Synthesis of new pyridazino[4,5-c]isoquinolinones by Suzuki cross-coupling reaction

Article abstract of DOI:10.1016/S0040-4020(02)00531-8

Suzuki cross-coupling reaction of 2-alkyl(methyl and benzyl)-5-chloro-4-methoxy- and 2-alkyl(methyl and benzyl)-4-chloro-5-methoxypyridazin-3(2H)-ones with 2-formylphenylboronic acid afforded the corresponding biaryl products which were cyclized with ammonia to yield hitherto undescribed pyridazino[4,5-c]isoquinolinones. Removal of the N-benzyl protective group in position 2 yielded the unsubstituted tricyclic pyridazinones.

Full text of DOI:10.1016/S0040-4020(02)00531-8

TETRAHEDRON
Pergamon
Tetrahedron 58 62002) 5645±5650
Synthesis of new pyridazino[4,5-c]isoquinolinones
by Suzuki cross-coupling reaction
a
b
b
Zsuzsanna Riedl, Bert U. W. Maes, Katrien Monsieurs, Guy L. F. Lemiere, Peter Matyus
b
c
Á
Â
Â
a,p
Â
È
and Gyorgy Hajos
aInstitute of Chemistry, Chemical Research Center, Hungarian Academy of Sciences,
P.O. Box 17, H-1525 Budapest, Hungary
bDepartment of Chemistry, University of Antwerp (RUCA), Groenenborgerlaan 171, B-2020 Antwerpen, Belgium
c
Í
Institute of Organic Chemistry, Semmelweis University, H-1092 Budapest, Hogyes E. u. 7., Hungary
Â
Cordially dedicated to Professor Andras Messmer on the occasion of his 80th birthday
Received 14 February 2002; revised 7 May 2002; accepted 23 May 2002
AbstractÐSuzuki cross-coupling reaction of 2-alkyl6methyl and benzyl)-5-chloro-4-methoxy- and 2-alkyl6methyl and benzyl)-4-chloro-5-
methoxypyridazin-362H)-ones with 2-formylphenylboronic acid afforded the corresponding biaryl products which were cyclized with
ammonia to yield hitherto undescribed pyridazino[4,5-c]isoquinolinones. Removal of the N-benzyl protective group in position 2 yielded
the unsubstituted tricyclic pyridazinones. q 2002 Elsevier Science Ltd. All rights reserved.
Recently, we have reported that Suzuki coupling of 5-iodo-
2-methylpyridazin-362H)-one with 2-aminophenylboronic
acids yielded new biaryl compounds that proved to be
appropriate starting material for a ring closure procedure
towards the synthesis of new tricyclic aza-b-carbolines.1
Furthermore, one of our most recent publications revealed
that the palladium catalysed Suzuki cross-coupling method-
ology can widely be applied on chloropyridazin-362H)-
ones, thereby allowing an easy access to a series of new
arylpyridazin-362H)-ones.2
easily accessible chloromethoxypyridazin-362H)-ones. In
this paper, we report the synthesis of hitherto unknown
pyridazino[4,5-c]isoquinolin-463H)-ones and pyridazino-
[4,5-c]isoquinolin-162H)-ones based upon palladium cata-
lysed cross-coupling of commercially available 2-formyl-
phenylboronic acid with 2-substituted 4-chloro-5-methoxy
and 5-chloro-4-methoxypyridazin-362H)-ones.
The synthetic procedure leading to the chloromethoxy-
pyridazinones is shown in Scheme 1. First, the cheap,
commercially available 4,5-dichloropyridazin-362H)-one
61) was N-alkylated yielding 2-benzyl-4,5-dichloropyrida-
zin-362H)-one 62a) and 2-methyl-4,5-dichloropyridazin-
362H)-one 62b).4±8 Suzuki cross-coupling of arylboronic
As a continuation of these studies, we probed new synthetic
strategies towards the synthesis of tricylic fused pyridazi-
nones, based upon Suzuki cross-coupling reactions3 on
Scheme 1.
Keywords: palladium; Suzuki reaction; tricyclic pyridazinones; ring closure; debenzylation.
Corresponding author. Tel.: 136-1-3257-550; fax: 136-1-3257-683; e-mail: ghajos@chemres.hu
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020602)00531-8

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Z. Riedl et al. / Tetrahedron 58 (2002) 5645±5650
Scheme 2.
acids with these 2-substituted 4,5-dichloropyridazin-362H)-
ones gives a mixture of two monoaryl isomers.2 Usually,
diarylated reaction product is formed depending on the
boronic acid used.2 Recently, we described a similar
non-selective behaviour in Sonogashira reactions on
4,5-dichloro-2-methylpyridazin-362H)-one.9 Because of
this selectivity problem, a chlorine atom is now replaced
by a methoxy group as a provisionally masked functionality.
The choice for a methoxy group is obvious since we2 and
others4,5,10 reported earlier that the chlorine substituents of
2-substituted 4,5-dichloropyridazin-362H)-ones can be
selectively replaced with sodium methanolate, depending
on the choice of the solvent. Reactions in solvents with
high dielectric constant 6e.g. methanol) give the 5-methoxy
derivative 64)4,5,10 whereas solvents with low dielectric
constant 6e.g. dioxane) favour formation of the 4-methoxy
compound 3.2,10
heated in a mixture of DME and 10% aqueous Na2CO3
solution. However, some starting material remained uncon-
sumed even after two days of re¯ux. Finally, we found that
stepwise addition of the boronic acid 63 equiv.) resulted in a
complete reaction after 24 h yielding 6a in 85%. This bene-
®cial effect of gradual addition, probably suppresses the
unwanted deboronation of the 2-formylphenylboronic acid
which most likely is responsible for the incomplete reaction
when the boronic acid is added at once. For the synthesis of
the isomer 5a, a smaller excess of boronic acid was required.
Compounds 5b and 6b were prepared under the same
reaction conditions as 5a and 6a, respectively.
Finally, when 5a, 5b, 6a and 6b were re¯uxed for a short
time 630 min) in a mixture of methanol and concentrated
aqueous ammonia, a ring closure to the tricyclic pyridazi-
nones 7a, 7b, 8a and 8b, respectively occurred. To the best
of our knowledge, these tricyclic pyridazinones represent
a new group of heterocyclic compounds. Although the
pyridazino[4,5-c]isoquinoline ring system has been
prepared by an entirely different procedure,13 no publication
has yet appeared on the synthesis of the pyridazino[4,5-c]-
isoquinolinones 7±10.
Then, we studied the introduction of the 2-formylphenyl
group on 3 and 4 via Suzuki cross-coupling reaction
6Scheme 2). Pyridazinone 4a was chosen as the test
substrate. Recently, we described that the ortho substituted
boronic acid 2,4-dichlorophenylboronic acid can be coupled
in high yield with 2-methyl-4-chloro-5-methoxypyridazin-
362H)-one 64b) in a two phase system of toluene/2 M
aqueous Na2CO3 solution in high yield using a large excess
of the boronic acid and tetrakis6triphenylphosphine)palla-
dium as a catalyst.2 However, for the coupling of 4a with
2-formylphenylboronic acid 63 equiv.) similar reaction
conditions were not suitable since a large amount of starting
material was still present after one day of re¯ux as shown by
TLC and DCI-MS analysis. Therefore, we focused on the
use of Gronowitz coupling conditions which have proven to
be bene®cial when phenylboronic acids with electron with-
drawing groups in the ortho position are used due to a
reduced hydrolytic deboronation side reaction of the
boronic acids.11,12 Thus, 4a, 2-formylphenylboronic acid
63 equiv.) and tetrakis6triphenylphosphine)palladium were
An interesting aspect of our new synthetic strategy is the
rationalization of the mechanism of the ring closure 6Fig. 1).
An obvious interpretation would be that the ®rst step is the
nucleophilic displacement of the methoxy group with an
amino moiety 6i.e. formation of A) followed by a conden-
sation of the amino and formyl groups to give 9. However,
attempts to transform related 4- and 5-methoxy derivatives
62-methyl-4-methoxy-5-phenylpyridazin-362H)-one and its
isomer 2-methyl-5-methoxy-4-phenylpyridazin-362H)-one)
into the corresponding amino derivatives under the same
reaction conditions as used for the ring closure procedure
were unsuccessful. This observation is in agreement with
literature data that indicate that methoxypyridazin-362H)-
ones are unreactive towards intermolecular substitution by

Z. Riedl et al. / Tetrahedron 58 (2002) 5645±5650
5647
Figure 1.
amines 6even under forced conditions, e.g. with morpholine
at elevated temperature).14,20 Instead, demethylation into
hydroxypyridazin-362H)-ones is observed in these cases.
Based on these test experiments and literature data we
believe that the cyclization consists of imine 6B) formation
followed by nucleophilic displacement of the methoxy
group 6B!9) rather than the reverse sequence. Since an
imine is a rather weak nucleophile, the good leaving
group properties of the methoxy group must be ascribed
to the formation of the new aromatic ring as the driving
force for the irreversible cyclization. Another possibility
for the ring closure of the proposed imine intermediate B
is that an electrocyclic reaction takes place 6B!C) followed
by elimination of methanol 6C!9). Clari®cation of the
exact reaction mechanism will be the subject of further
studies.
DMSO-d6 with TMS as the internal standard. Chemical
shifts are given in ppm and J values in Hz. Melting points
were determined on a BuÈchi apparatus and are uncorrected.
IR spectra were obtained as potassium bromide pellets or as
liquid ®lms between two potassium bromide pellets with a
Nicolet Magna 750 FT-IR 65b, 6b, 7b and 8b) or a Bruker
Vector 22 spectrometer 62a, 3a, 4a, 5a, 6a, 7a, 8a, 9 and 10).
For mass spectrometric analysis, samples were dissolved in
methanol 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 ¯ow rate of
5 mL/min methanol 60.1% formic acid), using the CapLC
HPLC system 6Waters, Millford). Product ion spectra were
recorded, and exact masses were measured on a quadrupole/
orthogonal-acceleration time-of-¯ight 6Q/oaTOF) tandem
mass spectrometer 6qTOF 2, Micromass, Manchester, UK)
equipped with a standard electrospray ionisation 6ESI)
interface. Cone voltage 635 V) and capillary voltage
63.3 kV) were optimised on one compound and used for
the series of experiments. Fragmentation was induced
by low energy collisional activation using Ar gas and a
collision energy of 15 eV. 4,5-Dichloro-2-methylpyrida-
zin-362H)-one5 62b), 4-chloro-5-methoxy-2-methylpyrida-
zin-362H)-one5 64b) and 5-chloro-4-methoxy-2-methyl-
pyridazin-362H)-one2a 63b) were synthesized via literature
procedures. Pd6PPh3)4 6Acros), 4,5-dichloropyridazin-3-
62H)-one 6Aldrich) and 2-formylphenylboronic acid
6Lancaster) were obtained from commercial sources. Flash
column chromatography was performed on Kieselgel 60
6Merck), 0.040±0.063 mm.
Study of the reactivity of 7 and 8 revealed that in the case of
the N-benzyl derivatives 67a and 8a) the benzyl group could
be smoothly removed with aluminium trichloride to
yield the unsubstituted fused pyridazinones 9 and 10
6Scheme 2).15±19 This transformation seems to be of par-
ticular synthetic interest, since further transformation of
the lactam moiety allows valuable functionalization of
these products. Study of the reactivity of these tricylic
pyridazinones as well as biological studies on the new
compounds is in progress.
1. Experimental
1.1. General
1.1.1. Synthesis of 2-benzyl-4,5-dichloropyridazin-
3.2H)-one .2a). A mixture of 4,5-dichloropyridazin-
362H)-one 61) 66.0 mmol, 0.99 g), benzyl bromide 66.3
mmol, 1.08 g), potassium carbonate 615.0 mmol, 2.07 g),
tetrabutylammonium bromide 60.3 mmol, 0.1 g) and
1H and 13C NMR spectra were recorded on a Varian Unity
1
400 spectrometer 6only the H and 13C NMR spectra of 5b
and 6b were measured on a 200 MHz machine) in CDCl3 or

5648
Z. Riedl et al. / Tetrahedron 58 (2002) 5645±5650
acetonitrile 615 mL) was stirred and heated under re¯ux for
1 h 6the re¯ux condenser was equipped with a drying tube).
After cooling, the solvent was evaporated under reduced
pressure. The residue was puri®ed by ®ltration on a small
silica gel column with dichloromethane as the eluent,
yielding the title compound 61.24 g, 81%); mp 858C
6white solid); nmax 6KBr): 1649, 1578, 1418, 1288, 1222,
969, 952, 897, 723, 694 cm21; dH 6DMSO-d6): 8.23 6s,
1H, H-6), 7.27±7.37 6m, 5H, Ph), 5.29 6s, 2H, CH2); dC
6DMSO-d6): 155.7, 136.1, 136.1, 135.7, 133.1, 128.6,
128.0, 127.7, 55.4; LRMS 6ESI): 255.0, 91.1; HRMS
6ESI) for C11H9Cl2N2O [M1H]1 found: 255.0089 calcd:
255.0092.
an additional portion of 2-formylphenylboronic acid
60.80 mmol, 0.120 g) was added. For the syntheses with
4a and 4b also after 6 and 12 h 1.0 mmol portions boronic
acid was added. The cooled reaction mixture was poured
onto 30 mL of H2O and extracted with CH2Cl2 63£30 mL).
The combined organic layers were dried on MgSO4, ®ltered,
and the ®ltrate evaporated to dryness. The residue was
puri®ed by ¯ash column chromatography on silica gel
with CH2Cl2±CH3OH 6100:1 for 5a and 5b, 100:0.5 for
6a and 6b) as the eluent.
1.2.1. 2-.1-Benzyl-5-methoxy-6-oxo-1,6-dihydropyrida-
zin-4-yl)benzaldehyde .5a). Yield: 0.54 g, 84%; mp
1328C 6white solid); nmax 6KBr): 1704, 1635, 1597, 1516,
1453, 1336, 1308, 1256, 1202, 1021, 934, 767, 743,
698 cm21; dH 6DMSO-d6): 9.92 6d, Jù0.3 Hz, 1H, CHO),
7.97 6br dd, Jˆ7.6, ,1.1 Hz, 1H, H-6), 7.89 6s, 1H, H-30),
7.78 6dt, Jˆ7.5, 1.4 Hz, 1H, H-4), 7.67 6br dt, Jù7.0,
,0.6 Hz, 1H, H-5), 7.49 6br dd, Jˆ7.6, ,0.9 Hz, 1H,
H-3), 7.28±7.41 6m, 5H, Ph), 5.32 6br s, 2H, CH2), 3.90
6s, 3H, OCH3); dC 6DMSO-d6): 191.9, 156.8, 151.2, 138.5,
136.59, 133.9, 133.8, 133.5, 130.6, 129.4, 129.2, 128.4,
128.0, 127.5, 126.3, 59.6, 54.3; LRMS 6ESI): 321.2, 91.1;
HRMS 6ESI) for C19H17N2O3 [M1H]1 found: 321.1233
calcd: 321.1239.
1.1.2. Synthesis of 2-benzyl-5-chloro-4-methoxypyrida-
zin-3.2H)-one .3a). To a magnetically stirred solution of
2-benzyl-4,5-dichloropyridazin-362H)-one 62a) 64.47 mmol,
1.14 g) in dry dioxane 620 mL) was added 1.0 mL of a
4.86 M NaOCH3 solution. The solution was stirred at
room temperature for 1 h 6the ¯ask was equipped with a
drying tube) and then poured into 100 mL H2O/150 mL
CH2Cl2. The organic layer was separated and dried on
MgSO4 and evaporated to dryness. The residue was puri®ed
by ¯ash column chromatography on silica gel with CH2Cl2
as the eluent; yield: 0.83 g, 74% 6oil); nmax 6liquid ®lm):
1638, 1587, 1455, 1311, 1260, 1028, 951, 727, 699,
618 cm21; dH 6DMSO-d6): 8.04 6s, 1H, H-6), 7.26±7.36
6m, 5H, Ph), 5.25 6s, 2H, CH2), 4.16 6s, 3H, OCH3); dC
6DMSO-d6): 156.4, 150.9, 137.5, 136.2, 128.4, 127.9,
127.6, 122.4, 60.2, 54.3; LRMS 6ESI): 251.1, 91.1; HRMS
6ESI) for C12H12ClN2O2 [M1H]1 found: 251.0594 calcd:
251.0587.
1.2.2. 2-.5-Methoxy-1-methyl-6-oxo-1,6-dihydropyrida-
zin-4-yl)benzaldehyde .5b). Yield: 0.36 g, 74%; mp 114±
1168C 6white solid); nmax 6KBr): 3065, 3011, 2940, 1692,
1648, 1600, 1521, 1442, 1408, 1305, 1202, 1045, 997, 921,
757 cm21; dH 6CDCl3): 9.92 6s, 1H, CHO), 8.01 6d, Jˆ
7.6 Hz, 1H, H-6), 7.70 6dt, Jˆ7.3, 1.3 Hz, 1H, H-4), 7.64
6s, 1H, H-30), 7.58 6t, Jˆ7.5 Hz, 1H, H-5), 7.32 6d, Jˆ
7.3 Hz, 1H, H-3), 4.05 6s, 3H, OCH3), 3.85 6s, 3H,
NCH3); dC 6CDCl3): 190.6, 137.8, 133.8, 133.6, 130.1,
129.3, 129.2, 60.2, 40.1; LRMS 6ESI): 245.1; HRMS
6ESI) for C13H13N2O3 [M1H]1 found: 245.0931 calcd:
245.0926.
1.1.3. Synthesis of 2-benzyl-4-chloro-5-methoxypyrida-
zin-3.2H)-one .4a). To a magnetically stirred solution of
2-benzyl-4,5-dichloropyridazin-362H)-one 62a) 64.47 mmol,
1.14 g) in dry methanol 620 mL) was added 1.3 mL of a
4.86 M NaOCH3 solution. The solution was stirred at
room temperature for 1 h 6the ¯ask was equipped with a
drying tube) and then poured into 100 mL H2O/150 mL
CH2Cl2. The organic layer was separated and dried over
MgSO4 and evaporated to dryness yielding the title
compound 60.95 g, 85%); mp 948C 6white solid); nmax
6KBr): 1638, 1601, 1457, 1407, 1315, 1282, 1207, 1172,
942, 875, 749, 700, 516 cm21; dH 6DMSO-d6): 8.28 6s,
1H, H-6), 7.26±7.36 6m, 5H, Ph), 5.29 6s, 2H, CH2), 4.07
6s, 3H, OCH3); dC 6DMSO-d6): 157.5, 155.2, 136.4, 128.4,
128.0, 127.9, 127.6, 114.3, 58.1, 54.8; LRMS 6ESI): 251.1,
91.1; HRMS 6ESI) for C12H12ClN2O2 [M1H]1 found:
251.0583 calcd: 251.0587.
1.2.3. 2-.2-Benzyl-5-methoxy-3-oxo-2,3-dihydropyrida-
zin-4-yl)benzaldehyde .6a). Yield: 0.54 g, 85%; mp
1088C 6white solid); nmax 6KBr): 1693, 1622, 1597, 1274,
1246, 1160, 703 cm21; dH 6DMSO-d6): 9.76 6d, Jˆ0.6 Hz,
1H, CHO), 8.34 6s, 1H, H-60), 7.90 6ddd, Jˆ7.6, 1.4, 0.5 Hz,
1H, H-6), 7.70 6dt, Jˆ7.6, 1.4 Hz, 1H, H-4), 7.57 6tdd, Jˆ
7.6, 1.2, 0.6 Hz, 1H, H-5), 7.40 6ddd, Jˆ7.8, 1.2, 0.5 Hz,
1H, H-3), 7.26±7.37 6m, 5H, Ph), 5.27 and 5.32 62£br d,
Jù14.1 Hz, 2H, CH2 diastereotopic), 3.91 6s, 3H, OCH3);
dC 6DMSO-d6): 191.5, 160.0, 155.6, 136.8, 134.1, 133.4,
133.3, 131.7, 128.9, 128.6, 128.4, 127.8, 127.7, 127.4,
117.5, 57.5, 54.2; LRMS 6ESI): 321.2; HRMS 6ESI) for
C19H17N2O3 [M1H]1 found: 321.1254 calcd: 321.1239.
1.2. General procedure for the Suzuki cross-coupling
reaction .5a, 5b, 6a, 6b)
1.2.4. 2-.5-Methoxy-2-methyl-3-oxo-2,3-dihydropyrida-
zin-4-yl)benzaldehyde .6b). Yield: 0.39 g, 80%; mp 163±
1658C 6white solid); nmax 6KBr): 3054, 2952, 2855, 1690,
1626, 1593, 1389, 1275, 1193, 1165, 965, 784, 760, 723,
696, 538 cm21; dH 6CDCl3): 9.82 6s, 1H, H-CHO), 7.97 6dd,
Jˆ7.5, 1.3 Hz, 1H, H-6), 7.90 6s, 1H, H-30), 7.64 6dt, Jˆ7.4,
1.5 Hz, 1H, H-4), 7.51 6t, Jˆ7.4 Hz, 1H, H-5), 7.32 6dd,
Jˆ7.5, 1.3 Hz, 1H, H-3), 3.85 6s, 3H, OCH3), 3.82 6s, 3H,
NCH3); dC 6CDCl3): 190.9, 155.6, 134.2, 133.4, 131.3,
128.8, 128.7, 126.7, 57.1, 40.4; LRMS 6ESI): 245.1,
The pyridazin-362H)-ones 3a, 3b, 4a or 4b 62.0 mmol) were
dissolved in dimethoxyethane 612 mL). Pd6PPh3)4 60.10
mmol, 0.12 g) was added at room temperature under an
argon ¯ow. After stirring at room temperature for 10 min,
2-formylphenylboronic acid 63.2 mmol, 0.480 g) and aq.
Na2CO3 610 wt%, 2 mL) were added. Subsequently, the
reaction mixture was re¯uxed 6oil bath temperature:
1108C) with stirring under argon atmosphere 6reaction
time: 3a and 3b 6 h, 4a and 4b 24 h). After 3 h of re¯ux,

Z. Riedl et al. / Tetrahedron 58 (2002) 5645±5650
5649
217.1; HRMS 6ESI) for C13H13N2O3 [M1H]1 found:
245.0938 calcd: 245.0926.
212.1; HRMS 6ESI) for C12H10N3O [M1H]1 found:
212.0816 calcd: 212.0824.
1.4. General procedure for the debenzylation of 7a and
8a
1.3. General procedure for the ring closure of 5 and 6
A
mixture of pyridazinoisoquinolinone 67a or 8a,
A mixture of pyridazin-362H)-one 65 or 6, 2.0 mmol),
CH3OH 640 mL) and NH4OH 620 mL, 28±30 wt%) was
heated at 608C for 0.5 h. After cooling, the precipitate was
®ltered off and rinsed well with CH3OH 630 mL).
1.0 mmol), AlCl3 66.0 mmol, 0.8 g) and toluene 630 mL)
was stirred and heated at 708C for 1 h 6the re¯ux condenser
was equipped with a drying tube). After cooling, H2O
65 mL) was added. Subsequently, the mixture was ®ltered
and rinsed well with H2O 680 mL). The residue was puri®ed
by ¯ash column chromatography on silica gel.
1.3.1. 3-Benzylpyridazino[4,5-c]isoquinolin-4.3H)-one
.7a). Yield: 0.53 g, 93%; mp 2408C 6white solid); nmax
6KBr): 1659, 1586, 1344, 773, 669 cm21; dH 6DMSO-d6):
9.67 6d, Jˆ0.8 Hz, 1H, H-6), 9.33 6s, 1H, H-1), 8.90 6br dd,
Jˆ8.4, 0.8 Hz, 1H, H-10), 8.41 6br ddd, Jˆ8.1 Hz, 1H,
H-7), 8.12 6ddd, Jˆ8.4, 7.0, ,1.3 Hz, 1H, H-9), 8.02
6ddd, Jˆ8.1, 7.0, ,1.1 Hz, 1H, H-8), 7.38 6br d, 2H,
o-Ph), 7.34 6br t, 2H, m-Ph), 7.28 6br t, 1H, p-Ph), 5.45 6s,
2H, CH2); dC 6DMSO-d6): 158.1, 157.1, 138.6, 137.1, 133.5,
132.8, 130.5, 129.7, 129.0, 128.7, 128.4, 127.8, 127.4,
123.3, 121.9, 54.3; LRMS 6ESI): 288.1, 106.1, 91.1;
HRMS 6ESI) for C18H14N3O [M1H]1 found: 288.1146
calcd: 288.1137.
1.4.1. Pyridazino[4,5-c]isoquinolin-4.3H)-one .9). Yield:
0.18 g, 93%; eluent for ¯ash column chromatography:
CH2Cl2±CH3OH 69:1); mp .3008C 6decomp.) 6white
solid); nmax 6KBr): 3154, 3022, 2921, 2873, 1660, 1556,
1341, 1232, 842, 766, 718 cm21; dH 6DMSO-d6): 9.65 6d,
Jù0.6 Hz, 1H, H-6), 9.25 6s, 1H, H-1), 8.89 6br dd, Jˆ8.4,
,0.6 Hz, 1H, H-10), 8.40 6br dd, Jˆ8.1, ,0.8 Hz, 1H, H-7),
8.11 6ddd, Jˆ8.4, 7.0, 1.4 Hz, 1H, H-9), 8.01 6ddd, Jˆ8.1,
7.0, 1.1 Hz, 1H, H-8); dC 6DMSO-d6): 159.3, 156.7, 139.0,
133.7, 132.7, 130.4, 129.7, 129.0, 128.9, 123.4, 122.5;
LRMS 6ESI): 198.1; HRMS 6ESI) for C11H8N3O [M1H]1
found: 198.0669 calcd: 198.0667.
1.3.2. 3-Methylpyridazino[4,5-c]isoquinolin-4.3H)-one
.7b). Yield: 0.38 g, 91%; mp 287±2958C 6white solid);
nmax 6KBr): 3062, 3043, 1656, 1580, 1341, 939, 786, 769,
696 cm21; dH 6CDCl3): 9.56 6d, Jˆ0.7 Hz, 1H, H-6), 8.86
6s, 1H, H-1), 8.51 6dd, Jˆ7.5, 0.7 Hz, 1H, H-10), 8.19 6dd,
Jˆ7.8, 1.4 Hz, 1H, H-7), 8.02 6ddd, Jˆ7.5, 7.1, ,1.3 Hz,
1H, H-9), 7.91 6ddd, Jˆ7.8, 7.1, ,1.4 Hz, 1H, H-8), 4.01 6s,
3H, NCH3); dC 6CDCl3): 159.7 6C-4), 157.3 6C-6), 139.3
6C-4a), 132.9 6C-9), 132.1 6C-1), 130.4 6C-8), 130.3
6C-10a), 129.4 6C-7), 129.3 6C-6a), 122.6 6C-10), 122.2
6C-1a), 40.5 6NCH3); LRMS 6ESI): 212.1; HRMS 6ESI)
for C12H10N3O [M1H]1 found: 212.0824 calcd: 212.0824.
1.4.2. Pyridazino[4,5-c]isoquinolin-1.2H)-one .10). Yield:
0.15 g, 80%; eluent for ¯ash column chromatography:
CH2Cl2±CH3OH 695:5); mp .3008C 6decomp.) 6white±
pink solid); nmax 6KBr): 3163, 3097, 3050, 3000, 2887,
1658, 1617, 1557, 1432, 1392, 1236, 1149, 869, 826, 816,
767, 583, 500 cm21; dH 6DMSO-d6): 13.23 6br s, 1H, NH),
9.82 6br dd, Jˆ8.4, ,1.1 Hz, 1H, H-10), 9.76 6d, Jù0.8 Hz,
1H, H-6), 8.57 6s, 1H, H-4), 8.41 6br d, Jù8.0 Hz, 1H, H-7),
8.12 6ddd, Jˆ8.4, 7.1, ,1.3 Hz, 1H, H-9), 7.99 6ddd, Jˆ8.0,
7.1, ,1.1 Hz, 1H, H-8); dC 6DMSO-d6): 161.2, 159.7,
143.5, 139.4, 133.3, 131.2, 129.6, 129.0, 128.3, 126.2,
117.5; LRMS 6ESI): 198.1; HRMS 6ESI) for C11H8N3O
[M1H]1 found: 198.0672 calcd: 198.0667.
1.3.3. 2-Benzylpyridazino[4,5-c]isoquinolin-1.2H)-one
.8a). Yield: 0.49 g, 86%; mp 1738C 6white solid); nmax
6KBr): 1643, 1495, 772, 751, 717, 697, 513 cm21; dH
6DMSO-d6): 9.82 6ddd, Jˆ8.5, ,1.1, ,0.7 Hz, 1H, H-10),
9.76 6d, Jù0.7 Hz, 1H, H-6), 8.67 6s, 1H, H-4), 8.41 6br ddd,
Jˆ8.1, ,1.4, ,0.7 Hz, 1H, H-7), 8.12 6ddd, Jˆ8.5, 7.0,
,1.4 Hz, 1H, H-9), 8.00 6ddd, Jˆ8.1, 7.0, ,1.1 Hz, 1H,
H-8), 7.40 6br d, 2H, o-Ph), 7.34 6br t, 2H, m-Ph), 7.28 6br
t, 1H, p-Ph), 5.49 6s, 2H, CH2); dC 6DMSO-d6): 159.9,
159.5, 143.0, 139.2, 137.0, 133.5, 131.2, 129.7, 129.2,
128.5, 128.4, 127.8, 127.4, 126.3, 117.3, 54.4; LRMS
6ESI): 288.1, 106.1; HRMS 6ESI) for C18H14N3O [M1H]1
found: 288.1138 calcd: 288.1137.
Acknowledgements
Funding by OTKA 33105, 31910, ETT 187/2000 and RAFO
RUCA is gratefully acknowledged. Dr B. Maes thanks the
Fund for Scienti®c Research 6FWO-Vlaanderen) for an
appointment as post-doctoral fellow. The authors wish to
Á
thank Professor Dr E. Esmans and Professor Dr F. Lemiere
for the use of their MS facilities, Professor Dr R. Dommisse for
the use of his NMR facilities, Dr O. Egyed for NMR assign-
ments, and Ing. J. Aerts, J. Schrooten, Ing. W. Van Dongen, V.
Van Heurck and Ing. J. Verreydt for technical assistance.
1.3.4. 2-Methylpyridazino[4,5-c]isoquinolin-1.2H)-one
.8b). Yield: 0.40 g, 95%; mp 149±1518C 6white solid);
nmax 6KBr): 3124, 3058, 3033, 2989, 1645, 1578, 1551,
References
1500, 1436, 1398, 1241, 1011, 902, 814, 792, 767 cm21
;
dH 6CDCl3): 9.98 6d, Jˆ8.4 Hz, 1H, H-10), 9.53 6s, 1H,
H-6), 8.55 6s, 1H, H-4), 8.15 6d, Jˆ8.1 Hz, 1H, H-7), 8.04
6ddd, Jˆ8.1, 7.0, ,1.5 Hz, 1H, H-9), 7.88 6ddd, Jˆ8.1, 7.0,
,1.1 Hz, 1H, H-8), 4.00 6s, 3H, NCH3); dC 6CDCl3): 161.4
6C-1), 159.5 6C-6), 143.8 6C-4a), 139.3 6C-4), 133.6 6C-9),
132.5 6C-10a), 129.8 6C-8), 128.7 6C-7), 127.8 6C-10),
127.6 6C-6a), 118.5 6C-1a), 40.5 6NCH3); LRMS 6ESI):
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