Synthesis and crystal structure of 5-pyrazol-4,5-dihydropyrazoles derivatives

Article abstract of DOI:10.1002/jhet.5570450539

(Chemical Equation Presented) A series of 1-acetyl(or phenyl)-3-aryl-5-(1- phenyl-3-methyl-5-aryloxyl-pyrazol)-4,5-dihydropyrazole derivatives have been efficiently synthesized under refluxing in glacial acetic acid with two kinds of hydrazines and five kinds of chalcones of 1-phenyl-methyl-5-phenoxyl-pyrazol-4- aldehyde. The structures were confirmed on the basis of ¹H NMR, IR, MS and element analysis, and the crystal structure of the compound 4c was determined by single crystal X-ray diffraction. The compound 4c belongs to monoclinic system with space group P2(1)/n, a = 11.8779(3) nm, b = 12.0901(2) nm, c = 17.7004(4) nm, α = 90°, β = 100.05(10)°, γ = 90°, Formula weight: 549.46, Triclinic V =2502.89(9) nm³, D _c =1.458 Mg/m³, Z = 4, F (000) = 1128.

Full text of DOI:10.1002/jhet.5570450539

Sep-Oct 2008
1485
Synthesis and Crystal Structure of
5-Pyrazol-4,5-dihydropyrazoles Derivatives
Zhengfeng Xie*a, Xuexia Moa, Gang Liua, Fangming Liu*a,b
a Education Ministry Key Laboratory of Oil & Gas Fine Chemicals, Xinjiang University,
Urumqi 830046, PR China
b College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University,
Hangzhou, 310012, PR China
e-mail address : xiezhf72@yahoo.com.cn; fmliu859@sohu.com
Received October 25, 2007
O
H3C
N
N
H3C
Hx
Hb
OPh
N
Ha
NH2NH2
MeCOOH
N
R1
H1
O
COCH3
Ph
H3C
CHO
H3C
3a~3e
H2
OPh
+
N
N
Ph
N
OPh
R1
N
N
N
H3C
Ph
Hx
Ph
R1
PhNHNH2
MeCOOH
2a~2e
1a~1e
N
Hb Ha
OPh
N
R1
Ph
4a~4e
3a:R1=H,R2=H; 3b:R1=CH3,R2=H;
4a:R1=H,R2=Ph; 4b:R1=CH3,R2=Ph; 4c:R1=Br,R2=Ph; 4d:R1=Cl,R2=Ph; 4e:R1=OCH3,R2=Ph
3c:R1=Br,R2=H; 3d:R1=Cl,R2=H;
3e:R1=OCH3,R2=H
A series of 1-acetyl(or phenyl)-3-aryl-5-(1-phenyl-3-methyl-5-aryloxyl-pyrazol)-4,5-dihydropyrazole
derivatives have been efficiently synthesized under refluxing in glacial acetic acid with two kinds of
hydrazines and five kinds of chalcones of 1-phenyl-methyl-5-phenoxyl-pyrazol-4-aldehyde. The structures
1
were confirmed on the basis of H NMR, IR, MS and element analysis, and the crystal structure of the
compound 4c was determined by single crystal X-ray diffraction. The compound 4c belongs to monoclinic
system with space group P2(1)/n, a = 11.8779(3) nm, b = 12.0901(2) nm, c = 17.7004(4) nm, ꢀ = 90°, ꢁ =
100.05(10)°, ꢂ = 90°, Formula weight: 549.46, Triclinic V =2502.89(9) nm3, Dc =1.458 Mg/m3, Z = 4, F
(000) = 1128.
J. Heterocyclic Chem., 45, 1485 (2008).
INTRODUCTION
Pyrazoles and pyrazolines bearing an unsaturated side-
chain had hitherto received less attention, although
various pyrazole and pyrazoline derivatives were found to
possess important biological and pharmaceutical
activities. Some of their most important effects include
anti-inflammatory, antimicrobial, antiviral, anticancer,
immunosuppressive activities [15,16], herbicidal effect
[17] and fluorescent property [7,18]. So, it is important to
find simple and convenient procedures for pyrazole and
pyrazoline preparations. Herein we report the synthesis of
5-pyrazol-4,5-dihydropyrazole derivatives and the single
crystal structure of the compound 4c.
