Pyridazine derivatives. Part 27: A joint theoretical and experimental approach to the synthesis of 6-phenyl-4,5-disubstituted-3(2H)-pyridazinones

Article abstract of DOI:10.1016/S0040-4020(02)00120-5

A theoretical study of the structures of a series of 5-substituted-6-phenyl-3(2H)-pyridazinones has been carried out using quantum-mechanical calculations. This study indicates a significant effect of the nature of the substituent at the 5-position on the

Full text of DOI:10.1016/S0040-4020(02)00120-5

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 2389±2395
Pyridazine derivatives. Part 27: A joint theoretical and
experimental approach to the synthesis of
6-phenyl-4,5-disubstituted-3(2H)-pyridazinonesq
Eddy Sotelo,a Nuria B. Centeno,b Jordi Rodrigob and Enrique RavinÄaa,p
a
   Â
Departamento de Quõmica Organica, Laboratorio de Quõmica Farmaceutica, Facultad de Farmacia,
Universidad de Santiago de Compostela, Santiago de Compostela 15706, Spain
bResearch Group on Biomedical Informatics, IMIM, UPF, Carrer Dr Aiguader 80, E-08003 Barcelona, Spain
Â
This paper is dedicated to Professor Margarita Suarez ofthe University ofHavana, Cuba, on the occasion ofher 56th birthday.
Received 12 October 2001; revised 21 January 2002; accepted 30 January 2002
AbstractÐA theoretical study ofthe structures ofa series of5-substituted-6-phenyl-3(2 H)-pyridazinones has been carried out using
quantum-mechanical calculations. This study indicates a signi®cant effect of the nature of the substituent at the 5-position on the reactivity
ofthis system. The results have also been con®rmed by means of 1H NMR measurements. The outcome ofthis work has guided the
development ofnovel and e®f cient synthetic pathways to obtain pharmacologically useuf l 6-phenyl-4,5-substituted-3(2 H)-pyridazinones.
q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Zardaverine and Pimobendan (Fig. 1), have been selected
for further clinical assays.5
The need to prevent thrombus formation without impairing
haemostasis has spurred extensive research aimed at the
development ofnon-thrombotic haemostatic agents and
platelet aggregation inhibitors. Current therapeutic
strategies to inhibit platelet function include the use of
Aspirin, Tri¯usal (tri¯uoromethylaspirin), Ticlopidine,
Sul®npyrazone, or Dipyridamole. However, most ofthese
compounds have a relatively low activity and the search for
promising new drugs in this therapeutic area is ofgreat
interest. The cyclic adenosine monophosphate (c-AMP)
phosphodiesterase III (PDE III) has been one ofthe most
studied targets in the search for new antiplatelet agents.2
Among the extensive family of PDE III inhibitors,
compounds containing the 3(2H)-pyridazinone ring have
been widely studied3±5 and several pyridazinones, such as
In the past we have studied the platelet inhibitory activity of
a series of6-aryl-3(2 H)-pyridazinones substituted at the
5-position.6±11 Preliminary pharmacological results reveal
that these compounds, unlike other pyridazinones, have a
mechanism that is not based on c-AMP PDE III but instead
their activity could be related to their capacity to inhibit the
12
in¯ux ofcalcium to the activated platelets.
More recently we have prepared a large number of5-substi-
tuted-6-phenyl-3(2H)-pyridazinones and tested their anti-
platelet activity.13,14 The structure±activity relationship
studies (SAR) on this series has shown that the most active
compounds are those that bear electron-withdrawing groups
in the 5-position (e.g. CHO, COOMe, CH2OCOCH3);
conversely, compounds containing electron-releasing
groups (e.g. NH2, NHNH2) are completely inactive.14 In
light ofthese results, we have concluded that the antiplatelet
activity in this series is determined by the chemical group
present at the 5-position ofthe 6-phenyl-3(2 H)-pyridazi-
none system.14
Taking into account these conclusions, and in order to
achieve a better understanding ofthe chemical basis ofr
the antiplatelet activity, we decided to carry out a quantum-
chemical characterisation ofa subset ofseveral representa-
tive 5-substituted-6-phenyl-3(2H)-pyridazinones. In the
work described in this paper we evaluated the in¯uence of
the nature ofthe substituent at the 5-position on the
Figure 1. Chemical structure ofpyridazinones Zardaverine and
Pimobendan.
q See Ref. 1.
