Ultrasound-assisted synthesis and antimicrobial activity of tetrazole-based pyrazole and pyrimidine derivatives

Article abstract of DOI:10.1515/hc-2017-0067

New tetrazole-based pyrazole and pyrimidine derivatives were synthesized by an ultrasound irradiation method. All compounds were characterized by infrared spectroscopy (IR), ¹H nuclear magnetic resonance (NMR), ¹³C NMR, mass spectrometry (MS) and elemental analysis and assessed in vitro for their efficacy as antimicrobial agents against four bacteria (Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa) and two fungi (Candida albicans, Aspergillus Niger). Compounds 8a, 8e, 9a, 9b and 9e show potent activity against the tested strains compared to the reference drugs chloramphenicol and clotrimazole.

Full text of DOI:10.1515/hc-2017-0067

Heterocycl. Commun. 2017; aop
Vidya S. Dofe*, Aniket P. Sarkate, Zarina M. Shaikh and Charansingh H. Gill
Ultrasound-assisted synthesis and antimicrobial
activity of tetrazole-based pyrazole and
pyrimidine derivatives
https://doi.org/10.1515/hc-2017-0067
respond to these antibiotics. Therefore, it is necessary to find
new and efficacious drugs to treat these problems. The sub-
stitution of fluorine in potential drug molecules can improve
their therapeutic efficacy through hydrogen bonding inter-
actions at the active sites of the enzyme [3]. Thus, fluorine
substitution remains an important aspect in the develop-
ment of more active and selective drug candidates.
The synthetic versatility of tetrazole is due to its wide-
spread applications in the field of medicinal chemistry.
Tetrazole is considered a carboxylic acid analog because
of their similar pKa values and planar delocalized systems.
An advantage of tetrazole derivatives over carboxylic
acids is that they are resistant to various biological deg-
radation processes contributing to longer bioavailability
of drugs [4, 5]. These factors, prime in the potential appli-
Received April 16, 2017; accepted September 18, 2017
Abstract: New tetrazole-based pyrazole and pyrimidine
derivatives were synthesized by an ultrasound irradiation
method. All compounds were characterized by infrared
spectroscopy (IR), 1H nuclear magnetic resonance (NMR),
13C NMR, mass spectrometry (MS) and elemental analy-
sis and assessed in vitro for their efficacy as antimicro-
bial agents against four bacteria (Staphylococcus aureus,
Bacillus subtilis, Escherichia coli, Pseudomonas aerugi-
nosa) and two fungi (Candida albicans, Aspergillus niger).
Compounds 8a, 8e, 9a, 9b and 9e show potent activity
against the tested strains compared to the reference drugs
chloramphenicol and clotrimazole.
Keywords: antimicrobial; pyrazole; pyrimidine; tetrazole; cations of tetrazole derivatives, are responsible for anti-
ultrasound.
cancer [6], antifungal [7], antitubercular [8], anti-HIV [9],
antioxidant [10] and hormonal properties of the bioactive
agents [11]. Pyrazole derivatives have showed significant
biological activities, such as antimicrobial [12], analgesic
[13], anti-inflammatory [14] and anticancer activities [15].
Pyrimidines also occupy a distinct and unique place in
medicinal chemistry [16]. Pyrimidine derivatives are of
interest due to their pharmacological properties such as
antitumor [17], antimalarial [18], antiviral [19], antifungal
[20], antibacterial [21], anti-inflammatory [22], analgesic
[23] and antiprotozoal [24] activities. In continuation of
our earlier work on design and synthesis of pharmaco-
logically significant heterocycles [25], herein we report an
efficient green synthesis and antimicrobial activity of new
tetrazole containing pyrazole and pyrimidine derivatives.
Introduction
Ultrasound-accelerated chemical reactions proceed via
the formation and adiabatic collapse of transient cavi-
tation bubbles. Ultrasound irradiation has become an
alternative energy source for organic reactions ordinar-
ily accomplished by heating. Many reactions can be con-
ducted smoothly by sonication to provide improved yields
and increased selectivity [1].
Life-threatening invasive infections caused by microor-
ganisms have increased to alarming levels all over the world
[2]. In the past decades, antibiotics have been used as antimi-
crobial drugs. However, many human pathogens no longer
Results and discussion
*Corresponding author: Vidya S. Dofe, Department of Chemistry, Dr.
Babasaheb Ambedkar Marathwada University, Aurangabad 431 004,
India, e-mail: vidya.dofe84@gmail.com
Aniket P. Sarkate: Department of Chemical Technology, Dr.
Babasaheb Ambedkar Marathwada University, Aurangabad 431 004,
India
Zarina M. Shaikh: Department of Microbiology, Maulana Azad
College of Arts, Science and Commerce, Aurangabad 431 001, India
Charansingh H. Gill: Department of Chemistry, Dr. Babasaheb
Ambedkar Marathwada University, Aurangabad 431 004, India
Chemistry
New tetrazole-based pyrazole derivatives 8a–f and
tetrazole-based pyrimidine derivatives 9a–f were syn-
thesized using conventional heating and ultrasound
irradiation methods (Scheme 1). The precursors 4a–f
were prepared in good yield according to the literature
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ꢀꢀꢀꢁ
2ꢀ
ꢀV.S. Dofe et al.: Tetrazole-based pyrazole and pyrimidine derivatives
F
R1
R1
R1
R1
OH
R3
F
R2
R3
OH
O
R1
R2
R3
O
R2
R3
O
O
R2
R3
OH
O
i
ii
iii
iv
O
R2
OH
1a–f
2a–f
3a–f
5a–f
4a–f
N
N
N
NH
F
F
R1
R1
R1
R2
R3
O
R2
R3
O
O
R2
R3
OH
N
v
vi
vii
O
N
F
O
O
CN
N
O
HN
N
NH
6a–f
7a–f
8a–f
viii
a: R1 = H; R2 = H; R3 = H
b: R1 = H; R2 = H; R3 = Cl
c: R1 = Me; R2 = H; R3 = H
d: R1 = H; R2 = H; R3 = Me
e: R1 = Cl; R2 = H; R3 = Cl
f: R1 = H; R2 = Me; R3 = Cl
N
N
N
R1
NH
R2
R3
OH
F
O
N
NH
9a–f
S
Scheme 1ꢀReagents and conditions: (i) acetic anhydride, pyridine, 100°C, 3–4 h; (ii) AlCl3, 150°C, 3–4 h; (iii) 4-fluorobenzaldehyde, KOH,
EtOH, room temperature (rt), 2–3 h; (iv) H2O2, NaOH, 0°C to rt, 2–3 h; (v) 2-chloroacetonitrile, K2CO3, DMF, rt, 3–4 h; (vi) sodium azide, zinc
bromide, H2O, reflux, 100°C, 4–5 h; (vii) hydrazine hydrate, ethanol, )))), 65°C, 45–55 min; (viii) thiourea, KOH, ethanol, )))), 65°C, 15–25 min.
