Synthesis of pyrazolylvinyl ketones from furan derivatives

Article abstract of DOI:10.1039/c9ob00701f

A new protocol for the synthesis of pyrazol-5-ylvinyl ketones, e.g. pyrazole-chalcones, employing furfuryl ketones as a triketone equivalent, has been developed. The reaction occurs under mild conditions and does not require the use of expensive materials

Full text of DOI:10.1039/c9ob00701f

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DOI: 10.1039/C9OB00701F
ARTICLE
Synthesis of pyrazolylvinyl ketones from furan derivatives
Nattawut Sawengngen,a Petrakis N. Chalikidi,b Sara Araby,a Frank Hampel,c Peter Gmeinera and
Olga V. Serdyuk*a
Received 00th January 20xx,
Accepted 00th January 20xx
A new protocol for the synthesis of pyrazol-5-ylvinyl ketones, e. g. pyrazole-chalcones, employing furfuryl ketones as a
triketone equivalent, has been developed. The reaction occurs under mild conditions and does not require the use of
expensive materials. Other important benefits include simplicity and atom efficiency of this approach.
DOI: 10.1039/x0xx00000x
Introduction
A common route for the synthesis of pyrazole-chalcones is the
Claisen–Schmidt condensation of corresponding pyrazole
The pyrazole ring is an important structural subunit in various
bioactive compounds including many marketed drugs.1 Pyra-
zole derivatives demonstrate potent anticancer activity by the
inhibition of topoisomerase II,2 tubulin,3 mTOR,4 proto-
oncogene B-RAF,5 cyclin-dependent kinases (CDK),6 phos-
phatidylinositide 3-kinases (PI3K),7 anaplastic lymphoma
kinases (ALK),8 and other pharmacologically relevant targets.9
On the other hand, heterocyclic chalcones turned out to be
privileged scaffolds with a great pharmacological potential in
medicinal chemistry.10 For example, pyrazole-chalcones bear-
ing a pyrazole ring instead of phenyl B-ring and an α,β-
unsaturated ketone motif, represent promising anticancer11
and antitumor agents (Figure 1).12 Furthermore, they can
serve as precursors of valuable linked pyrazoles.11b,13
aldehydes.14,15 However, the application of this method for the
preparation of pyrazol-5-yl derivatives has been a long time
limited due to the synthetic inaccessibility of pyrazol-5-yl
carbaldehydes. In 2017, the first pyrazol-5-ylvinyl ketones,
including chalcone analogues, were reported by Kamal et al.
(Figure 2). These compounds induced cell cycle arrest, mito-
chondrial membrane depolarization and apoptosis in a human
breast cancer cell line (MCF-7) in a nanomolar range and can
be considered as potential lead structures in the development
of tailored cancer therapeutics.16
MeO
MeO
OMe
OMe
OMe
MeO
OMe
OMe
Me
MeO
O
O
N
N
N
H
N
H
4
3
O
O
IC50 = 0.43 M
A
Ar
B
N
5
N

IC50 = 20.1 M
R
chalcone
pyrazole based chalcone
analogues (pyrazole-chalcones)
Fig. 2 Pyrazol-5-ylvinyl ketones possessing strong activity against breast cancer
cell line MCF-7.
Fig. 1 Structure of chalcone and pyrazole-chalcones.
The reported synthetic sequence included the Knorr pyrazole
synthesis, reduction of 1H-pyrazole-5-carboxylates to give
pyrazol-5-yl methanols, their oxidation to corresponding alde-
hydes, and the subsequent Claisen–Schmidt condensation
(Scheme 1a). The products were obtained in 23-40% yields
over 5 steps. We supposed that readily available furfuryl ke-
tones17 can be considered as a triketone equivalent and might
serve as efficient precursors of the desired molecules (Scheme
1b). Herein, we report a new simple method for the synthesis
of pyrazol-5-ylvinyl ketones, e.g. pyrazole-chalcones, from
furan derivatives.
a. Department of Chemistry and Pharmacy, Institute of Medicinal Chemistry,
University of Erlangen-Nuremberg, Nikolaus-Fiebiger-Str. 10, Erlangen, 91058,
Germany. E-mail: olga@serdyuk.de
b. K. L. Khetagurov North-Ossetian State University, Vatutina 43-46, Vladikavkaz,
362025, Russian Federation.
c. Department of Chemistry and Pharmacy, Institute of Organic Chemistry I,
University of Erlangen-Nuremberg, Nikolaus-Fiebiger-Str. 10, Erlangen, 91058,
Germany.
