One-pot synthesis of 1,3,5-triarylpyrazoles

Article abstract of DOI:10.1002/jhet.927

A series of novel 1,3,5-triarylpyrazoles were synthesized from flavanones, arylhydrazines, and trimethyl phosphate in an one-pot procedure. Facile reaction process, easy after-reaction workshop, and good yields are the distinct characteristics of the developed protocol. The target compounds were characterized by element analysis, infrared ray (IR), ¹H NMR spectra, and electrospray ionization-mass spectrometry. The structure of representative compound (C₂₃H₂₀N₂O₃, M_r = 372.42) was further confirmed by X-ray diffraction. It crystallizes in monoclinic, space group P 2₁/c, a = 8.9720(5), b = 24.5523(13), c = 8.9687(6) A, α = 90.0000, β = 102.6417(17), γ = 90.0000°, V = 1927.76(20) A³, Z = 4, μ(MoKα) = 0.086, F(000) = 784, D_c = 1.283 g/cm³, the final R = 0.0349 and wR = 0.0844 for 1668 observed reflections (I > 2σ(I)).

Full text of DOI:10.1002/jhet.927

Month 2013
One-Pot Synthesis of 1,3,5-Triarylpyrazoles
*
Shufang Huang, Huazhou Ying, and Yongzhou Hu
ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences
Zhejiang University, Hangzhou 310058, China
*
E-mail: huyz@zju.edu.cn
Received October 8, 2010
DOI 10.1002/jhet.927
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel 1,3,5-triarylpyrazoles 3a–3x were synthesized from flavanones, arylhydrazines, and
trimethyl phosphate in an one-pot procedure. Facile reaction process, easy after-reaction workshop, and good
yields are the distinct characteristics of the developed protocol. The target compounds were characterized
1
by element analysis, infrared ray (IR), H NMR spectra, and electrospray ionization-mass spectrometry.
The structure of representative compound 3h (C23H20N2O3, Mr = 372.42) was further confirmed by
X-ray diffraction. It crystallizes in monoclinic, space group P 21/c, a = 8.9720(5), b = 24.5523(13),
c = 8.9687(6) Å, α = 90.0000, β = 102.6417(17), g = 90.0000ꢀ, V = 1927.76(20) Å3, Z = 4, μ(MoKα)
= 0.086, F(000) = 784, Dc = 1.283 g/cm3, the final R = 0.0349 and wR = 0.0844 for 1668 observed
reflections (I > 2σ(I))
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
an one-pot procedure (Scheme 2), which was proved
to be feasible as follows.
Triaryl-substituted pyrazoles received substantial atten-
tion for their various biological activities, such as antican-
cer [1–3], anti-inflammatory [4], and so on [5]. Reported
methods for the synthesis of 1,3,5-triarylpyrazoles, as
cycloaddition using 3-aryl-2,3-epoxy-1-phenyl-1-propanones
or cyclocondensation from 1,3-diphenylpropane-1,3-dione
[6–9], usually result in the formation of isomers and involve
multiple synthetic steps [10]. Thus, with the aim of refining
and simplifying the synthetic protocol, we delivered a facile
and efficient method for the synthesis of 1,3,5-triaryl-
substituted pyrazoles from flavanones, arylhydrazines, and
PO(OCH3)3 in a one-pot procedure.
Various substituted flavanones (4) and arylhydrazines (5)
were investigated to explore the optimal reaction condition,
as well as the scope of our method. As shown in Table 1,
substrates with aromatic ring bearing electron-withdrawing
group, electron-detonating group, and no substituent were
involved, and most substrates led the corresponding prod-
ucts in moderate to good yields. Flavanone bearing
methoyxl group tended to lead a slightly higher yield, while
flavanone bearing electron-withdrawing group resulted
in low yield and the reaction did not go smoothly at low
temperature. High reaction temperature, up to 200ꢀC,
was required when 4-dinitrophenylhydrazine and 4-
methylsulfonyl phenyl hydrazine were used as the
reactants. It was also noteworthy to mention that ortho-
substituted phenylhydrazine significantly decreased reac-
tion yield (3k), due to steric effect.
Products 3a–3x were characterized by element analysis,
IR, 1H NMR spectra, and electrospray ionization-mass
spectrometry (ESI-MS). The structure of compound 3h
was further confirmed by X-ray analysis (Figs. 1 and 2,
CCDC(687044)). The selected bond lengths, bond angles,
and torsion angles of 3h are listed in Tables 3 and 4,
respectively. Further details can be found in Table 2.
Structure analysis indicated that all ring atoms in the
pyrazole moiety were nearly coplanar. The N(2)─C(4)
bond length was 1.363(2), which was remarkably shorter
RESULTS AND DISCUSSION
The synthetic procedure to obtain compound 3 (1,3,
5-triarylpyrazoles) was discovered accidentally in one of
our previous studies on pyrazole compound 2. Treating 1
((E)-1-phenyl-2-(2-phenyl-2,3-dihydrochromen-4-ylidene)
hydrazine) with PO(OCH3)3 in solvent at temperature
gave 3 in high yields instead of 2 (Scheme 1). Since 1
could be obtained through the reaction between compound
4 (2-phenyl-2,3-dihydrochromen-4-one) and compound
5 (1-phenylhydrazine), we supposed that compound 3
might be obtained directly from the reaction between
compounds 4 and 5 in the presence of PO(OCH3)3 in
© 2013 HeteroCorporation

S. Huang, H. Ying, and Y. Hu
Vol 000
Scheme 1
Scheme 2
the bond distances of N(2)─C(19) (1.425 Å), C(4)─C(13)
(1.475(2) Å), C(2)─C(5) (1.472(2) Å) were shorter than
that of typical C─N (1.50 Å) and C─C bond (1.54 Å).
