1,3-Dipolar cycloaddition in the synthesis of novel isoxazoline/pyrazole derivatives bearing 1,2,3-triazoles moiety

Article abstract of DOI:10.1002/jhet.1527

1,3-Dipolar cycloaddition of α,β-unsaturated ketones bearing 1,2,3-triazole moiety with nitrile oxides and sydnones obtained a series of novel 3,4,5-trisubstituted isoxazolines (5a-h) and 1,3,4-trisubstituted pyrazoles (7a-h) with different active pharmacophores in a single molecular scaffold. The structure of the target compounds was confirmed on the basis of IR, ¹H NMR, mass spectral, elemental analysis, and X-ray crystallographic analysis.

Full text of DOI:10.1002/jhet.1527

Month 2013 1,3-Dipolar Cycloaddition in the Synthesis of Novel Isoxazoline/Pyrazole
Derivatives Bearing 1,2,3-Triazoles Moiety
a
Yongming Zenga,b and Fangming Liu
*
aCollege of Materials and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, People’s Republic of China
bDepartment of Chemistry and Applied Chemistry, Chang Ji University, ChangJi 831100, People’s Republic of China
*
E-mail: fmliu859@sohu.com
Received April 21, 2011
DOI 10.1002/jhet.1527
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
N
O
Cl
C
N
Ar1
Ar2
N
Ar2
N OH
O
N
4a,b
5a-h
O
O
CHO
N
Ar1
N
Ar1
N
N
N
O
O
N
N
N
N
Ar1
N
Ar2
3a-d
O
1
N
N
N
6a,b
Ar2
7a-h
1,3-Dipolar cycloaddition of a,b-unsaturated ketones bearing 1,2,3-triazole moiety with nitrile oxides
and sydnones obtained a series of novel 3,4,5-trisubstituted isoxazolines (5a–h) and 1,3,4-trisubstituted
pyrazoles (7a–h) with different active pharmacophores in a single molecular scaffold. The structure of
1
the target compounds was confirmed on the basis of IR, H NMR, mass spectral, elemental analysis,
and X-ray crystallographic analysis.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
various simple dipolarophiles such as alkynes and alkenes
offers a convenient synthetic route for the preparation of
pyrazole derivatives [27], However, less attention has been
paid on the 1,3-dipolar cycloaddition of sydnones with more
complex dipolarophiles. Recently, literature reported a conve-
nient access to 1,3,4-trisubstituted pyrazoles by the reaction of
sydnones with unsymmetrical acetylenic ketones (dipolarophiles)
[28,29], but now, we found that replacing acetylenic ketones
with unsymmetrical propenones (a,b-unsaturated ketones)
can also afford 1,3,4-trisubstituted pyrazoles. In addition,
the biological activities of 1,2,3-triazole derivatives [30–32]
make them important targets for synthetic chemists.
Encouraged by all these facts and our continued interest in
the synthesis of novel heterocycles employing 1,3-dipolar
cycloaddition, we report herein the complete study of the
reaction of a,b-unsaturated ketones bearing 1,2,3-triazole
moiety with nitrile oxides and sydnones, leading to new 3,4,5-
trisubstituted isoxazolines and 1,3,4-trisubstituted pyrazoles
with different active pharmacophores in a single molecular
scaffold, which may have potential biological and medical
applications.
1,3-Dipolar cycloaddition has attracted much attention
because it is a versatile synthetic strategy for the construction
of five-membered ring heterocycles [1–3]. The nitrile oxide
cycloaddition to alkenes results in the formation of isoxazo-
lines, which are versatile intermediates for the synthesis of
bifunctional and naturally occurring compounds [4–8] and
also display important biological activities such as antibacte-
rial [9], antitubercular, phosphodiesterase inhibitory [10],
antiinflammatory [11], and immunostimulatory [12].