†
Electronic Supplementary Information (ESI) available: complete compound
characterisation data, copies of the 1H and 13C NMR spectra, copies of the HMBC,
HSQC, COSY, and NOESY spectra, complete LC-MS data, X-Ray data. CCDC 1877820
contains the supplementary crystallographic data for this paper. See
DOI: 10.1039/x0xx00000x
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a) Previous work: 5 steps
O
We supposed that the second reaction of the domino
sequence 1a→2a→3a could be affected by temperature. At 80
R1
View Article Online
DOI: 10.1039/C9OB00701F
O
O
OEt
O
R1
N
R1
Me
°C, the product 3a was apparently formed in higher yield
(Figure 3b). In 24 h, we observed the full conversion of 1a and
the formation of 3a as a main product (Figure 3c). The use of 2
equiv of phenyl hydrazine hydrochloride did not improve the
outcome of the reaction. In both experiments, with 1 equiv or
N
O
H
EtO
O
R1
R1
R1
O
N
N
N
N
H
N
H
N
R2
H
HO
H
.
2 equiv of PhNHNH2 HCl, the yield of 3a was 50%. Pyrazole 3a
b) This work: 3 steps
R2
O
O
O
N
was obtained as
a mixture of (E)- and (Z)-isomers.
S
S
R1
Br
R1
Nevertheless, it did not require further separation, while it was
quantitatively converted into the pure (E)-isomer under
heating with iodine (Scheme 3).18 Complete characterization
was performed for the desired product (E)-3a, the overall yield
of which was 50%.
OEt
R1
O
O
R2
N
R1
O
R2
R3
1
2
To illustrate the scope of the reaction, a series of furfuryl
ketones has been synthesized and subjected to the optimized
reaction conditions with phenyl hydrazine hydrochloride
(Scheme 3). Each product 3 was prepared in a pure (E)-form
through E/Z isomerization and fully characterized (Figure 4).
Scheme 1 Synthesis of pyrazol-5-ylvinyl ketones: previous approach and this
work.
Results and discussion
O
Ph
Et
First, we studied the reaction of easily available furfuryl ke-
tone 1a17c with phenyl hydrazine hydrochloride (Scheme 2).
The solution of furfuryl ketone 1a, phenyl hydrazine hydro-
chloride, and sodium acetate in ethanol was stirred at room
temperature. Surprisingly, the LC-MS data of the reaction
mixture in 5 min did not only indicate hydrazone 2a along with
the starting compound, but some traces of the target pyrazole
3a as well (Figure 3a. For complete data, see SI).

(E)-3e
+
N
N
J
= 12.7 Hz

HPrz
HAr
HAr
Ph
α
H
β
H
2
(Z)-3e
Ph
J
z
= 16.0 H
HPrz

HAr
O
α
H
HAr
β
H
N
1
N
Et

Ph
(E)-3e
6.5 6.4
8.0
7.9
7.8
7.7
7.6
7.5
7.4
7.3
7.2
7.1
7.0
6.9
6.8
6.7
6.6
6.3
6.2
Fig. 4 Monitoring of E/Z Isomerization: selected sections of the 1H NMR spectra
of (E)-3e [1] and (E,Z)-3e [2] in CDCl3.
PhNHNH2.HCl
NH
O
N
Me
Me
O
NaOAc, EtOH
80C
O
The yields of pyrazoles 3 were moderate to good (37-68%)
when R2 was a phenyl group bearing a halogen or electron-
neutral H atom. When R2 was methyl or methoxy-substituted
phenyl group, the corresponding pyrazoles 3d and 3f were
obtained in 42 and 32%, respectively. Obviously, electron
donating substituents reduce the electrophilicity of the
carbonyl that leads to lower yields of pyrazoles 3d and 3f.
