Synthesis of ethyl pyrimidine-4-carboxylates from unsymmetrical enamino diketones and their application in the first synthesis of pyrimido[4,5-d] pyridazin-8(7H)-ones

Article abstract of DOI:10.1055/s-0028-1083202

The reaction of unsymmetrical enamino diketones [RC(O)C(=CNMe ₂)C(O)CO₂Et, where R = Ph, 4-MeC₆H₄, 4-MeOC₆H₄, 4-BrC₆H₄, 4-ClC ₆H₄, 4-FC₆H₄, 4-O₂NC ₆H₄, 2-thienyl, benzofuran-2-yl, and CF₃] with N-C-N dinucleophiles, such as benzamidine hydrochloride or 1H-pyrazole-l- carboxamidine monohydrochloride, afforded a series of ethyl 2,5-disubstituted pyrimidine-4-carboxylates in a chemoselective and highly chemoselective manner (51-86%). Reaction of these two series of pyrimidines (R = Ph, 4-MeOC ₆H₄, 4-FC₆H₄, and 2-thienyl) with hydrazine monohydrate under mild conditions led to 2,5-substituted pyrimido[4,5-d]pyridazin-8(7H)-ones in high yields (81-92%). Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0028-1083202

PAPER
3639
Synthesis of Ethyl Pyrimidine-4-carboxylates from Unsymmetrical
Enamino Diketones and Their Application in the First Synthesis of
Pyrimido[4,5-d]pyridazin-8(7H)-ones
S
ynthesisof
P
e
yrimido[4,5
r
-
d
]pyrid
n
azin-8(7
H
)-o
a
ne
s
nda A. Rosa, Pablo Machado, Gabriela F. Fiss, Pâmela S. Vargas, Tanize S. Fernandes, Helio G. Bonacorso,
Nilo Zanatta, Marcos A. P. Martins*
Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria,
97105-900 Santa Maria, Brazil
Fax +55(55)3220 8031; E-mail: mmartins@base.ufsm.br
Received 25 June 2008; revised 12 August 2008
do[1,2-b]pyridazin-2(4)-ones7 and 6H-pyrimido[1,6-
b]pyridazin-6-one8 have also been reported.
Abstract: The reaction of unsymmetrical enamino diketones
[RC(O)C(=CNMe2)C(O)CO2Et, where R = Ph, 4-MeC6H4, 4-
MeOC6H4, 4-BrC6H4, 4-ClC6H4, 4-FC6H4, 4-O2NC6H4, 2-thienyl,
benzofuran-2-yl, and CF3] with N–C–N dinucleophiles, such as
benzamidine hydrochloride or 1H-pyrazole-1-carboxamidine
monohydrochloride, afforded a series of ethyl 2,5-disubstituted py-
rimidine-4-carboxylates in a chemoselective and highly chemo-
selective manner (51–86%). Reaction of these two series of
pyrimidines (R = Ph, 4-MeOC6H4, 4-FC6H4, and 2-thienyl) with
hydrazine monohydrate under mild conditions led to 2,5-substituted
pyrimido[4,5-d]pyridazin-8(7H)-ones in high yields (81–92%).
Recently, we described an efficient method to obtain a se-
ries of enamino diketones I (Figure 1) from C-acylation of
enamino ketones with ethyl oxalyl chloride.9,10 The reac-
tion of these precursors with N–N dinucleophiles such as
tert-butylhydrazine hydrochloride or methyl hydrazine-
carboxylate was shown to be highly attractive for the syn-
thesis of multifunctionalized pyrazoles.10 This synthetic
pathway afforded ethyl 4-substituted 1H-pyrazole-5-car-
boxylates as the sole product in high yields.10 Thus, the
enamino ketones have been shown to be powerful precur-
sors for the highly regioselective construction of new het-
erocyclic derivatives.
Key words: cyclizations, enones, ring closure, heterocycles, pyri-
midines, regioselectivity
Pyrimidines and fused pyrimidines have been the subject
of consistent interest because of the wide pharmacological
and agrochemical properties of such heterocycles.1 More
specifically, the pyrimidine scaffold has been used as an
integral part of nucleoside antibiotics, antibacterials, anti-
Parkinsonians, anti-inflammatory, and analgesic agents,
as well as selective antagonists of the human A3 adenosine
receptor.1
In this paper, we employed the unsymmetrical enamino
diketones I in a reaction with N–C–N dinucleophiles for
the synthesis of novel ethyl 2,5-disubstituted pyrimidine-
4-carboxylates II (Figure 1). Furthermore, we aimed to
use the pyrimidine-4-carboxylates as synthons for a
straightforward synthesis of unpublished 2,5-substituted
pyrimido[4,5-d]pyridazin-8(7H)-ones III (Figure 1).
R1
In the field of chemistry, constant efforts have been devot-
ed to the development of novel methods for the synthesis
of pyrimidine derivatives.2 However, methods dealing
with the synthesis of pyrimidine-4-carboxylate have been
poorly explored. Methods reported for the synthesis of
pyrimidine-4-carboxylate involve the reaction of ethyl
ethoxymethyleneoxalacetate,3a diethyl ethoxymethylene-
oxalacetate,3b or diethyl oxalpropionate4 with N–C–N
dinucleophiles. However, these methods have reported
disadvantages, mainly due to their limited scope and mod-
erate yields (52–75%). Nevertheless, pyrimidinecarboxy-
late derivatives have been obtained as important synthons
for the synthesis of pyrimidinecarboxylic acid, pyrimidin-
ecarboxamide, as well as fused pyrimidines.5 The reaction
of hydrazine with pyrimidine-1,2-dicarboxylic acid esters
gave 1,4-dihydroxypyridazines.6 In addition, bridgehead
nitrogen-containing heterocycles such as 2H(4H)-pyrimi-
O
O
O
OEt
N
N
R1
EtO2C
N
R1
Me2N
NH
O
R2
N
N
R2
O
I
II
III
R1 = CF3, aryl, heteroaryl
2 = Ph, pyrazol-1-yl
R
Figure 1
Investigations into suitable conditions for the synthesis of
a pyrimidinecarboxylate from enamino diketone 1a with
benzamidine hydrochloride (2) were performed first.
However, when the cyclocondensation reaction was car-
ried out in the presence of sodium hydroxide and using
acetonitrile under reflux, we were unable to obtain the de-
sired product. In these tests, it was observed that the
enamino diketone underwent cleavage, forming an enam-
ino ketone in a classical retro-Claisen reaction. Therefore,
we attempted to change the base by using potassium car-
bonate. The synthesis of 5-substituted 2-phenylpyrimi-
SYNTHESIS 2008, No. 22, pp 3639–3648
x
x.
x
x
.
2
0
0
8
Advanced online publication: 23.10.2008
DOI: 10.1055/s-0028-1083202; Art ID: M03208SS
© Georg Thieme Verlag Stuttgart · New York

3640
F. A. Rosa et al.
PAPER
dine-4-carboxylates was satisfactory when the reaction of
1a with benzamidine hydrochloride (2) was carried out in
the presence of potassium carbonate using acetonitrile un-
der reflux for one hour. This methodology was applied to
other enamino diketones 1b–j leading to the correspond-
ing pyrimidines 4 and 5 in good yields (50–86%)
(Table 1). Different from the reaction of compound 1 with
N–N dinucleophiles, where 4-substituted pyrazole-5-car-
boxylates were obtained with high chemoselectivity,10 the
reaction of enamino diketones 1 with benzamidine hydro-
chloride was chemoselective leading to a regioisomeric
mixture of 4 and 5 for R = Ph, 4-BrC6H4, 4-ClC6H4, 4-
O2NC6H4, and benzofuran-2-yl (Table 1). In general, the
ratio of compounds 4 and 5 seemed to be governed by
electronic effects of the substituent. As the electron-with-
drawing effect of the substituent (R) increased, the ratio of
product 5 also increased. This effect was maximized when
R = CF3 where, surprisingly, there was a change in the
chemoselectivity of the ring closure to give isomer 5j as
the sole product. This result may be related to the strong
electron-withdrawing effect of the trifluoromethyl group,
which increases the electron deficiency on the carbonyl
carbon linked to this group making this center more elec-
trophilic than the carbonyl carbon neighbor of the ester
moiety. The structures of 4 were determined by 1H and 13C
NMR spectroscopy and GC/MS. On the other hand, the
isomers 5 were determined by 1H and, when possible, 13C
NMR spectroscopy. Moreover, X-ray crystallography
data supported the structure of compound 4a (Figure 2,
Tables 4 and 5).11 The analysis of these data showed that
the pyrimidine ring was essentially planar with a maxi-
mum deviation from the mean plane of 0.008(1) Å.
