A short and convenient strategy for the synthesis of pyridazines via Diaza-Wittig reaction

Article abstract of DOI:10.1016/j.tetlet.2012.09.059

A convenient and selective synthesis of 6-substituted-4-hydroxy-3- methoxycarbonyl pyridazines has been developed via a diaza-Wittig reaction. The desired products substituted at the C6 position can be obtained from readily available starting materials under mild conditions. This represents an attractive new method for the synthesis of pyridazine derivatives.

Full text of DOI:10.1016/j.tetlet.2012.09.059

Tetrahedron Letters 53 (2012) 6489–6491
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Tetrahedron Letters
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A short and convenient strategy for the synthesis of pyridazines via
Diaza–Wittig reaction
Hassen Bel Abed a, Oscar Mammoliti b, Guy Van Lommen b, Piet Herdewijn a,
⇑
a Rega Institute for Medical Research, Laboratory of Medicinal Chemistry, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
b Galapagos, Laboratory of Medicinal Chemistry, General De Wittelaan L11 A3, B-2800 Mechelen, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 June 2012
Revised 10 September 2012
Accepted 14 September 2012
Available online 23 September 2012
A convenient and selective synthesis of 6-substituted-4-hydroxy-3-methoxycarbonyl pyridazines has
been developed via a diaza-Wittig reaction. The desired products substituted at the C6 position can be
obtained from readily available starting materials under mild conditions. This represents an attractive
new method for the synthesis of pyridazine derivatives.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Pyridazine
Diaza–Wittig
Diazo transfer reaction
Weiler dianion
Several compounds with pyridazine1 rings demonstrate biolog-
ical activity2 and several examples of these structures are naturally
occuring.3 In fact, pyridazines are key intermediates in the synthe-
sis of several fused heterocycles4 such as JNJ-38877605 (Fig. 1) and
have been explored as RAF/VEGFR2 inhibitors by Takeda Pharma-
ceutical.5 They have also proven to be attractive scaffolds from a
pharmacological point of view, acting for example as PDE10A
inhibitors6 for the treatment of psychotic disorders. Pyridazine
based drugs were recognized as selective GABA-A receptor antag-
onists,7 such as Minaprine (Fig. 1).
Herein, we describe the synthesis of a new pyridazine deriva-
tive in four steps with moderate to good yields. To the best of
our knowledge, the only existing procedure leading to 3-alkoxycar-
bonyl-4-hydroxy-6-substituted pyridazines is the one developed
by Zelesov et al.8 starting from furan-4,5-dione.
in acetic acid) and chlorination leads to the desired pyridazine 2
(Fig. 2).
Prompted by the need for a more reliable and versatile prepara-
tion of pyridazines allowing the introduction of various substitu-
ents such as alkyls, cycloalkyls, aryls, and heteroaryls, we
envisioned a more convenient synthesis of 6-substituted-4-hydro-
xy-3-methoxycarbonyl pyridazines starting from methyl acetoace-
tate 4.
In our search for operationally simple processes, we have inves-
tigated a new method to prepare pyridazines under mild condi-
tions. It has been decided to replace one of the ester groups of
dialkyl acetone dicarboxylate (methyl or ethyl) 3 by a ketone to
However, this method is limited to the synthesis of aryl substi-
tuted compounds at the C6 position such as compound 1 (Fig. 2).
Importantly, and of particular value for the development of a
versatile method for the synthesis of pyridazine derivatives, is that
the obtained compounds can be further modified in a site-selective
way. For example, selective reaction of 4,6-dichloro pyridazine9
2
Figure 1. Structures of some pharmaceutically important pyridazine derivatives.
at positions 4 and 6 is problematic. The starting material for the
synthesis of 4,6-dichloro pyridazine 2 is a dialkyl acetone dicarbox-
ylate (methyl or ethyl) 3 which after treatment with a diazo trans-
fer reagent followed by cyclization under harsh conditions (reflux
⇑
Corresponding author. Tel.: +32 16 337387; fax: +32 16 337340.
E-mail address: piet.herdewijn@rega.kuleuven.be (P. Herdewijn).
Figure 2. Pyridazines and dialkyl acetone dicarboxylate.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.059