In addition, X-ray analysis also revealed that the exis-
tence of an intramolecular hydrogen bond in the crystal
and the bond length of O(3)─H(1)…N(1) was 2.548(2)
(Table 5).
We speculated the mechanistic pathway for formation of
pyrazoles as follows (Scheme 3). First, (E)-1-phenyl-2-(2-phe-
nyl-2,3-dihydrochromen-4-ylidene)hydrazine was obtained
by the reaction of 2-phenyl-2,3-dihydrochromen-4-one with
1-phenylhydrazine, and the arylhydrazone pyrone ring
was opened. Then electronic rearrangement happened
and 2-(1,5-diphenyl-4,5-dihydro-1H-pyrazol-3-yl)phenol
was obtained. Finally, objective compound of 1,3,5-
triarylpyrazole was successfully synthesized using PO
(OCH3)3 as oxidant [11,12].
than a normal C─N bond (1.50 Å) but close to a typical
C─N bond (1.32 Å) [11]. It was considered that atom
N(2) made three sp2–sp2 σ bonds with its neighboring
atoms. Its lone pair electrons made Π bond with the
other four electrons (three from carbon atoms, one from
nitrogen atoms N(1)). The dihedral shaped by pyrazole
plane and aryl ring C(5)─C(6)─C(7)─C(8)─C(9)─C(10)
was 167.5ꢀ, which also illustrated a coplanar structure.
Due to the result of conjugation effect of aryl rings,
Table 1
One‐pot synthesis of 1,3,5‐triarylpyrozoles 3a–3x.
Entry
Compound
R1
R2
R3
Condition
Yield (%)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
H
H
H
H
H
H
H
H
4‐MeO
4‐Cl
4‐Cl
H
H
H
H
4‐Me
3‐MeO
3‐MeO
4‐MeO
4‐MeO
H
3,4‐diMeO
H
H
H
4‐Cl
H
4‐MeO
H
H
H
H
4‐NO2
H
4‐Cl
4‐NO2
4‐SO2Me
H
120ꢀC, 2 h
120ꢀC, 12 h
200ꢀC, 12 h
120ꢀC, 12 h
130ꢀC, 12 h
200ꢀC, 6 h
180ꢀC, 6 h
110ꢀC, 6 h
110ꢀC, 6 h
110ꢀC, 6 h
110ꢀC, 6 h
110ꢀC, 6 h
110ꢀC, 6 h
110ꢀC, 6 h
110ꢀC, 6 h
120ꢀC, 24 h
120ꢀC, 6 h
120ꢀC, 6 h
120ꢀC, 6 h
120ꢀC, 24 h
120ꢀC, 12 h
130ꢀC, 12 h
120ꢀC, 12 h
120ꢀC, 12 h
54
56
40
45
58
53
45
65
67
64
29
72
64
67
72
48
59
60
53
49
54
48
51
53
4,6‐diMeO
4,6‐diMeO
4,6‐diMeO
4,6‐diMeO
4,6‐diMeO
4,6‐diMeO
4,6‐diMeO
4,6‐diMeO
4,6‐diMeO
4,6‐diMeO
4‐MeO
4‐MeO
5‐COOH
4‐MeO
5‐Cl
9
H
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
2‐Cl
H
4‐F
4‐Cl
H
4‐NO2
4‐Br
H
H
H
4‐Br
H
H
3t
3u
3v
3w
3x
5‐Me
5‐Me
3‐CH2OCH2‐4
H
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
One-Pot Synthesis of 1,3,5-Triarylpyrazoles
Table 2
Details of X‐ray diffraction studies.
Complex
3h
CCDC No.
Formula
Mr (g/mol)
Crystal color
687044
23 H20 N2 O3
372.42
Colorless
Needle
C
Crystal habit
Crystal dimensions (mm)
Crystal system
Space group
0.32 × 0.18 × 0.11
Monoclinic
P 21/c
4
Z
a (Å)
b(Å)
8.9720(5)
24.5523(13)
8.9687(6)
90
102.6417(17)
90
Figure 1. Molecule structure of compound of 3h.
c(Å)
α (ꢀ)
β (ꢀ)
g (ꢀ)
Temperature (K)
296(1)
1927.8(2)
1.283
Volume (Å3)
CONCLUSION
D calcd. (g/cm3)
Radiation
In summary, we have successfully developed a novel
facile one-pot procedure for the synthesis of 1,3,5-triaryl
substituted pyrazoles from flavanones, arylhydrazines,
and PO(OCH3)3. The reaction products were prepared in
moderate to good yield with different substituents.
