Expeditious synthesis and single crystal structure of new pyrazole-fused 1,4-oxazine

Article abstract of DOI:10.1002/jhet.833

A series of 2,6-diphenyl-4H-pyrazolo[5,1-c][1,4]oxazin-4-ones has been synthesized via a lactonization of 1-(2-oxo-2-phenylethyl)-3-phenyl-1H-pyrazole- 5-carboxylic acids in the presence of Ac₂O at reflux temperature. The products were isolated by simple filtration in excellent yields and were characterized by IR, ¹H-NMR, and HRMS. The molecular structure was confirmed by the X-ray crystal analysis of one compound that was prone to crystallization.

Full text of DOI:10.1002/jhet.833

May 2012
Expeditious Synthesis and Single Crystal Structure of
New Pyrazole-Fused 1,4-Oxazine
691
*
Liang-Wen Zheng, Bao-Xiang Zhao, and Ying-Rui Liu
Institute of Organic Chemistry, School of Chemistry and Chemical Engineering,
Shandong University, Jinan 250100, People’s Republic of China
*
E-mail: bxzhao@sdu.edu.cn
Received October 13, 2010
DOI 10.1002/jhet.833
View this article online at wileyonlinelibrary.com.
A series of 2,6-diphenyl-4H-pyrazolo[5,1-c][1,4]oxazin-4-ones has been synthesized via a lactonization
of 1-(2-oxo-2-phenylethyl)-3-phenyl-1H-pyrazole-5-carboxylic acids in the presence of Ac2O at reflux
temperature. The products were isolated by simple filtration in excellent yields and were characterized by
1
IR, H-NMR, and HRMS. The molecular structure was confirmed by the X-ray crystal analysis of one
compound that was prone to crystallization.
J. Heterocyclic Chem., 49, 691 (2012).
INTRODUCTION
skeleton [17]. Although several methods are described for
the synthesis of various six-membered lactone moieties [18],
many of the established approaches are still severely limited
in their use of expensive catalysts, high toxic reagents and
solvents involved, low yields, or tedious post-processing
required.
Herein, we would like to report the synthesis of novel
pyrazolo-oxazine with excellent yields and a single crystal
structure.
Convenient routes to aromatic heterocycles are of ongoing
interest. In particular, there is an increasing interest in
pursuing the study of pyrazole-fused heterocycles, such
as pyrazolo-benzotriazine [1], pyrazolo-isoquinoline [2],
pyrazolo-indole [3], pyrazolo-naphthyridine [4], pyrazolo-
oxazepine [5], pyrazolo-phthalazine [6], pyrazolo-pyrimidine
[7], pyrazolo-pyridine [8], pyrazolo-pyridazinone [9],
pyrazolo-quinoline [10], pyrazolo-triazine [11], pyrazolo-
tetrazine [12], pyrazolo-pyrido-pyrimidine [13], pyrazolo-
pyrrolo-pyridine [14], and pyrazolo-triazolo-pyrimidine
[15]. Because of their bicyclic or polycyclic nature and
conformational constraints, these fused heterocycles may
be useful as building blocks in medicinal chemistry such as
anti-inflammatory, antifungal, antiplatelets, antituberculosis,
antibacterial, antitumor, anticonvulsant, antimalarial, and
analgesic agents.
RESULTS AND DISCUSSION
In our previous paper [17], we described that ethyl 1-
(2-aryl-2-oxoethyl)-3-ferrocenyl-1H-pyrazole-5-carbox-
ylate analogues undergo intramolecular esterification
reaction via soft enolate formation on treatment with
MgBr2ÁEt2O and N,N-diisopropylethylamine for 4 h to afford
2-ferrocenyl-6-substituted-4H-pyrazolo[5,1-c][1,4]oxazin-4-
ones in 11–44% yield. Thus, we explored first whether the
conditions were suitable for ethyl 3-(4-methoxyphenyl)-1-
(2-oxo-2-phenylethyl)-1H-pyrazole-5-carboxylate. The result
The molecular properties of pyrazolo-oxazine are
practically unknown. As part of our ongoing research
aiming at the synthesis of new anticancer compounds
[16], we are interested in construction of pyrazolo-oxazine
© 2012 HeteroCorporation

692
L.-W. Zheng, B.-X. Zhao, and Y.-R. Liu
Vol 49
Scheme 1
showed that target compound 3c can be obtained under the
reaction conditions in toluene refluxed with MgBr2ÁEt2O
and N,N-diisopropylethylamine for 4 h, but in only 26%
yield. Inspired with the result, we searched other reaction
conditions for the synthesis of target compounds.
