The first synthesis of furo[2,3-c]pyridazin-4(1H)-one derivatives

Article abstract of DOI:10.1016/j.tetlet.2015.11.068

We report a five step method for the synthesis of furo[2,3-c]pyridazin-4(1H)-one derivatives representing a novel heteroaromatic ring-system. The first synthesis of 3-carboxylic and methyl-3-carboxylate derivatives of the 1-phenyl and 1-(p-methoxyphenyl) compounds are reported.

Full text of DOI:10.1016/j.tetlet.2015.11.068

Tetrahedron Letters 57 (2016) 64–66
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Tetrahedron Letters
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The first synthesis of furo[2,3-c]pyridazin-4(1H)-one derivatives
⇑
}
Ádám Andor Kelemen, Balázs Péter Szabó, Péter Kovács, György Miklós Keseru
Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körújta 2, Budapest 1117, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a five step method for the synthesis of furo[2,3-c]pyridazin-4(1H)-one derivatives representing
a novel heteroaromatic ring-system. The first synthesis of 3-carboxylic and methyl-3-carboxylate deriva-
tives of the 1-phenyl and 1-(p-methoxyphenyl) compounds are reported.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 23 April 2015
Revised 1 September 2015
Accepted 23 November 2015
Available online 8 December 2015
Keywords:
Furo[2,3-c]pyridazin-4(1H)-one
Medicinal chemistry
LDA mediated cyclization
Pyridazin-4(1H)-one condensed ring-system
Introduction
are furan-condensed derivatives 2 as potent PDE-inhibitor neuro-
protective agents,6 and thiophene-analogues 3 claimed as antiviral
Heterocyclic ring-systems are important scaffolds of small-
molecule drugs, and good starting points for fragment-based
drug-discovery.1 However, only a small segment of the tractable
heterocyclic chemical space, namely only 32 ring-systems, occur
in half of the known drugs.2 The preceding studies showing the
importance of the unexplored space of the heterocyclic chemistry
offer a challenge and opportunity to discover innovative heterocy-
cles, as potential scaffolds and fragments for early drug discovery.3
Pitt et al. have collected all possible hetero-mono and bicycles with
C, N, O, S, and H atoms with only exocyclic carbonyls in a virtual
library of ca. 25,000 ring-systems.3 They have proposed 22 unique
low complexity ring-systems with good predicted synthetic
tractability. The heterocycles were selected by a team of medicinal
chemists by visual inspection as a challenge for innovative organic
chemistry. In our group we decided to take up the gauntlet and
have set an objective to synthesize a couple of ‘heterocyclic rings
of the future’3 that have the potential to innovate medicinal
chemistry.
compounds7 (Fig. 1).
We have first analyzed the synthetic literature regarding the
planned furan and thiophene condensed pyridazin-4(1H)-ones.
We concluded that the most viable strategy was the cyclization
of the N-heterocyclic ring onto the 5-membered ring through an
aliphatic or aromatic hydrazone of a b-oxo-ester. We considered
two rational disconnections of the furo[2,3-c]pyridazin-4(1H)-one
target (Fig. 2).
Strategy ‘a’ involves a break of a C–N bond (4), and needed a
furan-derivative, as a cyclization key-intermediate. Schnute et al.8
elaborated the synthesis of a furan-condensed pyridin-4(1H)-one
ring-system, shown in Figure 3. The synthesis involves an
intramolecular SNAr cyclization step. The key intermediate was
afforded through an ethoxy acrylate compound, and potassium
tert-butoxide was used in the cyclization step.
Another example for building the pyridazine-4(1H)-one con-
densed ring-system through a C–N cyclization (4) was elaborated
by El-Abadelah et al.9 as shown in Figure 4. They have applied
sodium hydride as base for the cyclization step.
For the first attempt we selected the furo[2,3-c]pyridazin-4
(1H)-one ring-system from the announced 22 new ring-systems.
The 1,2-pyridazine-4-one substructure is represented in some
medicinal chemistry examples, such as the cinnolin-4(1H)-one
type antibacterial drug Cinoxacin (1).4,5 However, only a limited
number of furan- and thiophene condensed ring-systems are pub-
lished with pharmaceutical relevance. Some of these few examples
An example for the second cyclization strategy is shown in Fig-
ure 5. Shalaby10 have published an unexpected cyclization mecha-
nism, providing ethyl 5-amino-3,4-diphenylfuro[2,3-c]pyridazine-
6-carboxylate and the corresponding thieno derivative.
According to our literature analysis we have selected Strategy
‘a’ as a synthetically affordable route, based on the following
points. Furan-derivatives are commercially available, and widely
used starting compounds for organic synthesis. The SNAr type
cyclization reaction through hydrazones and aminoacrylates is a
well-characterized methodology in the synthesis of cinnolones,
⇑
Corresponding author. Tel.: +36 1 382 6901.
E-mail address: keseru.gyorgy@ttk.mta.hu (G.M. Keseru).
}
http://dx.doi.org/10.1016/j.tetlet.2015.11.068
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