The synthesis of pyrazoles has received considerable
attention because of their applications in pharmaceutical
industries because of their antimicrobial [13], antiviral [14],
antitumor [15], antiinflammatory [16], cyclooxygenase-2
(COX-2), and non-nucleoside HIV-1 reverse transcriptase in-
hibitory properties [17,18]. Some well-known drugs such as
sildenafil (Viagra), rimonabant (Acomplia), and celecoxib
(Celebrex) are pyrazole derivatives. A number of methods
are available for the synthesis of pyrazoles [19–24]; the most
efficient and commonly used method involves the condensa-
tion of hydrazine with 1,3-dicarbonyl compounds. Regiose-
lective synthesis of the pyrazole ring remains a significant
challenge for organic chemists. Meanwhile, sydnones are
easily accessible aromatic compounds and versatile synthetic
intermediates with a masked azomethine imine or hydrazine
unit [25,26]. The 1,3-dipolar cycloaddition reaction with
RESULTS AND DISCUSSION
The target compounds 5a–h and 7a–h were prepared as
depicted in Scheme 1. In the initial step, the a,b-
© 2013 HeteroCorporation

Y. Zeng and F. Liu
Vol 000
Scheme 1
O
O
CHO
+
N
N
R
1
N
N
R
1
N
N
3a-d
R =H,OCH ,Cl,NO
2
1
2a-d
1
3
N
O
N
Cl
C
N
R
1
R
N
OH
2
O
N
R =H,CH
2
4a,b
3
R
2
5a-h
N
O
O
N
N
R
1
R
N
N
2
O
N
N
R
R =H,CH
2
6a,b
3
2
7a-h
5,7: a, R1=H, R2=H
b. R1=OCH3, R2=H
c. R1=Cl, R2=H
d. R1=NO2, R2=H
e, R1=H, R2=CH3 f. R1=OCH3, R2=CH3 g. R1=Cl, R2=CH3 h. R1=NO2, R2=CH3
1
unsaturated carbonyl compounds 3a–d were obtained by
Claisen–Schmidt condensation by reacting substituted
acetophenones 2a–d and 2-phenyl-4-formyl-1,2,3-triazole
1. Then, the reaction of chalcones 3 with arylnitrile oxides,
which is prepared in situ from arylhydroximinoyl chlorides
4a,b with triethylamine, stirring at room temperature in
dichloromethane yielded cycloadducts 5a–h. The progress
of each reaction was monitored by thin layer chromatogra-
phy. The IR spectrum of 5a exhibit C═O stretching at
1633 cmÀ1 and C═N stretching at 1496 cmÀ1 bands. In
8.27 ppm in the H NMR spectrum of 7c can be distin-
guished from the signals of C═C-H proton and N═C-H
proton, respectively. The protons belonging to the aromatic
ring were seen at d 8.01–7.25 as multiplet signals. A
singlet at d 3.84 ppm is attributed to the OCH3 protons.
Its mass spectrum revealed a peak corresponding to its
molecular ion at m/z 421(M+).
To elucidate the structure of these compounds, we ex-
amined the structure of 5e and 7f by X-ray crystallography.
The crystal data and structure refinement are shown in
Table 1. Selected bond lengths and angles are listed in
Table 2 and the hydrogen bond geometry in Table 3. The
C-HÁÁÁp stacking interactions in the crystal are given in
Table 4. The crystal structure of the compound 5e and 7f
is shown in Figures 1 and 2, respectively, and a perspective
view of the crystal packing in the unit cell is tabulated in
Figures 3 and 4, respectively.
X-ray diffraction study of the compound 5e has shown
that the title compound C25H20N4O2 crystallizes in the or-
thorhombic system with space grouping P2(1)2(1)2(1).
The isoxazole ring in this compound (5e) adopts an enve-
lope conformation, only with maximum deviation of
0.0555 Å for atom C10 for the plane defined by N4/O2/
C11/C12. In addition, the dihedral angle between the iso-
xazole ring and the C2–C7 phenyl ring is 9.21ꢀ, confirming
1
addition, The HNMR spectrum of compound 5a is in
agreement with the proposed structure. Two characteristic
doublets of the isoxazoline are recorded at 6.03 ppm for
Ha and 5.93 ppm for Hb with 5.6 Hz as coupling constant,
which reveals that the Ha and Hb are trans. The mass spec-
trum of compound 5a revealed the existence of the molec-
ular ion peaks M+ at 316 m/z and significant fragmentation
peaks, which is strong evidence for the structure.
Similarly, the chalcones n were subsequently treated
with sydnone 6a,b in the presence of triethylamine in
dichloromethane to afford 7a–h. The intense broad band
at 1656 cmÀ1 in the IR spectra of 7b was ascribed to the
stretching vibration of C═O. The C═N band was repre-
sented by two intense broads centered at about 1583 and
1522 cmÀ1. Two different sets of signals at 8.35 and
Journal of Heterocyclic Chemistry
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Month 2013
Isoxazoline, Pyrazole, 1,2,3-Triazole, Crystal Structure
Table 1
Table 2
Crystal data and structure refinement.
Selected bond lengths (Å) and bond angles (ꢀ).
