Synthesis of (E)- and (Z)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles

Article abstract of DOI:10.1007/s00706-008-0002-9

An efficient synthesis method for the preparation of a series of new (Z)- and (E)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles was developed. The reaction of (Z)- and (E)-3-styrylchromones with hydrazine hydrate afforded the corresponding (Z)- and (E)-3(5)-(2

Full text of DOI:10.1007/s00706-008-0002-9

Monatsh Chem (2009) 140:87–95
DOI 10.1007/s00706-008-0002-9
ORIGINAL PAPER
Synthesis of (E)- and (Z)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles
Vera L. M. Silva Æ Artur M. S. Silva Æ
´
Diana C. G. A. Pinto Æ Jose A. S. Cavaleiro Æ
´
Jose Elguero
Received: 1 June 2008 / Accepted: 4 June 2008 / Published online: 3 September 2008
Ó Springer-Verlag 2008
Abstract An efficient synthesis method for the prepara-
tion of a series of new (Z)- and (E)-3(5)-(2-hydroxy-
phenyl)-4-styrylpyrazoles was developed. The reaction of
(Z)- and (E)-3-styrylchromones with hydrazine hydrate
afforded the corresponding (Z)- and (E)-3(5)-(2-hydroxy-
phenyl)-4-styrylpyrazoles, except for nitro derivatives,
where both (Z)- and (E)-40-nitro-3-styrylchromones affor-
ded (E)-3(5)-(2-hydroxyphenyl)-4-(4-nitrostyryl)pyrazoles.
The reaction mechanism for these transformations is
discussed and the stereochemistries of all products were
established by NMR experiments.
activity, making them good candidates for the treatment of
neurodegenerative diseases (such as Parkinson’s and Alz-
heimer’s) [10, 11] and hypercholesterolemia [12]. In the last
decade, this type of compounds has received considerable
attention, since some well-known drugs such as sildenafil
(Viagra), rimonabant (Acomplia) and celecoxib (Celebrex)
are pyrazole derivatives [1]. The numerous applications of
pyrazoles have led to the development of numerous methods
for the synthesis of this family of compounds [5–7].
The important properties of 3(5)-(2-hydroxyphenyl)
pyrazoles as ultraviolet stabilizers [13, 14], analytical
reagents in the complexation of transition metal ions [15],
analgesic agents, platelet aggregation inhibitors [16], and
also potent inhibitors of Hsp90 ATP-ase activity [17–21]
highlight these particular compounds as targets for the
preparation of new derivatives or/and to develop new
strategies for their synthesis.
Keywords 3-Styrylchromones ꢀ
3(5)-(2-Hydroxyphenyl)-4-styrylpyrazoles ꢀ
Nitrogen heterocycles ꢀ NMR spectroscopy ꢀ
Reaction mechanism
Previously we have started a systematic study on
the synthesis of 3(5)-(2-hydroxyphenyl)pyrazoles by the
reaction of various chromone derivatives with hydrazines.
2-Styrylchromones [22], 2-methyl- and 2-phenylchromones
[23], 3-aroyl-5-hydroxyflavones [24], 3-(3-aryl-3-oxop-
ropenyl)chromones [25], 3-benzylchromones and their
thio analogs [26], and isoflavones [27] have hitherto been
used as starting materials for this purpose. As a result, simple
and convenient procedures have been worked out for the
synthesis of new 3,4- and 3,5-disubstituted and 3,4,5-tri-
substituted pyrazoles. The results obtained prompted us to
investigate the preparation of similar pyrazoles by the
reaction of 3-styrylchromones with hydrazine hydrate; pre-
liminary results from this study have been already reported
[28]. Herein we describe the complete study of the reaction
of (Z)- and (E)-3-styrylchromones with hydrazine hydrate,
leading to new (Z)- and (E)-3(5)-(2-hydroxyphenyl)-4-
styrylpyrazoles.
Introduction
Pyrazoles are well known five-membered heterocyclic
compounds possessing important pharmaceutical and agro-
chemical applications [1–7]. Certain derivatives have
demonstrated potent antitumoral and cytotoxicity against
several human cancer cell lines [8, 9], as well as significant
monoamine oxidase and HMG-CoA reductase inhibitory
V. L. M. Silva ꢀ A. M. S. Silva (&) ꢀ
D. C. G. A. Pinto ꢀ J. A. S. Cavaleiro
Chemistry Department and QOPNA,
University of Aveiro, Aveiro, Portugal
e-mail: artur.silva@ua.pt
J. Elguero
Instituto de Quımica Medica (CSIC), Madrid, Spain
´
´
123

88
V. L. M. Silva et al.
Results and discussion
Table 1 Synthesis of (Z)- and (E)-3(5)-(2-hydroxyphenyl)-4-sty-
rylpyrazoles 3a–3j, 3p–3r, and 4a–4o (*yields obtained when using
(Z)-3-styrylchromones 1l–1o as starting materials)
Synthesis
Compounds Substituents
1 and 2
Yield/% of 3 and 4
R1
R2
R3
R4
(Z)-3
(E)-4
The study started with the reaction of (Z)-3-styrylchromone
(1a) with two molar equivalents of hydrazine hydrate at
room temperature. The thin layer chromatography analysis
(TLC) revealed that after reacting for 2 h the starting
material had disappeared and (Z)-3(5)-(2-hydroxyphenyl)-
4-styrylpyrazole (3a) was obtained in 88% yield
(Scheme 1). The reaction of (E)-3-styrylchromone (2a)
with hydrazine hydrate under identical conditions gave (E)-
3(5)-(2-hydroxyphenyl)-4-styrylpyrazole (4a) in 75%
yield. The extension of the study to the reaction of (E)-3-
styrylchromones 2b–2o and (Z)-3-styrylchromones 1b–1j
led to the formation of (E)- and (Z)-3(5)-(2-hydroxy-
phenyl)-4-styrylpyrazoles 4b–4o and 3b–3j (Scheme 1,
Table 1).
a
b
c
d
e
f
H
H
H
H
88
89
89
81
94
89
74
70
75
OCH3
H
H
H
H
40
OCH3
H
H
70
OCH3 OCH3
H
H
92
H
H
H
Cl
Cl
Cl
Cl
95
OCH3
H
H
H
58
g
h
i
OCH3
H
97
OCH3 OCH3
H
65
H
H
H
OC2H5 93
OC2H5 92
70
j
H
OCH3
H
68
k
l
–
–
H
CF3
NO2
NO2
NO2
NO2
H
–
98
H
H
H
–
87; 98*
92; 95*
52; 95*
32; 73*
–
The same procedure was applied in the reaction of
(Z)-40-nitro-3-styrylchromone (1l) with hydrazine hyd-
rate, being (E)-3(5)-(2-hydroxyphenyl)-4-(4-nitrostyryl)
pyrazole (4l) obtained in excellent yield (98%). Due to this
unexpected result we decided to explore this transforma-
tion further, and other (Z)-40-nitro-3-styrylchromones
1m–1o were left to react with an excess of hydrazine
hydrate. In all cases, these reactions gave (E)-3(5)-(2-
hydroxyphenyl)-4-(4-nitrostyryl)pyrazoles 4m–4o in very
good yield ([73%). These results indicate that the 40-nitro
m
n
o
p
q
r
OCH3
H
H
H
–
OCH3
H
–
OCH3 OCH3
H
–
H
H
H
NO2
NO2
Quantitative
OCH3
H
H
80
87
–
OCH3 NO2
H
–
group has an important role in the (Z) ? (E)-isomerization
during the transformation of (Z)-40-nitro-3-styrylchromones
1l–1o into the corresponding (E)-4-(4-nitrostyryl)pyrazoles
4l–4o [28].