Pyrazoles and pyrazolines are important nitrogen-
containing five-membered heterocyclic compounds and
various methods have been developed for their synthesis
[1-4]. ꢀ,ꢁ-Unsaturated aldehydes and ketones are
convenient and easily available starting materials or
intermediates for the synthesis of a wide variety of
heterocyclic compounds [5-7]. The first synthesis of
pyrazoline framework by the reaction of an ꢀ,ꢁ-enone
with a hydrazine derivative was published by Fischer and
Knovenagel in the late nineteenth century [8]. Then the
reaction of ꢀ,ꢁ-unsaturated aldehydes and ketones with
hydrazine derivatives became one of the most popular
methods for the synthesis of pyrazolines [5-7,9-12].
Synthesis of tricyclic pyrazoles and pyrazolines by the
reaction of the exocyclic ꢀ,ꢁ-unsaturated ketones with
hydrazine derivatives has been achieved [13,14].
However, very few representatives of 5-pyrazol-4,5-
dihydropyrazoles have hitherto been described in the
literature.
RESULTS AND DISCUSSION
In our pervious studies, we have worked out a
convenient procedure for the synthesis of 3-aryl-5-(2-
phenyl-1,2,3-triazol-4-yl)pyrazoline derivatives [7]. As a
continuation, synthesis of 3-aryl-5-pyrazol-4,5-dihydro-
pyrazoles derivatives has been obtained by the reaction of

1486
Z.-F. Xie, X.-X. Mo, G. Liu, F.-M. Liu
Vol 45
were measured on a mettler FP-5 capillary melting point
apparatus and were uncorrected. Elemental analyses were
performed on a Perkin-Elmer 2400 elemental analyzer. The IR
spectra were determined as potassium bromide pellet on a
Bruker Equinox55 FT-IR spectrophotometer. The 1H NMR
spectra were recorded on a Varian Inova-400 spectrophotometer
using TMS as an internal standard. EI-ms spectra were recorded
with an Agilent 5975 apparatus. X-ray crystal structure was
obtained using R-AXIS SPIDER X-ray diffraction.
these ꢀ,ꢁ-unsaturated ketones 2a-e with hydrazine
hydrate or phenyl hydrazine.
In our experiments, ꢀ,ꢁ-unsaturated ketones 2a-e were
allowed to react with hydrazine hydrate in boiling acetic
acid to afford 1-acetyl-3-aryl-5-pyrazole-4,5-dihydropy-
razoles 3a-3e as sole isolable products. No other
pyrazoline type compounds could be detected in the crude
products. It was found that the initially formed pyrazoline
was completely N-acetylated under these reaction
conditions in each case.
In our study, ꢀ,ꢁ-unsaturated ketones 2a-e have also
reacted with phenyl hydrazine in hot acetic acid to
provide 3-aryl-1-phenyl-5-pyrazol-4,5-dihydropyrazoles
4a-4e.
The reaction of 2a-2e with hydrazine hydrate and
phenyl hydrazine were carried out in a molar ratio 1:1.1 in
acetic acid as solvent and all reaction were monitored by
TLC. The most satisfactory results were obtained when
the reactions were performed under hot acetic acid for 1 -
4 hrs. The crude solid pyrazoles 3a-3e and 4a-4e were
recrystallized from ethanol.
A suitable crystal of 4c was grown from absolute ethyl
alcohol and its solid-state structure was determined by X-
ray diffraction. Details of the structure determination and
refinement are given in the experimental section. The
drawing of the molecular structure and higher occupancy
in the three dimensional packing arrangement is shown in
Figures 1-2. Atomic coordinates of non-hydrogen atoms
(ꢂ10-4) and their thermal parameters are summarized in
Table 1. the crystal data and structure refinement of 4c are
listed in Table 2.
Figure 2. Packing of Molecules in a Unit Cell of 4c.
Table 1
Atomic coordinates of non-hydrogen atoms (ꢂ10-4) and their thermal
parameters.
x
y
z
U(eq)
35(1)
25(1)
24(1)
26(1)
26(1)
24(1)
23(1)
25(1)
24(1)
22(1)
22(1)
23(1)
38(1)
31(1)
24(1)
30(1)
24(1)
27(1)
26(1)
27(1)
Br
O
3436(1)
2674(1)
1359(2)
1331(2)
1592(2)
2052(2)
2320(2)
3120(2)
2357(2)
2112(2)
2345(2)
3691(2)
4767(2)
3320(2)
567(2)
7159(1)
8617(1)
9038(1)
9207(1)
6161(1)
6801(1)
8576(2)
8449(2)
8786(2)
7853(1)
7813(1)
9180(2)
10829(2)
6163(2)
9969(2)
10594(2)
8238(2)
8360(2)
7571(2)
7774(2)
2032(1)
-4419(1)
-1624(1)
-2400(1)
-3752(1)
-4264(1)
-1339(1)
-1903(1)
-2671(1)
-3233(1)
-3961(1)
-4158(1)
-4227(2)
-5978(1)
-2791(1)
-2404(1)
-538(1)
-54(1)
N1
N2
N3
N4
C1
C2
C3
C6
C7
C8
C12
C16
C20
C25
C26
C27
C29
C31
Figure 1. Molecular Structure of 4c.