[1,4]oxazin-4-one. The length of the C(1)—O(2) bond
1.376(3) Å indicates the conjugation between the lone
pair of the oxygen atom and p-system of the carbonyl
group. The distances of C(2)—C(5), 1.470(3) Å and of
C(12)—C(13), 1.470(3) Å are consistent with single
bonds between sp2-hybridized carbon atoms (Table 1).
All aromatic rings in the structure are planar within
0.005(2) Å deviation. The oxazine ring is planar with a
maximum deviation of À0.012(3) Å for the atom C(1)
though without aromatic property. It seems that the pres-
ence of the conjugated conformation enforces planarity of
the oxazine ring system. The methoxyl group is coplanar
to the benzene ring [the C(19)—O(3)—C(16)—C(15)
torsion angle is 1.7(3)ꢀ]. Moreover, it is also observed that
the whole molecule is planar with the torsion angle:
N(2)—C(12)—C(13)—C(14) À1.6(3)ꢀ, O(2)—C(2)—C(5)—
C(6)À2.9(3)ꢀ. The dihedral angles formed by substituted
benzene and unsubstituted benzene ring with pyrazole are
1.91(7)ꢀ and 6.54(10)ꢀ, respectively.
The synthetic strategy we adopted for the synthesis of
novel 2,6-diphenyl-4H-pyrazolo[5,1-c][1,4]oxazin-4-ones
3 are outlined in the Scheme 1. Starting material, ethyl
1-(2-oxo-2-phenylethyl)-3-phenyl-1H-pyrazole-5-carboxylate
analogue 1 can be easily prepared following the proce-
dure described in our latest paper [19]. Basic hydrolysis
of 1 followed by acidic treatment afforded 1-(2-oxo-2-
phenylethyl)-3-phenyl-1H-pyrazole-5-carboxylic acids 2.
The pyrazolo[5,1-c][1,4]oxazin-4-one derivatives 3 were
obtained by the lactonization of corresponding the
intermediates 2 in the presence of Ac2O at reflux tem-
perature in excellent yields (70–88%). The structures of
the novel pyrazole-fused oxazinone derivatives 3 were
determined by IR, 1H-NMR, and HRMS spectroscopy.
For example, in compound 3c, the C = O absorption was
The molecules of 3c are mutually parallel and dis-
posed in a herringbone fashion. Two intramolecular
H-bonds resulting from O(2) in oxazine moiety and
N(2) in pyrazole moiety are contributed for planar con-
formation (Fig. 2).
1
found at the region of 1743 cmÀ1. In the H-NMR spec-
tra, two signals for aromatic ortho H-atoms in the
methoxybenzene moiety appeared at the range of d = 7.82
and 6.99 ppm as doublet peaks (J = 8.7 Hz). The methoxy
group shows as singlet at d = 3.86 ppm. In addition, two
singlet signals appeared at d = 7.36 and 7.92 ppm are
consistent with protons in pyrazole and oxazine moiety,
respectively. In the HRMS, in accordance with the
molecular structure of C19H14N2O3, compound 3c gave a
[M + H]-ion peak at m/z 319.1080 (calcd: 319.1083).