R4
R3
R4
R2
R1
R3
(Z)
A
The reaction mechanism of the unsubstituted or 2-
substituted chromones with hydrazine has been reported
to involve a nucleophilic attack at C-2 of the chromone
nucleus and consequent ring opening, followed by the
intramolecular reaction between hydrazine and carbonyl
groups [22, 23, 28]. This seems to be the mechanism of the
reaction of 3-styrylchromones 1a–1j and 2a–2k with
hydrazine hydrate, which doesn’t involve the 3-styryl
group and consequently the configuration of the vinyl
system is unchanged during their transformation into the
corresponding (Z)- and (E)-4-styrylpyrazoles 3a–3j and
4a–4k. The results obtained with the (Z)-40-nitro-3-sty-
rylchromones 1l–1o suggested that the mechanism should
be different in these cases. While the nitro and carbonyl
groups are considered strong electron-withdrawing groups,
the nitro group is the more powerful one, suggesting that
after the nucleophilic attack at C-2 of the chromone
nucleus, the electronic conjugation should move towards
the 40-nitro-3-styryl moiety instead of the 4-carbonyl
group. This conjugate addition allowed the (Z)- ? (E)-
isomerization of the vinylic double bond of the styryl group
R2
O
O
OH
N
NH
3
R4
(Z)
R1
R3
1
A (for compounds 1l-o)
R2
R1
R2
O
(E)
R3
R4
A
(E)
N
NH
R1
O
OH
4
2
a: R1 = R2 = R3 = R4 = H
j:
k:
l:
R
1 = R3 = H; R 2 = OCH3; R4 = OC2H5
1 = R2 = R 3 = H; R4 = CF3
1 = R2 = R 3 = H; R4 = NO2
R
1 = OCH3; R 2 = R3 = H; R4 = NO2
1 = R3= H; R 2 = OCH3; R4 = NO2
1 = R2 = OCH3; R3 = H; R4 = NO2
1 = R2 = R 4 = H; R3 = NO2
b: R1 = OCH3; R2 = R3 = R4= H
c: R1 = R3 = R4 = H; R2= OCH3
d: R1 = R2 = OCH3; R3 = R4 = H
e: R1 = R2 = R3 = H; R4= Cl
f: R1 =OCH3; R2 = R3 = H; R4 = Cl
g: R1 = R3 = H; R2 = OCH3; R4 = Cl p:
h: R1 = R2 = OCH3; R3 = H; R4 = Cl q:
R
R
m:
n:
o:
R
R
R
R
1 = OCH3; R 2 = R4 = H; R3 = NO2
1 = R4 = H; R 2 = OCH3; R3 = NO2
i: R1 = R2 = R3 = H; R4 = OC2H5
r:
R
A: NH2NH2.H2O, MeOH, room temperature, under N2
Scheme 1
123

Synthesis of (E)- and (Z)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles
89
NH2NH2
resonances of the NH (dH = 9.88–10.64 ppm) and the
20-OH (dH = 10.01–10.75 ppm) groups. The spectra of
the pyrazoles 3p–3r and 4l–4o in DMSO-d6 also present
two broad singlets at high frequency values due to the
NH (dH = 9.76–10.27 ppm) and 20-OH (dH = 12.71–
13.01 ppm) proton resonances. In DMSO-d6 solution, both
1H- and 2H-tautomers of pyrazoles 3p–3r and 4l–4o are
probably present, since the 20-OH–N-2 hydrogen bond is
broken and another is formed, 20-OH–DMSO, which is
responsible for the 20-OH deshielding. The broadening of
R2
O
O
R2
O
O
NH2NH2
R1
O
R1
O
N
O
N
O
NO2
R2
OH
O
NHNH2
R2
R1
N
R1
O
N
O
1
several signals in the H and 13C NMR spectra of these
OH
NH
4-styrylpyrazoles 3p–3r and 4l–4o confirms the existence of
prototropy. The prototropy is relatively fast and average
signals are observed. In order to fully characterize these
compounds, we performed these spectra in DMSO-d6 with
some drops of TFA, which increases the prototropy.
Scheme 2
[28], the most stable configuration, and consequent ring
opening. The last step of this reaction mechanism is the
pyrazole ring closure through an intramolecular reaction of
the hydrazine and carbonyl groups (Scheme 2). In order to
reinforce the proposed mechanism, we studied the reaction
of (Z)-30-nitro-3-styrylchromones 1p–1r, in which there is
no electronic conjugation between the 30-nitro group and
the 3-styrylchromone moiety, with hydrazine hydrate. As
expected, (Z)-3(5)-(2-hydroxyphenyl)-4-(3-nitrostyryl)pyr-
azoles 3p–3r were obtained in very good yields ([80%),
which supports the proposed mechanism [28].
The most characteristic signals in the 13C NMR spectra
of the (Z)- and (E)-3(5)-(2-hydroxyphenyl)-4-styrylpyraz-
oles 3a–3j, 3p–3r and 4a–4o are the carbon resonances of
the pyrazole moiety C-3 (dC = 137.8–149.0 ppm) and C-5
(dC = 127.3–134.1 ppm), which were confirmed by the
connectivities found in their HMBC spectra (H-a ? C-3
and C-5; H-5 ? C-3, C-4). The characteristic C-4 reso-
nances (dC = 114.4–117.4 ppm) of the (Z)-i isomers 3a–3j
and 3p–3r appear at lower frequencies as a consequence of
the lack of coplanarity between the pyrazole moiety and
the phenyl ring of the styryl group. In contrast, the con-
jugation between the pyrazole moiety and the styryl group
in the (E)-i isomers 4a–4o explains the deshielding effect
on C-4 (dC = 117.6–119.5 ppm). Other important con-
nectivities found in the HMBC spectra of pyrazoles 3a–3j,
3p–3r and 4a–4o allowed the assignments of the remaining
quaternary carbon resonances (H-30 ? C-10; H-60 ? C-3,
C-4; H-a ? C-100; H-b ? C-200, 600; H-200,600 ? C-400).
NMR spectroscopy
The NMR spectra of 3(5)-(2-hydroxyphenyl)-4-styrylpy-
razoles 3a–3j and 4a–4k were run in CDCl3, while those of
3p–3r and 4l–4o were acquired in DMSO-d6 due to their
insolubility in the former solvent. The main features in the 1H
NMR spectra of these (Z)- and (E)-3(5)-(2-hydroxyphenyl)-
4-styrylpyrazoles are the resonances of: (i) H-5 appearing as
a singlet at dH = 7.16–7.74 ppm for 3a–3j and 3p–3r and
dH = 7.35–8.49 ppm for 4a–4o; (ii) the vinylic protons H-a
(dH = 6.15–6.80 ppm for 3a-3j and 3p-3r, and dH = 6.38–
7.25 ppm for 4a–4o) and H-b (dH = 6.37–6.80 ppm for
3a–3j and 3p–3r, and dH = 6.60–7.14 ppm for 4a–4o). The
values of the olefinic coupling constants (3JHa–Hb = 11.6–
12.1 Hz) in the case of compounds 3a–3j and 3p–3r indicate
a cis configuration for this vinylic moiety, whereas those of
compounds 4a–4o (3JHa–Hb = 16.0–17.4 Hz) indicate a
trans configuration. This is the main criterion for distin-
guishing between compounds 3a–3j, 3p–3r and 4a–4o.
Usually H-a and H-b appears in the spectrum as doublets, but
for some derivatives the H-a resonance appears as a double
doublet due to the coupling with H-b and H-5, the latter
appearing as a doublet in these cases instead of being a sin-
glet. In some cases the H-a and H-b resonances appear as a
singlet (4d) or as an AB spin system (4b, 4h, 4n).
