Synthesis of spiro-fused (C5)-pyrazolino-(C6)-triazinones, a new heterocyclic system

Article abstract of DOI:10.1016/j.tet.2009.05.091

Reaction of 4-hydrazinoquinazoline with 2,4-diketoesters gives the corresponding 3-acylmethyl-2H-[1,2,4]triazino[2,3-c]quinazolin-2-ones in a one-step procedure via cyclocondensation-Dimroth-like rearrangement. Spectroscopic studies as well as X-ray analy

Full text of DOI:10.1016/j.tet.2009.05.091

Tetrahedron 65 (2009) 5964–5972
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Synthesis of spiro-fused (C5)-pyrazolino-(C6)-triazinones, a new
heterocyclic system
,
a
b
Alexander V. Karpenko a , Sergey I. Kovalenko , Oleg V. Shishkin
*
a Department of Pharmaceutical Chemistry, Zaporozhye State Medical University, 26 Mayakovsky ave., Zaporozhye 69035, Ukraine
b STC ‘‘Institute for Single Crystals’’, National Academy of Sciences of Ukraine, 60 Lenina ave., Kharkov 61001, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
Reaction of 4-hydrazinoquinazoline with 2,4-diketoesters gives the corresponding 3-acylmethyl-2H-
[1,2,4]triazino[2,3-c]quinazolin-2-ones in a one-step procedure via cyclocondensation–Dimroth-like
rearrangement. Spectroscopic studies as well as X-ray analysis reveal that the obtained tri-
azinoquinazolines exist in their ketoimine tautomeric form. Treatment of these compounds with
hydrazine hydrate affords 30-(2-aminophenyl)-3-(het)aryl-spiro[pyrazoline-5,60(10H)-1,2,4-triazin]-
50(40H)-ones or 5-(het)arylpyrazole-3-carboxylic acid hydrazides depending on the reaction conditions.
The structure of the spiro-heterocycles was elucidated by means of single-crystal X-ray analysis and
confirmed by spectroscopic investigations.
Received 14 March 2009
Received in revised form 14 May 2009
Accepted 28 May 2009
Available online 6 June 2009
Keywords:
Heterocyclization
Rearrangement
Spiro-heterocycle
1,2,4-Triazino[2,3-c]quinazoline
X-ray analysis
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Our strategy was based on employing 2,4-diketoesters, which
are easily accessible key building blocks for heterocyclic systems
Triazino-annulated quinazolines are important in both hetero-
cyclic and medicinal chemistry.1,2 Several cases of biological activi-
ties have been claimed for [1,2,4]triazino[2,3-c]quinazolines3,4 but
insignificant amount of research activity has so far been directed
toward this class of compounds.5–16 Recently, we have presented
a novel one-step synthesis of 2H-[1,2,4]triazino[2,3-c]quinazolin-2-
construction18–20 and are known as a novel class of inhibitors of
HIV-1 integrase.21,22 These compounds, when treated with hydra-
zines, react at the
binucleophiles react at the
of pyridazine derivatives could not be excluded a priori.18,19 The use
b-dicarbonyl fragment whereas aromatic 1,2-
a-ketoester group, although formation
of
a-hydrazinoazines in this reaction was substantially re-
ones starting from 4-hydrazinoquinazoline and
a
-ketocarboxylic
stricted.23–25
acids or their esters (Scheme 1).17 However, this approach was only
applied to derivatives substituted with alkyl and (hetero)aryl
groups. Consequently, our interest was kindled by the desire to ex-
tendthe scopeof themethodfor preparationof thecorresponding3-
acylmethyl derivatives in order to examine their susceptibility for
attack of strong nitrogen nucleophiles, namely hydrazine hydrate.
2. Results and discussion
Condensation of 4-hydrazinoquinazoline (1) with different
(hetero)aryl substituted 2,4-diketoesters in glacial acetic acid
afforded the corresponding 3-acylmethyl derivatives 4 in good to
moderate yields (Scheme 2). Apparently, the key steps of this
synthesis were the formation of Schiff bases 2, and their cyclization
to the supposed intermediate triazinoquinazolines 3 followed by its
Dimroth-like rearrangement to [2,3-c] isomers 4; this was inferred
from related processes.17 Such an approach to 4 was found to be
advantageous for achieving the introduction of the acylmethyl
moiety into the triazinoquinazoline core.
O
N
N
N
N
N
N
OR1
Dimroth-like
rearrangement
R
NH
O
R
N
N
N
O
O
N
NH2
R
Scheme 1.
The obtained triazinoquinazolines 4 are novel compounds and
were characterized by means of elemental analyses and spectro-
scopic data as well. This allows to exclude possible formation of
pyrazole derivatives, which are considered as an alternative
structures to the target 4. Thus, in the 1H and 13C NMR spectra, the
* Corresponding author. Tel.: þ8 061 224 6925; fax: þ8 061 234 1571.
E-mail address: karalexander@gmail.com (A.V. Karpenko).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.091

A.V. Karpenko et al. / Tetrahedron 65 (2009) 5964–5972
5965
N
N
N
N
O
OH
CO2Me
NH
N
R
NH
N
N
O
O
AcOH, reflux, 1-8 h
N
O
N
(24 h for 4h)
NH2
R
1
3
R
CO2Me
2
N
N
N
N
N
N
O
N
R
N
O
R
CO2Me
4a-o, 49-79%
g
a
b
c
d
e
f
h
R
Ph 4-MeC6H4 4-MeOC6H4 3-NO2C6H4 4-NO2C6H4 2-FC6H4 4-FC6H4 2,5-F2C6H3
j
i
k
l
m
n
o
R
2-ClC6H4 4-ClC6H4 3-BrC6H4 4-BrC6H4 thiophen-2-yl furan-2-yl benzo[b]furan-2-yl
Scheme 2.
resonances of the triazinoquinazoline protons and carbons are di-
agnostic since they appear in the areas typical for this heterocycle17
and for CH2CO-group. Of particular use is the singlet of H-6 and
doublet of H-11, which occur in the narrow range of 8.94–9.01 and
8.55–8.59 ppm, respectively. The same deshielding was observed
also in a series of substituted 1,2,4-triazolo[1,5-c]quinazolines.26,27
Furthermore, signals occurring at lowest field values in the 13C NMR
spectra belong to the two C]O groups of the acylmethyl moiety
and C-2 at 183.0–195.4 and 160.5–164.1 ppm, respectively. The
measurement of the 1H NMR spectrum of 4e was unsuccessful due
to low solubility in DMSO-d6.
gives fragment ions with m/z 171 (base peak for 4e,g,j,l) or m/z 170
(4m). The mass spectrum of 4-chlorophenyl substituted derivative
4j is also characterized by clusters of rearrangement peaks [4-
ClC6H4C^OþM]þ and [4-ClC6H4C^OþM]þ.
Ultimately, the structure of 4c was determined by an X-ray
diffraction study as 3-[2-(4-methoxyphenyl)-2-oxoethyl]-2H-
[1,2,4]triazino[2,3-c]quinazolin-2-one (Fig. 1). According to the
crystal data (the numbering is given according to the structural
analysis), 4c includes two planar fragments, which are turned rel-
atively to each other due to the rotation around the C(10)–C(11)
bond (the C(9)–C(10)–C(11)–C(12) torsion angle is ꢀ74.9(4)ꢁ). The
non-planarity of molecule probably results from the repulsion be-
tween two carbonyl groups. The length of the O(2)–C(12) bond
(1.217(4) Å) reflects double character of this bond. This fact in
combination with the clearly single character of the C(10)–C(11)
and C(11)–C(12) bonds (1.495(4) Å and 1.512(5) Å, respectively)
indicates the existence of molecule 4c in its ketoimine tautomeric
form A. A shortened intramolecular contact H(6).N(4) 2.57 Å(the
van der Waals radii sum29 is 2.67 Å) is observed. This is in complete
agreement with the above deshielding of this proton observed in
1H NMR spectra.
In a similar way to the parent acylmethyl derivatives,28 com-
pounds 4 can also exist in ketoimine (A), enaminone (B) and enol
(C) tautomeric forms (Scheme 3). According to the 1H and 13C NMR
spectra, ketoimine form A is the only present tautomer of 3-acyl-
methyl triazinoquinazolines 4b–d,g,h,k–n. Other derivatives
4a,f,i,j,o also favor form A in DMSO-d6 solution, however minor
amounts of other tautomers were observed in the 1H NMR spectra.
The latter shows a low-field shift of H-6 (9.23–9.32 ppm) relative to
the H-6 of form A. This fact along with the distinctive position of the
methine proton (5.97–6.53 ppm) discloses slight changes in the
structure of the heterocycle thus indicating the presence of enol C
as a minor tautomeric form. According to the integral intensities in
the 1H NMR spectra, the equilibrium solutions of 4a,f,i,j,o in DMSO-
d6 were found to contain 2.5–15% of enol tautomer C.
N
N
N
N
N
N
O
H
N
O
N
O
N
O
O
O
NH
N
N
R
R
Figure 1. The molecular structure of compound 4c according to X-ray diffraction data
A
B
C
R
with the atom numbering used in structural analysis.
Scheme 3.
In continuation of our investigations regarding the chemistry
and synthetic potential of fused quinazolines,16,17,26,27 the obtained
triazinoquinazolines were subjected to the reaction with excess of
hydrazine hydrate (Scheme 4). Employing 3-acylmethyl derivatives
4 furnished the corresponding spiro-substituted heterocycles 5 in
good yields, providing derivatives of the novel heterocyclic system
spiro[pyrazoline-5,60(10H)-1,2,4-triazin]-50(40H)-one. However, it
was found that prolonged heating of 2-chloro (4i) and furan-2-yl
(4n) substituted triazinoquinazolines with a fourfold excess of
hydrazine hydrate in i-propanol did not lead to anticipated spiro-
The LC–MS positive-ion atmospheric pressure chemical ioniza-
tion (APCI) show the appropriately protonated molecular ions
[MH]þ, which confirm the expected molecular weights of 4. The MS
(EI) pattern is typical for this class of heterocyclic system17 and is
connected mainly with two processes. The first one is related to the
cleavage of the CH2–CO bond, leaving a characteristic ArC^Oþ
fragment (4c,e,g,j,l). The second route is concerned with C(2)–C(3)
and N(4)–N(5) bond breaking of the triazinoquinazoline, which

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A.V. Karpenko et al. / Tetrahedron 65 (2009) 5964–5972
derivatives. Instead, the unexpected 5-(het)aryl-1H-pyrazole-3-
carboxylic acid hydrazides (6a,b) were isolated. Their structure was
deduced via spectroscopic studies and independent synthesis,
which was performed starting from the appropriate benzoylpyr-
uvates using a known procedure.30 To elaborate feasible method for
the synthesis of spiro-derivatives 5i,n different conditions were
examined. As a result, it was found that proper stoichiometry (3
rather than 4 equiv of hydrazine hydrate) and reaction time
(heating for 30 min only) is crucial to keep the reaction on the
desired pathway. Further hydrazinolysis of 5i led to the 5-(2-
chlorophenyl)-1H-pyrazole-3-carboxylic acid hydrazide (6a),
which proves that hydrazides 6 arised from triazinoquinazolines 4
through successive degradation of the triazine ring in spiro-het-
erocycles 5.
