A facile method for the synthesis of 6-aryl-1-(3-chloropropanoyl)-4-[(E)-1- (2-furyl)methylidene)]-1,2,3,4-tetrahydr o-3-pyridazinones and 2-(2-chloroethyl)-5-[α-aracyl-β-(2-furyl)]-(E )-vinyl-1,3, 4-oxadiazoles

Article abstract of DOI:10.3390/50600895

The 6-aryl-1-(3-chloropropanoyl)-4-[(E)-1-(2-furyl)methylidene)]-1,2,3,4- tetra-hydro-3-pyridazinones (6a-d) were synthesized by the reaction of acid chloride 3 with α-aracyl(β-2-furyl)acrylic acid hydrazides (2a-d) in a high yield, one pot reaction. On the other hand, 2-(2-chloroethyl)-5-[α- aracyl-β-(2-furyl)]-(E)-vinyl-1,3,4-oxadiazoles (7a-d) were also prepared by cyclodehydration of N¹[α-aracyl-β-(2-furyl)acroyl- N²[3-chloro-propanoyl] hydrazine derivatives (4a-d). The proposed structures of the products were confirmed by elemental analysis, spectral data and chemical evidence.

Full text of DOI:10.3390/50600895

Molecules 2000, 5, 895-907
molecules
ISSN 1420-3049
http://www.mdpi.org
A Facile Method for the Synthesis of
6-Aryl-1-(3-Chloropropanoyl)-4-[(E)-1-(2-Furyl)Methylidene)]-
1,2,3,4-Tetrahydro-3-Pyridazinones and 2-(2-Chloroethyl)-5-
[a-Aracyl-b-(2-Furyl)]-(E)-Vinyl-1,3,4-Oxadiazoles
Abdel-Sattar S. Hamad* and Ahmed I. Hashem
Department of Chemistry, Faculty of Science, University of Ain Shams, Abbassia 11566, Cairo, Egypt
Tel.: +20 (2) 4831836, Fax: +20 (2) 4831836, E-mail: hamad@asunet.shams.eun.eg
Received: 19 January 2000; revised form: 5 June 2000 / Accepted: 22 June 2000 / Published: 27 June 2000
Abstract: The 6-aryl-1-(3-chloropropanoyl)-4-[(E)-1-(2-furyl)methylidene)]-1,2,3,4-tetra-
hydro-3-pyridazinones (6a-d) were synthesized by the reaction of acid chloride 3 with a-
aracyl(b-2-furyl)acrylic acid hydrazides (2a-d) in a high yield, one pot reaction. On the other
hand, 2-(2-chloroethyl)-5-[a-aracyl-b-(2-furyl)]-(E)-vinyl-1,3,4-oxadiazoles (7a-d) were
also prepared by cyclodehydration of N1[a-aracyl-b- (2-furyl)acroyl-N2[3-chloro-propanoyl]
hydrazine derivatives (4a-d). The proposed structures of the products were confirmed by
elemental analysis, spectral data and chemical evidence.
Keywords: 2(3H)-Furanone, 3-Oxopyridazines, dihydropyridazines, 1,3,4-Oxadiazoles.
Introduction
We have previously reported [1,2] a synthetic approach to 5-aryl-3-furfurylidene-2-(3H)-furanones
(1) via the condensation reactions of furan-2-carboxaldehyde with 3-aroylpropionic acids under Perkin
conditions, which yield the corresponding E-lactones as the only product, with no detectable amount of
1
the Z-isomers being identified by TLC and H NMR [3]. This result was consistent with the reports of
Awad et al. [5] and others' [6,7] concerning the condensation reaction of 5-methyl-furan-2-carbox-
aldehyde and/or 5-methyl thiophene-2-carboxaldehyde with 3-aroylpropionic acids under Perkin condi-
© 2000 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.

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Molecules 2000, 5
tions. The conversion of these 2(3H) furanones into benzofuran derivatives [1] and 5-oxo-2-pyrrolines
[4] have also been described by one of us.
Dihydropyridazinone rings are of chemical and biological interest, having been reported as having
antihypertensive activity [8]. In addition, Nannini et al. [9] has established that the pyridazinones display
analgesic and anti-inflammatory activities. On the other hand, 1,3,4-oxadiazoles and N2(acyl)-benzoic
hydrazides are reported to exhibit carcinostatic activity against several types of tumors [10] and antimi-
crobial effects against Mycobacterium tuberculosis and Mycobacterium lapreae [11]. The amino-3-
substituted propyl functionality is found in many compounds having vasodilator, antispasmodic, blood
platelet aggregation inhibition [12], antiarrhythmic [13] and anticholesterolesmic [14] activities.
This reported biological importance of 2(3H)-furanones, 4,5-dihydropyridazinones and 1,3,4-
oxadiazoles prompted us to attempt the conversion of 2(3H)-furanones (1a-d) into heterocyclic systems
of potential synthetic and biological importance, for example, the acrylic acid hydrazides (2a-d), 3-
pyridazinones (6a-d), N1[a-aracyl-b- (2-furyl)acroyl-N2[3-chloro propanoyl]hydrazine (4a-d) and 1,3,4-
oxadiazole derivatives (7a-d), dihydropyridazinones (8a-d).
Results and Discussion
We report here a simple method for the synthesis of 6-aryl-1-(3-chloropropanoyl)-4-[(E)-1-(2-
furyl)methylidene)]-1,2,3,4-tetrahydro-3-pyridazinones (6a-d) and 2-(2-chloroethyl)-5-[a-aracyl-b-(2-
furyl)]-(E)-vinyl-1,3,4-oxadiazoles (7a-d) in good yields via the interaction of hydrazides (2a-d) with
acid chloride (3) and POCl3 in a one pot reaction.
In this investigation, hydrazides (2a-d) proved to be useful precursors in the synthesis of several het-
erocyclic systems. When the 2(3H)furanones (1a-d) were allowed to react with hydrazine hydrate in
ethanol, ring opening occurs with the formation of the E-isomers of a-aracyl-b- (2-furyl)acrylic acid
hydrazides (2a-d) as the only products. There was no detectable amount of the corresponding Z-
isomers according to 1H NMR [3]. The configurational structures of the 2(3H)-furanones (1a-d) as E-
1
13
isomers were confirmed by H and C NMR, as illustrated in Tables 2 and 4. The infrared spectra of
-1
these products (2a-d) (cf. Table 1) show an absorption band at 3199.7-3104.2-3331 cm (broad band)
-1
-1
characteristic of the NH group, and bands at 1648-55 cm and 1668-97 cm for uC=O, characteristic
of the amide carbonyl and ketone groups, respectively. On heating the hydrazides (2a-d) in 1.0 N HCl
for 30-60 min, ring closure occurs, leading to the formation of the corresponding 3(2H)-pyridazinones,
namely the 6-aryl-4-furylmethyl-3(2H)-pyridazinones (8a-d). The infrared spectra of compounds (8a-d)
-1
(cf. Table 1) show a broad absorption band at 3150-3300 cm characteristic of the NH group and an
-1
absorption band at 1654-60 cm for uC=O, characteristic of the amide carbonyl group. The infrared
spectra of these compounds are similar to those reported for other pyridazinone derivatives [15-18].
The 1H NMR spectra of compounds (2a-d) exhibit singlet signals at 4.41 for (CH2COAr), a singlet at
d 6.67 for olefinic protons, triplet signals at d 7.07 for (-NH-NH2) and two signals dd for (-NH-NH2)
due to the strong electrical quadrupole moment effect [19]. In compounds (8a-d) the CH2 adjacent to

