Pyridazines. Part 34: Retro-ene-assisted palladium-catalyzed synthesis of 4,5-disubstituted-3(2H)-pyridazinones

Article abstract of DOI:10.1016/S0040-4039(03)01029-3

The efficient one-pot bis-functionalization of the 4,5-positions of the 3-pyridazinone ring has been performed using Suzuki, Sonogashira and Stille cross-coupling reactions assisted by a retro-ene fragmentation. This route allows access in a shorter synthetic sequence to several pharmacologically useful 3(2H)-pyridazinones.

Full text of DOI:10.1016/S0040-4039(03)01029-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4459–4462
Pyridazines. Part 34: Retro-ene-assisted palladium-catalyzed
synthesis of 4,5-disubstituted-3(2H)-pyridazinonesꢀ
Eddy Sotelo, Alberto Coelho and Enrique Ravin˜a*
Laboratorio de Qu´ımica Farmace´utica, Departamento de Qu´ımica Orga´nica, Facultad de Farmacia,
Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Received 9 April 2003; accepted 19 April 2003
Abstract—The efficient one-pot bis-functionalization of the 4,5-positions of the 3-pyridazinone ring has been performed using
Suzuki, Sonogashira and Stille cross-coupling reactions assisted by a retro-ene fragmentation. This route allows access in a shorter
synthetic sequence to several pharmacologically useful 3(2H)-pyridazinones. © 2003 Elsevier Science Ltd. All rights reserved.
The interesting pharmacological activities shown by
pyridazine derivatives have recently attracted the atten-
tion of several research groups from academia and
industry.2 The useful nature of pyridazinones has stim-
ulated the search for new synthetic approaches to
achieve substitution on these electron-deficient rings. In
particular, special interest has been directed to palla-
dium cross-coupling reactions and several excellent pal-
ladium-assisted procedures have been described for the
synthesis of both pyridazines and pyridazinones.3 Previ-
ous papers on this topic have illustrated how these
transformations represent a powerful tool to perform
pharmacomodulation in the pyridazinone series and,
for this reason, we became interested in developing a
short yet highly versatile route to prepare 4,5-substi-
tuted-3(2H)-pyridazinones. One key aspect has guided
this new design strategy: to perform palladium-cata-
lyzed reactions on pyridazinones it is necessary to pro-
tect the NH group since the acidic nature of the lactam
functionality usually interferes with the required
transformations.
The use of methoxymethyl (MOM) or benzyloxymethyl
(BOM) groups has recently been reported as a conve-
nient method for protection during these transforma-
tions.5 Furthermore, the use of Lewis acids (aluminum
chloride and boron tribromide) to perform the mild and
selective deprotection of 2-substituted-3-pyridazinones
bearing acid-sensitive functionalities has also been
reported.5c,6 As part of our ongoing medicinal chem-
istry program aimed at obtaining novel pyridazinone-
based antiplatelet agents,7 it was decided to prepare
several 4,5-substituted-3(2H)-pyridazinones 3a–e.
A
number of 4,5-diaryl-2-methyl-3-pyridazinones that are
structurally related to 3 have recently been described by
Lemie´re et al.8
In order to prepare compounds 3, which have a free
NH group, it was necessary to develop a short synthetic
strategy that avoided the use of previously described
2-blocked pyridazinones (such as 2-benzyl-, 2-benzyl-
oxymethyl- or 2-methoxymethyl-3-pyridazinones). In
these cases deprotection after the coupling reaction
requires hydrogenolysis or treatment with refluxing HCl
or Lewis acids. The ultimate aim of this study was to
find a new, simple, more convenient and labile protect-
ing group that can be easily removed under coupling
conditions. We describe here the rapid, efficient and
convenient one-pot synthesis of 4,5-substituted 3-(2H)-
pyridazinones 3 starting from the readily obtainable
4,5-dihalo-2-hydroxymethyl-3(2H)-pyridazinones 2.
A survey of the literature on protecting groups revealed
that methods for the protection of the amide or lactam
functionality are limited.4 There is a dearth of new
protecting groups and/or reagents that are able to
undergo deprotection under mild conditions and new
developments in this area are therefore of great interest.
Compounds 2 were obtained in satisfactory yields by
refluxing the corresponding 3(2H)-pyridazinone 1 in
35% formaldehyde solution (Scheme 1).9,10 The rela-
tively easy preparation of these compounds is a valu-
Keywords: pyridazinone; ene-adducts; palladium; catalysis.
ꢀ For the previous paper in this series, see Ref. 1.
* Corresponding author. Fax: +34 981594912; e-mail: qofara@usc.es
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01029-3

