Pyridazine derivatives. Part 39: Reactivity of 5-iodopyridazin-3(2H)-ones in palladium-catalysed reactions

Article abstract of DOI:10.1016/j.tet.2004.10.014

In the search for novel antiplatelet agents, convenient and efficient methods for the preparation of 2,5-disubstituted pyridazin-3(2H)-ones are reported that utilise palladium-catalysed cross-coupling reactions. A post-coupling base-promoted isomerisation

Full text of DOI:10.1016/j.tet.2004.10.014

Tetrahedron 60 (2004) 12177–12189
Pyridazine derivatives. Part 39: Reactivity of
5-iodopyridazin-3(2H)-ones in palladium-catalysed reactions*
a
Alberto Coelho, Eddy Sotelo, Hector Novoa, Oswald M. Peeters, Norbert Blaton
a
b
b
b
´
and Enrique Ravin˜aa,
*
a
´ ´ ´ ´
Laboratorio de Quımica Farmaceutica, Departamento de Quımica Organica, Facultad de Farmacia,
Universidad de Santiago de Compostela, Santiago de Compostela 15782, Spain
bLaboratorium voor Analytische Chemie en Medicinale Fysicochemie, Faculteit Farmaceutische Wetenschappen,
Katholieke Universiteit Leuven, E. Van Evenstraat 4, B-3000 Leuven, Belgium
Received 11 June 2004; revised 4 October 2004; accepted 7 October 2004
Available online 27 October 2004
Abstract—In the search for novel antiplatelet agents, convenient and efficient methods for the preparation of 2,5-disubstituted pyridazin-
3(2H)-ones are reported that utilise palladium-catalysed cross-coupling reactions. A post-coupling base-promoted isomerisation has been
observed during Sonogashira alkynylation of 5-iodopyridazin-3(2H)-ones (3) with 1-phenyl-2-propyn-1-ol. Variable amounts of
phthalazinones were isolated as by-products during the Heck alkenylation of 3. The usefulness of the hydroxymethyl fragment as a
protecting group during the synthesis of 5-substituted pyridazin-3(2H)-ones has been validated.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
transformations that were either difficult or impossible using
previously available methods. Curiously, however, refer-
ences describing the systematic use of these transformations
as part of pharmacomodulation processes for bioactive
prototypes have, to the best of our knowledge, not appeared.
Palladium chemistry involving heterocycles has unique
characteristics stemming from the inherently different
structural and electronic properties of heterocycles in
comparison to the corresponding carbocyclic aryl com-
pounds.4 The a and g activation of heteroaryl halides means
that Pd-catalysed chemistry may occur regioselectively at
the activated positions, a phenomenon rarely seen in
carbocyclic aryl halides.5–7 Curiously, despite the useful
nature of pyridazines, until a few years ago only a limited
number of synthetic approaches to achieve substitution on
In recent years, almost every part of the drug discovery
processes has undergone a radical change. However, one of
the few things that has not changed is the fact that the
majority of medicines are still small organic molecules and
a high proportion of these contain a heterocyclic ring.2 As a
consequence, low molecular weight heterocycles have a
central role in the development of therapeutic agents. In this
area the issues of bioavailability and toxicity must be
addressed in addition to bioactivity. It is therefore of general
interest to medicinal chemists to have straightforward
synthetic methodologies that provide access to a large
number of bioactive molecules. For these reasons, atom-
efficient transformations and reactions that have high
exploratory power are especially desirable during the
processes of lead finding and lead optimisation.
these electron-deficient rings had been described.8
A
number of methods have recently been reported in the
literature and, of these, reactions involving organometallics
have proved to be powerful tools for the preparation of the
desired compounds.9
In recent decades, the use of transition metal complexes in
organic chemistry has fuelled a revolution in this field.3
Such reactions have allowed the development of new
In the last two decades, our research group has explored the
chemistry10 and pharmacology11 of pyridazine derivatives.
Initially, the well known properties of 3-hydrazinopyrida-
zines as direct vasodilators attracted our attention12 but,
more recently, discovering of novel pyridazinone-based
antiplatelet agents has become our goal.13–16 These
studies have recently involved the use of different
* For the previous paper in this series, see Ref. 1.
Keywords: Pyridazinones; Palladium; Platelets; Ene-adducts; Crystal
structure.
* Corresponding author. Tel.: C34 981 594628; fax: C34 981 594912;
e-mail: qofara@usc.es
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.014

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A. Coelho et al. / Tetrahedron 60 (2004) 12177–12189
palladium-catalysed reactions,17–20 which have demon-
strated their versatility as tools to perform the pharmaco-
modulation and structural diversification at the 5-position of
the 6-phenylpyridazin-3(2H)-one system.16 We recently
described the antiplatelet activity of compounds I13 (Fig. 1)
and the discovery of several 5-alkylidene-6-phenylpyrida-
zin-3(2H)-ones II14 and III16 (Fig. 1), which are potent
antiplatelet agents. Another interesting result concerning the
biological activity of these derivatives is related to their
mechanism of action, which is different to other antiplatelet
agents that are already available. Recent experiments on
these compounds suggested that their antiplatelet effect is
related to their ability to affect protein phosphorylation.13,14
the best of our knowledge, only very recently a detailed
synthetic procedure to obtain 3a been published.27c These
derivatives were obtained by halogen exchange reactions
followed by reductive dehalogenation.27
Commercially available 4,5-dichloropyridazin-3(2H)-one
(1) was conveniently N-alkylated by treatment with methyl
iodide or benzyl bromide to afford 2-substituted 4,5-
dichloropyridazin-3(2H)-ones 2 (Scheme 1).28 Treatment
of 2 with a large excess of 57% hydriodic acid under
reflux during 24 h yielded the corresponding 2-substituted
5-iodopyridazin-3(2H)-ones 3 (Scheme 1). It is worth
´
27
mentioning here that, as reported by Matyus, the main
intermediates during these transformations are the corre-
sponding 2-substituted 4,5-diiodopyridazin-3(2H)-ones,
which can be isolated in high yields if reaction times are
shorter (3 h) or on using dioxane as the solvent (see Section
3). 5-Iodopyridazin-3(2H)-one 3c was obtained by remov-
ing the benzyl group in 3b by treatment with anhydrous
aluminium chloride in dry toluene.29
Once a small subset of 5-iodopyridazin-3(2H)-ones had
been obtained, we proceeded to study the functionalisation
of the 5 position of the heterocyclic scaffolds 3 (Scheme 2)
using Suzuki, Heck, Stille or Sonogashira cross-coupling
reactions. First, the palladium-catalysed transformations
were studied for the 2-benzyl- and 5-iodo-2-methylpyrida-
zin-3(2H)-ones 3a and 3b, which have a non-tautomeric
carbonyl group (Schemes 2–5).
Figure 1.
Preliminary results from the structure–activity relationship
(SAR) studies performed on this family of compounds have
suggested that the presence of the phenyl group at position 6
and the presence of a free NH at position 2 of the
heterocyclic ring (Fig. 1) may not be essential structural
requirements for biological action in this new mechanism of
action.21 In order to validate this hypothesis, we became
interested in the synthesis of 5-functionalised pyridazin-
3(2H)-ones IV, which have different substituents at position
5 and the appropriate group at position 2 (Me, Bn, H) but do
not incorporate the phenyl group at position 6 (Fig. 2). The
approach selected to obtain 2,5-disubstituted pyridazin-
3(2H)-ones IV involved the use of palladium-catalysed
cross-coupling reactions22 following the well known
Suzuki,23 Heck,24 Stille25 or Sonogashira26 methodologies.
These methods allowed the rapid and efficient introduction
of a wide range of substituents at position 5 of the
heterocycle.
Arylation of compounds 3a and 3b was smoothly performed
by reaction with the 4-chlorophenyl- or phenylboronic acids
in the presence of sodium carbonate as a base and
tetrakis(triphenylphosphine)palladium as a palladium
source in a 3:1 mixture of dimethoxyethane/water
(Scheme 2). This process afforded the corresponding
2-substituted 5-arylpyridazin-3(2H)-ones 4a–f in excellent
yields (Table 1). While our work was in progress, a paper
´
was published by Matyus et al. concerning the synthesis of
compound 4a and other 5-(aryl)-2-methylpyridazin-3(2H)-
ones as part of the synthesis of new pyridazino[4,5-
b]indoles.30
Pyridazinones 5 were obtained in excellent yields (Table 1)
by Stille cross-coupling of 3a–b with tributyl vinyl stannane
or tributylethoxyvinyl stannane at room temperature
(Scheme 2). The 5-acetyl-derivatives 5b and 5d were
prepared in a one-pot procedure by cleavage of the
corresponding enol-ether intermediate with 3 N hydro-
chloric acid.
The introduction of alkenyl groups at position 5 in 3a–b
was achieved by coupling with methyl acrylate or
acrylonitrile in dimethylformamide under the basic con-
ditions provided by triethylamine (Scheme 2). Different
palladium sources were tested for the Heck alkenylation of
the heterocycle. Firstly, methods were studied that employ
cocktails of palladium catalysts/phosphines [Pd(OAc)2/
PPh3, PdCl2(PPh3)2, PdCl2[P(o-Tolyl)3]2] and, secondly,
the use of palladium on charcoal under phosphine-free
conditions was investigated.24 In all experiments, the
expected 5-alkenylpyridazin-3(2H)-ones 6 were obtained
but it was found that PdCl2[P(o-Tolyl)3]2 was a superior
Figure 2.
2. Results and discussion
In order to achieve this objective, different 2-substituted
5-iodopyridazin-3(2H)-ones 3 were chosen as starting
materials (Scheme 1). Some of these derivatives have
been previously described by Matyus27a,b (3a and 3b) but, to
´

