Suzuki reactions on chloropyridazinones: An easy approach towards arylated 3(2H)-pyridazinones

Article abstract of DOI:10.1016/S0040-4020(00)01100-5

The synthesis of 4-aryl-5-methoxy-, 5-aryl-4-methoxy- and 4,5-diaryl-3(2H)-pyridazinones via Suzuki palladium-catalysed cross-coupling reactions with the corresponding chloro-3(2H)-pyridazinones is described.

Full text of DOI:10.1016/S0040-4020(00)01100-5

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1323±1330
Suzuki reactions on chloropyridazinones: an easy approach
towards arylated 3(2H)-pyridazinones
a,b
a
c
a,p
a
Ï
Á
Bert U. W. Maes, Omar R'kyek, Janez Kosmrlj, Guy L. F. Lemiere, Eddy Esmans,
Jef Rozenski,d Roger A. Dommissea and Achiel Haemersb
aDepartment of Chemistry, University of Antwerp (RUCA), Groenenborgerlaan 171, B-2020 Antwerpen, Belgium
bDepartment of Medicinal Chemistry, University of Antwerp (UIA), Universiteitsplein 1, B-2610 Antwerpen, Belgium
c
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Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, SI-1000 Ljubljana, Slovenia
dFaculty of Pharmaceutical Sciences, REGA Institute, Katholieke Universiteit Leuven, Minderbroedersstraat 10,
B-3000 Leuven, Belgium
Received 25 July 2000; revised 1 November 2000; accepted 16 November 2000
AbstractÐThe synthesis of 4-aryl-5-methoxy-, 5-aryl-4-methoxy- and 4,5-diaryl-3(2H)-pyridazinones via Suzuki palladium-catalysed
cross-coupling reactions with the corresponding chloro-3(2H)-pyridazinones is described. q 2001 Elsevier Science Ltd. All rights reserved.
2,4,5-Trisubstituted-3(2H)-pyridazinones are well-known
compounds in agrochemical and pharmaceutical research.
One of the oldest representatives of the former is Chlori-
dazon (5-amino-4-chloro-2-phenyl-3(2H)-pyridazinone).1
This commercial herbicide developed by BASF researchers
is still extensively used for weed control in sugar beet and
red table beet cultivation. Since the marketing of Chlori-
dazon (Pyraminw,1964) a large number of patents and
papers has been published dealing with the synthesis and
pesticidal activity of 2,4,5-trisubstituted-3(2H)-pyridazi-
nones.2±5 Recently Pyramitee, a 2-tert-butyl-5-(4-tert-
butylbenzylthio)-4-chloro-3(2H)-pyridazinone (Pyridaben)-
containing composition, has been commercialized.1,2m This
selective contact miticide/insecticide controls pests in apple,
pear and almond orchards. Besides the agrochemical appli-
cations of 2,4,5-trisubstituted-3(2H)-pyridazinones several
interesting pharmaceutical activities (e.g. analgesic, anti-
in¯ammatory, anticonvulsant, antitumour, antiviral, anti-
bacterial, antifungal) are reported.3±7 An important example
is Emorfazone (4-ethoxy-2-methyl-5-morpholino-3(2H)-
pyridazinone). This analgesic anti-in¯ammatory agent has
been launched as Pentoil, Pentoyl and Nandron.6
trisubstituted-3(2H)-pyridazinones.5,8±11 Therefore we
searched for a new, short, experimentally easy and generally
applicable method for the synthesis of arylated 3(2H)-pyri-
dazinones starting from cheap readily available starting
materials. We found that the Suzuki12±15 cross-coupling
reaction of arylboronic acids and chloro-3(2H)-pyridazi-
nones works smoothly (Tables 1, 2 and 3). The fact that a
CZCl bond undergoes oxidative addition is not self-evident
since it is well known that the oxidative insertion of
palladium into this bond requires a much higher energy
than in the case of a CZOTf, CZBr or CZI bond.13,14
Recently new ligands for the palladium catalyst were devel-
oped which make Suzuki palladium-catalysed cross-coupling
reactions possible with electron neutral and rich chloro-
benzene derivatives.16±21 In this case the use of strongly elec-
tron donating and sterically bulky ligands seem to be
essential. However, it is also known that the introduction of
electron withdrawing substituents onto or the incorporation
of nitrogen atoms into the benzene ring decreases the
required energy for oxidative addition. When this energy is
suf®ciently decreased palladium catalysts containing ligands
which are less electron donating are able to insert into the
CZCl bond.22±30 We found that chloro-3(2H)-pyridazinones
undergo oxidative addition with commonly used tetrakis
triphenylphosphine palladium, and we present here our
results on palladium-catalysed arylations of chloro-3(2H)-
pyridazinones with this complex as the catalyst.11,31
Since the 2,4,5-trisubstituted-3(2H)-pyridazinone skeleton
is so attractive from an agrochemical and pharmaceutical
point of view we started a research project dealing with the
synthesis of hitherto less-studied classes. To the best of
our knowledge only a few articles and patents deal
with the synthesis of 4-aryl-, 5-aryl- and 4,5-diaryl-2,4,5-
The reason that so much interest is shown by researchers
from academic and industrial laboratories with regard to
the use of chlorinated compounds in Suzuki palladium-
catalysed cross-coupling reactions is obvious: the chlori-
nated compounds are readily available and less expensive
Keywords: palladium and compounds; Suzuki reactions; pyridazinones.
Corresponding author. Tel.: 132-3-21-80-226; fax: 132-3-21-80-233;
e-mail: lemiere@ruca.ua.ac.be
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01100-5

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B. U. W. Maes et al. / Tetrahedron 57 (2001) 1323±1330
Table 2.
Table 1.
1 or 2 (2.55 mmol), boronic acid (7.65 mmol), Pd(PPh3)4 (3 mol%),
Na2CO3 (2 M, 4 mL).
than the corresponding bromo or iodo analogues.
Especially, the availability of chlorinated 1,2-diazines is
excellent. The preference for the Suzuki reaction above
other palladium-catalysed cross-coupling reactions is not
coincidental. It possesses the advantage that non-toxic,
easily removable boron-containing by-products are gener-
ated. On a laboratory scale the cost and environmental
factor may seem less relevant but in large-scale industrial
syntheses they are critical.
9 or 10 (1.28 mmol), boronic acid (1.92 mmol), Pd(PPh3)4 (3 mol%),
Na2CO3 (2 M, 1.4 mL).
4-(2-methylphenyl)-3(2H)-pyridazinone (27), produced an
incomplete reaction even after two days of re¯ux. Attempts
to use solid bases (K3PO4 in dioxane, KOtBu in toluene or
DME, KOH or Cs2CO3 in toluene) instead of aqueous
solutions in re¯uxing toluene, dioxane or DME were unsuc-
cessful. Since stronger bases are known to accelerate the
Suzuki cross-coupling reaction, Ba(OH)2´(H2O)8 was used
as a base instead of Na2CO3.32 These conditions gave
complete consumption of 19 but with only a 21% yield.
