Synthesis and antibacterial evaluation of tetrahydropyrimidine-5-carboxamide

Article abstract of DOI:10.14233/ajchem.2018.20850

A series of new dihydropyrimidine-2H-ones/thiones were synthesized and evaluated in vitro for their antibacterial activity. Characterization of newly synthesized dihydropyrimidones was done by physical and spectral data. All the synthesized compounds were evaluated for their antibacterial activity. Amongst all, compounds 3e and 4e registered high activity against the bacterial strain when compared to standard drug.

Full text of DOI:10.14233/ajchem.2018.20850

Asian Journal of Chemistry; Vol. 30, No. 2 (2018), 254-256
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2018.20850
Synthesis and Antibacterial Evaluation of Tetrahydropyrimidine-5-carboxamide
1,*
1
2,*
N. EDAYADULLA , S. ANAND and T. SHANKAR
1Department of Chemistry, VEL TECH, Avadi, Chennai-600 062, India
2Department of Chemistry, Manonmaniam Sundaranar University, Tirunelveli-627 012, India
*Corresponding authors: E-mail: edayam2004@gmail.com; atshankar80@gmail.com
Received: 9 June 2017;
Accepted: 17 August 2017;
Published online: 31 December 2017;
AJC-18686
A series of new dihydropyrimidine-2H-ones/thiones were synthesized and evaluated in vitro for their antibacterial activity. Characterization
of newly synthesized dihydropyrimidones was done by physical and spectral data. All the synthesized compounds were evaluated for their
antibacterial activity. Amongst all, compounds 3e and 4e registered high activity against the bacterial strain when compared to standard drug.
Keywords: Dihydropyrimidones, Biginelli reactions, Grindstone technique, Antibacterial.
General procedure for the preparation of 4-(aryl)-6-
methyl-2-oxo-N-phenyl-1,2,3,4-tetrahydropyrimidine-5-
carboxamides: A mixture of an heterocyclic aldehyde (0.01
mol), N-phenylacetoacetamide (0.01 mol), urea/thiourea (0.01
mol), cupric chloride (0.01 mol) and 2-3 drops of conc. HCl was
ground together to give a syrup under solvent-free condition
which was left overnight. The contents were poured into ice-
cold water and the product that separated was filtered, dried
and crystallized. All the compounds have been synthesized as
per reported procedure [10](Scheme-I).
INTRODUCTION
Biginelli compounds or dihydropyrimidinones (DHPMs)
exhibit a broad spectrum of biological activity. For example,
some of these compounds are very potent calcium channel
blockers and act as antihypertensive, antiviral, antitumor and
anti-inflammatory agents [1-8]. Previous studies on biological
activity of dihydropyridines (DHPs) have revealed that dihydro-
pyridines having carbamoyl moieties at 3rd and 5th positions
showed significant antituberculosis activity [9]. These obser-
vations have prompted us to undertake the designing of new
dihydropyrimidinones derivatives against microbial resistance.
The presence of several interacting functional groups in Biginelli
compounds determines their great synthetic potentiality [5].
Hence, the required dihydropyrimidinones were synthesized
according to the procedure described by Pathak et al. [10]. In
addition to this, we addressed the in vitro antibacterial evalua-
tion of synthesized compounds.
4-(Thiophen-2-yl)-6-methyl-2-oxo-N-phenyl-1,2,3,4-
tetrahydropyrimidine-5-carboxamide (3a):Yield: 88 %, m.p.:
152 °C (aq. EtOH); IR (KBr, νmax, cm-1): 3378, 3270 (NH), 1676
1
(C=O of amide). H NMR (300 MHz, CDCl3 + DMSO-d6): δ
2.11 (s, 3H, 6-CH3), 5.60 (s, 1H, H-4), 7.04-8.30 (m, 8H,Ar-H),
8.68 (s, 1H, 3-NH), 8.87 (s, 1H, 1-NH), 9.41 (s, 1H, NHof amide).
13C NMR (75 MHz): δ 18.1, 51.8, 109.5, 120.4, 121.6, 125.6,
128.0 128.9, 133.2, 137.6, 144.2, 147.1, 148.4, 152.3, 162.8.
