Synthesis of 4-benzoyl-1,5-diphenyl-1 H-pyrazole-3-carboxylic acid derivatives and their antimicrobial activities

Article abstract of DOI:10.1515/hc-2012-0167

The reaction of 1 H-pyrazole-3-carboxylic acid chloride (1) with various hydrazine derivatives 2a-c yielded the corresponding N,N-disubstituted 4-benzoyl-1,5-diphenyl-1 H-pyrazole-3-carbohydrazides 3a-c. These products underwent Friedel-Crafts acylations

Full text of DOI:10.1515/hc-2012-0167

ꢁꢁꢁꢂ
DOI 10.1515/hc-2012-0167ꢀ ꢀHeterocycl. Commun. 2013; 19(3): 183–187
Emine Şahan*, İsmail Yıldırım and Sevil Albayrak
Synthesis of 4-benzoyl-1,5-diphenyl-1H-
pyrazole-3-carboxylic acid derivatives and their
antimicrobial activities
Abstract: The reaction of 1H-pyrazole-3-carboxylic acid 1H-pyrazole-3-carboxylic acid chloride (1) by the reaction
chloride (1) with various hydrazine derivatives 2a–c with various diamines has been reported by Yıldırım and
yielded the corresponding N,N-disubstituted 4-benzoyl- co-workers [3–5], but no reaction of 1H-pyrazole-3-carbox-
1,5-diphenyl-1H-pyrazole-3-carbohydrazides 3a–c. These amides with nucleophiles has been described. Herein,
products underwent Friedel-Crafts acylations with arenes we report the synthesis and characterization of pyrazole
to afford compounds 4a–c. Treatment of 1 with aromatic derivatives 3a–c, 4a–c and 6a–c.
diamines produced 1H-pyrazole-3-carboxamides 5a–c,
which were allowed to react with phenylhydrazine to give
hydrazone derivatives 6a–c. The structures of all new
Results and discussion
1
13
compounds were established by IR, H and C NMR data
and elemental analyses. The new compounds were evalu-
ated for antimicrobial activities against Gram (-), Gram (+) Chemistry
bacteria and two yeasts using the disc diffusion method.
N,N-Dimethylhydrazide derivative 3a is the most active The 1H-pyrazole-3-carboxylic acid chloride 1 was pre-
compound of the series.
pared using the literature procedure [1, 2]. The reaction of
compound 1 with substituted hydrazines 2a–c led to the
Keywords: Friedel-Crafts reaction; N,N-dialkylhydrazine; formation of the corresponding products 3a–c in good
pyrazole-3-carboxylic acid.
yields (63–87%) (Scheme 1). The progress of the reac-
tion was monitored by thin layer chromatography (TLC)
until complete consumption of the starting materials was
observed. The structures of products 3 were confirmed by
*Corresponding author: Emine Şahan, Department of Chemistry,
Faculty of Sciences, Erciyes University, 38039 Kayseri, Turkey,
e-mail: eosahan@gmail.com
İsmail Yıldırım: Department of Chemistry, Faculty of Sciences,
Erciyes University, 38039 Kayseri, Turkey
Sevil Albayrak: Department of Biology, Faculty of Sciences, Erciyes
University, 38039 Kayseri, Turkey
1
13
elemental analysis, IR and H and C NMR spectroscopic
techniques.
Friedel-Crafts acylation of selected arenes with the
1H-pyrazole-3-carboxylic acid chloride 1 in the presence
O
O
R1
H2N - R1
2a-c
Ph
Ph
N
H
N
N
Introduction
Ph
Cl
N
O
3a-c
O
Ph
Ph
Pyrazole derivatives are an important class of heterocyclic
compounds [1–8] that have considerable pharmacological
activities including antibacterial, antifungal and hypogly-
cemic activities [9–14]. A number of hydrazide/hydrazone
derivatives have also been claimed to possess interesting
bioactivity, such as anticonvulsant, anti-inflammatory,
antimalarial, analgesic, antiplatelets, antituberculo-
sis and anticancer properties. Aroylhydrazide/hydra-
zones that are derivatives of heterocyclic compounds
such as pyridine have attracted particular attention
R2
N
O
Ph
R2
Ph
O
1
N
AlCl3
Ph
N
4a c
-
Ph
and : R1 = NMe2
: R = Me
2
2a
3a
4a
2b and 3b: R1 = NPh2
4b: R2 = Cl
4c: R2 = Br
2c and 3c: R1 = NHPh-4-Me
[15–19] in drug development [20]. Functionalization of Scheme 1ꢀ
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ꢁꢁꢁꢂ
184ꢀ
ꢀE. Şahan et al.: 4-Benzoyl-1,5-diphenyl-1H-pyrazole-3-carboxylic acid derivatives
Ph
Ph
N
NH
HN
N
O
O
NH HN
R
Ph
Ph
Ph
Ph
N
N
N
N
R
NH2
NH2
O
O
O
O
Ph
Ph
NH HN
R
Ph-NHNH2
Ph
Ph
Ph
Ph
1
N
N
N
N
[Ref. 4,5]
Ph
HN
Ph
NH
Ph
Ph
5a c
-
O
O
N
N
HN
R
NH
Ph
Ph
Ph
Ph
5a and 6a: R = H
5b and 6b: R = Cl
and : R = NO2
N
N
N
N
5c
6c
Ph
Ph
Scheme 2ꢀ
of anhydrous aluminum chloride to afford 4a–c is also
presented in Scheme 1. Recently, an analogous reaction
In vitro antimicrobial activity
of 1 with benzene was reported by ţener and co-workers All new compounds were evaluated against eight Gram
[9]. The formation of products 4a–c is strongly supported (-), five Gram (+) and two yeasts. The results with the
by the results of elemental analyses and spectroscopic active compounds 3a, 3c, 4b and 6b are shown in Table
measurements. The reactions of compound 1 with some 1. The antibacterial antibiotics ampicillin (AMP) and chlo-
aromatic diamines to give the corresponding dicarboxam- ramphenicol (C) were used as controls. Compounds 3b,
ide derivatives 5a–c have recently been reported (Scheme 4a, 4c, 6a and 6c were practically inactive against the
2) [4, 5]. Compounds 5a–c were allowed to react with tested microorganisms. All compounds had no inhibitory
phenylhydrazine to give new hydrazone derivatives 6a–c. effects on yeasts tested in the present study. Compound 5c
a
Table 1ꢁScreening for antimicrobial activity of selected compounds 3a, 3c, 4b and 6b .
Microorganisms
3a
3c
4b
6b
AMPc
C c
Gram (-)
ꢀAeromonas hydrophila ATCC 7965
ꢀEscherichia coli ATCC 25922
ꢀKlebsiella pneumoniae FMC 5
ꢀMorganella morganii
8.75 0.4b
8.5 0.7
10.0 0.0
9.5 0.7
8.25 0.4
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
27.0 0.0
6.5 0.0
14.0 0.0
–
24.0 0.0
26.0 0.0
25.0 0.0
8.0 0.0
18.0 0.0
17.0 0.0
13.0 0.0
11.0 0.0
22.0 0.0
19.0 0.0
15.0 0.0
17.0 0.0
ꢀSalmonella typhimurium NRRLE 4463
ꢀProteus mirabilis BC 3624
ꢀPseudomonas aeruginosa ATCC 27853
ꢀYersinia enterocolitica ATCC 1501
Gram (+)
6.5 0.0
–
ꢀBacillus brevis FMC 3
9.0 0.0
7.25 0.4
8.5 0.0
8.5 0.7
8.5 0.0
–
–
7.0 0.0
–
–
8.0 0.0
31.0 0.0
24.0 0.0
25.0 0.0
16.0 0.0
20.0 0.0
21.0 0.0
25.0 0.0
17.0 0.0
15.0 0.0
ꢀB. cereus RSKK 863
–
–
–
–
ꢀB. subtilis ATCC 6633
–
6.75 0.4
–
–
7.0 0.0
–
ꢀMycobacterium smegmatis RUT
ꢀStaphylococcus aureus ATCC 29213
Y e a s t
ꢀCandida albicans ATCC 1223
ꢀSaccharomyces cerevisiae BC 5461
–
–
–
–
–
–
–
–
–
–
–
–
aThe inhibition zones (mm) are shown.
bInhibition zones include diameter of disc (6 mm).
cAmpicillin (AMP, 10 μg); chloramphenicol (C, 30 μg). –, not detected.
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ꢀ185
(N-H), 2959 (aliph. C-H), 1670, 1650 cm-1 (C=O); 1H NMR: δ 3.00 (s, 6H,
CH3) 7.12–7.90 (m, 15H, ArH), 9.30 (s, 1H, NH); 13C NMR: δ 46.6, 122.1,
125.4, 127.7, 128.3, 128.5, 128.6, 129.1, 129.4, 129.5, 129.8, 133.2, 137.8,
138.6, 143.4, 144.2, 158.7, 191.3. Anal. Calcd for C25H22N4O2: C, 73.15; H,
5.40; N, 13.65. Found: C, 72.80; H, 5.67; N, 13.96.
was slightly effective against Mycobacterium smegmatis
among the tested microorganisms.
The strongest activity was displayed by compound 3a.
4-Benzoyl-1,5-diphenyl-3-[(N′,N′-diphenylhydrazino)
carbonyl]-1H-pyrazole (3b)ꢀWhite powder; mp 207–208°C; IR: υ
3284 (N-H), 1686, 1662 cm-1 (C=O); 1H NMR: δ 7.00–7.90 (m, 25H, ArH),
9.18 (s, 1H, NH); 13C NMR: δ 119.7, 120.2, 120.4, 122.4, 123.0, 125.4, 127.8,
128.2, 128.5, 128.6, 128.9, 129.1, 129.1, 129.3, 129.5, 129.9, 133.1, 138.0,
138.8, 144.1, 144.2, 145.9, 159.7, 191.2. Anal. Calcd for C35H26N4O2: C,
78.63; H, 5.90; N, 10.48. Found: C, 78.54; H, 5.43; N, 10.73.
Experimental
Solvents were dried by heating under reflux with appropriate drying
agents and distilled before use. Melting points were determined on
an Electrothermal 9200 apparatus and are uncorrected. Microanaly-
ses were performed on a Carlo Erba Elemental Analyzer, model 1108.
The IR spectra were recorded on a Shimadzu Model 8400 FT IR spec-
1
trophometer. The H NMR spectra (400 MHz) and 13C NMR spectra
4-Benzoyl-1,5-diphenyl-3-{N′-[(4-methylphenyl)hydrazino]
carbonyl}-1H-pyrazole (3c)ꢀWhite powder; mp 175–176°C; IR: υ
(100 MHz) were recorded on a Bruker-400 Ultra Shield instrument.
All experiments were followed by TLC using a DC Alufolien Kieselgel
60 F254 Merck and Camag TLC lamp (254/366 nm).
1
3269 (N-H), 2920 (aliph. C-H), 1678, 1662 cm-1 (C=O); H NMR: δ 3.02
(s, 3H, CH3) 6.70–7.85 (m, 20H, ArH), 8.75 (s, 1H, NH); 13C NMR: δ 40.8,
113.1, 113.4, 119.7, 122.3, 125.4, 127.9, 128.2, 128.5, 128.5, 128.6, 129.0,
129.1, 129.3, 129.5, 129.9, 133.1, 138.0, 138.8, 144.1, 144.3, 149.3, 159.5,
191.4. Anal. Calcd for C30H24N4O2: C, 76.25; H, 5.12; N, 11.86. Found: C,
76.05; H, 5.65; N, 11.30.
Antimicrobial assay
Bacterial strains used in the present study were obtained from the
Department of Biology, Faculty of Science, Erciyes University, Kay-
seri, Turkey. The bacterial strains were Aeromonas hydrophila ATCC
7965, Bacillus brevis FMC 3, Bacillus cereus RSKK 863, Bacillus subtilis
ATCC 6633, Escherichia coli ATCC 25922, Klebsiella pneumoniae ATCC
27736, Morganella morganii, Mycobacterium smegmatis RUT, Proteus
mirabilis BC 3624, Pseudomonas aeruginosa ATCC 27853, Salmonella
typhimurium NRRLE 4463, Staphylococcus aureus ATCC 29213 and
Yersinia enterocolitica ATCC 1501. The yeasts were Candida albicans
ATCC 1223 and Saccharomyces cerevisiae BC 5461 (Table 1). Antimi-
crobial activity testing was carried out by disc diffusion methods
[21] using 100 μL of suspension containing 106–107 colony forming
units (cfu)/mL of bacteria and yeasts spread on nutrient agar (NA)
and sabouraud dextrose agar (SDA). The sterile discs (6 mm) were
impregnated with 10 μL of compounds in dimethyl sulfoxide (DMSO;
500 mg/disc) placed in the middle of inoculated agar plates. DMSO
was added on the disc to provide negative control. Ampicillin (AMP,
10 μg) and chloramphenicol (C, 30 μg) were used as positive con-
trols. Yeasts C. albicans and S. cerevisiae were incubated at 25°C for
24–48 h in the inverted position. Other microorganisms were incu-
bated at 37°C for 18–24 h. At the end of the period, antimicrobial ac-
tivity was evaluated by measuring the zone of inhibition (mm), and
experiments were repeated twice.
General procedure for 4a–c
A mixture of acid chloride 1 (0.40 g) anhydrous AlCl3 (0.70 g) and an
aromatic compound (molar ratio 1:5:25) was heated at 100–140°C for
1–3 h in a calcium chloride guard tube fitted round bottom flask of
50 mL. Then, the mixture was poured onto HCl/ice-water for hydroly-
sis and extracted with diethyl ether. Then, petroleum ether was added
and the resulting solid was collected and crystallized from ethanol.
4-Benzoyl-1,5-diphenyl-3-(4-methylbenzoyl)-1H-pyrazole
(4a)ꢀCompound 4a was prepared from toluene with heating for 1 h
at 120°C; yield 61% (0.28 g); white powder; mp 192–193°C; IR: υ 1666,
1
1639 cm-1 (C=O); H NMR: δ 2.45 (s, 3H, CH3), 7.25–8.30 (m, 19H, Ar-
H); 13C NMR: δ 21.7, 124.2, 125.4, 128.1, 128.3, 128.4, 128.5, 128.9, 129.0,
129.2, 129.9, 130.7, 132.9, 134.0, 138.1, 139.1, 143.3, 143.9, 150.2, 186.4,
191.5. Anal. Calcd for C30H22N2O2: C, 81.43; H, 5.01; N, 6.33. Found: C,
81.18; H, 5.00; N, 5.99.
4-Benzoyl-1,5-diphenyl-3-(4-chlorobenzoyl)-1H-pyrazole
(4b)ꢀCompound 4b was prepared from chlorobenzene with heating
for 2 h at 100°C; yield 42% (0.20 g); white powder; mp 180–181°C;
1
IR: υ 1666, 1639 cm-1 (C=O); H NMR: δ 7.20–8.35 (m, 19H, Ar-H); 13C
NMR: δ 124.4, 125.4, 127.8, 128.4, 128.5, 129.1, 129.2, 129.3, 129.9, 132.1,
133.1, 134.8, 137.3, 139.0, 139.6, 143.4, 149.6, 185.3, 191.4. Anal. Calcd for
C29H19N2O2Cl: C, 75.24; H, 4.14; N, 6.05. Found: C, 75.28; H, 4.17; N, 5.57.
General procedure for 3a–c
A solution of acid chloride 1 (0.20 g), N,N-disubstituted hydrazine
2a–c (0.04 mL) (molar ratio 1:1) and a catalytic amount of pyridine in
xylene was heated under reflux for 2 h. Then the solvent was removed
and the remaining oily residue was treated with dry diethyl ether and
the mixture was stirred for 1 h. The resultant solid product 3 was crys-
tallized from toluene or cyclohexane and dried over P2O5.
4-Benzoyl-1,5-diphenyl-3-(4-bromobenzoyl)-1H-pyrazole
(4c)ꢀCompound 4c was prepared from bromobenzene with heating
for 2 h at 140°C; yield 56% (0.28 g); white powder; mp 172–173°C; IR:
1
υ 1660, 1649 cm-1 (C=O); H NMR: δ 7.25–8.30 (m, 19H, Ar-H); 13C NMR:
δ 124.4, 125.4, 125.4, 127.8, 127.9, 128.2, 128.4, 128.4, 128.4, 128.5, 128.6,
129.1, 129.1, 129.2, 129.3, 129.4, 129.8, 129.9, 130.6, 131.6, 132.2, 133.0, 133.1,
135.2, 136.5, 137.9, 138.1, 138.9, 143.5, 149.6, 185.5, 191.4. Anal. Calcd for
C29H19N2O2Br: C, 68.65; H, 3.77; N, 5.52. Found: C, 68.27; H, 4.12; N, 5.37.
