Chemoselectivity of multicomponent condensations of barbituric acids, 5-aminopyrazoles, and aldehydes

Article abstract of DOI:10.1055/s-0028-1088024

Multicomponent cyclocondensations between 5-aminopyrazoles, barbituric acids, and aromatic aldehydes under conventional thermal heating, microwave irradiation, or ultrasonic irradiation were studied and the temperature regime was found to be the main fact

Full text of DOI:10.1055/s-0028-1088024

PAPER
1375
Chemoselectivity of Multicomponent Condensations of Barbituric Acids,
5-Aminopyrazoles, and Aldehydes
C
hemoselectivi
l
ty of
M
e
ulticompon
n
ent Condens
a
ations A. Muravyova, Svetlana V. Shishkina, Vladimir I. Musatov, Irina V. Knyazeva, Oleg V. Shishkin,
Sergey M. Desenko, Valentin A. Chebanov*
State Scientific Institution ‘Institute for Single Crystals’ of National Academy of Sciences of Ukraine, Lenina ave. 60,
61001 Kharkiv, Ukraine
Fax +38(57)3409343; E-mail: chebanov@isc.kharkov.com
Received 3 November 2008; revised 19 December 2008
zolopyridines have been also found to be useful in
agriculture7 and for coloring wool, silk, and polyamides.8
Abstract: Multicomponent cyclocondensations between 5-ami-
nopyrazoles, barbituric acids, and aromatic aldehydes under con-
ventional thermal heating, microwave irradiation, or ultrasonic
irradiation were studied and the temperature regime was found to be
the main factor in controlling their chemoselectivity. At high tem-
peratures the starting materials react in two different ways yielding
pyrazolo[4¢,3¢:5,6]pyrido[2,3-d]pyrimidines or their dihydro ana-
logues depending on the nature of the N-substituent in the 5-ami-
nopyrazole. Treatment at room temperature results in a new four-
component reaction giving previously undisclosed heterocyclic
compounds, 4,6-diaryl-1,4,6,7-tetrahydro-2¢H-spiro[pyrazolo[3,4-
b]pyridine-5,5¢-pyrimidine]s. Facile multipurpose three-component
selective procedures to new spiroheterocycles are proposed.
A facile and widespread synthetic approach to azolopy-
ridines and pyrimidines is the multicomponent cyclocon-
densation of aminoazoles with CH-acids and carbonyl
compounds, which sometimes can lead to the formation of
several different reaction products;9 their selectivity may
be efficiently tuned by application of microwave and ul-
trasonic irradiation.9e,h,i However, the multicomponent
synthesis of pyrazolopyridopyrimidines involving barbi-
turic acid as a building block has not been described in the
literature and only unsuccessful attempts at similar con-
densations have been communicated.10 The usual way to
pyrazolopyridopyrimidines is by the modification of vici-
nal aminocarbonitriles or aminoamides of azolopyridines,
obtained by three-component reaction of aminoazole, al-
dehyde, and malononitrile or cyanoacetamide (Scheme
1).11 This method allows the synthesis of diverse types of
the target heterocycles, but cannot be conducted as an ef-
ficient one-pot procedure. Another way includes reaction
of 5-aminopyrazole-4-carbaldehydes with active methyl-
ene compounds, for example barbituric acids and cyclic
1,3-diketones, and leads to pyrazolopyridopyrimidines in
high yields.12 However, this route does not give the possi-
bility of introducing substituents into the pyridine ring
(Scheme 1).
Key words: heterocycles, multicomponent reactions, selectivity,
ultrasonication, microwave-assisted synthesis
The efficient synthesis of organic compounds by an ‘ideal
procedure’1 is one of the most important objectives in
modern synthetic chemistry for drug discovery and relat-
ed fields. Organic reactions should preferably be facile
and fast and the resulting products should be easily and
rapidly purified. Multicomponent reactions2 and the ap-
plication of ‘non-classical’ conditions, like controlled
microwave3 and ultrasonic4 irradiation, are powerful tools
in modern chemistry for the optimization of reactions and
the efficient preparation of new target compounds. The
use of these methods and their combinations in high-
throughput organic synthesis has become particularly
popular within the last fifteen years and numerous exam-
ples of such condensations for the construction of hetero-
cycles with interesting properties have been reported in
the literature.2–4
Ar
Ar
NH
R1
R1
CN
R2
X
R2NCX
N
N
N
pyridine, ∆
N
H
N
H
N
NH2
N
N
H
X = O, S
O
O
R1
The importance of azolopyrimidines in medicinal chemis-
try is widely known: many of these fused nitrogen hetero-
cycles are known as cardiovascular vasodilators, calcium
channel blocking agents, and potassium channel inhibi-
tors and openers.5 An interesting class of such heterocy-
cles is the azolopyridopyrimidines, which possess
antimycobacterial, fungicidal, anticancer, and antihistam-
ic activities and they are effective as central analgetics and
for the treatment of insomnia.6 Some derivatives of pyra-
R1
CHO
R2
R2
S
N
N
∆
+
N
N
NH2
N
N
HO
N
S
N
N
Ph
R2
Ph
R2
Scheme 1
Four-component condensations involving two equiva-
lents of barbituric acid and one equivalent of aldehyde and
ammonia leading to the formation of dihydropyridine ring
are also known.13
SYNTHESIS 2009, No. 8, pp 1375–1385
x
x
.
x
x
.2
0
0
9
Advanced online publication: 25.03.2009
DOI: 10.1055/s-0028-1088024; Art ID: T19908SS
© Georg Thieme Verlag Stuttgart · New York
Therefore, in the present work the multicomponent reac-
tions of 5-aminopyrazoles 1, barbituric acids 2, and aro-

1376
E. A. Muravyova et al.
PAPER
O
R4
O
R1
R1
R3
R3
X
N
DMF, ∆ 30 min
N
R4
+
+
O
N
N
N
or MW, 190 °C
3 min
NH2
HO
N
X
N
N
N
R3
R2
R2
R3
4a–l (50–95%)
1a–c
2a–c
3a–i
O
R4
O
R1
N
R1
R3
R3
X
N
DMF, ∆ 30 min
N
+
R4
+
O
N
NH2
HO
N
X
N
N
N
H
N
R3
R2
R2
R3
3a–d,f–h,j
1d,e
2a–c
5a–i (50–90%)
Scheme 2
matic aldehydes 3 were studied under conventional lo[4¢,3¢:5,6]pyrido[2,3-d]pyrimidines 5a–i in 50–90%
heating, microwave irradiation, or ultrasonic irradiation at yields (Scheme 2, Table 1). It should be noted that in case
various temperatures. It was established that the three- of compound 5b impurities of the corresponding hetero-
component reaction of 5-amino-3-methyl-1-phenyl-1H- aromatized heterocycle (~5%) were also observed in the
pyrazole (1a) with barbituric acids 2a,b and aldehydes 1H NMR spectrum.
3a–h in boiling N,N-dimethylformamide for 30 minutes
gave heteroaromatized 4-arylpyrazolo[4¢,3¢:5,6]pyri-
do[2,3-d]pyrimidines 4a–l (Scheme 2, Table 1). The
As the possible reason for the different reaction products
in the case of aminoazoles 1a and 1d,e, we considered the
influence of the N-phenyl substituent which enlarges the
work-up procedure was simple and consisted of the addi-
electron-donor properties of the aminoazole moiety and
tion of ethanol to the reaction mixture, filtration, and dry-
this can result in easier oxidation of the pyridine ring. The
ing on air at room temperature, which allowed the target
multicomponent reactions involving barbituric acid 2a,
aldehyde 3g, and 5-amino-3-methyl-1-(4-nitrophenyl)-
1H-pyrazole (1b), containing a nitrophenyl electron-with-
heterocycles 4a–l to be obtained in 50–95% yields with
purity ~95% according to 1H NMR.
From the other hand, it was unexpectedly found that re- drawing substituent, however, also led to oxidized hetero-
fluxing of the equimolar mixture of N-unsubstituted 3- cycle 4j. The reaction with participation of 5-amino-1,3-
methyl- and 3-phenyl-5-aminopyrazoles 1d,e with barbi- dimethyl-1H-pyrazole (1c), barbituric acids 2a,c, and al-
turic acids 2a–c and aromatic aldehydes 3a–d,f–h,j in dehydes 3e,i gave the same result, compounds 4k and 4l
N,N-dimethylformamide for 30 minutes after an identical were the sole isolated products after cooling and addition
work up procedure led to 4-aryl-4,9-dihydropyrazo- of ethanol to the reaction mixture.
