Synthesis and insecticidal evaluation of aryl pyrazole 5-fluorouracil compounds

Article abstract of DOI:10.3184/174751914X13955977912102

Twenty eight aryl pyrazole derivatives containing 5-fluorouracil were designed and synthesised via the key intermediate 1-aryl-3-methyl-1H-pyrazole-5- carboxylic acid. The structures of target compounds were confirmed by ¹H NMR, FT-IR, EA and t

Full text of DOI:10.3184/174751914X13955977912102

272 RESEARCH PAPER
VOL. 38 MAY, 272–279
JOURNAL OF CHEMICAL RESEARCH 2014
Synthesis and insecticidal evaluation of aryl pyrazole 5‑fluorouracil
compounds
Yue Chen, Xiao‑Dong Fu, Hai‑Ping Mu, Xiao‑Fei Qin and Rong Wan*
Department of Applied Chemistry, College of Science, Nanjing University of Technology, Nanjing 210009, P.R. China
Twenty eight aryl pyrazole derivatives containing 5‑fluorouracil were designed and synthesised via the key intermediate 1‑aryl‑
1
3‑methyl‑1H‑pyrazole‑5‑carboxylic acid. The structures of target compounds were confirmed by H NMR, FT‑IR, EA and their
insecticidal activities were evaluated. The bioassays revealed that aryl pyrazole derivatives containing 5‑fluorouracil exhibited
excellent insecticidal activities against Culex pipiens and Musca domestica at a concentration of 0.1%. Some compounds still
showed good insecticidal activities even at a concentration of 0.05%.
Keywords: aryl pyrazole, 5‑fluorouracil, insecticidal activity
Aryl pyrazole derivatives occupy an important position in
medicinal and pesticide chemistry because of their diverse
bioactivities. They are widely used as insecticides,1–7
fungicides8,9 and acaricides.10–12 For example, as shown in
Fig. 1, geranyl pyrazole‑5‑formate (Compound A), designed
and synthesised by Sun et al.2 was proved to possess an
excellent insecticidal activity against aphids. The aryl pyrazole
derivative (Compound B), displayed a strong action against
Plutella xylostella, Heliothis virescens and certain other
species of sucking insects.4 Chlorantraniliprole analogue
(Compound C), was reported to show an excellent performance
on controlling a spectrum of agronomic invertebrate pests.5
With growing applications on their synthesis and bioactivity,
chemists and biologists have directed considerable attention
to the research and application of aryl pyrazole derivatives in
recent years.
found that incorporation of 5‑fluorouracil with bioactive
1,3,4‑thiadiazole compounds resulted in higher insecticidal
activity.19 We conceived that 5‑fluorouracil group can be used
as an important skeleton to explore bioactive molecules. Based
on these results, we modified aryl pyrazole compounds with
5‑fluorouracil and did get many novel heterocyclic compounds
with superior bioactivities.20
Here, following our earlier report20, we describe the design
and synthesis of 28 aryl pyrazole derivatives containing
5‑fluorouracil (Fig. 2). The insecticidal activities of the target
compounds against Culex pipiens and Musca domestica were
tested and are discussed here. In order to discover structure–
activity relationships (SAR), different substituents were
introduced to the aromatic ring and SAR are also discussed
here in detail.
Results and discussion
On the other hand, 5‑fluorouracil plays an important role
in biologically active compounds. As a fluoropyrimidine,
the mechanism of cytotoxicity of 5‑fluorouracil has been
ascribed to the misincorporation of fluoronucleotides into
RNA and DNA and to the inhibition of the nucleotide synthetic
enzyme thymidylate synthase. 5‑Fluorouracil can be converted
intracellularly to several active metabolites: fluorodeoxyuridine
monophosphate (FdUMP), fluorodeoxyuridine triphosphate
(FdUTP) and fluorouridine triphosphate (FUTP), and these
active metabolites restrain the action of thymidylate synthase
and disrupt RNA and DNA synthesis and repair.13 Due to these
satisfying advantages, 5‑fluorouracil and its derivatives have
been widely used as antitumour agents in the treatment of colon
cancer,14,15 gastric cancer16,17 and oesophageal cancer.18 However,
there were little studies on the modification of heterocyclic
derivatives with 5‑fluorouracil. In our previous work, we
The synthetic route designed for the synthesis of target
compounds is shown in Scheme 1. Acetone (1) was advanced
via intermediate (2) to afford the series 3-(1-28) which, in turn,
were advanced via the series 4-(1-28) to give the series of aryl
pyrazole‑5‑carboxylic acids 5-(1-28) in 45–75% yields.2,21
Introduction of 2‑chloroacetic acid into 5‑fluorouracil (6) by
nucleophilic substitution provided 2‑(5‑fluorouracil‑1‑yl) acetic
acid (7) in 80% yield, which was further allowed to react with
2‑aminoethanol to give compound (8) in the presence of peptide
coupling reagents in 85% yield. The formation of intermediate
(8) can be viewed as a simple amidation reaction. Initially, we
attempted to employ 2‑(5‑fluorouracil‑1‑yl) acetic acid 7 to react
directly with 2‑aminoethanol to afford (8). However, attempts
by direct amidation were unsuccessful. Then, introduction of
peptide coupling reagents made the transformation possible.
O
HN
N
O
Br
O
CF3
R1
H
N
O
N
N
N
N
Br
N
O
O
O
l
C
R2
l
C
N
N
R1, R2 = alkyl, aryl
compound A
compound B
Fig. 1 Structures of some aryl pyrazole derivatives.
compound C
* Correspondent. E‑mail: rwan@njut.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2014 273
R1
N
O
N
O
R2
F
R1, R2 = alkyl, aryl
O
geranyl pyrazole-5-formate
O
N
O
N
NH
N
N
H
R4
O
O
F
O
N
R4 = aryl
O
N
target compound
R3
NH
N
S
N
H
O
R3 = aryl
1,3,4-thiadiazole 5-fluorouracil compond
Fig. 2 Design strategy of the target compounds.
O
O
O
b
a
COOEt
OEt
N
H
O
N
R
O
1
2
3-(1-28)
COOEt
c
e
d
N
N
N
H
O
COOEt
H
COO
N
N
N
R
R
R
3-(1-28)
4-(1-28)
5-(1-28)
O
N
O
F
O
HN
F
F
HN
HN
f
g
O
H
N
O
NH
N
O
H
O
H
H
COO
O
7
6
8
O
O
F
N
HN
O
H
N
R
N
O
h
O
NH
N
O
N
H
+
H
COO
N
F
N
NH
R
H
O
H
O
O
5-(1-28)
8
9-(1-28)
Scheme 1 (a) ref. 2; (b) R‑NHNH2, EtOH, 0–5 °C; (c) 36.5% hydrochloric acid, THF, reflux, 4 h; (d) 50% NaOH solution, reflux 4 h; (e) 36.5% hydrochloric
acid; (f) ref. 19; (g) NH2CH2CH2OH, PDCP, DMF; (h) CDI, DMAP, DMF, 20–25 °C.

274 JOURNAL OF CHEMICAL RESEARCH 2014
Key intermediates 5-(1-28) were, respectively, reacted with
compound 8 in the presence of peptide coupling reagents to
afford target compounds 9-(1-28). It is noteworthy that the
reaction cannot proceed smoothly by direct esterification. With
the introduction of a peptide coupling agent, such as PDCP,
CDI, HOBT and so on, pyrazole‑5‑carboxylic acids 5-(1-28)
can react smoothly with compound 8 to afford title compounds
9-(1-28) in satisfactory yields.
compounds, such as compounds 9-17 and 9-5 showed 92.2 and
80% activities respectively, which were similar to prallethrin.
Interestingly, compounds 9-21 and 9-28 demonstrated much
more potency than prallethrin with KT50 values of 1′54′′. In
addition, 9-17, 9-18, 9-19, 9-20 and 9-2 exhibited higher
activities than dextral tetramethrin, but less lower than
prallethrin (KT50 values were 2′25′′, 4′05′′, 3′30′′, 3′39′′, 4′11′′
and 2′06′′, respectively).
The insecticidal activities against Culex pipiens and Musca
domestica are presented in Table 1, target compounds displayed
excellent insecticidal activities against Culex pipiens. For
example, the knock down rates (24 h) of compounds 9-1, 9-2,
9-4, 9-7, 9-17, 9-18, 9-19, 9-20, 9-21, 9-22, 9-23, 9-25 and 9-28
were all 100%, equal to commercial insecticide prallethrin
(100%) and superior to dextral tetramethrin (75.6%); compound
9-3’s knock down rate is 82.5%, similar to commercial
prallethrin. Among these compounds, 9-21 and 9-28 were
more potent than the control prallethrin (with KT50 values of
1′42′′, 2′36′′ and 2′42′′ respectively）, while compounds 9-17,
9-18, 9-19, 9-20, 9-25, 9-1, 9-2, 9-3 and 9-4 showed slightly
less potency compared with prallethrin. In addition, the other
compounds possessed potential insecticidal activities.