Keywords: pyridazinones; conformational analysis; ESP charges.
Corresponding author. Fax: 134-981-594912; e-mail: qofara@usc.es
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00120-5

2390
E. Sotelo et al. / Tetrahedron 58 (2002) 2389±2395
Table 2. Energetic differences between the keto and enol forms
reactivity ofthe heterocyclic ring. In addition, we explored
the synthetic possibilities arising from the use of the
appropriate 5-substituted-6-phenyl-3(2H)-pyridazinones as
starting materials in the preparation of6-phenyl-4,5-
substituted-3(2H)-pyridazinones.
These results have particular preparative importance since
very few methods based on the direct introduction of a
substituent at the 4-position of5-substituted-3(2 H)-
pyridazinones have been described.15 Indeed, the methods
that have been reported usually use as starting materials
N-protected pyridazinones that have protecting groups that
are either very dif®cult or impossible to remove. Therefore,
methods for the direct introduction of substituents into the
pyridazinone ring are lacking and new developments are of
great interest because they should provide access to a wide
variety ofpharmacologically usuelf 4,5-disubstituted
compounds.
Compound
X
DEnergy
(keto±enol)
in kcal/mol
1a
1b
1c
1d
1e
1f
H
CHO
CN
SO2CH3
NH2
OCH2CH3
9.77
9.12
9.49
9.44
10.31
10.89
The lowest energy conformation of the keto form obtained from HF/3-21G
ab initio calculation (HF/3-21Gp for compound 1d), was the starting point
for the enol tautomer geometry, which was fully optimised at the same
quantum-mecanical level. Then, energies ofthe enol and keto forms were
compared to establish which is more stable.
2. Results and discussion
The synthesis ofthe 3(2 H)-pyridazinones 1a±f (Table 1)
has previously been described by our group.11,13 These
compounds have not been subjected to a detailed structural
examination until now and we report here the ®rst computa-
tional study on the structure±reactivity relationship in this
series.
releasing groups at the 5-position stabilise the keto form
to a greater extent, as can be seen from the data in Table 2.
The geometrical features of the lowest energy conformation
found for each compound are shown in Fig. 2. The con-
formational analysis of this series shows that the phenyl
substituent in position 6 is not coplanar with the pyridazi-
none ring. The degree ofdeviation ranges rfom 24 to 53 8
(Table 3) depending on the nature ofthe substituent. Rather
than the total volume ofthe substituent at position 5, the
degree ofdeviation seems to be related to the steric
hindrance caused by the moiety directly attached to the
carbon atom at position 5. The relatively low deviation
observed in 1f is probably due to the fact that the ethyl
moiety is in its all-extended conformation, whereas the
compound with the most marked deviation (1d) has not
only a voluminous group (SO2) attached to C5 but also a
methyl group in the g1 conformation.