Table 1 Synthesis of Pyrazolo[4¢,3¢:5,6]pyrido[2,3-d]pyrimidines 4a–l, 5a–i
Entry 5-Aminopyrazole
R1
Barbituric acid
R3
Aldehyde
R4
Product
Yield (%)
R2
X
O
O
O
O
O
O
S
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
2a
2a
2a
2a
2a
2a
2b
2b
2b
2a
2a
H
H
H
H
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
3f
4-EtC6H4
4a
4b
4c
4d
4e
4f
95a
60a
95a
90a
75a
85a
65a
55a
50a
55a
50a
Ph
4-MeSC6H4
4-O2NC6H4
4-NCC6H4
3
Ph
4
Ph
5
Ph
4-MeOC6H4
2,4,5-(MeO)3C6H2
4-EtC6H4
6
Ph
7
Ph
3a
3g
3h
3g
3e
4g
4h
4i
8
Ph
S
4-ClC6H4
9
Ph
S
3,4-(HO)2C6H3
4-ClC6H4
10
11
4-O2NC6H4
Me
O
O
4j
4-MeOC6H4
4k
Synthesis 2009, No. 8, 1375–1385 © Thieme Stuttgart · New York

PAPER
Chemoselectivity of Multicomponent Condensations
1377
Table 1 Synthesis of Pyrazolo[4¢,3¢:5,6]pyrido[2,3-d]pyrimidines 4a–l, 5a–i (continued)
Entry 5-Aminopyrazole
R1
Barbituric acid
R3
Aldehyde
R4
Product
Yield (%)
R2
Me
H
X
O
O
O
O
O
O
O
O
O
S
12
13
14
15
16
17
18
19
20
21
1c
1d
1d
1d
1d
1d
1d
1d
1e
1e
Me
Me
Me
Me
Me
Me
Me
Me
Ph
2c
2a
2c
2a
2a
2a
2a
2a
2a
2b
Me
H
3i
4-MeC6H4
4l
50a
85
50
75
85
70
55
90
75
55
3a
3b
3c
3d
3f
4-EtC6H4
5a
5b
5c
5d
5e
5f
H
Me
H
4-MeSC6H4
4-O2NC6H4
4-NCC6H4
H
H
H
H
H
2,4,5-(MeO)3C6H2
3,4-(HO)2C6H3
2-HO-3-EtOC6H3
4-ClC6H4
H
H
3h
3j
H
H
5g
5h
5i
H
H
3g
3g
Ph
H
H
4-ClC6H4
a Under MW irradiation.
Application of controlled microwave irradiation (temper- 1a,d in N,N-dimethylformamide in ultrasonic bath for
atures from 150 to 190 °C) to carry out multicomponent three hours yielded spiro compounds 6a–f in 63–98%
reaction involving N-unsubstituted pyrazoles 1d,e did not yields (Method A, Scheme 3, Table 2).
give positive results, as it was expected, and led to com-
plicated mixtures of several inseparable products. Howev-
It was additionally established that simple intensive stir-
ring of the same starting compounds in N,N-dimethyl-
er, using the microwave field to promote the reaction of 5-
formamide at room temperature with magnetic stirring for
aminopyrazoles 1a–c with barbituric acids and aldehydes
2–3 hours also allowed the target spiroheterocycles 6a–f
was successful. It was established that three-component
to be obtained in lower yields. It is interesting that a recent
reactions of aromatic aldehydes 3a–i and barbituric acids
report9h found that multicomponent condensations of 5-
aminopyrazoles with cyclic 1,3-diketones and aldehydes
under ultrasonic irradiation at room temperature yielded
Biginelli-type dihydropyrimidines, which were not ob-
2a–c with aminopyrazoles 1a–c can be efficiently carried
out under microwave irradiation in ethanol instead of
N,N-dimethylformamide at 170 °C for five minutes. The
most preferable microwave-assisted procedure for the
synthesis of pyrazolo[4¢,3¢:5,6]pyrido[2,3-d]pyrimidines
4, from the viewpoint of yields and purity of the target
compounds. consisted of the treatment of the starting
served in our case. On the other hand, the formation of
similar spiro compounds was described for the four-com-
ponent treatment of barbituric acid, urea, and aldehydes.14
A main disadvantage of the new four-component reaction
building blocks in N,N-dimethylformamide under micro-
is the impossibility of introducing two different substitu-
wave irradiation at 190 °C for three minutes.
ents R4 in positions 4 and 6. To avoid this limitation we
Surprisingly, it was observed that the multicomponent re-
developed a two-component procedure consisted of the
action involving 4-(methylsulfanyl)benzaldehyde (3b), 5-
reaction of arylidenebarbituric acids 7a,b and azometh-
amino-3-methyl-1-phenyl-1H-pyrazole (1a), and barbitu-
ines 8a,b; treatment of these compounds in N,N-dimethyl-
ric acid 2a in boiling N,N-dimethylformamide sometimes
formamide under sonication for three hours yielded
1
passed in an unusual manner yielding, according to H
spiroheterocycles 6g,h (Method B, Scheme 3, Table 2).
NMR and mass spectra, hitherto undisclosed 3-methyl-
However, this method requires the preliminary synthesis
4,6-bis[4-(methylsulfanyl)phenyl]-1-phenyl-1,4,6,7-tet-
of two starting compounds (6 and 7) and this makes the
rahydro-2¢H-spiro[pyrazolo[3,4-b]pyridine-5,5¢-pyrimi-
procedure less efficient and facile. Taking into account
such inconveniences, two additional three-component
synthetic pathways to target compounds 6 were elaborat-
dine]-2¢,4¢,6¢(1¢H,3¢H)-trione (6a).
Taking into account our previous results in tuning the
chemoselectivity of multicomponent reactions with par-
ed.
ticipation of similar starting compounds by application of
Heterocycles 6a,d–h were obtained by treatment of
high-temperature microwave-assisted and low-tempera-
azomethines 8a–e with barbituric acids 2a–c and corre-
sponding aromatic aldehydes 3a,b,g,e at room tempera-
ture under sonication or simple stirring of the reaction
mixture for three hours in 55–70% yields (Method C,
Scheme 3, Table 2). The most convenient and effective
ture ultrasonic-promoted procedures9e,h,i we tried to carry
out this four-component cyclocondensation under sonica-
tion at room temperature. It was found that treatment of
two equivalent of aromatic aldehyde 3b,e,g with one
equivalent of barbituric acid 2a–c and aminopyrazoles
Synthesis 2009, No. 8, 1375–1385 © Thieme Stuttgart · New York

1378
E. A. Muravyova et al.
PAPER
procedure for the synthesis spiro[pyrazolo[3,4-b]pyri- zoles 1a,d,e, and aldehydes 3b,e,g under ultrasonic irradi-
dine-5,5¢-pyrimidine]s 6 consists of the three-component ation or with magnetic stirring at ambient conditions
reaction of arylidenebarbituric acids 7a–e, 5-aminopyra- (Method D, Scheme 3, Table 2).
R3
Method A
R1
O
R4
O
N
X
R1
R3
X
O
DMF, r.t.
N
N
R4
N
R3
+
+ 2
OH
N
sonication or
stirring
H
NH2
N
N
N
H
O
N
R2
R4
R2
R3
1a,d
2a–c
6a–f (63–98%)
3b,e,g
R3
Method B
O
R4
O
R1
R4
N
X
R1
R3
N
R5
N
DMF, r.t.
+
N
R3
N
N
N
sonication
N
X
N
O
N
H
O
R2
R5
R2
R3
6g,h (60–75%)
7a,b
8a,b
R3
Method C
O
O
R1
R4
N
O
X
R1
R3
N
O
H
R5
DMF, r.t.
N
N
R4
R3
+
+
N
N
N
sonication or
stirring
X
N
O
N
N
H
R2
R5
R3
R2
2a–c
3a,b,e,g
8a–e
6a,d–h (55–70%)
R3
Method D
R1
O
R4
O
N
R4
X
R1
R3
X
O
DMF, r.t.
