Synthesis of the dibenzo[f,h]phthalazine and dibenzo[f,h]cinnoline skeleton via a 'Suzuki-Pd-catalyzed intramolecular arylation' and a 'Suzuki-Pschorr' approach

Article abstract of DOI:10.1016/S0040-4020(03)00953-0

Palladium-catalyzed intramolecular arylation of 2-benzyl-5-(2-bromophenyl)-4-phenylpyridazin-3(2H)-one yielded hitherto unknown 2-benzyldibenzo[f,h]phthalazin-1(2H)-one. The synthesis of this new tetracyclic pyridazinone from 2-benzyl-5-(2-aminophenyl)-4-phenylpyridazin-3(2H)-one via a Pschorr type reaction was also investigated. Similarly, the construction of 2-methyldibenzo[f,h]cinnolin-3(2H)-one from 2-methyl-5-(2-bromophenyl)-6-phenylpyridazin-3(2H)-one and 2-methyl-5-(2-aminophenyl)-6-phenylpyridazin-3(2H)-one is also reported. Removal of the N-benzyl protective group of 2-benzyl-dibenzo[f,h]phthalazin-1(2H)-one with AlCl₃ yielded unsubstituted dibenzo[f,h]phthalazin-1(2H)-one.

Full text of DOI:10.1016/S0040-4020(03)00953-0

Tetrahedron 59 (2003) 5919–5926
Synthesis of the dibenzo[f,h]phthalazine and dibenzo[f,h]cinnoline
skeleton via a ‘Suzuki–Pd-catalyzed intramolecular arylation’
and a ‘Suzuki–Pschorr’ approach
a,b
a
a
Pal Tapolcsanyi, Bert U. W. Maes,a Katrien Monsieurs, Guy L. F. Lemiere,
,
*
´
Zsuzsanna Riedl, Gyorgy Hajos, Bart Van den Driessche, Roger A. Dommisse
´
`
c
c
a
a
´
¨
b
,
*
´ ´
and Peter Matyus
aDepartment of Chemistry, University of Antwerp (RUCA), Groenenborgerlaan 171, B-2020 Antwerpen, Belgium
b
˝
Department of Organic Chemistry, Semmelweis University, Hogyes E. u. 7., H-1092 Budapest, Hungary
cChemical Research Center, Institute of Chemistry, Hungarian Academy of Sciences, P.O. Box 17, H-1525 Budapest, Hungary
Received 7 April 2003; revised 8 May 2003; accepted 5 June 2003
´ ´ ˝
Cordially dedicated to Professor Laszlo Toke on the occasion of his 70th birthday.
Abstract—Palladium-catalyzed intramolecular arylation of 2-benzyl-5-(2-bromophenyl)-4-phenylpyridazin-3(2H)-one yielded hitherto
unknown 2-benzyldibenzo[f,h]phthalazin-1(2H)-one. The synthesis of this new tetracyclic pyridazinone from 2-benzyl-5-(2-aminophenyl)-
4-phenylpyridazin-3(2H)-one via a Pschorr type reaction was also investigated. Similarly, the construction of 2-methyldibenzo[f,h]cinnolin-
3(2H)-one from 2-methyl-5-(2-bromophenyl)-6-phenylpyridazin-3(2H)-one and 2-methyl-5-(2-aminophenyl)-6-phenylpyridazin-3(2H)-one
is also reported. Removal of the N-benzyl protective group of 2-benzyl-dibenzo[f,h]phthalazin-1(2H)-one with AlCl3 yielded unsubstituted
dibenzo[f,h]phthalazin-1(2H)-one.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
Suzuki arylation of the chloropyridazin-3(2H)-one and (iii)
after the Suzuki arylation it should be available, as such or
modified, for further substitution or ring closure reactions.
Recently, our laboratories focused on the synthesis of
polycyclic pyridazinones via a new approach starting from
easily accessible 2-substituted 4,5-dichloropyridazin-
3(2H)-ones. This new strategy consists of a Suzuki arylation
of a chloropyridazin-3(2H)-one with a properly ortho
substituted arylboronic acid, followed by a ring closure
step (implying a SN reaction, lactonization, electrophilic
attack of a nitrene, etc.).1–3 In the frame of this project we
investigated Suzuki arylation on 2-substituted 4,5-dichloro-
pyridazin-3(2H)-ones.1a–c However, a selective reaction
could not be performed since a mixture of regioisomeric
monoarylated and the diarylated pyridazinones is formed;
the relative ratio depends on the arylboronic acid used. To
avoid this selectivity problem we have developed an
efficient procedure based on the application of ‘provision-
ally masked functionalities’ (PMF). The requirements for a
PMF could be formulated as follows: (i) it should be easily
and selectively introducible in the 4 or 5 position of the 4,5-
dichloropyridazin-3(2H)-one, (ii) it should be inert in the
Recently, we reported the use of a methoxy group as a PMF
for the synthesis of pyridazino[4,5-c]isoquinolinones and
isochromeno[3,4-d]pyridazinediones.1c,j This group meets
the above mentioned requirements since we1a,c and
others4–6 found that either of the chlorine substituents of
2-substituted 4,5-dichloropyridazin-3(2H)-ones can be
selectively replaced by a methoxy group. Besides, the
methoxy group of 4-aryl-5-methoxypyridazin-3(2H)-ones
can be transformed into a triflate1j which is a good leaving
group for palladium-catalyzed reactions. Via Suzuki aryla-
tion on these triflates, we obtained 4,5-diarylpyridazin-
3(2H)-ones with two differently substituted phenyl groups,
without selectivity problems.
