OCH CH3), 1.82
(s, 3H, CH3), 3.58 (s, 3H, OCH ), 4.01 (m, 2H, -OCH2CH ), 5.312(s, 1H, CH
pyrimidone ring ), 5.95 (s, 1H,3NH ), 6.37 (s, 1H, NH), 36.81-8.35 (m, 5H,
Ar-H ); 13C NMR (100MHz, CDCl ) δ ppm : 13.27, 18.63, 49.65, 52.43, 58.72,
100.61, 103.21, 127.48, 127.73, 3 128.80, 129.10, 132.84, 136.82, 143.89,
153.45, 158.68, 163.76, 168.22; ESI (M+) : m/z calcd for C18H19N3O4: 341.14;
found: 341.15
2.3.2 Synthesis of 2-hydroxy-4-formyl quinoline
2-hydroxy-4-formyl quinoline73 was prepared by the oxidation of
2-hydroxy- 4-methyl quinoline with selenium dioxide (SeO2) as reported
earlier in our laboratory.
5-methoxycarbonyl-4(4’-methoxyquinoline)-6-methyl-
3,4dihydropyrimidin-2(1H)-one
2.3.3 Synthesis of 2-formyl-4-methoxy quinoline
2-formyl-4-methoxy quinoline74 was prepared adopting the published
methodology.
(DHPM4): Cream white solid; Yield : 65% ; m.p. 178-181º C ; Anal.
Calcd. for C17H17N3O4: C 62.38, H 5.23, N 12.84%. Found: C 62.36, H 5.19, N
12.81%; IR (KBr, cm-1) : 3408 and 3252 ( stretching of N-H), 1662 and 1698
(C=O str) ; 1H NMR ( 400MHz , CDCl3) δ ppm : 1.28 (s, 3H, CH ), 3.72 (s, 6H,
OCH3), 5.08 (s, 1H, CH pyrimidone ring ), 5.51 (s, 1H, NH ), 6.233 (s, 1H, NH),
6.96 -8.28 (m, 5H, Ar-H ); 13C NMR (100MHz, CDCl3) δ ppm: 16.23, 49.68,
50.21, 54.89, 103.82, 112.53, 128.07, 128.13, 128.94, 129.55, 129.60, 136.39,
140.96, 153.81, 159.28, 165.45, 169.18 ; ESI (M+) : m/z calcd for C17H17N3O4:
327.12; found: 327.32
2.3.4 Experimental procedure for the Biginelli reaction
The synthesis of dihydropyrimidone/thione (DHPM/ DHPMT) through a
simple three component reaction is described as follows,
A dry 50 mL flask was charged with a mixture of 2-hydroxy-4-formyl
quinoline/ 2-formyl-4-methoxy quinoline (0.001 mol), ethyl acetoacetate/
methyl acetoacetate (0.001 mol), urea/ thiourea (0.001 mol) and NiNPs (8
mol%) were taken in 5 mL of ethanol . The reaction mixture were homogenized
with the help of a glass rod and irradiated in microwave oven (360 W) by
interval of 10 s for a designated time as required for the completion of the
reaction. The progress of the reaction was checked by thin layer chromatography
(TLC). After the completion of the reaction, the mixture was cooled at room
temperature. Then it was extracted with ethyl acetate. The organic layer was
dried over sodium sulphate and concentrated in vaccum to afford the crude
product. The crude products were purified by crystallization in ethanol.
2.3.5Analytical and spectral data for the synthesized compounds
5 - e t h o x y c a r b o n y l - 4 ( 2 ’ - h y d r o x y q u i n o l i n ) - 6 - m e t h y l -
3,4dihydropyrimidin-2(1H)-one (DHPM ): Pale white solid; Yield: 78%; m.p.
