Ultrasound Assisted Synthesis of Some Novel Bis-Pyridazine Derivatives

Article abstract of DOI:10.1002/jhet.2328

Bis-enaminone 3 was coupled with aryldiazonium chlorides 4a, 4b to afford the bis-arylhydrazonopropanals 6a, 6b. Compounds 6a, 6b could be utilized for the synthesis of a variety of bis-(dimethyl 2,3-dihydropyridazine-3,4-dicarboxylate), bis-(pyridazin-3(

Full text of DOI:10.1002/jhet.2328

March 2016
Ultrasound Assisted Synthesis of Some Novel Bis-Pyridazine Derivatives
595
a
Ahmed E. M. Mekkya,b and Abdullah S. Al-Bogami
*
aChemistry Department, Faculty of Science, King Abdulaziz University, North Jeddah, P.O. Box 80203,
Jeddah 21589, Saudi Arabia
bChemistry Department, Faculty of Science, Cairo University, Giza 12613, Egypt
*
E-mail: ataher2211@yahoo.com
Received June 26, 2014
DOI 10.1002/jhet.2328
Published online 11 May 2015 in Wiley Online Library (wileyonlinelibrary.com).
Bis-enaminone 3 was coupled with aryldiazonium chlorides 4a,b to afford the bis-arylhydrazonopropanals
6a,b. Compounds 6a,b could be utilized for the synthesis of a variety of bis-(dimethyl 2,3-dihydropyridazine-3,4-
dicarboxylate), bis-(pyridazin-3(2H)-one), bis-(2,3-dihydropyridazine-4-carbonitrile) and bis-(3-imino-2,3-
dihydropyridazine) derivatives, under ultrasonic irradiation. A comparative study of aforementioned reactions
was carried out under conventional method as well as under ultrasonic irradiation conditions.
J. Heterocyclic Chem., 53, 595 (2016).
INTRODUCTION
within a number of herbicides such as credazine and
pyridafol (Fig. 1). It is also found within the structure of
several drugs such as cadralazine (antihypertensive),
minaprine (antidepressant), pipofezine (antidepressant) and
hydralazine (vasodilator) (Fig. 1). The unique structural
array of these compounds has made them attractive synthetic
targets in chemistry.
Arylhydrazonals A are readily obtainable substances
whose chemistry has recently received considerable
attention [28–30]. The structures of these substances
contain an interesting array of functionalities, including
nucleophilic benzylic nitrogen, an imine carbon and an
electrophilic carbonyl carbon (Fig. 2). Owing to this
functionality, arylhydrazonals provide as useful starting
materials in the synthesis of five- and six-membered
heterocycles.
Motivated by the abovementioned findings, and in a
continuation of our interest in the synthesis of a wide range
of heterocyclic systems for biological screening in our
laboratory [31], we report herein the synthesis of novel
bis-pyridazines from readily obtainable, inexpensive
building block bis-arylhydrazonals, under both ultrasound
irradiation and conventional methods.
Ultrasound irradiation has gained attractiveness in the
past decade as a powerful technique for the promotion
of organic chemistry, offering a versatile and facile
pathway in a large variety of syntheses [1–11]. In com-
parison with conventional thermal heating, ultrasound
irradiation has some important advantages: significant
decreases of reaction time, enhanced yields and high
purity of the compounds. Consequently, ultrasound
irradiation has been used to accelerate a number of
synthetically useful reactions, especially in heterocyclic
compounds [12–16]. It is noteworthy to mention here
that the improvement induced by ultrasound in the
aforementioned reactions could be attributed to the
well-established cavitation theory of ultrasonic irradia-
tion in which it differs from the traditional energy
source (conventional heating) in duration, pressure and
energy per molecule. Because of immense temperature,
pressure and extraordinary heating rate generated by
cavitations bubble collapse, ultrasound provides an
unusual mechanism so reaction time decreases clearly
and high yield is obtained.