A. Coelho et al. / Tetrahedron 60 (2004) 12177–12189
12179
Scheme 1. (i) Me-I/K2CO3/Bu4NBr/acetonitrile, (ii) Bn-Br/K2CO3/Bu4NBr/acetonitrile, (iii) 57% HI, (iv) AlCl3/toluene.
Scheme 2. Method A: ArB(OH)2/Pd(PPh3)4/Na2CO3/DME–H2O. Method B: R-Sn(Bu)3/PdCl2(PPh3)2/Et3N/DMF/for compounds 5b and 5d then 3 N HCl.
Method C: CH2]CH–X/ PdCl2[P(o-Tolyl)3]2/Et3N/DMF.
Scheme 3.
Scheme 4.
Scheme 5.

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A. Coelho et al. / Tetrahedron 60 (2004) 12177–12189
Table 1. Structure of the obtained 2,5-substituted pyridazin-3(2H)-ones
Compound
R2
R5
Yield (%)
Compound
R2
R5
Yield (%)
4a
4b
4c
4d
5a
5b
5c
5d
6a
6b
6c
Me
Me
Bn
Bn
Me
Me
Bn
Bn
Me
Me
Bn
Ph
4-Cl–Ph
Ph
4-Cl–Ph
CH]CH2
CO–Me
CH]CH2
CO–Me
91
90
94
90
90
70
78
68
60
63
60
6d
8a
8b
8c
8d
8e
10a
10b
10c
10d
10e
Bn
Me
Bn
Me
Bn
Bn
H
H
H
H
H
CH]CH–CO2Me
^–CH2-OH
^–CH2-OH
CH]CH–CO-Ph
CH]CH–CO–Ph
^–CH(OH)–Ph
CH]CH2
Ph
^–CH2-OH
CH]CH–CO-Ph
CH]CH–CO2Me
68
70
93
89
70
30
65
60
88
60
62
CH]CH–CN
CH]CH–CO2Me
CH]CH–CN
catalyst for these processes and gave the corresponding
functionalised alkenes 6 in yields in the range 40–70%. In
contrast to similar experiments on the 5-bromopyridazin-
3(2H)-ones,1 we did not find any evidence of dehalogena-
tion during Heck alkenylation of 3a–b, most probably due to
the superior reactivity of the iodo-substituent.
established on the basis of the analytical and spectroscopic
data (see Section 3). The 1H NMR spectra of these products
contain doublets with a coupling constant of 15–16 Hz,
which confirms a trans stereochemistry for the double bond.
It is worth noting that this reaction produces the chalcones
8c–d with an E-selectivity greater than 95% after isolation
and purification by column chromatography. Other NMR
experiments and, in particular, the data extracted form
X-ray crystallography on a monocrystal of compound 8c
confirmed our assignment (Fig. 3).
Although the procedures described above give the
5-alkenylpyridazin-3(2H)-ones 6a–d as the main products,
an exhaustive investigation of the transformation allowed
the isolation of small amounts (5–15%) of phthalazinones as
by-products. For instance, the Heck alkenylation of 3b with
methyl acrylate gave, in addition to the expected acrylate 6d
(60%), the phthalazinone 7 (7%) (Scheme 3).
The structure of the unexpected phthalazinones was
unambiguously established by analytical and spectroscopic
methods (see Section 3). The presence of the methoxy-
carbonyl group at position 6 of phthalazinone 7 suggests
that a highly regioselective process is operating during its
formation.
Preliminary mechanistic proposals to explain the formation
of phthalazinones during this reaction have recently been
put forward.1 It is thought that this process involves a
tandem reaction that initially follows a Heck sp2 cascade
due to a second insertion of another olefin molecule into the
previously formed s-alkylpalladium complex. Further
experiments are now in progress to study the mechanism
of such a transformation in greater detail and to evaluate the
scope of this reaction in the synthesis of 2,6-disubstituted-1-
phthalazinones.
Figure 3. Plot showing the crystal structure and atomic numbering scheme
for 8c. Displacement ellipsoids are drawn at 50% probability level for non-
H atoms.
The crystal structure of 8c is essentially planar and shows a
trans configuration (Fig. 3). The crystal structure is
stabilised by means of weak intermolecular interactions
˚
(Fig. 4) of the type C–H/O [C4/O3Z3.404(3) A and
˚
C6/O9Z3.332(3) A]. A weak intramolecular interaction
˚
of the type C–H/O is also present [C7/O9Z2.788(3) A].
Standard Sonogashira conditions26 were employed to per-
form the alkynylation at position 5 of the heterocycle
(Scheme 4). Although these optimised conditions proved to
be applicable to 2-propyn-1-ol (Scheme 4, compounds
8a–b), the cross-coupling of 3a–b with 1-phenyl-2-propyn-
1-ol (Scheme 4) did not give the expected 2-substituted
5-(3-hydroxy-3-phenylprop-1-yn-yl)pyridazin-3(2H)-ones.
Instead, the isomeric E-chalcones 8c–d were obtained in
good yields (Table 1).
Formation of chalcones 8c–d under these conditions is
dissimilar to results described in previous papers concerning
the Sonogashira coupling between 1-phenyl-2-propyn-1-ol
and different electron-deficient halides.31–35 Several authors
initially proposed that chalcone formation during these
transformations could be related to the participation of
organo-palladium intermediates,31–33 but some recent
results35 (and our own findings20) have confirmed that a
base-catalysed isomerisation of the expected phenyl-sub-
stituted propargyl alcohol is a more likely explanation for
this transformation.
The structure of the heterocyclic chalcones 8c–d was

A. Coelho et al. / Tetrahedron 60 (2004) 12177–12189
12181
Quantitative isolation of 8d after stirring 8e in the presence
of a base (triethylamine or N,N-diisopropylethylamine) in a
range of solvents (DCM, MeOH, THF, DMF)—even at
room temperature—showed that chalcone formation occurs
as a consequence of the base-catalysed isomerisation of the
phenyl-substituted propargyl alcohol 8e. This process could
be facilitated by the electron-deficient nature of the
pyridazinone system, which increases the acidity of the
propargylic proton.36
The mechanistic pathway proposed for this transformation
is outlined in Figure 5. Sonogashira coupling of 3b with
1-phenyl-2-propyn-1-ol afforded the substituted propargyl
alcohol 8e, which, upon deprotonation at the propargyl
centre with triethylamine, led to a propargyl-allenyl anion.
Protonation of this species afforded the allene and, finally,
the allenol–enone tautomerism furnished the trans-
configured enone 8d (Fig. 5).
Our previous work on the 5-bromo-6-phenylpyridazin-
3(2H)-one showed the low reactivity of this compound in
palladium-catalysed reactions.17–20 However, the high
reactivity of the 2-substituted 5-iodopyridazin-3(2H)-ones
3a–b (some of the reactions described here can be
performed at room temperature) led us to examine such
transformations on the 5-iodopyridazin-3(2H)-one 3c on the
hypothesis that the change in the halogen (Br/I) could
produce an increase in reactivity during the cross-coupling
reactions.
Figure 4. Packing of molecules of 8c in the unit cell along the [010]
crystallographic direction. The most important intermolecular interactions
are denoted with dashed lines.
The detailed study of the Sonogashira coupling of 3b with
1-phenyl-2-propyn-1-ol [by carrying out the reaction at
room temperature (25 8C) and after a careful work up]
enabled the isolation of the expected phenyl-substituted
propargyl alcohol 8e (30%) together with 8d (67%)
(Scheme 5). Identification of intermediate 8e is supported
by both analytical and spectroscopic data (see Section 3).
Unfortunately, although not completely unexpected, a quick
screening experiment with 5-iodopyridazin-3(2H)-one 3c as
Figure 5.
Scheme 6.