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E. Sotelo et al. / Tetrahedron Letters 44 (2003) 4459–4462
Scheme 1. Reagents and conditions: (A) CH2O, reflux; (B) ArB(OH)2, Pd(PPh3)4, Na2CO3, DME/H2O, reflux; (C) organotin,
Pd(Ph3)2Cl2, toluene, reflux; (D) CuI, Pd(Ph3)2Cl2, DMF, 55°C.
using the appropriate reagents and conditions (Scheme
1) led to the expected 4,5-substituted-3(2H)-pyridazi-
nones 3f–g in excellent yields (Table 1).14,16 In accor-
dance with previous results,15 the Sonogashira coupling
of 1-phenyl-2-propyn-1-ol with 2b afforded the 4,5-
bis[E-(3-oxo-3-phenylpropenyl)]-3(2H)-pyridazinone
3h14 (Scheme 1), most probably due to the base-pro-
moted isomerization of the 4,5-bis(3-hydroxy-3-phenyl-
prop-1-ynyl)-3(2H)-pyridazinone intermediate.15
able aspect of this synthetic route. However, the most
noteworthy advantage regarding their synthetic appli-
cability as 2-blocked pyridazinones in cross-coupling
reactions is derived from their chemical and thermal
stability. These compounds are 1-O, 3-N, 5-O ene-
adducts11 that readily lose formaldehyde through a
retro-ene reaction promoted by a base and/or by heat.
Once position 2 had been blocked it was possible to
study the palladium-catalyzed reactions on 2 (Scheme
1). The first reaction studied was the bis-Suzuki aryla-
tion of 2, which required the presence of a base in the
reaction medium. The transformation was carried out
by heating under reflux a mixture of 2 and 2.5 equiv. of
the appropriate boronic acid under Suzuki conditions12
(Scheme 1).
As expected, all of the above transformations occur
with exclusive formation of 3(2H)-pyridazinones 3
regardless of whether the reaction conditions involve
the use of base or not. These results confirm that the
retro-ene reaction operating in these examples can be
promoted by heat. The fact that 3(2H)-pyridazinones 1
are not reactive under these conditions indicates that
the first step of these transformations most probably
involves the bis-palladium-catalyzed cross-coupling
reaction of 2 to afford a 4,5-substituted ene adduct 4,
which was not isolated (Scheme 2). In the second step
this intermediate loses formaldehyde to give 3 in a
transformation that may be regarded as a retro-ene
fragmentation promoted either by heat or the basic
medium required to perform the Suzuki or Sonogashira
reaction.
The Suzuki bis-arylation of 2a or 2b gave the 4,5-
diaryl-3(2H)-pyridazinones 3a–e in high yields after
12–24 h (Table 1).13,16 Similarly, Stille coupling of 2b
Table 1. Suzuki arylation of 2a. Physical data of com-
pounds 316
Compound
R
Method Yield (%) Mp (°C)
3a
3b
3c
3d
3e
3f
Phenyl
A
A
A
A
A
B
86
90
78
92
90
82
78
85
135–136
147–149
156–158
141–143
139–140
145–146
135–135
189–191
4-CH3-Phenyl
4-Cl-Phenyl
4-OCH3-Phenyl
4-N(CH3)2-Phenyl
COCH3
CHꢀCH2
CHꢀCHCOPh
In summary, a practical and efficient procedure has
been developed for the preparation of 4,5-substituted-
3(2H)-pyridazinones using 2-hydroxymethyl-4,5-dihalo-
3-pyridazinones as reactive intermediates. This one-pot
transformation is based on a base- and/or heat-pro-
moted retro-ene fragmentation. These results demon-
strate the synthetic utility of the 2-hydroxymethyl unit
3g
3h
B
C