N
R5
N
+
+
N
N
N
R3
sonication or
stirring
NH2
H
N
O
N
N
H
O
R5
R2
R3
R2
1a,d,e
7a–e
3b,e,g
6a,d–h (53–78%)
Scheme 3
Table 2 Synthesis of Spiropyrazolo[3,4-b]pyridine-5,5¢-pyrimidines 6a–h
Entry Substrates Method Substituents
Product
Yielda (%)
R1
R2
Ph
Ph
Ph
Ph
H
R3
R4
R5
X
1
2
1a + 2a + 3b (2 equiv)
A
A
A
A
A
A
B
B
C
C
C
Me
Me
Me
Me
Me
Ph
H
4-MeSC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
4-MeOC6H4
4-MeOC6H4
4-EtC6H4
–
O
O
O
S
6a
6b
6c
6d
6e
6f
95
98
80
82
80
63
75
60
70
70
55
1a + 2a + 3e (2 equiv)
1a + 2a + 3g (2 equiv)
1a + 2b + 3g (2 equiv)
1d + 2c + 3e (2 equiv)
1e + 2c + 3b (2 equiv)
7a + 8a
H
–
3
H
–
4
H
–
5
Me
Me
H
–
O
O
O
O
O
S
6
H
–
7
Me
Me
Me
Me
Me
H
4-MeOC6H4
4-MeOC6H4
4-MeSC6H4
4-ClC6H4
4-MeOC6H4
6g
6h
6a
6d
6e
8
7b + 9b
Ph
Ph
Ph
H
Me
H
4-MeSC6H4
4-MeSC6H4
4-ClC6H4
4-MeOC6H4
9
2a + 3b + 8c
10
11
2b + 3g + 8d
H
2c + 3e + 8a
Me
O
Synthesis 2009, No. 8, 1375–1385 © Thieme Stuttgart · New York

PAPER
Chemoselectivity of Multicomponent Condensations
Table 2 Synthesis of Spiropyrazolo[3,4-b]pyridine-5,5¢-pyrimidines 6a–h (continued)
Entry Substrates Method Substituents
1379
Product
Yielda (%)
R1
R2
R3
Me
H
R4
R5
X
O
O
O
O
S
12
13
14
15
16
17
18
19
20
2c + 3b + 8e
2a + 3a + 8a
2c + 3b + 8b
1a + 3b + 7c
1a + 3g + 7d
1d + 3e + 7e
1e + 3b + 7e
1d + 3e + 7a
1a + 3e + 7b
C
C
C
D
D
D
D
D
D
Ph
H
4-MeOC6H4
4-EtC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeSC6H4
4-ClC6H4
6f
55
65
55
75
78
53
54
65
55
Me
Me
Me
Me
Me
Ph
H
6g
6h
6a
6d
6e
6f
Ph
Ph
Ph
H
Me
H
4-MeSC6H4
4-MeSC6H4
4-ClC6H4
4-MeOC6H4
4-MeOC6H4
4-EtC6H4
H
Me
Me
H
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
O
O
O
O
H
Me
Me
H
6g
6h
Ph
Me
4-MeSC6H4
a Under sonication.
It should be noted that in Methods B and C if the reaction
mixture is refluxed, instead of ultrasonication or stirring at
room temperature, this leads to decomposition of azo-
methines 8 and formation of two isomeric products with
reverse location of the R4 and R5 substituents (see result of
X-ray analysis for compound 6h).
In addition, it was established that compounds 6a–h under
both refluxing in boiling N,N-dimethylformamide and
microwave irradiation at 150–180 °C could not be rear-
ranged into pyrazolo[4¢,3¢:5,6]pyrido[2,3-d]pyrimidines 4
or 5 and only numerous products of decomposition were
found after the above-mentioned treatments.
The structures of heterocycles of type 4, 5, and 6 were es-
tablished by elemental analyses in combination with MS
and NMR spectroscopic data and X-ray diffraction analy-
sis. The 1H NMR spectra of pyrazolo[4¢,3¢:5,6]pyrido[2,3-
d]pyrimidines 4a–l are very simple and exhibit the signals
of pyrimidine NH and terminal functional groups as well
as of aryl rings. However, even together with information
obtained from MS and 13C NMR spectra these data did not
give structure proof of the compounds synthesized. Final-
ly X-ray diffraction analysis carried out for heterocycle 4a
showed that it has a structure of 4-(4-ethylphenyl)-3-
methyl-1-phenyl-1H-pyrazolo[4¢,3¢:5,6]pyrido[2,3-d]pyr-
imidine-5,7(6H,8H)-dione (Figure 1).
Figure 1 Structure of compound 4a (X-ray diffraction data)
pounds 6a–d,g), multiplets of aromatic rings, and
necessary signals of other functional groups. 13C NMR
spectra of other signals contain a signal for the spiro-car-
bon at d = ca. 65. All this data allowed us to suggest the
spiroheterocyclic structure for compounds 6a–h. Finally,
this structure was proved by X-ray diffraction data ob-
tained for crystal of 6h obtained in boiling N,N-dimethyl-
formamide (Figure 2).
1H NMR spectra of heterocyclic compounds 5a–i together
with signals of functional groups and aromatic rings con-
tain two additional singlets at ca. d = 5 and 11–12 assigned
to methylene and amino groups of dihydropyridine moi-
ety, respectively.
In summary, the article describes the development of
chemoselective cyclocondensations based on multicom-
ponent treatment between 5-aminopyrazoles, barbituric
acids, and aromatic aldehydes. It was established that tem-
perature was the main factor in controlling the direction of
the reaction studied. Under reflux or microwave irradia-
tion at high temperatures (170–190 °C) the starting mate-
rials react in two different ways, in the case of N-
substituted aminopyrazoles the reaction yields pyrazo-
lo[4¢,3¢:5,6]pyrido[2,3-d]pyrimidines or their dihydro an-
alogues when the N-substituent is absent. Sonication of
the same reaction mixture or simple stirring at room tem-
MS spectra and elemental analysis of compounds 6a–h
showed that these heterocycles contain fragments of two
molecules of aromatic aldehyde, one pyrimidine and one
pyrazole ring. 1H NMR spectra exhibit the following sig-
nals: singlets of methylene protons and amino group of
tetrahydropyridine ring at d = ~4.8, 4.9, and 6.0–6.5, re-
spectively, pyrimidine NH singlets at d = 10–12 (for com-
Synthesis 2009, No. 8, 1375–1385 © Thieme Stuttgart · New York

1380
E. A. Muravyova et al.
PAPER
The structures were solved by direct method using SHELXTL pack-
age.18 The restrains for the bond lengths (Csp3–Csp3 1.54 Å, CAr–O
1.37 Å, Csp3–O 1.42 Å, CAr–S 1.77 Å, Csp3–S 1.79 Å) in the disor-
dered fragments were applied in the refinement of the structures.
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 hy-
drogen atoms). The hydrogen atom of the structure 6h participating
in the formation of the hydrogen bond was refined in isotropic ap-
proximation.
Full-matrix least-squares refinement of the structures against F2 in
anisotropic approximation for non-hydrogen atoms using 7155
(4a), 4824 (6h) reflections was converged to: wR2 = 0.081
(R1 = 0.042 for 2690 reflections with F > 4s(F), S = 0.708) for
structure 4a and wR2 = 0.194 (R1 = 0.066 for 2842 reflections with
F > 4s(F), S = 0.926) for structure 6h.19
Figure 2 Structure of compound 6h (X-ray diffraction data)
4-Aryl-1H-pyrazolo[4¢,3¢:5,6]pyrido[2,3-d]pyrimidines 4a–l;
General Procedure
perature leads to a new four-component reaction yielding
previously undisclosed heterocyclic compounds, 4,6-
diaryl-1,4,6,7-tetrahydro-2¢H-spiro[pyrazolo[3,4-b]pyri-
dine-5,5¢-pyrimidine]s.
A mixture of 5-aminopyrazole 1a–c (1.30 mmol, 1 equiv), barbitu-
ric acid 2a–c (1.30 mmol, 1 equiv), and aromatic aldehyde 3a–i (1.3
mmol, 1 equiv) in DMF (2 mL), contained in a round-bottom flask
equipped with condenser, was refluxed for 30 min. The mixture was
cooled and EtOH (20 mL) was added. The mixture was allowed to
stand and then filtered to give a solid product that was washed with
EtOH and dried on air at r.t.
Melting points were obtained on a standard melting point apparatus
in open capillary tubes. The 1H and 13C NMR spectra were recorded
in DMSO-d6 at 400 and 200 MHz (100 and 50 MHz for 13C) on Jeol
Lambda 400 and Varian Mercury VX-200 spectrometers. LR-MS
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.
4-Aryl-1H-pyrazolo[4¢,3¢:5,6]pyrido[2,3-d]pyrimidines 4a–l;
General Procedure for Microwave-Assisted Reactions
A mixture of 5-aminopyrazole 1a–c (1.30 mmol, 1 equiv), barbitu-
ric acid 2a–c (1.30 mmol, 1 equiv), and aromatic aldehyde 3a–i (1.3
mmol, 1 equiv) in DMF (2 mL), contained in a sealed microwave
vial, was heated in a single mode microwave reactor at 190 °C for 3
min with magnetic stirring. The mixture was cooled to r.t. by com-
pressed air and EtOH (20 mL) was added. The mixture was allowed
to stand and then filtered to give a solid product which was washed
with EtOH and dried on air at r.t.
Sonication was carried out with help of standard ultrasonic bath
producing irradiation at 44.2 kHz in round-bottom flasks equipped
with a condenser.
Microwave experiments were performed using the EmrysTM
Creator EXP and EmrysTM Initiator reactors from Biotage AB
(Uppsala, Sweden) possessing a single-mode microwave cavity
producing controlled irradiation at 2.45 GHz. Experiments were
carried out in sealed microwave process vials using high absorbance
level settings and IR temperature monitoring. Reaction times reflect
irradiation times at the set reaction temperature (fixed hold times).
