Facile synthesis, single-crystal structure, and biological evaluation of novel pyrazolo[5,1-d][1,2,5]triazepin-4-ones

Article abstract of DOI:10.1002/hlca.201100249

A facile ring-enlargement reaction of 2,6-diphenyl-4H-pyrazolo[5,1-c][1,4] oxazin-4-one is described, generating the pyrazolo[5,1-d][1,2,5]triazepin-4-ones in good yields. Structures of the prepared compounds were determined on the basis of IR, ¹

Full text of DOI:10.1002/hlca.201100249

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Facile Synthesis, Single-Crystal Structure, and Biological Evaluation of Novel
Pyrazolo[5,1-d][1,2,5]triazepin-4-ones
by Liang-Wen Zhenga), Hong-Zhuan Xuanc), Ying-Rui Liua), Bao-Xiang Zhao*a), Jin-Ting Liua), and
Jun-Ying Miaob)
a) Institute of Organic Chemistry, School of Chemistry and Chemical Engineering, Shandong University,
Jinan 250100, P. R. China (e-mail: bxzhao@sdu.edu.cn)
b) Institute of Developmental Biology, School of Life Science, Shandong University, Jinan 250100,
P. R. China
c) School of Life Science, Liaocheng University, Liaocheng 252059, P. R. China
A facile ring-enlargement reaction of 2,6-diphenyl-4H-pyrazolo[5,1-c][1,4]oxazin-4-one is descri-
bed, generating the pyrazolo[5,1-d][1,2,5]triazepin-4-ones in good yields. Structures of the prepared
1
compounds were determined on the basis of IR, H- and 13C-NMR, and HR-MS data. Moreover, the
molecular structure was confirmed by the X-ray crystal-structure analysis of one compound that was
prone to crystallization. Preliminary biological evaluation showed that the compounds 2e – 2h promote
the viability and inhibit the apoptosis of vascular endothelial cells at low concentration.
Introduction. – Small- and medium-sized N-containing heterocyclic skeletons, such
as fused triazepines with a bridgehead N-atom in the molecule exhibit remarkable
biological properties [1]. Although several methods for constructing 1,3,5-triazepine
can be found in the literature [2], the 1,2,5-triazepin skeleton has only received scant
attention [3].
It has been reported that the class of pyrazoles represents structurally diverse
molecules with widespread and diverse pharmacological properties such as anticancer
[4], antimicrobial [5], antiviral [6], antidepressant [7], antimycobacterial [8], anti-
inflammatory [9], anti-angiogenic [10], and antiglaucoma activities [11]. Moreover,
pyrazoles have found applications in drug development for the treatment of
dyslipidemia [12], obesity [13], and neuropathic pain [14]. However, pyrazole-fused
triazepin derivatives remain to be fully exploited, since most of them have not yet been
found in nature or have not been synthesized, or its biological properties have not been
evaluated.
We previously reported our efforts to identify novel potential agents, which
inhibited human umbilical vein endothelial cell (HUVEC) apoptosis, based on
pyrazole heterocycles [15]. More recently, we became interested in exploring pyrazole-
fused heterocycles that contain more heteroatoms, ultimately discovering novel
antithrombotic and anticancer agents [16]. In continuation of our search for bio-
logically potent molecules, we hereby report the synthesis and structure character-
ization of pyrazolo[5,1-d][1,2,5]triazepin-4-one derivatives, which could inhibit endo-
thelial cell apoptosis.
ꢀ 2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 95 (2012)
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Results and Discussion. – The general synthetic strategy to obtain pyrazole-fused
triazepin analogs is outlined in Scheme 1. Starting material 1 with various R1 and R2
substituents could be easily synthesized via cyclization of 3-aryl-1-(2-aryl-2-oxoethyl)-
1H-pyrazole-5-carboxylic acid in the presence of Ac2O [17]. Reaction of 1 with
NH2NH2 · H2O at reflux temperature in BuOH provided the desired pyrazolo[5,1-
d][1,2,5]triazepin-4-one 2 in 68 – 82% yield.
