Pyridazines. Part 26: Efficient and regioselective Pd-catalysed arylation of 4-bromo-6-chloro-3-phenylpyridazine

Article abstract of DOI:10.1055/s-2002-19761

The regioselective arylation at position 4 of 4-bromo-6-chloro-3-phenylpyridazine has been performed using a Suzuki cross-coupling reaction. This route allows access to a wide-ranging series of pharmacologically useful pyridazine derivatives and confirms

Full text of DOI:10.1055/s-2002-19761

LETTER
223
Pyridazines. Part 26:1 Efficient and Regioselective Pd-Catalysed Arylation of
4-Bromo-6-chloro-3-phenylpyridazine
Regioselective
P
d
d-Catalysed
d
A
rylation
o
y
4-Bromo-6-chloro
S
-
3-phenylpyri
o
dazine telo, Enrique Raviña*
Laboratorio de Química Farmacéutica, Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela,
15782 Santiago de Compostela, Spain
Fax +34(981)594912; E-mail: qofara@usc.es
Received 4 October 2001
Palladium chemistry involving heterocycles has unique
Abstract: The regioselective arylation at position 4 of 4-bromo-6-
characteristics stemming from the inherently different
structural and electronic properties of heterocycles in
chloro-3-phenylpyridazine has been performed using a Suzuki
cross-coupling reaction. This route allows access to a wide-ranging
series of pharmacologically useful pyridazine derivatives and con-
comparison to the corresponding carbocyclic aryl com-
firms the usefulness of chloropyridazines as a masking group for the pounds.9 As a consequence of and activation of het-
carbonyl moiety in cross-coupling reactions involving 5-bromo-
3(2H)-pyridazinones.
eroaryl halides, Pd-catalysed chemistry may occur
regioselectively at the activated positions, a phenomenon
rarely seen in carbocyclic aryl halides.10–12 Very recently,
Key words: arylations, palladium, catalysis, pyridazine
Lemière13 and Wermuth14 described excellent preparative
methods based on the oxidative insertion of palladium
into the C-Cl bond on a pyridazine ring using tet-
rakis(triphenylphosphine)palladium(0) as catalyst.
The pyridazine nucleus, which can be considered a bioi-
sostere of benzene and other heterocycles, has proved to
be a versatile system in Medicinal Chemistry. Among the
pyridazine derivatives developed in recent years as drugs
and pharmacological tools, 3(2H)-pyridazinones, ami-
nopyridazines and hydrazinopyridazines are well recogn-
ised pharmacophores that show a wide range of biological
activities (Figure 1).2 Despite the useful nature of py-
ridazines, there are only a limited number of synthetic ap-
proaches to achieve substitution on these electron-
deficient rings and, therefore, functionalisation of the py-
ridazine nucleus continues to be of synthetic interest. A
number of methods have recently been described in the
literature and, of these, reactions involving organometal-
lics have proved to be a powerful tool for the preparation
of the desired compounds. Several publications have dealt
with the use of bromo- and iodopyridazines in Pd-cataly-
sed reactions.3–8
a
These studies highlighted the activation of 3- and 6-chlo-
ropyridazines toward such reactions. However, to the best
of our knowledge, there is only a report in the literature15
describing the regioselectivity in palladium-catalysed
cross-coupling reactions involving dihalopyridazines and
their synthetic utilisation have not been sufficiently ex-
ploited.
While several previous reports have described palladium-
catalysed reactions involving pyridazines or pyridazino-
nes, our goal was the development of a general and highly
flexible route based on the different reactivities of the ha-
lides (Br/Cl at the 4- and 6-positions of the heterocycle,
respectively) toward oxidative addition in palladium
chemistry. In this paper we describe a convenient and
highly versatile palladium-assisted approach to the prepa-
ration of chemical libraries of 4-aryl-6-chloropyridazines
3, 3(2H)-pyridazinones 4, 6-aminopyridazines 5, 6-hy-
O
N
O
H
NH
NH
N
N
N
NH2
OH
O
OEt
N
N
N
N
N
N
N
O
OCHF2
OCH3
EMORFAZONE
Anti-inflamatory
PILDRALAZINE
Vasodilator
MINAPRINE
ZARDAVERINE
Antidepressant
Cardiotonic
Figure 1 Several pharmacologically useful pyridazine derivatives
Synlett 2002, No. 2, 01 02 2002. Article Identifier:
1437-2096,E;2002,0,02,0223,0226,ftx,en;G30701ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

224
E. Sotelo, E. Raviña
LETTER
O
O
O
Cl
O
X
H
H
Br
RO
O
N
N
N
N
RO
N
N
N
N
X= NHR
X=NHNH2
X= H
O
Ar
Ar
Ar
Ar
Ar
Ar
Ph
Ph
Ph
Ph
Ph
Ph
4
3
5-7
Scheme 1 Traditional retrosynthetic approach to compounds 3-7
drazinopyridazines 6 and pyridazines 7. The conventional rakis(triphenylphosphine)palladium(0) as catalyst, 2 M
synthesis of such compounds is possible in five steps aqueous sodium carbonate as base, 1 equivalent of the ap-
(Scheme 1), but this is a somewhat lengthy process16 and propriate boronic acid, toluene as solvent] to work
such approaches do not allow rapid access to a variety of smoothly. The transformation proceeded almost exclu-
structural analogues. We therefore focused on direct sively at position 5 of the heterocyclic nucleus to give the
methods of preparation involving palladium-catalysed 4-arylated-6-chloropyridazines 3 in moderate to excellent
carbon-carbon bond formation with organoboranes, yields (70-95%).21
which permit a rapid pharmacomodulation of this series of
compounds.
