Pyridazines part XXIII: Efficient arylation at position 5 of the 6-phenyl-(2H)-pyridazin-3-one system using a Suzuki cross-coupling reaction

Article abstract of DOI:10.1055/s-2001-13409

A highly efficient procedure for introducing aryl or heteroaryl rings at position 5 of the 6-phenyl-(2H)-pyridazin-3-one system using a Suzuki cross-coupling reaction has been developed in the search for new platelet aggregation inhibitors.

Full text of DOI:10.1055/s-2001-13409

PAPER
871
Pyridazines Part XXIII:1 Efficient Arylation at Position 5 of the 6-Phenyl-
(2H)-pyridazin-3-one System Using a Suzuki Cross-Coupling Reaction
Alberto Coelho, Eddy Sotelo, Isabel Estévez, Enrique Raviña*
Departamento de Química Orgánica, Laboratorio de Química Farmacéutica, Facultad de Farmacia, Universidad de Santiago de Compostela,
15706 Santiago de Compostela, Spain.
Received 29 December 2000; revised 14 February 2001
Dedicated to the Memory of Professor Raymond N. Castle
O
O
Abstract: A highly efficient procedure for introducing aryl or het-
eroaryl rings at position 5 of the 6-phenyl-(2H)-pyridazin-3-one
system using a Suzuki cross-coupling reaction has been developed
in the search for new platelet aggregation inhibitors.
H
H
N
N
N
N
5
X
Y
R
X = CH=CH, O, S
R = H, CHO, COOR,
CN, CH3, Cl
Key words: arylations, palladium, catalysis, pyridazin-3-ones
I
4
The pyridazine system, which has been known for almost
a century and may be considered as a bioisoster of ben-
zene or of other heterocycles, aroused little interest in me-
dicinal chemistry until its discovery in medicinally useful
natural compounds. Today the pyridazine nucleus and its
3-oxo derivatives [(2H)-pyridazin-3-ones] are recognised
as versatile pharmacophores with a variety of biological
activities2 and can be used to support other pharmacoph-
oric groups. Among the pyridazines developed in the past
15 years as drug candidates or pharmacological tools,
6-aryl-(2H)-pyridazin-3-ones and their 4,5-dihydro deriv-
atives have attracted particular attention due to their im-
portant cardiovascular effects.3 For example, many of the
pyridazines and 6-aryl-(2H)-pyridazin-3-ones obtained in
our laboratory during this period are endowed with anti-
hypertensive action4 or are powerful inhibitors of platelet
aggregation.5–8 Particularly, our studies on 5-amino6 and
5-oxygenated7 pyridazinones have led to the development
of new platelet antiaggregation agents with a non c-AMP
PDE III-based mechanism.8,9 These results have motivat-
ed us to prepare other 5-substituted-(2H)-pyridazin-3-
ones, having alkenyl groups at 5-position, which are po-
tent antiplatelet agents.10 In continuance of this work, we
have now designed a series of 5-aryl-6-phenyl-(2H)-py-
ridazin-3-ones 4, that can be considered as vinylogues of
the precursor pyridazinone I. The effects of the aryl ring
at position 5 are expected to induce steric perturbations
and would permit the modulation of the antiplatelet activ-
ity, affording compounds that would possess an enhanced
platelet inhibitory effect (Figure 1).
Figure 1
ones with aryl or heteroaryl substituents at position 5 are
unattractive because the required starting arylmethylphe-
nylketones II or heteroarylketoesters III are not commer-
cially available.
O
O
O
O
Br
Ar
H
H
RO
O
RO
O
N
N
N
N
Ar
Ar
Ar
III
IV
II
4
Figure 2
We have therefore focused on the direct preparation of
compounds 4 from readily obtainable, inexpensive 5-bro-
mo-6-phenyl-(2H)-pyridazin-3-one (1) by palladium-ca-
talysed carbon-carbon bond formation. The Suzuki cross-
coupling-based12 procedure to obtain compounds 4 offers
the potential of a more adaptable and simple method to in-
troduce a wide range of aryl residues at position 5 of ha-
lopyridazinones, which permit a rapid pharmacomodula-
tion of this series.