Scheme 1. Synthesis of 5,8-Dihydro-2,7-diphenyl-4H-pyrazolo[5,1-d][1,2,5]triazepin-4-ones
It was of interest to convert ethyl 3-aryl-1-(2-aryl-2-oxoethyl)-1H-pyrazole-5-
carboxylate derivatives 3 to the corresponding pyrazolo[5,1-d][1,2,5]triazepine deriv-
atives 2. As an approach towards the construction of 2, we initially chose a sequential
process of condensation and ring-closure reaction between d-keto esters and NH2NH2 ·
H2O via the intermediate hydrazide 4 [18]. Thus, for example, we carried out the
reaction of 3i with 1 equiv. or excess NH2NH2 · H2O in refluxing EtOH for 12 h to
obtain the desired compound 2i; however, our attempt unfortunately failed due to
competitive reactions (Scheme 2, Path a).
We next attempted at another route as shown in Scheme 2 (Path b). According to
our previous report [17], basic hydrolysis of 3i, followed by acidic treatment, afforded
3-(4-methoxyphenyl)-1-[2-(4-methoxyphenyl)-2-oxoethyl]-1H-pyrazole-5-carboxylic
acid. Then, treatment of the latter with Ac2O gave lactone 1i, which reacted with
NH2NH2 · H2O in BuOH to afford 2i and 4i in 75 and 15% yields, respectively.
A proposed ring-enlargement mechanism is outlined in Scheme 3. In boiling BuOH,
nucleophilic addition of NH2NH2 to the C¼O group of lactone 1i formed an enol
intermediate A that should isomerize to the ketone 4i. Although the enol A might be
more stable because of the conjugated structure, ketone 4i reacts via intramolecular
reaction with NH2 to result in the final cyclic hydrazide [19].
The structures of compounds 2a – 2i were established by IR, 1H-NMR, HR-MS, and
X-ray crystal diffraction of 2c (Fig. 1). Moreover, the assignment of NH in the target
compounds and C¼O in the by-products of type 4 were accomplished by spectroscopic
data. For example, IR spectra showed the characteristic stretching vibration at
1657 cmꢀ1 for the C¼O group of 2i, along with the absorption band at 3203 – 2933 cmꢀ1
due to the NH group. On the other hand, IR spectra of compound 4i showed
characteristic absorption bands at 1689 and 1668 cmꢀ1 corresponding to the ketone
1
C¼O and hydrazide C¼O group, respectively. The H-NMR spectra of 2i exhibited a
signal corresponding to the CONH moiety at d(H) 11.40 ppm as well as aromatic H-

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Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 2
Scheme 3

Helvetica Chimica Acta – Vol. 95 (2012)
137
atom signals in the range of 6.97 – 7.89 ppm. The significant feature of 4i was the
appearance of a singlet for NH2 at d(H) 4.45 ppm. The mass spectra of the two
compounds 2i and 4i showed peaks for the [M þ H]þ ion at m/z 363.1454 and 381.1570,
respectively, in full agreement with their assigned structures.
Fig. 1. ORTEP View of compound 2c, including the atom numbering. Displacement ellipsoids are drawn
at the 25% probability.
