Pyridazines XVII: An efficient Palladium-catalyzed cross-coupling reaction for the synthesis of 5-substituted 6-phenyl-2(2H)-pyridazin-3-ones

Article abstract of DOI:10.1055/s-1999-3567

(2H)-Pyridazin-3-ones substituted at 5-position were prepared via Palladium-catalyzed cross-coupling reactions starting from bromopyridazinones and several vinyl and alkynyl coupling reagents according to Stille, Heck and Sonogashira conditions. MOM was e

Full text of DOI:10.1055/s-1999-3567

1666
PAPER
Pyridazines XVII: An Efficient Palladium-Catalyzed Cross-Coupling
Reaction for the Synthesis of 5-Substituted 6-Phenyl-(2H)-pyridazin-3-ones1
Isabel Estevez, Alberto Coelho, Enrique Raviña*
Departamento de Química Orgánica. Laboratorio de Química Farmacéutica, Facultad de Farmacia, 15706. Universidad de Santiago de
Compostela, Spain
Fax +34(981)594912; E-mail qofara@usc.es
Received 14 January 1999; revised 5 May 1999
pyridazines from pyridazine triflates using Pd(0) cross-
Abstract: (2H)-Pyridazin-3-ones substituted at 5-position were
coupling reactions. However, to our knowledge, there is
no report in the literature for palladium cross-coupling re-
actions in the pyridazinone system.
prepared via Palladium-catalyzed cross-coupling reactions starting
from bromopyridazinones and several vinyl and alkynyl coupling
reagents according to Stille, Heck and Sonogashira conditions.
MOM was employed as efficacious protecting group.
We present here a highly efficient synthesis of 5-alkynyl
and 5-alkenylpyridazinones by using palladium coupling
reactions between MOM-protected 5-bromo-6-phenyl-
(2H)-pyridazin-3-ones and several alkynes and vinyltri-
alkylstannanes. Disappointingly all attempts at perform-
ing the cross-coupling reaction with N-unprotected
pyridazinones were completely unsuccessful. However,
use of protecting groups such as the MOM with a slightly
electron-withdrawing properties resulted in successful
couplings in high yields. 5-Bromo-6-phenyl-(2H)-py-
ridazin-3-one (1) was protected as the MOM derivative in
80% yield by the standard conditions (Scheme 1).
Key words: pyridazinones, Stille coupling reactions, Pd(0)-cataly-
sis, Heck reactions, organostannanes
(2H)-Pyridazin-3-one derivatives have attracted particu-
lar attention during the last decade due to the importance
of their biological activity. Especially, 6-aryl-(2H)-py-
ridazin-3-ones as well as their 4,5-derivatives show vari-
ous pharmacological activities such as reduction of blood
pressure, inhibition of platelet aggregation activities, anti-
thrombotic properties, and others.2 Imazodan and
pimobendam3 are PDE III inhibitors, developed as prom-
ising cardiotonic agents. Other pyridazinones such as
zardaverine4 show combined PDE-3/PDE-4 activity and
have been investigated for the treatment of asthma. Re-
cently, Coates and McKillop reported the synthesis of 6-
(o-hydroxyphenyl)-(2H)-pyridazin-3-ones as key inter-
mediates in the preparation of the prizidilol, which com-
bines b-blocking and vasodilatory properties.4
O
O
ClCH2OMe, DMAP
CH2Cl2, 0 °C, 1 h
NH
N
NCH2OMe
N
Br
Br
85%
Ph
Ph
1
2
Since a few years ago, we have been involved in the de-
velopment of efficient strategies to functionalize the py-
ridazinone system.1 We have focused our attention on
searching for platelet aggregation inhibitors. Particularly
our studies on 5-amino5 and 5-oxygenated6 pyridazinones
have led to the development of new platelet antiaggrega-
tion agents with non cAMP-PDE-3 based mechanism of
action.7 These results motivated us to study other 5-substi-
tuted pyridazinones that may possess this activity.8
Scheme 1
Cross-coupling reactions using alkenyl donors under the
Heck9 (Scheme 2) and Stille14 (Scheme3) conditions were
optimized for our system (Table 1). It was found that the
reaction of the bromo derivative 2 with bis(triphenylphos-
phine)palladium (II) chloride and tributylvinyltin (2.5
equiv) at 95°C for 3 hours, using anhydrous toluene as a
solvent were the best conditions in our hands.