As a continuation of this research we now report on new
approaches towards the synthesis of two 1,2-diazine
analogues of triphenylene, dibenzo[f,h]phthalazin-1(2H)-
one and dibenzo[f,h]cinnolin-3(2H)-one, starting from 4,5-
and 5,6-diarylpyridazin-3(2H)-ones respectively via a
palladium-catalyzed intramolecular arylation7,8 as well as
via a Pschorr9,10 type reaction. The dibenzo[f,h]cinnolin-
3(2H)-one skeleton has already been prepared by an entirely
different route;11 the dibenzo[f,h]phthalazin-1(2H)-one
Keywords: intramolecular arylation; palladium; Suzuki reaction; Pschorr
reaction; pyridazinone.
*
Corresponding authors. Tel.: þ32-3-218-02-05; fax: þ32-3-218-02-33;
bert.maes@ua.ac.be;
Tel./fax: þ36-1-217-08-51; matypet@szerves.sote.hu
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00953-0

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P. Tapolcsanyi et al. / Tetrahedron 59 (2003) 5919–5926
5920
skeleton however is hitherto unknown. Phenylated diben-
zo[f,h]cinnoline and dibenzo[f,h]phthalazine have only
been reported in a photocyclization study on 3,4,6-
triphenyl- and 3,4,5,6-tetraphenylpyridazines.12
yielded less than 10% of 7 and higher recoveries of
starting material in comparison with the reference
experiment. Finally, a higher yield (56%) of 7 could be
obtained by prolonging the reaction time from 16 to 64 h
(Table 1). In this case 10% of starting material remained
in the reaction mixture. Deprotection of 7 with AlCl3
smoothly gave unsubstituted dibenzo[f,h]phthalazin-
1(2H)-one (8) in good yield (Scheme 2).14 Under similar
reaction conditions as for the synthesis of 7 we studied
the cyclodehydrohalogenation of 2-methyl-5-(2-bromo-
phenyl)-6-phenylpyridazin-3(2H)-one (13) (Scheme 3). In
this case, the cyclization reaction was considerably faster
since no 13 remained after 8 h of heating. The desired 2-
methyldibenzo[f,h]cinnolin-3(2H)-one (14) could be iso-
lated in 46% yield after column chromatography and
subsequent recrystallization. The substrate for palladium-
catalyzed cyclodehydrobromination (13) was obtained from
5-chloro-2-methyl-6-phenylpyridazin-3(2H)-one (12) via
Suzuki arylation with 2-bromophenylboronic acid under
Gronowitz conditions as previously reported by us for related
Suzuki arylations with ortho substituted arylboronic acids on
this substrate1d,15 (Scheme 3). Interestingly, the C–Cl bond of
12 seems to be more reactive towards oxidative addition than
the C–Br bond of 2-bromophenylboronic acid in the studied
Suzuki reaction. In principal, based on the oxidative addition
rate of aryl halogenides to Pd(PPh3)2 catalyst, one could
expect that 2-bromophenylboronic acid would preferentially
react with itself, consuming all the boronic acid, yielding only
undesired coupling products. The preferential reaction of the
C–Cl bond of 12 can be explained by taking into account that
the studied carbon chlorine bond is part of a vinylogous
carbamoyl chloride which dramatically increases its reactivity
2. Results and discussion
First we focused on the construction of the dibenzo[f,h]phtha-
lazin-1(2H)-one and dibenzo[f,h]cinnolin-3(2H)-one skeleton
using a palladium-catalyzed intramolecular arylation
(Scheme 2).7,8 2-Benzyl-5-(2-bromophenyl)-4-phenylpyri-
dazin-3(2H)-one (6) was prepared from 2-benzyl-4-phenyl-
5-trifluoromethanesulfonyloxypyridazin-3(2H)-one (5) via
a Suzuki arylation with 2-bromophenylboronic acid under
the same conditions as previously reported by us for similar
reactions.1j The starting material for the Suzuki reaction (5)
was obtained from 4,5-dichloropyridazin-3(2H)-one (1)
using a reaction sequence (Scheme 1) developed earlier
in our laboratories:1a,j benzylation and methoxylation in a
one-pot reaction (2), Suzuki reaction (3), alkaline
hydrolysis (4) and subsequent triflate formation (5).
Cyclodehydrohalogenation of 6 could be realized in
DMA at 1308C with Pd(PPh3)2Cl2 precatalyst as Pd(0)
source and NaOAc as base (Scheme 2). Disappointingly,
the intramolecular palladium-catalyzed reaction was
rather slow. After 16 h only 30% of 2-benzyldibenzo-
[f,h]phthalazin-1(2H)-one (7) was obtained as well as
39% recovery of the starting material (6). Attempts to
add lithium halogenide salts to speed up the cyclization
reaction were unsuccessful and even slower reactions
were obtained (Table 1).13 Addition of LiCl or LiI
Scheme 1.
Scheme 2.

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5921
Table 1. Effect of lithium halogenide salts on the cyclodehydrohalogenation of 6
Additivea
7 (%)
6 (%)
Reaction time (h)
–
–
LiCl
LiI
30
56
7
39
10
63
90
16
64
16
16
4
Reaction conditions: 6, Pd(PPh3)2Cl2 (0.2 equiv.), NaOAc.3H2O (2 equiv.), DMA, 1308C.
3 equiv. of LiX were added.
a
Scheme 3.
for oxidative addition to Pd(PPh3)2 in comparison with
unactivated C–Cl bonds.16
sition of the diazonium salt occurred, followed by
intramolecular arylation (Scheme 5), and 14 could be
obtained in a higher overall yield (40% from 12) than with
the palladium-catalyzed ring closure approach (29% from
12). Interestingly, the combination of a Suzuki arylation
reaction with a protected 2-aminophenylboronic acid such
as 2-pivaloylaminophenylboronic acid followed by depro-
tection, diazotization and in situ Pschorr type ring closure
has never been reported yet.9,10
The moderate results obtained for the palladium-catalyzed
intramolecular arylation of 6 prompted us to search for an
alternative approach to construct 1,2-diazine analogues of
triphenylene (Schemes 4 and 5). Recently, we studied the
synthesis of 3-methyl-1-phenyl-3,5-dihydro-4H-pyrida-
zino[4,5-b]indol-4-one (18) making use of the thermal
cyclization reaction of 5-(2-azidophenyl)-2-methyl-6-phe-
nylpyridazin-3(2H)-one (17) involving the formation of a
nitrene (Scheme 5).1d The required azide was prepared from
the corresponding diazonium salt (16) by substitution with
NaN3. In the present study the reaction mixture containing
16 was simply allowed to reach room temperature instead of
adding NaN3 and further stirring at 0–58C. Now decompo-
Analogously, 7 was prepared from 5-(2-aminophenyl)-2-
benzyl-4-phenylpyridazin-3(2H)-one (10) via a Pschorr
type ring closure (Scheme 4). Compound 10 was syn-
thesized by Suzuki arylation of 5 with 2-(pivaloylamino)-
phenylboronic acid under the same conditions as used for
the preparation of 6 followed by deprotection of the
Scheme 4.