E. Sotelo et al. / Tetrahedron Letters 44 (2003) 4459–4462
4461
Scheme 2.
as a convenient protecting group for the lactam func-
tion in pyridazinone chemistry. The procedure is supe-
rior to existing processes and has allowed access to
several pharmacologically useful pyridazinones through
a short, high yielding synthetic sequence.
reflux (oil bath 110°C) 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,
1:2). Physical and spectral data for compounds 2: 2a:
Yield: 70%, mp 111–112°C. IR (KBr): 3400, 3100, 1670
cm−1 1H NMR (dimethyl sulfoxide-d6, 300 MHz): 8.19
.
References
(s, 1H, CH), 6.97 (t, J=7.6 Hz, 1H, OH), 5.34 (d,
J=7.6 Hz, 2H, CH2). 13C NMR (CDCl3, 300 MHz):
155.9, 136.8, 136.2, 133.6, 74.9. 2b: Yield: 65%, mp
1. Coelho, A.; Sotelo, E.; Ravin˜a, E. Stille-based
approaches in the synthesis of 6-phenyl-5-substituted-
3(2H)-pyridazinones. Chem. Pharm. Bull. 2003, 51, 417–
430.
138–140°C. IR (KBr): 3100–3000, 1668 cm−1 1H NMR
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(dimethyl sulfoxide-d6, 300 MHz): 8.13 (s, 1H, CH),
6.93 (t, J=7.3 Hz, 1H, OH), 5.33 (d, J=7.3 Hz, 2H,
CH2). 13C NMR (CDCl3, 300 MHz): 156.24, 137.8,
131.5, 130.6, 75.1.
2. (a) Frank, H., Heinisch, G. In Pharmacologically Active
Pyridazines; Ellis, G. P., West, G. B., Eds. Progress in
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5. (a) Este´vez, I.; Coelho, A.; Ravin˜a, E. Synthesis 1999,
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13. Representative procedure for bis-Suzuki arylations on
compounds 2. A mixture of 2 (1.6 mmol), arylboronic
acid (4 mmol), Pd(PPh3)4 (0.032 mmol) and Na2CO3
(0.67 g, 6.4 mmol) in 3:1 DME/H2O (18 mL) was
flushed with argon for 5 min. The mixture was stirred
and heated under reflux (oil bath 120°C) under argon
until the starting material had been consumed. The
reaction mixture was cooled, the solution was concen-
trated to dryness under reduced pressure and the
residue was purified by column chromatography on sil-
ica gel. Selected physical and spectral data for represen-
tative compounds 3. 4,5-Diphenyl-3(2H)-pyridazinone
(3a): Yield: 86%, mp 135–136°C. IR (KBr): 3100–3000,
1642 cm−1 1H NMR (dimethyl sulfoxide-d6, 300 MHz):
.
13.04 (bs, 1H), 7.74 (s, 1H), 7.04 (m, 6H), 6.95 (m,
4H). 4,5-Bis(4-tolyl)-3(2H)-pyridazinone (3b): Yield:
6. Sotelo, E.; Coelho, A.; Ravin˜a, E. Tetrahedron Lett.
2001, 42, 8633–8636.
90%, mp 147–149°C. IR (KBr): 3100–2923, 1639 cm−1
.
7. (a) Sotelo, E.; Fraiz, N.; Yan˜ez, M.; Laguna, R.; Cano,
E.; Brea, J. E.; Ravin˜a, E. Bioorg. Med. Chem. Lett.
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L. F.; Esmans, E.; Rozenski, J.; Dommisse, R. A.;
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9. Cho, S.; Chung, J.; Choi, W.; Kim, S.; Yoon, Y. J.
Heterocyclic Chem. 1994, 31, 1199–1208.
1H NMR (dimethyl sulfoxide-d6, 300 MHz): 13.16 (bs,
1H), 7.90 (s, 1H), 7.24–7.00 (m, 8H), 2.24 (s, 6H). 4,5-
Bis-(4-chlorophenyl)-3(2H)-pyridazinone (3c): Yield:
78%, mp 156–158°C. IR (KBr): 3500–2924, 1642 cm−1
.
1H NMR (dimethyl sulfoxide-d6, 300 MHz): 13.20 (bs,
1H), 7.96 (s, 1H), 7.64–7.31 (m, 4H), 7.28–6.99 (m,
4H).
14. Selected physical and spectral data for representative
compounds 3. 4,5-Diacetyl-3(2H)-pyridazinone (3f).
Yield: 82%, mp 189–191°C. IR (KBr): 3100–2958, 1690,
10. Representative procedure for the preparation of com-
pounds 2. A mixture of 1 (4.3 mmol) and 35% formal-
dehyde (34 mL, 43 mmol) was flushed with argon for 5
min. The suspension was stirred and heated under
1678 cm−1 1H NMR (dimethyl sulfoxide-d6, 300 MHz):
.
12.25 (s, 1H), 8.12 (s, 1H), 2.45 (s, 3H), 2.42 (s, 3H).
4,5-Bis-[E-(3-oxo-3-phenylpropenyl)]-3(2H)-pyridazinone

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E. Sotelo et al. / Tetrahedron Letters 44 (2003) 4459–4462
16. Complete details of the synthesis, spectral characteristics
(3h): Yield: 85%, mp 145–146°C. IR (KBr): 3150–3000,
1695, 1668 cm−1 1H NMR (dimethyl sulfoxide-d6, 300
MHz): 12.89 (s, 1H), 8.09 (s, 1H), 7.89–7.34 (m, 12H),
7.10 (d, J=16.3 Hz, 1H), 7.04 (d, J=15.2 Hz, 1H).
and biological evaluation of the compounds obtained will
be published elsewhere in a full paper. All compounds
gave satisfactory microanalytical data (C, H, N 0.4%)
and spectral data (1H, 13C, FTIR, MS). Yields given
correspond to isolated pure compounds.
.
15. Coelho, A.; Sotelo, E.; Ravin˜a, E. Tetrahedron 2003, 14,
2477–2488.