In respect of R1, alkyl groups are generally more favored, but
their electronic effect does not play crucial role, leading to
pyrazoles 3 in comparable yields. Thus, the reaction worked
well for furfuryl ketones bearing methyl, ethyl, and butyl
groups. When R1 was an aromatic phenyl group, pyrazole-
chalcone 3i was isolated in low 37%. Importantly, the reaction
1→3 could be performed on gram scale without detriment to
the yield. The structure of the product (E)-3h was confirmed by
the single-crystal X-Ray diffraction (Figure 5).
1a
MW: 200.2370
2a
MW: 290.3660
O
N
N
Me
3a (50% isolated yield), E/ Z (NMR) = 1.8 : 1
MW: 288.3500
Scheme 2 Model reaction. Conditions: 2 mmol of furfuryl ketone, 2 mmol of
phenyl hydrazine hydrochloride, 4 mmol of sodium acetate, 5 mL of EtOH.
mAU
m/z = 290.98
m/z = 288.97
m/z = 200.84
a) 5 min, r.t.
Next, the scope of hydrazines was investigated. The reaction
with hydrochlorides of phenyl hydrazine, p-tolyl hydrazine, and
p-methoxy phenyl hydrazine, afforded pyrazoles 3 in good
yields (52-53%). The pyrazole-chalcone 3m (R1 = Ph) was
isolated in 24% yield as a (E)-isomer. Interestingly, an
experiment with 2-bromophenyl hydrazine hydrochloride
provided hydrazone 2n instead of an expected pyrazole,
because of reduced nucleophilicity of the nitrogen and
b) 1 h, 80 °C
c) 24 h, 80 °C
Time, min
Fig. 3 LC-MS control of the reaction 1a→3a: UV chromatograms (254 nm).
2 | J. Name., 2012, 00, 1-3
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ARTICLE
additionally, the steric hindrance (Fig. 6). No further cyclization 2o was obtained in low yield. The prolongation of the reaction
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was observed at higher temperature, using i-PrOH as a solvent, time and the use of an excess of hydrDaOziIn: e10.d10ih39y/dCr9oOcBh0lo0r7i0d1eF
or under microwave irradiation. When the reaction was failed to produce any product.
performed with unprotected hydrazine dihydrochloride, azine
R2
R3NHNH2.HCl
I2, 5%
O
O
R1
3
(E,Z)-
N
R2
O
N
R3
toluene, 140 
MW, 2 h
C
R1
NaOAc, EtOH
80 oC, 24 h
1
(E)-3
OMe
Br
F
O
O
O
O
Me
Me
Me
Me
N
N
N
N
N
N
N
N
Ph
Ph
Ph
Ph
3a (54%) for gram scale
E/ Z = 1.8 : 1
3b (53%)
E/ Z = 1 : 2
3c (68%)
E/ Z = 7.5 : 1
3d (42%)
E/ Z = 1 : -
F
F
Me
O
O
O
O
Et
Bu
Et
Et
N
N
N
N
N
N
N
N
Ph
Ph
Ph
Ph
3e (50%)
3f (32%)
3g (53%)
3h (52%)d
E/ Z = 1.3 : 1
E/ Z = 1.3 : 1
E/ Z = 1.3 : 1
E/ Z = 1.1 : 1
F
F
F
O
O
O
F
O
Me
Et
Et
N
N
N
N
N
N
N
N
Ph
Me
Me
MeO
3i (37%)d
3j (53%)
3k (53%)
3l (52%)
E/ Z = 6.5 : 1
E/ Z = 64 : 1
E/ Z =12 : 1
E/ Z = 6.3 : 1
F
O
N
N
3m (24%)
E/ Z = 1 : -
MeO
Scheme 3 Reaction scope.a,b,c
a2 mmol scale. bIsolated yields. cThe ratio (E/Z) was determined according the NMR data. dE/Z Isomerization was performed in 6 h.
