Synthesis of furo[2,3-d]pyridazin-4(5h)-one and its N(5)-substituted derivatives

Article abstract of DOI:10.1002/hlca.201400042

We report the efficient preparation of furo[2,3-d]pyridazin-4(5H)-one and its N-substituted derivatives starting from methyl 2-methylfuran-3-carboxylate. The Me group was converted to the aldehyde group, which was then condensed with hydrazine derivatives

Full text of DOI:10.1002/hlca.201400042

Helvetica Chimica Acta – Vol. 97 (2014)
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Synthesis of Furo[2,3-d]pyridazin-4(5H)-one and Its N(5)-Substituted
Derivatives
by Emrah Karahana), Gani Kozaa)b), and Metin Balci*a)
a) Department of Chemistry, Middle East Technical University, TR-06800 Ankara
(fax: þ 90-312-2103200; e-mail: mbalci@metu.edu.tr)
b) Department of Chemistry, Ahi Evran University, TR-40100 Kırs¸ehir
We report the efficient preparation of furo[2,3-d]pyridazin-4(5H)-one and its N-substituted
derivatives starting from methyl 2-methylfuran-3-carboxylate. The Me group was converted to the
aldehyde group, which was then condensed with hydrazine derivatives. Then, the ester functionalities
were hydrolyzed to the corresponding acids, followed by treatment with SOCl2 to give N-substituted
furopyridazinone derivatives.
Introduction. – Pyridazinone derivatives are an important class of compounds, and
they have attracted the attention of chemists in recent decades due to their diverse
pharmacological activities [1]. Pyridazinone derivatives show anti-inflammatory,
antimicrobial, antitubercular, and antifungal activities, and some of them are used as
anti-inflammatory drugs. Recently, pyridazinones have also been reported as anti-
convulsant agents [2]. Phthalazinones, with a pyridazinone ring fused to a benzene ring,
are also particularly well-known for their biological activities (for selected recent
literature, see [3]). They are considered as potential anticancer agents, and they are
used in the treatment of autoimmune and inflammatory diseases [4]. Selected examples
of phthalazinone-based drugs, i.e., azelastine (1; histamine antagonist), poly(ADP-
ribose) polymerase-1 (PARP-1) inhibitor 2, and acetohydroxyacid synthase (AHAS)
inhibitor 3, are shown in Fig. 1 [5].
Since a thiophene ring is considered a bioisostere of a benzene ring, the replace-
ment of the benzene moiety in phthalazinones with a thiophene ring results in the
Fig. 1. Structures of some drugs with a phthalazinone core
ꢀ 2014 Verlag Helvetica Chimica Acta AG, Zꢁrich

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formation of thienopyridazinones [6]. There are only a few examples with a thieno-
pyridazinone scaffold in the literature [7]. Recently, it has been shown that thieno-
pyridazinone derivatives play an important role in both thromboxane A2 synthetase
inhibition and bronchodilation [8][9].
Derivatives of furo[2,3-d]pyridazin-4(5H)-one (4) are not well-known. Yamaguchi
et al. synthesized the furo-pyridazinone derivative 5 (Fig. 2), which exhibited a weak
bronchodilatory activity [8]. A fluorinated derivative 6 was recently synthesized by
Sandford and co-workers [9]. Therefore, an efficient synthetic methodology for the
preparation of furo-pyridazinone derivatives substituted at N(5) would be of interest.
Recently, we reported a facile synthesis of aminophthalazinone and aminofuro-
pyridazinone derivatives 7 [10]. Herein, we report a new method for the synthesis of
N(5)-substituted furopyridazinones.
Fig. 2. Structures of some furopyridazinones
Results and Discussion. – For the construction of the furo-pyridazinone skeleton,
first we synthesized methyl 2-methylfuran-3-carboxylate (10) [11] starting from 2-
chloroacetaldehyde (9) and methyl 3-oxobutanoate (8) by applying the procedure for
the synthesis of various substituted furan derivatives [12]. Then, the Me group in 10 was
oxidized to aldehyde 11 [13] by treatment with SeO2 at 1408 in anisole for 18 h. The
desired aldehyde 11 was formed in 40% yield (Scheme 1). All efforts to increase the
yield failed.
With aldehyde 11 in hand, we turned our attention to the synthesis of 12, which was
achieved by the reaction of substituted hydrazine derivatives with 11 at different
temperatures (Scheme 2).
The reactions of 11 with MeNHNH2, PhNHNH2 and (tert-butoxy)carbonyl
hydrazide (BocNHNH2) in THF furnished the hydrazones 12a – 12c, respectively.
Since most substituted phenylhydrazine derivatives are available as their HCl salt, the
condensation with aldehyde 11 did not occur in THF [14]. Therefore, the reaction was
carried out in the presence of pyridine in benzene, and the corresponding hydrazones
12d – 12h were obtained in high yields (Scheme 2). According to the 1H-NMR spectra,
Scheme 1. Synthesis of Methyl 2-Formylfuran-3-carboxylate (11)

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Scheme 2. Synthesis of Hydrazones 12 Derived from 11
(E)- and (Z)-isomers were formed in a ratio of 5 :1. Fortunately, this was not a
problem, since both isomers smoothly underwent cyclization.
After synthesis of various hydrazone derivatives 12a – 12h, we focused on the ring-
closure reaction. When methylhydrazone 12a was reacted with 2m KOH in THF/
MeOH at 408, it underwent a smooth cyclization to give the desired furo-pyridazinone
13a instead of the hydrolysis product, the carboxylic acid (Scheme 3). On the other
hand, treatment of the hydrazone 12b with 2m KOH in THF/MeOH resulted in the
formation of the carboxylic acid 14b. We assume that the initially formed anion of the
hydrazone moiety can be stabilized by the neighboring C¼O group so that the
decreased nucleophilicity of the N-atom hinders the intramolecular cyclization, and
hydrolysis of the ester functionality takes place. Treatment of 14b with SOCl2 at reflux
temperature of THF furnished the parent cyclization product 4, which was synthesized
previously in a multistep process starting from 2,3-dibromofuran [15]. The protecting
group in 13b, (tert-butoxy)carbonyl (Boc), was hydrolyzed during the course of the
reaction.
Finally, for the synthesis of N-phenyl substituted furo-pyridazinone derivatives
13c – 13h, the esters 12c – 12h were hydrolyzed to yield the corresponding carboxylic
acids 14c – 14h, which were then treated with SOCl2 in THF or benzene to give the
target furo-pyridazinone derivatives 13c – 13h in high yields (Scheme 4).
The presented results establish that cyclization of hydrazine derivatives is a
valuable method for the synthesis of fused heterocyclic compounds. We developed a
synthetic method for the construction of new N(5)-substituted furo-pyridazinone
derivatives starting from furancarbaldehyde 11, which can be easily prepared. Ap-

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Scheme 3. Synthesis of Furo[2,3-d]pyridazin-4(5H)-ones 4 and 13a
Scheme 4. Synthesis of Some Furo[2,3-d]pyridazin-4(5H)-one Derivatives 13c – 13h
plication of this methodology to other heterocycles opens up a new way to prepare
new pyridazinone-fused heterocycles.
Conclusions. – We have developed an efficient method for the synthesis of furo-
pyridazinone 6 and its N(5)-subistituted derivatives. The Me group of 10 was oxidized
to 2-formylfuran by treatment with SeO2, and then the aldehyde was coupled with
hydrazine derivatives. As the intramolecular cyclization of acyl chlorides is a valuable
method for the synthesis of heterocyclic compounds, the ester group was converted to
the acyl chloride, followed by spontaneous intramolecular cyclization.

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The authors are indebted to the Scientific and Technological Research Council of Turkey
(TꢀBITAK, Grant 108-M168), the Department of Chemistry at Middle East Technical University,
and the Turkish Academy of Sciences (TUBA) for their financial support of this work. G. K. thanks
TꢀBITAK for a post-doctoral fellowship.
Experimental Part
General. TLC: Merck, 0.2-mm silica-gel 60 F254 anal. aluminum plates. Column chromatography
(CC): silica gel (SiO2, 60 mesh; Merck). M.p.: Thomas-Hoover cap. melting-point apparatus. IR Spectra:
1
Perkin Elmer 980 spectrometer. H- and 13C-NMR spectra: Bruker instrument, at 400 and 100.6 MHz,
resp.; apparent splitting is given in all cases. High-resolution (HR) MS: Agilent Technologies 6224 TOF
LC/MS instrument. Elemental analyses: Leco-932 model CHNS analyzer.
Methyl 2-Methylfuran-3-carboxylate (10) [11a]. 2-Chloroacetaldehyde (9; 45%, 46.5 ml, 322.9 mmol)
was added dropwise to a stirred soln. of methyl 3-oxobutanoate (8; 30.0 g, 258.4 mmol) in pyridine
(100 ml) at r.t., and the resulting mixture was stirred at 508 for 16 h. The reaction was monitored with
TLC. After the completion of the reaction, the mixture was extracted with H2O (200 ml) and AcOEt
(3 ꢀ 200 ml). The combined org. extracts were washed with 2m HCl (250 ml), 5% NaHCO3 (250 ml),
10% NaOH (250 ml), and brine (250 ml), dried (MgSO4), and the solvent was evaporated. The crude
product was purified by CC (SiO2; hexane/AcOEt 4 :1): 10 (23.5 g, 65%). Colorless oil. IR (ATR): 2954,
1819, 1720, 1668, 1438, 1383, 1302, 1120, 1044. 1H-NMR (CDCl3): 7.20 (d, J ¼ 2.0, ¼CH); 6.60 (d, J ¼ 2.0,
¼CH); 3.79 (s, MeO); 2.54 (s, Me). 13C-NMR (CDCl3): 164.4; 159.3; 140.3; 113.2; 110.6; 51.2; 13.6. Anal.
calc. for C7H8O3 (140.14): C 59.99, H 5.75; found: C, 59.76; H, 5.64.
Methyl 2-Formylfuran-3-carboxylate (11) [13]. SeO2 (1.58 g, 14.24 mmol) was added to a stirred soln.
of 10 (1.0 g, 7.14 mmol) in anisole (20 ml), and the resulting mixture was heated at reflux temp. for 18 h.
After the completion of the reaction, the mixture was filtered and washed with H2O (50 ml) and AcOEt
(3 ꢀ 70 ml). Then, the combined org. extract was dried (MgSO4), and the solvent was evaporated. The
crude product was purified by CC (SiO2; hexane/AcOEt 5 :1): 11 (0.44 g, 40%). Yellow solid. M.p. 77 –
788. IR (ATR): 3153, 3130, 3014, 2960, 2882, 2846, 1715, 1671, 1575, 1480, 1435, 1403, 1365, 1303, 1264,
1
1211, 1180. H-NMR (CDCl3): 10.23 (d, J ¼ 0.7, CHO); 7.64 (dd, J ¼ 1.8, 0.7, ¼CH); 6.89 (d, J ¼ 1.8,
¼CH); 3.95 (s, MeO). 13C-NMR (CDCl3): 178.8; 162.0; 152.4; 146.6; 126.2; 112.9; 52.5. Anal. calc. for
C7H6O4 (154.12): C 54.55, H 3.92; found: C 54.33; H 3.91.