7f
5e
Compound 5e
Formula
CCDC
C26 H21 N5 O2
821936
C25 H20 N4 O2
821937
O(2)–N(4)
O(2)–C(9)
O(1)–C(13)
N(1)–C(9)
N(1)–N(2)
N(2)–N(3)
N(2)–C(25)
N(3)–C(8)
N(4)–C(12)
C(11)–C(12)
C(10)–C(9)
C(9)–C(8)
1.4088(19)
1.4532(19)
1.2144(19)
1.326(2)
1.3303(18)
1.3347(19)
1.425(2)
1.327(2)
1.277(2)
1.547(2)
1.482(2)
N(1)–N(2)–N(3)
N(1)–N(2)–C(25)
N(3)–N(2)–C(25)
N(1)–C(9)–C(8)
N(1)–C(9)–C(10)
C(8)–C(9)–C(10)
C(12)–C(11)–C(13)
C(12)–C(11)–C(10)
C(13)–C(11)–C(10)
N(4)–C(12)–C(5)
N(4)–C(12)–C(10)
C(5)–C(12)–C(10)
114.94(14)
122.27(13)
122.79(14)
108.35(15)
120.64(14)
131.01(16)
111.67(12)
100.41(12)
111.38(12)
121.63(14)
114.01(14)
124.33(13)
Formula weight
Temperature
Crystal Size, mm
Crystal system
Space group
a, Å
b, Å
c, Å
a, deg
b, deg
435.48
408.45
293(2) K
0.43 Â 0.27 Â 0.11
Triclinic
293(2) K
0.56 Â 0.42 Â 0.23
Orthorhombic
P2(1)2(1)2(1)
7.7924(2)
21.7321(4)
12.3162(2)
90
P-1
7.8621(11)
12.2253(18)
12.1903(16)
103.472(3)
104.323(3)
90.992(3)
1100.5(3)
2
1.314
3.07–27.48
0.086
9793
4553/0/299
90
90
1.396(2)
g, deg
Compound 7f
N(1)–C(12)
N(1)–N(2)
N(1)–C(5)
N(2)–C(10)
N(3)–N(4)
N(3)–C(9)
N(4)–N(5)
N(4)–C(20)
N(5)–C(8)
O(2)–C(13)
C(11)–C(13)
C(10)–C(9)
C(1)–C(2)
V, Å3
2085.69(7)
4
1.301
3.09–27.48
0.085
20445
1.341(3)
1.357(2)
1.423(3)
1.332(3)
1.328(2)
1.335(3)
1.334(3)
1.423(3)
1.314(3)
1.216(3)
1.470(3)
1.468(3)
1.505(3)
1.384(3)
1.376(3)
N(3)–N(4)–C(20)
N(3)–N(4)–N(5)
N(5)–N(4)–C(20)
C(12)–C(11)–C(13)
C(12)–C(11)–C(10)
C(10)–C(11)–C(13)
N(2)–C(10)–C(9)
N(2)–C(10)–C(11)
C(11)–C(10)–C(9)
C(8)–C(9)–C(10)
N(3)–C(9)–C(10)
N(3)–C(9)–C(8)
123.41(18)
115.10(18)
121.48(19)
126.0(2)
103.91(19)
129.8(2)
117.6(2)
111.4(2)
130.9(2)
132.3(2)
120.1(2)
107.6(2)
111.85(18)
128.54(19)
119.59(17)
Z
Dc, mg/m3
θ range, deg
m, mmÀ1
Reflections collected
Data/restraints/
parameters
Final R indices
[I > 2s(I)]
R indices (all data)
4765/0/281
R1 = 0.1039,
wR2 = 0.1945
R1 = 0.0575,
wR2 = 0.1620
R1 = 0.0334,
wR2 = 0.0912
R1 = 0.0475,
wR2 = 0.1156
C(12)–N(1)–N(2)
C(12)–N(1)–C(5)
N(2)–N(1)–C(5)
C(9)–C(8)
C(12)–C(11)
