Is samoquasine A indeed benzo[f]phthalazin-4(3H)-one? Unambiguous, straightforward synthesis of benzo[f]phthalazin-4(3H)-one and its regioisomer benzo[f]phthalazin-1(2H)-one

Article abstract of DOI:10.1016/j.tet.2007.02.031

In search for the structural elucidation of samoquasine A, a natural product isolated from the seeds of Annona squamosa L., two benzo[f]phthalazinone isomers have been synthesized. The synthetic pathway followed to build up these skeletons is based on the combination of two Suzuki reactions on a pyridazinone precursor and a ring closure reaction via a condensation reaction. ¹H NMR data of the synthesized compound allowed to establish that the structure of the natural product samoquasine A is not benzo[f]phthalazin-4(3H)-one, as previously suggested.

Full text of DOI:10.1016/j.tet.2007.02.031

Tetrahedron 63 (2007) 3870–3881
Is samoquasine A indeed benzo[f]phthalazin-4(3H)-one?
Unambiguous, straightforward synthesis of benzo[f]phthalazin-
4(3H)-one and its regioisomer benzo[f]phthalazin-1(2H)-one
a
Katrien Monsieurs, Pal Tapolcsanyi, Kristof T. J. Loones, Gabor Neumajer,
b
a
b
ꢀ
J. A. Dirk De Ridder, Kees Goubitz, Guy L. F. Lemiere, Roger A. Dommisse,
ꢀ
ꢀ
c,y
c
a
a
ꢁ
Peter Matyus and Bert U. W. Maes
b,
a,
*
*
ꢀ
ꢀ
aDepartment of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium
bDepartment of Organic Chemistry, Semmelweis University, H-1092 Budapest, HTgyes E. u. 7., Hungary
cLaboratory for Crystallography, HIMS, FNWI, Universiteit van Amsterdam, Valckenierstraat 65,
NL-1018 XE Amsterdam, The Netherlands
Received 22 December 2006; revised 2 February 2007; accepted 8 February 2007
Available online 13 February 2007
Abstract—In search for the structural elucidation of samoquasine A, a natural product isolated from the seeds of Annona squamosa L., two
benzo[f]phthalazinone isomers have been synthesized. The synthetic pathway followed to build up these skeletons is based on the combination
of two Suzuki reactions on a pyridazinone precursor and a ring closure reaction via a condensation reaction. 1H NMR data of the synthesized
compound allowed to establish that the structure of the natural product samoquasine A is not benzo[f]phthalazin-4(3H)-one, as previously
suggested.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
N
N
NH
NH
NH
O
O
O
The custard apple, Annona squamosa L. (Annonaceae), is a
tropical fruit tree that grows mainly in America and South-
East Asia. The seeds contain many polyketides (acetoge-
nins) showing a wide variety of different biological activities
as well as waxy substances containing long-chain fatty
acids. In 2000 investigation on seed extracts by Japanese re-
searchers resulted in the isolation of a new minor cytotoxic
alkaloid, samoquasine A.1a,2 A detailed spectroscopic anal-
ysis pointed benzo[h]quinazolin-4(3H)-one (1) as the chem-
ical structure of samoquasine A (Fig. 1). Two years later, the
same researchers stated, without further argumentation, the
alkaloid perlolidine (2) to be identical with samoquasine A
(Fig. 1), accordingly they withdrew the trivial name samo-
quasine A.1b In January 2003, a Taiwanese group reported
a synthesis for benzo[h]quinazolin-4(3H)-one (1).3 Compar-
ison of the 1H NMR spectral data of this compound with the
reported data of samoquasine A clearly confirmed that the
N
1
2
3
Figure 1. Benzo[h]quinazolin-4(3H)-one (1), perlolidine (2), and benzo-
[f]phthalazin-4(3H)-one (3).
chemical structure of samoquasine A is not benzo[h]quin-
azolin-4(3H)-one (1). In the same paper Wu’s group sug-
gested samoquasine A to be benzo[f]phthalazin-4(3H)-one
(3). The formal movement of the N-1 nitrogen in 1 from
position 1 to 2 is still in agreement with the reported NMR
data and observed long-range hydrogen–carbon correlations
in the HMBC spectrum of samoquasine A. In November
2003, Chakrabarty and co-workers provided further confir-
mation for the non-identity of samoquasine Awith 1.4 More-
over, they clearly showed on the basis of a difference in
melting points, solubility data, and the absence of a signal
in a specific region of the 13C NMR spectrum of perlolidine
that it is highly doubtful that the chemical structure of
samoquasine A is identical to that of 2.
Keywords: Suzuki reaction; Condensation; Natural product; Benzophthal-
azine.
* Corresponding authors. Fax: +32 3265 3233 (B.U.W.M.); fax: +36 1217
0851 (P.M.); e-mail addresses: peter.matyus@szerves.sote.hu; bert.maes@
ua.ac.be
y
In this manuscript, as a part of our studies on the synthesis of
aza-heterocyclic compounds with biological activities, we
Present address: SinPowCrys, August Van De Wielelei, 303/bus 3, B-2100
Antwerp, Belgium.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.031

K. Monsieurs et al. / Tetrahedron 63 (2007) 3870–3881
3871
now describe the first synthesis of benzo[f]phthalazin-
4(3H)-one (3), in order to confirm or reject this chemical
structure as the structure of the natural product, and to elab-
orate a new efficient and flexible approach to access this
class of compounds. We followed our well-established strat-
egy, in which we started from pyridazine precursors and uti-
lized the combination of a palladium-catalyzed C–C bond
forming process and a C–X (X¼N, O) or another C–C
bond forming reaction (for C–X: nucleophilic substitution,
condensation, lactonization, nitrene C–H insertion, and
Buchwald–Hartwig amination; for C–C: Pschorr reaction,
Heck-type reaction) to obtain pyridazino-fused ring sys-
tems.5 In this article, syntheses of benzophthalazinone
regioisomers, as new examples of such an approach, are de-
scribed by a combination of two Suzuki reactions (arylation,
methylation) with an intramolecular condensation reaction.
of the pyridazin-3(2H)-one, depending on the solvent, and
after the first Suzuki reaction the methoxy substituent can
be easily transformed into a leaving group making an appro-
priate substrate for a second Suzuki reaction yielding the 5-
substituted 4-methylpyridazinone (Schemes 1 and 2). For
the N-2 protection of the commercially available 4,5-di-
chloropyridazin-3(2H)-one (4) benzyl and benzyloxymethyl
groups were selected since these should be easily removable
at the end of the planned reaction sequence (Scheme 1).7,8
The applicability of the Suzuki reaction for the introduction
of aromatic rings in chloro-methoxypyridazin-3(2H)-ones
has extensively been investigated by the Antwerp team,
but it is well known that Suzuki reactions in general become
more problematic when used for the introduction of aliphatic
substituents.9 Only a few publications about Suzuki methyl-
ations were published when we first started to work on this
topic and during our study.9–15 Moreover, there was only
one report dealing with the specific methylation of a pyrid-
azinone skeleton, namely 4,5-dichloro-2-methylpyridazin-
3(2H)-one, by use of trimethylboroxine as methylating agent
and an oxime-derived palladacycle as the catalyst.13b In this
case, due to the presence of the two chlorine atoms, a mixture
of 2,4,5-trimethylpyridazin-3(2H)-one and 4-chloro-2,5-
dimethyl-pyridazin-3(2H)-one was formed. Unfortunately
the isolated yield of 4-chloro-2,5-dimethylpyridazin-3(2H)-
one was rather low (35%). Since our approach required a
4-methylpyridazin-3(2H)-one a different approach had to
be followed. As a first test experiment the Suzuki methyla-
tion reaction of 2-benzyloxymethyl-4-chloro-5-methoxy-
pyridazin-3(2H)-one (6a) with methylboronic acid was
attempted under standard Gronowitz reaction conditions
(Table 1, entry 1).16 The reaction was finished after 24 h
and produced the desired 2-benzyloxymethyl-5-methoxy-
2. Results and discussion
The retrosynthetic analysis opted for is shown in Figure 2.
2-Protected 5-(2-formylphenyl)-4-methylpyridazin-3(2H)-
one (10) could be considered as a convenient precursor for
3 via a cyclization that could be achieved by a condensation
reaction. The 4-methylpyridazinone should be accessible
from a suitable pyridazinone precursor, which allows a regio-
selective Suzuki reaction.
To avoid regioselectivity problems in a Suzuki reaction on
easily accessible 2-protected 4,5-dichloropyridazin-3(2H)-
ones, a provisionally masked functionality was introduced
in the 5-position of this compound.5,6 As we have recently
shown a methoxy group is optimal for this purpose since it
can be regioselectively introduced in the 4- or 5-position
N
X
N
N
R
O
O
R
O
H
N
R
O
N
N
N
NH
O
Y
CH3
Deprotection
Condensation
Suzuki reactions
3
Figure 2. Retrosynthetic analysis of benzo[f]phthalazin-4(3H)-one (3).
a)
b)
CH2OCH2Cl
N
H
O
N
R
N
R
O
N
R
O
MeB(OH)2
DBU, DMF, 0°C
CH3ONa
N
N
N
N
dry CH3OH
Pd(PPh3)4
MeO
Cl
O
CH2Cl
K2CO3
Cl
MeO
RT
2M Na2CO3
DME
Cl
Me
Cl
Cl
µW, 120°C
TBAB, CH3CN, reflux
4
5a: R=BOM : 70%
5b: R=Bn : 81%
7a: R=BOM : 74%
7b: R=Bn : 82%
6a: R=BOM : 91%
6b: R=Bn : 85%
Scheme 1. Synthesis of 2-substituted 4-methyl-5-methoxypyridazin-3(2H)-one (7).
For 11a:
85% H3PO4
B(OH)2
Phenol
N
R
O
N
R
O
O
H
N
R
O
N
R
KOH
Tf2O
Cs2CO3
THF
150 ºC
N
CHO
N
N
N
7
3
Et3N
CH2Cl2
-5 ºC
Pd(PPh3)4
2M Na2CO3
DME
For 11b:
AlCl3
H2O
reflux
HO
TfO
O
µW, 130 °C
Me
Me
Me
Toluene
70 ºC
reflux
9
10a: R=BOM : 82%
10b: R=Bn : 77%
11a: R=BOM : 92%
11b: R=Bn : 91%
8a: R=BOM : 88%
8b: R=Bn : 90%
Scheme 2. Synthesis of benzo[f]phthalazin-4(3H)-one (3).

3872
K. Monsieurs et al. / Tetrahedron 63 (2007) 3870–3881
Table 1. Methylation of 6a by Suzuki reaction
reaction with 2-formylphenylboronic acid under Gronowitz
reaction conditions (Scheme 2).
N
BOM
N
BOM
O
N
N
MeB(OH)2
MeO
O
MeO
Having precursors 10 in hands we investigated their ring
closure to benzo[f]phthalazin-4(3H)-ones 11. For these reac-
tions we used our experience in the ring closure reaction
of 20-methylbiphenyl-2-carbaldehydes to phenanthrenes.20
Remarkably, Cs2CO3 as base in DMF at a temperature of
200 ꢀC proved to be suitable for the phenanthrene synthesis.
Due to the temperature dependence of pKa, and carefully
designed conditions, the intramolecular condensation of
20-methylbiphenyl-2-carbaldehydes became feasible in the
presence of a weak base at high temperature. When compar-
ing the 2-substituted 5-(2-formylphenyl)-4-methylpyrida-
zin-3(2H)-ones (10) to 20-methylbiphenyl-2-carbaldehyde,
the methyl groups of 10 clearly will be more acidic due to
the electron withdrawing effect of the 4-pyridazinyl unit.
Therefore the high-boiling solvent was replaced by THF
and a reaction temperature of only 130 ꢀC was selected.
The results for the optimization of the ring closure reaction
of 2-benzyloxymethyl-5-(2-formylphenyl)-4-methylpyrida-
zin-3(2H)-one (10a) are summarized in Table 2. Again, mi-
crowave irradiation was utilized to heat up the reaction
mixture. We changed to the Mars unit (multimode) since
we earlier found that the heating efficiency of the Discover
unit (single mode), using the 80 mL closed vessel filled
with 20 mL of solvent with a low tan d value (like THF),
was low.21 The Mars microwave apparatus is a multimode
microwave oven with a maximum power output of
1200 W and more suitable for heating up larger volumes of
poor microwave energy-heat converters. Entry 1 shows
that the ring closure of 10a took place very smoothly under
the selected reaction conditions. The reaction is completed
after only 45 min and the 3-benzyloxymethylbenzo[f]phtha-
lazin-4(3H)-one (11a) could be isolated in excellent yield.
Also in this case a rough comparative experiment was set
up to have an indication if microwave effects have to be
taken into account.17 The reaction was thus repeated in
a closed vessel in a preheated oil bath with fiber optic tem-
perature measurement (Table 2, entry 2). The reaction
gave the same result as the one in which microwave irradia-
tion was used so also in this case only the temperature
parameter in the Arrhenius equation is responsible for
the fast reactions. Since the condensation proceeded so
smoothly the question rose if a temperature of 130 ꢀC is
really essential for the reaction to proceed. Therefore, the
ring closure reaction was also performed in refluxing THF.
Although a 45 min reaction time turned out to be insuffi-
cient, a complete conversion of the substrate could be
achieved after 2 h. The ring closure reaction of 10b to 3-
benzylbenzo[f]phthalazin-4(3H)-one (11b) was carried out
Pd(PPh3)4
2M Na2CO3
DME
Cl
Me
6a
7a
Entry Heating method
Temperature (ꢀC) Time (h) Yield (%)
1
Oil bath
(atm. pressure)
mW
mW
mW
Reflux
24
71
2
3
4
5
120
120
160
4
2
1
4
74
—
80
77
a
Preheated oil bath 120
(pressure tube)
a
No complete conversion of 6a.
4-methylpyridazin-3(2H)-one (7a) in good yield. To exam-
ine whether the reaction time could be shortened by raising
the reaction temperature we repeated the experiment in an
80 mL closed vessel at 120 ꢀC in a single mode microwave
apparatus (CEM, Discover). In this case complete conver-
sion of substrate was obtained in less than 4 h (Table 1, entry
2). Since online monitoring of the microwave experiment
(by taking aliquots) is not possible a similar experiment in
a reaction time of 2 h was also attempted. The reaction
time turned out to be insufficient for complete conversion
of 6a (Table 1, entry 3). By further increasing the reaction
temperature to 160 ꢀC, the reaction time could be further re-
duced to 1 h (Table 1, entry 4). Finally, a rough control ex-
periment was carried out in which a sealed tube containing
the reaction mixture was placed in a preheated oil bath.
The inner temperature of the mixture was monitored by fiber
optic temperature measurement and the temperature of the
oil bath was adjusted so that the inner temperature of the
mixture was 120 ꢀC.17 As in the case of microwave heating,
the reaction was finished in 4 h and about the same yield of
7a was obtained after work-up and purification (Table 1, en-
try 5). This rough comparison indicates that no (useful) spe-
cial microwave effects have to be taken into account for this
type of reaction. For the methylation of the 2-benzyl deriv-
ative 6b, also standard oil bath heating at reflux and micro-
wave irradiation at 120 ꢀC were tested. Both gave good
results, although in the case of the reflux experiment under
conventional heating a substantially longer reaction time
(5 days) was required. While our work was in progress an
alternative procedure for the methylation of halopyridazi-
nones has been published by Stevenson and co-workers, in
which trimethylaluminum is used as the transmetalating
agent with Pd(PPh3)4 as the catalyst.18 Unfortunately, meth-
ylation of 2-substituted 4,5-dichloropyridazin-3(2H)-ones
using 1 equiv of trimethylaluminum afforded 4,5-dimethyl-
pyridazin-3(2H)-ones and no regioselectivity could be
achieved.
Table 2. Ring closure reaction of 10a
N
O
H
N
BOM
BOM
O
N
N
4 equiv. Cs2CO3
THF
O
Once the methylation reaction was optimized, the methoxy
group on C-5 was converted to a triflate in two steps to obtain
a leaving group for a Suzuki reaction at this position
(Scheme 2). Our previously described reaction conditions
for both the hydrolysis and the subsequent triflation reaction
of methoxypyridazin-3(2H)-ones could be adopted without
any problem.19 Due to their potential instability, the triflates
9 were not purified but immediately subjected to a Suzuki
Me
10a
11a
Temperature (ꢀC) Time (min) Yield (%)
Entry Heating method
1
2
mW
130
45
45
92
94
Preheated oil bath 130
(pressure tube)

K. Monsieurs et al. / Tetrahedron 63 (2007) 3870–3881
3873
proved that the structure of the natural product samoquasine
A is not benzo[f]phthalazin-4(3H)-one (3).
Since the identity of the structure of samoquasine A remains
unsolved, it seemed worthwhile to synthesize also benzo-
[f]phthalazin-1(2H)-one (17), an isomer of benzo[f]phthal-
azin-4(3H)-one (3), which was also taken into consideration
as a possible candidate for the chemical structure of samo-
quasine A. Moreover the strategy we applied for the synthe-
sis of benzo[f]phthalazin-4(3H)-one (3), should only require
a minor adaptation to give access to its regioisomer benzo-
[f]phthalazin-1(2H)-one (17). Indeed, by carrying out the
methoxylation of 2-substituted 4,5-dichloropyridazin-3(2H)-
ones (5) in dry dioxane as the solvent instead of dry metha-
nol, the methoxy group is introduced at position 4 instead
of position 5.8 This small change allows to prepare the iso-
mer while all the subsequent reactions can be carried out
completely analogously to the above-described procedures
(Scheme 3). For the methylation reaction again both conven-
tional heating and microwave irradiation in a closed vessel
were tested and gave also similar results. The same goes
for the ring closure reaction, for which the microwave heated
reaction as well as the reaction under conventional heating in
a closed vessel and at reflux gave excellent yields, albeit that
also in this case the reflux experiment required a longer re-
action time. Since the earlier described deprotection reaction
on benzo[f]phthalazin-4(3H)-one (3) showed that both a
benzyloxymethyl and a benzyl group could be removed
smoothly at the end of the sequence, only a benzyl group
was chosen as the protective group for the synthesis of 17.
Comparison of the 1H NMR data of 17 with those described
for samoquasine A (Table 3) clearly revealed that also
benzo[f]phthalazin-1(2H)-one could be excluded as the
structure of samoquasine A. The structure of compound 17
was also confirmed by powder X-ray diffraction (Fig. 4).23
Figure 3. Powder X-ray diffraction confirms the structure of benzo[f]phtha-
lazin-4(3H)-one (3).
under the same microwave conditions as described in entry 1
of Table 2 and also proceeded smoothly.
Finally, the last step to obtain benzo[f]phthalazin-4(3H)-one
(3) consisted of the removal of the N-2 protecting group of
the pyridazinone moiety. The deprotection of 11a went
smoothly in orthophosphoric acid in the presence of phenol,7
and in the case of 11b AlCl3 was used as the deprotecting
agent (Scheme 2).8 Besides NMR, IR, and MS analysis
also powder X-ray diffraction confirmed the structure of
benzo[f]phthalazin-4(3H)-one (3) (Fig. 3).22 When we com-
pared the 1H NMR data of benzo[f]phthalazin-4(3H)-one (3)
with those reported for samoquasine A by Morita et al.,1 it
immediately turned out that there are major differences be-
tween both data sets (Table 3). Therefore we unambiguously
Table 3. Comparison of the 1H NMR data of samoquasine A, benzo[f]phtha-
lazin-4(3H)-one (3) and benzo[f]phthalazin-1(2H)-one (17)
N
H
4
N
1
N
H
O
5
6
O
N
10
7
10
9
9
8
Samoquasine A
7
5
6
8
Although the procedure described for the synthesis of
benzo[f]phthalazin-4(3H)-one (3) and benzo[f]phthalazin-
1(2H)-one (17) is very efficient and allows complete regio-
selectivity it consists of a considerable number of steps.
Therefore we also looked at a classical procedure in which
the pyridazinone moiety is attached onto a carbocyclic skel-
eton by reaction of an ortho-dicarbonyl compound with hy-
3
17
dH (CDCl3)1a
dH (CDCl3)
dH (CDCl3)
9.60 s
11.02 s
9.01 s
8.56 m
8.41 dd
8.16 d
NH
H-1
H-10
H-5
H-6
10.36 s
NH
8.40 dd
8.12 dd
7.87 dt
7.71 dt
7.55 d
7.30 d
10.10 dd
8.28 s
8.24 d
8.00 dd
7.83 ddd
7.77 ddd
7.69 d
H-10
H-4
H-6
H-7
H-9
H-8
H-5
ꢂ
drazine (Scheme 4). In the late sixties, Stanovnik and Tisler
8.03 m
7.81–7.75 m
H-7
H-8,9
described a simple two-step synthesis of 1,4-dichlorobenzo-
[f]phthalazine (20) starting from commercially available
1,2-naphthalenedicarboxylic anhydride (18).24 When
B(OH)2
CHO
N
Bn
O
N
1) KOH / H2O
reflux, 83%
N
N
Bn
O
N
Bn
O
N
Bn
O
N
N
CH3ONa
MeB(OH)2
5b
Me
OHC
dry dioxane
RT
Pd(PPh3)4
2M Na2CO3
DME
Pd(PPh3)4
2M Na2CO3
DME, reflux
2) Tf2O
Et3N
CH2Cl2, -5 ºC
Cl
Me
Me
OMe
OMe
OTf
12
13
14
79%
15
84%
N
Bn
O
N
H
O
N
N
Cs2CO3
AlCl3
THF
µW, 130 °C
Toluene, 70 ºC
97%
90%
17
16
Scheme 3. Synthesis of benzo[f]phthalazin-1(2H)-one (17).

3874
K. Monsieurs et al. / Tetrahedron 63 (2007) 3870–3881
Cl
C1: 0.377*
N
* Electrostatic Charge
N
C4: 0.278*
Cl
Figure 5. Electrostatic charge of 1,4-dichloro[f]phthalazine (20) calculated
at semiempirical PM3 level.
Cl
AcO Cl
C1
N
N
N
N
Figure 4. Powder X-ray diffraction confirms the structure of benzo[f]-
phthalazin-1(2H)-one (17).
C4
Cl OAc
Cl
Meisenheimer complex I
Meisenheimer complex II
E = - 61.57 kcal/mol (Heat of Form.)
Dipole moment: 10.15 Debye
E = - 60.46 kcal/mol (Heat of Form.)
Dipole moment: 8.53 Debye
1,4-dichlorobenzo[f]phthalazine (20) is subjected to acidic
hydrolysis, formation of two different regioisomeric
reaction products is theoretically possible: 1-chlorobenzo-
[f]phthalazin-4(3H)-one (21) and 4-chlorobenzo[f]phthala-
zin-1(2H)-one (22). 1-Chlorobenzo[f]phthalazin-4(3H)-one
(21) is a direct precursor for benzo[f]phthalazin-4(3H)-one
(3), while 4-chlorobenzo[f]phthalazin-1(2H)-one (22) can be
converted to benzo[f]phthalazin-1(2H)-one (17). Since we
expected a mixture of 21 and 22 in the hydrolysis reaction,
and consequently possible purification problems of the
isomers, this ‘classical’ route was not explored as a first
approach for 3. Interestingly, the acidic hydrolysis of com-
pound 20 turned out to be very regioselective since mainly
4-chlorobenzo[f]phthalazin-1(2H)-one (22) (50%) and only
a trace of 1-chlorobenzo[f]phthalazin-4(3H)-one (21) (6%)
could be isolated.
Figure 6. Calculated heat of formation for both Meisenheimer complexes.
difference between the respective transition states) also
favors the substitution of 1-chloro group (Fig. 6). (Note: (a)
Since the dipole moments of the Meisenheimer complexes
are comparable their solvations are expected to be similar.
(b) Since the reaction is performed in acetic acid it is possible
that a neutral (protonated) intermediate is formed.)
Since the acidic hydrolysis of 20 gave only compound 22
in a practical yield, only the synthesis of benzo[f]phthal-
azin-1(2H)-one (17) from 22 was attempted. Conversion
of 4-chlorobenzo[f]phthalazin-1(2H)-one (22) to benzo[f]-
phthalazin-1(2H)-one (17) could be easily accomplished in
good yield by classical catalytic transfer hydrogenolysis us-
ing Pd/C. Therefore the ‘classical’ approach starting from 18
ispreferredforthesynthesisofbenzo[f]phthalazin-1(2H)-one
(17) while a practical synthesis of benzo[f]phthalazin-4(3H)-
one (3) can only be done following the double Suzuki—intra-
molecular condensation approach. It is important to mention
that also for the synthesis of 17 the ‘classical’, naphthalene-
based approach has an important drawback since the
complete removal of the trace amount of 21 from 22 requires
multiple purifications via column chromatography.
The regioselectivity of the kinetically controlled nucleo-
philic substitution of a chlorine atom with an acetoxy group
(under the experimental conditions the reaction is irrevers-
ible) can be well understood on the basis of some structural
parameters obtained at semiempirical PM3 level. It was
found that the atomic charges (derived from the electrostatic
potential) on the relevant carbons differ significantly from
each other: C1 (0.38) possesses a more positive charge
than C4 (0.28) (Fig. 5), while the LUMO (3¼ꢁ1.3864 eV)
coefficients on the same carbons are very close in their
values (0.42 vs 0.44). Accordingly, substitution of 1-chloro
is preferred (Fig. 6). The same conclusion can be drawn by
the comparison of the heat of formation values of the res-
pective Meisenheimer intermediates possessing a negative
charge. Their thermodynamic stability difference (which
according to the Hammond postulate reflects the stability
3. Conclusions
In summary, syntheses of two benzo[f]phthalazinone
isomers, benzo[f]phthalazin-4(3H)-one (3) and benzo[f]-
phthalazin-1(2H)-one (17), were accomplished in efficient
and straightforward pathways with complete control of
Cl
N
N
21
HN
HN
Cl
Cl
O
O
O
O
O
trace
50%
3
.
N
N
H2NNH2 H2O HN
POCl3
CH3COOH
reflux
O
HN
CH3COOH
N
O
O
130°C
Pd / C
HCOONH4
O
reflux
54%
HN
N
HN
N
18
20
19
22
EtOH / MeOH
reflux
67%
Cl
17
99%
Scheme 4. Classical heterocyclic approach for the synthesis of benzo[f]phthalazinone 17.

K. Monsieurs et al. / Tetrahedron 63 (2007) 3870–3881
3875
1
regioselectivity. Comparison of their H NMR data with
reduced pressure, water (100 mL) was added and the mix-
ture was extracted with ether (3ꢂ100 mL), the combined or-
ganic layers were washed with water (100 mL), dried over
Na2SO4, evaporated, and the residue was recrystallized
from methanol. The mother liquid was purified by column
chromatography on silica gel using dichloromethane as the
eluent to yield the title compound 5a (2.49 g, 70%) as white
crystals. Mp: 74–74.5 ꢀC (lit.,25 72–72.5 ꢀC); (Found: C,
50.9; H, 3.7; N, 9.8%; Calcd for C12H10Cl2N2O2: C,
50.55; H, 3.5; N, 9.8%); nmax (KBr)/cmꢁ1: 1654, 1586,
1204, 1088, 1072, 946, 866, 750, 730, 702, and 610; dH
(200 MHz, CDCl3, Me4Si): 4.73 (2H, s, CH2Ph), 5.57 (2H,
s, 2-N–CH2), 7.20–7.40 (5H, m, Ph), 7.78 (1H, s, 6-H); dC
(50 MHz, CDCl3, Me4Si): 72.4 (t), 80.4 (t), 127.7 (d, 2C),
127.9 (d), 128.3 (d, 2C), 134.8 (s), 136.0 (d), 136.9 (s),
137.0 (s), 160.0 (s).
those described by Morita for samoquasine A clearly shows
that neither benzo[f]phthalazin-4(3H)-one nor its 1(2H)-one
regioisomer is identical with the structure of the natural
product.
4. Experimental
4.1. General
€
Melting points were determined on a Buchi apparatus and are
uncorrected. The IR data were recorded on a Bruker Vector
22 spectrometer using potassium bromide pellets. The
NMR spectra were recorded on one of the following spec-
trometers: a Bruker Avance II 400, a Bruker AM200, a
Bruker Avance 500 or a Varian MP 400. TMS was used as in-
ternal standard. J values are given in hertz. The numbering
used for the assignment of NMR-signals is as follows: pyri-
dazinone ring simple figures, 5-substituents primed figures,
4-substituents double primed figures and N-substituents tri-
ple primed figures. For mass-spectrometric analysis, samples
were dissolved in CH3OH containing 0.1% formic acid and
diluted to a concentration of approximately 10ꢁ5 mol/L. In-
jections of 1 mL were directed to the mass spectrometer at
a flow rate of 5 mL/min (CH3OH, 0.1% formic acid), using
a CapLC HPLC system. Accurate mass data were acquired
on a Q-TOF 2 mass spectrometer equipped with a standard
electrospray ionization (ESI) interphase. Cone voltage
(approx. 35 V) and capillary voltage (approx. 3.3 kV) were
optimized on one compound and used for all others. For
the determination of the accurate mass of the molecular ion
[M+H]+, a solution of polyethylene glycol 300 in CH3OH/
H2O with 1 mmol ammonium acetate was added just before
the mass spectrometer (at a rate of 1 mL/min) to the mobile
phase. The calculated masses of PEG [M+H]+and
[M+NH4]+ions were used as lock mass. The microwave reac-
tions were carried out in a CEM Mars (multimode microwave
apparatus) or in a CEM Discover (single mode microwave
apparatus), as specified. The following starting compounds
and reagents were obtained from commercial sources: 4,5-
dichloropyridazin-3(2H)-one, 1,8-diazabicyclo[5.4.0]un-
dec-7-ene, tetrakistriphenylphosphinepalladium(0), benzyl
chloromethyl ether, methylboronic acid, trifluoromethane-
sulfonic anhydride, 2-formylphenylboronic acid, cesium car-
bonate, phenol, orthophosphoric acid, aluminum trichloride,
Pd/C, and ammonium formate. All commercial products
were used without extra purification. Compounds 5b,8 6b,8
12,8 and 2024 were prepared according to literature proce-
dures. Flash column chromatography was performed on Kie-
selgel 60 (ROCC, 0.040–0.063 mm). THF was freshly
distilled from sodium. Semiempirical PM3 calculations
were carried out by using the Spartan software package
(’04 Mechanics Program; PC/x86; full geometry optimiza-
tion: analytical gradient, MM/amide correction).
4.1.2. 2-Benzyloxymethyl-4-chloro-5-methoxypyridazin-
3(2H)-one (6a). 2-Benzyloxymethyl-4,5-dichloropyrid-
azin-3(2H)-one 5a (1.146 g, 4.02 mmol) was dissolved in
anhydrous methanol (25 mL). It was slightly warmed to get
solution in methanol and then cooled back to room temper-
ature. NaOMe solution (5 M) (1.2 mL, 6 mmol) was added
and the mixture was stirred at room temperature for 1 h in
a flask equipped with a drying tube. The mixture was poured
into water (150 mL), extracted with dichloromethane
(3ꢂ100 mL), the organic layer was washed with water
(1ꢂ100 mL), dried over Na2SO4, and evaporated to dryness.
The crude product was purified by column chromatography
on a short silica gel column with a mixture of ethyl acetate
and dichloromethane (1:9) to yield the title compound 6a
(1.032 g, 91%) as white crystals. Mp: 109–110 ꢀC; (Found:
C, 55.3; H, 4.65; N, 9.9%; Calcd for C13H13ClN2O3: C,
55.6; H, 4.7; N, 10.0%); nmax (KBr)/cmꢁ1: 2922, 1638,
1604, 1496, 1458, 1436, 1410, 1396, 1384, 1314, 1280,
1204, 1172, 1096, 1028, 998, 942, 904, 876, 830, 764, 734,
692, 652, 630, 568, 510, and 474; dH (200 MHz, CDCl3,
Me4Si): 4.07 (3H, s, 5-OMe), 4.72 (2H, s, CH2Ph), 5.59
(2H, s, 2-N–CH2), 7.25–7.40 (5H, m, Ph), 7.84 (1H, s,
6-H); dC (50 MHz, CDCl3, Me4Si): 57.7 (q), 72.1 (t), 80.0
(t), 116.8 (s), 127.1 (d), 127.8 (d, 3C), 128.3 (d, 2C),
137.2 (s), 155.0 (s), 159.2 (s); MS (ESI): 281, 251; HRMS
(ESI) calcd for C13H14ClN2O3 [M+H]+: 281.0693, found
281.0683.
4.1.3. 2-Benzyloxymethyl-5-methoxy-4-methylpyrida-
zin-3(2H)-one (7a).
4.1.3.1. Method 1: classic oil bath heating at reflux
temperature.
2-Benzyloxymethyl-4-chloro-5-methoxy-
pyridazin-3(2H)-one 6a (471 mg, 1.68 mmol) was dissolved
in 1,2-dimethoxyethane (10 mL) under an argon atmo-
sphere. Pd(Ph3P)4 (101 mg, 5 mol %), methylboronic acid
(151 mg, 1.5 equiv), and aqueous 2 M Na2CO3 solution
(3.35 mL) were added. Then the mixture was refluxed for
24 h under argon atmosphere. After cooling, water
(20 mL) was added and the mixture was extracted with di-
chloromethane (5ꢂ20 mL), dried over MgSO4, evaporated
to dryness, and purified by column chromatography on a sil-
ica gel column; eluent: ethyl acetate/toluene (1:4) to yield
the title compound 7a (310 mg, 71%) as white crystals.
4.1.1. 2-Benzyloxymethyl-4,5-dichloropyridazin-3(2H)-
one (5a). A solution of 4,5-dichloropyridazin-3(2H)-one
4a (2 g, 12.12 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-
ene (2.3 mL) in DMF (40 mL) was cooled to 0 ꢀC and ben-
zyl chloromethyl ether (5.3 mL, purity: 60%) was added.
The mixture was allowed to reach room temperature and
stirred overnight. Then the solvent was removed under
4.1.3.2. Method 2: microwave heating in a closed
vessel at 120 ꢀC.
2-Benzyloxymethyl-4-chloro-5-

3876
K. Monsieurs et al. / Tetrahedron 63 (2007) 3870–3881
methoxypyridazin-3(2H)-one 6a (471 mg, 1.68 mmol) was
dissolved in 1,2-dimethoxyethane (10 mL) in an 80 mL
microwave vessel under an argon atmosphere. Pd(Ph3P)4
(101 mg, 5 mol %), methylboronic acid (151 mg, 1.5 equiv),
and 2 M aqueous Na2CO3 solution (3.35 mL) were added.
The vessel was flushed with argon, closed, and placed into
a microwave apparatus (CEM, Discover). The mixture was
irradiated for 240 min at 120 ꢀC with a set power of 150 W.
After cooling, water (20 mL) was added and the mixture was
extracted with dichloromethane (5ꢂ20 mL), dried over
MgSO4, evaporated to dryness, and purified by column chro-
matography on a silica gel column; eluent: ethyl acetate/
toluene (1:4) to yield the title compound 7a (325 mg,
74%) as white crystals.
1636, 1604, 1454, 1400, 1368, 1334, 1306, 1266, 1228,
1160, 1072, 980, 898, 870, 736, 702, 524, 508, and 490;
dH (400 MHz, CDCl3, Me4Si): 2.04 (3H, s, 4-Me), 3.93
(3H, s, 5-OMe), 5.32 (2H, s, 2-N–CH2), 7.23–7.34 (3H, m,
3000-H, 4000-H, and 5000-H), 7.41 (2H, m, 2000-H and 6000-H),
7.76 (1H, s, 6-H); dC (100 MHz, CDCl3, Me4Si): 8.7 (q),
55.2 (t), 56.8 (q), 120.1 (s), 127.0 (d), 127.8 (d), 128.6 (d,
2C), 128.7 (d, 2C), 136.3 (s), 155.6 (s), 162.4 (s); MS
(ESI): 91; HRMS (ESI) for C13H15N2O2 [M+1]: calcd
231.1138, found 231.1123.
4.1.5. 2-Benzyloxymethyl-5-hydroxy-4-methylpyridazin-
3(2H)-one (8a). 2-Benzyloxymethyl-5-methoxy-4-methyl-
pyridazin-3(2H)-one 7a (1.004 g, 3.86 mmol) and KOH
(11.8 g) in water (335 mL) was refluxed overnight (14 h).
After cooling, the mixture was filtered on a glass filter under
vacuum, cooled in an ice-water bath, and concentrated HCl
(20 mL) was added. The precipitate was immediately fil-
tered, washed till neutral, and dried in a drying gun. No
further purification was needed. The title compound 8a
was isolated in 88% yield (833 mg) as white powder-like
crystals. Mp: 159–160 ꢀC; (Found: C, 63.45; H, 5.7; N,
11.45%; Calcd for C13H14N2O3: C, 63.4; H, 5.7; N,
11.4%); nmax (KBr)/cmꢁ1: 3070, 3028, 3004, 2946, 1642,
1594, 1390, 1368, 1134, 1070, 748, 704, and 610; dH
(200 MHz, DMSO-d6, Me4Si): 1.88 (3H, s, 4-Me), 4.59
(2H, s, CH2Ph), 5.39 (2H, s, 2-N–CH2), 7.20–7.40 (5H,
m, Ph), 7.70 (1H, s, 6-H), 11.00 (1H, br s, 5-OH); dC
(50 MHz, DMSO-d6, Me4Si): 8.3 (q), 70.5 (t), 78.7 (t),
114.7 (s), 127.5 (d, 3C), 128.2 (d, 2C), 132.1 (d), 137.8
(s), 154.8 (s), 162.5 (s); MS (ESI): 139, 111, 91; HRMS
(ESI) for C13H15N2O3 [M+1]: calcd 247.1069, found
247.1077.
Mp: 60–61 ꢀC; (Found: C, 64.5; H, 6.2; N, 10.8%; Calcd for
C14H16N2O3: C, 64.6; H, 6.2; N, 10.8%); nmax (KBr)/cmꢁ1
:
1646, 1635, 1610, 1467, 1380, 1337, 1278, 1229, 1161,
1099, 777, and 740; dH (400 MHz, CDCl3, Me4Si): 2.05
(3H, s, 4-Me), 3.96 (3H, s, 5-OMe), 4.71 (2H, s, CH2Ph),
5.57 (2H, s, 2-N–CH2), 7.27–7.37 (5H, m, Ph), 7.80 (1H,
s, 6-H); dC (50 MHz, CDCl3, Me4Si): 8.5 (q), 56.8 (q),
71.7 (t), 79.3 (t), 119.9 (s), 127.5 (d), 127.6 (d), 127.7 (d,
2C), 128.2 (d, 2C), 137.5 (s), 155.6 (s), 163.0 (s); MS
(ESI): 153, 91; HRMS (ESI) for C14H17N2O3 [M+1]: calcd
261.1239, found 261.1249.
4.1.4. 2-Benzyl-5-methoxy-4-methylpyridazin-3(2H)-one
(7b).
4.1.4.1. Method 1: classic oil bath heating at reflux
temperature.
2-Benzyl-4-chloro-5-methoxypyridazin-
3(2H)-one 6b (1.767 g, 7.05 mmol) was dissolved in 1,2-
dimethoxyethane (42 mL) under an argon atmosphere.
Pd(Ph3P)4 (408 mg, 5 mol %), methylboronic acid (634 mg,
1.5 equiv), and aqueous 2 M Na2CO3 solution (14.8 mL)
wereadded. Thenthemixturewasrefluxedforfivedaysunder
argon atmosphere. After cooling, water (60 mL) was added
and the mixture was extracted with dichloromethane (5ꢂ
50 mL), dried over Na2SO4, evaporated to dryness, and puri-
fied by column chromatography on a silica gel column with
a mixture of ethyl acetate and toluene (2:8) as the eluent
to yield the title compound 7b (992 mg, 61%) as white
crystals.
4.1.6. 2-Benzyl-5-hydroxy-4-methylpyridazin-3(2H)-one
(8b). 2-Benzyl-5-methoxy-4-methylpyridazin-3(2H)-one
7b (970 mg, 4.21 mmol) and KOH (13 g) in water (370 mL)
was refluxed overnight (14 h). After cooling, the mixture
was filtered on a glass filter under vacuum, cooled in an
ice-water bath, and concentrated HCl (21 mL) was added.
The precipitate was filtered, washed with water till neutral,
and dried in a drying gun. No purification was needed. The
title compound 8b was isolated in 90% yield (816 mg) as
white powder-like crystals. Mp: 235–237 ꢀC; (Found: C,
66.5; H, 5.6; N, 13.0%; Calcd for C12H12N2O2: C, 66.65;
H, 5.6; N, 13.0%); nmax (KBr)/cmꢁ1: 3066, 2960, 2924,
1642, 1564, 1394, 1266, 1222, 1146, 742, and 696; dH
(400 MHz, DMSO-d6, Me4Si): 1.89 (3H, s, 4-Me), 5.19
(2H, s, 2-N–CH2), 7.22–7.34 (5H, m, Ph), 7.69 (1H, s, 6-
H), 10.82 (1H, br s, 5-OH); dC (100 MHz, DMSO-d6,
Me4Si): 8.4 (q), 53.7 (t), 114.7 (s), 127.2 (d), 127.6 (d,
2C), 128.3 (d, 2C), 131.5 (d), 137.3 (s), 154.4 (s), 161.7
(s); MS (ESI): 91; HRMS (ESI) for C12H13N2O2 [M+1]:
calcd 217.0977, found 217.0980.
4.1.4.2. Method 2: microwave heating in a closed vessel
at 120 ꢀC. 2-Benzyl-4-chloro-5-methoxypyridazin-3(2H)-
one 6b (421 mg, 1.68 mmol) was dissolved in 1,2-dime-
thoxyethane (10 mL) in an 80 mL microwave vessel under
an argon atmosphere. Pd(Ph3P)4 (101 mg, 5 mol %), methyl-
boronic acid (151 mg, 1.5 equiv), and 2 M aqueous Na2CO3
solution (3.35 mL) were added. The vessel was flushed with
argon, closed, and placed into a microwave apparatus (CEM,
Discover). The mixture was irradiated for 240 min at 120 ꢀC
with a set power of 150 W. After cooling, water (20 mL) was
added and the mixture was extracted with dichloromethane
(5ꢂ20 mL), dried over Na2SO4, evaporated to dryness, and
purified by column chromatography on a silica gel column
with a mixture of ethyl acetate and toluene (2:8) as the eluent
to yield the title compound 7b (320 mg, 82%) as white
crystals.
4.1.7. 2-Benzyloxymethyl-5-(2-formylphenyl)-4-methyl-
pyridazin-3(2H)-one (10a). 2-Benzyloxymethyl-5-hydroxy-
4-methylpyridazin-3(2H)-one 8a (464 mg, 1.88 mmol) was
suspended in dry dichloromethane (14 mL) in a flask equip-
ped with drying tube. Triethylamine (0.37 mL, 2.58 mmol)
was added and the obtained solution was cooled to ꢁ5 ꢀC
on an ice–acetone bath. Trifluoromethanesulfonic anhydride
(0.37 mL, 2.19 mmol) was added dropwise. The mixture
Mp: 89–91 ꢀC; (Found: C, 68.0; H, 6.1; N, 12.3%; Calcd for
C13H14N2O2: C, 67.8; H, 6.1; N, 12.2%); nmax (KBr)/cmꢁ1
:

K. Monsieurs et al. / Tetrahedron 63 (2007) 3870–3881
3877
was stirred at this temperature for 30 min, then 1 M HCl
(10 mL) and dichloromethane (50 mL) was added. The
organic layer was separated, washed with 1% NaHCO3
solution and brine, dried over Na2SO4, and evaporated to
dryness. The crude product 9a was used in the next step
without further purification.
was added, and the mixture was warmed to boiling. After
filtration and evaporation, the obtained yellow oil was puri-
fied by column chromatography on a silica gel column with
a mixture of ethyl acetate and dichloromethane (2.5:97.5) as
the eluent yielding the title compound 10b (1.709 g, 77%) as
a light yellow oil. (Found: C, 74.7; H, 5.3; N, 9.1%; Calcd for
C19H16N2O2: C, 75.0; H, 5.3; N, 9.2%); nmax (KBr)/cmꢁ1
:
The crude triflate was dissolved in 1,2-dimethoxyethane
(11 mL) under an argon atmosphere. Pd(Ph3P)4 (113 mg,
5 mol %), 2-formylphenylboronic acid (352 mg, 1.25
equiv), and aqueous 2 M Na2CO3 solution (2.25 mL) were
added. Then the mixture was refluxed for 7 h under an argon
atmosphere. After cooling, water (30 mL) was added and the
mixture was extracted with CHCl3 (3ꢂ30 mL), dried over
Na2SO4, and evaporated to dryness. The obtained black oil
was dissolved in ethyl acetate (40 mL), activated carbon
was added, and the mixture was warmed to boiling. After fil-
tration and evaporation, the obtained yellow oil was purified
by column chromatography on a silica gel column with
a mixture of ethyl acetate/chloroform (5:95) as the eluent
yielding the title compound 10a (520 mg, 82%) as a light
yellow oil. (Found: C, 71.6; H, 5.5; N, 8.3%; Calcd for
3064, 3034, 2926, 1704, 1642, 1598, 1380, 1336, 1298,
1260, 1238, 1216, 1200, 894, 766, 730, and 700; dH
(400 MHz, CDCl3, Me4Si): 1.99 (3H, s, 4-Me), 5.30 (1H, d,
J 13.5) and 5.47 (1H, d, J 13.5): 2-N–CH2, 7.24–7.40 (4H,
m, 60-H, 3000-H, 4000-H, and 5000-H), 7.51 (2H, m, 2000-H and
6000-H), 7.60 (1H, s, 6-H), 7.62 (1H, td, J 7.4 and 1.5, 40-H
or 50-H), 7.70 (1H, td, J 7.6 and 1.5, 40-H or 50-H), 8.03 (1H,
dd, J 7.8 and 1.4, 30-H), 9.92 (1H, s, 20-CHO); dC (100 MHz,
CDCl3, Me4Si): 14.1 (q), 55.7 (t), 128.0 (d), 128.6 (d, 2C),
128.9 (d, 2C), 129.6 (d), 130.0 (d), 130.2 (d), 133.4 (s),
134.2 (d), 136.3 (s), 137.0 (d), 137.3 (s), 137.9 (s), 139.0
(s), 160.6 (s), 190.3 (d); MS (ESI): 91; HRMS (ESI) for
C19H17N2O2 [M+1]: calcd 305.1290, found 305.1290.
4.1.9. 3-Benzyloxymethylbenzo[f]phthalazin-4(3H)-one
(11a).
C20H18N2O3: C, 71.8; H, 5.4; N, 8.4%); nmax (KBr)/cmꢁ1
:
3064, 3032, 2926, 2856, 1698, 1652, 1610, 1596, 1570,
1560, 1496, 1454, 1378, 1340, 1296, 1276, 1260, 1222,
1198, 1162, 1092, 1028, 982, 966, 892, 840, 824, 770,
742, and 698; dH (400 MHz, CDCl3, Me4Si): 1.99 (3H, s,
4-Me), 4.81 (2H, s, CH2Ph), 5.70 (1H, d, J 9.8) and 5.59
(1H, d, J 9.8): 2-N–CH2, 7.26 (1H, dd, J 7.6 and 1.5,
60-H), 7.28–7.42 (5H, m, Ph), 7.58 (1H, s, 6-H), 7.65 (1H,
td, J 7.6 and 1.4, 40-H or 50-H), 7.72 (1H, td, J 6.0 and 1.5,
40-H or 50-H), 8.04 (1H, dd, J 7.6 and 1.5, H-30), 9.90 (1H,
s, 20-CHO); dC (50 MHz, CDCl3, Me4Si): 13.9 (q), 72.1
(t), 80.0 (t), 127.7 (d, 3C), 128.2 (d, 2C), 129.7 (d), 129.9
(d), 130.6 (d), 133.2 (s), 134.3 (d), 136.8 (s), 137.3 (d),
137.6 (s), 138.0 (s), 139.5 (s), 161.3 (s), 190.4 (d); MS
(ESI): 199, 170, 157, 129, 91; HRMS (ESI) for
C20H19N2O3 [M+1]: calcd 335.1396, found 335.1392.
4.1.9.1. Method 1: classic oil bath heating at reflux
temperature. 2-Benzyloxymethyl-5-(2-formylphenyl)-4-
methylpyridazin-3(2H)-one 10a (250 mg, 0.75 mmol) was
dissolved in dry tetrahydrofuran (5 mL) in a two-neck flask
under an argon atmosphere and then Cs2CO3 (977 mg,
4 equiv) was added. The mixture was stirred and refluxed
in an oil bath for 2 h. After cooling, the mixture was filtered,
rinsed with tetrahydrofuran, and evaporated. The residue
was purified by column chromatography on a short silica
gel column with dichloromethane as the eluent to yield the
title compound 11a (187 mg, 79%) as white crystals.
4.1.9.2. Method 2: microwave heating in a closed
vessel at 130 ꢀC. 2-Benzyloxymethyl-5-(2-formylphenyl)-
4-methylpyridazin-3(2H)-one 10a (250 mg, 0.75 mmol) was
dissolved in dry tetrahydrofuran (5 mL) in an 80 mL micro-
wave vessel under an argon atmosphere. Cs2CO3 (977 mg,
4 equiv) was added and the vessel was flushed with argon,
closed, and placed into a microwave apparatus (CEM,
Mars). The mixture was irradiated for 45 min at 130 ꢀC
with a set power of 1200 W while stirring. After cooling,
the mixture was filtered, rinsed with tetrahydrofuran, and
evaporated. The residue was dissolved in dichloromethane
(50 mL), washed with water (2ꢂ20 mL), and dried over
MgSO4. The solvent was evaporated and the crude product
was purified by column chromatography on a short silica
gel column with a mixture of ethyl acetate and dichloro-
methane (5:95) to yield the title compound 11a (218 mg,
92%) as white crystals.
4.1.8. 2-Benzyl-5-(2-formylphenyl)-4-methylpyridazin-
3(2H)-one (10b). 2-Benzyl-5-hydroxy-4-methylpyridazin-
3(2H)-one 8b (1.576 g, 7.29 mmol) was suspended in dry di-
chloromethane (50 mL) in a flask equipped with drying tube.
Triethylamine (1.35 mL, 9.71 mmol) was added, and the ob-
tained solution was cooled to ꢁ5 ꢀC on an ice–acetone bath.
Trifluoromethansulfonic anhydride (1.35 mL, 7.99 mmol)
was added dropwise. The mixture was stirred at this temper-
ature for 30 min and then 1 M HCl (46 mL) was added. The
mixture was extracted with dichloromethane (3ꢂ50 mL).
The organic layer was washed with 1% NaHCO3 solution
(2ꢂ50 mL) and brine (50 mL), dried over MgSO4, and evap-
orated to dryness. The crude product 9b (2.49 g light brown
oil) was used in the next step without further purification.
Mp: 107–108 ꢀC; (Found: C, 76.1; H, 5.0; N, 8.9%; Calcd
for C20H16N2O2: C, 75.9; H, 5.1; N, 8.9%); nmax (KBr)/
cmꢁ1: 1647, 1582, 1345, 1299, 1196, 1168, 1082, 921,
911, 845, 805, 762, 743, 710, and 694; dH (400 MHz,
CDCl3, Me4Si): 4.80 (2H, s, CH2Ph), 5.76 (2H, s, 3-N–
CH2), 7.23 (1H, m, 4000-H), 7.30 (2H, m, 3000-H and 5000-H),
7.39 (2H, m, 2000-H and 6000-H), 7.73–7.81 (2H, m, 8-H and
9-H), 8.02 (1H, m, 7-H), 8.14 (1H, d, J 8.7, 6-H), 8.42
(1H, d, J 8.7, 5-H), 8.54 (1H, m, 10-H), 8.98 (1H, s, 1-H);
dC (100 MHz, CDCl3, Me4Si): 71.8 (t), 79.4 (t), 122.3 (d),
The crude triflate was dissolved in 1,2-dimethoxyethane
(43 mL) under an argon atmosphere. Pd(Ph3P)4 (415 mg,
5 mol %), 2-formylphenylboronic acid (1.340 g, 1.25 equiv),
and aqueous 2 M Na2CO3 solution (7.90 mL) were added.
Then the mixture was refluxed for 5.5 h under an argon atmo-
sphere. After cooling, water (50 mL) was added and the
mixture was extracted with CHCl3 (3ꢂ50 mL), dried over
MgSO4, and evaporated to dryness. The obtained black oil
was dissolved in ethyl acetate (40 mL), activated carbon

3878
K. Monsieurs et al. / Tetrahedron 63 (2007) 3870–3881
123.1 (d), 127.06 (s), 127.14 (s), 127.6 (d), 127.72 (s),
127.78 (d, 2C), 128.28 (d, 2C), 128.33 (d), 129.1 (d),
129.2 (d), 132.5 (d), 133.9 (d), 135.2 (s), 137.7 (s), 160.3
(s); MS: (ESI) 209; HRMS (ESI) for C20H17N2O2 [M+1]:
calcd 317.1290, found 317.1299.
using a mixture of ethyl acetate and dichloromethane (3:7) to
yield the title compound 3 (104 mg, 88%) as white crystals.
4.1.11.2. Starting from 3-benzylbenzo[f]phthalazin-
4(3H)-one (11b). 3-Benzylbenzo[f]phthalazin-4(3H)-one
11b (100 mg, 0.35 mmol) was dissolved in dry toluene
(10.5 mL), AlCl3 (279 mg, 6 equiv) was added and the mix-
ture was stirred, and heated in an oil bath (70 ꢀC) for an hour
(the condenser was equipped with a drying tube). After cool-
ing, water (10 mL) was added, the mixture was extracted
with dichloromethane (3ꢂ20 mL), washed with brine
(20 mL), dried over MgSO4, evaporated, and purified by
column chromatography using a mixture of ethyl acetate
and dichloromethane (3:7) to yield the title compound 3
(60 mg, 87%) as white crystals.
4.1.10. 3-Benzylbenzo[f]phthalazin-4(3H)-one (11b).
4.1.10.1. Method 1: classic oil bath heating at reflux
temperature. 2-Benzyl-5-(2-formylphenyl)-4-methylpyr-
idazin-3(2H)-one 10b (228 mg, 0.75 mmol) was dissolved
in dry tetrahydrofuran (5 mL) in a two-neck flask under an
argon atmosphere and then Cs2CO3 (977 mg, 4 equiv) was
added. The mixture was stirred and refluxed in an oil bath
for 10 h. After cooling, the mixture was filtered, rinsed
with tetrahydrofuran, and evaporated. The residue was puri-
fied by column chromatography on a small silica gel column
with dichloromethane as the eluent to yield the title com-
pound 11b (198 mg, 92%) as white crystals.
Mp: 251–252 ꢀC; (Found: C, 73.3; H, 4.0; N, 14.1%; Calcd
for C12H8N2O: C, 73.5; H, 4.1; N, 14.3%); nmax (KBr)/cmꢁ1
:
3296, 3148, 3020, 2917, 2891, 1654, 1561, 1516, 1480,
1428, 1409, 1344, 1301, 1262, 1216, 1170, 1161, 1105,
1072, 1030, 948, 935, 884, 867, 837, 796, 755, 706, 670,
602, 567, 538, 494, 479, and 426; dH (400 MHz, CDCl3,
Me4Si): 7.81–7.75 (2H, m, 8-H, 9-H), 8.03 (1H, m, 7-H),
8.16 (1H, d, J 8.6, 6-H), 8.41 (1H, dd, J 8.6 and 0.6, 5-H),
8.56 (1H, m, 10-H), 9.01 (1H, s, 1-H), 11.02 (1H, s, NH);
dC (100 MHz, CDCl3, Me4Si): 121.72 (5-C), 123.28 (10-
C), 127.19 (10a-C), 127.77 (4a-C), 127.84 (10b-C), 128.42
(9-C), 129.17 (8-C), 129.28 (7-C), 132.63 (6-C), 134.70
(1-C), 135.33 (6a-C), 160.76 (4-C); MS (ESI): 197, 154;
HRMS (ESI) for C12H9N2O [M+1]: calcd 197.0715, found
197.0724. The structure was confirmed by NOESY,
HMQC, and HMBC.
4.1.10.2. Method 2: microwave heating in a closed
vessel at 130 ꢀC. 2-Benzyl-5-(2-formylphenyl)-4-methyl-
pyridazin-3(2H)-one 10b (228 mg, 0.75 mmol) was dissolved
in dry tetrahydrofuran (5 mL) in an 80 mL microwave vessel
under an argon atmosphere. Cs2CO3 (977 mg, 4 equiv)
was added and the vessel was flushed with argon, closed,
and placed into a microwave apparatus (CEM, Mars). The
mixture was irradiated for 45 min at 130 ꢀC with a set power
of 1200 W while stirring. After cooling, the mixture was
filtered, rinsed with tetrahydrofuran, and evaporated. The
residue was dissolved in dichloromethane (50 mL), washed
with water (2ꢂ20 mL), and dried over MgSO4. The solvent
was evaporated and the crude reaction product was purified
by column chromatography on a small silica gel column
with dichloromethane to yield the title compound 11b
(196 mg, 91%) as white crystals.
4.1.12. 2-Benzyl-4-methoxy-5-methylpyridazin-3(2H)-
one (13).
4.1.12.1. Method 1: heating of the reaction mixture at
130 ꢀC in a Berghof autoclave. 2-Benzyl-5-chloro-4-
methoxypyridazin-3(2H)-one 12 (1.503 g, 6 mmol) was dis-
solved in 1,2-dimethoxyethane (36 mL) in a Teflon vessel of
a Berghof autoclave under an argon atmosphere. Pd(Ph3P)4
(348 mg, 5 mol %), methylboronic acid (540 mg, 1.5 equiv),
and 2 M aqueous Na2CO3 solution (12.6 mL) were added.
The vessel was flushed with argon, closed, and heated for
270 min at 130 ꢀC. After cooling, the mixture was poured
into water (50 mL) and extracted with dichloromethane
(5ꢂ20 mL). The combined organic layers were dried over
Na2SO4, evaporated, and purified by column chromato-
graphy on silica gel using dichloromethane as the eluent to
yield the title compound 13 (1.1 g, 79%) as white crystals.
Mp: 153–154 ꢀC; (Found: C, 79.7; H, 4.95; N, 9.8%; Calcd
for C19H14N2O: C, 79.7; H, 4.9; N, 9.8%); nmax (KBr)/cmꢁ1
:
1644, 1620, 1580, 1342, 758, 696, and 494; dH (500 MHz,
CDCl3, Me4Si): 5.51 (2H, s, 3-N–CH2), 7.28 (1H, m, 4000-
H), 7.35 (2H, m, 3000-H and 5000-H), 7.52 (2H, d, J 7.3, 2000-
H and 6000-H), 7.70–7.77 (2H, m, 8-H and 9-H), 7.98 (1H,
m, 7-H), 8.09 (1H, d, J 8.7, 6-H), 8.39 (1H, d, J 8.7, 5-H),
8.48 (1H, m, 10-H), 8.95 (1H, s, 1-H); dC (125 MHz,
CDCl3, Me4Si): 55.0 (t), 122.2 (d), 123.0 (d), 126.9 (s),
127.0 (s), 127.6 (s), 127.8 (d), 128.2 (d), 128.56 (d, 2C),
128.63 (d, 2C), 128.9 (d), 129.1 (d), 132.3 (d), 133.6 (d),
134.8 (s), 136.8 (s), 159.5 (s); MS (ESI): 106, 91, 88;
HRMS (ESI) for C19H15N2O [M+1]: calcd 287.1171, found
287.1180.
4.1.12.2. Method 2: microwave heating in a closed
vessel at 120 ꢀC. 2-Benzyl-5-chloro-4-methoxypyridazin-
3(2H)-one 12 (421 mg, 1.68 mmol) was dissolved in di
methoxyethane (10 mL) in an 80 mL microwave vessel under
an argon atmosphere. Pd(Ph3P)4 (101 mg, 5 mol %), methyl-
boronic acid (151 mg, 1.5 equiv), and 2 M aqueous Na2CO3
solution (3.35 mL) were added. The vessel was flushed with
argon, closed, and placed into a microwave apparatus (CEM,
Discover). The mixture was irradiated for 240 min at 120 ꢀC
with a set power of 150 W. After cooling, water (20 mL) was
added and the mixture was extracted with dichloromethane
(5ꢂ20 mL), dried over MgSO4, evaporated to dryness, and
purified by column chromatography on a silica gel column
4.1.11. Benzo[f]phthalazin-4(3H)-one (3).
4.1.11.1. Starting from 3-benzyloxymethylbenzo[f]-
phthalazin-4(3H)-one (11a). A mixture of 3-benzyl-
oxymethylbenzo[f]phthalazin-4(3H)-one 11a (190 mg,
0.6 mmol), phenol (62 mg, 1.1 equiv), and 85% orthophos-
phoric acid (9 mL) was heated and stirred in an oil bath
(150 ꢀC) for 5 h. After cooling, the mixture was poured
into ice-cold water (100 mL). The precipitate was filtered
and washed with water. The filtrate was neutralized with
NaOH and extracted with dichloromethane (6ꢂ20 mL).
The combined organic layers were combined with the pre-
cipitate, evaporated, and purified on a short silica gel column

K. Monsieurs et al. / Tetrahedron 63 (2007) 3870–3881
3879
withamixtureofethylacetateandtoluene(2:8)astheeluentto
yield the title compound 13 (322 mg, 75%) as white crystals.
was added, and the mixture was warmed to boiling. After fil-
tration and evaporation, the obtained yellow oil was purified
by column chromatography on a silica gel column with a
mixture of ethyl acetate and dichloromethane (5:95) as the
eluent. Then a second column chromatography was applied
with a mixture of toluene and ethyl acetate (9:1) as the eluent
to yield the title compound 15 (957 mg, 84%) as a light
yellow oil.
Mp: 43–45 ꢀC; (Found: C, 68.05; H, 6.1; N, 12.2%; Calcd
for C13H14N2O2: C, 67.8; H, 6.1; N, 12.2%); nmax (KBr)/
cmꢁ1: 1638, 1600, 1534, 1492, 1432, 1328, 1264, 1136,
1086, 1032, 986, 902, 794, 736, 696, 612, 582, and 518;
dH (200 MHz, CDCl3, Me4Si): 2.07 (3H, s, 5-Me), 4.14
(3H, s, 4-OMe), 5.29 (2H, s, 2-N–CH2), 7.25–7.45 (5H, m,
Ph), 7.56 (1H, s, 6-H); dC (50 MHz, CDCl3, Me4Si): 12.5
(q), 54.9 (t), 59.7 (q), 126.9 (d), 127.8 (d), 128.5 (d, 4C),
136.4 (s), 140.0 (d), 152.5 (s), 157.7 (s); MS (ESI): 231,
153; HRMS (ESI) for C13H15N2O2 [M+1]: calcd
231.1134, found 231.1128.
(Found: C, 74.7; H, 5.4; N, 9.1%; Calcd for C19H16N2O2: C,
75.0; H, 5.3; N, 9.2%); nmax (KBr)/cmꢁ1: 1698, 1642, 1598,
1494, 1452, 1428, 1384, 1330, 1298, 1250, 1198, 826, 784,
764, 730, 700, and 620; dH (200 MHz, CDCl3, Me4Si): 1.97
(3H, s, 5-Me), 5.29 (1H, d, J 13.7) and 5.37 (1H, d, J 13.7): 2-
N–CH2, 7.14–7.72 (8H, m, 400-H, 500-H, 600-H, and Ph), 7.74
(1H, s, 6-H), 7.98 (1H, d, J 7.6, 300-H), 9.84 (1H, s, 200-CHO);
dC (50 MHz, CDCl3, Me4Si): 17.1 (q), 55.4 (t), 127.8 (d),
128.5 (d, 3C), 128.7 (d, 2C), 129.1 (d), 130.36 (d), 130.39
(s), 133.9 (d), 134.3 (s), 135.2 (s), 136.3 (s), 137.4 (s),
139.0 (d), 159.4 (s), 190.9 (d); MS (ESI): 305, 91; HRMS
(ESI) for C19H17N2O2 [M+1]: calcd 305.1290, found
305.1281.
4.1.13. 2-Benzyl-4-hydroxy-5-methylpyridazin-3(2H)-
one (14). 2-Benzyl-4-methoxy-5-methylpyridazin-3(2H)-
one 13 (1.1 g, 4.78 mmol) and KOH (14.72 g) in water
(400 mL) was refluxed overnight (15 h). After cooling, the
mixture was filtered on a glass filter under vacuum, cooled
on an ice-water bath, and concentrated HCl (24 mL) was
added. The obtained precipitate was filtered, washed with
water till neutral, and dried in a drying gun. No further puri-
fication was needed. The title compound 14 was isolated in
good yield (857 mg, 83%) as pink crystals. An analytical
sample was obtained by recrystallization from toluene to
get white crystals. Mp: 153–155 ꢀC; (Found: C, 66.6; H,
5.6; N, 13.0%; Calcd for C12H12N2O2: C, 66.65; H, 5.6; N,
12.95%); nmax (KBr)/cmꢁ1: 3200, 1648, 1604, 1432, 1404,
1352, 1256, 746, and 700; dH (200 MHz, DMSO-d6,
Me4Si): 2.00 (3H, s, 5-Me), 5.24 (2H, s, 2-N–CH2), 7.00–
7.50 (5H, m, Ph), 7.72 (1H, s, 6-H), 10.64 (1H, s, 4-OH);
dC (50 MHz, DMSO-d6, Me4Si): 11.6 (q), 54.1 (t), 117.3
(s), 127.4 (d), 127.8 (d, 2C), 128.4 (d, 2C), 137.0 (s),
141.0 (d), 150.6 (s), 156.6 (s); MS (ESI): 217; HRMS
(ESI) for C12H13N2O2 [M+1]: calcd 217.0977, found
217.0970.
4.1.15. 2-Benzylbenzo[f]phthalazin-1(2H)-one (16).
4.1.15.1. Method 1: classic oil bath heating at reflux
temperature. 2-Benzyl-4-(2-formylphenyl)-5-methylpyr-
idazin-3(2H)-one 15 (228 mg, 0.75 mmol) was dissolved
in dry tetrahydrofuran (5 mL) in a two-neck flask under an
argon atmosphere and then Cs2CO3 (977 mg, 4 equiv) was
added. The mixture was stirred and refluxed in an oil bath
for 9.5 h. After cooling, the mixture was filtered, rinsed
with tetrahydrofuran, and evaporated. The residue was puri-
fied by column chromatography on a short silica gel column
with dichloromethane as the eluent to yield the title com-
pound 16 (199 mg, 93%) as white crystals.
4.1.15.2. Method 2: microwave heating in a closed
vessel at 130 ꢀC. 2-Benzyl-4-(2-formylphenyl)-5-methyl-
pyridazin-3(2H)-one 15 (228 mg, 0.75 mmol) was dissolved
in dry tetrahydrofuran (5 mL) in an 80 mL microwave vessel
under an argon atmosphere. Cs2CO3 (977 mg, 4 equiv) was
added, and the vessel was flushed with argon, closed, and
placed into a microwave apparatus (CEM, Mars). The mix-
ture was irradiated for 45 min at 130 ꢀC with a set power of
1200 W while stirring. After cooling, the mixture was
filtered, rinsed with tetrahydrofuran, and evaporated. The
residue was purified by column chromatography on a short
silica gel column with dichloromethane to yield the title
compound 16 (192 mg, 90%) as white crystals.
4.1.14. 2-Benzyl-4-(2-formylphenyl)-5-methylpyridazin-
3(2H)-one (15). 2-Benzyl-4-hydroxy-5-methylpyridazin-
3(2H)-one 14 (805 g, 3.72 mmol) was suspended in dry
dichloromethane (25 mL) in a flask equipped with drying
tube. Triethylamine (0.69 mL, 4.96 mmol) was added and
the obtained solution was cooled to ꢁ5 ꢀC on an ice–
acetone bath. Trifluoromethansulfonic anhydride (0.69 mL,
4.08 mmol) was added dropwise. The mixture was stirred
at this temperature for 30 min and then 1 M HCl (23.5 mL)
was added. The mixture was extracted with dichloromethane
(3ꢂ25 mL). The organic layer was washed with 1% NaHCO3
solution (2ꢂ25 mL) and brine (25 mL), dried over Na2SO4,
and evaporated to dryness. The crude product (1.25 g,
light brown oil) was used in the next step without further
purification.
4.1.15.3. Method 3: heating of the reaction mixture to
130 ꢀC in a closed vessel (oil bath temperature 150 ꢀC).
2-Benzyl-4-(2-formylphenyl)-5-methylpyridazin-3(2H)-one
15 (228 mg, 0.75 mmol) was dissolved in dry tetra-
hydrofuran (5 mL) in a closed vessel under an argon atmo-
sphere. Cs2CO3 (977 mg, 4 equiv) was added, and the
vessel was flushed with argon, closed, and placed into an
oil bath preheated to 150 ꢀC. The mixture was stirred and
heated for 4ꢂ45 min. After cooling, the mixture was filtered,
rinsed with tetrahydrofuran, and evaporated. The residue
was purified by column chromatography on a short silica
gel column with dichloromethane to yield the title com-
pound 16 (200 mg, 93%) as white crystals.
The crude triflate was dissolved in 1,2-dimethoxyethane
(21.5 mL) under an argon atmosphere. Pd(Ph3P)4 (207 mg,
5 mol %), 2-formylphenylboronic acid (669 g, 1.25 equiv),
and aqueous 2 M Na2CO3 solution (3.6 mL) were added.
Then the mixture was refluxed for 3 h under an argon atmo-
sphere. After cooling, water (40 mL) was added and the
mixture was extracted with CHCl3 (3ꢂ40 mL), dried over
Na2SO4, and evaporated to dryness. The obtained black oil
was dissolved in ethyl acetate (40 mL), activated carbon

3880
K. Monsieurs et al. / Tetrahedron 63 (2007) 3870–3881
Mp: 157–158 ꢀC; (Found: C, 79.7; H, 4.8; N, 9.8%; Calcd
for C19H14N2O: C, 79.7; H, 4.9; N, 9.8%); nmax (KBr)/
cmꢁ1: 1636, 1614, 1584, 1258, 1122, 1060, 818, 764, 748,
706, 610, and 510; dH (200 MHz, CDCl3, Me4Si): 5.54
(2H, s, 2-N–CH2), 7.20–7.40 (3H, m, 3000-H, 4000-H, and 5000-
H), 7.45–7.58 (2H, m, 2000-H and 6000-H), 7.54 (1H, d, J 8.6,
5-H), 7.62–7.82 (2H, m, 8-H and 9-H), 7.90 (1H, d, J 8.2,
7-H), 8.10 (1H, d, J 8.6, 6-H), 8.22 (1H, s, 4-H), 10.14
(1H, d, J 8.4, 10-H); dC (50 MHz, CDCl3, Me4Si): 55.4 (t),
122.4 (d), 123.2 (s), 127.7 (d), 128.3 (d, 2C), 128.4 (d),
128.5 (d, 4C), 129.0 (d), 130.2 (s), 130.3 (s), 134.2 (s),
134.9 (d), 137.1 (s), 137.6 (d), 160.2 (s); MS (ESI): 270,
91; HRMS (ESI) for C19H15N2O [M+1]: calcd 287.1184,
found 287.1194.
C12H8ClN2O [M+1]: calcd 231.0325, found 231.0319. The
structure was confirmed by NOESY, HSQC, and HMBC.
4.1.19. 4-Chlorobenzo[f]phthalazin-1(2H)-one (22).
Yield: 115 mg, 50%; Mp: 275–277 ꢀC (lit: 273–276 ꢀC);
dH (500 MHz, DMSO-d6, Me4Si): 7.90–7.83 (2H, m, 8-H
and 9-H), 8.02 (1H, d, J 8.8, 5-H), 8.19 (1H, dd, J 7.0 and
2.3, 7-H), 8.51 (1H, d, J 8.8, 6-H), 10.06 (1H, dd, J 7.5
and 2.0, 10-H), 13.20 (1H, s, 2-H); dC (DMSO, Me4Si):
121.4 (5-C), 123.6 (10b-C), 127.1 (10-C), 128.4 (7-C),
128.8 (10a-C), 129.2 (8-C or 9-C), 129.4 (8-C or 9-C),
129.5 (4a-C), 134.1 (6a-C), 136.0 (6-C), 137.4 (4-C),
160.3 (1-C); MS (ESI): 153, 140, 127; HRMS (ESI) for
C12H8ClN2O [M+1]: calcd 231.0325, found 231.0319. The
structure was confirmed by NOESY, HSQC, and HMBC.
4.1.16. Benzo[f]phthalazin-1(2H)-one (17). 2-Benzylbenzo-
[f]phthalazin-4(3H)-one 16 (180 mg, 0.63 mmol) was dis-
solved in dry toluene (19 mL), AlCl3 (504 mg, 3.78 mmol,
6 equiv) was added and the mixture was stirred, and heated
on an oil bath (70 ꢀC) for an hour (the condenser was equip-
ped with a drying tube). After cooling, water (25 mL) was
added, the mixture was extracted with dichloromethane
(3ꢂ40 mL) and CHCl3 (3ꢂ40 mL), dried over Na2SO4, evap-
orated, and purified by column chromatography using first di-
chloromethane and then a mixture of ethyl acetate and
dichloromethane (2:8) as the eluent to yield the title com-
pound 17 (120 mg, 97%) as white crystals. Mp: 264–
265 ꢀC; (Found: C, 73.6; H, 4.0; N, 14.25%; Calcd for
4.1.20. Benzo[f]phthalazin-1(2H)-one (17). 4-Chloro-
benzo[f]phthalazin-1(2H)-one 22 (104 mg, 0.45 mmol)
was dissolved in a mixture of ethanol (50 mL) and methanol
(10 mL) with heating. After cooling back to room tem-
perature, Pd/C (20 mg) and ammonium formate (142 mg,
5 equiv) was added, and the mixture was refluxed for 1 h.
The warm solution was filtered through Celite, washed
with ethanol, and evaporated to dryness. Water was added
(10 mL) and the mixture was vigorously stirred for 2 h,
filtered, washed with water, and dried. The crude product
was not further purified. Yield: 88 mg, 100%; Mp: 264–
267 ꢀC. The product is identical with the compound ob-
tained from the earlier described method.
C12H8N2O: C, 73.5; H, 4.1; N, 14.3%); nmax (KBr)/cmꢁ1
:
1632, 1594, 1548, 1504, 894, 818, 760, and 558; dH
(400 MHz, CDCl3, Me4Si): 7.69 (1H, d, J 8.5, 5-H), 7.77
(1H, ddd, J 8.0, 7.0, and 1.3, 8-H), 7.83 (1H, ddd, J 8.6, 7.0,
and 1.5, 9-H), 8.00 (1H, dd, J 8.0 and 1.5, 7-H), 8.24 (1H,
d, J 8.5, 6-H), 8.28 (1H, s, 4-H), 10.10 (1H, dd, J 8.6 and
1.3, 10-H), 10.36 (1H, s, NH); dC (100 MHz, CDCl3,
Me4Si): 122.73 (5-C), 123.77 (10b-C), 128.50 (10-C),
128.58 (7-C), 128.88 (8-C), 129.44 (9-C), 130.43 (10a-C),
131.04 (4a-C), 134.41 (6a-C), 135.59 (6-C), 139.13 (4-C),
161.47 (C-1); MS (ESI): 154, 140, 127; HRMS (ESI)
for C12H9N2O [M+1]: calcd 197.0715, found 197.0716.
The structure was confirmed by NOESY, HMQC, and
HMBC.
Acknowledgements
The authors acknowledge the financial support of the FWO-
Flanders (research grant 1.5.088.04), the University of
Antwerp, the Flemish Government enabling the purchase
of NMR equipment (Impulsfinanciering van de Vlaamse
Overheid voor Strategisch Basisonderzoek PFEU 2003)
and the Hungarian Ministry of Health (ETT-508/2006) as
well as the technical assistance of J. Aerts, G. Rombouts,
J. Schrooten, W. Van Lierde, and J. Verreydt and CEPROMA
ꢁ
(F. Lemiere and W. Van Dongen) for HRMS measurements.
References and notes
4.1.17. 1-Chlorobenzo[f]phthalazin-4(3H)-one (21) and 4-
chlorobenzo[f]phthalazin-1(2H)-one (22). 1,4-Dichloro-
benzo[f]phthalazine 20 (250 mg, 1 mmol) was suspended
in acetic acid (2 mL) and was refluxed on an oil bath
(130 ꢀC) for 2 h. After cooling, water was added (2 mL),
the yellow precipitate was filtered, washed with water, dried
on air, and subjected to column chromatography on silica gel
using a mixture of ethyl acetate and dichloromethane (1:9)
as the eluent. Repeating the column chromatography several
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