The reaction was also carried out in EtOH (2 mL) at 150 °C for 5
min. In this case the precipitate formed was filtered after cooling of
the mixture without addition of any other solvent.
4-(4-Ethylphenyl)-3-methyl-1-phenyl-1H-pyrazolo[4¢,3¢:5,6]py-
rido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4a)
Colorless solid; mp >300 °C.
1H NMR (200 MHz, DMSO-d6): d = 1.25 (t, J = 7.5 Hz, 3 H, CH3),
1.70 (s, 3 H, CH3), 2.69 (q, J = 7.5 Hz, 2 H, CH3), 7.17–8.24 (m, 9
Harom), 11.28 (s, 2 H, NH).
All solvents and chemicals were obtained from standard commer-
cial vendors and were used without any further purification.
The synthesis of the starting 5-aminopyrazoles 1a–e were carried
out by the described procedures.15 Arylidenebarbituric acids 7a–e
and Schiff bases 8a–e obtained according known methods.16,17
13C NMR (100 MHz, DMSO-d6): d = 161.8, 153.2, 151.4, 150.7,
150.3, 145.5, 143.7, 139.1, 133.7, 129.5, 128.0, 127.3, 126.3, 120.7,
114.2, 104.2, 28.5, 16.0, 14.4.
X-ray Diffraction Analysis of Compounds 4a and 6h
The colorless crystals of 4a 2 (C23H19N5O2)·C3H7NO·C6H6O) are
triclinic. At –173 K, a = 11.522(6), b = 13.364(8), c = 16.369(4) Å,
a = 79.58(4)°, b = 84.30(4)°, g = 63.27(6)°, V = 2214(2) Å3,
MS (EI, 70 eV): m/z (%) = 397 (100) [M+], 398 (29.5), 396 (26.8).
Mr = 914.03, Z = 2, space group P1, dcalc = 1.371 g/m3,
m
(MoKa) = 0.093 mm–1, F(000) = 964. Intensities of 13853 reflec-
tions (7323 independent, Rint = 0.037) were measured on the ‘Xcal-
ibur-3’ diffractometer (graphite monochromated MoKa radiation,
CCD detector, w-scanning, 2Qmax = 50°).
Anal. Calcd for C23H19N5O2: C, 69.51; H, 4.82; N, 17.62. Found: C,
69.48; H, 4.78; N, 17.60.
3-Methyl-4-[4-(methylsulfanyl)phenyl]-1-phenyl-1H-pyrazo-
lo[4¢,3¢:5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4b)
Colorless solid; mp >300 °C.
1H NMR (200 MHz, DMSO-d6): d = 1.80 (s, 3 H, CH3), 2.54 (s, 3
H, SCH3), 6.24–8.25 (m, 9 Harom), 11.16 (s, 1 H, NH), 11.76 (s, 1 H,
NH).
The colorless crystals of 6h (C32H31N5O4S) are triclinic. At 293 K,
a = 8.180(1), b = 10.823(2), c = 17.503(3) Å, a = 107.23(1)°,
b = 94.75(1)°, g = 96.92(1)°, V = 1457.7(4) Å3, Mr = 581.68, Z = 2,
space group P1, dcalc = 1.325 g/m3, m (MoKa) = 0.157 mm–1,
F(000) = 612. Intensities of 9458 reflections (4877 independent,
Rint = 0.032) were measured on the ‘Xcalibur-3’ diffractometer
(graphite monochromated MoKa radiation, CCD detector, w-scan-
ning, 2Qmax = 50°).
MS (EI, 70 eV): m/z (%) = 415 (100) [M+], 416 (38.5), 417 (13.3).
Anal. Calcd for C22H17N5O2S: C, 63.60; H, 4.12; N, 16.86. Found:
C, 63.63; H, 4.09; N, 16.84.
Synthesis 2009, No. 8, 1375–1385 © Thieme Stuttgart · New York

PAPER
Chemoselectivity of Multicomponent Condensations
1381
3-Methyl-4-(4-nitrophenyl)-1-phenyl-1H-pyrazolo[4¢,3¢:5,6]py-
rido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4c)
Yellow solid; mp >300 °C.
Anal. Calcd for C23H19N5OS: C, 66.81; H, 4.63; N, 16.94. Found:
C, 66.85; H, 4.60; N, 16.96.
4-(4-Chlorophenyl)-3-methyl-1-phenyl-7-thioxo-1,6,7,8-tetra-
hydro-5H-pyrazolo[4¢,3¢:5,6]pyrido[2,3-d]pyrimidin-5-one (4h)
Yellow solid; mp 297–298 °C.
1H NMR (200 MHz, DMSO-d6): d = 1.82 (s, 3 H, CH3), 7.32–8.34
1H NMR (200 MHz, DMSO-d6): d = 1.74 (s, 3 H, CH3), 7.29–8.35
(m, 9 Harom), 11.27 (s, 1 H, NH), 11.86 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 161.8, 152.8, 150.3, 150.0,
147.5, 147.3, 144.7, 138.5, 137.8, 134.5, 129.4, 129.2, 126.1, 123.0,
122.8, 120.4, 113.4, 103.9, 14.2.
(m, 9 Harom), 12.35 (s, 1 H, NH), 13.2 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 175.9, 159.1, 151.5, 149.7,
149.2, 145.1, 138.6, 134.5, 133.0, 129.7, 129.2, 127.7, 126.0, 120.1,
114.3, 105.6, 14.1.
MS (EI, 70 eV): m/z (%) = 414 (100) [M+], 415 (23.5).
Anal. Calcd for C21H14N6O4: C, 60.87; H, 3.41; N, 20.28. Found: C,
60.91; H, 3.45; N, 20.30.
MS (EI, 70 eV): m/z (%) = 419 (100) [M+], 420 (32.2), 421 (23.9).
4-(4-Cyanophenyl)-3-methyl-1-phenyl-1H-pyrazo-
lo[4¢,3¢:5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4d)
Colorless solid; mp >300 °C.
Anal. Calcd for C21H14ClN5OS: C, 60.07; H, 3.36; N, 16.68. Found:
C, 60.04; H, 3.32; N, 16.66.
4-(3,4-Dihydroxyphenyl)-3-methyl-1-phenyl-7-thioxo-1,6,7,8-
tetrahydro-5H-pyrazolo[4¢,3¢:5,6]pyrido[2,3-d]pyrimidin-5-one
(4i)
Yellow solid; mp >300 °C.
1H NMR (200 MHz, DMSO-d6): d = 1.85 (s, 3 H, CH3), 6.50–8.25
(m, 8 Harom), 9.03 (s, 1 H, OH), 9.10 (s, 1 H, OH), 11.10 (s, 1 H,
NH), 11.70 (s, 1 H, NH).
1H NMR (200 MHz, DMSO-d6): d = 1.71 (s, 3 H, CH3), 7.28–8.23
(m, 9 Harom), 11.24 (s, 1 H, NH), 11.83 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 161.3, 152.5, 150.0, 149.8,
148.2, 144.4, 141.2, 138.4, 131.3, 129.0, 128.7, 125.8, 120.3, 118.6,
112.8, 110.7, 103.4, 39.5, 13.7.
MS (EI, 70 eV): m/z (%) = 394 (100) [M+], 395 (25.9), 393 (24.1).
13C NMR (100 MHz, DMSO-d6): d = 165.7, 161.5, 153.0, 151.7,
150.5, 150.3, 150.0, 145.4, 144.7, 138.8, 129.3, 126.8, 120.4, 119.0,
115.6, 115.0, 114.1, 104.0, 89.1, 80.3, 14.0.
Anal. Calcd for C22H14N6O2: C, 67.00; H, 3.58; N, 21.31. Found: C,
66.98; H, 3.61; N, 21.29.
4-(4-Methoxyphenyl)-3-methyl-1-phenyl-1H-pyrazo-
lo[4¢,3¢:5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4e)
Colorless solid; mp >300 °C.
1H NMR (200 MHz, DMSO-d6): d = 1.76 (s, 3 H, CH3), 3.82 (s, 3
H, OCH3), 6.98–8.24 (m, 9 Harom), 11.11 (s, 1 H, NH), 11.70 (s, 1 H,
NH).
MS (EI, 70 eV): m/z (%) = 417 (100) [M+], 416 (26.8), 415 (18.9).
Anal. Calcd for C21H15N5O3S: C, 60.42; H, 3.62; N, 16.78. Found:
C, 60.45; H, 3.60; N, 16.77.
4-(4-Chlorophenyl)-3-methyl-1-(4-nitrophenyl)-1H-pyrazo-
lo[4¢,3¢:5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4j)
Yellow solid; mp >300 °C.
MS (EI, 70 eV): m/z (%) = 399 (100) [M+], 398 (40.6), 400 (16.6).
1H NMR (200 MHz, DMSO-d6): d = 1.71 (s, 3 H, CH3), 7.3–8.55
(m, 8 Harom), 11.26 (s, 1 H, NH), 11.88 (s, 1 H, NH).
Anal. Calcd for C22H17N5O3: C, 66.16; H, 4.29; N, 17.53. Found: C,
66.13; H, 4.33; N, 17.51.
MS (EI, 70 eV): m/z (%) = 448 (100) [M+], 450 (38.6), 449 (32.8).
3-Methyl-1-phenyl-4-(2,4,5-trimethoxyphenyl)-1H-pyrazo-
lo[4¢,3¢:5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4f)
Yellow solid; mp 276–277 °C.
Anal. Calcd for C21H13ClN6O4: C, 56.20; H, 2.92; N, 18.72. Found:
C, 56.18; H, 2.89; N, 18.71.
1H NMR (200 MHz, DMSO-d6): d = 1.87 (s, 3 H, CH3), 3.64 (s, 6
H, 2 OCH3), 3.87 (s, 3 H, OCH3), 6.78–8.24 (m, 7 Harom), 11.10 (s,
1 H, NH), 11.63 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 161.4, 153.0, 150.3, 150.1,
149.8, 148.2, 145.4, 142.5, 138.7, 129.3, 126.0, 120.5, 115.6, 114.2,
113.5, 104.6, 97.9, 56.4, 56.2, 55.8, 13.5.
4-(4-Methoxyphenyl)-1,3-dimethyl-1H-pyrazolo[4¢,3¢:5,6]pyri-
do[2,3-d]pyrimidine-5,7(6H,8H)-dione (4k)
Yellow solid; mp 288–289 °C.
1H NMR (200 MHz, DMSO-d6): d = 1.70 (s, 3 H, CH3), 3.81 (s, 3
H, OCH3), 3.86 (s, 3 H, NCH3), 6.95–7.19 (m, 4 Harom), 11.02 (s, 1
H, 1 NH), 11.60 (s, 1 H, 1 NH).
MS (EI, 70 eV): m/z (%) = 459 (100) [M+], 428 (47.8), 460 (26.2),
444 (18.5).
MS (EI, 70 eV): m/z (%) = 337 (100) [M+], 336 (50.6), 338 (13.2).
Anal. Calcd for C17H15N5O3: C, 60.53; H, 4.48; N, 20.76. Found: C,
60.51; H, 4.47; N, 20.74.
Anal. Calcd for C24H21N5O5: C, 62.74; H, 4.61; N, 15.24. Found: C,
62.77; H, 4.60; N, 15.22.
1,3,6,8-Tetramethyl-4-(4-methylphenyl)-1H-pyrazo-
lo[4¢,3¢:5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4l)
Yellow solid; mp 221–223 °C.
1H NMR (200 MHz, DMSO-d6): d = 1.68 (s, 3 H, CH3), 2.39 (s, 3
H, CH3), 3.14 (s, 3 H, CH3), 3.66 (s, 3 H, CH3), 3.94 (s, 3 H, CH3),
7.09–7.27 (m, 4 Harom).
4-(4-Ethylphenyl)-3-methyl-1-phenyl-7-thioxo-1,6,7,8-tetrahy-
dro-5H-pyrazolo[4¢,3¢:5,6]pyrido[2,3-d]pyrimidin-5-one (4g)
Colorless solid; mp 281–282 °C.
1H NMR (200 MHz, DMSO-d6): d = 1.25 (t, J = 7.8 Hz, 3 H, CH3),
1.74 (s, 3 H, CH3), 2.7 (q, J = 7.8 Hz, 2 H, CH3), 7.19–8.30 (m, 9
Harom), 12.27 (s, 1 H, NH), 13.10 (s, 1 H, NH).
MS (EI, 70 eV): m/z (%) = 349 (100) [M+], 348 (60.9), 350 (23.8).
13C NMR (100 MHz, DMSO-d6): d = 176.2, 159.2, 151.9, 151.3,
150.1, 145.6, 144.0, 139.0, 133.2, 129.5, 128.1, 127.3, 126.2, 120.4,
115.0, 105.9, 28.5, 15.9, 14.4.
Anal. Calcd for C19H19N5O2: C, 65.32; H, 5.48; N, 20.04. Found: C,
65.29; H, 5.51; N, 20.05.
MS (EI, 70 eV): m/z (%) = 413 (100) [M+], 414 (30.9), 412 (25.1),
384 (17.8).
Synthesis 2009, No. 8, 1375–1385 © Thieme Stuttgart · New York

1382
E. A. Muravyova et al.
PAPER
4-Aryl-4,9-dihydro-1H-pyrazolo[4¢,3¢:5,6]pyrido[2,3-d]pyrim-
idines 5a–i; General Procedure
3-Methyl-4-(2,4,5-trimethoxyphenyl)-4,9-dihydro-1H-pyrazo-
lo[4¢,3¢:5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (5e)
Colorless solid; mp >300 °C.
1H NMR (200 MHz, DMSO-d6): d = 1.85 (s, 3 H, CH3), 3.55 (s, 3
H, OCH3), 3.72 (s, 6 H, 2 OCH3), 5.11 (s, 1 H, 4-CH), 6.52–6.58 (m,
2 Harom), 8.61 (s, 1 H, NH), 9.88 (s, 1 H, NH), 10.37 (s, 1 H, 9-NH),
11.68 (s, 1 H, 1-NH).
13C NMR (100 MHz, DMSO-d6): d = 163.3, 150.8, 150.6, 148.3,
147.8, 145.9, 143.3, 135.5, 128.1, 114.3, 103.1, 99.8, 86.8, 57.3,
57.1, 56.3, 28.6, 9.8.
A mixture of 5-aminopyrazole 1d,e (1.30 mmol, 1 equiv), barbituric
acid 2a–c (1.30 mmol, 1 equiv), and aromatic aldehyde 3a–d,f–h,j
(1.3 mmol, 1 equiv) in DMF (2 mL), contained in a round-bottom
flask equipped with condenser, was refluxed for 30 min. The mix-
ture was cooled and EtOH (20 mL) was added. The mixture was al-
lowed to stand and then filtered to give the solid product, which was
washed with EtOH and dried on air at r.t.
4-(4-Ethylphenyl)-3-methyl-4,9-dihydro-1H-pyrazo-
lo[4¢,3¢:5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (5a)
Colorless solid; mp >300 °C.
MS (EI, 70 eV): m/z (%) = 385 (50.0) [M+], 354 (100), 153 (65.5),
168 (60.4).
1H NMR (200 MHz, DMSO-d6): d = 1.1 (t, J = 7.5 Hz, 3 H, CH3),
1.88 (s, 3 H, CH3), 2.5 (q, J = 7.5 Hz, 2 H, CH2), 4.82 (s, 1 H, 4-CH),
6.98–7.07 (m, 4 Harom), 8.71 (s, 1 H, NH), 9.94 (s, 1 H, NH), 10.44
(s, 1 H, 9-NH), 11.80 (s, 1 H, 1-NH).
13C NMR (100 MHz, DMSO-d6): d = 163.4, 150.5, 147.3, 145.1,
141.3, 127.6, 103.0, 87.3, 34.7, 28.2, 16.0, 10.0.
Anal. Calcd for C18H19N5O5: C, 56.10; H, 4.97; N, 18.17. Found: C,
56.14; H, 4.95; N, 18.16.
4-(3,4-Dihydroxyphenyl)-3-methyl-4,9-dihydro-1H-pyrazo-
lo[4¢,3¢:5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (5f)
Colorless solid; mp >300 °C.
1H NMR (200 MHz, DMSO-d6): d = 1.90 (s, 3 H, CH3), 4.68 (s, 1
H, 4-CH), 6.4–6.54 (m, 3 Harom), 8.49 (s, 1 H, OH), 8.65 (s, 1 H,
OH), 8.70 (s, 1 H, NH), 9.91 (s, 1 H, NH), 10.45 (s, 1 H, 9-NH),
11.78 (s, 1 H, 1-NH).
MS (EI, 70 eV): m/z (%) = 323 (23.4) [M+], 218 (100), 175 (26.6).
Anal. Calcd for C17H17N5O2: C, 63.15; H, 5.30; N, 21.66. Found: C,
63.17; H, 5.27; N, 21.63.
MS (EI, 70 eV): m/z (%) = 325 (40.7) [M+], 110 (100), 174 (67.7),
217 (88.3).
3,6,8-Trimethyl-4-[4-(methylsulfanyl) phenyl]-4,9-dihydro-1H-
pyrazolo[4¢,3¢:5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione
(5b)
Anal. Calcd for C15H13N5O4: C, 55.05; H, 4.00; N, 21.40. Found: C,
55.02; H, 4.03; N, 21.38.
Colorless solid; mp 195–196 °C.