Conclusion
We successfully applied 3-styrylchromones to prepare
(Z)- and (E)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles in
excellent yields. The influences of the 40- and 30-substit-
uents of 3-styrylchromones in this transformation were
studied, and it was demonstrated the reaction was ste-
reospecific except when a 40-nitro group is present. In this
case, the reaction of both (E)- and (Z)-40-nitro-3-styryl
chromones gave only (E)-3-(2-hydroxyphenyl)-4-(4-nitro-
styryl)pyrazoles.
Experimental
1
The H NMR spectra of (Z)- and (E)-3(5)-(2-hydroxy-
phenyl)-4-styrylpyrazoles 3a–3j and 4a–4k in CDCl3
present two high-frequency broad singlets due to the proton
Melting points were determined on a Reichert (Vienna,
Austria) Thermovar apparatus fitted with a microscope.
123

90
V. L. M. Silva et al.
NMR spectra were recorded on Bruker (Wissembourg,
France) Avance 300 spectrometer (300.13 MHz for 1H and
75.47 MHz for 13C), with CDCl3 used as solvent if not
stated otherwise. Chemical shifts (d) are reported in ppm
values and coupling constants (J) in Hz. The internal
4c, 164.9 mg, 70%; 3d, 210.4 mg, 81%; 4d, 239.0 mg,
92%; 3e, 224.8 mg, 94%; 4e, 227.2 mg, 95%; 3f,
234.4 mg, 89%; 4f, 152.8 mg, 58%; 3g, 194.9 mg, 74 %;
4g, 255.5 mg, 97 %; 3 h, 201.3 mg, 70%; 4h, 186.9 mg,
65%; 3i, 229.6 mg, 93%; 4i, 172.8 mg, 70%; 3j, 249.4 mg,
92%; 4j, 184.4 mg, 68%; 4k, 260.9 mg, 98%; 4l,
243.4 mg, 98%, [from (Z)-40-nitro-3-styrylchromone 1l]
and 216.0 mg, 87% [from (E)-40-nitro-3-styrylchromone
2l]; 4m, 258.3 mg, 95% [from (Z)-5-methoxy-40-nitro-3-
styrylchromone 1m] and 250.1 mg, 92% [from (E)-5-
methoxy-40-nitro-3-styrylchromone 2m]; 4n, 258.3 mg,
95% [from (Z)-7-methoxy-40-nitro-3-styrylchromone 1n]
and 141.4 mg, 52% from [(E)-7-methoxy-40-nitro-3-
styrylchromone 2n]; 4o, 216.2 mg, 73% [from (Z)-5,7-
dimethoxy-40-nitro-3-styrylchromone 1o] and 94.8 mg,
32% [from (E)-5,7-dimethoxy-40-nitro-3-styrylchromone
2o]; 3p, 247.7 mg, quantitative yield; 3q, 217.5 mg, 80%;
3r, 236.5 mg, 87%.
1
standard was TMS. H assignments were made using 2D
gCOSY spectra, while 13C assignments were made using
2D gHSQC and gHMBC experiments (delays for one bond
and long-range J C/H couplings were optimized for 145
and 7 Hz, respectively). Mass spectra (EI, 70 eV) were
measured on a VG Autospec (Fisons Instruments, Man-
chester, UK) Q and M mass spectrometers, while mass
spectra (ESI?) were measured on a Micromass (Man-
chester, UK) Q-TOF-2TH spectrometer [diluting 1 mm3 of
the sample chloroform solution (*10-5 M) in 200 mm3 of
0.1% trifluoroacetic acid/methanol solution; nitrogen was
used as nebulizer gas and argon as collision gas; the needle
voltage was set at 3,000 V, with the ion source set at 80 °C
and desolvation temperature at 150 °C; cone voltage was
35 V]. HRMS were in good agreement ( 0.5 ppm) with
the calculated values. Elemental analyses were obtained
with a LECO 932 CHN analyzer (University of Aveiro,
Portugal), and were in good agreement ( 0.4%) with the
calculated values. Preparative thin-layer chromatography
was carried out with Riedel (Seelze, Germany) silica gel
60, DGF254, and column chromatography using Merck
(Darmstadt, Germany) silica gel 60, 70–230 mesh. All
other chemicals and solvents used were obtained from
commercial sources and used as received or dried using
standard procedures. (Z)- and (E)-3-styrylchromones
1a–1j, 1l–1r, and 2a–2o were prepared according to [29].
(Z)-3(5)-(2-Hydroxy-6-methoxyphenyl)-4-styrylpyrazole
(3b, C18H16N2O2)
1
Mp 109–111 °C; H NMR: d = 3.70 (s, 60-OCH3), 6.52
(dd, J = 12.1, 1.1 Hz, H-a), 6.76 (d, J = 12.1 Hz, H-b),
6.81 (d, J = 8.3 Hz, H-50), 6.93 (dd, J = 8.4, 0.7 Hz, H-30),
7.20–7.29 (m, H-200,300,400,500,600), 7.53 (dd, J = 8.3, 8.4 Hz,
H-40), 7.56 (d, J = 1.1 Hz, H-5) ppm; 13C NMR: d = 55.4
(60-OCH3), 102.8 (C-30), 106.8 (C-10), 109.0 (C-50), 117.4
(C-4), 121.1 (C-a), 126.9 (C-400), 128.0 (C-b), 128.3 (C-
200,600), 128.5 (C-300,500), 130.3 (C-40), 131.4 (C-5), 138.1
(C-100), 142.6 (C-3), 155.5 (C-20), 157.9 (C-60) ppm; MS
(EI, 70 eV): m/z (%) = 292 (M1ꢀ, 34), 291 [(M–H)?, 4],
279 (13), 275 [(M–OH)?, 2], 261 [(M–OCH3)?, 5], 247
(2), 217 (22), 201 (100), 186 (28), 173 (10), 158 (6), 146
(3), 131 (3), 116 (3), 105 (9), 91 (13), 83 (22), 77 (16), 63
(10).
General method used for the synthesis of (Z)- and
(E)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles 3a–3j,
3p–3r and 4a–4o
(E)-3(5)-(2-Hydroxy-6-methoxyphenyl)-4-styrylpyrazole
(4b, C18H16N2O2)
Hydrazine hydrate (0.08 cm3, 1.61 mmol) was added to a
solution of the appropriate 3-styrylchromone 1a–1j, 1l–1r
or 2a–2o (8.06 9 10-1 mmol) in 50 cm3 methanol. The
reaction mixture was stirred at room temperature, under
nitrogen atmosphere, until the disappearance of the starting
material. The mixture was then poured into 100 cm3
CHCl3 and washed with 2 9 100 cm3 acidified water (pH
5). The organic layer was dried over anhydrous sodium
sulfate, the solvent was evaporated to dryness, and the solid
residue was purified by column chromatography using
CHCl3 as eluent. The residue obtained after solvent evap-
oration was recrystallized from a mixture of CH2Cl2/
cyclohexane. The (Z)- and (E)-3(5)-(2-hydroxyphenyl)-4-
styrylpyrazoles 3a–3j, 3p–3r and 4a–4o were obtained in
very good yields: 3a, 186.0 mg, 88%; 4a, 158.6 mg, 75%;
3b, 209.7 mg, 89%; 4b, 94.2 mg, 40%; 3c, 209.7 mg, 89%;
1
Mp 181–183 °C; H NMR (T = 45 °C): d = 3.75 (s, 60-
OCH3), 6.56 (dd, J = 8.3, 0.8 Hz, H-50), 6.69 (dd, J = 8.3,
0.8 Hz, H-30), 6.79 (AB, J = 16.5 Hz, H-a), 6.82 (AB,
J = 16.5 Hz, H-b), 7.18 (tt, J = 7.2, 1.4 Hz, H-400), 7.23–
7.30 (m, H-300,500, H-40), 7.34–7.37 (m, H-200,600), 7.89 (br s,
13
H-5) ppm; C NMR (T = 45 °C): d = 55.7 (60-OCH3),
103.1 (C-50), 106.7 (C-10), 109.4 (C-30), 119.4 (C-a, C-4),
126.1 (C-200,600), 127.2 (C-40), 127.7 (C-b), 128.6 (C-300,500),
130.7 (C-5), 131.1 (C-400), 137.8 (C-100), 138.6 (C-3), 155.7
(C-20), 158.0 (C-60) ppm; MS (EI, 70 eV): m/z (%) = 292
(M1ꢀ, 100), 276 (6), 261 [(M–OCH3)?, 10], 247 (2), 231
(2), 215 [(M–C6H5)?, 2], 201 (87), 189 [(M–C8H7)?, 3],
186 (20), 171 (2), 165 (4), 149 (3), 146 (5), 128 (3), 115
(12), 105 (2), 102 (4), 91 (6), 83 (4), 77 (6), 69 (2), 65 (4),
57 (4).