that these two planes are almost coplanar. The isoxazole
ring forms dihedral angles of 64.05ꢀ and 57.98ꢀ with the
1,2,3-triazole ring and the plane of phenyl ring C12–C19,
respectively. The 1,2,3-triazole ring is almost parallel to
the plane of phenyl C20–C25 because of an existing dihe-
dral angle of 0.74ꢀ. Within the molecule, the bond distances
of C13–O1 (1.2144 Å) are significantly shorter than a
normal single C-O bond (1.367(3) Å) but longer than a
typical C═O bond (1.119 Å). At the same time, the sum
of C10–C11–C13, C10–C11–C12, and C13–C11–C12
bond angles is 359.98º, and that of C11–C12–N4, C5–
C12–C11, and C5–C12–N4 is 360.05º, showing that atoms
C11 and C12 are of sp2 hybridization. X-ray crystal struc-
ture determination indicates that there are two independent
molecules in the unit. The packing in compound 5e is only
held by a C-H. . .Cg (p-Ring) (Table 3). Atoms C4, C14,
and C23 act as a hydrogen bond donor respectively, via
H. . .Cg bond to generate the super molecular structures.
The compound 7f has shown that the title compound
C26H21N5O2 crystallizes in the triclinic system with space
grouping P-1. The pyrazole ring as the center is planar,
which forms dihedral angles of 47.95ꢀ and 23.61ꢀ with
the two planes of phenyl rings C14–C19 and C2–C7, re-
spectively. The 1,2,3-triazole ring is twisted to the pyrazole
ring and the phenyl ring(C20–C25), forming a dihedral an-
gle of 15.22ꢀ and 7.01ꢀ, respectively. The C13–O2 bond
distance of 1.216(3) Å indicates clearly the double bond
nature of the O2═C13 bond. It is worth to illuminate that
there exist kinds of hydrogen-bonding interactions in the
crystal structure. The C12–H12. . .O1 is intramolecular
hydrogen-bonding interactions and weak intermolecular
hydrogen bond of the C–H. . .O as C8–H8. . .O2 (Table 4),
with symmetry code Àx,1 À y,1 À z. Furthermore, the CÁÁp
stacking interactions between the neighboring molecules
are also observed. (Fig. 2 and Table 3) The C10 atoms
are involved in O2ÁÁÁp interactions with the phenyl ring
(centroid Cg3, C2–C7, symmetry code: À1 À X,ÀY,1 À Z),
which increase ulteriorly the stability of the 3D supramolec-
ular architecture of the polymer.
CCDC-821936 for 5e and 821937 for 7f contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic
Data Centre (CCDC) via e-mail: deposit@ccdc.cam.ac.uk.
In conclusion, we have obtained two series of compounds
bearing 1,2,3-triazole via 1,3-dipolar cycloaddition reaction.
Meanwhile, the X-ray crystallography further confirmed the
molecular conformation of the titled compounds.
EXPERIMENTAL
All of the reactions were monitored by TLC. Melting points were
determined via a mettler FP-5 melting point apparatus (Ningbo
Biocotek Scientific Instrument Co., China) and were uncorrected.
Elemental analyses were analyzed on a Perkin-Elmer 2400 elemen-
tal analyzer (USA). The IR spectra were recorded on potassium
bromide pellet on a Bruker Equinox 55 FTIR spectrophotometer
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Y. Zeng and F. Liu
Vol 000
Table 3
C–H. . .p hydrogen bonds for the title compound (Å, ꢀ).
D-H. . .A
d(H. . .A)
d(D. . .A)
<(DHA)
Symmetry code
5e
7f
C(4)–H(4B)–Cg(4)
C(14)–H(14A)–Cg(5)
(23)–H(23A)–Cg(4)
2.88
2.88
2.92
3.671(2)
3.509(2)
3.668(2)
144
126
136
À1/2 + X,3/2 À Y,ÀZ
1 À X,1/2 + Y,À1/2 À Z
ÀX,À1/2 + Y,À1/2 À Z
À1 À X,ÀY,1 À Z
C(10)–O(2)–Cg(3)
3.931(3)
4.215
95.02(16)
Table 4
Hydrogen bonded geometry (distances and angles are given in Å and ꢀ).
D-H. . .A
d(D-H)
d(H. . .A)
d(D. . .A)
<(DHA)
Symmetry code
C(8)–H(8A). . .O(1)
C(20)–H(20A). . .O(2)
0.93
0.93
2.51
2.46
3.354(3)
3.006(3)
152
118
Àx,1 À y,1 À z
Intra
Figure 1. The crystal structure of the compound 5e. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
(Germany). The 1H NMR spectra were measured by a Varian
Inova-400 spectrophotometer (USA) using TMS as an internal
reference. Mass spectra were preformed on an Agilent 5975
apparatus (EI, 70eV) (USA). Compounds 1 [33], 3 [34], 4 [35],
and 6 [25,26] were prepared according to the known procedure.
General procedure for the preparation of 3-(4-substitued-
phenyl)-4-(4-substitued-benzoyl)-5-(2-phenyl-1,2,3-triazol-4-yl)-
4,5-dihydro-isoxazolines (5a–h). A mixture of the appropriate
hydroxamoyl chlorides 4 (1 mmol) and the chalcones 3 (1mmol)
was stirred in ethanol in CH2Cl2 (15 mL). After dissolution of the
(KBr) n: 3137 (Ar-H), 2920 (CH), 1633 (C═O), 1595, 1496
1
(C═N) cmÀ1; H NMR (CDCl3, 400MHz) d: 8.20–7.51 (m, 16H,
Ar-H, and N═C-H), 6.03–6.02 (d,1H, Ha, Jab =5.60Hz), 5.93–5.92
(d, 1H, Hb, Jab =5.60Hz); MS: m/z: 384 (M+), 291, 172, 105
(100%), 97, 77, 51; Anal. Calcd for C24H18N4O2: C, 73.08; H, 4.60;
N, 14.20. Found: C, 73.05; H, 4.66; N, 14.21.