Figure 2 ORTEP12 obtained from the crystal structure of ethyl 5-
benzoyl-2-phenylpyrimidine-4-carboxylate (4a)
Different from the 5-benzoyl group, the 2-phenyl group
shared the same plane as the pyrimidine ring system since
a dihedral angle of 4.46(4)° was formed between them,
while the benzoyl group deviated 65.70(7)° from the main
plane of the pyrimidine ring. The crystal packing was sta-
bilized mainly by van der Waals forces.
In an attempt to extend the scope of the cyclocondensation
reaction between enamino diketones and nucleophiles of
the N–C–N type, we performed the reaction of enamino
diketone 1a with 1H-pyrazole-1-carboxamidine mono-
hydrochloride (3). In this procedure the same reaction
conditions used for the synthesis of pyrimidine-4-carbox-
ylates 4 and 5 were employed.
Table 1 Regioselective Synthesis of 2,4,5-Substituted Pyrimidines from the Reaction of Enamino Diketones 1a–j with Benzamidine Hydro-
chloride (2)
m
O
O
O
O
K2CO3, MeCN,
reflux, 1 h
Ph
OEt
EtO
R
+
R
N
N
H2N
NH⋅HCl
O
O
Me2N
EtO2C
N
Ph
R
N
Ph
1
2
4
5
Enamino diketone
R
Pyrimidine
4a + 5a
4b
Ratio 4/5
10:1
1:0
Yielda (%)
1a
1b
1c
1d
1e
1f
Ph
84
86
78
81
72
82
78
70
81
50
4-MeC6H4
4-MeOC6H4
4-BrC6H4
4-ClC6H4
4-FC6H4
4c
1:0
4d + 5d
4e + 5e
4f
5:1
10:1
1:0
1g
1h
1i
4-O2NC6H4
2-thienyl
4g + 5g
4h
2:1
1:0
benzofuran-2-yl
CF3
4i + 5i
3:1
1j
5j
0:1
a Yield of the mixture of isomers 4 and 5.
Synthesis 2008, No. 22, 3639–3648 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrimido[4,5-d]pyridazin-8(7H)-ones
3641
However, the reaction time of one hour was not sufficient
for complete conversion of the starting material into the
desired product. Therefore, we increased the reaction time
to two hours and pyrimidine-4-carboxylate 6a was ob-
tained in pure form in 60% yield (Table 2). It is notewor-
thy that pyrimidine-4-carboxylate 6a was obtained with
high chemoselectivity as the sole product. For the other
precursors, 1b,d–g,i,j, the reaction with pyrazole-1-car-
boxamidine hydrochloride (3) was also carried out in the
presence of potassium carbonate in acetonitrile at reflux
for two hours affording the pyrimidine-4-carboxylates
6b,d–g,i,j in moderate to good yields (60–77%). Accord-
ing to data shown in Table 2, the reaction times for the
synthesis of compound 6c (R = 4-MeOC6H4) and com-
pound 6h (R = 2-thienyl) were three and six hours, re-
spectively. On the other hand, the reaction of enamino
diketone 1j (R = CF3) with pyrazole-1-carboxamidine hy-
drochloride (3) did not give the expected product. Data
seems to show the cleavage of the product via a retro-
Table 2 Regiospecific Synthesis of Ethyl 2,5-Substituted Pyrimi-
dine-4-carboxylates 6 from the Reaction of Enamino Diketones 1a–j
with 1H-Pyrazole-1-carboxamidine Monohydrochloride (3)
m
O
O
O
K2CO3, MeCN,
reflux, 2 h
N
R
N
OEt
N
R
+
EtO2C
N
N
N
O
H2N
Me2N
NH⋅HCl
6
1
3
Enamino diketone R
Pyrimidine Yielda (%)
1a
1b
1c
1d
1e
Ph
6a
6b
6cb
6d
6e
6f
60
65
67
70
67
60
75
65
77
–
4-MeC6H4
4-MeOC6H4
4-BrC6H4
4-ClC6H4
4-FC6H4
Claisen rearrangement, however, the product with loss of 1f
ethyl oxalate was not identified. Another interesting find-
ing was that, different from the reaction of precursor 1
1g
4-O2NC6H4
2-thienyl
6g
6hc
6i
with benzamidine hydrochloride (2), where in most cases
the reactions were chemoselective, the reaction of precur-
sor 1 with pyrazole-1-carboxamidine hydrochloride (3)
was highly chemoselective for all R groups. This fact may
be related with the lower reactivity of pyrazole-1-carbox-
amidine when compared to benzamidine. This lower reac-
tivity can be deduced from the longer reaction time
required for the conversion of enamino diketones 1 into
pyrimidines 6, which were synthesized from pyrazole-1-
carboxamidine, when compared to pyrimidines 4 and 5,
synthesized from benzamidine. In addition, semiempirical
AM1 calculations13 using the HyperChem 7.52 package14
supported the lower nucleophilicity of pyrazole-1-carbox-
amidine when compared to benzamidine. While the
former had a net charge on the NH2 and NH atoms of
–0.329 and –0.260, respectively, benzamidine presented a
net charge of –0.399 and –0.296 for NH2 and NH, respec-
tively. These findings suggest that the regiochemistry of
the formation of pyrimidines from enamino diketones 1 is
related to the reactivity of the amidine and also to the
structure of the enamino diketones. Consequently, the less
reactive amidines led to highly chemoselective attainment
of pyrimidines, while the more reactive amidines gave the
desired compounds only in a chemoselective manner.
Moreover, the electronic effects of moieties attached to
the enamino diketones drove the preference of the nucleo-
philic attack. In addition to the spectroscopic data, the
structure of compound 6h was determined from X-ray dif-
fraction (Figure 3, Tables 4 and 5).11
1h
1i
benzofuran-2-yl
CF3
d
1j
–
a Yield of isolated product.
b Reaction time of 3 h.
c Reaction time of 6 h.
d Product was not identified.
Figure 3 ORTEP12 obtained from the crystal structure of ethyl 2-
(pyrazol-1-yl)-5-(2-thienylcarbonyl)pyrimidine-4-carboxylate (6h)
packing of compound 6h was stabilized mainly by van der
Waals forces.
In compound 6h, the 2-(pyrazol-1-yl)pyrimidine system
showed an essentially planar structure, as the dihedral an-
gle formed between the pyrazol-1-yl and the pyrimidine
was 3.13(5)°, similar to the results already described in
the literature.15 On the other hand, the 2-thienylcarbonyl
group deviated 67.94(5)° from the mean plane of the py-
rimidine ring. Also, similar to pyrimidine 4a, the crystal
In an extension of our study on the reactivity of ethyl 2,5-
disubstituted pyrimidine-4-carboxylates, we were inter-
ested in the use of these compounds as synthons for the at-
tainment of novel pyrimido[4,5-d]pyridazin-8(7H)-ones
from the reaction of hydrazine monohydrate with ethyl
Synthesis 2008, No. 22, 3639–3648 © Thieme Stuttgart · New York

3642
F. A. Rosa et al.
PAPER
MeOC6H4, 4-FC6H4, and 2-thienyl), respectively. The py-
rimido[4,5-d]pyridazin-8(7H)-ones 7a,c,f,h and 8a,c,f,h
were obtained in good to excellent yields (81–92%) with
a high degree of purity and without the need for additional
purification (Table 3).
Table 3 Synthesis of 2,5-Substituted Pyrimido[4,5-d]pyridazin-
8(7H)-ones 7a,c,f,h and 8a,c,f,h from the Reaction of Ethyl 2,5-Sub-
stituted Pyrimidine-4-carboxylates with Hydrazine Monohydrate
O
R1
NH2NH2⋅H2O, EtOH,
r.t., 2 h
R1
EtO2C
N
N
N
Compound 7a was also identified by X-ray diffraction
(Figure 4, Tables 4 and 5).11 The crystal structure of this
compound showed that the dihedral angle formed be-
tween the two fused six-membered ring was 3.87(6)°.