Sonogashira15 has reported that Pd cross-coupling reac-
tions involving acetylenes are improved by using cuprous
iodide as a cocatalyst. Accordingly, bromopyridazinone
was coupled to alkynyl derivatives in 70–80% yield using
bis(triphenylphosphine)palladium(II) chloride and cu-
prous iodide in refluxing CH2Cl2 or acetonitrile (Scheme
4, Table 1).
Palladium-catalyzed coupling reactions have been report-
ed to be effective and versatile for, among others, alkeny-
lation or alkynylation of aryl/vinyl halides.9 Starting from
5-bromo-6-phenyl-(2H)-pyridazin-3-one we have investi-
gated this approach for the preparation of vinyl and alky-
nyl derivatives at the C-5 position as a practical, highly
efficient route to new pyridazinones. Only a few reports
have been published on palladium-catalyzed reactions of
pyridazines. Starting from halogenated (iodo and bromo)
precursors Yamanaka10 and Oshawa11 have reported on
the preparation of alkynyl derivatives of pyridazines via
palladium-catalyzed cross-coupling reactions. Recently,
Wermuth12 described an efficient synthesis of 3-alkynyl
The protecting group was cleaved13 in refluxing 6 N HCl
to afford compounds 10–13.
In summary, the palladium-catalyzed cross-coupling re-
action represents an efficient, previously unexplored route
Synthesis 1999, No. 9, 1666–1670 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Pyridazines XVII: An Efficient Palladium-Catalyzed Cross-Coupling Reaction
1667
Table 1 Palladium Cross-Coupling Reactions
Product
R
Coupling Reagent (R1)
Catalyst
Methoda
Time
mp (°C)
Yield (%)
3
4
5
MOM
MOM
MOM
styrene
Pd(Oac)2
(Ph3P)2PdCl2
(Ph3P)2PdCl2
A
B
B
48
3
3
red oil
yellow oil
116
40
90
80
tributylvinyltin
2-(tributylstannyl)-
thiophene
6
7
8
9
MOM
MOM
MOM
MOM
H
prop-2-yn-1-ol
propiolic acid
trimethylsilylacetylene
hex-5-yn-1-ol
styrene
(Ph3P)2PdCl2/CuI
(Ph3P)2PdCl2/CuI
(Ph3P)2PdCl2/CuI
(Ph3P)2PdCl2/CuI
Pd(OAc)2
C
C
C
C
A
B
C
4
4
5
112
212
yellow oil
orange oil
–
–
85
70
75
85
0
1
–
–
–
H
H
tributylvinyltin
prop-2-yn-1-ol
(Ph3P)2PdCl2
(Ph3P)2PdCl2/CuI
0
0
a Methods: A (Heck conditions): 4% Pd(OAc)2, Ph3P, Et3N, MeCN in a sealed tube, 2 d at 140ºC. B (Stille conditions): 5% (Ph3P)2PdCl2, 1.1
equiv stannane reagent in anhyd toluene, 3 h at 95 ºC under N2 atmosphere. C (Sonogashira conditions): 1% (Ph3P)2PdCl2, 2 equiv Et3N, 0.7%
CuI inCH2Cl2, 1–5 h at 80ºC.
Method A: Heck conditions
O
O
O
O
6N HCl
NCH2OMe
N
NH
N
Styrene, MeCN
Pd(AcO)2 / PPh3 / Et3N
sealed tube, 2 days
NCH2OMe
N
NCH2OMe
N
55 - 70%
R
R
Ph
Ph
Br
R
40%
4 - 9
Ph
Ph
10 - 13
4
5
6
7
8
9
vinyl
thienyl
Ph
13
10
11
3
2
C
C
C
C
CCH2OH
CCOOH
CTMS
Scheme 2
C(CH2)3CH2OH 12
Scheme 5
Method B: Stille conditions
O
O
Stannane reagent, toluene
5% PdCl2(PPh3)2, 95 °C, 3 h
NCH2OMe
N
NCH2OMe
N
ods should prove useful in the synthesis of further analog
systems. Work is in progress in our laboratory for study-
ing the scope of these new synthetic possibilities.