MoKα (λ = 0.71075 Å)
0.086
Absorption coefficient, μ (mm−1
F(000)
)
784.0
0.997–27.44
18,904
4403(Rint = 0.046)
4403/0/254
0.00
θ range(ꢀ) for data correction
Observed reflections
Independent reflections
Data/restraints/parameters
Maximum shift/error
Goodness‐of‐fit on F2
Final R indices[I > 2σ(I)]
Extinction coefficient
EXPERIMENTAL
1.001
R1 = 0.0349, wR2 = 0.0844
272(16)
Melting points were determined on a Buchi B-540 apparatus
1
and were uncorrected. All H NMR spectra were recorded on a
Largest diffraction peak and hole
0.40 and −0.34
(e; Å−3
)
Brüker AM 400 with tetramethylsilane (TMS) as internal stan-
dard. Chemical shifts were reported in δ values (ppm) relative
to internal TMS and J values were reported in Hertz. IR spectra
were recorded using KBr pellets on a Bruker Vector-22 FTIR
spectrophotometer. The elemental analysis was measured on a
EA-300 analyzer and the MS(ESI) were measured on Esquire-
LC-00075. X-ray diffraction data were collected on a Rigaku
RAXIS-RAPID.
(10 mL × 3); the extract was then washed with brine and
concentrated to give residue, which was purified by column
chromatography on silica gel and eluted with ethyl acetate/
petroleum ether (b.p.: 60–90ꢀC, v/v 1:5) to afford white powder
as the pure product (0.241 g, 65%). Single crystals of the title
compound were obtained by evaporating the petroleum ether/
ethyl acetate (5:1) solution slowly. The structure was solved by
direct methods with CrystalStructure 3.7.0 [14–16].
Representative procedure for preparation of 3h. 5,7-
Dimethoxylflavanone (1) was prepared according to the
literature [13]. Then the mixture of compound 1 (0.284 g, 1
mmol), phenylhydrazine hydrochloride 2 (0.173 g, 1.2 mmol),
and PO(OCH3)3 (1 mL) was stirred at 110ꢀC for 12 h. After
cooling to room temperature, the reaction mixture was
then added into water (20 mL) and then extracted with EtOAc
2-(1,5-Diphenyl-1H-pyrazol-3-yl)phenol 3a. Yield: 54%.
1
White powder, mp 83–85ꢀC. H NMR (400 MHz, CDCl3): δ =
10.84 (s, 1H, ─OH), 7.64 (dd, 1H, J = 7.6 Hz, 1.2 Hz, H-6″),
7.38–7.23 (m, 11H, H- 2′, 3′, 4′, 5′, 6′, 5″, 2″′, 3″′, 4″′, 5″′, 6″
′), 7.05 (dd, 1H, J = 7.6 Hz, 1.2 Hz, H-3″), 6.95 (td, 1H, J =
7.6 Hz, 1.2 Hz, H-4″), 6.88 (s, 1H, H-4); IR (KBr)ν: 3057,
2926, 1652, 1622, 1595, 1498, 1363, 1296, 1250, 827, 758, 694
cm−1; Anal. Calcd for C21H16N2O: C, 80.75; H, 5.16; N, 8.97;
Found: C, 80.58; H, 5.20; N, 9.08; MS (ESI): m/z = 313 [M+H]+.
2-(5-(4-Methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)phenol
3b. Yield: 56%. White powder, mp 90–92ꢀC. 1H NMR (400
MHz, CDCl3): δ = 7.63(dd, 1H, J = 7.6 Hz, 1.6 Hz, H-6″),
7.38–7.30 (m, 5H, H-2′, 3′, 4′, 5′, 6′), 7.25 (td, 1H, J = 7.6 Hz,
1.2 Hz, H-5″), 7.15 (d, 2H, J = 9.2 Hz, H-2″′, 6″′), 7.05 (dd,
1H, J = 7.6 Hz, 1.2 Hz, H-3″), 6.96 (td, 1H, J = 7.6 Hz, 1.2 Hz,
H-4″), 6.82 (s, 1H, H-4), 6.80 (d, 2H, H-3″′, 5″′); IR (KBr)ν:
3057, 2927, 1652, 1623, 1585, 1499, 1457, 1362, 1255, 837,
Figure 2. Packing arrangement in a unit cell of 3h.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Huang, H. Ying, and Y. Hu
Vol 000
Table 3
Selected bond lengths (Å) and bond angles (ꢀ) of 3h.
Bond
N(1)─N(2)
N(2)─C(19)
O(1)─C(6)
Bond
N(1)─N(2)─C(4)
N(2)─C(4)─C(3)
Distance
Bond
Distance
Bond
Distance
1.364(2)
1.425(2)
1.374(2)
Angle (ꢀ)
111.1(1)
106.6(2)
N(1)–C(2)
C(4)–C(13)
O(2)–C(8)
Bond
N(1)─C(2)─C(3)
1.341(2)
1.425(2)
1.380(2)
Angle (ꢀ)
109.6(2)
N(2)─C(4)
C(2)─C(5)
O(3)─C(10)
Bond
1.363(2)
1.473(2)
1.364(2)
Angle (ꢀ)
106.6(2)
C(2)─C(3)─C(4)
Table 4
Selected torsion angles (ꢀ) of 3h
Bond
Angle (ꢀ)
Bond
Angle (ꢀ)
N(1)–N(2)–C(19)–C(24)
N(1)–C(2)–C(5)–C(10)
C(2)–N(1)–N(2)–C(4)
N(2)–C(4)–C(13)–C(18)
−49.8(2)
−5.0(2)
−0.2(2)
−44.4(2)
C(19)–N(2)–C(4)–C(13)
C(3)–C(2)–C(5)–C(6)
C(4)–N(2)–C(19)–C(20)
−7.2(2)
−5.1(2)
−49.5(2)
798, 759, 695 cm−1; Anal. Calcd for C22H18N2O2: C, 77.17;
H, 5.30; N, 8.18; Found: C, 77.33; H, 5.27; N, 8.03; MS
(ESI): m/z = 343 [M+H]+.
2-(1-(4-Chlorophenyl)-5-phenyl-1H-pyrazol-3-yl)phenol
3e. Yield: 58%. White powder, mp 144–146ꢀC. 1H NMR
(400 MHz, CDCl3): δ = 10.84 (s, 1H, ─OH), 7.64 (dd, 1H, J =
7.6 Hz, 1.2 Hz, H-6″), 7.38–7.23 (m, 10H, H-2′, 3′, 5′, 6′, 5″,
2″′, 3″′, 4″′, 5″′, 6″′), 7.05 (dd, 1H, J = 8.0 Hz, 1.6 Hz, H-3″),
6.95 (td, 1H, J = 8.0 Hz, 1.6 Hz, H-4″), 6.89 (s, 1H, H-4); IR
(KBr)ν: 3058, 1632, 1622, 1584, 1499, 1458, 1361, 1290,
1263, 830, 795, 759, 692 cm−1; Anal. Calcd for C21H15ClN2O:
C, 72.73; H, 4.36; N, 8.08; Found: 72.69; H, 4.39; N, 8.12;
MS (ESI): m/z = 347 [M+H]+.
2-(5-(4-Chlorophenyl)-1-(4-nitrophenyl)-1H-pyrazol-3-yl)
phenol 3c. Yield: 40%. Yellow powder, mp 148–150ꢀC. 1H
NMR (400 MHz, CDCl3): δ = 10.58 (s, 1H, OH), 8.19 (d, 2H,
J = 9.2 Hz, H-3′, 5′), 7.63(dd, 1H, J = 7.6 Hz, 1.6 Hz, H-6″),
7.47 (d, 2H, J = 9.2 Hz, H-2′, 6′), 7.40 (d, 2H, J = 8.4 Hz, H-
3″′, 5″′), 7.36 (d, 2H, J = 8.4 Hz, H-2″′, 6″′), 7.25 (td, 1H, J =
7.6 Hz, 1.2 Hz, H-5′), 7.05 (dd, 1H, J = 7.6 Hz, 1.2 Hz, H-3″),
7.25 (td, 1H, J = 7.6 Hz, 1.2 Hz, H-4″), 6.92 (s, 1H, H-4); IR
(KBr)ν: 3060, 1636, 1622, 1584, 1498, 1446, 1362, 1344,
2-(1-(4-Nitrophenyl)-5-phenyl-1H-pyrazol-3-yl)phenol
1
3f. Yield: 53%. White powder, mp 150–152ꢀC. H NMR (400
1297, 1249, 830, 799, 759 cm−1
;
Anal. Calcd for
MHz, CDCl3): δ = 11.51 (s, 1H, ─OH), 8.19 (d, 2H, J = 9.2 Hz,
H-3′, 5′), 7.64 (dd, 1H, J = 7.6 Hz, 1.2 Hz, H-6″), 7.46 (d, 2H,
J = 9.2 Hz, H-2′, 6′), 7.38–7.23 (m, 6H, H-5″, 2″′, 3″′, 4″′, 5″′,
6″′), 7.05 (dd, 1H, J = 7.6 Hz, 1.2 Hz, H-3″), 6.95 (td, 1H, J =
7.6 Hz, 1.2 Hz, H-4″), 6.91 (s, 1H, H-4); IR (KBr)ν: 3059, 1632,
1586, 1499, 1438, 1362, 1347, 1297, 839, 794, 766 cm−1; Anal.
Calcd for C21H15N3O3: C, 70.58; H, 4.23; N, 11.76; Found:
70.52; H, 4.26; N, 11.81; MS (ESI): m/z = 358 [M+H]+.
C21H14ClN3O3: C, 64.37; H, 3.60; N, 10.72; Found: 64.31; H,
3.58; N, 10.69; MS (ESI): m/z = 392 [M+H]+.
2-(5-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)phenol
3d. Yield: 45%. White powder, mp 134–136ꢀC. 1H NMR
(400 MHz, CDCl3): δ = 10.75 (s, 1H, ─OH), 7.63 (dd, 1H, J =
8.0 Hz, 1.6 Hz, H-6″), 7.42–7.21 (m, 10H, H-2′, 3′, 4′, 5′, 6′,
5″, 2″′, 3″′, 5″′, 6″′), 7.05 (dd, 1H, J = 8.0 Hz, 1.2 Hz, H-3″),
6.95 (td, 1H, J = 8.0 Hz, 1.2 Hz, H-4″), 6.87 (s, 1H, H-4); IR
(KBr)ν: 3063, 1637, 1622, 1584, 1499, 1446, 1362, 1297,
1249, 830, 799, 759, 692 cm−1; Anal. Calcd for C21H15ClN2O:
C, 72.73; H, 4.36; N, 8.08; Found: 72.65; H, 4.38; N, 8.13;
MS (ESI): m/z = 347 [M+H]+.
Scheme 3
Table 5
Hydrogen‐bonding Geometry (Å) of 3h.