4-Benzoyl-3-[(N′,N′-dimethylhydrazino)carbonyl]-1,5-diphe-
nyl-1H-pyrazole (3a)ꢀWhite powder; mp 148–149°C; IR: υ 3209
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186ꢀ ꢀE. Şahan et al.: 4-Benzoyl-1,5-diphenyl-1H-pyrazole-3-carboxylic acid derivatives
NMR: δ 6.73–7.73 (m, 43H, ArH), 9.33 and 9.38 (2s, 2H, NH), 10.15,
10.19, 10.21 and 10.24 (4s, 4H, Ph-NH); 13C NMR: δ 113.4, 125.5, 125.5,
125.5, 125.6, 128.9, 129.3, 129.3, 129.4, 144.5, 159.8, 178.1. Anal. Calcd for
C64H47N10O2Cl: C, 75.10; H, 4.63; N, 13.68. Found: C, 74.87; H, 4.80; N,
13.15.
General procedure for 6a–c
A solution of compound 5a–c (0.30 g), phenylhydrazine (0.50 mL)
(molar ratio 1:13) and a catalytic amount of acetic acid in n-butanol
(10 mL) was heated under reflux for 15 h. The solvent was removed
and the remaining oily residue was treated with dry diethyl ether and
the mixture stirred for 1 h. The yellow solid product was crystallized
from benzene or xylene.
N,N′-Bis{4-[α-(phenylhydrazono)benzyl]-1,5-diphenyl-1H-pyra-
zol-3-yl-carbonyl}-4-nitro-1,2-phenylendiamine
(6c)ꢀYellow
1
powder; mp 257–258°C; IR: υ 3315 (N-H), 1678 cm-1 (C=O); H NMR: δ
6.74–8.32 (m, 43H, ArH), 9.38 and 9.40 (2s, 2H, NH), 10.40, 10.45, 10.54
and 10.56 (4s, 4H, Ph-NH); 13C NMR: δ 113.5, 125.5, 126.4, 128.5, 128.7,
129.0, 129.3, 129.5, 130.1, 159.8, 161.18, 170.9. Anal. Calcd for C64H47N11O4:
C, 73.79; H, 4.38; N, 13.35. Found: C, 73.70; H, 4.66; N, 13.85.
N,N′-Bis{4-[α-(phenylhydrazono)benzyl]-1,5-diphenyl-1H-pyra-
zol-3-yl-carbonyl}-1,2-phenylendiamine (6a)ꢀYellow powder;
mp 198–199°C. IR: υ 3225 (N-H), 1659 cm-1 (C=O); 1H NMR: δ 6.72–7.54
(m, 44H, ArH), 9.34 and 9.37 (2s, 2H, NH), 10.11 and 10.13 (2s, 2H, Ph-
NH); 13C NMR: δ 113.1, 120.2, 124.8, 125.0, 125.3, 125.9, 126.0, 126.1, 127.6,
128.0, 128.1, 128.3, 128.8, 129.0, 129.1, 129.3, 129.4, 129.7, 129.9, 136.3,
138.4, 143.8, 144.8, 145.1, 159.3, 170.0. Anal. Calcd for C64H48N10O2: C,
77.71; H, 4.98; N, 14.16. Found: C, 77.32; H, 4.91; N, 13.99.
Acknowledgments: The authors are grateful for the finan-
cial support by the Research Foundation of Erciyes Uni-
versity (Kayseri, Turkey), Project No. FBT-07-48.
N,N′-Bis{4-[α-(phenylhydrazono)benzyl]-1,5-diphenyl-1H-pyra-
zol-3-yl-carbonyl}-4-chloro-1,2-phenylendiamine (6b)ꢀYellow
Received November 19, 2012; accepted April 1, 2013; previously
published online May 10, 2013
1
powder; mp 239–240°C; IR: υ 3232, 3163 (N-H), 1662 cm-1 (C=O); H
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