(1.404(2) Å) is longer than its average value32 for acyclic com-
pounds (1.347 Å), but barely differs from the known bond lengths of
the structures 7 and 8, containing a similar six-membered het-
erocycle (Fig. 2).33,34 The amide fragment is somewhat nonplanar
(the O(1)–C(8)–N(2)–H(2 N) torsion angle is 14ꢁ) owing to some
pyramidality of the nitrogen atom. This perturbation, probably,
results in elongation of the N(2)–C(8) bond to 1.356(2) Å and
shortening of the C(8)–O(1) bond to 1.220(2) Å in comparison with
their average values in acyclic amides and
1.235 Å, respectively), which was also observed in structure 7.
These observations suggest the presence of certain distortion of
d-lactams (1.334 Å and
p
-
conjugation in the amide group and its presence mainly within the
N(2)–C(7)–N(3) fragment.
CH3
CH3
H
N
O
N
N
NH2
N2H4*H2O, 4 equiv.
O
O
NH
H
N
H
(3 equiv. for 5i,n)
N
O
O
N
O
N
N
O
N
S
i-PrOH, reflux, 5-8h
(0.5h for 5i,n),
54-91% yield
R
N
N
N
N
N
H
N
CH3
R
H3C
O H3C
CH3
N
H
5a-o
4a-o
7
8
N2H4*H2O,
N2H4*H2O,
4 equiv.
dioxane,
Figure 2. Selected 3-(het)aryl-1,6-dihydro-4H-[1,2,4]triazin-5-ones.
reflux, 5h,
65% yield
from 5i
i-PrOH,
reflux, 8h,
63-66% yield
O
N
NHNH2
O
OH
N2H4*H2O
EtOH, reflux, 3h,
74-78% yield
R'
CO2Me
R'
N
H
6a,b
R'=2-ClC6H4 (6a), furan-2-yl (6b)
Scheme 4.
Comparing the 1H NMR spectroscopic data of compounds 5 with
those of 4 reveals the disappearance of the signal of H-6. Instead,
the two-proton singlet of the NH2-group occurs at ca. 6.30 ppm
together with some upfield shift of the 2-aminophenyl protons,
which clearly indicates pyrimidine ring degradation. The diaster-
eotopic hydrogens of the CH2-group of the pyrazoline ring appear
Figure 3. The molecular structure of compound 5g according to X-ray diffraction data
with the atom numbering used in structural analysis.
2
as two distinct doublets with JHH¼17.6 Hz in the range 2.89–3.07
The N(4) and N(5) atoms have a pyramidal configuration (the
sum of bond angles centered at these atoms are 336ꢁ and 331ꢁ,
respectively). The N(4)–N(3) 1.393(2) Å and N(5)–N(6) 1.412(2) Å
bond lengths are considerably longer their average value 1.366 Å
and 3.77–4.04 ppm. Thus, spiranes 5 were formed as the only
tautomers. Besides, in the 13C NMR spectra more significant dif-
ferences are obvious; thus, in compounds 5, the signal of the spiro
C-atom occurred at 77.3–78.2 ppm serving as reliable evidence of
spiro-heterocycle formation. The imine carbon C(3) of the pyrazo-
line ring is subjected to the influence of substituents in the het(aryl)
ring and its signal is predictably shifted in the 13C NMR spectra
(142.3–150.4 ppm). Atom C(10) of the amide group is observed
almost in the same region (163.5–164.1 ppm) as the one in the
starting triazinoquinazolines.
indicating significant weakening of n-
tems of neighboring double bonds.
p conjugation with p-sys-
In Scheme 5, a possible reaction mechanism accounting for the
formation of spiro[pyrazoline-5,60(10H)-1,2,4-triazin]-50(40H)-ones
(5) is hypothesized. Triazinoquinazolines 4 contain several elec-
trophilic centers, which can serve as possible sites for hydrazine
attack. The most significant ones are the carbons of the exocyclic
C]O group and C-6 of the ring. An attempt to establish a place of
initial nucleophilic attack through isolation of possible in-
termediates failed since an interaction with 1 equiv of hydrazine
hydrate led to mixtures of starting material with the spiro-com-
pound. Thus, we stipulated that at the first stage simultaneous
addition of hydrazine at the indicated carbons occurs. Following the
successive interaction with another molecule of hydrazine, the
pyrimidine ring opens and the subsequent intermediate is pro-
duced. This, in turn, is attacked by hydrazine and spiro derivative
(5) is formed.
A supposed mechanism of the side process, which results in
formation of pyrazole-3-carboxylic acid hydrazides (6), is outlined
in Scheme 6. Some distortion of p-conjugation in NHC(O) group of
5 emerged from X-ray data and makes this site rather susceptible
for the nucleophilic attack. Therefore, we expect that the reaction of
hydrazine at the lactam carbon gives rise to eliminative triazine
ring fission in which hydrazide (6) is produced.
Whereas quasimolecular ions [MH]þ were observed in the LC–
MS of 5, the MS(EI) showed the appropriate fragmentation pattern,
thus additionally confirming their structure.
A characteristic
ꢂ
abundant peaks [MꢀH2O]þ were formed due to cascade intra-
molecular rearrangement–dehydration processes. In some cases
ꢂ
(5e,m), [MꢀH2O]þ becomes the base peak in the MS(EI).
The structure of compound 5g was established by an X-ray
diffraction study (Fig. 3). According to the crystallographic data (the
numbering is given according to the structural analysis), the five-
membered ring in compound 5g adopts an envelope conformation.
Deviation of the C(9) atom from the mean plane of the remaining
atoms of the ring is 0.36 Å. The six-membered ring adopts a twist-
boat conformation (the puckering parameters31 are S¼0.66,
q
¼53ꢁ,
J
¼29ꢁ). The C(8) and C(9) atoms deviate from the mean plane of
the remaining atoms of the ring by 0.35 Å and 0.80 Å, respectively.
The N(2) atom has an almost planar configuration (the sum of the
bond angles centered at this atom is 358ꢁ). The C(7)–N(2) bond

A.V. Karpenko et al. / Tetrahedron 65 (2009) 5964–5972
5967
N
N
B
N
O
A
B
:NH2NH2
N
O
A
R
H
N
4
N
N
NHNH2
:NH2NH2
N
O
H
N
N
:
N
O
NH2
NH
R
N
H+
OH
:NH2NH2
O
R
H
N
NHNH2
:NH2NH2
NHNH2
H
NHNH2
H
N
N
H
N
O
N
O
NH
N
NH
N
:
NH2
NH
R
NH
NH
N
N
HN
HN
N
R
H+
O
OH
R
NH2
N
NH
NH
HN
N
O
5
R
Scheme 5.
NH2
NH2
O
N
NH2
NH2NH2
H
NHNH2
H
NH2
NH
N
O
N2H4*H2O
N
O
N
N
R
N
N
H
H
N
H
N
N
H
R
R
O
H
N
H
N
H
N
N
5
6
R
N
H
NHNH2
Scheme 6.
3. Conclusions
reflection (ATR) or Bruker Tensor 27 spectrometer (KBr) and
expressed in cmꢀ1 1H and 13C NMR spectra (500 MHz for 1H and
.
We have presented the straightforward synthesis of variously
substituted derivatives of new spiro-heterocyclic system (5) start-
ing from easily available 4-hydrazinoquinazoline (1). At the first
stage 3-[2-(het)aryl-2-oxoethyl]-2H-[1,2,4]triazino[2,3-c]quinazo-
lin-2-ones (4) were obtained by the regioselective reaction of the
starting hydrazine 1 with various 2,4-diketoesters. This approach
represents a cascade cyclocondensation–Dimroth-like rearrange-
ment, and was found to be advantageous for achieving the in-
troduction of the acylmethyl moiety into the triazinoquinazoline
core. Next, the obtained triazinoquinazolines 4 were subjected to
the hydrazinolysis reaction, which leads to the novel spiro-ring
system through a tandem process. Applications of these new spi-
ro[pyrazoline-5,60(10H)-1,2,4-triazine] derivatives (5) in the syn-
thesis of nitrogen containing heterocycles will be reported in due
course.
125 MHz for 13C) were recorded on a Bruker Avance DRX-500
spectrometer with SiMe4 as internal standard in DMSO-d6 solution.
LC–MS were recorded using chromatography/mass spectrometric
system, which consists of high-performed liquid chromatograph
‘Agi1ent 1100 Series’ equipped with diode-matrix and mass-se-
lective detector ‘Agi1ent LC/MSD SL’ (atmospheric pressure chem-
ical ionizationdAPCI). Electron impact mass spectra (EI-MS) were
recorded on a Varian 1200 L instrument at 70 eV. The purity of all
obtained compounds was checked by lH NMR and LC–MS.
4-Hydrazinoquinazoline (1) was synthesized according to the
reported procedure.35 Other starting materials and solvents were
obtained from commercially available sources and used without
additional purification.
4.2. Typical procedure for the synthesis of 3-[2-(het)aryl-2-
oxoethyl]-2H-[1,2,4]triazino[2,3-c]quinazolin-2-ones (4)
4. Experimental section
4.1. General
An appropriate 2,4-diketoester (11 mmol) was added to a so-
lution of 4-hydrazinoquinazoline (1) (1.6 g, 10 mmol) in glacial
acetic acid (30 mL) and resulting mixture was refluxed for 1–8 h
or 24 h (4h). Then, it was concentrated to a volume of ca. 10 mL
under reduced pressure. The residue so obtained was treated
with EtOH (50 mL) and the mixture was kept several hours for
Melting points were determined in open capillary tubes. IR
spectra (4000–600 cmꢀ1) were recorded on a Bruker ALPHA FTIR
spectrometer using a module for measuring attenuated total

5968
A.V. Karpenko et al. / Tetrahedron 65 (2009) 5964–5972
crystallization. The precipitate was filtered and washed thor-
oughly with EtOH.