123

Synthesis of (E)- and (Z)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles
91
(Z)-3(5)-(2-Hydroxy-4-methoxyphenyl)-4-styrylpyrazole
(3c, C18H16N2O2)
(E)-3(5)-(2-Hydroxy-4,6-dimethoxyphenyl)-
4-styrylpyrazole (4d, C19H18N2O3)
1
Mp 102–104 °C; H NMR: d = 3.80 (s, 40-OCH3), 6.51
1H NMR: d = 3.71 (s, 60-OCH3), 3.81 (s, 40-OCH3), 6.12
(s, H-30), 6.28 (s, H-50), 6.78 (s, H-a, H-b), 7.12–7.22
(m, H-400), 7.29 (dd, J = 8.0, 7.3 Hz, H-300,500), 7.36 (d,
J = 7.3 Hz, H-200,600), 7.89 (br s, H-5) ppm; 13C NMR:
d = 55.4 (60-OCH3), 55.5 (40-OCH3), 91.5 (C-30), 93.7 (C-
50), 98.7 (C-10), 119.0 (C-4, C-a), 126.0 (C-200,600), 127.2
(C-400), 127.5 (C-b), 128.6 (C-300,500), 130.9 (C-5), 137.5
(C-100), 145.1 (C-3), 156.5 (C-20), 158.6 (C-60), 162.2 (C-40)
ppm; MS (EI, 70 eV): m/z (%) = 322 (M?ꢀ, 100), 321
[(M–H)?, 7], 307 [(M–CH3)?, 2], 305 [(M–OH)?, 6], 291
[(M–OCH3)?, 11], 277 (3), 245 [(M–C6H5)?, 5], 231 (88),
216 (11), 201 (4), 181 (3), 165 (5), 152 (4), 139 (3), 127
(3), 115 (11), 103 (3), 91 (6), 69 (6), 63 (3).
(dd, J = 8.6, 2.4 Hz, H-50), 6.51 (d, J = 11.6 Hz, H-a),
6.60 (d, J = 2.4 Hz, H-30), 6.65 (d, J = 11.6 Hz, H-b),
7.16–7.32 (m, H-200,300,500,600, H-5), 7.20 (t, J = 7.1 Hz, H-
400), 7.73 (d, J = 8.6 Hz, H-60), 10.64 (br s, NH and 20-OH)
13
ppm; C NMR: d = 55.2 (40-OCH3), 101.7 (C-30), 106.0
(C-50), 110.5 (C-10), 114.6 (C-4), 120.8 (C-a), 127.2 (C-
400), 128.3 (C-200,600), 128.6 (C-300,500), 128.8 (C-5), 129.0
(C-60), 131.0 (C-b), 137.0 (C-100), 148.4 (C-3), 157.2 (C-
20), 160.5 (C-40) ppm; MS (EI, 70 eV): m/z (%) = 292
(M1ꢀ, 100), 291 [(M–H)?, 28], 277 [(M–CH3)?, 12], 261
[(M–OCH3)?, 5], 249 (4), 231 (3), 221 (3), 215 [(M–
C6H5)?, 28], 202 (22), 201 (95), 191 (3), 186 (6), 178 (4),
167 (3), 158 (8), 152 (5), 146 (7), 128 (6), 119 (1), 115
(19), 102 (5), 91 (9), 77 (12), 69 (5), 63 (10).
(Z)-4-(4-Chlorostyryl)-3(5)-(2-hydroxyphenyl)pyrazole
(3e, C17H13ClN2O)
Mp 154–156 °C; 1H NMR: d = 6.58 (d, J = 11.8 Hz,
H-a), 6.64 (d, J = 11.8 Hz, H-b), 6.93 (ddd, J = 7.5, 7.6,
1.0 Hz, H-50), 7.06 (dd, J = 8.2, 1.0 Hz, H-30), 7.19–7.29
(m, H-200,300,500,600, H-40), 7.32 (s, H-5), 7.80 (dd, J = 7.6,
1.6 Hz, H-60), 10.10 (br s, NH), 10.55 (br s, 20-OH) ppm;
13C NMR: d = 115.1 (C-4), 116.9 (C-30), 117.1 (C-10),
119.3 (C-50), 121.5 (C-a), 128.1 (C-60), 128.5 (C-300,500),
128.6 (C-5), 129.5 (C-40), 129.96 (C-200,600), 130.0 (C-b),
132.9 (C-400), 135.4 (C-100), 148.9 (C-3), 155.8 (C-20) ppm;
MS (EI, 70 eV): m/z (%) = 298 [(M?ꢀ, 37Cl), 30], 296
[(M?ꢀ, 35Cl), 75], 295 (22), 260 (5), 202 (5), 185 [(M–
C6H4Cl)?, 25], 172 (17), 171 (100), 151 (5), 140 (5), 115
(21), 102 (8), 89 (7), 77 (6), 63 (7).
(E)-3(5)-(2-Hydroxy-4-methoxyphenyl)-4-styrylpyrazole
(4c, C18H16N2O2)
1
Mp 115–116 °C; H NMR: d = 3.82 (s, 40-OCH3), 6.54
(dd, J = 8.6, 2.4 Hz, H-50), 6.63 (d, J = 2.4 Hz, H-30),
6.87 (d, J = 16.2 Hz, H-b), 7.13 (d, J = 16.2 Hz, H-a),
7.26 (t, J = 7.3 Hz, H-400), 7.36 (dd, J = 7.3, 7.8 Hz, H-
300,500), 7.46 (d, J = 7.8 Hz, H-200,600), 7.53 (d, J = 8.6 Hz,
H-60), 7.79 (s, H-5), 10.18 (br s, NH and 20-OH) ppm; 13C
NMR: d = 55.3 (40-OCH3), 101.8 (C-30), 106.2 (C-50),
110.4 (C-10), 117.8 (C-4), 119.0 (C-a), 126.2 (C-200,600),
127.5 (C-400), 127.6 (C-5), 128.7 (C-300,500), 129.3 (C-60),
129.7 (C-b), 137.3 (C-100), 147.7 (C-3), 157.1 (C-20), 160.7
(C-40) ppm; MS (EI, 70 eV): m/z (%) = 292 (M?ꢀ, 100),
291 [(M–H)?, 26], 277 [(M–CH3)?, 5], 261 [(M–OCH3)?,
4], 249 (3), 231 (3), 221 (2), 215 [(M–C6H5)?, 25], 202
(22), 201 [(M–C7H7)?, 96], 186 (5), 178 (3), 158 (5), 146
(11), 128 (2), 115 (14), 102 (4), 91 (5), 77 (6), 69 (2),
63 (4).