204-205º C; Anal.Calcd. for C17H17N3O4: 1C 62.38, H 5.23, N 12.84 %. Found:
C 62.36, H 5.25, N 12.83 %; IR (KBr, cm-1) : 3384 and 3264 ( stretching of
5 - e t h o x y c a r b o n y l - 4 ( 4 ’ - m e t h o x y q u i n o l i n e ) - 6 - m e t h y l -
3,4dihydropyrimidin-2(1H)-thione
(DHPMT3): Brown solid; Yield: 64% ; m.p. 207-210º C ; Anal. Calcd. for
C18H19N3O3S: C 60.49, H 5.36, N 11.76%. Found: C 60.47, H 5.33, N 11.72%;
IR (KBr, cm-1) : 3365 and 3258 ( stretching of N-H), 1662 (C=O str) and 1196
1
(C=S str) ; H NMR ( 400MHz , CDCl3) δ ppm : 1.08 (s, 3H, CH ), 3.42
(t, 3H, OCH CH ), 3.65 (s, 3H, OCH ), 5.13 (s, 1H, CH pyrimidone3 ring ),
5.24 (s, 1H, 2NH3), 6.01 (s, 1H, NH),3 6.83-8.10 (m, 5H, Ar-H ); 13C NMR
(100MHz, CDCl3) δ ppm: 16.94, 49.21, 50.79, 54.20, 113.82, 122.53, 126.51,
128.7, 128.33, 128.91, 129.65, 129.60, 136.79, 140.01, 153.81, 158.28, 162.45,
168.18 ; ESI (M+) : m/z calcd for C H19N O S: 357.11; found: 357.36
5-methoxycarbonyl-4(41’8 -me3th3oxyquinoline)-6-methyl-
3,4dihydropyrimidin-2(1H)-thione
1
N-H), 1680 and 1662 (C=O str) ; H NMR ( 400MHz , CDCl3) δ ppm : 1.47
(t, 3H, -OCH2CH ), 1.89 (s, 3H, CH3), 3.86 (m, 2H, - OCH2 ), 5.10 (s, 1H, CH
pyrimidone ring )3, 5.98 (s, 1H, NH ), 7.25 (s, 1H, NH), 12.36 (s, 1H, OH), 7.49
-8.27 (m, 5H, Ar-H ); 13C NMR (100MHz, CDCl3) δ ppm : 15.17, 19.65, 47.6,
61.62, 98.79, 116.41, 117.96, 119.85, 122.60, 125.32, 130.46, 138.77, 147.84,
152.60, 164.06, 172.54; ESI (M+) : m/z calcd for C17H17N3O4: 327.12; found:
327.33
(DHPMT4): Reddish Brown solid; Yield: 68% ; m.p. 230-233º C; Anal.
Calcd. for C17H17N3O3S: C 59.46, H 4.99, N 12.24%. Found: C 59.44, H 4.97,
N 12.26%; IR (KBr, cm-1) : 3408 and 3252 ( stretching of N-H), 1662 (C=O
1
str) and 1186 (C=S str); H NMR ( 400MHz , CDCl3) δ ppm : 1.02 (s, 3H,
CH3), 3.82 (s, 6H, OCH3), 4.95 (s, 1H, CH pyrimidone ring ), 5.23 (s, 1H, NH
), 6.01 (s, 1H, NH), 6.52-8.32 (m, 5H, Ar-H ); 13C NMR (100MHz, CDCl3) δ
ppm:18.90, 51.75, 57.32, 58.95, 99.10, 108.05, 115.86, 120.04, 121.31, 122.09,
125.16, 130.72, 139.11, 148.36,162.08, 176.62, 183.98; ESI (M+) : m/z calcd
for C17H17N3O3S: 343.10; found: 343.78.
5 - m e t h o x y c a r b o n y l - 4 ( 2 ’ - h y d r o x y q u i n o l i n ) - 6 - m e t h y l -
3,4dihydropyrimidin-2(1H)one (DHPM ): White solid; Yield: 80%; m.p. 211-
214º C; Anal.Calcd. for C16H15N3O4: C 261.34, H 4.83, N 13.41%. Found: C
61.38, H 4.85, N 13.42 %; IR (KBr, cm-1): 3413 and 3283 ( stretching of N-H),
1678 and 1689 (C=O str) ; 1H NMR ( 400MHz , CDCl3) δ ppm : 1.89 (s, 3H,
CH3), 3.65 (s, 3H, OCH3), 4.81 (s, 1H, CH pyrimidone ring ), 5.42 (s, 1H, NH
), 6.74 (s, 1H, NH), 10.46 (s, 1H, OH), 7.82 -8.90 (m, 5H, Ar-H ); 13C NMR
(100MHz, CDCl3) δ ppm :16.88, 47.96, 51.85, 108.12, 112.65, 120.54, 122.18,
123.36, 127.74, 129.02, 137.74, 143.46, 148.77, 156.34, 165.23, 175.48; ESI
(M+) : m/z calcd for C16H15N O : 313.11; found: 313.61
5-ethoxycarbonyl-34(42’-hydroxyquinolin)-6-methyl-3, 4-
dihydropyrimidin-2(1H)-thione (DHPMT1): Reddish Brown solid; Yield:
81%; m.p. 216-217º C; Anal.Calcd. for C17H17N3O3S: C 59.46, H 4.99, N
3975

J. Chil. Chem. Soc., 63, Nº 2 (2018)
Table I. Synthesis of functionalised dihydropyrimidone (DHPMs)/ dihydropyrimithione (DHPMTs) derivatives.