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A. Coelho et al. / Tetrahedron 60 (2004) 12177–12189
coupling is the presence of a group at position 2 of the
heterocyclic ring that is able to block the enolisable
carbonyl group.
5-Substituted pyridazin-3(2H)-ones 9 were prepared using a
synthetic strategy recently described by our group that uses
a hydroxymethyl group as a thermolabile protecting group
for position 2 of the pyridazinone during cross-coupling
reactions (Fig. 6).37
Figure 6.
Straightforward hydroxymethylation of 3c by treatment
with 35% formaldehyde solution afforded 2-hydroxy-
methyl-5-iodopyridazin-3(2H)-one 3f (90%) (Scheme 6).
Since pyridazinone 3c is not reactive under these conditions,
the proposed pathway to explain this sequence would
involve the initial cross-coupling reactions on 3f to afford
a 5-substituted ene-adduct 9, which would subsequently
lose formaldehyde in a process that may be regarded as a
retro-ene fragmentation (Fig. 6).
The excellent reactivity of the 1-O, 3-N, 5-O ene-adduct38
3f toward Suzuki, Sonogashira, Stille or Heck conditions
was readily demonstrated by the efficient preparation of
different 5-aryl-, 5-alkynyl- or 5-alkenylpyridazin-3(2H)-
ones 10 in a one-pot procedure (Scheme 7, Table 1).
These results confirm the versatility and usefulness of the
hydroxymethyl group as a convenient thermolabile group to
protect position 2 of halopyridazinones during palladium-
catalysed reactions.
Scheme 7. Method A: Bu3Sn–CH]CH2/PdCl2(PPh3)2/Et3N/DMF.
Method B: PhB(OH)2 Pd(PPh3)4/Na2CO3/DME–H2O. Method C: HC^
C–CH(OH)R/PdCl2(PPh3)2/CuI/Et3N/DMF. Method D: CH2]CH–
COOMe/PdCl2[P(o-Tolyl)3]2/Et3N/DMF.
The reactivity of the iodine atom in the ene-adduct 3f
allowed to confirm that formation of compounds 10 is not a
concerted process. The isolation and identification of
intermediates 11a and 11b during some of these
transformations, when performed at room temperature, are
completely consistent with the pathway shown in Fig. 6
(Scheme 8). Thus, when the starting pyridazinone 3f was
submitted to Stille or Sonogashira cross-coupling
reaction conditions at room temperature during 2–3 h, the
5-substituted 2-hydroxymethylpyridazin-3(2H)-ones 9
could be isolated from the reaction mixtures. Reactions
times greater than 24 h led to 5-substituted pyridazin-3(2H)-
ones 10.
the starting material under different experimental pro-
cedures showed that the degree of transformation was less
than 30% during Suzuki, Stille or Sonogashira coupling and
most of the starting material was recovered (Scheme 6). All
attempts to perform Heck alkenylation of 3c employing
methyl acrylate as the olefin led to formation of N-alkyl
derivatives 3d and 3e. Isolation of these derivatives results
from Michael addition of position 2 of the heterocycle to the
highly activated and sterically unhindered methyl acrylate.
In this transformation, after alkylation at position 2 has been
achieved, the Heck alkenylation of 3d yields the
corresponding 5-alkenyl-2-alkylpyridazin-3(2H)-one 3e
(Scheme 6).
Compared to 5-bromo-2-methoxymethyl-6-phenylpyrida-
zin-3(2H)-one, the 2-substitued 5-iodopyridazin-3(2H)-
ones 3 proved to be much more reactive toward
These results are in accordance with previous studies17–20
and confirm that a critical factor to ensure the successful
Scheme 8.

A. Coelho et al. / Tetrahedron 60 (2004) 12177–12189
12183
palladium-catalysed reactions. This superior reactivity
could be due to the change in the halogen, the absence of
the phenyl group at position 6 of the heterocycle (which
would reduce steric hindrance) or, most probably, a
combination of these effects.
XSCANS.40 Cell refinement: XSCANS.40 Data reduction:
XSCANS.40 Program used to solve structure: SIR92.41
Program used to refine structure: SHELXL97.42 Molecular
graphics: DIAMOND.43 Software used to prepare material
for publication: PLATON.44
In summary, practical and efficient palladium-assisted
procedures to perform the structural diversification of the
5-position of 2-substituted pyridazinones have been
developed. The palladium-mediated alkynylation of 3
using 1-phenyl-2-propyn-1-ol affords E-chalcones in excel-
lent yields. A study of this transformation allowed the
isolation of an intermediate and confirmed the electron-
deficient nature of the starting 5-iodopyridazin-3(2H)-one to
be the key factor during the base-catalysed isomerisation
process. Furthermore, part of this work has demonstrated
the synthetic utility of the 2-hydroxymethyl unit as a
convenient protecting group for the lactam function during
couplings on 5-iodopyridazin-3(2H)-one.
2-Substituted 4,5-dichloropyridazin-3(2H)-ones 2 were
obtained by following previously described procedures.28
3.1. Synthesis of 2-substituted 5-iodopyridazin-3(2H)-
ones 3. General procedure
A solution of 2-substituted 4,5-dichloropyridazin-3(2H)-
one 2 (28 mmol) in 57% hydriodic acid (41 mL) was stirred
and heated under reflux (oil bath 140 8C) until the starting
material had been consumed (24 h). After cooling, the
solution was treated with 30% sodium thiosulphate and then
extracted with dichloromethane. The organic phase was
dried over sodium sulphate, and concentrated to dryness under
reduced pressure. The residue was purified twice by column
chromatography on silica gel. Further purification was
achieved by recrystallisation from the appropriate solvent.
3. Experimental
3.1.1. 5-Iodo-2-methylpyridazin-3(2H)-one 3a. Purifi-
cation by column chromatography on silica gel using
AcOEt/hexane (1:3) as eluent. Mp 179–180 8C (isopropa-
nol). Yield 81%. IR (KBr): nmax/cmK1 1654 (CO). 1H NMR
(CDCl3, 300 MHz), d (ppm): 7.89 (d, JZ1.9 Hz, 1H, H6),
7.44 (d, JZ1.9 Hz, 1H, H4), 3.71 (s, 3H, CH3). 13C NMR
(CDCl3, 75 MHz), d (ppm): 159.0, 142.0, 138.2, 102.2,
40.3. MS (70 eV) m/z (%): 236 (MC, 100), 208 (42), 165
(82), 127 (55). Anal. Calcd for C5H5IN2O, C 25.45, H 2.14,
N 11.87; found, C 25.47, H 2.15, N 11.96.
Melting points were determined on a Gallenkamp melting
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 obtained on a Varian
MAT-711 instrument. High-resolution mass spectra were
obtained on an Autospec Micromass spectrometer.
Elemental analyses were performed on a Perkin–Elmer
240B apparatus at the Microanalysis Service of the
University of Santiago de Compostela. The reactions were
monitored by TLC with 2.5 mm Merck silica gel GF 254
strips, and the purified compounds each showed a single
spot; unless stated otherwise, iodine vapour and/or UV light
were used for detection of compounds. Commercially
available starting materials and reagents were purchased
and used without further purification.
3.1.2. 2-Benzyl-5-iodopyridazin-3(2H)-one 3b. Purifi-
cation by column chromatography on silica gel using
AcOEt/hexane (1:8) as eluent. Mp 132–133 8C (isopropa-
nol). Yield 88%. IR (KBr): nmax/cmK1 1654 (CO), 1560
(aromatics). 1H NMR (CDCl3, 300 MHz), d (ppm): 7.91 (d,
JZ2.0 Hz, 1H, H6), 7.46 (d, JZ2.0 Hz, 1H, H4), 7.40 (m,
2H, aromatics), 7.33 (m, 3H, aromatics), 5.25 (s, 2H, CH2).
13C NMR (CDCl3, 75 MHz), d (ppm): 159.0, 142.3, 138.8,
135.9, 129.2, 129.0, 128.5, 102.8, 55.4. MS (70 eV) m/z
(%): 312 (MC, 24), 165 (38), 125 (42), 111 (64), 97 (100).
Anal. Calcd for C11H9IN2O, C 42.33, H 2.91, N 8.98; found,
C 42.43, H 3.01, N 9.07.
The X-ray crystallographic determination of 8c was
performed on a Siemens P4 four-circle diffractometer with
graphite monochromated Cu Ka radiation. The intensity
data were collected using 2q–u scans, with u scan width
equal to the difference of the background and the high
ubackground plus the separation between the Ka1 and Ka2
positions; 2792 reflections measured (3.71!q!68.878,
K1!h!6, K9!k!9, K16!l!16), 2111 unique
(merging RZ0.0599) and 1462 observed [F2R2s(F)2]
reflections. Empirical absorption correction via j scans was
applied.39 Three standard reflections were monitored every
100 reflections (intensity decay: 3%).
2-Substituted 4,5-diiodopyridazin-3(2H)-ones can be
successfully obtained employing the general procedure
previously described for the 2-substituted 5-iodopyridazin-
3(2H)-ones 3 but shorting reaction times to 3 h.
3.1.3. 4,5-Diiodo-2-methylpyridazin-3(2H)-one. Purifi-
cation by column chromatography on silica gel using
AcOEt/hexane (1:6) as eluent. Mp 156–157 8C (isopropa-
nol). Yield 75%. IR (KBr): nmax/cmK1 1650 (CO). 1H NMR
(CDCl3, 300 MHz), d (ppm): 7.80 (s, 1H, H6), 3.76 (s, 3H,
CH3). 13C NMR (CDCl3, 75 MHz), d (ppm): 159.0, 141.4,
121.0, 116.5, 41.8. MS (70 eV) m/z (%): 362 (MC, 88), 333
(28), 270 (100).
The crystal structure of 8c was solved by direct methods and
Fourier synthesis. Non-H atoms were refined anisotropically
by full-matrix least-squares techniques. H atoms were
calculated geometrically and included in the refinement,
but were restrained to ride on their parent atoms. The
isotropic displacement parameters of the H atoms were fixed
to 1.3 times Ueq of their parent atoms. Data collection:
3.1.4. 2-Benzyl-4,5-diiodopyridazin-3(2H)-one. Purifi-
cation by column chromatography on silica gel using