D─H…A
D─H
H…A
D…A
D─H…A
O(3)─H(1)…N(1)
0.945
1.716
2.548(2)
144.8
Symmetry codes: x, y, z.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
One-Pot Synthesis of 1,3,5-Triarylpyrazoles
2-(1-(4-(Methylsulfonyl)phenyl)-5-phenyl-1H-pyrazol-3-yl)
2-(1-(4-Fluorophenyl)-5-(4-methoxyphenyl)-1H-pyrazol-3-
yl)-3,5-dimethoxyphenol 3m. Yield: 56%. White powder, mp
115–117ꢀC. 1H NMR (400 MHz, CDCl3): δ = 7.68–7.63 (m,
2H, H-3′, 5′); 7.25–7.20 (m, 4H, H-2′, 6′, 2″′, 6″′), 7.11(s, 1H,
H-4), 6.88 (d, 2H, J = 8.8 Hz, H-3″′, 5″′), 6.24 (d, 1H, J =
2.0 Hz, H-5″), 6.11 (d, 1H, J = 2.0 Hz, H-3″), 3.91 (s, 3H,
─OCH3), 3.83 (s, 3H, ─OCH3), 3.77 (s, 3H, ─OCH3); IR
(KBr)ν: 3088, 1649, 1587, 1499, 1434, 1383, 1288, 1156,
904, 766 cm−1; Anal. Calcd for C24H21FN2O4: C, 68.56; H,
5.03; N, 6.66; Found: C, 68.71; H, 5.11; N, 6.59; MS (ESI):
m/z = 421 [M+H]+.
1
phenol 3g. Yield: 30%. White powder, mp 96–98ꢀC. H NMR
(400 MHz, CDCl3): δ = 10.54 (s, 1H, ─OH), 7.92 (d, 2H, J =
8.4 Hz, H-3′, 5′), 7.64 (dd, 1H, J = 8.0 Hz, 1.6 Hz, H-6″), 7.53
(d, 2H, J = 8.4 Hz, H-2′, 6′), 7.45–7.39 (m, 3H, H-3″′, 4″′, 5″
′), 7.32–7.27 (m, 3H, H-5″, 2″′, 6″′), 7.07 (d, 1H, J = 8.0 Hz,
H-3″), 6.97 (td, 1H, J = 8.0 Hz, 0.8 Hz, H-4″), 6.93 (s, 1H, H-
4), 3.09 (s, 3H, -SO2CH3); IR (KBr)ν: 3057, 1652, 1622, 1585,
1497, 1450, 1361, 1318, 1297, 1249, 917, 825, 762 cm−1; Anal.
Calcd for C22H18N2O3S: C, 67.67; H, 4.65; N, 7.17; Found:
67.74; H, 4.61; N, 7.24; MS (ESI): m/z = 391 [M+H]+.
2-(1,5-Diphenyl-1H-pyrazol-3-yl)-3,5-dimethoxyphenol
3h. Yield: 65%. White powder, mp 155–156ꢀC. 1H NMR
(400 MHz, CDCl3): δ = 11.97 (s, 1H, ─OH), 7.36–7.26 (m, 10H,
H-5″′, 6″′, 2′, 3′, 4′, 5′, 6′, 2″′, 3″′, 4″′), 7.19 (s, 1H, H-4), 6.28
(d, 1H, J = 2.0 Hz, H-5″), 6.15 (d, 1H, J = 2.0 Hz, H-3″), 3.92 (s,
3H, ─OCH3), 3.84 (s, 3H, ─OCH3); IR (KBr)ν: 3064, 1628,
1595, 1498, 1434, 1383, 1287, 1217, 822, 766, 738, 697 cm−1;
Anal. Calcd for C23H20N2O3: C, 74.18; H, 5.41; N, 7.52; Found:
74.29; H, 5.44; N, 7.58; MS (ESI): m/z = 373 [M+H]+.
2-(1-(4-Chlorophenyl)-5-phenyl-1H-pyrazol-3-yl)-3,5-
dimethoxyphenol 3n. Yield: 67%. White powder, mp 149–
151ꢀC. 1H NMR (400 MHz, CDCl3): δ = 7.35–7.21 (m, 9H, H-2′,
3′, 5′, 6′, 2″′, 3″′, 4″′, 5″′, 6″′), 7.15(s, 1H, H-4), 6.24 (d, 1H, J =
2.0 Hz, H-5″), 6.11 (d, 1H, J = 2.0 Hz, H-3″), 3.89 (s, 3H,
─OCH3), 3.81 (s, 3H, ─OCH3); IR (KBr)ν: 3030, 2927, 1644,
1590, 1503, 1431, 1388, 1278, 917, 876, 752, 697 cm−1; Anal.
Calcd for C23H19ClN2O3: C, 67.90; H, 4.71; N, 6.89; Found: C,
67.83; H, 4.66; N, 6.81; MS (ESI): m/z = 407 [M+H]+.