NH
N
R2
R2
N
7, 8
O
4, 6
Pyrimidine R1
R2
Ph
Pyrimido-
pyridazinone (%)
Yielda
The pyrimido[4,5-d]pyridazinone ring system was ob-
tained as an almost planar ring, similar to the above re-
ported pyrimidines, with a maximum deviation from the
mean plane of 0.056(1) Å. The 2- and 5-phenyl groups
made dihedral angles of 4.29(5)° and 50.62(5)°, respec-
tively, with the pyrimido[4,5-d]pyridazinone ring system.
Finally, the crystal packing of compound 7a was stabi-
lized mainly by NH···O hydrogen bonds.
4a
4c
4f
Ph
7a
7c
7f
90
87
91
92
92
90
81
84
4-MeOC6H4
4-FC6H4
2-thienyl
Ph
Ph
Ph
Ph
4h
6a
6c
6f
7hb
8a
8c
8f
pyrazol-1-yl
pyrazol-1-yl
pyrazol-1-yl
pyrazol-1-yl
In summary, we have developed a useful synthetic path-
way to access novel pyrimidine-4-carboxylates from the
reaction of unsymmetrical enamino diketones with differ-
ent amidines. Our findings showed that the chemoselec-
tivity depended on both the structure of the N–C–N
dinucleophiles used as well as the structure of the enami-
no diketones. Moreover, these new pyrimidine-4-carbox-
ylates are versatile precursors for the synthesis of other
heterocyclic compounds such as pyrimido[4,5-d]py-
ridazin-8(7H)-ones. These compounds were obtained for
the first time in this paper with excellent yields and in a
simple procedure.
4-MeOC6H4
4-FC6H4
2-thienyl
6h
8h
a Yield of isolated product.
b Reaction time of 2 h at reflux
pyrimidine-4-carboxylates 4 and 6 (Table 3). To the best
of our knowledge, these compounds have not yet been re-
ported in the literature. The reaction of pyrimidine 4a with
hydrazine monohydrate was carried out in ethanol at room
temperature for two hours affording pyrimido[4,5-d]py-
ridazin-8(7H)-one 7a in excellent yield (90%).
Unless otherwise indicated, all common reagents were used as ob-
tained from commercial suppliers without further purification. The
solvents were dried and purified according to recommended proce-
dures.16 All meting points were measured using a Reichert-Thermo-
var apparatus. 1H and 13C NMR spectra were acquired on a Bruker
DPX 200 or Bruker DPX 400 spectrometer (1H at 200.13 MHz or
400.13 MHz and 13C at 50.32 MHz or 100.13 MHz, respectively) at
300 K, 5 mm sample tubes, and with digital resolution of 0.01
ppm. CDCl3, or DMSO-d6 were used as solvents containing TMS as
internal standard. GC-MS EI was registered in an Agilent 6890N
series connected to an Agilent G1530CN GC and interfaced by a
Pentium PC. The GC was equipped with a split-splitless injector,
autosampler cross-linked HP-5 capillary column (30 m, 0.32 mm
i.d.), and He was used as the carrier gas.
The series of pyrimido[4,5-d]pyridazin-8(7H)-ones 7 and
8 were exemplified from four 5-substituted 2-phenylpyri-
midine-4-carboxylates 4a,c,f,h (R = Ph, 4-MeOC6H4, 4-
FC6H4, and 2-thienyl) and four 5-substituted 2-(pyrazol-
1-yl)pyrimidine-4-carboxylates 6a,c,f,h (R = Ph, 4-
The crystal data were recorded on a Bruker Kappa Apex II CCD
area detector with graphite monochromatized MoKa radiation
(l = 0.71073 Å). The data were processed with SAINT and SAD-
ABS. The structure was solved by direct methods (SHELXS-97)
and additional atoms were located in the difference Fourier map and
refined on F2 (SHELXL-97) using the SHELXTL17 and WinGX18
packages. The CHN elemental analyses were performed on a
Perkin-Elmer 2400 CHN elemental analyzer (University of São
Paulo – USP/Brazil).
5-Substituted 2-Phenylpyrimidine-4-carboxylates 4; General
Procedure
A mixture of enamino diketone 1 (1 mmol) and benzamidine hydro-
chloride (2, 0.187 g, 1.2 mmol) in the presence of K2CO3 (0.165 g,
1.2 mmol) was stirred under reflux in anhyd MeCN (20 mL) for 1
h. Then the mixture was cooled to r.t. and the solvent was evaporat-
ed under vacuum. The residue was washed with H2O (2 × 20 mL)
Figure 4 ORTEP12 obtained from the crystal structure of 2,5-diphe-
nylpyrimido[4,5-d]pyridazin-8(7H)-one (7a)
Synthesis 2008, No. 22, 3639–3648 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrimido[4,5-d]pyridazin-8(7H)-ones
3643
Table 4 Crystallography Data and Refinement Method for Compounds 4a, 6h, and 7a
Crystal data
4a
6h
7a
CCDC No.
686848
686847
687296
Molecular formula
Temperature
C20H16N2O3
296(2) K
C15H12N4O3S
302(2) K
C18H12N4O
296(2) K
Color
translucent
0.42 × 0.26 × 0.14
monoclinic, C2/c
translucent
0.35 × 0.32 × 0.11
monoclinic, C2/c
translucent
0.51 × 0.16 × 0.12
monoclinic, P21/n
Crystal size (mm)
Symmetry
Unit cell dimension (Å, °)
a = 24.1621(6), b = 10.1640(3),
c = 13.9791(4), b = 95.239(2)°
a = 23.1436(9), b = 9.8587(3),
c = 13.5503(4), b = 94.094(3)°
a = 8.4407(2), b = 20.0835(5),
c = 11.0274(3), b = 102.489(2)°
Volume (Å3, Z)
3418.70(2), 8
3083.83(2), 8
1825.12(8), 4
r
calcd (g·cm–3), F(000)
1.291, 1392
1.414, 1360
1.377, 792
m (mm–1)
0.088
0.230
0.201
q range for data collection
Reflections collected
Independent reflections (Rint)
Completeness to q
Solution
1.69 to 28.28°
21418
1.76 to 28.33°
38410
2.67 to 31.55°
27698
4237(0.0447)
3829(0.0530)
6064(0.0436)
99.9%
99.7%
99.3%
direct methods SHELXS-97
full-matrix least-squares on F2
4237/0/226
direct methods SHELXS-97
full-matrix least-squares on F2
3829/0/209
direct methods SHELXS-97
full-matrix least-squares on F2
6064/0/244
Refinement method
Data/restraints/parameters
GOF on F2
0.998
1.020
1.063
Final R indices [I>2s(I)]
R indices (all data)
R1 = 0.0524, wR2 = 0.1533
R1 = 0.1145, wR2 = 0.2041
R1 = 0.0567, wR2 = 0.1552
R1 = 0.1063, wR2 = 0.1910
R1 = 0.0476, wR2 = 0.1220
R1 = 0.0877, wR2 = 0.1400
Table 5 Selected Bond Lengths (Å), Bond Angles (°), and Torsional Bond Angles (°) for Compounds 4a, 6h, and 7a
Compound 4a
Compound 6h
Compound 7a
N(1)–C(2)
C(2)–N(1)
1.341(2)
1.479(3)
1.511(3)
1.512(3)
1.389(2)
124.14(18)
117.08(18)
1.4(3)
C(2)–N(1)
1.337(3)
1.402(3)
1.518(3)
1.521(3)
1.381(3)
123.5(2)
117.91(19)
–6.6(3)
1.327(2)
1.483(2)
1.490(2)
1.224(2)
1.361(2)
1.2958(17)
118.16(12)
125.43(12)
121.30(13)
46.8(2)
C(2)–C(21)
N(21)–C(2)
C(21)–C(2)
C(51)–C(5)
C(5)–C(51)
C(5)–C(51)
C(4)–C(41)
C(4)–C(41)
C(8)–O(8)
C(4)–C(5)
C(4)–C(5)
N(7)–C(8)
O(41)–C(41)–C(4)
O(51)–C(51)–C(5)
O(51)–C(51)–C(511)–C(516)
O(51)–C(51)–C(5)–C(6)
N(3)–C(4)–C(41)–O(41)
N(1)–C(2)–C(21)–C(26)
O(41)–C(41)–C(4)
O(51)–C(51)–C(5)
S–C(511)–C(51)–O(51)
C(6)–C(5)–C(51)–O(51)
N(3)–C(4)–C(41)–O(41)
N(22)–N(21)–C(2)–N(3)
N(6)–C(5)
N(1)–C(8A)–C(8)
C(4)–C(4A)–C(5)
O(8)–C(8)–N(7)
N(6)–C(5)–C(51)–C(52)
C(22)–C(21)–C(2)–N(1)
–62.4(3)
–11.5(3)
177.39(18)
–64.5(3)
–13.9(3)
–0.3(3)
–4.6(2)
Synthesis 2008, No. 22, 3639–3648 © Thieme Stuttgart · New York

3644
F. A. Rosa et al.
PAPER
and extracted with CH2Cl2 (3 × 30 mL) and the organic layers were
dried (Na2SO4), and evaporated under vacuum. Recrystallization
(hexane) afforded the pure pyrimidines.