In the title molecule of 3c, two benzene rings are
bonded to pyrazolo[5,1-c][1,4]oxazin-4-one moiety at
C(2) and C(12) as showed in Figure 1. The double bond
length of C(2)—C(3) reveals unambiguous proof of the
reaction between hydroxyl of enolate and carboxyl group
and definitely assigned the structure of pyrazolo[5,1-c]
Figure 1. Molecular structure and atomic numbering showing 30%
probability displacement ellipsoids in structure 3c.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2012
Expeditious Synthesis and Single Crystal Structure of New Pyrazole-Fused 1,4-Oxazine
693
Table 1
Selected bond lengths (Å) and angles (ꢀ) for the compound 3c.
General procedure for the synthesis of 2,6-diphenyl-4H-
pyrazolo[5,1-c][1,4]oxazin-4-ones. To a mixture of 1 (2.5 mmol)
in 50 mL of EtOH/H2O (v/v = 4:1), KOH (566 mg, 10.1 mmol)
was added at ambient temperature. The reaction mixture was
stirred and heated to reflux for 1–2 h, until TLC indicated the
end of reaction. Solvent was removed under reduced pressure,
and the residue was distilled in 100-mL H2O. The mixture was
neutralized (pH = 5) using aqueous HCl (10%). The crude
product was filtered from the formed suspension and washed
with water. Product 2 was obtained without further purification.
A mixture of 1-(2-oxo-2-phenylethyl)-3-phenyl-1H-pyrazole-
5-carboxylic acid 2 (2.0 mmol) and acetic anhydride (10–15 mL)
was stirred and heated under nitrogen atmosphere. The reaction
mixture was maintained under reflux for 4 h, until TLC indicated
the end of reaction. After this time, the reaction mixture stood
over night and the solid formed was collected by filtration and
washed with ethanol and water to afford crystals. As a result
of this process, the compounds 3 were prepared in total yield
of 70–88%.
O(1)—C(1)
O(2)—C(1)
O(2)—C(2)
N(1)—N(2)
N(1)—C(4)
N(1)—C(3)
N(2)—C(12)
C(1)—C(4)
C(2)—C(3)
C(2)—C(5)
C(4)—C(11)
C(11)—C(12)
C(12)—C(13)
1.210 (2)
1.376 (3)
1.396 (2)
1.346 (2)
C(1)—O(2)—C(2)
N(2)—N(1)—C(4)
N(2)—N(1)—C(3)
C(4)—N(1)—C(3)
122.96 (16)
112.48 (15)
124.46 (16)
123.03 (16)
104.63 (16)
117.8 (2)
1.372 (2) N(1)—N(2)—C(12)
1.388 (2)
1.349 (3)
1.440 (3)
1.334 (3)
1.470 (3)
1.373 (3)
O(1)—C(1)—O(2)
O(1)—C(1)—C(4)
O(2)—C(1)—C(4)
C(3)—C(2)—O(2)
C(2)—C(3)—N(1)
N(1)—C(4)—C(1)
126.0 (2)
116.23 (18)
120.42 (17)
118.67 (18)
118.64 (17)
106.44 (17)
105.29 (18)
1.410 (3) N(1)—C(4)—C(11)
1.470 (3) C(4)—C(11)—C(12)
There are two C—H⋯p contacts between H atoms
and the p-electrons of the rings (Table 2). The contact
from phenylic atom H(9) to the centre of the benzene ring
[C(5)—C(6)—C(7)—C(8)—C(9)—C(10)] has a distance
of 2.78 Å, and the angle at the H atom is 137ꢀ. The
second, slightly longer, contact links methylic atom HA
at a distance of 2.79 Å to the centre of the oxazine ring
and the angle at the H atom is 148ꢀ. Furthermore, in this
structure, a C—O⋯p contact to the centre of the core
oxazine can be observed. The distance from O(1) to the
centre of the oxazine ring is 2.994(2) Å and the angle at
O(1) is 136.97(18)ꢀ. It is interesting to note that there
is no p-p stacking interaction between aromatic rings.
2,6-Diphenyl-4H-pyrazolo[5,1-c][1,4]oxazin-4-one (3a). White
solid, yield: 72%, mp. 216–217ꢀC; IR (KBr): 1745 (C = O) cmÀ1
.