Pyridazines are rare in nature, possibly reflecting the
scarcity of naturally occurring hydrazines, common building
blocks for the synthesis of these heterocycles. Many com-
pounds containing pyridazine moiety have demonstrated
versatile biological activities including antiviral, anticancer,
antibacterial, anti-inflammatory, antifungal, antihyperten-
sive, antidepressant and analgesic properties [17–27]. The
pyridazine structure is a popular pharmacophore. It found
RESULTS AND DISCUSSION
The reaction of 4,4′-diacetyldiphenylether (1) with
dimethylformamide–dimethylacetal (DMF–DMA) was
carried out in toluene under ultrasonic irradiation
afforded a single product (as examined by TLC) that
© 2015 HeteroCorporation

596
A. E. M. Mekky and A. S. Al-Bogami
Vol 53
Figure 1. Selected herbicides and drugs pyridazine.
2.95 and 3.16 due to N,N-dimethylamino protons, two
doublets at δ 5.71 and 7.85 (J = 12.3 Hz) due to olefinic
protons, in addition to aromatic protons signals in the re-
gion δ 7.05–7.93. The value of the coupling constant
(J = 12.3 Hz) for the ethylenic protons designated that the
enaminone 3 exists exclusively in the E-configuration.
The bis-enaminone 3 smoothly coupled with aromatic
diazonium salts in the presence of sodium acetate to yield
the inseparable arylazo intermediate 5a,b, which are
readily hydrolyzed in the reaction course into the bis-
arylhydrazonopropanals 6a,b (Scheme 1).The structures
of the bis-arylhydrazonopropanals 6a,b were confirmed
by their elemental analyses and spectral data. For example,
Figure 2. Functionalities of arylhydrazonals.
was identified as (2E,2′E)-1,1′-(4,4′-oxybis(4,1-phenylene))
bis(3-(dimethylamino)prop-2-en-1-one) (3) within 4 h
(Scheme 1), while the same reaction carried out via reflux
in toluene required 18 h.
The elemental analysis and spectral data were in com-
plete agreement with the assigned structure 3. For example,
1
the H NMR spectrum of 6a displayed formyl signal at δ
10.21, in addition to aromatic protons signals in the region
δ 7.21–8.09 and D2O exchangeable singlet signal due to
NH proton at δ 14.63. The mass spectrum of 6a revealed
a molecular ion peak at m/z = 654.
1
its H NMR spectrum displayed two singlet signals at δ
Scheme 1. Synthesis of bis-enaminone 3 and bis-arylhydrazonopropanals 6a,b.
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Ultrasound Assisted Synthesis of Some Novel Bis-Pyridazine Derivatives Using
Bis-Arylhydrazonopropanals
597
The arylhydrazonopropanals can be used as potential
precursors for the synthesis of many heterocyclic systems,
especially pyridazine derivates throughout this study.
Thus, the one-pot three-component reactions of bis-
arylhydrazonals 6a,b with dimethyl acetylenedicarboxylate
(DMAD) in the presence of triphenylphosphine (Ph3P)
proceeded spontaneously in CH2Cl2 under ultrasonic irradi-
ation and were complete within 6 h in high yields (Table 1).
The reaction leads to formation of one product (as examined
by TLC), in each case, where the initially formed
phosphorane ylide underwent addition–cyclization as a re-
sult of Wittig reaction [32,33] (Scheme 2). These products
were identified as 9a,b based on their elemental analyses
and their IR, 1H NMR and 13C NMR spectral data. The mass
spectra of the products displayed molecular ion peaks at
appropriate m/z values.
electrophilic double bond in acrylonitrile followed by nor-
mal aldol condensation (Pathway A). Compounds 15a,b
can be also formed via non isolable Baylis–Hillman inter-
mediate 16a,b (Pathway B) which followed by the addition
of hydrazone NH to electrophilic double bond and elimina-
tion of water. The structures of these products were con-
1
firmed based on their elemental analyses and their IR, H
and 13C NMR spectral data. Table 1 shows that ultrasound
technique reduced the time of reactions from several days
to few hours and enhanced the yields from 56 to 60%
(under conventional conditions) to 74–80% (Scheme 3).
Treatment of bis-arylhydrazonopropanals 6a,b with active
methylene nitrile compounds 18a–c afforded bis-(3-imino-
2,3-dihydropyridazine) derivatives 20a–f (Scheme 4). The
structure of bis-(3-imino-2,3-dihydropyridazine) derivatives
20a–f was assigned on the basis of their elemental analyses
and spectral data, for example, the 1H NMR spectrum of com-
pound 20a revealed singlet signal at δ 7.74 due to pyridazine
5-H in addition to aromatic four doublets at δ 7.15–8.14 and
D2O exchangeable singlet signal due to NH proton at δ
8.23. The mass spectrum of the same compound revealed a
peak corresponding to its molecular ion at m/z 750.