Single crystals of 2c suitable for X-ray single-crystal analysis were obtained at room
temperature by partial evaporation of the solvent from AcOEt solution. The
compound was constituted as pyrazolo[5,1-d][1,2,5]triazepine frame which is the core
of the structure, and it has two phenyl rings attached at C(8) and C(12). All bond
lengths and bond angles in the phenyl rings are in the normal range. In the triazepine
ring, the bond length of C(11)¼O(2) (1.2343(19) ꢂ) is slightly longer than that in the
corresponding reactant 1c [18]. Moreover, the bond length C(11)ꢀN(3) and bond angle
C(11)ꢀN(3)ꢀN(4) are 1.366(2) ꢂ and 130.24(14)8, respectively (Table 1). This implies
delocalization of the lone pair of electrons on the N-atom over the pyrazole and
benzylideneamine moiety in 2c. All the aromatic rings are almost planar. Furthermore,
the pyrazole ring and the attached substituted phenyl ring are almost coplanar with a
Table 1. Selected Bond Lengths [ꢂ] and Angles [8] of Compound 2c
N(4)ꢀC(12)
N(3)ꢀC(11)
C(10)ꢀC(11)
N(2)ꢀC(13)
C(12)ꢀN(4)ꢀN(3)
N(3)ꢀC(11)ꢀO(2)
C(11)ꢀC(10)ꢀC(9)
C(10)ꢀN(2)ꢀC(13)
C(13)ꢀC(12)ꢀN(4)
N(2)ꢀN(1)ꢀC(8)
1.284(2)
1.366(2)
1.467(2)
1.454(2)
N(3)ꢀN(4)
C(11)ꢀO(2)
N(1)ꢀN(2)
C(10)ꢀN(2)
N(4)ꢀN(3)ꢀC(11)
O(2)ꢀC(11)ꢀC(10)
C(11)ꢀC(10)ꢀN(2)
N(2)ꢀC(13)ꢀC(12)
C(10)ꢀN(2)ꢀN(1)
C(9)ꢀC(10)ꢀN(2)
1.4025(19)
1.2343(19)
1.3439(18)
1.354(2)
119.28(15)
119.33(15)
130.72(15)
124.72(14)
122.68(15)
104.59(13)
130.24(14)
120.93(15)
122.78(15)
109.11(14)
112.80(13)
106.49(15)

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dihedral angle of 7.76(6)8. The two phenyl rings in compound 2c were neither coplanar
nor perpendicular, being close to 458 (47.91(6)8).
The triazepine ring adopts a twist-boat conformation, similar to those observed in
the crystal structures of azepine [20]. The seven-membered ring consists of two
coplanar halves (Fig. 1). The first is defined by atoms N(3), N(4), C(12), and C(13).
The second half of the ring is composed of atoms C(13), N(2), C(10), and C(11), with
the largest deviation from this plane not exceeding 0.007(2) ꢂ. The dihedral angle
between the two halves is 61.89(8)8, which is within the range of 57.74 – 63.938, values
found for this group of the similar compounds [21].
In the crystal lattice, the C¼O group of the triazepinone interacts with the NH of the
adjacent molecules through a pair of linear N(3)ꢀH(3)A ··· O(2) H-bonds to form an
eight-membered R22(8) ring motif (Table 2). A C(15)ꢀH(15) ··· O(1) H-bond leads to
self-assembly of 2c molecules into C(13) chains, and pairs of C(1)ꢀH(1)A ··· O(2) H-
bonds join two 2c molecules into centrosymmetric dimers of R22(24) type. Moreover,
the C(13)ꢀH(13)B ··· O(2) H-bonds convert the mentioned chains to a 2D network.
Furthermore, some other CꢀH ··· p interactions may supply further Coulombic
stabilization and take part in formation of the three-dimensional structure (Fig. 2).
Table 2. H-Bond Geometry for 2c
XꢀH ··· A/pa)
d(XꢀH) d(H ··· A/p) d(X ··· A/p) /(XꢀH ··· A/p) Symmetry codes
[ꢂ]
0.90(2) 2.02(2)
1.03(3) 2.47(3)
[ꢂ]
[ꢂ]
[8]
N(3)ꢀH(3)A ··· O(2)
C(1)ꢀH(1)A ··· O(2)
2.908(2)
3.497(3)
3.168(3)
3.368(3)
3.687(3)
3.609(3)
175(2)
172(2)
121.6(14)
151.1(16)
148.0(19)
138(2)
ꢀ x, 1 ꢀ y, 2 ꢀ z
ꢀ 1 ꢀ x, ꢀ y, 1 ꢀ z
1 þ x, y, z
C(13)ꢀH(13)B ··· O(2) 0.98(2) 2.54(2)
C(15)ꢀH(15) ··· O(1) 0.96(2) 2.49(2)
1 þ x, 1 þ y, 1 þ z
ꢀ 1 ꢀ x, ꢀ 1 ꢀ y, 1 ꢀ z
1 ꢀ x, ꢀ y, 2 ꢀ z
C(1)ꢀH(1)C ··· Cg2
C(17)ꢀH(17) ··· Cg1
1.00(3)
0.95(2) 2.85(3)
2.80(2)
a) Cg1 and Cg2 are the centriods of pyrazole ring and the substituted phenyl ring, respectively.