4.2.6. 3-[2-(2-Fluorophenyl)-2-oxoethyl]-2H-[1,2,4]triazino-
[2,3-c]quinazolin-2-one (4f)
Yellow solid (2.40 g, 72%), mp 240–242 ꢁC. IR (ATR, cmꢀ1): 3035,
2975, 2936, 1680, 1660, 1626, 1593, 1506, 1478, 1467, 1452, 1384,
1318, 1275, 1262, 1225, 1209, 1194, 1177, 1150, 1125, 1099, 1031, 975,
4.2.1. 3-(2-Phenyl-2-oxoethyl)-2H-[1,2,4]triazino[2,3-c]quinazolin-
2-one (4a)
Pale yellow solid (2.35 g, 74%), mp 286–288 ꢁC. IR (ATR, cmꢀ1):
3063, 1623, 1511, 1471, 1440, 1417, 1318, 1269, 1255, 1203, 1123, 902,
910, 858, 825, 812, 780, 767, 753, 691, 680, 623. 1H NMR:
d
¼4.47 (s,
2H, CH2)/6.46
(s, CH), 7.39 (m, 2H, H-30,50), 7.73 (m, 1H, H-40), 7.81
*
775, 723, 689, 637, 621. 1H NMR:
d
¼4.58 (s, 2H, CH2)/6.51
*
(s, CH),
(t, 1H, J¼7.8, H-10), 7.93 (m, 2H, H-8,60), 8.04 (t, 1H, J¼7.8, H-9), 8.57
7.54
*
/7.59 (t, 2H, J¼7.8, H-30,50), 7.72 (t, 1H, J¼7.8, H-40), 7.82 (t, 1H,
(d,1H, J¼7.8, H-11), 8.98/9.32
*
(s, 1H, H-6) (tautomeric ratio, %: CH2/
J¼7.8, H-10), 7.94 (d, 1H, J¼8.0, H-8), 8.04 (t, 1H, J¼7.8, H-9), 8.09 (d,
CH
*
¼95:5). 13C NMR
d
¼45.3 (4J¼6.6 Hz), 117.5 (2J¼22.6 Hz), 120.1,
2H, J¼8.0, H-20,60), 8.31
*
/8.58 (d, 1H, J¼8.0, H-11), 8.99/9.31
*
(s, 1H,
¼41.7,
125.2 (2J¼11.1 Hz), 125.4, 125.9, 128.3, 129.7, 131.0, 136.1, 136.2
(3J¼9.3 Hz), 144.3, 144.4, 152.4, 154.8, 160.5, 161.5 (1J¼254.8 Hz),
192.9. LC–MS, m/z¼335 (MHþ). Anal. Calcd for C18H11FN4O2: C,
64.67; H, 3.32; N, 16.76. Found: C, 64.55; H, 3.28; N, 16.84.
H-6) (tautomeric ratio, %: CH2/CH
*
¼97.5:2.5). 13C NMR
d
120.1, 125.9, 128.3, 128.9 (2C), 129.3 (2C), 129.6, 134.3, 136.0, 136.5,
144.3, 144.4, 152.3, 155.4, 160.6, 195.4. LC–MS, m/z¼317 (MHþ).
Anal. Calcd for C18H12N4O2: C, 68.35; H, 3.82; N, 17.71. Found: C,
68.41; H, 3.75; N, 17.79.
4.2.7. 3-[2-(4-Fluorophenyl)-2-oxoethyl]-2H-[1,2,4]triazino-
[2,3-c]quinazolin-2-one (4g)
4.2.2. 3-[2-(4-Methylphenyl)-2-oxoethyl]-2H-[1,2,4]triazino-
[2,3-c]quinazolin-2-one (4b)
Yellow solid (1.90 g, 57%), mp 224–226 ꢁC (dioxane–H2O). IR
(ATR, cmꢀ1): 3061, 3036, 1682, 1652, 1627, 1595, 1508, 1469, 1410,
1390, 1369, 1343, 1327, 1279, 1263, 1225, 1204, 1163, 1130, 1102,
1035, 1013, 991, 980, 912, 862, 839, 817, 776, 776, 688, 625. 1H NMR:
Yellow solid (1.70 g, 51%), mp 236–238 ꢁC. IR (ATR, cmꢀ1): 3065,
3038, 2988, 2923, 1681, 1663, 1628, 1595, 1510, 1464, 1407, 1319,
1305, 1276, 1260, 1200, 1183, 1121, 1101, 979, 912, 823, 797, 787, 688,
d
¼4.58 (s, 2H, CH2), 7.42 (t, 2H, J¼8.7, H-20,60), 7.82 (t, 1H, J¼7.8, H-
624. 1H NMR:
d
¼2.41 (s, 3H, CH3), 4.54 (s, 2H, CH2), 7.39, 7.98 (d, 2H,
10), 7.94 (d, 1H, J¼8.0, H-8), 8.05 (t, 1H, J¼7.8, H-9), 8.18 (dd, 2H,
J¼8.0, HPhenyl), 7.82 (t, 1H, J¼7.8, H-10), 7.94 (d, 1H, J¼8.0, H-8), 8.05
3J¼8.7, 3JH–F¼3.1, H-30,50), 8.57 (d, 1H, J¼8.0, H-11), 8.94 (s, 1H, H-6).
(t, 1H, J¼7.8, H-9), 8.57 (d, 1H, J¼8.0, H-11), 8.99 (s, 1H, H-6). 13C
13C NMR
d
¼41.7, 116.4 (2C, JCF¼22.1 Hz), 120.2, 125.9, 128.3, 129.7,
2
NMR
d
¼21.7, 41.6, 120.2, 125.9, 128.3, 129.0 (2C), 129.6, 129.9 (2C),
132.0 (2C, 3JCF¼9.7 Hz), 133.3, 136.1, 144.3, 144.4, 152.4, 155.3, 160.1
ꢂ
134.1, 136.0, 144.3, 144.4, 144.8, 152.3, 155.5, 160.6, 194.9. LC–MS,
m/z¼331 (MHþ). Anal. Calcd for C19H14N4O2: C, 69.08; H, 4.27; N,
16.96. Found: C, 69.19; H, 4.21; N, 16.84.
(1JCF¼254.8 Hz),160.6, 194.1. EI-MS, m/z (Irel, %)¼335 (4.1), 334 (Mþ
,
21.8), 238 (6.2), 197 (3.7), 172 (16.6), 171 (100.0), 170 (6.4), 163 (3.4),
155 (3.2), 144 (4.5), 135 (5.6), 129 (35.7), 123 (9.7), 103 (5.5), 102
(5.6), 95 (13.3), 75 (18.4), 70 (6.1), 63 (3.8), 53 (3.1), 50 (3.1). LC–MS,
m/z¼335 (MHþ). Anal. Calcd for C18H11FN4O2: C, 64.67; H, 3.32; N,
16.76. Found: C, 64.52; H, 3.26; N, 16.85.
4.2.3. 3-[2-(4-Methoxyphenyl)-2-oxoethyl]-2H-[1,2,4]triazino-
[2,3-c]quinazolin-2-one (4c)
Yellow solid (2.48 g, 71%), mp 276–278 ꢁC. IR (ATR, cmꢀ1): 3071,
2977, 2901, 1662, 1620, 1592, 1572, 1517, 1470, 1457, 1439, 1417, 1397,
1385, 1324, 1314,1272, 1249, 1202, 1182, 1170,1126, 1110,1023,1007,
4.2.8. 3-[2-(2,5-Difluorophenyl)-2-oxoethyl]-2H-[1,2,4]-
triazino[2,3-c]quinazolin-2-one (4h)
977, 910, 838, 802, 775, 751, 699, 687, 668, 622. 1H NMR:
d
¼3.88 (s,
Pink solid (2.80 g, 79%), mp 260–262 ꢁC. IR (ATR, cmꢀ1): 3035,
2988, 2929, 1687, 1660, 1629, 1602, 1512, 1486, 1468, 1420, 1385,
1327, 1276, 1261, 1218, 1193, 1177, 1146, 1125, 1105, 1033, 1025, 971,
3H, OCH3), 4.52 (s, 2H, CH2), 7.10 (d, 2H, J¼8.1, H-30,50), 7.82 (t, 1H,
J¼7.8, H-10), 7.94 (d, 1H, J¼8.0, H-8), 8.05 (m, 3H, H-9,20,60), 8.58 (d,
1H, J¼8.0, H-11), 8.98 (s, 1H, H-6). 13C NMR
d
¼41.4, 56.1, 114.5 (2C),
957, 911, 894, 778, 760, 687, 625, 605. 1H NMR:
d
¼4.49 (s, 2H, CH2),
120.2, 125.9, 128.3, 129.5, 129.6, 131.3 (2C), 136.1, 144.3, 144.4, 152.3,
7.49, 7.62, 7.73 (m, 1H, H-30,40,60), 7.82 (t, 1H, J¼7.8, H-10), 7.94 (d,
1H, J¼8.0, H-8), 8.05 (t, 1H, J¼7.8, H-9), 8.58 (d, 1H, J¼8.0, H-11),
8.98 (s, 1H, H-6). LC–MS, m/z¼353 (MHþ). Anal. Calcd for
C18H10F2N4O2: C, 61.37; H, 2.86; N,15.90. Found: C, 61.30; H, 2.92; N,
15.77.
ꢂ
155.6, 160.6, 164.1, 193.7. EI-MS, m/z (Irel, %)¼346 (Mþ , 13.8), 175
(5.2),172 (6.1),171 (40.4),136 (10.9),135 (100.0),129 (17.8),102 (5.2),
92 (5.2). LC–MS, m/z¼348, 347 (MHþ). Anal. Calcd for C19H14N4O3: C,
65.89; H, 4.07; N, 16.18. Found: C, 65.95; H, 3.92; N, 16.31.
4.2.4. 3-[2-(3-Nitrophenyl)-2-oxoethyl]-2H-[1,2,4]triazino-
[2,3-c]quinazolin-2-one (4d)
Dark red solid (2.25 g, 62%), mp 264–266 ꢁC (DMF–H2O). IR
(ATR, cmꢀ1): 3034, 2987, 2902, 1652, 1605, 1563, 1522, 1501, 1479,
1463,1395,1347,1323,1285,1256,1217,1200,1158,1129,1107,1066,
1033, 1011, 962, 911, 887, 831, 809, 786, 742, 697, 687, 651. 1H NMR:
4.2.9. 3-[2-(2-Chlorophenyl)-2-oxoethyl]-2H-[1,2,4]triazino-
[2,3-c]quinazolin-2-one (4i)
Pink solid (2.23 g, 64%), mp 237–239 ꢁC. IR (ATR, cmꢀ1): 3034,
2976, 2925, 1688, 1661, 1625, 1597, 1585, 1508, 1466, 1427, 1383,
1322, 1302, 1275, 1261, 1186, 1175, 1125, 1066, 1042, 1031, 976, 910,
783, 767, 757, 723, 689, 669, 623. 1H NMR:
d
¼4.50 (s, 2H, CH2)/5.97
*
d
¼4.68 (s, 2H, CH2), 7.82 (t, 1H, J¼7.8, H-10), 7.90 (t, 2H, J¼7.8, H-50),
(s, CH), 7.47
/7.54 (m, 1H, H-30), 7.61 (m, 2H, H-40,50), 7.82 (t, 1H,
*
7.94 (d, 1H, J¼8.0, H-8), 8.05 (t, 1H, J¼7.8, H-9), 8.51 (d, 2H, J¼7.8, H-
40,60), 8.59 (d, 1H, J¼7.9, H-11), 8.76 (s, 1H, H-20), 8.94 (s, 1H, H-6).