To this end, we initially determined the favoured geometry
ofthe compounds in question ( 1a±f) by means ofa
systematic conformational search at the ab initio Hartree±
Fock level using the 3-21G basis set (3-21Gp for compound
1d). Preliminary semiempirical molecular orbital calcula-
tions (data not shown), both in the gas phase and in solution,
failed to reproduce the results obtained from IR and 13C
NMR experiments (Table 1), suggesting that the keto
form is the predominant one. Conversely, ab initio HF/
3-21G results indicate that the keto form is more stable
than the enol form by about 10 kcal/mol (Table 2). We
therefore decided to carry out our conformational search
at the HF/3-21G level despite its greater computational
cost. The results ofthe energy calculations on the keto±
enol tautomerism show that the presence ofelectron-
The results ofthe theoretical calculations were compared,
wherever possible, with the data obtained by X-ray crystal-
lography. We found a different degree of agreement
between the conformations characterised quantum-
mechanically and those determined by X-ray analysis
(Table 3). The lowest energy conformation found for
compound 1e matches its X-ray structure.16 The X-ray
structure ofcompound 1f (Fig. 3), however, contains three
molecules in the asymmetric unit, one ofwhich is very
similar to the lowest energy conformation found in our
calculations. The greatest discrepancies arise in the case
ofcompound 1d, where we believe that the conformation
exhibited in the X-ray structure (Fig. 3) is probably
in¯uenced by the packing forces in the crystal. Overall,
these ®ndings all suggest that the energy barrier ofthe
torsional angle between the pyridazinone and the phenyl
ring should be very low and is in¯uenced by both the
substituent in position 5 and the environment.
Table 1. Structure and representative spectroscopic data ofthe 6-phenyl-5-
substituted-3(2H)-pyridazinones studied
Compound
X
Absorption
band ofthe
Chemical
shift for
CvO (ppm)
Chemical
shift for
H4 (ppm)
CvO (cm21
)
1a
1b
1c
1d
1e
1f
H
CHO
CN
SO2CH3
NH2
OCH2CH3
1644
1650
1672
1695
1670
1656
160
159
163
159
162
162
6.98
7.37
7.84
7.88
5.73
6.36
Taking into account the important modi®cations caused by
the chemical group at position 5 on the H4 signal in the 1H

E. Sotelo et al. / Tetrahedron 58 (2002) 2389±2395
2391
Figure 2. Ab initio HF/3-21G (HF/3-21Gp for compound 1d) optimised geometries for the lowest energy conformations of compounds 1a±1f.
Table 3. Characterisation oflowest energy conofrmations ofthe six compounds studied quantum-mechanically and comparison with X-ray data (where
available)
Compound
X
Calculated conformation
X-Ray conformation
N1±C6±C10 ±C20
(in 8)1
Conformation
ofthe 5-
substituent (8)
N1±C6±C10 ±C20
(8)
Conformation
ofthe 5-
substituent (8)
1a2
1b2
1c2
1d
1e
H
CHO
CN
SO2CH3
NH2
OCH2CH3
24.4
51.2
44.2
53.1
52.3
31.4
±
2174.6
±
60.6
±
174.3; 2176.5
±
±
81.9
±
2173.3; 163.4
92.0
251.3
32.7
1f
a
For each compound, another conformation with the same value of the dihedral N1±C6±C10 ±C20, but opposite sign is found that is energetically degenerate.
X-Ray data are not available.
b
NMR spectra (Table 1) ofcompounds in this series, we can
hypothesize about the synthetic exploitation ofthese
systems. In order to analyse the electronic characteristics
ofthe 4-position, we calculated the partial charge at this
site. In order to obtain accurate values we calculated the
ESP ®tting charges using the Merz±Kollman atomic radii
at the HF/6-21G level (HF/6-21Gp for compound 1d). The
predicted values are shown in Table 4 and are in reasonably
good agreement with the experimental data (1H NMR).
Interestingly, the results highlight the importance ofthe
electronic characteristics ofthe carbon atom in the
Table 4. Calculated partial charges at the 4-position
1
Compound
X
Partial charge at the 4-position
4-position, a feature that has been con®rmed by H NMR
data on the series ofcompounds under investigation.
Analysis ofthe partial charge values shows, as one would
expect, a notable change in the electronic nature ofC 4 due to
the electronic effect of the chemical group at position 5. The
presence ofelectron-withdrawing groups in the 5-position
produces a signi®cant decrease in the negative charge at the
1e
1f
1a
1c
1b
1d
NH2
20.4927
20.3773
20.1255
20.0532
20.0327
20.0274
OCH2CH3
H
CN
CHO
SO2CH3

2392
E. Sotelo et al. / Tetrahedron 58 (2002) 2389±2395
Scheme 1. Reagents: (i) Br2/AcOH, (ii) NaNO2/AcOH, (iii) 5-(2-Nitroarylidene)-2,2-dimethyl-1,3-dioxan-4,6-dione/MeOH.