1H-NMR (CDCl3, 400 MHz) d: 7.41 (t, 1H, J = 7.2, Ar—H), 7.46
(s, 1H, pyrazole-H), 7.47–7.51 (m, 5H, Ar—H), 7.76 (d, 2H,
J = 7.6, Ar—H), 7.89 (d, 2H, J = 7.2, Ar—H), 7.95 (s, 1H,
oxazine-H); HRMS (C18H13N2O2): calcd. for [M + H]+ 289.0977,
found 289.0978.
2-(4-Chlorophenyl)-6-phenyl-4H-pyrazolo[5,1-c][1,4]oxazin-
4-one(3b). White solid, yield: 71%, mp. 265–266ꢀC; IR (KBr):
1
1737 (C = O) cmÀ1. H-NMR (CDCl3, 400 MHz) d: 7.43–7.44
(m, 2H, Ar—H), 7.46 (s, 1H, pyrazole-H), 7.48–7.51 (m, 3H,
Ar—H), 7.76 (d, 2H, J = 7.0, Ar—H), 7.83 (d, 2H, J = 8.3,
Ar—H), 7.94 (s, 1H, oxazine-H); HRMS (C18H12ClN2O2):
calcd. for [M + H]+ 323.0587, found 323.0570.
2-(4-Methoxyphenyl)-6-phenyl-4H-pyrazolo[5,1-c][1,4]oxazin-4-
one (3c). Yellow solid, yield: 76%, mp. 207–209ꢀC; IR (KBr):
CONCLUSIONS
1
1743 (C = O) cmÀ1; H-NMR (CDCl3, 400 MHz) d: 3.86 (s, 3H,
An expeditious method for preparing 2,6-diphenyl-
4H-pyrazolo[5,1-c][1,4]oxazin-4-one derivatives was de-
scribed, and the structure of synthesized compounds was
OCH3), 6.99 (d, 2H, J = 8.7, Ar—H), 7.36 (s, 1H, pyrazole-H),
7.45 (t, 1H, J = 7.6, Ar—H), 7.47 (t, 2H, J = 7.6, Ar—H), 7.75 (d,
2H, J = 7.6, Ar—H), 7.82 (d, 2H, J = 8.7, Ar—H), 7.92 (s, 1H,
oxazine-H); HRMS (C19H15N2O3): calcd. for [M + H]+ 319.1083;
found 319.1080.
1
determined by IR, H-NMR, and HRMS. Moreover, the
molecular structure was confirmed by the X-ray crystal
analysis. Currently, investigations are underway to elucidate
the bioactivity of these pyrazole-fused oxazinone and the
results will be reported in due course.
6-(4-Chlorophenyl)-2-phenyl-4H-pyrazolo[5,1-c][1,4]oxazin-
4-one (3d).
Yellow solid, yield: 81%, mp. 222–223ꢀC; IR
(KBr): 1757 (C = O) cmÀ1
;
1H-NMR (CDCl3, 400 MHz) d:
7.41 (t, 1H, J = 7.2, Ar—H), 7.45 (s, 1H, pyrazole-H), 7.46
EXPERIMENTAL
General.
Analytical TLC was carried out with Merck
silica gel (60 F254). Melting points were determined
with an XD-4 digital micro melting point apparatus and
are uncorrected. 1H-NMR spectra were recorded on
a
Bruker Avance 400 (400 MHz) spectrometer, using
CDCl3 as solvent and TMS as internal standard. The
chemical shifts (d) were measured in ppm with respect
to the solvent (CDCl3: 1H: d = 7.26 ppm). IR spectra
were measured as KBr plates with an IR spectrophotometer
Avtar 370 FTIR (Termo Nicolet). HRMS spectra were
recorded with a LTQ Orbitrap Hybrid mass spectrograph.
Reagents and solvents used were commercially available
analytical grade materials used as supplied, without further
purification.
Figure 2. Packing diagram of the structure 3c, C—H(O)⋯p interac-
tions were showed with dashed lines.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

694
L.-W. Zheng, B.-X. Zhao, and Y.-R. Liu
Vol 49
Table 2
C—H/O⋯p interaction geometry for compound 3c.