The sulforhodamine B (SRB) assay as described first by Skehan et al. was
developed to be used in the disease-oriented, large-scale anticancer drug-discovery
program of the National Cancer Institute (NCI) that was launched in 1985 [22]. Up to
now, SRB protein staining has been widely used for cell proliferation and chemo-
sensitivity testing, replacing tetrazolium-based assays.
Regulation of vascular endothelial cell (VEC) survival and apoptosis plays a crucial
role during development, and in numerous physiologic and pathologic processes. First,
we observed the morphological image of the VECs treated with compounds 2a – 2i
under a phase-contrast microscope in this study. We found that there were no obvious
morphological changes of the cells, even if the cells were treated with compounds at a
concentration of 2.5 mm for 24 h. To evaluate the effects on the growth of VECs, we
carried out the SRB assay with the compounds at 12 and 24 h, respectively. To our
surprise, it was found that the quantities of the cells treated with the synthesized
compounds were increased as shown in Fig. 3. Compounds 2c and 2e – 2h promoted
VEC growth by ca. 10% at 2.5 mm for 12 and 24 h compared with the control group.
Compounds 2d and 2i could markedly promote the cell growth after the treatment for
12 h. Other compounds did not affect the growth of VECs (data not shown).

Helvetica Chimica Acta – Vol. 95 (2012)
139
Fig. 2. Molecular packing in compound 2c, showing details of the H-bond connectivities
Fig. 3. Effects of compounds 2a – 2i on cell viability of VECs at the concentration of 2.5 mm for 12 and 24 h
(*: p < 0.05, **: p < 0.01 vs. control group, n ¼ 3)
Analyzing endothelial apoptosis is necessary not only for the understanding of
several physiologic and pathologic processes but also for evaluating treatments that
inhibit endothelial cell apoptosis. To further demonstrate the apoptotic level, we
examined the morphological changes induced by compounds 2a – 2i in VECs using
Hoechst 33258 staining. Granulation of the nucleus appeared as fluorescent blue in the
detail of the Hoechst 33258 stained cells (those in which vehicle was absent). Since
nucleus granulation is a feature of the morphological change in apoptosis, these results
indicate that 2e – 2h may inhibit partly apoptosis in VECs compared with the control
group at the concentration of 2.5 mm after 12 h (Fig. 4), whereas the ratio of apoptotic

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Fig. 4. Inhibition of VEC apoptosis by compounds 2a – 2i at the concentration of 2.5 mm for 12 and 24 h.
Ratio of apoptotic cells vs. control. Results are presented as mean ꢁ SE (n ¼ 3, *: P < 0.05 vs. control, **:
P < 0.01 vs. control).
cells in the experimental groups treated with compounds 2e – 2h for 24 h was restored
to their original level. These results suggested that the anti-apoptotic effects of
compounds 2e – 2h at low concentration may be in accordance with the proliferation of
the VECs.
Conclusions. – A series of novel pyrazolo[5,1-d][1,2,5]triazepin-4-ones were
synthesized. The structures of the prepared compounds 2a – 2i were determined by
spectroscopic methods. The representative X-ray single-crystal structure character-
ization of 2c was also performed. The biological assay revealed that compounds 2e – 2h
promoted the VEC growth and inhibited the apoptosis of VECs at the concentration of
2.5 mm.
Support for this research by the National Natural Science Foundation of China (Project No. 90813022
and 20972088) is gratefully acknowledged.
Experimental Part
General. The purity of the obtained compounds was checked by TLC on silica gel (SiO2) 60 F254
plates (Merck) in AcOEt/petroleum ether 1:1 and 1:2, detection with UV light. M.p.: XD-4 Digital
micro melting point apparatus; uncorrected. IR Spectra: Avatar 370 FT-IR (ThermoNicolet)
spectrophotometer in KBr disks; ˜n in cmꢀ1. 1H- and 13C-NMR spectra: Bruker Avance 400 spectrometer
at 400 (1H) and 100 (13C) MHz; in (D6)DMSO solns.; d in ppm rel. to Me4Si as internal standard, J in Hz.
