Preparation and Properties of Some New Pyrazole Derivatives

Full text of DOI:10.1080/00304948.2020.1846449

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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Preparation and Properties of Some New Pyrazole
Derivatives
Feyza Tınmaz , İlhan Özer İlhan & Senem Akkoç
To cite this article: Feyza Tınmaz , İlhan Özer İlhan & Senem Akkoç (2021) Preparation and
Properties of Some New Pyrazole Derivatives, Organic Preparations and Procedures International,
53:1, 89-94, DOI: 10.1080/00304948.2020.1846449
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ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
2021, VOL. 53, NO. 1, 89–94
https://doi.org/10.1080/00304948.2020.1846449
OPPI BRIEF
Preparation and Properties of Some New Pyrazole
Derivatives
a
a
b
_
€
_
Feyza Tınmaz , Ilhan Ozer Ilhan , and Senem Akkoc¸
b
aFaculty of Sciences, Department of Chemistry, Erciyes University, Kayseri, Turkey; Faculty of Pharmacy,
Department of Basic Pharmaceutical Sciences, Suleyman Demirel University, Isparta, Turkey
ARTICLE HISTORY Received 7 March 2020; Accepted 11 June 2020
Pyrazoles and their derivatives constitute a structurally varied set of five-membered het-
erocyclic compounds and provide a rich source of materials suitable for drug design
and discovery. Pyrazoles exhibit many different biological activities such as enzyme
inhibitory,1–3 anticancer,4,5 antibacterial,6,7 antioxidant,8 anti-inflammatory,9 neuropro-
tective,9 and antimetastatic5 properties. In particular, highly substituted pyrroles are
desirable entities in the discovery process.10,11 We would now like to report the con-
venient and concise syntheses of some novel pyrazoles, in which the five-membered
nucleus is highly substituted, using classical reactions.
Thus, the useful precursor 4-benzoyl-1-(2,4-dinitrophenyl)-5-phenyl-1H-pyrazole-3-
carbonyl chloride (1)12 (Scheme 1) was treated with aromatic amines in toluene to pro-
vide the novel pyrazoles 2-5, in moderate yields averaging 66% (see Experimental sec-
tion). The structures of the newly synthesized compounds were determined and
1
confirmed by elemental analysis and by H-NMR, 13C-NMR, and IR spectra.
In cognate preparations, we used the reactions of chalcones 6 and 7 with the appropriate
acid hydrazides to form the dihydropyrazoles 8 and 9 (Scheme 2). These reactions took
place in 85% and 70% yields, respectively. Again the compounds were fully characterized.
Our synthetic procedures outlined below used simple, convenient and classical methods.
It is our hope that these procedures will stimulate further research into these highly
substituted and potentially useful heterocycles.
Experimental section
All the chemicals, which were obtained in analytical purity, were purchased from
Merck, Carlo Erba, Sigma-Aldrich and Fluka. FT-IR spectra were recorded in cmꢀ1
using a Shimadzu 8400 FT-IR spectrophotometer. 1H- and 13C-NMR spectra were
recorded on a Bruker 400 MHz Ultra Shield NMR Spectrophotometer. Elemental ana-
lysis were taken using a Carlo-Erba 1180 HP 105 Model elemental analyzer apparatus.
The melting points were taken with an Electrothermal Brand 9200 Model device and
are corrected. The open structures of compounds 2-5 are given in Scheme 1.
CONTACT Senem Akkoc¸
senemakkoc@sdu.edu.tr; senemakkoc44@gmail.com
Department of Basic
Pharmaceutical Sciences, Faculty of Pharmacy, Suleyman Demirel University, 32260, Isparta, Turkey
ß 2020 Taylor & Francis Group, LLC

90
F. TINMAZ
Scheme 1. Preparation of pyrazoles 2-5.
4-Benzoyl-1-(2,4-dinitrophenyl)-5-phenyl-1H-pyrazole-3-carbonyl chloride (1)
4-Benzoyl-5-phenylfuran-2,3-dione (1.00 mmol) and 1-(2,4-dinitrophenyl)hydrazine
(1.00 mmol) were dissolved in benzene and refluxed for 2h. The reaction was followed
with thin layer chromatography (TLC), using silica gel 60 GF254 eluted with chloro-
form/ethyl acetate (20/1). After the reaction was completed, solvent was removed using
a rotary evaporator. A yellow product, namely 4-benzoyl-1-(2,4-dinitrophenyl)-5-phe-
nyl-1H-pyrazole-3-carboxylic acid, was formed upon the addition of 10 ml of cyclohex-
ane. This starting material was recrystallized from toluene. Compound 1 was
subsequently obtained from 1.00 g of 4-benzoyl-1-(2,4-dinitrophenyl)-5-phenyl-1H-pyra-
zole-3-carboxylic acid and 0.15 mL of thionyl chloride upon heating at 85 ꢁC for 4h.
The acid chloride was isolated by filtration. Compound 1 was recrystallized from xylene.
1
Yield: 50%, m.p.: 238 ꢁC. IR (cmꢀ1): 1775 and 1680 (C ¼ O). H NMR (400 MHz, ppm,
CDCl3): 7.77-7.10 (m, 13H, ArH). 13C NMR (100 MHz, ppm, CDC13): 191.00 and
161.50 (C¼O), 150.05 (CNO2), 140.10, 135.13, 132.75, 130.21, 129.73, 129.30, 128.97,
128.19, 127.55, 122.05, 121.05.12
Anal. Calc. for C23H13ClN4O6: C, 57.93; H, 2.75; N, 11.75. Found: C, 57.73; H, 2.81; N, 11.71.

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
91
Scheme 2. Synthesis of chalcones and dihydropyrazoles.
4-Benzoyl-1-(2,4-dinitrophenyl)-N,5-diphenyl-1H-pyrazole-3-carboxamide (2)
Aniline (0.019 g, 1.00 mmol) was added to a solution of 1 (0.09 g, 1.00 mmol) in toluene
(1 mL). The reaction mixture was refluxed for 2h. The relative reaction time was deter-
mined by TLC (silica gel 60 GF254 using chloroform/ethyl acetate (20/1)). The product
was isolated by filtration. The new compound was crystallized from ethyl alcohol. Yield:
62%, color: orange, m.p: 278 ꢁC. FT-IR (cmꢀ1): 3303 (-NH-), 3089 and 3024 (C-H),
…
…
1667 and 1643 (C ¼ O), 1531-1442 (C C and C N), 1343 and 1285 (asymmetric
—
—
1
N ¼ O). H-NMR (400 MHz, ppm, DMSO-d6), d: 10.85 (-NH), 7.15-9.10 (m, 18 H, Ar-
H). 13C-NMR (100 MHz, ppm, DMSO-d6), d: 192.39 and 159.39 (C¼O), 147.86, 145.15,
136.20, 132.32, 131.14, 129.71, 129.47, 129.17, 126.56, 123.88, 121.15 and 115.22 (Ar-C).
Anal. Calc. for C29H19N5O6: C, 65.29; H, 3.56; N, 13.13. Found: C, 65.58; H, 3.77; N, 12.99.
4-Benzoyl-N-(4-chlorophenyl)-1-(2,4-dinitrophenyl)-5-phenyl-1H-pyrazole-3-
carboxamide (3)
This new compound was synthesized from 0.100 g of 1 and 0.027 g of p-chloroaniline in
toluene (1 mL). The reaction mixture was refluxed for 4h. The reaction was followed
with TLC (silica gel 60 GF254 using chloroform/ethyl acetate (20/1). The precipitated
product was filtered off from the reaction mixture and recrystallized from ethyl alcohol.
Yield: 70%, color: yellow, m.p: 183 ꢁC. FT-IR (cmꢀ1): 3087 (-N-H), 2852 (C-H), 1646
(C ¼ O), 1594 and 1427 (C C and C N), 1512 (N-O), 1342 (N ¼ O). 1H-NMR
…
…
—
—
(400 MHz, ppm, CDCl3), d: 9.12 (-NH), 7.10-8.68 (m, 17 H, Ar-H). 13C-NMR
(100 MHz, ppm, CDCl3), d: 194.28 and 158.09 (C¼O), 154.45, 147.96, 145.02, 138.50,
136.29, 135.99, 134.39, 131.53, 130.20, 130.11, 129.69, 129.30, 128.55, 128.23, 125.93,
122.03 and 121.05 (Ar-C).
Anal. Calc. for C29H18N506Cl: C, 61.32; H, 3.17; N, 12.33. Found: C, 60.99; H, 3.28;
N, 12.58.

92
F. TINMAZ
4-Benzoyl-1-(2,4-dinitrophenyl)-N-(4-nitrophenyl)-5-phenyl-1H-pyrazole-3-
carboxamide (4)
This new compound was synthesized from 0.100 g of 1 and 0.029 g of p-nitroaniline in
toluene (1 mL) for 2h. The reaction was followed with TLC (silica gel 60 GF254 in
chloroform/ethyl acetate (20/1). The precipitated product was filtered off from the reac-
tion mixture and ꢀr1ecrystallized from ethyl alcohol. Yield: 65%, color: orange, m.p:
158 ꢁC. FT-IR (cm ): 3063 and 2871 (CH), 1710 and 1680 (C ¼ O), 1597-1496 (C
C
…
—
1
…
and C N), 1339 (N ¼ O). H-NMR (400 MHz, ppm, DMSO-d6), d: 8.97 (-NH), 6.58-
—
8.81 (m, 17 H, Ar-H). 13C-NMR (100 MHz, ppm, DMSO-d6), d: 191.64 and 159.12
(C¼O), 156.17, 150.52, 147.97, 145.28, 137.74, 137.51, 136.07, 135.40, 134.71, 132.53,
130.87, 129.70, 129.57, 129.44, 129.04, 127.26, 126.87, 123.74, 121.16 and 112.83 (Ar-C).
Anal. Calc. for C29H18N608: C, 60.21; H, 3.11; N, 14.53. Found: C, 60.00; H, 3.12; N, 14.69.
4-Benzoyl-1-(2,4-dinitrophenyl)-N-(naphthalen-1-yl)-5-phenyl-1H-pyrazole-3-
carboxamide (5)
This new compound was synthesized from 0.100 g of 1, 0.030 g of 1-naphthylamine in tolu-
ene (1mL). The reaction mixture was refluxed for 2h. The reaction was followed with TLC
(silica gel 60 GF254 using chloroform/ethyl acetate (20/1). The precipitated product was fil-
tered off from the reaction mixtuꢀre1 and recrystallized from ethyl alcohol. Yield: 68%, color:
orange, m.p: 303 ꢁC. FT-IR (cm ): 3325 (-NH-), 3105 (C-H), 1608 (C ¼ O), 1596-1495
1
…
…
(C C and C N), 1339 and 1282 (asymmetric N ¼ O). H-NMR (400 MHz, ppm, CDCl3),
—
—
d: 11.07 (-NH), 7.18-9.64 (m, 20H, Ar-H). 13C-NMR (100 MHz, ppm, CDCl3), d: 192.69 and
172.71 (C¼O), 161.98, 160.06, 152.53, 150.49, 147.63, 145.14, 138.74, 137.55, 136.99, 135.31,
135.06, 134.12, 131.74, 130.39, 129.81, 129.25, 128.79, 128.71, 128.05, 127.74, 127.17, 126.45,
124.35, 124.09, 120.79, 118.82, 118.71 and 113.15 (Ar-C).
Anal. Calc. for C33H21N506: C, 67.92; H, 3.60; N, 12.01. Found: C, 68.28; H, 3.99; N, 12.15.
Chalcones
Water and ethyl alcohol (200/140 mL) were added to 22.0g of NaOH in a round bottom
flask. After the NaOH was dissolved and the vessel placed on ice, the appropriate acetophe-
none derivative (p-methylacetophenone (0.38 moles) or p-methoxyacetophenone (0.38
moles)) was slowly added to this mixture. Then, the benzaldehyde derivative (p-methylben-
zaldehyde or p-methoxybenzaldehyde) (0.38 moles) was added to the reaction mixture. The
reaction was stirred in the salt-ice bath for 6 h, and the reaction temperature was kept near
-10 ꢁC. The precipitated solid product was filtered and washed several times with the mixture
of water and ethyl alcohol. It was dried over P2O5 in a vacuum desiccator. The two respective
chalcones, namely, 1,3-di-p-tolylprop-2-en-1-one (6), or 1,3-bis(4-methoxyphenyl)prop-2-
en-1-one (7), were each obtained as yellow solids.
1,3-Di-p-tolylprop-2-en-1-one (6)13
This known compound was synthesized from 1.00 mmol of p-methylacetophenone, and
1.00 mmol of p-methylbenzaldehyde. Compound 6 was purified by recrystallization

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
93
from ethyl alcohol. Yield: 73%, color: yellow, m.p: 129-132 ꢁC. IR (cmꢀ1): 3029, 2971,
1
2939, 2915, 2854, 1654, 1953, 1566, 1517, 1378, 994, 813, and 736. H-NMR (600 MHz,
ppm, CDCl3) d: 7.92 (d, 2H, J: 8.1), 7.78 (d, 1H, J: 15.6), 7.53 (d, 2H, J: 8.0), 7.48
(d, 1H, J: 15.6), 7.29 (d, 2H, J: 8.1), 7.21 (d, 2H, J: 8.0), 2.38 (s, 3H), 2.42 (s, 3H).
13C-NMR (150.92 MHz, ppm, CDCl3) d: 190.06, 144.42, 143.42, 140.87, 135.79, 132.28,
129.65, 129.26, 128.59, 128.40, 121.14, 21.61 and 21.47.
Anal. Calc. for C17H16O: C, 86.40; H, 6.82. Found: C, 86.51; H, 6.74.
1,3-bis(4-Methoxyphenyl)prop-2-en-1-one (7)14
This known compound was synthesized from 51 mL of p-methoxyacetophenone, and
46 mL of p-methoxybenzaldehyde. Yield: 81%, color: yellow, m.p: 95-97 ꢁC. IR (cmꢀ1):
1
1650, 1590, 1560, 822, 810, 750, and 670. H-NMR (ppm) d: 8.00 (d, 2H, J: 8.55), 7.75
(d, 1H, J: 15.56), 7.40 (d, 1H, J: 15.55), 7.56 (d, 2H, J: 8.26), 6.94 (d, 2H, J: 8.44), 6.89
(d, 2H, J: 8.22), 3.84 (s, 3H), 3.81 (s, 3H). 13C-NMR (ppm) d: 188.59, 163.19, 161.44,
143.67, 131.27, 130.60, 130.02, 127.72, 119.46, 114.30, 113.71, 55.36 and 55.29.
Anal. Calc. for C17H16O3: C, 76.10; H, 6.01. Found: C, 76.25; H, 6.12.
Dihydropyrazoles
(3,5-Di-p-tolyl-4,5-dihydropyrazol-1-yl)(2-nitrophenyl)methanone (8)
This new compound was synthesized from 0.39 g of 6, 0.29 g of o-nitrobenzoic hydra-
zide, and 0.09 g of NaOH in 6 mL of ethyl alcohol. The reaction mixture was refluxed
for 5h. After this time, ice was added to the reaction medium and the product was pre-
cipitated. The precipitated product was recrystallized from cyclohexane. Yield: 85%,
color: white, m.p: 152.4 ꢁC. FT-IR (cmꢀ1): 3068, 3002, 2936 and 2836 (C-H), 1631
1
(C ¼ O), 1512 (N-O). H-NMR (400 MHz, ppm, CDCl3), d: 7.09-8.21 (m, 12 H, Ar-H),
5.73 (t, 1 H, J: 4 Hz, CH), 3.83 and 3.23 (dd, 2 H, J: 12 Hz, J: 4 Hz, CH2), 2.48 (s, 6 H,
CH3). 13C-NMR (100 MHz, ppm, CDCl3), d: 164.13 (C¼O), 155.96 (C¼N), 147.13,
141.01, 138.30, 137.63, 133.78, 133.65, 132.19, 130.03, 129.89, 129.66, 129.38, 128.62,
128.45, 128.00, 127.26, 126.78, 125.88 and 123.59 (Ar-C), 60.56 (-CH), 42.78 (-CH2-),
21.51 and 21.17 (-CH3).
Anal. Calc. for C24H21N3O3: C, 72.18; H, 5.26; N, 10.53. Found: C, 71.98; H, 5.28; N, 10.75.
1-(3,5-bis(4-Methoxyphenyl)-4,5-dihydropyrazol-1-yl)-2-phenylethanone (9)
This new compound, according to the same conditions and procedure as for 8, was
synthesized from 0.92 g of 7, 0.52 g of phenylacetic hydrazide, 0.20 g of NaOH and 6 mL
of ethyl alcohol. The product was crystallized from methyl alcohol. Yield: 70%, color:
white, m.p: 114.5 ꢁC. FT-IR (cmꢀ1): 3022, 2956 and 2927 (C-H), 1652 (Ph-C ¼ O), 1245
1
(C-O). H-NMR (400 MHz, ppm, CDCl3), d: 7.73-6.79 (m, 13 H, Ar-H), 5.53 and 5.50
(dd, 1H, J: 4 Hz, J: 4 Hz, NCHCH2), 4.16 (s, 2H, -CH2-C ¼ O), 3.91 and 3.88 (s, 6 H,
-OCH3), 3.20 (d, 2H, J: 4 Hz, CHCH2). 13C-NMR (100 MHz, ppm, CDCl3), d: 168.90
(C¼O), 161.38, 158.95, 153.93, 135.51, 133.99, 130.61, 129.59, 128.95, 128.33, 128.25,
126.96, 126.56, 124.08, 114.20, 114.16 and 113.68 (Ar-C), 59.58 (NCHCH2), 55.43,
55.27, 42.31 and 41.18 (NCHCH2, -CH2-C ¼ O and -OCH3).

94
F. TINMAZ
Anal. Calc. for C25H24N2O: C, 74.91; H, 6.01; N, 6.99. Found: C, 75.05; H, 6.25; N, 7.00.
Acknowledgment
We would like to thank the Erciyes University Research Fund for their financial support under
project number FYL-2012-4254.
ORCID
Senem Akkoc¸
http://orcid.org/0000-0002-1260-9425
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