Reactions of 6-aryl-5-benzoyl-4-dichloromethyl-4-hydroxy- hexahydropyrimidin-2-ones with hydrazine hydrate: A new simple and efficient route to 4-aryl-5-phenyl-3,4-dihydropyrimido[4,5-d]pyridazin-2(1 H)-ones

Article abstract of DOI:10.1007/s11172-009-0270-5

Cyclocondensation of 5-aroyl-4-dichloromethyl-4-hydroxy-6- phenylperhydropyrimidin-2-ones with 85% hydrazine hydrate in boiling toluene afforded pyrimido[4,5- d]pyridazines.

Full text of DOI:10.1007/s11172-009-0270-5

Russian Chemical Bulletin, International Edition, Vol. 58, No. 9, pp. 1981—1985, September, 2009
1981
Reactions of 6ꢀarylꢀ5ꢀbenzoylꢀ4ꢀdichloromethylꢀ4ꢀhydroxyꢀ
hexahydropyrimidinꢀ2ꢀones with hydrazine hydrate:
a new simple and efficient route to 4ꢀarylꢀ5ꢀphenylꢀ
3,4ꢀdihydropyrimido[4,5ꢀd]pyridazinꢀ2(1H)ꢀones
V. A. Mamedov, L. V. Mustakimova, S. V. Vdovina, A. T. Gubaidullin, and I. A. Litvinov
A. E. Arbuzov Institute of Organic and Physical Chemistry,
Kazan Research Center of the Russian Academy of Sciences,
8 ul. Akad. Arbuzova, 420088 Kazan, Russian Federation.
Fax: +7 (843) 273 2253. Eꢀmail: mamedov@iopc.ru
Cyclocondensation of 5ꢀaroylꢀ4ꢀdichloromethylꢀ4ꢀhydroxyꢀ6ꢀphenylperhydropyrimidinꢀ
2ꢀones with 85% hydrazine hydrate in boiling toluene afforded pyrimido[4,5ꢀd]pyridazines.
Key words: the Biginelli reaction, pyrimidines, cyclocondensation, pyrimido[4,5ꢀd]ꢀ
pyridazines, IR spectroscopy, NMR spectroscopy, Xꢀray diffraction analysis.
Tetraazanaphthalene derivatives play a substantial part
in vital functions and are drug components. Compounds
containing the pyrazino[2,3ꢀd]pyrimidine (pteridine)
system1,2 are leaders in the number of natural and synꢀ
thetic drugs derived therefrom. In addition, other tetraꢀ
azanaphthalenes such as pyrimido[5,4ꢀd]pyrimidines,3
pyrimido[4,5ꢀc]pyridazines,4 and pyrimido[4,5ꢀd]pyridꢀ
azines3,5—10 attract attention because of their cardiotonic
and hypotensive effects and diuretic properties that inꢀ
hibit phosphodiesterase (PDE) and its subtypes (PDE1—
PDE11) responsible for erectile dysfunctions. Neverꢀ
theless, simple methods for the synthesis of such heteroꢀ
cyclic systems are lacking. Known routes to pyrimidoꢀ
pyridazines involve expensive pyrimidine3,7,8,11 or pyridꢀ
azine derivatives.4
Here we present a new simple and efficient method
for the preparation of pyrimido[4,5ꢀd]pyridazines from
accessible starting materials. We found that 6ꢀarylꢀ5ꢀbenꢀ
Scheme 1
R = H (a), Br (b), OMe (c)
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1919—1923, September, 2009.
1066ꢀ5285/09/5809ꢀ1981 © 2009 Springer Science+Business Media, Inc.

1982
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009
a
Mamedov et al.
b
O(26)
C(33)
C(33)
C(32)
C(32)
C(34)
C(35)
C(24)
C(34)
C(35)
C(24)
C(23)
C(22)
C(26)
C(31)
C(30)
C(23)
C(25)
C(20)
C(25)
C(31)
C(30)
C(22)
C(20)
C(2)
C(21)
C(3)
C(2)
C(3)
C(21)
C(2A)
C(6A)
C(2A)
N(4)
N(4)
N(5)
N(1)
C(8)
N(1)
C(8)
N(5)
C(6A)
C(6)
O(8)
C(6)
N(7)
N(7)
O(8)
Fig. 1. Molecular geometries of compounds 2a (a) and 2c (b) in the crystal with atomic thermal displacement ellipsoids (p = 50%) for
the nonꢀhydrogen atoms. The hydrogen atoms are depicted as circles of conventional radii.
these structures along the crystallographic axis 0c gives
rise to a bilayer crystal structure (Fig. 2, b).
zoylꢀ4ꢀdichloromethylꢀ4ꢀhydroxyhexahydropyrimidinꢀ
2ꢀones 1a—c 12 (easily prepared by the Biginelli reaction
from aroyl(dichloroacetyl)methane, an aromatic aldeꢀ
hyde, and urea) react with 85% hydrazine hydrate to give
4ꢀarylꢀ5ꢀphenylꢀ3,4ꢀdihydropyrimido[4,5ꢀd]pyridazinꢀ
2(1H)ꢀones 2a—c in high (87—93%) yields (Scheme 1).
It should be noted that a 20ꢀfold excess of hydrazine
hydrate is required for successful completion of the reacꢀ
tion; when hydrazine hydrate is used in smaller amounts,
the reaction time increases and the yields of compounds
2a—c decrease.
Convincing evidence for isomers 2a—c (rather than
other plausible isomers 2´a—c or 2″a—c) was provided by
Xꢀray diffraction of pyrimido[4,5ꢀd]pyridazines 2a,c.
Their molecular structures are shown in Fig. 1. Both comꢀ
pounds form monoclinic crystals; the asymmetric parts
of their unit cells contain one crystallographically indeꢀ
pendent molecule. The structures were solved in the
centrosymmetric space group P21/c. Their conformations
are similar, except for small differences in the angles
between the phenyl substituents and the conventional
plane of the pyrimido[4,5ꢀd]pyridazine fragment (the
angles for the planes C(20)—C(25) and C(30)—C(35) are
64.3 and 85.9° in 2a and 61.3 and 87.8° in 2c, respecꢀ
tively).
In the 1H NMR spectra of pyrimido[4,5ꢀd]pyridazines
2b and 2a,c (the latter were identified by Xꢀray diffracꢀ
tion), the signal positions and multiplicity are identical
(except for the signals of the C(4)H protons in the aryl
substituent). This suggests that these compounds exist in
solutions (as well as in crystals) as 4Hꢀisomers 2 rather
than 5Hꢀ or 8aHꢀisomers 2´ and 2″, respectively. An inꢀ
crease in the recording temperature from 35 to 105 °C did
not change the spectral pattern (i.e., the 4Hꢀisomer
did not isomerize into other plausible structures).
Experimental
Melting points were determined on a Boetius hotꢀstage. IR
spectra were recorded on a Vectorꢀ22 FTIR spectrometer
(Bruker) in Nujol in the 400—3600 cm–1 range. 1H NMR specꢀ
tra were recorded on an Avanceꢀ600 spectrometer (Bruker)
(600.13 (1H) and 150.926 MHz (13C)). Chemical shifts are given
on the δ scale with reference to the signals for residual protons
and 13C atoms in DMSOꢀd6 (δH 2.52, δC 40.45).
6ꢀArylꢀ5ꢀbenzoylꢀ4ꢀdichloromethylꢀ4ꢀhydroxyhexahydroꢀ
pyrimidinꢀ2ꢀones 1a—c were obtained by the Biginelli reaction
from benzoyl(dichloroacetyl)methane, an appropriate aromatic
aldehyde, and urea as described earlier.12
4,5ꢀDiphenylꢀ3,4ꢀdihydropyrimido[4,5ꢀd]pyridazinꢀ2(1H)ꢀ
one (2a). Hydrazine hydrate (85%, 1.54 g, 26.18 mmol)
was added to a mixture of perhydropyrimidinone 1a (0.50 g,
1.31 mmol) in toluene (10 mL). The reaction mixture was reꢀ
fluxed with a Dean—Stark trap for 20 h. After ~1 h, crystals
The nature of the substituent in the phenyl fragment
does not affect intermolecular interactions in the crystals
of these compounds. In both cases, ribbonꢀlike supramoꢀ
lecular structures are stabilized by the hydrogen bonds
N—H...N and N—H...O (Fig. 2, a). Parallel stacking of

Synthesis of pyrimido[4,5ꢀd]pyridazinꢀ2(1H)ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009 1983
a
b
Fig. 2. a. Formation of ribbonꢀlike supramolecular structures in the crystal of compound 2a by means of the N—H...N and N—H...O
hydrogen bonds (indicated with dashed lines). The view along the crystallographic axis 0c is shown. b. Molecular packing in the crystal
structure 2c. The view along the crystallographic axis 0b is shown. Hydrogen bonds are indicated with dashed lines.

1984
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009
Mamedov et al.
began to form in the boiling homogeneous mixture. The amount
of trapped water was 0.23 mL. The solvent and the excess hydrꢀ
azine hydrate were removed in a water aspirator vacuum. The
resulting semicrystalline substance was diluted with ethanol
(10 mL). The crystals that formed were filtered off, dried in air,
recrystallized from DMSO, washed with PriOH (2×10 mL), and
dried again in air. The yield was 0.36 g (91.0%), white crystals,
m.p. 301—302 °C. Found (%): C, 71.70; H, 4.81; N, 18.52.
C18H14N4O. Calculated (%): C, 71.51; H, 4.67; N, 18.53. IR,
ν/cm–1: 3252, 3142, 1701, 1678, 1606, 1570, 1498, 1271, 1255,
1123, 1096, 969, 514, 477. 1H NMR (DMSOꢀd6), δ: 5.57 (d,
1 H, 1 H(4), J = 2.7 Hz); 6.74 (d, 2 H, H(2´) + H(6´), J = 6.4 Hz);
7.19 (m, 3 H, H(3´) + H(5´) + H(4´)); 7.29 (d, 2 H, H(2″) +
H(6″), J = 7.3 Hz); 7.43 (dd, 2 H, H(3″) + H(5″), J = 7.3 Hz,
J = 7.1 Hz); 7.48 (dd, 1 H, H(4″), J = 7.1 Hz, J = 7.1 Hz); 7.98
(br.s, 1 H, N(3)H); 8.90 (s, 1 H, H(8)); 10.17 (br.s, 1 H, N(1)H).
4ꢀ(4ꢀBromophenyl)ꢀ5ꢀphenylꢀ3,4ꢀdihydropyrimido[4,5ꢀd]ꢀ
pyridazinꢀ2(1H)ꢀone (2b) was obtained in a similar way from
perhydropyrimidinone 1b (0.50 g, 1.09 mmol) and hydrazine
hydrate (1.28 g, 21.8 mmol). Yield 0.36 g (87.0%), white crysꢀ
tals, m.p. 310—311 °C. Found (%): C, 56.67; H, 3.49; Br, 21.12;
N, 14.73. C18H13BrN4O. Calculated (%): C, 56.71; H, 3.44;
Br, 20.96; N, 14.70. IR, ν/cm–1: 3284, 3058, 1704, 1679, 1267,
1125, 775, 705, 480, 411. 1H NMR (DMSOꢀd6), δ: 5.59 (d, 1 H,
H(4), J = 2.9 Hz); 6.68 (d, 2 H, H(3´) + H(5´), J = 8.2 Hz);
7.31 (d, 2 H, H(2″) + H(6″), J = 7.1 Hz); 7.38 (d, 2 H, H(2´) +
H(6´), J = 8.2 Hz); 7.44 (dd, 2 H, H(3″) + H(5″), J = 7.1 Hz,
J = 7.6 Hz); 7.48 (dd, 1 H, H(4″), J = 7.6 Hz, J = 7.6 Hz); 7.95
(br.s, 1 H, N(3)H); 8.86 (s, 1 H, H(8)); 10.15 (br.s, 1 H, N(1)H).
13C NMR (DMSOꢀd6), δ: 116.45 (br.s, C(8a)); 122.03 (dd,
C(4a), J = 10.8 Hz, J = 10.8 Hz); 129.33 (dd, C(2´) + C(6´) +
C(2″) + C(6″), J = 164.3 Hz, J = 6.3 Hz); 129.52 (ddd, C(3″) +
C(5″), J = 162.8 Hz, J = 6.3 Hz, J = 6.3 Hz); 129.96 (ddd,
C(4″), J = 161.6 Hz, J = 7.2 Hz, J = 7.2 Hz); 132.46 (dd,
C(3´) + C(5´), J = 167.6 Hz, J = 5.4 Hz); 136.96 (dd, C(1´),
J = 7.5 Hz, J = 7.5 Hz); 137.94 (br.s, C(4´)); 140.10 (d, C(8),
J = 185.0 Hz); 142.50 (ddd, C(1″), J = 6.4 Hz, J = 6.0 Hz,
J = 4.8 Hz); 152.58 (d, C(5), J = 5.4 Hz); 158.83 (s, C(2)).
4ꢀ(4ꢀMethoxyphenyl)ꢀ5ꢀphenylꢀ3,4ꢀdihydropyrimido[4,5ꢀd]ꢀ
pyridazinꢀ2(1H)ꢀone (2c) was obtained in a similar way from
perhydropyrimidinone 1c (0.50 g, 1.22 mmol) and hydrazine
hydrate (1.43 g, 24.4 mmol). Yield 0.38 g (93.0%), white crysꢀ
tals, m.p. 316—317 °C (from DMSO). Found (%): C, 68.69;
H, 4.74; N, 16.52. C19H16N4O2. Calculated (%): C, 68.66;
H, 4.85; N, 16.86. IR, ν/cm–1: 3253, 3146, 3035, 2953, 1702,
1680, 1608, 1581, 1502, 1270, 1249, 1124, 1098, 970, 776, 514.
1H NMR (DMSOꢀd6), δ: 3.68 (s, 3 H, CH3O); 5.51 (d, 1 H,
H(4), J = 2.9 Hz); 6.67 (d, 2 H, H(3´) + H(5´), J = 8.6 Hz);
6.75 (d, 2 H, H(2´) + H(6´), J = 8.6 Hz); 7.31 (d, 2 H, H(2″) +
H(6″), J = 7.1 Hz); 7.45 (dd, 2 H, H(3″) + H(5″), J = 7.1 Hz,
J = 7.1 Hz); 7.49 (dd, 1 H, H(4″), J = 7.1 Hz, J = 7.1 Hz); 7.90
(br.s, 1 H, N(3)H); 8.87 (s, 1 H, H(8)); 10.12 (br.s, 1 H, N(1)H).
Singleꢀcrystal Xꢀray diffraction analysis of compounds 2a,c
was performed at the Xꢀray Diffraction Division of the Collecꢀ
tive Use Center of the Spectroanalytical Center based on the
Diffraction Investigations Laboratory of the A. E. Arbuzov
Institute of Organic and Physical Chemistry (Kazan Research
Center, Russian Academy of Sciences). Crystallographic
parameters and the data collection and refinement statistics for
structures 2a,c are given in Table 1. Experiments were carried
out at 20 °C on a Bruker AXS SMART APEX II automatic
Table 1. Crystallographic parameters and the data collection
statistics for compounds 2a,c
Parameter
2а
2с
Crystal color
Crystal shape
Molecular formula
Molecular weight
Crystal system
Space group
a/Å
Colorless
Prisms
C
18H14N4O
302.33
C19H16N4O2
332.36
Monoclinic
P21/с
P21/с
17.311(3)
7.736(1)
12.353(2)
103.323(2)
1609.6(4)
4
16.384(1)
7.7381(7)
12.341(1)
110.307(1)
1467.4(2)
4
b/Å
c/Å
β/deg
V/Å3
Z
dcalc/g cm–3
μ/cm–1
1.369
0.89
1.371
0.92
Absorption correction
Radiation, λ/Å
F(000)
Multiꢀscan
MoꢀKα, 0.71073
632
696
Number of measured
reflections
13042
19019
Rint
0.0250
2640
0.1615
1064
Number of independent
reflections with I > 2σ(I)
Final residuals
R = 0.0424,
Rw = 0.1082
1.039
R = 0.0391,
Rw = 0.0578
0.652
GOOF
Number of refined parameters
264
227
threeꢀcircle diffractometer fitted with a CCD area detector
(graphite monochromator, MoꢀKα radiation). The structures
were solved by the direct methods and refined first isotropically
and then anisotropically (for all nonꢀhydrogen atoms) with the
SHELXTL13 and WinGX programs.14 The coordinates of
the hydrogen atoms of the amino groups were determined from
difference electronꢀdensity maps (the other H atoms were
located from stereochemical considerations) and refined using
appropriate riding models. Experimental data were collected
and edited, and the unit cell parameters were refined, with the
APEX2 program.15 Intermolecular interactions were analyzed,
and the molecular structures were drawn, with the PLATON
program.16
The atomic coordinates in structures 2a,c and their thermal
parameters have been deposited with the Cambridge Crystalꢀ
lographic Data Center (http://www.ccdc.cam.ac.uk; CCDC
Nos 687 136 and 687 137, respectively).
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 07ꢀ03ꢀ00613ꢀa)
and the Federal Target Program “Investigations and
developments in the priority scientific and technical fields
of Russia for 2007—2012” (State Contract No. 02.512.11.2237).
References
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Synthesis of pyrimido[4,5ꢀd]pyridazinꢀ2(1H)ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009 1985
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Received July 29, 2008;
in revised form June 5, 2009