Pyridazines. Part 35: Traceless solid phase synthesis of 4,5- and 5,6-diaryl-3(2H)-pyridazinones

Article abstract of DOI:10.1055/s-2003-39882

A new method for the traceless solid phase synthesis of 3(2H)-pyridazinones has been developed employing dihydropyran-functionalized resin. The procedure has permitted the preparation of several diarylpyridazinones through a Suzuki cross-coupling reaction and cleavage conditions that promoted a retro-ene fragmentation.

Full text of DOI:10.1055/s-2003-39882

LETTER
1113
Pyridazines. Part 35:1 Traceless Solid Phase Synthesis of 4,5- and 5,6-Diaryl-
3(2H)-pyridazinones
T
raceless Solid
d
Phase Synth
d
esis of 4,5-
a
y
nd 5,6-Diaryl-3(2
H
S
)-pyridazinon
o
es telo, Enrique Raviña*
Laboratorio de Química Farmacéutica, Departamento de Química Orgánica. Facultad de Farmacia, Universidad de Santiago de Compostela,
15782. Santiago de Compostela, Spain
E-mail: qofara@usc.es
Received 10 February 2003
Several works on palladium-catalyzed reactions have
Abstract: A new method for the traceless solid phase synthesis of
shown that these transformations represent a powerful
3(2H)-pyridazinones has been developed employing dihydropyran-
functionalized resin. The procedure has permitted the preparation of
several diarylpyridazinones through a Suzuki cross-coupling reac-
tool to perform pharmacomodulation in the pyridazinone
series9,10 and, for this reason, we became interested in de-
veloping a solid-phase route to carry out these kinds of
transformations. One key aspect has guided our design
strategy: to perform palladium-catalyzed reactions on py-
ridazinones it is necessary to protect the NH-group since
the acidic nature of the lactam functionality of this group
usually interferes with the transformations.10 Bearing this
point in mind, for the solid phase chemistry it is important
to select a suitable scaffold and linker combination that is
able not only to attach the pyridazinone ring onto the solid
support but also to protect the heterocycle at the same
time. The most obvious approach to carry out a traceless
solid phase 3(2H)-pyridazinone synthesis would be to use
the pyridazinone N–H as a resin attachment point, which
could subsequently be cleaved to give the free 3(2H)-py-
ridazinone. There have, however, not been any reports in
the literature of such a strategy being successfully accom-
plished. Although one can envisage attaching the 3(2H)-
pyridazinone unit to directly onto Merrifield resin by a
simple alkylation, there are several problems associated
with this direct approach. Firstly, even in typical solution
chemistry there are several protecting groups at position 2
that are sometimes difficult to remove.
tion and cleavage conditions that promoted a retro-ene fragmenta-
tion.
Key words: solid phase, pyridazinone, ene-adducts, palladium
The high speed synthesis of organic molecules, and in par-
ticular the synthesis of heterocyclic compounds, by solid
phase or solution phase methods is rapidly becoming es-
tablished as an enabling technology in modern medicinal
chemistry.2 An important objective in solid phase organic
synthesis (SPOS) is the development of chemistries appli-
cable to combinatorial techniques that are not limited by
the tether and where target molecules can be efficiently
cleaved from the resin by a specialized reagent or trans-
formation. However, the need for the attachment of sub-
strates onto solid supports through the use of linkers
inevitably leaves behind molecular vestiges upon cleav-
age. The biological activity of compounds made in this
way could be altered due to the presence of these molecu-
lar appendages. In an attempt to circumvent this problem,
traceless linkers and cyclization cleavage procedures have
been introduced.3 The pyridazine nucleus and its 3-oxo
derivatives [3(2H)-pyridazinones] have been recognized
as versatile pharmacophores in medicinal chemistry and
they show a wide range of biological actions.4 Curiously,
only a few studies on the SPOS of pyridazine derivatives
have been described5 and, therefore, the development of
convenient, versatile and efficient solid phase routes to
access chemical libraries of these compounds is highly de-
sirable.