F
O
Br
Et
NH
N
N
N
Et
O
Et
O
F
F
2n (50%)
2o (24%)
Fig. 6 Isolated hydrazone 2n and azine 2o.
Fig. 5 Structure of (E)-3h.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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A plausible mechanism for the reaction 1 → 3 is presented at
Scheme 4. It starts with the formation of hydrazone 2. The
subsequent nucleophilic attack of nitrogen on the C(2) atom of
the furan ring affords spyrocyclic intermediate A. The ring
opening of A results in the formation of intermediate B which
undergoes further aromatization to give the final compounds
3.
Experimental
General remarks
All commercial products and solvents were used without
further purification. All reactions were run under the air unless
noted otherwise.
View Article Online
DOI: 10.1039/C9OB00701F
The reactions under microwave irradiation were conducted in
Microwave Synthesis Reactor «Biotage® Robot Eight» using
sealed microwave reaction vessels. TLC analyses were
performed on Merck 60 F254 aluminum plates in combination
with UV detection (254 nm). Flash chromatography was
performed on silica gel 200-300 mesh using mixture EtOAc/i-
hexane as eluents. Melting points were determined on a Mel-
Temp II Laboratory Devices apparatus; the values are
uncorrected. NMR spectra were recorded on a Bruker AV-600
(1H NMR at 600 MHz and 13C NMR at 151 MHz) and Bruker AV-
400 (1H NMR at 400 MHz and 13C NMR at 101 MHz)
spectrometers. Proton chemical shifts (δ) are reported in parts
per million (ppm) relative to tetramethylsilane (TMS) with the
solvent resonance employed as the internal standard (CDCl3 δ
= 7.26 ppm). Data are reported as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, dd = doublet of doublets, dt = doublet of triplets),
coupling constants (J) and integration. Coupling constants (J)
are reported in Hertz (Hz). Carbon chemical shifts are reported
in ppm from tetramethylsilane (TMS) with the solvent
resonance as the internal standard (CDCl3 δ = 77.16 ppm).
IR spectra were measured on PerkinElmer Spectrum BX
spectrophotometer (KBr and NaCl plates). HRMS-ESI spectra
were recorded at the Chair of Organic Chemistry, Friedrich
Alexander University of Erlangen-Nuremberg. LC-MS data were
obtained on a BRUKER ESQUIRE 2000 using electrospray
ionization (ESI), DAD detector, and a Kinetex C8 analytical
column (2.1 mm x 75 mm, 2.6 μm).
R3
R3NHNH2.HCl
O
NH
R1
N
2 equiv NaOAc
R2
R1
O
R2
O
2
1
R3
N
R3
N
R3
R1
R1
N
N
N
N
O
O
O
R2
R1
R2
R2
A
B
(E,Z)-3
Scheme 5 Proposed mechanism.
Importantly, an active enone fragment, one of the key
structural benefits of compounds 3, can be utilized for further
functionalization of products, leading to the great structural
diversity.19 Thus, the reaction of 3g with 1-(2-
methoxyphenyl)piperazine produced a product of aza-Michael
addition in 50% yield (Scheme 6). This simple experiment
illustrates that various functionalities can be easily
incorporated into the reported scaffold via standard chemical
transformations to affect pharmacological properties.
H
N
F
F
N
OMe
O
General procedure for the synthesis of pyrazoles 3
N
O
Hydrazine hydrochloride (2 mmol) and anhydrous NaOAc (4
mmol) were added to a solution of furfuryl ketone 1 (2 mmol)
in ethanol (5 mL), and the mixture was stirred for 24 hours at
80 °C (TLC and LC-MS control). Then, the reaction mixture was
poured into H2O (100 mL) and extracted with EtOAc (4 × 25
mL). The combined organic phases were washed with brine,
dried over anhydrous Na2SO4, filtered, and evaporated under
reduced pressure. The resulting crude product was purified by
flash chromatography using EtOAc/i-Hex as eluents to give a
mixture of (E,Z)-isomers which was isomerized to give (E)-3.