4-(Thiophen-3-yl)-6-methyl-2-oxo-N-phenyl-1,2,3,4-
tetrahydropyrimidine-5-carboxamide (3b): Yield: 84 %,
m.p.: 143-145 °C (aq. EtOH); IR (KBr, νmax, cm-1): 3379, 3272
EXPERIMENTAL
Melting points were recorded in open capillary tube and
are uncorrected. IR spectra were recorded in KBr on 8400S
Shimadzu FT-IR Spectrophotometer and NMR spectra were
scanned on a Bruker 300 MHz Spectrometer in CDCl3/DMSO-
d6 using TMS as internal standard. The chemical shifts are
expressed in δ-scale. Elemental analyses were carried out on
Perkin-Elmer 2400 II instrument. Purity of synthesized com-
pounds was checked by TLC using silica gel-G and spots were
detected in iodine chamber.
1
(NH), 1678 (C=O of amide). H NMR (300 MHz, CDCl3 +
DMSO-d6): δ 2.12 (s, 3H, 6-CH3), 5.58 (s, 1H, H-4), 7.10-
8.22 (m, 8H, Ar-H), 8.69 (s, 1H, 3-NH), 8.90 (s, 1H, 1-NH),
9.38 (s, 1H, NH of amide). 13C NMR (75 MHz): δ 21.1, 51.4,
110.2, 121.7, 126.2, 128.4 129.1, 134.1, 138.2, 145.2, 148.1,
148.8, 153.4, 163.1.
4-(Pyridin-2-yl)-6-methyl-2-oxo-N-phenyl-1,2,3,4-
tetrahydropyrimidine-5-carboxamide (3c): Yield: 89 %,

Vol. 30, No. 2 (2018)
Synthesis and Antibacterial Evaluation of Tetrahydropyrimidine-5-carboxamide 255
O
Ar
O
NH
2
HN
NH
CuC l2 / HCl
Room temp.
N
H
Aldehydes
Z
NH
2
Me
N
H
Z
M e
O
b
Z = O (3 a-f
Z = S (4 a-f
)
)
2 a-f
1
S
N
a
=
S
c
=
=
N H
=
f
=
d
e =
N
N
H
Scheme-I: Synthetic route for the synthesis of 3,4-dihydropyrimidines
m.p.: 178 °C (aq. EtOH); IR (KBr, νmax, cm-1): 3378, 3268 (NH),
1682 (C=O of amide) . 1H NMR (300 MHz, CDCl3 + DMSO-
d6): δ 2.24 (s, 3H, 6-CH3), 5.54 (s, 1H, H-4), 7.20-8.26 (m,
9H, Ar-H), 8.06 (s, 1H, 3-NH), 8.16 (s, 1H, 1-NH), 8.72 (s,
1H, NH of amide). 13C NMR (75 MHz): δ 18.2, 51.8, 107.8,
119.8, 123.2, 126.2, 126.9, 127.4, 128.2, 128.4, 138.2, 143.1,
150.2, 163.7.
4-(Pyridin-3-yl)-6-methyl-2-oxo-N-phenyl-1,2,3,4-
tetrahydropyrimidine-5-carboxamide (3d): Yield: 92.5 %,
m.p.: 129-130 °C (aq. EtOH); IR (KBr, νmax, cm-1): 3380, 3278
(NH), 1677 (C=O of amide) . 1H NMR (300 MHz, CDCl3 +
DMSO-d6): δ 2.22 (s, 3H, 6-CH3), 5.55 (s, 1H, H-4), 7.14-
8.20 (m, 9H, Ar-H), 8.24 (s, 1H, 3-NH), 8.30 (s, 1H, 1-NH),
9.22 (s, 1H, NH of amide). 13C NMR (75 MHz): δ 18.6, 52.4,
108.8, 121.8, 123.1, 127.5, 128.9, 130.4, 131.8 132.4, 138.2,
143.1, 150.2, 163.7.
4-(Pyrrol-2-yl)-6-methyl-2-oxo-N-phenyl-1,2,3,4-tetra-
hydropyrimidine-5-carboxamide (3e):Yield: 83 %, m.p.: 184
°C (aq. EtOH); IR (KBr, νmax, cm-1): 3380, 3278 (NH), 167
(C=O of amide) . 1H NMR (300 MHz, CDCl3 + DMSO-d6): δ
2.22 (s, 3H, 6-CH3), 5.48 (s, 1H, H-4), 6.32-7.14 (s, 3H, Ar-
H), 7.56-8.19 (s, 5H, Ar-H), 8.24 (s, 1H, 3-NH), 8.30 (s, 1H,
1-NH), 9.18 (s, 1H, NH of amide), 10.92 (s, 1H, pyrrole-NH).
13C NMR (75 MHz): δ 18.8, 52.6, 109.4, 111.2, 120.4, 123.1,
127.5, 128.9, 130.4, 131.5 132.3, 137.8, 142.9, 151.4, 162.8.