-141(2)
2569(2)
1769(2)
3077(2)
3632(2)
EXPERIMENTAL
983(1)
All reagents were of commercial availability. Reactions were
monitored by thin-layer chromatography (TLC). Melting points
-239(1)

Sep-Oct 2008
Synthesis and Crystal Structure of 5-Pyrazol-4,5-dihydropyrazoles Derivatives
1487
Table 2
Crystal data and structure refinement for 4c.
washed with water. The solid was crystallized from ethanol to
give yellow crystals 2a-e:
2a: yield 81%; mp 140~141 °C; 1H NMR (400 MHz, CDCl3)
ꢃ: 7.60~6.92 (m, 15H, Ar-H), 7.55~7.53 (d, 1H, H-2), 7.32~7.31
(d, 1H, H-1), 2.47 (s, 3H, CH3); IR (KBr) ꢀ: 3049, 2969, 1649,
1498, 1329, 852 cm-1; Anal. Calcd. for C25H20N2O2: C 78.95, H
5.26, N 7.37; found C 78.96, H 5.21, N 7.39.
Empirical formula
C31H25BrN4O
549.46
Formula weight
Temperature (K)
Wavelength
Crystal system
Space group
a (Å)
153(2)
0.71073 A
Monoclinic
P2(1)/n
2b: yield 92%; mp 148~149 °C; 1H NMR (400 MHz, CDCl3)
ꢃ: 7.57~6.90 (m, 14H, Ar-H), 7.55~7.53 (d, 1H, H-2), 7.33~7.31
(d, 1H, H-1), 2.44 (s, 3H, CH3); IR (KBr) ꢄ: 3053, 2964, 1650,
1489, 1320, 670 cm-1; Anal. Calad for C26H22N2O2: C 79.19, H
5.58, N 7.11; found C 79.22, H 5.56, N 7.10.
11.8779(3)
12.0901(2)
17.7004(4)
90
b (Å)
c (Å)
1
ꢀ (°)
2c: yield 85%; mp 146~148 °C; H NMR (400 MHz, CDCl3)
ꢃ: 7.62~6.98 (m, 14H, Ar-H), 7.55~7.53 (d, 1H, H-2), 7.33~7.31
(d, 1H, H-1), 2.51 (s, 3H, CH3); IR (KBr) ꢄ: 3053, 2964, 1650,
1489, 1320, 670 cm-1; Anal. Calad for C25H19BrN2O2: C 65.36, H
4.12, N 6.10; found C 65.39, H 4.14, N 6.08.
ꢁ (°)
100.05(10)
90
ꢂ (°)
V (Å3)
2502.89(9)
4
Z
2d: yield 94%; mp 133~134 °C; 1H NMR (400 MHz, CDCl3)
ꢃ: 7.63~6.96 (m, 14H, Ar-H), 7.55~7.53 (d, 1H, H-2), 7.33~7.31
(d, 1H, H-1), 2.52 (s, 3H, CH3); IR (KBr) ꢄ: 3054, 2969, 1650,
1493, 1329, 643 cm-1; Anal. Calad for C25H19ClN2O2: C 72.38, H
4.58, N 6.76; found C 72.36, H 4.60, N 6.73.
D
calc, Mg/m3
1.458
Absorption coefficient (mm-1) 1.675
F (000)
1128
Crystal size (mm)
ꢁ range, deg
0.38 ꢀ0.12 ꢀ0.07
3.15-27.48
20281
1
2e: yield 92%; mp 117~119 °C; H NMR (400 MHz, CDCl3)
Reflections collected
Independent refls.
