Diverse directions of heterocyclizations involving derivatives of 5-aminopyrazoles and N -arylmaleimides

Article abstract of DOI:10.1055/s-0030-1258421

Heterocyclization reactions between derivatives of 5-aminopyrazoles and N-arylmaleimides were studied and it was established that several directions are possible. Cyclizations involving 1,3-unsubstituted 5-aminopyrazoles yielded mixtures of two regioisomeric compounds, pyrazolo[1,5-a]pyrimidine-7- carboxamides and pyrazolo[3,4-b]pyridine-4-carboxamides. Reactions of 4-substituted 5-aminopyrazoles in boiling acetic acid or N,N-dimethylformamide in most cases gave pyrazolo[1,5-a]pyrimidine-7-carboxamides as the sole product. The treatment of 1-substituted 5-aminopyrazoles with maleimides possesses high selectivity only in N,N-dimethylformamide yielding pyrazolopyridines while in acetic acid the formation mixtures with pyrrolopyrazolones is observed. The key intermediates of the reaction studied were isolated and discussed. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258421

PAPER
783
Diverse Directions of Heterocyclizations Involving Derivatives of
5-Aminopyrazoles and N-Arylmaleimides
H
eterocyclization
o
s
of
D
erivati
m
ves of 5-Aminopyr
a
a
zoles and
N
-ArylmaleimidesV. Rudenko,a Sergey A. Komykhov,*a Sergey M. Desenko,a,b Vladimir I. Musatov,a Oleg V. Shishkin,a
Irina S. Konovalova,a Elena V. Vashchenko,a Valentin A. Chebanov*a
a
State Scientific Institution ‘Institute for Single Crystals’ of National Academy of Sciences of Ukraine,
Lenin Ave. 60, 61001 Kharkiv, Ukraine
Fax +38(57)3410273; E-mail: komykhov@isc.kharkov.com; E-mail: chebanov@isc.kharkov.com
Karazin Kharkiv National University, Svobody sq., 4, 61077 Kharkiv, Ukraine
b
Received 5 November 2010; revised 10 January 2011
successful examples of such cyclocondensation tuning se-
lectivity was exhibited involving 5-aminopyrazole deriv-
atives and 1,3-cyclohexanones (compounds I–III),3a,b
barbituric acids (compounds IV and V)3c or (phenyl)pyru-
Abstract: Heterocyclization reactions between derivatives of 5-
aminopyrazoles and N-arylmaleimides were studied and it was es-
tablished that several directions are possible. Cyclizations involving
1,3-unsubstituted 5-aminopyrazoles yielded mixtures of two regio-
isomeric compounds, pyrazolo[1,5-a]pyrimidine-7-carboxamides vic acid (compounds VI–VIII).3d–3f
and pyrazolo[3,4-b]pyridine-4-carboxamides. Reactions of 4-sub-
A promising reagent for such heterocyclizations are N-
stituted 5-aminopyrazoles in boiling acetic acid or N,N-dimethyl-
formamide in most cases gave pyrazolo[1,5-a]pyrimidine-7-
carboxamides as the sole product. The treatment of 1-substituted 5-
aminopyrazoles with maleimides possesses high selectivity only in
N,N-dimethylformamide yielding pyrazolopyridines while in acetic
acid the formation mixtures with pyrrolopyrazolones is observed.
The key intermediates of the reaction studied were isolated and dis-
cussed.
substituted maleimides, which are able to play the role of
1,2(1,3)-bielectrophiles or dipolarophiles in reactions
with dienophiles. However, there are few publications
dealing with the cyclizations of maleimides with thio-
ureas,4 o-aminothiophenols,5a aminopyrimidines,5b ali-
phatic diamines,5c 2-mercapto-1,2,4-triazole,5d and 3-
aminocrotonate.5e
Key words: heterocycle, N-arylmaleimide, 5-aminopyrazole, pyra-
zolopyridine, pyrazolopyrimidine
R3
O
R3
O
R1
N
N
N
R2
R1
R2
Partially hydrogenated azoloazines are a challenging class
of heterocyclic compounds due to their known pharmaco-
logical activity1 and the possibility to utilize them as a
facile model for studying principle matters of organic
chemistry, like conformational flexibility, tautomerism,
electronic effects, etc. One synthetic approach to these
compounds is by two- or multicomponent reactions be-
tween aminoazoles and a,b-unsaturated carbonyls or their
precursors.2 Polyfunctional aminoazoles are most attrac-
tive for scientists because of the possibility of implement-
ing several independent directions for their reactions with
electrophiles. From this perspective, a versatile aminoa-
zole that contains several competitive non-equivalent re-
action centers is 5-aminopyrazole. It is known that
cyclocondensation of its derivatives with 1,3-biselectro-
philes like a,b-unsaturated ketones, acetoacetic acid es-
ters, acetoacetamides, or acetylacetone can lead to the
formation of different types of final product.2 However,
very often such heterocyclizations give mixtures of sever-
al heterocyclic compounds. This problem of chemoselec-
tivity can be solved in several ways, for instance, by
variation of the reaction parameters, such as temperature,
solvent type, catalytic system, activation methods, etc.
For example (Figure 1), in our recent publications several
N
N
H
N
H
R2
R2
H
I
II
R3
R1
R3
O
N
R1
R2
N
OH
R2
N
N
N
N
H
N
N
O
H
H
R2
O
R2
III
IV
R2
R1
O
O
R3
N
O
O
R4
N
NH
N
R2
N
H
N
O
N
HN
R2
N
R3
O
H
R1
V
VI
O
OH
Ph
O
HO
N
NH
N
N
OH
H
N
N
H
R1
H
R1
Ph
HN
R2
O
O
NH
R2
VII
VIII
Figure 1 Some reaction products obtained in controlled hetero-
cyclizations involving 5-aminopyrazoles
SYNTHESIS 2011, No. 5, pp 0783–0793
x
x
.
x
x
.2
0
1
1
Advanced online publication: 03.02.2011
DOI: 10.1055/s-0030-1258421; Art ID: T21610SS
© Georg Thieme Verlag Stuttgart · New York

784
R. V. Rudenko et al.
PAPER
In our earlier publications6 it was shown that the direction with N-arylmaleimides 4a,b,d–f,h–q can also yield two
of the cyclocondensation of N-arylmaleimide with 3-ami- different types of final heterocyclic system 7 and 8
no-1,2,4-triazole depended on the type of solvent and led (Scheme 1). The highest level of selectivity was found
to different final heterocyclic systems, triazolo[4,3-a]- or when the treatment was carried out in boiling N,N-di-
triazolo[1,5-a]pyrimidinones6 which are attractive as tar- methylformamide or acetic acid. In these cases, formation
gets for medicinal chemistry.
of minor products 8a,f in 30% yield was observed only for
reactions of 5-amino-4-phenyl-1H-pyrazole (2a) with ma-
leimides 4a,k, while for other starting materials no trace
of such isomers was found even in the mother liquor.
In the present article we disclose our recent results in the
study of heterocyclizations of 5-aminopyrazoles with N-
arylmaleimides leading to several types of fused pyridine,
pyrimidine, and imidazole derivatives. In our study, the 5- On the other hand, it was established that reactions of 1,3-
aminopyrazoles 1a–d, which have free endocyclic 1-NH disubstituted 5-aminopyrazoles 3a,b with several N-aryl-
and 4-CH reaction centers, as well as aminopyrazoles maleimides 4a,h,j in boiling acetic acid also yielded mix-
2a–d or 3a,b, containing a substituent at position 1 or 4, tures of two isomeric heterocycles 9a,f,h (80–85%) and
respectively, were used to cover all possible directions for 10a,f,h (15–20%). The minor isomers 10 were not isolat-
the reactions.
ed and fully characterized. Carrying out the same reac-
tions by refluxing of equimolar amounts of the starting
materials in N,N-dimethylformamide led to a sufficient in-
crease in the selectivity of the process and formation of a
single, final compound, pyrazolopyrimidinones 9a–i, in
moderate yields (Scheme 1, Table 1).
It was found that short-term reflux (5–15 min) of equimo-
lar amounts of aminopyrazole 1a–d and N-arylmaleimide
4a–k in acetic acid or N,N-dimethylformamide led to the
formation of mixtures of two final heterocyclic com-
pounds 5 and 6 in different ratios (Scheme 1, Table 1).
In several articles published earlier7a–c it was reported that
a similar reaction of N-arylmaleimides with 6-amino-
uracil in acetonitrile or propan-2-ol yielded adducts
formed with the participation of the 5-CH or NH2 groups
of the aminoazine. But as both of these adducts were not
further transformed into the corresponding heterocyclic
compounds the question about possible intermediates in
such a reaction arose.
No correlation was found between the electronic or steric
character of substituents R1 and R2 and the final com-
pound ratios in the mixtures. All attempts to separate pre-
paratively the mixtures obtained by recrystallization from
polar or nonpolar solvents, by reprecipitation from N,N-
dimethylformamide, dimethyl sulfoxide, or acetic acid, or
by chromatography were unsuccessful.