The biological activities of the typical candidates 9-21 and
9-28 were further investigated by conducting the assay at
a concentration of 0.05%. The knock down rates and KT50
values are listed in Table 2. The results indicate that the two
compounds still exhibit promising insecticidal activities even
at a lower concentration. The knock down rates of 9-21 and
9-28 were both 100% against Culex pipiens and 100%, and
85.6% against Musca domestica, respectively. The KT50 values
of compound 9-21 were only 4′13′′ and 3′40′′ respectively,
appearing far more superior to commercial insecticide dextral
tetramethrin (KT50 values: 9′21′′ and 7′34′′ respectively).
On the basis of steric and electronic effects, we provide a
rational account of structure–activity relationships. From the
data presented in Table 1, we find that compounds substituted
at the 4‑position of benzene displayed higher insecticidal
activities than those substituted at the 2‑ and 3‑positions. For
example, compounds 9-11, 9-13 and 9-2 exhibited 17.8%,
25.6% and 100% insecticidal activities against Culex pipiens
Also indicated in Table 1, title compounds, such as 9-1,
9-3, 9-4, 9-6, 9-7, 9-18, 9-19, 9-21, 9-22, 9-23, 9-25 and 9-28
possessed excellent activity against Musca domestica with
100% knock down rates, the same as prallethrin (100%). Other
Table 1 Insecticidal activities of target compound 9-(1-28)
Insecticidal activities at conc. 0.1%
Compound
R
Culex pipiens
Musca domestica
KT50
Knock down rate (24 h)/%
KT50
Knock down rate (24 h)/%
9-1
9-2
9-3
9-4
9-5
9-6
9-7
9-8
4‑Cl‑Ph
4‑F‑Ph
3‑Cl‑Ph
2,4‑F2‑Ph
2,6‑F2‑Ph
3,4‑F2‑Ph
3,5‑F2‑Ph
2‑Br‑Ph
3‑Br‑Ph
2,6‑Cl2‑Ph
2‑F‑Ph
2,4‑Cl2‑Ph
3‑F‑Ph
2,3,4‑F3‑Ph
4‑Br‑Ph
4′42′′
4′55′′
5′36′′
5′48′′
/
20′48′′
8′54′′
/
100.0
100.0
82.5
100.0
0.0
40.0
100.0
7.8
3′48′′
4′11′′
6′17′′
5′36′′
15′45′′
4′30′′
6′54′′
/
100.0
65.6
100.0
100.0
80.0
100.0
100.0
25.6
10.0
55.2
33.3
37.8
5.6
15.6
9-9
/
/
/
/
20.0
20.0
17.8
/
9-10
9-11
9-12
9-13
9-14
9-15
9-16
9-17
9-18
9-19
9-20
9-21
9-22
9-23
9-24
9-25
9-26
9-27
9-28
18′44′′
/
0.0
/
/
/
25.6
70.0
62.2
2.2
18′44′′
16′48′′
/
15′30′′
18′04′′
/
55.6
0.0
2‑Cl‑Ph
Ph
3′07′′
5′14′′
4′51′′
3′00′′
1′42′′
7′48′′
8′41′′
/
4′51′′
/
/
2′36′′
8′30′′
2′42′′
100.0
100.0
100.0
100.0
100.0
100.0
100.0
20.0
100.0
35.6
27.8
2′25′′
4′05′′
3′30′′
3′39′′
1′54′′
8′56′′
7′33′′
/
8′33′′
/
/
1′54′′
4′14′′
2′06′′
92.2
100.0
100.0
60.0
100.0
100.0
100.0
55.6
100.0
35.6
27.8
4‑CH3O‑Ph
4‑CH3‑Ph
4‑NO2‑Ph
2,6‑Cl2‑4‑CF3‑Ph
3‑CH3‑Ph
2‑CH3‑Ph
3,5‑(CH3)2‑Ph
4‑OCF3‑Ph
4‑CF3‑Ph
3‑CF3‑Ph
3‑Chloro‑pyridin‑2‑yl
100.0
75.6
100.0
100.0
62.2
100.0
Dextral tetramethrin
Prallethrin
KT50, Killing time of 50%.

JOURNAL OF CHEMICAL RESEARCH 2014 275
Table 2 Insecticidal activities of title compounds 9-21 and 9-28
Insecticidal activities at conc. 0.05%
Culex pipiens Musca domestica
Compounds
9-21
R
KT50
knock down rate (24 h)/%
KT50
Knock down rate (24 h)/%
2,6‑Cl2‑4‑CF3‑Ph
3‑Chloro‑pyridin‑2‑yl
4′13′′
9′17′′
9′21′′
100.0
100.0
63.0
3′40′′
5′14′′
7′34′′
100.0
85.6
57.5
9-28
Dextral tetramethrin
KT50, Killing time of 50%.
of tetrahydrofuran, water (20 mL)/ethanol (5 mL) was added to the
residue 4. The solution was brought to pH 9–10 with 50% sodium
hydroxide solution and heated to reflux for 4 h. After cooling to room
temperature, the resulting mixture was brought to pH 1–2 with 36.5%
hydrochloric acid. Precipitated solid was filtered and the filter cake
was recrystallised from ethanol to obtain white to yellow solids 5-(1-
28).
at 0.1%, respectively. Compounds 9-16, 9-3 and 9-1 displayed
the same result (2.2%, 82.5% and 100% insecticidal activities,
respectively). Furthermore, the comparison of biological
activities among 9-11, 9-13 and 9-2 against Musca domestica
(values are 33.3%, 5.6% and 65.6% respectively) also give a
similar result.
Otherwise, it seems that compounds 9-19 and 9-22, which
contain electron‑donating substituents, are found to display
better insecticidal activities (the knock down rates were both
100% against Culex pipiens) than compounds with electron‑
withdrawing substituents on the benzene ring (9-26 and 9-27:
35.6% and 27.8%, respectively).
1‑(4‑Chlorophenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylic acid (5-1):
Yield 74.8%; m.p. 212–213 °C (lit.23 212–214 °C).
1‑(4‑Fluorophenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylic acid (5-2):
1
Yield 65.2%; m.p. 194–195 °C; H NMR (DMSO‑d6, δ): 2.24 (s, 3H,
pyrazole‑CH3), 6.83 (s, 1H, pyrazole‑CH), 7.25–7.29 (m, 2H, Ph‑H),
7.50–7.53 (m, 2H, Ph‑H), 13.30 (s, 1H, CO–OH). Anal. calcd for
C11H9FN2O2 (220.06): C, 60.00; H, 4.12; N, 12.72; found: C, 59.97; H,
4.09; N, 12.75%.
Conclusions
In conclusion, more than 28 aryl pyrazole derivatives containing
5‑fluorouracil were designed, synthesised and evaluated in this
study. The results of bioassays indicate that most of the target
compounds exhibited satisfactory insecticidal activities against
Culex pipiens and Musca domestica at the concentration of
0.1%. Furthermore, compounds 9-21 and 9-28 still exhibited
excellent insecticidal activities against Culex pipiens and
Musca domestica even at a lower concentration of 0.05%. In
particular, compound 9-21 possessed the best insecticidal
activity with the lowest KT50 value (4′13′′ and 3′40′′) and the
highest 24 h knock down rate (100%), which is superior to
commercial dextral tetramethrin. These findings indicate that
the incorporation of the 5‑fluorouracil fragment improves
the insecticidal activities of the aryl pyrazole derivatives
as expected and warrant further studies for designing new
molecules with good biological activities. Further studies on
structural optimisation and structure–activity relationships of
these aryl pyrazole derivatives are in progress.
1‑(3‑Chlorophenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylic acid (5-3):
Yield 70.2%; m.p. 190–192 °C; H NMR (DMSO‑d6, δ): 2.34 (s, 3H,
pyrazole‑CH3), 6.72 (s, 1H, pyrazole‑CH), 7.57 (s, 3H, Ph‑H), 7.68
(s, 1H, Ph‑H), 13.30 (s, 1H, CO–OH). Anal. calcd for C11H9ClN2O2
(236.04): C, 55.83; H, 3.83; N, 11.84; found: C, 55.85; H, 3.85; N,
11.80%.
1
1‑(2,4‑Difluorophenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylic
acid
1
(5-4): Yield 46.5%; m.p. 153–157 °C; H NMR (DMSO‑d6, δ): 2.15
(s, 3H, pyrazole‑CH3), 6.71 (s, 1H, pyrazole‑CH), 7.27–7.32 (m, 1H,
Ph‑H), 7.65–7.80 (m, 2H, Ph‑H), 13.30 (s, 1H, CO–OH). Anal. calcd for
C11H8F2N2O2 (238.06): C, 55.47; H, 3.39; N, 11.76; found: C, 55.50; H,
3.35; N, 11.69%.
1‑(2,6‑Difluorophenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylic
acid
(5-5): Yield 56.4%; m.p. 155–161 °C; 1H NMR (DMSO‑d6, δ): 2.13 (s,
3H, pyrazole‑CH3), 6.75 (s, 1H, pyrazole‑CH), 7.42 (t, J=6.0 Hz, 2H,
Ph‑H), 7.69–7.71 (m, 1H, Ph‑H), 13.29 (s, 1H, CO–OH). Anal. calcd for
C11H8F2N2O2 (238.06): C, 55.47; H, 3.39; N, 11.76; found: C, 55.51; H,
3.37; N, 11.71%.