LC–MS, m/z¼363, 362 (MHþ). Anal. Calcd for C18H11N5O4: C, 59.84;
H, 3.07; N, 19.38. Found: C, 59.94; H, 2.95; N, 19.24.
J¼7.8, H-10), 7.95 (m, 2H, H-8,60), 8.05 (t, 1H, J¼7.8, H-9), 8.57 (d, 1H,
J¼8.0, H-11), 9.01/9.23
*
(s, 1H, H-6) (tautomeric ratio, %: CH2/
CH
*
¼90:10). 13C NMR
¼45.1, 120.1, 126.0, 128.0, 128.3, 129.7, 130.7,
d
130.8, 131.2, 133.5, 136.1, 137.7, 144.3, 144.4, 152.4, 154.6, 160.5,
196.6. LC–MS, m/z¼354, 353, 351 (MHþ). Anal. Calcd for
C18H11ClN4O2: C, 61.64; H, 3.16; N, 15.97. Found: C, 61.55; H, 3.11; N,
15.88.
4.2.5. 3-[2-(4-Nitrophenyl)-2-oxoethyl]-2H-[1,2,4]triazino-
[2,3-c]quinazolin-2-one (4e)
Black solid (2.30 g, 64%), mp >300 ꢁC. IR (ATR, cmꢀ1): 3064,
1665, 1615, 1604, 1594, 1564, 1516, 1500, 1465, 1425, 1389, 1338,
1318, 1294, 1256, 1216, 1194, 1184, 1159, 1129, 1108, 1068, 1030, 1015,
979, 937, 914, 900, 856, 832, 809, 784, 754, 729, 710, 690, 670, 622.
4.2.10. 3-[2-(4-Chlorophenyl)-2-oxoethyl]-2H-[1,2,4]triazino-
[2,3-c]quinazolin-2-one (4j)
Yellow solid (2.65 g, 75%), mp 256–258 ꢁC. IR (ATR, cmꢀ1):
3095–2842, 1689, 1660, 1618, 1604, 1587, 1512, 1468, 1398, 1386,
1368, 1324, 1271, 1254, 1203, 1178, 1125, 1089, 1026, 1005, 977, 956,
ꢂ
EI-MS: m/z (I, %)¼361 (Mþ , 13.8), 172 (14.9), 171 (100.0), 150 (10.9),
129 (23.9), 104 (8.8), 102 (10.5). Anal. Calcd for C18H11N5O4: C,
59.84; H, 3.07; N, 19.38. Found: C, 59.92; H, 2.96; N, 19.24.
909, 836, 820, 769, 728, 686, 659, 622. 1H NMR:
d
¼4.58 (s, 2H, CH2)/

A.V. Karpenko et al. / Tetrahedron 65 (2009) 5964–5972
5969
6.50
*
(s, CH), 7.82 (td, 1H, 3J¼8.0, 4J¼1.5, H-10), 7.93 (d, 2H, J¼8.0, H-
7.66 (d, 1H, J¼3.4, H-30), 7.81 (t, 1H, J¼7.8, H-10), 7.94 (d, 1H, J¼7.9,
H-8), 8.05 (m, 2H, H-9,50), 8.57 (d, 1H, J¼7.9, H-11), 8.99 (s, 1H, H-6).
8), 8.05 (td, 1H, 3J¼8.0, 4J¼1.5, H-9), 8.10, 7.57
*
/7.66 (d, 2H, J¼8.0,
HPhenyl), 8.57 (dd, 1H, 3J¼7.9, 4J¼1.5, H-11), 8.99/9.30
*
(s, 1H, H-6)
13C NMR
d¼41.3, 113.3, 120.1, 120.2, 125.9, 128.3, 129.6, 136.1, 144.3,
(tautomeric ratio, %: CH2/CH
*
¼95:5). 13C NMR
d¼41.7, 120.1, 125.9,
144.4, 148.8, 151.8, 152.4, 154.6, 160.5, 183.0. LC–MS, m/z¼307
(MHþ). Anal. Calcd for C16H10N4O3: C, 62.75; H, 3.29; N, 18.29.
Found: C, 62.88; H, 3.41; N, 18.25.
128.3, 129.5 (2C), 129.6, 130.8 (2C), 135.2, 136.0, 139.2, 144.3, 144.4,
152.3, 155.2, 160.6, 194.5. EI-MS, m/z (Irel, %)¼493 (2.8), 492 (3.6),
491 (13.2), 490 (5.6), 489 ([4-ClC6H4C^OþM]þ, 21.3), 464 (2.2), 463
(7.1), 461 ([4-ClC6H4þM]þ, 10.5), 452 (3.9), 426 (3.1), 425 (4.4), 354
4.2.15. 3-(2-Benzo[b]furan-2-yl-2-oxoethyl)-2H-[1,2,4]triazino-
[2,3-c]quinazolin-2-one (4o)
Yellow solid (1.75 g, 49%), mp 283–285 ꢁC (DMF–H2O). IR (ATR,
cmꢀ1): 3057, 3036, 2929, 1686, 1662, 1629, 1596, 1561, 1509, 1468,
1332, 1324, 1277, 1262, 1155, 1133, 912, 881, 823, 782, 751, 744, 689,
ꢂ
ꢂ
(10.5), 353 (44.7), 352 ([Mþ2]þ , 54.5), 351 (75.9), 350 (Mþ , 78.8),
333 (4.8), 327 (3.0), 326 (3.1), 325 (4.4), 324 (4.6), 322 (5.0), 239
(8.1), 213 (3.5), 212 (3.0), 211 (3.4), 197 (3.8), 181 (6.6), 179 (14.8),
172 (27.7), 171 (100.0), 143 (3.0), 141 (9.0), 139 (27.7), 129 (23.0), 111
(8.8), 102 (3.5), 76 (3.9), 75 (5.7). LC–MS, m/z¼353 ([MHþ2]þ), 351
(MHþ). Anal. Calcd for C18H11ClN4O2: C, 61.64; H, 3.16; N, 15.97.
Found: C, 61.56; H, 3.07; N, 15.90.
640. 1H NMR:
d
¼4.53 (s, 2H, CH2)/6.53
*
(s, CH), 7.33
*
/7.41, 7.48
*
/7.59
/7.89
(t, 1H, J¼8.0, H-50,60), 7.82 (t, 1H, J¼7.8, H-10), 7.71
*
/7.75, 7.84
*
(d,1H, J¼8.0, H-40,70), 7.94 (d,1H, J¼7.9, H-8), 7.97
*
/8.05 (t,1H, J¼7.8,
H-9), 8.12 (s, 1H, H-30), 8.58 (d, 1H, J¼7.9, H-11), 9.00/9.25
*
(s, 1H, H-
4.2.11. 3-[2-(3-Bromophenyl)-2-oxoethyl]-2H-[1,2,4]triazino-
[2,3-c]quinazolin-2-one (4k)
6) (tautomeric ratio, %: CH2/CH
*
¼85:15). LC–MS, m/z¼358, 357
(MHþ). Anal. Calcd for C20H12N4O3: C, 67.41; H, 3.39; N, 15.72.
Found: C, 67.49; H, 3.48; N, 15.62.
Pink solid (2.83 g, 72%), mp >300 ꢁC. IR (ATR, cmꢀ1): 3047, 2988,
2925, 1693, 1663, 1625, 1594, 1562, 1506, 1467, 1407, 1392, 1323,
1277, 1261, 1209, 1177, 1156, 1127, 1101, 1091, 1067, 1033, 1012, 979,
964, 911, 872, 853, 819, 791, 781, 724, 697, 688, 677, 664, 642, 624.
4.3. Typical procedure for the synthesis of 30-(2-amino-
phenyl)-3-(het)aryl-spiro[pyrazoline-5,60(10H)-1,2,4-triazin]-
50(40H)-ones (5)
1H NMR:
d
¼4.60 (s, 2H, CH2), 7.56 (t, 1H, J¼8.0, H-50), 7.82 (t, 1H,
J¼8.0, H-10), 7.92 (d, 2H, J¼7.8, H-60), 7.94 (d,1H, J¼8.0, H-8), 8.04 (t,
1H, J¼8.0, H-9), 8.09 (d, 1H, J¼8.1, H-40), 8.23 (s, 1H, H-20), 8.58 (d,
1H, J¼8.0, H-11), 8.98 (s, 1H, H-6). LC–MS, m/z¼397 ([MHþ2]þ),
396, 395 (MHþ). Anal. Calcd for C18H11BrN4O2: C, 54.70; H, 2.81; N,
14.18. Found: C, 54.81; H, 2.93; N, 14.10.
To an appropriate triazinoquinazoline 4 (10 mmol) in i-PrOH
ꢂ
(15 mL) was added N2H4 H2O (2.0 mL, 40 mmol) and resulting
mixture was refluxed for 6–8 h. On cooling, the precipitate was
filtered and washed with i-PrOH.
Compounds 4i,n under these reaction conditions afforded 6a
(1.57 g, 66%, i-propanol–H2O) and 6b (1.22 g, 63%) correspondingly.
4.2.12. 3-[2-(4-Bromophenyl)-2-oxoethyl]-2H-[1,2,4]triazino-
[2,3-c]quinazolin-2-one (4l)
Pink solid (2.75 g, 70%), mp >300 ꢁC (DMF–H2O). IR (ATR,
cmꢀ1): 3034, 2987, 2927, 2902, 1683, 1654, 1627, 1596, 1584, 1508,
1468, 1391, 1370,1342, 1327, 1280, 1261, 1204,1179, 1158, 1128, 1103,
1070, 1034, 1018, 1007, 989, 912, 857, 831, 820, 806, 791, 776, 753,
4.3.1. 30-(2-Aminophenyl)-3-phenyl-spiro[pyrazoline-5,60(10H)-
1,2,4-triazin]-50(40H)-one (5a)
White solid (2.80 g, 87%), mp 236–238 ꢁC (dioxane–H2O). IR
(ATR, cmꢀ1): 3374, 3260, 3221, 1690, 1616, 1568, 1526, 1494, 1445,
1350,1300,1262,1130, 1063, 1008, 998, 971, 863, 745, 685, 660, 640,
719, 707, 688, 660, 625. 1H NMR:
d
¼4.57 (s, 2H, CH2), 7.83 (t, 1H,
J¼7.8, H-10), 7.95 (d, 1H, J¼8.0, H-8), 7.81, 8.02 (d, 2H, J¼8.2, H-
611. 1H NMR:
d
¼2.95, 3.84 (d, 1H, J¼17.6, CH2), 6.32 (br s, 2H, NH2),
20,30,50,60), 8.05 (t, 1H, J¼7.8, H-9), 8.58 (d, 1H, J¼8.0, H-11), 8.99 (s,
6.55 (t, 1H, J¼7.6, H-50), 6.71 (d, 1H, J¼7.8, H-30), 7.05 (t, 1H, J¼7.8, H-
40), 7.35 (d, 1H, J¼7.6, H-60), 7.40 (t, 3H, J¼7.6, H-3,4,5), 7.65 (d, 2H,
J¼7.4, H-2,6), 8.22, 8.14 (s, 1H, NH), 10.84 (s, 1H, NH–CO). 13C NMR
ꢂ
ꢂ
1H, H-6). EI-MS, m/z (Irel, %)¼396 ([Mþ2]þ , 8.2), 394 (Mþ , 8.7), 324
(5.8), 185 (29.6), 183 (38.4), 172 (16.5), 171 (100.0), 157 (10.3), 155
(10.3), 129 (29.0), 102 (8.9). LC–MS, m/z¼397 ([MHþ2]þ), 396, 395
(MHþ). Anal. Calcd for C18H11BrN4O2: C, 54.70; H, 2.81; N, 14.18.
Found: C, 54.83; H, 2.90; N, 14.07.
d
¼39.0, 77.7, 113.2, 115.3, 116.0, 125.6, 125.9, 127.9, 128.8, 129.0,
129.4, 129.9, 133.3, 140.3, 147.6, 148.1, 164.0. LC–MS, m/z¼322, 321
(MHþ). Anal. Calcd for C17H16N6O: C, 63.74; H, 5.03; N, 26.23.
Found: C, 63.88; H, 5.12; N, 26.11.
4.2.13. 3-[2-Thiophen-2-yl-2-oxoethyl]-2H-[1,2,4]triazino-
[2,3-c]quinazolin-2-one (4m)
4.3.2. 30-(2-Aminophenyl)-3-(4-methylphenyl)-spiro[pyrazoline-
5,60(10H)-1,2,4-triazin]-50(40H)-one (5b)
Yellow solid (2.35 g, 73%), mp 256–258 ꢁC. IR (ATR, cmꢀ1): 3087,
2973, 2936, 2904, 1655, 1620, 1606, 1586, 1506, 1466, 1405, 1385,
1361, 1325, 1240, 1201, 1174, 1123, 1099, 1082, 1047, 1026, 1004, 976,
946, 907, 860, 774, 741, 699, 687, 669, 661, 644, 623. 1H NMR:
White solid (2.30 g, 69%), mp 206–208 ꢁC (dioxane–H2O). IR
(ATR, cmꢀ1): 3382, 3215, 1689, 1613, 1595, 1503, 1436, 1363, 1348,
1313, 1233, 1216, 1131, 1076, 1039, 1009, 972, 932, 884, 864, 813,
d
¼4.52 (s, 2H, CH2), 7.31 (t, 1H, J¼4.0, H-40), 7.79 (t, 1H, J¼7.8, H-10),
788, 753, 741, 690, 666, 647, 614. 1H NMR:
d
¼2.92, 3.80 (d, 1H,
7.91 (d, 1H, J¼7.9, H-8), 8.03 (t, 1H, J¼8.0, H-9), 8.09 (d, 1H, J¼4.9, H-
J¼17.6, CH2), 6.32 (br s, 2H, NH2), 6.54 (t, 1H, J¼7.6, H-50), 6.70 (d,
1H, J¼8.1, H-30), 7.04 (t, 1H, J¼7.8, H-40), 7.20 (d, 2H, J¼8.1, H-3,5),
7.41 (d, 1H, J¼7.8, H-60), 7.54 (d, 2H, J¼8.1, H-2,6), 8.13, 8.10 (s, 1H,
30), 8.18 (d, 1H, J¼3.2, H-50), 8.55 (d, 1H, J¼8.0, H-11), 8.97 (s, 1H, H-
6). 13C NMR
d
¼42.0, 120.1, 125.9, 128.3, 129.4, 129.6, 135.2, 136.1,
136.2, 143.4, 144.3, 144.4, 152.3, 154.7, 160.6, 188.0. EI-MS, m/z
NH), 10.82 (s, 1H, NH–CO). 13C NMR
116.0, 125.8 (2C), 127.8, 129.6 (2C), 129.8, 130.6, 138.2, 140.2, 147.6,
148.2, 164.0. LC–MS, m/z¼335 (MHþ). Anal. Calcd for C18H18N6O: C,
64.66; H, 5.43; N, 25.13. Found: C, 64.77; H, 5.51; N, 25.05.
d
¼21.4, 39.1, 77.6, 113.1, 115.2,
ꢂ
ꢂ
(Irel, %)¼325 (5.2), 324 ([Mþ2]þ , 13.4), 322 (Mþ , 34.5), 321
(100.0), 170 (13.1), 168 (6.3). LC–MS, m/z¼323 (MHþ). Anal. Calcd
for C16H10N4O2S: C, 59.62; H, 3.13; N, 17.38. Found: C, 59.70; H,
3.21; N, 17.29.
4.3.3. 30-(2-Aminophenyl)-3-(4-methoxyphenyl)-spiro[pyrazoline-
5,60(10H)-1,2,4-triazin]-50(40H)-one (5c)
4.2.14. 3-(2-Furan-2-yl-2-oxoethyl)-2H-[1,2,4]triazino-
[2,3-c]quinazolin-2-one (4n)
White solid (3.20 g, 91%), mp 214–216 ꢁC (dioxane–H2O). IR
(KBr, cmꢀ1): 3470, 3299, 3252, 1703, 1620, 1606, 1589, 1516, 1499,
1451, 1417, 1402, 1351, 1260, 1179, 1130, 1047, 1029, 979, 903, 867,
Yellow solid (2.40 g, 78%), mp 266–268 ꢁC. IR (ATR, cmꢀ1): 3132,
3108, 3040, 2921, 2852, 1679, 1658, 1622, 1589, 1507, 1460, 1387,
1328, 1266, 1212, 1151, 1126, 1079, 1037, 1010, 986, 909, 881, 797,
835, 781, 758, 734, 661, 604. 1H NMR:
d
¼2.91, 3.80 (d, 1H, J¼17.6,
771, 688, 650, 620. 1H NMR:
d
¼4.37 (s, 2H, CH2), 6.79 (m, 1H, H-40),
CH2), 6.32 (br s, 2H, NH2), 6.54 (t, 1H, J¼7.6, H-50), 6.70 (d, 1H, J¼8.1,

5970
A.V. Karpenko et al. / Tetrahedron 65 (2009) 5964–5972
H-30), 6.95 (d, 2H, J¼8.5, H-3,5), 7.04 (t, 1H, J¼7.8, H-40), 7.41 (d, 1H,
J¼7.8, H-60), 7.59 (d, 2H, J¼8.5, H-2,6), 7.97, 8.11 (s, 1H, NH), 10.81 (s,
3,5), 7.41 (d, 1H, J¼7.8, H-60), 7.68 (m, 2H, H-2,6), 8.06, 8.11 (s, 1H,
NH), 10.74 (s, 1H, NH–CO). 13C NMR
d¼39.1, 77.8, 113.1, 115.3, 116.0
1H, NH–CO). 13C NMR
d¼39.3, 55.7, 77.6, 113.2, 114.5 (2C), 115.3,
(2C, 2JCF¼21.7 Hz), 116.0, 127.8, 127.9 (2C, 3JCF¼8.4 Hz), 129.9, 130.0,
140.3, 147.3, 147.6, 162.5 (1JCF¼245.5 Hz), 163.9. LC–MS, m/z¼338
116.0, 126.0, 127.4 (2C), 127.8, 129.8, 140.2, 147.6, 148.3, 160.0, 164.1.
ꢂ
ꢂ
LC–MS, m/z¼351 (MHþ). EI-MS, m/z (Irel, %)¼351 (13.7), 350 (Mþ
,
(Mþ), 337. EI-MS, m/z (Irel, %)¼339 (10.1), 338 (Mþ , 100.0), 321
ꢂ
ꢂ
100.0), 344 (9.8), 334 (16.4), 333 (26.8), 332 ([MꢀH2O]þ , 71.1), 331
(27.6), 321 (10.7), 319 (34.8), 200 (22.9), 198 (24.9), 197 (5.9), 159
(16.3). Anal. Calcd for C18H18N6O2: C, 61.70; H, 5.18; N, 23.99. Found:
C, 61.79; H, 5.25; N, 23.85.
(12.4), 320 ([MꢀH2O]þ , 42.4), 188 (25.1), 172 (15.9), 71 (9.9). Anal.
Calcd for C17H15FN6O: C, 60.35; H, 4.47; N, 24.84. Found: C, 60.49; H,
4.58; N, 24.72.
4.3.8. 30-(2-Aminophenyl)-3-(2,5-difluorophenyl)-spiro-
[pyrazoline-5,60(10H)-1,2,4-triazin]-50(40H)-one (5h)
Beige solid (1.92 g, 54%), mp 212–214 ꢁC (dioxane–H2O). IR (ATR,
cmꢀ1):3471, 3369,3253,1694,1611,1591,1566,1492,1444,1363,1336,
1290,1245,1171,1045,1024, 968, 908, 891, 812, 788, 748, 698, 664. 1H
4.3.4. 30-(2-Aminophenyl)-3-(3-nitrophenyl)-spiro[pyrazoline-
5,60(10H)-1,2,4-triazin]-50(40H)-one (5d)
Yellow solid (2.90 g, 79%), mp 216–218 ꢁC (dioxane–H2O). IR
(ATR, cmꢀ1): 3466, 3363, 3267, 3206, 1698, 1613, 1592, 1529, 1502,
1450, 1349, 1292, 1021, 970, 915, 884, 856, 833, 791, 760, 751, 736,
NMR:
d
¼2.99, 3.89 (d,1H, J¼17.6, CH2), 6.28 (br s, 2H, NH2), 6.54 (t,1H,
694, 670. 1H NMR:
d
¼3.02, 3.90 (d, 1H, J¼17.6, CH2), 6.30 (br s, 2H,
J¼7.6, H-50), 6.70 (d, 1H, J¼8.1, H-30), 7.05 (t, 1H, J¼7.8, H-40), 7.21 (m,
NH2), 6.55 (t, 1H, J¼7.6, H-50), 6.71 (d, 1H, J¼8.1, H-30), 7.05 (t, 1H,
J¼7.8, H-40), 7.42 (d, 1H, J¼7.8, H-60), 7.69 (t, 1H, J¼7.8, H-5), 8.03 (d,
1H, J¼7.8, H-6), 8.15 (d, 1H, J¼8.1, H-4), 8.18 (s, 1H, NH), 8.39 (s, 1H,
1H, H-3), 7.31 (m,1H, H-5), 7.40 (d,1H, J¼7.8, H-60), 7.51 (m, 1H, H-6),
8.15,8.60(s,1H, NH),10.85(s,1H, NH–CO).13CNMR
d¼39.5, 77.7,113.0,
113.8 (2JCF¼26.1 Hz, JCF¼4.4 Hz), 115.2, 116.0, 116.8 (2JCF¼24.3 Hz,
3
H-2), 8.64 (s, 1H, NH), 10.88 (br s, 1H, NH–CO). 13C NMR
d
¼38.6,
3JCF¼9.3 Hz), 118.6 (2JCF¼24.8 Hz, JCF¼9.3 Hz), 122.7, 127.9, 129.9,
3
78.2, 113.1, 115.3, 116.0, 119.6, 122.9, 127.9, 129.9, 130.7, 131.9, 135.1,
140.4, 145.8, 147.6, 148.6, 163.6. LC–MS, m/z¼365 (Mþ), 364. Anal.