Anal. Calcd for C20H15BrN2O3: C, 58.41; H, 3.68; N, 6.81. Found:
C, 58.53; H, 3.86; N, 6.95.
Ethyl 2-[4-(4-Bromophenyl)-2-phenylpyrimidin-5-yl]-2-oxo-
acetate (5d)
Ethyl 5-Benzoyl-2-phenylpyrimidine-4-carboxylate (4a)
Yield: 0.253 g (76%); mp 76–78 °C.
1H NMR (200 MHz, CDCl3): d = 1.08 (t, 3 H, OCH2CH3), 3.93 (q,
2 H, OCH2CH3), 7.55–8.62 (m, 5 H, Ph), 7.71 (s, 4 H, C6H4), 9.13
(s, 1 H, H5).
1H NMR (200 MHz, CDCl3): d = 1.17 (t, 3 H, OCH2CH3), 4.21 (q,
2 H, OCH2CH3), 7.50–8.58 (m, 10 H, 2 Ph), 9.01 (s, 1 H, H6).
13C NMR (50 MHz, CDCl3): d = 13.5 (CH3), 62.7 (OCH2), 128.7,
128.8, 128.9, 129.3, 131.9, 133.8, 135.9, 136.4 (2 Ph), 129.5 (C5),
155.7 (C4), 158.1 (C6), 164.1 (CO2), 165.6 (C2), 192.6 (CO).
13C NMR (50 MHz, CDCl3): d = 13.5 (CH3), 62.8 (OCH2), 125.2,
126.0, 128.7, 130.8, 132.1, 132.2, 136.2, 136.3 (Ph, C6H4), 129.1
(C5), 159.4 (C6), 160.9 (C4), 165.0 (CO2), 166.0 (C2), 186.3 (CO).
MS (EI, 70 eV): m/z (%) = 332 (M+, 22), 303 (7), 288 (100), 259
(36), 232 (14), 105 (50), 77 (22).
Ethyl 5-(4-Chlorobenzoyl)-2-phenylpyrimidine-4-carboxylate
(4e)
Yield: 0.240 g (65%); mp 102–104 °C.
Anal. Calcd for C20H16N2O3: C, 72.58; H, 4.85; N, 8.34. Found: C,
72.47; H, 5.12; N, 8.52.
1H NMR (200 MHz. CDCl3): d = 1.22 (t, 3 H, OCH2CH3), 4.25 (q,
2 H, OCH2CH3), 7.48–7.76 (m, 4 H, C6H4), 7.54–8.57 (m, 5 H, Ph),
8.98 (s, 1 H, H6).
13C NMR (50 MHz, CDCl3): d = 13.6 (CH3), 62.8 (OCH2), 128.7,
128.9, 129.2, 130.6, 132.0, 134.8, 135.8, 140.5 (Ph, C6H4), 129.3
(C5), 155.5 (C4), 157.9 (C6), 164.0 (CO2), 165.8 (C2), 191.5 (CO).
Ethyl 2-(2,4-Diphenylpyrimidin-5-yl)-2-oxoacetate (5a)
1H NMR (200 MHz, CDCl3): d = 1.02 (t, 3 H, OCH2CH3), 3.82 (q,
2 H, OCH2CH3), 7.47–8.65 (m, 10 H, 2 Ph), 9.13 (s, 1 H, H5).
Ethyl 5-(4-Methylbenzoyl)-2-phenylpyrimidine-4-carboxylate
(4b)
MS (EI, 70 eV): m/z (%) = 366 (M+, 60), 322 (56), 293 (50), 259
Yield: 0.298 g (86%); mp 56–58 °C.
(21), 227 (4), 139 (100), 111 (27), 104 (30).
1H NMR (200 MHz, CDCl3): d = 1.18 (t, 3 H, OCH2CH3), 2.44 (s,
3 H, CH3), 4.22 (q, 2 H, OCH2CH3), 7.30–7.72 (m, 4 H, C6H4),
7.54–8.57 (m, 5 H, Ph), 8.99 (s, 1 H, H6).
Anal. Calcd for C20H15ClN2O3: C, 65.49; H, 4.12; N, 7.64. Found:
C, 65.40; H, 3.79; N, 7.30.
Ethyl 2-[4-(4-Chlorophenyl)-2-phenylpyrimidin-5-yl]-2-oxo-
acetate (5e)
13C NMR (50 MHz, CDCl3): d = 13.5 (CH3), 21.6 (CH3), 62.7
(OCH2), 128.6, 128.8, 129.4, 129.5, 131.8, 133.9, 135.9, 145.0 (Ph,
C6H4), 129.7 (C5), 155.6 (C4), 158.0 (C6), 164.1 (CO2), 165.4 (C2),
192.2 (CO).
1H NMR (200 MHz, CDCl3): d = 1.08 (t, 3 H, OCH2CH3), 3.92 (q,
2 H, OCH2CH3), 7.54–7.65 (m, 4 H, C6H4), 7.54–8.63 (m, 5 H, Ph),
9.12 (s, 1 H, H5).
MS (EI, 70 eV): m/z (%) = 346 (M+, 39), 302 (100), 289 (17), 273
(17), 119 (23), 91 (41).
Ethyl 5-(4-Fluorobenzoyl)-2-phenylpyrimidine-4-carboxylate
(4f)
Anal. Calcd for C21H18N2O3: C, 72.82; H, 5.24; N, 8.09. Found: C,
72.47; H, 5.22; N, 8.42.
Yield: 0.288 g (82%); mp 91–93 °C.
1H NMR (200 MHz, CDCl3): d = 1.21 (t, 3 H, OCH2CH3), 4.26 (q,
2 H, OCH2CH3), 7.18–7.86 (m, 4 H, C6H4), 7.54–8.57 (m, 5 H, Ph),
8.98 (s, 1 H, H6).
Ethyl 5-(4-Methoxybenzoyl)-2-phenylpyrimidine-4-carboxy-
late (4c)
Yield: 0.282 g (78%); mp 94–96 °C.
13C NMR (50 MHz, CDCl3): d = 13.6 (CH3), 62.8 (OCH2), 116.1 (d,
1H NMR (200 MHz, CDCl3): d = 1.19 (t, 3 H, OCH2CH3), 3.89 (s,
3 H, OCH3), 4.24 (q, 2 H, OCH2CH3), 6.97–7.80 (m, 4 H, C6H4),
7.54–8.57 (m, 5 H, Ph), 8.98 (s, 1 H, H6).
13C NMR (50 MHz, CDCl3): d = 13.6 (CH3), 55.5 (OCH3), 62.6
(OCH2), 114.1, 128.7, 128.8, 129.5, 131.8, 136.0, 164.2 (Ph, C6H4),
130.0 (C5), 155.5 (C4), 157.9 (C6), 164.2 (CO2), 165.4 (C2), 191.2
(CO).
2J = 22 Hz, C6H4), 132.0 (d, 3J = 11 Hz, C6H4), 133.0 (d, 4J = 3 Hz,
1
C6H4), 166.1 (d, J = 257 Hz, C6H4), 128.7, 128.9, 132.0, 135.8
(Ph), 129.5 (C5), 155.5 (C4), 157.9 (C6), 164.0 (CO2), 165.7 (C2),
191.2 (CO).
MS (EI, 70 eV): m/z (%) = 350 (M+, 23), 321 (4), 306 (100), 277
(21), 250 (14), 123 (50), 95 (16).