HR-MS: LTQ Orbitrap Hybrid mass spectrometer; in m/z.
5,8-Dihydro-2,7-diphenyl-4H-pyrazolo[5,1-d][1,2,5]triazepin-4-ones 2. To a soln. of 2,6-diphenyl-
4H-pyrazolo[1,5-a][1,4]oxazin-4-one (1; 1.0 mmol) in BuOH (25 ml), NH2NH2 · H2O (1.2 mmol) was
added. The mixture was stirred and heated to reflux for 2.5 – 6 h, until TLC indicated the end of the
reaction. After cooling, a white solid was filtered off and washed with a small amount of EtOH. Pure
products of 2 were obtained by column chromatography (SiO2; AcOEt/petroleum ether 1:1) in good
yields.
5,8-Dihydro-2,7-diphenyl-4H-pyrazolo[5,1-d][1,2,5]triazepin-4-one (2a). White solid. Yield: 248 mg
1
(82%). M.p. 230 – 2328. IR: 3201 – 2946 (NH), 1658 (C¼O). H-NMR: 5.61 (s, CH2); 7.34 (t, J ¼ 7.2, 1
arom. H); 7.40 (s, 1 pyrazole H); 7.42 (t, J ¼ 7.2, 2 arom. H); 7.50 – 7.54 (m, 3 arom. H); 7.86 (d, J ¼ 7.2, 2

Helvetica Chimica Acta – Vol. 95 (2012)
141
arom. H); 7.91 – 7.94 (m, 2 arom. H); 11.55 (s, CONH). HR-MS: 303.1234 ([M þ H]þ, C18H15N4Oþ; calc.
303.1246).
2-(4-Chlorophenyl)-5,8-dihydro-7-phenyl-4H-pyrazolo[5,1-d][1,2,5]triazepin-4-one (2b). White sol-
1
id. Yield: 230 mg (68%). M.p. 276 – 2778. IR: 3206 – 2916 (NH), 1663 (C¼O). H-NMR: 5.62 (s, CH2);
7.46 (s, 1 pyrazole H); 7.48 (d, J ¼ 8.6, 2 arom. H); 7.51 – 7.53 (m, 3 arom. H); 7.89 (d, J ¼ 8.6, 2 arom. H);
7.91 – 7.93 (m, 2 arom. H); 11.59 (s, CONH). HR-MS: 337.0847 ([M þ H]þ, C18H14ClN4Oþ; calc.
337.0856).
5,8-Dihydro-2-(4-methoxyphenyl)-7-phenyl-4H-pyrazolo[5,1-d][1,2,5]triazepin-4-one (2c). White
solid. Yield: 245 mg (74%). M.p. 217 – 2198. IR: 3217 – 2936 (NH), 1668 (C¼O). 1H-NMR: 3.78 (s,
MeO); 5.58 (s, CH2); 6.97 (d, J ¼ 8.8, 2 arom. H); 7.31 (s, 1 pyrazole H); 7.48 – 7.52 (m, 3 arom. H); 7.78 (d,
J ¼ 8.8, 2 arom. H); 7.90 – 7.92 (m, 2 arom. H); 11.52 (s, CONH). 13C-NMR: 49.0; 55.6; 106.6; 114.6;
125.0; 127.2; 127.3; 129.4; 131.2; 134.8; 137.6; 150.5; 155.6; 158.2; 159.8. HR-MS: 333.1341 ([M þ H]þ,
C19H17N4Oþ2 ; calc. 333.1352).
7-(4-Chlorophenyl)-5,8-dihydro-7-phenyl-4H-pyrazolo[5,1-d][1,2,5]triazepin-4-one (2d). White sol-
1
id. Yield: 246 mg (73%). M.p. 280 – 2828. IR: 3196 – 2927 (NH), 1669 (C¼O). H-NMR: 5.61 (s, CH2);
7.34 (t, J ¼ 7.4, 1 arom. H); 7.41 (s, 1 pyrazole H); 7.42 (t, J ¼ 7.4, 2 arom. H); 7.58 (d, J ¼ 8.6, 2 arom. H);
7.65 (d, J ¼ 7.4, 2 arom. H); 7.94 (d, J ¼ 8.6, 2 arom. H); 11.60 (s, CONH). HR-MS: 337.0865 ([M þ H]þ,
C18H14ClN4Oþ; calc. 337.0856).