1‑(3,4‑Difluorophenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylic
acid
Experimental
1
(5-6): Yield 56.4%; m.p. 189–193 °C; H NMR (DMSO‑d6, δ): 2.33
(s, 3H, pyrazole‑CH3), 6.70 (s, 1H, pyrazole‑CH), 7.45–7.47 (m, 1H,
Ph‑H), 7.68–7.71 (m, 1H, Ph‑H), 7.82–7.87 (m, 1H, Ph‑H), 13.33 (s, 1H,
CO–OH). Anal. calcd for C11H8F2N2O2 (238.06): C, 55.47; H, 3.39; N,
11.76; found: C, 55.42; H, 3.43; N, 11.68%.
Unless otherwise noted, reagents were purchased from commercial
suppliers and are used without further purification. All solvents were
analytical reagents and were further purified or dried before use when
necessary. Reactions were monitored by TLC with visualisation by
UV light. The melting points were determined on an X‑4 microscope
electrothermal apparatus (Beijing Tech Instruments Co., Beijing, P.R.
China) and were corrected in advance. 1H NMR spectra were recorded
on a Bruker AV‑500 spectrometer and a Bruker AV‑300 spectrometer
in DMSO‑d6 with tetramethylsilane (TMS) as internal standard.
FT‑IR spectra in KBr were recorded by a PerkinElmer PE‑683 IR
spectrometer. Elemental analyses were determined on an Elementer
Vario EL III analyser.
1‑(3,5‑Difluorophenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylic
acid
1
(5-7): Yield 62.3%; m.p. 187–189 °C; H NMR (DMSO‑d6, δ): 2.38
(s, 3H, pyrazole‑CH3), 6.72 (s, 1H, pyrazole‑CH), 7.40–7.50 (m, 3H,
Ph‑H), 13.29 (s, 1H, CO–OH). Anal. calcd for C11H8F2N2O2 (238.06): C,
55.47; H, 3.39; N, 11.76; found: C, 55.49; H, 3.42; N, 11.80%.
1‑(2‑Bromophenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylic acid (5-8):
1
Yield 67.5%; m.p. 189–191 °C; H NMR (DMSO‑d6, δ): 2.08 (s, 3H,
pyrazole‑CH3), 6.73 (s, 1H, pyrazole‑CH), 7.51–7.56 (m, 3H, Ph‑H),
7.97 (d, J=5.6 Hz, 1H, Ph‑H), 13.30 (s, 1H, CO–OH). Anal. calcd for
C11H9BrN2O2 (278.98): C, 47.00; H, 3.23; N, 9.97; found: C, 46.97; H,
3.25; N, 10.01%.
Synthesis of 3‑methyl‑1‑aryl‑1H‑pyrazole‑5‑carboxylic acid (5);
general procedure
Ethyl 2,4‑dioxo pentanoate 2(3.16 g, 20 mmol) was gradually added
to the solution containing aryl hydrazine (20 mmol) in ethanol
(20 mL) below 5 °C (see ref. 22 and Scheme 1). The progress of the
reaction was monitored by TLC. Upon completion, the solution was
evaporated in vacuo. The residue 3 was dissolved in tetrahydrofuran
(20 mL) and 36.5% hydrochloric acid (15 mL) solution. The reaction
was kept at reflux and monitored by TLC. After the evaporation
1‑(3‑Bromophenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylic acid (5-9):
1
Yield 70.6%; m.p. 176–180 °C; H NMR (DMSO‑d6, δ): 2.39 (s, 3H,
pyrazole‑CH3), 6.77 (s, 1H, pyrazole‑CH), 7.52–7.55 (m, 1H, Ph‑H),
7.83 (d, J=5.2 Hz, 1H, Ph‑H), 7.91 (d, J=5.2 Hz, 1H, Ph‑H), 7.85
(s, 1H, Ph‑H), 13.39 (s, 1H, CO–OH). Anal. calcd for C11H9BrN2O2
(278.98): C, 47.00; H, 3.23; N, 9.97; found: C, 47.07; H, 3.26; N, 9.91%.

276 JOURNAL OF CHEMICAL RESEARCH 2014
1‑(2,6‑Dichlorophenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylic
acid
C13H14N2O2 (230.11): C, 67.81; H, 6.13; N, 12.17; found: C, 67.75; H, 6.19;
N, 12.20%.
1
(5-10): Yield 52.9%; m.p. 120–123 °C; H NMR (DMSO‑d6, δ): 2.12
(s, 3H, pyrazole‑CH3), 6.81 (s, 1H, pyrazole‑CH), 7.59–7.61 (m, 1H,
Ph‑H), 7.65–7.80 (m, 2H, Ph‑H), 13.31 (s, 1H, CO–OH). Anal. calcd for
C11H8Cl2N2O2 (270.00): C, 48.73; H, 2.97; N, 10.33; found: C, 48.75; H,
2.94; N, 10.40%.
1‑(4‑Trifluoromethoxyphenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylic
1
acid (5-25): Yield 65.2%; m.p. 167–173 °C; H NMR (DMSO‑d6, δ):
2.33 (s, 3H, pyrazole‑CH3), 6.71 (s, 1H, pyrazole‑CH), 7.52–7.56 (m,
2H, Ph‑H), 7.82–7.85 (m, 2H, Ph‑H), 13.31 (s, 1H, CO–OH). Anal.
calcd for C12H9F3N2O3 (286.21): C, 50.36; H, 3.17; N, 9.79; found: C,
50.31; H, 3.21; N, 9.82%.
1‑(2‑Fluorophenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylic acid (5-11):
1
Yield 52.8%; m.p. 183–185 °C; H NMR (DMSO‑d6, δ): 2.16 (s, 3H,
pyrazole‑CH3), 6.71 (s, 1H, pyrazole‑CH), 7.40 (d, J=6.5 Hz, 1H,
Ph‑H), 7.49–7.53 (m, 1H, Ph‑H), 7.56–7.61 (m, 2H, Ph‑H), 13.30 (s, 1H,
CO–OH). Anal. calcd for C11H9FN2O2 (220.06): C, 60.00; H, 4.12; N,
12.72; found: C, 60.07; H, 4.17; N, 12.70%.
1‑(4‑Trifluoromethylphenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylic
acid (5-26): Yield 71.5%; m.p. 172–175 °C; H NMR (DMSO‑d6, δ):
2.43 (s, 3H, pyrazole‑CH3), 6.80 (s, 1H, pyrazole‑CH), 7.86–7.88 (m,
2H, Ph‑H), 8.03–8.06 (m, 2H, Ph‑H), 13.34 (s, 1H, CO–OH). Anal.
calcd for C12H9F3N2O2 (270.06): C, 53.34; H, 3.36; F, 21.09; N, 10.37;
found: C, 53.30; H, 3.39; N, 10.30%.
1
1‑(2,4‑Dichlorophenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylic
acid
(5-12): Yield 67.9%; m.p. 224–225 °C (lit.24 195–205 °C).
1‑(3‑Trifluoromethylphenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylic
acid (5-27): Yield 56.9%; m.p. 183–187 °C; 1H NMR (DMSO‑d6,
δ): 2.38 (s, 3H, pyrazole-CH3), 6.77 (s, 1H, pyrazole‑CH), 7.80 (t,
J=7.2 Hz, 1H, Ph‑H), 7.85 (s, 1H, Ph‑H), 7.89 (s, 1H, Ph‑H), 7.93
(s, 1H, Ph‑H), 13.32 (s, 1H, CO–OH). Anal. calcd for C12H9F3N2O2
(270.06): C, 53.34; H, 3.36; F, 21.09; N, 10.37; found: C, 53.40; H, 3.31;
N, 10.42%.
1‑(3‑Fluorophenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylic acid (5-13):
Yield 61.5%; m.p. 188–191 °C; H NMR (DMSO‑d6, δ): 2.35 (s, 3H,
1
pyrazole‑CH3), 6.71 (s, 1H, pyrazole‑CH), 7.33–7.35 (m, 1H, Ph‑H),
7.50 (d, J=7.9 Hz, 1H, Ph‑H), 7.58 (d, J=8.7 Hz, 1H, Ph‑H), 7.67–7.70
(m, 1H, Ph‑H), 13.30 (s, 1H, CO–OH). Anal. calcd for C11H9FN2O2
(220.06): C, 60.00; H, 4.12; N, 12.72; found: C, 59.95; H, 4.17; N,
12.68%.
1‑(3‑Chloropyridin‑2‑yl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylic acid
(5-28): Yield 55.3%. m.p. 171–174 °C, H NMR (DMSO‑d6, δ): 2.28
1‑(2,3,4‑Trifluorophenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylic acid
(5-14): Yield 59.0%; m.p. 177–180 °C, H NMR (DMSO‑d6, δ): 2.19
1
1
(s, 3H, pyrazole‑CH3), 6.85 (s, 1H, pyrazole‑CH), 7.60–7.62 (m, 1H,
pyridine‑H), 8.17 (d, J=6.8 Hz, 1H, pyridine‑H), 8.52 (dd, J=4.6 Hz,
1H, pyridine‑H), 13.29 (s, 1H, CO–OH). Anal. calcd for C10H8ClN3O2
(237.03): C, 50.54; H, 3.39; N, 17.68; found: C, 50.60; H, 3.43; N,
17.63%.
(s, 3H, pyrazole‑CH3), 6.73 (s, 1H, pyrazole‑CH), 7.49–7.56 (m, 2H,
Ph‑H), 13.31 (s, 1H, CO–OH). Anal. calcd for C11H7F3N2O2 (256.05): C,
51.57; H, 2.75; N, 10.94; found: C, 51.60; H, 2.79; N, 10.90%.
1‑(4‑Bromophenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylic acid (5-15):
Yield 52.8%; m.p. 185–187 °C (lit.25 182–184 °C).
1‑(2‑Chlorophenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylic
acid
Synthesis of 2‑(5‑fluorouracil‑1‑yl)‑N‑(2‑hydroxyethyl)acetamide 8
2‑Aminoethanol (2.14 g, 35 mmol) was added dropwise to a stirred
solution of 2‑(5‑fluorouracil‑1‑yl) acetic acid 7 (which was synthesised
according to the literature)19 (5.0 g, 27 mmol), PDCP (32.4 mmol)
and anhydrous DMF (133 mL) at room temperature. The mixture
was stirred for half an hour. Triethylamine (78 mmol) was added
dropwise to the reaction solution. The reaction was carried out at
room temperature and monitored by TLC. Upon completion, the
reaction solution was evaporated in vacuo and water (50 mL) was
added. The resulting precipitate was collected by filtration. The filter
cake was washed with water, dried, and recrystallised from EtOH:
DMF=10:1 to give white crystals (5.24 g, 85%), m.p. 230–233 °C (lit.29
245–247 °C).
1
(5-16): Yield 64.4%; m.p. 188–191 °C; H NMR (DMSO‑d6, δ): 2.08
(s, 3H, pyrazole‑CH3), 6.72 (s, 1H, pyrazole‑CH), 7.50–7.59 (m, 3H,
Ph‑H), 7.66–7.70 (m, 1H, Ph‑H), 13.32 (s, 1H, CO–OH). Anal. calcd for
C11H9ClN2O2 (236.04): C, 55.83; H, 3.83; N, 11.84; found: C, 55.78; H,
3.80; N, 11.78%.
1‑Phenyl‑3‑methyl‑1H‑pyrazole‑5‑carboxylic acid (5-17): Yield
58.2%; m.p. 192–194 °C (lit.25 181–182 °C).
1‑(4‑Methoxyphenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylic acid
1
(5-18): Yield 60.2%; m.p. 164–168 °C; H NMR (DMSO‑d6, δ): 2.24
(s, 3H, pyrazole‑CH3), 3.80 (s, 3H, CH3‑O), 6.79 (s, 1H, pyrazole‑CH),
6.90 (d, J=6.9 Hz, 2H, Ph‑H), 7.41 (d, J=5.7 Hz, 2H, Ph‑H), 13.31 (s,
1H, CO–OH). Anal. calcd for C12H12N2O3 (232.08): C, 62.06; H, 5.21; N,
12.06; found: C, 62.10; H, 5.19; N, 12.10%.
1‑(4‑Methylphenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylic acid (5-19:
Yield 59.4%; m.p. 203–206 °C (lit.27 203 °C).
Synthesis of 2‑(2‑(5‑fluorouracil‑1‑yl) acetamido) ethyl 1‑(arylphenyl)‑
3‑methyl‑1H‑pyrazole‑5‑carboxylate 9; general procedure
1‑(4‑Nitrophenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylic acid (5-20):
Yield 58.4%; m.p. 231–233 °C (lit.28 237–238 °C).
A solution of compound 5-(1-28) (5 mmol), CDI (6 mmol), DMAP
(6 mmol) and anhydrous DMF (30 mL) was added to a 50 mL round‑
bottom flask fitted with a magnetic stirrer. The mixture was stirred for
half an hour and then compound 8 was added to the reaction solution
in portions. The reaction was monitored by TLC. The solution was
evaporated under a reduced pressure to get the crude product which
was purified via silica gel column chromatography using ethyl acetate
as the eluting solution to obtain title compounds 9-(1-28).
1‑(2,6‑Dichloro‑4‑(trifluoromethyl)phenyl‑3‑methyl‑1H‑pyrazole‑
1
5‑carboxylic acid (5-21): Yield 50.3%; m.p. 202–204 °C; H NMR
(DMSO‑d6, δ): 2.27 (s, 3H, pyrazole-CH3), 6.83 (s, 1H, pyrazole‑
CH), 7.62–7.64 (m, 2H, Ph‑H), 13.30 (s, 1H, COO‑H). Anal. calcd for
C12H7F3Cl2N2O2 (337.98): C, 42.50; H, 2.08; N, 8.26; found: C, 42.58; H,
2.01; N, 8.20%.
1‑(3‑Methylphenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylic acid (5-22):
Yield 56.3%; m.p. 158–160 °C, H NMR (DMSO‑d6, δ): 2.25 (s, 3H,
Ph‑CH3), 2.33 (s, 3H, pyrazole‑CH3), 6.81 (s, 1H, pyrazole‑CH),
7.17–7.22 (m, 3H, Ph‑H), 7.40–7.42 (m, 1H, Ph‑H), 13.30 (s, 1H, CO–
OH). Anal. calcd for C12H12N2O2 (216.09): C, 66.65; H, 5.59; N, 12.69;
found: C, 66.60; H, 5.62; N, 12.60%.
2‑(2‑(5‑Fluorouracil‑1‑yl)acetamido)ethyl‑1‑(4‑chlorophenyl)‑
3‑methyl‑1H‑pyrazole‑5‑carboxylate (9-1): Yield 68.4%; m.p.
248–250 °C; IR (KBr): 3340, 2848, 1741, 1716, 1697, 1670, 1558,
1
1226 cm–1
;
1H NMR (DMSO‑d6, δ): 2.27 (s, 3H, pyrazole-CH3),
3.35–3.36 (m, 2H, CONH–CH2), 4.15 (t, J=5.6 Hz, 2H, COO–CH2),
4.28 (s, 2H, N–CH2–CO), 6.92 (s, 1H, pyrazole‑CH), 7.42–7.43 (m,
2H, Ph‑H), 7.67–7.70 (m, 2H, Ph‑H), 7.97 (d, J=6.8 Hz, 1H, CF=CH),
8.30 (s, 1H, CO–NH), 11.80 (s, 1H, CO–NH–CO). Anal. calcd for
C19H17ClFN5O5 (449.09): C, 50.73; H, 3.81; N, 15.57; found: C, 50.75; H,
3.80; N, 15.53%.
2‑(2‑(5‑Fluorouracil‑1‑yl)acetamido)ethyl‑1‑(4‑fluorophenyl)‑
3‑methyl‑1H‑pyrazole‑5‑carboxylate (9-2): Yield 74.2%; m.p.
225–228 °C; IR (KBr): 3346, 2827, 1743, 1704, 1670, 1660, 1558,
1230 cm–1; 1H NMR (DMSO‑d6, δ): 2.27 (s, 3H, pyrazole-CH3),
3.35–3.36 (m, 2H, CONH–CH2), 4.15 (t, J=5.6 Hz, 2H, COO–CH2),
4.28 (s, 2H, N–CH2–CO), 6.92 (s, 1H, pyrazole‑CH), 7.28–7.31(m,
1‑(2‑Methylphenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylic acid (5-23):
1
Yield 63.5%; m.p. 164–166 °C; H NMR (DMSO‑d6, δ): 1.95 (s, 3H,
Ph‑CH3), 2.06 (s, 3H, pyrazole‑CH3), 6.69 (s, 1H, pyrazole‑CH), 7.31
(d, J=6.5 Hz, 1H, Ph‑H), 7.43 (t, J=6.8 Hz, 1H, Ph‑H), 7.49–7.55 (m,
2H, Ph‑H), 13.29 (s, 1H, CO–OH). Anal. calcd for C12H12N2O2 (216.09):
C, 66.65; H, 5.59; N, 12.69; found: C, 66.69; H, 5.55; N, 12.72%.
1‑(3,5‑Dimethylphenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylic
acid
1
(5-24): Yield 54.3%; m.p. 162–164 °C; H NMR (DMSO‑d6, δ): 2.33
(s, 3H, pyrazole‑CH3), 2.48 (s, 6H, Ph‑CH3), 6.67 (s, 1H, pyrazole‑
CH), 7.01–7.10 (m, 3H, Ph‑H), 13.30 (s, 1H, CO–OH). Anal. calcd for

JOURNAL OF CHEMICAL RESEARCH 2014 277
2H, Ph‑H), 7.47–7.50 (m, 2H, Ph‑H), 7.98 (d, J=6.8 Hz, 1H, CF=CH),
8.30 (s, 1H, CO–NH), 11.81 (s, 1H, CO–NH–CO). Anal. calcd for
C19H17F2N5O5 (433.12): C, 52.66; H, 3.95; N, 16.16; found: C, 52.70; H,
3.89; N, 16.11%.
4.34 (s, 2H, N–CH2–CO), 6.85 (s, 1H, pyrazole‑CH), 7.56–7.60 (m,
1H, Ph‑H), 7.67 (d, J=8.0 Hz, 1H, Ph‑H), 7.77 (d, J=8.0 Hz, 1H,
Ph‑H), 7.87 (s, 1H, Ph‑H), 8.06 (d, J=6.8 Hz, 1H, CF=CH), 8.48 (t,
J=5.6 Hz, 1H, CO–NH), 11.90 (s, 1H, CO–NH–CO). Anal. calcd for
C19H17BrFN5O5 (493.04): C, 46.17; H, 3.47; N, 14.17; found: C, 46.26; H,
3.40; N, 14.23%.
2‑(2‑(5‑Fluorouracil‑1‑yl)acetamido)ethyl‑1‑(2,6‑dichlorophenyl)‑
3‑methyl‑1H‑pyrazole‑5‑carboxylate (9-10): Yield 56.8%; m.p.
186–188 °C; IR (KBr): 3410, 2828, 1727, 1701, 1667, 1649, 1569,
1244 cm–1; 1H NMR (DMSO‑d6, δ): 2.15 (s, 3H, pyrazole-CH3),
3.45–3.47 (m, 2H, CONH–CH2), 4.31 (t, J=5.6 Hz, 2H, COO–CH2),
4.33 (s, 2H, N–CH2–CO), 6.90 (s, 1H, pyrazole‑CH), 7.60–7.63 (m, 1H,
Ph‑H), 7.65–7.85 (m, 2H, Ph‑H), 8.05 (d, J=4.0 Hz, 1H, CF=CH), 8.52
(t, J=4.0 Hz, 1H, CO–NH), 11.81 (s, 1H, CO–NH–CO). Anal. calcd for
C19H16Cl2FN5O5 (483.05): C, 47.12; H, 3.33; N, 14.46; found: C, 47.25; H,
3.36; N, 14.50%.
2‑(2‑(5‑Fluorouracil‑1‑yl) acetamido)ethyl‑1‑(2‑fluorophenyl)‑
3‑methyl‑1H‑pyrazole‑5‑carboxylate (9-11): Yield 68.4%; m.p.
228–230 °C; yield, 57.4%; m.p. 230–233 °C. IR (KBr): 3349, 2837,
1738, 1722, 1706, 1681, 1580, 1242 cm–1; 1H NMR (DMSO‑d6, δ):
2.19 (s, 3H, pyrazole‑CH3), 3.42–3.47 (m, 2H, CONH–CH2), 4.26
(t, J=5.7 Hz, 2H, COO–CH2), 4.31 (s, 2H, N–CH2–CO), 6.80 (s, 1H,
pyrazole‑CH), 7.43 (d, J=6.9 Hz, 1H, Ph‑H), 7.52–7.58 (m, 1H, Ph‑H),
7.60–7.68 (m, 2H, Ph‑H), 7.99 (d, J=6.9 Hz, 1H, CF=CH), 8.39 (t,
J=5.1 Hz, 1H, CO–NH), 11.80 (s, 1H, CO–NH–CO). Anal. calcd for
C19H17F2N5O5 (433.12): C, 52.66; H, 3.95; N, 16.16; found: C, 52.55; H,
3.91; N, 16.10%.
2‑(2‑(5‑Fluorouracil‑1‑yl)acetamido)ethyl‑1‑(2,4‑dichlorophenyl)‑
3‑methyl‑1H‑pyrazole‑5‑carboxylate (9-12): Yield 58.4%; m.p.
227–230 °C; IR (KBr): 3442, 2824, 1735, 1700, 1681, 1658, 1581,
1219 cm–1; 1H NMR (DMSO‑d6, δ): 2.13 (s, 3H, pyrazole-CH3),
3.41–3.47 (m, 2H, CONH–CH2), 4.25 (t, J=5.7 Hz, 2H, COO–CH2),
4.30 (s, 2H, N–CH2–CO), 6.80 (s, 1H, pyrazole‑CH), 7.66 (s, 1H,
Ph‑H), 7.95–7.97 (m, 2H, Ph‑H), 7.99 (d, J=6.6 Hz, 1H, CF=CH),
8.40 (s, 1H, CO–NH), 11.81 (s, 1H, CO–NH–CO). Anal. calcd for
C19H16Cl2FN5O5 (483.05): C, 47.12; H, 3.33; N, 14.46; found: C, 47.23; H,
3.38; N, 14.52%.
2‑(2‑(5‑Fluorouracil‑1‑yl)acetamido)ethyl‑1‑(3‑fluorophenyl)‑
3‑methyl‑1H‑pyrazole‑5‑carboxylate (9-13): Yield 57.4%; m.p.
230–233 °C; IR (KBr): 3412, 2828, 1714, 1703, 1685, 1660, 1570,
1228 cm–1; 1H NMR (DMSO‑d6, δ): 2.37 (s, 3H, pyrazole-CH3),
3.44–3.45 (m, 2H, CONH–CH2), 4.26 (s, 2H, COO–CH2), 4.30 (s, 2H,
N–CH2–CO), 6.80 (s, 1H, pyrazole‑CH), 7.36–7.39 (m, 1H, Ph‑H),
7.44 (d, J=7.5 Hz, 1H, Ph‑H), 7.50 (d, J=9.5 Hz, 1H, Ph‑H), 7.60–7.64
(m, 1H, Ph‑H), 7.99 (d, J=6.5 Hz, 1H, CF=CH), 8.39 (s, 1H, CO–NH),
11.80 (s, 1H, CO–NH–CO). Anal. calcd for C19H17F2N5O5 (433.12): C,
52.66; H, 3.95; N, 16.16; found: C, 52.60; H, 3.99; N, 16.20%.
2‑ (2‑ (5 ‑ Fluoro u ra cil‑1‑yl)a ce ta mido)e thyl‑1‑ (2, 3,4 ‑
trifluorophenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylate (9-14): Yield
62.4%; m.p. 203–205 °C; IR (KBr): 3302, 2839, 1739, 1697, 1674, 1662,
1558, 1229 cm–1; 1H NMR (DMSO‑d6, δ): 2.22 (s, 3H, pyrazole-CH3),
3.41–3.47 (m, 2H, CONH–CH2), 4.26 (t, J=8.0 Hz, 2H, COO–CH2),
4.29 (s, 2H, N–CH2–CO), 6.82 (s, 1H, pyrazole‑CH), 7.52–7.62 (m, 2H,
Ph‑H), 8.00 (d, J=3.0 Hz, 1H, CF=CH), 8.40 (t, J=6.0 Hz, 1H, CO–
NH), 11.82 (s, 1H, CO–NH–CO). Anal. calcd for C19H15F4N5O5 (469.10):
C, 48.62%; H, 3.22%; N, 14.92%; found: C, 48.75; H, 3.31; N, 14.81%.
2‑(2‑(5‑Fluorouracil‑1‑yl)acetamido)ethyl‑1‑(4‑bromophenyl)‑
3‑methyl‑1H‑pyrazole‑5‑carboxylate (9-15): Yield 64.1%; m.p.
147–150 °C; IR (KBr): 3413, 2824, 1719, 1703, 1681, 1661, 1578,
1229 cm–1; 1H NMR (DMSO‑d6, δ): 2.35 (s, 3H, pyrazole-CH3),
3.43–3.45 (m, 2H, CONH–CH2), 4.26 (t, J=5.4 Hz, 2H, COO–CH2),
4.29 (s, 2H, N–CH2–CO), 6.79 (s, 1H, pyrazole‑CH), 7.55 (d, J=8.7 Hz,
2H, Ph‑H), 7.77 (d, J=8.7 Hz, 2H, Ph‑H), 7.99 (d, J=6.9 Hz, 1H,
CF=CH), 8.40 (t, J=5.7 Hz, 1H, CO–NH), 11.82 (s, 1H, CO–NH–CO).
Anal. calcd for C19H17BrFN5O5 (493.04): C, 46.17; H, 3.47; N, 14.17;
found: C, 46.23; H, 3.51; N, 14.19%.
2‑(2‑(5‑Fluorouracil‑1‑yl)acetamido)ethyl‑1‑(3‑chlorophenyl)‑
3‑methyl‑1H‑pyrazole‑5‑carboxylate (9-3): Yield 69.5%; m.p.
205–211 °C. IR (KBr): 3344, 2847, 1724, 1715, 1701, 1675, 1549,
1239 cm–1; 1H NMR (DMSO‑d6, δ): 2.36 (s, 3H, pyrazole-CH3),
3.44–3.46 (m, 2H, CO–NH–CH2), 4.26 (t, J=5.4 Hz, 2H, COO–CH2),
4.29 (s, 2H, N–CH2–CO), 6.80 (s, 1H, pyrazole‑CH), 7.59 (s, 3H,
Ph‑H), 7.70 (s, 1H, Ph‑H), 7.99 (d, J=6.6 Hz, 1H, CF=CH), 8.39 (t,
J=4.8 Hz, 1H, CO–NH), 11.80 (s, 1H, CO–NH–CO). Anal. calcd for
C19H17ClFN5O5 (449.09): C, 50.73; H, 3.81; N, 15.57; found: C, 50.65; H,
3.85; N, 15.60%.
2‑(2‑(5‑Fluorouracil‑1‑yl)acetamido)ethyl‑1‑(2,4‑difluorophenyl)‑
3‑methyl‑1H‑pyrazole‑5‑carboxylate (9-4): Yield 68.4%; m.p.
169–172 °C; IR (KBr): 3420, 2829, 1728, 1710, 1666, 1659, 1577,
1221 cm–1; 1H NMR (DMSO‑d6, δ): 2.18 (s, 3H, pyrazole-CH3),
3.43–3.45 (m, 2H, CO–NH–CH2), 4.25 (t, J=5.7 Hz, 2H, COO–CH2),
4.29 (s, 2H, N–CH2–CO), 6.80 (s, 1H, pyrazole‑CH), 7.30–7.36 (m, 1H,
Ph‑H), 7.59–7.75 (m, 2H, Ph‑H), 7.99 (d, J=3.0 Hz, 1H, CF=CH), 8.41
(t, J=5.7 Hz, 1H, CO–NH), 11.80 (s, 1H, CO–NH–CO). Anal. calcd for
C19H16F3N5O5 (451.11): C, 50.56; H, 3.57; N, 15.52; found: C, 50.60; H,
3.65; N, 15.59%.
2‑(2‑(5‑Fluorouracil‑1‑yl)acetamido)ethyl‑1‑(2,6‑difluorophenyl)‑
3‑methyl‑1H‑pyrazole‑5‑carboxylate (9-5): Yield 70.1%; m.p.
167–169 °C; IR (KBr): 3413, 2829, 1737, 1707, 1689, 1666, 1552,
1240 cm–1; 1H NMR (DMSO‑d6, δ): 2.16 (s, 3H, pyrazole-CH3),
3.41–3.44 (m, 2H, CO–NH–CH2), 4.24 (t, J=5.6 Hz, 2H, COO–CH2),
4.28 (s, 2H, N–CH2–CO), 6.84 (s, 1H, pyrazole‑CH), 7.45 (t, J=6.0 Hz,
2H, Ph‑H), 7.72–7.76 (m, 1H, Ph‑H), 7.99 (d, J=3.0 Hz, 1H, CF=CH),
8.43 (t, J=3.9 Hz, 1H, CO–NH), 11.85 (s, 1H, CO–NH–CO). Anal.
calcd for C19H16F3N5O5 (451.11): C, 50.56; H, 3.57; N, 15.52; found: C,
50.49; H, 3.50; N, 15.71%.
2‑(2‑(5‑Fluorouracil‑1‑yl)acetamido)ethyl‑1‑(3,4‑difluorophenyl)‑
3‑methyl‑1H‑pyrazole‑5‑carboxylate (9-6): Yield 67.5%; m.p.
236–240 °C; IR (KBr): 3420, 2820, 1752, 1717, 1688, 1663, 1580,
1221 cm–1; 1H NMR (DMSO‑d6, δ): 2.35 (s, 3H, pyrazole-CH3),
3.44–3.45 (m, 2H, CONH–CH2), 4.25 (t, J=5.7 Hz, 2H, COO–CH2),
4.29 (s, 2H, N–CH2–CO), 6.79 (s, 1H, pyrazole‑CH), 7.46–7.49 (m,
1H, Ph‑H), 7.61–7.70 (m, 1H, Ph‑H), 7.76–7.83 (m, 1H, Ph‑H), 7.99 (d,
J=2.4 Hz, 1H, CF=CH), 8.39 (t, J=5.4 Hz, 1H, CO–NH), 11.81 (s, 1H,
CO–NH–CO). Anal. calcd for C19H16F3N5O5 (451.11): C, 50.56; H, 3.57;
N, 15.52; found: C, 50.70; H, 3.67; N, 15.70%.
2‑(2‑(5‑Fluorouracil‑1‑yl)acetamido)ethyl‑1‑(3,5‑difluorophenyl)‑
3‑methyl‑1H‑pyrazole‑5‑carboxylate (9-7): Yield 71.6%; m.p.
190–193 °C; IR (KBr): 3343, 2849, 1722, 1702, 1674, 1654, 1552,
1248 cm–1; 1H NMR (DMSO‑d6, δ): 2.41 (s, 3H, pyrazole-CH3),
3.43–3.47 (m, 2H, CONH–CH2), 4.26 (t, J=6.0 Hz, 2H, COO–CH2),
4.29 (s, 2H, N–CH2–CO), 6.81 (s, 1H, pyrazole‑CH), 7.43–7.47 (m, 3H,
Ph‑H), 7.99 (d, J=7.0 Hz, 1H, CF=CH), 8.39 (t, J=5.5 Hz, 1H, CO–
NH), 11.80 (s, 1H, CO–NH–CO). Anal. calcd for C19H16F3N5O5 (451.11):
C, 50.56; H, 3.57; N, 15.52; found: C, 50.69; H, 3.53; N, 15.45%.
2‑(2‑(5‑Fluorouracil‑1‑yl)acetamido)ethyl‑1‑(2‑bromophenyl)‑
3‑methyl‑1H‑pyrazole‑5‑carboxylate (9-8): Yield 72.1%; m.p.
201–202 °C; IR (KBr): 3410, 2828, 1717, 1703, 1697, 1663, 1563,
1225 cm–1; 1H NMR (DMSO‑d6, δ): 2.12 (s, 3H, pyrazole-CH3),
3.42–3.46 (m, 2H, CONH–CH2), 4.25 (t, J=5.6 Hz, 2H, COO–CH2),
4.30 (s, 2H, N–CH2–CO), 6.81 (s, 1H, pyrazole‑CH), 7.56–7.62 (m, 3H,
Ph‑H), 7.90 (d, J=8.0 Hz, 1H, Ph‑H), 8.02 (d, J=6.8 Hz, 1H, CF=CH),
8.46 (t, J=5.6 Hz, 1H, CO–NH), 11.86 (s, 1H, CO–NH–CO). Anal.
calcd for C19H17BrFN5O5 (493.04): C, 46.17; H, 3.47; N, 14.17; found: C,
46.29; H, 3.44; N, 14.09%.
2‑(2‑(5‑Fluorouracil‑1‑yl)acetamido)ethyl‑1‑(3‑bromophenyl)‑
3‑methyl‑1H‑pyrazole‑5‑carboxylate (9-9): Yield 75.3%; m.p.
202–203 °C; IR (KBr): 3343, 2848, 1724, 1703, 1683, 1676, 1549,
1237 cm–1; 1H NMR (DMSO‑d6, δ): 2.41 (s, 3H, pyrazole-CH3),
3.48–3.50 (m, 2H, CONH–CH2), 4.30 (t, J=5.6 Hz, 2H, COO–CH2),
2‑(2‑(5‑Fluorouracil‑1‑yl)acetamido)ethyl‑1‑(2‑chlorophenyl)‑
3‑methyl‑1H‑pyrazole‑5‑carboxylate (9-16): Yield 56.3%; m.p.

278 JOURNAL OF CHEMICAL RESEARCH 2014
225–228 °C; IR (KBr): 3337, 2843, 1741, 1706, 1674, 1645, 1553,
1223 cm–1; 1H NMR (DMSO‑d6, δ): 2.12 (s, 3H, pyrazole-CH3),
3.40–3.49 (m, 2H, CONH–CH2), 4.25 (t, J=5.7 Hz, 2H, COO–CH2),
4.30 (s, 2H, N–CH2–CO), 6.80 (s, 1H, pyrazole‑CH), 7.57–7.67 (m, 3H,
Ph‑H), 7.74–7.77 (m, 1H, Ph‑H), 7.99 (d, J=6.6 Hz, 1H, CF=CH), 8.42
(t, J=5.4 Hz, 1H, CO–NH), 11.82 (s, 1H, CO–NH–CO). Anal. calcd for
C19H17ClFN5O5 (449.09): C, 50.73; H, 3.81; N, 15.57; found: C, 50.63; H,
3.85; N, 15.63%.
2‑(2‑(5‑Fluorouracil‑1‑yl)acetamido)ethyl‑1‑phenyl‑3‑methyl‑1H‑
pyrazole‑5‑carboxylate (9-17): Yield 68.4%; m.p. 176–178 °C; IR
(KBr): 3346, 2840, 1739, 1697, 1674, 1662, 1558, 1236 cm–1; 1H NMR
(DMSO‑d6, δ): 2.28 (s, 3H, pyrazole-CH3), 3.35–3.37 (m, 2H, CONH–
CH2), 4.15 (t, J=5.6 Hz, 2H, COO–CH2), 4.29 (s, 2H, N–CH2–CO),
6.92 (s, 1H, pyrazole‑CH), 7.42–7.49 (m, 5H, Ph‑H), 7.98 (d, J=6.8 Hz,
1H, CF=CH), 8.30 (t, J=5.6 Hz, 1H, CO–NH), 11.82 (s, 1H, CO–NH–
CO). Anal. calcd for C19H18FN5O5 (415.13): C, 54.94; H, 4.37; N, 16.86;
found: C, 54.85; H, 4.34; N, 16.81%.