Anal. Calcd for C20H15FN2O3: C, 68.57; H, 4.32; N, 8.00. Found: C,
68.41; H, 4.73; N, 7.91.
MS (EI, 70 eV): m/z (%) = 362 (M+, 81), 333 (21), 318 (68), 288
(13), 135 (100), 107 (7).
Ethyl 5-(4-Nitrobenzoyl)-2-phenylpyrimidine-4-carboxylate
(4g)
Yield: 0.194 g (51%); mp 136–138 °C.
Anal. Calcd for C21H18N2O4: C, 69.60; H, 5.01; N, 7.73. Found: C,
69.76; H, 5.34; N, 7.70.
1H NMR (200 MHz, CDCl3): d = 1.25 (t, 3 H, OCH2CH3), 4.27 (q,
2 H, OCH2CH3), 7.56–8.59 (m, 5 H, Ph), 7.98–8.34 (m, 4 H, C6H4),
9.00 (s, 1 H, H6).
Ethyl 5-(4-Bromobenzoyl)-2-phenylpyrimidine-4-carboxylate
(4d)
Yield: 0.277 g (67%); mp 111–113 °C.
1H NMR (200 MHz, CDCl3): d = 1.22 (t, 3 H, OCH2CH3), 4.26 (q,
2 H, OCH2CH3), 7.55–8.57 (m, 5 H, Ph), 7.67 (s, 4 H, C6H4), 8.98
(s, 1 H, H6).
13C NMR (50 MHz, CDCl3): d = 13.6 (CH3), 63.0 (OCH2), 124.0,
128.8, 129.2, 130.3, 132.4, 135.9, 143.2, 150.5 (Ph, C6H4), 128.9
(C5), 155.3 (C4), 159.6 (C6), 164.1 (CO2), 166.2 (C2), 191.3 (CO).
13C NMR (50 MHz, CDCl3): d = 13.6 (CH3), 62.8 (OCH2), 128.7,
128.9, 129.3, 130.7, 132.0, 132.2, 135.3, 135.8 (Ph, C6H4), 129.1
(C5), 155.5 (C4), 157.9 (C6), 164.0 (CO2), 165.8 (C2), 191.8 (CO).
MS (EI, 70 eV): m/z (%) = 412 (M + 2, 39), 410 (M+, 30), 368 (100),
366 (83), 339 (21), 259 (31), 185 (31), 155 (10).
MS (EI, 70 eV): m/z (%) = 377 (M+,7), 333 (100), 304 (50), 231
(30), 150 (30), 104 (82).
Anal. Calcd for C20H15N3O5: C, 63.66; H, 4.01; N, 11.14. Found: C,
63.58; H, 4.09; N, 11.02.
Synthesis 2008, No. 22, 3639–3648 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrimido[4,5-d]pyridazin-8(7H)-ones
3645
Ethyl 2-[4-(4-Nitrophenyl)-2-phenylpyrimidin-5-yl]-2-oxoace-
tate (5g)
of K2CO3 (0.165 g, 1.2 mmol) was stirred under reflux in anhyd
MeCN (20 mL) for 2 h (for R = 4-MeOC6H4 the reaction time was
3 h and R = 2-thienyl was 6 h). Then the mixture was cooled to r.t.
and the solvent was evaporated under vacuum. The residue was
washed with H2O (2 × 20 mL) and extracted with CH2Cl2 (3 × 30
mL) and the combined organic layers were dried (Na2SO4), and
evaporated under vacuum. Recrystallization (hexane) afforded the
pure pyrimidines 6a–i.
1H NMR (CDCl3): d = 1.13 (t, 3 H, OCH2CH3), 3.98 (q, 2 H,
OCH2CH3), 7.56–8.59 (m, 5 H, Ph), 7.87–8.38 (m, 4 H, C6H4), 9.20
(s, 1 H, H6).
13C NMR (50 MHz, CDCl3): d = 13.7 (CH3), 63.0 (OCH2), 124.0,
128.8, 128.9, 130.1, 132.2, 135.6, 141.0, 149.1 (Ph, C6H4), 125.3
(C5), 157.9 (C6), 160.8 (C4), 164.0 (CO2), 166.2 (C2), 185.5 (CO).
Ethyl 5-Benzoyl-2-(1H-pyrazol-1-yl)pyrimidine-4-carboxylate
(6a)
Yield: 0.193 g (60%); mp 86–88 °C.
1H NMR (200 MHz, CDCl3): d = 1.18 (t, 3 H, OCH2CH3), 4.22 (q,
2 H, OCH2CH3), 6.58–8.70 (m, 3 H, pyrazol-1-yl), 7.52–7.80 (m, 5
H, Ph), 8.98 (s, 1 H, H6).
13C NMR (50 MHz, CDCl3): d = 13.5 (CH3), 63.0 (OCH2), 109.6,
128.9, 129.3, 130.0, 134.0, 136.2, 144.9 (Ph, pyrazol-1-yl), 129.0
(C5), 155.9 (C4), 157.7 (CO2), 160.3 (C6), 163.2 (C2), 191.6 (CO).
Ethyl 2-Phenyl-5-(2-thienylcarbonyl)pyrimidine-4-carboxylate
(4h)
Yield: 0.237 g (70%); mp 131–133 °C.
1H NMR (200 MHz, CDCl3): d = 1.24 (t, 3 H, OCH2CH3), 4.31 (q,
2 H, OCH2CH3), 7.17–7.81 (m, 3 H, 2-thienyl), 7.54–8.57 (m, 5 H,
Ph), 9.07 (s, 1 H, H6).
13C NMR (50 MHz, CDCl3): d = 13.6 (CH3), 62.7 (OCH2), 128.5,
128.7, 128.9, 131.9, 134.9, 135.8, 135.8, 143.5 (Ph, 2-thienyl),
129.3 (C5), 155.6 (C4), 157.6 (C6), 164.0 (CO2), 165.7 (C2), 184.4
(CO).
MS (EI, 70 eV): m/z (%) = 322 (M+, 5), 278 (61), 249 (100), 222
(33), 145 (16), 105 (61), 77 (87).
MS (EI, 70 eV): m/z (%) = 338 (M+, 20), 309 (4), 294 (100), 281
(11), 265 (21), 238 (37), 111 (72).
Anal. Calcd for C17H14N4O3: C, 63.35; H, 4.38; N, 17.38. Found: C,
63.31; H, 4.51; N, 17.05.
Anal. Calcd for C18H14N2O3S: C, 63.89; H, 4.17; N, 8.28. Found: C,
63.65; H, 4.46; N, 8.05.
Ethyl 5-(4-Methylbenzoyl)-2-(1H-pyrazol-1-yl)pyrimidine-4-
carboxylate (6b)
Yield: 0.218 g (65%); mp 94–96 °C.
Ethyl 5-(Benzofuran-2-ylcarbonyl)-2-phenylpyrimidine-4-car-
boxylate (4i)
Yield: 0.226 g (61%); mp 83–85 °C.
1H NMR (200 MHz, CDCl3): d = 1.19 (t, 3 H, OCH2CH3), 2.45 (s,
3 H, CH3), 4.23 (q, 2 H, OCH2CH3), 6.57–8.70 (m, 3 H, pyrazol-1-
yl), 7.31–7.70 (m, 4 H, C6H4), 8.96 (s, 1 H, H6).
13C NMR (50 MHz, CDCl3): d = 13.3 (CH3), 21.5 (CH3), 62.8
(OCH2), 109.4, 129.4, 129.4, 129.8, 133.6, 144.7, 145.1 (C6H4,
pyrazol-1-yl), 129.1 (C5), 155.7 (C4), 157.5 (CO2), 160.1 (C6),
163.0 (C2), 191.0 (CO).
1H NMR (CDCl3): d = 1.21 (t, 3 H, OCH2CH3), 4.27 (q, 2 H,
OCH2CH3), 7.37–7.73 (m, 5 H, benzofuran-2-yl), 7.55–8.60 (m, 5
H, Ph), 9.21 (s, 1 H, H6).
13C NMR (CDCl3): d = 13.7 (CH3), 62.8 (OCH2), 110.7, 112.4,
115.4, 122.8, 123.5, 124.2, 128.2, 129.0, 132.0, 135.8, 152.0, 156.0
(benzofuran-2-yl, phenyl), 156.3 (C4), 158.3 (C6), 160.6 (CO2),
164.3 (C2), 181.4 (CO).
MS (EI, 70 eV): m/z (%) = 336 (M+, 49), 307 (19), 292 (100), 263
(81), 249 (51), 236 (41), 217 (16), 119 (10), 91 (61).
MS (EI, 70 eV): m/z (%) = 372 (M+, 100), 328 (41), 299 (13), 272
(68), 145 (60), 105 (11), 89 (20).
Anal. Calcd for C18H16N4O3: C, 64.28, H, 4.79; N, 16.66. Found: C,
64.21, H, 4.73; N, 16.87.
Anal. Calcd for C22H16N2O4: C, 70.96; H, 4.33; N, 7.52. Found: C,
70.92; H, 4.64; N, 7.50.
Ethyl 5-(4-Methoxybenzoyl)-2-(1H-pyrazol-1-yl)pyrimidine-4-
carboxylate (6c)
Yield: 0.236 g (67%); oil.
1H NMR (200 MHz, CDCl3): d = 1.20 (t, 3 H, OCH2CH3), 3.89 (s,
3 H, OCH3), 4.25 (q, 2 H, OCH2CH3), 6.57–8.70 (m, 3 H, pyrazol-
1-yl), 6.98–7.78 (m, 4 H, C6H4), 8.94 (s, 1 H, H6).
Ethyl 2-[4-(Benzofuran-2-yl)-2-phenylpyrimidin-5-yl]-2-oxo-
acetate (5i)
1H NMR (CDCl3): d = 1.10 (t, 3 H, OCH2CH3), 4.10 (q, 2 H,
OCH2CH3), 7.37–7.94 (m, 5 H, benzofuran-2-yl), 7.55–8.60 (m, 5
H, Ph), 9.01 (s, 1 H, H6).
13C NMR (50 MHz, CDCl3): d = 13.4 (CH3), 55.5 (OCH3), 62.8
(OCH2), 109.4, 114.1, 129.4, 129.8, 131.8, 144.7, 164.3 (C6H4,
pyrazol-1-yl), 129.1 (C5), 155.7 (C4), 157.3 (CO2), 160.0 (C6),
163.2 (C2), 189.9 (CO).
MS (EI, 70 eV): m/z (%) = 352 (M+, 100), 323 (8), 308 (45), 279
(48), 251 (9), 135 (69), 107 (15).
Ethyl 2-[2-Phenyl-4-(trifluoromethyl)pyrimidin-5-yl]-2-oxo-
acetate (5j)
Yield: 0.162 g (50%); mp 70–72 °C.
1H NMR (CDCl3): d = 1.41 (t, 3 H, OCH2CH3), 4.45 (q, 2 H,
OCH2CH3), 7.56–8.56 (m, 5 H, Ph), 9.11 (s, 1 H, H6).
13C NMR (CDCl3): d = 13.8 (CH3), 63.7 (OCH2), 120.1 (q, 1J = 277
Hz, CF3), 124.8 (C5), 128.9, 129.3, 132.8, 134.9 (Ph), 153.5 (q,
1J = 37 Hz, C4), 159.4 (C6), 159.9 (CO2), 166.6 (C2), 183.4 (CO).
Anal. Calcd for C18H16N4O4: C, 61.36; H, 4.58; N, 15.90. Found: C,
61.08; H, 4.73; N, 15.85.
MS (EI, 70 eV): m/z (%) = 324 (M+, 3), 251 (100), 223 (8), 121 (8),
103 (7), 77 (6).
Ethyl 5-(4-Bromobenzoyl)-2-(1H-pyrazol-1-yl)pyrimidine-4-
carboxylate (6d)
Yield: 0.281 g (70%); mp 136–138 °C.
Anal. Calcd for C15H11F3N2O3: C, 55.56; H, 3.42; N, 8.64. Found:
C, 55.05; H, 3.60; N, 8.52.
1H NMR (200 MHz, CDCl3): d = 1.23 (t, 3 H, OCH2CH3), 4.26 (q,
2 H, OCH2CH3), 6.58–8.70 (m, 3 H, pyrazol-1-yl), 7.66 (s, 4 H,
C6H4), 8.95 (s, 1 H, H6).
13C NMR (50 MHz, CDCl3): d = 13.5 (CH3), 63.1 (OCH2), 109.7,
129.4, 129.9, 130.6, 132.2, 135.0, 145.0 (C6H4, pyrazol-1-yl), 128.7
(C5), 156.0 (C4), 157.5 (CO2), 160.1 (C6), 163.0 (C2), 190.6 (CO).
5-Substituted 2-(1H-Pyrazol-1-yl)pyrimidine-4-carboxylates 6;
General Procedure
A mixture of b-enamino diketone 1 (1 mmol) and 1H-pyrazole-1-
carboxamidine hydrochloride (3, 0.176 g, 1.2 mmol) in the presence
Synthesis 2008, No. 22, 3639–3648 © Thieme Stuttgart · New York

3646
F. A. Rosa et al.
PAPER
MS (EI, 70 eV): m/z (%) = 400 (M+, 7), 358 (100), 327 (44), 300
(20), 249 (14), 221 (10), 183 (40), 157 (14).
Anal. Calcd for C15H12N4O3S: C, 54.87; H, 3.68; N, 17.06. Found:
C, 54.81; H, 3.88; N, 17.00.
Anal. Calcd for C17H13BrN4O3: C, 50.89; H, 3.27; N, 13.96. Found:
C, 51.17; H, 3.57; N, 13.78.
Ethyl 5-(Benzofuran-2-ylcarbonyl)-2-(1H-pyrazol-1-yl)pyrimi-
dine-4-carboxylate (6i)
Yield: 0.279 g (77%); mp 108–110 °C.
Ethyl 5-(4-Chlorobenzoyl)-2-(1H-pyrazol-1-yl)pyrimidine-4-
carboxylate (6e)
Yield: 0.239g (67%); mp 108–110 °C.
1H NMR (200 MHz, CDCl3): d = 1.22 (t, 3 H, OCH2CH3), 4.26 (q,
2 H, OCH2CH3), 6.58–8.69 (m, 3 H, pyrazol-1-yl), 7.49–7.75 (m, 4
H, C6H4), 8.95 (s, 1 H, H6).
13C NMR (50 MHz, CDCl3): d = 13.6 (CH3), 63.1 (OCH2), 109.7,
129.2, 130.0, 130.6, 134.6, 140.7, 145.0 (C6H4, pyrazol-1-yl), 128.8
(C5), 156.0 (C4), 157.5 (CO2), 160.1 (C6), 163.1 (C2), 190.4 (CO).
1H NMR (200 MHz, CDCl3): d = 1.21 (t, 3 H, OCH2CH3), 4.28 (q,
2 H, OCH2CH3), 6.58–8.72 (m, 3 H, pyrazol-1-yl), 7.36–7.75 (m, 5
H, benzofuran-2-yl), 9.20 (s, 1 H, H6).
13C NMR (50 MHz, CDCl3): d = 13.6 (CH3), 63.1 (OCH2), 109.7,
112.3, 115.5, 123.5, 124.4, 126.7, 129.1, 130.0, 145.1, 151.7, 155.9
(benzofuran-2-yl, pyrazol-1-yl), 127.6 (C5), 156.0 (C4), 158.2
(CO2), 160.5 (C6), 163.3 (C2), 180.2 (CO).
MS (EI, 70 eV): m/z (%) = 362 (M+, 75), 318 (37), 289 (17), 262
(100), 234 (13), 194 (23), 145 (58), 89 (56).
MS (EI, 70 eV): m/z (%) = 356 (M+, 8), 312 (58), 283 (100), 256
(36), 217 (14), 139 (51), 111 (60).
Anal. Calcd for C19H14N4O4: C, 62.98; H, 3.89; N, 15.46. Found: C,
62.76; H, 3.98; N, 15.23.
Anal. Calcd for C17H13ClN4O3: C, 57.23; H, 3.67; N, 15.70. Found:
C, 57.10; H, 3.83; N, 15.99.
2,5-Substituted Pyrimido[4,5-d]pyridazin-8(7H)-ones 7 and 8;
General Procedure
Ethyl 5-(4-Fluorobenzoyl)-2-(1H-pyrazol-1-yl)pyrimidine-4-
carboxylate (6f)
Yield: 0.204 g (60%); mp 101–103 °C.