It is noteworthy that, the best results were obtained using
a stoichiometric amount, bis-arylhydrazonals (1.0 equiva-
lent), DMAD (2.0 equivalents) and Ph3P (2.0 equivalents).
In the absence of Ph3Ph no products formed, whilst in the
presence catalytic amount of Ph3P, the products were
obtained as trace.
Additionally, to highlight even more the importance of
ultrasound for promoting bis-pyridazine derivative synthe-
sis, the reaction of bis-arylhydrazonals with DMAD in the
presence of Ph3P was performed under conventional
method in CH2Cl2 at room temperature for 48 h. The prod-
ucts were obtained at 53–57% yields (Table 1). These
yields are lower than those obtained under ultrasonic
irradiation. Moreover, the reaction time using ultrasound
irradiation was shorter.
The reaction is assumed to proceed via initial condensa-
tion of the active methylene of 18a–c to the formyl group
of 6a,b followed by addition of the NH to the nitrile
function to give the final isolable product. Table 2 shows that
ultrasound technique reduced the time of reactions from
several hours to minutes and enhanced the yields from 60
to 75% (under conventional conditions) to 83 to 90%.
In a similar manner, bis-arylhydrazonopropanals 6a,b
condensed with diethyl malonate to yield the bis-(ethyl 3-
oxo-2,3-dihydropyridazine-4-carboxylate) derivatives 22a,b,
respectively (Scheme 2).
Furthermore, the bis-arylhydrazonopropanals 6a,b
reacted with hippuric acid in acetic anhydride under ultra-
sonic irradiation to give the bis-(4-benzamido-3-oxo-2,3-
dihydropyridazine) derivatives 25a,b, respectively. Thus,
initial cyclization of hippuric acid would generate in situ
the oxazolone 23. This condenses with 6a,b yielding
the hydrazones 24a,b which then arranged into
bis-(4-benzamido-3-oxo-2,3-dihydropyridazine) derivatives
25a,b via the attack of NH moiety at the ring carbonyl group
(Scheme 4).
Also, to find specific effect of ultrasound on these
reactions, all previously mentioned reactions were carried
out under the same conditions in the absence of ultrasound
irradiation (Table 2). It was observed that the reaction time
increased considerably and the yield of the product de-
creased. Thus the ultrasound was found to have a beneficial
effect on the synthesis of bis-pyridazinone derivatives 22a,
b and 25a,b in which decreased time of the above reactions
from 6 to 8 h in conventional procedure to 40–60 min, in
addition to a noticeable improvement yield of reactions
under ultrasonic irradiations.
1
The H NMR spectrum of 9a exhibited two singlets
identified as methoxy groups at δ 3.69 and δ 4.33 along
with a sharp singlet for methine proton at δ 6.07 and singlet
for 5-H pyridazine at δ 7.35 in addition to aromatic protons
signals at δ 7.30–8.12.
Also, bis-arylhydrazonals 6a,b were allowed to react
with Wittig reagent 10 in refluxing toluene for 10 h to
afford the bis-pyridazinone derivatives 13a,b, respectively
(Scheme 2). Furthermore, the reactions discussed above
were completed within 2 h under ultrasound irradiation.
The yields were also improved (Table 1). The structures
of the isolated products were established based on their
elemental analyses and their spectral data. For example,
the 1H NMR spectrum of 10a displayed two doublets
identified as H-4 pyridazine and H-5 pyridazine at δ 7.09
and δ 7.52 in addition to four doublets for aromatic protons
at δ 7.13–8.09.
The reaction of bis-arylhydrazonopropanals 6a,b with
acrylonitrile in the presence of 1,4-diazabicyclo[2.2.2]
octane (DABCO) as a catalyst and ethanol as a solvent,
resulted in the formation of compounds 15a,b, which could
be formed through intermediate 14a,b that results most
likely via initial addition of hydrazone NH to the
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A. E. M. Mekky and A. S. Al-Bogami
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Table 1
Synthesis of bis-(dimethyl 2,3-dihydropyridazine-3,4-dicarboxylate) derivatives 9a,b, bis-(pyridazin-3(2H)-ones) 13a,b and bis-(2,3-dihydropyridazine-
4-carbonitrile) derivatives 15a,b under both ultrasonic irradiation and conventional method.
