Synthesis of 5H-pyridazino[4,5-b]indoles and their benzofurane analogues utilizing an intramolecular Heck-type reaction

Article abstract of DOI:10.1016/j.tet.2004.01.024

The title ring systems were prepared from pyridazin-3(2H)-one precursors in novel, efficient pathways. 2-Methylbenzo[b]furo[2,3-d]pyridazin-1(2H)-one was synthesized via a regioselective nucleophilic substitution reaction of a 2-methyl-4,5-dihalopyridazin-3(2H)-one with phenol followed by an intramolecular Heck-type reaction. The same molecule and its 6-phenyl analogue were also prepared via reaction of 2-methyl-5-iodopyridazin-3(2H)-one or 2-methyl-5-chloro-6-phenylpyridazin-3(2H)-one, respectively, with 2-bromophenol or 2-iodophenol followed by Pd-catalyzed cyclodehydrohalogenation. Moreover, a new approach for the synthesis of 2-methyl-2,5-dihydro-1H-pyridazino[4,5-b] indol-1-ones was also elaborated utilizing a Heck-type ring closure reaction on 5-[(2-bromophenyl)amino]-2-methylpyridazin-3(2H)-ones which were obtained via Buchwald-Hartwig amination of 2-methyl-5-halopyridazin-3(2H)-ones with 2-bromoaniline.

Full text of DOI:10.1016/j.tet.2004.01.024

Tetrahedron 60 (2004) 2283–2291
Synthesis of 5H-pyridazino[4,5-b]indoles and their benzofurane
analogues utilizing an intramolecular Heck-type reaction
a
Beata Dajka-Halasz, Katrien Monsieurs, Oliver Elias, Laszlo Karolyhazy, Pal Tapolcsanyi,
b
a
a
a
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´
´
´
´
c
´
´
´
´
´
´
Bert U. W. Maes,b Zsuzsanna Riedl, Gyorgy Hajos, Roger A. Dommisse, Guy L. F. Lemiere,
c
b
b
,
*
´
Janez Kosmrlj and Peter Matyus
`
¨
d
a
,
*
ˇ
´
´
a
¨
Department of Organic Chemistry, Semmelweis University, Hogyes E. u. 7., H-1092 Budapest, Hungary
bDepartment of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium
cChemical Research Center, Institute of Chemistry, Hungarian Academy of Sciences, P.O. Box 17, H-1525 Budapest, Hungary
d
ˇ ˇ
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, SI-1000 Ljubljana, Slovenia
Received 3 November 2003; revised 18 December 2003; accepted 9 January 2004
´
Cordially dedicated to Professor Sandor Antus on the occasion of his
60th birthday and to Professor Herman Desseyn on the occasion of his 65th birthday
Abstract—The title ring systems were prepared from pyridazin-3(2H)-one precursors in novel, efficient pathways. 2-Methylbenzo[b]
furo[2,3-d]pyridazin-1(2H)-one was synthesized via a regioselective nucleophilic substitution reaction of a 2-methyl-4,5-dihalopyridazin-
3(2H)-one with phenol followed by an intramolecular Heck-type reaction. The same molecule and its 6-phenyl analogue were also prepared
via reaction of 2-methyl-5-iodopyridazin-3(2H)-one or 2-methyl-5-chloro-6-phenylpyridazin-3(2H)-one, respectively, with 2-bromophenol
or 2-iodophenol followed by Pd-catalyzed cyclodehydrohalogenation. Moreover, a new approach for the synthesis of 2-methyl-2,5-dihydro-
1H-pyridazino[4,5-b]indol-1-ones was also elaborated utilizing a Heck-type ring closure reaction on 5-[(2-bromophenyl)amino]-2-
methylpyridazin-3(2H)-ones which were obtained via Buchwald–Hartwig amination of 2-methyl-5-halopyridazin-3(2H)-ones with
2-bromoaniline.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
methodology for the synthesis of pyridazino-annelated ring
systems based on an intramolecular Heck-type reaction with
a p-system of the pyridazin-3(2H)-one core.
The 5H-pyridazino[4,5-b]indole skeleton, an aza-analogue
of b-carboline, is well known for its interesting pharmaco-
logical properties. For instance, 5H-pyridazino[4,5-b]indole
derivatives show a wide variety of cardiovascular activities
such as inhibition of blood platelet aggregation, thrombox-
ane synthetase and phosphodiesterase as well as inotropic
and antihypertensive activity.1a–k Interestingly, the structur-
ally closely related benzo[b]furo[2,3-d]pyridazine ring
system has been far less investigated.1l,m Encouraged by
the pharmacological value of these ring systems, we decided
to probe a new and short approach towards the synthesis of
5H-pyridazino[4,5-b]indoles and benzo[b]furo[2,3-d]pyri-
dazines. Recently, our laboratories published several
examples on the synthesis of diazino-fused polycyclic
heteroaromatic compounds based on the Suzuki coupling of
a (pseudo)halopyridazin-3(2H)-one with ortho substituted
arylboronic acids.2 In this paper we describe an entirely new
Of the target ring systems, only the synthesis of 5H-
pyridazino[4,5-b]indoles has been thoroughly studied.2a,e,3,4
The oldest and standard procedure is based on the reaction
of a 2,3-dicarbonylated indole with a hydrazine.3a–c More
recently, an inverse electron demand Diels–Alder reaction
of indoles with 1,2,4,5-tetrazines was utilized for the
preparation of 5H-pyridazino[4,5-b]indoles.4 In 2001, we
reported the first pyridazine-based approach, providing the
first example for a palladium-catalyzed strategy for the
synthesis of this skeleton.2a This approach relies on a Suzuki
cross-coupling of easilyaccessible5-iodo-2-methylpyridazin-
3(2H)-one5 (1) with a protected 2-aminophenylboronic acid
(2) (Scheme 1). Subsequent deprotection and diazotization
of amine 4 followed by an in situ SN1 reaction with sodium
azide yielded arylazide 5. The thermal reaction of this
compound, presumably via an electrocyclic reaction of a
nitrene intermediate, led to the tricyclic fused ring system.
The latter approach is totally different from the two other
strategies since the pyridazino-indole core is built up
starting from a pyridazin-3(2H)-one rather than from an
indole moiety.
Keywords: Palladium; Buchwald–Hartwig amination; Intramolecular
Heck-type reaction; Pyridazinone; Aza-b-carboline.
*
Corresponding authors. Tel.: þ32-3-265-32-05; fax: þ32-3-265-32-33
(B.U.W.M.); tel./fax: þ36-1-217-08-51 (P.M.);
e-mail addresses: bert.maes@ua.ac.be; matypet@szerves.sote.hu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.01.024

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2284
Scheme 1.