1H NMR (200 MHz, CDCl3): d = 1.22 (t, 3 H, OCH2CH3), 4.27 (q,
2 H, OCH2CH3), 6.59–8.70 (m, 3 H, pyrazol-1-yl), 7.20–7.84 (m, 4
H, C6H4), 8.96 (s, 1 H, H6).
A mixture of ethyl pyrimidine-4-carboxylate 4 or 6 (1 mmol) and
hydrazine monohydrate (0.06 g, 1.2 mmol) was stirred under r.t. (or
under reflux for 7h) in anhyd EtOH (20 mL) for 2 h. When the re-
action was complete, the product was obtained by filtration of the
precipitate formed. The precipitate was washed with EtOH (3 × 10
mL) affording the pyrimido[4,5-d]pyridazinones with sufficient pu-
rity, without the need to use another method of purification.
13C NMR (50 MHz, CDCl3): d = 13.5 (CH3), 63.0 (OCH2), 109.6,
2
129.9, 144.9 (pyrazol-1-yl), 116.1 (d, J = 22 Hz, C6H4), 132.0 (d,
4
1
3J = 10 Hz, C6H4), 132.7 (d, J = 3 Hz, C6H4), 166.1 (d, J = 257,
C6H4), 128.9 (C5), 155.9 (C4), 157.5 (CO2), 160.0 (C6), 163.1 (C2),
190.0 (CO).
2,5-Diphenylpyrimido[4,5-d]pyridazin-8(7H)-one (7a)
Yield: 0.270 g (90%); mp 296–298 °C.
1H NMR (50 MHz, DMSO-d6): d = 7.60–8.51 (m, 10 H, 2 Ph), 9.31
(s, 1 H, H4), 13.38 (s, 1 H, NH).
MS (EI, 70 eV): m/z (%) = 340 (7), 296 (60), 267 (100), 240 (32),
13C NMR (100 MHz, DMSO-d6): d = 120.3 (C4a), 128.3, 128.5,
128.6, 128.9, 129.1, 131.7, 133.1, 135.8 (2 Ph), 144.0 (C5), 149.1
(C8a), 157.5 (CO), 158.8 (C4), 164.0 (C2).
MS (EI, 70 eV): m/z (%) = 300 (M+, 100), 271 (23), 169 (7), 140
(11), 105 (19), 77 (10).
213 (9), 173 (10), 145 (10), 123 (55), 95 (50).
Anal. Calcd for C17H13FN4O3: C, 60.00; H, 3.85; N, 16.46. Found:
C, 59.72; H, 3.91; N, 16.24.
Ethyl 5-(4-Nitrobenzoyl)-2-(1H-pyrazol-1-yl)pyrimidine-4-car-
boxylate (6g)
Yield: 0.275 g (75%); mp 166–168 °C.
1H NMR (200 MHz, CDCl3): d = 1.25 (t, 3 H, OCH2CH3), 4.27 (q,
2 H, OCH2CH3), 6.60–8.70 (m, 3 H, pyrazol-1-yl), 7.97–8.35 (m, 4
H, C6H4), 8.98 (s, 1 H, H6).
Anal. Calcd for C18H12N4O: C, 71.99; H, 4.03; N, 18.66. Found: C,
71.74; H, 4.14; N, 18.85.
5-(4-Methoxyphenyl)-2-phenylpyrimido[4,5-d]pyridazin-
8(7H)-one (7c)
13C NMR (50 MHz, CDCl3): d = 13.6 (CH3), 63.3 (OCH2), 109.9,
124.0, 130.0, 130.1, 140.8, 145.2, 150.5 (C6H4, pyrazol-1-yl), 128.3
(C5), 156.2 (C4), 157.4 (CO2), 160.1 (C6), 163.0 (C2), 190.2 (CO).
Yield: 0.287 g (87%); mp 316–318 °C.
1H NMR (50 MHz, DMSO-d6): d = 3.86 (s, 3 H, OCH3), 7.14–7.65
(m, 4 H, C6H4), 7.60–8.53 (m, 5 H, Ph), 9.35 (s, 1 H, H4), 13.30 (s,
1 H, NH).
MS (EI, 70 eV): m/z (%) = 367 (M+, 5), 323 (59), 294 (100), 248
13C NMR (100 MHz, DMSO-d6): d = 55.2 (OCH3), 114.1, 125.5,
128.4, 128.9, 130.5, 132.0, 136.0, 159.3 (Ph, C6H4), 120.6 (C4a),
144.0 (C5), 149.3 (C8a), 157.7 (CO), 160.1 (C4), 164.0 (C2).
(36), 221 (33), 104 (33).
Anal. Calcd for C17H13N5O5: C, 55.59; H, 3.57; N, 19.07. Found: C,
55.37; H, 3.72; N, 19.25.
Anal. Calcd for C19H14N4O2: C, 69.08; H, 4.27; N, 16.96. Found: C,
68.84; H, 4.44; N, 16.91.
Ethyl 2-(1H-Pyrazol-1-yl)-5-(2-thienylcarbonyl)pyrimidine-4-
carboxylate (6h)
Yield: 0.213 g (65%); mp 96–98 °C.
5-(4-Fluorophenyl)-2-phenylpyrimido[4,5-d]pyridazin-8(7H)-
one (7f)
Yield: 0.289 g (91%); mp 277–279 °C.
1H NMR (50 MHz, DMSO-d6): d = 7.44–7.78 (m, 4 H, C6H4), 7.62–
8.54 (m, 5 H, Ph), 9.35 (s, 1 H, H4), 13.41 (s, 1 H, NH).
1H NMR (200 MHz, CDCl3): d = 1.25 (t, 3 H, OCH2CH3), 4.32 (q,
2 H, OCH2CH3), 6.57–8.70 (m, 3 H, pyrazol-1-yl), 7.18–7.83 (m, 3
H, 2-thienyl), 9.05 (s, 1 H, H6).
13C NMR (50 MHz, CDCl3): d = 13.4 (CH3), 62.9 (OCH2), 109.5,
128.4, 129.8, 134.8, 136.0, 143.0, 144.8 (2-thienyl, pyrazol-1-yl),
128.7 (C5), 155.7 (C4), 157.5 (CO2), 159.6 (C6), 162.9 (C2), 183.1
(CO).
13C NMR (100 MHz, DMSO-d6): d = 115.7 (d, 2J = 22 Hz, C6H4),
4
3
129.7 (d, J = 3 Hz, C6H4), 131.5 (d, J = 9 Hz, C6H4), 162.7 (d,
1J = 247 Hz, C6H4), 120.5 (C4a), 143.4 (C5), 149.2 (C8a), 157.8
(CO), 159.1 (C4), 164.1 (C2).
MS (EI, 70 eV): m/z (%) = 328 (M+, 31), 284 (91), 271 (13), 255
(11), 228 (62), 201 (11), 111 (100), 83 (20).
Synthesis 2008, No. 22, 3639–3648 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrimido[4,5-d]pyridazin-8(7H)-ones
3647
MS (EI, 70 eV): m/z (%) = 318 (M+, 100), 289 (69), 245 (100), 142
(20), 115 (20).
1H NMR (100 MHz, DMSO-d6): d = 6.72–8.78 (m, 3 H, pyrazol-1-
yl), 7.29–7.81 (m, 3 H, 2-thienyl), 9.74 (s, 1 H, H4), 13.39 (br, 1 H,
NH).
13C NMR (50 MHz, DMSO-d6): d = 109.9, 128.2, 128.5, 129.3,
130.2, 135.6, 144.7 (2-thienyl, pyrazol-1-yl), 120.0 (C4a), 138.4
(C5), 150.6 (C8a), 155.3 (CO), 157.1 (C4), 161.4 (C2).
Anal. Calcd for C18H11FN4O: C, 67.92; H, 3.48; N, 17.60. Found:
C, 67.80; H, 3.56; N, 17.52.
2-Phenyl-5-(2-thienyl)pyrimido[4,5-d]pyridazin-8(7H)-one (7h)
Yield: 0.282 g (92%); mp 252–254 °C.
1H NMR (50 MHz, DMSO-d6): d = 7.29–7.81 (m, 3 H, 2-thienyl),
7.61–8.52 (m, 5 H, Ph), 9.73 (s, 1 H, H4), 13.37 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 119.9 (C4a), 128.1, 128.4,
128.9, 129.1, 132.0, 135.6, 135.8 (Ph, 2-thienyl), 138.5 (C5), 149.2
(C8a), 157.4 (CO), 158.2 (C4), 164.1 (C2).