Cross-coupling reactions catalysed by transition metals
represent a powerful method for the formation of carbon-
carbon bonds13 and have been especially popular due to
their application in the preparation of complex natural
products, heterocycles and in supramolecular chemis-
try.13,14 Curiously, very little appears to have been pub-
lished on palladium-catalysed reactions of pyridazines.15
Although we recently reported the synthesis of several
5-vinyl- and 5-alkynyl-6-phenyl-(2H)-pyridazin-3-ones
by the Stille, Heck or Sonogashira approaches,16 no suc-
cessful arylation of the pyridazinone system using Suzuki
cross-coupling methodology has hitherto been described.
Neutral 3- and 6-halopyridazines have been coupled with
arylboronic acids17 but the difference in acidity between
Most syntheses of 5-substituted-(2H)-pyridazin-3-ones
proceed via traditional methods,11 involving condensation
of hydrazine with appropriate substituted lactones or
1,4-dicarbonyl compounds (Figure 2). Concretely, these
synthetic routes to obtain 6-phenyl-(2H)-pyridazin-3-
Synthesis 2001, No. 6, 04 05 2001. Article Identifier:
1437-210X,E;2001,0,06,0871,0876,ftx,en;T04600SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

872
A. Coelho et al.
PAPER
these substrates and pyridazinones11 leads one to expect
significantly different coupling behaviour.
able 1 Effect of the Base on the Cross-Coupling Reaction be-
ween 1 and Benzeneboronic Acid in Toluene–Ethanol and using Tet-
akis(triphenylphosphine)palladium as Catalyst
As part of a program aimed to develop simple and more
efficient syntheses of pharmacologically useful pyridazi-
nones, we herein report the application of simple and
practical Suzuki cross-coupling reactions to synthesise a
variety of novel 5-aryl or 5-heteroaryl-6-phenyl-(2H)-py-
ridazin-3-ones 4a-f.
ase
Yield (%)a
aHCO3
8
10
–
a2CO3
aOH
In a preliminary experiment we have used 5-bromo-6-
phenyl-(2H)-pyridazin-3-one (1)6 as starting material.
Disappointingly all attempts to perform the cross-cou-
pling reaction between 1 and arylboronic acids under clas-
sical Suzuki conditions [sodium or potassium carbonate
as base, tetrakis(triphenylphosphine)palladium as catalyst
and a mixture of toluene/ethanol as solvent] afforded only
10% of the coupling products. More than 85% of precur-
sor 1 was recovered. Furthermore, experiments with ben-
zeneboronic acid, varying the solvent (DMF, THF or 1,2-
methoxyethane) and/or base (triethylamine, sodium bicar-
bonate, potassium carbonate, sodium or potassium hy-
droxide), and the 6-phenyl-5-iodo-(2H)-pyridazin-3-one
failed to improve the results.
OH
–
Determined by GC
charged due to the formation of a salt, which decreases the
reactivity of the halide. Hence, Pd-insertion into the C-Br
bond becomes more difficult. In order to confirm this hy-
pothesis, we proceeded to subject 5-bromo-2-methyl-6-
phenylpyridazin-3-one and phenylboronic acid to the
above-described coupling conditions. Satisfyingly, they
afforded the desired 5-phenylated product 6 in nearly
quantitative yield (95%), showing that the low reactivity
of this system is due to the acidity of the NH group at po-
sition 2.
O
O
O
O
H
H
CH3
ArB(OH)2
Pd[(PPh)3]4
CH3
N
N
N
N
ArB(OH)2
Pd[(PPh)3]4
N
N
N
N
Br
Ar
Br
Ph
4
1
6
Figure 3
Figure 4
The above failures are not attributable to the approach of
the palladium catalyst to the C-Br bond of the substrate,
being impeded by the bulky phenyl ring at position 6. Our
recent structural studies in this series, employing molecu-
lar modelling techniques10 and X-ray crystallographic
analyses,18 have shown that for the 5-substituted 6-phe-
nyl-(2H)-pyridazin-3-ones the phenyl group at C-6 is es-
sentially orthogonal to the heterocyclic ring and should
therefore not hinder cross-coupling.
In subsequent work, we protected the NH group of 1 with
the methoxymethyl (MOM) group which can be removed
more easily than the methyl group of 6 by treatment of the
2-methoxymethylpyridazinones with hydrochloric ac-
id.10,16 After some optimisation, we found that the reaction
of the MOM-protected substrate 2 with arylboronic acids
able 2 5-Aryl-6-phenyl-(2H)-pyridazin-3-ones 4a–f and Their 2-
ethoxymethyl Precursors 3a–f Prepared from 2
As part of these studies we have evaluated the effect of
several bases on the phenylation of 1 using a 2:1 mixture
of toluene/ethanol as solvent (Table 1). Although none of
these experiments permits to obtain compound 4 in high
yield, we have observed an important effect of the base on
the coupling reaction. Thus, strong bases (sodium or po-
tassium hydroxide) completely suppressed the reaction.
The low reactivity experienced and the negative effect of
strong bases on the coupling reaction are attributable to
the acidity of the NH group or rather to the lactam func-
tion [(2H)-Pyridazin-3-one is about as acidic as phenol
with a PKa of 10.5].
ompound Ar
Yield
(%)
Compound Yielda
(%)
a
Phenyl
98
4a
4b
4c
93
85
90
b
c
4-Cl-phenyl 89
4-CH3-phe- 96
nyl
d
4-CHO-phe- 92
nyl
4d
90
e
f
2-Furyl
94
4e
4f
88
It is well established that an important requirement for the
Suzuki coupling is the halide being electron-deficient.19
Under the basic conditions required for the Suzuki aryla-
tion, the 5-bromopyridazin-3-one 1 becomes negatively
2-Thienyl
18/70b
10/65b
Yields of the one-pot procedure.
Yield using DME as solvent.
Synthesis 2001, No. 6, 871–876 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
873
took place in nearly quantitative yields (Table 2), using phenylpyridazin-3-one (70%). However, a 70% yield of
2:1 toluene-ethanol as solvent, potassium carbonate as 3f was obtained when, following Gronowitz´s recommen-
base and tetrakis(triphenylphosphine)palladium as palla- dations concerning troublesome couplings,20 we carried
dium source (Scheme 1).
out the reaction in 1,2-dimethoxyethane (DME).
The MOM protecting group was easily cleaved from the
5-aryl-2-methoxymethyl-6-phenylpyridazin-3-ones 3a-f
by treatment with refluxing 6 N HCl for 6 h, which afford-
ed the pyridazinones 4a-f in 65–93 % yields.
O
MOM
N
N
Ar
Furthermore, we found that the sequence 2 Æ 3 Æ 4 could
be carried out in a one-pot reaction, monitoring the
progress of the cross-coupling reaction by TLC and add-
ing 6 N HCl when the reaction was complete (Scheme 1).
The broader potential of this new synthetic route is illus-
trated not only by using different arylboronic acids, but
also by the successful preparation of compounds 5a-c,
which were required for our structure-activity relationship
studies (Scheme 2).
ii
O
O
H
MOM
3a–e
N
N
i
N
N
Br
Br
iii
iv
O
H
2
1
N
N
Ar
In conclusion, we have applied the Suzuki cross-coupling
methodology to develop a general, rapid, and practical
one-pot synthesis of 5-aryl-6-phenyl-(2H)-pyridazin-3-
ones 4 starting from the 2-methoxymethyl derivative of
readily available 5-bromo-6-phenyl-(2H)-pyridazin-3-
one 1. Further investigations are now in progress in order
to obtain new 5-aroyl derivatives by carbonylation proce-
dures. A full account of the antiplatelet activity and mech-
anism of action of this series will be published in due
course.
4a–e
Scheme 1 Reagents and conditions: (i) ClMOM-CH2Cl2, DMAP,
(i-Pr)2NEt, 0 ºC, 12 h; (ii) ArB(OH)2, Pd(PPh3)4, K2CO3, EtOH–to-
luene, reflux, 2–6 h; (iii) 6 N HCl, reflux, 6 h; (iv) a) ArB(OH)2,
Pd(PPh3)4, K2CO3, EtOH–toluene, reflux, 2–6 h; b) 6 N HCl, reflux,
8 h
Unexpectedly, the reaction of 2 with 2-thienylboronic
acid under the above conditions gave only a poor yield
(10%) of the required 2-methoxymethyl-6-phenyl-5-(2-
thienyl)pyridazin-3-one (3f) and most of the substrate 2
was simply debrominated to give the 2-methoxymethyl-6-
Melting points were measured on a Gallenkamp apparatus and are
uncorrected. Infrared spectra were recorded on a Perkin-Elmer 1640
FT-IR spectrophotometer. 1H NMR spectra were obtained on Bruk-
er WM250 and AM300 spectrometers using tetramethylsilane as in-
able 3 Spectroscopic Data of Pyridazin-3-ones 3a–f
ompound
Mp (°C)
Oil
IR (KBr) (cm–1)
MS m/z
(%)
1H NMR (CDCl3) , J (Hz)b
a
1562,
1590
292 (M+, 27),
249 (100)
7.34–7.20 (m, 10H, Ph), 6.98 (s, 1H, H-4), 5.56 (s, 2H, N-
CH2), 3.44 (s, 3H, OCH3)
b
c
d
e
f
136.0–136.5a
1656,
1592
326 (M+, 8),
225 (100)
7.40–7.30 (m, 5H, Ph), 7.17 (d, J = 8.3, 2H, Ar), 7.04 (d,
J = 8.03, 2H, Ar), 6.95 (s, 1H, H-4), 5.55 (s, 2H, CH2), 3.55
(s, 3H, CH3)
Oil
1667,
1588
262 (M+, 100)
7.32–7.24 (m, 5H, Ph), 7.14 (d, J = 8.0, 2H, Ar), 6.98 (d,
J = 8.0, 2H, Ar), 6.94 (s, 1H, H-4), 5.54 (s, 2H, CH2), 3.55 (s,
3H, OCH3), 2.15 (s, 3H, C-CH3)
Oil
1710,
1664
320 (M+, 12),
219 (100)
9.98 (s, 1H, CHO), 7.78 (d, J = 8.3, 2H, Ar), 7.30 (d, J = 8.3,
2H, Ar), 7.25–7.14 (m, 5H, Ph), 6.99 (s, 1H, H-4), 5.53 (s,
2H, CH2), 3.55 (s, 3H, CH3)
102.0–102.7a
1661,
1589
282 (M+, 16),
181 (100)
7.51–7.37 (m, 6H, 5H Ph + 1H furan), 7.31 (s, 1H, H-4), 6.28
(dd, J = 3.5 and 1.8, 1H, furan), 5.66 (d, J = 3.5, 1H, furan),
5.49 (s, 2H, CH2), 3.51 (s, 3H, CH3)
Oil
1671,
1592
298 (M+, 15),
197 (100)
7.33 (m, 6H, 5H Ph + 1H thiophene), 7.04 (s, 1H, H-4), 6.86
(dd, J = 3.9 and 4.7, 1H, thiophene), 6.71 (d, J = 2.9, 1H,
thiophene), 5.47 (s, 2H, CH2), 3.49 (s, 3H, CH3)
Recrystallised from acetonitrile.
NMR data were recorded at 300 MHz.
Synthesis 2001, No. 6, 871–876 ISSN 0039-7881 © Thieme Stuttgart · New York

874
A. Coelho et al.
PAPER
able 4 Analytical and Spectroscopic Data of Pyridazin-3-ones 4a–f
ompound Mp (°C)a IR (KBr) (cm–1) MS m/z (%) 1H NMR (CDCl3/TMS) , J (Hz)b
Analysis Calcd/Found (%)
C
H
a
178.5–180.6 1668
248 (M+, 100)
11.58 (br s, 1H, NH), 7.38–7.20 (m, 10H, 77.40/
Ph), 7.01 (s, 1H, H-4) 77.43
4.87/
4.90
1589
b
c
222.0–222.8 1664
282 (M+, 10),
247 (100)
11.65 (br s, 1H, NH), 7.40–7.30 (m, 5H, 67.97/
3.92/
3.95
1587
Ph), 7.16 (d, J = 8.4, 2H, Ar), 7.05 (d,
J = 8.4, 2H, Ar), 6.97 (s, 1H, H-4)
67.98
198.0–200.0 1663
262 (M+, 100)
276 (M+, 100)
238 (M+,100)
11.40 (br s, 1H, NH), 7.41–7.29 (m, 5H, 77.84/
5.38/
5.38
1584
Ph), 7.18 (d, J = 8.0, 2H, Ar), 7.06 (d,
J = 8.0, 2H, Ar), 7.01 (s, 1H, H-4), 2.33
(s, 3H, CH3)
77.88
d
e
f
172.3–173.0 1665
13.07 (br s, 1H, NH), 9.98 (s, 1H, CHO) 73.90/
7.78 (d, J = 8.2, 2H, Ar), 7.29 (d, J = 8.2, 73.92
2H, Ar), 7.25–7.11 (m, 5H, Ph), 6.98 (s,
1H, H-4)
4.38/
4.39
1588
235.0–235.5 1662
12.05 (br s, 1H, NH), 7.48–7.33 (m, 7H, 70.58/
4.23/
4.25
1580
5H Ph +1H furan + H-4), 6.28 (dd,
J = 3.5 and 1.8, 1H, furan), 5.64 (d,
J = 3.5, 1H, furan)
70.62
201.0–202.1 1667
256 (M+, 15), 167
(100)
11.41 (br s, 1H, NH), 7.35 (m, 6H, 5H Ph 66.12/
+ 1H, thiophene), 7.10 (s, 1H, H-4), 7.00 66.13
(dd, J = 1.2 and 3.7, 1H, thiophene), 6.81
(dd, J = 3.7 and 5.1, 1H, thiophene)
3.96/
3.94
1588
Recrystallised from acetonitrile.
NMR data were recorded at 300 MHz.
ternal standard (chemical shifts are d values, J in Hz). Mass spectra
were determined on a Varian MAT-711 instrument. Elemental anal-
yses were performed on a Perkin-Elmer 240B apparatus at the Mi-
croanalysis Service of the University of Santiago de Compostela.
The progress of the reactions was monitored by thin layer chroma-
tography with 2.5 mm Merck silica gel GF 254 strips, and the puri-
fied compounds each showed a single spot. Unless otherwise stated,
iodine vapor and/or UV light were used for detection. Chromato-
graphic separations were performed on silica gel columns by flash
chromatography (Kieselgel 40, 0.040–0.063 mm).
Coupling Reaction Affording Compounds 3; General
Procedure
5-Bromo-2-methoxymethyl-6-phenylpyridazin-3-one (2) (0.47 g,
1.6 mmol) was mixed with arylboronic acid (2.2 mmol), Pd(PPh3)4
(0.018 g, 0.016 mmol) and K2CO3 (0.49 g, 5.08 mmol) in toluene-
EtOH (2:1, 15 mL) (15 mL of DME for compound 3f), flushed with
argon for 5 min, and the mixture was then stirred and refluxed (oil
bath, 120 °C) under argon until the starting material had disap-
peared (TLC monitoring). After cooling, the solution was concen-
trated to dryness under reduced pressure and the residue was
purified by column chromatography on silica gel.
5-Bromo-2-methoxymethyl-6-phenylpyridazin-3-one (2)
A mixture of bromopyridazinone 1 (1.70 g, 6.77 mmol), 4-N,N-
dimethylaminopyridine (0.10 g) and i-Pr2NEt (1.20 g, 1.62 mL,
10.1 mmol) in anhyd CH2Cl2 (12 mL) was stirred at 0 °C (ice bath)
for 30 min. Methoxymethyl chloride (1.35 g, 1.28 mL, 1.69 mmol)
was added and the mixture was stirred for 1 h at 0 °C and then al-
lowed to warm to r.t. while stirring was continued for 2 h. The re-
action mixture turned purple. Evaporation of the solvent gave a
yellow oil which was purified by column chromatography (eluent:
EtOAc–hexane, 1:3) affording a white solid, which was recrystal-
lised from EtOAc to give compound 2 (1.71 g, 85%) as colourless
needles; mp 103.0 °C.
One-pot Procedure for the Coupling Reaction; General
Procedure
5-Bromo-2-methoxymethyl-6-phenylpyridazin-3-one (2) (0.47 g,
1.6 mmol) was mixed with arylboronic acid (2.2 mmol), Pd(PPh3)4
(0.018 g, 0.016 mmol) and K2CO3 (0.49 g, 5.08 mmol) in toluene-
EtOH (2:1, 15 mL) (15 mL of DME for compound 4f) was flushed
with argon for 5 min, and the mixture was then stirred and refluxed
(oil bath, 120 °C) under argon until the starting material had disap-
peared (TLC monitoring). 6 N HCl (20 mL) was subsequently add-
ed and the reaction mixture was refluxed (oil bath, 120 °C) for 6 h,
allowed to cool to r.t., and concentrated to dryness under reduced
pressure. The residue was then purified by column chromatography
on silica gel.
IR (KBr): = 1669 (CO), 1748 (C-O-C) 1588 (aromatics) cm–1.
1H NMR (300 MHz, CDCl3): = 7.63 (m, 2H, Ar), 7.40 (m, 3H, Ar),
7.21 (s, 1H, H-4), 5.45 (s, 2H, CH2), 3.42 (s, 3H, CH3).
Cleavage of the MOM Group from Compounds 3a–f; General
Procedure
MS m/z (%): 296 (5), 294 (5), 265 (25).
A solution of the 2-methoxymethylpyridazin-3-one 3a–f (5 mmol)
in EtOH (20 mL) was treated with 6 N HCl (10 mL) and the result-
ing mixture was refluxed (oil bath, 120 °C) for 6 h. After cooling the
solvent was removed, the residue was extracted with CH2Cl2 (3 25
Synthesis 2001, No. 6, 871–876 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
875
tered through a pad of silica and the filtrate was concentrated under
reduced pressure, giving a solid that was purified by column chro-
matography on silica gel to afford pure 5c (80%).
O
O
O
H
N
N
H
H
ii
i
N
N
N
N
Mp 215.0–216.1 °C (CH3CN).
IR (KBr): = 1725, 1664, 1580 cm–1.
CH2OH
CN
CHO
1H NMR (250 MHz, CDCl3): = 13.30 (br s, 1H, NH), 7.95 (d,
J = 8.2 Hz, 2H, Ar), 7.33–7.14 (m, 7H, 5H Ph + 2H Ar), 7.02 (s, 1H,
H-4), 3.94 (s, 3H, CH3).
5a
5b
4d
iii
MS (70 eV) m/z (%): 306 (M+, 100), 249 (40), 189 (54).
O
H
Anal. Calcd for C19H16N2O3: C, 71.74; H, 4.06; N, 15.38. Found: C,
71.76; H, 4.06; N, 15.34.
N
N
COOMe
5,6-Diphenyl-2-methylpyridazin-3-one (6)
5-bromo-2-methyl-6-phenylpyridazin-3-one (2) (0.42 g, 1.6 mmol)
was mixed with phenylboronic acid (0.26 g, 2.2 mmol), Pd(PPh3)4
(0.018 g, 0.016 mmol) and K2CO3 (0.49 g, 5.08 mmol) in toluene–
EtOH (2:1, 15 mL). The vessel was flushed with argon for 5 min
and the mixture was then stirred and refluxed (120 °C) under argon
until the starting material had disappeared (TLC monitoring). After
cooling, the solution was evaporated to dryness under reduced pres-
sure and the residue was purified by column chromatography on sil-
ica gel to give pure 6 (95%).
5c
Scheme 2 Reagents and conditions: (i) NaBH4/MeOH; (ii)
NH2OH•HCl/TFA, reflux, 3 h; (iii) NaCN/MeOH/MnO2
mL) and dried (Na2SO4). Then the solution was concentrated to ob-
tain a solid, which was recrystallised from the appropriate solvent.
5-(4-Hydroxymethylphenyl)-6-phenyl-(2H)-pyridazin-3-one
(5a)
Mp 125.3–126.9 °C (CH3CN).
IR (KBr): = 1652, 1590 cm–1.
1H NMR (250 MHz, CDCl3): = 7.35–7.17 (m, 9H, Ph + H-4),
7.11–7.05 (m, 2H, Ph), 3.91 (s, 3H, CH3).
MS (70 eV) m/z (%): 262 (M+, 100), 234 (80), 191 (94), 165 (60).
NaBH4 (0.026 g, 0.69 mmol) was slowly added to a solution of the
aldehyde 4d (0.12 g, 0.46 mmol) in MeOH (25 mL) and the suspen-
sion was then stirred at r.t. for 30 min, carefully treated with water
(25 mL) and extracted with CH2Cl2 (3 25 mL). The combined or-
ganic layers were dried (Na2SO4) followed by solvent evaportion,
leaving a white solid which upon purification by column chroma-
tography (eluent: EtOAc–hexane, 1:2) afforded 5a (78 mg, 65%).
Acknowledgement
Mp 203.8–205.0 °C (CH3CN).
IR (KBr): = 1668, 1584 cm–1.
Financial support for this work by the Xunta de Galicia under Pro-
ject XUGA 8151389 is gratefully acknowledged.
1H NMR (250 MHz, CDCl3): = 13.30 (br s, 1H, NH), 7.31–7.19
(m, 5H, Ph), 7.15–7.08 (m, 4H, Ar), 6.84 (s, 1H, H-4), 5.24 (t,
J = 5.7 Hz, 1H, OH), 4.46 (d, J = 5.7 Hz, 2H, CH2).
References
(1) (a) Part of this work was presented at the 7th International
Symposium on the Chemistry and Pharmacology of
Pyridazines, Santiago de Compostela, Spain, September
2000. (b) For the previous paper in this series, see: Sotelo,
E.; Pita, B.; Raviña, E. Tetrahedron Lett. 2000, 41, 2863.
(2) Frank, H.; Heinisch, G. Pharmacologically Active
Pyridazines. Part 1; In Progress in Medicinal Chemistry,
Vol. 27; Ellis, G. P., West, G. B., Eds.; Elsevier: Amsterdam,
1990, 1.
(3) Frank, H.; Heinisch, G. Pharmacologically Active
Pyridazines. Part 2; In Progress in Medicinal Chemistry,
Vol. 29; Ellis, G. P., Luscombe, D. K., Eds.; Elsevier:
Amsterdam, 1992, 141.
MS (70 eV) m/z (%): 278 (M+, 100), 247 (55).
Anal. Calcd for C17H14N2O2: C, 73.37; H, 5.07; N, 10.07. Found: C,
73.40; H, 5.03; N, 10.09.
5-(4-Cyanophenyl)-6-phenyl-(2H)-pyridazin-3-one (5b)
A mixture of the aldehyde 4d (0.138 g, 0.5 mmol), NH2OHHCl
(0.052 g, 0.75 mmol) and TFA (10 mL) was refluxed (oil bath,
120 °C) for 3 h. After cooling, the solvent was removed at reduced
pressure and the residue was poured into ice giving a solid that was
filtered off and recrystallised from CH3CN to give pure 5b (89%).
Mp 247.0–248.5 °C (CH3CN).
IR (KBr): = 1665, 1582 cm–1.
(4) (a) Raviña, E.; García-Mera, G.; Santana, L.; Orallo, F.;
Calleja, J. M. Eur. J. Med. Chem. 1985, 20, 475. (b) García
Domínguez, N.; Raviña, E.; Santana, L.; Terán, C.; García
Mera, G.; Orallo, F.; Crespo, M.; Fontenla, J. Arch. Pharm.
(Weinheim, Ger.) 1988, 321, 735. (c) Terán, C.; Raviña, E.;
Santana, L.; García Domínguez, N.; García Mera, G.;
Fontenla, J.; Orallo, F.; Calleja, J. M. Arch. Pharm.
(Weinheim, Ger.) 1989, 322, 331.
1H NMR (250 MHz, CDCl3): = 13.40 (br s, 1H, NH), 7.76 (d,
J = 7.4 Hz, 2H, Ar), 7.33 (d, J = 7.4 Hz, 2H, Ar), 7.24 (m, 3H, Ph),
7.12 (m, 2H, Ph), 6.95 (s, 1H, H-4).
MS (70 eV) m/z (%): 273 (M+, 100), 244 (30).
Anal. Calcd for C17H11N3O: C, 71.74; H, 4.06; N, 15.38. Found: C,
71.76; H, 4.06; N, 15.34.
(5) (a) Raviña, E.; Terán, C.; Santana, L.; García Domínguez,
N.; Estévez, I. Heterocycles 1990, 31, 1967. (b) Gil Longo,
J.; Laguna, R.; Verde, I.; Castro, M.; Orallo, F.; Fontenla, J.;
Calleja, J. M.; Raviña, E.; Terán, C. J. Pharm. Sci. 1993, 82,
286.
5-(4-Methoxycarbonylphenyl)-6-phenyl-(2H)-pyridazin-3-one
(5c)
NaCN (0.05 g, 1 mmol) was added to a stirred solution of the alde-
hyde 4d (0.138 g, 0.5 mmol) in EtOH (15 mL) and stirring was con-
tinued for 15 min. Then MnO2 (8.9 g, 10 mmol) was added and
stirring was continued for further 12 h. The suspension was then fil-
(6) Estévez, I.; Raviña, E.; Sotelo, E. J. Heterocycl. Chem. 1998,
35, 1421.
Synthesis 2001, No. 6, 871–876 ISSN 0039-7881 © Thieme Stuttgart · New York

876
A. Coelho et al.
PAPER
(7) Sotelo, E.; Raviña, E.; Estévez, I. J. Heterocycl. Chem. 1999,
36, 985.
(15) (a) Konno, S.; Sagi, M.; Siga, F.; Yamanaka, H.
Heterocycles 1992, 34, 225. (b) Oshawa, A.; Abe, Y.; Igeta,
H. Chem. Pharm. Bull. 1980, 28, 3488. (c) Toussaint, D.;
Suffert, J.; Wermuth, C. G. Heterocycles 1994, 38, 1273.
(d) Rohr, M.; Toussaint, D.; Chayer, S.; Mann, A.; Suffert,
J.; Wermuth, C. G. Heterocycles 1996, 43, 1459.
(16) Estévez, I.; Coelho, A.; Raviña, E. Synthesis 1999, 9, 1666.
(17) Maes, B.; Lemiére, G. L. F.; Dommisse, R.; Augustyns, K.;
Haemers, A. Tetrahedron 2000, 56, 1777.
(18) Novoa, H.; Blaton, N. M.; Peeters, O. M.; DeRanter, C. J.;
Pita, B.; Sotelo, E.; Raviña, E.; Suárez, M. Acta Crystallogr.,
Sect. C 2000, 56, 345.
(19) Suzuky, A. Recent Advances in the Cross-Coupling
Reactions of Organoboron Derivatives with Organic
Electrophiles,; In Perspectives in Organopalladium
Chemistry for the XXI Century; Tsuji, J., Ed.; Elsevier:
Amsterdam, 1999, 145.
(8) Laguna, R.; Rodriguez-Liñares, B.; Cano, E.; Estévez, I.;
Raviña, E.; Sotelo, E. Chem. Pharm. Bull. 1997, 45, 151.
(9) Montero-Lastres, A.; Fraiz, N.; Cano, E.; Laguna, R.;
Estévez, I.; Raviña, E. Biol. Pharm. Bull. 1999, 22, 1376.
(10) Sotelo, E. PhD Thesis; University of Santiago de
Compostela: Spain, 2000.
(11) (a) Brown, D. J. The Pyridazines I; In Chemistry of
Heterocyclic Compounds, Vol. 56; Taylor, E. C., Wipf, P.,
Eds.; Wiley: New York, 2000, 23. (b) Coates, W. J.
Pyridazines and their Benzo Derivatives; In Comprehensive
Heterocyclic Chemistry, Vol. 6; Katritzky, A. R., Rees, C.
W., Eds.; Pergamon Press: New York, 1996, 63.
(12) (a) Miyara, N.; Yanagi, T.; Suzuki, A. Synth. Commun.
1981, 11, 513. (b) Kalinin, V. N. Synthesis 1992, 413.
(13) Tsuji, J. Palladium Reagents and Catalysts; Wiley:
Chichester, 1995.
(20) (a) Gronowitz, S.; Lawitz, K. Chem. Scr. 1983, 22, 265.
(b) Gronowitz, S.; Stevens, M. F. G. J. Chem. Soc., Perkin
Trans. 1 1994, 3311.
(14) (a) Malleron, J. L.; Fiaud, J. C.; Legros, J. Y. Handbook of
Palladium-Catalysed Organic Reactions; Academic Press:
San Diego, 1997. (b) Diederich, F.; Stang, P. J. Metal-
Catalysed Cross-Coupling Reactions; Wiley-VCH:
Weinheim, 1998.
Synthesis 2001, No. 6, 871–876 ISSN 0039-7881 © Thieme Stuttgart · New York