Although, our earlier developed palladium-catalyzed pro-
cedure could in principle be extended to the preparation of
5H-pyridazino[4,5-b]indoles substituted at the benzene ring,
and furthermore a modified route using protected 2-
hydroxyphenylboronic acids could be developed for the
synthesis of their furo analogues, this type of Suzuki based
methodology has a serious drawback since it requires (at
least) equimolar amounts of substituted 2-amino- or 2-
hydroxyphenylboronic acids which are not commercially
available. Therefore, we decided to develop a new
palladium-catalyzed approach, based on easily available
halogenated pyridazin-3(2H)-ones, via a combination of a
substitution and an intramolecular Heck-type reaction.6,7
The 5-phenoxypyridazin-3(2H)-ones, required for the
benzofuropyridazines, are easily available through a
nucleophilic substitution reaction on halopyridazin-3(2H)-
ones with phenol whereas the 5-phenylaminopyridazin-
3(2H)-ones, required for the pyridazinoindoles, were
thought to be conveniently accessible via a Buchwald–
Hartwig amination reaction.8,9f–j
pyridazinone (route a) or at the attached phenoxy- or
phenylamino-ring (route b) (Scheme 2). To determine
which route gives the best result, we decided to explore
the above-mentioned strategies in the synthesis of the
benzo[b]furo[2,3-d]pyridazine skeleton. As reported in the
literature 4-bromo-2-methyl-5-phenoxypyridazin-3(2H)-
one (8a) and 4-chloro-2-methyl-5-phenoxypyridazin-
3(2H)-one (8b) can be obtained via phenolysis of the
corresponding 4,5-dibromo- (7a) and 4,5-dichloro-2-
methylpyridazin-3(2H)-one (7b) in refluxing acetonitrile
using potassium carbonate as the base.9g However, we
found that 2-methyl-4,5-diphenoxypyridazin-3(2H)-
one was also formed under these reaction conditions.
Therefore, in analogy to the room temperature monoalk-
oxylation of 2-substituted 4,5-dihalopyridazin-3(2H)-ones
with sodium alkanolates, we tried to perform phenolysis of
4,5-dibromo- (7a) and 4,5-dichloro-2-methylpyridazin-
3(2H)-one (7b) in acetonitrile at room temperature with
1 equivalent of commercially available sodium phenolate
trihydrate (Scheme 3). After 19 h stirring at room
temperature we obtained 61% of 4-bromo-2-methyl-5-
phenoxypyridazin-3(2H)-one (8a) and 62% of 4-chloro-2-
methyl-5-phenoxypyridazin-3(2H)-one (8b). Interestingly,
in these reaction mixtures we also found 20% of the
For the subsequent ring closure step two routes can be
considered: the halogen atom participating in the intra-
molecular Heck-type reaction can be present either at the
Scheme 2.
Scheme 3.

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2285
Scheme 4.
isomeric 5-halo-2-methyl-4-phenoxypyridazin-3(2H)-ones
(9a and 9b).10,11 To the best of our knowledge, the
formation of 2-substituted 5-halo-4-phenoxypyridazin-
3(2H)-ones from the corresponding 2-substituted 4,5-
dihalopyridazin-3(2H)-ones and phenol has not yet been
reported. The 5-(2-bromophenoxy)-2-methylpyridazin-
3(2H)-one (10), required for the other route, was obtained
in a moderate yield from 5-iodo-2-methylpyridazin-3(2H)-
one (1), under the reaction conditions reported for the
synthesis of 2-substituted 4-halo-5-phenoxypyridazin-
3(2H)-ones from 2-substituted 4,5-dihalopyridazin-3(2H)-
ones (Scheme 4).9g Similarly, 5-(2-iodophenoxy)- (12a) and
5-(2-bromophenoxy)-2-methyl-6-phenylpyridazin-3(2H)-
one (12b) were prepared by phenolysis of 5-chloro-2-
methyl-6-phenylpyridazin-3(2H)-one12 (11) (Scheme 5).
intramolecular Heck-type reaction of the isomeric deriva-
tive 10 afforded 13 in excellent yield (99%) (Scheme 8).
Disappointingly, and unexpectedly, the presence of a 6-
phenyl group in 12 has apparently a strong effect on the
yield of cyclization since 2-methyl-4-phenylbenzo[b]-
furo[2,3-d]pyridazin-1(2H)-one (14) was isolated in only
49% yield (Scheme 9). The use of 5-(2-iodophenoxy)-2-
methyl-6-phenylpyridazin-3(2H)-one (12a), the iodo ana-
logue of 12b, gave 14 in a slightly higher yield (58%)
(Scheme 9).
Scheme 7.
Scheme 5.
Intramolecular Heck-type reaction of 8a was carried out
under the reaction conditions (Pd(PPh3)2Cl2, NaOAc.3H2O,
DMA, 130 8C)13 we recently published for the construction
of angularly annelated pyridazine ring systems, and afforded
the desired 2-methylbenzo[b]furo[2,3-d]pyridazin-1(2H)-
one (13) in 68% yield (Scheme 6).2f,14 Since compound
8b contains an activated carbon chlorine bond the same
reaction conditions were tested for the cyclodehydrochlor-
ination of this substrate (Scheme 6).15 Unfortunately, less
than 15% of 13 was obtained from 8b and a lot of starting
material remained unreacted in the crude reaction mixture,
as judged by TLC and MS analysis. After some optimization
work we found that compound 13 could be obtained in a
similar yield as starting from 8a when DMF was used as
solvent, Na2CO3 as base and Bu4NBr as additive (compare
Schemes 6 and 7).14,16–18 Interestingly, under the same
reaction conditions as used for the cyclization of 8a, the
Scheme 8.
Scheme 9.
These results clearly indicate that, for the synthesis of the
benzo[b]furo[2,3-d]pyridazine skeleton, the intramolecular
Heck-type reaction of 5-(2-halophenoxy)pyridazin-3(2H)-
ones (route b) is superior to that of 4-halo-5-phenoxypyri-
dazin-3(2H)-ones (route a).19 Therefore, we decided to
explore a reaction pathway similar to the former route for
the synthesis of the 5H-pyridazino[4,5-b]indole skeleton by
utilizing 5-(2-bromophenylamino)-2-methylpyridazin-
3(2H)-one (15), easily available from 5-iodo-2-methyl-
pyridazin-3(2H)-one (1) (Scheme 10). Nucleophilic
Scheme 6.

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2286
addition to Pd(BINAP) in comparison with unactivated
C–Cl bonds.15 In addition, the amino substituent of 2-
bromoaniline sterically and electronically deactivates the
C–Br bond for the oxidative addition to Pd(BINAP)
catalyst.23 Interestingly, the reaction did not end up with
the formation of 17. In a one pot process the intermediately
formed 17 cyclized via an intramolecular Heck-type
reaction yielding 2-methyl-4-phenyl-2,5-dihydro-1H-
pyridazino[4,5-b]indol-1-one (18) in 55% overall yield
(Scheme 11).