Calcd for C17H15N7O3: C, 55.89; H, 4.14; N, 26.84. Found: C, 55.98; H,
4.20; N, 26.75.
140.3,142.3,147.6,155.9 (1JCF¼245.9 Hz),158.6 (1JCF¼239.7 Hz),163.6.
LC–MS, m/z¼357 (MHþ). Anal. Calcd for C17H14F2N6O: C, 57.30; H,
3.96; N, 23.58. Found: C, 57.41; H, 4.08; N, 23.48.
4.3.9. 30-(2-Aminophenyl)-3-(2-chlorophenyl)-spiro[pyrazoline-
5,60(10H)-1,2,4-triazin]-50(40H)-one (5i)
4.3.5. 30-(2-Aminophenyl)-3-(4-nitrophenyl)-spiro[pyrazoline-
5,60(10H)-1,2,4-triazin]-50(40H)-one (5e)
Orange solid (2.60 g, 71%), mp 228–230 ꢁC (dioxane–H2O). IR
(KBr, cmꢀ1): 3464, 3352, 3288, 1711, 1615, 1565, 1507, 1452, 1407,
1370,1338,1293, 1167, 1109, 1042, 1009, 974, 908, 851, 832, 767, 750.
To a suspension of 4i (3.51 g, 10 mmol) in i-PrOH (15 mL) was
ꢂ
added N2H4 H2O (1.5 mL, 30 mmol) and resulting mixture was
refluxed for 0.5 h. On cooling, the precipitate was filtered, washed
with i-PrOH and air-dried to give yellow solid (2.74 g, 77%), mp
186–188 ꢁC (dioxane–H2O). IR (ATR, cmꢀ1): 3451, 3338, 3080, 2923,
1693, 1629, 1607, 1571, 1501, 1456, 1429, 1401, 1365, 1345, 1320,
1291, 1269, 1155, 1073, 1032, 1005, 967, 902, 871, 826, 750, 673, 650,
1H NMR:
d
¼2.99, 3.88 (d, 1H, J¼17.6, CH2), 6.31 (br s, 2H, NH2), 6.54
(t, 1H, J¼7.6, H-50), 6.70 (d, 1H, J¼8.1, H-30), 7.05 (t, 1H, J¼7.8, H-40),
7.41 (d, 1H, J¼7.8, H-60), 7.86 (d, 2H, J¼8.8, H-3,5), 8.23 (m, 3H, NH,
H-2,6), 8.98 (s, 1H, NH), 10.92 (s, 1H, NH–CO). 13C NMR
d¼38.3, 78.2,
637. 1H NMR:
d
¼3.07, 4.04 (d, 1H, J¼17.6, CH2), 6.32 (br s, 2H, NH2),
113.0, 115.3, 116.1, 124.4 (2C), 126.3 (2C), 127.9, 129.9, 139.8, 140.4,
6.54 (t, 1H, J¼7.6, H-50), 6.71 (d, 1H, J¼7.8, H-30), 7.05 (t, 1H, J¼7.8, H-
40), 7.35 (m, 2H, H-4,5), 7.41 (d, 1H, J¼7.8, H-60), 7.48 (dd, 1H, 3J¼7.2,
4J¼2.0, H-3), 7.74 (dd, 3J¼7.2, 4J¼2.0, H-6), 8.19, 8.46 (s, 1H, NH),
145.3, 146.8, 147.6, 163.4. LC–MS, m/z¼364 ([MꢀH]þ). EI-MS, m/z
ꢂ
(Irel, %)¼366 (21.0), 365 (Mþ , 67.1), 349 (20.0), 348 (62.0), 347
ꢂ
([MꢀH2O]þ , 100.0), 337 (27.1), 334 (15.4), 306 (14.2), 301 (13.7),
10.87 (s, 1H, NH–CO). 13C NMR
127.9, 129.9, 130.0, 130.4, 131.1, 131.2, 132.0, 140.3, 146.2, 147.6, 163.7.
LC–MS, m/z¼357, 355 (MHþ). Anal. Calcd for C17H15ClN6O: C, 57.55;
H, 4.26; N, 23.69. Found: C, 57.69; H, 4.31; N, 23.55.
d¼41.5, 77.9, 113.1, 115.3, 116.0, 127.6,
247 (16.0), 217 (14.0), 216 (73.3), 205 (10.0), 176 (11.9), 171 (12.9),
170 (12.2), 162 (18.5), 161 (27.1), 135 (14.6), 133 (17.3), 129 (10.5),
120 (10.3),119 (66.7),118 (84.0),105 (11.0),104 (15.6),103 (11.6),102
(13.2), 92 (19.9), 91 (24.0), 90 (10.9). Anal. Calcd for C17H15N7O3: C,
55.89; H, 4.14; N, 26.84. Found: C, 55.96; H, 4.21; N, 26.71.
4.3.10. 30-(2-Aminophenyl)-3-(4-chlorophenyl)-spiro[pyrazoline-
5,60(10H)-1,2,4-triazin]-50(40H)-one (5j)
White solid (3.04 g, 86%), mp 206–208 ꢁC (dioxane–H2O). IR
(KBr, cmꢀ1): 3386, 3303, 3256, 3214, 1690, 1620, 1595, 1494, 1450,
1402, 1352, 1312, 1093, 1038, 1010, 933, 865, 758, 693, 670, 647, 615,
4.3.6. 30-(2-Aminophenyl)-3-(2-fluorophenyl)-spiro[pyrazoline-
5,60(10H)-1,2,4-triazin]-50(40H)-one (5f)
White solid (2.84 g, 84%), mp 190–192 ꢁC (dioxane–H2O). IR (ATR,
cmꢀ1): 3373, 3273, 3228, 1691, 1613, 1591, 1488, 1448, 1429, 1340,
1294, 1218, 1130, 1098, 1008, 971, 864, 814, 743, 688, 651. 1H NMR:
538. 1H NMR:
d
¼2.93, 3.82 (d, 1H, J¼17.6, CH2), 6.32 (br s, 2H, NH2),
6.54 (t, 1H, J¼7.8, H-50), 6.70 (d, 1H, J¼8.1, H-30), 7.05 (t, 1H, J¼7.8, H-
40), 7.41 (d, 1H, J¼8.1, H-60), 7.45 (d, 2H, J¼8.5, H-3,5), 7.66 (d, 2H,
J¼8.5, H-2,6), 8.16, 8.36 (s, 1H, NH), 10.86 (s, 1H, NH–CO). 13C NMR
d
¼2.99, 3.90 (d,1H, J¼17.6, CH2), 6.31 (br s, 2H, NH2), 6.54 (t,1H, J¼7.6,
H-50), 6.70 (d,1H, J¼8.1, H-30), 7.05 (t, 1H, J¼7.8, H-40), 7.25 (m, 2H, H-
3,5), 7.37 (t, 1H, J¼7.1, H-4), 7.41 (d, 1H, J¼7.8, H-60), 7.78 (t, 1H, J¼7.8,
d
¼38.8, 77.8, 113.1, 115.2, 116.0, 127.5 (2C), 127.8, 129.1 (2C), 129.9,
H-6), 8.16, 8.41 (s, 1H, NH), 10.85 (s, 1H, NH–CO). 13C NMR
d¼40.9,
132.2, 133.1, 140.3, 146.9, 147.6, 163.8. EI-MS, m/z (Irel, %)¼358 (7.6),
ꢂ ꢂ
77.5, 113.1, 115.3, 116.0, 116.8 (2JCF¼22.1 Hz),121.1 (2JCF¼11.5 Hz), 125.1
(4JCF¼2.7 Hz), 127.9, 128.5 (3JCF¼4.0 Hz), 129.9, 130.5 (3JCF¼8.4 Hz),
140.3, 143.5 (3JCF¼3.5 Hz), 147.6, 159.8 (1JCF¼250.0 Hz), 163.8. LC–MS,
m/z¼339 (MHþ). Anal. Calcd for C17H15FN6O: C, 60.35; H, 4.47; N,
24.84. Found: C, 60.47; H, 4.54; N, 24.78.
357 (34.3), 356 ([Mþ2]þ , 44.3), 354 (Mþ , 100.0), 340 (9.1), 339
ꢂ
(23.2), 337 (52.2), 336 ([MꢀH2O]þ , 78.6), 327 (4.2), 326 (4.9), 325
(12.9), 324 (5.2), 323 (9.2), 310 (4.1), 309 (5.0), 296 (3.1), 294 (5.8),
206 (6.0), 205 (14.7), 204 (29.9), 203 (22.4), 192 (4.7), 191 (4.8), 162
(3.5). LC–MS, m/z¼355 (MHþ), 353. Anal. Calcd for C17H15ClN6O: C,
57.55; H, 4.26; N, 23.69. Found: C, 57.67; H, 4.32; N, 23.56.