Taking into account the aspects described above, we de-
signed a general traceless approach to generate disubsti-
tuted-3(2H)-pyridazinone libraries in the solid phase by
using the Ellman’s resin. The first results of this project
allow to prepare diaryl-3(2H)-pyridazinones 6 and 7 and
are represented in this paper. Compounds 6 and 7 are
structurally related to the well documented cyclo-oxygen-
ase-2 inhibitors.11 To compliment these objectives we
chose as reactive scaffolds the 2-hydroxymethylhalopy-
ridazinones 2,12 which can be prepared in excellent yields
by refluxing 1 in 35% formaldehyde solution (Scheme 1).
One of these compounds (1a) have been successfully used
recently by our group as reactive intermediates in palladi-
um-catalyzed transformations.13 Compounds 2 are 1-O, 3-
N, 5-O ene adducts14 that lose formaldehyde in a retro-ene
transformation catalyzed by the action of bases and/or
heat. In our previous attempts to adapt this chemistry onto
the solid support we observed that this retro-ene transfor-
mation can also be promoted in almost quantitative yield
by the conditions usually employed to remove the sub-
strates form the solid support (20% TFA/CH2Cl2 solution,
50 °C, 12 h, Scheme 1).
As part of our efforts aimed towards the preparation and
biological evaluation of pyridazine derivatives,6–8 we
wish to describe here our studies that have identified a
highly efficient and versatile traceless solid phase route to
prepare chemical libraries of 4,5- and 5,6-substituted-
3(2H)-pyridazinones amenable to automated high-speed
parallel synthesis.
Synlett 2003, No. 8, Print: 24 06 2003.
Art Id.1437-2096,E;2003,0,08,1113,1116,ftx,en;D03103ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

1114
E. Sotelo, E. Raviña
LETTER
O
R
O
OH
O
Retro-ene
Na2CO3/THF
or
20% TFA/CH2Cl2
60 °C
H
N
Y
X
H
Y
X
Y
X
35% CH2O
60–80%
N
N
N
N
N
R
R
1a–c
2a–c
1a–c
a) R = Ph, Y = H, X = Br, b) R = H, Y = Cl, X = Cl, c) R = H, Y = Br , X = Br
Scheme 1
The solid phase synthesis of 4,5- and 5,6-diaryl pyridazi- employ short reaction times (15–20 min) for the cleavage
nones 6 and 7 is achieved through the previous prepara- process.
tion of immobilized 5-halo- and 4,5-dihalopyridazinones
2. Alcohols 2 are attached to Ellman’s DHP-linked poly-
Isolation of compounds 1 under cleavage conditions can
be rationalised in terms of the initially formed 2-hy-
droxymethyl-3-pyridazinones 2 losing formaldehyde in a
second step, which can be recognized as a retro-ene frag-
mentation. Although we focused our attention on the di-
rect preparation of 3(2H)-pyridazinones, these results are
styrene resin (Aldrich) using PPTS in 1,2-dichloroethane
(Scheme 2).15 This operation was repeated twice to ensure
quantitative conversion of 2 to 3. The progress of the re-
action was qualitatively monitored by IR spectroscopy by
following the appearance of the carbonyl band of the het-
particularly important since such conditions could permit
erocyclic ring (1660–1670 cm–1). Similar transformations
the introduction of a new point of diversity, at position 2
of the heterocyclic system, in the chemical libraries pre-
but starting from the 3(2H)-pyridazinones 1a–c allow to
obtain the corresponding supported derivatives but only in
pared by this methodology.
low yields.
We next turned our attention to the introduction of aryl
groups in 3 by following the well established palladium-
catalyzed Suzuki approach (Scheme 4).16 Thus, treatment
O
O
OH
O
O
of 3 with an excess of the appropriate aryl boronic acid
(2.5 equiv per reactive halogen), a catalytic amount of
Pd(PPh3)4 (0.05 equiv) and 2 M Na2CO3 as base in di-
chloroethane at 80 °C (12 h), provided the expected aryl-
ated immobilized 3-pyridazinones 4 and 5.17 In order to
avoid submitting the resin to the harsh cleavage condi-
tions (50 °C, 12 h), the desired products 6 and 7 were
cleaved from the resin using 20% TFA/ CH2Cl2 (15 min)
and the cleavage solutions were subsequently heated at 50
°C during 10 hours.18
Y
X
Y
X
O
O
N
N
N
O
N
PPTS, C2H4Cl2
60 °C
R
R
2a–c
3a–c
a) R = Ph, Y = H, X = Br, b) R = H, Y = Br, X = Br
c) R = H, Y = Cl, X = Cl
Scheme 2
The coupling efficiency was determined by mass balance
after cleavage of the material from the support
(Scheme 3). These methods allowed us to isolate, depend-
ing on the conditions, the 2-hydroxymethyl-pyridazino-
nes 2 using the traditional cleavage conditions (20% TFA/
CH2Cl2, r.t., 15 min) or the 3(2H)-pyridazinones 1 by
heating the mixture (20% TFA/CH2Cl2) at 50 °C during
12 hours (Scheme 3). It is important to point out that in
order to isolate compounds 2 as pure samples one must
As expected, the acetal linkage was totally stable to the
conditions of the Suzuki coupling (2 M Na2CO3, 70 °C)
and we did not observe cleavage of the heterocycle from
the support. Arylpyridazinones 6 and 7 were obtained in
74–86%19 yield and 80–96% purity, as determined by
HPLC.20 Complete characterization of the compounds ob-
tained was performed by the analytical and spectroscopic
methods (MS, IR and NMR experiments) and by compar-
ing the data with those of authentic samples previously
prepared by us (Table 1).9,12
O
O
OH
O
Y
X
H
Y
X
Y
X
O
O
20%
N
N
N
N
N
O
20%
TFA-CH2Cl2
60°C
N
TFA-CH2Cl2
R
R
R
2a–c
3a–c
1a–c
a) R = Ph, Y = H, X = Br, b) R = H, Y = Br, X = Br
c) R = H, Y = Cl, X = Cl
Scheme 3
Synlett 2003, No. 8, 1113–1116 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
Traceless Solid Phase Synthesis of 4,5- and 5,6-Diaryl-3(2H)-pyridazinones
1115
O
O
O
OH
O
X
X
Ar
Ar
H
Ar
Ar
Suzuki
20%
Ar
Ar
THP O
N
N
THP O
N
N
N
N
60 °C
N
Coupling
TFA/CH2Cl2
N
6a–d
3b X= Cl
3c X= Br
4a–d
O
O
OH
O
O
H
Suzuki
20%
THP O
N
N
THP O
N
N
N
60 °C
N
Coupling
N
TFA/CH2Cl2
N
Br
Ar
Ar
Ar
Ph
Ph
Ph
Ph
3a
5a–d
a) Ar = Ph, b) Ar = 4-CH3-Ph, c) Ar = 4-CH3O-Ph, d) Ar = 4-Cl-Ph
7a–d
Scheme 4
Table 1 Diaryl-3(2H)-pyridazinones Prepared
(3) (a) Smith, A. L.; Thompson, C. G.; Leeson, P. D. Bioorg.
Med. Chem. Lett. 1996, 6, 1483. (b) Smith, A. L.;
Stevenson, G. I.; Swain, C. J.; Castro, J. L. Tetrahedron Lett.
1998, 39, 8317. (c) Guillier, F.; Orain, D.; Bradley, M.
Chem. Rev. 2000, 100, 2091.
(4) Frank, H.; Heinisch, G. Pharmacologically Active
Pyridazines. Part 2. In Progress in Medicinal Chemistry,
Vol. 29; Ellis, G. P.; Luscombe, D. K., Eds.; Elsevier:
Amsterdam, 1992, 141.
(5) (a) Goualt, N.; Cupif, J. F.; Picaro, S.; Lecat, A.; David, M.
J. Pharm. Pharmacol. 2001, 7, 981. (b) Parrot, I.;Wermuth,
C. G.; Hibert, M. Tetrahedron Lett. 1999, 40, 7975.
(6) Laguna, R.; Rodriguez-Liñares, B.; Cano, E.; Estévez, I.;
Raviña, E.; Sotelo, E. Chem. Pharm. Bull. 1997, 45, 1151.
(7) Sotelo, E.; Fraiz, N.; Yañez, M.; Laguna, R.; Cano, E.; Brea,
J.; Raviña, E. Bioorg. Med. Chem. Lett. 2002, 12, 1575.
(8) Sotelo, E.; Fraiz, N.; Yañez, M.; Terrades, V.; Laguna, R.;
Cano, E.; Raviña, E. Bioorg. Med. Chem. 2002, 10, 2873.
(9) (a) Estévez, I.; Coelho, A.; Raviña, E. Synthesis 1999, 9,
1666. (b) Coelho, A.; Sotelo, E.; Estévez, I.; Raviña, E.
Synthesis 2001, 6, 871.
Compound
Ar
Yield (%)a
Purity (%)b
6a
6b
6c
6d
7a
7b
7c
7d
Ph
86
83
80
79
81
80
76
74
80
83
81
85
93
96
91
93
4-CH3Ph
4-OCH3Ph
4-ClPh
Ph
4-CH3Ph
4-OCH3Ph
4-ClPh
a Yields of crude product based on experimentally determined loading
of Ellman’s resin-bound alcohol.
b Purity of the compounds was based on the integration area from
HPLC traces of crude products (254 nm UV detection).
(10) (a) R´kyek, O.; Maes, B. U. W.; Jonkers, T. H. M.; Lemière,
G. L. F.; Dommisse, R. A. Tetrahedron 2001, 57, 10009.
(b) Komrlj, J.; Maes, B. U. W.; Lemière, G. L. F.; Haemers,
A. Synlett 2000, 11, 1581.
(11) de Leval, X.; Delarge, J.; Somers, F.; Tullio, P. D.; Henrotin,
Y.; Pirotte, B.; Dogné, J. M. Curr. Med. Chem. 2000, 7,
1041.
In summary, we have developed a novel and efficient sol-
id phase synthesis of 4,5- and 5,6-diaryl-3(2H)-pyridazi-
nones following a Suzuki-type C–C coupling reaction
assisted by a retro-ene transformation. This procedure is
the first example of a traceless solid phase synthesis of py-
ridazinones. The results of further studies on the scope
and generality of this and other palladium-mediated solid
phase strategies for the synthesis of libraries of pyridazi-
nones will be reported in due course.
(12) Selected physical and spectroscopic data of representative
compounds 2. Compound 2a: Yield: 89%, mp 237–238 °C.
IR (KBr): 3100, 1680 cm–1. 1H NMR (300 MHz, CDCl3):
d = 7.55–7.47 (m, 5 H, Ph), 7.40 (s, 1 H, CH), 5.58 (d, J = 8.1
Hz, 2 H, CH2), 4.74 (t, J = 8.1 Hz, 1 H, OH). Compound 2b:
Yield: 70%, mp 113–114 °C. IR (KBr): 3400, 2960, 1670
cm–1. 1H NMR (300 MHz, DMSO-d6): 8.19 (s, 1 H, CH),
6.97 (t, J = 7.6 Hz, 1 H, OH), 5.34 (d, J = 7.6 Hz, 2 H, CH2).
(13) Coelho, A.; Raviña, E.; Sotelo, E. Synlett 2002, 12, 6062.
(14) Ripoll, J.; Vallé, Y. Synthesis 1993, 659.
(15) General Procedure for the Preparation of Immobilized
Pyridazinones 3: The amount of 300 mg of Ellman’s resin
(Aldrich, 0.420 mmol) was loaded into a reactor on a PLS
6 × 4 organic synthesizer (Advanced ChemTech) and treated
with 2 (1.26 mmol), PPTS (0.63 mmol) and dichloroethane
(4 mL). The mixture was heated at 70 °C during 12 h,
drained, washed sequentially with dichloroethane (3 × 5
mL), CH2Cl2 (3 × 5 mL), DMF (3 × 5 mL), CH2Cl2 (3 × 5
mL), MeOH (3 × 5 mL), Et2O (3 × 5 mL) and dried in a
vacuum dessicator.
Acknowledgment
This work was financially supported by Comisión Española de
Ciencia y Tecnología CICYT and the European Community (EFRD
fund Project 1FD 97-2371-C03-03).
References
(1) For the previous paper in this series, see: Sotelo, E.; Raviña,
E. Tetrahedron Lett., in press.
(2) (a) Szostak, W. Chem. Rev. 1997, 97, 349. (b) Thompson,
L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555. (c) Fruchtel,
J. S.; Jung, G. Angew. Chem., Int. Ed. Engl. 1996, 35, 17.
Synlett 2003, No. 8, 1113–1116 ISSN 1234-567-89 © Thieme Stuttgart · New York

1116
E. Sotelo, E. Raviña
LETTER
mixture of CH3CN–H2O. The solvent was then removed
(16) (a) Miyara, N.; Yanagi, T.; Suzuki, A. Synth Commun. 1981,
11, 513. (b) Tsuji, J. Palladium Reagents and Catalysts;
Wiley: Chichester, 1995.
under presure to give pyridazinones 6 and 7.
(19) Selected physical and spectroscopic data of compounds 6
and 7: Compound 6a: Mp 135–136 °C. IR (KBr): 3100–
2600, 1642 cm–1. 1H NMR (300 MHz, DMSO-d6): d = 13.05
(br s, 1 H, NH), 7.74 (s, 1 H, CH), 7.04–6.92 (m, 10 H, Ph).
Compound 6b: Mp 147–149 °C. IR (KBr): 3100–2600, 1639
cm–1. 1H NMR (300 MHz, DMSO-d6): d = 13.16 (br s, 1 H,
NH), 7.90 (s, 1 H, CH), 7.52–7.00 (m, 8 H, Ph), 2.24 (s, 6 H,
2 × CH3). Compound 7a: Mp178–180 °C. IR (KBr): 3100–
2600, 1668, 1589 cm–1. 1H NMR (300 MHz, DMSO-d6): d =
11.58 (br s, 1 H, NH), 7.38–7.20 (m, 10 H, Ph), 7.01 (s, 1 H,
CH). Compound 7b: Mp 198–200 °C. IR (KBr): 3100–2600,
1642 cm–1. 1H NMR (300 MHz, DMSO-d6): d = 11.40 (br s,
1 H, NH), 7.41–7.29 (m, 5 H, Ph), 7.18 (d, J = 8.0, 2 H,
phenyl), 7.07 (d, J = 8.0, 2 H, phenyl), 7.01 (s, 1 H, CH),
2.33 (s, 3 H, CH3).
(17) General Procedure for Suzuki Arylation of Immobilized
Halopyridazinones 3: The amount of 100 mg of
pyridazinone-derivatized support 3 (0.120 mmol) was
loaded into a reactor on a PLS 6 × 4 organic synthesizer
(Advanced ChemTech) and treated with the appropriate
boronic acid (0.300 mmol for 1a and 0.600 mmol for 1b,c),
Pd(PPh3)4 (0.05 equiv), 2 M Na2CO3 (0.7 mL) and DME (3
mL). The mixture was heated at 70 °C during 12 h, drained,
washed sequentially with DME (3 × 5 mL), DME/H2O
(3 × 5 mL), 0.2 N HCl (3 × 5 mL), EtOAc (3 × 5 mL),
MeOH (3 × 5 mL), Et2O (3 × 5 mL) and dried in a vacuum
dessicator.
(18) General Procedure for Cleveage of 4,5- and 5,6-
Diarylpyridazinones Form Solid Support: The above
resin (75 mg) was treated with 20% TFA in CH2Cl2 (2 mL)
for 15 min. After filtration and washing with CH2Cl2 the
combined filtrates were heated at 50 °C for 12 h,
concentrated to give a residue wich was re-dissolved in a 1:1
(20) HPLC analyses were performed using a 5 mm 4.6 × 150 mm
reverse phase column (70% acetonitrile/30% H2O) over 40
min, flow rate 0.5 mL/min.
Synlett 2003, No. 8, 1113–1116 ISSN 1234-567-89 © Thieme Stuttgart · New York