Ultrasonic irradiation
Time Yield (%)
Conventional method
Time Yield (%)
Entry
Compound
1
6 h
75
48 h
53
2
3
4
5
6
6 h
78
83
89
74
80
48 h
57
70
80
56
60
2 h
10 h
2 h
10 h
20 h
14 days
20 h
14 days
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Ultrasound Assisted Synthesis of Some Novel Bis-Pyridazine Derivatives Using
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599
Scheme 2. Synthesis of bis-(dimethyl 2,3-dihydropyridazine-3,4-dicarboxylate) derivatives 9a,b, bis-(pyridazin-3(2H)-ones) 13a,b.
EXPERIMENTAL
All organic solvents were purchased from
CONCLUSION
General.
A novel and efficient approach has been developed for
the synthesis of bis-pyridazine derivatives under ultrasonic
irradiation via utilization of bis-arylhydrazonopropanals as
important synthon for synthesis of them. In general, im-
provements in rates (shorter reaction times) and yield of
reactions are observed when reactions were carried out un-
der sonication compared with classical condition. Since the
same products produced under both conventional and ul-
trasonic conditions, we have false sonochemistry type of
reaction. The cavitation effect provides the mechanical
energy for all subsequent chemical reactions, including
bond scission induced by viscous frictional forces [34,35].
commercial sources and used as received unless otherwise
stated. All other chemicals were purchased from Merck, Aldrich
or Acros and used without further purification. Thin-layer
chromatography (TLC) was performed on precoated Merck 60
GF254 silica gel plates with a fluorescent indicator and
detection by means of UV light at 254 and 360 nm. The melting
points were measured on a Stuart melting point apparatus and
are uncorrected. IR spectra were recorded on a Smart iTR,
which is an ultra-high-performance, versatile Attenuated Total
Reflectance (ATR) sampling accessory on the Nicolet iS10
FT-IR spectrometer. The NMR spectra were recorded on a
1
Bruker Avance III 400 (9.4 T, 400.13 MHz for H, 100.62 MHz
for 13C and 376.25 MHz for 19F) spectrometer with a 5-mm
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Scheme 3. Synthesis of bis-(2,3-dihydropyridazine-4-carbonitrile) derivatives 15a,b.
Scheme 4. Synthesis of bis-(3-imino-2,3-dihydropyridazine) derivatives 20a–f, bis-(ethyl 3-oxo-2,3-dihydropyridazine-4-carboxylate) derivatives 22a,b
and bis-(4-benzamido-3-oxo-2,3-dihydropyridazine) derivatives 25a,b.
BBFO probe, at 298 K. Chemical shifts (δ in ppm) are given
relative to the NMR solvent signals (DMSO-d6 2.50 and
39.50 ppm, CDCl3 7.26 and 77.00 ppm for 1H and 13C NMR,
respectively). Mass spectra were recorded on a Thermo ISQ
Single Quadrupole GC-MS. Elemental analyses were carried out
on a EuroVector instrument C, H, N, S analyzer EA3000 Series.
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Table 2
Synthesis of bis-(3-imino-2,3-dihydropyridazine) derivatives 20a–f, bis-(ethyl 3-oxo-2,3-dihydropyridazine-4-carboxylate) derivatives 22a,b and bis-(4-
benzamido-3-oxo-2,3-dihydropyridazine) derivatives 25a,b under both ultrasonic irradiation and conventional method.
Ultrasonic irradiation
Time Yield (%)
Conventional method
Time Yield (%)
Entry
Compound
1
50 min
45 min
60 min
40 min
85
6 h
6 h
6 h
8 h
68
2
3
4
90
83
90
72
62
73
70
5
40 min
87
8 h
6
55 min
85
8 h
66
(Continued)
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Table 2.
(Continued)
Ultrasonic irradiation
Conventional method
Entry
Compound
Time
Yield (%)
Time
Yield (%)
7
40 min
90
8 h
75
8
40 min
40 min
55 min
88
87
85
8 h
8 h
8 h
70
70
67
9
10
Sonication was performed by Techno-gazsonicator (with a
frequency of 37 kHz and ultrasonic peak max. 320 W).
4,4′-Diacetyldiphenylether (1) was prepared according to the
continued for 4 h until the starting materials were no longer de-
tectable by TLC. The product was obtained and purified (92%
yield) as described above in conventional reaction.