General Procedure for the Synthesis of Hydrazone Derivatives 12 [14]. Hydrazine derivative
(6.5 mmol) was added dropwise to a stirred soln. of aldehyde 11 (1.0 g, 6.49 mmol) mmol) in THF
(10 ml), and the resulting soln. was stirred at r.t. for 3 h. The reaction was monitored with TLC. After the
completion of the reaction, the solvent was removed and H2O (30 ml) was added, and the resulting
mixture was extracted with AcOEt (3 ꢀ 30 ml), dried (MgSO4), and evaporated to give the
corresponding hydrazone derivative.
Methyl 2-[(Methylhydrazono)methyl]furan-3-carboxylate (12a). Yellow oil. (0.70 g, 96%). IR
(ATR): 3394, 3210, 2951, 1701, 1589, 1437, 1319, 1290, 1196, 1167, 1058, 1031. 1H-NMR (CDCl3): 7.83 (s,
N¼CH); 7.23 (d, J ¼ 2.0, ¼CH); 6.61 (d, J ¼ 2.0, ¼CH); 6.22 (br. s, NH); 3.76 (s, MeO); 2.94 (s, Me).
13C-NMR (CDCl3): 163.8; 155.4; 141.3; 122.4; 113.1; 111.0; 51.3; 33.7. Anal. calc. for C8H10N2O3 (182.18):
C 52.74, H 5.53; N 15.38; found: C 52.49, H 5.47, N 15.20.
tert-Butyl 2-{[3-(Methoxycarbonyl)furan-2-yl]methylidene}hydrazinecarboxylate (12b). (tert-But-
oxy)carbonyl hydrazide (0.26 g, 1.95 mmol) and 11 (0.3 g, 1.95 mmol) in THF (10 ml) was reacted at 508
for 3 h as described above to give 12b (0.51 g, 98%). Yellow solid. M.p. 122 – 1238. IR (ATR): 3201, 2977,
1701, 1536, 1498, 1367, 1276, 1248, 1154, 1038. 1H-NMR (CDCl3): 8.44 (br. s, NH); 8.28 (br. s, N¼CH);
7.43 (d, J ¼ 1.9, ¼CH); 6.73 (d, J ¼ 1.9, ¼CH); 3.85 (s, MeO); 1.53 (s, Me). 13C-NMR (CDCl3): 163.3;
152.6; 152.3; 143.3; 132.4, 117.7, 111.4; 81.7; 51.8; 28.1. HR-MS: 291.0961 ([M þ Na]þ, C12H16N2NaO5þ
;
calc. 291.0959).
Methyl 2-[(Phenylhydrazono)methyl]-3-furoate (12c). PhNHNH2 (0.64 ml, 6.49 mmol) and 11
(1.0 g, 6.49 mmol) in THF (20 ml) were reacted at r.t. for 2 h as described above to afford 12c (1.5 g,
95%). Yellow solid. M.p. 133 – 1348. IR (ATR): 3275, 3127, 3068, 3022, 2951, 1687, 1587, 1494, 1306, 1254,

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1206, 1170, 1058. 1H-NMR (CDCl3): 8.24 (s, N¼CH); 8.04 (br. s, NH); 7.40 (d, J ¼ 2.0, ¼CH); 7.29 (br. dd,
J ¼ 8.4, 7.4, ¼CH); 7.13 (br. dd, J ¼ 8.4, 1.0, ¼CH); 6.92 (tt, J ¼ 7.4, 1.0, ¼CH); 6.73 (d, J ¼ 2.0, ¼CH); 3.87
(s, MeO). 13C-NMR (CDCl3): 163.7; 154.0; 143.5; 142.4; 129.3; 126.4; 121.0; 115.1; 113.2; 111.4; 51.7.
Anal. calc. for C13H12N2O3 (244.25): C 63.93, H 4.95, N 11.47; found: C 63.81, H 4.94, N 11.29.
Methyl 2-{[(4-Methylphenyl)hydrazono]methyl}furan-3-carboxylate (12d). 4-Methylphenylhydrazi-
nium chloride (0.52 g, 3.24 mmol) in pyridine (0.26 ml, 3.24 mmol) was added to a stirred soln. of
aldehyde 11 (0.5 g, 3.24 mmol) in benzene (30 ml), and the mixture was stirred at r.t. for 3 h. The mixture
was worked up as described above. The product was purified by CC (SiO2; hexane/AcOEt 3 :1) to furnish
12d (0.75 g, 89.5%). Brown solid. M.p. 155 – 1578. IR (ATR): 3282, 2988, 2950, 2913, 1685, 1582, 1530,
1508, 1441, 1304, 1250, 1059, 1038. 1H-NMR (CDCl3): 8.21 (s, N¼CH); 7.96 (br. s, NH); 7.40 (d, J ¼ 1.9,
¼CH); 7.10 (br. d, A of AA’BB’, J ¼ 8.4, ¼CH); 7.04 – 7.02 (br. d, B of AA’BB’, J ¼ 8.4, ¼CH); 6.73 (d,
J ¼ 1.9, ¼CH); 3.86 (s, MeO); 2.29 (s, Me). 13C-NMR (CDCl3): 163.7; 154.2; 142.2; 141.3; 130.4; 129.8;
125.8; 114.7; 113.2; 111.4; 51.6; 20.6. HR-MS: 259.1088 ([M þ H]þ, C14H15N2O3þ ; calc. 259.1084).