2,7-Bis(4-chlorophenyl)-5,8-dihydro-4H-pyrazolo[5,1-d][1,2,5]triazepin-4-one (2e). White solid.
Yield: 304 mg (82%). M.p. 238 – 2398. IR: 3188 – 2936 (NH), 1665 (C¼O). 1H-NMR: 5.60 (s, CH2);
7.45 (s, 1 pyrazole H); 7.48 (d, J ¼ 8.6, 2 arom. H); 7.58 (d, J ¼ 8.6, 2 arom. H); 7.88 (d, J ¼ 8.6, 2 arom. H);
7.93 (d, J ¼ 8.6, 2 arom. H); 11.61 (s, CONH). HR-MS: 371.0456 ([M þ H]þ, C18H13Cl2N4Oþ; calc.
371.0466).
7-(4-Chlorophenyl)-5,8-dihydro-2-(4-methoxyphenyl)-4H-pyrazolo[5,1-d][1,2,5]triazepin-4-one
(2f). White solid. Yield: 289 mg (79%). M.p. 186 – 1878. IR: 3231 – 2932 (NH), 1653 (C¼O). 1H-NMR:
3.78 (s, MeO); 5.57 (s, CH2); 6.97 (d, J ¼ 8.3, 2 arom. H); 7.31 (s, 1 pyrazole H); 7.57 (d, J ¼ 8.3, 2 arom.
H); 7.78 (d, J ¼ 8.3, 2 arom. H); 7.93 (d, J ¼ 8.3, 2 arom. H); 11.57 (s, CONH). 13C-NMR: 48.9; 55.6; 106.8;
114.6; 125.0; 127.2; 129.1; 129.5; 133.6; 136.0; 137.6; 150.6; 154.4; 158.1; 159.8. HR-MS: 367.0951 ([M þ
H]þ, C19H16ClN4Oþ2 ; calc. 367.0962).
5,8-Dihydro-7-(4-methoxyphenyl)-2-phenyl-4H-pyrazolo[5,1-d][1,2,5]triazepin-4-one (2g). White
solid. Yield: 242 mg (73%). M.p. 204 – 2058. IR: 3202 – 2938 (NH), 1664 (C¼O). 1H-NMR: 3.82 (s,
MeO); 5.57 (s, CH2); 7.06 (d, J ¼ 8.9, 2 arom. H); 7.33 (t, J ¼ 7.9, 1 arom. H); 7.38 (s, 1 pyrazole H); 7.42 (t,
J ¼ 7.9, 2 arom. H); 7.85 (d, J ¼ 7.9, 2 arom. H); 7.89 (d, J ¼ 8.9, 2 arom. H); 11.43 (s, CONH). HR-MS:
333.1351 ([M þ H]þ, C19H17N4Oþ2 ; calc. 333.1352).
2-(4-Chlorophenyl)-5,8-dihydro-7-(4-methoxyphenyl)-4H-pyrazolo[5,1-d][1,2,5]triazepin-4-one
(2h). White solid. Yield: 267 mg (73%). M.p. 270 – 2718. IR: 3201 – 2939 (NH), 1663 (C¼O). 1H-NMR:
3.82 (s, MeO); 5.57 (s, CH2); 7.06 (d, J ¼ 8.8, 2 arom. H),7.42 (s, 1 pyrazole H); 7.47 (d, J ¼ 8.5, 2 arom. H);
7.87 (d, J ¼ 8.5, 2 arom. H); 7.89 (d, J ¼ 8.8, 2 arom. H); 11.45 (s, CONH). HR-MS: 367.0972 ([M þ H]þ,
C19H16ClN4Oþ2 ; calc. 367.0962).
2,7-Bis(4-methoxyphenyl)-5,8-dihydro-4H-pyrazolo[5,1-d][1,2,5]triazepin-4-one (2i). White solid.