Introducing an aryl or alkyl substituent at position 1 or 4
to the 5-aminopyrazole should lead to formation one of
the possible regioisomers. However, it was established
that heterocyclization of 5-amino-4-arylpyrazoles 2a–d
In our study it was found that reaction of aminopyrazole
3a with N-phenylmaleimide (4a) in boiling propan-2-ol
gave an adduct 11 (Scheme 2). Subsequent reflux of 11 in
N,N-dimethylformamide yielded the corresponding pyra-
H
H
N
O
N
O
N
R2
R2
O
R1
N
O
AcOH , Δ
NH
N
N
or DMF, Δ
R2
N
R1
+
+
R1
NH2
N
N
O
N
H
H
H
O
4a–k
1a–e
5a–q
6a,c,f–h,k,l,n–q
R2
HN
H
N
O
R2
O
O
N
NH
AcOH , Δ
or DMF, Δ
N
N
N
N
O
+
NH2
+
4a,b,d–f,h–q
NH
R1
N
R1
H
R1
2a–d
7a–s
8a,f
R2
H
N
HN
O
R2
O
O
AcOH, Δ
+
N
N
O
N
R1
N
N
H
N
H
R1
R1
N
N
9a,f,h
10a,f,h
+
4a,e,g,h,j–m
NH2
3a,b
DMF, Δ
9a–i
Scheme 1
Synthesis 2011, No. 5, 783–793 © Thieme Stuttgart · New York

PAPER
Heterocyclizations of Derivatives of 5-Aminopyrazoles and N-Arylmaleimides
785
Table 1 Synthesis of Compounds 5a–r, 6a,b,d,e,g–m,o–r, 7a–r,
and 9a–i (continued)
O
DMF, Δ
9a
Ph
N
5-Aminopyrazole N-Arylmaleimide
Productsa
Yield
(%)
i-PrOH, Δ
R1
R2
2-MeO-5-ClC6H3 5m
4k 4-FC6H4
4e 4-MeO-3-ClC6H3 5o + 6o (95:5) 67
4d 2,4-Cl2C6H3 5p + 6p (90:10) 63
4e 4-MeO-3-ClC6H3 5q + 6q (50:50) 65
O
3a
+ 4a
N
NH2
N
1d 4-ClC6H4
1d 4-ClC6H4
1d 4-ClC6H4
1e 4-FC6H4
1e 4-FC6H4
2a Ph
4i
70
AcOH, Δ
9a + 10a
Ph
5n + 6n (90:10) 64
11
O
R1
N
O
N
R2
N
N
N
R1
R2
N
H
N
H
O
NH2
O
12
13
4a Ph
7a + 8a (70:30) 70
Scheme 2
2a Ph
4h 2-ClC6H4
7b
74
78
68
72
2a Ph
4i
4e
4l
2-MeO-5-ClC6H3 7c
4-MeO-3-ClC6H3 7d
zolo[3,4-b]pyridine-4-carboxamide 9a, while boiling in
acetic acid gave again a mixture of two compounds 9a and
10a.
2a Ph
2a Ph
2-F3CC6H4
7e
Thus, adducts like 11 can be key intermediates in the het-
erocyclization reaction between 5-aminopyrazoles and N-
arylmaleimides while the formation of several final prod-
ucts should be explained by competition between alterna-
tive reaction centers. For example, heterocyclization of 11
with participation of different carboxamide groups gives
either pyridinone derivatives 9 or pyrrolopyrazolones 10.
In the case of aminopyrazoles 2 the key intermediates are
compounds 12, the cyclization of which yields the corre-
sponding pyrazolopyrimidinones 7 or imidazopyrazo-
lones 8. For 1,4-unsubstituted aminopyrazoles 1, the
formation of adducts like 11 and 12 possibly accounts for
the isolation of two types of heterocyclic systems, com-
pounds 5 and 6.
2a Ph
4k 4-FC6H4
7f + 8f (65:35) 70
2a Ph
4m 4-EtO2CC6H4
4b 4-MeOC6H4
4h 2-ClC6H4
7g
7h
7i
80
78
75
76
77
65
71
72
80
74
66
72
75
34
46
30
48
40
52
35
44
46
2b 4-ClC6H4
2b 4-ClC6H4
2b 4-ClC6H4
2b 4-ClC6H4
4n 3,4-OCH2OC6H3 7j
4f 3-MeOC6H4 7k
2c 2-MeOC6H4 4o 2,4-(MeO)2C6H3 7l
2c 2-MeOC6H4 4j
2,4-Me2C6H3
7m
7n
7o
7p
7q
7r
2c 2-MeOC6H4 4d 2,4-Cl2C6H3
2c 2-MeOC6H4 4p 4-BrC6H4
2c 2-MeOC6H4 4q 3,4-F2C6H3
Table 1 Synthesis of Compounds 5a–r, 6a,b,d,e,g–m,o–r, 7a–r,
and 9a–i
5-Aminopyrazole N-Arylmaleimide
Productsa
Yield
(%)
2d 4-FC6H4
2d 4-FC6H4
2d 4-FC6H4
3a Ph
4d 2,4-Cl2C6H3
4h 2-ClC6H4
4q 3,4-F2C6H3
4a Ph
R1
1a Me
1a Me
1a Me
1a Me
1b Ph
1b Ph
1b Ph
1b Ph
1b Ph
R2
4b 4-MeOC6H4
5a + 6a (90:10) 64
7s
4c
2,5-(MeO)2C6H3 5b 68
9a
4d 2,4-Cl2C6H3
4e
5c + 6c (90:10) 58
3a Ph
4g 3,4-(MeO)2C6H3 9b
4k 4-FC6H4 9c
4-MeO-3-ClC6H3 9d
4-MeO-3-ClC6H3 5d
62
64
3a Ph
4a Ph
5e
3a Ph
4e
4l
4j
4b 4-MeOC6H4
5f + 6f (80:20) 65
5g + 6g (85:15) 55
2a Ph
2-F3CC6H4
9e
9f
4f
3-MeOC6H4
3a Ph
2,4-Me2C6H3
4g 3,4-(MeO)2C6H3 5h + 6h (95:5) 66
3a Ph
4m 4-EtO2CC6H4
4h 4-ClC6H4
4a Ph
9g
9h
9i
4h 2-ClC6H4
5i
70
69
3a Ph
1c 4-MeOC6H4 4i
1c 4-MeOC6H4 4j
2-MeO-5-ClC6H3 5j
3b Me
2,4-Me2C6H3
5k + 6k (95:5) 62
5l + 6l (90:10) 65
a Ratio of compounds (%) in the mixture isolated according to 1H
NMR data.
1c 4-MeOC6H4 4k 4-FC6H4
Synthesis 2011, No. 5, 783–793 © Thieme Stuttgart · New York

786
R. V. Rudenko et al.
PAPER
Additionally, it was established that adducts of type 13,
obtained by reaction of aminoazoles 1 with appropriate
maleimides in acetic acid at ca. 50 °C, did not undergo
further cyclization into heterocyclic compounds under re-
flux in N,N-dimethylformamide or acetic acid.
The structures of the compounds synthesized were estab-
1
lished by mass spectrometry, H and 13C NMR spectros-
copy, and elemental analysis.
For example, the isomeric character of compounds 5 and
6 was shown by mass spectra data and elemental analysis.
1H and 13C NMR spectra of these heterocycles exhibit
similar sets of signals including doublets of doublets for
the ABX system, broad singlets for the carboxamide and
azine NH, multiplets for the aryl protons as well as the
corresponding signals for the terminal substituents. The
formation of the pyridine or pyrimidine ring was postulat-
ed on the basis of the presence of a singlet for either the
pyrazole CH (compounds 5) or the pyrazole NH (com-
pounds 6). Additional useful information was obtained
from NOE experiments (Figure 2).
Figure 3 Molecular structure of compound 7l (X-ray diffraction
data)
In summary, the heterocyclizations of N-arylmaleimides
with 5-aminopyrazoles were studied in detail, and the in-
fluence of the reaction parameters and the aminoazole
structure on the direction of the reaction was established.
It was found that the reaction involving 1,4-unsubstituted
5-aminopyrazoles always gave mixtures of two regioiso-
mers. Introducing substituents in positions 1 or 4 of the
aminopyrazoles and variation of the solvent significantly
increased the selectivity of the heterocyclizations and the
corresponding pyrazolopyridine or pyrazolopyrimidine
derivatives to be synthesized. In both cases, the best re-
sults were observed when N,N-dimethylformamide was
used as the reaction medium. The key intermediates of the
heterocyclization were proposed and their behavior was
analyzed.
R2
R2
HN
HN
R1
H
H
O
O
H
O
O
H
N
H
N
N
N
H
R1
N
N
H
H
H
Melting points were obtained on a standard melting point apparatus
in open capillary tubes. 1H and 13C NMR spectra were recorded in
DMSO-d6 at 200 MHz (50 MHz for 13C) on Varian Mercury VX-
200 spectrometers. HRMS were measured on a GC-MS Varian
1200L (ionizing voltage 70 eV). Elemental analysis was made on a
EuroVector EA-3000. TLC analyses were performed on pre-coated
(silica gel 60 HF254) plates.
6
5
R2
O
R2
HN
HN
H
Me
N
Me
N
H
O
O
N
N
N
N
O
H
H
Ph
Ph
All solvents and chemicals were obtained from standard commer-
cial vendors and were used without any purification.
9
10
Figure 2 Some data of NOE experiments for compounds 5, 6, 9 and
10
The starting 5-aminopyrazoles 1a–e were synthesized by literature
procedures.8
X-ray Diffraction Analysis of Compound 7l
For instance, alternative structures (like 8 or 10) for the
products of heterocyclizations of compounds 1 and 4 were
excluded according to the presence of NOE correlation
between the carboxamide NH and the methyne CH, which
was absent in the case of compounds 8 and 10 (Figure 2).
Correlation between the ortho-proton of the aryl substitu-
ent and the methyne group gave additional evidence for
pyridine, but not pyrimidine, ring formation in com-
pounds 6.
Colorless crystals of 7l (C22H22N4O5) are triclinic. At 293K,
a = 7.987(1), b = 11.667(1), c = 11.751(1) Å, a = 71.09(1)°,
b = 80.27(1)°, g = 81.78(1)°, V = 1016(1) Å3, Mr = 422.44, Z = 2,
space group P1, dcalc = 1.380 g/cm3, m(MoKa) = 0.100 mm–1,
F(000) = 444. Intensities of 6147 reflections (3528 independent,
Rint = 0.015) were measured on the «Xcalibur-3» diffractometer
(graphite monochromated MoKa radiation, CCD detector, w-scan-
ning, 2Qmax = 50°).
The structure was solved by direct method using SHELXTL pack-
age.10 Positions of the hydrogen atoms were located from electron
density difference maps and refined by riding model with
Uiso = nUeq of the carrier atom (n = 1.5 for methyl group and n = 1.2
for other hydrogen atoms). Full-matrix least-squares refinement of
the structures against F2 in anisotropic approximation for non-hy-
drogen atoms using 3488 reflections was converged to: wR2 = 0.104
(R1 = 0.040 for 2544 reflections with F>4s(F), S = 1.055).11
The structure of heterocycles 7 was also established using
X-ray diffraction data obtained for compound 7l
(Figure 3).
It was additionally established that the tetrahydropyrimi-
dine ring of 7l adopts an asymmetric half-chair conforma-
tion (the puckering parameters9 are S = 0.52, Q = 41.9°,
Y = 22.4°).
Synthesis 2011, No. 5, 783–793 © Thieme Stuttgart · New York

PAPER
Heterocyclizations of Derivatives of 5-Aminopyrazoles and N-Arylmaleimides
787
N,2-Aryl- and N-Aryl-2-methyl-5-oxo-4,5,6,7-tetrahydropyra-
zolo[1,5-a]pyrimidine-7-carboxamides 5a–q (Mixture with
6a,c,f–h,k,l,n–q); General Procedure
A mixture of 3-substituted 5-aminopyrazole 1a–e (0.002 mol) and
N-arylmaleimide 4a–k (0.002 mol) in AcOH (0.5 mL) was placed
in a vial and refluxed for 5–10 min. After cooling, acetone (10 mL)
was added. The mixture was allowed to stand (up to 24 h) and then
the precipitate that had formed was filtered to give the solid product,
which was additionally washed with acetone and dried in air at r.t.
MS (EI, 70 eV): m/z (%) = 334 (15) [M+], 336 (5), 151 (21), 150
(100), 123 (9).
Anal. Calcd for C15H15ClN4O3: C, 53.82; H, 4.52; N, 16.74. Found:
C, 53.6; H, 4.5; N, 16.5.
5-Oxo-N,2-diphenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimi-
dine-7-carboxamide (5e)
Colorless solid; mp 272–273 °C.
IR (KBr): 3430, 2990, 1719, 1693, 1587, 1561, 1317 cm–1.
2
1H NMR (200 MHz, DMSO-d6): d = 2.79 (dd, JAB = 17.1 Hz,
N-(4-Methoxyphenyl)-2-methyl-5-oxo-4,5,6,7-tetrahydropyra-
zolo[1,5-a]pyrimidine-7-carboxamide (5a)
Inseparable mixture with 6a; colorless solid.
1H NMR (200 MHz, DMSO-d6): d = 2.07 (s, 3 H, CH3), 2.69 (dd,
2JAB = 16.8 Hz, 3JAX = 2.1 Hz, 1 H, 6-Ha), 3.29 (dd, 3JBX = 7.8 Hz,
1 H, 6-Hb), 3.72 (s, 3 H, CH3O), 5.04 (dd, 1 H, 7-Hx), 5.42 (s, 1 H,
3-H), 6.89 (m, 2 Harom), 7.49 (m, 2 Harom), 10.32 (br s, 1 H, NH),
10.63 (br s, 1 H, NHpyr).
13C NMR (100 MHz, DMSO-d6): d = 166.3, 164.5, 155.6, 148.0,
140.3, 131.0, 120.8, 113.7, 88.6, 56.5, 54.9, 33.5, 13.1.
MS (EI, 70 eV): m/z (%) = 300 (18) [M+], 151 (32), 150 (100), 123
3JAX = 1.9 Hz, 1 H, 6-Ha), 3.45 (dd, 3JBX = 7.8 Hz, 1 H, 6-Hb), 5.31
(dd, 1 H, 7-Hx), 6.07 (s, 1 H, 3-H), 7.08–7.75 (m, 10 Harom), 10.69
(br s, 1 H, NH), 10.91 (br s, 1 H, NHpyr).
13C NMR (100 MHz, DMSO-d6): d = 167.2, 165.0, 150.7, 141.4,
138.2, 132.9, 128.8, 128.5, 127.7, 125.0, 123.9, 119.3, 86.5, 57.2,
33.9.
MS (EI, 70 eV): m/z (%) = 332 (15) [M+], 212 (100).
Anal. Calcd for C19H16N4O2: C, 68.66; H, 4.85; N, 16.86. Found: C,
68.7; H, 4.9; N, 16.7.
(14).
N-(4-Methoxyphenyl)-5-oxo-2-phenyl-4,5,6,7-tetrahydropyra-
zolo[1,5-a]pyrimidine-7-carboxamide (5f)
Inseparable mixture with 6f; colorless solid.
N-(2,5-Dimethoxyphenyl)-2-methyl-5-oxo-4,5,6,7-tetrahydro-
pyrazolo[1,5-a]pyrimidine-7-carboxamide (5b)
Colorless solid; mp 183–184 °C.
2
1H NMR (200 MHz, DMSO-d6): d = 2.79 (dd, JAB = 16.9 Hz,
3JAX = 2.1 Hz, 1 H, 6-Ha), 3.45 (dd, 3JBX = 7.9 Hz, 1 H, 6-Hb), 3.77
(s, 3 H, CH3O), 5.23 (dd, 1 H, 7-Hx), 6.00 (s, 1 H, 3-H), 6.92–7.70
(m, 9 Harom), 10.57 (br s, 1 H, NH), 10.76 (br s, 1 H, NHpyr).
IR (KBr): 3436, 3301, 2929, 1684, 1606, 1554, 1489, 1277, 1223
cm–1.
1H NMR (200 MHz, DMSO-d6): d = 2.13 (s, 3 H, CH3), 2.80 (dd,
2JAB = 16.9 Hz, 3JAX = 2.1 Hz, 1 H, 6-Ha), 3.26 (dd, 3JBX = 7.9 Hz,
1 H, 6-Hb), 3.66 (s, 3 H, CH3O), 3.78 (s, 3 H, CH3O), 5.40 (dd, 1 H,
7-Hx), 5.47 (s, 1 H, 3-H), 6.60–7.74 (m, 3 Harom), 9.45 (br s, 1 H,
NH), 10.74 (br s, 1 H, NHpyr).
MS (EI, 70 eV): m/z (%) = 362 (20) [M+], 213 (28), 212 (100), 123
(11).
N-(3-Methoxyphenyl)-5-oxo-2-phenyl-4,5,6,7-tetrahydropyra-
zolo[1,5-a]pyrimidine-7-carboxamide (5g)
13C NMR (100 MHz, DMSO-d6): d = 167.2, 164.9, 152.9, 149.1,
142.8, 140.6, 127.4, 112.0, 108.6, 106.7, 89.2, 56.4, 56.2, 55.3,
33.1, 13.6.
Inseparable mixture with 6g; colorless solid.
1H NMR (200 MHz, DMSO-d6): d = 2.80 (dd, JAB = 16.9 Hz,
2
3JAX = 1.1 Hz, 1 H, 6-Ha), 3.46 (dd, 3JBX = 7.8 Hz, 1 H, 6-Hb), 3.71
(s, 3 H, CH3O), 5.27 (dd, 1 H, 7-Hx), 6.07 (s, 1 H, 3-H), 6.65–7.77
(m, 9 Harom), 10.57 (br s, 1 H, NH), 10.91 (br s, 1 H, NHpyr).
MS (EI, 70 eV): m/z (%) = 330 (16) [M+], 151 (15), 150 (100).
Anal. Calcd for C16H18N4O4: C, 58.17; H, 5.49; N, 16.96. Found: C,
58.0; H, 5.3; N, 16.6.
13C NMR (100 MHz, DMSO-d6): d = 167.1, 164.9, 159.5, 150.7,
141.4, 139.3, 132.9, 129.5, 128.4, 127.6, 125.0, 111.6, 109.6, 105.0,
86.4, 57.3, 55.9, 33.8.
MS (EI, 70 eV): m/z (%) = 362 (12) [M+], 213 (28), 212 (100), 158
(11).
N-(2,4-Dichlorophenyl)-2-methyl-5-oxo-4,5,6,7-tetrahydropy-
razolo[1,5-a]pyrimidine-7-carboxamide (5c)
Inseparable mixture with 6c; colorless solid.
1H NMR (200 MHz, DMSO-d6): d = 2.10 (s, 3 H, CH3), 2.80 (dd,
2JAB = 17.1 Hz, 3JAX = 1.1 Hz, 1 H, 6-Ha), 3.31 (dd, 3JBX = 7.6 Hz,
1 H, 6-Hb), 5.33 (dd, 1 H, 7-Hx), 5.46 (s, 1 H, 3-H), 7.40–7.84 (m, 3
Harom), 9.98 (br s, 1 H, NH), 10.74 (br s, 1 H, NHpyr).
13C NMR (100 MHz, DMSO-d6): d = 167.6, 164.7, 149.0, 140.6,
133.2, 129.5, 128.8, 127.6, 126.4, 125.6, 89.2, 56.1, 33.3, 13.5.
N-(3,4-Dimethoxyphenyl)-5-oxo-2-phenyl-4,5,6,7-tetrahydro-
pyrazolo[1,5-a]pyrimidine-7-carboxamide (5h)
Inseparable mixture with 6h; colorless solid.
2
1H NMR (200 MHz, DMSO-d6): d = 2.78 (dd, JAB = 16.8 Hz,
3JAX = 0.9 Hz, 1 H, 6-Ha), 3.44 (dd, 3JBX = 7.9 Hz, 1 H, 6-Hb), 3.71
(s, 6 H, 2 CH3O), 5.22 (dd, 1 H, 7-Hx), 6.06 (s, 1 H, 3-H), 6.88–7.77
(m, 8 Harom), 10.43 (br s, 1 H, NH), 10.86 (br s, 1 H, NHpyr).
MS (EI, 70 eV): m/z (%) = 338 (8) [M+], 340 (3), 151 (23), 150
(100), 123 (8).
13C NMR (100 MHz, DMSO-d6): d = 166.2, 164.5, 150.5, 148.7,
145.4, 141.1, 132.7, 131.6, 128.0, 127.3, 124.7, 112.7, 111.6, 105.2,
86.1, 57.0, 55.8, 55.4, 33.6.
N-(3-Chloro-4-methoxyphenyl)-2-methyl-5-oxo-4,5,6,7-tet-
rahydropyrazolo[1,5-a]pyrimidine-7-carboxamide (5d)
Colorless solid; mp 195–196 °C.
IR (KBr): 3432, 2994, 1691, 1685, 1587, 1560, 1320, 1027 cm–1.
1H NMR (200 MHz, DMSO-d6): d = 2.07 (s, 3 H, CH3), 2.71 (dd,
2JAB = 16.8 Hz, 3JAX = 1.9 Hz, 1 H, 6-Ha), 3.30 (dd, 3JBX = 7.6 Hz,
1 H, 6-Hb), 3.82 (s, 3 H, CH3O), 5.03 (dd, 1 H, 7-Hx), 5.42 (s, 1 H,
3-H), 7.10–7.76 (m, 3 Harom), 10.5 (br s, 1 H, NH), 10.66 (br s, 1 H,
NHpyr).
MS (EI, 70 eV): m/z (%) = 392 (14) [M+], 213 (38), 212 (100).
N-(2-Chlorophenyl)-5-oxo-2-phenyl-4,5,6,7-tetrahydropyrazo-
lo[1,5-a]pyrimidine-7-carboxamide (5i)
Colorless solid; mp 267–268 °C.
IR (KBr): 3435, 3257, 2941, 2920, 1698, 1596, 1544, 1445, 1380.
2
1H NMR (200 MHz, DMSO-d6): d = 2.87 (dd, JAB = 16.9 Hz,
3JAX = 1.1 Hz, 1 H, 6-Ha), 3.47 (dd, 3JBX = 7.8 Hz, 1 H, 6-Hb), 5.52
Synthesis 2011, No. 5, 783–793 © Thieme Stuttgart · New York

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R. V. Rudenko et al.
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(dd, 1 H, 7-Hx), 6.10 (s, 1 H, 3-H), 7.16–7.71 (m, 9 Harom), 10.01 (br
s, 1 H, NH), 10.96 (br s, 1 H, NHpyr).
13C NMR (50 MHz, DMSO-d6): d = 167.4, 164.8, 151.2, 141.4,
133.9, 132.8, 129.4, 128.5, 127.8, 127.5, 126.6, 125.9, 125.1, 86.6,
56.6, 33.5.
MS (EI, 70 eV): m/z (%) = 366 (15) [M+], 368 (2), 213 (47), 212
(100), 169 (18).
2-(4-Chlorophenyl)-N-(4-fluorophenyl)-5-oxo-4,5,6,7-tetrahy-
dropyrazolo[1,5-a]pyrimidine-7-carboxamide (5n)
Inseparable mixture with 6n; colorless solid.
2
1H NMR (200 MHz, DMSO-d6): d = 2.81 (dd, JAB = 17.1 Hz,
3JAX = 1.4 Hz, 1 H, 6-Ha), 3.45 (dd, 3JBX = 7.6 Hz, 1 H, 6-Hb), 5.26
(dd, 1 H, 7-Hx), 6.10 (s, 1 H, 3-H), 7.13–7.80 (m, 8 Harom), 10.64 (br
s, 1 H, NH), 10.75 (br s, 1 H, NHpyr).
MS (EI, 70 eV): m/z (%) = 384 (12) [M+], 386 (5), 249 (7), 248 (29),
247 (20), 246 (100).
Anal. Calcd for C19H15ClN4O2: C, 62.21; H, 4.12; N, 15.27. Found:
C, 62.1; H, 4.1; N, 15.3.
N-(3-Chloro-4-methoxyphenyl)-2-(4-chlorophenyl)-5-oxo-
4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-7-carboxamide
(5o)
N-(5-Chloro-2-methoxyphenyl)-2-(4-methoxyphenyl)-5-oxo-
4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-7-carboxamide
(5j)
Inseparable mixture with 6o; colorless solid.
Colorless solid; mp 244–245 °C.
2
1H NMR (200 MHz, DMSO-d6): d = 2.81 (dd, JAB = 16.8 Hz,
IR (KBr): 3435, 3263, 2988, 2919, 1682, 1604, 1546, 1532, 1461,
1548, 1035 cm–1.
3JAX = 1.1 Hz, 1 H, 6-Ha), 3.44 (dd, 3JBX = 7.5 Hz, 1 H, 6-Hb), 3.81
(s, 3 H, CH3O), 5.21 (dd, 1 H, 7-Hx), 6.10 (s, 1 H, 3-H), 7.10–7.80
(m, 7 Harom), 10.61 (br s, 1 H, NH), 10.94 (br s, 1 H, NHpyr).
2
1H NMR (200 MHz, DMSO-d6): d = 2.86 (dd, JAB = 17.0 Hz,
3JAX = 1.1 Hz, 1 H, 6-Ha), 3.43 (dd, 3JBX = 8.1 Hz, 1 H, 6-Hb), 3.76
(s, 3 H, CH3O), 3.78 (s, 3 H, CH3O), 5.56 (dd, 1 H, 7-Hx), 6.02 (s, 1
H, 3-H), 6.95–8.11 (m, 7 Harom), 9.79 (br s, 1 H, NH), 10.95 (br s, 1
H, NHpyr).
MS (EI, 70 eV): m/z (%) = 430 (15) [M+], 432 (5), 249 (17), 248
(66), 247 (36), 246 (100).
N-(2,4-Dichlorophenyl)-2-(4-fluorophenyl)-5-oxo-4,5,6,7-tet-
rahydropyrazolo[1,5-a]pyrimidine-7-carboxamide (5p)
Inseparable mixture with 6p; colorless solid.
MS (EI, 70 eV): m/z (%) = 426 (10) [M+], 428 (5), 243 (24), 242
(100).
2
1H NMR (200 MHz, DMSO-d6): d = 2.85 (dd, JAB = 17.6 Hz,
Anal. Calcd for C21H19ClN4O4: C, 59.09; H, 4.49; N, 13.13. Found:
C, 58.8; H, 4.3; N, 12.9.
3JAX = 1.5 Hz, 1 H, 6-Ha), 3.47 (dd, 3JBX = 7.7 Hz, 1 H, 6-Hb), 5.49
(dd, 1 H, 7-Hx), 6.09 (s, 1 H, 3-H), 7.18–7.86 (m, 7 Harom), 10.1 (br
s, 1 H, NH), 10.97 (br s, 1 H, NHpyr).
N-(2,4-Dimethylphenyl)-2-(4-methoxyphenyl)-5-oxo-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine-7-carboxamide (5k)
Inseparable mixture with 6k; colorless solid.
1H NMR (200 MHz, DMSO-d6): d = 2.13 (s, 3 H, CH3), 2.23 (s, 3
H, CH3), 2.81 (dd, 2JAB = 16.3 Hz, 3JAX = 1.1 Hz, 1 H, 6-Ha), 3.39
(dd, 3JBX = 7.0 Hz, 1 H, 6-Hb), 3.78 (s, 3 H, CH3O), 5.32 (dd, 1 H,
7-Hx), 5.98 (s, 1 H, 3-H), 6.93–7.72 (m, 7 Harom), 9.70 (br s, 1 H,
NH), 10.84 (br s, 1 H, NHpyr).
MS (EI, 70 eV): m/z (%) = 418 (5) [M+], 231 (24), 230 (100), 187
(15), 120 (21).
N-(3-Chloro-4-methoxyphenyl)-2-(4-fluorophenyl)-5-oxo-
4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-7-carboxamide
(5q)
Inseparable mixture with 6q; colorless solid.
MS (EI, 70 eV): m/z (%) = 390 (13) [M+], 243 (33), 242 (100).
2
1H NMR (200 MHz, DMSO-d6): d = 2.80 (dd, JAB = 16.8 Hz,
3JAX = 1.6 Hz, 1 H, 6-Ha), 3.43 (dd, 3JBX = 7.9 Hz, 1 H, 6-Hb), 3.80
(s, 3 H, CH3O), 5.20 (dd, 1 H, 7-Hx), 6.06 (s, 1 H, 3-H), 7.05–7.82
(m, 7 Harom), 10.55 (br s, 1 H, NH), 10.9 (br s, 1 H, NHpyr).
N-(4-Fluorophenyl)-2-(4-methoxyphenyl)-5-oxo-4,5,6,7-tet-
rahydropyrazolo[1,5-a]pyrimidine-7-carboxamide (5l)
Inseparable mixture with 6l; colorless solid.
MS (EI, 70 eV): m/z (%) = 414 (10) [M+], 231 (32), 230 (100), 187
2
1H NMR (200 MHz, DMSO-d6): d = 2.79 (dd, JAB = 17.1 Hz,
(15).
3JAX = 1.1 Hz, 1 H, 6-Ha), 3.43 (dd, 3JBX = 8.1 Hz, 1 H, 6-Hb), 3.76
(s, 3 H, CH3O), 5.20 (dd, 1 H, 7-Hx), 5.99 (s, 1 H, 3-H), 6.92–7.70
(m, 8 Harom), 10.62 (br s, 1 H, NH), 10.75 (br s, 1 H, NHpyr).
N,3-Diaryl-5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-
7-carboxamides 7a–s; General Procedure
MS (EI, 70 eV): m/z (%) = 380 (16) [M+], 243 (28), 242 (100).
A mixture of 4-aryl-5-aminopyrazole 2a–d (0.002 mol) and N-aryl-
maleimide 4a,b,d–f,h–q (0.002 mol) in AcOH (1 mL) was placed
in a vial and refluxed for 5–15 min. After cooling acetone (10 mL)
was added. The mixture was allowed to stand (~24 h) and then the
precipitate formed was filtered to give the solid product which was
additionally washed with acetone and dried in air at r.t.
N-(5-Chloro-2-methoxyphenyl)-2-(4-chlorophenyl)-5-oxo-
4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-7-carboxamide
(5m)
Colorless solid; mp 277–278 °C.
IR (KBr): 3435, 3291, 2926, 1687, 1683, 1603, 1542, 1486, 1254,
1090, 1026 cm–1.
5-Oxo-N,3-diphenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimi-
dine-7-carboxamide (7a)
Obtained as a mixture with 8a; colorless solid.
2
1H NMR (200 MHz, DMSO-d6): d = 2.86 (dd, JAB = 17.1 Hz,
3JAX = 1.1 Hz, 1 H, 6-Ha), 3.43 (dd, 3JBX = 8.1 Hz, 1 H, 6-Hb), 3.78
(s, 3 H, CH3O), 5.60 (dd, 1 H, 7-Hx), 6.14 (s, 1 H, 3-H), 7.04–8.09
(m, 7 Harom), 9.83 (br s, 1 H, NH), 11.0 (br s, 1 H, NHpyr).
2
1H NMR (200 MHz, DMSO-d6): d = 2.83 (dd, JAB = 16.5 Hz,
3JAX = 2.0 Hz, 1 H, 6-Ha), 3.46 (dd, 3JBX = 7.6 Hz, 1 H, 6-Hb), 5.28
(dd, 1 H, 7-Hx), 7.06–7.61 (m, 10 Harom), 7.69 (s, 1 H, 2-H), 10.54
(br s, 1 H, NH), 10.74 (br s, 1 H, NHpyr).
MS (EI, 70 eV): m/z (%) = 430 (7) [M+], 432 (5), 249 (11), 248 (39),
247 (27), 246 (100).
MS (EI, 70 eV): m/z (%) = 332 (33) [M+], 333 (6), 213 (36), 212
Anal. Calcd for C20H16Cl2N4O3: C, 55.70; H, 3.74; N, 12.99. Found:
C, 55.5; H, 3.7; N, 12.9.
(100), 185 (17), 184 (20).
Synthesis 2011, No. 5, 783–793 © Thieme Stuttgart · New York

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Heterocyclizations of Derivatives of 5-Aminopyrazoles and N-Arylmaleimides
789
2-(2-Oxo-7-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-3-
yl)-N-phenylacetamide (8a)
(dd, 1 H, 7-Hx), 7.17–7.78 (m, 9 Harom), 7.73 (s, 1 H, 2-H), 10.12 (br
s, 1 H, NH), 10.78 (br s, 1 H, NHpyr).
Obtained as a mixture with 7a; colorless solid.
MS (EI, 70 eV): m/z (%) = 400 (13) [M+], 212 (37), 185 (17), 169
(12), 168 (12).
1H NMR (200 MHz, DMSO-d6): d = 3.09 (dd, JAB = 16.0Hz,
2
3JAX = 5.0 Hz, 1 H, Ha), 3.25 (dd, 3JBX = 5.0 Hz, 1 H, Hb), 4.99 (dd,
1 H, 3-Hx), 6.98–7.62 (m, 10 Harom), 7.82 (s, 1 H, 6-H), 10.13 (br s,
1 H, NH), 11.7 (br s, 1 H, NHpyr).
Anal. Calcd for C20H15F3N4O2: C, 60.00; H, 3.78; N, 13.99. Found:
C, 59.95; H, 3.75; N, 14.0.
N-(4-Fluorophenyl)-5-oxo-3-phenyl-4,5,6,7-tetrahydropyrazo-
lo[1,5-a]pyrimidine-7-carboxamide (7f)
Obtained as a mixture with 8f; colorless solid.
N-(2-Chlorophenyl)-5-oxo-3-phenyl-4,5,6,7-tetrahydropyrazo-
lo[1,5-a]pyrimidine-7-carboxamide (7b)
Colorless solid; mp 240–241 °C.
2
1H NMR (200 MHz, DMSO-d6): d = 2.83 (dd, JAB = 16.5 Hz,
IR (KBr): 3444, 3272, 3033, 2903, 1693, 1679, 1590, 1528, 1445,
1366, 1301, 1178 cm–1.
3JAX = 2.0 Hz, 1 H, 6-Ha), 3.46 (dd, 3JBX = 7.5 Hz, 1 H, 6-Hb), 5.22
(dd, 1 H, 7-Hx), 7.05–7.65 (m, 9 Harom), 7.69 (s, 1 H, 2-H), 10.62 (br
s, 1 H, NH), 10.74 (br s, 1 H, NHpyr).
2
1H NMR (200 MHz, DMSO-d6): d = 2.85 (dd, JAB = 16.6 Hz,
3JAX = 1.4 Hz, 1 H, 6-Ha), 3.51 (dd, 3JBX = 7.9 Hz, 1 H, 6-Hb), 5.49
(dd, 1 H, 7-Hx), 7.15–7.73 (m, 9 Harom), 7.74 (s, 1 H, 2-H), 10.04 (br
s, 1 H, NH), 10.65 (br s, 1 H, NHpyr).
N-(4-Fluorophenyl)-2-(2-oxo-7-phenyl-2,3-dihydro-1H-imida-
zo[1,2-b]pyrazol-3-yl)acetamide (8f)
Obtained as a mixture with 7f; colorless solid.
MS (EI, 70 eV): m/z (%) = 366 (15) [M+], 367 (5), 368 (10), 369 (4),
212 (100).
1H NMR (200 MHz, DMSO-d6): d = 3.08 (dd, JAB = 16.6 Hz,
2
3JAX = 5.0 Hz, 1 H, Ha), 3.23 (dd, 3JBX = 5.0 Hz, 1 H, Hb), 5.00 (dd,
1 H, 3-Hx), 7.05–7.65 (m, 9 Harom), 7.82 (s, 1 H, 6-H), 10.2 (br s, 1
H, NH), 11.7 (br s, 1 H, NHpyr).
Anal. Calcd for C19H15ClN4O2: C, 62.21; H, 4.12; N, 15.27. Found:
C, 62.15; H, 4.05; N, 15.3.
N-(5-Chloro-2-methoxyphenyl)-5-oxo-3-phenyl-4,5,6,7-tet-
rahydropyrazolo[1,5-a]pyrimidine-7-carboxamide (7c)
Colorless solid; mp 229–230 °C.
Ethyl 4-(5-Oxo-3-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]py-
rimidine-7-carboxamido)benzoate (7g)
Colorless solid; mp 290–291 °C.
IR (KBr): 3436, 3289, 2939, 1702, 1690, 1594, 1543, 1257, 1225,
1026 cm–1.
IR (KBr): 3428, 3265, 3128, 2906, 1723, 1695, 1682, 1606, 1547,
1533, 1411, 1368, 1271, 1253 cm–1.
2
1H NMR (200 MHz, DMSO-d6): d = 2.82 (dd, JAB = 16.6 Hz,
1H NMR (200 MHz, DMSO-d6): d = 1.31 (t, J = 7.0 Hz, 3 H, CH3),
3JAX = 1.7 Hz, 1 H, 6-Ha), 3.44 (dd, 3JBX = 7.9 Hz, 1 H, 6-Hb), 3.88
(s, 3 H, CH3O), 5.59 (dd, 1 H, 7-Hx), 7.07–8.07 (m, 8 Harom), 7.74
(s, 1 H, 2-H), 9.9 (br s, 2 H, NH).
2
3
2.88 (dd, JAB = 16.5 Hz, JAX = 2.0 Hz, 1 H, 6-Ha), 3.48 (dd,
3JBX = 7.6 Hz, 1 H, 6-Hb), 4.28 (q, 2 H, CH2), 5.28 (dd, 1 H, 7-Hx),
7.18–7.97 (m, 9 Harom), 7.70 (s, 1 H, 2-H), 10.58 (br s, 1 H, NH),
10.92 (br s, 1 H, NHpyr).
MS (EI, 70 eV): m/z (%) = 396 (10) [M+], 397 (3), 398 (4), 212
(100).
13C NMR (100 MHz, DMSO-d6): d = 167.3, 165.8, 165.1, 142.3,
138.9, 136.1, 131.1, 130.1, 128.4, 126.5, 125.7, 125.0, 118.9, 105.5,
60.3, 57.3, 33.7, 14.0.
Anal. Calcd for C20H17ClN4O3: C, 60.53; H, 4.32; N, 14.12. Found:
C, 60.35; H, 4.25; N, 14.3.
MS (EI, 70 eV): m/z (%) = 404 (6) [M+], 212 (100), 185 (7).
N-(3-Chloro-4-methoxyphenyl)-5-oxo-3-phenyl-4,5,6,7-tet-
rahydropyrazolo[1,5-a]pyrimidine-7-carboxamide (7d)
Colorless solid; mp 265–266 °C.
Anal. Calcd for C22H20N4O4: C, 65.34; H, 4.98; N, 13.85. Found: C,
65.2; H, 4.75; N, 13.83.
IR (KBr): 3430, 3247, 2908, 1689, 1680, 1600, 1504, 1368, 1235,
1187, 1065 cm–1.
3-(4-Chlorophenyl)-N-(4-methoxyphenyl)-5-oxo-4,5,6,7-tet-
rahydropyrazolo[1,5-a]pyrimidine-7-carboxamide (7h)
Colorless solid; mp 273–274 °C.
2
1H NMR (200 MHz, DMSO-d6): d = 2.83 (dd, JAB = 16.6 Hz,
3JAX = 1.8 Hz, 1 H, 6-Ha), 3.45 (dd, 3JBX = 7.8 Hz, 1 H, 6-Hb), 3.82
(s, 3 H, CH3O), 5.20 (dd, 1 H, 7-Hx), 7.11–7.77 (m, 8 Harom), 7.69
(s, 1 H, 2-H), 10.63 (br s, 1 H, NH), 10.76 (br s, 1 H, NHpyr).
IR (KBr): 3447, 3257, 3139, 1698, 1666, 1606, 1509, 1237, 1036
cm–1.
2
1H NMR (200 MHz, DMSO-d6): d = 2.79 (dd, JAB = 16.6 Hz,
13C NMR (100 MHz, DMSO-d6): d = 166.6, 165.9, 150.9, 138.8,
136.1, 131.8, 131.1, 128.4, 126.5, 125.7, 121.0, 120.6, 119.3, 113.0,
105.4, 57.1, 56.1, 33.9.
MS (EI, 70 eV): m/z (%) = 396 (14) [M+], 397 (5), 398 (7), 212
(100).
3JAX = 1.7 Hz, 1 H, 6-Ha), 3.43 (dd, 3JBX = 7.9 Hz, 1 H, 6-Hb), 3.70
(s, 3 H, CH3O), 5.19 (dd, 1 H, 7-Hx), 6.86–7.51 (m, 8 Harom), 7.70
(s, 1 H, 2-H), 10.42 (br s, 1 H, NH). 10.79 (br s, 1 H, NHpyr).
MS (EI, 70 eV): m/z (%) = 396 (27) [M+], 397 (7), 398 (10), 248
(23), 246 (100).
Anal. Calcd for C20H17ClN4O3: C, 60.53; H, 4.32; N, 14.12. Found:
C, 60.32; H, 4.24; N, 14.2.
Anal. Calcd for C20H17ClN4O3: C, 60.53; H, 4.32; N, 14.12. Found:
C, 60.4; H, 4.3; N, 14.2.
5-Oxo-3-phenyl-N-[2-(trifluoromethyl)phenyl]-4,5,6,7-tetrahy-
dropyrazolo[1,5-a]pyrimidine-7-carboxamide (7e)
Colorless solid; mp 227–228 °C.
N-(2-Chlorophenyl)-3-(4-chlorophenyl)-5-oxo-4,5,6,7-tetrahy-
dropyrazolo[1,5-a]pyrimidine-7-carboxamide (7i)
Colorless solid; mp 243–244 °C.
IR (KBr): 3429, 3280, 3025, 2906, 1699, 1684, 1610, 1532, 1496,
1370, 1311, 1175 cm–1.
IR (KBr): 3434, 2936, 1690, 1675, 1596, 1546, 1523, 1444, 1374,
1309 cm–1.
2
1H NMR (200 MHz, DMSO-d6): d = 2.78 (dd, JAB = 16.6 Hz,
2
1H NMR (200 MHz, DMSO-d6): d = 2.85 (dd, JAB = 16.6 Hz,
3JAX = 1.8 Hz, 1 H, 6-Ha), 3.53 (dd, 3JBX = 7.9 Hz, 1 H, 6-Hb), 5.42
3JAX = 1.7 Hz, 1 H, 6-Ha), 3.51 (dd, 3JBX = 7.9 Hz, 1 H, 6-Hb), 5.48
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(dd, 1 H, 7-Hx), 7.18–7.73 (m, 8 Harom), 7.76 (s, 1 H, 2-H), 10.04 (br
s, 1 H, NH), 10.80 (br s, 1 H, NHpyr).
MS (EI, 70 eV): m/z (%) = 400 (16) [M+], 401 (8), 402 (9), 403 (3),
1H NMR (200 MHz, DMSO-d6): d = 2.15 (s, 3 H, CH3), 2.24 (s, 3
H, CH3), 2.82 (dd, 2JAB = 16.4 Hz, 3JAX = 2.0 Hz, 1 H, 6-Ha), 3.45
(dd, 3JBX = 7.9 Hz, 1 H, 6-Hb), 3.78 (s, 3 H, CH3O), 5.33 (dd, 1 H,
7-Hx), 6.91–7.31 (m, 7 Harom), 7.55 (s, 1 H, 2-H), 9.70 (br s, 1 H,
NH), 10.14 (br s, 1 H, NHpyr).
MS (EI, 70 eV): m/z (%) = 390 (12) [M+], 391 (4), 243 (16), 242
(59), 212 (100).
248 (35), 246 (100).
Anal. Calcd for C19H14Cl2N4O2: C, 56.87; H, 3.52; N, 13.96. Found:
C, 56.8; H, 3.4; N, 13.9.
N-(1,3-Benzodioxol-5-yl)-3-(4-chlorophenyl)-5-oxo-4,5,6,7-tet-
rahydropyrazolo[1,5-a]pyrimidine-7-carboxamide (7j)
Colorless solid; mp 272–273 °C.
Anal. Calcd for C22H22N4O3: C, 67.68; H, 5.68; N, 14.35. Found: C,
67.6; H, 5.5; N, 14.2.
N-(2,4-Dichlorophenyl)-3-(2-methoxyphenyl)-5-oxo-4,5,6,7-tet-
rahydropyrazolo[1,5-a]pyrimidine-7-carboxamide (7n)
Colorless solid; mp 223–224 °C.
IR (KBr): 3435, 3328, 3075, 1706, 1694, 1592, 1520, 1020 cm–1.
IR (KBr): 3438, 3256, 3080, 2907, 1694, 1663, 1487, 1449, 1222,
1037 cm–1.
2
1H NMR (200 MHz, DMSO-d6): d = 2.81 (dd, JAB = 16.5 Hz,
3JAX = 1.8 Hz, 1 H, 6-Ha), 3.45 (dd, 3JBX = 7.8 Hz, 1 H, 6-Hb), 5.19
(dd, 1 H, 7-Hx), 5.99 (s, 2 H, OCH2O), 6.85–7.51 (m, 7 Harom), 7.72
(s, 1 H, 2-H), 10.48 (br s, 2 H, NH).
2
1H NMR (200 MHz, DMSO-d6): d = 2.85 (dd, JAB = 16.9 Hz,
3JAX = 2.3 Hz, 1 H, 6-Ha), 3.45 (dd, 3JBX = 7.9 Hz, 1 H, 6-Hb), 3.76
(s, 3 H, CH3O), 5.46 (dd, 1 H, 7-Hx), 6.92–7.80 (m, 7 Harom), 7.57
(s, 1 H, 2-H), 10.05 (br s, 2 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 166.5, 165.1, 147.1, 143.5,
138.8, 136.4, 132.5, 130.3, 130.1, 128.5, 128.3, 112.5, 108.1, 104.4,
101.5, 101.1, 57.3, 33.9.
MS (EI, 70 eV): m/z (%) = 430 (10) [M+], 432 (6), 243 (15), 242
(55), 213 (15), 212 (100).
MS (EI, 70 eV): m/z (%) = 410 (10) [M+], 411 (2), 412 (4), 248 (50),
246 (100).
Anal. Calcd for C20H16Cl2N4O3: C, 55.7; H, 3.74; N, 12.99. Found:
C, 55.6; H, 3.8; N, 13.1.
Anal. Calcd for C20H15ClN4O4: C, 58.47; H, 3.68; N, 13.64. Found:
C, 58.4; H, 3.7; N, 13.7.
N-(4-Bromophenyl)-3-(2-methoxyphenyl)-5-oxo-4,5,6,7-tet-
rahydropyrazolo[1,5-a]pyrimidine-7-carboxamide (7o)
Colorless solid; mp 271–272 °C.
3-(4-Chlorophenyl)-N-(3-methoxyphenyl)-5-oxo-4,5,6,7-tet-
rahydropyrazolo[1,5-a]pyrimidine-7-carboxamide (7k)
Colorless solid; mp 267–268 °C.
IR (KBr): 3435, 3307, 2918, 1698, 1674, 1369, 1284, 1023 cm–1.
IR (KBr): 3434, 3315, 3061, 1698, 1681, 1595, 1543, 1489, 1396,
1245, 1182, 1026 cm–1.
2
1H NMR (200 MHz, DMSO-d6): d = 2.83 (dd, JAB = 16.9 Hz,
1H NMR (200 MHz, DMSO-d6): d = 2.82 (dd, JAB = 16.5 Hz,
2
3JAX = 2.3 Hz, 1 H, 6-Ha), 3.43 (dd, 3JBX = 7.9 Hz, 1 H, 6-Hb), 3.78
(s, 3 H, CH3O), 5.22 (dd, 1 H, 7-Hx), 6.92–7.65 (m, 8 Harom), 7.52
(s, 1 H, 2-H), 9.97 (br s, 1 H, NH), 10.7 (br s, 1 H, NHpyr).
3JAX = 2.0 Hz, 1 H, 6-Ha), 3.47 (dd, 3JBX = 7.6 Hz, 1 H, 6-Hb), 3.72
(s, 3 H, CH3O), 5.23 (dd, 1 H, 7-Hx), 6.65–7.51 (m, 8 Harom), 7.72
(s, 1 H, 2-H), 10.54 (br s, 1 H, NH), 10.7 (br s, 1 H, NHpyr).
MS (EI, 70 eV): m/z (%) = 442 (16) [M+], 440 (14), 243 (18), 242
(47), 213 (14), 212 (100).
MS (EI, 70 eV): m/z (%) = 396 (17) [M+], 397 (4), 398 (5), 248 (33),
246 (100).
Anal. Calcd for C20H17BrN4O3: C, 54.44; H, 3.88; N, 12.7. Found:
C, 54.3; H, 3.8; N, 12.8.
Anal. Calcd for C20H17ClN4O3: C, 60.53; H, 4.32; N, 14.12. Found:
C, 60.3; H, 4.3; N, 14.1.
N-(3,4-Difluorophenyl)-3-(2-methoxyphenyl)-5-oxo-4,5,6,7-tet-
rahydropyrazolo[1,5-a]pyrimidine-7-carboxamide (7p)
Colorless solid; mp 257–258 °C.
N-(2,4-Dimethoxyphenyl)-3-(2-methoxyphenyl)-5-oxo-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine-7-carboxamide (7l)
Colorless solid; mp 188–189 °C.
IR (KBr): 3436, 3341, 3082, 1693, 1676, 1621, 1521, 1219, 1024
cm–1.
IR (KBr): 3434, 3345, 3190, 2939, 1695, 1681, 1618, 1537, 1373,
1225, 1078 cm–1.
2
1H NMR (200 MHz, DMSO-d6): d = 2.83 (dd, JAB = 17.1 Hz,
2
1H NMR (200 MHz, DMSO-d6): d = 2.86 (dd, JAB = 16.6 Hz,
3JAX = 2.6 Hz, 1 H, 6-Ha), 3.44 (dd, 3JBX = 7.9 Hz, 1 H, 6-Hb), 3.78
(s, 3 H, CH3O), 5.20 (dd, 1 H, 7-Hx), 6.91–7.82 (m, 7 Harom), 7.53
(s, 1 H, 2-H), 10.18 (br s, 1 H, NH), 10.82 (br s, 1 H, NHpyr).
3JAX = 2.0 Hz, 1 H, 6-Ha), 3.39 (dd, 3JBX = 7.9 Hz, 1 H, 6-Hb), 3.73
(s, 3 H, CH3O), 3.78 (s, 3 H, CH3O), 3.83 (s, 3 H, CH3O), 5.47 (dd,
1 H, 7-Hx), 6.45–7.78 (m, 7 Harom), 7.57 (s, 1 H, 2-H), 9.42 (br s, 1
H, NH), 10.2 (br s, 1 H, NHpyr).
MS (EI, 70 eV): m/z (%) = 398 (72) [M+], 399 (19), 243 (19), 242
(83), 213 (23), 212 (100).
13C NMR (100 MHz, DMSO-d6): d = 166.1, 164.5, 156.8, 155.5,
150.7, 140.0, 136.3, 129.2, 127.4, 122.0, 120.3, 119.8, 119.7, 111.5,
104.4, 101.7, 99.0, 56.6, 55.7, 55.1, 55.0, 33.1.
Anal. Calcd for C20H16F2N4O3: C, 60.3; H, 4.05; N, 14.06. Found:
C, 60.2; H, 3.9; N, 14.1.
MS (EI, 70 eV): m/z (%) = 422 (26) [M+], 423 (12), 243 (19), 242
(66), 212 (100).
N-(2,4-Dichlorophenyl)-3-(4-fluorophenyl)-5-oxo-4,5,6,7-tet-
rahydropyrazolo[1,5-a]pyrimidine-7-carboxamide (7q)
Colorless solid; mp 265–266 °C.
Anal. Calcd for C22H22N4O5: C, 62.55; H, 5.25; N, 13.26. Found: C,
62.4; H, 5.2; N, 13.2.
IR (KBr): 3435, 3309, 2934, 1694, 1587, 1525, 1448, 1382, 1299,
1235 cm–1.
N-(2,4-Dimethylphenyl)-3-(2-methoxyphenyl)-5-oxo-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine-7-carboxamide (7m)
Colorless solid; mp 239–240 °C.
2
1H NMR (200 MHz, DMSO-d6): d = 2.84 (dd, JAB = 17.1 Hz,
3JAX = 2.0 Hz, 1 H, 6-Ha), 3.47 (dd, 3JBX = 7.9 Hz, 1 H, 6-Hb), 5.48
(dd, 1 H, 7-Hx), 7.15–7.76 (m, 7 Harom), 7.71 (s, 1 H, 2-H), 10.14 (br
s, 1 H, NH), 10.84 (br s, 1 H, NHpyr).
IR (KBr): 3436, 3304, 2918, 1698, 1664, 1529, 1369, 1301, 1236,
1023 cm–1.
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Heterocyclizations of Derivatives of 5-Aminopyrazoles and N-Arylmaleimides
791
MS (EI, 70 eV): m/z (%) = 418 (16) [M+], 420 (5), 231 (15), 230
N-(3,4-Dimethoxyphenyl)-3-methyl-6-oxo-1-phenyl-4,5,6,7-tet-
(100).
rahydro-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (9b)
Colorless solid; mp 265–266 °C.
IR (KBr): 3435, 3284, 2919, 1680, 1650, 1517, 1237, 1027 cm–1.
Anal. Calcd for C19H13Cl2FN4O2: C, 54.43; H, 3.13; N, 13.36.
Found: C, 54. 6; H, 3.1; N, 13.2.
1H NMR (200 MHz, DMSO-d6): d = 2.16 (s, 3 H, CH3), 2.64 (dd,
2JAB = 15.9 Hz, 3JAX = 4.0 Hz, 1 H, 5-Ha), 2.87 (dd, 3JBX = 6.9 Hz,
1 H, 5-Hb), 3.72 (s, 6 H, 2 CH3O), 3.82 (dd, 1 H, 4-Hx), 6.87–7.49
(m, 8 Harom), 10.08 (br s, 1 H, NH), 10.32 (br s, 1 H, NHpyr).
N-(2-Chlorophenyl)-3-(4-fluorophenyl)-5-oxo-4,5,6,7-tetrahy-
dropyrazolo[1,5-a]pyrimidine-7-carboxamide (7r)
Colorless solid; mp 231–232 °C.
IR (KBr): 3433, 3330, 2946, 1693, 1595, 1525, 1442, 1377, 1233,
1060 cm–1.
MS (EI, 70 eV): m/z (%) = 406 (8) [M+], 227 (17), 226 (100), 77
(17).
2
1H NMR (200 MHz, DMSO-d6): d = 2.84 (dd, JAB = 16.4 Hz,
Anal. Calcd for C22H22N4O4: C, 65.01; H, 5.46; N, 13.78. Found: C,
64.8; H, 5.5; N, 13.6.
3JAX = 2.0 Hz, 1 H, 6-Ha), 3.50 (dd, 3JBX = 7.9 Hz, 1 H, 6-Hb), 5.48
(dd, 1 H, 7-Hx), 7.15–7.71 (m, 8 Harom), 7.72 (s, 1 H, 2-H), 10.04 (br
s, 1 H, NH), 10.83 (br s, 1 H, NHpyr).
N-(4-Fluorophenyl)-3-methyl-6-oxo-1-phenyl-4,5,6,7-tetrahy-
dro-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (9c)
Colorless solid; mp 277–278 °C.
MS (EI, 70 eV): m/z (%) = 384 (9) [M+], 386 (3), 231 (25), 230
(100).
Anal. Calcd for C19H14ClFN4O2: C, 59.31; H, 3.67; N, 14.56.
Found: C, 59.2; H, 3.6; N, 14.5.
IR (KBr): 3435, 3266, 3079, 2920, 1681, 1656, 1615, 1509, 1408,
1215 cm–1.
1H NMR (200 MHz, DMSO-d6): d = 2.14 (s, 3 H, CH3), 2.66 (dd,
2JAB = 16.1 Hz, 3JAX = 4.2 Hz, 1 H, 5-Ha), 2.86 (dd, 3JBX = 7.0 Hz,
1 H, 5-Hb), 3.86 (dd, 1 H, 4-Hx), 7.11–7.66 (m, 9 Harom), 10.30 (br
s, 2 H, NH).
N-(3,4-Difluorophenyl)-3-(4-fluorophenyl)-5-oxo-4,5,6,7-tet-
rahydropyrazolo[1,5-a]pyrimidine-7-carboxamide (7s)
Colorless solid; mp 270–271 °C.
IR (KBr): 3435, 3288, 2928, 1687, 1664, 1601, 1441, 1380, 1061
cm–1.
13C NMR (50 MHz, DMSO-d6): d = 170.7, 169.7, 158.1 (d, 1J = 240
Hz, 1 C, p-CAr), 145.0, 139.7, 137.9, 135.0 (d, J = 2.9 Hz, 1 C CAr-
NH), 129.1, 126.8, 122.8, 122.2 (d, J = 7.6 Hz, 2 C, o-CAr), 115.25
(d, J = 22.3 Hz, 2 C, m-CAr), 99.3, 36.3, 34.9, 12.0.
2
1H NMR (200 MHz, DMSO-d6): d = 2.84 (dd, JAB = 16.4 Hz,
3JAX = 2.0 Hz, 1 H, 6-Ha), 3.23 (dd, 3JBX = 7.9 Hz, 1 H, 6-Hb), 5.21
(dd, 1 H, 7-Hx), 7.15–7.80 (m, 7 Harom), 7.68 (s, 1 H, 2-H), 10.82 (br
s, 2 H, NH).
MS (EI, 70 eV): m/z (%) = 364 (8) [M+], 366 (2), 227 (9), 226 (100).
Anal. Calcd for C20H17FN4O2: C, 65.93; H, 4.70; N, 15.38. Found:
C, 65.8; H, 4.65; N, 16.3.
MS (EI, 70 eV): m/z (%) = 386 (17) [M+], 387 (5), 231 (22), 230
(100).
Anal. Calcd for C19H13F3N4O2: C, 59.07; H, 3.39; N, 14.5. Found:
C, 58.9; H, 3.3; N, 14.5.
N-(3-Chloro-4-methoxyphenyl)-3-methyl-6-oxo-1-phenyl-
4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-4-carboxamide
(9d)
N-Aryl-3-methyl-6-oxo-1-phenyl- or N-Aryl-1,3-dimethyl-6-
oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-4-carbox-
amides 9a–i; General Procedure
A mixture of 5-aminopyrazole 3a,b (0.002 mol) and N-arylmaleim-
ide 4a,e,g,h,j–m (0.002 mol) in DMF (1 mL) was placed in a flask
and refluxed for 3 h. After cooling, acetone (10 mL) was added. The
mixture was allowed to stand and then the precipitate that had
formed was filtered to give the solid product which was additionally
washed with acetone and dried in air at r.t.
Colorless solid; mp 250–251 °C.
IR (KBr): 3434, 3288, 3053, 2918, 1677, 1654, 1650, 1603, 1501,
1441, 1382, 1061 cm–1.
1H NMR (200 MHz, DMSO-d6): d = 2.14 (s, 3 H, CH3), 2.65 (dd,
2JAB = 15.7 Hz, 3JAX = 4.2 Hz, 1 H, 5-Ha), 2.87 (dd, 3JBX = 7.0 Hz,
1 H, 5-Hb), 3.82 (s, 3 H, CH3O), 3.88 (dd, 1 H, 4-Hx), 7.10–7.78 (m,
8 Harom), 10.24 (br s, 1 H, NH), 10.42 (br s, 1 H, NHpyr).
13C NMR (50 MHz, DMSO-d6): d = 170.6, 169.6, 150.7, 145.0,
139.7, 137.8, 132.4, 129.1, 126.7, 122.8, 121.1, 120.1, 119.3, 112.9,
99.2, 56.1, 36.3, 34.8, 12.0.
3-Methyl-6-oxo-N,1-diphenyl-4,5,6,7-tetrahydro-1H-pyrazo-
lo[3,4-b]pyridine-4-carboxamide (9a)
Colorless solid; mp 250–251 °C.
MS (EI, 70 eV): m/z (%) = 410 (8) [M+], 412 (3), 227 (18), 226
(100), 199 (24), 77 (24).
IR (KBr): 3435, 3298, 3062, 2922, 1698, 1659, 1599, 1537, 1500,
1445, 1385 cm–1.
1H NMR (200 MHz, DMSO-d6): d = 2.15 (s, 3 H, CH3), 2.66 (dd,
2JAB = 15.9 Hz, 3JAX = 4.6 Hz, 1 H, 5-Ha), 2.87 (dd, 3JBX = 6.8 Hz,
1 H, 5-Hb), 3.89 (dd, 1 H, 4-Hx), 7.03–7.63 (m, 10 Harom), 10.23 (br
s, 1 H, NH), 10.40 (br s, 1 H, NHpyr).
Anal. Calcd for C21H19ClN4O3: C, 61.39; H, 4.66; N, 13.64. Found:
C, 61.2; H, 4.7; N, 13.6.
3-Methyl-6-oxo-1-phenyl-N-[2-(trifluoromethyl)phenyl]-
4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-4-carboxamide
(9e)
13C NMR (50 MHz, DMSO-d6): d = 170.7, 169.7, 145.0, 139.7,
138.7, 137.9, 129.1, 128.6, 126.7, 123.5, 122.7, 119.4, 99.3, 36.3,
34.9, 12.0.
MS (EI, 70 eV): m/z (%) = 346 (5) [M+], 227 (16), 226 (100), 77
(16).
Colorless solid; mp 260–261 °C.
IR (KBr): 3433, 3280, 2916, 1680, 1655, 1518, 1237, 1030 cm–1.
1H NMR (200 MHz, DMSO-d6): d = 2.21 (s, 3 H, CH3), 2.61 (dd,
2JAB = 16.1 Hz, 3JAX = 3.3 Hz, 1 H, 5-Ha), 2.94 (dd, 3JBX = 7.0 Hz,
1 H, 5-Hb), 4.00 (dd, 1 H, 4-Hx), 7.29–7.77 (m, 9 Harom), 9.86 (br s,
1 H, NH), 10.43 (br s, 1 H, NHpyr).
Anal. Calcd for C20H18N4O2: C, 69.35; H, 5.24; N, 16.17. Found: C,
69.3; H, 5.2; N, 16.1.
Anal. Calcd for C21H17F3N4O2: C, 60.87; H, 4.14; N, 13.52. Found:
C, 60.7; H, 4.0; N, 13.4.
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N-(2,4-Dimethylphenyl)-3-methyl-6-oxo-1-phenyl-4,5,6,7-tet-
rahydro-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (9f)
Colorless solid; mp 279–280 °C.
IR (KBr): 3436, 3280, 2920, 1682, 1650, 1532, 1501 cm–1.