;
Orange solid, m.p. 175–177°C; IR: ν 1632 (CO) cmꢀ1 1H
reported literature [36].
NMR (CDCl3): δ 2.95 (s, 6H, 2CH3), 3.16 (s, 6H, 2CH3), 5.71
(d, 2H, ¼CH―CO, J = 12.3 Hz), 7.05 (d, 4H, ArH, J = 8.4 Hz),
7.85 (d, 2H, ¼CH―N, J = 12.3 Hz), 7.93 (d, 4H, ArH,
J = 8.4 Hz); 13C NMR (CDCl3): δ 32.54, 40.33, 87.04, 113.60,
124.79, 131.18, 149.46, 154.28, 182.61; MS: 364 (M+);
C22H24N2O3: Anal. Calcd: C, 72.50; H, 6.64; N, 7.69. Found:
C, 72.41; H, 6.60; N, 7.75%.
General procedure and characterization data
Synthesis of (2E,2′E)-1,1′-(4,4′-oxybis(4,1-phenylene))bis(3-
(dimethylamino)prop-2-en-1-one) (3).
Silent reaction: To a
solution of 4,4′-diacetyldiphenylether (1) (10 mmol) in toluene
(30 mL), dimethylformamide-dimethylacetal (DMF–DMA) (40 mmol)
was added and refluxed for 18 h (until no starting materials
showed by in TLC). The excess toluene and DMF–DMA were
distilled off under reduced pressure. The residual solid was taken
up in ether (20 mL), and the resulting crystals were collected by
filtration, washed thoroughly with ether, dried and finally
recrystallized from dry benzene to afford the enaminone 3 in
(80% yield).
Sonicated reaction: This process was performed on the same scale
described above for silent reaction. All the reactions were kept at
room temperature 50°C which is attained by addition or removal
of water in ultrasonic bath. The sonochemical reaction was
General procedure for the synthesis of bis-arylhydrazonopropanals
6a,b. A solution of appropriate aryldiazonium salts 4a,b (20 mmol)
was prepared by adding a solution of sodium nitrite (3 g into
15 mL of water) to a cold solution of arylamine hydrochloride
(20 mmol of arylamine in 10 mL of concentrated HC1) with
stirring. The resulting solution was then added to a cold
solution of bis-enaminone 3 in ethanol (50 mL) containing
sodium acetate (8 g). The mixture was stirred at room
temperature for 3 h, and the solid obtained was collected by
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Ultrasound Assisted Synthesis of Some Novel Bis-Pyridazine Derivatives Using
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filtration and crystallized from ethanol to give the corresponding
bis-arylhydrazonopropanals 6a,b.
3,3′-(4,4′-Oxybis(4,1-phenylene))bis(3-oxo-2-(2-(4-(trifluo-
141.02, 145.17, 160.69, 161.90, 162.83, 189.20; MS: 798 (M+);
C44H38N4O11: Anal. Calcd: C, 66.16; H, 4.79; N, 7.01. Found: C,
66.11; H, 4.73; N, 7.10%.
General procedure for the synthesis of bis-(pyridazin-3(2H)-
romethyl)phenyl)hydrazono)propanal) (6a).
Orange solid,
m.p. 102–104°C; IR: ν 3430 (NH), 1674, 1652 (2CO) cmꢀ1; H
NMR (CDCl3): δ 7.21 (d, 4H, ArH, J= 8.8 Hz), 7.45 (d, 4H, ArH,
J= 8.4 Hz), 7.67 (d, 4H, ArH, J= 8.4 Hz), 8.09 (d, 4H, ArH,
J= 8.8 Hz), 10.21 (s, 2H, 2CHO), 14.63 (s, 2H, 2NH, D2O-exchange-
able); 13C NMR (CDCl3): δ 111.59, 113.66, 115.76, 122.37, 125.03,
127.43, 128.13, 128.31, 139.13, 155.18, 184.60, 185.36; 19F NMR
(CDCl3): δ ꢀ67.01; MS: 654 (M+); C32H20F6N4O5: Anal. Calcd: C,
58.72; H, 3.08; N, 8.56. Found: C, 58.67; H, 3.12; N, 8.49%.
1
one) derivatives 13a,b..
Silent reactions: A mixture of the
appropriate bis-arylhydrazonal derivatives 6a,b (10 mmol) and
the ylides 10 (20 mmol) in toluene (30 mL) was heated under
reflux with stirring until the starting materials could no longer
be detected by TLC. The solvent was evaporated under reduced
pressure, and the residue was then treated with ethanol. Solid
products were collected by filtration, then recrystallized from a
mixture of DMF/EtOH (1:10) to give the corresponding
compounds 13a,b.
3,3′-(4,4′-Oxybis(4,1-phenylene))bis(3-oxo-2-(2-(4-methylphenyl)
Sonicated reactions: These processes were performed on the same
scale described above for silent reactions. The mixture was irradi-
ated with ultrasound at 50°C for 2 h. The addition or removal of
water controlled the temperature of the water bath. After comple-
tion of the reaction, as indicated by TLC monitoring, the products
were obtained and purified as described above in silent reaction.
6,6′-(4,4′-Oxybis(benzoyl))bis(2-(4-(trifluoromethyl)phenyl)-
hydrazono)propanal) (6b).
Orange solid, m.p. 114–116°C;
IR: ν 3428 (NH), 1670, 1648 (CO) cmꢀ1; H NMR (CDCl3): δ
7.13 (d, 4H, ArH, J = 8.8 Hz), 7.19 (d, 4H, ArH, J = 8.4 Hz), 7.33
(d, 4H, ArH, J = 8.4 Hz), 8.06 (d, 4H, ArH, J = 8.8 Hz), 10.18 (s,
2H, 2CHO), 14.84 (s, 2H, 2NH, D2O-exchangeable); 13C NMR
(CDCl3): δ 19.93, 110.87, 113.60, 115.62, 121.74, 127.31,
128.02, 128.43, 138.85, 155.20, 184.71, 185.64; MS: 546 (M+);
C32H26N4O5: Anal. Calcd: C, 70.32; H, 4.79; N, 10.25. Found: C,
70.39; H, 4.73; N, 10.19%.
1
pyridazin-3(2H)-one) (13a).
Brown solid, m.p. 132–134°C;
IR: ν 1680, 1633 (2CO) cmꢀ1; H NMR (DMSO-d6): δ 7.09 (d,
2H, pyridazine-5-CH, J= 6 Hz), 7.14 (d, 4H, ArH, J= 8 Hz), 7.53
(d, 2H, pyridazine-4-CH, J= 6 Hz), 7.87 (d, 4H, ArH, J=8 Hz),
7.98 (d, 4H, ArH, J= 8.4 Hz), 8.08 (d, 4H, ArH, J =8.4Hz); 13C
NMR (DMSO-d6): δ 118.13, 124.49, 125.89, 126.52, 127.54,
127.80, 129.96, 131.74, 138.10, 139.63, 143.95, 160.87, 161.51,
188.47; 19F NMR (DMSO-d6): δ ꢀ67.37; MS: 702 (M+);
C36H20F6N4O5: Anal. Calcd: C, 61.54; H, 2.87; N, 7.97. Found: C,
61.49; H, 2.80; N, 7.91%.
1
General procedure for the synthesis of bis-(dimethyl 2,3-
dihydropyridazine-3,4-dicarboxylate) derivatives 9a,b. Silent
reactions: To a solution of Ph3P (20 mmol) and the appropriate
bis-arylhydrazonal derivatives 6a,b (10mmol) in dichloromethane
(20 mL) was added dropwise to a solution of dimethylacetylene
dicarboxylate (20 mmol). The mixture was left standing at
room temperature for 48 h and then treated with ethanol.
The solid product was collected by filtration, and then
recrystallized from ethanol to give the corresponding
compounds 9a,b.
Sonicated reactions: These processes were performed on the
same scale described above for silent reactions. The mixture
was irradiated with ultrasound at 30°C for 6 h. The addition
or removal of water controlled the temperature of the water
bath. After completion of the reaction, as indicated by TLC
monitoring, the reaction mixture was treated with ethanol.
The products were obtained and purified as described above
in silent reaction.
6,6′-(4,4′-Oxybis(benzoyl))bis(2-(4methylphenyl)pyridazin-
3(2H)-one) (13b).