12184
A. Coelho et al. / Tetrahedron 60 (2004) 12177–12189
AcOEt/hexane (1:8) as eluent. Mp 97–98 8C (isopropanol).
Yield 68%. IR (KBr): nmax/cmK1 1651 (CO). 1H NMR
(CDCl3, 300 MHz), d (ppm): 7.58 (s, 1H, H6), 7.44 (m, 2H,
(CDCl3, 75 MHz), d (ppm): 171.7, 165.9, 160.3, 138.2,
134.3, 128.2, 125.5, 52.7, 52.3, 47.8, 32.8, 31.3. MS (70 eV)
m/z (%): 266 (MC, 55), 234 (45), 207 (40), 179 (100).
HRMS m/z calcd for C12H14IN2O5 (MC): 266.0903, found:
266.0907.
aromatics), 7.30 (m, 3H, aromatics), 5.32 (s, 2H, CH2). 13
C
NMR (CDCl3, 75 MHz), d (ppm): 158.6, 145.4, 136.1,
135.5, 135.3, 129.5, 129.1, 128.7, 56.2. MS (70 eV) m/z
(%): 438 (MC, 14), 347 (25), 242 (58).
3.2.3. 2-Hydroxymethyl-5-iodopyridazin-3(2H)-one 3f. A
mixture of 3c (1.5 g, 6.75 mmol) and 35% formaldehyde
(50 mL) was flushed with argon for 5 min. The suspension
was stirred and heated under reflux (oil bath 110 8C) under
argon until the starting material had been consumed. The
mixture was cooled and the suspension was concentrated to
dryness under reduced pressure. The resulting solid was
purified by column chromatography on silica gel (AcOEt/
hexane, 1:3). Further purification was achieved by
recrystallisation from isopropanol. Mp 140–141 8C (iso-
propanol). Yield 90%. IR (KBr): nmax/cmK1 3261 (OH),
1651 (CO). 1H NMR (CDCl3, 300 MHz), d (ppm): 8.13 (d,
JZ2.1 Hz, 1H, H6), 7.59 (d, JZ2.1 Hz, 1H, H4), 6.77 (t, JZ
7.6 Hz, 1H, OH), 5.25 (d, JZ7.6 Hz, 2H, CH2). 13C NMR
(CDCl3, 75 MHz), d (ppm): 158.3, 142.2, 138.3, 105.7,
73.5. MS (70 eV) m/z (%): 252 (MC, 20), 236 (30), 223
(100). HRMS m/z calcd for C5H5IN2O2 (MC): 251.9396,
found: 251.9399.
3.1.5. 5-Iodopyridazin-3(2H)-one 3c. To a suspension of
anhydrous aluminium chloride (0.66 g, 5.03 mmol) in dry
toluene (8 mL) under an argon atmosphere was slowly
added the 2-benzyl-5-iodopyridazin-3(2H)-one 3b (0.31 g,
1.0 mmol) and the mixture was stirred and heated (oil bath
120 8C) until the starting material had been consumed. After
cooling, ice-water was added, the mixture stirred for 10 min
and then extracted with dichloromethane. The organic phase
was dried over sodium sulphate and concentrated to dryness
under reduced pressure. The residue was purified by column
chromatography on silica gel using AcOEt/hexane (1:10) as
eluent. Further purification was achieved by recrystallisa-
tion from isopropanol. Mp 147–148 8C (isopropanol). Yield
90%. IR (KBr): nmax/cmK1 3004 (NH), 1651 (CO). 1H NMR
(CDCl3, 300 MHz), d (ppm): 12.57 (bs, 1H, NH), 8.00 (d,
JZ1.9 Hz, 1H, H6), 7.54 (d, JZ1.9 Hz, 1H, H4). 13C NMR
(CDCl3, 75 MHz), d (ppm): 161.1, 143.6, 139.1, 105.3. MS
(70 eV) m/z (%): 222 (MC, 100), 194 (20), 127 (41). Anal.
Calcd for C4H3IN2O, C 21.64, H 1.36, N 12.62; found, C
21.64, H 1.45, N 12.66.
3.3. General procedure for the Suzuki coupling of 3
The 2-substituted 5-iodopyridazin-3(2H)-one 3 (1.7 mmol)
was mixed with the corresponding arylboronic acid
(2.2 mmol), Pd(PPh3)4 (0.016 mmol) and K2CO3
(5.08 mmol) in a 3:1 mixture of DME/H2O (15 mL) and
flushed with argon for 5 min. The mixture was then stirred
and heated under reflux (oil bath 100 8C) under argon until
the starting material had been consumed. After cooling, the
solution was filtered through a pad of Celite and the filtrate
was evaporated to dryness to give an oily residue, which
was purified by column chromatography on silica gel.
Further purification was achieved by recrystallisation from
the appropriate solvent.
3.2. Reaction of methyl acrylate with 3c under Heck
conditions (synthesis of 3d and 3e)
A mixture of 5-iodopyridazin-3(2H)-one 3c (1.00 mmol),
bis(tri-o-tolyl-phosphine)palladium(II)
dichloride
(0.10 mmol), triethylamine (1.52 mmol) and methyl
acrylate (2.00 mmol) in DMF (10 mL) in a sealed tube
was heated under reflux (oil bath 110 8C) under argon until
the starting material had been consumed. The mixture was
allowed to cool to room temperature, filtered through a pad
of Celite and the filtrate was evaporated to dryness to give a
brown oily residue. The residue was purified by column
chromatography (AcOEt/hexane, 1:4) to give 3d and 3e.
Further purification was achieved by recrystallisation.
3.3.1. 2-Methyl-5-phenylpyridazin-3(2H)-one 4a. Purifi-
cation by column chromatography on silica gel using
AcOEt/hexane (1:1) as eluent. Mp 119–120 8C (isopropa-
nol). Yield 91%. IR (KBr): nmax/cmK1 1658 (CO), 1590
(aromatics). 1H NMR (CDCl3, 300 MHz), d (ppm): 8.00 (d,
JZ2.2 Hz, 1H, H6), 7.55 (m, 2H, aromatics), 7.46 (m, 3H,
aromatics), 7.00 (d, JZ2.2 Hz, 1H, H4), 3.83 (s, 3H, CH3).
13C NMR (CDCl3, 75 MHz), d (ppm): 160.3, 144.2, 136.0,
134.3, 130.6, 129.8, 127.2, 124.7, 40.3. MS (70 eV) m/z
(%): 186 (MC, 40), 158 (28), 130 (10), 115 (100). Anal.
Calcd for C11H10N2O, C 70.95, H 5.41, N 15.04; found, C
71.05, H 5.43, N 15.04.
3.2.1. Methyl-3-(4-iodo-6-oxo-pyridazin-1(6H)-yl)pro-
panoate 3d. Mp 58–60 8C (isopropanol). Yield 9%. IR
(KBr): nmax/cmK1 1730 (COO), 1640 (CO). 1H NMR
(CDCl3, 300 MHz), d (ppm): 7.91 (d, JZ1.9 Hz, 1H, H6),
7.46 (d, JZ1.9 Hz, 1H, H4), 4.38 (t, JZ7.1 Hz, 2H, CH2),
3.68 (s, 3H, OCH3), 2.81 (t, JZ7.1 Hz, 2H, CH2). 13C NMR
(CDCl3, 75 MHz), d (ppm): 171.6, 158.9, 142.3, 138.6,
103.0, 52.3, 47.7, 39.6. MS (70 eV) m/z (%): 308 (MC, 34),
249 (49), 222 (100). HRMS m/z calcd for C8H9IN2O3 (MC):
307.9658, found: 307.9660.
3.3.2. 5-(40-Chlorophenyl)-2-methylpyridazin-3(2H)-one
4b. Purification by column chromatography on silica gel
using AcOEt/hexane (1:1) as eluent. Mp 167–168 8C
(isopropanol). Yield 90%. IR (KBr): nmax/cmK1 1654
3.2.2. Methyl (2E)-3-[1-(3-methoxy-3-oxopropyl)-6-oxo-
1,6-dihydropyridazin-4-yl]acrylate 3e. Mp 120–122 8C
(isopropanol). Yield 85%. IR (KBr): nmax/cmK1 1733
(COO), 1636 (CO). 1H NMR (CDCl3, 300 MHz), d
(ppm): 7.89 (d, JZ2.1 Hz, 1H, H6), 7.40 (d, JZ16.1 Hz,
1H, CH), 6.90 (d, JZ2.1 Hz, 1H, H4), 6.53 (d, JZ16.1 Hz,
1H, CH), 4.41 (t, JZ7.0 Hz, 1H, H2), 3.82 (s, 3H, CH3),
3.68 (s, 3H, CH3), 2.83 (t, JZ7.0 Hz, 1H, CH2). 13C NMR
1
(CO), 1589 (aromatics). H NMR (CDCl3, 300 MHz), d
(ppm): 7.98 (d, JZ2.3 Hz, 1H, H6), 7.52–7.48 (m, 4H,
aromatics), 7.00 (d, JZ2.3 Hz, 1H, H4), 3.81 (s, 3H, CH3).
13C NMR (CDCl3, 75 MHz), d (ppm): 161.0, 143.0, 137.0,
135.5, 132.7, 130.1, 128, 5, 124.7, 40.4. MS (70 eV) m/z
(%): 220 (MC, 48), 192 (20), 149 (100). Anal. Calcd for

A. Coelho et al. / Tetrahedron 60 (2004) 12177–12189
12185
C11H9ClN2O, C 59.88, H 4.11, N 12.70; found, C 60.10, H
4.15, N 12.72.
3.4.2. 5-Acetyl-2-methylpyridazin-3(2H)-one 5b. Purifi-
cation by column chromatography on silica gel using
AcOEt/hexane (1:2) as eluent. Mp 145–146 8C (isopropa-
nol). Yield 70%. IR (KBr): nmax/cmK1 1654 (CO), 1560
(aromatics). 1H NMR (CDCl3, 300 MHz), d (ppm): 8.15 (d,
JZ2.2 Hz, 1H, H6), 7.30 (d, JZ2.2 Hz, 1H, H4), 3.80 (s,
3H, CH3), 2.54 (s, 3H, CH3). 13C NMR (CDCl3, 75 MHz), d
(ppm): 195.9, 160.9, 137.8, 133.7, 129.5, 40.7, 26.9. MS
(70 eV) m/z (%): 152 (MC, 100), 124 (14), 109 (70). Anal.
Calcd for C7H8N2O2, C 55.26, H 5.30, N 18.41; found, C
55.32, H 5.42, N 18.46.
3.3.3. 2-Benzyl-5-phenylpyridazin-3(2H)-one 4c. Purifi-
cation by column chromatography on silica gel using
AcOEt/hexane (1:2) as eluent. Mp 126–127 8C (isopropa-
nol). Yield 94%. IR (KBr): nmax/cmK1 1655 (CO), 1590
(aromatics). 1H NMR (CDCl3, 300 MHz), d (ppm): 8.00 (d,
JZ2.0 Hz, 1H, H6), 7.55–7.46 (m, 7H, aromatics), 7.36–
7.27 (m, 3H, aromatics), 7.00 (d, JZ2.0 Hz, 1H, H4), 5.37
(s, 2H, CH2). 13C NMR (CDCl3, 75 MHz), d (ppm): 160.8,
143.9, 136.6, 136.3, 134.2, 130.6, 129.7, 129.1, 129.0,
128.3, 127.2, 125.2, 55.2. MS (70 eV) m/z (%): 262 (MC,
35), 220 (10), 158 (20), 115 (100). Anal. Calcd for
C17H14N2O, C 77.84, H 5.38, N 10.68; found, C 77.90, H
5.56, N 10.67.
3.4.3. 2-Benzyl-5-vinylpyridazin-3(2H)-one 5c. Purifi-
cation by column chromatography on silica gel using
AcOEt/hexane (1:6) as eluent. Mp 60–62 8C (isopropanol).
Yield 78%. IR (KBr): nmax/cmK1 1653 (CO), 1586
1
(aromatics). H NMR (CDCl3, 300 MHz), d (ppm): 7.91
(d, JZ2.0 Hz, 1H, H6), 7.39 (m, 2H, aromatics), 7.28 (m,
3H, aromatics), 6.72 (d, JZ2.0 Hz, 1H, H4), 6.44 (dd, JZ
6.7, 11.0 Hz, 1H, CH), 5.88 (d, JZ16.6 Hz, 1H, CH), 5.54
(d, JZ11.0 Hz, 1H, CH), 5.27 (s, 2H, CH2). 13C NMR
(CDCl3, 75 MHz), d (ppm): 160.9, 140.5, 136.7, 134.8,
131.7, 129.0, 128.9, 128.2, 125.4, 122.3, 55.1. MS (70 eV)
m/z (%): 212 (MC, 75), 91 (62), 65 (100). HRMS m/z calcd
for C13H12N2O (MC): 212.0901, found: 212.0903.
3.3.4. 2-Benzyl-5-(4-chlorophenyl)pyridazin-3(2H)-one
4d. Purification by column chromatography on silica gel
using AcOEt/hexane (1:2) as eluent. Mp 145–146 8C
(isopropanol). Yield 90%. IR (KBr): nmax/cmK1 1656
1
(CO), 1588 (aromatics). H NMR (CDCl3, 300 MHz), d
(ppm): 8.00 (d, JZ2.2 Hz, 1H, H6), 7.51–7.43 (m, 7H,
aromatics), 7.32 (m, 2H, aromatics), 7.00 (d, JZ2.2 Hz, 1H,
H4), 5.36 (s, 2H, CH2). 13C NMR (CDCl3, 75 MHz), d
(ppm): 160.6, 142.8, 136.8, 136.5, 135.9, 132.7, 130.0,
129.2, 129.0, 128.5, 128.4, 125.3, 55.3. MS (70 eV) m/z
(%): 312 (MC, 24), 165 (38), 125 (42), 111 (64), 97 (100).
Anal. Calcd for C17H13ClN2O, C 68.81, H 4.42, N 9.44;
found, C 69.14, H 4.54, N 9.53.
3.4.4. 5-Acetyl-2-benzylpyridazin-3(2H)-one 5d. Purifi-
cation by column chromatography on silica gel using
AcOEt/hexane (1:4) as eluent. Mp 105–106 8C (isopropa-
nol). Yield 68%. IR (KBr): nmax/cmK1 1661 (CO), 1547
(aromatics). 1H NMR (CDCl3, 300 MHz), d (ppm): 8.17 (d,
JZ2.1 Hz, 1H, H6), 7.44 (d, JZ2.1 Hz, 1H, H4), 7.40 (m,
2H, aromatics), 7.30 (m, 3H, aromatics), 5.33 (s, 2H, CH2),
2.53 (s, 3H, CH3). 13C NMR (CDCl3, 75 MHz), d (ppm):
196.0, 160.2, 137.3, 135.9, 134.0, 130.2, 129.2, 129.0,
128.6, 55.9, 26.9. MS (70 eV) m/z (%): 228 (MC, 100), 186
(20), 124 (20). Anal. Calcd for C13H12N2O2, C 68.41, H
5.30, N 12.27; found, C 68.63, H 5.34, N 12.28.
3.4. General procedure for the Stille coupling of 3
A mixture of 2-substituted 5-iodopyridazin-3(2H)-one
3
(3.40 mmol), bis(triphenylphosphine)palladium(II)
dichloride (0.16 mmol) and the corresponding tributyl-
stannane (3.73 mmol) in anhydrous toluene (20 mL) was
heated under reflux under argon until the starting material
had been consumed. The mixture was allowed to cool to
room temperature, filtered through a pad of Celite and the
filtrate was evaporated to dryness to give a yellow oily
residue. For the synthesis of compounds 5b and 5d the oily
residue containing the corresponding enol-ether was heated
under reflux in 3 N hydrochloric acid during 12 h. After
extraction with dichloromethane, the organic phase was
dried (Na2SO4) and evaporated under reduced pressure. The
residue was purified by column chromatography and further
purification was achieved by recrystallisation from the
appropriate solvent.
3.5. General procedure for the Heck coupling of 3
A
degassed (argon) mixture of the 2-substituted
5-iodopyridazin-3(2H)-one 3 (1.00 mmol), bis(tri-o-tolyl-
phosphine)-palladium(II) dichloride (0.10 mmol), triethyl-
amine (1.52 mmol) and the corresponding alkene
(2.00 mmol) in DMF (10 mL) in a sealed tube was heated
under reflux (oil bath 110 8C) under argon until the starting
material had been consumed. The mixture was allowed to
cool to room temperature, filtered through a pad of Celite
and the filtrate was evaporated to dryness to give a
brown oily residue. The residue was purified by column
chromatography and further purification was achieved by
recrystallisation from the appropriate solvent.
3.4.1. 2-Methyl-5-vinylpyridazin-3(2H)-one 5a. Purifi-
cation by column chromatography on silica gel using
AcOEt/hexane (1:8) as eluent. Mp 101–102 8C (isopropa-
nol). Yield 90%. IR (KBr): nmax/cmK1 1654 (CO). 1H NMR
(CDCl3, 300 MHz), d (ppm): 7.83 (d, JZ2.0 Hz, 1H, H6),
6.72 (d, JZ2.0 Hz, 1H, H4), 6.48 (dd, JZ6.7, 10.9 Hz, 1H,
CH), 5.93 (d, JZ16.6 Hz, 1H, CH), 5.58 (d, JZ10.9 Hz,
1H, CH), 3.74 (s, 3H, CH3). 13C NMR (CDCl3, 75 MHz), d
(ppm): 161.3, 140.6, 134.4, 131.7, 124.8, 122.1, 40.1. MS
(70 eV) m/z (%): 136 (MC, 100), 108 (26). Anal. Calcd for
C7H8N2O, C 61.75, H 5.92, N 20.58; found, C 61.79, H
5.94, N 20.57.
3.5.1. (2E)-3-(1-Methyl-6-oxo-1,6-dihydropyridazin-
4-yl)acrylonitrile 6a. Purification by column chromato-
graphy on silica gel using AcOEt/hexane (1:2) as eluent. Mp
155–156 8C (isopropanol). Yield 63%. IR (KBr): nmax/cmK1
1
2230 (CN), 1670 (CO). H NMR (CDCl3, 300 MHz), d
(ppm): 7.87 (d, JZ2.1 Hz, 1H, H6), 7.18 (d, JZ16.7 Hz,
1H, CH), 6.90 (d, JZ2.1 Hz, 1H, H4), 6.07 (d, JZ16.7 Hz,
1H, CH), 3.77 (s, 3H, CH3). 13C NMR (CDCl3, 75 MHz), d
(ppm): 160.3, 144.3, 136.9, 135.4, 132.8, 127.6, 116.4, 40.4.