3,5-Dimethoxy-2-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)phenol
3i. Yield: 67%. White amorphous powder, mp 174–176ꢀC. 1H
NMR (400 MHz, CDCl3): δ = 11.98 (s, 1H, ─OH), 7.36–7.28
(m, 5H, H-2′, 3′, 4′, 5′, 6′), 7.20 (d, 2H, J = 8.0 Hz, H-2″′, 6″′),
7.16 (s, 1H, H-4), 7.14 (d, 2H, J = 8.0 Hz, H-3″′, 5″′), 6.26 (d,
1H, J = 1.2 Hz, H-5″), 6.13 (d, 1H, J = 1.2 Hz, H-3″), 3.92 (s,
3H, ─OCH3), 3.83 (s, 3H, ─OCH3), 2.37 (s, 3H, CH3); IR
(KBr)ν: 3058, 2928, 1630, 1597, 1500, 1434, 1383, 1287, 860,
825, 799, 697 cm−1; Anal. Calcd for C24H22N2O3: C, 74.59; H,
5.74; N, 7.25; Found: 74.46; H, 5.40; N, 7.52; MS (ESI): m/z =
387 [M+H]+.
2-(1-(4-Bromophenyl)-5-(3,4-dimethoxyphenyl)-1H-pyrazol-
3-yl)-5-methoxyphenol 3o. Yield: 56%. White powder, mp 182–
1
183ꢀC. H NMR (400 MHz, CDCl3): δ = 10.81 (s, 1H, ─OH),
7.51 (d, 1H, J = 8.8 Hz, H-6″), 7.48 (d, 2H, J = 8.8 Hz, H-3′, 5′),
7.21 (d, 2H, J = 8.8 Hz, H-2′, 6′), 6.85 (s, 2H, H-4, 5″′), 6.74 (s,
2H, H-2″′, 6″′), 6.59 (d, 1H, J = 2.0 Hz, H-3″), 6.53 (dd, 1H, J =
8.8 Hz, 2.0 Hz, H-5″), 3.91 (s, 3H, ─OCH3), 3.84 (s, 3H,
─OCH3), 3.74 (s, 3H, ─OCH3); IR (KBr)ν: 3046, 1652, 1597,
1489, 1431, 1380, 1288, 904, 766 cm−1; Anal. Calcd for
C24H21BrN2O4: C, 59.89; H, 4.40; N, 5.82; Found: C, 60.01; H,
4.37; N, 5.81; MS (ESI): m/z = 481 [M+H]+.
3,5-Dimethoxy-2-(5-(3-methoxyphenyl)-1-phenyl-1H-pyrazol-
3-yl)phenol 3j. Yield: 56%. White powder, mp 141–142ꢀC. 1H
NMR (400 MHz, CDCl3): δ = 7.35–7.22 (m, 7H, H-2′, 3′, 4′,
5′, 6′, 5″′, 6″′), 6.98 (s, 1H, H-4), 6.89–6.86 (m, 2H, H-2″′, 4″
′), 6.22 (d, 1H, J = 2.0 Hz, H-5″), 6.09 (d, 1H, J = 2.0 Hz, H-
3″), 3.91 (s, 3H, ─OCH3), 3.81 (s, 6H, ─OCH3×2); IR (KBr)ν:
3049, 1635, 1595, 1499, 1427, 1385, 1290, 933, 880, 822, 766,
738, 690 cm−1; Anal. Calcd for C24H22N2O4: C, 71.63; H, 5.51;
N, 6.96; Found: C, 71.51; H, 5.58; N, 7.05; MS (ESI): m/z =
403 [M+H]+.
3,5-Dimethoxy-2-(1-(4-nitrophenyl)-5-phenyl-1H-pyrazol-
1
3-yl)phenol 3p. Yield: 48%. White powder, mp 177–178ꢀC. H
NMR (400 MHz, CDCl3): δ = 11.58 (s, 1H, OH), 8.19 (d, 2H,
J = 9.2 Hz, H-3′, 5′), 7.47 (d, 2H, J = 9.2 Hz, H-2′, 6′), 7.44–
7.39 (m, 3H, H-3″′, 4″′, 5″′), 7.34–7.31 (m, 2H, H-2″′, 6″′),
7.24 (s, 1H, H-4), 6.27 (d, 1H, J = 2.0 Hz, H-5″), 6.14 (d, 1H, J
= 2.0 Hz, H-3″), 3.91 (s, 3H, ─OCH3), 3.84 (s, 3H, ─OCH3);
IR (KBr)ν: 3058, 2970, 1653, 1585, 1521, 1457, 1362, 933,
887, 822, 735, 692 cm−1; Anal. Calcd for C23H19N3O5: C,
66.18; H, 4.59; N, 10.07; Found: C, 66.29; H, 4.56; N, 10.13;
MS (ESI): m/z = 418 [M+H]+.