4.3.7. 30-(2-Aminophenyl)-3-(4-fluorophenyl)-spiro[pyrazoline-
5,60(10H)-1,2,4-triazin]-50(40H)-one (5g)
4.3.11. 30-(2-Aminophenyl)-3-(3-bromophenyl)-spiro[pyrazoline-
5,60(10H)-1,2,4-triazin]-50(40H)-one (5k)
Off-white solid (2.90 g, 86%), mp 214–216 ꢁC (dioxane–H2O). IR
(KBr, cmꢀ1): 3380, 3265, 3225, 1692, 1621, 1604, 1512, 1450, 1413,
Pale yellow solid (3.40 g, 85%), mp 216–218 ꢁC (dioxane–H2O). IR
(ATR, cmꢀ1): 3375, 3265, 3221, 1688, 1616, 1554, 1521, 1503, 1469,
1448, 1422, 1359, 1299, 1259, 1160, 1129, 1069, 1040, 1010, 972, 885,
1356,1303, 1234, 933, 834, 760, 695, 668, 651, 615. 1H NMR:
d
¼2.95,
3.82 (d, 1H, J¼17.6, CH2), 6.24 (br s, 2H, NH2), 6.54 (t, 1H, J¼7.6, H-
50), 6.70 (d, 1H, J¼8.1, H-30), 7.05 (t, 1H, J¼7.8, H-40), 7.21 (m, 2H, H-
863, 756, 728, 693, 665, 640, 615. 1H NMR:
d¼2.94, 3.82 (d, 1H,

A.V. Karpenko et al. / Tetrahedron 65 (2009) 5964–5972
5971
J¼17.6, CH2), 6.30 (br s, 2H, NH2), 6.54 (t, 1H, J¼7.6, H-50), 6.70 (d,
1H, J¼8.1, H-30), 7.05 (t, 1H, J¼7.8, H-40), 7.35 (t, 1H. J¼7.8, H-5), 7.41
(d, 1H, J¼7.8, H-60), 7.51 (d, 1H, J¼7.8, H-4), 7.63 (d, 1H, J¼7.8, H-6),
7.79 (s, 1H, H-2), 8.14, 8.44 (s, 1H, NH), 10.85 (s, 1H, NH–CO). 13C
1326, 1277, 1255, 1234, 1119, 1019, 969, 928, 872, 846, 821, 799, 752,
698, 636, 612. 1H NMR:
d
¼2.97, 3.86 (d, 1H, J¼17.6, CH2), 6.30 (br s,
2H, NH2), 6.54 (t, 1H, J¼7.6, H-50), 6.70 (d, 1H, J¼8.1, H-30), 7.05 (t,
1H, J¼7.8, H-40), 7.12 (s, 1H, H-3), 7.26 (t, 1H, J¼7.8, H-5), 7.32 (t, 1H,
J¼7.8, H-6), 7.41 (d, 1H, J¼7.8, H-60), 7.58 (d, 1H, J¼8.1, H-7), 7.64 (d,
1H, J¼7.8, H-4), 8.23, 8.68 (s, 1H, NH), 10.90 (br s, 1H, NH–CO). 13C
NMR
d
¼38.7, 77.9,113.1, 115.2,116.0,122.5, 124.8, 127.9, 128.1; 129.9,
131.2 (2C), 135.7, 140.3, 146.4, 147.6, 163.7. LC–MS, m/z¼399
([MꢀH]þ), 397. Anal. Calcd for C17H15BrN6O: C, 51.14; H, 3.79; N,
21.05. Found: C, 51.26; H, 3.90; N, 20.92.
NMR
d
¼38.7, 77.7, 105.7, 111.5, 113.1, 115.3, 116.0, 121.8, 123.8, 125.5,
127.9, 128.7, 129.9, 139.4, 140.4, 147.6, 150.4, 154.8, 163.5. LC–MS,
m/z¼361 (MHþ). Anal. Calcd for C19H16N6O2: C, 63.33; H, 4.48; N,
23.32. Found: C, 63.45; H, 4.59; N, 23.21.
4.3.12. 30-(2-Aminophenyl)-3-(4-bromophenyl)-spiro[pyrazoline-
5,60(10H)-1,2,4-triazin]-50(40H)-one (5l)
Yellow solid (2.90 g, 73%), mp 220–222 ꢁC (dioxane–H2O). IR (KBr,
cmꢀ1): 3419, 3315, 1700, 1608, 1587, 1491, 1451, 1416, 1399, 1342,
1312,1295,1162,1132,1071,1007, 903, 875, 821, 754, 715, 670, 610.1H
4.4. Reaction of 5i with hydrazine hydrate
ꢂ
To a 5i (10 mmol) in dioxane (10 mL) was added N2H4 H2O
NMR:
d
¼2.93, 3.82 (d, 1H, J¼17.6, CH2), 6.31 (br s, 2H, NH2), 6.54 (t,
(2.0 mL, 40 mmol) and resulting mixture was refluxed for 8 h. After
cooling, the mixture was poured into water. Obtained precipitate
was filtered.
1H, J¼7.6, H-50), 6.70 (d, 1H, J¼8.1, H-30), 7.04 (t,1H, J¼7.8, H-40), 7.40
(d,1H, J¼7.8, H-60), 7.58 (s, 4H, H-2,3,5,6), 8.15, 8.36 (s,1H, NH),10.85
(s, 1H, NH–CO). 13C NMR
d¼38.8, 77.8, 113.1, 115.2, 116.0, 121.7, 127.7
Otherwise the compounds 6a,b was also prepared using the
(2C), 127.8, 129.9, 132.0 (2C), 132.6, 140.3, 146.9, 147.6, 163.8. LC–MS,
reported method.30
ꢂ
m/z¼399 ([MꢀH]þ), 397. EI-MS, m/z (Irel, %)¼400 ([Mþ2]þ , 6.1), 398
ꢂ
ꢂ
(Mþ , 5.7), 383 (5.8), 382 (8.9), 381 (5.0), 380 ([MꢀH2O]þ , 6.4), 283
(8.4), 282 (55.9), 281 (7.0), 280 (46.6), 252 (11.5), 251 (99.5), 250 (9.7),
249 (100.0), 197 (3.8), 196 (13.7), 195 (5.1), 194 (16.2), 184 (9.1), 183
(3.1), 182 (6.1), 171 (5.1), 170 (8.5), 169 (4.4), 157 (7.1), 155 (8.7), 143
(3.1),129 (3.1),119 (11.5),118 (10.9),115 (9.8),114 (11.1),113 (9.6),103
(4.5),102 (6.3), 91 (3.4). Anal. Calcd for C17H15BrN6O: C, 51.14; H, 3.79;
N, 21.05. Found: C, 51.25; H, 3.88; N, 20.94.
4.4.1. 5-(2-Chlorophenyl)-1H-pyrazole-3-carboxylic acid
hydrazide (6a)
White solid (1.76 g, 74%), mp 194–196 ꢁC (lit.30 mp 195–196 ꢁC).
IR (ATR, cmꢀ1): 3321, 3219, 2974, 1658, 1600, 1538, 1475, 1452, 1394,
1286, 1252, 1199, 1074, 1045, 962, 927, 880, 831, 787, 747, 716, 675,
625. 1H NMR:
d
¼4.80 (s, 2H, NH2), 6.8–8.0 (m, 5H, HAr), 9.61 (s, 1H,
NH), 13.66 (s, 1H, NH). LC–MS, m/z¼239 (MHþ), 237. Anal. Calcd for
C10H9ClN4O: C, 50.75; H, 3.83; N, 23.67. Found: C, 50.62; H, 3.70; N,
23.81.
4.3.13. 30-(2-Aminophenyl)-3-(thiophen-2-yl)-spiro[pyrazoline-
5,60(10H)-1,2,4-triazin]-50(40H)-one (5m)
Brown solid (2.24 g, 69%), mp 256–258 ꢁC (dioxane–H2O). IR
(KBr, cmꢀ1): 3475, 3300, 2914, 1703, 1622, 1607, 1586, 1496, 1451,
1392, 1371, 1335, 1308, 1276, 1125, 1017, 986, 902, 859, 840, 776, 747,
4.4.2. 5-(Furan-2-yl)-1H-pyrazole-3-carboxylic acid hydrazide (6b)
Off-white solid (1.50 g, 78%), mp 185–187 ꢁC (i-propanol–H2O).
IR (ATR, cmꢀ1): 3278, 3180, 1650, 1583, 1555, 1531, 1515, 1407, 1391,
1369, 1320, 1257, 1124, 1078, 1012, 954, 895, 828, 791, 724. 1H NMR:
704, 661. 1H NMR:
d¼2.95, 3.83 (d, 1H, J¼17.6, CH2), 6.31 (br s, 2H,
NH2), 6.53 (t, 1H, J¼7.6, H-50), 6.69 (d, 1H, J¼8.1, H-30), 7.04 (t, 1H,
J¼7.8, H-40), 7.08 (dd, 1H, JH4–H5¼5.1, JH4–H3¼3.6, H-4), 7.24 (d, 1H,
JH3–H4¼3.6, H-3), 7.40 (d, 1H, J¼7.8, H-60), 7.50 (d, 1H, JH5–H4¼5.1, H-
d
¼4.47 (s, 2H, NH2þH2O), 6.58 (s, 1H, Hpyrazol), 6.76 (m, 1H, H-4fu-
ran), 6.95 (m, 1H, H-3furan), 7.73 (m, 1H, H-5furan), 9.64 (s, 1H, NH),
9.94 (s, 1H, NH). LC–MS, m/z¼191 ([MꢀH]þ). Anal. Calcd for
C8H8N4O2: C, 50.00; H, 4.20; N, 29.15. Found: C, 50.12; H, 4.09; N,
29.26.
5), 8.13, 8.16 (s, 1H, NH), 10.84 (s, 1H, NH–CO). 13C NMR
d¼39.5, 77.8,
113.1,115.3,116.0,126.9,127.0,127.8,128.0,129.9,136.9,140.3,144.5,
ꢂ
147.6, 163.8. EI-MS, m/z (Irel, %)¼328 (6.6), 327 (15.5), 326 (Mþ
,
ꢂ
88.5), 311 (5.3), 310 (19.0), 309 (69.3), 308 ([MꢀH2O]þ , 100.0), 295
(17.5), 293 (5.2), 279 (7.1), 208 (11.4), 177 (55.6),165 (12.0), 162 (7.2),
136 (9.0), 134 (8.9), 133 (6.1), 125 (5.9), 121 (6.6), 119 (36.0), 118
(33.2), 110 (12.7), 109 (11.3), 108 (6.3), 104 (6.3), 92 (9.6), 91 (12.8).
LC–MS, m/z¼327 (MHþ). Anal. Calcd for C15H14N6OS: C, 55.20; H,
4.32; N, 25.75. Found: C, 55.32; H, 4.44; N, 25.70.