Á. A Kelemen et al. / Tetrahedron Letters 57 (2016) 64–66
65
O
N
O
O
N
O
O
N
O
N
O
O
O
N
OH
N
N
H
N
N
N
S
Cl
1
2
3
CH3
Figure 1. Bioactive compounds containing condensed-pyridazine-4-one scaffolds.
O
a
O
procedure (Fig. 6). The 2-lithiation of furan-3-carboxylic acid 13
was carried out using lithium diisopropylamide in THF, followed
by the addition of hexachloroethane,9 which gave the 2-chloro
compound 14 in good yield. The initial reaction conditions for
the conversion of the carboxylic acid to acyl chloride involved oxa-
lyl chloride under reflux conditions. The use of a high boiling point
solvent, such as toluene, resulted in decomposition of the furan
ring during work-up. However the removal of the unreacted oxalyl
chloride by distillation was not consummate, in the case of using
dichloromethane as solvent.11 We found that the optimal condi-
tions for the synthesis of the corresponding acyl chloride deriva-
tives 15 involved the use of thionyl chloride in DCM under reflux
conditions. Contrary to literature strategies (Figs. 3 and 4) we have
applied the method published by Hughes and colleagues12 for the
synthesis of the ketoester. The strategy of El-Abadelah et al. involv-
ing Friedel–Crafts acylation of 2,5-dichlorothiophene applied harsh
conditions. For this reason we could utilize milder reaction condi-
b
N
N
O
O
N
N
H
H
4
5
Figure 2. Retrosynthetic disconnections to the furo[2,3-c]pyridazin-4(1H)-one
ring-system.
O
O
O
O
a,b,c
OEt
OEt
O
O
N
R
Cl
6
7
Figure 3. Synthetic route to furo[2,3-b]pyridin-4(7H)-ones. (a) (EtO)3CH, Ac2O,
135 °C; (b) RNH2, THF, 25 °C; (c) t-BuOK, 30–40 °C; R = CH3 (67%), C2H5 (50%), Ph
(34%).
tions with the lithiation of the ethyl acetate a-carbon followed by
the acylation with the furanyl chlorides resulting in ethyl 3-(2-
chlorofuran-3-yl)-3-oxopropanoate 16. This CH acidic compound
was treated with phenyl-, and p-methoxyphenyldiazonium salts
to afford phenyl-hydrazinylidene derivatives 17a,b. Benzenediazo-
nium chlorides resulted in poor yields due to decomposition of the
salt under the reaction conditions. The stability of the diazonium
reagent was increased by using the corresponding tetrafluorobo-
rate salts. In case of the methoxy-derivative, the crystallization of
the p-anisidine precursor for diazotisation was crucial for good
yields.
Two hydrazone derivatives 17a,b were synthesized as key-
intermediates for the cyclization reaction. The cyclization step
was first performed on the 2-chlorinated p-methoxy and p-unsub-
stituted phenylhydrazones. The main event of the cyclization reac-
tion is attack of the (partially) negatively charged hydrazine-
nitrogen on the electron-deficient furan carbon in the second posi-
tion. The use of sodium hydride is a well-known approach5 for the
cyclization of cinnolines and other pyridazine-condensed ring-sys-
tems. However, we have noticed that the use of sodium hydride
resulted in hydrolysis of the cyclized ester during work up, giving
compounds 18a,b. We used lithium diisopropyl amide (LDA) as an
alternative reagent for the cyclization in order to achieve improved
yields. We propose that the lithiation occurs on the protonated-
nitrogen providing an electron-rich reaction center to attack at
the position 2 on the furan ring, surrounded by electron-withdrawing
atoms (chlorine, furan oxygen) shown in Figure 7. The application
O
O
O
N
O
OMe
OMe
a
Cl
Cl
N
N
S
S
NH
Cl
8
9
R
R
Figure 4. Synthetic route to thieno[2,3-c]pyridazin-4-(1H)-ones. (a) NaH, THF,
15 °C, R = H (55%), Cl (60%), OCH3 (52%).
and further furo-, thieno-condensed examples as discussed
previously.
Results and discussion
We report the first synthesis of a new heterocycle furo[2,3-c]
pyridazine-4(1H)-one ring-system and some of its 1-phenyl-3-car-
boxylic acid derivatives. The accomplished synthetic route is sum-
marized in Figure 6.
We envisioned the key step being the LDA mediated cyclization
of hydrazone derivatives 17a,b, where the presence of the 2-chloro
substituent is required. Therefore, commercially available furan-3-
carboxylic acid 13 was used as a starting material for the five-step
Ph
Ph
N
Ph
N
H2N
EtOOC
N
N
Ph
Ph
Ph
a
N
N
N
X
XH
N
EtOOC
X
10
11
12
Figure 5. Synthetic strategy for ethyl 5-amino-3,4-diphenylfuro and thieno[2,3-c]pyridazine-6-carboxylates through C-C cyclization. (a) NaOEt, BrCH2COOEt, 3 h, reflux,
X = O (70%), X = S (55%).