C—H/O⋯p
C—H/O (Å)
H/O⋯Cga (Å)
C⋯Cg (Å)
C—H/O⋯Cg (ꢀ)
C(9)—H(9)⋯Cg(1)b
C(19)—H(19)A⋯Cg(2)c
C(1)—O(1)⋯Cg(2)d
0.93
0.96
1.210 (2)
2.78
2.79
2.994 (2)
3.513 (3)
3.647 (3)
3.965 (3)
137
148
136.97 (18)
aCg(1) and Cg(2) are centroids of the unsubstituted benzene ring and oxazine ring, respectively.
bSymmetry code: À1/2 À x, y, À1/2 + z.
c
Àx, 1 À y, À1/2 + z.
d1/2 À x, y, 1/2 + z.
(d, 2H, J = 8.6, Ar—H), 7.47 (t, 2H, J = 7.2, Ar—H), 7.69 (d, 2H,
J = 8.6, Ar—H), 7.89 (d, 2H, J = 7.2, Ar—H), 7.93 (s, 1H,
oxazine-H); HRMS (C18H12ClN2O2): calcd. for [M + H]+
323.0587, found 323.0587.
solution. The diffraction measurement was carried out by
graphite monochromated Mo Ka radiation with l = 0.71073 Å
on a Bruker SMART CCD diffractometer at room temperature.
The structure was solved with direct methods using the
SHELXS-97 program, and refined on F2 by full-matrix least-
squares with the SHELXL-97 package [20]. All data were
corrected by multiscan method using SADABS program. The
hydrogen atoms were placed at calculated positions with 0.96 Å
(methyl CH3) and 0.93 Å (aromatic CH) using a riding model.
Molecular graphics were designed by using XP and DIAMOND
3.2 [21]. PLATON program was also used for structure analysis
2,6-Bis(4-chlorophenyl)-4H-pyrazolo[5,1-c][1,4]oxazin-4-
one (3e).
Yellow solid, yield: 84%, mp. 284–285ꢀC; IR
(KBr): 1756 (C = O) cmÀ1
;
1H-NMR (CDCl3, 400 MHz)
d: 7.42 (d, 2H, J = 8.6, Ar—H), 7.45 (s, 1H, pyrazole-H),
7.47 (d, 2H, J = 8.4, Ar—H), 7.69 (d, 2H, J = 8.6, Ar—H),
7.82 (d, 2H, J = 8.4, Ar—H), 7.90 (s, 1H, oxazine-H);
HRMS (C18H11Cl2N2O2): calcd. for [M + H]+ 357.0198,
found 357.0199.
6-(4-Chlorophenyl)-2-(4-methoxyphenyl)-4H-pyrazolo[5,1-c]
Table 3
[1,4]oxazin-4-one (3f).
Yellow soliÀd1, yield: 88%, mp.
255–256ꢀC; IR (KBr): 1754 (C = O) cm
;
1H-NMR (DMSO,
Summary of crystal data and structure refinement.
400 MHz) d: 3.81 (s, 3H, OCH3), 7.05 (d, 2H, J = 8.8, Ar—H),
7.58 (d, 2H, J = 8.8, Ar—H), 7.77 (s, 1H, pyrazole-H), 7.89 (d,
2H, J = 8.8, Ar—H), 7.93 (d, 2H, J = 8.8, Ar—H), 8.85 (s, 1H,
oxazine-H); HRMS (C19H14ClN2O3): calcd. for [M + H]+
353.0693, found 353.0693.