4-position (by a factor of 4 in 1d with regard to 1a), thus
generating an electrophilic character at position 4. On the
other hand, the presence ofelectron-releasing groups in
the 5-position generates nucleophilic character at C4. The
strategical placement ofthe substituent at the end ofthe
double bond ofthe d afce ofthe heterocyclic ring and
the presence ofa carbonyl group both have important
repercussions on the reactivity ofthe 4-position ofthe
diazinone system.
compounds 2d and 2e in high yield (Scheme 2). These
products have a cyano group in the 4-position. The synthesis
of 2d and 2e represents the ®rst direct cyanation on a
pyridazinone ring.18 The proposed mechanism for this
transformation involves the 1,4-addition of cyanide to the
a,b-unsaturated system and subsequent spontaneous
aromatization ofthe 4,5-dihydro-3(2 H)-pyridazinone inter-
mediate, which was not isolated. Finally, 1,2-addition of
cyanide to the formyl group in 1e leads to the cyanhydrine
2d. This mild and ef®cient multi-step one-pot reaction is the
subject offurther study in our laboratory in order to assess
the limits ofthis approach.
By considering all these predictions, and also on the basis of
the modi®cations in the reactivity at the 4-position caused
by the electronic effect of the neighbouring group, we have
developed novel and highly ef®cient synthetic alternatives
that allow the synthesis of4,5-substituted-3(2 H)-pyridazi-
nones and heterobicyclic compounds.
The 3(2H)-pyridazinones 2a±2e that were prepared were
fully characterised by their analytical and spectroscopic
data. The IR spectra ofcompounds 2a±2e contain peaks
showing presence ofNH and carbonyl groups at 3380±
3280 and 1680 cm21, respectively. The structures ofthese
compounds can be easily con®rmed by the absence ofthe H 4
Firstly, we studied the reactivity ofthe heterocyclic
enaminone 1e, the strong push±pull effect on this compound
facilitates their reaction with different electrophiles
(Scheme 1). Compound 1e (in accordance with its enamine
nature) can be easily brominated in the 4-position by
treatment with bromine in acetic acid to afford compound
2a. In turn, nitrosation of 1e gives the 5-amino-4-nitroso-6-
phenyl-3(2H)-pyridazinone 2b as a deep-red solid in
excellent yield. Compound 1e also shows high reactivity
towards Michael addition and, therefore, reaction of 1e
with 5-arylidene Meldrum's acid derivatives as Michael
donorsÐfollowing a Hantzsch-like approachÐinvolving
the imino±enamine tautomerism and subsequent 6-exo-
trig cyclization that allows the annulation ofthe hetero-
cycle. This process leads to the bicyclic 2,5-dioxo-4-(2-
nitrophenyl)-8-phenyl-1,2,3,4,5,6-hexahydropyrido[2,3-d]-
pyridazine 2c in high yield, as we described recently.17
1
signal in the H NMR spectra. Further experiments are
now in progress aimed at obtaining new 4,5-substituted
In contrast, compounds 1b and 1g, which have electron-
withdrawing groups at position 5, show a high reactivity
towards the cyanide anion. Thus, treatment of 1b or 1g
with an excess ofsodium cyanide in methanol gives
Scheme 2. Reagents: (i) NaCN/MeOH.