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Molecules 2000, 5
the furan ring exhibited a singlet at d 3.92, the olefinic proton of the unsaturated double bond showed a
doublet signal at d 7.56 and the (-NH-) group a singlet at d13.23 ppm.
The interaction of a-aracyl-b-(2-furyl)acrylic acid hydrazides (2a-d) with 3-chloropropanoyl chloride
(3) was studied also under different conditions at 0-15oC and 80oC. When the reaction took place at 0-
15oC over 4-5 h, it gave a 85% yield of N1[a-aracyl-b- (2-furyl)acroyl-N2[3-chloropropanoyl]-hydrazine
compounds (4a-d), but when the reaction took place at 80oC over 30-60 min, HCl was liberated to give
an 80-92% yield of 6-aryl-1-(3-chloropropanoyl)-4-[(E)-1-(2-furyl)methylidene)]-1,2,3,4-tetrahydro-3-
pyridazinones (6a-d) as illustrated in Scheme 1.
O
NH
O
N
Ar
vi
8
Ar
O
O
i
ii
O
NH
N
O
O
NHNH
O
Cl
2
Cl
Cl
O
Ar
O
Ar
O
3
O
2
1
6
iii
v
Cl
Cl
O
O
3
Ar
N N
O
O
H
N
Cl
iv
H
O
Ar
v
O
N N
Cl
N
Cl
O
O
O
H
O
O
Ar
7
4
5
Ar = a = C H , b = C H CH (P), c = C H OCH (P), d = C H Cl (P)
6
5
6
4
3
6
4
3
6 4
Scheme 1. Reagents and conditions: i) NH NH . H O/ethanol, stirring at RT for 2 days: ii) Benzene,
2
2
2
o
heat/30-60 mins; iii) benzene , stirring at 0-15 C for 4-5hrs.; iv) heating with POCl for 1h.; v) Benzene, heat
3
with 1.0 N HCl for 30-60 mins; vi) Stirred and heating with 1.0 N HCl in benzene for 1h.
Scheme 1.
In a parallel experiment using benzene solvent in the presence of acid catalyst (1.0 N HCl) at 80oC
the hydrazine compounds (4a-d) cyclised and only formation of products (6a-d) was noted, as evi-
denced by TLC after 1h. We believe the liberation of HCl aided the ring closure of the hydrazine de-
rivatives compounds (4a-d) under the reaction conditions at 80oC to provide compounds (6a-d). These