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5922
Scheme 5.
N-pivaloyl group with strong acid.17 Due to solubility
problems of 2-benzyl-4-phenyl-5-(2-pivaloylaminophenyl)-
pyridazin-3(2H)-one (9) in aqueous sulphuric acid, ethanol
was used as a co-solvent for the amide hydrolysis. In this
way 10 could be obtained in excellent yield (90%). The
diazotization/Pschorr type ring closure of 10 is clearly a
superior method for the preparation of 7 since a 70% yield
(56% overall yield from 5) was obtained in only 3 h reaction
time in comparison with 56% (49% overall yield from 5)
after 64 h for the intramolecular Pd-catalyzed arylation.
flow rate of 5 mL/min CH3OH (0.1% formic acid), using a
CapLC HPLC system (Waters, Millford). Product ion
spectra and accurate mass data were acquired on a
quadrupole-time-of-flight mass spectrometer (QTofII,
Micromass, Manchester, UK) equipped with a standard
electrospray ionisation (ESI) interface. Cone voltage (35 V)
and capillary voltage (3.3 kV) were optimized on one
compound and used for all others. For the determination of
the high-resolution m/z-values of the molecular ion
[MþH]þ, 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 mass of PEG [MþH]þ and
[MþNH4]þ ions was used as a lock mass for the
measurement of the accurate mass values of the samples.
For the product ion experiments the mass of the [MþH]þ
was used as lock mass for the fragments. Fragmentation was
induced by low energy collisional activation using different
collision energies between 20 and 30 eV. IR spectra were
recorded on a Bruker Vector 22 spectrometer. Starting
compounds were synthesized by literature procedures: 5-
chloro-2-methyl-6-phenylpyridazin-3(2H)-one19 (12) and
2-pivaloylaminophenylboronic acid,20 or were purchased
from commercial sources: 4,5-dichloropyridazin-3(2H)-one
(1) (Aldrich), benzyl bromide (Acros), phenylboronic acid
(Aldrich), 2-bromophenylboronic acid (Aldrich), trifluor-
omethanesulfonic anhydride (Acros, Aldrich), Pd(PPh3)4
(Acros) and PdCl2(PPh3)2 (Fluka). The synthesis of 3-
methyl-1-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indol-4-
one (18) from 12 has been published earlier by our
laboratories.1d Flash column chromatography was per-
formed on Kieselgel 60 (Merck), 0.040–0.063 mm.
In conclusion, we have studied the synthesis of diben-
zo[f,h]phthalazin-1(2H)-one and dibenzo[f,h]cinnolin-
3(2H)-one via a ‘Suzuki–Intramolecular Pd-catalyzed
arylation’ and a ‘Suzuki–Pschorr’ approach. The latter
combination to build up phenanthrene units is unprece-
dented and looks very attractive as a general tool for the
efficient synthesis of phenanthrene containing polycyclic
aromatic hydrocarbons and their aza-analogues.18
3. Experimental
3.1. General
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 (or 6-
substituents) primed figures, 5-substituents double primed
figures and N-substituents triple primed figures. 1H- and 13
C
NMR assignments of compounds 7 and 14 are based on 2D
NMR techniques. For mass-spectrometric 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
3.1.1. 2-Benzyl-4-chloro-5-methoxypyridazin-3(2H)-one
(2). A mixture of 4,5-dichloropyridazin-3(2H)-one (1)
(1.65 g, 10 mmol), potassium carbonate (2.79 g,
20.2 mmol) and benzyl bromide (1.20 mL, 10.1 mmol) in

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5923
methanol (55 mL) (distilled from magnesium) was stirred
and heated under reflux for 8 h (the reflux condenser was
equipped with a drying tube). After cooling down the
reaction mixture, the solvent was evaporated under reduced
pressure and water was added (100 mL). Subsequently, the
water phase was extracted with CH2Cl2 (3£100 mL), dried
on MgSO4, evaporated to dryness and subjected to flash
column chromatography on silica gel with CH2Cl2 as the
eluent to yield the title compound as white crystals (1.25 g,
50%). The characterization data were identical with those
previously reported by us for the preparation of 2 from 2-
benzyl-4,5-dichloropyridazin-3(2H)-one.1c
J¼13.6 Hz, 1H, 2-CH2, diastereotopic), 5.34 (d, J¼13.6 Hz,
1H, 2-CH2, diastereotopic); dC (CDCl3): 160.0, 140.5,
139.9, 138.4, 136.38, 136.37, 133.0, 132.4, 131.2, 130.05,
130.01, 129.2, 128.6, 128.5, 128.0, 127.7, 127.5, 122.6,
56.1; MS (ESI): 417, 91; HRMS (ESI) for C23H18BrN2O
[MþH]þ: calcd 417.0602, found 417.0617.