The use of 1,2-dimethoxyethane (DME) as solvent togeth-
er with aqueous Na2CO3 is regarded as a very convenient
In this area we recently described the palladium-assisted system for troublesome Suzuki couplings22 and we there-
alkenylation,17 alkynylation17 and arylation18 of 5-bromo- fore decided to study the cross-coupling reaction of 2 un-
6-phenyl-3(2H)-pyridazinone 1. During the course of der these conditions. These experiments (Table) allowed
these studies we observed that the NH group of the lactam us to obtain 4-aryl-6-chloro-3-phenylpyridazines 3 in
function completely inhibits palladium-catalysed reac- similar yields and with shorter reaction times. The use of
tions. Indeed, prior to submitting the 3(2H)-pyridazinone other bases [K3PO4, NaOH, Ba(OH)2], solvents (DMF, di-
to the catalytic cycle it is essential to protect the NH group oxane, toluene/ethanol) or catalysts (Pd2dba3/P-tBu3) was
in these compounds. Oxidative insertion of palladium into also explored (using 2 and the phenyl and 4-methylphe-
the C-Cl bond requires a higher energy than the case of a nylboronic acids) but yields were no higher than those ob-
C-Br bond and, in addition, 3(2H)-pyridazinones are not tained under the conventional conditions.
particularly reactive - it is usually necessary to transform
Table Synthesis of 4-Aryl-6-chloro-3-phenylpyridazines 3.27
them into a suitable derivative, such as a 2-alkylpyridazi-
none, prior to reaction. For these reasons, we decided to
Compound
R
Mp °C (solvent)
Yield (%)
explore the utility of 6-chloropyridazine as a protecting
group for the enolizable lactam (C=O) moiety in com-
pound 1. The reverse hydrolysis process has seldom been
used, probably because of the fact that most 6-chloropy-
ridazines are prepared from the corresponding 3(2H)-py-
ridazinones, and so their utility to mask the carbonyl
group in troublesome reactions has not been exploited in
terms of synthetic procedures. This alternative approach
has significant advantages in the synthesis of pyridazine
derivatives 4-7.
3a
3b
3c
3d
3e
3f
Ph
111–112 (iso-PrOH)
126–127 (iso-PrOH )
139–141 (iso-PrOH )
150–152 (iso-PrOH )
129–130 (EtOH)
90
95
70
96
83
85
73
4-CH3-Ph
4-Cl-Ph
4-OCH3-Ph
2-Furan
2-Thiophene
4-CHO-Ph
141–143 (EtOH)
3g
116-118 (MeOH)
Cl
Cl
O
ArB(OH)2,
Na2CO3
H
POCl3
N
N
N
N
N
N
It is worth mentioning here that, although the two proce-
dures described above take place under aqueous condi-
tions, we did not detect any by-products due to the
hydrolytic degradation of the 6-chloropyridazines 2 or 3.
In accordance with previous studies9,20 we obtained the
best yields in the Suzuki coupling when either toluene or
DME was used as solvent in reactions with boronic acids
bearing electron-donating substituents (OCH3, CH3).
Long reaction times arising from the use of less reactive
boronic acids (4-Cl-Ph and 4-CHO-Ph) led to decreases in
the yields of the coupling products, probably due to hy-
drolytic deboronation or slow transmetalation. For exam-
ple, the use of 4-chlorophenylboronic acid led to mixtures
of products from which only a moderate yield (70%) of 3c
was obtained. The heteroarylboronic acids show compa-
Pd[P(Ph)3]4
DME-H2O
Br
Ar
Br
Ph
Ph
Ph
2
3
1
Scheme 2
As shown in Scheme 2, the readily obtainable 5-bromo-6-
phenyl-3(2H)-pyridazinone 117 was converted into 4-bro-
mo-6-chloro-3-phenylpyridazine 2 in high yield by direct
chlorination using phosphorus oxychloride.19 We then
proceeded to study the arylation of 2 using various substi-
tuted arylboronic acids. After some optimisation of the
experimental conditions we found the cross-coupling re-
action of 2 under classical Suzuki conditions20 [5% tet-
Synlett 2002, No. 2, 223–226 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Regioselective Pd-Catalysed Arylation of 4-Bromo-6-chloro-3-phenylpyridazine
225
rable reactivity. In order to assess the scope of our new ap- carbonyl function in Suzuki arylations. This procedure is
proach, we performed several experiments using a superior to existing processes and has allowed us to ac-
variable excess of the boronic acid (1.1-1.3 equivalent), a cess, in a clearly shorter synthetic sequence, several phar-
process that gave the 4-arylated-6-chloropyridazines 3 in macologically useful pyridazine derivatives.
moderate yields (70-85%). The use of a large excess of the
organoboron compound leads to reaction mixtures arising
References
from the formation of mono- as well as diarylpyridazines,
1
(1) For the previous paper in this series, see: Efficient and
selective deprotection of phar-macologically useful 2-
MOM-pyridazinones using Lewis acids in: Sotelo, E.;
Coelho, A.; Raviña, E. Tetrahedron Lett.; 2001, 43, 8633.
(2) (a) Frank, H.; Heinisch, G. In Pharmacologically Active
Pyridazines Part 1, Progressing Medicinal Chemistry; Ellis,
G. P.; West, G. B., Eds.; Elsevier: Amsterdam, 1990, 271.
(b) Frank, H.; Heinisch, G. In Pharmacologically Active
Pyridazines Part 2, Progress in Medicinal Chemistry, Chap.
29; Ellis, G. P.; Luscombe, D. K., Eds.; Elsevier:
Amsterdam, 1992, 141.
(3) Rohr, M.; Toussaint, D.; Chayer, S.; Mann, A.; Suffer, J.;
Wermuth, W. G. Heterocycles 1996, 43, 1459.
(4) Enguehard, C.; Hervet, M.; Allouchi, H.; Debouzy, J. C.;
Gueiffier, A. Synthesis 2001, 4, 595.
(5) (a) Turck, A.; Mojovic, L.; Queguiner, G. Bull. Soc. Fr.
1993, 130, 488. (b) Konno, S.; Sagi, M.; Siga, F.;
Yamanaka, H. Heterocycles 1992, 34, 225.
as evidenced by TLC, H NMR spectroscopy and mass
spectrometry.
The total regioselectivity obtained in the biaryl cross-cou-
pling reaction on 2 is not wholly expected considering the
high reactivity previously shown by the C-Cl bond at po-
sition 6 of the pyridazine nucleus in the Pd-insertion pro-
cess.13,14 We can explain this selectivity by considering
the fact that, although oxidative addition into the C-Cl
bond occurs easily, the energy involved in this transfor-
mation is even higher than in the case of a similar process
involving the C-Br bond. It is this major energy difference
that allows the use the 6-chloropyridazines as a masking
group for the carbonyl moiety in palladium-assisted cross-
coupling reactions of 5-bromo-3(2H)-pyridazinones. The
selective arylation at the 4-position of 4-bromo-6-chloro-
3-phenylpyridazine is considered to be synthetically use-
ful because the chloro-substituent at position 6 of the py-
ridazine ring can be easily converted to give a wide range
of functionalities.
(6) (a) Draper, T. L.; Bailey, T. R. J. Org. Chem. 1995, 60, 748.
(b) Oshawa, A.; Abe, Y.; Igeta, H. Chem. Pharm. Bull. 1980,
28, 3488.
(7) Guery, S.; Parrot, I.; Rival, Y.; Wermuth, C. G. Synthesis
2001, 5, 699.
Once the coupling conditions had been optimised we suc-
cessfully completed the transformation of 6-chloropy-
ridazines 321 into 3(2H)-pyridazinones 4,23 6-
aminopyridazines 5,24 6-hydrazynopyridazines 625 or py-
ridazines 726 following the previously described proce-
dures (Scheme 3).16 The application of this procedure to
other dihalopyridazines is currently under investigation.
We are also applying this methodology to the preparation
of chemical libraries of compounds 3-7 using combinato-
rial techniques.
(8) Krajsovszky, G.; Matyus, P.; Riedl, Z.; Csanyi, D.; Hajos, G.
Heterocycles 2001, 55, 1105.
(9) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic
Chemistry; Elsevier: Amsterdam, 2000, 3.
(10) Bessard, Y.; Roduit, J. P. Tetrahedron 1999, 55, 393.
(11) Minato, A.; Suzuki, K.; Tamao, K.; Kumada, M. J. Chem.
Soc., Chem. Commun. 1984, 511.
(12) Tilley, J. W.; Zawoiski, S. J. Org. Chem. 1988, 53, 386.
(13) (a) Komrlj, J.; Maes, B. U. W.; Lemière, G. L. F.; Haemers,
A. Synlett 2000, 11, 1581. (b) Maes, B. U. W.; Lémiere, G.
L. F.; Domminisse, R.; Augusyns, K.; Haemers, A.
Tetrahedron 2000, 56, 1777.
(14) Parrot, I.; Rival, Y.; Wermuth, C. G. Synthesis 1999, 7,
1163.
(15) Trecourt, F.; Turck, A.; Plé, N.; Paris, A.; Quéguiner, G. J.
Heterocyclic Chem. 1995, 32, 1057.
(16) Brown, D. J. In The Pyridazines I, Chemistry of Heterocyclic
Compounds, Vol. 56; Taylor, E. C.; Wipf, P., Eds.; Wiley:
New York, 2000, 23.
Cl
O
NHR
H
AcOH
RNH2
N
N
N
N
N
N
Ar
Ar
Ar
Ph
Ph
Ph
5
4
3
HCOONH4
Pd/C
NH2NH2
(17) Estévez, I.; Coelho, A.; Raviña, E. Synthesis 1999, 9, 1666.
(18) Coelho, A.; Sotelo, E.; Estevez, I.; Raviña, E. Synthesis
2001, 6, 871.
(19) 4-Bromo-6-chloro-3-phenylpyridazine 2: 89%, mp: 111-112
°C (dec.), iso-PrOH. IR (KBr): 1590, 1480 cm-1. 1H NMR
(DMSO-d6, 300 MHz): 8.44 (s, 1 H, CH), 7.70 (m, 2 H,
Aromatics), 7.54 (m, 3 H, Aromatics) ppm.
H2N NH
N
N
N
N
Ar
Ar
Ph
Ph
7
6
(20) Suzuki, A. In Recent Advances in the Cross-coupling
Reactions of Organoboron Deri-vatives with Organic
Electrophiles, Perspectives in Organopalladium Chemistry
for the XXI Century; Tsuji, J., Ed.; Elsevier: Amsterdam,
1999, 145.
(21) Cross-coupling Reactions, General Procedure: 5-Bromo-3-
chloro-6-phenylpyridazine 2 (0.25 g, 0.93 mmol) was mixed
with the arylboronic acid (0.93 mmol), Pd(PPh3)4 (5 mg,
0.006 mmol) and Na2CO3 (0.49 g, 5.08 mmol) in 30 mL of a
3:1 mixture of DME–H2O. The mixture was flushed with
Scheme 3
In summary, we have developed a practical, efficient and
regioselective palladium-assisted procedure based on the
different reactivity of halides toward oxidative addition of
palladium species’. The chemoselectivity observed dem-
onstrates the synthetic usefulness of the 6-chloropy-
ridazine moiety as a convenient masking group for the
Synlett 2002, No. 2, 223–226 ISSN 0936-5214 © Thieme Stuttgart · New York

226
E. Sotelo, E. Raviña
LETTER
argon for 5 min and then stirred and heated at reflux (oil bath
90 °C) under argon until the starting material had
disappeared (8-12 h). The mixture was allowed to cool and
concentrated to dryness under reduced pressure. The residue
was extracted into CH2Cl2 (3 20 mL), dried (Na2SO4) and
then purified by column chromatography on silica gel to
afford the 6-chloropyridazines 3, which were recrystallised
from the appropriate solvent (Table).
Selected physical and spectral data for compounds 3. 3a:
90%, mp: 111-112 °C (dec.), iso-PrOH. IR (KBr): 1563,
1092, 695 cm-1. 1H NMR (DMSO-d6, 300 MHz): 8.61 (s, 1
H, CH), 8.23 (m, 2 H, Aromatics), 7.79 (m, 2 H, Aromatics),
7.57 (m, 6 H, Aromatics) ppm. 3b: 95%, mp: 126-127 °C,
iso-PrOH. IR (KBr): 1559, 1089, 696 cm-1. 1H NMR
(DMSO-d6, 300 MHz): 8.54 (s, 1 H, CH), 8.14 (d, J = 8.0 Hz,
2 H, Aromatics), 7.76 (m, 2 H, Aromatics), 7.55 (m, 3 H,
Aromatics), 7.37 (d, J = 8.0 Hz, 2 H, Aroma tics), 2.38 (s, 3
H, CH3) ppm. 3d: 95%, mp: 150-152 °C iso-PrOH. IR
(KBr): 1560, 1090, 697 cm-1. 1H NMR (DMSO-d6, 300
MHz): 8.39 (s, 1 H, CH), 8.08 (d, J = 8.8 Hz, 2 H,
Aromatics), 7.61 (m, 2 H, Aromatics), 7.41 (m, 3 H,
Aromatics), 6.97 (d, J = 8.8 Hz, 2 H, Aromatics), 3.70 (s, 3
H, OCH3) ppm.
7.33 (m, 7 H, 5 H Aromatics + 1 H furan + H4), 6.28 (dd,
J = 3.5, 1.8 Hz, 1 H, furan), 5.64 (d, J = 3.5 Hz, 1 H; furan)
ppm.
(24) Aminopyridazines 5 were prepared heating at reflux 3a-f in
presence of the appropriate amine (3 equivalents) in ethanol
(24-72 h). 3,4-Diphenyl-6-(2-methoxyethylamino)pyrid-
azine 5a: 78%, (72 h) mp: 199-201 °C, iso-PrOH. IR (KBr):
3000, 1590 cm-1. 1H NMR (DMSO-d6, 300 MHz): 7.69-7.21
(m, 10 H, Aromatics), 6.94 (s, 1 H, H4), 3.64 (t, J = 7.1 Hz,
2 H, CH2), 3.35 (s, 3 H, CH3), 3.29 (t, J = 7.1 Hz, 2 H, CH2)
ppm.
(25) Hydrazinopyridazines 6 were prepared heating at reflux 3a-
f in presence of 3 equivalents of hydrazine hydrate in ethanol
(3-4 h). 3,4-Diphenyl-6-hydrazinopyridazine 6a: 89%, mp:
153-155 °C, iso-PrOH.28 IR (KBr): 3500-300, 1576 cm-1. 1H
NMR (CDCl3, 300 MHz): 8.12 (m, 3 H, Aromatics), 7.67
(m, 2 H, Aromatics), 7.54 (s, 1 H, CH), 7.51 (m, 6 H,
Aromatics), 6.08 (2, 1 H, NH), 3.48 (s, 2 H, NH2) ppm.
(26) Pyridazines 7 were prepared by reductive dechlorination of
3a-f(HCOONH4/Pd-C, MeOH). 3,4-diphenylpyridazine 7a:
88%, mp: 106-107 °C, iso-PrOH.29 IR (KBr): 1590 cm-1. 1H
NMR (DMSO-d6, 300 MHz): 9.21 (d, J = 5.2 Hz, 1 H, CH),
7.50 (d, J = 5.2 Hz, 1 H, CH), 7.46 (m, 10 H, Aromatics)
ppm.
(27) Complete details of the synthesis and spectral characteristics
of the compounds obtained will be published elsewhere in a
full paper. All compounds gave satisfactory microanalytical
(C, H, N 0.4%) and spectral data (1H, 13C, FTIR, MS).
Yields given correspond to isolated pure compounds.
(28) Abdel-Motti, F. M.; Abdel-Megeid, F. M. E.; Zaki, M. E.;
Shamrokh, A. H. Egypt. J. Pharm. Sci. 1998, 38, 87.
(29) Meresz, O.; Foster-Verner, P. A. J. Chem. Soc., Chem.
Commun. 1972, 16, 950.
(22) (a) Gronowitz, S.; Lawitz, K. Chem. Scr. 1983, 22, 265.
(b) Gronowitz, S.; Stevens, M. F. G. J. Chem. Soc., Perkin
Trans. 1 1994, 3311.
(23) 3(2H)-Pyridazinones 4 were prepared heating at reflux 3a-f
in neat acetic acid during 3-7 h. 4a: 86%, mp: 178.5-180.6
°C, Acetonitrile. IR (KBr): 3000, 1668, 1589cm-1. 1H NMR
(DMSO-d6, 300 MHz): 11.58 (bs, 1 H, NH), 7.38-7.20 (m,
10 H Aromatics), 7.01 (s, 1 H, H4) ppm. 4e: 84%, mp: 235.0-
235.5 °C, iso-PrOH. IR (KBr): 3000, 1662, 1580 cm-1.
1H NMR (DMSO-d6, 300 MHz): 12.05 (bs, 1H, NH), 7.48-
Synlett 2002, No. 2, 223–226 ISSN 0936-5214 © Thieme Stuttgart · New York