4.5. X-ray diffraction
The crystals of C19H14N4O3 (4c) are monoclinic. At 100 K
a¼13.781(5), b¼8.091(5), c¼14.656(5) Å,
b
¼107.57(1)ꢁ, V¼1558(1)
Å3, Mr¼346.34, Z¼4, space group P21/n, dcalcd¼1.477 g/cm3,
m
(MoKa)¼0.104 mmꢀ1, F(000)¼720. Intensity of 6443 reflections
(2731 independent, Rint¼0.056) were measured on an automatic
4.3.14. 30-(2-Aminophenyl)-3-(furan-2-yl)-spiro[pyrazoline-
5,60(10H)-1,2,4-triazin]-50(40H)-one (5n)
‘Xcalibur-3’ diffractometer (graphite monochromated MoKa radia-
tion, CCD detector,
u
scanning, 2Qmax¼50ꢁ).
Compound 5n was prepared from 4n (3.06 g, 10 mmol) and
The crystals of C17H15FN6O (5g) are monoclinic. At 293 K
N2H4 H2O (1.5 mL, 30 mmol) in a similar manner as 5i.
a¼16.488(7), b¼10.570(4), c¼9.513(3) Å,
b
¼106.24(7)ꢁ, V¼1591.8(8)
ꢂ
Dark-brown solid (2.02 g, 65%), mp 193–195 ꢁC. IR (ATR, cmꢀ1):
3474, 3299, 1697, 1621, 1585,1496,1449,1394,1368, 1327, 1276,1256,
1228,1181,1155,1125,1005, 974, 898, 884, 841, 745, 708, 650.1H NMR:
(2) Å3, Mr¼338.35, Z¼4, space group P21/c, dcalcd¼1.412 g/cm3,
m
(MoKa)¼0.102 mmꢀ1, F(000)¼704. Intensity of 106,047 reflections
(5990 independent, Rint¼0.0265) were measured on an automatic
d
¼2.89, 3.77 (d,1H, J¼17.6, CH2), 6.32 (br s, 2H, NH2), 6.56 (t,1H, J¼7.6,
‘Xcalibur-3’ diffractometer (graphite monochromated MoKa radia-
H-50), 6.59 (dd, 1H, JH4–H5¼3.4, JH4–H3¼1.8, H-4), 6.72 (m, 2H, H-30,3),
7.06 (t, 1H, J¼7.6, H-40), 7.42 (d,1H, J¼7.8, H-60), 7.75 (d,1H, J¼1.7, H-5),
tion, CCD detector,
u
scanning, 2Qmax¼55ꢁ).
The structures were solved by direct method using SHELXTL
package.36 Positions of the hydrogen atoms were located from
electron density difference maps and refined usding ‘riding’ model
with Uiso¼nUeq of the carrier atom (n¼1.5 for methyl group and
n¼1.2 for other hydrogen atoms) for structure 4c and using iso-
tropic approximation for structure 5g.
8.16, 8.23 (s, 1H, NH), 10.86 (s, 1H, NH–CO). 13C NMR
d¼39.0, 77.3,
109.7, 112.2, 113.1, 115.2, 116.0, 127.9, 129.9, 140.3, 140.4, 143.9, 147.6,
148.5, 163.7. LC–MS, m/z¼311 (MHþ). Anal. Calcd for C15H14N6O2: C,
58.06; H, 4.55; N, 27.08. Found: C, 58.20; H, 4.59; N, 26.94.
4.3.15. 30-(2-Aminophenyl)-3-(benzo[b]furan-2-yl)-spiro-
[pyrazoline-5,60(10H)-1,2,4-triazin]-50(40H)-one (5o)
Off-white solid (3.10 g, 86%), mp 240–242 ꢁC (dioxane–H2O). IR
(ATR, cmꢀ1): 3420, 3289, 3243, 1698, 1613, 1589, 1499, 1449, 1363,
Full-matrix least-squares refinement of the structures against F2
in anisotropic approximation for non-hydrogen atoms using 2680
(4c), 3596 (5g) reflections was converged to: wR2¼0.149 (R1¼0.070
for 1687 reflections with F>4
s
(F), S¼1.112) for structure 4c and

5972
A.V. Karpenko et al. / Tetrahedron 65 (2009) 5964–5972
14. Ibrahim, S. S.; Abdel-Halim, A. M.; Gabr, Y.; El-Edfawy, S.; Abdel-Rahman, R. M.
J. Chem. Res., Miniprint 1997, 5, 1041–1063.
15. Madkour, H. M. F. ARKIVOC 2004, i, 36–54.
16. Kovalenko, S. I.; Karpenko, A. V.; Krivoshey, O. V.; Shishkina, S. V.; Shishkin, O. V.
Synth. Commun. 2007, 37, 3719–3727.
17. Karpenko, O. V.; Kovalenko, S. I.; Chekotylo, O. O.; Shishkina, S. V. Heterocycles
2007, 71, 619–626.
18. Saloutin, V. I.; Burgart, Ya. V.; Chupakhin, O. N. Russ. Chem. Rev. 1999, 68,
203–214.
19. Perevalov, S. G.; Burgart, Ya. V.; Saloutin, V. I.; Chupakhin, O. N. Russ. Chem. Rev.
2001, 70, 921–938.
20. Nolsoe, J. M. J.; Weigelt, D. J. Heterocycl. Chem. 2009, 46, 1–9.
21. Hazuda, D. J.; Felock, P.; Witmer, M.; Wolfe, A.; Stillmock, K.; Grobler, J. A.;
Espeseth, A.; Gabryelski, L.; Schleif, W.; Blau, C.; Miller, M. D. Science 2000, 287,
646–650.
22. Prikazchikova, T. A.; Sycheva, A. M.; Agapkina, Yu. Yu.; Aleksandrov, D. A.;
Gottikh, M. B. Russ. Chem. Rev. 2008, 77, 421–434.
wR2¼0.096 (R1¼0.039 for 2289 reflections with F>4 (F), S¼0.998)
s
for structure 5g. The final atomic coordinates, and crystallographic
data for molecules 4c and 5g have been deposited to the Cambridge
Crystallographic Data Centre, 12 Union Road, CB2 1EZ, UK (fax:
þ44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk) and are
available on request quoting the deposition numbers CCDC 722354
for 4c and CCDC 722356 for 5g.
Acknowledgements
The authors are grateful to the ‘Enamine Ltd.’ (Kiev, Ukraine) for
the financial support of this work. Participation of Svetlana
V. Shishkina and Irina V. Omelchenko in the X-ray diffraction study
is also acknowledged.
23. Amer, A.; Zimmer, H. J. Heterocycl. Chem. 1983, 20, 1231–1238.
24. Amer, A.; Weisz, K.; Zimmer, H. Heterocycles 1987, 26, 1853–1862.
25. Rashed, N.; El Massry, A. M.; El Ashry, E. S. H.; Amer, A.; Zimmer, H. J. Heterocycl.
Chem. 1990, 27, 691–694.
References and notes
26. Karpenko, A. V.; Kovalenko, S. I.; Shishkina, S. V.; Shishkin, O. V. Monatsh. Chem.
2006, 137, 1543–1549.
27. Antipenko, L. N.; Karpenko, A. V.; Kovalenko, S. I.; Katsev, A. M.; Komarovska-
Porokhnyavets, E. Z.; Novikov, V. P.; Chekotilo, A. A. Chem. Pharm. Bull. 2009, 57,
580–585.
1. Shaban, M. A. E.; Taha, M. A. M.;Sharshira, E. M. Adv. Heterocycl. Chem.1991,52,110–113.
2. El Ashry, E. S. H.; Rashed, N.; Mousaad, A.; Ramadan, E. Adv. Heterocycl. Chem.
1994, 61, 267–270.
3. Abdel-Hamide, S. G. J. Indian Chem. Soc. 1997, 74, 613–618.
4. Bansal, E.; Ram, T.; Sharma, S.; Tyagi, M.; Rani, A. P.; Bajaj, K.; Tyagi, R.; Goel, B.;
Srivastava, V. K.; Guru, J. N.; Kumar, A. Indian J. Chem., Sect. B 2001, 40, 307–312.
5. Trepanier, D. L.; Sunder, S.; Braun, W. H. J. Heterocycl. Chem. 1974, 11, 747–750.
6. Trepanier, D. L.; Sunder, S. J. Heterocycl. Chem. 1975, 12, 321–326.
7. Trepanier, D.L.; Sunder, S.U.S. Patent 3,922,274,1975; Chem. Abstr.1975, 84, 59592.
8. Trepanier, D.L.; Sunder, S. U.S. Patent 3,919,216, 1975; Chem. Abstr. 1975, 84,
121903.
28. Stanovnik, B.; Tisler, M.; Katritzky, A. R.; Denisko, O. V. Adv. Heterocycl. Chem.
2001, 91, 49–60.
29. Zefirov, Yu. V. Kristallografiya 1997, 42, 936–958 (Russ. Ed.); Crystallogr. Rep.
1997, 42, 865–887 (Engl. Transl.); (Chem. Abstr. 1997, 128, 68627).
30. Musante, C.; Fatutta, S. Gazz. Chim. Ital. 1958, 88, 879–896.
31. Zefirov, N. S.; Palyulin, V. A.; Dashevskaya, E. E. J. Phys. Org. Chem. 1990, 3,
147–158.
32. Burgi, H.-B.; Dunitz, J. D. Structure Correlation; VCH: Weinheim, 1994; Vol. 2,
741–784.
9. Trepanier, D.L.; Sunder, S. U.S. Patent 3,919,219, 1975; Chem. Abstr. 1975, 84,
121906.
33. Drexler, K.; Dehne, H.; Reinke, H.; Michalik, M. Sulfur Lett. 1998, 21, 163–177.
34. Chupakhin, O. N.; Zyryanov, G. V.; Rusinov, V. L.; Krasnov, V. P.; Levit, G. L.;
Korolyova, M. A.; Kodess, M. I. Tetrahedron Lett. 2001, 42, 2393–2395.
35. Claesen, M.; Vanderhaeghe, H. Bull. Soc. Chim. Belg. 1959, 68, 220–224; Chem.
Abstr. 1960, 54, 9939b.
10. Trepanier, D.L.; Sunder, S. U.S. Patent 3,919,220, 1975; Chem. Abstr. 1975, 84,
121907.
11. Doleschall, G.; Lempert, K. Tetrahedron 1976, 32, 1735–1740.
12. Kutscher, B.; Engel, J.; Metzenauer, P.; Achterrath-Tuckermann, U.; Szelenyi, I.
Ger. Offen. 4,239,540, 1994; Chem. Abstr. 1994, 121, 179621.
13. Allimony, H. A.; El-Shaaer, H. M.; Abdel-Hamide, S. G.; Abdel-Aziz, S. A.; Abdel-
Rahman, R. M. Indian J. Chem., Sect. B 1996, 35, 1026–1030.
36. Sheldrick, G. M. SHELXTL PLUS. PC Version. A System of Computer Programs for the
Determination of Crystal Structure from X-ray Diffraction Data. Rev. 5.1; 1998.