Brown solid, m.p. 127–129°C; IR: ν
1689, 1642 (2CO) cmꢀ1; H NMR (DMSO-d6): δ 7.01 (d, 2H,
pyridazine-5-CH, J = 6 Hz), 7.14 (d, 4H, ArH, J = 8 Hz), 7.35 (d,
2H, pyridazine-4-CH, J = 6 Hz), 7.69 (d, 4H, ArH, J = 8 Hz), 7.84
(d, 4H, ArH, J = 8 Hz), 8.03 (d, 4H, ArH, J = 8.4 Hz); 13C NMR
(DMSO-d6): δ 20.11, 118.23, 125.97, 126.34, 127.28, 127.72,
130.17, 132.44, 138.23, 139.60, 144.01, 160.70, 161.46, 188.40;
MS: 594 (M+); C36H26N4O5: Anal. Calcd: C, 72.72; H, 4.41; N,
9.42. Found: C, 72.66; H, 4.46; N, 9.39%.
1
General procedure for the synthesis of bis-(2,3-
Tetramethyl 6,6′-(4,4′-oxybis(benzoyl))bis(2-(4-(trifluoromethyl)
dihydropyridazine-4-carbonitrile) derivatives 15a,b.
Silent
phenyl)-2,3-dihydropyridazine-3,4-dicarboxylate) (9a).
Yellow
solid, m.p. 225–227°C; IR: ν 1703, 1690, 1635 (3CO) cmꢀ1; H
NMR (DMSO-d6): δ 3.74 (s, 6H, 2CH3), 3.88 (s, 6H, 2CH3), 6.33
(s, 2H, pyridazine-3-CH), 7.25 (d, 4H, ArH, J = 8.4Hz), 7.79 (s,
2H, pyridazine-5-CH), 7.93 (d, 4H, ArH, J = 8.4 Hz), 8.05 (d, 4H,
ArH, J = 8.4 Hz), 8.30 (d, 4H, ArH, J = 8.4 Hz); 13C NMR
(DMSO-d6): δ 51.76, 53.28, 84.41, 112.54, 117.50, 123.84,
124.81, 126.19, 127.70, 129.91, 137.21, 142.04, 144.93, 147.14,
161.47, 163.54, 164.36, 189.17; 19F NMR (DMSO-d6): δ ꢀ67.28;
MS: 906 (M+); C44H32F6N4O11: Anal. Calcd: C, 58.28; H, 3.56;
N, 6.18. Found: C, 58.19; H, 3.60; N, 6.21%.
1
reactions: A mixture of the appropriate bis-arylhydrazonal
derivatives 6a,b (1 mmol), acrylonitrile (4 mmol) and DABCO
(2 mmol) was mixed and stirred for 14 days in ethanol (the
reaction progress was followed using TLC). The mixture was
then poured onto water and acidified with dilute hydrochloric
acid. Solid products were collected by filtration, then
recrystallized from a mixture of DMF/EtOH (1:10) to give the
corresponding compounds 15a,b, respectively.
Sonicated reactions: These processes were performed on the same
scale described above for silent reactions. The mixture was irradi-
ated with ultrasound at 50°C for 20 h. The addition or removal of
water controlled the temperature of the water bath. After comple-
tion of the reaction, as indicated by TLC monitoring, the products
were obtained and purified as described above in silent reaction.
Tetramethyl 6,6′-(4,4′-oxybis(benzoyl))bis(2-(4-methylphenyl)-
2,3-dihydropyridazine-3,4-dicarboxylate) (9b).
Yellow
solid, m.p. 270–272°C; IR: ν 1705, 1693, 1630 (3CO) cmꢀ1; H
NMR (DMSO-d6): δ 2.40 (s, 6H, 2CH3), 3.68 (s, 6H, 2CH3), 3.80
(s, 6H, 2CH3), 6.27 (s, 2H, pyridazine-3-CH), 7.23 (d, 4H, ArH,
J = 8.4 Hz), 7.35 (s, 2H, pyridazine-5-CH), 7.69 (d, 4H, ArH,
J = 8.4 Hz), 7.89 (d, 4H, ArH, J = 8.4 Hz), 8.01 (d, 4H, ArH,
J = 8.4 Hz); 13C NMR (DMSO-d6): δ 20.97, 51.35, 53.36, 78.25,
114.12, 118.94, 127.64, 128.97, 129.78, 130.31, 138.21, 139.81,
1
6,6′-(4,4′-Oxybis(benzoyl))bis(2-(4-(trifluoromethyl)phenyl)-
2,3-dihydropyridazine-4-carbonitrile) (15a).