3.2.3. N-[2-(2-Benzyl-3-oxo-4-phenyl-2,3-dihydropyrida-
zin-5-yl)phenyl]pivalamide (9). The residue was purified
by flash column chromatography on silica gel with a
mixture of ethyl acetate and CH2Cl2 (2.5:97.5) as the eluent
and crystallized from ethyl acetate to yield the title
compound as white needles (1.034 g, 89%); mp 227–
2298C; nmax (KBr): 3297, 3064, 2972, 1674, 1627, 1595,
1575, 1515, 1479, 1447, 1331, 1263, 1170, 959, 760, 730,
695 cm21; dH (CDCl3): 7.76 (s, 1H, H-6), 7.65 (ddd, J¼8.1,
1.0,0 0.5 Hz, 1H, 0H00 -300 or H-600), 7.50 (br d, J¼8 Hz, 2H, H-
2000,6 00or H-2000,6 0 ), 7.360–00 7.12 (0m00 , 11H, H-30,40,50,300(or
600),4 ,500,2000(or 2 ), 3000, 4 , 5000, 6 (or 60)), 6.80 (br s, 1H,
1 -NH), 5.42 (two br s, 2H, 2-CH2, diastereotopic), 1.07 (s,
9H, C(CH3)3); dC (CDCl3): 176.5, 159.5, 138.6, 138.4,
138.1, 136.3, 134.3, 131.8, 130.2, 129.73, 129.72, 129.1,
128.9, 128.7, 128.6, 128.0, 127.9, 125.5, 124.6, 56.1, 39.4,
27.4; MS (ESI): 438, 91; HRMS (ESI) for C28H28N3O2
[MþH]þ: calcd 438.2182, found 438.2181.
3.2. General procedure for the synthesis of 2-benzyl-5-
methoxy-4-phenylpyridazin-3(2H)-one (3), 2-benzyl-5-
(2-bromophenyl)-4-phenylpyridazin-3(2H)-one (6) and
N-[2-(2-benzyl-3-oxo-4-phenyl-2,3-dihydropyridazin-5-
yl)phenyl]pivalamide (9) via Suzuki arylation
A mixture of compound 2 or 5 (3: 500 mg, 2 mmol; 6:
670 mg, 1.63 mmol; 9: 1.086 g, 2.65 mmol), arylboronic
acid (3: 366 mg, 3 mmol; 6: 490 mg, 2.44 mmol; 9: 704 mg,
3.97 mmol) and toluene (3: 12 mL; 6: 10 mL; 9: 20 mL) was
flushed with N2 for 5 min under magnetic stirring followed
by the addition of Pd(PPh3)4 (3: 70 mg, 0.06 mmol; 6:
60 mg, 0.05 mmol; 9: 160 mg, 1.14 mmol) and aqueous
Na2CO3 (2 M, 3: 2.2 mL; 6: 1.8 mL; 9: 2.90 mL) under a
stream of N2 gas. The reaction mixture was stirred and
refluxed in an oil bath (temperature of oil bath: 1208C)
under a N2 atmosphere (3: 6 h; 6, 9: 3 h). After cooling,
the solvent was evaporated to dryness under reduced
pressure. Ethyl acetate (3, 6: 50 mL; 9: 80 mL) was
added and the suspension was placed in an ultrasonic
bath for a few minutes. The mixture was filtered through
Celite, washed thoroughly with ethyl acetate (200 mL)
and the filtrate was subsequently evaporated to dryness.
For the synthesis of 9 an extra washing with CH2Cl2
(500 mL) was performed.
3.2.4. 2-Benzyl-5-hydroxy-4-phenylpyridazin-3(2H)-one
(4). A mixture of compound 3 (558 mg, 1.91 mmol), KOH
(8.51 g, 152 mmol) and water (260 mL) was stirred and
heated overnight under reflux in an oil bath (temperature
of oil bath: 1208C). After cooling, the mixture was
acidified with concentrated HCl and placed in
a
refrigerator for four hours. The precipitate was filtered,
washed well with water until neutral and dried under
vacuum to yield the title compound as a white powder
(505 mg, 95%); mp 216–2178C; nmax (KBr): 3062, 2701,
1627, 1580, 1552, 1497, 1453, 1377, 1318, 1276, 1164, 1054,
776,756,726,698,570 cm21; dH (DMSO-d6):11.15(brs, 1H,
5-OH),7.85(s, 1H, H-6), 7.48(brd,J¼7 Hz, 2H, H-20,60),7.37
(br t0,00 J¼7 Hz, 0002H, H-30,50), 7.34–7.24 (m, 6H,
H-40,2 ,3000,4000,5000,6 ), 5.23 (s, 2H, 2-CH2); dC (DMSO-d6):
160.4, 154.0, 137.2, 132.4, 131.1, 130.3, 128.4, 127.8, 127.4,
127.3, 117.0, 54.0; MS (ESI): 91; HRMS (ESI) for
C17H15N2O2 [MþH]þ: calcd 279.1134, found 279.1133.
3.2.1. 2-Benzyl-5-methoxy-4-phenylpyridazin-3(2H)-one
(3). The residue was purified by flash column chromato-
graphy on silica gel with a mixture of ethyl acetate and
hexane (2:8) as the eluent to yield the title compound as
white crystals (566 mg, 97%); mp 107–1088C; nmax (KBr):
3058, 3035, 3004, 2952, 1624, 1601, 1494, 1446, 1406,
1352, 1333, 1313, 1268, 1155, 1065, 972, 782, 750, 736,
696, 591, 520 cm21; dH (CDCl3): 7.91 (s, 1H, H-6), 7.52 (br
d, J¼8 Hz, 2H, H-20, -60 or H-2000, -6000), 7.48 (br d, J¼07 Hz,
2H,00H0 -20,60 or H-2000,6000), 7.41 (br t, J¼8 Hz, 2H, H-300,050 or
H-30 , 5000), 7.37 (br t, J¼7 Hz, 3H, H-30,50 or H-3000,5 and
H-4 or H-4000), 7.31 (br t, J¼7 Hz, 1H, H-40 or H-4000), 5.37
(s, 2H, 2-CH2), 3.87 (s, 3H, 5-OCH3); dC (CDCl3): 160.9,
154.7, 136.5, 130.4, 130.3, 129.0, 128.6, 128.4, 128.0,
127.9, 127.8, 121.7, 57.2, 55.6; MS (ESI): 91; HRMS (ESI)
for C18H17N2O2 [MþH]þ: calcd 293.1290, found 293.1285.
3.2.5. 2-Benzyl-4-phenyl-5-trifluoromethanesulfonyloxy-
pyridazin-3(2H)-one (5). Compound
4
(465 mg,
1.67 mmol) and triethylamine (0.31 mL, 2.22 mmol) were
dissolved in dry CH2Cl2 (12 mL) in a two-necked flask
equipped with a drying tube and a septum, and placed in an
ice-acetone bath (258C). Trifluoromethanesulfonic anhy-
dride (0.31 mL, 1.84 mmol) was added dropwise to the
cooled solution and stirred for 30 min at 258C. The mixture
was then poured onto 1 M HCl (8.5 mL) and water (50 mL)
was added. Subsequently, the water phase was extracted
with CH2Cl2 (3£30 mL). The combined organic layers were
washed with 1% NaHCO3 solution and brine, dried over
MgSO4 and evaporated to dryness. The obtained oil
(673 mg, 98%) was used in further transformations without
purification and characterization.
3.2.2. 2-Benzyl-5-(2-bromophenyl)-4-phenylpyridazin-
3(2H)-one (6). The residue was purified by flash column
chromatography on silica gel with CH2Cl2 as the eluent to
yield the title compound as a pale yellow oil (603 mg, 88%);
nmax (KBr): 3441, 3058, 1645, 1601, 1494, 1425, 1336,
1254, 1025, 942, 755, 731, 697, 672, 654, 605 cm21; dH
(CDCl3): 7.76 (s, 1H, H-6), 7.60–6.90 (m, 14H), 5.50 (d,
3.2.6. 5-(2-Aminophenyl)-2-benzyl-4-phenylpyridazin-
3(2H)-one (10). A mixture of compound 9 (200 mg,

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5924
0.457 mmol), ethanol (40 mL) and aqueous sulphuric acid
(40% (v), 40 mL) was refluxed overnight. After cooling,
water was added (40 mL) and the ethanol was evaporated
under reduced pressure. The pH of the residue was adjusted
to 8–9 by addition of aqueous ammonia (25%) during
cooling. The mixture was then extracted with CH2Cl2
(5£40 mL), dried over MgSO4, evaporated to dryness and
crystallized from methanol to yield yellow prisms (146 mg,
90%); mp 138–1398C; nmax (KBr): 3428, 3373, 3338, 3062,
3030, 2953, 1625, 1584, 1494, 1455, 1427, 1341, 1307,
1257, 1157, 1121, 1075, 1032, 939, 859, 797, 747, 724, 699,
639, 604, 574, 484 cm21; dH (CDCl3): 7.80 (s, 1H, H-6),
7.57 (br dd, J¼8, 10.5 0Hz, 2H, 0H-20,60 or H0-002000,6000), 7.38–
7.19 (m, 8H, H-30,4 ,5 ,2000(or 2 ),3000,4000,5000,6 00 (or 60)), 7.09
(ddd, J¼8.1, 7.3, 1.5 Hz, 1H, H-400 or H-5 ), 6.89 (ddd,
J¼7.6, 1.5, 0.3 Hz, 1H, H-600 or H-300), 6.69 (ddd, J¼7.7,
7.3, 1.1 Hz, 1H,00 H-500 or H-400), 6.57 (ddd, J¼8.1, 1.1,
0.3 Hz, 1H, H-3 or H-600), 5.40 (two br s, 2H, 2-CH2,
diastereotopic), 3.45 (br s, 2H, 200-NH2); dC (CDCl3): 159.8,
143.2, 139.1, 138.4, 136.4, 132.6, 130.1, 130.0, 129.8,
129.3, 128.8, 128.6, 128.0, 127.9, 120.6, 118.9, 116.2, 56.0;
MS (ESI): 354, 91; HRMS (ESI) for C23H20N3O [MþH]þ:
calcd 354.1606, found 354.1619.
3.3.2. 2-Methyldibenzo[f,h]cinnolin-3(2H)-one (14). The
residue was subjected to flash column chromatography on
silica gel with a mixture of ethyl acetate and chloroform
(1:9) as the eluent and recystallized from a mixture of
chloroform and methanol to yield the title compound as
yellow crystals (217 mg, 46%); mp 233–2348C; nmax
(KBr): 3440, 3057, 1650, 1594, 1563, 1490, 1449, 1271,
1233, 1007, 865, 759, 730, 710 cm21; dH (CDCl3): 8.67 (dd,
J¼8.0, 1.4 Hz, 1H, H-12), 8.35 (br d, J¼8.1 Hz, 1H, H-8),
8.28 (br d, J¼8.1 Hz, 1H, H-9), 8.20 (br d, J¼8.1 Hz, 1H, H-
5), 7.71 (s, 1H, H-4), 7.68 (ddd, J¼8.3, 7.2, 1.2 Hz, 1H, H-
7), 7.61 (ddd, J¼8.1, 7.1, 1.5 Hz, 1H, H-10), 7.55 (br t, 2H,
H-6,11), 4.07 (s, 3H, 2-CH3); dC (CDCl3): 161.0 (C-3),
137.5 (C-12b), 134.5 (C-4a), 132.1 (C-8a), 131.3 (C-7),
130.7 (C-8b), 129.7 (C-10), 128.6 (C-11), 128.4 (C-6),
128.3 (C-12a), 126.3 (C-4b), 125.1 (C-5), 124.1 (C-12),
123.8 (C-8), 123.2 (C-9), 118.9 (C-4), 41.1 (2-CH3); MS
(ESI): 218, 189, 165; HRMS (ESI) for C17H13N2O
[MþH]þ: calcd 261.1028, found 261.1028.
3.4. General procedure for the synthesis of
2-benzyldibenzo[f,h]phthalazin-1(2H)-one (7) and
2-methyldibenzo[f,h]cinnolin-3(2H)-one (14) via Pschorr
reaction
3.3. General procedure for the synthesis of
2-benzyldibenzo[f,h]phthalazin-1(2H)-one (7) and
2-methyldibenzo[f,h]cinnolin-3(2H)-one (14) via
intramolecular Pd-catalyzed arylation
Compound 10 or 15 (7: 104 mg, 0.294 mmol; 14: 440 mg,
1.6 mmol) was dissolved in concentrated HCl (7: 6 mL; 14:
13 mL) and cooled to 08C while stirring. Aqueous NaNO2
solution (7: 61 mg, 0.882 mmol in 3 mL of water; 14:
235 mg, 3.4 mmol in 9 mL of water) was added dropwise at
such a rate that the temperature of the mixture did not
exceed 58C. The reaction mixture was stirred further at this
temperature for 1.5 h, and at room temperature for an
additional 1.5 h. Subsequently, the mixture was neutralized
using a saturated Na2CO3 solution, extracted with CH2Cl2
or CHCl3 (3£20 mL), dried over Na2SO4 or MgSO4 and
evaporated to dryness.
A solution of compound 6 or 13 (7: 337 mg, 0.81 mmol;
14: 621 mg, 1.82 mmol) in dimethyl acetamide (7: 8 mL;
14: 15 mL) was flushed with N2 for 5 min, NaOAc.3H2O
(7: 220 mg, 1.62 mmol; 14: 495 mg, 3.64 mmol), and
PdCl2(PPh3)2 (7: 113 mg, 0.16 mmol; 14: 255 mg,
0.36 mmol) were added, and the mixture was stirred
and heated under N2 atmosphere in an oil bath at 1308C
for 64 h (in the case of 7) or 8 h (in the case of 14). After
cooling, the solvent was evaporated under reduced
pressure and water (30 mL) was added. Subsequently,
the mixture was extracted with CH2Cl2 or CHCl3
(3£30 mL), dried over Na2SO4 or MgSO4 and evaporated
to dryness.
3.4.1. 2-Benzyldibenzo[f,h]phthalazin-1(2H)-one (7). The
residue was purified by flash column chromatography on
silica gel with CH2Cl2 as the eluent to yield the title
compound as white crystals (69 mg, 70%).
3.3.1. 2-Benzyldibenzo[f,h]phthalazin-1(2H)-one (7). The
residue was subjected to flash column chromatography on
silica gel with CH2Cl2 as the eluent to yield the title
compound as white crystals (152 mg, 56%); mp 184–
1858C; nmax (KBr): 3027, 2952, 1636, 1584, 1496, 1443,
1374, 1262, 1227, 1166, 1072, 758, 729, 720, 699 cm21; dH
(CDCl3): 10.27 (dd, J¼7.2, 2.6 Hz, 1H, H-12), 8.92 (s, 1H,
H-4), 8.65 (br d, J¼8 Hz, 1H, H-8), 8.64 (br d, J¼10 Hz,
1H, H-9), 8.43 (ddd, J¼8.2, 1.2, 0.6 Hz, 1H, H-5), 7.75 (m,
3H, H-7,10,11), 7.67 (ddd, J¼8.2, 7.0, 1.2 Hz, 1H, H-6),
7.57 (b0r00 d, J¼7 Hz, 2H, H-2000,6000), 7.37 (br t, 2H, J¼7 Hz,
H-3000,5 ), 7.30 (tt, J¼7.3, 1.4 Hz, 1H, H-4000), 5.57 (s, 2H, 2-
CH2); dC (CDCl3): 159.9 (C-1), 137.0 (C-1000), 132.9 (C-4),
132.7 (C-8a), 131.4 (C-8b), 129.7 (C-7), 129.5 (C-12),
3.4.2. 2-Methyldibenzo[f,h]cinnolin-3(2H)-one (14). The
residue was recrystallized from a mixture of chloroform and
methanol to yield the title compound as yellow crystals
(265 mg, 64%).
3.4.3. Dibenzo[f,h]phthalazin-1(2H)-one (8). A mixture of
compound
7
(101 mg, 0.3 mmol), AlCl3 (240 mg,
1.8 mmol) and toluene (10 mL) was stirred and heated at
708C for 1 h (the reflux condenser was equipped with a
drying tube). After cooling, water was added (10 mL) and
the mixture was extracted with CHCl3 (6£30 mL), dried
over MgSO4 and evaporated to dryness. The residue was
subjected to flash column chromatography on silica gel with
a mixture of methanol and toluene (5:95) as the eluent to
yield the title compound as white-pink crystals (43 mg,
58%); mp 3258C (decomp.); nmax (KBr): 3440, 3155, 3036,
2917, 1644, 1558, 1449, 1248, 1159, 1141, 1010, 879, 782,
762, 737, 722 cm21; dH (DMSO-d6): 13.27 (br s, 1H, 2-H),
10.27 (dd, J¼8.4, 1.3 Hz, 1H, H-12), 9.35 (s, 1H, H-4),
9.00–8.92 (three br d, 3H, H-5,8,9), 7.96–7.79 (four br t,
000
129.0 (C-10), 128.7 (C-2000,6000), 128.6 (C-3000,5 ), 128.5 (C-
000
4a), 128.12 (C-11), 128.09 (C-12a), 127.8 (C-4 ), 127.7 (C-
6), 125.7 (C-4b), 123.9 (C-5), 123.6 (C-12b), 123.4 (C-8),
122.3 (C-9), 55.8 (2-CH2); MS (ESI): 259, 231, 91; HRMS
(ESI) for C23H17N2O [MþH]þ: calcd 337.1341, found
337.1334.

´
P. Tapolcsanyi et al. / Tetrahedron 59 (2003) 5919–5926
5925
Therein, M. U.S. Patent 6,004,960, 1999. (f) Coelho, A.;
4H, H-6,7,10,11); dC (DMSO-d6): 160.6, 133.8, 132.0,
130.8, 130.1, 129.01, 128.98, 128.4, 128.0, 127.9, 127.3,
125.5, 125.1, 123.6, 123.0, 122.4; MS (ESI): 247, 229, 218,
204, 190, 177, 165; HRMS (ESI) for C16H11N2O [MþH]þ:
calcd 247.0871, found 247.0872.
´
Sotelo, E.; Estevez, I.; Ravin˜a, E. Synthesis 2001, 871–876.
(g) Coelho, A.; Ravin˜a, E.; Sotelo, E. Synlett 2002,
2062–2064. For Suzuki arylations on iodopyridazin-3(2H)-
´ ´
ones see: (h) Krajsovszky, G.; Matyus, P.; Riedl, Z.; Csanyi,
´
D.; Hajos, G. Heterocycles 2001, 55, 1105–1111. For Suzuki
arylations on trifluoromethane-sulfonyloxypyridazin-3(2H)-
ones see: (i) see Ref. 1e. (j) Maes, B. U. W.; Monsieurs, K.;
` ´
Loones, K.; Lemiere, G. L. F.; Dommisse, R.; Matyus, P.;
3.4.4. 5-(2-Bromophenyl)-2-methyl-6-phenylpyridazin-
3(2H)-one (13). A mixture of compound 12 (441 mg,
2 mmol) and Pd(PPh3)4 (120 mg, 0.1 mmol) in dimethox-
yethane (12 mL) was stirred for 20 min under N2 atmos-
phere at room temperature. 2-Bromophenylboronic acid
(500 mg, 2.5 mmol) and aqueous Na2CO3 (2 M, 2 mL) were
added and the mixture was stirred and refluxed in an oil bath
(temperature oil bath: 1108C) under a N2 atmosphere for 5 h.
After cooling, the reaction mixture was poured onto ice-
water (30 mL), extracted with CH2Cl2 (3£30 mL), dried
over MgSO4 and evaporated to dryness. The residue was
purified by flash column chromatography on silica gel with
a mixture of ethyl acetate and hexane (1:4) as the eluent and
recrystallized from methanol to yield the title compound as
white crystals (424 mg, 62%); mp 151–1528C; nmax (KBr):
3047, 2948, 1666, 1594, 1574, 1561, 1491, 1471, 1442,
1425, 1392, 1326, 1263, 1158, 1003, 994, 952, 901, 797,
778, 762, 745, 728, 701, 656, 568 cm21; dH (CDCl3): 7.51
(ddd, J¼7.9, 1.2, 0.3 Hz, 1H, H-300), 7.029 (td, J¼07.5, 1.2 Hz,
1H, H-500), 7.27–7.18 00(m, 5-H, H-2 ,30,40,50,6 ), 7.20 (td,
J¼7.7, 1.7 Hz, 1H, H-4 ), 7.16 (ddd, J¼7.6, 1.7, 0.3 Hz, 1H,
H-600), 6.90 (s, 1H, H-4), 3.93 (s, 3H, 2-CH3); dC (CDCl3):
160.0, 146.0, 145.0, 137.1, 135.3, 133.1, 130.6, 130.3,
129.9, 128.8, 128.6, 128.0, 127.5, 122.3, 40.3; MS (ESI):
282, 261, 259, 247, 233, 220, 204, 203, 181, 144, 133, 130,
118, 102, 77; HRMS (ESI) for C17H14BrN2O [MþH]þ:
calcd 341.0289, found 341.0283.
´
Riedl, Z.; Hajos, G. Tetrahedron 2002, 58, 9713–9721.
2. Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11,
513–519.
3. For recent reviews on the Suzuki reaction see: (a) Hassan, J.;
´
Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev.
2002, 102, 1359–1469. (b) Suzuki, A. J. Organomet. Chem.
2002, 653, 83–90. (c) Kotha, S.; Lahiri, K.; Kashinath, D.
Tetrahedron 2002, 58, 9633–9695.
4. Cho, S.-D.; Choi, W.-Y.; Yoon, Y.-J. J. Heterocycl. Chem.
1996, 33, 1579–1582.
5. Barlin, G. B.; Lakshminarayanan, P. J. Chem. Soc., Perkin
Trans. 1 1977, 1038–1044.
6. Lyga, J. W. J. Heterocycl. Chem. 1988, 25, 1757–1760.
7. For a recent review dealing with direct arylation via cleavage
of activated and unactivated C–H bonds see: Miura, M.;
Nomura, M. Top. Curr. Chem. 2002, 219, 211–241.
8. For examples on the synthesis of polycyclic aromatic
hydrocarbons via intramolecular Pd-catalyzed arylation see:
(a) Rice, J. E.; Cai, Z. W. Tetrahedron Lett. 1992, 33,
1675–1678. (b) Rice, J. E.; Cai, Z. W. J. Org. Chem 1993, 58,
1415–1424. (c) Reisch, H. A.; Bratcher, M. S.; Scott, L. T.
Org. Lett. 2000, 2, 1427–1430. (d) Wang, L.; Shevlin, P. B.
Org. Lett. 2000, 2, 3703–3705. (e) Marcinow, Z.; Sygula, A.;
Ellern, A.; Rabideau, P. W. Org. Lett. 2001, 3, 3527–3529.
(f) Mehta, G.; Sarma, P. V. V. S. Tetrahedron Lett. 2002, 43,
6557–6560. (g) Wegner, H. A.; Scott, L. T.; de Meijere, A.
J. Org. Chem. 2003, 68, 883.
Acknowledgements
9. (a) Pschorr, R. Chem. Ber. 1896, 29, 496. In principal the
observed ring closure reaction can occur via a heterolytic or a
homolytic dediazoniation of the aryldiazonium ion. Although
a heterolytic cleavage (SN1) seems very likely, a homolytic
dediazoniation cannot be excluded since an excess of nitrite is
used in the diazotization reaction. Since this anion is known to
be a likely candidate for an electron transfer reaction to the
diazonium ion, the observed ring closure might also occur via
the formation of an aryl radical. For a review dealing with the
homolytic dediazoniation of arenediazonium ions and the
subsequent reactions of the formed aryl radicals see: Galli, C.
Chem. Rev. 1988, 88, 765–792.
´
Dr P. Tapolcsanyi thanks the RAFO RUCA for a post-
doctoral grant. Professor Dr B. U. W. Maes is grateful to the
FWO-Flanders for financial support to perform a research
stay in Budapest. Funding by RAFO RUCA, OTKA 33105,
OTKA 31910 and ETT 187/2000 is gratefully acknowl-
edged. The authors wish to thank Professor Dr E. Esmans
and Professor Dr F. Lemiere for the use of their MS facilities
and Ing. J. Aerts, J. Schrooten, R. Tuytten, Ing. W. Van
Dongen and Ing. J. Verreydt for technical assistance.
`
10. For examples on the synthesis of phenanthrene units via
Pschorr reaction see: (a) Sako, S. Bull. Chem. Soc. Jpn 1934, 9,
55–74. (b) Foldeak, S. Tetrahedron 1971, 27, 3465–3476. (c)
Ibuki, E.; Ozasa, S.; Fujioka, Y.; Kitamura, H. Chem. Pharm.
Bull. 1980, 28, 1468–1476. (d) Ozasa, S.; Fujioka, Y.;
Fujiwara, M.; Ibuki, E. Chem. Pharm. Bull. 1980, 28,
3210–3222. (e) Duclos, R. I.; Tung, J. S.; Rapoport, H.
J. Org. Chem. 1984, 49, 5243–5246. (f) Giese, B. Radicals in
Organic Synthesis: Formation of Carbon–Carbon Bonds.
Organic Chemistry Series; Pergamon: London, 1986; vol. 5.
pp 217–220. (g) Wassmundt, F. W.; Kiesman, W. F. J. Org.
Chem. 1995, 60, 196–201. (h) Hanson, P.; Lovenich, P. W.;
Rowell, S. C.; Walton, P. H.; Timms, A. W. J. Chem. Soc.,
Perkin Trans. 2 1999, 49–63.
References
1. For Suzuki arylations on chloropyridazin-3(2H)-ones see: (a)
ˇ
`
Maes, B. U. W.; R’kyek, O.; Kosmrlj, J.; Lemiere, G. L. F.;
Esmans, E.; Rozenski, J.; Dommisse, R. A.; Haemers, A.
Tetrahedron 2001, 57, 1323–1330. (b) Maes, B. U. W.;
ˇ
Kosmrlj, J.; Lemiere, G. L. F. J. Heterocycl. Chem. 2002, 39,
`
535–543. Riedl, Z.; Maes, B. U. W.; Monsieurs, K.; Lemiere,
`
´
G. L. F.; Matyus, P.; Hajos, G. Tetrahedron 2002, 58,
´
´ ´
5645–5650. (d) Tapolcsanyi, P.; Krajsovszky, G.; Ando, R.;
´
Lipcsey, P.; Horvath, Gy.; Matyus, P.; Riedl, Z.; Hajos, G.;
´ ´
`
Maes, B. U. W.; Lemiere, G. L. F. Tetrahedron 2002, 58,
10137–10143. For Suzuki arylations on bromopyridazin-
3(2H)-ones see: (e) Li, C. S.; Gauthier, J. Y.; Lau, C. K.;
11. (a) Cort, L. A.; Mahesar, M. A. J. Chem. Soc., Perkin Trans. 1

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5926
1979, 2034–2043. (b) Schmidt, P.; Druey, J. Helv. Chim. Acta
1954, 37, 134–140.
sence of electron withdrawing groups on, as well as the
incorporation of nitrogen atoms in the ring of the aryl chloride
makes oxidative addition of aryl chlorides to palladium
catalysts with traditional triarylphosphane ligands possible:
(a) Fitton, P.; Rick, E. A. J. Organomet. Chem. 1971, 28,
287–291. (b) Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed.
2002, 41, 4176–4211. The conjugate base of the 2-bromo-
phenylboronic acid might sterically and electronically retard
oxidative addition of the ortho C–Br bond to Pd(0). This also
explains the selectivity observed in the Suzuki reaction on 12
(see Ref. 8g).
12. Tsuchiya, T.; Arai, H.; Tonami, T.; Igeta, H. Chem. Pharm.
Bull. 1971, 19, 2204–2207.
13. For the effect of halide anions on Pd-catalyzed reactions see:
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1991, 113, 8375. (b) Amatore, C.; Jutand, A. Acc. Chem. Res.
2002, 33, 314–321. (c) Fagnou, K.; Lautens, M. Angew.
Chem. Int. Ed. 2002, 41, 26–47.
14. 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,
´
17. (a) Timari, G.; Soos, T.; Hajos, G. Synlett 1997, 1067–1068.
´
´
´
(b) Csanyi, D.; Timari, G.; Hajos, G. Synth. Commun. 1999,
´
´
29, 3959–3969. (c) see Ref. 1d,h.
18. For a recent review on modern routes to polycyclic aromatic
hydrocarbons see: Hagen, S.; Hopf, H. Top. Curr. Chem. 1998,
196, 45–89.
´ ´ ´
1309–1316. (e) Zara-Kaczian, E.; Matyus, P. Heterocycles
1993, 36, 519–528. (f) see Ref. 1c.
15. Gronowitz, S.; Bobosik, V.; Lawitz, K. Chem. Scr. 1984, 23,
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19. Estevez, I.; Ravin˜a, E.; Sotelo, E. J. Heterocycl. Chem. 1998,
35, 1421–1428.
20. Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G. Tetrahedron
1993, 49, 49–64.
´
16. The rate of oxidative addition of aryl halogenides to the
Pd(PPh3)2 catalyst is ArI.ArBrqArCl. However, the pre-