12186
A. Coelho et al. / Tetrahedron 60 (2004) 12177–12189
MS (70 eV) m/z (%): 161 (MC, 20), 133 (16), 90 (43), 58
(100). Anal. Calcd for C8H7N3O, C 59.62, H 4.38, N 26.07;
found, C 59.67, H 4.42, N 26.12.
5-iodopyridazin-3(2H)-one 3 (1.0 mmol), PdCl2(PPh3)2
(0.02 mmol) and CuI (0.02 mmol) in DMF (10 mL) was
added triethylamine (2.1 mmol) and the corresponding
alkyne (1.50 mmol). The mixture was stirred at room
temperature under argon until the starting material had been
consumed. The mixture was cooled to room temperature,
diluted with dichloromethane and filtered through Celite.
The filtrate was concentrated in vacuo and the residue
purified by column chromatography on silica gel. Further
purification was achieved by recrystallisation from the
appropriate solvent.
3.5.2. Methyl (2E)-3-(1-methyl-6-oxo-1,6-dihydropyri-
dazin-4-yl)acrylate 6b. Purification by column chromato-
graphy on silica gel using AcOEt/hexane (1:2) as eluent. Mp
194–196 8C (isopropanol). Yield 60%. IR (KBr): nmax/cmK1
1
1723 (COO), 1636 (CO). H NMR (CDCl3, 300 MHz), d
(ppm): 7.87 (d, JZ1.9 Hz, 1H, H6), 7.40 (d, JZ16.0 Hz,
1H, CH), 6.91 (d, JZ1.9 Hz, 1H, H4), 6.52 (d, JZ16.0 Hz,
1H, CH), 3.76 (s, 3H, CH3), 3.74 (s, 3H, CH3). 13C NMR
(CDCl3, 75 MHz), d (ppm): 166.0, 160.6, 138.3, 138.0,
134.0, 127.8, 125.3, 52.6, 40.4. MS (70 eV) m/z (%): 194
(MC, 100), 163 (24), 135 (60). Anal. Calcd for C9H10N2O3,
C 55.67, H 5.19, N 14.43; found, C 55.71, H 5.19, N 14.45.
3.6.1. 2-Methyl-5-(3-hydroxyprop-1-yn-1-yl)pyridazin-
3(2H)-one 8a. Purification by column chromatography on
silica gel using AcOEt/hexane (1:3) as eluent. Mp 134–
135 8C (isopropanol). Yield 70%. IR (KBr): nmax/cmK1
1
3342 (OH), 2210 (C^C), 1650 (CO). H NMR (CDCl3,
3.5.3. (2E)-3-(1-Benzyl-6-oxo-1,6-dihydropyridazin-
4-yl)acrylonitrile 6c. Purification by column chromato-
graphy on silica gel using AcOEt/hexane (1:8) as eluent. Mp
123–125 8C (isopropanol). Yield 68%. IR (KBr): nmax/cmK1
1654 (CO), 1560 (aromatics). 1H NMR (CDCl3, 300 MHz),
d (ppm): 7.82 (d, JZ2.2 Hz, 1H, H6), 7.52–7.38 (m, 5H,
aromatics), 7.12 (d, JZ16.7 Hz, 1H, CH), 6.89 (d, JZ
2.2 Hz, 1H, H4), 6.03 (d, JZ16.7 Hz, 1H, CH), 5.29 (s, 2H,
CH2). 13C NMR (CDCl3, 75 MHz), d (ppm): 159.9, 144.3,
136.8, 136.3, 136.0, 130.2, 129.2, 129.0, 128.5, 128.0,
115.3, 55.4. MS (70 eV) m/z (%): 237 (MC, 54), 209 (13),
181 (9), 91 (100). Anal. Calcd for C14H11N3O, C 70.87, H
4.67, N 17.71; found, C 70.89, H 4.88, N 17.75.
300 MHz), d (ppm): 7.68 (d, JZ1.9 Hz, 1H, H6), 6.99 (d,
JZ1.9 Hz, 1H, H4), 4.50 (bs, 1H, OH), 3.80 (s, 2H, CH2),
3.75 (s, 3H, CH3). 13C NMR (CDCl3, 75 MHz), d (ppm):
160.5, 137.7, 130.5, 128.6, 98.0, 79.1, 51.3, 40.6. MS
(70 eV) m/z (%): 164 (MC, 100), 136 (35). Anal. Calcd for
C8H8N2O2, C 58.53, H 4.91, N 17.06; found, C 58.61, H
4.89, N 16.97.
3.6.2. 2-Benzyl-5-(3-hydroxyprop-1-yn-1-yl)pyridazin-
3(2H)-one 8b. Purification by column chromatography on
silica gel using AcOEt/hexane (1:2) as eluent. Mp 125–
126 8C (isopropanol). Yield 93%. IR (KBr): nmax/cmK1
1640 (CO), 1579 (aromatics). 1H NMR (CDCl3, 300 MHz),
d (ppm): 7.64 (d, JZ1.8 Hz, 1H, H6), 7.40–7.34 (m, 2H,
aromatics), 7.33–7.25 (m, 3H, aromatics), 6.97 (d, JZ
1.8 Hz, 1H, H4), 5.27 (s, 2H, CH2), 4.42 (t, JZ6.3 Hz, 1H,
OH), 3.94 (d, JZ6.3 Hz, 2H, CH2). 13C NMR (CDCl3,
75 MHz), d (ppm): 160.1, 138.1, 136.0, 131.1, 129.2, 129.0,
128.6, 128.4, 98.4, 79.2, 55.7, 51.2. MS (70 eV) m/z (%):
240 (MC, 44), 213 (8), 184 (14), 156 (10), 136 (23), 104
(36), 91 (100). Anal. Calcd for C14H12N2O2, C 69.99, H
5.03, N 11.66; found, C 70.06, H 5.01, N 11.67.
3.5.4. Methyl (2E)-3-(1-benzyl-6-oxo-1,6-dihydropyrida-
zin-4-yl)acrylate 6d. Purification by column chromato-
graphy on silica gel using AcOEt/hexane (1:3) as eluent.
112–113 (isopropanol). Yield 60%. IR (KBr): nmax/cmK1
1
1726 (COO), 1654 (CO). H NMR (CDCl3, 300 MHz), d
(ppm): 7.90 (d, JZ2.2 Hz, 1H, H6), 7.44–7.25 (m, 6H, 5H
aromaticsCCH), 6.92 (d, JZ2.2 Hz, 1H, H4), 6.50 (d, JZ
16.1 Hz, 1H, CH), 5.31 (s, 2H, CH2), 3.82 (s, 3H, CH3). 13
C
NMR (CDCl3, 75 MHz), d (ppm): 165.3, 160.0, 138.3,
136.3, 134.3, 129.1, 129.0, 128.5, 128.4, 128.3, 125.3, 55.5,
52.7. MS (70 eV) m/z (%): 270 (MC, 31), 211 (14), 91
(100). Anal. Calcd for C15H14N2O3, C 66.66, H 5.22, N
10.36; found, C 66.68, H 5.24, N 10.49.
3.6.3.
2-Methyl-5-[(1E)-3-oxo-3-phenylprop-1-en-
1-yl]pyridazin-3(2H)-one 8c. Purification by column
chromatography on silica gel using AcOEt/hexane (1:3) as
eluent. Mp 193–194 8C (MeOH). Yield 89%. IR (KBr):
nmax/cmK1 1666 (CO), 1645 (CO), 1586 (aromatics). H
1
3.5.5. Methyl 2-benzyl-1-oxo-1,2-dihydrophthalazin-6-
carboxylate 7. Purification by column chromatography on
silica gel using AcOEt/hexane (1:3) as eluent. Mp 156–
157 8C (isopropanol). Yield 7%. IR (KBr): nmax/cmK1 1725
NMR (CDCl3, 300 MHz), d (ppm): 8.09 (d, JZ1.9 Hz, 1H,
H6), 7.70 (m, 2H, aromatics), 7.31 (d, JZ15.5 Hz, 1H, CH),
7.21–6.68 (m, 5H, 3H, aromatics, 1H, CH, 1H, H4), 3.69 (s,
3H, CH3). 13C NMR (CDCl3, 75 MHz), d (ppm): 189.3,
160.8, 138.6, 137.6, 137.4, 134.3, 134.1, 129.3, 129.0,
128.6, 127.9, 40.5. MS (70 eV) m/z (%): 240 (MC, 100),
211 (40). Anal. Calcd for C14H12N2O2, C 69.99, H 5.03, N
11.66; found, C 70.07, H 5.01, N 11.66.
1
(COO), 1645 (CO), 1494 (aromatics). H NMR (CDCl3,
300 MHz), d (ppm): 8.50 (d, JZ8.50 Hz, 1H, CH), 8.37–
8.33 (m, 2H, aromatics), 8.23 (s, 1H, CH), 7.48–7.41 (m,
2H, aromatics), 7.34–7.25 (m, 3H, aromatics), 5.41 (s, 2H,
CH2), 3.99 (s, 3H, CH3). 13C NMR (CDCl3, 75 MHz), d
(ppm): 166.2, 159.5, 138.2, 137.0, 134.7, 132.0, 131.3,
130.5, 129.1, 129.0, 128.3, 128.2, 127.8, 55.2, 53.2. MS
(70 eV) m/z (%): 294 (MC, 19), 266 (5), 190 (85). Anal.
Calcd for C17H14N2O3, C 69.38, H 4.79, N 9.52; found, C
69.45, H 4.87, N 9.55.
X-ray structure analysis. Crystals of 8c were grown by
slow evaporation from a methanol solution. Crystal
˚
data.C14H12N2O2, MZ240.26, triclinic, aZ5.5013(4) A,
˚
˚
bZ7.8346(5) A, cZ13.6808(9) A, aZ87.116(6)8, bZ
3
˚
86.082(6)8, gZ85.108(5)8, VZ585.54(7) A [by least-
squares refinement on diffractometer angles for 34 auto-
3.6. General procedure for the Sonogashira coupling of 3
matically centered reflections with 10.73!q!27.748, lZ
˚
ꢀ
1.54178 A, TZ293(2) K], space group P1, ZZ2, DcZ
To a degassed (argon) suspension of 2-substituted
1.363(1) g cmK3, mZ0.758 mm-1.