Br
R
60 - 80%
R
Ph
Ph
4, 5
2
4
5
vinyl
thienyl
Melting points (uncorrected) were determined using a Gallenkamp
capillary apparatus. 1H NMR spectra were recorded in CDCl3 on a
Bruker 300 MHz spectrometer. Chemical shifts (d) are reported in
ppm. EI-MS were recorded on a Varian MAT-711 mass spectrom-
eter. Relative intensity values are listed in parenthesis. IR spectra
were recorded on a Perkin-Elmer 1600FT spectrophotometer. Ele-
mental combustion analyses were performed on a Perkin Elmer
240B apparatus at the Microanalyses Service at the Universidad de
Santiago de Compostela. TLC was performed on 0.25 mm silica gel
F254 (E. Merck) aluminum foil plates. CC (Column chromatogra-
phy) were performed using Kieselgel 60. All reagents and solvents
were purified by standard distillation procedures. Synthesis of 4-
phenyl-2,3-dibromocrotonolactone and 5-bromo-6-phenyl-(2H)-
pyridazin-3-one were reported previously.6 Spectroscopic data for
synthesized compounds are described in Table 2.
Method C: Sonogashira conditions
O
O
Acetylenes, CH2Cl2
1% PdCl2(PPh3)2 / CuI / Et3N
70 °C, 1-5 h,
NCH2OMe
NCH2OMe
N
N
Br
70 - 85%
R
Ph
6 - 9
Ph
R
2
6
7
8
9
CH2OH
COOH
TMS
5-Bromo-2-methoxymethyl-6-phenylpyridazin-3-one (2)
(CH2)3CH2OH
Bromopyridazinone 1 (1.7 g, 6.77 mmol), 4-dimethylaminopyri-
dine (DMAP) (5 mg) and i-Pr2NEt (1.76 mL, 10.1 mmol) were sus-
pended in anhyd CH2Cl2 (12 mL) and stirred at 0ºC (ice bath). Then
methoxymethyl chloride (1.28 mL, 16.9 mmol) was added and the
mixture stirred for 1 h at 0°C and then the reaction was allowed to
warm to r.t. and stirred for 2 h more. The colour of the solution
turned purple. Evaporation of the solvents gave a yellow oil which
was purified by CC using EtOAc/hexane (1:3) as eluent to afford
Scheme 4
for functionalizing the C-5 position of the (2H)-pyridazin-
3-one system. Given the current interest in the biological
activity of compounds with a such structure, these meth-
Synthesis 1999, No. 9, 1666–1670 ISSN 0039-7881 © Thieme Stuttgart · New York

1668
I. Estevez et al.
PAPER
Table 2 Infrared, 1H NMR and Electron Impact Mass Spectra of Synthesized Compounds
Product
IR (KBr or film)
n (cm-1
1H NMR (300 MHz, CDCl3/TMS)
d, J (Hz)
MS (EI)
m/z (%)
)
2
1669 (C=O), 1748 (COCH3)
1672 (C=O), 1250 (COC)
1669 (C=O); 1092 (C=C)
3.42 (s, 3 H, OCH3), 5.45 (s, 2 H, CH2O), 7.21 (s, 1 H, CH=C),
296 (5), 294 (5), 265
(25), 220 (40), 219
(29)
7.40 (m, 3 H, C6H5), 7.63 (m, 2 H, C6H5)
3
4
2.02 (s, 3 H, OCH3), 4.10 (m, 2 H, CH=CH), 5.51 (s, 2 H,
OCH2), 7.24 (s, 1 H, CH pyridazinone), 7.52 (m, 5 H, Ph), 7.8
(m, 2 H, C6H5), 7.91 (m, 3H, C6H5)
318 (20), 304 (20),
287 (25), 273 (22),
142 (100)
3.48 (s, 1 H, OCH3), 5.47 (s, 2 H, OCH2), 5,50 (d, 1 H, J = 11.0,
HC=CH2), 5.83 (d, 1 H, J = 17.7, HC=CH2), 6.41 (dd, 1 H, J =
11.0, 17.7, HC=CH2), 7.04 (s, 1 H, CHC=C), 7.42 (s, 5 H,
C6H5)
242 (18), 212 (76),
199 (75), 141 (100),
115 (64)
5
6
1671 (C=O), 1320 (C=O=C)
3.53 (s, 1 H, CH3O), 5.51 (s, 1 H, CH2O), 6.72 (dd, 1 H, J = 1.2,
3.7, thiophene), 6.90 (dd, 1 H, J = 3.7, 5.1, thiophene), 7.11 (s,
1 H, HC=CO), 7.32 (m, 6 H,C6H5+thiophene)
298 (15), 268 (68),
240 (23), 197 (100),
152 (21)
2200 (C≡C), 1650 (CO), 1590
(C=C)
3.46 (s, 3 H, OCH3), 4.38 (s, 2 H, CH2OH), 5.52 (s, 2 H, CH2O),
7.12 (s, 1 H, HC=CO), 7.42 (m, 3 H,C6H5), 7.69 (m, 2 H, C6H5)
284 (11), 256 (17),
191 (15), 149 (48),
118 (44)
7
8
9
3500 (OH), 1650 (CO), 1320
(C=O=C)
3.52 (s, 3 H, OCH3), 5.51 (s, 2 H, CH2O), 7.07 (s, 1 H, HC=CO,
284 (11), 256 (17),
207 (9), 191 (15)
pyridazinone), 7.52 (m, 3 H, C6H5), 7.65 (m, 2 H, C6H5)b
2200 (C≡C), 1680 (CO), 1320
(C=O=C)
1.12 [s, 9 H, (CH3)3], 3.53 (s, 3 H, -OCH3), 5.46 (s, 2 H, CH2O),
7.05 (s, 1 H, CH=C), 7.42 (m, 3 H, C6H5), 7.69 (m, 2 H, C6H5)
308 (35), 293 (15),
235 (5), 73 (100)
3540 (OH), 2200 (C≡C), 1680
(CO), 1320 (C=O=C)
1.51 (m, 4 H, CH2CH2CH2), 2.4 (t, 2 H, J = 6.6, C≡C-CH2), 3.5
(s, 3 H, OCH3), 3.6 (t, 2 H, J = 6.0, CH2OH), 5.46 (s, 2 H,
CH2O), 7.05 (s, 1 H, CH=C), 7.42 (m, 3 H, C6H5), 7.69 (m, 2
H, C6H5)
312 (18), 282 (100),
254 (23), 178 (16),
152 (28)
10
3100 (NH), 1680 (CO)
3150 (NH), 1680 (CO).
5.50 (s, 2 H, CH2OH), 7,12 (s, 1 H, CH=C), 7.45 (s, 5H, C6H5),
277 (12), 244 (27),
225 (33), 208 (32),
181 (100)
11.2 (s, 1 H, NH)a.
11
12
7.29 (s, 1 H, CHCO), 7.50 (s, 5 H, C6H5), 12 (s, 1 H, NH)a,b
236 (8), 203(75)
268.134c
3450 (OH), 2500 (NH),
2250(C≡C), 1625 (C=O)
1.50 (m, 4 H, CH2CH2C=C), 2.42–2.82 (m, 2 H, CH2C≡C),
3.61 (m, 2 H, CH2OH), 7.07 (s, 1 H, HC=C), 7.41 (m, 3 H,
C6H5), 7.65 (m, 2 H, C6H5), 12.12 (br s, 1 H, NH)a
13
2849 (NH), 1672,9 (CO)
6.8 (d, 1 H, J = 5.4 thiophene), 7.0 (dd, 1 H, J = 5.3, 1.7,
thiophene), 7.1 (s, 1 H, HC=C), 7.35 (m, 6 H, C6H5+thiophene),
11.41 (br s, 1 H, NH)a
256 (1), 167 (85),
149 (100)
a NH Protons are exchangeable with D2O.
b Recorded in DMSO-d6.
c HRMS.
colourless needles; yield: 1.71 g (85%); mp 103°C (EtOAc) (Table
2).
removed in vacuo. The residue was purified by CC on silica gel us-
ing EtOAc/ hexane (1:2) as eluent to give 0.22 g (40%) of 3 as a red
oil (Table 2).