procedure [26, 27]. Compounds 4a–f were converted activity against Candida albicans (NCIM 3471) and Asper-
into corresponding substituted 3-hydroxychromones gillus niger (NCIM 596). The minimum inhibitory concen-
5a–f by oxidative cyclization using hydrogen peroxide tration (MIC) values were determined by the micro-broth
in ethanol. The hydroxychromones 5a–f were alkylated dilution method. The antibacterial drug chloramphenicol
with 2-chloroacetonitrile in the presence of K2CO3 in and antifungal drug clotrimazole were used as reference
N,N′-dimethylformamide (DMF) at room temperature to antibiotics. The results are shown in Table 1. Of interest
afford the substituted 2-(2-(4-fluorophenyl)-4-oxo-4H- are high activities of compounds 9a and 9e against A.
chromen-3-yloxy)acetonitriles 6a–f. The reaction of 6a–f niger. Compound 9e is also active against C. albicans. The
with sodium azide and zinc bromide in water at 100°C fur- activities of 8e, 9a and 9b against S. aureus exceed those
nished 3-[(1H-tetrazol-5-yl)methoxy)-2-(4-fluorophenyl]- of the reference drug chloramphenicol.
4H-chromen-4-one derivatives 7a–f. Treatment of 7a–f
with hydrazine hydrate in ethanol under ultrasound irra-
diation yielded the desired pyrazoles 8a–f. In addition,
treatment of compounds 7a–f with thiourea in ethanolic
KOH under ultrasound irradiation furnished the desired
pyrimidines 9a–f. All synthesized compounds were char-
Table 1ꢀAntimicrobial screening results of bioactive compounds 8
and 9 using the micro-broth dilution method.
No.
ꢁ
ꢁ
ꢁ
Minimum inhibitory concentration (μg/mL)
1
acterized by H nuclear magnetic resonance (NMR), 13C
Bacteriaꢁ
Fungi
ꢁ
NMR, mass spectrometry (MS) and elemental analysis.
Saꢁ
Bsꢁ
Ecꢁ
Pa
Caꢁ
An
8e
9a
9b
9e
ꢂ
ꢂ
ꢂ
ꢂ
25ꢂ
25ꢂ
25ꢂ
50ꢂ
50ꢂ
–ꢂ
200ꢂ
200ꢂ
75ꢂ
50ꢂ
25ꢂ
–ꢂ
50ꢂ
175ꢂ
125ꢂ
75ꢂ
200ꢂ
150ꢂ
100ꢂ
75ꢂ
75ꢂ
75ꢂ
100ꢂ
50ꢂ
–ꢂ
50
25
Antimicrobial activity
50
12.5
–
25
All compounds were evaluated for antibacterial activ-
ity against Gram-positive bacteria Staphylococcus aureus
(NCIM 2079) and Bacillus subtilis (NCIM 2920) and Gram-
negative bacteria Escherichia coli (NCIM 2065) and Pseu-
Chloramphenicolꢂ
Clotrimazole
50ꢂ
50ꢂ
ꢂ
–ꢂ
–ꢂ
50ꢂ
Sa, Staphylococcus aureus; Bs, Bacillus subtilis; Ec, Escherichia
coli; Pa, Pseudomonas aeruginosa; Ca, Candida albicans; An,
domonas aeruginosa (NCIM 2200) and for antifungal Aspergillus niger.
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V.S. Dofe et al.: Tetrazole-based pyrazole and pyrimidine derivativesꢃ ꢃ3
7.24–7.29 (m, 3H, ArH), 7.53 (d, 1H, Jꢁ=ꢁ7 Hz, ArH), 7.93 (d, 1H, Jꢁ=ꢁ7.7 Hz,
ArH), 8.26 (m, 2H, ArH), 9.38 (s, 1H, OH); 13C NMR (DMSO-d6): δ 15.3,
115.1, 115.3, 121, 122.3, 123.6, 127.1, 127.9, 129.6, 133.7, 138.7, 143.5, 152.8,
Conclusion
Newly synthesized compounds 8e, 9a, 9b and 9e are
highly potent antimicrobial agents.
+
161.3, 163.7, 173. ESI-MS. Calcd for C16H11FO3 (Mꢁ+ꢁH) : m/z 271.077.
Found: m/z 271.2154.
2-(4-Fluorophenyl)-3-hydroxy-6-methyl-4H-chromen-4-one
(5d)ꢀThis compound was synthesized from (E)-3-(4-fluorophenyl)-
1-(2-hydroxy-5-methylphenyl)prop-2-en-1-one (4d); a yellow solid,
yield 73%; mp 171–173°C; 1H NMR (DMSO-d6): δ 2.46 (s, 3H, CH3), 7.27
(t, 2H, Jꢁ=ꢁ8.6 Hz, ArH), 7.54 (s, 2H, ArH), 7.91 (s, 1H, ArH), 8.27–8.30
(m, 2H, ArH), 9.31 (s, 1H, OH); 13C NMR (DMSO-d6): δ 20.5, 115, 115.2,
117.7, 120.9, 123.8, 127.7, 129.8, 130.6, 134.5, 138.7, 143.9, 152.8, 161.3,
Experimental
The progress of each reaction was monitored by thin-layer chromatog-
raphy (TLC) using Merck silica gel 60 F254 plates and visualized with
ultraviolet (UV) light and iodine. Melting points were determined in
open capillaries and are uncorrected. Infrared spectra were recorded
on a Carry 600 Series Fourier-transform infrared spectroscopy (FT-IR)
spectrophotometer using KBr pellets. 1H NMR (400 MHz) and 13C NMR
(100 MHz) spectra were recorded on a Bruker AVANCE II 400 NMR
spectrometer in CDCl3 or DMSO-d6. Mass spectra were recorded on a
Waters quadrupole time-of-flight (Q-TOF) micro instrument equipped
with an electrospray ionization (ESI) source. Elemental analysis was
performed on a Perkin-Elmer EAL-240 elemental analyzer.
+
163.8, 172.8. ESI-MS. Calcd for C16H11FO3 (Mꢁ+ꢁH) : m/z 271.0770. Found:
m/z 271.0234.
6,8-Dichloro-2-(4-fluorophenyl)-3-hydroxy-4H-chromen-4-one
(5e)ꢀThis compound was synthesized from (E)-1-(3,5-dichloro-
2-hydroxyphenyl)-3-(4-fluorophenyl)prop-2-en-1-one (4e); a yellow
1
solid; yield 75%; mp 203–205°C; H NMR (DMSO-d6): δ 7.25 (t, 2H,
Jꢁ=ꢁ8.8 Hz, ArH), 7.82 (d, 1H, Jꢁ=ꢁ2.6 Hz, ArH), 7.96 (d, 1H, Jꢁ=ꢁ2.2 Hz,
ArH), 8.29 (m, 2H, ArH), 9.81 (s, 1H, OH); 13C NMR (DMSO-d6): δ 115.2,
115.4, 122.8, 123, 123.7, 127.1, 128.8, 129.8, 132.6, 139.2, 144.5, 148.4,
+
161.5, 164, 171.3. ESI-MS. Calcd for C15H7Cl2FO3 (Mꢁ+ꢁH) : m/z 324.9835.