A. Coelho et al. / Tetrahedron 60 (2004) 12177–12189
12187
1
A prism-like colourless crystal (0.46!0.06!0.02 mm3)
was used for the analysis. CCDC 231679 contains the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.
uk/data_request/cif, or by emailing data_request@ccdc.
cam.ac.uk, or by contacting The Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
UK; fax:C44 1223 336033.
65%. IR (KBr): nmax/cmK1 1664 (CO). H NMR (CDCl3,
300 MHz), d (ppm): 12.30 (bs, 1H, NH), 7.93 (d, JZ1.8 Hz,
1H, H6), 6.77 (d, JZ1.8 Hz, 1H, H4), 6.50 (dd, JZ6.7,
11.0 Hz, 1H, CH), 5.96 (d, JZ16.6 Hz, 1H, CH), 5.62 (d,
JZ11.0 Hz, 1H, CH). 13C NMR (CDCl3, 75 MHz), d
(ppm): 163.0, 135.8, 131.8, 131.5, 125.4, 122.9. MS (70 eV)
m/z (%): 122 (MC, 84), 58 (100). HRMS m/z calcd for
C6H6N2O (MC): 122.0554, found: 122.0556.
3.6.4. 2-Benzyl-5-[(1E)-3-oxo-3-phenylprop-1-en-1-
yl]pyridazin-3(2H)-one 8d. Purification by column chro-
matography on silica gel using AcOEt/hexane (1:8) as
eluent. Mp 174–175 8C (isopropanol). Yield 70%. IR (KBr):
3.6.7. 5-Phenylpyridazin-3(2H)-one 10b. Purification by
column chromatography on silica gel using AcOEt/hexane
(1:2) as eluent. Mp 193–194 8C (isopropanol). Yield 60%.
IR (KBr): nmax/cmK1 1662 (CO), 1534 (aromatics). 1H
NMR (DMSO-d6 300 MHz), d (ppm): 13.10 (bs, 1H, NH),
8.29 (d, JZ2.1 Hz, 1H, H6), 7.83–7.78 (m, 2H, aromatics),
7.52–7.48 (m, 3H, aromatics), 7.11 (d, JZ2.1 Hz, 1H, H4).
13C NMR (DMSO-d6 75 MHz), d (ppm): 162.3, 143.6,
136.2, 133.9, 130.6, 129.6, 127.5, 124.5. MS (70 eV) m/z
(%): 172 (MC, 100), 144 (45), 115 (85). Anal. Calcd for
C10H8N2O, C 69.76, H 4.68, N 16.27; found, C 69.77, H
4.89, N 16.34.
1
nmax/cmK1 1646 (CO), 1629 (CO), 1578 (aromatics). H
NMR (CDCl3, 300 MHz), d (ppm): 8.15 (d, JZ2.0 Hz, 1H,
H6), 7.92 (d, JZ8.2 Hz, 2H, aromatics), 7.54 (d, JZ
15.5 Hz, 1H, CH), 7.42 (m, 5H, aromatics), 7.10 (m, 4H, 3H
aromaticsCH4), 6.75 (d, JZ15.5 Hz, 1H, CH), 5.01 (s, 2H,
CH2). 13C NMR (CDCl3, 75 MHz), d (ppm): 189.3, 160.3,
138.5, 137.6, 137.4, 136.3, 134.7, 134.1, 129.3, 129.2,
129.1, 129.0, 128.6, 128.5, 128.4, 55.44. MS (70 eV) m/z
(%): 316 (MC, 72), 197 (58), 184 (100). Anal. Calcd for
C20H16N2O2, C 75.93, H 5.10, N 8.86; found, C 75.95, H
5.09, N 8.85.
3.6.8. 5-(3-Hydroxyprop-1-yn-1-yl)pyridazin-3(2H)one
10c. Purification by column chromatography on silica gel
using AcOEt/hexane (1:8) as eluent. Mp 179–180 8C
(isopropanol). Yield 68%. IR (KBr): nmax/cmK1 3500–300
(NH), 2226 (C^C), 1640 (CO). 1H NMR (DMSO-d6
300 MHz), d (ppm): 13.14 (bs, 1H, NH), 7.79 (d, JZ1.9 Hz,
1H, H6), 6.91 (d, JZ1.9 Hz, 1H, H4), 5.51 (t, JZ5.44 Hz,
1H, OH), 3.71 (d, JZ5.44 Hz, 2H, CH2). 13C NMR (CDCl3,
75 MHz), d (ppm): 160.2, 137.4, 130.9, 128.5, 98.9, 78.8,
49.7. MS (70 eV) m/z (%): 150 (MC, 100), 121 (85), 94
(50). Anal. Calcd for C7H6N2O, C 56.00, H 4.03, N 18.66;
found, C 56.13, H 4.11, N 18.72.
3.6.5. 2-Benzyl-5-(3-hydroxy-3-phenylprop-1-yn-1-
yl)pyridazin-3(2H)-one 8e. This compound was obtained
by following the general procedure described above for the
Sonogashira alkynylation of compounds 3 but at room
temperature. Careful work up and purification by column
chromatography on silica gel using AcOEt/hexane (1:3) as
eluent afforded 8e (30%) and 8d (67%). 8e: Mp 133–134 8C
(isopropanol). IR (KBr): nmax/cmK1 3254 (OH), 2218
(C–^–C), 1645 (CO), 1581 (aromatics). 1H NMR (CDCl3,
300 MHz), d (ppm): 7.64 (d, JZ1.9 Hz, 1H, H6), 7.53 (m,
2H, aromatics), 7.36–7.12 (m, 8H, aromatics), 6.96 (d, JZ
1.9 Hz, 1H, H4), 5.65 (d, JZ6.0 Hz, 1H, CH), 5.25 (s, 2H,
CH2), 3.72 (d, JZ6.0 Hz, 1H, OH). 13C NMR (CDCl3,
75 MHz), d (ppm): 159.8, 139.9, 137.7, 136.1, 131.4, 129.2,
129.1, 129.0, 128.4, 128.0, 126.9, 90.0, 80.2, 65.0, 55.1,
31.3. MS (70 eV) m/z (%): 316 (MC, 100), 91 (75). Anal.
Calcd for C20H16N2O2, C 75.93, H 5.10, N 8.86; found, C
75.98, H 5.12, N 8.90.
3.6.9. 5-[(1E)-3-Oxo-3-phenylprop-1-en-1-yl]pyridazin-
3(2H)-one 10d. Purification by column chromatography
on silica gel using AcOEt/hexane (1:2) as eluent. Mp 193–
194 8C (MeOH). Yield 60%. IR (KBr): nmax/cmK1 1660
1
(CO), 1615 (CO), 1576 (aromatics). H NMR (DMSO-d6
300 MHz), d (ppm): 13.42 (bs, 1H, NH),, 8.10 (d, JZ
8.12 Hz, 2H, aromatics), 8.01 (d, JZ1.9 Hz, 1H, H6), 7.53
(d, JZ15.5 Hz, 1H, CH), 7.46 (m, 3H, aromatics), 7.28 (d,
JZ15.5 Hz, 1H, CH), 7.06 (d, JZ1.9 Hz, 1H, H4). 13C
NMR (CDCl3, 75 MHz), d (ppm): 189.2, 161.5, 138.7,
137.7, 137.5, 134.4, 134.2, 129.4, 129.1, 128.7, 128.0. MS
(70 eV) m/z (%): 226 (MC, 100), 197 (84), 105 (48). Anal.
Calcd for C13H10N2O2, C 69.02, H 4.46, N 12.38; found, C
69.11, H 4.42, N 12.48.
Base-promoted isomerisation of intermediate 8e. A mixture
of 2-benzyl-5-(3-hydroxy-3-phenylprop-1-yn-1-yl)pyrida-
zin-3(2H)-one 8e (50 mg), MeOH (7 mL) and a catalytic
amount of triethylamine was heated under reflux until the
starting material had been completely transformed into
the chalcone 8d. The solvent was evaporated in vacuo and
the resulting residue was purified by column chromato-
graphy on silica gel using AcOEt/hexane (1:8) as eluent.
The compound obtained had identical physical and spectro-
scopic properties to 8d. Mp 174–175 8C (isopropanol).
3.6.10. Methyl (2E)-3-(6-oxo-1,6-dihydropyridazin-4-
yl)acrylate 10e. Purification by column chromatography
on silica gel using AcOEt/hexane (1:1) as eluent. Mp 205–
207 8C (MeOH). Yield 62%. IR (KBr): nmax/cmK1 1719
(COO), 1657 (CO). 1H NMR (DMSO-d6 300 MHz), d
(ppm): 13.07 (bs, 1H, NH), 8.27 (d, JZ1.8 Hz, H6), 7.45 (d,
JZ16.2 Hz, 1H, CH), 7.15 (d, JZ1.8 Hz, H4), 6.90 (d, JZ
16.2 Hz, 1H, CH), 3.34 (s, 3H, CH3). 13C NMR (CDCl3,
75 MHz), d (ppm): 166.0, 161.2, 139.0, 138.5, 135.1, 129.0,
125.3, 52.7. MS (70 eV) m/z (%): 180 (MC, 100). Anal.
Calcd for C8H8N2O3, C 53.33, H 4.48, N 15.55; found, C
53.42, H 4.56, N 15.56.
Compounds 11a–b and 10a–c were obtained by following
the general procedures previously described for the Suzuki,
Heck, Stille or Sonogashira reactions but starting from the
2-hydroxymethyl-5-iodopyridazin-3(2H)-one 3f.
3.6.6. 5-Vinylpyridazin-3(2H)-one 10a. Purification by
column chromatography on silica gel using AcOEt/hexane
(1:3) as eluent. Mp 279–280 8C (dec) (isopropanol). Yield