E. Sotelo et al. / Tetrahedron 58 (2002) 2389±2395
2393
Figure 3. X-Ray structure ofcompounds 1d and 1f.
pyridazinones and evaluating the effect of the new group on
the antiplatelet activity ofcompounds in this series.
point apparatus and are uncorrected. IR spectra were
measured using a Perkin±Elmer 1640 FTIR spectro-
photometer with samples as potassium bromide pellets. The
NMR spectra were recorded on Bruker AM300 and XM500
spectrometers. Chemical shifts are given as d values against
tetramethylsilane as internal standard and J values are given
in Hz. Mass spectra were determined on a Varian MAT-711
instrument. High resolution mass spectra ofcompound 2d
was determined on a Autospec Micromass. Elemental
analyses were performed on a Perkin±Elmer 240B apparatus
at the Microanalysis Service ofthe University ofSantiago de
Compostela. The reactions were monitored by TLC with
2.5 mm Merck silica gel GF 254 strips, and the puri®ed
compounds each showed a single spot; unless stated other-
wise, iodine vapour and/or UV light were used for detection
ofcompounds. Commercially available starting materials
and reagents were purchased from commercial sources
and were used without further puri®cation.
In summary, we have described a structural study that has
allowed the evaluation ofthe eeffct ofthe substituent at
position 5 on the reactivity ofcompounds in this series.
These results have been used to support the development
ofnovel and e®fcient synthetic procedures to prepare
highly functionalized and heterofused pyridazinones using
5-substituted-6-phenyl-3(2H)-pyridazinones as starting
materials. In light ofthese results, and taking in account
our previous pharmacological results, we can clearly
conclude that the nature ofthe group in the 5-position of
the 6-phenyl-3(2H)-pyridazinone system not only deter-
mines the pharmacological activity but also produces a
notable, and synthetically exploitable, modi®cation in the
reactivity ofthe heterocyclic ring.
3. Experimental
3.1. Computational details
Melting points were determined on a Gallenkamp melting
Three-dimensional models ofthe studied compounds were

2394
E. Sotelo et al. / Tetrahedron 58 (2002) 2389±2395
initially built using the Builder module ofInsightII (v. 95.0,
from Biosym/MSI, San Diego, CA, USA). A systematic
search using an increment of30 8 for every considered
dihedral angle was carried out. Those conformations
exhibiting bumps were discarded as starting points. The
geometries ofthe selected starting points were uflly
optimised quantum-mechanically by energy minimisation
at the ab initio Hartree±Fock level, using the 3-21G basis
set (or 3-21Gp in the case ofcompound 1d because ofthe
presence of a sulfur atom). Starting from the lowest energy
conformation obtained, a point calculation at HF/6-31G
level (HF/6-31Gp for compound 1d) was used to ®t ESP
charges using the Merz±Kollman radii. The GAUSSIAN
94 program (Gaussian Inc., Pittsburgh, PA, USA) was
used throughout all quantum-mechanics computations.
none (1e) (0.70 g, 3.7 mmol) and sodium acetate trihydrate
(0.66 g, 4.8 mmol) in acetic acid (15 mL) at 08C was added
slowly a solution ofbromine (0.65 mL, 4.4 mmol) in acetic
acid (3 mL). The resulting mixture was stirred at room
temperature during 45 min and then added to ice/water.
The solid that precipitated was collected by ®ltration.
Further puri®cation was carried out by recrystallization
from isopropanol to give 0.91 g of 2a as a white solid
(92%). Mp 323.4±325.08C (dec.), IR: nmax/cm21 3422±
1
3185 (NH2), 1643 (CO), 1578 (aromatics); H NMR: dH
(300 MHz, DMSO-d6) 12.64 (1H, brs, NH, deuterium
oxide exchangeable), 7.48 (5H, m, aromatics), 6.04 (2H,
brs, deuterium oxide exchangeable, NH2). C10H8BrN3O
requires C: 45.13; H: 3.03; N: 15.79, found: C: 45.21; H:
3.17; N: 15.72.