Compound
3c
Empirical formula
Formula weight
Crystal system
Space group
a (Å)
C19H14N2O3
318.32
Orthorhombic
Pca21
11.361 (3)
17.813 (5)
7.517 (2)
90
90
90
4
6-(4-Methoxyphenyl)-2-phenyl-4H-pyrazolo[5,1-c][1,4]oxazin-
4-one (3g). Yellow solid, yield: 70%, mp. 189–190ꢀC; IR (KBr):
1
1742 (C = O) cmÀ1; H-NMR (CDCl3, 400 MHz) d: 3.87 (s, 3H,
b (Å)
c (Å)
OCH3), 7.00 (d, 2H, J = 8.7, Ar—H), 7.41 (t, 1H, J = 7.5,
Ar—H), 7.44 (s, 1H, pyrazole-H), 7.47 (t, 2H, J = 7.5, Ar—H),
7.69 (d, 2H, J = 8.7, Ar—H), 7.85 (s, 1H, oxazine-H), 7.89
(d, 2H, J = 7.5, Ar—H); HRMS (C19H15N2O3): calcd. for
[M + H]+ 319.1083, found 319.1084.
a (ꢀ)
b (ꢀ)
g (ꢀ)
Z
Dx (g/cm3)
Crystal size (mm)
1.390
2-(4-Chlorophenyl)-6-(4-methoxyphenyl)-4H-pyrazolo[5,1-c]
0.16 Â 0.14 Â 0.10
m (mmÀ1
F(000)
)
0.096
664
7659
1465
[1,4]oxazin-4-one (3h).
Yellow solid, yield: 80%, mp.
254–256ꢀC; IR (KBr): 1759 (C = O) cmÀ1
;
1H-NMR (CDCl3,
Reflection collected
Unique reflection
Data/restraints/parameters
θ Range for data collection (ꢀ)
R(int)
400 MHz) d: 3.88 (s, 3H, OCH3), 7.00 (d, 2H, J = 8.8, Ar—H),
7.40 (s, 1H, pyrazole-H), 7.44 (d, 2H, J = 8.4, Ar—H), 7.69 (d,
2H, J = 8.8, Ar—H), 7.82 (d, 2H, J = 8.4, Ar—H), 7.83 (s, 1H,
oxazine-H); HRMS (C19H14ClN2O3): calcd. for [M + H]+
353.0693, found 353.0691.
1465/0/218
2.13 À 25.04
0.0225
Ranges of indices h, k, l
À13 ≤ h ≤ 12, À21 ≤ k ≤ 21,
2,6-Bis(4-methoxyphenyl)-4H-pyrazolo[5,1-c][1,4]oxazin-4-
one (3i). Yellow solid, yield: 86%, mp. 247–250ꢀC; IR (KBr):
À8 ≤ l ≤ 7
Absorption correction
Multiscan (Tmin = 0.985,
Tmax = 0.990)
Full-matrix least-squares on F2
R1 = 0.0269, oR2 = 0.0651a
1.060
1
1750 (C = O) cmÀ1; H-NMR (CDCl3, 400 MHz) d: 3.86 (s, 3H,
Refinement method
OCH3), 3.87 (s, 3H, OCH3), 6.98 (d, 2H, J = 8.8, Ar—H), 7.00
(d, 2H, J = 8.2, Ar—H), 7.34 (s, 1H, pyrazole-H), 7.68 (d, 2H,
J = 8.8, Ar—H), 7.80 (s, 1H, oxazine-H), 7.81 (d, 2H, J = 8.4,
Ar—H); HRMS (C20H17N2O4): calcd. for [M + H]+ 349.1188,
found 349.1184.
Final R indices [I > 2s(I)]
Goodness of fit on F2
Δr (max./min) (e ÅÀ3
)
0.104; À0.099
CCDC No.
784,526
aWeighting scheme: o = 1/[s2(Fo)2 + (0.0386P)2 + 0.1142P] where
P = (Fo2 + 2Fc)2/3.
X-ray crystal-structure analysis. Crystal suitable for X-ray
analysis was grown by slow evaporation from ethyl acetate
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2012
Expeditious Synthesis and Single Crystal Structure of New Pyrazole-Fused 1,4-Oxazine
695
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[22]. The crystal data and details concerning data collection and
structural refinement are given in Table 3.
Acknowledgments. We are grateful for the financial support from
National Natural Science Foundation of China (90813022 and
20972088).
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet