Synthesis of 4-aryl-5-hydroxy- and 5-aryl-4-hydroxypyridazin-3(2H)-ones and their use in the preparation of 4,5-diarylpyridazin-3(2H)-ones and hitherto unknown isochromeno[3,4-d]pyridazinediones

Article abstract of DOI:10.1016/S0040-4020(02)01285-1

Easily accessible 2-substituted 4-aryl-5-methoxy- and 2-substituted 5-aryl-4-methoxypyridazin-3(2H)-ones were transformed into the corresponding aryl-hydroxypyridazin-3(2H)-ones by alkaline hydrolysis. The use of these compounds in the synthesis of 2-substituted 4,5-diarylpyridazin-3(2H)-ones with two differently substituted aryl groups was investigated. Two aryl-hydroxypyridazin-3(2H)-ones, 2-(2-benzyl-5-hydroxy-3-oxo-2,3-dihydropyridazin-4-yl)benzaldehyde and 2-(1-benzyl-5-hydroxy-6-oxo-1,6-dihydropyridazin-4-yl)benzaldehyde, were transformed into 2-benzyl-1H-isochromeno[3,4-d]pyridazine-1,6(2H)-dione and 3-benzyl-3H-isochromeno[3,4-d]pyridazine-4,6-dione, respectively, via oxidation of the formyl group with KMnO₄ followed by lactonization.

Full text of DOI:10.1016/S0040-4020(02)01285-1

Tetrahedron 58 (2002) 9713–9721
Synthesis of 4-aryl-5-hydroxy- and 5-aryl-4-hydroxypyridazin-
3(2H)-ones and their use in the preparation of
4,5-diarylpyridazin-3(2H)-ones and hitherto unknown
isochromeno[3,4-d]pyridazinediones
a
a
a
Bert U. W. Maes,a Katrien Monsieurs, Kristof T. J. Loones, Guy L. F. Lemiere,
,
*
`
a
Roger Dommisse, Peter Matyus, Zsuzsanna Riedl and Gyorgy Hajos
b
c
c
´
´
´
¨
aDepartment of Chemistry, University of Antwerp (RUCA), Groenenborgerlaan 171, B-2020 Antwerpen, Belgium
b
¨
Institute of Organic Chemistry, Semmelweis University, H-1092 Budapest, Hogyes E.u. 7., Hungary
cChemical Research Center, Institute of Chemistry, Hungarian Academy of Sciences, P.O. Box 17, H-1525 Budapest, Hungary
Received 30 July 2002; revised 30 September 2002; accepted 3 October 2002
Abstract—Easily accessible 2-substituted 4-aryl-5-methoxy- and 2-substituted 5-aryl-4-methoxypyridazin-3(2H)-ones were transformed
into the corresponding aryl-hydroxypyridazin-3(2H)-ones by alkaline hydrolysis. The use of these compounds in the synthesis of
2-substituted 4,5-diarylpyridazin-3(2H)-ones with two differently substituted aryl groups was investigated. Two aryl-hydroxypyridazin-
3(2H)-ones, 2-(2-benzyl-5-hydroxy-3-oxo-2,3-dihydropyridazin-4-yl)benzaldehyde and 2-(1-benzyl-5-hydroxy-6-oxo-1,6-dihydropyrida-
zin-4-yl)benzaldehyde, were transformed into 2-benzyl-1H-isochromeno[3,4-d]pyridazine-1,6(2H)-dione and 3-benzyl-3H-iso-
chromeno[3,4-d]pyridazine-4,6-dione, respectively, via oxidation of the formyl group with KMnO4 followed by lactonization. q 2002
Elsevier Science Ltd. All rights reserved.
Recently, our laboratory described a smooth approach
towards the synthesis of 2-substituted 4-aryl-5-methoxy-
and 2-substituted 5-aryl-4-methoxypyridazin-3(2H)-ones
via Suzuki arylation of the corresponding chloropyridazin-
3(2H)-ones.1a–c,2 Since a hydroxyl group allows further
synthetic transformations, we decided to study the alkaline
hydrolysis of the methoxy group of these arylated methoxy
pyridazinones to the corresponding hydroxypyridazinones.3
hydrolysis of 1, the synthesis of other 2-substituted 4-aryl-
5-hydroxypyridazin-3(2H)-ones was tried (Table 1). Due to
the low solubility of several of the 2-substituted 4-aryl-5-
methoxypyridazin-3(2H)-ones (1–8) in the hot aqueous
KOH solution, often larger amounts of this 0.57 M KOH
solution were required. Despite this drawback, the 4-aryl-5-
hydroxypyridazin-3(2H)-ones (9–16) were obtained in
good to excellent yields in reasonable reaction times. An
analogous hydrolysis study on the isomeric 2-substituted
5-aryl-4-methoxypyridazin-3(2H)-ones (17–20) gave
similar results (Table 2).
5-Methoxy-2-methyl-4-(2-methylphenyl)pyridazin-3(2H)-
one (1) was chosen as a test substrate. Attempts to hydrolyze
the 5-methoxy group of 1 with 4 equiv. of KOH in water
under reflux gave only a very slow reaction. More than 6
days were required to consume all the starting material.
Using a larger excess of KOH (20 equiv. instead of 4 equiv.,
0.57 M solution) increased the reaction rate and gave a
complete hydrolysis after 24 h of reflux (Table 1). It seems
that the presence of an aryl ring in the 4 position of the
pyridazin-3(2H)-one is responsible for this slow hydrolysis
rate since 4-chloro-5-methoxypyridazin-3(2H)-one can be
hydrolyzed within 3 h of reflux using only 1.1 equiv. of
KOH.3d Under the same conditions as used for the
These new 2-substituted 4-aryl-5-hydroxy- and 2-substi-
tuted 5-aryl-4-hydroxypyridazin-3(2H)-ones seemed of
particular synthetic interest. They can be transformed into
the corresponding trifluoromethanesulfonyloxypyridazin-
3(2H)-ones by reaction with trifluoromethanesulfonic
anhydride in dichloromethane at 258C using triethylamine
as a base (Tables 3 and 4).1e,4 A subsequent Suzuki arylation
on these triflates yields 2-substituted 4,5-diarylpyridazin-
3(2H)-ones (25–29 and 30–32) with two differently
substituted aryl groups (Tables 3 and 4). Compounds of
this type have recently been patented since they show
interesting cyclo-oxygenase-2 inhibition properties.1e
Theoretically, such 4,5-diarylpyridazin-3(2H)-ones can
also be synthesized by performing a selective Suzuki
reaction on 2-substituted 4,5-dichloro- or 2-substituted
Keywords: palladium; Suzuki reaction; pyridazinones; hydrolysis;
coumarins.
*
Corresponding author. Tel.: þ32-3-218-02-05; fax: þ32-3-218-02-33;
e-mail: bert.maes@ua.ac.be
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01285-1

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B. U. W. Maes et al. / Tetrahedron 58 (2002) 9713–9721
Table 1. Hydrolysis of 2-substituted 4-aryl-5-methoxypyridazin-3(2H)-ones
Starting material
1R
2R
Time (h)
24
Reaction product
Yield (%)
63a
1
CH3
9
2
3
4
CH3
CH3
CH3
8
7
10
11
12
84a
89a
99a
12
5
CH3
CH3
4
13
14
99b
6
7
7.5
99b
24
29
15
16
93c
79d
8
a
Reaction conditions: 1–4 (1 mmol), 35 mL of a 0.57 M KOH solution, 1108C (oil bath).
Reaction conditions: 5, 6 (1 mmol), 85 mL of a 0.57 M KOH solution, 1108C (oil bath).
Reaction conditions: 7 (1 mmol), 206 mL of a 0.57 M KOH solution, 1108C (oil bath).
Reaction conditions: 8 (1 mmol), 175 mL of a 0.57 M KOH solution, 1108C (oil bath).
b
c
d
4,5-dibromopyridazin-3(2H)-ones followed by a second
step shorter than that based on the isomer since N-benzyl-
ation and substitution of the 5-chlorine of 4,5-dichloro-
pyridazin-3(2H)-one can be performed in one step.
Therefore 2-benzyl-4,5-diarylpyridazin-3(2H)-ones can be
obtained in an equal number of synthetic steps as the patent
protocol when 2-benzyl-4-chloro-5-methoxypyridazin-
3(2H)-one is used. Furthermore, the 2-benzyl group of the
2-benzyl-4,5-diarylpyridazin-3(2H)-ones can be removed
with AlCl3 allowing further functionalization at the N-2
position.6
Suzuki reaction. However, such an approach is fairly
unfavorable since we and others found only a poor
regioselectivity (two monoaryl-isomers and diarylated
product; ratios depending on the boronic acid used) when
performing Suzuki arylations on 2-substituted 4,5-dichloro-
and 2-substituted 4,5-dibromopyridazin-3(2H)-ones.1a,e In
the above-mentioned patent a general alternative five-step
methodology based on a selective Suzuki reaction on
2-benzyl-4-bromo-5-trifluoromethanesulfonyloxypyrida-
zin-3(2H)-one is described (Fig. 1).1e However also in this
case selectivity problems occur since a mixture of 2-benzyl-
4-bromo-5-arylpyridazin-3(2H)-one and 2-benzyl-4,5-
diarylpyridazin-3(2H)-one was obtained.5 The new method-
ology (Fig. 2) we present in this paper, based on 2-benzyl-4-
chloro-5-methoxypyridazin-3(2H)-one and its isomer, is a
good alternative for the reported patent procedure since
regioselectivity problems are avoided. The method based on
2-benzyl-4-chloro-5-methoxypyridazin-3(2H)-one is one
Recently, we described the synthesis of two isomeric
pyridazino[4,5-c]isoquinolinones,1c
2-benzylpyrida-
zino[4,5-c]isoquinolin-1(2H)-one and 3-benzylpyrida-
zino[4,5-c]isoquinolin-4(3H)-one, by reaction of 2-(2-
benzyl-5-methoxy-3-oxo-2,3-dihydropyridazin-4-yl)-ben-
zaldehyde (33) or 2-(1-benzyl-5-methoxy-6-oxo-1,6-
dihydropyridazin-4-yl)benzaldehyde (35), respectively,
with ammonia. Alkaline hydrolysis of the methoxy group

B. U. W. Maes et al. / Tetrahedron 58 (2002) 9713–9721
Table 2. Hydrolysis of 2-substituted 5-aryl-4-methoxypyridazin-3(2H)-ones
9715
Starting material
1R
2R
Time (h)
5
Reaction product
Yield (%)
86a
17
CH3
21
18
19
5
6
22
23
24
86b
99c
80d
20
24
a
Reaction conditions: 17 (1 mmol), 70 mL of a 0.57 M KOH solution, 1108C (oil bath).
Reaction conditions: 18 (1 mmol), 170 mL of a 0.57 M KOH solution, 1108C (oil bath).
Reaction conditions: 19 (1 mmol), 155 mL of a 0.57 M KOH solution, 1108C (oil bath).
Reaction conditions: 20 (1 mmol), 140 mL of a 0.57 M KOH solution, 1108C (oil bath).
b
c
d
Table 3. Introduction of a second aryl group into 2-substituted 4-aryl-5-hydroxypyridazin-3(2H)-ones
Starting material
1R
2R
3R
Timea (h)
Reaction product
Yield (%)
72b
9
CH3
CH3
8
25
12
16
16
4
2
3
26
27
28
73c
72c
73c
16
3
29
54c
a
Reaction time for the synthesis of the triflate group: 0.5 h in all cases. Indicated reaction times refer to the Suzuki reaction.
Reaction conditions: aryl-trifluoromethanesulfonyloxypyridazinone, boronic acid (3 equiv.), Pd(PPh3)4 (0.03 equiv.), Na2CO3 (2 M, 1 mL/mmol
pyridazinone), toluene, 1208C (oil bath).
Reaction conditions: aryl-trifluoromethanesulfonyloxypyridazinone, boronic acid (2 equiv.), Pd(PPh3)4 (0.03 equiv.), Na2CO3 (2 M, 1 mL/mmol
pyridazinone), toluene, 1208C (oil bath).
b
c

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B. U. W. Maes et al. / Tetrahedron 58 (2002) 9713–9721
Table 4. Introduction of a second aryl group into 2-substituted 5-aryl-4-hydroxypyridazin-3(2H)-ones
Starting material
1R
2R
3R
Timea (h)
Reaction product
Yield (%)
77b
21
CH3
4
30
23
7
31
32
88b
88b
24
3.5
a
Reaction time for the synthesis of the triflate group: 0.5 h in all cases. Indicated reaction times refer to the Suzuki reaction.
Reaction conditions: aryl-trifluoromethanesulfonyloxypyridazinone, boronic acid (2 equiv.), Pd(PPh3)4 (0.03 equiv.), Na2CO3 (2 M, 1 mL/mmol
pyridazinone), toluene, 1208C (oil bath).
b
Figure 1. Synthesis of 2-benzyl-4,5-diarylpyridazin-3(2H)-ones: patented method. (a) Benzyl bromide, 8N KOH, DMF, 508C; (b) 8N KOH, HMPA, 120–
1258C; (c) trifluoromethanesulfonic anhydride, Et3N, CH2Cl2, 08C; (d) Suzuki arylation.
Figure 2. Synthesis of 2-benzyl-4,5-diarylpyridazin-3(2H)-ones: new method. (a) Benzyl bromide, K2CO3, Bu4NBr, MeOH, reflux; (b) ArxB(OH)2,
Pd(PPh3)4, 2 M Na2CO3, toluene, reflux; (c) KOH, H2O, reflux; (d) trifluoromethanesulfonic anhydride, Et3N, CH2Cl2, 258C; (e) benzyl bromide, K2CO3,
Bu4NBr, CH3CN, reflux; (f) NaOCH3, dioxane, rt.
of 33 with KOH in water as described above gives 2-(2-
benzyl-5-hydroxy-3-oxo-2,3-dihydropyridazin-4-yl)benzal-
dehyde which was not isolated (scheme 1). After cooling
down the reaction mixture, the aldehyde moiety of the
hydroxypyridazin-3(2H)-one was oxidized by addition of
KMnO4. When the oxidation reaction was finished, the
precipitated MnO2 was filtered off. The obtained filtrate was
subsequently acidified with concentrated H2SO4 leading to
hitherto unknown 2-benzyl-1H-isochromeno[3,4-d]pyrida-
zine-1,6(2H)-dione (34) in a one pot procedure (scheme 1).
Surprisingly, attempts to use a similar protocol on the
isomeric 2-(1-benzyl-5-methoxy-6-oxo-1,6-dihydropyrida-
zin-4-yl)benzaldehyde (35) leads to the uncyclized 2-(1-
benzyl-5-hydroxy-6-oxo-1,6-dihydropyridazin-4-yl)ben-
zoic acid (36). Lactonization of 36 with a catalytic amount
of concentrated H2SO4 in DME at 608C leads to the desired

B. U. W. Maes et al. / Tetrahedron 58 (2002) 9713–9721
9717
Scheme 1.
3-benzyl-3H-isochromeno[3,4-d]pyridazine-4,6-dione (37).
The synthesis of the 5,6-dihydro-2H-pyrano[2,3-d]pyrida-
zine-2,5-dione skeleton, a debenzo analogue of 34,
all others. Fragmentation was induced by low energy
collisional activation using a collision energy of 30 eV
(method 1). Alternatively, data dependant acquisition of
product ion spectra was performed using an alternating
collision energy of 20, 25 and 30 eV (method 2). Method 1
was used for compounds 9–15 and 21–23, method 2 for
compounds 16, 24–32, 34 and 37. IR spectra were recorded
on a Bruker Vector 22 spectrometer. The 4-aryl-5-
methoxypyridazin-3(2H)-ones and 5-aryl-4-methoxypyri-
dazin-3(2H)-ones were prepared as described earlier.1a,c
Trifluoromethanesulfonic anhydride (Acros, Aldrich) and
Pd(PPh3)4 (Acros) were purchased from commercial
sources. Dioxane (Acros) was dried over sodium/benzo-
phenone and freshly distilled before use. Flash column
chromatography was performed on Kieselgel 60 (Merck),
0.040–0.063 mm.
has already been described by Stanovnik, Kappe and
3e,7–9
´
Matyus.
and 37 have not been reported before and are the first
However, the azabenzocoumarins of type 34
representatives of a new tricyclic ring system.
In conclusion, alkaline hydrolysis of the methoxy group of
easily accessible 2-substituted 4-aryl-5-methoxy- and
5-aryl-4-methoxypyridazin-3(2H)-ones yields 2-substituted
4-aryl-5-hydroxy- and 5-aryl-4-hydroxypyridazin-3(2H)-
ones. Transformation of the hydroxyl group of these
compounds into a triflate and subsequent Suzuki arylation
reaction on the aryl-trifluoromethanesulfonyloxypyridazin-
3(2H)-ones gives 4,5-diarylpyridazin-3(2H)-ones with two
different aryl groups in good yield without selectivity
problems. Another illustration of the usefulness of the aryl-
hydroxypyridazin-3(2H)-ones is provided by the synthesis
of hitherto unknown azabenzocoumarins.
1.1. General procedure for the synthesis of aryl-
hydroxypyridazin-3(2H)-ones (9–16 and 21–24)
A mixture of the pyridazin-3(2H)-one (1–8, 17–20:
1 mmol), KOH (1–4: 20 mmol; 17: 40 mmol; 5, 6:
48.5 mmol; 20: 80 mmol; 19: 88.5 mmol; 18: 97 mmol; 8:
100 mmol; 7: 119 mmol) and H2O (1–4: 35 mL; 17: 70 mL;
5,6: 85 mL; 20: 140 mL; 19: 155 mL; 18: 170 mL; 8:
175 mL; 7: 206 mL) was stirred and heated under reflux
(temperature of oil bath¼1108C) until the starting material
had disappeared as judged by TLC analysis. After cooling
down, the reaction mixture was acidified with concentrated
HCl (1–4: 4 mL; 17: 8 mL; 5,6: 10 mL; 20: 16 mL; 19:
18 mL; 18: 19.5 mL; 8: 20 mL; 7: 23.5 mL) and placed in
the refrigerator overnight. The precipitated hydroxypyrida-
zin-3(2H)-one was filtered off, rinsed well with water and
dried under vacuum.
1. Experimental
NMR spectra were recorded on a Varian Unity 400
spectrometer with TMS as the internal standard. Chemical
shifts are given in ppm and J values in Hz. The numbering
used for the assignment of NMR-signals is as follows:
pyridazinone ring simple figures, 4-substituents primed
figures, 5-substituents double primed figures and
N-substituents triple primed figures. 1H and 13C NMR
assignments of compounds 9–16, 21–32 are based on
reference spectra; assignments of compounds 34 and 37 are
based on 2D-NMR techniques. For mass-spectrometry
analysis, samples were dissolved in CH3OH containing
0.1% formic acid and diluted to a concentration of
approximately 1025 mol/L. 1 mL injections were directed
to the mass spectrometer at a flow rate of 5 mL/min CH3OH
(0.1% formic acid), using the CapLC HPLC system
(Waters, Millford). Product ion spectra and exact mass
measurements were performed on a quadrupole-time-of-
flight mass spectrometer (Q-Tof-2, Micromass, Manchester,
UK) equipped with a standard electrospray ionisation (ESI)
interface. Cone voltage (35 V) and capillary voltage
(3.3 kV) were optimised on one compound and used for
The following compounds were prepared in this manner.
1.1.1. 5-Hydroxy-2-methyl-4-(2-methylphenyl)pyrida-
zin-3(2H)-one (9):. Yield: 0.14 g, 63%; nmax (KBr): 3068,
2959, 2698, 1629, 1551, 1381, 1303, 1157, 1055, 878, 746,
722, 685, 639, 474 cm21; dH (DMSO-d6): 10.90 (br s, 1H,
OH), 7.78 (s, 01H, H-6), 7.14–7.26 (m, 3H, H-30,40,50), 7.07
(br d, 1H, H-6 ), 3.62 (s, 3H, NCH3); dC (DMSO-d6): 160.48
(C-3), 154.43 (C-5), 136.82 (C-200), 131.41 (C-6), 131.27
(C-10), 130.26 (C-60), 129.42 (C-3 ), 127.56 (C-40), 125.05

9718
B. U. W. Maes et al. / Tetrahedron 58 (2002) 9713–9721
(C-50), 117.78 (C-4), 39.32 (NCH3); MS (ESI): 217, 142,
128, 117, 115, 105, 103; HRMS (ESI) for C12H13N2O2
[MþH]þ: calcd 217.0977, found 217.0970.
(DMSO-d6): 11.33 (br s, 1H, OH), 7.79 (s, 1H, H-6), 7.67 (d,
J¼2.1 Hz, 1H, H-30), 7.45 (dd, J¼0 8.2 Hz, J¼2.1 Hz, 1H,
H-50), 7.30 (d, J¼8.2 Hz, 1H, H-6 ), 3.62 (s, 3H, NCH3);
dC (DMSO-d6): 159.82 (C-6), 155.21 (C-5), 134.59
(C-200), 133.57 (C-600), 133.24 (C-40), 131.43 (C-6), 130.01
(C-1 ), 128.53 (C-3 ), 126.94 (C-50), 114.64 (C-4), 39.25
(NCH3); MS (ESI): 271, 235, 196, 159; HRMS (ESI)
for C11H9N2O2Cl2 [MþH]þ: calcd 271.0041, found
271.0040.
1.1.2. 5-Hydroxy-2-methyl-4-phenylpyridazin-3(2H)-
one (10). Yield: 0.17 g, 84%; nmax (KBr): 3061, 2677,
1616, 1579, 1412, 1373, 1313, 1150, 1058, 894, 761, 696,
573, 469, 422 cm21; dH (DMSO-d6): 11.04 (br s, 1H, OH),
7.79 (s, 1H, H-6), 70.48 (br d, J<7 Hz, 2H, H-20,60), 7.37 (br
t, J<7 Hz, 2H, H-3 ,50), 7.30 (br t, J<7 Hz, 1H, H-40), 3.62
(s, 3H, NCH3); dC (DMSO-d6): 160.58 (C-3), 153.95 (C-5),
131.68 (C-6), 131.20 (C-10), 130.22 (C-20,60), 127.36 (C-40),
127.32 (C-30,50), 116.80 (C-4), 39.49 (NCH3); MS (ESI):
203, 128, 91, 77; HRMS (ESI) for C11H11N2O2 [MþH]þ:
calcd 203.0821, found 203.0821.
1.1.7. 5-Hydroxy-4-(4-methoxyphenyl)-2-phenylpyrida-
zin-3(2H)-one (15). Yield: 0.27 g, 93%; nmax (KBr):
3064, 2837, 2689, 1600, 1577, 1512, 1384, 1294, 1252,
1181, 1029, 840, 766, 696, 585 cm21; dH (DMSO-d6): 7.89
(s, 1H, H-6), 7.34–07.56 (m, 7H, PhþH-20,60), 6.93 (d,
J¼9.0 Hz, 2H, H-30,5 ), 3.78 (s, 3H, OCH3); dC (DMSO-d6):
160.64 (C-3), 159.54 (C-40), 153.68 (C-5), 142.06 (C-1000),
133.19 (C-6), 131.62 (C-20,60), 128.32 (C-3000,5000), 127.43
(C-4000), 125.83 (C-2000,6000), 123.10 (C-10), 116.98 (C-4),
112.82 (C-30,50), 55.01 (OCH3); MS (ESI): 295, 176, 161,
147, 119, 93, 92; HRMS (ESI) for C17H15N2O3 [MþH]þ:
calcd 295.1083, found 295.1074.
1.1.3. 5-Hydroxy-4-(4-methoxyphenyl)-2-methylpyrida-
zin-3(2H)-one (11). Yield: 0.21 g, 89%; nmax (KBr): 3066,
2974, 2699, 1626, 1610, 1581, 1551, 1371, 1295, 1252,
1178, 1150, 1057, 1024, 837, 797, 675, 615, 548 cm21; dH
(DMSO-d6): 10.91 (s, 1H, OH), 7.76 (s, 1H, H-6), 7.48 (d,
J¼8.9 Hz, 2H, H-20,60), 6.94 (d, J¼8.9 Hz, 2H, H-30,50),
3.78 (s, 3H, OCH3), 3.61 (s, 3H, NCH3); dC (DMSO-d6):
160.72 (C-3)0, 158.51 (C-40), 153.55 (C-5), 131.64 (C-6),
131.540 (C-2 ,60), 123.17 (C-10), 116.47 (C-4), 112.82
(C-30,5 ), 55.00 (OCH3), 39.53 (NCH3); MS (ESI): 233,
218, 217, 201, 190, 162, 161, 158, 147, 143, 133, 121, 119;
HRMS (ESI) for C12H13N2O3 [MþH]þ: calcd 233.0926,
found 233.0927.
1.1.8. 2-Benzyl-5-hydroxy-4-(4-methylthiophenyl)pyri-
dazin-3(2H)-one (16). Yield: 0.26 g, 79%; nmax (KBr):
3438, 3062, 2915, 2719, 2360, 1625, 1572, 1495, 1410,
1377, 1303, 1265, 1154, 1093, 1055, 815, 748, 698, 592,
496 cm21; dH (DMSO-d6): 11.29 (br s, 1H, OH), 7.87 (s,
1H, H-6), 7.48000(d, J¼0008.7 Hz, 2H, H-20,60), 7.35–7.280 (m,
5H, H-2000,3000,4 ,5000,6 ), 7.26 (d, J¼8.7 Hz, 2H, H-3 ,50),
5.23 (s, 2H, CH2), 2.49 (s, 3H, SCH3); dC (DMSO-d6):
160.34 (C-3), 153.95 (C-5), 137.41(C-1000 or C-40), 137.20
1.1.4. 5-Hydroxy-2-methyl-4-(4-methylthiophenyl)pyri-
dazin-3(2H)-one (12). Yield: 0.25 g, 99%; nmax (KBr):
3061, 2683, 1617, 1572, 1547, 1494, 1411, 1365, 1301,
000
(C-1 or C-40), 132.35 (C-6), 130.75 (C-20,60), 128.33
000
1151, 1095, 1052, 1011, 894, 762, 660, 590, 497, 475 cm21
;
(C-3 ,5000), 127.75 (C-2000,6000), 127.59 (C-4000), 127.27 (C-10),
dH (DMSO-d6): 11.06 (br s, 1H, OH), 7.78 (s, 1H, H-6), 7.47
(d, J¼8.6 Hz, 2H, H-20,60), 7.26 (d, J¼8.6 Hz, 2H, H-30,50),
3.61 (s, 3H, NCH3), 2.49 (s, 3H, SCH3); dC (DMSO-d6):
160.48 (C-3), 153.82 (C-5), 137.32 (C-40), 131.56 (C-6),
130.66 (C-20,60), 127.60 (C-10), 124.82 (C-30,50), 116.11
(C-4), 39.44 (NCH3), 14.57 (SCH3); MS (ESI): 234, 233,
201, 163, 57; HRMS (ESI) for C12H13N2O2S [MþH]þ:
calcd 249.0698, found 249.0692.
124.85 (C-30,50), 116.35 (C-4), 54.01 (CH2), 14.61 (SCH3);
MS (ESI): 325, 91; HRMS (ESI) for C18H17N2O2S
[MþH]þ: calcd 325.1011, found 325.0995.
1.1.9. 4-Hydroxy-5-(4-methoxyphenyl)-2-methylpyrida-
zin-3(2H)-one (21). Yield: 0.20 g, 86%; nmax (KBr): 3192,
2843, 1635, 1598, 1519, 1371, 1302, 1255, 1186, 1140,
1030, 931, 842, 786, 750, 612, 522 cm21; dH (DMSO-d6):
10.8 (br00s, 010 H, OH), 7.96 (s, 1H, H-6), 7.67 (d, J¼8.9 Hz,
2H, H-3 ,5 ), 7.03 (d, J¼8.9 Hz, 2H, H-200,600), 3.80 (s, 3H,
OCH3), 3.70 (s, 3H, NCH3); dC (DMSO-d6): 159.30 (C-400),
157.36 (C-3), 148.40 (C-4), 138.14 (C-6), 129.84 (C-200,600),
124.51 (C-100), 118.19 (C-5), 113.96 (C-300,500), 55.21
(OCH3), 39.19 (NCH3); MS (ESI): 233, 218, 217, 201,
190, 162, 133, 119, 91; HRMS (ESI) for C12H13N2O3
[MþH]þ: calcd 233.0926, found 233.0939.
1.1.5. 5-Hydroxy-2-methyl-4-(3-trifluoromethylphenyl)-
pyridazin-3(2H)-one (13). Yield: 0.27 g, 99%; nmax (KBr):
3070, 2683, 1628, 1580, 1556, 1415, 1376, 1325, 1282,
1173, 1130, 1080, 889, 810, 764, 702, 662, 565, 474 cm21
;
dH (DMSO-d6): 11.4 (br s, 1H, OH), 7.86 (br s, 1H, H-20),
7.84 (s, 1H, H-6), 7.820(br d, J<7.7 Hz, 1H, H-60), 7.67 (br
d, J<7.7 Hz, 1H, H-4 ), 7.62 (br t, J<7.7 Hz, 1H, H-50),
3.64 (s, 3H, NCH3); dC (DMSO-d6): 160.31 (C-3), 154.51
(C-50), 134.33 (C-60), 132.34 (C-10), 131.71 (C-6), 128.45
(C-5 ), 128.31 (q, JCF¼31.5 Hz, C-30), 126.74 (q,
JCF¼3.8 Hz, C-20), 124.26 (q, JCF¼272.4 Hz, CF3),
124.04 (q, JCF¼3.8 Hz, C-40), 114.97 (C-4), 39.53
(NCH3); MS (ESI): 251, 231, 204, 203, 167; HRMS (ESI)
for C12H10N2O2F3 [MþH]þ: calcd 271.0694, found
271.0691.
1.1.10. 4-Hydroxy-5-(4-methoxyphenyl)-2-phenylpyri-
dazin-3(2H)-one (22). yield: 0.25 g, 86%; nmax (KBr):
3184, 2924, 1640, 1619, 1607, 1590, 1514, 1386, 1372,
1252, 1184, 1140, 1025, 835, 781, 763, 694, 521 cm21; dH
(DMSO-d6): 11.0 (br s, 1H, OH), 8.16 (s, 1H, H-6), 7.75 (d,
J¼8.7 Hz, 2H, H-200,600), 7.64 (br d, 000J<7.9 Hz, 2H,
H-2000,6000), 7.53 (br000t, J<7.6 Hz, 2H, H-3 ,5000), 7.44 (br t,
J<7.2 Hz, 1H, H-4 ), 7.06 (d, J¼8.7 Hz, 2H, H-300,500), 3.82
(s, 3H, OCH3); dC (DMSO-d6): 159.30 (C-400), 157.12 (C-3),
149.09 (C-4), 141.44 (C-1000), 139.29 (C-6), 129.9500(0C-200,600),
128.53 (C-3000,5000), 127.81 (C-4000), 125.32 (C-2000,6 ), 124.25
(C-100), 117.71 (C-5), 113.94 (C-300,500), 55.17 (OCH3); MS
1.1.6. 4-(2,4-Dichlorophenyl)-5-hydroxy-2-methylpyri-
dazin-3(2H)-one (14). Yield: 0.27 g, 99%; nmax (KBr):
3100, 2699, 1630, 1583, 1555, 1411, 1367, 1299, 1264,
1158, 1104, 1078, 1041, 1015, 872, 824, 601, 490 cm21; dH

B. U. W. Maes et al. / Tetrahedron 58 (2002) 9713–9721
9719
(ESI): 174, 148, 146, 133, 92; HRMS (ESI) for C17H15N2O3
[MþH]þ: calcd 295.1083, found 295.1081.
ultrasonic bath for a few minutes. The mixture was filtered,
washed thoroughly with EtOAc, and the filtrate was
evaporated to dryness under reduced pressure. The residue
was purified by flash column chromatography on silica gel.
1.1.11. 4-Hydroxy-2-phenyl-5-(3-thienyl)pyridazin-
3(2H)-one (23). Yield: 0.27 g, 99%; nmax (KBr): 3253,
3120, 3104, 1625, 1590, 1495, 1312, 1199, 1121, 852, 800,
772, 761, 687 cm21; dH (DMSO-d6): 11.35 (br s, 1H, OH),
8.42 (s, 1H, H-6), 8.22 (br d, J<3 Hz, 1H, H-200), 7.79 (br d,
J<5 Hz, 1H, H-400), 7.71 (br dd, J<50H00 z, J<3 Hz, 1H,
H-500), 7.64 (br d, 00J0 <7.6 Hz, 2H, H-2 ,6000), 7.53 00(0 br t,
J<7.6 Hz, 2H, H-3 ,5000), 7.46 (br t, J<7.3 Hz, H-4 ); dC
(DMSO-d6): 157.11 (C-3), 148.69 (C-4), 141.39 (C-1000),
138.68 (C-6), 132.49 (C-300), 128.53 (C-3000,5000), 127.80
(C-4000), 127.15 (C-200 or C-400 or C-500),00126.33 (C-200 or C-400
or C-500), 126.09 (C-200 or C-400 or C-5 ), 125.30 (C-2000,6000),
113.41 (C-5); MS (ESI): 150, 124, 122, 97, 92, 77; HRMS
(ESI) for C14H11N2O2S [MþH]þ: calcd 271.0541, found
271.0562.
The following compounds were prepared in this manner.
1.2.1. 5-(4-Fluorophenyl)-2-methyl-4-(2-methylphenyl)-
pyridazin-3(2H)-one (25). Yield: 0.11 g, 72%; eluent for
flash column chromatography: heptane–EtOAc (1:2); nmax
(KBr): 1630, 1597, 1579, 1509, 1481, 1339, 1233, 1162,
1104, 1011, 842, 792, 761, 711, 624 cm21; dH (DMSO-d6):
8.05 (s, 1H, H-6), 7.19 (dd, JHH¼9.0, JHF¼5.5 Hz, 2H,
H-200,600), 7.22–7.16 (m, 2H, H-30 and H-40), 7.11 (t, JHH
¼
JHF¼9.0 Hz, 2H, H-300,500), 7.09–7.04 (m, 1H, H-50), 6.92
(br d, J<7.8 Hz, 1H, H-60), 3.75(s, 3H, NCH3), 2.02 (s, 3H,
CH3); dC (DMSO-d6): 161.97 (d, JCF¼246.4 Hz, C-400),
158.93 (C-3), 140.30 (C-5), 137.24 (C-6), 1036.87 (C-20 or
C-4), 136.24 (C-20 or C-4), 133.09 (C-1 ), 130.95 (d,
JCF¼3.8 Hz, C-100), 130.84 (d, JCF¼8.4 Hz, C-200,600),
129.81 (C-600or C-30), 129.63 (C-60 or C-30), 128.08 (C-40),
125.32 (C-5 ), 115.24 (d, JCF¼21.4 Hz, C-300,500), 40.01
(NCH3), 19.18 (CH3); MS (ESI): 295; HRMS (ESI) for
C18H16N2OF [MþH]þ: calcd 295.1247, found 295.1238.
1.1.12. 2-Benzyl-4-hydroxy-5-(4-methylthiophenyl)pyri-
dazin-3(2H)-one (24). Yield: 0.26 g, 80%; nmax (KBr):
3129, 1636, 1610, 1496, 1399, 1373, 1260, 794, 710 cm21
;
dH(DMSO-d6): 8.03 (s, 1H, H-6), 7.67 (d, J¼8.6 Hz, 2H,
H-20,60), 7.34 (d, J¼8.6 Hz, 2H, H-30,50), 7.28–7.25 (m, 5H,
Ph), 5.30 (s, 2H, CH2), 2.51 (s, 3H, SCH3); dC (DMSO-d6):
157.06 (C-3), 149.14 (C-4), 138.79 (C-400), 138.50 (C-6),
136.64 (C-1000), 128.91 (C-200,600), 128.49 (C-100), 128.37
1.2.2. 5-(4-Fluorophenyl)-2-methyl-4-(4-methylthio-
phenyl)pyrdidazin-3(2H)-one (26). Yield: 0.12 g, 73%;
eluent for flash column chromatography: heptane–EtOAc
(1:2); nmax (KBr): 2923, 1629, 1598, 1511, 1404, 1376,
1342, 1297, 1222, 1157, 848, 822, 591 cm21; dH (DMSO-
d6): 7.99 (s, 1H, H-6), 7.24 (dd, JHH¼8.9, JHF¼5.5 Hz, 2H,
H-200,600), 7.17 (t, JHH¼JHF¼8.9 Hz, 2H, H-300,500), 7.15 (d,
J¼8.7 Hz, 2H, H-20,60), 7.09 (d, J¼8.7 Hz, 2H, H-30,50),
3.74 (s, 3H, NCH3), 2.44 (s, 3H, SCH3); dC (DMSO-d6):
161.92 (d, JCF¼246.4 Hz, C-400), 159.30 (C-3), 139.33 (C-5
or C-40), 138.48 (C-5 or C-40), 137.72 0(0C-6), 135.52 (C-4),
131.29 (d, JCF¼9.2 Hz, C-200,600þC-1 ), 130.83 (C-20,60),
129.04 (C-10), 124.72 (C-30,50), 115.44 (d, JCF¼21.4 Hz,
C-300,500), 40.12 (NCH3), 14.20 (SCH3); MS (ESI): 327, 279;
HRMS (ESI) for C18H16N2OSF [MþH]þ: calcd 327.0967,
found 327.0954.
000
(C-3 ,5000), 127.89 (C-2000,6000), 127.46 (C-4000), 125.57
00
(C-3 ,500), 117.93 (C-5), 54.24 (CH2), 14.42 (SCH3); MS
(ESI): 325, 91; HRMS (ESI) for C18H17N2O2S [MþH]þ:
calcd 325.1011, found 325.1008.
1.2. General procedure for the synthesis of
diarylpyridazin-3(2H)-ones (25–29 and 30–32)
A mixture of the pyridazin-3(2H)-one (9, 12, 21, 23, 24:
0.5 mmol; 16: 1.4 mmol), Et3N (9, 12, 21, 23, 24: 0.093 mL;
16: 0.26 mL), and dry dichloromethane (9, 12, 21, 23, 24:
3.5 mL; 16: 7 mL) was placed in an ice-acetone bath
(258C). Under magnetic stirring, trifluoromethanesulfonic
anhydride (9, 12, 21, 23, 24: 0.093 mL (0.55 mmol); 16:
0.26 mL (1.1 mmol)) was added dropwise to the cooled
solution. The reaction mixture was stirred for 30 min at
258C (the flask was equipped with a drying tube). The
mixture was then poured into dilute HCl (9, 12, 21, 23, 24:
2.5 mL 1 M HCl; 16: 7.3 mL 1 M HCl). Water (30 mL) was
added, and the aqueous phase was extracted with CH2Cl2
(3£30 mL). The combined organic layers were washed with
a NaHCO3 solution (1%, 60 mL) and with brine (60 mL).
After drying over MgSO4, the organic phase was evaporated
to dryness under reduced pressure.
1.2.3. 2-Benzyl-4-(4-methylthiophenyl)-5-phenylpyrida-
zin-3(2H)-one (27). Yield: 0.39 g, 72%; eluent for flash
column chromatography: heptane–EtOAc (8:2); nmax
(KBr): 3028, 2916, 2360, 1640, 1595, 1488, 1437, 1397,
1337, 1300, 1262, 1240, 1155, 1096, 1076, 939, 862, 817,
765, 740, 699, 635, 563, 514, 473 cm21; dH (DMSO-d6):
8.04 (s, 1H, H-6), 7.43–7.29 (m, 8H, H-2000,3000,4000,5000,6000þH-
200,600 or H-300,500), 7.22–7.190(m, 2H, H-200,600 or H-300,500),
7.13 (0d, J¼9.0 Hz, 2H, H-2 ,60), 7.09 (d, J¼9.0 Hz, 2H,
H-30,5 ), 5.33 (s, 2H, CH2), 2.43 (s, 3H, CH3); dC
(DMSO-d6): 159.11 (C-3), 140.20 (C-5), 138.41 (C-40),
138.35 (C-6)0, 136.68 (C-1000), 135.89 (C-4), 134.83 (C-100),
130.89 (C-2 ,60), 129.12 (C-10), 129.00 (C-020 00), 128.46
(C-400), 128.42 (C-3000,5000), 128.39 0 (C-3 ), 128.18
(C-2000,6000), 127.55 (C-4000), 124.63 (C-3 ,50), 54.78 (CH2),
14.21 (SCH3); MS (ESI): 385, 91; HRMS (ESI) for
C24H21N2OS [MþH]þ: calcd 385.1370, found 385.1370.
To the crude triflated pyridazin-3(2H)-one the appropriate
boronic acid (12, 16, 21, 23, 24: 2 equiv.; 9: 3 equiv.),
Pd(PPh3)4 (0.03 equiv.), Na2CO3 (2 M, 1 mL for 1 mmol of
the crude pyridazinone) and toluene (7 mL) were added.
The reaction mixture was flushed with N2 for 5 min under
magnetic stirring, and afterwards stirred and heated under
reflux (oil bath temperature¼1208C) under a N2 atmosphere
until the starting material had disappeared as judged by TLC
and/or DCI-MS analysis. After cooling, the reaction mixture
was evaporated to dryness under reduced pressure. EtOAc
(40 mL) was added, and the suspension was placed in an
1.2.4. 2-Benzyl-5-(4-fluorophenyl)-4-(4-methylthiophe-
nyl)pyridazin-3(2H)-one (28). Yield: 0.41 g, 73%; eluent
for flash column chromatography: heptane–EtOAc (8:2);

9720
B. U. W. Maes et al. / Tetrahedron 58 (2002) 9713–9721
nmax (KBr): 3034, 2920, 2360, 1645, 1594, 1509, 1489,
1435, 1348, 1234, 1160, 1096, 941, 861, 836, 823, 740, 696,
612, 583, 525, 500, 480, 456 cm21; dH (DMSO-d6): 8.04 (s,
7.4 Hz, 1H, H-4000), 7.43 (dd, J¼5.0, 2.9 Hz, 1H, H-500), 7.31
(dd, JHH¼9.0 Hz, JHF¼5.7 Hz, 2H, H-20,60), 7.20 (t,
JHH¼9.0 Hz, JHF<9.0 Hz, 2H, H-30,50), 6.67 (dd, J¼5.0,
1.4 Hz, 1H, H-4000); dC (DMSO-d6): 161.91 (d,
JCF¼245.7 Hz, C-4 ), 159.01 (C-3), 141.73 (C-1000),
138.51(C-6), 135.31 (C-300 or C-4 or C-5), 135.10 (C-300 or
C-4 or C-5), 134.076 (C-300 or C-4 or C-5), 132.16 (d,
JCF¼8.4 Hz, C-20,6 ), 129.73 (d, JCF¼3.8 Hz, C-10), 128.51
000 000
1H, H-6), 7.44–7.29 (m, 5H, H-2000,3 ,4 ,5000,6000), 7.26 (dd,
00 00
JHH¼9.0 Hz, JHF¼5.5 Hz, 2H, H-2 ,6 ), 7.16 (t, JHH
¼
JHF¼9.0 Hz, 2H, H-300,500), 7.14 (d, J¼8.8 Hz, 2H, H-20,60),
7.10 (d, J¼8.8 Hz, 2H, H-30,50), 5.32 (s, 2H, CH2), 2.44
(SCH3); dC (DMSO-d6): 161.94 (d, JCF¼246.4 Hz, C-400),
159.05 (C-3), 139.29 (C-5 or C-40), 138.55 (C-5 or C-40),
138.27 (C-6), 136.66 (C-1000), 136.04 (C-4), 131.37 (d,
JCF¼8.4 Hz, C-200,600), 131.22 (d, JCF¼3.8 Hz, C-100),
130.89 (C-20,60), 128.98 00(0C-10), 128.42 (C-3000,5000), 128.20
(C-2000,6000), 127.5500 (C-4 ), 124.69 (C-30,50), 115.43 (d,
JCF¼22.1 Hz, C-3 ,500), 54.78 (CH2), 2.44 (SCH3); MS
(ESI): 403, 91; HRMS (ESI) for C24H20N2OSF [MþH]þ:
calcd 403.1280, found 403.1270.
000
(C-3 ,5000), 127.89 (C-4000 or C-200 or C-400 or C-500), 127.76
000
(C-4 or C-200 or C-400 or C-500), 127.63 (C-400000or C-200 or
C-400 or C-500), 126.78 (C-4000 or C-200 or C-4 or C-5000),
125.54 (C-2000 or C-6000), 115.00 (d, JCF¼21.4 Hz, C-30,5 );
MS (ESI): 349; HRMS (ESI) for C20H14N2OSF [MþH]þ:
calcd 349.0811, found 349.0801.
1.2.8. 2-Benzyl-4-(4-fluorophenyl)-5-(4-methylthio-
phenyl)pyridazin-3(2H)-one (32). Yield: 0.18 g, 88%;
eluent for flash column chromatography: heptane–EtOAc
(2:1); nmax (KBr): 1639, 1597, 1229, 1157, 1120, 836,
700 cm21; dH (DMSO-d6): 8.06 (s, 1H, H-6), 7.42–7.28 (m,
5H, Ph), 7.22 (dd, JHH¼9.0 Hz, JHF¼5.5 Hz, 2H, H-200,600),
7.16 (t, JHH¼JHF¼8.8 Hz, 2H, H-300,500), 7.15–7.08 (m, 4H,
H-20,30,50,60), 5.32 (s, 2H, CH2), 2.44 (s, 3H, SCH3); dC
(DMSO-d6): 161.71 (d, JCF¼245.8 Hz, C-40), 159.08 (C-3),
139.98 (C-5 or C-400), 139.57 (C-5 or C-400), 138.26 (C-6),
136.68 (C-1000), 135.14 (C-4), 132.59 (d, JCF¼8.4 Hz, C-20,60),
130.92 (C-100), 129.58 (C-200,600), 129.31 (d, JCF¼3.8 Hz,
C-10), 128.44 (C-3000,5000), 128.24 (C-2000,6000), 127.58 (C-4000),
125.31 (C-300,500), 114.70 (d, JCF¼21.4 Hz, C-30,50), 54.80
(CH2), 14.09 (SCH3); MS (ESI): 403, 91; HRMS (ESI) for
C24H20N2OSF [MþH]þ: calcd 403.1280, found 403.1275.
1.2.5. 2-Benzyl-4-(4-methylthiophenyl)-5-(3-trifluoro-
methylphenyl)pyridazin-3(2H)-one (29). Yield: 0.34 g,
54%; eluent for flash column chromatography: heptane–
EtOAc (8:2); nmax (KBr): 3035, 2360, 2342, 1635, 1599,
1317, 1174, 1160, 1128, 1078, 819, 730, 704, 569, 503,
456 cm21; dH (DMSO-d6): 8.12 (s, 1H, H-6), 7.67–7.64 (br.
d, 10H0 , H-400 or H-600), 7.58–7.50 0(00m, 3H, H-200,500þH-400 or
H-6 ), 7.44–7.29 (m, 5H, H-2 ,3000,4000,5000,6000), 7.14 (0d,
J¼8.7 Hz, 2H, H-20,60), 7.10 (d, J¼8.7 Hz, 2H, H-30,5 ),
5.35 (s, 2H, CH2), 2.42 (s, 3H, CH3); dC (DMSO-d6): 159.01
(C-3), 138.85 (C-5 or C-40), 138.81(C-5 or C-40), 137.96
(C-6), 136.73 (C-100 or C-1000), 136.62 (C-100 or C-1000), 135.86
(C-4), 133.17 (C-600), 130.8400 (C-20,60), 129.46 (C-500),
129.10 (q, JCF¼32.1 Hz, C-3 ), 128.78 (C-10), 128.44
(C-3000,5000), 128.22 (C-2000,6000), 127.59 (C-4000), 125.9700(q,
JCF¼3.8 Hz, C-400 or C-200), 125.09 (q, JCF¼3.8 Hz, C-4 or
C-200), 124.92 (C-30,50), 123.72 (q, JCF¼272.4 Hz, CF3),
54.82 (CH2), 14.41 (SCH3); MS (ESI): 453, 91; HRMS
(ESI) for C25H20N2OSF3 [MþH]þ: calcd 453.1248, found
453.1264.
1.3. Synthesis of isochromeno[3,4-d]pyridazinediones (34
and 37)
1.3.1. 2-Benzyl-1H-isochromeno[3,4-d]pyridazine-
1,6(2H)-dione (34). A mixture of 2-(2-benzyl-5-methoxy-
3-oxo-2,3-dihydropyridazin-4-yl)benzaldehyde
(33)
1.2.6. 4-(4-Fluorophenyl)-5-(4-methoxyphenyl)-2-
methylpyridazin-3(2H)-one (30). Yield: 0.12 g, 77%;
eluent for flash column chromatography: heptane–EtOAc
(1:2); nmax (KBr): 1637, 1607, 1530, 1514, 1501, 1469,
1457, 1378, 1342, 1295, 1250, 1233, 1221, 1180, 1157,
1023, 871, 838, 806, 607, 553, 540 cm21; dH (DMSO-d6):
8.00 (s, 1H, H-6), 7.20 (dd, JHH¼9.0 Hz, JHF¼5.7 Hz, 2H,
H-20,60), 7.11 (t, JHH¼JHF¼9.0 Hz, 2H, H-30,50), 7.10 (d,
J¼8.9 Hz, 2H, H-200,600), 6.86 (d, J¼8.9 Hz, 2H, H-300,500),
3.73 (s, 6H, OCH3 and NCH3); dC (DMSO-d6): 161.54 (d,
JCF¼245.9 Hz, C-40), 159.39 (C-3 or C-400), 159.36 (C-3 or
C-400), 140.20 (C-50), 137.92 (C-6), 134.28 0(0C-4), 132.48 (d,
JCF¼8.4 Hz, C-2 ,060), 130.52 (C-200,6 ), 129.57 (d,
(0.5 mmol), KOH (10 mmol) and H2O (18 mL) was stirred
and refluxed for 24 h. The reaction mixture was cooled
down to room temperature and a solution of KMnO4
(0.55 mmol) in H2O (10 mL) was added dropwise. The
mixture was stirred at room temperature for 7 h. Sub-
sequently, the precipitated MnO2 was filtered off and the
filtrate was acidified with concentrated H2SO4 (1.1 mL) and
cooled in ice for 30 min and then left overnight at room
temperature. The precipitate was filtered off and purified by
flash column chromatography on silica gel with dichloro-
methane as the eluent; yield: 0.07 g, 45%; nmax (KBr): 2925,
2854, 1749, 1644, 1596, 1549, 1456, 1384, 1365, 1287,
1257, 1233, 1155, 1121, 1090, 1073, 1039, 1021, 836, 790,
740, 697, 686 cm21; dH (CDCl3): 9.46 (ddd, J¼8.2, 1.2,
0.5 Hz, 1H, H-10), 8.41 (ddd, J¼7.9, 1.5, 0.5 Hz, 1H, H-7),
8.02 (s, 1H, H-4), 7.91 (ddd, J¼8.2, 7.5, 1.5 Hz, 1H, H-9),
7.71 (ddd, J¼7.9, 7.5, 1.2 Hz, 1H, H-8), 7.49–7.45 (m, 2H,
HPh-2,6), 7.37–7.25 (m, 3H, HPh-3,4,5), 5.44 (s, 2H, CH2);
dC (CDCl3): 159.19 (C-6), 158.64 (C-1), 150.87 (C-4a),
135.93 (CPh-1), 134.80 (C-9), 132.20 (C-10a), 130.72 (C-8),
130.19 (C-7), 130.10 (C-4), 128.75 and 128.73 (CPh-2,6 and
CPh-3,5), 128.16 (CPh-4), 128.02 (C-10), 121.74 (C-6a),
111.62 (C-10b), 55.83 (CH2); MS (ESI): 305, 91; HRMS
(ESI) for C18H13N2O3 [MþH]þ: calcd 305.0926, found
305.0936.
00
JCF¼3.8 Hz, C-1 ), 126.64 (C-1 ), 114.67 (d,
00
JCF¼21.4 Hz, C-30,50), 113.94 (C-300,5 ), 55.11 (OCH3),
40.03 (NCH3); MS (ESI): 311, 267; HRMS (ESI) for
C18H16N2O2F [MþH]þ: calcd 311.1196, found 311.1202.
1.2.7. 4-(4-Fluorophenyl)-2-phenyl-5-(3-thienyl)pyrida-
zin-3(2H)-one (31). Yield: 0.15 g, 88%; eluent for flash
column chromatography: heptane–EtOAc (1:1); nmax
(KBr): 1637, 1606, 1504, 1229, 852, 835, 800, 782, 763,
696, 559 cm21; dH (DMSO-d6): 8.34 (s, 1H, H-6), 7.75 (dd,
J¼2.9,0001.4 Hz, 1H, H-200), 7.62 (br 000d, 000J<8.4 Hz, 2H,
H-2000,6 ), 7.52 (br t, J<7.9 Hz, 2H, H-3 ,5 ), 7.50 (br t, J<

B. U. W. Maes et al. / Tetrahedron 58 (2002) 9713–9721
9721
F.; Esmans, E.; Rozenski, J.; Dommisse, R. A.; Haemers, A.
Tetrahedron 2001, 57, 1323–1330. (b) Maes, B. U. W.;
1.3.2. 3-Benzyl-3H-isochromeno[3,4-d]pyridazine-4,6-
dione (37). A mixture of 2-(1-benzyl-5-methoxy-6-oxo-
1,6-dihydropyridazin-4-yl)benzaldehyde (35) (1 mmol),
KOH (20 mmol) and H2O (35 mL) was stirred and refluxed
for 24 h. The reaction mixture was cooled down to room
temperature and a solution of KMnO4 (1.1 mmol) in H2O
(20 mL) was added dropwise. The mixture was stirred at
room temperature for 7 h. Subsequently, the precipitated
MnO2 was filtered off and the filtrate was acidified with
concentrated H2SO4 (2.2 mL) and cooled in ice for 30 min
and then left overnight at room temperature. The precipitate
was filtered off and dried in vacuo yielding 2-(1-benzyl-5-
ˇ
Kosmrlj, J.; Lemiere, G. L. F. J. Heterocycl. Chem. 2002, 39,
`
535–543. (c) Riedl, Z.; Maes, B. U. W.; Monsieurs, K.;
´
` ´
Lemiere, G. L. F.; Matyus, P.; Hajos, G. Tetrahedron 2002, 58,
5645–5650. For Suzuki arylations on bromopyridazin-3(2H)-
´
ones see: (d) Coelho, A.; Sotelo, E.; Estevez, I.; Ravin˜a, E.
Synthesis 2001, 871–876. (e) Li, C. S.; Gauthier, J. Y.; Lau,
C. K.; Therein, M. US Patent 6004960, 1999. For Suzuki
arylations on iodopyridazin-3(2H)-ones see: (f) Krajsovszky,
´ ´ ´
G.; Matyus, P.; Riedl, Z.; Csanyi, D.; Hajos, G. Heterocycles
2001, 55, 1105–1111.
hydroxy-6-oxo-1,6-dihydropyridazin-4-yl)benzoic
acid
2. Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11,
513–519.
3. Examples on alkaline hydrolysis of methoxy substituted
(36) in 82% (0.26 g) yield. A mixture of 36 (0.5 mmol)
and concentrated H2SO4 (0.1 mL) in 1,2-dimethoxyethane
(100 mL) was stirred and heated at 608C for 48 h. The
reaction mixture was poured on ice water (80 mL) and
extracted with chloroform (3£100 mL). The combined
organic layers were dried over MgSO4 and evaporated
under reduced pressure. The residue was purified by flash
column chromatography on silca gel using dichloromethane
as the eluent; yield: 0.13 g, 84%; nmax (KBr): 1750, 1663,
1617, 1455, 1343, 1315, 1260, 1224, 1059, 758, 747, 696,
689 cm21; dH (DMSO-d6): 8.95 (s, 1H, H-1), 8.48 (br d,
J<7.9 Hz, 1H, H-10), 8.33 (dd, J<7.9, 0.9 Hz, 1H, H-7),
8.06 (ddd, J¼8.0, 7.4, 1.4 Hz, 1H, H-9), 7.87 (ddd, J<7.9,
7.4, 1.1, 1H, H-8), 7.37–7.34 (m, 4H, HPh-2,3,5,6), 7.34–
7.27 (m, 1H, HPh-4), 5.38 (s, 2H, CH2); dC (DMSO-d6):
159.03 (C-6), 153.07 (C-4), 144.99 (C-4a), 136.34 (CPh-1),
135.64 (C-9), 132.44 (C-1), 131.66 (C-8), 130.64 (C-10a),
129.86 (C-7), 128.42 (CPh-3,5), 127.90 (CPh-2,6), 127.59
(CPh-4), 124.08 (C-10), 122.34 (C-6a), 115.76 (C-10b),
54.40 (CH2); MS (ESI): 305; HRMS (ESI) for C18H13N2O3
[MþH]þ: calcd 305.0926, found 305.0938.
ˇ ´
pyridazin-3(2H)-ones: (a) Konecnu, V. Chem. Zvesti 1976,
30, 663–673. (b) Takaya, M.; Yamashita, T.; Ozeki, K.
Yakugaku Zasshi 1978, 98, 413–417. (c) Cho, S. D.; Chung,
J. W.; Choi, W. Y.; Kim, S. K.; Yoon, Y. J. J. Heterocycl.
Chem. 1994, 31, 1199–1208. (d) Cho, S. D.; Choi, W. Y.;
Yoon, Y. J. J. Heterocycl. Chem. 1996, 33, 1579–1582.
(e) Kappe, T. J. Heterocycl. Chem. 1998, 35, 1111–1122.
(f) Brown, D. J. The Pyridazines. Supplement I. Wiley, 2000; p
255.
`
4. R’kyek, O.; Maes, B. U. W.; Jonckers, T. H. M.; Lemiere, G. L.
F.; Dommisse, R. A. Tetrahedron 2001, 57, 10009–10016.
5. Performing a selective Suzuki reaction on 2-benzyl-4-bromo-5-
trifluoromethanesulfonyloxypyridazin-3(2H)-one
with
4-methylthiophenylboronic acid under conditions described in
the patent of Li et al.1e yielded a mixture of 2-benzyl-4-bromo-
5-(4-methylthiophenyl)pyridazin-3(2H)-one (30%) and
2-benzyl-4,5-bis-(4-methylthiophenyl)-pyridazin-3(2H)-one
(3%). Although formation of the monoarylated compound is
favoured only a low yield was obtained. Moreover, it is
very hard to separate 2-benzyl-4-bromo-5-(4-methylthio-
phenyl)pyridazin-3(2H)-one from the minor compound
2-benzyl-4,5-bis-(4-methylthiophenyl)pyridazin-3(2H)-one
due to similar polarity properties.
Acknowledgements
Funding by RAFO RUCA, OTKA 33105, OTKA 31910 and
ETT 187/2000 is gratefully acknowledged. Dr B. Maes
thanks the Fund for Scientific Research (FWO-Vlaanderen)
for an appointment as post-doctoral fellow. The authors
wish to thank Professor Dr E. Esmans and Professor Dr
6. For the debenzylation of 2-benzylpyridazin-3(2H)-ones with
AlCl3 see: (a) Kaji, K.; Nagashima, H.; Oda, H. Chem. Pharm.
Bull. 1984, 32, 1423–1432. (b) Haider, N.; Heinisch, G.
J. Chem.Soc., Perkin Trans. 1 1986, 169–172. (c) Haider, N.;
Heinisch, G. J. Chem.Soc., Perkin Trans. 1 1988, 401–405.
(d) Haider, N.; Heinisch, G.; Volf, I. Heterocycles 1989, 29,
`
F. Lemiere for the use of their MS facilities, and Ing.
J. Aerts, J. Schrooten, Ing. W. Van Dongen, V. Van Heurck
and Ing. J. Verreydt for technical assistance.
´ ´ ´
1309–1316. (e) Zara-Kaczian, E.; Matyus, P. Heterocycles
1993, 36, 519–528. (f) See Ref. 1c.
ˇ
7. Kmetic, M.; Stanovnik, B.; Tisler, M.; Kappe, T. Heterocycles
1993, 35, 1331–1339.
´
8. Matyus, P.; Fuji, K.; Tanaka, K. Heterocycles 1994, 37,
References
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9. Toplak, R.; Selic, L.; Sorsak, G.; Stanovnik, B. Heterocycles
1997, 45, 555–565.
ˇ
1. For Suzuki arylations on chloropyridazin-3(2H)-ones see:
ˇ `
(a) Maes, B. U. W.; R’kyek, O.; Kosmrlj, J.; Lemiere, G. L.