3.2.5. 5-Amino-4-nitroso-6-phenyl-3(2H)-pyridazinone
(2b). To a solution of5-amino-6-phenyl-3(2 H)-pyridazi-
none (1e) (0.50 g, 2.7 mmol) in a 1:1 mixture ofacetic
acid/water (25 mL) at 658C was added slowly a solution
ofsodium nitrite (0.36 g, 5.3 mmol) in water (4 mL). The
reaction mixture was stirred at 658C during 2 h and the solid
that precipitated was collected by ®ltration. Further puri®-
cation was carried out by recrystallization from a 1:1
mixture ofethyl acetate/methanol to give 0.45 g of 2b as
a red solid (80%). Mp 238.7±240.08C (dec.), IR: nmax/cm21
3422±3185 (NH2), 1633 (CO), 1588 (aromatics); 1H NMR:
dH (300 MHz, DMSO-d6) 12.39 (1H, brs, NH, deuterium
oxide exchangeable), 7.90 (2H, m, aromatics), 7.40 (3H,
m, Aromatics), 3.38 (2H, brs, deuterium oxide exchange-
able, NH2). HRMS m/z calcd for C10H8N4O2 (M1):
216.1963, found: 216.1952.
3.2. X-Ray structure analysis
Crystals of 1d and 1f (Fig. 3) were grown by slow evapora-
tion from ethanol solutions. The X-ray determination was
performed on a MACH3 Enraf Nonius diffractometer with
graphite monochromated Cu Ka radiation.
3.2.1. 5-Methylsulfonyl-6-phenyl-3(2H)-pyridazinone (1d).
Crystal data. C11H10N2O3S, Mˆ250.27, orthorhombic,
Ê
aˆ7.4065 (6), bˆ10.4442 (8), cˆ28.7383 (17) A,
Ê 3
bˆ90.008, Vˆ2223.1 (3) A by least-squares re®nement on
diffractometer angles for 25 automatically centred re¯ections
Ê
with 18.91,u,42.898, lˆ1.54184 A, Tˆ293(2) K, space
group Pbca, Zˆ8, Dcˆ1.496 Mg/m3, mˆ2.599 mm21. A
colourless prismatic crystal (0.32£0.24£0.08 mm3) was
used for the analysis. Detailed crystallographic data for
compound 1d have been deposited at the Cambridge Crystal-
lographic Data Centre (deposition number CCDC 166861)
and are available on request.
3.2.6. 2,5-Dioxo-4-(2-nitrophenyl)-8-phenyl-1,2,3,4,5,6-
hexahydropyrido[2,3-d]pyridazine (2c). An equi-
molecular mixture of5-(2-nitroarylidene)-2,2-dimethyl-
1,3-dioxan-4,6-dione (40 mmol) and 5-amino-6-phenyl-
3(2H)-pyridazinone (1e) in methanol (50 mL) was re¯uxed
during 20 h and the resulting solution was poured into ice/
water. The solid that precipitated was collected by ®ltration
and recrystallized from ethanol to give 2c as a white solid
(90%). Mp 264.08C (dec.), IR: nmax/cm21 3384 (NH), 3111
(CH), 1715, 1645 (CvO), 1576, 1518 (CvC), 1530 (NO2)
and 1341 (NO2); 1H NMR: dH (300 MHz, DMSO-d6) 13.09
(1H, brs, NH, deuterium oxide exchangeable), 9.53 (1H, brs,
NH, deuterium oxide exchangeable), 8.01 (1H, dd, Jˆ7.7,
0.9 Hz, aromatics), 7.61±7.49 (2H, m, Ph), 7.47 (5H, s,
aromatics), 7.18 (1H, dd, Jˆ7.7, 0.9 Hz, aromatics), 4.78
(1H, dd, Jˆ7.2, 1.6 Hz, H-4), 3.34 (1H, dd, Jˆ7.2, 9.6 Hz,
H-3), 2.60 (1H, dd, Jˆ9.6, 1.6 Hz, H-30). C19H14N4O4
requires C: 62.98; H: 3.89; N: 15.46, found: C: 62.80; H:
3.77; N: 15.35.
3.2.2.
5-Amino-6-phenyl-3(2H)-pyridazinone
(1e).
Crystal data. C10H9N3O, Mˆ187.20, Orthorhombic, Pbca,
Ê
aˆ8.752 (2), bˆ10.525 (5), cˆ20.619 (5) A, Vˆ1899.3
Ê 3
(11) A by least-squares re®nement on diffractometer angles
for 25 automatically centred re¯ections with 10.78
Ê
,u,28.128, lˆ1.54184 A, Tˆ293(2) K, space group
Pbca, Zˆ8, Dcˆ1.309 Mg/m3, mˆ0.73 mm21. A light-
green prismatic crystal (0.48£0.20£0.14 mm3) was used
for the analysis. Detailed crystallographic data for com-
pound 1e have been deposited at the IUCr electronic
archives (deposition number SK1336) and are available on
request.
3.2.3. 5-Ethoxy-6-phenyl-3(2H)-pyridazinone (1f). Crystal
data. C12H12N2O2, Mˆ216.24, monoclinic, aˆ13.0709(13),
Ê
bˆ7.6595(7), cˆ16.4920(13) A, bˆ99.130(8)8, Vˆ
Ê 3
1643.4(3) A by least-squares re®nement on diffractometer
angles for 25 automatically centred re¯ections with 21.65±
3.2.7.
4-Cyano-5-(10-cyanohydroxymethyl)-6-phenyl-
Ê
3(2H)-pyridazinone (2d). To a stirred solution ofthe
aldehyde 1b (0.10 g, 0.5 mmol) in ethanol (10 mL) was
added, in several portions, sodium cyanide (0.07 g,
0.15 mmol) and the stirring was maintained during 1 h.
The reaction mixture was poured into ice and then extracted
with ethyl acetate. The organic extracts were dried
(anhydrous sodium sulfate) and concentrated under reduced
pressure to give an oily residue that was puri®ed by column
chromatography (hexane/ethyl acetate, 1:1). Subsequent
42.698, lˆ1.54184 A, Tˆ293(2) K, space group P21, Dcˆ
1.321 Mg/m3, mˆ0.751 mm21. A colourless prismatic crys-
tal (0.44£0.32£0.20 mm3) was used for the analysis. Detailed
crystallographic data for compound 1f have been deposited at
the Cambridge Crystallographic Data Centre (deposition
number CCDC 166799) and are available on request.
3.2.4. 5-Amino-4-bromo-6-phenyl-3(2H)-pyridazinone
(2a). To a mixture of5-amino-6-phenyl-3(2 H)-pyridazi-

E. Sotelo et al. / Tetrahedron 58 (2002) 2389±2395
2395
zines, Santiago de Compostela, Spain, September 13±16,
2000. For the previous paper in this series, see: Sotelo, E.;
RavinÄa, E. Ef®cient and Regioselective Pd-catalysed Aryl-
ation of4-Bromo-6-chloro-8-phenylpyridazine. Synlett 2002,
223.
recrystallization from isopropanol afforded the cyanhydrine
2d as yellow prisms (90%). Mp 145.5±147.08C (dec.), IR
1
(KBr): nmax/cm21 3808±3065, 1663, 1590. H NMR: dH
(300 MHz, DMSO-d6): 13.94 (1H, brs, NH, deuterium
oxide exchangeable), 7.55±7.48 (5H, m, aromatics), 4.02
(1H, s, CH). HRMS (Autospec Micromass) m/z calcd for
C13H8N4O2 (M1): 252.0647, found: 252.0650.
2. Campbell, S. F.; Danilewicz, J. C. Ann. Rep. Med. Chem.
1978, 22, 84.
3. Bristol, J. A.; Sircar, I.; Moss, W. H.; Evans, D. B.; Weishaan,
E. J. Med. Chem. 1984, 27, 1099.
3.2.8. 4-Cyano-5-methoxycarbonyl-6-phenyl-3(2H)-pyri-
dazinone (2e). To a stirred solution ofthe ester 1g (0.10 g,
0.4 mmol) in methanol (20 mL) was added slowly sodium
cyanide (0.04 g, 0.8 mmol) and the stirring was maintained
during 36 h at room temperature. The solvent was removed
under reduced pressure and the resulting residue was poured
into ice to afford a yellow solid that was puri®ed by
recrystallization from isopropanol (70%). Mp 190.2±
191.08C, IR (KBr): nmax/cm21 1735, 1668, 1588. 1H
NMR: dH (300 MHz, DMSO-d6): 14.63 (1H, brs, NH,
deuterium oxide exchangeable), 7.50 (3H, m, aromatics),
7.40 (2H, m, aromatics), 7.36 (1H, s, OCH3). C13H9N3O3
requires C: 61.17; H: 3.55; N: 16.46, found: C: 61.24; H:
3.55; N: 16.56.