In conclusion, we have studied the synthesis of the
benzo[b]furo[2,3-d]pyridazine and 5H-pyridazino[4,5-
b]indole ring systems via a new approach by combination
of a nucleophilic substitution reaction or a selective
Buchwald–Hartwig reaction on a 5-halopyridazin-3(2H)-
one with an intramolecular Heck-type reaction. These
syntheses represent the first report of Heck-type reactions
with C–H activation on a pyridazin-3(2H)-one core. The
presented Pd-catalyzed strategy is especially useful for the
synthesis of benzo[b]furo[2,3-d]pyridazines and 5H-pyri-
dazino[4,5-b]indoles substituted in the benzene ring since it
only requires easily accessible substituted 2-bromophenols
and 2-bromoanilines, respectively.
Scheme 10.
substitution of the iodine atom of 1 via an addition–
elimination mechanism with 2-bromoaniline did not occur as
expected.20 Buchwald–Hartwig amination with 2-bromo-
aniline seemed therefore to be worth trying.
We recently reported on the Pd-catalyzed amination of
4-chloropyridazin-3(2H)-ones with substituted anilines.21b
When we applied these reaction conditions for the
amination of 1 with 2-bromoaniline, 15 was obtained in
excellent yield (85%) (Scheme 10). Although the amination
reaction of 1 using 5 equiv.21b of K2CO3 was considerably
faster than using only 1 equiv., the same yield could be
obtained in an overnight reaction.21,22 In the final step of the
synthesis of the pyridazinoindole system, Pd-catalyzed
cyclodehydrobromination of 15 was carried out under the
conditions used for cyclization of 8a, giving the desired
2-methyl-2,5-dihydro-1H-pyridazino[4,5-b]indol-1-one
(16) in 73% yield (Scheme 10).
2. Experimental
2.1. General
All melting points were determined on a Kofler apparatus,
except for the melting points of compounds 8a, 8b, 9a, 9b,
and 18 which were determined on a Bu¨chi apparatus. All the
reported melting points are uncorrected. The IR spectra of
compounds 10, 12a, 12b and 13–16 were recorded on a
Perkin–Elmer 1600 FT-IR instrument in potassium bromide
pellets. The IR spectra of compounds 1, 8a, 8b, 9a, 9b and
18 were recorded on a Bruker Vector 22 spectrometer in
potassium bromide pellets. The 1H- and 13C NMR spectra of
compounds 10, 12a, 12b and 13–16 were recorded on a
Bruker AM 200 MHz spectrometer in the solvent indicated
using TMS as the internal standard. The assignments of 13C
NMR spectra of 10, 12a, 12b and 13–16 were supported by
DEPT-135 spectra. The 1H and 13C NMR spectra of
compounds 1, 8a, 8b, 9a, 9b and 18 were recorded on
a Varian Unity 400 spectrometer in the solvent indicated
with TMS as the internal standard. All coupling constants
are given in Hz and chemical shifts are given in ppm. The
numbering used for the assignment of NMR-signals is
as follows for non-cyclized compounds: pyridazinone
ring simple figures, 5-substituents primed figures and 4- or
In analogy to the synthesis of 2-methyl-4-phenylbenzo[b]-
furo[2,3-d]pyridazin-1(2H)-one (14) we attempted to
prepare the nitrogen analogue 2-methyl-4-phenyl-2,5-
dihydro-1H-pyridazino[4,5-b]indol-1-one (18) from the
same starting material. Remarkably, Buchwald–Hartwig
reaction of 5-chloro-2-methyl-6-phenylpyridazin-3(2H)-
one (11) with 2-bromoaniline worked smoothly and no
homocoupling of the bromoaniline was observed
(Scheme 11). The C–Cl bond of 11 seems to be more
reactive in the oxidative addition step than the C–Br bond
of 2-bromoaniline. The preferential reaction of the C–Cl
bond of 11 can be explained by taking into account that this
C–Cl bond is part of a vinylogous carbamoyl chloride
which dramatically increases its reactivity for oxidative
Scheme 11.

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2287
6-substituents double primed figures. For the cyclized
compounds, the IUPAC numbering was followed. 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 injec-
tions were directed to the mass spectrometer at a 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 (approx. 35 V) and capillary voltage
(approx. 3.3 kV) were optimised 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 masses of PEG [MþH]þ and [MþNH4]þ
ions were used as lock mass for the measurement of the
accurate mass values of the samples. For the product ion
experiments (MS) 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. Product ion spectra were
recorded using data-dependant acquisition selecting auto-
matically the parent ion, as it is the most abundant ion upon
injection of the sample. This automation reduced the
programming of the product ion acquisition. Parent ions
were selected with low resolution ([MþH]þ ^2 Da) unless
otherwise stated. Therefore compounds containing chlorine
and bromine show the presence of isotopes. All signals with
a signal to noise ratio $5/1 were reported. For column
chromatography of compounds 10, 12a, 12b and 13–16
Kieselgel 60 (Aldrich, 0.063–0.2 mm silica gel) was used,
while for compounds 1, 8a, 8b, 9a, 9b and 18 Kieselgel 60
(ROCC, 0.040–0.063 mm) was used. The starting com-
pounds 4,5-dibromo-2-methylpyridazin-3(2H)-one9j,k
(7a), 4,5-dichloro-2-methylpyridazin-3(2H)-one9j,k (7b)
and 5-chloro-2-methyl-6-phenylpyridazin-3(2H)-one12
(11) were prepared according to known literature pro-
cedures. 2-Bromophenol (Aldrich), 2-iodophenol (Aldrich),
2-bromoaniline (Aldrich), Pd(OAc)2 (Fluka), racemic
BINAP (Strem), Pd(PPh3)2Cl2 (Acros and Aldrich), sodium
phenolate trihydrate (Aldrich) and tetrabutylammonium
bromide (Acros) were obtained from commercial sources.
For the Buchwald–Hartwig aminations anhydrous p.a.
K2CO3 (Acros) and p.a. toluene (Acros) were used.
using heptane–diethyl ether (1:1) as the eluent to yield the
title compound (1.135 g, 74%); mp 182–183 8C; Rf
(heptane–diethyl ether 1:1): 0.28; IR (KBr): nmax: 2926,
1642, 1568, 1503, 1451, 1413, 1368, 1310, 1285, 1244,
1164, 1008, 917, 871, 744, 638, 618, 592, 492 cm21; dH
(CDCl3): 7.90 (d, J¼2.05 Hz, 1H, H-6), 7.46 (d, J¼2.05 Hz,
1H, H-4), 3.72 (s, 3H, CH3); dC (CDCl3): 159.05 (C-3),
141.62 (C-4 or C-6), 137.89 (C-4 or C-6), 102.26 (C-5),
39.91 (CH3); MS (ESI): 237, 110; HRMS (ESI) for
C5H5N2OI [MþH]þ: calcd: 236.9525, found: 236.9513.
2.3. General procedure for the reaction of 7a or 7b with
sodium phenolate trihydrate
A mixture of 4,5-dihalo-2-methylpyridazin-3(2H)-one
(5 mmol) and sodium phenolate trihydrate (5 mmol) in
acetonitrile (50 mL) was stirred at room temperature for
19 h. Then water was added (70 mL) and the mixture was
extracted with CH2Cl2 (3£70 mL). The combined organic
layers were dried over MgSO4 and evaporated in vacuo. The
crude product contains two isomers, which were separated
via column chromatography on silica gel using hexane–
ethyl acetate (8:2) as the eluent.
The following compounds were prepared in this manner.
2.3.1. 4-Bromo-2-methyl-5-phenoxypyridazin-3(2H)-one
(8a). Yield: 0.860 g, 61%; mp 141–142 8C; Rf (hexane–
ethyl acetate 8:2): 0.17; IR (KBr): nmax: 3051, 2925, 1644,
1600, 1581, 1484, 1453, 1418, 1382, 1315, 1275, 1218,
1167, 1146, 1062, 1012, 896, 822, 782, 738, 693, 635,
455 cm21; dH (CDCl3): 7.44 (dd, J¼8.6, 7.3 Hz, 2H, H-30,
-50), 7.35 (s, 1H, H-6), 7.28 (tt, J¼7.4,0<1.2 Hz, 1H, H-40),
7.09 (dd, J¼8.7, <1.1 Hz, 2H, H-20,-6 ) 3.82 (s, 3H, CH3);
dC (CDCl3): 159.06 (C-3), 155.66 and 153.88 (C-10 or C-5),
130.42 (C-30,-50), 128.99 (C-6), 125.90 (C-40), 119.57
(C-20,-60), 111.45 (C-4), 40.88 (CH3); MS (ESI): 283, 281,
207, 205, 201, 77; HRMS (ESI) for C11H10N2O2Br (79Br)
[MþH]þ: calcd: 280.9926, found: 280.9918.
2.3.2. 5-Bromo-2-methyl-4-phenoxypyridazin-3(2H)-one
(9a). Yield: 0.281 g, 20%; mp 113–114 8C; Rf (hexane–
ethyl acetate 8:2): 0.21; IR (KBr): nmax: 3057, 1649, 1587,
1491, 1480, 1472, 1429, 1278, 1241, 1222, 1183, 1170,
1151, 1076, 1044, 973, 937, 916, 776, 753, 689, 528 cm21
;
dH (CDCl3): 7.89 (s, 1H, H-6), 7.32 (dd, J¼8.7, 7.5 Hz, 2H,
H-300,-500), 7.12 (tt, J¼7.5, 10.01 Hz, 1H, H-400), 6.96 (dd,
J¼8.7, 1.1 Hz, 2H, H-200,-6 ), 3.75 (s, 3H, CH3); dC
(CDCl3): 156.28 and 155.59 and 149.59 (C-3, C-4 or
C-100), 138.25 (C-6), 129.59 00(C-300,-500), 123.97 (C-400),
117.09 (C-5), 116.45 (C-200,-6 ), 39.99 (CH3); MS (ESI):
283, 281, 207, 205, 175, 95, 77; HRMS (ESI) for
C11H10N2O2Br (79Br) [MþH]þ: calcd: 280.9926, found:
280.9912.
2.2. Synthesis of 5-iodo-2-methylpyridazin-3(2H)-one5
(1)
A round-bottom flask was charged with 4,5-dichloro-2-
methylpyridazin-3(2H)-one (6.50 mmol) and 57% HI
(10.7 mL). The mixture was heated at 140 8C for 25 h.
After cooling to room temperature, crushed ice (100 g) and
water (50 mL) were added and the mixture was cautiously
neutralized with potassium carbonate. Subsequently, small
portions of solid sodium thiosulfate were added until the
suspension turned yellow. Then, the water phase was
extracted with CH2Cl2 (3£100 mL). The combined organic
layers were dried on MgSO4 and evaporated in vacuo. The
crude product was purified with column chromatography
2.3.3. 4-Chloro-2-methyl-5-phenoxypyridazin-3(2H)-one
(8b). Yield: 0.738 g, 62%; mp 131 8C; Rf (hexane–ethyl
acetate 8:2): 0.20; IR (KBr): nmax: 3057, 1649, 1603, 1583,
1486, 1454, 1382, 1320, 1279, 1220, 1171, 1154, 1074,
1015, 898, 875, 836, 784, 741, 694, 651, 522, 0461 cm21; dH
(CDCl3): 7.45 (s, 1H, H-6), 7.44 (m, 2H, H-3 ,-50), 7.27 (tt,
J¼7.5, <1.2 Hz, 1H, H-40), 7.09 (dd, J¼8.6, <1.2 Hz, 2H,
H-20,60), 3.82 (s, 3H, CH3); dC (CDCl3): 158.80 (C-3),

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153.95 and 153.510 (C-10 or C-5), 130.44 (C-30,-50)0, 129.38
(C-6), 125.87 (C-4 ), 120.16 (C-4), 119.45 (C-20,-6 ), 40.73
(CH3); MS (ESI): 239, 237, 163, 161, 95, 77; HRMS (ESI)
for C11H10N2O2Cl (35Cl) [MþH]þ: calcd: 237.0431, found:
237.0432.
-400,-500,-50), 6.99–7.09 (m, 2H, H-40,-60), 5.88 (s, 1H, H-4),
3.83 (s, 3H, 2-CH3); dC (CDCl3): 167.7 and 157.9 (C-3,
C-5), 152.5 (C-10), 140.6 (C-6), 140.5 (C-30), 132.7 (C-100),
130.4 and 129.3 and 128.3 (C-400,-40,-50), 129.1 and 1280.3
(C-200,-300,-500,-600), 122.4 (C-60), 107.2 (C-4), 89.9 (C-2 ),
39.8 (CH3); MS (ESI): 405, 277; HRMS (ESI) for
C17H14IN2O2 [MþH]þ: calcd: 405.0100, found: 405.0080.
2.3.4. 5-Chloro-2-methyl-4-phenoxypyridazin-3(2H)-one
(9b). Yield: 0.232 g, 20%; mp 119–120 8C; Rf (hexane–
ethyl acetate 8:2): 0.31; IR (KBr): nmax: 3060, 2924, 1649,
1589, 1484, 1471, 1430, 1282, 1227, 1185, 1170, 1151,
1076, 1048, 1022, 963, 918, 897, 823, 777, 754, 732, 689,
627, 531 cm21; dH (CDCl3): 7.80 (s, 1H, H-6), 7.32 (dd,
J¼7.3, 8.8 Hz, 2H, H-300,-500), 7.12 (tt, J¼7.5, <1.2 Hz, 1H,
H-400), 6.96 (dd, J¼8.7, <1.1 Hz, 2H, H-200,-600), 3.76 (s, 3H,
CH3); dC (CDCl3): 156.59 and 155.66 and 147.57 (C-3 or
C-4 or C-100), 136.58 (C-6), 129.59 (C-300,-500), 127.56
(C-5), 123.97 (C-400), 116.45 (C-200-600), 40.08 (CH3); MS
(ESI): 239, 237, 161, 131, 95, 77; HRMS (ESI) for
C11H10N2O2Cl (35Cl) [MþH]þ: calcd: 237.0431, found:
237.0435.
2.4.3. 5-(2-Bromophenoxy)-2-methyl-6-phenylpyridazin-
3(2H)-one (12b). Reaction time: 38 h; eluent for flash
column chromatography: toluene–acetone (7:3); yield:
0.342 g, 45% as white prisms; mp 146–147 8C; Rf
(toluene–acetone): 0.32; IR (KBr): nmax 3061, 1661,
1598, 1512, 1467, 1413, 1327, 1262, 1213, 1145, 1058,
991, 944, 922, 854, 782, 745, 697, 574 cm21; dH (CDCl3):
7.88–7.93 (m, 2H, H-200,-600), 7.68 (d, J¼9.6 Hz, 1H, H-30),
7.34–7.51 (m, 4H, H-50,-300,-400,-500), 7.01–7.26 (m, 2H,
H-40,-60), 5.89 (s, 1H, H-4), 3.83 (s, 3H, 2-CH3); dC
(CDCl3): 161.7 and 157.9 (C-3, C-5), 149.5 (C-10), 140.6
(C-6), 134.4 (C-30), 132.7 (C-100), 129.400and 129.3 and 128.1
(C-4000, -40, -50), 128.9 and 128.3 (C-2 ,-300 -500,-600), 123.3
(C-6 ), 115.9 (C-20), 107 (C-4), 38.8 (CH3); MS (ESI): 357,
277, 129, 128; 82 (precursor monoisotopic); HRMS (ESI)
for C17H14BrN2O2 (79Br) [MþH]þ: calcd: 357.0239, found:
357.0233.
2.4. General procedure for the reaction of 1 or 11 with
2-halophenols
A round-bottom flask equipped with a reflux condenser and
a drying tube was charged with 1 (2.12 mmol) or 11
(2.26 mmol for 12a; 2.12 mmol for 12b), K2CO3
(1.2 equiv.), dry acetonitrile (10.0 mL for 10 and 12a;
15 mL for 12b) and 2-halophenol (1.2 equiv.). The mixture
was refluxed until the starting material had been consumed
as judged by TLC analysis. The solid K2CO3 was removed
by filtration and the filtrate was subsequently concentrated.
Then water (25 mL) was added to the residue and
the mixture was extracted with chloroform (4£25 mL).
The combined organic phases were dried over MgSO4. The
solvent was evaporated in vacuo, and the compounds were
purified by column chromatography.
2.4.4. Synthesis of 5-[(2-bromophenyl)amino]-2-methyl-
pyridazin-3(2H)-one (15). A round-bottom flask was
purged with Ar and charged with Pd(OAc)2 (0.03 mmol),
racemic BINAP (0.03 mmol) and toluene (5 mL). While
stirring, the mixture was flushed with Ar for approximately
10 min. In another flask 5-iodo-2-methylpyridazin-3(2H)-
one (1) (1.5 mmol), 2-bromoaniline (1.2 equiv.) and K2CO3
(1 equiv.) were weighed. Subsequently, the catalyst solution
was added and the flask rinsed well with an additional
amount of toluene (5 mL). The resulting mixture was
flushed with Ar for a few minutes under magnetic stirring
and subsequently heated in an oil bath (oil bath temperature
120 8C, Ar atmosphere) until the starting material had been
consumed as judged by TLC and MS analysis. The reaction
mixture was filtered over celite and rinsed well with
dichloromethane (200 mL). The solvent was evaporated in
vacuo and the residue purified by column chromatography
using ethyl acetate–chloroform (9:1) as the eluent. Reaction
time: 24 h; yield: 0.357 g, 85% as white prisms; mp 193–
1958 C; Rf (ethyl acetate–chloroform 9:1): 0.39; IR (KBr):
The following compounds were prepared in this manner.
2.4.1. 5-(2-Bromophenoxy)-2-methylpyridazin-3(2H)-
one (10). Reaction time: 40 h; eluent for flash column
chromatography: toluene–ethyl acetate (8:2); yield:
0.276 g, 46% as white prisms; mp 98–100 8C; Rf (ethyl
acetate–chloroform 9:1): 0.68; IR (KBr) nmax: 3015, 1659,
1604, 1574, 1542, 1475, 1393, 1338, 1278, 1207, 1188,
1157, 1021, 853 cm21; dH (CDCl3): 7.81 (d, J¼2.8 Hz, 1H,
H-6), 7.14–7.70 (m, 4H, phenyl aromatic protons), 5.84 (d,
1H, H-4), 3.75 (s, 3H, CH3); dC (CDCl3): 161.8 (C-3), 158.9
(C-10), 149.4 (C-5), 134.04 (C-6), 131.3 (C-30), 129.30 (C-50),
128.1 (C-4), 123.0 (C-4 ), 115.9 (C-20), 106.8 (C-6 ), 54.5
(CH3); MS (ESI): 281, 201, 155, 127, 110 (precursor
monoisotopic); HRMS (ESI) for C11H10BrN2O2 (79Br)
[MþH]þ: calcd: 280.9926, found: 280,9926.
n
max: 3214, 1625, 1589, 1521, 1439, 1341, 1278, 1026, 846,
754 cm21; dH (CDCl3): 7.58 (d, J¼2.8 Hz, 1H, H-6), 7.01–
7.70 (m, 4H, phenyl aromatic protons), 6.31 (br s, 1H, NH),
6.26 (d, 1H, H-4), 3.72 (s, 3H, CH3); dC (CDCl3): 161.8
(C-3), 145.2 (C-10), 136.4 (C-5), 133.6 (C-6), 130.8 (C-30),
128.5 (C-50), 126.4 (C-4), 123.2 (C-40), 117.5 (C-20), 101.9
(C-60), 39.5 (CH3); MS (ESI): 282, 280, 200, 171, 158, 145,
142, 130, 117, 57; HRMS (ESI) for C11H11BrN3O (79Br)
[MþH]þ: calcd: 280.0085, found: 280.0092.
2.4.2. 5-(2-Iodophenoxy)-2-methyl-6-phenylpyridazin-
3(2H)-one (12a). Reaction time: 21 h; eluent for flash
column chromatography: toluene–acetone (7:3); yield:
0.430 g, 47% as white cubes; mp 174–175 8C; Rf
(toluene–acetone): 0.50; IR (KBr): nmax: 3059, 1655,
1596, 1505, 1464, 1405, 1327, 1273, 1210, 1150, 1057,
1019, 991, 851, 777, 738, 690, 595, 569 cm21; dC (CDCl3):
7.87–7.97 (m, 3H, H-200,-600,-30), 7.26–7.51 (m, 4H, H-300,
2.5. General procedure for the Pd-catalyzed
cyclodehydrohalogenation of 8a, 10, 12a, 12b and 15
A
mixture of the appropriate halocompound 8a
(0.60 mmol), 10, 15 (0.71 mmol), 12a (0.87 mmol), or
12b (1.00 mmol), bis(triphenylphosphine)palladium
dichloride (20 mol%) and NaOAc·3H2O (2.5 equiv.) in

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B. Dajka-Halasz et al. / Tetrahedron 60 (2004) 2283–2291
2289
dimethyl acetamide (10 mL for 8a, 10, 12b and 15; 6 mL for
12a) was stirred at 130 8C under Ar atmosphere for the
reaction times indicated below. The mixture was then
evaporated to dryness in vacuo. Water (10 mL) was added
and the mixture was subsequently extracted with chloro-
form (3£10 mL). The combined organic phases were dried
over MgSO4. The solvent was evaporated in vacuo, and the
compounds were purified by column chromatography.
158.3 (C-1), 138.3 (C-4a), 136.6 (C-5a), 126.3 and 126.9
(C-4 and C-9), 122.1 (C-9a), 121.5 and 121.6 (C-7 and C-8),
112.6 (C-6), 111.3 (C-9b), 38.5 (CH3). MS (ESI): 200, 143,
116; HRMS (ESI) for C11H10N3O [MþH]þ: calcd:
200.0824, found: 200.0823.
2.6. Pd-catalyzed cyclodehydrohalogenation of 8b
A mixture of the halocompound 8b (1.0 mmol), bis(triphenyl
phosphine)palladium dichloride (0.234 mmol), Na2CO3
(2.5 mmol) and Bu4NBr (1.0 mmol) in DMF (4 mL) was
stirred at 162 8C under N2 atmosphere for 20 h. The mixture
was then evaporated to dryness in vacuo. Water (20 mL) was
added and it was extracted with chloroform (3£20 mL). The
combinedorganicphasesweredried overMgSO4. Thesolvent
was evaporated in vacuo, and the compounds were purified by
column chromatography, using heptane–ethyl acetate (8:2) as
the eluent, to yield 13 (0.119 g; 60%).
The following compounds were prepared in this manner.
2.5.1. 2-Methylbenzo[b]furo[2,3-d]pyridazin-1(2H)-one
(13). (a) When started from 8a. Reaction time: 22 h; eluent
for flash column chromatography: hexane–ethyl acetate
(8:2); yield: 0.082 g, 68%.
(b) When started from 10. Reaction time: 6 h; eluent for
flash column chromatography: toluene–ethyl acetate (8:2);
yield: 0.140 g, 99%.
2.7. Synthesis of 2-methyl-4-phenyl-2,5-dihydro-1H-
pyridazino[4,5-b]indol-1-one (18) via a one-pot Pd-
catalyzed amination—Pd-catalyzed
White needles; mp 148–150 8C; Rf (ethyl acetate–chloro-
form 9:1): 0.82; IR (KBr): nmax: 3094, 1669, 1578, 1444,
1377, 1331, 1189, 1058, 880, 752 cm21; dH (CDCl3): 8.32
(s, 1H, H-4); 8.26 (m, 1H, H-9), 7.45–7.67 (m, 3H, aromatic
protons), 3.96 (s, 3H, CH3); dC (CDCl3): 159.0 (C-1), 154.4
and 155.8 (C-4a,-5a), 128.6 (C-4), 125.0 and 126.3 (C-7,
-9), 123.3 (C-8), 117.6 and 122.2 (C-9a,-9b), 112.0 (C-6),
39.7 (CH3). MS (ESI): 201, 144, 116, 89; HRMS (ESI) for
C11H9N2O2 [MþH]þ: calcd: 201.0664, found: 201.0658.
cyclodehydrohalogenation reaction
A round-bottom flask was purged with Ar and charged
with Pd(OAc)2 (0.20 mmol), racemic BINAP (0.20 mmol)
and toluene (6 mL). While stirring, the mixture was flushed
with Ar for approximately 10 min. In another flask 5-chloro-
2-methyl-6-phenylpyridazin-3(2H)-one (11) (1.0 mmol), 2-
bromoaniline (1.2 equiv.) and K2CO3 (10 equiv.) were
weighed. Subsequently, the catalyst solution was added
and the flask was rinsed well with an additional amount of
toluene (6 mL). The resulting mixture was flushed with Ar
for a few minutes under magnetic stirring and subsequently
heated in an oil bath (oil bath temperature 120 8C, Ar
atmosphere) until the starting material had been consumed
as judged by TLC and MS analysis. The reaction mixture
was evaporated to dryness in vacuo. Then water (50 mL)
was added to the residue and the mixture was extracted with
chloroform (3£50 mL). The combined organic phases were
dried over MgSO4. The solvent was evaporated in vacuo
and the residue purified by flash column chromatography,
using a 1:1 mixture of ethyl acetate and heptane as the
eluent. Reaction time: 27 h; yield: 0.153 g, 55%; mp
.250 8C (decomp.); Rf (ethyl acetate–heptane 1:1): 0.41;
IR (KBr): nmax: 3063, 2943, 1623, 1581, 1549, 1494, 1448,
1380, 1324, 1278, 1247, 1215, 1071, 1018, 789, 754, 702,
604 cm21; dH (CDCl3): 8.78 (br s, 1H, NH), 8.49 (br d,
J¼7.9 Hz, 1H, H-9), 7.80 (dd, J¼8.24, 1.37 Hz, 2H, Ph-2,6),
7.60–7.48 (m, 5H, Ph-3,4,5 and H-6 and H-7 or H-8), 7.40
(ddd, J¼8.09, 6.87, 1.37 Hz, 1H, H-7 or H-8), 4.01 (s, 3H,
CH3); dC (CDCl3): 159.04 (C-1), 137.99 and 136.45 and
135.33 and 134.26 (CPh-1, C-4, C-4a, C-5a), 129.57 (CPh-4),
129.45 (CPh-2,6), 127.66 (CPh-3,5), 127.01 (C-9), 123.36
(C-9a), 123.18 and 122.52 (C-7, C-8), 113.60 (C-9b),
111.54 (C-6), 39.30 (CH3); MS (ESI): 276, 219, 144;
HRMS (ESI) for C17H14N3O [MþH]þ: calcd: 276.1137,
found: 276.1139.
2.5.2. 2-Methyl-4-phenylbenzo[b]furo[2,3-d]pyridazin-
1(2H)-one (14). (a) When started from 12a. Reaction time:
10 h; eluent for flash column chromatography: toluene–
acetone (7:3) mixture. After column chromatography the
product was crystallized from acetone. Yield: 0.140 g, 58%.
(b) When started from 12b. Reaction time: 11 h; eluent for
flash column chromatography: petroleum ether [bp 40–
708]-ethyl acetate (2:1) mixture. Yield: 0.136 g, 49%.
Beige needles; mp 154–155 8C; Rf (toluene/acetone 7:3):
0.69; (petroleum ether [bp 40–708]-ethyl acetate 2:1): 0.55;
IR (KBr): nmax: 1662, 1574, 1508, 1443, 1377, 1323, 1271,
1181, 1111, 1057, 1019, 890, 786, 748, 697, 599 cm21; dH
(CDCl3): 8.32 (d, J¼7.4 Hz, 1H, H-9), 8.16–8.20 (m, 2H,
00
00
H-2 ,-6 ), 7.68 (d, J¼7.4 Hz, 1H, H-6), 7.45–7.61 (m, 5H,
H-3 ,-4 ,-500,-7,-8), 4.03 (s, 3H, 2-CH3); dC (CDCl3):158.8
(C-1), 155.6 and 153.1 (C-4a,-5a), 135.7 (C-4), 132.030 (C-100),
129.7 and 128.5 and 124.900and 123.2 (C-7,-8,-9,-4 ), 128.7
and 127.6 (C-200,-300,-500,-6 ), 122.3 (C-9a), 117.7 (C-9b),
111.9 (C-6), 39.8 (CH3); MS (ESI): 277, 220, 77; HRMS
(ESI) for C17H13N2O2 [MþH]þ: calcd: 277.0977, found:
277.0965.
00
00
2.5.3. 2-Methyl-2,5-dihydro-1H-pyridazino[4,5-b]indol-
1-one (16). Reaction time: 3 h; eluent used for flash column
chromatography: ethyl acetate–chloroform (9:1) mixture;
yield: 0.103 g, 73% as white cubes; mp .250 8C; Rf (ethyl
acetate–chloroform 9:1): 0.55; IR (KBr): nmax: 3177, 1629,
1548, 1448, 1383, 1330, 1234, 1074, 996, 735 cm21; dH
(DMSO-d6): 12.23 (br s, 1H, NH), 8.39 (s, 1H, H-4), 8.19 (d,
J¼7.6 Hz, 1H, H-9), 7.66 (d, J¼8.2 Hz, 1H, H-6), 7.29–
7.53 (m, 2H, H-7,8), 3.79 (s, 3H, CH3); dC (DMSO-d6):
Acknowledgements
Funding by RAFO RUCA, OTKA 33105, OTKA 31910,

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B. Dajka-Halasz et al. / Tetrahedron 60 (2004) 2283–2291
2290
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ETT 121/2003, 1/047 NKFP MediChem and EU project
FP5-QLK2-CT-2002-90436 is gratefully acknowledged.
The authors wish to thank Professor Dr. E. Esmans and
`
Professor Dr. F. Lemiere for the use of their HRMS facilities
and Ing. J. Aerts, G. Rombouts, J. Schrooten, Ing. W. Van
Dongen, W. Van Lierde and Ing. J. Verreydt for their
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Monsieurs, K.; Loones, K.; Lemiere, G. L. F.; Dommisse, R.;
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Matyus, P.; Riedl, Z.; Hajos, G. Tetrahedron 2002, 58,
´
´ ´
9713–9721. (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. (e) Hajos, G.; Riedl, Z.; Timari, G.; Matyus, P.;
`
Maes, B. U. W.; Lemiere, G. L. F. Molecules 2003, 8,
´
480–487. (f) Tapolcsanyi, P.; Maes, B. U. W.; Monsieurs, K.;
` ´
Lemiere, G. L. F.; Riedl, Z.; Hajos, G.; Van den Driessche, B.;
´
Dommisse, R. A.; Matyus, P. Tetrahedron 2003, 59,
5919–5926.
9. For the synthesis of 2-substituted 5-alkoxy-4-halopyridazin-
3(2H)-ones via selective alkanolysis of 2-substituted 4,5-
dihalopyridazin-3(2H)-ones see: (a) Barlin, G. B.; Lakshmi-
narayanan, P. J. Chem. Soc., Perkin Trans. 1 1977,
1038–1044. (b) Lyga, J. W. J. Heterocycl. Chem. 1988, 25,
1757–1760. (c) Cho, S.-D.; Choi, W.-Y.; Yoon, J. Heterocycl.
Chem. 1996, 33, 1579–1582. (d) Brown, D. J. The
pyridazines. Supplement I; Wiley: New York, 2000; p 220.
3. For the synthesis of 5H-pyridazino[4,5-b]indoles via the
reaction of a 2,3-dicarbonylated indole with a hydrazine see:
ˇ
(a) Tisler, M.; Stanovnik, B. In Condensed pyridazines
including cinnolines and phthalazines; Castle, R. N., Ed.;
Wiley-Interscience, 1973; pp 766–800. (b) Nogrady, T.;
ˇ `
(e) Maes, B. U. W.; R’kyek, O.; Kosmrlj, J.; Lemiere, G. L. F.;

´
B. Dajka-Halasz et al. / Tetrahedron 60 (2004) 2283–2291
2291
Esmans, E.; Rozenski, J.; Dommisse, R. A.; Haemers, A.
Tetrahedron 2001, 57, 1323–1330. For the synthesis of 2-
substituted 5-aryloxy-4-halopyridazin-3(2H)-ones via pheno-
lysis of 2-substituted 4,5-dihalopyridazin-3(2H)-ones see: (f)
Kang, Y.-J.;Chung, H.-A.; Kweon, D.-H.;Cho, S.-D.;Lee,S.-G.;
Kim, S.-K.; Yoon, Y.-J. J. Heterocycl. Chem. 1998, 35,
595–600. (g) Kweon, D.-H.; Kang, Y.-J.; Chung, H.-A.;
Yoon, J. Heterocycl. Chem. 1998, 35, 819–826. (h) Kweon,
D.-H.; Chung, J.-W.; Cho, S.-D.; Kim, S.-K.; Yoon,
J. Heterocycl. Chem. 1998, 35, 1401–1403. (i) Chung, H.-A.;
Kim, J.-J.; Cho, S.-D.; Lee, S.-G.; Yoon, J. Heterocycl. Chem.
2002, 39, 685–689. For general reviews dealing with the
synthesis of 2-substituted 4,5-dihalopyridazin-3(2H)-ones and
the regioselective nucleophilic substitution of the addition–
elimination type on these substrates with O, S and N
cyclodehydrochlorination of 8b we used 2-benzyl-4-chloro-5-
phenoxypyridazin-3(2H)-one. Several reaction conditions
have been tried for the cyclization of this substrate: (1)
Pd(OAc)2, Na2CO3 (2.5 equiv.), DMF, reflux: starting
material and hydrodechlorinated substrate, (2) Pd(OAc)2,
Na2CO3 (2.5 equiv.), DMF, Bu4NBr (1 equiv.), reflux: mainly
hydrodechlorinated substrate and only traces of the desired
reaction product, (3) Pd(PPh3)2Cl2, Na2CO3 (2.5 equiv.),
DMF, Bu4NBr (1 equiv.), reflux (Jefferey’s conditions):17
37% hydrodechlorinated substrate and 42% of the desired
cyclodehydrochlorinated reaction product, (4) Pd(PPh3)2Cl2,
Na2CO3 (2.5 equiv.), toluene, Bu4NBr (1 equiv.): no reaction.
17. Pd(PPh3)2X2, M2CO3 and Bu4NY in DMF are the Jefferey’s
reaction conditions. For intermolecular Heck reactions under
Jefferey’s conditions see: Jefferey, T. Tetrahedron 1996, 52,
10113–10130.
´ ´
nucleophiles see: (j) Matyus, P.; Czako, K. Trends Heterocycl.
´ ´
Chem. 1993, 3, 249–264. (k) Tapolcsanyi, P.; Matyus, P.
18. For the effect of halide anions on Pd-catalyzed reactions see:
(a) Amatore, C.; Azzabi, M.; Jutand, A. J. Am. Chem. Soc.
1991, 113, 8375–8384. (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.
Targets Heterocycl. Syst. 2002, 6, 369–398.
10. Identification of the 4-halo-2-methyl-5-phenoxypyridazin-
3(2H)-one (8) and 5-halo-2-methyl-4-phenoxypyridazin-
3(2H)-one (9) isomers has been done via comparison of the
1H NMR spectra (CDCl3) of the hydrogenolysis reaction
products of 8 and 9 (Pd/C, H2, NEt3, CH3OH, room
temperature). We observed in each case, starting from the
bromo- as well as from the chloro-phenoxypyridazin-3(2H)-
ones, a coupling constant of 4.7 Hz for the hydrogenolysed
halo-phenoxypyridazin-3(2H)-one isomer with the higher Rf
value on TLC (eluent: hexane–ethyl acetate: 80–20) and a
coupling constant of 2.8 Hz for the isomer with the lower Rf
value on TLC (eluent: hexane–ethyl acetate: 80–20). A
coupling constant of 2.8 Hz is typical for a 4,6 relation on a
pyridazin-3(2H)-one core whereas a value of 4.7 Hz is
consistent with a 5,6 relation. For typical J4,6 and J5,6 values
on mono-substituted pyridazin-3(2H)-ones see: (a) Katz, D. Z.;
Wise, D. S.; Townsend, L. B. J. Heterocycl. Chem. 1983, 20,
369–379. (b) See Ref. 9g.
19. (a) It is often considered that the Pd-catalyzed cyclodehy-
drohalogenation involving C–H bond activation, occurs via
the intramolecular electrophilic attack of the oxidative
addition complex on the p system: (a) See Ref. 8. (b)
´ ´
Echavarren, A. M.; Gomez-Lor, B.; Gonzalez, J. J.; de Frutos,
´
O. Synlett 2003, 585–597, If one accepts this model the Pd-
catalyzed cyclodehydrohalogenation involving the cleavage of
a vinylic C–H bond (e.g., in 10) should occur more readily
than when an aromatic C–H bond is involved (e.g., in 8) since
the mechanistic pathway does not include loss of aromaticity.
This is in accordance with the results we obtained when
comparing the Pd-catalyzed cyclization of 8a with 10.
ˇ `
20. Maes, B. U. W.; Kosmrlj, J.; Lemiere, G. L. F. J. Heterocycl.
Chem. 2002, 39, 535–543.
21. For publications dealing with the rate accelerating effect of
large excesses of carbonate bases on Pd-catalyzed aminations
see: (a) Watanabe, M.; Nishiyama, M.; Yamamoto, T.; Koie,
11. For the related alkanolysis of 4,5-dichloropyridazin-3(2H)-
ones with sodium alkanolates in acetonitrile at room
temperature a mixture of two alkoxy-chloropyridazin-3(2H)-
one isomers was also obtained: see Ref. 9b.
ˇ
Y. Tetrahedron Lett. 2000, 41, 481–483. (b) Kosmrlj, J.;
`
Maes, B. U. W.; Lemiere, G. L. F.; Haemers, A. Synlett 2000,
´
12. Estevez, I.; Ravin˜a, E.; Sotelo, E. J. Heterocycl. Chem. 1998,
1421–1428.
`
1581–1584. (c) Jonckers, T. H. M.; Maes, B. U. W.; Lemiere,
G. L. F.; Dommisse, R. Tetrahedron 2001, 57, 7027–7034. (d)
`
Maes, B. U. W.; Loones, K. T. J.; Jonckers, T. H. M.; Lemiere,
G. L. F.; Dommisse, R. A.; Haemers, A. Synlett 2002,
1995–1998.
13. PdX2, 4PPh3 and NaOAc in DMA are the Spencer’s reaction
conditions. For intermolecular Heck reactions under ‘Spencer’s’
conditions see: (a) Spencer, A. J. Organomet. Chem. 1983,
258, 101–108. (b) Spencer, A. J. Organomet. Chem. 1984,
270, 115–120.
22. When 5 equiv. of K2CO3 were used 40% of 5-[(2-bromophe-
nyl)amino]-2-methylpyridazin-3(2H)-one (15) and a recovery
of 52% of 5-iodo-2-methylpyridazin-3(2H)-one (1) were
obtained after refluxing for 3 h, whereas the use of 1 equiv.
of the same base under the same reaction conditions gave a
yield of 30% of 15 and a recovery of 63% of 1 in the same
reaction time.
14. The most important side reaction observed in the Pd-catalyzed
cyclodehydrohalogenation of 8a and 8b is hydrodehalogena-
tion. The formation of 2-methyl-5-phenoxypyridazin-3(2H)-
one has been proven by NMR analysis of the column
chromatography fractions that revealed the presence of a
compound with a molecular mass of 202.
23. A similar selective behaviour has recently been reported by us
for the Suzuki reaction of 11 with 2-bromophenylboronic acid.
In this case the conjugate base of 2-bromophenylboronic acid
probably sterically and electronically retards oxidative
addition of the ortho C–Br bond to the Pd(0) catalyst: see
Ref. 2e. Interestingly, also Armin de Meijere’s group reported
selectivity when using 2-bromophenylboronic acid in the
Suzuki cross-coupling reaction with 1-bromonaphthalene:
Wegner, H. A.; Scott, L. T.; de Meijere, A. J. Org. Chem.
2003, 68, 883–887.
15. The rate of oxidative addition of aryl halogenides to a
Pd(PPh3)2 or Pd(BINAP) catalyst is ArI.ArBrqArCl.
However, the presence of electron withdrawing groups on,
as well as the incorporation of nitrogen atoms in the benzene
ring of the aryl chloride makes oxidative addition of aryl
chlorides to palladium catalysts with traditional triarylphos-
phane ligands possible: (a) Fitton, P.; Rick, E. A.
J. Organomet. Chem. 1971, 28, 287–291. (b) See Ref. 8g.
16. As a model compound for the optimisation of the Pd-catalyzed