We found that the low yield of 28 is due to a competitive
decomposition of starting material (19) by the strong
aqueous base. Re¯uxing 28 for 24 h in a two-phase system
of aqueous Ba(OH)2 and toluene gave nearly complete
recovery of 28, while treatment of 19 under the same
conditions gave complete decomposition of 19. Finally,
we observed that increasing the amount of 2,4-
dichlorobenzeneboronic acid from 1.5 to 2.5 equivalents
gives a complete reaction in 15 h.
Suzuki reaction of 2-methyl- and 2-phenyl-4,5-dichloro-
3(2H)-pyridazinone (1, 2) with 3 equivalents of several
arylboronic acids gave 2-methyl- and 2-phenyl-4,5-diaryl-
3(2H)-pyridazinones in very good yields (Table 1).
Attempts to perform selective arylations on 1 and 2 using
only one equivalent of boronic acid failed. DCI-MS spectra
of the reaction mixtures showed the formation of mono- as
well as diaryl-3(2H)-pyridazinones. When a strong electron
donating group such as a methoxy group is present on the
3(2H)-pyridazinone skeleton (9, 10, 19, 20) excellent results
were obtained (Tables 2 and 3). Even 4-chloro-5-methoxy-
2-methyl-3(2H)-pyridazinone (19), in which the chlorine
atom is surrounded by two groups at the ortho position,
gave Suzuki reaction with ortho-substituted boronic acids.
Only in the case of the synthesis of 4-(2,4-dichlorophenyl)-
5-methoxy-2-methyl-3(2H)-pyridazinone (28) the standard
conditions (1,5 equivalents of boronic acid per chlorine
atom, 3 mol% of Pd catalyst, 2 M Na2CO3) used for all
syntheses, including the synthesis of 5-methoxy-2-methyl-
Since chloro-3(2H)-pyridazinones are cheap and easily
accessible we believe that we have developed a simple

B. U. W. Maes et al. / Tetrahedron 57 (2001) 1323±1330
1325
Table 3.
ppm and J values in Hz. The numbering used for the assign-
ment of NMR signals is as follows: pyridazinone ring,
simple ®gures; 4-substituents, primed ®gures; 5-substitu-
ents, double primed ®gures; and N-substituents, triple
primed ®gures. LRMS were performed on a Quattro II triple
quadrupole mass spectrometer (Micromass, Manchester,
UK) equipped with a standard electrospray ionization
(ESI) interface. Samples were infused in a AcOH±2%
MeOH (20:80) mixture at 50 mL/min. The capillary voltage
was set at 3.74 V, the cone voltage at 40 V. Product ions
were generated in the collision cell, using 3.5£1023 mbar Ar
as a collision gas and a collision energy of 25 eV. HRMS
values were recorded on a quadrupole-time of ¯ight
mass spectrometer (QTof2, Micromass, Manchester, UK)
equipped with a standard electrospray ionization (ESI)
interface. Samples were infused in a 2-propanol±water
(1:1) mixture at 3 mL/min. IR spectra were obtained as
potassium bromide pellets with a Bruker vector 22 spectro-
meter. Melting points were determined on a BuÈchi B-545
apparatus and are uncorrected. 4,5-Dichloro-2-methyl-
3(2H)-pyridazinone (1) (Avocado and Lancaster), 4,5-
dichloro-2-phenyl-3(2H)-pyridazinone (2) (Avocado), 4-
chloro-5-methoxy-2-methyl-3(2H)-pyridazinone
(19)
(Avocado) and Pd(PPh3)4 (Acros) were obtained from
commercial sources. The boronic acids were purchased
from Aldrich and Lancaster. Flash column chromatography
was performed on Kieselgel 60 (Merck), 0.040±0.063 mm.
1.1. General procedure for the synthesis of compounds
3±8 via the Suzuki cross-coupling reaction
A mixture of 2-substituted-4,5-dichloro-3(2H)-pyridazi-
none (1 or 2, 2.55 mmol), boronic acid (7.65 mmol),
Pd(PPh3)4 (0.090 g, 0.078 mmol), toluene (15 mL) and
aqueous Na2CO3 (4 mL, 2 M) was ¯ushed with N2 for
5 min under magnetic stirring. The reaction mixture was
stirred and heated under re¯ux (temperature of oil
bathˆ1208C) under a N2 atmosphere until starting material
had disappeared as judged by TLC and/or DCI-MS. After
cooling, the reaction mixture was evaporated to dryness
under reduced pressure. EtOAc (80 mL) was added and
the suspension was placed in an ultrasonic bath for a few
minutes. The mixture was ®ltered, washed thoroughly with
EtOAc (200 mL) and the ®ltrate evaporated to dryness
under reduced pressure. The residue was puri®ed by ¯ash
column chromatography on silica gel.
19 or 20 (1.28 mmol), boronic acid (21±27, 29±30: 1.92 mmol; 28:
3.2 mmol), Pd(PPh3)4 (3 mol%), Na2CO3 (2 M, 1.4 mL).
The following compounds were prepared in this manner.
1.1.1. 2-Methyl-4,5-diphenyl-3(2H)-pyridazinone (3).
Yield: 98%; eluent for ¯ash column chromatography: hep-
tane±EtOAc (7:3); mp 1728C (white solid); nmax: 3061,
2939, 1630, 1590, 1445, 1342, 1302, 1016, 765,
700 cm21; dH: 8.00 (s, 1H, H-6), 7.30±7.23 (m, 6H, H-30,
H-40, H-300, H-400), 7.12±7.18 (m, 4H, H-20, H-200), 3.75 (s,
3H, NCH3); dC: 159.31 (C-3), 140.44 (C-5), 137.74 (C-6),
135.99 (C-4), 134.75 (C-100), 132.98 (C-10), 130.18 (C-20),
128.98 (C-200), 128.36 (C-400), 128.26 (C-300), 127.85 (C-40),
127.54 (C-30), 40.11 (NCH3); LRMS (ESI): 263 (100%),
178; HRMS (ESI) for C17H15N2O [M1H]1: calcd
263.1184, found 263.1203; C17H14N2O: calcd C 77.84, H
5.38, N 10.68, found C 77.59, H 5.40, N 10.79.
and powerful method with broad application for the syn-
thesis of arylated 3(2H)-pyridazinones. Future research
towards the application of this methodology to the synthesis
of hitherto less easily accessible or unknown carbon-
substituted 3(2H)-pyridazinones is in progress.
1. Experimental
1H-NMR and 13C-NMR spectra were recorded on a Varian
Unity 400 or a Bruker 400 spectrometer in DMSO-d6, with
TMS as the internal standard. Chemical shifts are given in

1326
B. U. W. Maes et al. / Tetrahedron 57 (2001) 1323±1330
1.1.2. 4,5-Bis(4-methoxyphenyl)-2-methyl-3(2H)-pyrida-
zinone (4). Yield: 97%; eluent for ¯ash column chromato-
graphy: heptane±EtOAc (6:4); mp 1698C (yellow solid);
(400-OCH3), 54.98 (40-OCH3); LRMS (ESI): 385 (100%);
HRMS (ESI) for C24H21N2O3 [M1H]1: calcd 385.1552,
found 385.1613; C24H20N2O3: calcd C 74.98, H 5.24, N
7.29, found C 75.05, H 5.33, N 7.37.
n
max: 3045, 2939, 2842, 1630, 1608, 1514, 1503, 1297,
1251, 1172, 1024, 840, 820, 561 cm21; dH: 7.95 (s, 1H,
H-6), 7.11 (d, Jˆ8.9 Hz, 2H, H-200), 7.09 (d, Jˆ8.9 Hz,
2H, H-20), 6.86 (d, Jˆ8.9 Hz, 2H, H-300), 6.83 (d,
Jˆ8.9 Hz, 2H, H-30), 3.73 (2£s, 6H, 2£OCH3), 3.72 (s,
3H, NCH3); dC: 159.56 (C-3), 159.18 (C-400), 158.76
(C-40), 139.51 (C-5), 137.97 (C-6), 134.83 (C-4), 131.69
(C-20), 130.41 (C-200), 127.09 (C-100), 125.12 (C-10),
113.88 (C-300), 113.11 (C-30), 55.05 and 54.93 (40-OCH3
and 400-OCH3), 40.02 (NCH3); LRMS (ESI): 323 (100%),
307, 279; HRMS (ESI) for C19H19N2O3 [M1H]1: calcd
323.1395, found 323.1376; C19H18N2O3: calcd C 70.79, H
5.63, N 8.69, found C 70.81, H 5.55, N 8.40.
1.1.6. 4,5-Bis(4-¯uorophenyl)-2-phenyl-3(2H)-pyridazi-
none (8). Yield: 100%; eluent for ¯ash column chromato-
graphy: CH2Cl2±EtOAc (99:1); mp 1798C (white solid);
n
max: 3076, 3042, 1639, 1601, 1504, 1228, 1133, 847,
759, 691, 616, 523 cm21; dH: 8.19 (s, 1H, H-6), 7.63 (br
d, Jˆ7.7 Hz, 2H, H-2000), 7.52 (br t, Jˆ7.7 Hz, 2H, H-3000),
7.43 (br t, Jˆ7.7 Hz, 1H, H-4000), 7.29 (dd, JHHˆ8.6 Hz
JHFˆ5.7 Hz, 2H, H-200), 7.26 (dd, JHHˆ8.6 Hz, JHFˆ
5.7 Hz, 2H, H-20), 7.18 (t, JHFˆ8.6 Hz, 2H, H-300), 7.12 (t,
JHHˆJHFˆ8.6 Hz, 2H, H-30); dC: 162.03 (d, JCFˆ246.9 Hz,
C-400), 161.68 (d, JCFˆ245.7 Hz, C-40), 158.95 (C-3),
141.72 (C-1000), 139.58 (C-5), 138.77 (C-6), 136.64 (C-4),
132.62 (d, JCFˆ8.3 Hz, C-20), 131.44 (d, JCFˆ9.1 Hz, C-200),
130.89 (d, JCFˆ3.1 Hz, C-100), 129.05 (d, JCFˆ3.0 Hz, C-10),
128.56 (C-3000), 127.98 (C-4000), 125.57 (C-2000), 115.49 (d,
JCFˆ22.1 Hz, C-300), 114.72 (d, JCFˆ21.3 Hz, C-30); LRMS
(ESI): 361 (100%); HRMS (ESI) for C22H15F2N2O
[M1H]1: calcd 361.1152, found 361.1167; C22H14F2N2O:
calcd C 73.33, H 3.92, N 7.77, found C 73.29, H 3.99, N
7.63.
1.1.3. 4,5-Bis(4-¯uorophenyl)-2-methyl-3(2H)-pyridazi-
none (5). Yield: 100%; eluent for ¯ash column chromato-
graphy: CH2Cl2±EtOAc (96:4); mp 1888C (white solid);
n
max: 3060, 3044, 1629, 1598, 1505, 1297, 1227, 1171,
849, 831, 550 cm21; dH: 8.00 (s, 1H, H-6), 7.21 (dd, JHH
ˆ
9.0 Hz, JHFˆ5.5 Hz, 2H, H-200), 7.18 (dd, JHHˆ9.0 Hz,
JHFˆ5.5 Hz, 2H, H-20), 7.14 (t, JHHˆJHFˆ9.0 Hz, 2H, H-
300), 7.10 (t, JHHˆJHFˆ9.0 Hz, 2H, H-30), 3.73 (s, 3H,
NCH3); dC: 159.24 (C-3), 139.70 (C-5), 137.66 (C-6),
135.14 (C-4), 132.50 (d, JCFˆ8.4 Hz, C-20), 131.33 (d,
JCFˆ8.4 Hz, C-200), 131.04 (d, JCFˆ3.0 Hz, C-100), 129.10
(d, JCFˆ3.8 Hz, C-10), 115.41 (d, JCFˆ21.3 Hz, C-300), 114.67
(d, JCFˆ21.4 Hz, C-30), 40.12 (NCH3); LRMS (ESI): 299
(100%); HRMS (ESI) for C17H13F2N2O [M1H]1: calcd
299.0995, found 299.1017; C17H12F2N2O: calcd C 68.45, H
4.05, N 9.39, found C 68.30, H 4.18, N 9.28.
1.2. Synthesis of 2-methyl- and 2-phenyl-5-chloro-4-
methoxy-3(2H)-pyridazinone (9, 10)33
1.2.1. 5-Chloro-4-methoxy-2-methyl-3(2H)-pyridazinone
(9). To a magnetically stirred solution of 4,5-dichloro-2-
methyl-3(2H)-pyridazinone (4.47 mmol, 0.8 g) in 20 mL
of dry dioxane was added 1 mL of a 4.86 M NaOCH3 solu-
tion. The solution was stirred at room temperature for 1 h
and then poured into 100 mL H2O/150 mL CH2Cl2. The
organic layer was separated and dried over MgSO4 and
evaporated to dryness. The residue was puri®ed by ¯ash
column chromatography: CH2Cl2±EtOAc (99:1); yield:
70±80% (sublimation-sensitive product); mp 868C (white
solid); nmax: 3076, 3034, 2946, 2843, 1633, 1593, 1300,
1059, 960, 621, 500 cm21; dH: 7.99 (s, 1H, H-6), 4.14 (s,
3H, OCH3), 3.64 (s, 3H, NCH3); dC: 156.47 (C-3), 150.42
(C-4), 136.78 (C-6), 122.32 (C-5), 60.00 (OCH3), 39.51
(NCH3); LRMS (ESI): 175/177, product ions from 175:
162, 134, 119, 117, 115, 106 (100%), 105, 99, 91, 83, 78,
73; HRMS (ESI) for C6H8ClN2O2 [M1H]1: calcd
175.0274, found 175.0287; C6H7ClN2O2: calcd C 41.28, H
4.04, N 16.05, found C 41.05, H 4.24, N 15.99.
1.1.4. 2,4,5-Triphenyl-3(2H)-pyridazinone (6). Yield:
97%; eluent for ¯ash column chromatography: CH2Cl2±
heptane (8:2); mp 1818C (white solid); nmax: 3057, 1640,
1590, 1489, 1300, 1134, 761, 698 cm21; dH: 8.19 (s, 1H,
H-6), 7.64 (br d, Jˆ8 Hz, 2H, H-2000), 7.53 (br t, Jˆ8 Hz, 2H,
H-3000), 7.44 (br t, Jˆ8 Hz, 1H, H-4000), 7.19±7.33 (m, 10H,
4-Ph and 5-Ph); dC: 158.97 (C-3), 141.78 (C-1000), 140.29
(C-5), 138.84 (C-6), 137.46 (C-4), 134.59 (C-100), 132.89
(C-10), 130.27 (C-20), 129.01 (C-200), 128.51 (C-3000 and
C-400), 128.32 (C-300), 127.96 (C-40), 127.90 (C-4000),
127.56 (C-30), 125.58 (C-2000); LRMS (ESI): 325 (100%),
191; HRMS (ESI) for C22H17N2O [M1H]1: calcd 325.1340,
found 325.1383; C22H16N2O: calcd C 81.46, H 4.97, N 8.64,
found C 81.23, H 5.01, N 8.59.
1.1.5. 4,5-Bis(4-methoxyphenyl)-2-phenyl-3(2H)-pyrida-
zinone (7). Yield: 87%; eluent for ¯ash column chromato-
graphy: CH2Cl2±EtOAc (98:2); mp 1748C (white solid);
1.2.2. 5-Chloro-4-methoxy-2-phenyl-3(2H)-pyridazinone
(10). To a magnetically stirred solution of 4,5-dichloro-2-
phenyl-3(2H)-pyridazinone (4.47 mmol, 1.08 g) in 20 mL
of dry dioxane was added 1 mL of a 4.86 M NaOCH3 solu-
tion. The solution was stirred at room temperature for 1 h
and then poured into 100 mL H2O/150 mL CH2Cl2. The
organic layer was separated and dried over MgSO4 and
evaporated to dryness. The residue was puri®ed by ¯ash
column chromatography: CH2Cl2; yield: 72%; mp 1178C
(white solid); nmax: 3066, 2961, 1639, 1608, 1400, 1299,
1147, 949, 757, 685, 569 cm21; dH: 8.16 (s, 1H, H-6),
7.50±7.53 (m, 5H, NPh), 4.17 (s, 3H, OCH3); dC: 156.22
(C-3), 151.37 (C-4), 140.87 (C-1000), 137.74 (C-6), 128.58
(C-3000), 128.26 (C-4000), 125.71 (C-2000), 122.16 (C-5), 60.21
n
max: 3015, 2956, 2927, 2833, 1646, 1602, 1500, 1292,
1248, 1179, 1030, 820, 700, 615, 559, 541 cm21; dH: 8.13
(s, 1H, H-6), 7.61 (br d, Jˆ7.9 Hz, 2H, H-2000), 7.51 (br t,
Jˆ7.7 Hz, 2H, H-3000), 7.42 (br t, Jˆ7.3 Hz, 1H, H-4000), 7.17
(d, Jˆ8.6 Hz, 2H, H-200), 7.15 (d, Jˆ8.6 Hz, 2H, H-20), 6.88
(d, Jˆ8.6 Hz, 2H, H-300), 6.83 (d, Jˆ8.6 Hz, 2H, H-30), 3.73
(s, 3H, 400-OCH3), 3.72 (s, 3H, 40-OCH3); dC: 159.36 (C-400),
159.27 (C-3), 158.90 (C-40), 141.92 (C-1000), 139.40 (C-5),
139.16 (C-6), 136.21 (C-4), 131.84 (C-20), 130.58 (C-200),
128.53 (C-3000), 127.85 (C-4000), 126.92 (C-100), 125.66
(C-2000), 125.07 (C-10), 113.98 (C-300), 113.20 (C-30), 55.12

B. U. W. Maes et al. / Tetrahedron 57 (2001) 1323±1330
1327
(OCH3); LRMS (ESI): 237/239, product ions from 237: 221,
194, 165, 119, 103, 77 (100%); HRMS (ESI) for
C11H10ClN2O2 [M1H]1: calcd 237.0430, found 237.0381;
C11H9ClN2O2: calcd C 55.83, H 3.83, N 11.84, found C
55.92, H 3.85, N 11.79.
7.94 (s, 1H, H-6), 7.62 (dd, JHHˆ9 Hz JHFˆ5.5 Hz, 2H,
H-200), 7.31 (t, JHHˆJHFˆ9 Hz, 2H, H-300), 3.99 (s, 3H,
OCH3), 3.68 (s, 3H, NCH3); dC: 162.20 (d, JCFˆ247.2 Hz,
H-200), 157.39 (C-3), 150.26 (C-4), 137.54 (C-6), 131.12 (d,
JCFˆ8.4 Hz, C-200), 128.15 (d, JCFˆ3.8, C-100), 127.66
(C-5), 115.43 (d, JCFˆ21.4 Hz, C-300), 59.50 (OCH3),
39.45 (NCH3); LRMS (ESI): 235, 220, 219 (100%), 162,
135, 120; HRMS (ESI) for C12H12FN2O2 [M1H]1: calcd
235.0882, found 235.0887; C12H11FN2O2: calcd C 61.53, H
4.73, N 11.96, found C 61.50, H 4.93, N 11.73.
1.3. General procedure for the synthesis of compounds
11±18 and 21±30 via the Suzuki cross-coupling reaction
A mixture of 2-substituted-3(2H)-pyridazinone (9, 10, 19 or
20, 1.28 mmol), boronic acid (1.92 mmol) (for the synthesis
of 28, 3.2 mmol 2,4-dichlorobenzeneboronic acid was
used), Pd(PPh3)4 (0.045 g, 0.039 mmol), toluene (8 mL)
and Na2CO3 (1.4 mL, 2 M) was ¯ushed with N2 for 5 min
under magnetic stirring. The reaction mixture was stirred
and heated under re¯ux (temperature of oil bathˆ1208C)
under a N2 atmosphere until starting material had dis-
appeared as judged by TLC and/or DCI-MS. After cooling,
the reaction mixture was evaporated to dryness under
reduced pressure. EtOAc (40 mL) was added and the
suspension was placed in an ultrasonic bath for a few
minutes. The mixture was ®ltered, washed thoroughly
with EtOAc (100 mL) and the ®ltrate evaporated to dryness
under reduced pressure. The residue was puri®ed by ¯ash
column chromatography on silica gel.
1.3.4. 4-Methoxy-2-methyl-5-(3-tri¯uoromethylphenyl)-
3(2H)-pyridazinone (14). Yield: 100%; eluent for ¯ash
column chromatography: CH2Cl2±EtOAc (97:3); mp 898C
(white solid); nmax: 3075, 3014, 2953, 2858, 1635, 1597,
1450, 1326, 1160, 1116, 809, 702, 512 cm21; dH: 8.00 (s,
1H, H-6), 7.88 (br s, 1H, H-200), 7.86 (br d, Jˆ7.8 Hz, 1H,
H-600), 7.80 (br d, Jˆ7.8 Hz, 1H, H-400), 7.72 (t, Jˆ7.8 Hz,
1H, H-500), 4.02 (s, 3H, OCH3), 3.70 (s, 3H, NCH3); dC:
157.28 (C-3), 150.66 (C-4), 137.32 (C-6), 132.95 (br,
C-600), 132.91 (C-100), 129.59 (C-500), 129.25 (q,
JCFˆ31.8 Hz, C-300), 127.05 (C-5), 125.40 (br, C-200 and
C-400), 123.93 (q, JCFˆ272.6 Hz, CF3), 59.68 (OCH3),
39.71 (NCH3); LRMS (ESI): 285, 270, 269 (100%), 214,
212; HRMS (ESI) for C13H12F3N2O2 [M1H]1: calcd
285.0850, found 285.0893; C13H11F3N2O2: calcd C 54.93,
H 3.90, N 9.86, found C 54.66, H 4.01, N 9.93.
The following compounds were prepared in this manner.
1.3.5. 4-Methoxy-2-methyl-5-(3-thienyl)-3(2H)-pyridazi-
none (15). Yield: 85%; eluent for ¯ash column chromato-
graphy: CH2Cl2±EtOAc (94:6); mp 728C (yellow solid);
1.3.1.
none (11). Yield: 100%; eluent for ¯ash column chromato-
graphy: heptane±EtOAc (7:3); mp 788C (white solid); nmax
4-Methoxy-2-methyl-5-phenyl-3(2H)-pyridazi-
:
n
max: 3094, 2942, 2854, 1629, 1593, 1311, 1245, 1049,
3059, 3023, 2982, 2942, 1653, 1600, 1449, 1314, 1003, 923,
751, 697, 509 cm21; dH: 7.99 (s, 1H, H-6), 7.61 (br d,
Jˆ8 Hz, 2H, H-200), 7.56±7.49 (m, 3H, H-300 and H-400),
4.04 (s, 3H, OCH3), 3.75 (s, 3H, NCH3); dC: 157.40 (C-3),
150.24 (C-4), 137.60 (C-6), 131.75 (C-100), 128.71 (C-200),
128.71 (C-400), 128.61 (C-5), 128.39 (C-300), 59.42 (OCH3),
39.51 (NCH3); LRMS (ESI): 217, 201 (100%), HRMS (ESI)
for C12H13N2O2 [M1H]1: calcd 217.0976, found 217.0981;
C12H12N2O2: calcd C 66.65, H 5.59, N 12.96, found C 66.66,
H 5.63, N 12.88.
980, 858, 803, 606, 503 cm21; dH: 8.23 (s, 1H, H-6), 8.17
(dd, Jˆ3 Hz, Jˆ1.3 Hz, 1H, H-200), 7.70 (dd, Jˆ5.1 Hz,
Jˆ3 Hz, 1H, H-500), 7.64 (dd, Jˆ5.1 Hz Jˆ1.3 Hz, 1H,
H-400), 4.08 (s, 3H, OCH3), 3.76 (s, 3H, NCH3); dC:
157.46 (C-3), 149.15 (C-4), 136.85 (C-6), 131.85 (C-300),
127.51 (C-400), 127.20 (C-200), 126.52 (C-500), 123.16
(C-5), 59.15 (OCH3), 39.33 (NCH3); LRMS (ESI): 223,
208 (100%), 151, 108; HRMS (ESI) for C10H11N2O2S
[M1H]1: calcd 223.0541, found 223.0529; C10H10N2O2S:
calcd C 54.04, H 4.53, N 12.60, found C 54.00, H 4.67, N
12.69.
1.3.2. 4-Methoxy-5-(4-methoxyphenyl)-2-methyl-3(2H)-
pyridazinone (12). Yield: 100%; eluent for ¯ash column
chromatography: CH2Cl2±EtOAc (9:1); mp 1048C (white
solid); nmax: 3053, 3009, 2978, 2939, 2843, 1641, 1606,
1515, 1294, 1250, 1192, 1031, 923, 844, 608 cm21; dH:
7.95 (s, 1H, H-6), 7.56 (d, Jˆ9 Hz, 2H, H-200), 7.05 (d,
Jˆ9 Hz, 2H, H-300), 3.97 (s, 3H, 4-OCH3), 3.81 (s, 3H,
400-OCH3), 3.69 (s, 3H, NCH3); dC: 159.70 (C-400), 157.54
(C-3), 149.81 (C-4), 137.68 (C-6), 130.26 (C-200), 128.48
(C-5), 123.81 (C-100), 113.99 (C-300), 59.31 (4-OCH3),
55.19 (400-OCH3), 39.40 (NCH3); LRMS (ESI): 247, 232
(100%), 231, 217, 132; HRMS (ESI) for C13H15N2O3
[M1H]1: calcd 247.1082, found 247.1113; C13H14N2O3:
calcd C 63.40, H 5.73, N 11.38, found C 63.69, H 5.77, N
11.40.
1.3.6. 4-Methoxy-2,5-diphenyl-3(2H)-pyridazinone (16).
Yield: 100%; eluent for ¯ash column chromatography:
CH2Cl2±EtOAc (98:2); mp 1248C (white solid); nmax
:
2941, 1650, 1590, 1493, 1307, 991, 770, 694 cm21; dH:
8.12 (s, 1H, H-6), 7.63 (br d, Jˆ7 Hz, 2H, H-200), 7.60 (br
d, Jˆ7 Hz, 2H, H-2000), 7.52 (br t, Jˆ7 Hz, 4H, H-300 and
H-3000), 7.47 (br t, Jˆ7 Hz, 1H, H-400), 7.43 (br t, Jˆ7 Hz,
1H, H-4000), 4.01 (s, 3H, OCH3); dC: 157.23 (C-3), 151.25
(C-4), 141.35 (C-1000), 138.81 (C-6), 131.71 (C-100), 128.99
(C-400), 128.88 (C-200), 128.57 (C-300), 128.57 (C-3000),
128.37 (C-5), 128.03 (C-4000), 125.65 (C-2000), 59.77
(OCH3); LRMS (ESI): 279, 263, 236, 201 (100%), 144,
119; HRMS (ESI) for C17H15N2O2 [M1H]1: calcd
279.1133, found 279.1064; C17H14N2O2: calcd C 73.37, H
5.07, N 10.07, found C 73.51, H 5.24, N 9.87.
1.3.3. 5-(4-¯uorophenyl)-4-methoxy-2-methyl-3(2H)-pyri-
dazinone (13). Yield: 100%; eluent for ¯ash column
chromatography: CH2Cl2±EtOAc (94:6); mp 988C (white
solid); nmax: 3067, 3043, 2948, 2851, 1640, 1605, 1514,
1319, 1235, 1161, 999, 926, 826, 739, 602, 494 cm21; dH:
1.3.7. 4-Methoxy-5-(4-methoxyphenyl)-2-phenyl-3(2H)-
pyridazinone (17). Yield: 100%; eluent for ¯ash column
chromatography: CH2Cl2±EtOAc (98:2); mp 1378C (white

1328
B. U. W. Maes et al. / Tetrahedron 57 (2001) 1323±1330
solid); nmax: 3085, 2993, 2962, 2932, 2837, 1644, 1607,
1513, 1305, 1256, 1189, 991, 831, 769, 695, 527 cm21
solid); nmax: 3086, 3031, 3001, 2950, 2917, 2851, 1627,
1592, 1487, 1337, 1266, 1165, 970, 866, 822, 501 cm21
;
;
dH: 8.13 (s, 1H, H-6), 7.63 (d, Jˆ8.8 Hz, 2H, H-200), 7.59
(br d, Jˆ7.5 Hz, 2H, H-2000), 7.51 (br t, Jˆ7.5 Hz, 2H,
H-3000), 7.43 (br t, Jˆ7.5 Hz, 1H, H-4000), 7.07 (d,
Jˆ8.8 Hz, 2H, H-300), 3.99 (s, 3H, 4-OCH3), 3.82 (s, 3H,
400-OCH3); dC: 159.85 (C-400), 157.25 (C-3), 150.62 (C-4),
141.36 (C-1000), 138.79 (C-6), 130.38 (C-200), 128.54 (C-3000),
128.15 (C-5), 127.95 (C-4000), 125.61 (C-2000), 123.65 (C-100),
114.08 (C-300), 59.55 (4-OCH3), 55.23 (400-OCH3); LRMS
(ESI): 309, 294 (100%), 293, 174; HRMS (ESI-MS) for
C18H17N2O3 [M1H]1: calcd 309.1239, found 309.1227;
C18H16N2O3: calcd C 70.12, H 5.23, N 9.09, found C
69.99, H 5.44, N 9.01.
dH: 8.20 (s, 1H, H-6), 7.38 (d, Jˆ8.4 Hz, 2H, H-20), 7.26
(d, Jˆ8.4 Hz, 2H, H-30), 3.90 (s, 3H, OCH3), 3.66 (s, 3H,
NCH3), 2.49 (s, 3H, SCH3); dC: 160.02 (C-3), 154.81 (C-5),
137.94 (C-40), 130.74 (C-20), 128.26 (C-6), 127.01 (C-10),
124.75 (C-30), 118.79 (C-4), 57.35 (OCH3), 39.89 (NCH3),
14.48 (SCH3); LRMS (ESI): 263, 248, 217, 215 (100%),
177; HRMS (ESI) for C13H15N2O2S [M1H]1: calcd
263.0854, found 263.0894; C13H14N2O2S: calcd C 59.52,
H 5.38, N 10.68, found C 59.68, H 5.60, N 10.46.
1.3.12. 4-(4-Fluorophenyl)-5-methoxy-2-methyl-3(2H)-
pyridazinone (24). Yield: 100%; eluent for ¯ash column
chromatography: CH2Cl2±EtOAc (94:6); mp 1508C (white
solid); nmax: 3014, 2987, 2951, 2853, 1629, 1597, 1501,
1334, 1222, 1166, 969, 840, 544 cm21; dH: 8.22 (s, 1H,
H-6), 7.46 (dd, JHHˆ9.0 Hz, JHFˆ5.7 Hz, 2H, H-20), 7.20
(d, JHHˆJHFˆ9.0 Hz, 2H, H-30), 3.91 (s, 3H, OCH3), 3.66 (s,
3H, NCH3); dC: 161.48 (d, JCFˆ245.1 Hz, C-40), 159.99
(C-3), 154.93 (C-5), 132.42 (d, JCFˆ8.1 Hz, C-20), 128.27
(C-6), 126.86 (d, JCFˆ3.6 Hz, C-10), 118.28 (C-4), 114.38
(d, JCFˆ21.4 Hz, C-30), 57.38 (OCH3), 39.87 (NCH3);
LRMS (ESI): 235 (100%), 219, 173, 163, 149, 146, 136;
HRMS (ESI) for C12H12FN2O2 [M1H]1: calcd 235.0882,
found 235.0907; C12H11FN2O2: calcd C 61.53, H 4.73, N
11.96, found C 61.82, H 4.92, N 11.67.
1.3.8. 4-Methoxy-2-phenyl-5-(3-thienyl)-3(2H)-pyridazi-
none (18). Yield: 100%; eluent for ¯ash column chromato-
graphy: CH2Cl2; mp 1168C (white solid); nmax: 3136, 2955,
1633, 1597, 1400, 1254, 1169, 956, 812, 691 cm21; dH: 8.40
(s, 1H, H-6), 8.17 (br d, Jˆ2.9 Hz, 1H, H-200), 7.70 (br d,
Jˆ4.9 Hz, 1H, H-400), 7.53 (dd, Jˆ4.9 Hz, Jˆ2.9 Hz, 1H,
H-500), 7.51 (br s, 2H, H-2000), 7.50 (br t, Jˆ8 Hz, 2H, H-3000),
7.42 (br t, Jˆ8 Hz, 1H, H-4000), 4.08 (s, 3H, OCH3); dC:
159.51 (C-3), 154.15 (C-4), 141.98 (C-1000), 130.14 (C-300),
129.42 (C-6 and C-400), 128.52 (C-3000), 128.11 (C-200),
127.87 (C-4000), 125.97 (C-2000), 123.68 (C-500), 114.96
(C-5), 57.62 (OCH3); LRMS (ESI): 285, 151 (100%), 92;
HRMS (ESI) for C15H13N2O2S [M1H]1: calcd 285.0697,
found 285.0722; C15H12N2O2S: calcd C 63.36, H 4.25, N
9.85, found C 63.25, H 4.02, N 9.90.
1.3.13. 5-Methoxy-2-methyl-4-(3-tri¯uoromethylphenyl)-
3(2H)-pyridazinone (25). Yield: 97%; eluent for ¯ash
column chromatography: CH2Cl2±EtOAc (99:1); mp 1418C
(white solid); nmax: 3125, 3094, 3003, 2958, 2855, 1629,
1589, 1440, 1345, 1261, 1164, 1115, 963, 701, 475 cm21;
dH: 8.26 (s, 1H, H-6), 7.77 (br s, 1H, H-20), 7.73 (br d,
Jˆ7.7 Hz, 1H, H-60), 7.68 (br d, Jˆ7.7 Hz, 1H, H-40), 7.62
(t, Jˆ7.7 Hz, 1H, H-50), 3.93 (s, 3H, OCH3), 3.68 (s, 3H,
NCH3); dC: 159.77 (C-3), 155.27 (C-5), 134.38 (C-60),
131.80 (C-10), 129.38 (C-50), 129.17 (q, JCFˆ31.5 Hz,
C-30), 129.05 (C-6), 127.53 (q, JCFˆ3.8 Hz, C-20), 125.19
(q, JCFˆ3.8 Hz, C-40), 124.93 (q, JCFˆ272.5 Hz, CF3),
117.48 (C-4), 57.52 (OCH3), 39.88 (NCH3); LRMS (ESI):
285, 265 (100%), 245; HRMS (ESI) for C13H12F3N2O2
[M1H]1: calcd 285.0850, found: 285.0887; C13H11F3N2O2:
calcd C 54.93, H 3.90, N 9.86, found C 54.86, H 4.02, N 9.99.
1.3.9.
5-Methoxy-2-methyl-4-phenyl-3(2H)-pyridazi-
none (21). Yield: 100%; eluent for ¯ash column chromato-
graphy: CH2Cl2±EtOAc (95:5); mp 1288C (white solid);
n
max: 3086, 3055, 3007, 2949, 2852, 1630, 1591, 1460,
1339, 1265, 1164, 968, 864, 780, 698, 492 cm21; dH: 8.22
(s, 1H, H-6), 7.30±7.43 (m, 5H, Ph), 3.90 (s, 3H, OCH3),
3.67 (s, 3H, NCH3); dC: 160.02 (C-3), 154.87 (C-5), 130.69
(C-10), 130.16 (C-20), 128.27 (C-6), 127.67 (C-40), 127.39
(C-30), 119.40 (C-4), 57.30 (OCH3), 39.80 (NCH3); LRMS
(ESI): 217, 201 (100%), 131, 128, 118; HRMS (ESI) for
C12H13N2O2 [M1H]1: calcd 217.0976, found 217.0969;
C12H12N2O2: calcd C 66.65, H 5.59, N 12.96, found C
66.66, H 5.65, N 13.08.
1.3.10. 5-Methoxy-4-(4-methoxyphenyl)-2-methyl-3(2H)-
pyridazinone (22). Yield: 100%; eluent for ¯ash column
chromatography: CH2Cl2±EtOAc (97:3); mp 1058C (white-
yellow solid); nmax: 2963, 2840, 1624, 1468, 1264, 1166,
1105, 1029, 828, 803, 569 cm21; dH: 8.19 (s, 1H, H-6), 7.41
(d, Jˆ9.0 Hz, 2H, H-20), 6.94 (d, Jˆ9.0 Hz, 2H, H-30), 3.90
(s, 3H, 5-OCH3), 3.78 (s, 3H, 40-OCH3), 3.67 (s, 3H, NCH3);
dC: 160.17 (C-3), 158.74 (C-40), 154.54 (C-5), 131.56
(C-20), 128.27 (C-6), 122.58 (C-10), 119.14 (C-4), 112.86
(C-30), 57.25 (5-OCH3), 54.99 (40-OCH3), 39.82 (NCH3);
LRMS (ESI): 247, 231, 215, 203, 201 (100%) 161, 148;
HRMS (ESI) for C13H15N2O3 [M1H]1: calcd 247.1082,
found 247.1077; C13H14N2O3: calcd C 63.40, H 5.73, N
11.38, found C 63.64, H 5.48, N 11.47.
1.3.14. 5-Methoxy-4-(3-methoxyphenyl)-2-methyl-3(2H)-
pyridazinone (26). Yield: 100%; eluent for ¯ash column
chromatography: CH2Cl2±EtOAc (95:5); mp 778C (white
solid); nmax: 2956, 1628, 1597, 1461, 1286, 1162, 1040,
963, 782, 698, 476 cm21; dH: 8.20 (s, 1H, H-6), 7.29 (t,
Jˆ8.0 Hz, 1H, H-50), 6.96 (d, Jˆ8.0 Hz, 1H, H-60), 6.95 (br
s, 1H, H-20), 6.90 (br d, Jˆ8.0 Hz, 1H, H-40), 3.89 (s, 3H, 5-
OCH3), 3.73 (s, 3H, 30-OCH3), 3.66 (s, 3H, NCH3); dC: 159.98
(C-3), 158.51 (C-30), 155.01 (C-5), 131.98 (C-10), 128.49 (C-
50), 128.28 (C-6), 122.54 (C-60), 119.33 (C-4), 115.98 (C-20),
113.19 (C-40), 57.33 (5-OCH3), 54.97 (30-OCH3), 39.86
(NCH3); LRMS (ESI): 247, 231, 215, 203, 201 (100%),
161, 148; HRMS (ESI) for C13H15N2O3 [M1H]1: calcd
247.1082, found: 247.1092; C13H14N2O3: calcd C 63.40, H
5.73, N 11.38, found C 63.33, H 5.59, N 11.45.
1.3.11. 5-Methoxy-2-methyl-4-(4-methylthiophenyl)-3(2H)-
pyridazinone (23). Yield: 100%; eluent for ¯ash column
chromatography: CH2Cl2±EtOAc (95:5); mp 1118C (white
1.3.15. 5-Methoxy-2-methyl-4-(2-methylphenyl)-3(2H)-
pyridazinone (27). Yield: 100%; eluent for ¯ash column

B. U. W. Maes et al. / Tetrahedron 57 (2001) 1323±1330
1329
chromatography: CH2Cl2±EtOAc (9:1); mp 1278C (white
Acknowledgements
solid); nmax: 3121, 3064, 3022, 2991, 2949, 2857, 1628,
1591, 1463, 1333, 1262, 1185, 960, 872, 744, 604,
472 cm21; dH: 8.20 (s, 1H, H-6), 7.24 (m, 2H, H-30 and
H-40), 7.18 (m, 1H, H-50), 7.05 (br d, Jˆ7.4 Hz, 1H,
H-60), 3.84 (s, 3H, 5-OCH3), 3.67 (s, 3H, NCH3), 2.04 (s,
3H, 20-CH3); dC: 160.08 (C-3), 155.56 (C-5), 136.74 (C-20),
131.00 (C-10), 130.15 (C-60), 129.61 (C-30), 128.13 (C-6),
127.92 (C-40), 125.26 (C-50), 120.22 (C-4), 57.26 (OCH3),
39.81 (NCH3), 19.22 (20-CH3); LRMS (ESI): 231 (100%),
215, 199, 145, 142, 132; HRMS (ESI) for C13H15N2O2
[M1H]1: calcd 231.1133, found: 231.1159; C13H14N2O2:
calcd C 67.81, H 6.13, N 12.17, found C 67.69, H 6.27, N
11.56.
We thank Ing. J. Aerts, Ing. W. Bollaert, J. Schrooten, Ing.
W. Van Dongen, V. Van Heurck and Ing. J. Verreydt for
technical assistance. Bert U. W. Maes is grateful for a grant
Ï
from the foundation ªRosa Blanckaertº. Dr Janez Kosmrlj
thanks the University of Antwerp (RAFO RUCA) for a post-
doctoral grant.
References
1. BASF Website.
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k) US 4844729, l) US 4874861, m) US 4877787, n) US
4906627, o) US 4910201, p) US 4929617, q) US 4945091,
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Ï
3. Tisler, M.; Stanovnik, B. Adv. Heterocycl. Chem. 1979, 24,
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Ï
4. Tisler, M.; Stanovnik, B. Adv. Heterocycl. Chem. 1990, 49,
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1.3.16. 4-(2,4-Dichlorophenyl)-5-methoxy-2-methyl-3(2H)-
pyridazinone (28). Yield: 90%; eluent for ¯ash column
chromatography: CH2Cl2±EtOAc (98:2); mp 1318C (white
solid); nmax: 3086, 3053, 2955, 1622, 1597, 1462, 1340,
1276, 1169, 964, 875, 488 cm21; dH: 8.26 (s, 1H, H-6),
7.67 (d, Jˆ2.1 Hz, 1H, H-30), 7.46 (dd, Jˆ8.3 Hz,
Jˆ2.1 Hz, 1H, H-50), 7.30 (d, Jˆ8.3 Hz, 1H, H-60), 3.90
(s, 3H, OCH3), 3.67 (s, 3H, NCH3); dC: 159.26 (C-3),
155.95 (C-5), 134.29 (C-20), 133.53 (C-40), 133.38 (C-60),
129.55 (C-10), 128.61 (C-30), 127.92 (C-6), 127.07
(C-50), 116.81 (C-4), 57.46 (OCH3), 39.67 (NCH3); LRMS
(ESI): 285/287/289, product ions from 285: 249
(100%), 235, 207, 186; HRMS (ESI) for C12H11Cl2N2O2
[M1H]1: calcd 285.0197, found 285.0199; C12H10Cl2N2O2:
calcd C 50.55, H 3.54, N 9.82, found C 50.48, H 3.60,
N 9.77.
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7. Frank, H.; Heinisch, G. In Progress in Medicinal Chemistry,
Ellis, G. P., Luscombe, D. K., Eds.; Elsevier Science: Amster-
dam, 1992; 29, pp 141±183.
1.3.17. 5-Methoxy-2,4-diphenyl-3(2H)-pyridazinone (29).
Yield: 100%; eluent for ¯ash column chromatography:
CH2Cl2±EtOAc (98:2); mp 1278C (white solid); nmax
:
8. Sadek, K. U.; Selim, M. A.; Abdel-Motaleb, R. M. Bull. Chem.
Soc. Jpn. 1990, 63, 652±654.
3057, 2944, 2857, 1641, 1592, 1490, 1262, 955, 765, 694,
567 cm21; dH: 8.13 (s, 1H, H-6), 7.65 (br d, Jˆ7 Hz, 2H,
H-20), 7.61 (br d, Jˆ7 Hz, 2H, H-2000), 7.53 (br t, Jˆ7 Hz,
4H, H-30 and H-3000), 7.48 (br t, Jˆ7 Hz, 1H, H-40), 7.45 (br
t, Jˆ7 Hz, 1H, H-4000), 4.03 (s, 3H, OCH3); dC: 157.22 (C-3),
151.24 (C-5), 141.34 (C-1000), 138.81 (C-6), 131.70 (C-10),
128.98 (C-40), 128.87 (C-20), 128.56 (C-30 and C-3000),
128.36 (C-4), 128.01 (C-4000), 125.63 (C-2000), 59.76
(OCH3); LRMS (ESI): 279, 263 (100%), 236, 144, 119;
HRMS (ESI) for C17H15N2O2 [M1H]1: calcd 279.1133,
found 279.1179; C17H14N2O2: calcd C 73.37, H 5.07, N
10.07, found C 73.38, H 5.15, N 10.10.
9. Elagamey, A. A.; El-Taweel, F. M. A.; Khodeir, M. N. M.
Pharmazie 1992, 47, 418±420.
10. Weismuller, J.; Babczinski, P.; Lurssen, K.; Santel, H. J.;
Schmidt, R. R.; Krauskopf, B. US Patent 5097028, 1992.
11. While our work was in progress a patent appeared dealing with
Suzuki palladium-catalysed cross-coupling reactions on
bromo-3(2H)-pyridazinones: Li, C. S.; Gauthier, J. Y.; Lau,
C. K.; Therien, M. US Patent 6004960, 1999.
12. Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11,
513±519.
13. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457±2483.
14. Martin, A. R.; Yang, Y. Acta Chem. Scand. 1993, 47, 221±
230.
1.3.18. 5-Methoxy-4-(4-methoxyphenyl)-2-phenyl-3(2H)-
pyridazinone (30). Yield: 94%; eluent for ¯ash column
chromatography: heptane±EtOAc (2:1); mp 1468C (white
solid); nmax: 3066, 3024, 2951, 2846, 1634, 1609, 1447,
1297, 1257, 1182, 1036, 843, 760, 692, 557 cm21; dH:
8.39 (s, 1H, H-6), 7.33±7.56 (m, 5H, Ph), 7.44 (d,
Jˆ8.9 Hz, 2H, H-20), 6.96 (d, Jˆ8.9 Hz, 2H, H-30), 3.97
(s, 3H, 5-OCH3), 3.78 (s, 3H, 40-OCH3); dC: 159.97 (C-3),
158.88 (C-40), 154.37 (C-5), 141.93 (C-1000), 131.71 (C-20),
129.78 (C-6), 128.49 (C-3000), 127.77 (C-4000), 125.84 (C-2000),
122.48 (C-10), 120.02 (C-4), 112.94 (C-30), 57.48 (5-OCH3),
55.04 (40-OCH3); LRMS (ESI): 309, 175 (100%); HRMS
(ESI) for C18H17N2O3 [M1H]1: calcd 309.1239, found
309.1203; C18H16N2O3: calcd C 70.12, H 5.23, N 9.09,
found C 69.88, H 5.40, N 8.84.
15. Stanforth, S. P. Tetrahedron 1998, 54, 263±303.
16. Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed. 1998, 37, 3387±
3388.
17. Bei, X.; Crevier, T.; Guram, A. S.; Jandeleit, B.; Powers, T. S.;
Turner, H. W.; Uno, T.; Weinberg, W. H. Tetrahedron Lett.
1999, 40, 3855±3858.
18. Bei, X.; Turner, H. W.; Weinberg, W. H.; Guram, A. S.;
Petersen, J. F. J. Org. Chem. 1999, 64, 6797±6803.
19. Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org.
Chem. 1999, 64, 3804±3805.
20. Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am.
Chem. Soc. 1999, 121, 9550±9561.
21. Zhang, C.; Trudell, M. L. Tetrahedron Lett. 2000, 41, 595±
598.

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Chem. 1988, 53, 2052±2055.
29. Parrot, I.; Rival, Y.; Wermuth, C. G. Synthesis 1999, 1163±
1168.
Á
30. Maes, B. U. W.; Lemiere, G. L. F.; Dommisse, R.; Augustyns,
K.; Haemers, A. Tetrahedron 2000, 56, 1777±1781.
31. While our work was in progress an article appeared dealing
with Stille, Sonogashira and Heck palladium-catalysed cross-
coupling reactions on bromo-3(2H)-pyridazinones: Estevez,
I.; Coelho, A.; RavinÄa, E. Synthesis 1999, 1666±1670.
24. Mitchell, M. B.; Wallbank, P. J. Tetrahedron Lett. 1991, 32,
2273±2276.
25. Ali, N. M.; McKillop, A.; Mitchell, M. B.; Rebelo, R. A.;
Wallbank, P. J. Tetrahedron 1992, 48, 8117±8126.
 Â
26. Turck, A.; Ple, N.; Mojovic, L.; Queguiner, G. Bull. Chem.
32. Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 207±210.
33. Lyga, J. W. J. Heterocycl. Chem. 1988, 25, 1757±1760.
Soc. Fr. 1993, 130, 488±492.
27. Janietz, D.; Bauer, M. Synthesis 1993, 33±34.
 Â
28. Frecourt, F.; Turck, A.; Ple, N.; Paris, A.; Queguiner, G.
Â
J. Heterocycl. Chem. 1995, 32, 1057±1062.