6490
H. Bel Abed et al. / Tetrahedron Letters 53 (2012) 6489–6491
xy ketoester 5 in moderate yields. These aldol products are easily
degraded (water elimination) to give the corresponding enone.11
After treatment of 5 with p-ABSA (p-acetamido benzene sulfonyl
azide) in acetonitrile, the diazo derivative 6 was obtained in good
yields.12 A mild oxidation of 6 using IBX13 (1-hydroxy-1,2-benzio-
doxol-3(1H)-one 1-oxide) in acetonitrile for 2 h under reflux led to
the corresponding
a-diazo-b-ketoester 7 in good yields. The final
stages14 of the synthesis (the formation of phosphazine 8 and the
subsequent diaza-Wittig reaction) occur as a tandem process to
obtain the pyridazine 9 in moderate to good yields. Different at-
tempts have been done using triphenyl phosphine to convert the
a-diazo-b-ketoester 7 into pyridazine 9 without success, while
the use of HMPT (hexamethylphosphorous triamide) at room tem-
perature led to phosphazine and pyridazine ring formation
(Scheme 1).
This procedure allowed the introduction of different groups at
the C6 position of the pyridazine ring, such as alkyls, cycloalkyls,
aryls, and heteroaryls by selecting the appropriate aldehyde as
starting material (Table 1). In this respect this procedure proved
to be more selective than a strategy based on palladium cross-
coupling.
Scheme 1. Synthesis of 6-substituted-4-hydroxy-3-methoxycarbonyl pyridazines.
Table 1
Synthesis of 6-substituted-4-hydroxy-3-methoxycarbonyl pyridazines from interme-
diate 6
Entry
Aldehyde derivative
Propionaldehyde
Product
OH O
Yielda (%)
68
We observed that better yields were obtained with alkyl alde-
hydes or cycloalkyl aldehydes than with aryl aldehydes and het-
eroaryl aldehydes. In order to cover
a wide variety of
O
O
1
N
substitutions, different attempts using aryl aldehydes containing
electron withdrawing groups like p-nitrobenzaldehyde have been
explored but did not give the required b-hydroxy ketoester 5 in
our hands.
N
9a
OH O
In conclusion, we have developed a concise and convenient
procedure for the synthesis of 6-substituted-4-hydroxy-3-
methoxycarbonyl pyridazines involving a Diaza–Wittig reaction
as a key-step, allowing the introduction of a variety of substitu-
tions from alkyls, cycloalkyls to aryls and heteroaryls at the C6
position. This method, likewise, allows the synthesis of pyridazines
with different substitutions at C4 and C6 positions, which is more
difficult starting from the 4,6-dichloro pyridazine 2. In order to
further extend the scope of this process, we are currently exploring
the synthesis of fused pyridazines from 6-substituted-4-hydroxy-
3-methoxycarbonyl pyridazine derivatives.
N
N
2
3
Isobutyraldehyde
75
62
9b
OH O
O
O
N
N
Cyclohexane carboxaldehyde
9c
OH O
N
N
4
5
Benzaldehyde
60
45
Acknowledgments
9d
OH O
Hassen Bel Abed is indebted to the IWT (Agentschap voor Inno-
vatie door Wetenschap en Technologie) and the Galapagos com-
pany for providing a PhD-scholarship (Baekeland-project 90704).
He is also grateful to Dr. Mongi and Dr. Fouzia for their kind
suggestions.
O
N
N
p-Anisaldehyde
O
9e
OH O
O
O
Supplementary data
N
N
6
7
2-Furfural
27
33
O
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
09.059.
9f
OH O
N
N
Thiophene-2-carboxaldehyde
S
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9g
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14. Typical procedure for 9e: To a solution of 7e (7.24 mmol, 1.0 equiv) in 20 mL of
dichloromethane was added 1.32 mL of HMPT (hexamethylphosphorous
triamide) (7.24 mmol, 1.0 equiv). The mixture was then stirred at room
temperature overnight. After completion of the reaction (TLC), the reaction
mixture was quenched with the addition of water. The organic phase was then
washed several times with water, dried over Na2SO4, and concentrated in
vacuo. Flash column chromatography on silica gel (ethyl acetate/methanol
90:10) afforded the desired product 9e as an orange powder (850 mg, 45%). 1
H
NMR (500 MHz, DMSO-d6) 7.77 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 6.81
(s, 1H), 3.84 (s, 6H). 13C NMR (125 MHz, DMSO-d6) 164.2, 161.7, 148.2, 129.0,
122.8, 115.0, 114.7, 55.6, 52.5. HRMS Calculated for C13H12N2O4 261.0831,
Found 261.0871.