Date/restraints/parameters
Goodness-of-fit on F2
Final R indices [I>2s(I)]
R1
ꢃ: 7.66~7.01 (m, 14H, Ar-H), 7.55~7.53 (d, 1H, H-2), 7.33~7.32
(d, 1H, H-1), 3.78 (s, 3H, OCH3), 2.52 (s, 3H, CH3); IR (KBr) ꢄ:
3058, 2968, 1650, 1499, 1334, 655 cm-1; Anal. Calad for
C26H22N2O3: C 76.10, H 5.37, N 6.83; found C 76.11, H 5.36, N
6.80
5723(Rint=0.0276)
5723/0/335
0.999
0.0326
0.1062
1-H-(Phenyl)-3-aryl-5-(1-phenyl-3-methyl-5-aryloxyl-pyr-
azol)-4,4-dihydropyrazoline (3a-e, 4a-e). To a solution of 2a-e
(1 mmole) in acetic acid (10 mL) was added hydrazine hydrate
(1.1 mmoles) or phenyl hydrazine (1.1 mmoles). Then the
mixture was refluxed and monitored by TLC for about 2-4 hr.
After the reaction has completed and cooled to room
temperature, the mixture was poured into an ice-water mixture
producing a large quantity of solid precipitate. Then the mixture
was neutralized with a solution of Na2CO3. After standing
overnight the mixture was collected by filtration and crystallized
from ethanol to gain the target compounds 3a-e, 4a-e. The
melting point, yield, IR, MS and elemental analysis of the
compounds are shown in Table 3, and the 1H NMR data of
compounds in Table 4.
wR2
Final R indices (all date)
R1
0.0443
wR2
0.1309
extinction coefficient
0.0046(9)
The synthesis of 1-phenyl-3-methyl-5-aryloxyl-pyrazol-4-
methylene-para-substitutedacetiphenones(2a-e) [20]. Aceto-
phenone 1a-e (20 mmoles) was added to a solution of 1-phenyl-
3-methyl-5-aryloxyl-pyrazol-4-carboxaldehyde (20 mmoles) in
aqueous KOH (10 mL, 35 % KOH) at 0 °C. The reaction
mixture was stirred for 2 hours at ice bath. After standing
overnight the yellow solid was collected by filtration and
Table 3
The melting Point, yield, IR and elemental analysis of the compounds 3a-e, 4a-e.
No
Molecular
Formula
m.p.
°C
Yield
(%)
Analysis %
IR
ꢂ/cm-1
EI-ms(70eV)
m/z
Calcd./Found
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
C27H24N4O2
C28H26N4O2
C27H23BrN4O2
C27H23ClN4O2
C28H26N4O3
C31H26N4O
180-182
151-152
161-163
162-164
172-173
140-141
167-169
141-143
155-157
125-127
72
62
58
65
55
60
56
54
56
49
74.29(74.24)5.54(5.53)12.84(12.92)
74.65(74.71)5.82(5.86)12.44(12.39)
62.92(62.88)4.50(4.51)10.87(10.82)
68.86(68.82)4.92(4.94)11.90(11.85)
72.09(72.13)5.62(5.65)12.01(11.96)
79.15(79.09)5.53(5.49)11.92(11.94)
79.34(79.30)5.79(5.77)11.57(11.60)
67.76(67.70)4.56(4.60)16.20(16.15)
73.74(73.71)4.96(4.95)11.10(11.05)
76.80(76.77)5.60(5.56)11.20(11.25)
3049,2919,1665,1595,1320,852
3052,2922,1659,1597,1327,697
3058,2917,1663,1593,1325,734
3055,2918,1661,1595,1326,558
3060,2923,1659,1596,1327,749
3059,2917,1595,1503,1320,855
3055,2913,1560,1510,1309,672
3061,2915,1599,1505,1322,855
3062,2919,1597,1506,1319,736
3063,2921,1602,1511,1320,755
436 [M]+, 250
450 [M]+, 250
516 [M+2]+, 514 [M]+
472 [M+2]+, 470[M]+
466 [M]+, 250
470 [M]+, 91
C32H28N4O
484 [M]+, 91
C31H25BrN4O
C31H25ClN4O
C32H28N4O2
550 [M+2]+, 548 [M]+
506 [M+2]+, 504 [M]+
500 [M]+, 91

1488
Z.-F. Xie, X.-X. Mo, G. Liu, F.-M. Liu
Vol 45
Table 4
1H NMR data of compounds 3a-e, 4a-e.