N
Et
N
N
N
Et
DCM, r. t.
24 h
N
OMe
4 (50%)
3g
Scheme 6 Aza-Michael addition.
Conclusions
Isomerization (E,Z)-3 → (E)-3
In summary, we have described a novel synthetic route to
pyrazol-5-ylvinyl ketones, employing furfuryl ketones as a
triketone equivalent. The method shows a wide substrate
scope, working especially well for furfuryl ketones bearing an
alkyl group at the furan ring. Due to the availability of starting
compounds, simplicity of the protocol, and atom efficiency of
our approach, the developed procedure represents a valuable
alternative to the known 5 step strategy. Further exploration
of the reaction scope, in particular, the use of removable
protecting groups, is underway in our laboratory.
Microwave reaction vessel was charged with (E,Z)-3 (0.2
mmol), I2 (0.0034 g, 0.013 mmol) and toluene (5 mL). The
reaction mixture was stirred at 140 °C in a microwave reactor
for 2-6 hours. After completion of the reaction, toluene and
iodine were removed under reduced pressure to afford pure
(E)-3.
For compounds with R1=Me the isomerization might be
achieved by heating of the reaction mixture with iodine at 80
°C.
4 | J. Name., 2012, 00, 1-3
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Characterization data of representative compounds (E)-3
(E)-(4-(1,3-Diphenyl-1H-pyrazol-5-yl)but-3-en-2-one ((E)-3a). (NaCl): 1691 (C=O), 1611, 1499, 1443, 1352, 1234, 1185, 956
Yield 0.29 g (50%). Yellow solid. M. p. 110–112 °C. 1H NMR cm-1. HRMS (ESI): m/z calcd. for C21H20N2O [M+H]+: 317.1654;
(400 MHz, CDCl3): δ = 7.92–7.91 (m, 2H), 7.58–7.35 (m, 9H), found: 317.1657.
ARTICLE
132.1, 131.7, 129.7, 129.6, 107.3, 38.7, 25.3, 12.0 ppm. IR
View Article Online
DOI: 10.1039/C9OB00701F
7.09 (s, 1H), 6.74 (dd, J = 16.1, 1.4 Hz, 1H), 2.32 (d, J = 1.4 Hz, (E)-1-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-5-yl)pent-1-
3H) ppm. 13C NMR (101 MHz, CDCl3): δ = 196.9, 151.9, 139.3, en-3-one ((E)-3g). Yield 0.34 g (53%). Yellow solid. M. p. 111–
138.4, 131.9, 129.0, 128.5, 128.3, 128.3, 128.2, 127.9, 125.3, 113 °C. 1H NMR (600 MHz, CDCl3): δ = 7.87–7.84 (m, 2H), 7.55–
125.1, 103.1, 27.6 ppm. IR (NaCl): 1691 (C=O), 1608, 1502, 7.46 (m, 5H), 7.39 (d, J = 16.0 Hz, 1H), 7.14–7.10 (m, 2H), 7.01
1348, 1241, 943 cm-1. HRMS (ESI): m/z calcd. for C19H16N2O (s, 1H), 6.74 (d, J = 16.0 Hz, 1H), 2.62 (q, J = 7.3 Hz, 2H), 1.14 (t,
[M+H]+: 289.1341; found: 289.1335.
J = 7.3 Hz, 3H) ppm. 13C NMR (101 MHz, CDCl3): δ = 200.2,
(E)-4-(3-(4-Bromophenyl)-1-phenyl-1H-pyrazol-5-yl)but-3-en- 164.2, 161.7, 151.4, 140.2, 138.8, 129.6, 128.0, 128.0, 127.6,
2-one ((E)-3b). Yield 0.38 g (53%). Yellow solid. M. p. 108–110 127.6, 125.6, 115.8, 115.6, 103.3, 34.8, 8.1 ppm. IR (NaCl):
°C. 1H NMR (400 MHz, CDCl3): δ = 7.69–7.65 (m, 2H), 7.48–7.40 1669 (C=O), 1609, 1499, 1446, 1231, 1156, 763 cm-1. HRMS
(m, 7H), 7.25 (d, J = 16.1 Hz, 1H), 6.95 (s, 1H), 6.63 (d, J = 16.1 (ESI): m/z calcd. for C20H17FN2O [M+H]+: 321.1403; found:
Hz, 1H), 2.22 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3): δ = 321.1392.