2‑(2‑(5‑Fluorouracil‑1‑yl)acetamido)ethyl‑1‑(4‑methoxyphenyl)‑
3‑methyl‑1H‑pyrazole‑5‑carboxylate (9-18): Yield 71.1%; m.p.
202–203 °C. IR (KBr): 3314, 2827, 1731, 1697, 1670, 1660, 1558,
1230 cm–1; 1H NMR (DMSO‑d6, δ): 2.26 (s, 3H, pyrazole-CH3),
3.35–3.36 (m, 2H, CONH–CH2), 3.81 (s, 3H, O–CH3), 4.14 (t,
J=5.5 Hz, 2H, COO–CH2), 4.29 (s, 2H, N–CH2–CO), 6.88 (s, 1H,
pyrazole‑CH), 6.99 (d, J=8.9 Hz, 2H, Ph‑H), 7.33 (d, J=8.9 Hz, 2H,
Ph‑H), 7.97 (d, J=6.8 Hz, 1H, CF=CH), 8.30 (s, 1H, CO–NH), 11.82 (s,
1H, CO–NH–CO). Anal. calcd for C20H20FN5O6 (445.14): C, 53.93; H,
4.53; N, 15.72; found: C, 53.82; H, 4.45; N, 15.81%.
2‑(2‑(5‑Fluorouracil‑1‑yl)acetamido)ethyl‑1‑(4‑methylphenyl)‑
3‑methyl‑1H‑pyrazole‑5‑carboxylate (9-19): Yield 65.9%; m.p.
198–201 °C; IR (KBr): 3250, 2840, 1731, 1716, 1697, 1670, 1580,
1226 cm–1; 1H NMR (DMSO‑d6, δ): 2.27 (s, 3H, pyrazole-CH3),
2.49–2.51 (m, 3H, Ph‑CH3), 3.35–3.36 (m, 2H, CONH–CH2), 4.14
(t, J=5.5 Hz, 2H, COO–CH2), 4.28 (s, 2H, N–CH2–CO), 6.89 (s, 1H,
pyrazole‑CH), 7.25–7.26 (m, 2H, Ph‑H), 7.28–7.30 (m, 2H, Ph‑H), 7.97
(d, J=5.4 Hz, 1H, CF=CH), 8.29 (s, 1H, CO–NH), 11.81 (s, 1H, CO–
NH–CO). Anal. calcd for C20H20FN5O5 (429.14): C, 55.94; H, 4.69; N,
16.31; found: C, 55.75; H, 4.64; N, 14.40%.
2‑(2‑(5‑Fluorouracil‑1‑yl)acetamido)ethyl‑1‑(2‑metnylphenyl)‑
3‑methyl‑1H‑pyrazole‑5‑carboxylate (9-23): Yield 75.3%; m.p.
187–189 °C; IR (KBr): 3420, 2815, 1730, 1712, 1697, 1679, 1568,
1241 cm–1; 1H NMR (DMSO‑d6, δ): 1.96 (s, 3H, Ph-CH3), 2.08 (s, 3H,
pyrazole‑CH3), 3.42–3.46 (m, 2H, CONH–CH2), 4.24 (t, J=6.0 Hz,
2H, COO–CH2), 4.30 (s, 2H, N–CH2–CO), 6.78 (s, 1H, pyrazole‑CH),
7.32 (d, J=7.5 Hz, 1H, Ph‑H), 7.39 (t, J=7.0 Hz, 1H, Ph‑H), 7.45–7.50
(m, 2H, Ph‑H), 7.99 (d, J=7.0 Hz, 1H, CF=CH), 8.40 (t, J=5.5 Hz, 1H,
CO–NH), 11.80 (s, 1H, CO–NH–CO). Anal. calcd for C20H20FN5O5
(429.14): C, 55.94; H, 4.69; N, 16.31; found: C, 55.82; H, 4.72; N,
16.42%.
2‑(2‑(5‑Fluorouracil‑1‑yl)acetamido)ethyl‑1‑(3,5‑dimethylphenyl)‑
3‑methyl‑1H‑pyrazole‑5‑carboxylate (9-24): Yield 65.9%; m.p.
223–226 °C; IR (KBr): 3302, 2826, 1713, 1702, 1687, 1661, 1570,
1
1228 cm–1; H NMR (DMSO‑d6, δ): 2.36 (s, 3H, pyrazole-CH3), 2.50
(s, 6H, Ph‑CH3), 3.44–3.46 (m, 2H, CONH–CH2), 4.25 (t, J=5.5 Hz,
2H, COO–CH2), 4.28 (s, 2H, N–CH2–CO), 6.76 (s, 1H, pyrazole‑CH),
7.02–7.15 (m, 3H, Ph‑H), 7.99 (d, J=6.5 Hz, 1H, CF=CH), 8.39 (t,
J=5.5 Hz, 1H, CO–NH), 11.81 (s, 1H, CO–NH–CO). Anal. calcd for
C21H22FN5O5 (443.16): C, 56.88; H, 5.00; N, 15.79; found: C, 56.79; H,
4.94; N, 15.89%.
2‑(2‑(5‑Fluorouracil‑1‑yl)acetamido)ethyl‑1‑(4‑trif luoro‑
methoxyphenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylate (9-25): Yield
71.5%; m.p. 172–175 °C; IR (KBr): 3412, 2825, 1722, 1702, 1680, 1662,
1577, 1226 cm–1; 1H NMR (DMSO‑d6, δ): 2.36 (s, 3H, pyrazole-CH3),
3.42–3.46 (m, 2H, CONH–CH2), 4.26 (t, J=5.7 Hz, 2H, COO–CH2),
4.29 (s, 2H, N–CH2–CO), 6.80 (s, 1H, pyrazole‑CH), 7.56–7.59 (m, 2H,
Ph‑H), 7.72–7.75 (m, 2H, Ph‑H), 7.99 (d, J=6.9 Hz, 1H, CF=CH), 8.39
(t, J=5.4 Hz, 1H, CO–NH), 11.81 (s, 1H, CO–NH–CO). Anal. calcd for
C20H17F4N5O6 (499.11): C, 48.10; H, 3.43; N, 14.02; found: C, 48.01; H,
3.46; N, 14.11%.
2‑(2‑(5‑Fluorouracil‑1‑yl)acetamido)ethyl‑1‑(4‑trif luoro‑
methylphenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylate (9-26): Yield
60.2%; m.p. 145–148 °C; IR (KBr): 3411, 2825, 1720, 1698, 1685, 1660,
1578, 1227 cm–1; 1H NMR (DMSO‑d6, δ): 2.47 (s, 3H, pyrazole-CH3),
3.48–3.53 (m, 2H, CONH–CH2), 4.32 (t, J=5.6 Hz, 2H, COO–CH2),
4.35 (s, 2H, N–CH2–CO), 6.89 (s, 1H, pyrazole‑CH), 7.89–7.91 (m, 2H,
Ph‑H), 7.99–8.01 (m, 2H, Ph‑H), 8.05 (d, J=4.0 Hz, 1H, CF=CH), 8.46
(t, J=4.0 Hz, 1H, CO–NH), 11.88 (s, 1H, CO–NH–CO). Anal. calcd for
C20H17F4N5O5 (483.12): C, 49.70; H, 3.54; N, 14.49; found: C, 49.65; H,
3.64; N, 14.56%.
2‑(2‑(5‑Fluorouracil‑1‑yl)acetamido)ethyl‑1‑(3‑trif luoro‑
methylphenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylate (9-27): Yield
61.6%; m.p. 226–228 °C; IR (KBr): 3347, 2849, 1729, 1703, 1677, 1676,
1552, 1226 cm–1; 1H NMR (DMSO‑d6, δ): 2.39 (s, 3H, pyrazole-CH3),
3.43–3.46 (m, 2H, CONH–CH2), 4.27 (t, J=5.6 Hz, 2H, COO–CH2),
4.30 (s, 2H, N–CH2–CO), 6.84 (s, 1H, pyrazole‑CH), 7.83 (t, J=8.0 Hz,
1H, Ph‑H), 7.90 (s, 1H, Ph‑H), 7.93 (s, 1H, Ph‑H), 7.96 (s, 1H, Ph‑H),
8.02 (d, J=6.8 Hz, 1H, CF=CH), 8.44 (t, J=5.6 Hz, 1H, CO–NH),
11.85 (s, 1H, CO–NH–CO). Anal. calcd for C20H17F4N5O5 (483.12): C,
49.70; H, 3.54; N, 14.49; found: C, 49.79; H, 3.44; N, 14.53%.
2‑(2‑(5‑Fluorouracil‑1‑yl)acetamido)ethyl‑1‑(4‑nitrophenyl)‑
3‑methyl‑1H‑pyrazole‑5‑carboxylate (9-20): Yield 62.1%; m.p.