1H NMR(CDCl3, 400MHz), ꢀ
No
3a
7.65 ~ 6.84 (m, 15 H, Ar-H), 5.41 (dd, 1 H, Jax = 12.8 Hz, Jbx=5.6 Hz, H-x), 3.56 (dd, 1H, Jax= 12.8 Hz, Jab = 17.6 Hz, H-a),
3.26 (dd, 1 H, Jbx = 5.6 Hz, Jab = 17.6 Hz, H-b), 2.44 (s, 3 H, CH3), 2.02 (s, 3H, CH3)
3b
3c
3d
3e
4a
4b
4c
4d
4e
7.55 ~ 6.68 (m, 14 H, Ar-H), 5.36 (dd, 1 H, Jax = 13.2 Hz, Jbx =7.6 Hz, H-x), 3.53 (dd, 1 H, Jax = 13.2 Hz, Jab = 16.8 Hz, H-a),
3.24 (dd, 1H ,Jbx = 7.6 Hz, Jab = 16.8 Hz, H-b), 2.44 (s, 3 H, CH3), 2.25 (s, 3 H, CH3) , 2.01 (s, 3H, CH3)
7.56 ~ 6.57 (m, 14 H, Ar-H), 5.38 (dd, 1 H, Jax = 12.4 Hz, Jbx = 5.2 Hz, H-x), 3.52 (dd, 1 H, Jax = 12.4 Hz, Jab = 17.6 Hz, H-a),
3.27 (dd, 1 H, Jbx = 5.2 Hz, Jab = 17.6 Hz, H-b), 2.45 (s, 3 H, CH3) , 2.03 (s, 3H, CH3)
7.54 ~ 6.54 (m, 14 H, Ar-H), 5.41 (dd, 1 H Jax = 12.4 Hz, Jbx = 5.2 Hz, H-x), 3.55 (dd, 1 H, Jax = 12.4 Hz, Jab = 17.6 Hz, H-a),
3.26 (dd, 1 H, Jbx = 5.2 Hz, Jab = 17.6 Hz, H-b), 2.45 (s, 3 H, CH3) , 2.03 (s, 3H, CH3)
7.56 ~ 6.62 (m, 14 H, Ar-H), 5.39 (dd, 1 H, Jax = 13.2 Hz, Jbx = 8.4 Hz, H-x), 3.57 (dd, 1 H, Jax = 13.2 Hz, Jab = 17.2 Hz, H-a),
3.27 (dd, 1 H, Jbx = 8.4 Hz, Jab = 17.2 Hz, H-b), 3.80 (s, 3 H, OCH3), 2.44 (s, 3 H, CH3) , 2.02 (s, 3H, CH3)
7.67 ~ 6.79 (m, 20 H, Ar-H), 5.13 (dd, 1 H, Jax = 12.8 Hz, Jbx = 7.6 Hz, H-x), 3.53 (dd, 1 H, Jbx = 12.8 Hz, Jab = 17.2 Hz, H-b),
3.15 (dd, 1 H, Jax = 7.6 Hz, Jab = 17.2 Hz, H-a), 2.44 (s, 3 H, CH3)
7.61 ~ 6.65 (m, 19 H, Ar-H), 5.11 (dd, 1 H, Jax = 12.4 Hz, Jbx = 7.2 Hz, H-x), 3.53 (dd, 1 H, Jbx = 12.4 Hz, Jab = 16.8 Hz, H-b),
3.16 (dd, 1 H, Jax = 7.2 Hz, Jab = 16.8 Hz, H-a), 2.44 (s, 3 H, CH3), 2.25 (s, 3 H, CH3)
7.64 ~ 6.61 (m, 19 H, Ar-H), 5.12 (dd, 1 H, Jax = 12.8 Hz, Jbx = 7.2 Hz, H-x), 3.52 (dd, 1 H, Jbx = 12.8 Hz, Jab = 16.8 Hz, H-b),
3.15 (dd, 1 H, Jax = 7.2 Hz, Jab = 16.8 Hz, H-a), 2.44 (s, 3 H, CH3)
7.67 ~ 6.55 (m, 19 H, Ar-H), 5.10 (dd, 1 H, Jax = 12.8 Hz, Jbx = 7.6 Hz, H-x), 3.56 (dd, 1 H, Jbx = 12.8 Hz, Jab = 16.8 Hz, H-b),
3.16 (dd, 1 H, Jax = 7.6 Hz, Jab = 16.8 Hz, H-a), 2.44 (s, 3 H, CH3)
7.65 ~ 6.73 (m, 19 H, Ar-H), 5.12 (dd, 1 H, Jax = 12.4 Hz, Jbx = 7.6 Hz, H-x), 3.53 (dd, 1 H, Jbx = 12.4 Hz, Jab = 17.2 Hz, H-b),
3.15 (dd, 1H, Jax = 7.6 Hz, Jab = 17.2 Hz, H-a), 3.82 (s, 3 H, OCH3), 2.44 (s, 3 H, CH3)
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Acknowledgement. The authors thank the financial support
of the National Natural Science Foundation of China (No:
20562011).
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