MS (EI, 70 eV): m/z (%) = 296 (M+, 100), 267 (15), 172 (18), 146
(7), 120 (6).
Anal. Calcd for C13H8N6OS: C, 52.70; H, 2.72; N, 28.36. Found: C,
52.58; H, 2.91; N, 28.16.
Acknowledgment
MS (EI, 70 eV): m/z (%) = 306 (M+, 100), 277 (25), 250 (13), 147
(16), 120 (18).
The authors thank the Conselho Nacional de Desenvolvimento
Científico e Tecnológico em Pesquisa (CNPq/PADCT) and
Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul
(FAPERGS) for financial support. The fellowships from CNPq,
CAPES and FAPERGS are also acknowledged.
Anal. Calcd for C16H10N4OS: C, 62.73; H, 3.29; N, 18.29. Found:
C, 62.64; H, 3.58; N, 18.11.
5-Phenyl-2-(1H-pyrazol-1-yl)pyrimido[4,5-d]pyridazin-8(7H)-
one (8a)
Yield: 0.267 g (92%); mp 299–301 °C.
1H NMR (100 MHz, DMSO-d6): d = 6.70–8.77 (m, 3 H, pyrazol-1-
yl), 7.60–7.71 (m, 5 H, Ph), 9.33 (s, 1 H, H4), 13.39 (br, 1 H, NH).
References
(1) (a) Nargund, L. V. G.; Badiger, V. V.; Yarnal, S. U. Eur. J.
Med. Chem. 1994, 29, 245. (b) Ouf, N. H.; Amr A. El-G, E.;
Fayed, A. A. Monatsh. Chem. 2008, 139, 281. (c) Tafi, A.;
Bernardine, C.; Botta, M.; Corelli, F.; Andreini, M.;
Martineli, A.; Ortore, G.; Baraldi, P. G.; Fruttarolo, F.;
Borea, P. A.; Tuccinardi, T. J. Med. Chem. 2006, 49, 4085.
(d) Orjales, A.; Mosquera, R.; López, B.; Olivera, R.;
Labeaga, L.; Núñez, M. T. Bioorg. Med. Chem. 2008, 16,
2183. (e) Danel, K.; Pedersen, E. B.; Nielsen, C. J. Med
Chem. 1998, 41, 191; and references therein.
13C NMR (50 MHz, DMSO-d6): d = 109.8, 128.8, 129.1, 129.5,
130.2, 133.2, 144.6 (Ph, pyrazol-1-yl), 120.5 (C4a), 144.1 (C5),
150.5 (C8a), 155.3 (CO), 157.3 (C4), 161.7 (C2).
MS (EI, 70 eV): m/z (%) = 290 (M+, 100), 261 (24), 195 (5), 166 (7),
140 (10), 77 (9).
Anal. Calcd for C15H10N6O2: C, 62.07; H, 3.47; N, 28.95. Found: C,
62.00; H, 3.56; N, 28.90.
(2) (a) Brown, D. J. In Comprehensive Heterocyclic Chemistry,
Vol. 3; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon:
Oxford, 1984. (b) Undheim, K.; Benneche, T. In
Comprehensive Heterocyclic Chemistry II, Vol. 6;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F., Eds.;
Pergamon: Oxford, 1996. (c) Martins, M. A. P.; Frizzo, C.
P.; Moreira, D. N.; Zanatta, N.; Bonacorso, H. G. Chem. Rev.
2008, 108, 2015. (d) Martins, M. A. P.; Cunico, W.; Pereira,
C. M. P.; Sinhorin, A. P.; Flores, A. F. C.; Bonacorso, H. G.;
Zanatta, N. Curr. Org. Synth. 2004, 1, 391.
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1342. (b) Krapcho, A. P.; Maresch, M. J.; Helgason, A. L.;
Rosner, K. E.; Hacker, M. P. J. Heterocycl. Chem. 1993, 30,
1597.
(4) Bradshaw, J. S.; Huszthy, P.; Izatt, R. M. J. Heterocycl.
Chem. 1994, 31, 1047.
5-(4-Methoxyphenyl)-2-(1H-pyrazol-1-yl)pyrimido[4,5-d]py-
ridazin-8(7H)-one (8c)
Yield: 0.288 g (90%); mp 278–280 °C.
1H NMR (50 MHz, DMSO-d6): d = 3.86 (s, 3 H, OCH3), 6.71–8.77
(m, 3 H, pyrazol-1-yl), 7.14–7.64 (m, 4 H, C6H4), 9.34 (s, 1 H, H4),
13.33 (br, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 55.2 (OCH3), 109.8, 114.2,
125.5, 130.1, 130.5, 144.6, 160.1 (C6H4, pyrazol-1-yl), 120.6 (C4a),
144.6 (C5), 150.5 (C8a), 155.2 (CO), 157.3 (C4), 161.8 (C2).
MS (EI, 70 eV): m/z (%) = 320 (M+, 1), 266 (100), 163 (12), 135
(11), 111 (50), 77 (9).
Anal. Calcd for C16H12N6O2: C, 60.00; H, 3.78; N, 26.24. Found: C,
59.90; H, 3.89; N, 26.39.
(5) Riley, T. A.; Hennen, W. J.; Dalley, N. K.; Wilson, B. E.;
Robins, R. K.; Larson, S. B. J. Heterocycl. Chem. 1987, 24,
955.
5-(4-Fluorophenyl)-2-(1H-pyrazol-1-yl)pyrimido[4,5-d]py-
ridazin-8(7H)-one (8f)
Yield: 0.250 g (81%); mp 284–286 °C.
(6) Jones, R. G. J. Am. Chem. Soc. 1956, 78, 159.
(7) (a) Kuderna, J. G.; Skiles, R. D.; Pilgram, K. J. Org. Chem.
1971, 36, 3506. (b) Mátyus, P.; Szilágyi, G.; Kasztreiner, E.;
Rabloczky, G. J. Heterocycl. Chem. 1988, 25, 1535.
(8) Treu, M.; Jordis, U.; Lee, V. J. Molecules 2001, 6, 959.
(9) Rosa, F. A.; Machado, P.; Rossatto, M.; Vargas, P. S.;
Bonacorso, H. G.; Zanatta, N.; Martins, M. A. P. Synlett
2007, 3165.
1H NMR (50 MHz, DMSO-d6): d = 6.71–8.77 (m, 3 H, pyrazol-1-
yl), 7.43–7.76 (m, 4 H, C6H4), 9.33 (s, 1 H, H4), 13.41 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 109.6, 130.0, 144.4 (pyrazol-
1-yl), 115.5 (d, 2J = 22 Hz, C6H4), 129.5 (d, 4J = 3 Hz, C6H4), 131.2
3
1
(d, J = 9 Hz, C6H4), 162.6 (d, J = 247 Hz, C6H4), 120.5 (C4a),
143.1 (C5), 150.4 (C8a), 155.2 (CO), 157.1 (C4), 161.4 (C2).
MS (EI, 70 eV): m/z (%) = 308 (M+, 100), 279 (26), 207 (15), 184
(10) Rosa, F. A.; Machado, P.; Vargas, P. S.; Bonacorso, H. G.;
Zanatta, N.; Martins, M. A. P. Synlett 2008, 1673.
(11) Crystallographic data for compounds 4a, 6h, and 7a reported
in this paper, have been deposited with the Cambridge
Crystallographic Data Centre (CCDC Number 686848,
686847, and 687296, respectively). Copies of the data can be
obtained, free of charge, on application to CCDC 12 Union
(11), 158 (12), 95 (9).
Anal. Calcd for C15H9FN6O: C, 58.44; H, 2.94; N, 27.26. Found: C,
58.35; H, 2.98; N, 27.39.
2-(1H-Pyrazol-1-yl)-5-(2-thienyl)pyrimido[4,5-d]pyridazin-
8(7H)-one (8h)
Yield: 0.249 g (84%); mp 286–288 °C.
Synthesis 2008, No. 22, 3639–3648 © Thieme Stuttgart · New York

3648
F. A. Rosa et al.
PAPER
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Synthesis 2008, No. 22, 3639–3648 © Thieme Stuttgart · New York