197.4, 151.3, 140.0, 138.8, 131.9, 131.9, 129.6, 129.0, 128.9, (E)-1-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-5-yl)hept-1-
128.8, 127.4, 125.6, 122.4, 103.5, 28.2 ppm. IR (NaCl): 1736 en-3-one ((E)-3h). Yield 0.36 g (52%). White solid. M. p. 121–
(C=O), 1604, 1503, 1447, 1349, 1246, 1145, 983 cm-1. HRMS 123 °C. 1H NMR (400 MHz, CDCl3): δ = 7.80–7.77 (m, 2H), 7.47–
(ESI): m/z calcd. for C19H15BrN2O [M+H]+: 367.0446; found: 7.41 (m, 5H), 7.30 (d, J = 16.0 Hz, 1H), 7.07–7.03 (m, 2H), 6.95
367.0441.
(s, 1H), 6.67 (d, J = 16.0 Hz, 1H), 2.51 (t, J = 7.4 Hz, 2H), 1.59–
1.50 (m, 2H), 1.29–1.25 (m, 2H), 0.85 (t, J = 7.3 Hz, 3H) ppm.
(E)-4-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-5-yl)but-3-en-
2-one ((E)-3c). Yield 0.42 g (68%). Yellow solid. M. p. 145–147 13C NMR (151 MHz, CDCl3): δ = 198.8, 162.7, 161.1, 150.4,
°C. 1H NMR (400 MHz, CDCl3): δ = 7.79–7.76 (m, 2H), 7.46–7.38 139.1, 137.9, 128.5, 127.7, 127.1, 127.0, 126.5, 126.5, 124.6,
(m, 5H), 7.26 (d, J = 16.1 Hz, 1H), 7.07–7.01 (m, 2H), 6.93 (s, 114.7, 114.6, 102.2, 40.3, 25.3, 21.4, 12.8 ppm. IR (NaCl): 1660
1H), 6.63 (d, J = 16.1 Hz, 1H), 2.22 (s, 3H) ppm. 13C NMR (101 (C=O), 1608, 1498, 1447, 1224, 1157, 956 cm-1. HRMS (ESI):
MHz, CDCl3): δ = 197.4, 164.2, 161.7, 151.5, 140.0, 138.8, m/z calcd. for C22H21FN2O [M+H]+: 349.1716; found: 349.1703.
129.5, 128.9, 128.9, 127.6, 127.5, 125.6, 115.8, 115.6, 103.4, (1-(2-Bromophenyl)-2-(2-(5-ethylfuran-2-yl)-1-(4-
28.1 ppm. IR (NaCl): 1741 (C=O), 1622, 1507, 1487, 1377, 1236, fluorophenyl)ethylidene)-hydrazine (2n). Yield 0.4 g (50%).
1
982, 956 cm-1. HRMS (ESI): m/z calcd. for C19H15FN2O [M+H]+: Yellow solid. M. p. 76–78 °C (EtOAc/i-Hex = 1:7). H NMR (600
307.1247; found: 307.1241.