66
Á. A Kelemen et al. / Tetrahedron Letters 57 (2016) 64–66
O
O
O
O
O
a
b
c
d
OH
Cl
OEt
OH
O
O
O
O
O
Cl
14
Cl
15
Cl
13
16
Cl
O
O
O
O
N
O
O
H
N
d
e,f
OH
g,h
OMe
N
R
N
N
O
O
N
OEt
17a,b
18a,b
19a,b
R
R
Figure 6. Synthetic route to 1-phenyl-1H,4H-furo[2,3-c]pyridazin-4-one derivatives. (a) LDA, C2Cl6, THF, 4 h, À78 °C to RT, 14, 45%, (b) SOCl2, DCM, reflux, overnight (c)
LiHMDS, EtOAc, 45 min, À78 °C to RT, 16, 79% calculated to 14, (d) aryldiazonium salt, NaOAc, EtOH, 1 h, RT, 17a, R = H, 51%, 17b, R = OCH3, 59%, (e) NaH, THF, overnight, 50 °C,
18a, R = H, 24%, 18b, R = OCH3, 32%, (f) LDA, THF, overnight, À78 °C to RT, 18a, R = H, 78%, 18b, R = OCH3, 74%, (g) CH2N2, DCM, 2 h, RT, 19a, R = H, 93%, (h) DBU, MeI, MeCN, 3 h,
RT, 19a, R = H, 95%, 19b, R = OCH3, 92%.
O
N
O
gratitude to Orsolya Egyed for NMR spectra and to Péter Gulyássy
and László Drahos (RCNS HAS) for exact mass (MS) measurements.
We are thankful to all members of the Medicinal Chemistry
Research Group (Research Centre for Natural Sciences) for valuable
ideas.
OEt
O
Li
N
Cl
This work was supported by National Brain Research Program
KTIA-NAP-13-1-2013-0001.
R = H, OMe
R
Figure 7. Proposed mechanism for the LDA-mediated cyclization reaction. R = H,
OCH3.
Supplementary data
Supplementary data (synthetic procedures, and analytical data)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2015.11.068.
of an LDA-mediated cyclization resulted in improved yields; how-
ever hydrolysis occurred in the same manner.
The hydrolyzed ester products of the successful cyclization
reactions were afforded as carboxylate salts and isolated by adjust-
ing the pH of the aqueous phase to acidic. The structure of the
cyclized products was further validated by synthesizing the corre-
sponding methyl esters. Two alternative esterification methods
were performed, one with diazomethane13 in DCM, and the other
one with DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) and MeI
(methyl iodide) in acetonitrile.14
In conclusion we have synthesized four derivatives of the new
heterocyclic ring-system including 4-oxo-1-phenyl-1H,4H-furo
[2,3-c]pyridazine-3-carboxylic acid (18a), methyl 4-oxo-1-phe-
nyl-1H,4H-furo[2,3-c]pyridazine-3-carboxylate (19a), 1-(4-meth-
oxyphenyl)-4-oxo-1H,4H-furo[2,3-c]pyridazine-3-carboxylic acid
(18b), and methyl 1-(4-methoxyphenyl)-4-oxo-1H,4H-furo[2,3-c]
pyridazine-3-carboxylate (19b). Next, we aim to synthesize further
derivatives of this new heterocyclic ring-system that allow its
exploitation in drug discovery projects.
References and notes
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Acknowledgments
The authors are thankful for Judit Beagle (University of Dayton)
for helpful consultation. Furthermore we would like to express our