Methyl 2-{[(4-Methoxyphenyl)hydrazono]methyl}-3-furoate (12e). 4-Methoxyphenylhydrazinium
chloride (0.28 g, 1.62 mmol) and pyridine (0.13 ml, 1.62 mmol) were added to a stirred soln. of 11 (0.25 g,
1.62 mmol) in benzene (15 ml), and the mixture was stirred at 508 for 2 h. The product was isolated as
described above. The crude product was then purified by CC (SiO2; hexane/AcOEt 3 :1) to give 12e
(0.41 g, 92%). Brown solid. M.p. 127 – 1298. IR (ATR): 3273, 2997, 2951, 2901, 1693, 1584, 1534, 1507,
1439, 1300, 1237, 1134, 1058, 1036. 1H-NMR (CDCl3): 8.20 (s, N¼CH); 7.94 (br. s, NH); 7.39 (d, J ¼ 1.9,
¼CH); 7.07 (br. d, A of AA’BB’, J ¼ 8.2, ¼CH); 6.87 (br. d, B of AA’BB’, J ¼ 8.4, ¼CH); 6.72 (d, J ¼ 1.9,
¼CH); 3.86 (s, MeO); 3.78 (s, Me). 13C-NMR (CDCl3): 163.7; 154.2; 142.1; 137.5; 125.5; 118.7; 114.7;
114.5; 112.0; 111.4; 55.6; 51.6. Anal. calc. for C14H14N2O4 (272.27): C 61.31, H 5.14 N 10.21; found: C
61.32, H 5.14. N, 9.82.
Methyl 2-{[(4-Chlorophenyl)hydrazono]methyl}furan-3-carboxylate (12f). 4-Chlorophenylhydrazi-
nium chloride (0.58 g, 3.24 mmol) in pyridine (0.26 ml, 3.24 mmol) were added to a stirred soln. of 11
(0.5 g, 3.24 mmol) in benzene (30 ml), and the mixture was stirred at 758 for 30 min. The product was
isolated as described above: 12f (0.87 g, 96%). M.p. 152 – 1548. IR (ATR): 3734, 3690, 3279, 2988, 2952,
2900, 1686, 1581, 1527, 1485, 1442, 1266, 1252, 1058, 1039. 1H-NMR (CDCl3): 8.24 (s, N¼CH); 7.99 (br. s,
NH); 7.41 (d, J ¼ 1.9, ¼CH); 7.24 (br. d, A of AA’BB’, J ¼ 8.3, ¼CH); 7.06 (br. d, B of AA’BB’, J ¼ 8.3,
¼CH); 6.74 (d, J ¼ 1.9, ¼CH); 3.86 (s, MeO). 13C-NMR (CDCl3): 163.6; 153.7; 142.6; 142.2; 129.3; 127.0;
125.7; 115.6; 114.3; 111.5; 51.7. Anal. calc. for C13H11ClN2O3: C 56.03, H 3.98, N 9.53; found: C 56.28, H
3.77, N 9.27.
Methyl 2-{[(4-Fluorophenyl)hydrazono]methyl}furan-3-carboxylate (12g). 4-Fluorophenylhydrazi-
nium chloride (0.53 g, 3.24 mmol) and pyridine (0.26 ml, 3.24 mmol) were added to a stirred sol. of 11
(0.5 g, 3.24 mmol) in benzene (15 ml), and the mixture was stirred at r.t. for 2 h. The product was isolated
as described above. 12g (0.77 g, 90%). White solid. M.p. 135 – 1368. IR (ATR): 3278, 3138, 3020, 2955,
1686, 1589, 1534, 1505, 1439, 1272, 1257, 1060, 1039. 1H-NMR (CDCl3): 8.24 (s, N¼CH); 8.06 (br. s, NH);
7.41 (d, J ¼ 1.9, ¼CH); 7.10 – 7.06 (m, ¼CH); 7.03 – 6.97 (m, ¼CH); 6.74 (d, J ¼ 1.9, ¼CH); 3.86 (s, MeO).
13C-NMR (CDCl3): 163.6; 157.8 (d, J ¼ 231.4); 153.9; 142.4; 139.9 (d, J ¼ 1.8); 126.5; 115.9 (d, J ¼ 22.8);
115.2; 114.2 (d, J ¼ 7.5); 111.5; 51.7. Anal. calc. for C13H11FN2O3 (262.24): C 59.54, H 4.23, N 10.68; found:
C 59.16, H 3.97, N,10.25.
Methyl 2-{[(2,4-Difluorophenyl)hydrazono]methyl}furan-3-carboxylate (12h). (2,4-Difluorophen-
yl)hydrazinium chloride (0.48 g, 2.6 mmol) and pyridine (0.21 ml, 2.6 mmol) were added to a stirred soln.
of 11 (0.4 g, 2.6 mmol) in benzene (30 ml), and stirring was continued at 808 for 2 h. The product was
purified by CC (SiO2: hexane/ethyl acetate 4 :1) to yield 12h (0.61 g, 84%). Yellow solid. M.p. 127 – 1298.
IR (ATR): 3304, 2930, 2880, 1707, 1625, 1525, 1503, 1432, 1299, 1256, 1198, 1174, 1137, 1058, 1037.
1H-NMR (CDCl3): 8.32 (s, N¼CH); 8.03 (br. s, NH); 7.57 – 7.51 (m, ¼CH); 7.42 (d, J ¼ 1.9, ¼CH); 6.88 –
6.81 (m, ¼CH); 6.75 (d, J ¼ 1.9, ¼CH); 3.87 (s, MeO). 13C-NMR (CDCl3): 163.5; 156.6 (dd, J ¼ 241.6,
10.9); 153.4; 149.3 (dd, J ¼ 242.8, 11.7); 142.7; 128.7 (dd, J ¼ 9.2, 3.3); 128.5; 116.0; 115.3 (dd, J ¼ 8.8, 3.4);
111.6; 111.5 (dd, J ¼ 22.0, 3.5); 103.7 (dd, J ¼ 26.7, 22.0); 51.7. Anal. calc. for C13H10F2N2O3 (280.23): C
55.72, H 3.60, N 10.00; found: C 56.05, H 3.56, N 9.64.
5-Methylfuro[2,3-d]pyridazin-4(5H)-one (13a [7b]). A soln. of KOH (3.57 ml, 7.14 mmol, 2m) in
MeOH was added to a stirred soln. of 12a (0.65 g, 3.57 mmol) in a mixture of THF (20 ml), MeOH

Helvetica Chimica Acta – Vol. 97 (2014)
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(10 ml), and H2O (1 ml). The mixture was stirred at 408 for 3 h. The solvent was evaporated to give a
crude product, which was then treated with H2O (30 ml). The mixture was extracted with AcOEt (3 ꢀ
50 ml), dried (MgSO4), and concentrated. The product was purified by CC (SiO2; hexane/AcOEt 2 :1):
13a (0.32 g, 60%). White solid. M.p. 107 – 1088. IR (ATR): 3118, 3101, 3054, 3039, 1647, 1575, 1502, 1379,
1274, 1142, 1004. 1H-NMR (CDCl3): 8.18 (d, J ¼ 0.7, N¼CH); 7.67 (d, J ¼ 2.0, ¼CH), 7.04 (dd, J ¼ 2.0, 0.7,
¼CH); 3.85 (s, Me). 13C-NMR (CDCl3): 158.9; 153.0; 146.6; 126.0; 122.6; 107.2; 39.6. Anal. calc. for
C7H6N2O2 (150.13): C 56.00, H 4.03, N 18.66; found: C 55.98; H 4.04, N 18.49.
2-({[(tert-Butoxy)carbonyl]hydrazono}methyl)furan-3-carboxylic Acid (14b). A soln. of KOH
(1.96 ml, 3.92 mmol, 2m) in MeOH (10 ml) was added to a stirred soln. of 12b (0.52 g, 1.94 mmol) in THF
(10 ml), MeOH (5 ml), and H2O (0.5 ml). The mixture was stirred at 808 for 3 h (TLC monitoring).
After the completion of the reaction, the solvent was removed to give the crude product, which was then
treated with H2O (50 ml). The aq. phase was extracted with AcOEt (2 ꢀ 50 ml) and acidified with 1m HCl
to pH 2, and then extracted with AcOEt (3 ꢀ 50 ml) and H2O. The combined org. extract was washed
with H2O, dried (MgSO4), and concentrated to give 14b (0.43 g, 87%). Brown solid. M.p. 164 – 1658. IR
1
(ATR): 3100, 2978, 2930, 1696, 1669, 1483, 1440, 1391, 1280, 1162, 1050, 1035. H-NMR ((D6)DMSO):
13.03 (br. s, COOH); 11.19 (s, NH); 8.47 (s, N¼CH); 7.81 (d, J ¼ 1.9, ¼CH); 6.78 (d, J ¼ 1.9, ¼CH); 1.45
(s, Me). 13C-NMR ((D6)DMSO): 163.7; 152.3; 152.2; 144.3; 132.6; 118.6; 112.2; 80.1; 28.1. Anal. calc. for
C11H14N2O5 (254.24): C 51.97, H 5.55, N 11.02; found: C 51.69 H, 5.40, N 10.64.
Furo[2,3-d]pyridazin-4(5H)-one (4) [7b]. To a stirred soln. of 14b (0.27 g, 1.06 mmol) in THF
(10 ml) was added SOCl2 dropwise (0.15 ml, 2.12 mmol), and the resulting mixture was stirred at reflux
temp. overnight. After the completion of the reaction (TLC monitoring), the solvent was evaporated,
and the crude product was purified by CC (SiO2; AcOEt/hexane 1:1) to give 4 (0.1 g, 69%). White solid.
1
M.p. 203 – 2048. IR (ATR): 3155, 3128, 3101, 2970, 2922, 1655, 1572, 1501, 1422, 1380, 1183. H-NMR
((D6)DMSO): 12.93 (br. s, NH); 8.53 (d, J ¼ 0.7, N¼CH); 8.20 (d, J ¼ 2.0, ¼CH); 7.13 (dd, J ¼ 2.0, 0.7,
¼CH). 13C-NMR ((D6)DMSO): 159.3; 153.0; 147.9; 127.2; 122.1; 106.5. Anal. calc. for C6H4N2O2
(136.11): C 52.95, H 2.96, N 20.58; found: C 52.72, H 3.09, N 20.15.