(4-Methoxyphenyl)(3-phenyl-5-(2-phenyl-2H-1,2,3-triazol-4-yl)-
4,5-dihydroisoxa zol-4-yl) methanone (5b). This compound was
obtained as white crystals in yield 43%, mp 110–111ꢀC; IR(KBr)
n: 3139 (Ar-H), 2915 (CH), 1643 (C═O), 1585, 1492 (C═N)
1
reactants,
a
solution of triethylamine (0.5 mL) was added
cmÀ1; H NMR (CDCl3, 400MHz) d: 8.31–7.82 (m, 15H, Ar-H
dropwise. Then, the solution was stirred at room temperature for
further 2 days. The solid mass separated out was filtered off, the
filtrate was evaporated under reduced pressure, and the residue
and N═C-H), 6.21–6.20 (d,1H, Ha, Jab =5.40Hz), 6.02–6.01
(d, 1H, Hb, Jab = 5.40 Hz), 3.85 (s, 3H, OCH3); MS: m/z: 424 (M+),
321, 172, 135 (100%), 107, 77, 51; Anal. Calcd for C25H20N4O3: C,
70.74; H, 4.75; N, 13.20. Found: C, 70.67; H, 4.82; N, 13.15.
was chromatographed on
a silica gel column by using
ethylacetate: petroleum ether (1:8) as eulent to afford the
corresponding oxazoline derivatives 5a–h.
Phenyl-(3-phenyl-5-(2-phenyl-2H-1,2,3-triazol-4-yl)-4,5-
dihydroisoxazol-4-yl)methanone (5a). This compound was
obtained as white crystals in yield 38%, mp 167–168ꢀC; IR
(4-Chlorophenyl)(3-phenyl-5-(2-phenyl-2H-1,2,3-triazol-4-
yl)-4,5-dihydroisoxazol-4-yl) methanone (5c). This compound
was obtained as white crystals in yield 37%, mp 139–140ꢀC; IR
(KBr) n: 3140 (Ar-H), 2933(CH), 1638 (C═O), 1588, 1483
1
(C═N), 763 (C-Cl) cmÀ1; H NMR (CDCl3, 400 MHz) d: 8.12–
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Isoxazoline, Pyrazole, 1,2,3-Triazole, Crystal Structure
Figure 2. The crystal structure of the compound 5f. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Figure 3. The molecular packing of 5e. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
7.43 (m, 15H, Ar-H and N═C-H), 5.98-5.97 (d,1H, Ha,
Jab = 5.20 Hz), 5.86–5.85 (d, 1H, Hb, Jab = 5.20Hz); MS: m/z:
430 (M++2), 428 (M+), 363, 325, 172, 139 (100%), 111, 77, 51;
Anal. Calcd for C24H17ClN4O2: C, 67.21; H, 4.00; N, 13.06.
Found: C, 67.08; H, 4.13; N, 13.11.
C25H20N4O2: C, 73.51; H, 4.94; N, 13.72. Found: C, 73.45; H,
4.99; N, 13.75.
(4-Methoxyphenyl)(3-(4-tolyl)-5-(2-phenyl-2H-1,2,3-triazol-4-
yl)-4,5-dihydroisoxazol-4-yl) methanone (5f). This compound was
obtained as white crystals in yield 45%, mp 102–103ꢀC; IR(KBr)
(4-Nitrophenyl)(3-phenyl-5-(2-phenyl-2H-1,2,3-triazol-4-yl)-
4,5-dihydroisoxazol-4-yl) methanone (5d). This compound was
obtained as white crystals in yield 33%, mp 145–146ꢀC; IR
(KBr) n: 3141 (Ar-H), 2899 (CH), 1621 (C═O), 1589, 1488
n: 3133 (Ar-H), 2941 (CH), 1677 (C═O), 1595, 1494 (C═N) cmÀ1
;
1H NMR (CDCl3, 400MHz) d: 8.25–7.72 (m, 14H, Ar-H and
N═C-H), 6.12–6.10 (d,1H, Ha, Jab = 5.20 Hz), 5.99–5.98 (d, 1H,
Hb, Jab = 5.20 Hz), 3.87 (s, 3H, OCH3), 2.35 (s, 3H, CH3);
MS: m/z:438 (M+), 321, 172, 135 (100%), 107, 92, 77, 51; Anal.