Yield: 272 mg (75%). M.p. 193 – 1948. IR: 3203 – 2933 (NH), 1657 (C¼O). 1H-NMR: 3.78 (s, MeO); 3.82
(s, MeO); 5.54 (s, CH2); 6.97 (d, J ¼ 8.8, 2 arom. H); 7.06 (d, J ¼ 8.9, 2 arom. H); 7.28 (s, 1 pyrazole H);
7.77 (d, J ¼ 8.8, 2 arom. H); 7.89 (d, J ¼ 8.9, 2 arom. H); 11.40 (s, CONH). 13C-NMR: 48.8; 55.6; 55.9;
106.4; 114.6; 114.8; 125.1; 126.9; 127.1; 129.1; 137.6; 150.4; 155.6; 158.3; 159.7; 161.8. HR-MS: 363.1454
([M þ H]þ, C20H19N4Oþ3 ; calc. 363.1457).
2,7-Bis(4-methoxyphenyl)-8H-pyrazolo[5,1-d][1,2,5]triazepin-4-ol: White solid. Yield: 57 mg
1
(15%). M.p. 190 – 1928. IR: 3332 – 3248 (NH), 1689 (C¼O), 1668 (CONH). H-NMR: 3.79 (s, MeO);
3.88 (s, MeO); 4.45 (s, NH2); 6.08 (s, CH2); 7.01 (d, J ¼ 8.7, 2 arom. H); 7.10 (d, J ¼ 8.8, 2 arom. H); 7.26 (s,
1 pyrazole H); 7.67 (d, J ¼ 8.7, 2 arom. H); 8.03 (d, J ¼ 8.8, 2 arom. H); 9.84 (s, CONH). HR-MS: 381.1570
([M þ H]þ, C20H21N4Oþ4 ; calc. 381.1563).
X-Ray Crystal-Structure Analysis. Crystals suitable for X-ray analysis were grown by slow
evaporation of the solvent from AcOEt soln. The diffraction measurement was carried out by graphite
monochromated MoKa radiation (l ¼ 0.71073 ꢂ) on a Bruker SMART CCD diffractometer at r.t. The

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Helvetica Chimica Acta – Vol. 95 (2012)
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 [23]. All data were corrected by multi-scan method
using SADABS program [24]. The H-atoms were placed at calculated positions with 0.96 ꢂ (Me) and
0.93 ꢂ (aromatic CH) using a riding model. Molecular graphics were designed by using XP and
DIAMOND 3.2 [25]. PLATON Program was also used for structure analysis [26]. The crystal data and
details concerning data collection and structural refinement are collected in Table 3. CCDC-819054
contains the supplementary crystallographic data for this article. These data can be obtained free of
charge via http://www.ccdc.cam.ac.uk/data_request/cif.
Table 3. Crystallographic Data of Compound 2c
Empirical formula
Mr
C19H16N4O2
332.36
Crystal dimensions [mm]
Crystal system
Space group
0.15 ꢂ 0.15 ꢂ 0.10
triclinic
ꢀ
P1
Z
2
Unit cell parameters:
a [ꢂ]
b [ꢂ]
7.0499(9)
9.9557(12)
c [ꢂ]
13.1850(17)
a [8]
102.526(2)
b [8]
104.162(2)
g [8]
104.260(2)
1.328
0.090
348
Dx [g/cm3]
m [mmꢀ1
F(000)
]
Reflection collected
Data/restraints/parameters
q Range for data collection [8]
R(int)
4448
3209/0/290
2.21 – 26.00
0.0203
Ranges of indices h, k, l
Absorption correction
Refinement method
Final R indices [I > 2s(I)]
Goodness-of-fit on F2
ꢀ 8 ꢃ h ꢃ 8, ꢀ 12 ꢃ k ꢃ 6, ꢀ 11 ꢃ l ꢃ 16
multi-scan (Tmin ¼ 0.987, Tmax ¼ 0.991)
full-matrix least-squares on F2
R1 ¼ 0.0480, wR2 ¼ 0.1207a)
1.018
D1 (max./min) [e ꢂꢀ3
]
0.252; ꢀ 0.346
a) Weighting scheme: w ¼ 1/[s2(Fo)2 þ (0.0806P)2 þ 0.0618P] where P ¼ (Fo2 þ 2F2c )/3.
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Received June 15, 2011