S.No
1
Entry
Ar
X
O
R1
Productb
N
OH
CHO
OC2H5
O
DHPM1
C2H5
HN
N
OH
O
N
H
CH3
N
OH
CHO
N
OCH3
O
2
3
4
DHPM2
DHPMT1
DHPMT2
O
S
S
CH3
C2H5
CH3
HN
OH
OH
OH
O
N
H
CH3
N
OH
CHO
N
OC2H5
O
HN
S
N
H
CH3
N
OH
CHO
N
OCH3
O
HN
S
N
H
CH3
H3CO
OCH3
N
N
OC2H5
O
5
DHPM3
O
C2H5
HN
CHO
O
N
H
CH3
H3CO
OCH3
N
N
OCH3
O
6
7
DHPM4
DHPMT3
DHPMT4
O
S
S
CH3
C2H5
CH3
HN
CHO
CHO
CHO
O
N
H
CH3
H3CO
OCH3
N
N
OC2H5
O
HN
S
N
H
CH3
H3CO
OCH3
N
N
OCH3
O
8
HN
S
N
H
CH3
a-
b-
NiNPs
Quinoline aldehyde (0.001 mol), ethyl acetoacetate/ methyl acetoacetate (0.001 mol), urea/ thiourea (0.001 mol) and NiNPs (8 mol%) , 5 mL of ethanol
3976

J. Chil. Chem. Soc., 63, Nº 2 (2018)
Fig. 1: General structures of the synthesised compounds.
2.4 Biological Activity
2.4.1 Antimicrobial Studies
The newly synthesized compounds were initially screened for their
antimicrobial activity against the Gram-positive bacterium, Methicillin resistant
Staphylococcus aureus (MRSA), Gram-negative bacterium, Pseudomonas
aeruginosa (MTCC 201) and a yeast strain, Fluconazole resistant Candida
albicans (FRCA). Well diffusion assay was carried out to determine the
antibacterial activity75. For the well diffusion assay, 17 h old bacterial cultures
were inoculated over the agar surface of Muller Hinton agar plates using
sterile cotton swabs. After 10 min, wells were cut using a cork borer and each
well was loaded with 10 µl of each compound from 10 mg/ml stock (100 µl/
well) along with DMSO control. The plates were incubated at 37°C for 24 h.
Susceptibility was assessed on the basis of diameter of the zone of inhibition
(ZOI) against the test pathogens and the results are presented Table 5. Among
them, the compound DHPMT3 showed moderate to good antimicrobial activity
against MRSA and FRCA than the other compounds with ZOI up to 19 mm
and 18 mm respectively. But none of the compounds, viz dihydropyrimidone
(DHPMs)/ dihydropyrimithione (DHPMTs) derivatives showed antibacterial
activity against Pseudomonas aeruginosa.(MTCC 201)
Fig. 2: FTIR spectrum of the Ni(II)Y
The XRD patterns of the Ni(II)Y was recorded at room temperature, as
shown in Fig. 3. The XRD patterns of Ni(II)Y shows the 2-theta values at
10.1°, 11.9°and 15.7 ° for the corresponding reflection of 220, 311 and 331
respectively as depicted in (Fig. 3)
The in vitro minimum inhibitory concentration (MIC) of all the 10
compounds against MRSA and FRCA were determined by the method of
National Committee for Clinical Laboratory (NCCLS)76. The MIC values
are summarized in Table VI. The standard antibiotics, Streptomycin and
Fluconazole triclosan were used as controls.
2.4.2 Radical Scavenging activity
Free radical scavenging action is considered to be one among the various
mechanisms for anti oxidation77.