General procedure for synthesis of compounds 5a–f
Found: m/z 325.0267.
6-Chloro-2-(4-fluorophenyl)-3-hydroxy-7-methyl-4H-chromen-
4-one (5f)ꢀThis compound was synthesized from (E)-1-(5-chloro-
2-hydroxy-4-methylphenyl)-3-(4-fluorophenyl)prop-2-en-1-one (4f); a
A mixture of (E)-3-(4-fluorophenyl)-1-(2-hydroxyphenyl)prop-2-en-1-
one (4a–f, 1 mmol), ethanol (15 mL), NaOH (10%, 5 mL) and hydrogen
peroxide (30%, 1.5 mL) was stirred vigorously for 30 min and then
kept for 2–3 h in ice. The progress of the reaction was monitored by
TLC using ethyl acetate/hexane as an eluent. After completion of the
reaction, the mixture was poured into ice water and acidified with 1
m hydrochloric acid (HCl). The precipitate was collected by filtration,
washed with water and crystalized from chloroform/ethanol to afford
a pure product.
1
yellow solid, yield 79%; mp 222–224°C; H NMR (DMSO-d6): δ 2.5 (s,
3H, CH3), 7.28 (m, 2H, ArH), 7.64 (br s, 1H, ArH), 8.03 (s, 1H, ArH),
8.27 (br s, 2H, ArH), 9.54 (s, 1H, OH); 13C NMR (DMSO-d6): δ 20.3,
115.1, 115.3, 120.1, 120.5, 124, 127.5, 129.9, 130.1, 138.8, 141.8, 144.3,
+
152.8, 161.4, 163.9, 171.8. ESI-MS. Calcd for C16H10ClFO3 (Mꢁ+ꢁH) : m/z
305.0381. Found: m/z 305.0251.
2-(4-Fluorophenyl)-3-hydroxy-4H-chromen-4-one (5a)ꢀThis com-
pound was synthesized from (E)-3-(4-fluorophenyl)-1-(2-hydroxyphe-
General procedure for synthesis of compounds 6a–f
nyl)prop-2-en-1-one (4a); a yellow solid; yield 74%; mp 152–154°C; IR:
1
3297 (OH), 2925 (ArH), 1618 (C=O, pyrone), 1572 cm−1 (C=C); H NMR To a stirred solution of 5a–f (1 mmol) in DMF was added potassium
(CDCl3: δ 7.11 (br s, 1H, ArH), 7.22 (t, 2H, Jꢁ=ꢁ8.5 Hz, ArH), 7.42 (m 1H, ArH), carbonate (2 mmol) and portion-wise 2-chloroacetonitrile (1 mmol) at
7.58 (d, 1H, Jꢁ=ꢁ8.5 Hz, ArH), 7.71 (m, 1H, ArH), 8.24 (d, 1H, Jꢁ=ꢁ1.8 Hz, room temperature for about 3–4 h. The mixture was quenched with
ArH), 8.26 (s, 1H, OH), 8.27–8.30 (m, 1H, ArH); 13C NMR (CDCl3): δ 115.7, crushed ice and the resultant precipitate was filtered and crystallized
115.9, 118.2, 120.7, 124.6, 125.5, 127.3, 129.9, 133.7, 138.2, 144.1, 155.3, 162.3, from ethanol.
+
164.8, 173.4. ESI-MS. Calcd for C15H9FO3 (Mꢁ+ꢁH) : m/z 257.0. Found:
m/z 257.0.
2-(2-(4-Fluorophenyl)-4-oxo-4H-chromen-3-yloxy)acetonitrile
(6a)ꢀThis compound was prepared from 5a; a white solid; yield
6-Chloro-2-(4-fluorophenyl)-3-hydroxy-4H-chromen-4-one 78%; mp 140–142°C; IR: υ 3012 (Ar-H), 2965 (C-H), 2346 (C≡N), 1634
(5b)ꢀThis compound was synthesized from (E)-1-(5-chloro- (C=O), 1604 (C=C), 1238 (C-F) cm−1; H NMR (CDCl3): δ 5.11 (s, 2H,
1
2-hydroxyphenyl)-3-(4-fluorophenyl)prop-2-en-1-one (4b);
a yellow OCH2), 7.20–2.27 (m, 2H,ArH), 7.45 (m, 1H, ArH), 7.57 (dd, 1H, Jꢁ=ꢁ1.1,
solid; yield 77%; mp 213–215°C; 1H NMR (DMSO-d6): δ 7.08–7.25 (m, 2H, 8.6 Hz, ArH), 7.74 (ddt, 1H, Jꢁ=ꢁ1.5, 7.8, 8.0 Hz, ArH), 8.08 (m, 2H, ArH),
ArH), 7.68–7.82 (m, 2H, ArH), 8.12–8.23 (m, 2H, ArH), 8.51 (s, 1H, ArH), 8.25 (dd, 1H, Jꢁ=ꢁ1.5, 7.8 Hz, ArH); 13C NMR (CDCl3): δ 56.1, 115.1, 115.9,
9.08 (br s, 1H, OH); 13C NMR (DMSO-d6): δ 114.1, 117.5, 120.6, 125.4, 127.4, 116.1, 118.1, 123.8, 125.4, 125.8, 126.1, 131.3, 134.2, 137.5, 155.3, 156.4,
128.4, 129.7, 130.2, 133.6, 148.5, 155.4, 157.6, 160.8, 162.5, 172.9. ESI-MS. 163.1, 165.6, 174.1. Anal. Calcd for C17H10FNO3: C, 69.15; H, 3.41; N, 4.74.
+
Calcd for C15H8ClFO3 (Mꢁ+ꢁH) : m/z 291.0224. Found: m/z 291.2223.
Found: C, 69.07; H, 3.35; N, 4.68.
2-(4-Fluorophenyl)-3-hydroxy-8-methyl-4H-chromen-4-one 2-(6-Chloro-2-(4-fluorophenyl)-4-oxo-4H-chromen-3-yloxy)ace-
(5c)ꢀThis compound was synthesized from (E)-3-(4-fluorophenyl)- tonitrile (6b)ꢀThis compound was prepared from 5b; a white solid,
1-(2-hydroxy-3-methylphenyl)prop-2-en-1-one (4c); a yellow solid, yield 86%; mp 168–170°C; IR: υ 3069 (Ar-H), 2952 (C-H), 2360 (C≡N),
1
yield 69%; mp 160–162°C; H NMR (DMSO-d6): δ 2.54 (s, 3H, CH3), 1628 (C=O), 1600 (C=C), 1144 (C-F) 755 (C-Cl) cm−1; 1H NMR (DMSO-d6):
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δ 5.14 (s, 2H, OCH2), 7.34 (t, 2H, Jꢁ=ꢁ8.0 Hz, ArH), 7.73 (d, 1H, Jꢁ=ꢁ8.0 Hz, 1606 (C=O), 1554 (C=C), 1238 (C-F) cm−1; 1H NMR (DMSO-d6): δ 5.47 (s,
ArH), 7.79 (dd, 1H, Jꢁ=ꢁ2.6, 9.2 Hz, ArH), 8.07 (d, 1H, Jꢁ=ꢁ2.6 Hz, ArH), 2H, OCH2), 7.26 (t, 2H, Jꢁ=ꢁ9.0 Hz, ArH), 7.48–7.52 (m, 1H, ArH), 7.70 (d,
8.13 (m, 2H, ArH); 13C NMR (DMSO-d6): δ 56.4, 115.5, 115.7, 120.4, 124, 1H, Jꢁ=ꢁ8.0 Hz, ArH), 7.82 (ddd, 1H, Jꢁ=ꢁ8.5, 7.1, 1.7 Hz, ArH), 8.01–8.05
124.3, 125.7, 130.3, 131.1, 131.2, 134.1, 137.6, 153.1, 155.4, 162.4, 165, 172.1. (m, 2H, ArH), 8.16 (dd, 1H, Jꢁ=ꢁ8.0, 1.7 Hz, ArH); 13C NMR (DMSO-d6):
Anal. Calcd for C17H9ClFNO3: C, 61.93; H, 2.75; N, 4.25. Found: C, 61.98; δ 61.8 (O-CH2), 115.3, 115.6, 118.3, 123.4, 124.9, 125.1, 126.2, 130.9, 131,
H, 2.82; N, 4.33.
134.1, 138.2, 154.7, 154.9, 162 (tetrazole C), 164.5 (C-F), 173.5 (C=O).
Anal. Calcd for C17H11FN4O3: C, 60.36; H, 3.28; N, 16.56. Found: C,
2-(2-(4-Fluorophenyl)-8-methyl-4-oxo-4H-chromen-3-yloxy) 60.29; H, 3.25; N, 16.51.
acetonitrile (6c)ꢀThis compound was prepared from 5c; a white
solid; yield 71%; mp 176–178°C; IR: υ 3032 (Ar-H), 2915 (C-H), 2360
3-[(1H-Tetrazol-5-yl)methoxy]-6-chloro-2-(4-fluorophenyl)-4H-
chromen-4-one (7b)ꢀThis compound was prepared from 6b; a
white solid; yield 85%; mp 203–205°C; IR: υ 3435 (N-H), 3035 (Ar-
1
(C≡N), 1633 (C=O), 1604 (C=C), 1193 (C-F) cm−1; H NMR (CDCl3): δ
2.58 (s, 3H, CH3), 5.12 (s, 2H, OCH2), 7.23–7.27 (m, 2H, ArH), 7.34 (t, 1H,
Jꢁ=ꢁ7.0 Hz, ArH), 7.57 (d, 1H, Jꢁ=ꢁ7.0 Hz, ArH), 8.07–8.13 (m, 3H, ArH);
13C NMR (CDCl3): δ 15.8, 56, 115.1, 115.9, 116.2, 123.4, 123.8, 125.1, 126.5,
127.6, 131.3, 135, 137.4, 153.8, 155.8, 163.1, 165.6, 174.4. Anal. Calcd for
C18H12FNO3: C, 69.90; H, 3.91; N, 4.53. Found: C, 69.96; H, 3.94; N, 4.56.
1
H), 2992 (C-H), 1622 (C=O), 1605 (C=C), 1197 (C-F), 718 (C-Cl) cm−1; H
NMR (DMSO-d6): δ 5.42 (s, 2H, OCH2), 7.17 (t, 2H, Jꢁ=ꢁ9.0 Hz, ArH), 7.64
(d, 1H, Jꢁ=ꢁ9.0 Hz, ArH), 7.72 (dd, 1H, Jꢁ=ꢁ9.0, 2.6 Hz, ArH), 7.98 (m, 2H,
ArH), 8.04 (d, 1H, Jꢁ=ꢁ2.6 Hz, ArH); 13C NMR (DMSO-d6): δ 61.7 (O-CH2),
115.4, 115.6, 120.7, 123.8, 124.5, 125.9, 125.9, 129.9, 131, 134, 138.2, 153.2,
155.2, 162.1 (tetrazole C), 164.6 (C-F), 172.5 (C=O). Anal. Calcd for
C17H10ClFN4O3: C, 54.78; H, 2.70; N, 15.03. Found: C, 54.84; H, 2.72; N,
15.23.
2-(2-(4-Fluorophenyl)-6-methyl-4-oxo-4H-chromen-3-yloxy)
acetonitrile (6d)ꢀThis compound was prepared from 5d; a white
solid; yield 74%; mp 162–164°C; IR: υ 3087 (Ar-H), 2974 (C-H), 2369
1
(C≡N), 1632 (C=O), 1603 (C=C), 1187 (C-F) cm−1; H NMR (DMSO-d6): δ
2.53 (s, 3H, CH3), 5.15 (s, 2H, OCH2), 7.36 (s, 2H, ArH), 7.61 (s, 2H, ArH),
7.90 (s, 1H, ArH), 8.12 (s, 2H, ArH); 13C NMR (DMSO-d6); δ 20.5, 56.4,
115.5, 115.7, 118, 122.9, 124.1, 126.2, 131.1, 131.1, 134.8, 135.4, 136.3, 137.5,
153, 154.9, 162.3, 173.1. Anal. Calcd for C18H12FNO3: C, 69.90; H, 3.91; N,
4.53. Found: C, 69.82; H, 3.95; N, 4.66.
3-[(1H-Tetrazol-5-yl)methoxy]-2-(4-fluorophenyl)-8-methyl-4H-
chromen-4-one (7c)ꢀThis compound was prepared from 6c; a
white solid; yield 73%; mp 198–200°C; IR: υ 3435 (N-H), 3035 (Ar-H),
1
2992 (C-H), 1622 (C=O), 1605 (C=C), 1197 cm−1 (C-F); H NMR (DMSO-
d6): δ 2.33 (s, 3H, CH3), 5.61 (s, 2H, OCH2), 6.97 (s, 1H, ArH), 7.10–7.22
(m, 2H, ArH), 7.53 (s, 1H, ArH), 7.69–7.80 (m, 3H, ArH), 8.41 (s, 1H, NH);
13C NMR (DMSO-d6): δ 15.1 (CH3), 63.5 (O-CH2), 114.9, 115.2, 122.3, 123,
124.3, 126.6, 127.1, 128.2, 130.4, 134.2, 139, 149.5, 152.6, 161.5 (tetrazole
C), 164 (C-F), 173.8 (C=O). Anal. Calcd for C18H13FN4O3: C, 61.36; H, 3.72;
N, 15.90. Found: C, 61.45; H, 3.69; N, 15.98.
2-(6,8-Dichloro-2-(4-fluorophenyl)-4-oxo-4H-chromen-3-yloxy)
acetonitrile (6e)ꢀThis compound was prepared from 5e; a white
solid; yield 77%; mp 177–179°C; IR: υ 3064 (Ar-H), 2916 (C-H), 2361
1
(C≡N), 1625 (C=O), 1601 (C=C), 1180 (C-F) 717 (C-Cl) cm−1; H NMR
(CDCl3): δ 5.12 (s, 2H, OCH2), 7.26 (t, 2H, Jꢁ=ꢁ8.6 Hz, ArH), 7.77 (d,
1H, Jꢁ=ꢁ2.2 Hz, ArH), 8.10 (d, 1H, Jꢁ=ꢁ2.2 Hz, ArH), 8.18 (m, 2H, ArH);
13C NMR (CDCl3): δ 56.1, 114.8, 116.2, 116.4, 123.8, 124.6, 125.5, 131.2,
131.5, 131.6, 134.2, 137.6, 149.4, 156.3, 163.5, 166, 172.5. Anal. Calcd for
C17H8Cl2FNO3: C, 56.07; H, 2.21; N, 3.85. Found: C, 56.18; H, 2.24; N, 3.79.
3-[(1H-Tetrazol-5-yl)methoxy]-2-(4-fluorophenyl)-6-methyl-4H-
chromen-4-one (7d)ꢀThis compound was prepared from 6d; a
white solid; yield 75%; mp 202–204°C; IR: υ 3423 (N-H), 3021 (Ar-H),
1
2918 (C-H), 1602 (C=O), 1554 (C=C), 1174 cm−1 (C-F); H NMR (DMSO-
d6): δ 2.46 (s, 3H, CH3), 5.47 (s, 2H, OCH2), 7.27 (t, 2H, Jꢁ=ꢁ9.0 Hz, ArH),
7.57–7.63 (m, 2H, ArH), 7.90 (s, 1H, ArH), 8.00 (dd, 2H, Jꢁ=ꢁ9.0, 5.3 Hz,
ArH); 13C NMR (DMSO-d6): δ 20.4 (CH3), 61.8 (O-CH2), 115.3, 115.5, 118,
123.1, 124.1, 126.3, 126.3, 130.9, 134.7, 135.2, 138.2, 153, 154.7, 162 (tetra-
zole C), 164.5 (C-F), 173.4 (C=O). Anal. Calcd for C18H13FN4O3: C, 61.36;
H, 3.72; N, 15.90. Found: C, 61.34; H, 3.65; N, 15.81.
2-(6-Chloro-2-(4-fluorophenyl)-7-methyl-4-oxo-4H-chromen-3-
yloxy)acetonitrile (6f)ꢀThis compound was prepared from 5f; a
white solid, yield 82%; mp 170–172°C; IR: υ 3013 (Ar-H), 2915 (C-H),
2360 (C≡N), 1599 (C=O), 1552 (C=C), 1203 (C-F) 750 (C-Cl) cm−1; 1H NMR
(DMSO-d6): 2.54 (s, 3H, CH3), 5.14 (s, 2H, OCH2), 7.35 (s, 2H, ArH), 7.70
(s, 1H, ArH), 8.04 (s, 1H, ArH), 8.12 (s, 2H, ArH); 13C NMR (DMSO-d6): δ
20.3, 56.4, 115.5, 115.6, 115.7, 120.3, 122.4, 124.2, 125.9, 125.9, 131.1, 131.1,
137.5, 142.9, 153.1, 155.1, 167.4, 172.1. Anal. Calcd for C18H11ClFNO3: C,
62.89; H, 3.23; N, 4.07. Found: C, 62.93; H, 3.28; N, 4.11.
3-[(1H-Tetrazol-5-yl)methoxy]-6,8-dichloro-2-(4-fluorophenyl)-
4H-chromen-4-one (7e)ꢀThis compound was prepared from (6e); a
white solid; yield 80%; mp 194–196°C; IR: υ 3423 (N-H), 3040 (Ar-H),
2917 (C-H), 1660 (C=O), 1603 (C=C), 1158 (C-F), 760 cm−1 (C-Cl); 1H NMR
(DMSO-d6): δ 5.50 (s, 2H, OCH2), 7.24 (t, 2H, Jꢁ=ꢁ8.4 Hz, ArH), 7.33–7.37
(m, 1H, ArH), 8.00 (d, 2H, Jꢁ=ꢁ5.5 Hz, ArH), 8.08 (dd, 1H, Jꢁ=ꢁ8.4, 5.5 Hz,
ArH); 13C NMR (DMSO-d6): δ 62 (O-CH2), 115.6, 115.8, 123, 123.8, 125.2,
129.6, 131, 133.5, 138.6, 139.4, 148.9, 154.6, 162.2 (tetrazole C), 164.7
(C-F), 172 (C=O). Anal. Calcd for C17H9Cl2FN4O3: C, 50.15; H, 2.23; N,
13.76. Found: C, 50.33; H, 2.32; N, 13.87.
General procedure for synthesis of compounds 7a–f
To a mixture of sodium azide (1.5 mmol) and zinc bromide (1.5 mmol)
in water (20 mL) was added compound 6a–f (1 mmol). The mixture
was then heated at reflux for 4–5 h with vigorous stirring. After com-
pletion of the reaction, as monitored by TLC using chloroform/ meth-
anol as an eluent, the mixture was quenched with crushed ice, and 3-[(1H-Tetrazol-5-yl)methoxy]-6-chloro-2-(4-fluorophenyl)-7-
the resultant solid was filtered and crystallized from ethanol.
methyl-4H-chromen-4-one (7f)ꢀThis compound was prepared
from 6f; a white solid; yield 78%; mp 178–180°C; IR: υ 3495 (N-H),
3-[(1H-Tetrazol-5-yl)methoxy]-2-(4-fluorophenyl)-4H-chromen- 3077 (Ar-H), 2924 (C-H), 1638 (C=O), 1618 (C=C), 1166 (C-F) 771 cm−1
4-one (7a)ꢀThis compound was prepared from 6a; a white solid, (C-Cl); 1H NMR (DMSO-d6): δ 2.44 (s, 3H, CH3), 5.45 (s, 2H, OCH2), 7.30
yield: 81%; mp 200–202°C; IR: υ 3444 (N-H), 3030 (Ar-H), 2917 (C-H), (t, 2H, Jꢁ=ꢁ9.0 Hz, ArH), 7.73–7.76 (m, 1H, ArH), 7.92–7.96 (m, 3H, ArH);
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V.S. Dofe et al.: Tetrazole-based pyrazole and pyrimidine derivativesꢃ ꢃ5
13C NMR (DMSO-d6): δ 20.1 (CH3), 61.8 (O-CH2), 115.4, 115.7, 120.6, 122.5, 3955 (OH), 3346 (NH), 1865 (C=N), 1258 (C-F) cm−1; 1H NMR (DMSO-d6):
123.9, 126.1, 130.6, 130.9, 131, 138.1, 142.7, 153, 154.9, 162 (tetrazole C), δ 2.52 (s, 3H, CH3), 5.19 (s, 2H, OCH2), 6.35–6.42 (m, 2H, ArH), 6.92–
164.5 (C-F), 172.4 (C=O). Anal. Calcd for C18H12ClFN4O3: C, 55.90; H, 6.94 (m, 2H, ArH), 7.64–7.89 (m, 3H, ArH), 10.84 (br s, 1H, OH), 12.78
3.13; N, 14.49. Found: C, 55.97; H, 3.21; N, 14.58.
(br s, 1H, NH), 13.73 (br s, 1H, NH); 13C NMR (DMSO-d): δ 16.0, 64.2,
99.6, 115.5, 115.7, 116.5, 119.8, 119.9, 127.6, 127.7, 129.7, 129.8, 136.6, 154.2,
154.9, 155.8, 161.1, 163.6. Anal. Calcd for C18H15FN6O2: C, 59.01; H, 4.13;
N, 22.94. Found: C, 58.96; H, 4.27; N, 22.98.
General procedure for synthesis of compounds 8a–f
2-[4-((1H-Tetrazol-5-yl)methoxy]-5-(4-fluorophenyl)-1H-pyrazol-
3-yl]-4,6-dichlorophenol (8e)ꢀThis compound was prepared from
7e; a yellow solid; conventional method time 330 min, yield 71%;
ultrasound-assisted method time 45 min, yield 95%; mp 225–227°C;
Conventional methodꢀHydrazine hydrate (1 mmol) was added to
a solution of 7a–f (1 mmol) in ethanol (10 mL) and the mixture was
heated for 5–6 h. After completion of the reaction, as monitored by
TLC, 10 mL of water was added, and the resultant precipitate was
filtered, dried under reduced pressure and crystallized from ethanol.
1
IR: υ 3936 (OH), 3386 (NH), 1855 (C=N), 1282 (C-F) cm−1; H NMR
(CDCl3): δ 5.15 (s, 2H, OCH2), 6.42 (t, 2H, Jꢁ=ꢁ8.8 Hz, ArH), 6.91 (d,
1H, Jꢁ=ꢁ2.6 Hz, ArH), 7.69 (d, 1H, Jꢁ=ꢁ2.6 Hz, ArH), 7.90 (dd, 2H, Jꢁ=ꢁ8.8,
5.2 Hz, ArH), 10.81 (br s, 1H, OH), 12.73 (br s, 1H, NH), 13.82 (br s, 1H,
NH); 13C NMR (CDCl3): δ 64.6, 99.9, 115.3, 115.4, 116.8, 120.1, 120.2, 127.9,
128.0, 129.4, 129.6, 137.3, 154.7, 155.0, 156.2, 161.3, 163.8. Anal. Calcd for
C17H11Cl2FN6O2: C, 48.47; H, 2.63; N, 19.95. Found: C, 48.55; H, 2.61; N,
19.98.
Ultrasound-assisted methodꢀHydrazine hydrate (1 mmol) was
added to a solution of 7a–f (1 mmol) in ethanol (10 mL) and the mix-
ture was ultrasonicated for 45–55 min at 65°C. After completion of the
reaction, as monitored by TLC, 10 mL of water was added, and the
resultant precipitate was filtered, dried and crystallized from ethanol.
2-[4-((1H-Tetrazol-5-yl)methoxy)-5-(4-fluorophenyl)-1H-pyrazol-
3-yl]phenol (8a)ꢀThis compound was prepared from 7a; a yellow
solid; conventional method time 340 min, yield 70%; ultrasound-
assisted method time 51 min, yield 88%; mp 269–271°C; IR: υ 3943
2-[4-((1H-Tetrazol-5-yl)methoxy]-5-(4-fluorophenyl)-1H-pyrazol-
3-yl]-4-chloro-5-methylphenol (8f)ꢀThis compound was prepared
from 7f; a yellow solid; conventional method time 330 min, yield 72%;
ultrasound-assisted method time 45 min, yield 92%; mp 278–280°C;
1
(OH), 3352 (NH), 1884 (C=N), 1246 (C-F) cm−1; H NMR (DMSO-d6): δ
1
IR: υ 3945 (OH), 3335 (NH), 1852 (C=N), 1273 (C-F) cm−1; H NMR
5.08 (s, 2H, OCH2), 6.89 (t, 1H, Jꢁ=ꢁ7.3 Hz, ArH), 6.96 (d, 1H, Jꢁ=ꢁ8.1 Hz,
ArH), 7.19–7.23 (m, 3H, ArH), 7.63–7.88 (m, 3H, ArH), 10.80 (br s, 1H,
OH), 12.69 (br s, 1H, NH), 13.54 (br s, 1H, NH); 13C NMR (DMSO-d6): δ
64.0, 99.5, 115.4, 115.6, 116.1, 119.2, 119.3, 127.7, 127.8, 129.0, 129.1, 136.5,
153.0, 153.1, 154.9, 160.5, 162.9. Anal. Calcd for C17H13FN6O2: C, 57.95; H,
3.72; N, 23.85. Found: C, 57.92; H, 3.69; N, 23.76.
(DMSO-d6): δ 2.52 (s, 3H, CH3), 5.19 (s, 2H, OCH2), 6.52 (s, 1H, ArH),
6.89 (s, 2H, ArH), 7.72–7.75 (m, 2H, ArH), 7.93 (s, 1H, ArH), 10.86 (br s,
1H, OH), 12.71 (br s, 1H, NH), 13.88 (br s, 1H, NH); 13C NMR (DMSO-d6):
δ 16.4, 64.8, 99.4, 115.9, 116.0, 116.8, 119.6, 119.7, 127.9, 128.0, 129.5, 129.7,
136.8, 154.4, 155.1, 155.9, 160.8, 163.5. Anal. Calcd for C18H14ClFN6O2: C,
53.94; H, 3.52; N, 20.97. Found: C, 53.96; H, 3.50; N, 21.01.
2-[4-((1H-Tetrazol-5-yl)methoxy)-5-(4-fluorophenyl)-1H-pyrazol-
3-yl]-4-chlorophenol (8b)ꢀThis compound was prepared from 7b;
a yellow solid; conventional method time 315 min, yield 75%; ultra-
sound-assisted method time 45 min, yield 93%; mp 228–230°C; IR: υ
General procedure for synthesis of compounds 9a–f
3905 (OH), 3387 (NH), 1852 (C=N), 1216 (C-F) cm−1; 1H NMR (DMSO-d6): Conventional methodꢀTo a mixture of compound 7a–f (1 mmol)
δ 5.08 (s, 2H, OCH2), 6.97 (d, 1H, Jꢁ=ꢁ8.4 Hz, ArH), 7.24–7.30 (m, 3H, and KOH (1.5 mmol) in ethanol (10 mL), thiourea (1.5 mmol) was
ArH), 7.58–7.89 (m, 3H, ArH), 10.72 (br s, 1H, OH), 12.86 (s, 1H, NH), added and the mixture was heated for 3–4 h. After completion of the
13.68 (s, 1H, NH); 13C NMR (DMSO-d6): δ 64.3, 99.5, 115.7, 117.3, 117.6, reaction, as monitored by TLC, the reaction mass was cooled to room
123.0, 126.5, 126.6, 127.7, 127.8, 128.5, 136.7, 153.4, 153.7, 153.8, 160.6, temperature, poured on crushed ice and acidified with concentrated
163.0. Anal. Calcd for C17H12ClFN6O2: C, 52.79; H, 3.13; N, 21.73. Found: HCl. The resultant solid was filtered and crystallized from ethanol.
C, 52.63; H, 3.10; N, 21.68.
Ultrasound-assisted methodꢀTo a mixture of compound 7a–f
2-[4-((1H-Tetrazol-5-yl)methoxy)-5-(4-fluorophenyl)-1H-pyrazol- (1 mmol) and KOH (1.5 mmol) in ethanol (10 mL), thiourea (1.5 mmol)
3-yl]-6-methylphenol (8c)ꢀThis compound was prepared from 7c; was added and the reaction mass was ultrasonicated for 15–25 min
a yellow solid; conventional method time 350 min, yield 77%; ultra- at 65°C. After completion of the reaction, as monitored by TLC, the
sound-assisted method time 54 min, yield 84%; mp 250–252°C; IR: υ mixture was cooled to room temperature, poured on crushed ice and
1
3918 (OH), 3346 (NH), 1815 (C=N), 1245 (C-F) cm−1; H NMR (CDCl3): δ acidified with concentrated HCl. The resultant precipitate was fil-
2.57 (s, 3H, CH3), 5.14 (s, 2H, OCH2), 6.91–6.98 (m, 2H, ArH), 7.36 (t, 1H, tered and crystallized from ethanol.
Jꢁ=ꢁ7.7 Hz, ArH), 7.59 (d, 1H, Jꢁ=ꢁ7.7 Hz, ArH), 7.65–7.69 (m, 3H, ArH), 10.79
(br s, 1H, OH), 12.80 (s, 1H, NH), 13.71 (s, 1H, NH); 13C NMR (CDCl3): δ 5-[(1H-Tetrazol-5-yl)methoxy]-6-(4-fluorophenyl)-4-(2-hydroxy-
15.8, 63.9, 99.8, 115.1, 115.9, 116.2, 119.4, 119.5, 127.6, 127.7, 129.5, 129.7, phenyl)pyrimidine-2(1H)-thione (9a)ꢀThis compound was pre-
137.0, 153.4, 153.6, 155.3, 160.7, 163.1. Anal. Calcd for C18H15FN6O2: C, pared from 7a; a yellow solid; conventional method time 230 min,
59.01; H, 4.13; N, 22.94. Found: C, 59.13; H, 3.98; N, 22.81.
yield 73%; ultrasound-assisted method time 21 min, yield 87%; mp
163–165°C; IR υ: 3919 (OH), 3423 (NH), 3313 (NH), 3040 (CH) cm−1;
2-[4-((1H-Tetrazol-5-yl)methoxy]-5-(4-fluorophenyl)-1H-pyrazol- 1H NMR (DMSO-d6): δ 4.79 (s, 2H, OCH2), 7.19 (t, 2H, Jꢁ=ꢁ8.8 Hz, ArH),
3-yl]-4-methylphenol (8d)ꢀThis compound was prepared from 7d; 7.26–7.30 (m, 2H, ArH), 7.43–7.46 (m, 1H, ArH), 7.76 (m, 1H, ArH), 7.97
a yellow solid; conventional method time 320 min, yield 79%; ultra- (dd, 2H, Jꢁ=ꢁ5.5, 8.8 Hz, ArH), 10.10 (br s, 1H, OH), 10.81 (br s, 1H, NH),
sound-assisted method time 48 min, yield 91%; mp 240–242°C; IR: υ 11.19 (br s, 1H, NH); 13C NMR (DMSO-d6): δ 74.5, 115.2, 115.4, 116.5, 117.4,
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6ꢀ ꢀV.S. Dofe et al.: Tetrazole-based pyrazole and pyrimidine derivatives
119.1, 120.0, 120.9, 129.5, 130.1, 130.5, 131.7, 135.5, 155.8, 157.9, 159.6, conventional method time 210 min, yield 76%; ultrasound-assisted
161.4, 198.7. Anal. Calcd for C18H13FN6O2S: C, 54.54; H, 3.31; N, 21.20; S, method time 21 min, yield 92%; mp 277–279°C; IR: υ 3954 (OH), 3473
1
8.09. Found: C, 54.47; H, 3.45; N, 21.06; S, 8.22.
(NH), 3323 (NH), 3036 (CH) cm−1; H NMR (DMSO-d6): δ 2.45 (s, 3H,
CH3), 4.86 (s, 2H, OCH2), 6.18 (t, 2H, Jꢁ=ꢁ8.8 Hz, ArH), 7.67–7.70 (m, 2H,
5-[(1H-Tetrazol-5-yl)methoxy]-4-(5-chloro-2-hydroxyphenyl)- ArH), 7.98–8.01 (m, 2H, ArH), 10.15 (br s, 1H, OH), 10.91 (br s, 1H, NH),
6-(4-fluorophenyl)pyrimidine-2(1H)-thione (9b)ꢀThis com- 11.32 (br s, 1H, NH); 13C NMR (DMSO-d6): δ 17.3, 67.5, 115.9, 116.0, 116.9,
pound was prepared from 7b; a yellow solid; conventional method 117.3, 119.6, 120.6, 121.4, 130.3, 130.7, 131.5, 131.9, 137.4, 155.6, 157.2,
time 220 min, yield 80%; ultrasound-assisted method time 15 min, 160.4, 162.6, 194.2. Anal. Calcd for C19H14ClFN6O2S: C, 51.30; H, 3.17; N,
yield 95%; mp 148–150°C; IR: υ 3975 (OH), 3424 (NH), 3383 (NH), 18.89; S, 7.21. Found: C, 51.38; H, 3.22; N, 18.91; S, 7.13.
1
3067 (CH) cm−1; H NMR (DMSO-d6): δ 4.81 (s, 2H, OCH2), 6.90 (d,
1H, Jꢁ=ꢁ8.8 Hz, ArH), 7.19 (t, 2H, Jꢁ=ꢁ8.8 Hz, ArH), 7.25 (dd, 1H, Jꢁ=ꢁ8.8,
2.6 Hz, ArH), 7.32 (d, 1H, Jꢁ=ꢁ2.6 Hz, ArH), 8.00 (m, 2H, ArH), 10.10
Antimicrobial activity
(br s, 1H, OH), 10.81 (br s, 1H, NH), 11.19 (br s, 1H, NH); 13C NMR
(DMSO-d6): δ 63.5, 115.4, 115.6, 117.9, 122.5, 122.8, 129.4, 130.4, 130.9,
Antibacterialactivityofthesynthesizedcompoundswastestedinvitro
131.6, 131.7, 146.4, 157.9, 159.6, 161.7, 162.2, 164.7, 190.6. Anal. Calcd for
against Gram-positive bacteria S. aureus (NCIM 2079) and B. subtilis
C18H12ClFN6O2S: C, 50.18; H, 2.81; N, 19.51; S, 7.44. Found: C, 50.25; H,
(NCIM 2920) and Gram-negative bacteria E. coli (NCIM 2065) and
2.87; N, 19.49; S, 7.48.
P. aeruginosa (NCIM 2200). The compounds were also screened for
antifungal activity against C. albicans (NCIM 3471) and A. niger (NCIM
5-[(1H-Tetrazol-5-yl)methoxy]-6-(4-fluorophenyl)-4-(2-hydroxy-
596). Compounds were diluted in dimethyl sulfoxide (DMSO) with
3-methylphenyl)pyrimidine-2(1H)-thione (9c)ꢀThis compound
1 μg/mL concentrations for bioassay. Micro-broth dilution method
was prepared from 7c; a yellow solid; conventional method time
[28] was used to determine the MICs of compounds in 96-well micro-
220 min, yield 74%; ultrasound-assisted method time 24 min, yield
titer plates. Test compounds were serially diluted in growth media.
82%; mp 215–217°C; IR: υ 3935 (OH), 3475 (NH), 3364 (NH), 3057 (CH)
Plates were incubated at 30°C for fungi and 37°C for bacteria for 24 h.
1
cm−1; H NMR (DMSO-d6): δ 2.49 (s, 3H, CH3), 4.85 (s, 2H, OCH2), 6.95
All experiments were carried out in triplicates.
(s, 1H, ArH), 7.18–7.20 (m, 2H, ArH), 7.69 (s, 1H, ArH), 7.92–7.96 (m,
3H, ArH), 10.16 (br s, 1H, OH), 10.87 (br s, 1H, NH), 11.21 (br s, 1H,
NH); 13C NMR (DMSO-d6): δ 15.8, 68.7, 115.7, 115.8, 118.1, 122.8, 122.9,
Acknowledgments: V.S.D. is grateful to the Council of Sci-
129.0, 130.2, 131.3, 131.8, 132.2, 146.9, 158.2, 159.3, 161.5, 161.9, 165.0,
entific and Industrial Research (CSIR), New Delhi, India,
for providing Senior Research Fellowship and Sophisti-
cated Analytical Instrumentation Facility (SAIF). Panjab
University provided spectral data. We are thankful to the
Head, Department of Chemistry, Dr. Babasaheb Ambedkar
Marathwada University, for providing laboratory facility.
We also thank the Department of Microbiology, Maulana
Azad College of Arts, Science and Commerce, Aurang-
abad, for providing biological assay results.
195.2. Anal. Calcd for C19H15FN6O2S: C, 55.60; H, 3.68; N, 20.48; S, 7.81.
Found: C, 55.57; H, 3.72; N, 20.39; S, 7.76.
5-[(1H-Tetrazol-5-yl)methoxy]-6-(4-fluorophenyl)-4-(2-hydroxy-
5-methylphenyl)pyrimidine-2(1H)-thione (9d)ꢀThis compound
was prepared from 7d; a yellow solid; conventional method time
235 min, yield 75%; ultrasound-assisted method time 24 min, yield
94%; mp 314–316°C; IR: υ 3954 (OH), 3424 (NH), 3364 (NH), 3095 (CH)
1
cm−1; H NMR (DMSO-d6): δ 2.44 (s, 3H, CH3), 4.87 (s, 2H, OCH2), 6.97
(t, 2H, Jꢁ=ꢁ8.8 Hz, ArH), 7.17–7.23 (m, 2H, ArH), 7.74 (s, 1H, ArH), 7.90
(dd, 2H, Jꢁ=ꢁ8.8, 5.5 Hz, ArH), 10.11 (br s, 1H, OH), 10.82 (br s, 1H, NH),
11.19 (br s, 1H, NH); 13C NMR (DMSO-d6): δ 16.3, 68.4, 115.9, 116.0, 118.5,
123.1, 123.4, 128.6, 129.8, 131.2, 131.5, 132.6, 147.7, 158.4, 160.2, 161.6,
161.8, 165.3, 194.9. Anal. Calcd for C19H15FN6O2S: C, 55.60; H, 3.68; N,
20.48; S, 7.81. Found: C, 55.65; H, 3.61; N, 20.55; S, 7.74.
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5-[(1H-Tetrazol-5-yl)methoxy]-4-(3,5-dichloro-2-hydroxyphenyl)-
6-(4-fluorophenyl)pyrimidine-2(1H)-thione (9e)ꢀThis compound
was prepared from 7e; a yellow solid; conventional method time
195 min, yield 78%; ultrasound-assisted method time 18 min, yield
91%; mp 183–185°C; IR: υ 3935 (OH), 3453 (NH), 3390 (NH), 3054 (CH)
1
cm−1; H NMR (DMSO-d6): δ 4.83 (s, 2H, OCH2), 6.24 (t, 2H, Jꢁ=ꢁ8.5 Hz,
ArH), 7.37–7.39 (m, 1H, ArH), 7.78 (d, 2H, Jꢁ=ꢁ5.5 Hz, ArH), 7.92 (dd, 1H,
Jꢁ=ꢁ8.5, 5.5 Hz, ArH), 10.09 (br s, 1H, OH), 10.87 (br s, 1H, NH), 11.24 (br s,
1H, NH); 13C NMR (DMSO-d6): δ 67.1, 115.6, 115.9, 116.8, 117.7, 119.5, 120.2,
121.0, 129.8, 130.2, 130.7, 131.2, 136.1, 156.4, 157.5, 159.9, 162.0, 193.6.
Anal. Calcd for C18H11Cl2FN6O2S: C, 46.46; H, 2.38; N, 18.06; S, 6.89.
Found: C, 46.40; H, 2.48; N, 18.01; S, 6.97.
5-[(1H-Tetrazol-5-yl)methoxy]-4-(5-chloro-2-hydroxy-
4-methylphenyl)-6-(4-fluorophenyl)pyrimidine-2(1H)-thione
(9f)ꢀThis compound was prepared from 7f; a yellow solid;
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