12188
A. Coelho et al. / Tetrahedron 60 (2004) 12177–12189
1996; Vol. 6. (c) Haider, N.; Holzer, W. In Science of
Synthesis; Yamamoto, Y., Ed.; Georg Thieme: Stuttgart, 2003.
9. (a) Rohr, M.; Toussaint, D.; Chayer, S.; Mann, A.; Suffert, J.;
Wermuth, W. G. Heterocycles 1996, 43, 1459. (b) Parrot, I.;
Rival, Y.; Wermuth, C. G. Synthesis 1999, 1163. (c) Turck, A.;
3.6.11. 2-Hydroxymethyl-5-vinylpyridazin-3(2H)-one
11a. Purification by column chromatography on silica gel
using AcOEt/hexane (1:5) as eluent. Mp 91–93 8C (iso-
propanol). Yield 65%. IR (KBr): nmax/cmK1 1660 (CO). 1H
NMR (CDCl3, 300 MHz), d (ppm): 7.91 (d, JZ1.8 Hz, 1H,
H6), 6.77 (d, JZ1.8 Hz, 1H, H4), 6.52 (dd, JZ6.7, 11.0 Hz,
1H, CH), 5.97 (d, JZ16.6 Hz, 1H, CH), 5.63 (d, JZ
11.0 Hz, 1H, CH), 5.52 (d, JZ6.1 Hz, 2H, CH2), 5.01 (bs,
1H, OH). 13C NMR (CDCl3, 75 MHz), d (ppm): 161.9,
141,9, 135.1, 131.5, 125.5, 123.0, 76.67. MS (70 eV) m/z
(%): 152 (MC, 42), 122 (100), 58 (52). HRMS m/z calcd for
C7H8N2O2 (MC): 152.0586, found: 152.0594.
´
Mojovic, L.; Queguiner, G. Bull. Soc. Fr. 1993, 130, 488.
´
´
´
(d) Trecourt, F.; Turck, A.; Ple, N.; Paris, A.; Queguiner, G.
J. Heterocycl. Chem. 1995, 32, 1057. (e) Draper, T. L.; Bailey,
T. R. J. Org. Chem. 1995, 60, 748. (f) Oshawa, A.; Abe, Y.;
Igeta, H. Chem. Pharm. Bull. 1980, 28, 3488. (g) Guery, S.;
Parrot, I.; Rival, Y.; Wermuth, C. G. Synthesis 2001, 699.
´ ´ ´
(h) Krajsovszky, G.; Matyus, P.; Riedl, Z.; Csanyi, D.; Hajos,
G. Heterocycles 2001, 55, 1105. (i) R’kyek, O.; Maes,
`
B. U. W.; Jonckers, T. H. M.; Lemiere, G. L. F.; Dommisse,
R. A. Tetrahedron 2001, 57, 10009. (j) Maes, B. U. W.;
`
Lemiere, G. L. F.; Dommisse, R.; Augustyns, K.; Haemers, A.
Tetrahedron 2000, 56, 1777. (k) Maes, B. U. W.; R’kyek, O.;
3.6.12. 2-Hydroxymethyl-5-(3-hydroxyprop-1-yn-1-
yl)pyridazin-3(2H)-one 11b. Purification by column chro-
matography on silica gel using AcOEt/hexane (1:8) as
eluent. Mp 118–120 8C (isopropanol). Yield 70%. IR (KBr):
1
nmax/cmK1 1640 (CO). H NMR (DMSO-d6 300 MHz), d
ˇ
`
Kos, J.; Lemiere, G. L. F.; Esmans, E.; Rozenski, J.;
Dommisse, R.; Haemers, A. Tetrahedron 2001, 57, 1323.
10. (a) Sotelo, E.; Pita, B.; Ravin˜a, E. Tetrahedron Lett. 2000, 41,
(ppm): 7.879 (d, JZ1.9 Hz, 1H, H6), 7.01 (d, JZ1.9 Hz,
1H, H4), 6.76 (t, JZ7.6 Hz, 1H, OH), 5.52 (t, JZ5.1 Hz,
1H, OH), 5.27 (d, JZ7.6 Hz, 2H, CH2) 4.34 (d, JZ5.1 Hz,
2H, CH2). 13C NMR (CDCl3, 75 MHz), d (ppm): 159.1,
137.1, 131.0, 128.5, 98.7, 78.7, 73.9, 49.7. MS (70 eV) m/z
(%): 180 (MC, 76), 150 (100), 121 (55). HRMS m/z calcd
for C8H8N2O3 (MC): 180.0535, found: 180.0551.
´
2863. (b) Pita, B.; Sotelo, E.; Suarez, M.; Ravin˜a, E.; Ochoa,
E.; Verdecia, Y.; Novoa, H.; Blaton, N.; De Ranter, C.;
Peeters, O. Tetrahedron 2000, 56, 2473. (c) Sotelo, E.;
Centeno, N. B.; Rodrigo, J.; Ravin˜a, E. Tetrahedron 2002, 58,
2389. (d) Sotelo, E.; Ravin˜a, E. Synth. Commun. 2002, 32,
1675.
´
´
11. (a) Laguna, R.; Rodrıguez-Lin˜ares, B.; Cano, E.; Estevez, I.;
Ravin˜a, E.; Sotelo, E. Chem. Pharm. Bull. 1997, 45, 1151.
(b) Laguna, R.; Montero, A.; Cano, E.; Ravin˜a, E.; Sotelo, E.;
Acknowledgements
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Estevez, I. Acta Pharm. Hung. 1996, 43, 43.
Financial support from the Xunta de Galicia (Project PGIDT
01PX20309PR) is gratefully acknowledged. We are also
grateful to Professor Bert Maes for valuable discussions and
suggestions.
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