898
Molecules 2000, 5
compounds were shown by direct comparison (m.p and mixed m.p) and also by TLC to be identical in
all aspects with the authentic products obtained by the action of 1.0 N HCl in benzene solvent with
N1[a-aracyl-b- (2-furyl)acroyl-N2[3-chloropropionyl]hydrazine compounds (4a-d). Acid catalysis
proved to be essential and reaction was essentially complete after 30-60 min at 80oC (ca. 92% yield).
1
The H NMR spectra of (4a-d) exhibited singlet signals for the CH2 protons at d 4.41 ppm and also
show two doublet signals at 9.8 and 10.11 ppm for the hydrazine (-NH-NH-) group.
The alternative mode of ring closure of N1[a-aracyl-b- (2-furyl)acroyl-N2[3-chloropropionyl]-
hydrazine compounds (4a-d), that is attack by the N1, would lead to the formation of the corresponding
N-(3-chloropropionyl)aminopyrrolines (5a-d) as intermediates. But these N-aminopyrrolines (5) are not
formed, and the pyridazinones (6a-d) are the only isolable products obtained from this reaction. We be-
lieve that the N-aminopyrrolines (5a-d) are unstable under the acid catalyzed reaction conditions and if
formed, they might undergo ring expansion [1b] yielding the corresponding 3(2H) pyridazinones (6a-d).
This behavior is in accordance with the reported rearrangements of N-aminophthalimides in acid me-
dium to the corresponding phthalaza-1,4-diones [15]. The structure of compounds (6a-d) was con-
1
firmed by H NMR (300 MHz), microanalysis and infrared spectral data. The IR spectra show an ab-
-1
sorption band for the uC=O stretching vibrations of cyclic carboxamides at 1666-1678 cm , character-
-1
istic of the 3(2H) pyridazinone ring, and in the 1725-1733 cm region for the C=O of the open alkyl-
-1
carboximide, as well as a broad band at 3227-3337 cm characteristic of the NH group. The spectra of
compounds (6a-d) (cf, Table 1) are similar to those of 1-benzoyl-6-aryl-4-thienylidene-1,6-
1
13
dihydropyridazin-3-(2H)ones [20]. The H and C NMR data showed evidence for the formation of a
bicyclic structure as shown in Tables 2 and 3. In compounds (6a-d), as expected, the two olefins (=C-
1
13
H) have different chemical shifts both in the H and C NMR spectra. These highly conjugated struc-
tures show a typical two singlet signal for the C-H in the 1H NMR spectrum at d 6.6-6.7 and 7.08-7.13
for CH=C-Ar and Fur-CH=C- respectively, because in the case of Fur-CH=C- there is a long range
coupling with the furan-H and this evidence can be obtained from the coupling constants between H(7)
and furan-H(9) as illustrated in Table 2. Further evidence to support our assignments was obtained from
the 13C NMR spectrum of compound (6b) that showed the carbons of the highly conjugated system at
C(5) and C(7) to be at d 118.7 and 126.25 respectively as shown in Table 3. It is clear also from the 1H
NMR spectrum of the compounds (6a-d) that in the ClCH2CH2CO- system, the CH2 adjacent to the
carbonyl appears as a triplet at d 3.722 ppm and the other CH2 adjacent to the chlorine nuclei are com-
pletely decoupled from directly attached protons, and appear as two triplet signals at 2.54-2.77 ppm,
due to the strong electrical quadrupole moment effect [19].

899
Molecules 2000, 5
6b
Figure 1. MM2 Calculations for compound 6b.
Steric Energy
Minimize Energy
0.7590
Stretch:
14.1377
14.7873
-0.7962
-3.2895
37.3133
10.1824
Stretch:
Bend:
Bend:
15.6902
0.0215
-6.0891
-5.2474
9.1168
-5.3897
Stretch-Bend:
Torsion:
Stretch-Bend:
Torsion:
Non-1,4 VDW:
1,4 VDW:
Non-1,4 VDW:
1,4 VDW:
Dipole/Dipole:
Dipole/Dipole:-3.8562
Total steric energy for structure (6b):
Total of the minimum energy for the structure
68.479 kcal/mole
(6b): 8.8612 kcal/mol
Another piece of evidence to support our assignment the structure of compound (6b) was obtained
through MM2 calculations for the minimum and total steric energy, as illustrated in Figure 1. It is im-
portant to point out that we have examined steric energies from 68.479 kcal/mole to the lowest energy
structure at 8..86 kcal/mole over 392 iterations. Minimization terminated normally because the gradient
norm was less than the minimum gradient norm.
The interaction of hydrazides (2a-d) with POCl3 provided 2-(b-chloroethyl)-5-[a-aracyl-b-(2-
furyl)](E)-vinyl-1,3,4-oxadiazoles (7a-d) as the only products in 75-83% yield.. The infrared spectra
-1
(IR) of these products (cf. Table 1) show an absorption band at 1695-1698 cm for uC=O, character-
1
istic of the ketone carbonyl group, and 1578-1617 cm-1 for uC=N. The H NMR spectrum of com-
pounds (7a-d) exhibit singlet signals at d 4.37 for (CH2COAr) and a singlet signal at d 6.65 for the ole-
finic proton and the disappearance the signals of the hydrazo group as illustrated in Table 2.