2-(1-(2-Chlorophenyl)-5-(3-methoxyphenyl)-1H-pyrazol-3-
yl)-3,5-dimethoxyphenol 3k. Yield: 29%. White powder, mp
2-(1-(4-Bromophenyl)-5-phenyl-1H-pyrazol-3-yl)-3,5-
dimethoxyphenol 3q. Yield: 56%. White powder, mp 144–
1
135–137ꢀC. H NMR (400 MHz, CDCl3): δ = 7.51 (dd, J = 7.6
1
Hz, 1.6 Hz, H-6′), 7.49 (dd, J = 7.6 Hz, 1.2 Hz, H-3′), 7.37–
7.22 (m, 4H, H-2′, 4′, 5′, 5″′, 6″′), 7.11 (s, 1H, H-4), 6.89–6.86
(m, 2H, H-2″′, 4″′), 6.24 (d, 1H, J = 2.0 Hz, H-5″), 6.11 (d,
1H, J = 2.0 Hz, H-3″), 3.91 (s, 3H, ─OCH3), 3.81 (s, 6H,
─OCH3×2); IR (KBr)ν: 3058, 1629, 1599, 1497, 1427, 1388,
146ꢀC. H NMR (400 MHz, CDCl3): δ = 11.78 (s, 1H, H-OH),
7.46 (d, 2H, J = 8.8 Hz, H-3′, 5′), 7.38–7.35 (m, 3H, H-3″′, 4″′,
5″′), 7.32–7.29 (m, 2H, H-2″′, 6″′), 7.19 (d, 2H, J = 8.8 Hz, H-
2′, 6′), 7.18 (s, 1H, H-4), 6.26 (d, 1H, J = 2.4 Hz, H-5″), 6.13 (d,
1H, J = 2.4 Hz, H-3″), 3.91 (s, 3H, ─OCH3), 3.84 (s, 3H,
─OCH3); IR (KBr)ν: 3059, 1643, 1598, 1497, 1438, 1361, 1290,
1070, 933, 886, 738, 692 cm−1; Anal. Calcd for C23H19BrN3O5:
C, 61.21; H, 4.24; N, 6.21; Found: C, 61.12; H, 4.29; N, 6.32;
MS (ESI): m/z = 418 [M+H]+.
2-(1,5-Diphenyl-1H-pyrazol-3-yl)-5-methoxyphenol
3r. Yield: 60%. White powder, mp 146–148ꢀC. 1H NMR
(400 MHz, CDCl3): δ = 10.94 (s, 1H, OH), 7.52 (d, 1H, J = 8.0
Hz, H-6″), 7.38–7.27 (m, 10H, H-2′, 3′, 4′, 5′, 6′, 2″′, 3″′, 4″′, 5″′,
6″′), 6.78 (s, 1H, H-4), 6.60 (d, 1H, J = 2.8 Hz, H-3″), 6.53 (dd, 1H,
J = 8.0 Hz, 2.8 Hz, H-5″), 3.83 (s, 3H, ─OCH3); IR (KBr)ν: 3064,
1632, 1585, 1498, 1439, 1361, 1286, 1263, 977, 830, 799, 763, 694
cm−1; Anal. Calcd for C22H18N2O2: C, 77.17; H, 5.30; N, 8.18;
Found: C, 77.29; H, 5.35; N, 8.24; MS (ESI): m/z = 343 [M+H]+.
1288, 1156, 884, 752, 690 cm−1
;
Anal. Calcd for
C24H21ClN2O4: C, 65.98; H, 4.84; N, 6.41; Found: C, 66.06; H,
4.81; N, 6.52; MS (ESI): m/z = 437 [M+H]+.
3,5-Dimethoxy-2-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-
3-yl)phenol 3l. Yield: 72%. White powder, mp 180–182ꢀC. 1H
NMR (400 MHz, CDCl3): δ = 7.40–7.31 (d, 5H, H-2′, 3′, 4′, 5′,
6′), 7.23 (d, 2H, J = 8.8 Hz, H-2″′, 6″′), 7.01(s, 1H, H-4), 6.90 (d,
2H, J = 8.8 Hz, H-3″′, 5″′), 6.22 (d, 1H, J = 2.0 Hz, H-5″), 6.09 (d,
1H, J = 2.0 Hz, H-3″), 3.91 (s, 3H, ─OCH3), 3.81 (s, 3H,
─OCH3), 3.76 (s, 3H, ─OCH3); IR (KBr)ν: 3030, 2827, 1633,
1600, 1499, 1433, 1378, 1277, 858, 799, 762, 695 cm−1; Anal.
Calcd for C24H22N2O4: C, 71.63; H, 5.51; N, 6.96; Found: C,
71.55; H, 5.56; N, 6.90; MS (ESI): m/z = 403 [M+H]+.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Huang, H. Ying, and Y. Hu
Vol 000
830, 755, 692 cm−1; Anal. Calcd for C22H18N2O: C, 80.96; H,
5.56; N, 8.58; Found: C, 80.79; H, 5.51; N, 8.63; MS (ESI): m/z
= 327 [M+H]+.
2-(5-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-5-methoxyphenol
3s. Yield: 53%. White powder, mp 152–154ꢀC.1H NMR
(400 MHz, CDCl3): δ = 10.85 (s, 1H, ─OH), 7.51 (d, 1H, J = 8.8
Hz, H-6″), 7.40–7.29 (m, 7H, H-3″′, 5″′, 2′, 3′, 4′, 5′, 6′), 7.22 (d,
2H, J = 8.8 Hz, H-2″′, 6″′), 6.78 (s, 1H, H-4), 6.59 (d, 1H, J =
2.4 Hz, H-3″), 6.53 (dd, 1H, J = 8.8 Hz, 2.4 Hz, H-5″), 3.83 (s,
3H, ─OCH3); IR (KBr)ν: 3063, 2951, 1637, 1558, 1489, 1445,
1369, 1289, 1093, 947, 836, 795, 759, 697 cm−1; Anal. Calcd for
C22H17ClN2O2: C, 70.12; H, 4.55; N, 9.41; Found: C, 70.19; H,
4.65; N, 9.33; MS (ESI): m/z = 377 [M+H]+.