4-(Indol-2-yl)-6-methyl-2-oxo-N-phenyl-1,2,3,4-tetra-
hydro-pyrimidine-5-carboxamide (3f): Yield: 93 %, m.p.:
134 °C (aq. EtOH); IR (KBr, νmax, cm-1): 3378, 3284 (NH),
1672 (C=O of amide) . 1H NMR (300 MHz, CDCl3 + DMSO-
d6): δ 2.18 (s, 3H, 6-CH3), 5.34 (s, 1H, CH-4), 7.21-7.62 (m,
10H, Ar-H), 7.88 (s, 1H, 3-NH), 8.76 (s, 1H, 1-NH), 9.32 (s,
1H, NH of amide), 11.02 (s, 1H, Indole-NH). 13C NMR (75
MHz): δ 18.5, 51.8, 108.4, 111.2, 121.6, 123.7, 126.9, 128.9,
130.4, 131.5 132.3, 137.8, 142.9, 151.4, 162.8.
4-(Thiophen-2-yl)-6-methyl-2-thioxo-N-phenyl-1,2,3,4-
tetrahydropyrimidine-5-carboxamide (4a): Yield: 86 %,
m.p.: 132 °C (aq. EtOH); IR (KBr, νmax, cm-1): 3269, 3178
(NH), 1676 (C=O of amide), 1440 (C=S) . 1H NMR (300 MHz,
CDCl3 + DMSO-d6): δ 2.18 (s, 3H, 6-CH3), 5.60 (s, 1H, H-4),
7.04-8.30 (m, 8H, Ar-H), 8.72 (s, 1H, 3-NH), 8.96 (s, 1H, 1-
NH), 9.48 (s, 1H, NH of amide). 13C NMR (75 MHz): δ 19.8,
52.2, 109.5, 120.4, 121.6, 125.6, 128.0 128.9, 133.2, 137.6,
144.2, 147.1, 148.4, 152.3, 162.8.
4-(Thiophen-3-yl)-6-methyl-2-thioxo-N-phenyl-1,2,3,4-
tetrahydropyrimidine-5-carboxamide (4b): Yield: 85 %,
m.p.: 163-165 °C (aq. EtOH); IR (KBr, νmax, cm-1): 3264, 3172
(NH), 1678 (C=O of amide), 1438 (C=S) . 1H NMR (300 MHz,
CDCl3 + DMSO-d6): δ 2.12 (s, 3H, 6-CH3), 5.60 (s, 1H, H-4),
7.10-8.22 (m, 8H, Ar-H), 8.72 (s, 1H, 3-NH), 8.98 (s, 1H, 1-
NH), 9.44 (s, 1H, NH of amide). 13CNMR (75 MHz, CDCl3 +
DMSO-d6): δ 21.1, 51.4, 110.2, 121.7, 126.2, 128.4 129.1,
134.1, 138.2, 144.6, 146.8, 147.2, 152.6, 163.8.
4-(Pyridin-2-yl)-6-methyl-2-thioxo-N-phenyl-1,2,3,4-
tetrahydropyrimidine-5-carboxamide (4c): Yield: 92 %,
m.p.: 186 °C (aq. EtOH); IR (KBr, νmax, cm-1): 3278, 3168 (NH),
1682 (C=O of amide), 1440 (C=S) . 1H NMR (300 MHz, CDCl3
+ DMSO-d6): δ 2.24 (s, 3H, 6-CH3), 5.54 (s, 1H, H-4), 7.12-
8.32 (m, 9H, Ar-H), 8.24 (s, 1H, 3-NH), 8.42 (s, 1H, 1-NH),
8.78 (s, 1H, NH of amide). 13C NMR (75 MHz): δ 18.2, 51.8,
107.8, 119.8, 123.2, 126.2, 126.9, 127.4, 128.2, 128.4, 138.2,
143.1, 150.2, 163.7.
4-(Pyridin-3-yl)-6-methyl-2-thioxo-N-phenyl-1,2,3,4-
tetrahydropyrimidine-5-carboxamide (4d): Yield: 90 %,
m.p.: 137 °C (aq. EtOH); IR (KBr, νmax, cm-1): 3280, 3174
(NH), 1677 (C=O of amide), 1436 (C=S). 1HNMR (300 MHz,
CDCl3 + DMSO-d6): δ 2.22 (s, 3H, 6-CH3), 5.48 (s, 1H, H-4),
7.16-8.25 (m, 9H, Ar-H), 8.32 (s, 1H, 3-NH), 8.42 (s, 1H, 1-
NH), 9.26 (s, 1H, NH of amide). 13C NMR (75 MHz): δ 18.6,
52.4, 108.8, 121.8, 123.1, 127.5, 128.9, 130.4, 131.8 132.4,
138.2, 143.1, 150.2, 163.7.