Calcd for C26H22N4O3: C, 71.22; H, 5.06; N, 12.78. Found: C,
71.15; H, 5.10; N, 12.81.
1
(C═N) cmÀ1; H NMR (CDCl3, 400 MHz) d: 8.15–7.49 (m, 15H,
Ar-H and N═C-H), 6.00–5.99 (d,1H, Ha, Jab = 4.80 Hz), 5.88–5.87
(d, 1H, Hb, Jab =4.80Hz); MS: m/z:439 (M+), 336, 172, 150(100%),
122, 77, 51; Anal. Calcd for C24H17N5O4: C, 65.60; H, 3.90; N,
15.94. Found: C, 65.58; H, 4.09; N, 14.81.
(4-Chlorophenyl)(3-(4-tolyl)-5-(2-phenyl-2H-1,2,3-triazol-4-yl)-
4,5-dihydroisoxazol-4-yl) methanone (5g). This compound was
obtained as white crystals in yield 36%, mp 156–157ꢀC; IR
(KBr) n: 3127 (Ar-H), 2955 (CH), 1678 (C═O), 1598, 1491
Phenyl-(3-(4-tolyl)-5-(2-phenyl-2H-1,2,3-triazol-4-yl)-4,5-
dihydroisoxazol-4-yl) methanone (5e). This compound was
obtained as white crystals in yield 41%, mp 217–218ꢀC; IR
(KBr) n: 3130 (Ar-H), 2945 (CH), 1678 (C═O), 1595, 1491
(C═N), 761 (C-Cl) cmÀ1 1H NMR (CDCl3, 400 MHz) d:
;
8.15–7.18(m, 14H, Ar-H and N═C-H), 5.96–5.95 (d,1H, Ha,
Jab = 4.80 Hz), 5.84–5.83 (d, 1H, Hb, Jab = 4.80 Hz), 2.32
(s, 3H, CH3); MS: m/z:444 (M++2), 442 (M+), 377, 339, 186,
153 (100%), 125, 77, 51; Anal. Calcd for C25H19ClN4O2: C,
67.80; H, 4.32; N, 12.65. Found: C, 67.77; H, 4.36; N, 12.60.
(C═N) cmÀ1 1H NMR (CDCl3, 400 MHz) d: 8.20–7.13
;
(m, 15H, Ar-H and N═C-H), 6.01–6.00 (d,1H, Ha, Jab = 5.60 Hz),
5.90–5.89 (d, 1H, Hb, Jab = 5.60 Hz), 2.33 (s, 3H, CH3); MS:
m/z:408 (M+), 303, 158, 105 (100%), 77, 51; Anal. Calcd for
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Y. Zeng and F. Liu
Vol 000
Figure 4. The molecular packing of 5f. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
(4-Nitrophenyl)(3-(4-tolyl)-5-(2-phenyl-2H-1,2,3-triazol-4-
yl)-4,5-dihydroisoxazol-4-yl) methanone (5h). This compound
was obtained as white crystals in yield 33%, mp 161–162ꢀC; IR
(KBr) n: 3136 (Ar-H), 2958 (CH), 1688 (C═O), 1592, 1495
N═C-H), 8.01–7.55 (m, 14H, Ar-H), 3.84 (s, 3H, OCH3); MS:
m/z:421 (M+,100%), 392, 362,314, 196, 135, 92, 77, 57; Anal.
Calcd for C25H19N5O2: C, 71.25; H, 4.54; N, 16.62. Found: C,
71.23; H, 4.55; N, 16.64.
(C═N) cmÀ1
;
1H NMR (CDCl3, 400 MHz) d: 8.16–7.79
(4-Chlorophenyl)(phenyl-4-(2-phenyl-2H-1,2,3-triazol-4-yl)-
pyrazol-3-yl) methanone (7c). This compound was obtained
as white crystals in yield 71%, mp 224–225ꢀC; IR(KBr) n:
2954 (Ar-H), 1633(C═O), 1589, 1516, 1474 (C═N, C═C),
(m, 14H, Ar-H and N═C-H), 6.03–6.02(d,1H, Ha, Jab =5.60Hz),
5.92–5.91 (d, 1H, Hb, Jab = 5.60 Hz), 2.33 (s, 3H, CH3); MS:
m/z:453(M+), 350, 186, 164(100%), 136, 77, 51; Anal. Calcd for
C25H19N5O4: C, 66.22; H, 4,22; N, 15.44. Found: C, 66.20; H,
4.25; N, 15.48.