(E)-4-(4-Chlorostyryl)-3(5)-(2-hydroxyphenyl)pyrazole
(4e, C17H13ClN2O)
Mp 163–164 °C; 1H NMR: d = 6.84 (d, J = 16.3 Hz,
H-a), 6.97 (ddd, J = 7.8, 7.2, 1.1 Hz, H-50), 7.07 (dd,
J = 7.7, 1.1 Hz, H-30), 7.13 (d, J = 16.3 Hz, H-b), 7.28–
7.31 (m, H-40), 7.32 (d, J = 8.6 Hz, H-200,600), 7.40 (d,
J = 8.6 Hz, H-300,500), 7.58 (dd, J = 7.8, 1.5 Hz, H-60),
7.85 (s, H-5), 10.06 (br s, NH and 20-OH) ppm; 13C NMR:
d = 117.0 (C-30), 117.1 (C-10), 118.2 (C-4), 119.4 (C-a),
119.6 (C-50), 127.4 (C-300,500), 127.7 (C-5), 128.5 (C-60),
128.6 (C-b), 128.9 (C-200,600), 129.6 (C-40), 133.2 (C-400),
135.7 (C-100), 147.7 (C-3), 155.5 (C-20) ppm; MS (EI,
70 eV): m/z (%) = 298 [(M?ꢀ, 37Cl), 29], 296 [(M?ꢀ, 35Cl),
78], 295 [(M–H)?,15], 281 (3), 260 (3), 242 (1), 231 (2),
215 (2), 202 (3), 185 [(M–C6H4Cl)?, 16], 177 (2), 172
(12), 171 (100), 165 (1), 155 (1), 149 (4), 130 (3), 120 (2),
115 (12), 102 (5), 89 (4), 77 (3), 63 (4).
(Z)-3(5)-(2-hydroxy-4,6-dimethoxyphenyl)-
4-styrylpyrazole (3d, C19H18N2O3)
1
Mp 78–79 °C; H NMR: d = 3.75 (s, 60-OCH3), 3.81
(s, 40-OCH3), 6.11 (d, J = 2.1 Hz, H-50), 6.15 (d,
J = 12.0 Hz, H-a), 6.21 (d, J = 2.1 Hz, H-30), 6.45 (d,
J = 12.0 Hz, H-b), 7.18–7.30 (m, H-300,400,500), 7.29 (s, H-
5), 7.34 (d, J = 7.1 Hz, H-200,600) ppm; 13C NMR:
d = 55.3 (60-OCH3), 55.4 (40-OCH3), 91.3 (C-50), 93.3
(C-30), 99.7 (C-10), 117.1 (C-4), 121.3 (C-a), 126.9 (C-400),
127.6 (C-b), 128.4 (C-300,500), 128.5 (C-200,600), 131.4 (C-5),
138.2 (C-100), 143.2 (C-3), 156.5 (C-20), 158.7 (C-60), 161.8
(C-40) ppm; MS (EI, 70 eV): m/z (%) = 322 (M?ꢀ, 94), 321
[(M–H)?, 13], 309 (14), 291 [(M–OCH3)?, 15], 279 (3),
259 (4), 247 (21), 231 (100), 216 (14), 203 (7), 187 (6), 179
(2), 173 (4), 161 (7), 152 (4), 131 (3), 115 (10), 105 (12),
91 (12), 77 (17), 69 (9), 63 (7).
(Z)-4-(4-Chlorostyryl)-3(5)-(2-hydroxy-6-methoxy-
phenyl)pyrazole (3f, C18H15ClN2O2)
1
Mp 97–98 °C; H NMR: d = 3.73 (s, 60-OCH3), 6.58 (d,
1H, J = 8.2 Hz, H-30), 6.71 (d, J = 8.6 Hz, H-50), 6.76–
123

92
V. L. M. Silva et al.
6.80 (m, H-a, H-b), 7.16–7.32 (m, H-200,300,500,600), 7.24–
7.37 (m, H-40), 7.41 (s, H-5) ppm; 13C NMR: d = 55.6 (60-
OCH3), 102.8 (C-30), 106.9 (C-10), 109.3 (C-50), 115.4
(C-4), 119.9 (C-a), 126.0 (C-b), 127.9 (C-300,500), 128.5
(C-200,600), 130.7 (C-5, C-40), 132.5 (C-400), 136.0 (C-100),
147.7 (C-3), 155.5 (C-20), 157.7 (C-60) ppm; MS (EI,
70 eV): m/z (%) = 328 [(M?ꢀ, 37Cl), 19], 326 [(M?ꢀ, 35Cl),
50], 325 (4), 313 (13), 311 [(M–CH3)?, 11], 295
[(M–OCH3)?, 6], 246 (2), 216 (20), 215 [(M–C6H4Cl)?,
3], 201 (100), 186 (30), 173 (11), 158 (6), 149 (4), 139 (8),
127 (4), 115 (7), 102 (5), 89 (8), 83 (6), 77 (11), 63 (8).
(C-50), 110.3 (C-10), 117.6 (C-4), 119.6 (C-a), 127.4 (C-
200,600), 127.7 (C-5), 128.3 (C-b), 128.9 (C-300,500), 129.2 (C-
60), 133.1 (C-400), 135.8 (C-100), 147.7 (C-3), 157.1 (C-20),
160.8 (C-40) ppm; MS (EI, 70 eV): m/z (%) = 328 [(M1ꢀ,
37Cl), 42], 326 [(M1ꢀ, 35Cl), 93], 325 (26), 311 [(M–CH3)?,
4], 295 [(M–OCH3)?, 4], 215 [(M–C6H4Cl)?, 29], 202
(23), 201 (100), 186 (6), 177 (4), 165 (5), 158 (9), 151 (4),
137 (6), 125 (4), 115 (13), 102 (5), 85 (16), 75 (6), 63 (8).
(Z)-4-(4-Chlorostyryl)-3(5)-(2-hydroxy-4,6-dimethoxy-
phenyl)pyrazole (3h, C19H17ClN2O3)
1
Mp 68–69 °C; H NMR: d = 3.72 (s, 60-OCH3), 3.80 (s,
(E)-4-(4-Chlorostyryl)-3(5)-(2-hydroxy-6-methoxy-
phenyl)pyrazole (4f, C18H15ClN2O2)
40-OCH3), 6.08 (d, J = 1.9 Hz, H-50), 6.19 (d, J = 1.9 Hz,
H-30), 6.19 (d, J = 11.9 Hz, H-a), 6.37 (d, J = 11.9 Hz,
H-b), 7.20 (d, J = 8.7 Hz, H-300,500), 7.25 (d, J = 8.7 Hz,
H-200,600), 7.31 (br s, H-5) ppm; 13C NMR: d = 55.2
(60-OCH3), 55.4 (40-OCH3), 91.2 (C-50), 93.4 (C-30), 99.7
(C-10), 116.8 (C-4), 122.0 (C-a), 126.3 (C-b), 128.4
(C-300,500), 129.8 (C-200,600), 131.0 (C-5), 132.4 (C-400),
136.5 (C-100), 144.1 (C-3), 156.5 (C-20), 158.6 (C-60), 161.8
(C-40) ppm; MS (EI, 70 eV): m/z (%) = 358 [(M?ꢀ, 37Cl),
35], 356 [(M?ꢀ, 35Cl), 100], 355 (5), 339 [(M–OH)?, 4],
325 [(M–OCH3)?, 8], 299 (2), 245 [(M–C6H4Cl)?, 4], 231
(85), 219 [(M–C8H6Cl)?, 1], 215 (12), 201 (2), 187 (2),
178 (7), 149 (4), 115 (5), 101 (2), 77 (2), 69 (6).