General Procedure for the Hydrolysis of Hydrazone Derivatives (12c – 12h). A soln. of KOH (0.97 –
2.7 ml, 2 mol-equiv., 2m) in MeOH was added to a stirred soln. of 12c – 12h (0.24 – 0.76 g) in THF (10 –
20 ml), MeOH (5 – 10 ml), and H2O (0.5 – 1 ml). The mixture was stirred at appropriate temp. (TLC
monitoring). After the completion of the reaction, the solvent was removed to give the crude product,
which was then treated with H2O (50 ml). The aq. phase was extracted with AcOEt (3 ꢀ 50 ml), and
acidified with 1m HCl to pH 2, and then extracted with AcOEt (3 ꢀ 50 ml) and H2O. The combined org.
extract was washed with H2O, dried (MgSO4), and concentrated to give the acid 14c – 14h.
2-[(Phenylhydrazono)methyl]furan-3-carboxylic Acid (14c). Compound 12c (0.66 g, 2.70 mmol)
was hydrolyzed at r.t. for 3 h as described above: 14c (0.57 g, 92%). Brown solid. M.p. 196 – 1978. IR
(ATR): 3301, 3124, 2997, 2874, 2676, 2573, 1670, 1583, 1498, 1277, 1255, 1130, 1050. 1H-NMR
((D6)DMSO): 12.88 (br. s, COOH); 10.88 (s, NH); 8.36 (s, N¼CH); 7.73 (d, J ¼ 1.9, ¼CH); 7.23 (br. t, J ¼
8.4, ¼CH); 7.04 (br. d, J ¼ 8.6, ¼CH); 6.80 (br. t, J ¼ 7.3, ¼CH); 6.75 (d, J ¼ 1.9, ¼CH). 13C-NMR
((D6)DMSO): 164.0; 153.7; 144.4; 142.8; 129.1; 125.9; 119.6; 115.1; 112.3; 111.7. Anal. calc. for
C12H10N2O3 (230.22): C 62.60, H 4.38, N 12.17; found: C 62.21, H 4.40, N 11.82.
2-{[(4-Methylphenyl)hydrazono]methyl}furan-3-carboxylic Acid (14d). The ester 12d (0.24 g,
0.93 mmol) was hydrolyzed at r.t. for 6 h as described above. 14d (0.20 g, 88%). Brown solid. M.p.
188 – 1908. IR (ATR): 3725, 3690, 3293, 2988, 2900, 2565, 1670, 1581, 1508, 1434, 1308, 1271, 1252, 1051,
1024. 1H-NMR ((D6)DMSO): 12.89 (br. s, COOH); 10.85 (s, NH); 8.37 (s, 1 H); 7.77 (d, J ¼ 1.9, N¼CH);
7.12 – 7.10 (br. d, A of AA’BB’, J ¼ 8.0, ¼CH); 7.02 – 7.00 (br. d, B of AA’BB’, J ¼ 8.0, ¼CH); 6.80 (d, J ¼
1.9, ¼CH); 2.27 (s, Me). 13C-NMR ((D6)DMSO): 164.1; 153.9; 142.6; 142.1; 129.5; 128.3; 125.2; 114.8;
112.4; 111.7; 20.2. Anal. calc. for C13H12N2O3 (244.25): C 63.93, H 4.95, N 11.97; found: C 63.54, H 4.85, N
11.62.
2-{[(4-Methoxyphenyl)hydrazono]methyl}furan-3-carboxylic Acid (14e). The ester 12e (0.26 g,
0.95 mmol) was hydrolyzed at reflux temp. for 18 h as described above: 14e (0.22 g, 89%). Brown solid.
M.p. 169 – 1718. IR (ATR): 3735, 3690, 3649, 2988, 2900, 2837, 1693, 1506, 1454, 1405, 1237, 1191, 1079,
1038. 1H-NMR ((D6)DMSO): 12.75 (br. s, COOH); 10.73 (s, NH); 8.29 (s, N¼CH); 7.70 (d, J ¼ 1.9,
¼CH); 7.00 – 6.98 (br. d, A of AA’BB’, J ¼ 7.9, ¼CH); 6.87 – 6.84 (br. d, B of AA’BB’, J ¼ 7.9, ¼CH); 6.74

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Helvetica Chimica Acta – Vol. 97 (2014)
(d, J ¼ 1.9, ¼CH); 3.69 (s, MeO). 13C-NMR ((D6)DMSO): 164.0; 154.0; 153.2; 142.5; 138.3; 124.6; 114.6;
114.3; 113.4; 111.6; 55.2. Anal. calc. for C13H12N2O4 (260.25): C 60.00, H 4.65, N 10.76; found: C 60.01, H,
4.65, N 10.43.
2-{[(4-Chlorophenyl)hydrazono]methyl}furan-3-carboxylic Acid (14f). The ester 12f (0.76 g,
2.73 mmol) was hydrolyzed at reflux temp. for 18 h as described above: 14f (0.57 g, 79%). Brown
solid. M.p. 198 – 2008. IR (ATR): 3734, 3675, 3231, 3174, 3100, 2988, 2900, 1697, 1582, 1488, 1418, 1266,
1194, 1075. 1H-NMR ((D6)DMSO): 12.93 (br. s. COOH); 10.99 (s, NH); 8.36 (s, N¼CH); 7.75 (d, J ¼ 1.9,
¼CH); 7.29 – 7.25 (br. d, A of AA’BB’, J ¼ 8.1, ¼CH); 7.06 – 7.02 (br. d, B of AA’BB’, J ¼ 8.1, ¼CH); 6.76
(d, J ¼ 1.9, ¼CH). 13C-NMR ((D6)DMSO): 164.0; 153.4; 143.3; 143.1; 128.9; 126.6; 122.9; 115.6; 113.7;
111.8. Anal. calc. for C12H9ClN2O3 (264.66): C 54.46, H 3.43, N 10.58; found: C 54.33, H 3.43, N 10.19.
2-{[(4-Fluorophenyl)hydrazono]methyl}furan-3-carboxylic Acid (14g).The ester 12g (0.69 g,
2.63 mmol) was hydrolyzed at 758 for 6 h as described above: 14g (0.49 g, 75%). Brown solid. M.p.