General procedure for the preparation 1-(4-substitued-
phenyl)-3-(4-substitued-benzoyl)-4-(2-phenyl-1,2,3-triazol-4-
yl)-pyrazoles (7a–h). 3-Arylsydnone 6 (1 mmol) and chalcones
3 (1 mmol) were dissolved in 10 mL dry xylene and refluxed
for 3–4 h. After completion of the reaction (monitored by TLC
and evolution of CO2), the solvent was removed by distillation
under reduced pressure. The resulting crude product was purified
by column chromatography with ethylacetate: petroleum ether
(1:5; v/v) as eulent to afford the corresponding pyrazole
derivatives 7a–h.
1
755(C-Cl) cmÀ1; H NMR (CDCl3, 400 MHz) d: 8.44 (s, 1H,
C═C-H), 8.36 (s, 1H, N═C-H), 8.08–7.41 (m, 14H, Ar-H);
MS: m/z:427 (M++2), 425 (M+,100%,), 396, 362, 314, 196,
139, 111, 77, 51; Anal. Calcd for C24H16ClN5O: C, 67.69; H,
3.79; N, 16.44. Found: C,67.66; H, 3.81; N, 16.46.
(4-Nitrophenyl)(phenyl-4-(2-phenyl-2H-1,2,3-triazol-4-yl)-
pyrazol-3-yl) methanone (7d). This compound was obtained as
white crystals in yield 68%, mp 201–202ꢀC; IR(KBr) n: 3002
1
(Ar-H), 1656 (C═O), 1576, 1520, 1461 (C═N, C═C) cmÀ1; H
NMR (CDCl3, 400 MHz) d: 8.45 (s, 1H, C═C-H), 8.37 (s, 1H,
N═C-H), 8.00–7.54 (m, 14H, Ar-H); MS: m/z:436 (M+, 100%),
407, 361, 314, 196, 150, 91, 64; Anal. Calcd for C24H16N6O3:
C, 66.05; H, 3.70; N, 19.26. Found: C, 66.02; H, 3.72; N, 19.24.
Phenyl-(1-(4-methylphenyl)-4-(2-phenyl-2H-1,2,3-triazol-4-
yl)-pyrazol-3-yl) methanone (7e). This compound was obtained
as white crystals in yield 74%, mp 149–151ꢀC; IR(KBr) n: 3011
Phenyl-(phenyl-4-(2-phenyl-2H-1,2,3-triazol-4-yl)-pyrazol-3-
yl) methanone (7a). This compound was obtained as white
crystals in yield 63%, mp 197–198ꢀC; IR(KBr) n: 2950 (Ar-H),
1
1655 (C═O), 1587, 1512, 1472 (C═N, C═C) cmÀ1; H NMR
(CDCl3, 400 MHz) d: 8.42 (s, 1H, C═C-H), 8.33 (s, 1H, N═C-
H), 8.01–7.40 (m, 15H, Ar-H); MS: m/z:391 (M+), 362, 314,
196, 105, 91, 77 (100%), 64, 51; Anal. Calcd for C24H17N5O:
C, 73.64; H, 4.38; N, 17.89. Found: C, 73.62; H, 4.40; N, 17.87.
(4-Methoxyphenyl)(phenyl-4-(2-phenyl-2H-1,2,3-triazol-4-
yl)-pyrazol-3-yl) methanone (7b). This compound was obtained
as white crystals in yield 76%, mp 171–172ꢀC; IR(KBr) n: 2977
(Ar-H), 1675 (C═O), 1588, 1508, 1459 (C═N, C═C) cmÀ1
;
1H NMR (CDCl3, 400 MHz) d: 8.43 (s, 1H, C═C-H), 8.33 (s, 1H,
N═C-H), 8.01–7.13 (m, 14H, Ar-H), 2.43 (s, 3H, CH3); MS:
m/z:405 (M+, 100%), 376, 328, 210, 118, 91, 65; Anal. Calcd for
C25H19N5O: C, 74.06; H, 4.72; N, 17.27. Found: C, 74.03; H, 4.74;
N, 17.26.
(4-Methoxyphenyl)(1-(4-methylphenyl)-4-(2-phenyl-2H-1,2,3-
triazol-4-yl)-pyrazol-3-yl) methanone (7f). This compound was
obtained as white crystals in yield 73%, mp 139–140ꢀC; IR
1
(Ar-H), 1656(C═O), 1583, 1522, 1461 (C═N, C═C) cmÀ1; H
NMR (CDCl3, 400 MHz) d: 8.35 (s, 1H, C═C-H), 8.27 (s, 1H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Isoxazoline, Pyrazole, 1,2,3-Triazole, Crystal Structure
[10] Venkata, P.; Sarala, B.; Nidhi, G. M.; Nagarajan, R.; Raghu,
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[12] Ryng, S.; Machon, Z.; Wieczorek, Z.; Zimecki, M.; Mokrosz,