1
Mp 204–205 °C; H NMR: d = 3.78 (s, 60-OCH3), 6.58
(dd, J = 7.9, 0.8 Hz, H-50), 6.72 (dd, J = 8.2, 0.8 Hz,
H-30), 6.76 (d, J = 16.0 Hz, H-a), 6.82 (d, J = 16.0 Hz,
H-b), 7.26 (d, J = 8.8 Hz, H-300,500), 7.27–7.32 (m, H-40),
7.31 (d, J = 8.8 Hz, H-200,600), 7.95 (s, H-5) ppm; 13C
NMR: d = 55.6 (60-OCH3), 102.8 (C-10,30), 109.3 (C-50),
117.8 (C-4), 119.9 (C-a), 126.1 (C-b), 127.2 (C-200,600),
128.8 (C-300,500), 128.9 (C-40), 130.7 (C-5), 132.7 (C-400),
136.1 (C-100), 140.9 (C-3), 155.5 (C-20), 157.6 (C-60) ppm;
MS (EI, 70 eV): m/z (%) = 328 [(M?ꢀ, 37Cl), 38], 326
[(M?ꢀ, 35Cl), 89], 325 (5), 310 (6), 311 [(M–CH3)?, 4], 295
[(M–OCH3)?, 11], 215 [(M–C6H4Cl)?, 3], 201 (100), 186
(28), 177 (3), 176 (3), 138 (5), 125 (5), 115 (10), 102 (4),
89 (4), 77 (4), 63 (4).
(E)-4-(4-Chlorostyryl)-3(5)-(2-hydroxy-4,6-dimethoxy-
phenyl)pyrazole (4h, C19H17ClN2O3)
Mp 100–102 °C; 1H NMR: d = 3.71 (s, 60-OCH3), 3.81 (s,
40-OCH3), 6.15 (s, H-30), 6.22 (s, H-50), 6.74 (AB,
J = 17.2 Hz, H-a,b), 7.13–7.31 (m, H-200,300,500,600), 7.80
(Z)-4-(4-Chlorostyryl)-3(5)-(2-hydroxy-4-methoxy-
phenyl)pyrazole (3g, C18H15ClN2O2)
1
13
Mp 158–160 °C; H NMR: d = 3.82 (s, 40-OCH3), 6.51
(br s, H-5) ppm; C NMR: d = 55.4 (60-OCH3), 55.6 (40-
(dd, J = 8.7, 2.5 Hz, H-50), 6.55 (d, J = 12.0 Hz, H-a),
6.61 (d, J = 2.5 Hz, H-30), 6.62 (d, J = 12.0 Hz, H-b),
7.18–7.23 (m, H-200,300,500,600), 7.29 (s, H-5), 7.70 (d,
J = 8.7 Hz, H-60), 10.63 (br s, NH and 20-OH) ppm; 13C
NMR: d = 55.3 (40-OCH3), 101.7 (C-30), 106.1 (C-50),
110.3 (C-10), 114.4 (C-4), 121.6 (C-a), 128.4 (C-5), 128.5
(C-300,500), 128.9 (C-60), 129.9 (C-b), 130.0 (C-200,600), 132.9
(C-400), 135.4 (C-100), 149.0 (C-3), 157.4 (C-20), 160.7 (C-
40) ppm; MS (EI, 70 eV): m/z (%) = 328 [(M?ꢀ, 37Cl), 42],
326 [(M?ꢀ, 35Cl), 93], 325 (26), 311 [(M–CH3)?, 4], 295
[(M–OCH3)?, 4], 215 [(M–C6H4Cl)?, 29], 202 (23), 201
(100), 186 (6), 177 (4), 165 (5), 158 (9), 151 (4), 137 (6),
125 (4), 115 (13), 102 (5), 85 (16), 75 (6), 63 (8).
OCH3), 91.6 (C-30), 93.6 (C-50), 98.6 (C-10), 119.5 (C-a, C-
4), 126.2 (C-b), 128.7 (C-200,600), 130.7 (C-300,500), 130.9 (C-
5), 133.1 (C-400), 136.1 (C-100), 148.8 (C-3), 156.1 (C-20),
158.7 (C-60), 162.2 (C-40) ppm; MS (EI, 70 eV): m/z
(%) = 358 [(M?ꢀ, 37Cl), 11], 356 [(M?ꢀ, 35Cl), 29], 355
(2), 339 [(M–OH)?, 2], 325 [(M–OCH3)?, 4], 284 (1), 256
(1), 245 [(M–C6H4Cl)?, 5], 231 (29), 215 (4), 201 (2), 178
(4), 170 (30), 149 (3), 134 (1), 125 (100), 115 (2), 94 (5),
89 (19), 83 (2), 69 (4), 63 (11).
(Z)-4-(4-Ethoxystyryl)-3(5)-(2-hydroxyphenyl)pyrazole
(3i, C19H18N2O2)
1
Mp 107–109 °C; H NMR: d = 1.39 (t, J = 7.0 Hz, 400-
OCH2CH3), 4.00 (q, J = 7.0 Hz, 400-OCH2CH3), 6.45 (dd,
J = 11.8, 0.8 Hz, H-a), 6.63 (d, J = 11.8 Hz, H-b), 6.75
(d, J = 8.7 Hz, H-300,500), 6.92 (ddd, J = 7.2, 7.8, 1.3 Hz,
H-50), 7.05 (dd, J = 8.2, 1.3 Hz, H-30), 7.23 (d, J = 8.7 Hz,
H-200,600), 7.24–7.27 (m, H-40), 7.37 (d, J = 0.8 Hz, H-5),
7.86 (dd, J = 7.8, 1.6 Hz, H-60), 10.21 (br s, NH), 10.70
(E)-4-(4-Chlorostyryl)-3(5)-(2-hydroxy-4-methoxy-
phenyl)pyrazole (4g, C18H15ClN2O2)
1
Mp 170–172 °C; H NMR: d = 3.84 (s, 40-OCH3), 6.54
(dd, J = 8.6, 2.5 Hz, H-50), 6.63 (d, J = 2.5 Hz, H-30), 6.82
(d, J = 16.2 Hz, H-b), 7.10 (d, J = 16.2 Hz, H-a), 7.32 (d,
J = 8.6 Hz, H-300,500), 7.39 (d, J = 8.6 Hz, H-200,600), 7.49
(d, J = 8.6 Hz, H-60), 7.80 (br s, H-5), 10.12 (br s, NH)
13
(br s, 20-OH) ppm; C NMR: d = 14.8 (400-OCH2CH3),
63.4 (400-OCH2CH3), 114.2 (C-300,500), 115.7 (C-4), 116.8
(C-30), 117.3 (C-10), 119.0 (C-a), 119.3 (C-50), 128.1
13
ppm; C NMR: d = 55.3 (40-OCH3), 101.9 (C-30), 106.2
123

Synthesis of (E)- and (Z)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles
93
(C-60), 128.6 (C-5), 129.27 (C-40), 129.34 (C-100), 129.9 (C-
200,600), 131.0 (C-b), 148.7 (C-3), 155.8 (C-20), 158.1 (C-400)
ppm; MS (EI, 70 eV): m/z (%) = 306 (M?ꢀ, 100), 305
[(M–H)?, 15], 291 [(M–CH3)?, 3], 278 (9), 277 [(M–
C2H5)?, 34], 261 [(M–C2H5O)?, 2], 247 (4), 232 (3), 222
(3), 205 (3), 191 (1), 185 [(M–C8H9O)?, 11], 176 (2), 171
(78), 160 (1), 155 (4), 140 (2), 131 (8), 115 (8), 107 (3),
102 (7), 91 (4), 77 (9), 65 (6).