289–292 °C. IR (KBr): 3348, 2825, 1739, 1697, 1674, 1662, 1558,
1232 cm–1; 1H NMR (DMSO‑d6, δ): 2.27 (s, 3H, pyrazole-CH3),
3.35–3.36 (m, 2H, CONH–CH2), 4.15 (s, 2H, COO–CH2), 4.28 (s,
2H, N–CH2–CO), 6.92 (s, 1H, pyrazole‑CH), 7.94 (m, 1H, Ph‑H),
8.05–8.06 (m, 2H, Ph‑H), 8.30 (s, 1H, Ph‑H), 8.39 (d, J=0.2 Hz, 1H,
CF=CH), 8.39 (s, 1H, CO–NH), 11.81 (s, 1H, CO–NH–CO). Anal.
calcd for C19H17FN6O7 (460.11): C, 49.57; H, 3.72; N, 18.25; found: C,
49.75; H, 3.74; N, 18.19%.
2‑(2‑(5‑Fluorouracil‑1‑yl)acetamido)ethyl‑1‑(2,6‑dichloro‑4‑
(trifluoromethyl)phenyl phenyl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylate
(9-21): Yield 78.9%; m.p. 195–198 °C. IR (KBr): 3350, 2827, 1739,
1
1697, 1674, 1662, 1558, 1236 cm–1; H NMR (DMSO‑d6, δ): 2.28 (s,
2‑(2‑(5‑Fluorouracil‑1‑yl)acetamido)ethyl‑1‑(3‑chloropyridin‑
2‑yl)‑3‑methyl‑1H‑pyrazole‑5‑carboxylate (9-28): Yield 70.2%;
m.p. 158–160 °C; IR (KBr): 3343, 2839, 1739, 1697, 1674, 1662, 1558,
1232 cm–1; 1H NMR (DMSO‑d6, δ):2.31 (s, 3H, pyrazole-CH3),
3.28–3.30 (m, 2H, CONH–CH2), 4.12 (t, J=5.6 Hz, 2H, COO–CH2),
4.28 (s, 2H, N–CH2–CO), 6.96 (s, 1H, pyrazole‑CH), 7.63–7.66 (m,
1H, pyridine‑H), 7.98 (d, J=6.8 Hz, 1H, pyridine‑H), 8.20–8.22 (m,
1H, pyridine‑H), 8.29–8.31 (m, 1H, CF=CH), 8.54 (d, J=6.2 Hz, 1H,
CO–NH), 11.81 (s, 1H, CO–NH–CO). Anal. calcd for C18H16ClFN6O5
(450.08): C, 47.96; H, 3.58; N, 18.64; found: C, 47.84; H, 3.48; N,
18.57%.
3H, Ph‑CH3), 3.35–3.37 (m, 2H, CONH–CH2), 4.15 (t, J=5.6 Hz, 2H,
COO–CH2), 4.29 (s, 2H, N–CH2–CO), 6.92 (s, 1H, pyrazole‑CH),
7.63–7.65 (m, 2H, Ph‑H), 7.98 (d, J=0.65 Hz, 1H, CF=CH), 8.30 (t,
J=5.8 Hz,1H, CO–NH), 11.81 (s, 1H, CO–NH–CO). Anal. calcd for
C20H15F4Cl2N5O5 (551.04): C, 43.50; H, 2.74; N, 12.68; found: C, 43.42;
H, 2.71; N, 12.52%.
2‑(2‑(5‑Fluorouracil‑1‑yl)acetamido)ethyl‑1‑(3‑methylphenyl)‑
3‑methyl‑1H‑pyrazole‑5‑carboxylate (9-22): Yield 64.2%; m.p.
184–187 °C; IR (KBr): 3348, 2829, 1739, 1701, 1676, 1663, 1542,
1237 cm–1; 1H NMR (DMSO‑d6, δ): 2.27 (s, 3H, Ph-CH3), 2.35 (s, 3H,
pyrazole‑CH3), 3.35–3.37 (m, 2H, CONH–CH2), 4.14 (m, 2H, COO–
CH2), 4.28 (s, 2H, N–CH2–CO), 6.90 (s, 1H, pyrazole‑CH), 7.19–7.25
(m, 3H, Ph‑H), 7.32–7.35 (m, 1H, Ph‑H), 7.98 (d, J=6.5 Hz, 1H,
CF=CH), 8.30 (s, 1H, CO–NH), 11.82 (s, 1H, CO–NH–CO). Anal.
calcd for C20H20FN5O5 (429.14): C, 55.94; H, 4.69; N, 16.31; found: C,
56.02; H, 4.65; N, 16.29%.
Biological assay
All bioassays were performed on representative test organisms reared
in the laboratory. The bioassay was repeated at 25±1 °C and 60%
relative humidity according to statistical requirements. Evaluations are

JOURNAL OF CHEMICAL RESEARCH 2014 279
4
L. Olivier, D. Patricia, T. Stephan, E. Andrew and J. Andre, WO
2007093402, 2007.
C.D. Alan and L.G. Pilip, WO 2003062226, 2003.
Q.Q. Zhan, Y.Q. Li, L.X. Xiong and Q.Q. Wang, J. Agric. Food Chem.,
2010, 58, 4992.
C.D. The‑wei, B.H.M. Martinus, K. Anke, T. Maria‑Theresia, S. Stefan, D.
Uwe, H. Jamin and S. Karl, WO 2003074493, 2003.
H. Markus, L. Norbert, E. Christoph, W.‑N. Ulrike and D.H. Wilhelm, DE
4405207, 1995.
based on KT50 and knock down rate (24 h). The standard deviations of
the tested biological values were ±5%.
5
6
Insecticidal activities against Culex pipiens and Musca domestica:
The bioassays were performed according to the literature.30 Pests
(20) were released into the cylinder from an orifice and the aerosol
insecticide was sprayed into the cylinder from the spraying hole. After
1 minute, the numbers of the test pests knocked down at regular time
intervals were counted. For each compound, insecticidal activities
were expressed as the mean of values obtained in three independent
experiments.
7
8
9
F.B. Lawrence, T.A. Edmund, L.J. Keith, WO 2008124092, 2008.
10 S. Mio, E. Okui and T. Imai, JP 2008260706, 2008.
11 M. Hiroshi, I. Tomoaki, T. Shinji and M. Masayuki, JP 2005008628, 2005.
12 E. Yasuhiro and S. Yuichi, WO 2013015429, 2013.
13 D.B. Longley, D.P. Harkin and P.G. Johnston, Nat. Rev. Cancer, 2003, 3,
330.
14 C.Y. Cheng, Y.H. Lin and C.C. Su, Mol. Med. Rep., 2010, 3, 227.
15 S.C. Lee, J.Y. Chan and S. Pervaiz, Cancer. Lett., 2010, 288, 36.
16 G. Saroj, J. Surg. Oncol., 1982, 21, 94.
This work was supported by the Key Technology R&D Program
of the Science and Technology Department of Jiangsu Province
(No. BE2011352) for financial support. We thank Jiangsu
Pesticide Research Institute Co., Ltd, and Jiangsu Yangnong
Chemical Co., Ltd for facilities for testing the insecticidal
activity.
17 H.J. Won, T.K. Ha and C.H. Sung, Anti‑Cancer Drugs, 2010, 21, 270.
18 M. Zemanova, L. Petruzelka and A. Pazdro, Diseas. Esophagus, 2010, 23,
160.
19 R. Wan, J.Q. Zhang, F. Han, P. Wang, P. Yu and Q. He, Nucleosides,
Nucleotides Nucleic Acids, 2011, 30, 280.
20 R. Wan, Y. Chen, H.P. Mu, Y. Yang, X.D. Fu, X.F. Qin and C. Shen, CN
103214465, 2013.
21 I.L. Finar and R.J. Hurlock, J. Chem. Soc., 1958, 3259.
22 A.C. Boris and J.W. William, J. Label Compd. Radiopharm., 2005, 48, 407.
23 C. Gyogyszer, NL 6613374, 1965.
Received 22 December 2012; accepted 1 March 2014
Paper 1302359 doi: 10.3184/174751914X13955977912102
Published online: 6 May 2014
References
24 S. Erich, EP 333131, 1989.
1
2
3
G.P. Lahm, T.M. Stevenson, T.P. Selby, Bioorg. Med. Chem. Lett., 2007, 17,
6274.
Y.F. Sun, H.L. Qiao, Yun. L.S.X. Yang, C.H. Rui, P. Pelosi and X.L. Yang,
J. Agric. Food Chem., 2011, 59, 2456.
F.B. Lawrence, L.G. Pilip, M.S. Frederick, S. Ying and S.T. Martin, WO
03016284, 2003.
25 M. Carlo, Gazz. Chim. Ital., 1949, 79, 666.
26 B.A. Tertov, Khim. Geterotsikl. Soed., 1975, 392.
27 N. Tetsuo, Bull. Chem. Soc. Japan, 1965, 38, 362.
28 K.C. Chang, Austral. J. Chem., 1979, 32, 1727.
29 P. Helmut, Coll. Czech. Chem. Commun., 1982, 47, 2806.
30 M.Z. Qi and J.W. Zhao, CN 101632381, 2010.