MHz, CDCl3): δ = 8.36 (s, 1H), 7.87–7.84 (m, 2H), 7.62–7.60 (m,
(E)-4-(3-(4-Methoxyphenyl)-1-phenyl-1H-pyrazol-5-yl)but-3-
1H), 7.44–7.43 (m, 1H), 7.29–7.26 (m, 1H), 7.11–7.06 (m, 2H),
en-2-one ((E)-3d). Yield 0.27 g (42%). Beige solid. M. p. 125– 6.76–6.73 (m, 1H), 6.12 (d, J = 3.1 Hz, 1H), 5.89 (d, J = 3.1 Hz,
127 °C (EtOAc/Hex = 1:4). 1H NMR (400 MHz, CDCl3): δ = 7.85– 1H), 4.07 (s, 2H), 2.61 (q, J = 7.6 Hz, 2H), 1.19 (t, J = 7.6 Hz, 3H)
7.83 (m, 2H), 7.58–7.47 (m, 5H), 7.34 (d, J = 16.1 Hz, 1H), 7.02– ppm. 13C NMR (101 MHz, CDCl3): δ = 164.2, 161.8, 157.8,
6.98 (m, 3H), 6.73 (d, J = 16.1 Hz, 1H), 3.87 (s, 3H), 2.33 (s, 3H) 146.3, 142.7, 142.7, 142.2, 132.3, 128.5, 127.8, 127.7, 120.9,
ppm. 13C NMR (101 MHz, CDCl3): δ = 197.6, 159.8, 152.2, 115.5, 115.3, 114.7, 108.0, 104.8, 27.1, 21.5, 12.2 ppm. IR
139.7, 138.9, 129.5, 129.2, 128.7, 128.6, 127.1, 125.6, 125.1, (NaCl): 2974, 1602, 1508, 1232, 1158, 1012, 843 cm-1. HRMS
114.1, 103.1, 55.4, 28.1 ppm. IR (NaCl): 1667 (C=O), 1652, (ESI): m/z calcd. for C20H18BrFN2O [M+H]+: 401.0665; found:
1613, 15919, 1498, 1452, 1438, 1426, 1361, 1243, 1179. HRMS 401.0631.
(ESI): m/z calcd. for C20H18N2O2 [M+Na]+: 341.1266; found: 1,2-Bis(2-(5-ethylfuran-2-yl)-1-(4-
341.1255.
fluorophenyl)ethylidene)hydrazine (2o). Yield 0.22 g (24%).
1
(E)-1-(1,3-Diphenyl-1H-pyrazol-5-yl)pent-1-en-3-one ((E)-3e). Yellow solid. M. p. 76–78 °C. H NMR (600 MHz, CDCl3): δ =
Yield 0.15 g (50%). Yellow solid. M. p. 98–101 °C. 1H NMR (600 7.96–7.94 (m, 2H), 7.09–7.06 (m, 2H), 5.77–5.74 (m, 2H), 4.22
MHz, CDCl3): δ = 7.89–7.88 (m, 2H), 7.55–7.35 (m, 9H), 7.07 (s, (s, 2H), 2.52 (q, J = 7.5 Hz, 2H), 1.13 (t, J = 7.6 Hz, 3H) ppm. 13
C
1H), 6.76 (d, J = 16.0 Hz, 1H), 2.62 (q, J = 7.3 Hz, 2H), 1.14 (t, J = NMR (151 MHz, CDCl3): δ = 164.7, 163.0, 158.0, 156.5, 148.2,
7.3 Hz, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 200.1, 152.3, 133.4, 129.4, 129.3, 115.4, 115.2, 107.3, 104.7, 28.3, 21.3, 12.1
140.0, 139.0, 132.4, 129.5, 128.7, 128.6, 128.6, 128.3, 128.1, ppm. IR (NaCl): 1592, 1504, 1458, 1232, 1153, 1020, 840 cm-1.
127.8, 125.8, 125.6, 103.4, 34.7, 8.0 ppm. IR (NaCl): 1691 HRMS (ESI): m/z calcd. for C28H26F2N2O2 [M+H]+: 461.2041;
(C=O), 1613, 1498, 765 cm-1. HRMS (ESI): m/z calcd. for found: 461.2025.
C20H18N2O [M+H]+: 303.1497, found: 303.1494.