1H NMR (200 MHz, DMSO-d6): d = 1.90 (s, 3 H, CH3), 2.38 (s, 3
H, SCH3), 3.04 (s, 3 H, NCH3), 3.44 (s, 3 H, NCH3), 4.94 (s, 1 H, 4-
CH), 7.03–7.14 (m, 4 Harom), 9.8 (s, 1 H, 9-NH), 11.92 (s, 1 H, 1-
NH).
MS (EI, 70 eV): m/z (%) = 369 (15.9) [M+], 246 (100), 247 (15.3),
137 (15.20).
4-(3-Ethoxy-2-hydroxyphenyl)-3-methyl-4,9-dihydro-1H-pyra-
zolo[4¢,3¢:5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (5g)
Colorless solid; mp >300 °C.
1H NMR (200 MHz, DMSO-d6): d = 1.31 (t, J = 6.9 Hz, 3 H, CH3),
1.86 (s, 3 H, CH3), 3.94 (q, J = 6.9 Hz, 2 H, CH3), 5.2 (s, 1 H, 4-CH),
6.32–6.66 (m, 3 Harom), 8.78 (s, 1 H, NH), 8.84 (s, 1 H, OH), 10.03
(s, 1 H, NH), 10.60 (s, 1 H, 9-NH), 11.80 (s, 1 H, 1-NH).
13C NMR (100 MHz, DMSO-d6): d = 164.6, 150.2, 147.9, 147.5,
146.1, 143.6, 135.7, 134.9, 121.0, 119.4, 110.9, 102.9, 87.1, 64.4,
28.1, 15.3, 9.8.
Anal. Calcd for C18H19N5O2S: C, 58.52; H, 5.18; N, 18.96. Found:
C, 58.55; H, 5.20; N, 18.93.
3-Methyl-4-(4-nitrophenyl)-4,9-dihydro-1H-pyrazo-
lo[4¢,3¢:5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (5c)
Yellow solid; mp >300 °C.
MS (EI, 70 eV): m/z (%) = 355 (100) [M+], 218 (73.2), 110 (75.0),
1H NMR (200 MHz, DMSO-d6): d = 1.86 (s, 3 H, CH3), 5.05 (s, 1
H, 4-CH), 7.4–8.1 (m, 4 Harom), 8.92 (s, 1 H, NH), 10.08 (s, 1 H,
NH), 10.55 (s, 1 H, 9-NH), 11.92 (s, 1 H, 1-NH).
13C NMR (100 MHz, DMSO-d6): d = 163.4, 155.2, 150.4, 147.6,
146.1, 145.6, 136.4, 129.1, 123.7, 101.5, 86.2, 35.5, 9.9.
MS (EI, 70 eV): m/z (%) = 340 (22.6) [M+], 218 (100), 175 (38.7),
338 (51.1).
138 (46.8).
Anal. Calcd for C17H17N5O4: C, 57.46; H, 4.82; N, 19.71. Found: C,
57.44; H, 4.80; N, 19.70.
4-(4-Chlorophenyl)-3-phenyl-4,9-dihydro-1H-pyrazo-
lo[4¢,3¢:5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (5h)
Colorless solid; mp >300 °C.
1H NMR (200 MHz, DMSO-d6): d = 5.25 (s, 1 H, 4-CH), 7.12–7.49
(m, 9 Harom), 9.06 (s, 1 H, NH), 10.05 (s, 1 H, NH), 10.55 (s, 1 H, 9-
NH), 12.66 (s, 1 H, 1-NH).
Anal. Calcd for C15H12N6O4: C, 52.94; H, 3.55; N, 24.70. Found: C,
52.91; H, 3.52; N, 24.69.
13C NMR (100 MHz, DMSO-d6): d = 162.8, 150.4, 147.5, 146.8,
146.0, 138.3, 130.8, 129.8, 129.5, 129.2, 128.6, 128.1, 126.7, 101.9,
87.4, 31.2.
MS (EI, 70 eV): m/z (%) = 391 (30) [M+], 280 (100), 393 (17.0),
237 (19.8).
4-(4-Cyanophenyl)-3-methyl-4,9-dihydro-1H-pyrazo-
lo[4¢,3¢:5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (5d)
Colorless solid; mp >300 °C.
1H NMR (200 MHz, DMSO-d6): d = 1.85 (s, 3 H, CH3), 4.98 (s, 1
H, 4-CH), 7.33–7.68 (m, 4 Harom), 8.87 (s, 1 H, NH), 10.04 (s, 1 H,
NH), 10.53 (s, 1 H, 9-NH), 11.90 (s, 1 H, 1-NH).
Anal. Calcd for C20H14ClN5O2: C, 61.31; H, 3.60; N, 17.87. Found:
C, 61.33; H, 3.57; N, 17.86.
13C NMR (100 MHz, DMSO-d6): d = 163.4, 153.2, 150.5, 147.8,
145.7, 136.3, 132.4, 128.9, 119.5, 109.0, 101.7, 86.3, 35.6, 9.9.
MS (EI, 70 eV): m/z (%) = 320 (16.5) [M+], 218 (100), 175 (34.6),
219 (12.6).
4-(4-Chlorophenyl)-3-phenyl-7-thioxo-1,4,6,7,8,9-hexahydro-
5H-pyrazolo[4¢,3¢:5,6]pyrido[2,3-d]pyrimidin-5-one (5i)
Colorless solid; mp >300 °C.
Anal. Calcd for C16H12N6O2: C, 60.00; H, 3.78; N, 26.24. Found: C,
59.97; H, 3.81; N, 26.23.
Synthesis 2009, No. 8, 1375–1385 © Thieme Stuttgart · New York

PAPER
Chemoselectivity of Multicomponent Condensations
1383
1H NMR (200 MHz, DMSO-d6): d = 5.29 (s, 1 H, 4-CH), 7.1–7.49
(m, 9 Harom), 8.85 (s, 1 H, NH), 10.60 (s, 1 H, NH), 12.02 (s, 1 H, 9-
NH), 12.75 (s, 1 H, 1-NH).
4,6-Bis(4-methoxyphenyl)-3-methyl-1-phenyl-1,4,6,7-tetrahy-
dro-2¢H-spiro[pyrazolo[3,4-b]pyridine-5,5¢-pyrimidine]-
2¢,4¢,6¢(1¢H,3¢H)-trione (6b)
Colorless solid; mp 219–220 °C.
MS (EI, 70 eV): m/z (%) = 407 (29.9) [M+], 296 (100), 409 (18.8),
219 (28.4).
1H NMR (200 MHz, DMSO-d6): d = 1.57 (s, 3 H, CH3), 3.71 (s, 6
H, 2 OCH3), 4.68 (d, J = 7.6 Hz, 1 H, 6-CH), 4.84 (s, 1 H, 4-CH),
6.06 (d, J = 7.6 Hz, 1 H, 7-NH), 6.83–7.82 (m, 13 Harom), 11.02 (s,
1 H, NH), 11.18 (s, 1 H, NH).
Anal. Calcd for C20H14ClN5OS: C, 58.89; H, 3.46; N, 17.17. Found:
C, 58.86; H, 3.49; N, 17.14.
4,6-Aryl-1,4,6,7-tetrahydro-2¢H-spiro[pyrazolo[3,4-b]pyridine-
5,5¢-pyrimidine]s 6a–f; General Procedure for Method A
A mixture of 5-aminopyrazole 1a,d (1.30 mmol, 1 equiv), barbituric
acid 2a–c (1.30 mmol, 1 equiv), and aldehyde 3b,e,g (2.6 mmol, 2
equiv) in DMF (1 mL), contained in a round-bottom flask, was son-
icated in ultrasonic bath at r.t. for 3 h. Then EtOH (30 mL) was add-
ed and the mixture was allowed to stand; it was filtered to give the
solid product, which was washed with EtOH and dried on air at r.t.
13C NMR (100 MHz, DMSO-d6): d = 172.9, 167.8, 159.8, 159.2,
149.6, 145.9, 144.8, 140.0, 129.8, 129.3, 128.9, 128.4, 125.6, 121.4,
114.2, 102.8, 66.0, 58.0, 55.6, 55.5, 46.7, 14.3.
MS (EI, 70 eV): m/z (%) = 537 (14) [M+], 291 (100), 290 (53), 246
(61), 184 (64).
Anal. Calcd For C30H27N5O5: C, 67.03; H, 5.06; N, 13.03. Found:
C, 67.05; H, 5.02; N, 13.02.
This synthesis can be also carried out with intensively magnetic stir-
ring instead of ultrasonication with some lower yields.
4,6-Bis(4-chlorophenyl)-3-methyl-1-phenyl-1,4,6,7-tetrahydro-
2¢H-spiro[pyrazolo[3,4-b]pyridine-5,5¢-pyrimidine]-
2¢,4¢,6¢(1¢H,3¢H)-trione (6c)
4,6-Aryl-1,4,6,7-tetrahydro-2¢H-spiro[pyrazolo[3,4-b]pyridine-
5,5¢-pyrimidine]s 6g,h; General Procedure for Method B
A mixture of arylidenebarbituric acid 7a,b (2 mmol, 1 equiv) and
appropriate Schiff base 8a,b (2 mmol, 1 equiv) in DMF (1 mL),
contained in a round-bottom flask equipped with a condenser, was
refluxed for 30 min. The mixture was cooled, EtOH (30 mL) was
added, and the mixture was allowed to stand; it was filtered to give
the solid product, which was washed with EtOH and dried on air at
r.t.
Colorless solid; mp 255–256 °C.
1H NMR (200 MHz, DMSO-d6): d = 1.59 (s, 3 H, CH3), 4.77 (d,
J = 7.3 Hz, 1 H, 6-CH), 4.94 (s, 1 H, 4-CH), 6.35 (d, J = 7.3 Hz, 1
H, 7-NH), 7.06–7.8 (m, 13 Harom), 11.17 (s, 1 H, NH), 11.36 (s, 1 H,
NH).
MS (EI, 70 eV): m/z (%) = 547 (14.1) [M+], 549 (10.1), 294 (100.0),
295 (85.0), 296 (35.0).
Anal. Calcd For C28H21Cl2N5O3: C, 61.55; H, 3.87; N, 12.82.
Found: C, 61.51; H, 3.85; N, 12.80.
4,6-Aryl-1,4,6,7-tetrahydro-2¢H-spiro[pyrazolo[3,4-b]pyridine-
5,5¢-pyrimidine]s 6a,d–h; General Procedure for Method C
A mixture of barbituric acid 2a–c (1.30 mmol, 1 equiv), aromatic al-
dehyde 3a,b,e,g (1.3 mmol, 1 equiv), and Schiff base 8a–e in DMF
(1 mL), contained in a round-bottom flask, was sonicated in an ul-
trasonic bath at r.t. for 3 h. Then EtOH (30 mL) was added and the
mixture was allowed to stand; it was filtered to give the solid prod-
uct, which was washed with EtOH and dried on air at r.t.
4,6-Bis(4-chlorophenyl)-3-methyl-1-phenyl-2¢-thioxo-1,4,6,7-
tetrahydro-2¢H-spiro[pyrazolo[3,4-b]pyridine-5,5¢-pyrimi-
dine]-4¢,6¢(1¢H,3¢H)-dione (6d)
Colorless solid; mp 210–211 °C.
1H NMR (200 MHz, DMSO-d6): d = 1.58 (s, 3 H, CH3), 4.7 (d,
J = 7.3 Hz, 1 H, 6-CH), 4.97 (s, 1 H, 4-CH), 6.45 (d, J = 7.3 Hz, 1
H, 7-NH), 7.06–7.8 (m, 13 Harom), 12.2 (s, 1 H, NH), 12.3 (s, 1 H,
NH).
13C NMR (100 MHz, DMSO-d6): d = 177.7, 170.2, 164.9, 145.7,
144.6, 139.9, 135.9, 134.8, 131.1, 133.0, 130.4, 129.4, 129.0, 125.8,
121.8, 101.9, 66.5, 58.6, 46.6, 14.4.
4,6-Aryl-1,4,6,7-tetrahydro-2¢H-spiro[pyrazolo[3,4-b]pyridine-
5,5¢-pyrimidine]s 6a,d–h; General Procedure for Method D
A mixture of 5-aminopyrazole 1a,d,e (1.30 mmol, 1 equiv), aromat-
ic aldehyde 3b,e,g (1.3 mmol, 1 equiv), and arylidenebarbituric acid
7a–e in DMF (1 mL), contained in a round-bottom flask, was soni-
cated in ultrasonic bath at r.t. for 3 h. Then EtOH (30 mL) was add-
ed and the mixture was allowed to stand; it was filtered to give the
solid product, which was washed with EtOH and dried on air at r.t.
MS (EI, 70 eV): m/z (%) = 561 (17) [M+], 562 (11), 563 (4.7), 295
(100), 297 (98), 266 (96).
Anal. Calcd For C28H21Cl2N5O2S: C, 59.79; H, 3.76; N, 12.45.
Found: C, 59.72; H, 3.74; N, 12.44.
3-Methyl-4,6-bis[4-(methylsulfanyl)phenyl]-1-phenyl-1,4,6,7-
tetrahydro-2¢H-spiro[pyrazolo[3,4-b]pyridine-5,5¢-pyrimi-
dine]-2¢,4¢,6¢(1¢H,3¢H)-trione (6a)
4,6-Bis(4-methoxyphenyl)-1¢,3,3¢-trimethyl-1,4,6,7-tetrahydro-
2¢H-spiro[pyrazolo[3,4-b]pyridine-5,5¢-pyrimidine]-
2¢,4¢,6¢(1¢H,3¢H)-trione (6e)
Colorless solid; mp 281–282 °C.
1H NMR (200 MHz, DMSO-d6): d = 1.59 (s, 3 H, CH3), 2.43 (s, 6
H, 2 SCH3), 4.71 (d, J = 7.5 Hz, 1 H, 6-CH), 4.88 (s, 1 H, 4-CH),
6.16 (d, J = 7.5 Hz, 1 H, 7-NH), 7.01–7.82 (m, 13 Harom), 11.11 (br
s, 2 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 172.3, 167.2, 149.2, 145.5,
144.4, 139.6, 139.2, 137.9, 133.0, 132.2, 129.0, 128.7, 125.5, 125.5,
125.3, 121.0, 102.1, 65.8, 57.3, 46.2, 14.3, 14.2, 13.92.
Yellow solid; mp 225–226 °C.
1H NMR (200 MHz, DMSO-d6): d = 1.52 (s, 3 H, CH3), 2.74 (s, 3
H, NCH3), 2.79 (s, 3 H, NCH3), 3.66 (s, 3 H, OCH3), 3.68 (s, 3 H,
OCH3), 4.68 (d, J = 7.3 Hz, 1 H, 6-CH), 4.88 (s, 1 H, 4-CH), 5.83
(d, J = 7.3 Hz, 1 H, 7-NH), 6.75–7.06 (m, 8 Harom), 11.54 (s, 1 H,
NH).
13C NMR (100 MHz, DMSO-d6): d = 170.4, 164.6, 162.5, 159.6,
158.7, 152.5, 149.7, 135.3, 131.9, 130.1, 129.0, 128.4, 114.6, 113.7,
100.1, 66.2, 60.4, 55.1, 54.9, 45.8, 28.0, 27.3, 11.2.
MS (EI, 70 eV): m/z (%) = 569 (13) [M+], 307 (100), 306 (37), 308
(21), 442 (20).
MS (EI, 70 eV): m/z (%) = 489 (29.7) [M+], 216 (100), 273 (74.6),
274 (68), 490 (20).
Anal. Calcd For C30H27N5O3S2: C, 63.25; H, 4.78; N, 12.29. Found:
C, 63.22; H, 4.80; N, 12.26.
Anal. Calcd For C26H27N5O5: C, 63.79; H, 5.56; N, 14.31. Found:
C, 63.82; H, 5.54; N, 14.30.
Synthesis 2009, No. 8, 1375–1385 © Thieme Stuttgart · New York

1384
E. A. Muravyova et al.
PAPER
4,6-Bis(4-methoxyphenyl)-1¢,3¢-dimethyl-3-phenyl-1H-1,4,6,7-
tetrahydro-2¢H-spiro[pyrazolo[3,4-b]pyridine-5,5¢-pyrimi-
dine]-2¢,4¢,6¢(1¢H,3¢H)-trione (6f)
(3) See, for example: (a) Kappe, C. O. Angew. Chem. Int. Ed.
2004, 43, 6250. (b) Hayes, B. L. Aldrichimica Acta 2004,
37, 266. (c) Roberts, B. A.; Strauss, C. R. Acc. Chem. Res.
2005, 38, 653. (d) De La Hoz, A.; Diaz-Ortiz, A.; Moreno,
A. Chem. Soc. Rev. 2005, 34, 164. (e) Kappe C. O., Stadler
A.; Microwaves in Organic and Medicinal Chemistry;
Wiley-VCH: Weinheim, 2005.
(4) See, for example: (a) Bonrath, W.; Paz Schmidt, R. In
Advances in Organic Synthesis; Atta-ur-Rahman, Ed.;
Bentham Science: Amsterdam, 2005, Chap. 3, 81–117.
(b) Mason, T. J.; Luche, J.-L. In Chemistry Under Extreme
or Non-Classical Conditions; van Eldick, R.; Hubbard, C.
D., Eds.; John Wiley: Chichester, 1997. (c) Cravotto, G.;
Cintas, P. J. Chem. Soc. Rev. 2006, 35, 180. (d) Mason, T.