4. Sircar, I.; Duell, B. L.; Cain, M. H.; Burke, S. E.; Bristol, J. A.
J. Med. Chem. 1986, 29, 2142.
5. Combs, D. H. Drugs Future 1993, 18, 139.
Â
6. RavinÄa, E.; Garcõa-Mera, G.; Santana, L.; Orallo, F.; Calleja,
J. M. Eur. J. Med. Chem. 1985, 20, 475.
Â
Â
Â
7. Teran, C.; RavinÄa, E.; Santana, L.; Garcõa, G.; Garcõa-Mera,
G.; Fontenla, J. A.; Orallo, F.; Calleja, J. M. Arch. Pharm.
(Weinheim) 1989, 322, 331.
  Â
8. RavinÄa, E.; Teran, C.; Santana, L.; Garcõa, N.; Estevez, I.
Heterocycles 1990, 31, 1967.
Â
Â
9. RavinÄa, E.; Teran, C.; Domõnguez, N. G.; Masaguer, C. F.;
Gil-Longo, J.; Orallo, F.; Calleja, J. M. Arch. Pharm.
(Weinheim) 1991, 324, 455.
Â
10. Estevez, I.; RavinÄa, E.; Sotelo, E. J. Heterocycl. Chem. 1998,
35, 1421.
11. Sotelo, E.; Ravina, E.; Estevez, I. J. Heterocycl. Chem. 1999,
Â
Acknowledgements
Ä
36, 985.
Â
12. Montero-Lastres, A.; Fraiz, N.; Cano, E.; Laguna, R.; Estevez,
The authors wish to express their gratitude to Dr Manuel
Pastor for helpful discussions. This work was supported by
the Spanish Interministerial Commission for Science and
Technology (CICYT) and by the Xunta de Galicia (Project
XUGA 8151389). We thank the CESCA (Centre de Super-
Â
computacio de Catalunya) for the use of computational
facilities. We also thank the Spanish Instituto de Coopera-
Â
cion Iberoamericana (ICI) for a doctoral fellowship for
Eddy Sotelo.
I.; Ravina, E. Biol. Pharm. Bull. 1999, 22, 1376.
Ä
Â
13. Laguna, R.; Rodriguez-Linares, B.; Cano, E.; Estevez, I.;
RavinÄa, E.; Sotelo, E. Chem. Pharm. Bull. 1997, 45, 1151.
14. Sotelo, E. PhD Thesis, University ofSantiago de Compostela,
Spain, 2000.
Ä
15. Matyus, P.; Fuji, K.; Tanaka, K. Heterocyles 1994, 37, 171.
16. Novoa de Armas, H.; Blaton, N. M.; Peeters, O. M.; De
Â
Ranter, C. J.; Pita, B.; Sotelo, E.; Ravina, E.; Suarez, M.
Acta Crystallogr., C 2000, 56, 345.
Ä
Â
17. Pita, B.; Sotelo, E.; Suarez, M.; RavinÄa, E.; Ochoa, E.;
Verdecia, Y.; Novoa, H.; Blaton, N.; De Ranter, C.; Peeters,
O. Tetrahedron 2000, 56, 2473.
References
1. Part ofthis work was presented at the Seventh International
Symposium on the Chemistry and Pharmacology ofPyrida-
18. Sotelo, E.; Pita, B.; RavinÄa, E. Tetrahedron Lett. 2000, 41,
2863.