1-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-5-yl)-1-(4-(2-
(E)-1-(1-Phenyl-3-(p-tolyl)-1H-pyrazol-5-yl)pent-1-en-3-one
methoxyphenyl)piperazin-1-yl)pentan-3-one (4)
1
((E)-3f). Yield 0.2 g (32%). Yellow solid. M. p. 129–132 °C. H Pyrazolylvinyl ketone 3g (0.045 g, 0.14 mmol) and 1-(2-
NMR (600 MHz, CDCl3): δ = 7.78–7.77 (m, 2H), 7.54–7.45 (m, methoxyphenyl)piperazine (0.028 mL, 0.16 mmol) were mixed
5H), 7.39 (d, J = 16.0 Hz, 1H), 7.26–7.23 (m, 2H), 7.04 (s, 1H), in 4 mL of DCM. Sodium triacetoxyborohydride (0.038 g, 0.18
6.74 (d, J = 16.0 Hz, 1H), 2.61 (q, J = 7.3 Hz, 2H), 2.39 (s, 3H), mmol) was added to the above solution and the mixture was
1.14 (t, J = 7.3 Hz, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = stirred at room temperature under nitrogen for 24 h. The
204.1, 156.4, 143.9, 143.0, 142.2, 133.6, 133.4, 133.4, 132.6, solution was washed with brine, dried over anhydrous Na2SO4,
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J. Name., 2013, 00, 1-3 | 5
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Organic & Biomolecular Chemistry
Page 6 of 6
ARTICLE
Journal Name
chalcone analogues, see: (b) M. N. Gomes, E. N. Muratov,
M. Pereira, J. C. Peixoto, L. P. Rosseto, P. V. LV. ieCwraArvtiocl,e CO.nliHne.
Andrade, B. J. Neves. Molecules 2017,D2O2I:, 1102.11003.9/(Cc)9OPB. 0S0in70g1hF,
A. Anand, V. Kumar. Eur. J. Med. Chem. 2014, 85, 758. (d) V.
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filtered, and evaporated under reduced pressure. The resulting
crude product was purified by flash chromatography using
EtOAc/i-Hex as eluents to give 4. Yield 0.036 g (50%).
1H NMR (400 MHz, CDCl3): δ = 7.84–7.75 (m, 4H), 7.52–7.40
(m, 3H), 7.12– 6.81 (m, 6H), 6.52 (s, 1H), 4.56–5.53 (m, 1H),
3.82 (s, 3H), 3.15–2.91 (m, 6H), 2.56–2.44 (m, 6H), 1.04 (t, J =
7.3 Hz, 3H) ppm. 13C NMR (101 MHz, CDCl3): δ = 208.69,
150.13, 142.82, 140.99, 129.03, 128.22, 127.47, 127.39,
126.34, 125.62, 123.06, 120.89, 118.14, 115.59, 115.38,
110.94, 102.74, 55.30, 54.80, 50.89, 48.83, 42.99, 36.70, 7.68
ppm. HRMS (ESI): m/z calcd. for C31H33FN4O2 [M+H]+:
513.2666; found: 513.2657.
11 For selected examples, see: (a) U. Sankappa Rai, A. M. Isloor,
P. Shetty, K. S. R. Pai, H. K. Fun. Arab. J. Chem. 2015, 8, 317.
(b) B. Insuasty, A. Tigreros, F. Orozco, J. Quiroga, R. Abonia,
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13 (a) R. Pundeer, V. Kiran Sushma, C. Sharma, K. R. Aneja, O.
Prakash, O. Med. Chem. Res. 2013, 22, 4715. (b) G. P. Rosa,
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
14 For selected recent examples, see: (a) E. S. Ramadan, E. M.
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We thank Prof. Dr. Vladimir Abaev (K. L. Khetagurov North-
Ossetian State University) and Dr. Jürgen Einsiedel
(Department of Chemistry and Pharmacy, Institute of
Medicinal Chemistry, University of Erlangen-Nuremberg) for
helpful discussion.
16 A. B. Shaik, G. K. Rao, G. B. Kumar, N. Patel, V. S. Reddy, I.
Khan, S. R. Routhu, C. G. Kumar, I. Veena, K. C. Shekar, M.
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6 | J. Name., 2012, 00, 1-3
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