M. Eur J Med Chem 1998, 33, 831.
(KBr) n: 2989 (Ar-H), 1657 (C═O), 1571, 1522, 1472 (C═N,
1
C═C) cmÀ1; H NMR (CDCl3, 400MHz) d: 8.35 (s, 1H, C═C-
H), 8.26 (s, 1H, N═C-H), 8.02–7.63 (m, 13H, Ar-H), 3.85
(s, 3H, OCH3), 2.42 (s, 3H, CH3); MS: m/z:435 (M+, 100%),
406, 328, 210, 135, 118, 91, 77, 64, 51; Anal. Calcd for
C26H21N5O2: C, 71.71; H, 4.86; N, 16.08. Found: C, 71.70;
H, 4.87; N, 16.10.
[13] Mahajan, R. N.; Havaldar, F. H.; Fernandes, P. S. J. Indian
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Chem 1999, 130, 1167.
(4-Chlorophenyl)(1-(4-methylphenyl)-4-(2-phenyl-2H-1,2,3-
triazol-4-yl)-pyrazol-3-yl) methanone (7g). This compound was
obtained as white crystals in yield 71%, mp 168–170ꢀC; IR
(KBr) n: 2923 (Ar-H), 1650 (C═O), 1597, 1526, 1497 (C═N,
[15] Hatheway, G. J.; Hansch, C.; Kim, K. H.; Milstein, S. R.;
Schimidt, C. L.; Smith, R. N.; Quin, F. R. J Med Chem 1978, 21, 563.
[16] Badawey, E.; El-Ashmawey, I. M. Eur J Med Chem 1998, 33, 349.
[17] Hashimoto, H.; Imamura, K.; Haruta, J.; Wakitani, K. J Med
Chem 2002, 45, 1511.
[18] Genin, M. J.; Biles, C.; Keiser, B. J.; Poppe, S. M.; Swaney,
S. M.; Tarpley, W. G.; Yagi, Y.; Romero, D. L. J. Med Chem 2000, 43, 1034.
[19] Saikia, A.; Barthakur, M. G.; Borthakur, M.; Saikia, C. J.;
Bora, U.; Boruah, R. C. Tetrahedron Lett 2006, 47, 43.
[20] Nikpour, F.; Beigvand, M. Monatsh Chem 2008, 139, 821.
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C═C), 758(C-Cl) cmÀ1 1H NMR (CDCl3, 400 MHz) d: 8.46
;
(s, 1H, C═C-H), 8.37 (s, 1H, N═C-H), 8.00–7.18 (m, 13H, Ar-H),
2.44 (s, 3H, CH3); MS: m/z:441 (M++2), 439 (M+, 100%), 410,
376, 328, 210, 139, 111, 91, 77, 64, 51; Anal. Calcd for
C25H18ClN5O: C, 68.26; H, 4.12; N, 15.92. Found: C, 68.24;
H, 4.13; N, 15.90.
(4-Nitrophenyl)(1-(4-methylphenyl)-4-(2-phenyl-2H-1,2,3-
triazol-4-yl)-pyrazol-3-yl) methanone (7h). This compound
was obtained as white crystals in yield 69%, mp 234–235ꢀC;
IR(KBr) n: 2956 (Ar-H), 1677 (C═O), 1582, 1511, 1470
[22] Martinsm, M. A. P.; Peres, R. L.; Frizzo, C. P.; Scapin, E.;
Moreira, D. N.; Fiss, G. F.; Zanatta, N.; Bonacorso, H. G. J Heterocyclic
Chem 2009, 46, 1247.
1
(C═N, C═C) cmÀ1; H NMR (CDCl3, 400 MHz) d: 8.41 (s, 1H,
[23] Šimůnek, P.; Svobodová, M.; Macháček, V. J Heterocyclic
Chem 2009, 46, 650.
[24] İlhan, I. Ö.; Saripinar, E.; Akçamur, Y. J Heterocyclic Chem
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Chem Int Ed 1962, 1, 49.
C═C-H), 8.32 (s, 1H, N═C-H), 8.03–7.63 (m, 13H, Ar-H), 2.42
(s, 3H, CH3); MS: m/z:450 (M+, 100%), 420, 328, 210, 120, 91, 77,
65, 57; Anal. Calcd for C25H18N6O3: C, 66.66; H, 4.03; N, 18.66.
Found: C, 66.65; H, 4.04; N, 18.68.
[26] Shinge, P. S.; Latthe, P. R.; Badami, B. V. Synth. Commun
2005, 35, 2169.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet