Synthesis and anti-microbial activities of 1,3,5-trisubstituted-pyrazole derivatives containing a pyridyl moiety

Article abstract of DOI:10.4067/S0717-97072015000100018

Claisen condensation of ethyl isonicotinate with different acetophenones gave the corresponding pyridyl-β-diketones, while the treatment with hydrazine hydrate yielded 3,5-disubstituted-1H-pyrazoles, which then converted 1,3,5-trisubstituted-pyrazole deri

Full text of DOI:10.4067/S0717-97072015000100018

J. Chil. Chem. Soc., 60, Nº 1 (2015)
SYNTHESIS AND ANTI-MICROBIAL ACTIVITIES OF 1,3,5-TRISUBSTITUTED-PYRAZOLE
DERIVATIVES CONTAINING A PYRIDYL MOIETY
DUN-JIA WANG*, HUA LIU, YAN-FANG KANG, YAN-JUN HU, XIAN-HONG WEI
Hubei Collaborative Innovation Center for Rare Metal Chemistry, College of Chemistry and Chemical Engineering,
Hubei Normal University, Huangshi 435002, China
ABSTRACT
Claisen condensation of ethyl isonicotinate with different acetophenones gave the corresponding pyridyl-b-diketones, while the treatment with hydrazine
hydrate yielded 3,5-disubstituted-1H-pyrazoles, which then converted 1,3,5-trisubstituted-pyrazole derivatives containing a pyridyl moiety by N-acylation with
acyl chloride. The structures of all newly synthesized compounds are established by FTIR, 1H NMR, mass spectroscopy and elemental analysis, and in the case
of compound 2e, analyzed by single-crystal X-ray diffraction further. The anti-microbial activities of the title compounds have been tested by disc diffusion
method against Escherichia coli, Staphylococcus aureus, Pyricularia oryzae and Rhizoctnia solani. The results showed that compounds 3c and 4c exhibited good
inhibitory activity against all the tested organisms.
Key words: 1,3,5-Trisubstituted-pyrazole, b-Diketone, Synthesis, Anti-microbial activity
____________
phenyl ring and pyrazole ring exhibit some differences in the molecules. The
torsion angles C6-C1-C7-C8, C2-C1-C7-C8, C6-C1-C7-C12, C2-C1-C7-C12,
C11-C10-C15-C13 and C9-C10-C15-C13 are 153.16 (0.19)o, -25.36 (0.29)o,
-26.02 (0.28)o, 155.47 (0.21)o, -27.05 (0.31)o and 150.25 (0.21)o in molecule
(A), respectively, while C21-C26-C27-C28, C25-C26-C27-C28, C21-C26-
C27-C32, C25-C26-C27-C32, C31-C30-C33-C34 and C29-C30-C33-C34 are
147.95 (0.21)o, -31.02 (0.29)o, -31.47 (0.29)o, 149.56 (0.20)o, -20.95 (0.31)o
and 158.28 (0.19)o in molecule (B), respectively. The dihedral angles for the
two benzene rings and the benzene ring with the pyrazole ring are 25.86o and
25.97o in molecule (A), respectively, but in molecule (B), the dihedral angles
are 31.30o and 21.65o, respectively.
1. INTRODUCTION
Pyrazole derivatives are an interesting class of organic compounds, which
are found to be associated with diverse pharmacological properties such as anti-
microbial [1,2], anti-inflammatory [3], antihypertensive [4], antidepressant [5],
antiviral [6] and anticancer [7] activities. The synthesis and applications of
these compounds have received considerable attention in recent years [8-10].
In addition, the pyridyl ring is also a prominent heterocyclic scaffold in lot
of bioactive molecules. Many pyridine-based compounds have been reported
to exhibit versatile bioactivities, such as insecticidal, fungicidal, anticancer
and antibacterial activities [11-13]. Keeping this in view, we choose the
pyridyl ring as one of the aryl substituents about the central pyrazole ring to
synthesize a series of new 1,3,5-trisubstituted-pyrazole derivatives containing
a pyridyl moiety. Herein we synthesized some novel 1-acyl-3-(4-pyridyl)-5-
aryl-pyrazole derivatives and presented the initial results of anti-microbial
activities against Escherichia coli, Staphylococcus aureus, Pyricularia oryzae
and Rhizoctnia solani of the title compounds.
2. RESULTS AND DISCUSSION
2.1 Chemistry
The synthesis of 1,3,5-trisubstituted-pyrazole derivatives is conducted
as outlined in Scheme 1. The pyridyl-b-diketones 1a-e were prepared via
Claisen condensation of the required methyl ketones with ethyl isonicotinate in
benzene using sodium amide as the condensing agent. The structures of 1a-e
were established under the basis of their elemental analysis and spectral data.
Their 1H NMR spectra exhibited the single peaks at d = 4.60-4.68 attributed to
the keto-CH2 protons, the single peaks at d = 6.83-6.93 assigned to the vinylic
protons in enol and the single peaks at d= 16.52-16.68 due to the enolic OH
protons. The IR spectra data also demonstrated the presence of the C=O and
enolic C=C stretching vibrations at 1600-1591 cm-1 and 1545-1511 cm-1 in the
pyridyl-b-diketones, respectively.
Scheme 1. The synthetic routes for compounds 3a-e and 4a-e.
The title compounds 3a-e and 4a-e were obtained by N-acylation of the
1H-pyrazoles 2a-e with acyl chloride in the presence of triethylamine. Their
1
structures were confirmed by elemental analysis, FTIR, H NMR and mass
Treatment of the pyridyl-b-diketones 1a-e with hydrazine monohydrate
in refluxing ethanol for 3h gave the 1H-pyrazoles 2a-e. The IR spectra for
compounds 2a-e displayed the typical bands of the N-H stretching vibrations
at 3135-3115 cm-1 and their 1H NMR spectra exhibited the single peaks at d =
6.85-7.00 due to the 4-position protons of 1H-pyrazoles, but the N-H resonance
of the pyrazole ring were not observed in CDCl . This is in agreement with the
result in the literature [14]. In the case of 2e, 3the structure was additionally
solved by single-crystal X-ray diffraction. There are two molecules (A and B) in
the asymmetric unit in the crystal structure. The labeled displacement ellipsoid
plots of these two molecules are shown in Fig. 1. The comparison between
molecule (A) and molecule (B) shows no significant differences in bond lengths
and bond angles. However, their torsion angles and dihedral angles between the
spectroscopy. Their IR spectra showed the absorption bands at 1740-1710 cm-1
attributed to the C=O stretching vibration of the N-acylation products. Their
1H NMR spectra revealed the single peaks at d = 6.73-7.19 corresponding to
the vinylic protons of the pyrazole ring. The molecular ion peaks (M+) for
these compounds were observed in accordance with the Nitrogen Rule. The
mass spectra of the title compounds were compared to confirm elemental
compositions.
2.2 Anti-microbial activity
The screening results of in vitro anti-microbial activities of compounds
3a-e and 4a-e are summarized in Table 1. All test data were the average values
from triplicate runs. It is obvious from the data that these compounds possess
e-mail: dunjiawang@163.com
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J. Chil. Chem. Soc., 60, Nº 1 (2015)
inhibitory activities to a certain degree against the tested microorganisms. It was
observed that compounds 3c and 4c exhibited much higher activities against
Escherichia coli, Staphylococcus aureus, Pyricularia oryzae and R. solani
among all synthesized compounds, but compounds 3d and 4d revealed much
lower activities. By the preliminary structure-activity relationship analysis,
it was concluded that compounds 3a-e had slightly better anti-microbial
activities than compounds 4a-e attributed to the strong electron-withdrawing
property of the N1 acetyl group in the pyrazole nucleus [15]. Especially, the
pyrazole derivatives with 4-fluorophenyl moiety at 5-position of the pyrazole
ring showed potent anti-microbial activities against the tested microorganisms,
being significantly higher than the rest (R = phenyl, 4-methylphenyl,
4-methoxyphenyl and 4-phenylphenyl). As a result, it indicated that the
electronic nature of the substituent groups at para positions in the phenyl ring
played a significant role in anti-microbial activities.
activity as the same could lead to the discovery of some potential agents.
4. EXPERIMENTAL
Melting points were determined using X-4 digital melting point apparatus
and are uncorrected. Infrared spectra were recorded on a Nicolet FTIR 5700
spectrophotometer with KBr pellets. The 1H NMR spectra were measured on an
advance IIITM 300 MHz NB Digital NMR spectrometer in CDCl3 solution with
TMS as internal standard. Electrospray ionization mass spectra (ESI–MS) were
performed with a Finnigan LCQ Advantage Max spectrometer. The elemental
analysis (C, H, N) was carried out on a Perkin-Elmer 2400 elemental analyzer.
Reagents were of analytical grade and were used without further purification.
4.1 Typical procedure for the synthesis of the pyridyl-b-diketones
To a suspension of sodium amide (1.4 g, 36 mmol) and ethyl isonicotinate
(6.65 g, 44 mmol) in benzene (50 mL), A solution of the aryl methyl ketones
(22 mmol) in benzene was added dropwise under stirring at 50 °C. The reaction
mixture was refluxed for about 7 h until the dark yellow product precipitated.
The precipitate was filtered off and washed with 5 % acetic acid until pH = 6.
The crude products were recrystallized from ethanol (95 %) to give the pyridyl-
b-diketones (1a-e).
4.1.1 1-Phenyl-3-(4-pyridyl)-1,3-propandione (1a)
Colorless needles, yield 70.5 %, mp 81-82 oC; 1H NMR (CDCl3, 300 MHz)
d: 4.65 (s, 0.08H, keto CH2), 6.89 (s, 1H, enol CH), 7.50-7.63 (m, Ar-H, 3H),
7.79 (d, 2H, Py-H, J = 5.7 Hz), 8.01 (d, 2H, Ar-H, J = 7.8 Hz), 8.80 (d, 2H
Py-H, J = 5.7 Hz), 16.55 (br s, 1H, enol OH) ppm; IR (KBr) n: 3419 (w), 3089
(m), 3040 (m), 2920 (m), 1591 (s), 1542 (s), 1480 (m), 1401 (m), 1290 (m),
1228 (m), 1064 (m), 764 (s), 692 (s) cm-1; ESI-MS m/z: 226.13 [M+1]+. Anal.
calcd. for C14H NO2: C 74.65, H 4.92, N 6.22; found C 74.89, H 4.88, N 6.25.
4.1.2 1-(4-1M1 ethylphenyl)-3-(4-pyridyl)-1,3-propandione (1b)
o
1
Yellow crystals, yield 68.2 %, mp 102-103 C; H NMR (CDCl3, 300
MHz) d: 2.44 (s, 3H, CH ), 4.62 (s, 0.02H keto CH ), 6.86 (s, 1H, enol CH),
7.31 (d, 2H, Ar-H, J = 8.31 Hz), 7.78 (d, 2H, Py-H, 2J = 5.7 Hz), 7.91 (d, 2H,
Ar-H, J = 8.1 Hz), 8.79 (d, 2H, Py-H, J = 5.7 Hz), 16.61 (br s, 1H, enol OH)
ppm; IR (KBr) n: 3434 (w), 3108 (m), 3029 (m), 2919 (m), 1599 (s), 1534 (s),
1486 (s), 1296 (m), 1231 (m), 1056 (m), 982 (m), 839 (m), 792 (s) cm-1; ESI-
MS m/z: 240.05 [M+1]+. Anal. calcd. for C15H13NO2: C 75.30, H 5.48, N 5.85;
found C 75.66, H 5.43, N 5.90.
Fig. 1 View of compound 2e with the atom-labeling scheme and 50%
probability displacement ellipsoids.
Table 1 Anti-microbial data of 1,3,5-trisubstituted-pyrazole derivatives.
Antibacterial activity
Antifungal activity Zone
Zone of Inhibition in
of Inhibition in mm
4.1.3 1-(4-Fluorophenyl)-3-(4-pyridyl)-1,3-propandione (1c)
o
1
Yellow powder, yield 72.6 %, mp 113-114 C; H NMR (CDCl , 300
MHz) d: 4.62 (s, 0.03H keto CH2), 6.84 (s, 1H, enol CH), 7.20 (t, 2H, Ar-3H, J =
8.4 Hz), 7.78 (d, 2H, Py-H, J = 5.7 Hz), 8.01-8.06 (m, 2H, Ar-H), 8.80 (d, 2H,
Py-H, J =6.0 Hz), 16.52 (br s, 1H, enol OH) ppm; IR (KBr) n: 3438 (w), 3075
(m), 3021 (m), 1600 (s), 1545 (m), 1507 (m), 1299 (m), 1227 (s), 1161 (m), 844
(m), 787 (s) cm-1; ESI-MS m/z: 244.07 [M+1]+. Anal. calcd. for C14H10FNO2: C
69.13, H 4.14, N 5.76; found C 69.27, H 4.11, N 5.79.
Compound
mm
S. aureus
E. coli
14
11
22
9
P. oryzae
16
R. solani
13
3a
15
12
21
10
16
15
9
3b
12
10
3c
23
22
4.1.4 1-(4-Methoxyphenyl)-3-(4-pyridyl)-1,3-propandione (1d)
o
1
Bright yellow powder, yield 68.4 %, mp 121-122 C; H NMR (CDCl3,
300 MHz) d: 3.90 (s, 3H, OCH3), 4.60 (s, 0.03H keto CH2), 6.83 (s, 1H, enol
CH), 7.00 (d, 2H, Ar-H, J = 8.7 Hz), 7.78 (d, 2H, Py-H, J = 6.0 Hz), 8.00 (d,
2H, Ar-H, J = 9.0 Hz), 8.79 (d, 2H, Py-H, J = 6.0 Hz), 16.68 (br s, 1H, enol OH)
ppm; IR (KBr) n: 3443 (w), 3031 (m), 2960 (m), 2900 (m), 2840 (w), 1598 (s),
1511 (m), 1311 (m), 1260 (s), 1177 (s), 1018 (m), 843 (w), 786 (s) cm-1; ESI-
MS m/z: 256.21 [M+1]+. Anal. calcd. for C15H13NO3: C 70.58, H 5.13, N 5.49;
found C 70.81, H 5.09, N 5.56.
3d
12
11
3e
16
13
11
20
10
17
31
-
15
16
4a
14
12
4b
10
12
4c
4d
21
9
22
20
4.1.5 1-(4-Phenylphenyl)-3-(4-pyridyl)-1,3-propandione (1e)
10
8
o
1
Yellow powder, yield 70.1 %, mp 134-135 C; H NMR (CDCl3, 300
MHz) d: 4.68 (s, 0.03H keto CH ), 6.93 (s, 1H, enol CH), 7.40-7.52 (m, 3H,
Ar-H), 7.66 (d, 2H, Ar-H, J = 7.82Hz), 7.74 (d, 2H, Ar-H, J = 8.1 Hz), 7.82 (d,
2H, Py-H, J = 5.1 Hz), 8.09 (d, 2H, Ar-H, J = 8.4 Hz), 8.81 (d, 2H, Py-H, J =
5.4 Hz), 16.61 (br s, 1H, enol OH) ppm; IR (KBr) n: 3445 (w), 3041 (m), 1592
(s), 1517 (s), 1485 (s), 1409 (m), 1303 (s), 1217 (s), 1058 (m), 993 (m), 847
(s), 768 (s) cm-1; ESI-MS m/z: 302.28 [M+1]+. Anal. calcd. for C20H15NO2: C
79.72, H 5.02, N 4.65; found C 79.94, H 4.98, N 4.68.
4e
15
30
-
16
15
Norfloxacin
Triadimefon
-
-
28
30
3. CONCLUSIONS
4.2 Typical procedure for the synthesis of the 1H-pyrazoles
In conclusion, a series of new 1,3,5-trisubstituted-pyrazole derivatives
containing a pyridyl moiety were synthesized by Claisen condensation,
cyclization and N-acylation and their structures were characterized by FTIR, 1H
NMR, MS spectroscopy and elemental analysis. The anti-microbial activities
of these compounds were evaluated against Escherichia coli, Staphylococcus
aureus, Pyricularia oryzae and Rhizoctnia solani. The results showed that these
compounds showed certain degree of anti-bacterial and anti-fungal activities
and compounds 3c and 4c were much higher active against the organisms
employed among all synthesized compounds. Thus, this study provides a lead
for synthesis and evaluation of more pyrazole derivatives for anti-microbial
Hydrazine hydrate (6.0 mmol) was added dropwise to a solution of the
required pyridyl-b-diketone (5.0 mmol) in 30 mL absolute ethanol under
stirring and the mixture was refluxed at 78 oC for 3h. Then the mixture was
cooled to room temperature and the solvent was removed by evaporation under
reduced pressure to form a precipitate. The precipitate was recrystallized from
ethanol (95 %) to obtain the 1H-pyrazoles (2a-e).
4.2.1 3-(4-Pyridyl)-5-phenyl-1H-pyrazole (2a)
Colorless powder, yield 88.9 %, mp 202-204 oC; IR (KBr): n 3115 (b, s),
3010 (m), 1602 (s), 1487 (m), 1467 (m), 1427 (m), 1391 (m), 1183 (m), 1057
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J. Chil. Chem. Soc., 60, Nº 1 (2015)
1
(m), 1000 (m), 957 (m), 826 (m), 759 (s), 708 (s) cm-1; H NMR (300 MHz,
(w), 2985 (w), 2840 (w), 1735 (s), 1670 (m), 1610 (m), 1505 (m), 1427 (m),
1367 (m), 1300 (s), 1250 (s), 1180 (m), 1109 (m), 1029 (s), 945 (s), 810 (s)
CDCl3): d 6.96 (s, 1H, C=CH), 7.39-7.50 (m, 3H, Ar-H), 7.67 (d, 2H, Ar-H, J
= 7.5 Hz), 7.72 (d, 2H, Py-H, J = 4.8 Hz), 8.68 (d, 2H, Py-H, J = 4.5 Hz) ppm;
ESI-MS: m/z 221.16 M+; Anal. calcd. for C14H11N3: C 76.00; H 5.01; N 18.99;
found C 76.24; H 4.97; N 19.03.
1
cm-1; H NMR (300 MHz, CDCl ): d 2.81 (s, 3H, CH3), 3.86 (s, 3H, CH3),
6.73 (s, 1H, C=CH), 6.94-7.01 (m3, 2H, Ar-H), 7.39 (d, 2H, Ar-H, J = 7.8 Hz),
7.76-7.84 (m, 2H, Py-H), 8.68-8.71 (m, 2H, Py-H) ppm; ESI-MS: m/z 293.85
[M+1]+; Anal. calcd. for C17H15N3O2: C 69.61; H 5.15; N 14.33; found C 69.89;
H 5.11; N 14.37.
4.2.2 3-(4-Pyridyl)-5-(4-methylphenyl)-1H-pyrazole (2b)
Colorless powder, yield 91.3 %, mp 210-211 oC; IR (KBr): n 3116 (m),
3071 (m), 3006 (m), 2920 (w), 2855 (w), 1604 (s), 1510 (m), 1461 (m), 1185
(m), 1063 (m), 965 (m), 865 (w), 822 (s) cm-1; 1H NMR (300 MHz, CDCl3): d
2.38 (s, 3H, CH3), 6.89 (s, 1H, C=CH), 7.21 (d, 2H, Ar-H, J = 7.8 Hz), 7.53 (d,
2H, Ar-H, J = 7.8 Hz), 7.66 (d, 2H, Py-H, J = 4.8 Hz), 8.63 (d, 2H, Py-H, J =
5.1 Hz) ppm; ESI-MS: m/z 235.07 M+; Anal. calcd. for C15H13N3: C 76.57; H
5.57; N 17.86; found C 76.80; H 5.52; N 17.89.
4.3.5 1-Acetyl-3-(4-pyridyl)-5-(4-phenylphenyl) pyrazole (3e)
Yellow crystals, yield 85.9 %, mp 166-168oC; IR (KBr): n 3090 (w), 3035
(w), 2920 (w), 2860 (w), 1740 (s), 1609 (m), 1559 (m), 1485 (m), 1421 (m),
1
1368 (m), 1295 (s), 1216 (m), 1108 (m), 1017 (m), 946 (m), 832 (s) cm-1; H
NMR (300 MHz, CDCl3): d 2.84 (s, 3H, CH3), 6.83 (s, 1H, C=CH), 7.38-7.56
(m, 5H, Ar-H), 7.63-7.72 (m, 4H, Ar-H), 7.82-7.98 (m, 2H, Py-H), 8.68-8.74
(m, 2H, Py-H) ppm; ESI-MS: m/z 339.89 [M+1]+; Anal. calcd. for C22H17N3O:
C 77.86; H 5.05; N 12.38; found C 78.11; H 5.01; N 12.42.
4.4 Typical procedure for the synthesis of the1-benzoyl-pyrazoles
Same procedure as for the 1-acetyl-pyrazoles, but the reaction mixture
with the required 1H-pyrazoles (2.0 mmol), triethylamine (4.0 mmol) and
benzoyl chloride (4.0 mmol). The 1-benzoyl pyrazoles (4a-e) were obtained.
4.4.1 1-Benzoyl-3-(4-pyridyl)-5-phenylpyrazole (4a)
4.2.3 3-(4-Pyridyl)-5-(4-fluorophenyl)-1H-pyrazole (2c)
Colorless powder, yield 92.9 %, mp 189-191 oC; IR (KBr): n 3135 (b, s),
3048 (m), 1607 (s), 1507 (s), 1458 (m), 1232 (s), 1168 (m), 1099 (m), 1064
(m), 973 (m), 836 (s), 800 (s), 698 (m) cm-1; H NMR (300 MHz, CDCl3): d
1
6.90 (s, 1H, C=CH), 7.13 (t, 2H, Ar-H, J = 8.1 Hz), 7.64 (d, 2H, Ar-H, J = 8.7
Hz), 7.67 (d, 2H, Py-H, J = 5.1 Hz), 8.66 (d, 2H, Py-H, J = 4.8 Hz) ppm; ESI-
MS: m/z 239.14 M+; Anal. calcd. for C14H10FN3: C 70.28; H 4.21; N 17.56;
found C 70.50; H 4.18; N 17.60.
Yellow powder, yield 87.6 %, mp 111-113oC; IR (KBr): n 3066 (m), 1710
(s), 1633 (s), 1521 (m), 1488 (m), 1446 (m), 1405 (m), 1295 (s), 1241 (m),
1193 (m), 1076 (m), 903 (s), 818 (s), 766 (s) cm-1; 1H NMR (300 MHz, CDCl3):
d 7.13 (s, 1H, C=CH), 7.47-7.59 (m, 3H, Ar-H), 7.70-7.75 (m, 2H, Ar-H),
8.02-8.05 (m, 3H, Ar-H), 8.18 (d, 2H, Ar-H, J = 7.2 Hz), 8.35 (d, 2H, Py-H, J
= 6.6 Hz), 8.85 (d, 2H, Py-H, J = 5.7 Hz) ppm; ESI-MS: m/z 326.03 [M+1]+;
Anal. calcd. for C21H15N3O: C 77.52; H 4.65; N 12.91; found C 77.80; H 4.61;
N 12.95.
4.2.4 3-(4-Pyridyl)-5-(4-methoxyphenyl)-1H-pyrazole (2d)
Colorless needles, yield 90.5 %, mp 196-197 oC; IR (KBr): n 3117 (m),
3072 (m), 3026 (m), 2915 (w), 2845 (w), 1607 (s), 1509 (s), 1458 (m), 1290
(m), 1252 (s), 1180 (s), 1029 (m), 964 (m), 828 (s), 793 (m), 697 (m) cm-1; 1H
NMR (300 MHz, CDCl3): d 3.85 (s, 3H, OCH ), 6.85 (s, 1H, C=CH), 6.96 (d,
2H, Ar-H, J = 7.8 Hz), 7.58 (d, 2H, Ar-H, J =38.1 Hz), 7.69 (d, 2H, Py-H, J =
3.3 Hz), 8.65 (d, 2H, Py-H, J = 2.1 Hz) ppm; ESI-MS: m/z 251.10 M+; Anal.
calcd. for C15H13N3O: C 71.70; H 5.21; N 16.72; found C 71.92; H 5.17; N
16.74.
4.4.2 1-Benzoyl-3-(4-pyridyl)-5-(4-methylphenyl) pyrazole (4b)
Yellow powder, yield 82.6 %, mp 130-131oC; IR (KBr): n 3079 (m), 2940
(w), 2885 (w), 1713 (s), 1633 (s), 1497 (m), 1435 (m), 1317 (s), 1185 (m), 900
4.2.5 3-(4-Pyridyl)-5-(4-phenylphenyl)-1H-pyrazole (2e)
Colorless powder, yield 92.8 %, mp 267-269 oC; IR (KBr): n 3133 (m),
3031 (m), 1603 (s), 1480 (m), 1424 (m), 1351 (m), 1226 (m), 1181 (m), 1058
(s), 820 (s), 719 (m) cm-1; H NMR (300 MHz, CDCl ): d 2.41 (s, 3H, CH3),
1
7.11 (s, 1H, C=CH), 7.37 (d, 2H, Ar-H, J = 8.1 Hz), 7.353-7.60 (m, 2H, Ar-H),
7.70-7.77 (m, 3H, Ar-H), 8.04 (d, 2H, Ar-H, J = 7.2 Hz), 8.34 (d, 2H, Py-H, J
= 4.5 Hz), 8.84 (d, 2H, Py-H, J = 5.4 Hz) ppm; ESI-MS: m/z 340.25 [M+1]+;
Anal. calcd. for C22H17N3O: C 77.86; H 5.05; N 12.38; found C 78.13; H 5.01;
N 12.41.
1
(m), 1000 (m), 955 (m), 837 (s), 762 (s), 693 (m) cm-1; H NMR (300 MHz,
CDCl ): d 7.00 (s, 1H, C=CH), 7.40-7.42 (m, 3H, Ar-H), 7.47 (d, 2H, Ar-H,
J = 7.32 Hz), 7.50 (d, 2H, Ar-H, J = 6.9 Hz), 7.65 (d, 2H, Ar-H, J = 7.8 Hz),
7.72 (d, 2H, Py-H, J = 6.3 Hz), 8.69 (d, 2H, Py-H, J = 5.1 Hz) ppm; ESI-MS:
m/z 297.11 M+; Anal. calcd. for C20H15N3: C 80.78; H 5.08; N 14.13; found C
80.99; H 5.04; N 14.18.
4.3 Typical procedure for the synthesis of the1-acetyl-pyrazoles
Acetyl chloride (4.0 mmol) was added dropwise to a mixture of the
corresponding 1H-pyrazoles (2.0 mmol) and triethylamine (4.0 mmol) in 20
mL THF. The mixture was refluxed for 5h until the precipitate was formed.
The precipitate was filtered and the filtrate was concentrated to obtain a solid
product. The solid was recrystallized from ethanol-cyclohexane (1:1) to give
the 1-acetyl pyrazoles (3a-e).
4.4.3 1-Benzoyl-3-(4-pyridyl)-5-(4-fluorophenyl) pyrazole (4c)
Yellow powder, yield 85.2 %, mp 128-139oC; IR (KBr): n 3058 (m), 1721
(s), 1634 (s), 1601 (m), 1491 (s), 1434 (m), 1318 (s), 1232 (m), 1166 (m), 1099
1
(m), 906 (m), 818 (s), 719 (m) cm-1; H NMR (300 MHz, CDCl3): d 7.09 (s,
1H, C=CH), 7.17 (t, 2H, Ar-H, J = 8.4 Hz), 7.45-7.50 (m, 2H, Ar-H), 7.54 (t,
2H, Ar-H, J = 7.8 Hz), 7.71-7.76 (m, 1H, Ar-H), 8.02-8.10 (m, 2H, Ar-H), 8.31
(d, 2H, Py-H, J = 6.0 Hz), 8.80 (d, 2H, Py-H, J = 6.0 Hz) ppm; ESI-MS: m/z
344.00 [M+1]+; Anal. calcd. for C21H14FN3O: C 73.46; H 4.11; N 12.24; found
C 73.69; H 4.08; N 12.28.
4.3.1 1-Acetyl-3-(4-pyridyl)-5-phenylpyrazole (3a)
4.4.4 1-Benzoyl-3-(4-pyridyl)-5-(4-methoxyphenyl) pyrazole (4d)
Yellow powder, yield 80.0 %, mp 96-97 oC; IR (KBr): n 3086 (m), 2994
(m), 2830 (m), 1717 (s), 1633 (s), 1497 (s), 1422 (m), 1322 (s), 1293 (s), 1255
(s), 1184 (s), 1107 (m), 1031 (m), 953 (m), 902 (s), 814 (s), 715 (m) cm-1; 1H
NMR (300 MHz, CDCl ): d 3.85 (s, 3H, OCH ), 6.94 (d, 2H, Ar-H, J = 6.9
Hz), 7.11 (s, 1H, C=CH)3, 7.41 (d, 2H, Ar-H, J =38.7 Hz), 7.55 (t, 2H, Ar-H, J =
7.5 Hz), 7.68-7.74 (m, 1H, Ar-H), 8.02 (d, 2H, Ar-H, J = 7.2 Hz), 8.34 (d, 2H,
Py-H, J = 6.6 Hz), 8.90 (d, 2H, Py-H, J = 6.3 Hz) ppm; ESI-MS: m/z 356.05
[M+1]+; Anal. calcd. for C22H17N3O2: C 74.35; H 4.82; N 11.82; found C 74.62;
H 4.78; N 11.86.
Yellow powder, yield 87.2 %, mp 129-131oC; IR (KBr): n 3089 (m), 3005
(m), 2936 (w), 2855 (w), 1740 (s), 1620 (m), 1557 (m), 1491 (m), 1434 (m),
1368 (m), 1299 (s), 1219 (m), 1105 (m), 1026 (m), 945 (s), 831 (m), 761 (s),
1
690 (s) cm-1; H NMR (300 MHz, CDCl3): d 2.83 (s, 3H, CH3), 6.85 (s, 1H,
C=CH), 7.42-7.52 (m, 5H, Ar-H), 8.02 (d, 2H, Py-H, J = 6.0 Hz), 8.76 (d,
2H, Py-H, J = 6.0 Hz) ppm; ESI-MS: m/z 263.75 [M+1]+; Anal. calcd. for
C16H13N O: C 72.99; H 4.98; N 15.96; found C 73.26; H 4.94; N 15.99.
4.3.32 1-Acetyl-3-(4-pyridyl)-5-(4-methylphenyl) pyrazole (3b)
Yellow powder, yield 86.6 %, mp 138-139oC; IR (KBr): n 3085 (m), 3024
(m), 2922 (w), 2860 (w), 1731 (s), 1673 (m), 1614 (m), 1561 (w), 1494 (w),
1421 (m), 1370 (m), 1331 (s), 1230 (m), 946 (m), 816 (s) cm-1; 1H NMR (300
MHz, CDCl ): d 2.42 (s, 3H, CH3), 2.81 (s, 3H, CH3), 6.78 (s, 1H, C=CH),
7.29 (d, 2H,3Ar-H, J = 8.7 Hz), 7.39 (d, 2H, Py-H, J = 6.0 Hz), 7.77-7.80 (m,
2H, Ar-H), 8.68 (d, 2H, Py-H, J = 6.0 Hz) ppm; ESI-MS: m/z 277.84 [M+1]+;
Anal. calcd. for C17H15N3O: C 73.63; H 5.45; N 15.15; found C 73.85; H 5.41;
N 15.18.
4.4.5 1-Benzoyl-3-(4-pyridyl)-5-(4-phenylphenyl) pyrazole (4e)
Colorless powder, yield 84.3 %, mp 136-138 oC; IR (KBr): n 3062 (m),
3012 (m), 1711 (s), 1632 (s), 1603 (m), 1516 (m), 1488 (m), 1447 (m), 1409
1
(m), 1295 (s), 1200 (s), 949 (m), 902 (s), 830 (s), 767 (m), 716 (s) cm-1; H
NMR (300 MHz, CDCl ): d 7.19 (s, 1H, C=CH), 7.36-7.49 (m, 3H, Ar-H),
7.54-7.76 (m, 9H), 8.07 3(d, 2H, Ar-H, J = 6.9 Hz), 8.35 (d, 2H, Py-H, J = 6.3
Hz), 8.87 (d, 2H, Py-H, J = 6.3 Hz) ppm; ESI-MS: m/z 402.39 [M+1]+; Anal.
calcd. for C27H19N3O: C 80.78; H 4.77; N 10.47; found C 80.94; H 4.73; N
10.50.
4.3.3 1-Acetyl-3-(4-pyridyl)-5-(4-fluorophenyl) pyrazole (3c)
Bright yellow powder, yield 84.8 %, mp 142-143 oC; IR (KBr): n 3100
(m), 3010 (m), 2960 (w), 2870 (w), 1739 (s), 1608 (m), 1506 (m), 1425 (m),
4.5 Procedure for anti-microbial activity
1371 (m), 1321 (s), 1225 (s), 1160 (m), 1107 (m), 947 (m), 817 (s) cm-1; H
The synthesized compounds (3a-e and 4a-e) were screened for their in
vitro antibacterial activity against Escherichia coli and Staphylococcus aureus
and antifungal activity against Pyricularia oryzae and Rhizoctnia solani. The
anti-microbial activity was performed by disc diffusion method [16, 17] at a
concentration of 50 mg L-1. Muller-Hinton agar (Hi-Media) was employed
as culture medium and DMSO was used as solvent control for anti-microbial
activity. Norfloxacin and Triadimefon were used as standard for antibacterial
1
NMR (300 MHz, CDCl3): d 2.81 (s, 3H, CH3), 6.79 (s, 1H, C=CH), 7.09-7.19
(m, 2H, Ar-H), 7.41-7.45 (m, 2H, Ar-H), 7.87 (d, 2H, Py-H, J = 5.1 Hz), 8.69
(d, 2H, Py-H, J = 5.1 Hz) ppm; ESI-MS: m/z 281.88 [M+1]+; Anal. calcd. for
C16H12FN O: C 68.32; H 4.30; N 14.94; found C 68.56; H 4.27; N 14.98.
4.3.431-Acetyl-3-(4-pyridyl)-5-(4-methoxyphenyl) pyrazole (3d)
Yellow powder, yield 83.6 %, mp 158-159oC; IR (KBr): n 3106 (m), 3000
2859

J. Chil. Chem. Soc., 60, Nº 1 (2015)
and antifungal activities, respectively. The inhibition zones were measured in
mm at the end of an incubation period of 24 h at 37 °C for bacteria and 72 h at
24 °C for fungi.
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SUPPLEMENTARY MATERIAL
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8. R. Kalirajan, L. Rathore, S. Jubie, B. Gowramma, S. Gomathy, S. Sankar,
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Crystallographic data have been deposited with the Cambridge
Crystallographic Data Center. Supplementary publication No. CCDC 965134.
Copies of data may be obtained free of charge from the Director, CCDC, 12
Union Road, Cambridge, CB2 1EZ, UK (Fax: +44–1223–336033; email:
deposit@ccdc. cam.ac.uk).
10. A.V. Gadakh, C. Pandit, S. S. Rindhe, B.K. Karale, Bioorg. Med. Chem.
Lett. 20, 5572, (2010).
11. W.-L. Dong, J.-Y. Xu, L.-X. Xiong, X.-H. Liu, Z.-M. Li, Chin. J. Chem.
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12. F.A. Bassyouni, H.A. Tawfik, A.M. Soliman, M.A. Rehim, Res. Chem.
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ACKNOWLEDGMENT
Financial support for this work from National Natural Science Foundation
of China (no. 21273065).
13. M.A. El-borai, H.F. Rizk, M.F. Abd-Aal, I.Y. El-Deeb, Eur. J. Med.
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