2-(5-(Benzo[d][1,3]dioxol-5-yl)-1-phenyl-1H-pyrazol-3-yl)-
4-methylphenol 3x. Yield: 53%. White powder, mp 80–82ꢀC. 1H
NMR (400 MHz, CDCl3): δ = 10.62 (s, 1H, ─OH), 7.42 (d, 1H, J
= 2.0 Hz, H-6″), 7.40–7.31 (m, 5H, H-2′, 3′, 4′, 5′, 6′), 7.05 (dd,
1H, J = 8.4 Hz, 2.0 Hz, H-4″), 6.94 (d, 1H, J = 8.4 Hz, H-3″),
6.79 (m, 3H, H-2″′, 5″′, 6″′), 6.72 (s, 1H, H-4), 5.99 (s, 2H,
─OCH2O─), 2.34 (s, 3H, ─CH3); IR (KBr)ν: 3058, 1642,
1589, 1499, 1444, 1362, 1263, 925, 830, 763, 694 cm−1; Anal.
Calcd for C23H18N2O3: C, 74.58; H, 4.90; N, 7.56; Found: C,
74.68; H, 4.86; N, 7.63; MS (ESI): m/z = 371 [M+H]+.
3-(1,5-Diphenyl-1H-pyrazol-3-yl)-4-hydroxybenzoic acid
1
3t. Yield: 49%. White powder, mp 241–242ꢀC. H NMR (400
MHz, CDCl3): δ = 11.56 (s, 1H, ─OH), 8.46 (d, 1H, J = 2.0
Hz, H-2″), 8.03 (dd, 1H, J = 8.8 Hz, 2.0 Hz, H-4″), 7.41–7.29
(m, 10H, H-2′, 3′, 4′, 5′, 6′, 2″′, 3″′, 4″′, 5″′, 6″′), 7.10 (d, 1H,
J = 8.8 Hz, H-5″), 7.02 (s, 1H, H-4); IR (KBr)ν: 3424, 1690,
1633, 1588, 1489, 1433, 1363, 1286, 830, 758, 690 cm−1; Anal.
Calcd for C22H16N2O3: C, 74.15; H, 4.53; N, 7.86; Found: C,
74.26; H, 4.49; N, 7.80; MS (ESI): m/z = 357 [M+H]+.
Acknowledgment. This study was financially supported by the
National Key Tech Project for Major Creation of New drugs (No.
2009ZX09501-003) and the Fundamental Research Funds for the
Central Universities (No. KYJD038).
5-Methoxy-2-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-
3-yl)phenol 3u. Yield: 52%. White powder, mp 181–183ꢀC.1H
NMR (400 MHz, CDCl3): δ = 13.53 (s, 1H, ─OH), 7.86 (d,
1H, J = 7.2 Hz, H-6″), 7.44 (d, 1H, J = 15.2 Hz, H-4), 7.15 (d,
2H, J = 9.2 Hz, H-2″′, 6″′), 6.80 (d, 2H, H-3″′, 5″′), 6.49 (dd,
1H, J = 7.2Hz, 2.4 Hz, H-5″), 6.48 (d, 1H, J = 2.4 Hz, H-3″),
3.96 (s, 3H, ─OCH3), 3.94 (s, 3H, ─OCH3); IR (KBr)ν: 3057,
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1622, 1590, 1498, 1433, 1358, 1263, 877, 830, 799, 694 cm−1
;
Anal. Calcd for C23H20N2O3: C, 74.18; H, 5.41; N, 7.52;
Found: C, 74.24; H, 5.44; N, 7.46; MS (ESI): m/z = 373 [M+H]+.
4-Chloro-2-(1,5-diphenyl-1H-pyrazol-3-yl)phenol
3v. Yield: 48%. White powder, mp 98–100ꢀC.1H NMR
(400 MHz, CDCl3): δ = 10.83 (s, 1H, OH), 7.59 (d, 1H, J = 2.4
Hz, H-6″), 7.39–7.26 (m, 10H, H-2′, 3′, 4′, 5′, 6′, 2″′, 3″′, 4″′,
5″′, 6″′), 7.18 (dd, 1H, J = 8.8 Hz, 2.4 Hz, H-4″), 6.98 (d, 1H,
J = 8.8 Hz, H-3″), 6.85 (s, 1H, H-4); IR (KBr)ν: 3057, 1637,
1595, 1498, 1456, 1361, 1263, 977, 830, 787, 765, 695 cm−1;
Anal. Calcd for C21H15ClN2O: C, 72.73; H, 4.36; N, 8.08;
Found: C, 72.63; H, 4.41; N, 7.94; MS (ESI): m/z = 347 [M+H]+.
2-(1,5-Diphenyl-1H-pyrazol-3-yl)-4-methylphenol
3w. Yield: 51%. White powder, mp 94–96ꢀC. 1H NMR
(400 MHz, CDCl3): δ = 10.49 (s, 1H, ─OH), 7.42 (d, 1H, J =
1.6 Hz, H-6″), 7.39–7.24 (m, 10H, H-2′, 3′, 4′, 5′, 6′, 2″′, 3″′, 4″
′, 5″′, 6″′), 7.06 (dd, 1H, J = 8.0 Hz, 1.6Hz, H-4″), 6.95 (d, 1H,
J = 8.0 Hz, H-3″), 6.87 (s, 1H, H-4), 2.34 (s, 3H, ─CH3); IR
(KBr)ν: 3066, 1639, 1594, 1498, 1433, 1362, 1279, 1263, 917,
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet