274
Chemistry Letters 2001
Solid Phase Synthesis of Pyridazine Derivatives Using Polymer-Bound Sodium Benzenesulfinate
Yu Chen, Yulin Lam,* and Soo-Ying Lee
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore
(Received November 1, 2000; CL-000996)
A new solid phase synthesis of 3,6-disubstituted pyridazine
derivatives, resulting from the reaction of polymer-bound sodi-
um benzenesulfinate with α-bromoketone substrates followed
by condensation with hydrazine, is described. Mild basic con-
ditions for the condensation reaction simultaneously release the
desired product from the solid support. The crystal structure of
3,6-bis(p-chlorophenyl)pyridazine is reported.
cleaved the product from the solid support to give the dehydro-
genated 3,6-disubstituted pyridazine derivatives. Unlike in
solution-phase synthesis,13 no N-aminopyrrole derivatives were
observed in the product mixture even under refluxing ethanol
conditions.
Rapid developments in solid phase organic synthesis have
been made recently, driven largely by the impetus of combina-
torial and parallel syntheses in drug1 and materials2 develop-
ments. Central to the effective application of solid phase organ-
ic synthesis is the choice of linker through which the organic
molecule is attached to the solid support. The linker must be
inert to the synthetic sequence and subsequently permit the final
product to be chemoselectively released from the resin.
Sodium benzenesulfinate is used widely in the preparation
of sulfone which plays an important role in organic synthesis.3
However the use of polymer-bound sodium benzenesulfinate
resin 1 in solid phase synthesis has received little attention.4–6
We were interested in the solid-phase synthesis of pyridazine
derivatives as they have been shown to exhibit various antitu-
mour, antibacterial and herbicidal activites.7 Spurred by the
diverse biological activities of these compounds, a variety of
solution-phase strategies have been developed earlier.8–10
Herein, we describe the solid-phase synthesis of 3,6-disubstitut-
ed pyridazine derivatives on sodium benzenesulfinate resin. To
our knowledge, only one earlier report on the solid phase route
to pyridazines has been published. This was achieved through
the Diels–Alder reactions of 3,6-disubstituted-1,2,4,5-tetrazines
on a solid phase format.11
In our reaction (Scheme 1), sodium benzenesulfinate resin
1 in DMF was treated with a variety of α-bromoketone (5
equiv) in the presence of tetrabutylammonium iodide (1 equiv)
and potassium iodide (5 equiv) for 1 day to afford β-ketosul-
fone resin 2 in a reaction which could be monitored by KBr FT-
IR.12 Formation of up to 94% of sulfone by transformation of
the resin-bound sodium benzenesulfinate was observed during
this step.
The resulting resin-bound intermediate 2 was treated with
α-bromoketone (5 equiv) in the presence of a base (1.2 equiv)
for 2 days to give the 1,4-diketo resin 3. During the synthesis
of pyridazine 4a, two different systems were used for this alky-
lation step. The first system utilized NaOMe/THF as base
whilst the other system was treated with K2CO3/DMF. We
found that K2CO3/DMF gave cleaner results with an overall
yield of 42% as compared to 15% in the reaction with
NaOMe/THF. Hence K2CO3/DMF was used for the synthesis
of the other members of the 3,6-disubstituted pyridazine library.
Treatment of 3 with hydrazine (5 equiv) for 12 h resulted not
only in the condensation reaction but also simultaneously
In the library synthesis, 7 representative α-bromoketones
containing various functionalities were tested. Using the
process illustrated in Scheme 1, 20 pyridazines were synthe-
sized and analyzed by H NMR and high resolution MS (Table
1).
1
Single crystals of 3,6-bis(p-chlorophenyl)pyridazine 4g
were obtained from diethyl ether/dichloromethane mixture.
Intensity data were collected at room temperature using a
Siemens R3m/V diffractometer with Mo Kα radiation (λ =
0.71060 Å). Lorentz and polarization corrections, structure
solution by direct methods, full-matrix least-squares refine-
ments and preparation of figures were all performed by the
SHELXTL-Plus PC program package.14,15 All non-hydrogen
atoms were refined anisotropically whereas hydrogen atoms
were placed at calculated positions with isotropic displacement
coefficient being assigned a value that is 1.6 times that of the
atom to which it is attached. Tables of atomic coordinates,
bond lengths and angles and thermal parameters have been
deposited in the Cambridge Crystallographic Data Centre.
Figure 1 depicts the structure and defines the atomic num-
bering of the molecule. The pyridazine and phenyl rings are
planar but the molecule as a whole is skewed with the phenyl
groups C1C2C3C4C5C6 and C11C12C13C14C15C16 being
oriented at 18.9° and 10.0° respectively to the pyridazine ring.
In summary, this paper demonstrated the first direct syn-
thesis of pyridazines on a solid-phase format. This application
to the synthesis of large pyridazine libraries is presently under
investigation.
Copyright © 2001 The Chemical Society of Japan
Chen, Yu