2-Methoxymethyl-6-phenyl-5-styrylpyridazin-3-one (3); Meth-
od A: Heck Conditions; Typical Procedure
5-Substituted 2-Methoxymethyl-6-phenylpyridazin-3-ones 4, 5;
Method B: Stille Conditions; General Procedure
To a mixture of 5-bromopyridazinone 2 (500 mg, 1.69 mmol), Ph3P
(45 mg, 0.172 mmol) and Pd(AcO)2 (15.2 mg, 0.067 mmol) in deox-
ygenated MeCN (15 mL) was added styrene (0.218 mg, 3.56 mmol)
and Et3N (0.36mL, 2.54 mmol) via a syringe and heated to 120ºC
with stirring in a thick-walled Pyrex sealed tube with a screw cap
under argon atmosphere for 2 d. The color of the mixture changed
from yellow to black. The mixture was cooled to r.t. and filtered
through a pad of Celite. The filtrate was evaporated and the solvent
A suspension of 5-bromopyridazinone 2 (3.38 mmol) in anhyd tol-
uene (16 mL), Pd(PPh3)2Cl2 (1.18 mg, 0.167 mmol) and tributylvi-
nyltin or 2-(tributylstannyl)thiophene (3.728 mmol) was refluxed
under argon for 2 h. During the course of the reaction the color
changed from yellow to black, with the formation of a precipitate.
The mixture was allowed to cool to r.t., filtered through a pad of
Celite and the filtrate was evaporated (Table 2).
Synthesis 1999, No. 9, 1666–1670 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Pyridazines XVII: An Efficient Palladium-Catalyzed Cross-Coupling Reaction
1669
2-Methoxymethyl-6-phenyl-5-vinylpyridazin-3-one (4)
After treatment of 5-bromopyridazinone 2 (1 g) in anhyd toluene
(16 mL) with (Ph3P)2PdCl2 (1.18 mg) and tributylvinyltin (1.089
mL) as described in Method B, the resulting yellow oily residue was
purified by CC on silica gel eluting with EtOAc/hexane (1:1) to af-
ford 4 as a yellow oil; yield: 0.75 g (90%).
6-Phenyl-5-(3-hydroxypro-1-ynyl)-(2H)-pyridazin-3-one (10)
Pure 10 was obtained by refluxing 6 (150 mg) in 10mL of 6 N HCl
for 12 h. After extraction and evaporation of CH2Cl2 a pale yellow
oil was obtained which was recrystallized from EtOAc to give col-
orless star form needles; yield: 71 mg (55%); mp 200ºC.
Anal. calc. for C13H10N2O2: C, 69.02; H, 4.46; N, 12.38. Found: C,
69.25; H, 4.65; N, 12.20.
2-Methoxymethyl-6-phenyl-5-(2-thienyl)pyridazin-3-one (5)
This was synthesized following Method B by treating 2 (1 g) with
2-(tributylstannyl)thiophene (1.183 mL) as the coupling reagent.
CC with EtOAc/hexane (1:1) of the brown residue afforded a white
oil which was recrystallized from i-PrOH to give colourless nee-
dles; yield: 0.8 g (80%); mp 116°C (i-PrOH).
3-(6-Oxo-3-phenyl-1,6-dihydropyridazin-4-yl)-propinoic acid
(11)
MOM was removed by refluxing 7 (200 mg) in 6 N HCl for 7 h ac-
cording to the above method. The product was extracted with
CH2Cl2, the organic phase dried (Na2SO4) and evaporated. The re-
sidual white solid was recrystallized from EtOAc; yield: 100 mg
(60%); mp 200ºC.
5-Alkynyl-2-methoxymethyl-6-phenylpyridazin-3-ones 6-9;
Method C: Sonogashira Conditions; General Procedure
To a degassed (N2) solution of the corresponding alkyne (1.52
mmol of 2-propyn-1-ol, trimethylsilylacetylene, propiolic acid or 1-
hexyn-5-ol), 5-bromopyridazinone 2 (1.02 mmol) and Et3N (0.282
mL, 2.032 mmol) in CH2Cl2 (16 mL) were added CuI (1.33 mg,
0.007 mmol) and (Ph3P)2PdCl2 (7.156 mg, 0.0101 mmol). The mix-
ture was heated at 70°C under N2 for 4 h. During this time the solu-
tion turned dark brown with the formation of black precipitates. The
mixture was cooled to r.t., diluted with CH2Cl2 (7 mL) and filtered
through Celite. The filtrate was concentrated in vacuo and purified
(Table 2).
5-(6-Hydroxyhexy-1-nyl)-6-phenyl-(2H)-pyridazin-3-one (12)
This was deprotected as described above by treating 9 (200 mg)
with 6 N HCl (15 mL) for 2 h to afford a yellow orange oil; yield:
163 mg (70%).
HRMS: m/z calc. for C16H16N2O2: 268.125, found:268.134.
6-Phenyl-5-thienyl-(2H)-pyridazin-3-one (13)
MOM was removed as previously by treating 5 (200 mg) with 6 N
HCl (15 mL) for 1 d at r.t. Extraction with CH2Cl2 and evaporation
afforded a pale yellow solid residue, which was recrystallized from
EtOAc; yield: 165 mg (70%); mp 234°C.
2-Methoxymethyl- 6-phenyl-5-(3-hydroxy-1-propinyl)py-
ridazin-3-one (6)
Prop-2-yn-1-ol (0.09 mL) was added to 5-bromopyridazinone 2
(300mg) in CH2Cl2 following Method C. CC on silica gel using
EtOAc/hexane (3:1) as eluent affording a pale yellow oil which
Anal. calc. for C14H10N2OS: C, 66.12; H, 3.96; N, 11.61. Found: C,
66.59; H, 3.82; N, 11.55.
crystallized on standing to give white needles; yield: 231 mg (85%); Acknowledgement
mp 112°C.
We gratefully acknowledge the financial aid from Xunta de Galicia
under grant XUGA 20319B97 and Universidad de Santiago de
Compostela for a grant to Isabel Estevez.
3-(1-Methoxymethyl-6-oxo-3-phenyl-1,6-dihydropyridazin-4-
yl)propinoic Acid (7)
This compound was synthesized following Method C by treatment
of 2 (300 mg) with propiolic acid (0.96 mL) as the coupling reagent.
The oily residue was purified by CC using EtOAc/hexane (3:1) as
eluent and then recrystallized from EtOAc to afford colourless crys-
tals as stars. Yield:200 mg (70%), mp 212 °C.
References
(1) Presented at the 6th International Symposium on the Chemistry
and Pharmacology of Pyridazines, Clearwater Beach, Florida,
USA, November 4–7, 1998.
Pyridazines XVI: Estevez, I.; Raviña, E.; Laguna, R.; Cano,
E.; M. Merino, V. Bioorganic & Medicinal Chemistry,
submitted.
2-Methoxymethyl-6-phenyl-5-(trimethylsilylethynyl)pyridazin-
3-one (8)
This compound was synthesized following Method C using 2 (300
mg) and trimethylsilylacetylene (0.2 mL) as the coupling reagent.
The oily yellow residue was purified by CC using EtOAc/hexane
(4:1) as eluent to afford a dark yellow oil; yield: 240 mg (75%).
(2) (a) Curram,V.; Ross, A. J. Med. Chem. 1974, 17, 273.
(b) McEvoy, F.; Allen, G.R. J. Med. Chem. 1974, 17, 281.
(c) Thyes, M.; Lehmann, H.D.; Gries, J.; Koning, H.;
Kretzschmar, R.; Knuze, J.; Lebkucher, R.; Lenke, D. J. Med.
Chem. 1983, 26, 800.
(3) (a) Bristol, J. A.; Sircar, I.; Moos,W. H.; Evans, D. B.;
Weishaar, R. F. J. Med. Chem. 1985, 27, 1099.
(b) Hornerjager, P.; Heiss, A.; Schafer-Karting, M. Naunyn-
Schmiedeberg’s Arch. Pharmacol. 1984, 325, 259.
(c) Schudt, C.; Winder, S.; Muller, B.; Ukena, D. Biochem.
Pharmacol. 1991, 42, 153.
5-(6-Hydroxy-1-hexynyl)-2-methoxymethyl-6-phenyl-3-py-
ridazinone (9)
This compound was synthesized following Method C after treating
2 (300 mg) with hex-1-yn-5-ol (147 mg). The oily residue was pu-
rified by CC using EtOAc/hexane (6:1) as eluent to afford a yellow-
orange oil; yield: 265 mg (85%).
(4) Coates, W. J.; McKillop, A. Synthesis 1993, 334.
(5) Estévez, I.; Sotelo, E; Raviña, E. J. Heterocycl. Chem. 1998,
35, 1421.
(6) (a) Raviña, E.; García Mera, G.; Santana, L.; Orallo, F.;
Calleja, J. M. Eur. J. Med. Chem. 1985, 20, 475.
(b) Raviña, E.; Terán, C.; Santana, L.; García Domínguez, N;
Estévez, I. Heterocycles 1990, 31,1967.
(7) (a) Laguna, R.; Montero, A.; Cano, E.; Raviña, E.; Sotelo, E.;
Estevez, I. Acta Pharmaceutica Hungarica 1996, 66, S43;
Chem. Abstr. 1997, 126, 165993.
5- Substituted 6-Phenyl-(2H)-pyridazin-3-ones 10-13; General
Procedure
Deprotection of MOM derivatives was carried out by refluxing the
corresponding 5-substituted pyridazinones 5–9 in an excess of 6 N
HCl during 6-24 h. The reaction was allowed to cool to r.t. and the
product was extracted with CH2Cl2 (3 × 15 mL), dried (Na2SO4) and
evaporated. The pure products were isolated after CC or recrystalli-
zation.
Synthesis 1999, No. 9, 1666–1670 ISSN 0039-7881 © Thieme Stuttgart · New York

1670
I. Estevez et al.
PAPER
(12) (a) Toussaint, D.; Suffert, J.; Wermuth, C. G. Heterocycles
(b) Laguna, R.; Rodriguez-Liñares, B.; Cano, E.; Estevez, I.;
Raviña, E.; Sotelo, E. Chem. Pharm. Bull. 1997, 45, 1151.
(c) Montero, A.; Laguna, R.; Cano, E.; Estevez, I.; Raviña, E.,
6-Aryl-3(2H)-pyridazinones inhibit calcium entry in
stimulated platelets. Biol. Pharm. Bull., submitted.
1994, 38, 1273.
(b) Rohr, M.; Toussaint, D.; Chayer, S.; Mann, A.; Suffert, J.;
Wermuth, C. G. Heterocycles 1996, 43,1459.
(13) BOM Protection/deprotection in 4,5-disubstituted
pyridazinones were reported previously:
Zára-Kaczián, E.; Mátyus, P. Heterocycles 1993, 36, 519.
(14) Stille, J. K. Angew. Chem. 1986, 98, 504, Angew. Chem., Int.
Ed. Engl. 1986, 25, 508.
(8) Strong dipole in the azine system neighboring an NH group, a
hydrogen bonding region at the end of the molecule, a flat
topography and a lipophilic group at the 5-position (see Ref.
3)
(9) Heck, R. F. Palladium Reagents in Organic Synthesis,
Academic Press: New York, 1985.
(15) Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara N.
Synthesis 1980, 627.
(10) Konno, S.; Sagi, M.; Siga, F.; Yamanaka, H. Heterocycles
1992, 34, 225.
(11) Oshawa, A.; Abe, Y.; Igeta, H. Chem. Pharm. Bull. 1980, 28,
3488.
Article Identifier:
1437-210X,E;1999,0,09,1666,1670,ftx,en;H00499SS.pdf
Synthesis 1999, No. 9, 1666–1670 ISSN 0039-7881 © Thieme Stuttgart · New York