4-(Pyrrol-2-yl)-6-methyl-2-thioxo-N-phenyl-1,2,3,4-tetra-
hydropyrimidine-5-carboxamide (4e): Yield: 86 %, m.p.:
177-179 °C (aq. EtOH); IR (KBr, νmax, cm-1): 3268, 3166 (NH),
1662 (C=O of amide), 1434 (C=S) . 1H NMR (300 MHz, CDCl3
+ DMSO-d6): δ 2.22 (s, 3H, 6-CH3), 5.48 (s, 1H, H-4), 6.32-
7.14 (s, 3H, Ar-H), 7.56-8.19 (s, 5H, Ar-H), 8.24 (s, 1H, 3-
NH), 8.30 (s, 1H, 1-NH), 9.24 (s, 1H, NH of amide), 10.96 (s,
1H, pyrrole-NH). 13C NMR (75 MHz, CDCl3 + DMSO-d6): δ
20.8, 52.6, 109.4, 111.2, 121.4, 123.1, 127.5, 128.9, 130.4,
131.5, 132.3, 137.8, 142.9, 150.4, 161.6.
4-(Indol-2yl)-6-methyl-2-thioxo-N-phenyl-1,2,3,4-
tetrahydro-pyrimidine-5-carboxamide (4f): Yield: 91 %;
m.p.: 127 °C (aq. EtOH); IR (KBr, νmax, cm-1): 3270, 3184 (NH),
1672 (C=O of amide), 1440 (C=S) . 1H NMR (300 MHz, CDCl3
+ DMSO-d6): δ 2.26 (s, 3H, 6-CH3), 5.44 (s, 1H, CH-4), 7.26-
7.88 (m, 10H, Ar-H), 7.96 (s, 1H, 3-NH), 8.67 (s, 1H, 1-NH),

256 Edayadulla et al.
Asian J. Chem.
9.43 (s, 1H, NH of amide), 10.98 (s, 1H, Indole-NH). 13C NMR
(75 MHz): δ 20.5, 52.0, 108.4, 111.2, 121.6, 123.7, 126.9,
128.9, 130.4, 131.5 132.3, 137.8, 142.9, 151.4, 164.8.
catalyst used is easily available and inexpensive.Adopting the
above technique, six dihydropyrimidine-2H-ones (3a-f) and
six dihydropyrimidine-2H-thiones (4a-f) have been prepared
and characterized by IR and 1H NMR. Furthermore, dihydro-
pyrimidinone derivative contains carbamoyl group in 5-position.
These observations have prompted us to undertake the synthesis
of new dihydropyrimidinones derived from N-phenylaceto-
acetamide as 1,3-dicarbonyl component with a great interest
to evaluate them for further pharmacological studies.
RESULTS AND DISCUSSION
Antibacterial activity: The antibacterial activity was
assessed by the disk diffusion method [11-14]. Compounds
3a-f and 4a-f were evaluated for in vitro activity against
Staphylococcus aureus and Salmonella typhi at a concentration
of 10 µg/mL in meat peptone agar medium. Amikacin was
used as a standard for antibacterial screening. For each bio-
logical activity test, two to three experiments were performed
and the average zone of inhibition was reported in Table-1.
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TABLE-1
ANTIBACTERIAL ACTIVITY OF COMPOUNDS 3a-f AND 4a-f
Zone of inhibition
(mm) at 10 µg/mL
Zone of inhibition
(mm) at 10 µg/mL
Compd.
No.
Compd.
No.
S.
S.
S.
S.
aureus
typhi
aureus
typhi
3a
3b
3c
3d
3e
11
10
12
11
14
13
16
12
11
10
13
18
14
22
4a
4b
4c
4d
4e
10
12
13
11
15
12
16
12
11
13
16
20
15
22
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4f
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(Standard)
Amikacin
(Standard)
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antibacterial activity. Compounds 3e, 3f, 4c and 4e exhibited
high activity against Gram-positive bacteria, S. aureus; of these
4e registered very high activity against S. aureus. Compounds
3e, 3f, 4d, 4e and 4f showed high activity against Gram-
negative bacteria, S. typhi; of these 3e and 4e registered very
high activity against S. typhi and all other compounds showed
moderate antibacterial activity.
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Conclusion
In summary, a simple, efficient and more eco-friendly
grinding technique is developed for the synthesis of 3,4-dihydro-
pyrimidinone using heterocyclic aldehyde. Moreover, the