900
Molecules 2000, 5
Table 1. Infrared (IR) and 1H NMR (300 MHz) spectral data for compounds 1a-8d.
Infrared bands (IR)umax
Cpd
No
Aryl
group
1H NMR (300 MHz, DMSO); dH [2H6] DMSO
-1
(Nujol)/ cm
u
u
u
-NH
C=O
-C=N
d = 6.78 (dd, 1H, J = 1.8, 3.6 Hz, furan-H4), 7.20 (s, 1H, -
CH=C-Ar), 7.25 (d, 1H, J = 3.3 Hz, furan-H3), 7.40 (d, 1H, J =
0.6 Hz, fur-C=CH-), 7.48-7.50 (m, 3H, Ph-H), 7.80-7.84 (dd, 2H,
J = 2.1, 7.8 Hz, Ph-Ho), 8.04 (d, J = 1.5 Hz, furan-H5) ppm.
d = 2.32 (s, 3H, Ar-Me), 6.72 (q, 1H, J = 1.8, 3.6 Hz, furan-H4),
7.08 (s, 1H, -CH=C-Ar), 7.17 (d, 1H, J = 3 Hz, furan-H3), 7.22
(d, 2H, J = 8.7 Hz, Ar-H), 7.27 (s, 1H, fur-C=CH-), 7.48 (d, 2H,
J = 8.7 Hz, Ar-H), 7.98 (d, 1H, J = 1.5 Hz, furan-H5) ppm.
d = 3.82 (s, 3H, Ar-OMe), 6.76 (q, 1H, J = 1.8, 3.6 Hz, furan-
H4), 7.07 (d, 2H, J = 9 Hz, Ar-H), 7.11 (s, 1H, -CH=C-Ar), 7.20
(d, 1H, J = 3.3 Hz, furan-H3), 7.25 (s, 1H, fur-C=CH-), 7.78 (d,
2H, J = 9 Hz, Ar-H), 8.00 (d, 1H, J = 1.5 Hz, furan-H5) ppm.
C6H5
1754.0
1783.1
1a
1b
C6H5OCH3
C6H5OCH3
1786.0
1752.0
1c
d = 6.66 (dd, 1H, J = 1.8, 3.6 Hz, furan-H4), 6.73 (d, 1H, J = 1.2
Hz,-CH=C-fur), 6.99 (d, 1H, J = 3.6 Hz, furan-H3), 7.13 (s, 1H,
CH=C-Ar), 7.46 (d, 2H, J = 9 Hz, Ar-H), 7.57 (d, 2H, J = 8.7
Hz, Ar-H), 7.76 (d, 1H, J = 2.1 Hz, furan-H5) ppm.
1d
C6H5Cl
C6H5
d = 3.01-3.08 (dd, 2H, J = 2.4, 2.7 Hz, -NHNHa2), 3.17-3.24 (dd,
2H, J = 2.4, 2.7 Hz, -NHNHb2), 4.41 (s, 2H, -CH2COPh), 6.57
(dd, 1H, J = 1.8, 3.3 Hz, furan-H4), 6.67 (s, 1H, fur-CH=C-),
6.74 (d, 1H, J = 3.3 Hz, furan-H3), 7.07 (t, 1H, J = 2.4 Hz,-CO-
NHNH2), 7.27-7.29 (m, 3H, Ph-H), 7.35 (d, 2H, J = 4.5 Hz, Ph-
1655-1697 3199.7-3331
1648-1687 3104.3-3325
1648-1672 3242.3-3324
1652-1668 3235.6-3317
2a
2b
2c
2d
Ho), 7.76 (d, J = 1.8 Hz, furan-H5) ppm.
d = 2.32 (s, 3H, Ar-Me), 3.015-3.085 (dd, 2H, J = 2.4, 2.7 Hz, -
NHNHa2), 3.17-3.24 (dd, 2H, J = 2.4, 2.7 Hz, -NHNHb2), 4.38
(s, 2H, -CH2COAr), 6.57 (dd, 1H, J = 1.8, 3.3 Hz, furan-H4),
6.67 (s, 1H, Fur-CH=C-), 6.74 (d, 1H, J = 3.3 Hz, furan-H3),
7.07 (t, 1H, J = 2.4 Hz,-CO-NHNH2), 7.22 (d, 2H, J = 8.7 Hz,
C6H5OCH3
Ar-H), 7.35 (d, 2H, J = 8.7 Hz, Ar-H), 7.78 (d, J = 1.8 Hz, furan-
H5) ppm.
d = 3.82 (s, 3H, Ar-OMe), 3.10 (dd, 2H, J = 2.4, 2.7 Hz, -
NHNHa2), 3.22 (dd, 2H, J = 2.4, 2.7 Hz, -NHNHb2), 4.32 (s, 2H,
-CH2-COAr), 6.57 (dd, 1H, J = 1.8, 3.3 Hz, furan-H4), 6.7 (s,
C6H5OCH3
1H, fur-CH=C-), 6.74 (d, 1H, J = 3.3 Hz, furan-H3), 7.1 (t, 1H, J
= 2.4 Hz,-CO-NHNH2), 7.22 (d, 2H, J = 8.7 Hz, Ar-H), 7.30 (d,
2H, J = 8.7 Hz, Ar-H), 8.0 (d, J = 1.8 Hz, furan-H5) ppm.
d = 3.01-3.08 (dd, 2H, J = 2.4, 2.7 Hz, -NHNHa2), 3.17-3.24 (dd,
2H, J = 2.4, 2.7 Hz, -NHNHb2), 4.48 (s, 2H, -CH2-COAr), 6.57
(dd, 1H, J = 1.8, 3.3 Hz, furan-H4), 6.67 (s, 1H, fur-CH=C-),
7.07 (t, 1H, J = 2.4 Hz,-CO-NHNH2), 7.38 (d, 2H, J = 8.7 Hz,
C6H5Cl
Ar-H), 7.48 (d, 2H, J = 8.7 Hz, Ar-H), 7.74 (d, 1H, J = 3.3 Hz,
furan-H3), 7.76 (d, J = 1.8 Hz, furan-H5) ppm.

901
Molecules 2000, 5
Continuation of the Table 1.
Infrared bands (IR)umax
-1
Cpd
No
Aryl
group
1H NMR (300 MHz, DMSO); dH [2H6] DMSO
(Nujol)/ cm
u
u
u
-NH
C=O
-C=N
d = 2.57-2.67 (pentet, 1H, J = 6.6 Hz, ClCHa2CH2CO-) 2.69-2.78
(pentet, 1H, J = 6 Hz, ClCHb2CH2CO-), 3.71 (t, 2H, J = 6 Hz,
ClCH2CH2CO-), 3.84 (s, 2H, -CH2CO Ph), 6.64 (dd, 1H, J = 1.8,
C6H5
1633-1705
1628-1672
3100-3287
3140-3250
4a
4b
3.6 Hz, furan-H4), 6.70 (d, 1H, J = 0.9Hz, fur-CH=C-), 6.96 (d,
1H, J = 3.3 Hz, furan-H3), 7.44-7.61 (m, 5H, Ph-H), 7.76 (d, J =
1.5 Hz, furan-H5), 9.40 (d, 1H, J = 3.3 Hz,-CONHNHCO-), 10.18
(d, 1H, J = 3.9 Hz,-CONHNH CO-), ppm.
d = 2.32 (s, 3H, Ar-Me), d = 2.48-2.64 (pentet, 1H, J = 6.6Hz,
ClCHa2CH2CO-), 2.68-2.77 (pentet, 1H, J= 6Hz, ClCHb2CH2CO-
), 3.72 (t, 2H, J = 6Hz, ClCH2 CH2CO-), 3.84 (s, 2H, -CH2COAr),
6.72 (dd, 1H, J = 1.8, 3.6 Hz, furan-H4), 7.1 (s, 1H, Fur-CH=C-),
7.17 (d, 1H, J = 3 Hz, furan-H3), 7.22 (d, 2H, J = 8.7 Hz, Ar-H),
7.51 (d, 2H, J = 8.7 Hz, Ar-H), 7.98 (d, J = 1.8 Hz, furan-H5), 9.41
(d, 1H, J = 3.3 Hz,-CONHNH CO-), 10.68 (d, 1H, J = 3.9 Hz,-
CONHNHCO-), ppm.
C6H5OCH3
d = 3.81 (s, 3H, Ar-Me), 2.48-2.64 (pentet, 1H, J = 6.6 Hz,
ClCHa2CH2CO-), 2.68-2.77 (pentet, 1H, J = 6 Hz, ClCHb2CH2CO-
), 3.72 (t, 2H, J = 5.7 Hz, ClCH2CH2 CO-), 3.85 (s, 2H, -
CH2COAr), 6.72 (dd, 1H, J = 1.8, 3.6 Hz, furan-H4), 7.1 (s, 1H,
C6H5OCH3
1633-1688
3150-3245
4c
Fur-CH=C-) 7.17 (d, 1H, J = 3 Hz, furan-H3), 7.22 (d, 2H, J = 8.7
Hz,Ar-H), 7.51 (d, 2H, J = 8.7 Hz, Ar-H), 7.98 (d, J = 1.8 Hz, fu-
ran-H5), 9.45 (d, 1H, J = 3.3 Hz, -CONHNHCO-), 10.61 (d, 1H, J
= 3.9 Hz,-CONHNHCO-), ppm.
d =2.66 (pentet, 1H, J = 7.2 Hz, ClCHa2CH2CO-), 2.71 (pentet,
1H, J = 6 Hz, ClCHb2CH2CO-), 3.72 (t, 2H, J = 5.7 Hz,
ClCH2CH2CO-), 3.85 (s, 2H, -CH2COAr), 6.65 (dd, 1H, J = 1.8,
3.6 Hz, furan-H4), 6.99 (d, 1H, J = 3 Hz, furan-H3), 7.13 (s, 1H,
fur-CH=C-), 7.48 (d, 2H, J = 9 Hz,Ar-H), 7.58 (d, 2H, J = 8.7 Hz,
Ar-H), 7.77 (d, J = 2.1 Hz, furan-H5), 9.41 (d, 1H, J = 3.3 Hz,-
CONHNHCO-), 10.68 (d, 1H, J = 3.9 Hz,-CONHNH CO-), ppm.
d = 2.57-2.67 (pentet, 1H, J = 6.6 Hz, ClCHa2CH2CO-) 2.69-2.78
C6H5Cl
1600-1708
1666-1715
3150-3333
3227-3337
4d
6a
(pentet, 1H, J = 5.7 Hz, ClCHb2CH2CO-), 3.71 (t, 2H, J = 6 Hz,
ClCH2CH2CO-), 6.65 (dd, 1H, J = 1.8, 3.6 Hz, furan-H4), 6.7 (d,
C6H5
1H, J = 0.9 Hz, -CH=C-Ar), 6.97 (d, 1H, J = 3.3 Hz, furan-H3), 7.1
(s, 1H, Fur-CH=C-), 7.44-7.61 (m, 5H, Ph-H), 7.76 (d, J = 1.5 Hz,
furan-H5), 8.76 (s, 1H, -CONH-) ppm.
d = 2.32 (s, 3H, Ar-Me), 2.62 (pentet, 1H, J = 6.6 Hz,
ClCHa2CH2CO-), 2.70 (pentet, 1H, J = 6 Hz, ClCHb2 CH2CO-),
3.722 (t, 2H, J = 6 Hz, ClCH2CH2 CO-), 6.59 (s, 1H, -CH=C-Ar),
C6H5OCH3
6b
6.72 (dd, 1H, J = 1.8, 3.6 Hz, furan-H4), 7.08 (s, 1H, furan-CH=C-
), 7.17 (d, 1H, J = 3 Hz, furan-H3), 7.22-7.25 (d, 2H, J = 8.7
Hz,Ar-H), 7.48-7.51 (d, 2H, J = 8.7 Hz, Ar-H), 7.98 (d, J = 1.8 Hz,
furan-H5), 10.68 (s, 1H, -CONH-) ppm.
1672-1728.3
3287.8

902
Molecules 2000, 5
Continuation of the Table 1.
Infrared bands (IR)umax
-1
Cpd.
No
Aryl
group
1H NMR (300 MHz, DMSO); dH [2H6] DMSO
(Nujol)/ cm
u
u
u
-NH
C=O
-C=N
d = 2.60-2.68 (pentet, 1H, J = 6 Hz, ClCHa2CH2CO-), 2.69-
2.76 (pentet, 1H, J = 6 Hz, ClCHb2CH2CO-), 3.72 (t, 2H, J
= 6 Hz, ClCH2CH2CO-), 3.85 (s, 3H, Ar-OMe), 6.59 (s,
1H, -CH=C-Ar), 6.72 (dd, 1H, J = 1.8, 3.6 Hz, furan-H4),
7.08 (s, 1H, fur-CH=C-), 7.17 (d, 1H, J = 3 Hz, furan-H3),
7.22-7.25 (d, 2H, J = 8.7 Hz,Ar-H), 7.48-7.51 (d, 2H, J =
8.7 Hz, Ar-H), 7.98 (d, J = 1.8 Hz, furan-H5), 10.66 (s, 1H,
-CONH-) ppm.
C6H5OCH3
1668-1733
3278
6c
d =2.60-2.68 (pentet, 1H, J = 6 Hz, ClCHa2CH2CO-), 2.69-
2.76 (pentet, 1H, J = 6 Hz, ClCHb2CH2CO-), 3.72 (t, 2H, J
= 6 Hz, ClCH2CH2CO-), 6.66 (dd, 1H, J = 1.8, 3.6 Hz, fu-
ran-H4), 6.74 (d, 1H, J = 1.2 Hz, -CH=C-Ar), 6.99 (d, 1H, J
= 3.6 Hz, furan-H3), 7.13 (s, 1H, furan-CH=C-), 7.46 (d,
2H, J = 9 Hz,Ar-H), 7.57 (d, 2H, J = 8.7 Hz, Ar-H), 7.77 (d,
J = 2.1 Hz, furan-H5), 8.78 (s, 1H, -CONH-) ppm.
C6H5Cl
1678-1722
3257.3-3311
6d
7a
7b
d = 2.49 (t, 1H, J = 6.6 Hz, ClCH2CH2CO-), 3.53 (t, 1H, J
= 6.6 Hz, ClCH2CH2CO), 4.37 (s, 2H, -CH2CO Ph), 6.65
C6H5
1695 1578-1612
1692.3 1588-1611
(dd, 1H, J = 1.8, 3.6 Hz, furan-H4), 6.97 (d, 1H, J = 3.3 Hz,
furan-H3), 7.13 (s, 1H, furan-CH=C-), 7.44-7.61 (m, 5H,
Ph-H), 7.76 (d, J = 1.5 Hz, furan-H5) ppm.
d = 2.32 (s, 3H, Ar-Me), 2.62-2.70 (t, 1H, J = 6.6 Hz,
ClCH2CH2CO), 3.722 (t, 1H, J = 6 Hz, ClCH2CH2CO-) 4.41
(s, 2H, -CH2COAr), 6.71 (dd, 1H, J = 1.8, 3.6 Hz, furan-H4),
C6H5OCH3
7.08 (s, 1H, furan-CH=C-), 7.17 (d, 1H, J = 3 Hz, furan-H3),
7.22-7.25 (d, 2H, J = 9 Hz,Ar-H), 7.48-7.51 (d, 2H, J = 9 Hz,
Ar-H), 7.98 (d, J = 1.8 Hz, furan-H5) ppm.
d = 2.60-2.76 (t, 1H, J = 6 Hz, ClCH2CH2CO-), 3.72 (t, 1H,
J = 6 Hz, ClCH2CH2CO-), 4.42 (s, 2H, -CH2COAr), 3.85
(s, 3H, Ar-OMe), 6.72 (dd, 1H, J = 1.8, 3.6 Hz, furan-H4),
7.08 (s, 1H, furan-CH=C-), 7.17 (d, 1H, J = 3 Hz, furan-
H3), 7.22-7.25 (d, 2H, J = 8.7 Hz,Ar-H), 7.48-7.51 (d, 2H, J
= 8.7 Hz, Ar-H), 7.98 (d, J = 1.8 Hz, furan-H5) ppm.
C6H5OCH3
7c
1693.2 1589-1609
d = 2.75 (t, 2H, J = 6 Hz, ClCH2CH2CO-), 3.72 (t, 1H, J =
6 Hz, ClCH2CH2CO-), 4.36 (s, 1H, -CH2COAr), 6.66 (dd,
1H, J = 1.8, 3.6 Hz, furan-H4), 6.99 (d, 1H, J = 3.6 Hz,
furan-H3), 7.13 (s, 1H, furan-CH=C-), 7.46 (d, 2H, J = 9
Hz,Ar-H), 7.57 (d, 2H, J = 8.7 Hz, Ar-H), 7.77 (d, J = 2.1
Hz, furan-H5) ppm.
C6H5Cl
1698 1590-1617
7d
8a
d = 3.90 (s, 2H, -furan-CH2-), 6.22 (d, 1H, J = 3 Hz, furan-
H3), 6.39 (dd, 1H, J = 1.8, 3 Hz, furan-H4), 7.42-7.49 (m,
3H, Ph-H), 7.56 (d, 1H, J = 0.9 Hz, -CH=C-Ar), 7.42-7.76
(dd, 2H, J = 1.2, 5.1 Hz, Ph-H), 7.79 (d, J = 1.8 Hz, furan-
H5), 13.23 (s, 1H, -CONH-) ppm.
C6H5
1655 1605 2150-3300

903
Molecules 2000, 5
Continuation of the Table 1.
Infrared bands (IR)umax
-1
Cpd.
No
Aryl
group
1H NMR (300 MHz, DMSO); dH [2H6] DMSO
(Nujol)/ cm
u
u
u
-NH
C=O
-C=N
d = 2.32 (s, 3H, Ar-Me), 3.92 (s, 2H, -furan-CH2-), 6.23 (d,
1H, J = 3 Hz, furan-H3), 6.42 (dd, 1H, J = 1.8, 3.6 Hz, fu-
C6H5OCH3
C6H5OCH3
C6H5Cl
1660
1660
1660
1610
1610
1613
2850-3300
3800-3400
3900-3400
8b
8c
8d
ran-H4), 7.25 (d, 2H, J = 8.7 Hz,Ar-H), 7.47 (s, 1H,
-
CH=C-Ar), 7.51 (d, 2H, J = 8.7 Hz, Ar-H), 7.98 (d, J = 1.8
Hz, furan-H5), 13.46 (s, 1H, -CONH-) ppm.
d = 3.85 (s, 3H, Ar-OMe), 3.93 (s, 2H, -furan-CH2-), 6.72
(d, 1H, J = 3 Hz, furan-H3), 7.17 (dd, 1H, J = 1.8, 3.6 Hz,
furan-H4), 7.08 (s, 1H, furan-CH=C-), 7.26 (d, 2H, J = 8.7
Hz,Ar-H), 7.49 (d, 1H, J = 0.9 Hz, -CH=C-Ar), 7.51 (d,
2H, J = 8.7 Hz, Ar-H), 7.48 (d, J = 1.8 Hz, furan-H5),
13.65 (s, 1H, -CONH-) ppm.
d =3.95 (s, 2H, -furan-CH2-), 6.66 (d, 1H, J = 3.6 Hz, fu-
ran-H3), 7.1 (dd, 1H, J = 1.8, 3.6 Hz, furan-H4), 7.44 (d,
1H, J = 1.2 Hz, -CH=C-Ar), 7.46 (d, 2H, J = 9 Hz,Ar-H),
7.57 (d, 2H, J = 8.7 Hz, Ar-H), 7.97 (d, J = 1.8 Hz, furan-
H5), 13.38 (s, 1H, -CONH-) ppm.
Experimental
General
1H NMR spectra were recorded on Varian Plus 300 (300 MHz) or Bruker XL 300 (300 MHz) in-
13
struments, the C NMR spectra (with DEPT 135) on a Bruker WP80 or XL 300 instrument. Infrared
spectra listed as recorded ‘neat’ refer to a thin film of material on NaCl disks, and were taken on a Per-
kin Elmer 1600 FT-IR spectrometer. Mass spectra were recorded on a Kratos Concept instrument.
Melting points were measured on an Electrothermal digital melting point apparatus and are uncorrected.
The TLC analyses were carried out using Macherey-Nagel 0.25mm layer fluorescent UV
plates with
254
the indicated solvent system. Elemental analyses were performed by M-H-W Laboratories (Phoenix,
AZ) at University of Minho, Braga, Portugal.
a-(2-Furyl)methylidene-(E)-g-aryl-2(3H)-furanones (1a-d)
2(3H)-Furanones (1a-d) were prepared following the literature method [2]. The structures of the
products were confirmed by 1H and 13C NMR spectral data as listed in Tables 1 and 2.
a-Aracycl-b-(2-furyl)acrylic acid hydrazides (2a-d) [2]
Hydrazine hydrate (1 mol) was added to a suspension of the 2-(3H)-furanones (1a-d) (1 mol) in ab-
solute ethanol (20 mL). The reaction mixture was allowed to stand at room temperature with occasional

904
Molecules 2000, 5
shaking from time to time and then left overnight. The reaction was monitored by TLC and was shown
to be complete after 2 days. Evaporation of the solvent by rotatory evaporator gave a colorless solid
that was filtered off and recrystallized from a suitable solvent to give colorless crystals in 75-85% yield,
as listed in Table 2.
4-Furylmethyl-6-aryl-3(2H)pyridazin-3-ones (8a-d)
1.0 N HCl (5 mL) was added dropwise with stirring at 25-35oC over 30-60 min to a solution of the
a-aracycl-b-(2-furyl)acrylic acid hydrazides (2a-d) (1 mole) in benzene (20 mL); after completion of the
addition the solid was continue stirring for 1h, then filtered off and washed thoroughly with water. The
product obtained was recrystallized from a suitable solvent as shown in Table 2.
N1[a-Aracyl-b-(2-furyl)acroyl- N2[3-chloropropionyl]hydrazine (4a-d)
To a solution of the a-aracycl-b-(2-furyl)acrylic acid hydrazides (2a-d) (1 mol) in benzene (50 mL)
was added 3-chloro-propionyl chloride (3) (1.01 mol) and the mixture stirred at 0-15o C for 5 h. The
progress of the reaction was monitored by TLC and shown to be complete after 5-6 hrs and when the
color become yellow. The solid separated out were collected and re-crystallized from ethanol to yield
the title compounds in 80-92% yield (cf. Table 2).
6-Aryl-1-(3-chloropropanoyl)-4-[(E)-1-(2-furyl)methylidene)]-1,2,3,4-tetrahydro-3-pyridazinones (6a-d)
To a solution of the a-aracycl-b-(2-furyl)acrylic acid hydrazides (2a-d) (1 mol) in benzene (50 mL)
was added 3-chloropropionyl chloride (3) (1.1 mol) and the reaction mixture was refluxed at 80oC for
30-60 min. The progress of the reaction was monitored by TLC during this time and the reaction was
shown to be complete after 1h when the color become yellow. The solvent was removed by rotatory
evaporator and the solids which separated out were collected and then recrystallized from ethanol to
yield the products in 80-92% yield (cf. Table 2). In a parallel experiment with hydrazine derivatives (4a-
d) in benzene solvent in the presence of acid catalyst (1.0 N HCl) using the same reaction conditions
previously mentioned, the only products which could be identified by TLC after 30-60 min. were com-
pounds (6a-d). These compounds were shown by direct comparison of m.p and mixed m.p, TLC and
spectral data to be identical in all aspects with authentic samples.
2-(b-Chloroethyl)-5-[a-aracyl-b-(2-furyl)]-(E)-vinyl-1,3,4-oxadiazoles (7a-d)
A mixture of the N1[a-aracyl-b-(2-furyl)acroyl-N2[3-chloropropionyl]hydrazine compounds (4a-d)
(1 mol) and POCl3 (10 mL) were stirred and heated at 106oC for 1 h., then allowed to cool, poured
onto crushed ice and washed with aqueous 1.0 N NaHCO3. The yellowish solid precipitate was filtered
off, washed with water and recrystallized from benzene-petroleum ether (b.p. 100-120oC) mixture to
produce compounds (7a-d) (cf. Table 2). These experiments were repeated using Ac2O as dehydrating
agent instead of POCl3 and there is no indication for any change in the yields.

905
Molecules 2000, 5
Table 2. Physical data for compounds 1a-8d.
o
MF
Recryst.
Solvent
Analysis [Calc./Found]
Cpd.
No.
Aryl
Group
m.p C
Yield
C
H
N
C
C
C
C
H O
C6H5
C6H5CH
15 10 3
195-198
205-207
C6H5OCH3 215-217
78%
88%
91%
75.63/75.56 4.20/4.19
76.19/76.20 4.76/4.63
71.64/71.42 4.47/4.56
66.05/66.24 3.30/3.42
1a
1b
1c
1d
H O
16 12 3
3
EtOH
H
O
16 12 4
H ClO
235-238 dec. 75%
C6H5Cl
15 9
3
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
H
N O
66.67/66.85 5.18/5.07
67.60/67.56 5.63/5.54
64.00/63.88 5.33/5.23
59.11/59.01 4.27/4.19
10.37/10.53
9.86/9.71
9.33/9.12
9.19/9.32
C6H5
C6H5
15 14 2 3
134-135
172-173
76%
72%
78%
73%
2a
2b
2c
2d
H
N O
CH3
16 16 2 3
EtOH
MeOH
EtOH
Benz.
EtOH
C6H5OCH3 125-126
H
N O
16 16 2 4
216-217
C6H5Cl
H
ClN O
15 13 2 3
H
N O Cl
59.91/60.10 4.71/4.82
60.88/60.92 5.07/4.99
58.38/58.12 4.86/4.77
54.68/54.33 4.05/4.25
7.76/7.55
7.47/7.67
7.17/7.27
7.08/7.20
C6H5
C6H5
18 17 2 4
135-136
173-175
82%
85%
83%
80%
4a
4b
4c
4d
H
N O Cl
CH3
19 19 2 4
C6H5OCH3 110-112
H
N O Cl
19 19 2 5
215-217
C6H5Cl
H
N O Cl
18 16 2 4
2
2
2
H
N O Cl
63.06/63.02 4.37/4.16
63.95/63.69 4.76/4.47
61.20/61.15 4.56/4.45
8.17/8.28
7.85/7.55
7.51/7.57
7.42/7.76
C6H5
C6H5
18 15 2 3
160-162
182-183
80%
92%
92%
89%
6a
6b
6c
6d
H
N O Cl
CH3
19 17 2 3
C6H5OCH3 173-175
H
N O Cl
19 17 2 4
57.29/57.25
3.71/3.22
205-206
C6H5Cl
H
N O Cl
18 14 2 3
H
N O Cl
63.06/63.02 4.37/4.16
63.95/63.69 4.76/4.47
61.20/61.15 4.56/4.45
8.17/8.28
7.85/7.55
7.51/7.57
7.42/7.76
C6H5
C6H5CH3
18 15 2 3
157-158
175-177
75%
83%
82%
79%
7a
7b
7c
7d
H
N O Cl
19 17 2 3
C6H5OCH3 180-182
H
N O Cl
19 17 2 4
57.29/57.25
3.71/3.22
165-167
C6H5Cl
H
N O Cl
18 14 2 3
H N2O2
15 12
H
16 14
H
16 14
H
15 11
C6H5
C6H5CH3
207-210
239-240
75%
79%
80%
77%
71.42/71.53 4.76/4.87 11.11/10.95
72.1872.13 5.26/5.00 10.52/10.60
68.08/68.38 4.96/5.14 9.92/10.13
62.82/62.64 3.83/3.80 9.77/9.80
8a
8b
8c
8d
N2O2
C6H5OCH3 172-173
N2O3
210-212
C6H5Cl
N2O2Cl
Table 3. 13C Chemical shifts (dC[2H6]DMSO) for 6-(4-methylphenyl)-1-(3-chloropropanoyl)-4-[(E)-1-
(2-furyl)methylidene)]-1,2,3,4-tetrahydro-3-pyridazinones (6a-d).
O
7
9
8
2
4
H
N
10
3
18
1
5
O
N
Cl
11
17
O
6
19
12
13
14
6b
15
Me
16
C-3
C-4
C-5
C-6
C-7
C-8
C-9
C-10
C-11
168.74 123.53
118.7
C-14
126.9
151.86
C-15
139.3
126.25
C-16
20.9
147.1 113.4 99.24
117.14
C-12
C-13
C-17
C-18
C-19
36.1
146.4
129.2
168.2 53.4

906
Molecules 2000, 5
Table 4. 13C Chemical shifts (dC[2H6]DMSO) for a-(2-furyl)methylidene-(E)-g-aryl-2(3H)-furanones
1a and 1c.
8
9
6
7
O
2
10
O
3
1
O
4
5
11
12
13
1a, c
14
R
15
Cpd
No.
1a
C-2
C-3
C-4
C-5
C-6
C-7
C-8
C-9
C-10 C-11 C-12
C-13
C-14 C-15
168.58 130.4 119.7 154.6 121.1 151.4 113.9 99.24 120.27 147.8 125.1 129.1 127.84 ----
168.74 144.8 118.8 154.8 121.4 151.5 113.7 99.97 120.25 147.4 126.9 114.64 161.04 55.4
1c
Acknowledgements: The authors gratefully thank Professor Dr. M. Fernanda Proenca, Departamento de
Química, Universidade do Minho, 4710 Braga, Portugal for the use of the facilities to obtain the NMR
spectra.
References and Notes
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Molecules 2000, 5
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Samples Availability: Available from the authors.
© 2000 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.