J. Chem. Soc. Rev. 1997, 26, 443. (e) Muravyova, E. A.;
Desenko, S. M.; Musatov, V. I.; Knyazeva, I. V.; Shishkina,
S. V.; Shishkin, O. V.; Chebanov, V. A. J. Comb. Chem.
2007, 9, 798.
(5) (a) Huang, Z.; Ma, Q.; Bobbitt, J. M. J. Org. Chem. 1993, 58,
4837. (b) Vicente, J.; Chicote, M. T.; Guerrero, R.;
de Arellano, M. C. R. Chem. Commun. 1999, 1541.
(c) Alajarin, R.; Avarez-Buila, J.; Vaquero, J. J.; Sunkel, C.;
Fau, J.; Statkov, P.; Sanz, J. Tetrahedron: Asymmetry 1993,
4, 617. (d) Bossert, F.; Vater, W. Med. Res. Rev. 1989, 9,
291. (e) Triggle, D. J.; Langs, D. A.; Janis, R. A. Med. Res.
Rev. 1989, 9, 123. (f) Tsuda, Y.; Mishina, T.; Obata, M.;
Araki, K.; Inui, J.; Nakamura, T. WO 8,504,172, 1985.
(g) Tsuda, Y.; Mishina, T.; Obata, M.; Araki, K.; Inui, J.;
Nakamura, T. JP 61,227,584, 1986. (h) Tsuda, Y.; Mishina,
T.; Obata, M.; Araki, K.; Inui, J.; Nakamura, T. EP
0,217,142, 1987. (i) Atwal, K. S.; Vaccaro, W.; Lloyd, J.;
Finlay, H.; Yan, L.; Bhandaru, R. S. US 2007,099,899,
2007. (j) Atwal, K. S.; Moreland, S. Bioorg. Med. Chem.
Lett. 1991, 1, 291.
(6) (a) Sanghvi, Y. S.; Larson, S. B.; Wills, R. C.; Robins, R. K.;
Revankar, G. R. J. Med. Chem. 1989, 32, 945. (b) Bell, M.
R.; Ackerman, J. H. US 4,920,128, 1990. (c) Farghaly, A.
M.; Habib, N. S.; Hazzaa, A. B.; El-Sayed, O. A. J. Pharm.
Sci. 1989, 3, 90. (d) Ganjee, A.; Adair, O. O.; Queener, S. F.
J. Med. Chem. 2003, 46, 5074. (e) Rosowsky, A.; Chen, H.;
Fu, H.; Queener, S. F. Bioorg. Med. Chem. 2003, 11, 59.
(f) Dishington, A. P.; Johnson, P. D.; Kettle, J. G.
Tetrahedron Lett. 2004, 45, 3733.
Yellow solid; mp 156–157 °C.
1H NMR (200 MHz, DMSO-d6): d = 2.67 (s, 3 H, NCH3), 2.83 (s, 3
H, NCH3), 3.49 (s, 3 H, OCH3), 3.69 (s, 3 H, OCH3), 4.81 (d, J = 7.3
Hz, 1 H, 6-CH), 5.28 (s, 1 H, 4-CH), 6.02 (d, J = 7.3 Hz, 1 H, 7-
NH), 6.40–7.10 (m, 13 Harom), 12.07 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 170.6, 164.6, 162.5, 159.6,
158.2, 149.6, 129.8, 128.6, 128.5, 128.2, 127.6, 127.1, 126.8, 113.7,
113.0, 99.6, 65.8, 60.6, 55.1, 54.8, 46.4, 35.7, 30.7, 28.1, 27.3.
MS (EI, 70 eV): m/z (%) = 551 (30.8) [M+], 277 (100), 273 (70.6),
274 (62.2).
Anal. Calcd For C31H29N5O5: C, 67.50; H, 5.30; N, 12.70. Found:
C, 67.47; H, 5.33; N, 12.67.
4-(4-Ethylphenyl)-6-(4-methoxyphenyl)-3-methyl-1H-1,4,6,7-
tetrahydro-2¢H-spiro[pyrazolo[3,4-b]pyridine-5,5¢-pyrimi-
dine]-2¢,4¢,6¢(1¢H,3¢H)-trione (6g)
Yellow solid; mp 219–220 °C.
1H NMR (200 MHz, DMSO-d6): d = 1.11 (t, J = 7.6 Hz, 3 H, CH3),
1.51 (s, 3 H, CH3), 2.56 (q, J = 7.6 Hz, 2 H, CH2), 3.70 (s, 3 H,
OCH3), 4.66 (d, J = 7.3 Hz, 1 H, 6-CH), 4.80 (s, 1 H, 4-CH), 5.78
(d, J = 7.3 Hz, 1 H, 7-NH), 6.79–7.15 (m, 8 Harom), 9.95 (s, 1 H,
NH), 10.85 (s, 1 H, NH), 11.06 (s, 1 H, NH).
MS (EI, 70 eV): m/z (%) = 459 (31) [M+], 457 (55), 332 (39.5), 215
(52).
Anal. Calcd For C25H25N5O4: C, 65.35; H, 5.48; N, 15.24. Found:
C, 65.37; H, 5.51; N, 15.23.
6-(4-Methoxyphenyl)-1¢,3,3¢-trimethyl-4-[4-(methylsulfan-
yl)phenyl]-1-phenyl-1,4,6,7-tetrahydro-2¢H-spiro[pyrazolo[3,4-
b]pyridine-5,5¢-pyrimidine]-2¢,4¢,6¢(1¢H,3¢H)-trione (6h)
Colorless solid; mp 252–253 °C.
1H NMR (200 MHz, DMSO-d6): d = 1.59 (s, 3 H, CH3), 2.41 (s, 3
H, SCH3), 2.77 (s, 3 H, NCH3), 2.84 (s, 3 H, NCH3), 3.69 (s, 3 H,
OCH3), 4.76 (d, J = 7.3 Hz, 1 H, 6-CH), 4.95 (s, 1 H, 4-CH), 6.24
(d, J = 7.3 Hz, 1 H, 7-NH), 6.80–7.80 (m, 13 Harom).
13C NMR (100 MHz, DMSO-d6): d = 170.2, 164.9, 159.6, 158.9,
149.6, 145.5, 144.2, 139.6, 138.0, 133.0, 132.8, 132.2, 132.0, 129.0,
128.7, 128.1, 125.6, 125.5, 121.1, 113.8, 101.9, 66.5, 58.6, 55.0,
46.6, 28.2, 27.5, 14.2, 13.9.
(7) Tseng, C. P. US 4,838,925, 1989.
(8) (a) Hahn, W. E.; Muszynski, M. Chem. Stosow. 1986, 30,
421. (b) Muszynski, M.; Hahn, W. E. PL 130681, 1984;
Chem. Abstr. 1986, 104, 159328a.
MS (EI, 70 eV): m/z (%) = 581 (93) [M+], 565 (37.8), 290 (100),
426 (54.9), 306 (40.1).
(9) (a) Chebanov, V. A.; Desenko, S. M. Curr. Org. Chem.
2006, 10, 297. (b) Chebanov, V. A.; Sakhno, Ya. I.;
Desenko, S. M.; Chernenko, V. N.; Musatov, V. I.;
Shishkina, S. V.; Shishkin, O. V.; Kappe, C. O. Tetrahedron
2007, 63, 1229. (c) Quiroga, J.; Insuasty, B.; Hormaza, A.;
Saitz, C.; Jullian, C. J. Heterocycl. Chem. 1998, 35, 575.
(d) Drizin, I.; Holladay, M. W.; Yi, L.; Zhang, G. Q.;
Gopalakrishnan, S.; Gopalakrishnan, M.; Whiteaker, K. L.;
Buckner, S. A.; Sullivan, J. P.; Carroll, W. A. Bioorg. Med.
Chem. Lett. 2002, 12, 1481. (e) 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. (f) Gladkov, E. S.; Chebanov, V. A.;
Desenko, S. M.; Shishkin, O. V.; Shishkina, S. V.; Dallinger,
D.; Kappe, C. O. Heterocycles 2007, 63, 469.
Anal. Calcd For C32H31N5O4S: C, 66.07; H, 5.37; N, 12.04. Found:
C, 66.03; H, 5.33; N, 12.03.
References
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Synthesis 2009, No. 8, 1375–1385 © Thieme Stuttgart · New York

PAPER
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Chemoselectivity of Multicomponent Condensations
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(19) The final atomic coordinates, and crystallographic data for
molecules 4a and 6h have been deposited with the
Cambridge Crystallographic Data Centre, 12 Union Road,
CB2 1EZ, UK [fax: +44 (1223)336033, e-mail:
deposit@ccdc.cam.ac.uk] and are available on request
quoting the deposition numbers CCDC 706772 for 4a and
CCDC 706773 for 6h.
Synthesis 2009, No. 8, 1375–1385 © Thieme Stuttgart · New York