DPPH radical scavenging activity
The capacity of compounds to scavenge the ‘‘stable’’ free radical
DPPH was monitored. Various concentrations of compounds solutions (0.3
mL) were mixed with solution containing DPPH radicals. The mixture was
shaken vigorously and left to stand for 2 h in the dark (until stable absorption
values were obtained). The reduction of the DPPH radical was determined by
measuring the absorption at 517 nm. The radical scavenging activity (RSA)
was calculated as a percentage of DPPH discolouration using the equation:
% RSA ¼ [(ADPPH AS)/ADPPH] 100, where AS is the absorbance of the
solution when the compound has been added at a particular level and ADPPH
is the absorbance of the DPPH solution. Mean values from three independent
samples were calculated for each compound and standard deviations were less
than 5%. Ascorbic acid was used as standard.
Fig. 3: The powder XRD patterns of the Ni(II)Y
The electron microscopic studies (FESEM and TEM) of the Ni(II)Y was
shown in the (Fig.4a & Fig.4b). From the (Fig.4a) the FESEM image shows
the shape of the particle is cubic angular, where as TEM image (Fig.4b) of the
Ni(II)Y also shows the angular shape .
3.2 Optimisation of reaction conditions
3.2.1 Effect of catalyst concentration on the substrate selectivity
RESULTS AND DISCUSSION
The efficiency of the organic transformation can be increased by the use
of nano sized catalyst because of their extremely small size and relatively
large surface area. Our initial focus was to optimize the effect of catalyst on
the reaction condition. The catalyst concentration were varied over a range
of 2-10 mol % Nickel (II) exchanged zeolite [Ni(II)Y] nano particles. Table
II shows the effect of catalyst concentration on the reaction of 2-hydroxy-4-
formyl quinoline/ 2-formyl-4-methoxy quinoline, methyl/ ethyl acetoacetate
and urea/thiourea. The yield of the corresponding dihydropyrimidione /
dihydropyrimidinthione showed an increase with the increase in catalyst
concentration from 2 to 8 mol %. A further addition of the catalyst had no
noticeable effect on the yield. This may be due to the fact that beyond a certain
concentration, more catalyst sites exist than that required by the reactant
3.1 Characterization [Ni(II)Y] nano particles
The Nickel (II) exchanged zeolite [Ni(II)Y] nano particles were synthesized
by procedure reported earlier by G.R.Reddy et al72 and characterized using IR
spectra, powder X ray diffraction, Scanning Electron Microscope (FESEM)
and Tunneling Electron Microscope (TEM).
The FT-IR spectrum of Ni (II)Y is shown in Fig 2. The Ni(II)Y bands in
the range of 3300- 3350 cm-1 is due to the adsorbing tendency of the surface
present hydroxyl groups and the peak at 1645 cm-1 because of the bending
frequency of –OH groups of the Ni(II)Y. The bands at 1200–450 cm-1 are
because of lattice (Si/Al)O4 vibrations. In this region a peak at 510 cm-1 is
due to the formation interaction of Ni(II) ion with the lattice present (Si/Al)
O4 units.
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J. Chil. Chem. Soc., 63, Nº 2 (2018)
molecules, and hence the addition of catalyst does not increase the rate of the reaction. Therefore, in all the further reactions, 8 mol% of the catalyst were used.
The variations of the amount of catalyst are summarized in Table II. Best results were obtained under solvent free microwave irradiation (Entry 4) using 8
mol %.
Fig.4a: FESEM image of the Ni(II)Y.
Fig.4b: TEM image of the Ni(II)Y.
Table II. Effect of catalyst concentration on the yield, for the synthesis
noted that up to 360 W, as the power increases; there is increase in the yield
with a corresponding decrease in reaction time. Hence the different reaction
conditions were optimized at 360 W. After the course of the reaction, the
NiNPs were recovered by centrifuging the aqueous layer. The catalyst was
easily recovered by simple filtration after dilution of the reaction mixture
with ethyl acetate and was reused after being vacuum dried. The stability and
activity of the catalyst was tested in the recycle- use experiments. The nickel
nanoparticles were recycled four times and it was observed that during the
recycle experiments there was no apparent loss in the yield of the product
which supports the stability and activity of the catalyst.
of DHPM1
Catalyst conc. mol %
Yield %
2
4
6
8
10
78
63
70
72
78
3.2.2 Effect of variation of microwave power
We have also carried out the model reaction under microwaves using
different powers. During the optimization of reactions, model reaction was
studied by varying microwave power (120, 160, 240, 360, 400, 500 W). We
Fig.5 : Effect of catalyst concentration on the yield, for the synthesis of
DHPM1
Table III. Effect of radiation in terms of power (in Watts) on reaction time (in mins) and product yield (%)
Power, W
120
Reaction time, min
Yield, %
18
12
9
30
44
57
78
160
240
360
3.5
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J. Chil. Chem. Soc., 63, Nº 2 (2018)
(a) – Nickel nanoparticles/ 10 mL of ethanol/ Microwave irradiation
Scheme 1. Schematic pathway for the synthesis of densely functionalized dihydropyrimidone (DHPMs)/
dihydropyrimithione (DHPMTs) involving 2-hydroxy-4-formyl quinolines.
(a) – Nickel nanoparticles/ 10 mL of ethanol/ Microwave irradiation
Scheme 2. Schematic pathway for the synthesis of densely functionalized dihydropyrimidone (DHPMs)/
dihydropyrimithione (DHPMTs) involving 2-formyl-4-methoxy quinoline.
3.3 Reaction conditions and spectral analysis
corresponds to that of the CH of the pyrimidone ring indicating the fusion off
To explore the influence of catalyst and ratio of the components, equimolar
mixtures of 2-hydroxy-4-formyl quinoline (1), ethyl acetoacetate (2), urea (3)
and NiNPs (8 mol%) were taken in 5 mL of ethanol, homogenized and irradiated
in synthetic microwave oven (360 W) by interval of 10 s. The completion of
the reaction was checked by Thin Layered Chromatography (TLC). After the
completion of the reaction, the mixture was cooled, poured into crushed ice and
extracted with ethyl acetate. The organic layer was dried over sodium sulphate
and concentrated in vacuum to afford the crude product. The crude products
were purified by crystallization in ethanol.
the quinoline aldehyde to the dihydropyrimidone ring. The two singlets at δ
5.98 and 7.25 were accounted for NH groups. A broad peak corresponding
to OH group was observed at δ value 12.36. The aromatic protons appeared
between δ 7.46 to 8.27 for five protons. A multiplet around δ 3.86 corresponds
to OCH2-. A singlet around 1.89 corresponds to the three methyl protons of
CH3 and a triplet at 1.47 corresponds to the three methyl protons of OCH2CH3.
The 13C NMR of the compound under investigation confirms the presence
of 17 carbons. The ESI Mass spectrum m/z 327.33 is in agreement with the
molecular formula of the compound, thus identifying the compound DHPM1 to
be 5-ethoxycarbonyl-4(2’-hydroxy quinolin)-6-methyl-3,4 dihydropyrimidin-
2(1H)-one by all the spectral studies, we extended the reaction to all the other
derivatives.
The IR spectrum of the product gave sharp bands at 3384 cm-1 and 3264
cm-1 corresponding to N-H str , 1680 cm-1and 1662 cm-1 to C=O str. The
NMR studies of compound reveals, the appearance of sharp singlet at δ 5.10
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J. Chil. Chem. Soc., 63, Nº 2 (2018)
Further the optimized conditions were equally applied for the synthesis of
other derivatives and the structures of the newly synthesized compounds were
established from their spectral data.
3.4 Proposed Mechanism for the synthesis of dihydropyrimidone/
dihydropyrimithione heterocycles
Although different theoretical and experimental mechanistic approaches
78, 79 has been previously reported, we presume that the reaction could have
proceeded comprehensively following the mechanism as proposed earlier by
Sheik Mansoor et al80 in which the Nickel (II) exchanged zeolite [Ni(II)Y]
nanoparticles, that would have catalysed the formation of an acyl intermediate
or N-alkylidene urea, formed by the reaction between aldehyde and urea, which
probably is the “rate determining step”. The mechanism opens a new avenue
towards the understanding of Biginelli reaction, where in the key step in the
cyclocondensation process involves the formation of N- carbamoyliminium
ion intermediate. The coordination of the lone-pair of the nitrogen atom in
the N-acylimine with the Nickel (II) exchanged zeolite [Ni(II)Y] could lead
to the in situ formation of an N-carbamoyliminium ion, which is sufficiently
electrophilic to react with the enol form of ethyl acetoacetate affording the
open chain intermediate. Interception of the iminium ion by ethyl acetoacetate
produces an open chain ureide which subsequently undergoes further
intramolecular cyclization, with loss of H2O to yield dihydropyrimidone
(DHPMs)/ dihydropyrimithione (DHPMTs) derivatives.
Scheme 3. Suggested mechanism for the Biginelli reaction catalysed by Ni Nanoparticles.
3.5 Biological Results and Discussion
3.5.1 Antimicrobial Screening
All of the newly prepared compounds were screened for antimicrobial
activity against two human bacterial pathogens, the Gram-positive
Methicillin resistant Staphylococcus aureus (MRSA) and the Gram-negative
The MIC results of tested compounds showed that most of the compounds
were active against MRSA and FRCA at low concentration than their parent
compounds. However none of the compound showed activity against Gram-
negative bacterium, Pseudomonas aeruginosa. Interestingly the compound
entry DHPM1 exhibited good antibacterial and anti-yeast activities at MIC 3.5
and 6.9µg/mL and it was much lower than the MIC of the other compounds as
in Table V. Further, the compound entry DHPM3 and DHPM4 showed good
antibacterial and anti-yeast activities at MIC of 7.4µg/mL. The derivatives of
dihydropyrimithione on an average showed similar antibacterial and anti-yeast
activities at MIC of 15.3µg/mL.
Pseudomonas aeruginosa (MTCC 201) and
a human yeast pathogen,
Fluconazole resistant Candida albicans (FRCA). Among the synthesized
compounds, entry DHPMT3 exhibited maximum antibacterial activity towards
MRSA and antifungal activity against FRCA as depicted in Table IV. None
of the compound exhibited antibacterial activity against the Gram-negative
bacterium, Pseudomonas aeruginosa.
Table IV. Antimicrobial activity of synthesized dihydropyrimidone (DHPMs)/ dihydropyrimithione (DHPMTs) derivatives and against human pathogens.
Entry
Strain
Zone of inhibition (mm)
Gram positive
bacterium
Gram negative
bacterium
Fungal strain
MRSA
18
MTCC 201
FRCA
17
N
DHPM1
DHPM2
N
N
N
N
N
N
N
N
13
N
15
DHPMT1
DHPMT2
DHPM3
15
17
12
15
12
18
16
N
12
15
DHPM4
11
DHPMT3
DHPMT4
Streptomycin
Fluconazole
19
17
24
N
N
N- No Inhibition
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J. Chil. Chem. Soc., 63, Nº 2 (2018)
Table V. Minimum inhibitory concentration of the synthesized compounds
against MRSA and FRCA.
were established from their spectral data. Excellent yields, shorter reaction
time, renewable nano catalyst and easy workup are the major advantageous
features of this green protocol. The efficacy of the biological activity of the
synthesised compounds were examined against two human bacterial pathogens,
the Gram-positive Methicillin resistant Staphylococcus aureus (MRSA) and
the Gram-negative Pseudomonas aeruginosa (MTCC 201) and a human yeast
pathogen, Fluconazole resistant Candida albicans (FRCA). The synthesized
compounds exhibited moderate to good activity against MRSA and antifungal
activity against FRCA. None of the compound exhibited antibacterial activity
against the Gram-negative bacterium, Pseudomonas aeruginosa. Further,
the synthesised compounds demonstrated higher antioxidant activity. The
significance of this study demonstrates a remarkable subject of intense research
in therapeutics.
Entry
Strain
Minimum inhibitory concentration (MIC) (µg/ml)
Gram-positive bacterium
MRSA
Fungal strain
FRCA
DHPM1
DHPM2
3.5
7.4
6.9
ND
15.3
ND
7.4
DHPMT1
DHPMT2
DHPM3
15.3
15.3
7.4
ACKNOWLEDGEMENT
DHPM4
7.4
7.4
The author (P.D) gratefully acknowledges the financial assistance received
for the work from “Maulana Azad National Fellowship” MANF–SRF rendered
by the “Ministry of Minority affairs” through University Grants Commission
(UGC), New Delhi.
DHPMT3
DHPMT4
Streptomycin
Fluconazole
62.8
62.8
3.9
62.8
ND
ND
ND
ND
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