199 – 2008. IR (ATR): 3241, 3213, 3041, 2961, 2562, 1696, 1556, 1505, 1455, 1316, 1223, 1189, 1076, 1025.
1H-NMR ((D6)DMSO): 12.87 (br. s, COOH); 10.89 (s, NH); 8.34 (s, N¼CH); 7.73 (d, J ¼ 1.9, ¼CH);
7.11 – 7.01 (m, ¼CH); 6.75 (d, J ¼ 1.9, ¼CH). 13C-NMR ((D6)DMSO): 164.1; 156.4 (d, J ¼ 234.9); 153.7;
142.9; 141.0 (d, J ¼ 1.0); 125.9; 115.7 (d, J ¼ 22.5); 115.2; 113.4 (d, J ¼ 7.6); 111.8. Anal. calc. for
C12H9FN2O3 (248.21): C 58.07, H 3.65, N 11.29; found: C 58.16, H 3.87, N 10.91.
2-{[(2,4-Difluorophenyl)hydrazono]methyl}furan-3-carboxylic Acid (14h). The ester 12h (0.50 g,
1.78 mmol) was hydrolyzed at 508 for 4 h as described above: 14h (0.35 g, 74%). Brown solid. M.p. 241 –
1
2438. IR (ATR): 3363, 3002, 2970, 2571, 1738, 1679, 1595, 1506, 1441, 1365, 1216, 1204, 1136. H-NMR
((D6)DMSO): 12.91 (br. s, COOH); 10.77 (s, NH); 8.60 (s, N¼CH); 7.75 (d, J ¼ 1.9, ¼CH); 7.41 (dt, J ¼
6.0, 9.3, ¼CH); 7.22 (ddd, J ¼ 11.8, 8.9, 2.8, ¼CH); 7.03 – 6.98 (br. t, J ¼ 8.6, ¼CH); 6.76 (d, J ¼ 1.9, ¼CH).
13C-NMR ((D6)DMSO): 163.9; 155.3 (dd, J ¼ 238.0, 10.9); 153.3; 148.7 (dd, J ¼ 243.7, 12.2); 143.2; 129.7
(dd, J ¼ 9.9, 3.0); 128.7; 116.1; 114.4 (dd, J ¼ 8.9, 4.2); 111.9; 111.5 (dd, J ¼ 22.0, 3.3); 103.9 (dd, J ¼ 27.0,
22.3). Anal. calc. for C13H12N2O3 (266.20): C 63.93, H 4.95, N 11.97; found: C 63.54, H 4.85, N 11.45.
General Procedure for the Synthesis of Furo-pyridazinone Derivatives 13c – 13h. SOCl2 (0.15 –
0.28 ml, 2 mol equiv.) was added dropwise to a stirred soln. of acid 14c – 14h (0.27 – 0.44 g, 1.02 –
1.91 mmol) in THF (20 ml), and the mixture was stirred at reflux temp. for 18 h (TLC monitoring).
After the completion of the reaction, the solvent and excess SOCl2 were evaporated, and the crude
product was purified by CC (SiO; hexaneAcOEt) to give 13c – 13h.
5-Phenylfuro[2,3-d]pyridazin-4(5H)-one (13c). The acid 14c (0.46 g, 2 mmol) was reacted as
described above: 13c (0.38 g, 93%). White solid. M.p. 93 – 948. IR (ATR): 3156, 3105, 3057, 1674, 1581,
1493, 1456, 1379, 1297, 1266, 1152, 1116. 1H-NMR (CDCl3): 8.35 (d, J ¼ 0.7, N¼CH); 7.73 (d, J ¼ 1.9,
¼CH); 7.58 (m, ¼CH); 7.49 (m, ¼CH); 7.40 (tt, J ¼ 7.4, 1.2, ¼CH); 7.13 (dd, J ¼ 1.9, 0.7, ¼CH). 13C-NMR
(CDCl3): 158.4; 152.6; 146.9; 141.7; 128.8; 128.1; 127.0; 126.0; 123.5; 107.8. Anal. calc. for C12H8N2O2
(212.20): C 67.92, H 3.80, N 13.20; found: C 67.88, H 3.72, N 12.96.
5-(4-Methylphenyl)furo[2,3-d]pyridazin-4(5H)-one (13d). The acid 14d (0.46 g, 1.88 mmol) was
reacted as described above. CC was performed with hexane/AcOEt (2 :1). 13d (0.29 g, 68%). White
powder. M.p. 92 – 948. IR (ATR): 3113, 3042, 2987, 2901, 1681, 1584, 1498, 1380, 1296, 1274, 1152, 1119,
1
1062, 1024. H-NMR (CDCl3): 8.33 (d, J ¼ 0.6, N¼CH); 7.73 (d, J ¼ 2.0, ¼CH); 7.46 – 7.43 (br. d, A of
AA’BB’, J ¼ 8.3, ¼CH); 7.31 – 7.27 (br. d, B of AA’BB’, J ¼ 8.3, ¼CH); 7.13 (dd, J ¼ 2.0, 0.6 ¼CH); 2.41 (s,
Me). 13C-NMR (CDCl3): 158.5; 152.6; 146.8; 139.2; 138.0; 129.4; 126.9; 125.8; 123.4; 107.8; 21.1. Anal.
calc. for C13H10N2O2 (226.23): C 69.02, H 4.46, N 12.38 found: C 68.72, H 4.48, N 11.99.