1H NMR (50 MHz, DMSO-d6): d = 2.15 (s, 3 H, CH3), 2.21 (s, 3 H,
CH3), 2.25 (s, 3 H, CH3), 2.64 (dd, 2JAB = 16.1 Hz, 3JAX = 3.8 Hz, 1
H, 5-Ha), 2.89 (dd, 3JBX = 7.0 Hz, 1 H, 5-Hb), 3.94 (dd, 1 H, 4-Hx),
6.94–7.49 (m, 8 Harom), 9.44 (br s, 1 H, NH), 10.00 (br s, 1 H, NHpyr).
13C NMR (50 MHz, DMSO-d6): d = 170.8, 169.6, 145.0, 139.7,
138.9, 134.5, 133.2, 131.9, 130.7, 129.0, 126.6, 126.3, 125.2, 122.7,
99.5, 35.6, 35.2, 20.3, 17.5, 11.9.
3-(5-Amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)-1-phenylpyr-
rolidine-2,5-dione (11)
A mixture of aminopyrazole 3a (0.005 mol) and N-phenylmale-
imide (4a, 0.005 mol) in i-PrOH (10 mL) was refluxed for 3 h. The
mixture was allowed to stand and then filtered to give the solid
product which was washed with i-PrOH and dried in air at r.t. to
give 11 as a colorless solid; mp 184–185 °C.
IR (KBr): 3428, 3359, 2921, 1708, 1630, 1595, 1500, 1374, 1159
cm–1.
1H NMR (200 MHz, DMSO-d6): d = 2.04 (s, 3 H, CH3), 2.83 [dd,
3
3
2JAB = 18.1 Hz, JAX = 6.0 Hz, 1 H, Ha(pyr)], 3.25 (dd, JBX = 9.7
Hz, 1 H, 5-Hb), 4.36 (dd, 1 H, 4-Hx), 5.22 (br s, 2 H, NH2). 7.27–
7.60 (m, 10 Harom).
MS (EI, 70 eV): m/z (%) = 374 (16) [M+], 375 (4), 227 (13), 226
(100), 77 (17).
13C NMR (50 MHz, DMSO-d6): d = 177.3, 175.3, 146.0, 144.8,
139.1, 132.6, 128.9, 128.8, 128.2, 126.9, 125.9, 122.8, 98.4, 35.9,
35.5, 12.7.
Anal. Calcd for C22H22N4O2: C, 70.57; H, 5.92; N, 14.96. Found: C,
70.4; H, 5.9; N, 14.8.
MS (EI, 70 eV): m/z (%) = 346 (55) [M+], 347 (15), 345 (41), 266
(84), 226 (45), 199 (30), 173 (30), 119 (100).
Ethyl (3-Methyl-6-oxo-1-phenyl-4,5,6,7-tetrahydro-1H-pyrazo-
lo[3,4-b]pyridine-4-carboxamido)benzoate (9g)
Colorless solid; mp 195–196 °C.
Anal. Calcd for C20H18N4O2: C, 69.35; H, 5.24; N, 16.17. Found: C,
69.3; H, 5.2; N, 16.1.
IR (KBr): 3629, 3422, 3315, 2929, 1713, 1683, 1598, 1533, 1329,
1269, 1171, 1100 cm–1.
Transformation of 11 into 9a
1H NMR (200 MHz, DMSO-d6): d = 1.31 (t, J = 7.1 Hz, 3 H, CH3),
2.15 (s, 3 H, CH3), 2.68 (dd, 2JAB = 15.7 Hz, 3JAX = 4.0 Hz, 1 H, 5-
Ha), 2.90 (dd, 3JBX = 7.0 Hz, 1 H, 5-Hb), 3.93 (dd, 1 H, 4-Hx), 4.28
(q, 2 H, CH2), 730–7.95 (m, 9 Harom), 10.39 (br s, 1 H, NH), 10.52
(br s, 1 H, NHpyr).
Pyrrolidine-2,5-dione 11 (0.003 mol) and DMF (2 mL) were placed
in a flask and the mixture refluxed for 3 h. The mixture was poured
into H2O (20 mL) and precipitated compound 9a was filtered off
and dried in air at r.t.
MS (EI, 70 eV): m/z (%) = 418 (12) [M+], 419 (4), 227 (16), 226
(100).
Acknowledgment
The authors thank Dr. Dmitry Sofronov for recording IR spectra.
Anal. Calcd for C23H22N4O4: C, 66.02; H, 5.30; N, 13.39. Found: C,
64.8; H, 5.5; N, 13.6.
References
N-(4-Chlorophenyl)-3-methyl-6-oxo-1-phenyl-4,5,6,7-tetrahy-
dro-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (9h)
Colorless solid; mp 290–291 °C.
(1) See, for example: (a) Alajarin, R.; Avarez-Buila, J.;
Vaquero, J. J.; Sunkel, C.; Fau, J.; Statkov, P.; Sanz, J.
Tetrahedron: Asymmetry 1993, 4, 617. (b) Bossert, F.;
Vater, W. Med. Res. Rev. 1989, 9, 291. (c) Trigle, D. J.;
Langs, D. A.; Janis, R. A. Med. Res. Rev. 1989, 9, 123.
(d) Tsuda, Y.; Mishina, T.; Obata, M.; Araki, K.; Inui, J.;
Nakamura, T. WO 8,504,172, 1985; Chem. Abstr. 1986, 104,
207298. (e) Tsuda, Y.; Mishina, T.; Obata, M.; Araki, K.;
Inui, J.; Nakamura, T. JP 61,227,584, 1986; Chem. Abstr.
1988, 109, 120988. (f) Tsuda, Y.; Mishina, T.; Obata, M.;
Araki, K.; Inui, J.; Nakamura, T. EP 0,217,142, 1987; Chem.
Abstr. 1987, 106, 213976. (g) Atwal, K. S.; Vaccaro, W.;
Lloyd, J.; Finlay, H.; Yan, L.; Bhandaru, R. S. WO
0,140,231, 2001; Chem. Abstr. 2003, 135, 19660.
(h) Atwal, K. S.; Moreland, S. Bioorg. Med. Chem. Lett.
1991, 1, 291. (i) Kappe, C. O. Eur. J. Med. Chem. 2000, 35,
1043.
IR (KBr): 3421, 3231, 2921, 1706, 1656, 1596, 1543, 1492, 1400,
1185, 1091 cm–1.
1H NMR (200 MHz, DMSO-d6): d = 2.14 (s, 3 H, CH3), 2.66 (dd,
2JAB = 16.3 Hz, 3JAX = 4.3 Hz, 1 H, 5-Ha), 2.88 (dd, 3JBX = 6.7 Hz,
1 H, 5-Hb), 3.86 (dd, 1 H, 4-Hx), 7.31–7.66 (m, 9 Harom), 10.21 (br
s, 1 H, NH), 10.36 (br s, 1 H, NHpyr).
MS (EI, 70 eV): m/z (%) = 380 (11) [M+], 382 (4), 227 (16), 226
(100), 77 (22).
Anal. Calcd for C20H17ClN4O2: C, 63.08; H, 4.50; N, 14.71. Found:
C, 62.95; H, 4.6; N, 14.7.
1,3-Dimethyl-6-oxo-N-phenyl-4,5,6,7-tetrahydro-1H-pyrazo-
lo[3,4-b]pyridine-4-carboxamide (9i)
Colorless solid; mp 298–299 °C.
(2) (a) Chebanov, V. A.; Gura, K. A.; Desenko, S. M. Top.
Heterocycl. Chem. 2010, 23, 41. (b) Chebanov, V. A.;
Desenko, S. M.; Gurley, T. W. Azaheterocycles Based on
a,b-Unsaturated Carbonyls; Springer: Heidelberg, 2008.
(c) Chebanov, V. A.; Desenko, S. M. Curr. Org. Chem.
2006, 10, 297.
(3) (a) Chebanov, V. A.; Saraev, V. E.; Desenko, S. M.;
Chernenko, V. N.; Shishkina, S. V.; Shishkin, O. V.; Kobzar,
K. M.; Kappe, C. O. Org. Lett. 2007, 9, 1691.
IR (KBr): 3435, 3326, 3185, 3039, 1675, 1656, 1599, 1526, 1442,
1385 cm–1.
1H NMR (200 MHz, DMSO-d6): d = 2.03 (s, 3 H, CH3), 2.57 (dd,
2JAB = 16.1 Hz, 3JAX = 4.4 Hz, 1 H, 5-Ha), 2.75 (dd, 3JBX = 6.9 Hz,
1 H, 5-Hb), 3.55 (s, 3 H, 1-CH3), 3.78 (dd, 1 H, 4-Hx), 7.00–7.60 (m,
5 Harom), 10.10 (br s, 1 H, NH), 10.54 (br s, 1 H, NHpyr).
13C NMR (50 MHz, DMSO-d6): d = 170.9, 169.2, 142.3, 139.9,
138.6, 128.4, 123.2, 119.3, 96.4, 36.4, 34.7, 34.1, 11.7.
MS (EI, 70 eV): m/z (%) = 284 (5) [M+], 164 (100), 77 (5).
(b) Chebanov, V. A.; Saraev, V. E.; Desenko, S. M.;
Chernenko, V. N.; Knyazeva, I. V.; Groth, U.; Glasnov, T.
N.; Kappe, C. O. J. Org. Chem. 2008, 73, 5110.
(c) Muravyova, E. A.; Shishkina, S. V.; Musatov, V. I.;
Shishkin, O. V.; Desenko, S. M.; Chebanov, V. A. Synthesis
2009, 1375. (d) Chebanov, V. A.; Sakhno, Ya. I.; Desenko,
Anal. Calcd for C15H16N4O2: C, 63.37; H, 5.67; N, 19.71. Found: C,
63.1; H, 5.2; N, 19.7.
Synthesis 2011, No. 5, 783–793 © Thieme Stuttgart · New York

PAPER
Heterocyclizations of Derivatives of 5-Aminopyrazoles and N-Arylmaleimides
793
S. M.; Chernenko, V. N.; Musatov, V. I.; Shishkina, S. V.;
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J. Heterocycl. Chem. 2011, in press.
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(c) Tetsuro, S.; Yuki, M.; Tetsuo, I.; Teruo, S.; Kenichi, S.
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(10) Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112.
(11) The final atomic coordinates and crystallographic data for
molecule 7l have been deposited with the Cambridge
Crystallographic Data Centre, 12 Union Road, CB2 1EZ,
UK [fax: +44 (1223)336033; e-mail:
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deposit@ccdc.cam.ac.uk] and is available on request
quoting the deposition number CCDC 792559.
Synthesis 2011, No. 5, 783–793 © Thieme Stuttgart · New York