OCH2CH3), 6.38 (d, J = 16.4 Hz, H-a), 6.50 (dd, J = 8.7,
1.7 Hz, H-50), 6.60 (d, J = 16.4 Hz, H-b), 6.61 (d,
J = 1.7 Hz, H-30), 6.75 (d, J = 8.5 Hz, H-300,500), 7.23 (d,
J = 8.5 Hz, H-200,600), 7.35 (br s, H-5), 7.76 (d,
J = 8.7 Hz, H-60), 9.88 (br s, NH), 10.75 (br s, 20-OH)
ppm; 13C NMR: d = 14.8 (400-OCH2CH3), 55.3 (40-OCH3),
63.5 (400-OCH2CH3), 101.8 (C-30), 106.1 (C-50), 110.5 (C-
10), 114.7 (C-300,500), 116.7 (C-a), 117.8 (C-4), 127.4 (C-
200,600, C-5), 129.2 (C-60), 129.4 (C-b), 129.9 (C-100), 147.6
(C-3), 157.1 (C-20), 158.6 (C-400), 160.6 (C-40) ppm; MS
(EI, 70 eV): m/z (%) = 336 (M1ꢀ, 100), 321 [(M–CH3)?,
2], 307 (24), 291 (2), 277 (3), 263 (3), 247 (3), 235 (3), 221
(2), 215 (12), 201 (67), 186 (4), 168 (2), 154 (10), 137 (3),
131 (5), 115 (3), 103 (3), 77 (5), 65 (2).
(E)-4-(4-Ethoxystyryl)-3(5)-(2-hydroxyphenyl)pyrazole
(4i, C19H18N2O2)
1
Mp 149–151 °C; H NMR: d = 1.40 (t, J = 7.0 Hz, 400-
OCH2CH3), 4.06 (q, J = 7.0 Hz, 400-OCH2CH3), 6.84 (d,
J = 16.2 Hz, H-b), 6.90 (d, J = 8.7 Hz, H-300,500), 6.95
(ddd, J = 7.8, 8.6, 0.9 Hz, H-50), 7.01 (d, J = 16.2 Hz, H-
a), 7.07 (dd, J = 7.0, 0.9 Hz, H-30), 7.26 (ddd, J = 8.6,
7.0, 1.5 Hz, H-40), 7.40 (d, J = 8.7 Hz, H-200,600), 7.64 (dd,
J = 7.8, 1.5 Hz, H-60), 7.81 (br s, H-5), 10.14 (br s, NH and
(E)-3(5)-(2-Hydroxyphenyl)-4-(4-trifluoromethylstyryl)
pyrazole (4k, C18H13F3N2O)
Mp 186–188 °C; 1H NMR: d = 6.92 (d, J = 16.2 Hz,
H-b), 6.98 (ddd, J = 7.5, 7.0, 0.8 Hz, H-50), 7.09 (dd,
J = 8.2, 0.8 Hz, H-30), 7.25 (d, J = 16.2 Hz, H-a), 7.30
(ddd, J = 8.2, 7.5, 1.6 Hz, H-40), 7.56 (d, J = 8.1 Hz,
H-200,600), 7.57 (dd, J = 7.0, 1.6 Hz, H-60), 7.61 (d,
J = 8.1 Hz, H-300,500), 7.89 (s, H-5), 10.01 (br s, NH and
13
20-OH) ppm; C NMR: d = 14.8 (400-OCH2CH3), 63.5
(400-OCH2CH3), 114.7 (C-300,500), 116.6 (C-a), 116.9 (C-30),
117.4 (C-10), 118.8 (C-4), 119.5 (C-50), 127.5 (C-200,600, C-
5), 128.5 (C-60), 129.4 (C-40), 129.6 (C-b), 129.9 (C-100),
147.5 (C-3), 155.6 (C-20), 158.6 (C-400) ppm; MS (EI,
70 eV): m/z (%) = 306 (M?ꢀ, 100), 305 [(M–H)?, 13], 291
[(M–CH3)?, 2], 277 [(M–C2H5)?, 35], 260 (2), 247 (4),
232 (3), 222 (2), 205 (2), 191 (1), 185 [(M–C8H9O)?, 10],
176 (1), 171 (71), 165 (3), 155 (4), 140 (2), 139 (6), 131
(8), 120 (3), 115 (7), 107 (3), 102 (6), 91 (5), 83 (3), 77 (8),
65 (6).
13
20-OH) ppm; C NMR: d = 117.0 (C-10), 117.1 (C-30),
118.0 (C-4), 119.6 (C-50), 121.4 (C-a), 125.7 (q,
J = 3.9 Hz, C-300,500), 126.0 (q, J = 284.6 Hz, CF3),
126.3 (C-200,600), 127.9 (C-5), 128.3 (C-b), 128.5 (C-60),
128.7 (q, J = 31.8 Hz, C-400), 129.7 (C-40), 140.6 (C-100),
143.2 (C-3), 155.6 (C-20) ppm; MS (EI, 70 eV): m/z
(%) = 330 (M?ꢀ, 92), 329 [(M–H)?, 32], 311 (12), 301 (6),
275 (4), 260 (3), 243 (2), 233 (4), 214 (2), 202 (4), 185
(29), 171 (100), 164 (4), 155 (14), 140 (5), 115 (15), 102
(8), 89 (4), 65 (5).
(Z)-4-(4-Ethoxystyryl)-3(5)-(2-hydroxy-4-methoxy-
phenyl)pyrazole (3j, C20H20N2O3)
1
Mp 167–169 °C; H NMR: d = 1.40 (t, J = 7.0 Hz, 400-
OCH2CH3), 3.82 (s, 40-OCH3), 4.00 (q, J = 7.0 Hz, 400-
OCH2CH3), 6.42 (d, J = 11.8 Hz, H-a), 6.50 (dd, J = 8.6,
2.6 Hz, H-50), 6.61 (d, J = 2.6 Hz, H-30), 6.62 (d,
J = 11.8 Hz, H-b), 6.75 (d, J = 8.7 Hz, H-300,500), 7.23
(d, J = 8.7 Hz, H-200,600), 7.35 (d, J = 0.6 Hz, H-5), 7.76
(d, J = 8.6 Hz, H-60), 10.50 (br s, NH and 20-OH) ppm; 13C
NMR: d = 14.8 (400-OCH2CH3), 55.3 (40-OCH3), 63.4 (400-
OCH2CH3), 101.7 (C-30), 105.9 (C-50), 110.5 (C-10), 114.2
(C-300,500), 115.1 (C-4), 119.1 (C-a), 128.3 (C-5), 128.9
(C-60), 129.4 (C-100), 129.9 (C-200,600), 131.0 (C-b), 143.8
(C-3), 157.4 (C-20), 158.1 (C-400), 160.6 (C-40) ppm; MS
(EI, 70 eV): m/z (%) = 336 (M1ꢀ, 100), 321 [(M–CH3)?,
1], 307 (18), 291 (2), 277 (2), 263 (2), 247 (2), 235 (2), 221
(2), 215 (9), 201 (67), 186 (3), 165 (2), 154 (6), 138 (2),
131 (4), 115 (2), 103 (2), 77 (3), 65 (1).