5-(4-Methoxyphenyl)furo[2,3-d]pyridazin-4(5H)-one (13e). The acid 14e (0.30 g, 1.15 mmol) was
reacted as described above. CC was performed with hexane/AcOEt (3 :1). 13e (0.21 g, 75%). White
powder. M.p. 116 – 1188. IR (ATR): 3145, 2965, 2900, 1680, 1509, 1498, 1252, 1173, 1143, 1110, 1058, 1032,
1011. 1H-NMR (CDCl3): 8.33 (d, J ¼ 0.7, N¼CH); 7.73 (d, J ¼ 2.0, ¼CH); 7.50 – 7.46 (br. d, A of AA’BB’,
J ¼ 8.1, ¼CH); 7.12 (dd, J ¼ 2.0, 0.7, ¼CH); 7.02 – 6.98 (br. d, B of AA’BB’, J ¼ 8.1, ¼CH); 3.85 (s, Me).
13C-NMR (CDCl3): 159.1; 158.6; 152.6; 146.9; 134.6; 127.1; 126.9; 123.4; 114.0; 107.8; 55.5. Anal. calc. for
C13H10N2O3 (242.23): C 64.46, H 4.16, N 11.56; found: C 64.03, H 4.20, N 11.23.
5-(4-Chlorophenyl)furo[2,3-d]pyridazin-4(5H)-one (13f). The acid 14f (0.27 g, 1.02 mmol) was
reacted as described above. 13f (0.23 g, 92%). White solid. M.p. 166 – 1888. IR (ATR): 3152, 3105, 2929,
1679, 1490, 1380, 1301, 1259, 1141, 1108, 1088, 1013. 1H-NMR (CDCl3): 8.35 (d, J ¼ 0.6, N¼CH); 7.74 (d,

Helvetica Chimica Acta – Vol. 97 (2014)
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J ¼ 2.0, ¼CH); 7.58 – 7.54 (m, A of AA’BB’, ¼CH), 7.48 – 7.44 (m, B of AA’BB’, ¼CH), 7.13 (dd, J ¼ 2.0,
0.6, ¼CH). 13C-NMR (CDCl3): 158.3; 152.6; 147.1; 140.1; 133.8; 128.9; 127.4; 127.2; 123.5; 107.8. Anal.
calc. C12H7ClN2O2 (246.65): C 58.43, H 2.86, N 11.36; found: C 58.79, H 2.81, N 11.02.
5-(4-Fluorophenyl)furo[2,3-d]pyridazin-4(5H)-one (13g). The acid 14g (0.4 g, 1.61 mmol) was
reacted as described above. CC was performed with hexane/AcOEt (2 :1). 13g (0.26 g, 70%). White
powder. M.p. 122 – 1238. IR (ATR): 2922, 1739, 1688, 1507, 1496, 1381, 1262, 1216, 1141, 1106, 1060, 1012,
1012. 1H-NMR (CDCl3): 8.35 (d, J ¼ 0.6, N¼CH); 7.74 (d, J ¼ 2.0, ¼CH); 7.59 – 7.54 (m, A of AA’BB’X,
¼CH); 7.20 – 7.15 (m, B of AA’BB’X, ¼CH); 7.13 (dd, J ¼ 2.0, 0.6, ¼CH). 13C-NMR (CDCl3): 163.2; 159.6
(d, J ¼ 228.3); 152.6; 147.1; 137.6 (d, J ¼ 3.2); 127.8 (d, J ¼ 8.5); 127.2; 123.5; 115.7 (d, J ¼ 22.8); 107.8.
Anal. calc. for C12H7FN2O2 (230.19) C 62.61, H 3.07, N 12.17: found: C 62.44, H 3.00, N 12.05.
5-(2,4-Difluorophenyl)furo[2,3-d]pyridazin-4(5H)-one (13h). The acid 14h (0.3 g, 1.13 mmol) was
reacted as described above. CC was performed with hexane/AcOEt (3 :2). 13h (0.20 g, 70%). White
powder. M.p. 183 – 1858. IR (ATR): 3059, 2988, 2900, 1683, 1614, 1510, 1497, 1253, 1147, 1056. 1H-NMR
(CDCl3): 8.35 (d, J ¼ 0.6, N¼CH); 7.76 (d, J ¼ 2.0, ¼CH); 7.43 (dt, J ¼ 9.3, 5.7, ¼CH); 7.13 (dd, J ¼ 2.0, 0.6,
¼CH); 7.05 – 6.98 (m, ¼CH). 13C-NMR (CDCl3): 162.7 (dd, J ¼ 251.1, 10.9); 158.0; 157.6 (dd, J ¼ 255.5,
12.7); 152.7; 147.1; 129.9 (dd, J ¼ 10.2, 1.7); 127.7; 125.7 (dd, J ¼ 12.8, 3.7); 123.1; 111.7 (dd, J ¼ 22.6, 3.6);
107.7; 105.0 (dd, J ¼ 26.3, 23.8). Anal. calc. for C12H6F2N2O2 (248.19): C 58.07, H 2.44, N 11.29; found: C
57.66, H 2.35, N 11.07.
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Received February 3, 2014