(E)-3(5)-(2-Hydroxy-6-methoxyphenyl)-4-(4-nitro-
styryl)pyrazole (4m, C18H15N3O4)
Mp 231–233 °C; 1H NMR (DMSO-d6 with TFA):
d = 3.70 (s, 60-OCH3), 6.62 (d, J = 8.3 Hz, H-50), 6.66
(d, J = 8.3 Hz, H-30), 6.93 (d, J = 16.5 Hz, H-a), 7.10 (d,
J = 16.5 Hz, H-b), 7.30 (t, J = 8.3 Hz, H-40), 7.60 (d,
J = 8.8 Hz, H-200,600), 8.13 (d, J = 8.8 Hz, H-300,500), 8.49
(s, H-5), 9.76 (without TFA; s, NH), 12.80 (without TFA; s,
20-OH) ppm; 13C NMR (DMSO-d6 with TFA): d = 56.1
(60-OCH3), 102.8 (C-50), 103.5 (C-10), 109.4 (C-30), 119.5
(C-4), 123.5 (C-a), 124.6 (C-300,500), 126.4 (C-b), 127.2 (C-
200,600), 132.5 (C-40), 133.5 (C-5), 138.3 (C-3), 144.5 (C-
100), 146.7 (C-400), 157.5 (C-20), 159.2 (C-60) ppm; MS (EI,
70 eV): m/z (%) = 337 (M1ꢀ, 88), 336 [(M–H)?, 5], 320
[(M–OH)?, 8], 307 [(M–NO)?, 26], 306 [(M–OCH3)?,
10], 290 (17), 276 (8), 262 (11), 244 (7), 229 (2), 215 (5),
201 (100), 186 (24), 171 (20), 128 (7), 115 (12), 91 (12), 69
(22), 57 (30).
(E)-4-(4-Ethoxystyryl)-3(5)-(2-hydroxy-4-methoxy-
phenyl)pyrazole (4j, C20H20N2O3)
1
Mp 165–167 °C; H NMR: d = 1.42 (t, J = 7.0 Hz, 400-
OCH2CH3), 3.82 (s, 40-OCH3), 4.02 (q, J = 7.0 Hz, 400-
123

94
V. L. M. Silva et al.
(E)-3(5)-(2-Hydroxy-4-methoxyphenyl)-4-(4-nitro-
(Z)-3(5)-(2-Hydroxy-4-methoxyphenyl)-4-(3-nitro-
styryl)pyrazole (4n, C18H15N3O4)
styryl)pyrazole (3r, C18H15N3O4)
Mp 197–198 °C; 1H NMR (DMSO-d6 with TFA):
d = 3.76 (s, 40-OCH3), 6.54–6.57 (m, H-50), 6.53 (d,
J = 2.4 Hz, H-30), 7.13 (AB, J = 17.4 Hz, H-a, H-b), 7.25
(d, J = 8.9 Hz, H-60), 7.64 (d, J = 8.8 Hz, H-200,600), 8.05
(br s, H-5), 8.16 (d, J = 8.8 Hz, H-300,500), 10.14 (without
TFA; br s, NH), 12.77 (without TFA; br s, 20-OH) ppm; 13C
NMR (DMSO-d6 with TFA): d = 55.7 (40-OCH3), 102.6
(C-30), 106.4 (C-50), 108.0 (C-10), 118.5 (C-4), 123.6 (C-a),
124.8 (C-300,500), 127.1 (C-b), 127.5 (C-200,600), 132.6 (C-60),
133.4 (C-5), 142.5 (C-3), 144.8 (C-100), 147.0 (C-400), 157.5
(C-20), 162.8 (C-40) ppm; MS (EI, 70 eV): m/z (%) = 337
(M?ꢀ, 100), 336 [(M–H)?, 28], 320 [(M–OH)?, 3], 307
[(M–NO)?, 9], 290 (17), 247 (2), 231 (2), 215 [(M–
C6H4NO2)?, 15], 201 (74), 186 (3), 169 (3), 163 (3), 145
(2), 115 (5), 102 (2), 89 (3), 78 (4), 63 (10).
Mp 115–117 °C; 1H NMR (DMSO-d6 with TFA):
d = 3.63 (s, 40-OCH3), 6.34 (dd, J = 8.6, 2.3 Hz, H-50),
6.40 (d, J = 2.3 Hz, H-30), 6.43 (d, J = 12.0 Hz, H-a),
6.62 (d, J = 12.0 Hz, H-b), 7.18 (d, J = 8.6 Hz, H-60),
7.32 (t, J = 8.0 Hz, H-500), 7.40–7.44 (m, H-600), 7.73 (s,
H-5), 7.83 (t, J = 2.0 Hz, H-200), 7.89 (ddd, J = 8.0, 2.0,
0.9 Hz, H-400), 10.20 and 10.63 (without TFA; br s, NH),
12.80 and 13.15 (without TFA; br s, 20-OH) ppm; 13C
NMR (DMSO-d6 with TFA): d = 56.2 (40-OCH3), 103.0
(C-30), 107.0 (C-50), 107.6 (C-10), 117.0 (C-4), 122.1 (C-a),
123.4 (C-400), 124.0 (C-200), 131.0 (C-500), 131.5 (C-b),
132.8 (C-60), 134.0 (C-5), 135.9 (C-600), 139.8 (C-100),
143.7 (C-3), 149.4 (C-300), 158.1 (C-20), 163.9 (C-40) ppm.
MS (ESI?): m/z (%) = 338 [(M ? H)?, 25].
The following products have been reported in the liter-
ature and in this work were identified on the basis of their
melting points: (Z)-3(5)-(2-hydroxyphenyl)-4-styrylpyraz-
ole (3a, C17H14N2O), Mp 119–121 °C (Lit.: 119–121 °C)
[28]; (Z)-3(5)-(2-hydroxyphenyl)-4-(3-nitrostyryl)pyrazole
(3p, C17H13N3O3), Mp 108–110 °C (Lit.: 108–110 °C)
[28]; (E)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazole (4a,
C17H14N2O), Mp 138–140 °C (Lit.: 138–140 °C) [28];
(E)-3(5)-(2-hydroxyphenyl)-4-(4-nitrostyryl)pyrazole (4l,
C17H14N3O3), Mp 212–214 °C (Lit.: 212–214 °C) [28].
(E)-3(5)-(2-Hydroxy-4,6-dimethoxyphenyl)-
4-(4-nitrostyryl)pyrazole (4o, C19H17N3O5)
Mp 220–222 °C; 1H NMR (DMSO-d6 with TFA):
d = 3.70 (s, 60-OCH3), 3.78 (s, 40-OCH3), 6.24 (s, H-30,
H-50), 6.93 (d, J = 16.5 Hz, H-a), 7.09 (d, J = 16.5 Hz,
H-b), 7.63 (d, J = 8.8 Hz, H-200,600), 8.16 (d, J = 8.8 Hz,
H-300,500), 8.40 (s, H-5), 9.79 (without TFA; br s, NH),
12.71 (without TFA; br s, 20-OH) ppm; 13C NMR (DMSO-
d6 with TFA): d = 55.4 (40-OCH3), 55.9 (60-OCH3), 90.5
(C-30), 94.1 (C-50), 96.3 (C-10), 118.9 (C-4), 123.9 (C-a),
124.4 (C-300,500), 125.2 (C-b), 126.8 (C-200,600), 133.6 (C-5),
137.8 (C-3), 144.5 (C-100), 146.2 (C-400), 157.9 (C-20),
159.7 (C-60), 162.7 (C-40) ppm; MS (EI, 70 eV): m/z
(%) = 368 [(M 1 H)?, 22], 367 (M1ꢀ, 100), 350 [(M–
OH)?, 7], 337 (15), 320 (11), 306 (3), 290 (4), 277 (1), 261
(2), 245 (3), 231 (82), 215 (12), 205 (3), 189 (3), 174 (8),
159 (3), 139 (2), 131 (5), 115 (5), 91 (3), 77 (5), 69 (4), 57
(2).
Acknowledgments Thanks are due to the University of Aveiro,
FCT and FEDER for funding the Organic Chemistry Research Unit.
One of us (VLMS) is also grateful to FCT and FSE for a Ph.D. grant
(SFRH/BD/6647/2001).
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