Yellow solid,
1
m.p. 186–188°C; IR: ν 2217 (CN), 1708 (CO) cmꢀ1; H NMR
(DMSO-d6): δ 4.73 (s, 4H, pyridazine-3-CH2), 7.15 (s, 2H,
pyridazine-5-CH), 7.26 (d, 4H, ArH, J = 8.4 Hz), 7.52 (d, 4H, ArH,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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A. E. M. Mekky and A. S. Al-Bogami
Vol 53
J= 8.4 Hz), 7.79 (d, 4H, ArH, J= 8.4 Hz), 7.99 (d, 4H, ArH,
J=8.4Hz); 13C NMR (DMSO-d6): δ 46.77, 105.93, 116.28,
119.55, 122.69, 124.73, 125.55, 127.18, 130.32, 135.77, 139.17,
144.90, 148.30, 161.52, 188.09; 19F NMR (DMSO-d6): δ ꢀ67.47;
MS: 724 (M+); C38H22F6N6O3: Anal. Calcd: C, 62.99; H, 3.06; N,
11.60. Found: C, 62.88; H, 3.10; N, 11.63%.
J= 7 Hz), 4.12 (q, 4H, 2CH2, J= 7 Hz), 7.24 (d, 4H, ArH,
J= 8.4 Hz), 7.80 (s, 2H, pyridazine-5-CH), 7.90 (d, 4H, ArH,
J= 8.4 Hz), 8.01 (d, 4H, ArH, J= 8.4 Hz), 8.21 (d, 4H, ArH,
J= 8.4 Hz), 8.35 (s, 2H, 2NH, D2O-exchangeable); 13C NMR
(DMSO-d6): δ 14.13, 61.69, 117.66, 121.88, 124.36, 125.35,
125.60, 126.34, 127,95, 129.81, 137.00, 139.97, 142.20,
155.09, 160.79, 161.29, 187.31; 19F NMR (DMSO-d6): δ
ꢀ67.68; MS: 844 (M+); C42H30F6N6O7: Anal. Calcd: C,
6,6′-(4,4′-Oxybis(benzoyl))bis(2-(4-methylphenyl)-2,3-dihy-
dropyridazine-4-carbonitrile) (15b).
Yellow solid, m.p.
195–197°C; IR: ν 2220 (CN), 1711 (CO) cmꢀ1 1H NMR
;
59.72; H, 3.58; N, 9.95. Found: C, 59.63; H, 3.61; N, 9.98%.
(DMSO-d6): δ 2.34 (s, 6H, 2CH3), 4.79 (s, 4H, pyridazine-3-CH2),
7.29 (s, 2H, pyridazine-5-CH), 7.42 (d, 4H, ArH, J= 8.4 Hz), 7.69–
7.74 (m, 8H, ArH), 8.02 (d, 4H, ArH, J=8.4 Hz); 13C NMR
(DMSO-d6): δ 19.85, 44.25, 104.79, 116.38, 120.16, 126.63,
128.38, 130.27, 131.35, 133.37, 135.80, 141.87, 144.56, 161.15,
186.76; MS: 616 (M+); C38H28N6O3: Anal. Calcd: C, 73.92; H,
4.63; N, 13.67. Found: C, 74.01; H, 4.58; N, 13.63%.
Diethyl 6,6′-(4,4′-oxybis(benzoyl))bis(3-imino-2-(4-methyl-
phenyl)-2,3-dihydropyridazine-4-carboxylate) (20d).
Yellow
solid, m.p. 195–197°C; IR: ν 3400 (NH), 1720, 1628 (2CO)
1
cmꢀ1; H NMR (DMSO-d6): δ 1.05 (t, 6H, 2CH3, J = 7 Hz), 2.34
(s, 6H, 2CH3), 4.14 (q, 4H, 2CH2, J = 7 Hz), 7.21 (d, 4H, ArH,
J = 8 Hz), 7.38 (d, 4H, ArH, J = 8 Hz), 7.80 (s, 2H, pyridazine-5-
CH), 7.92–7.98 (m, 8H, ArH), 8.22 (s, 2H, 2NH, D2O-exchange-
able); 13C NMR (DMSO-d6): δ 14.05, 20.24, 61.72, 118.08,
121.26, 125.61, 127.45, 128.95, 129.29, 131,13, 135.48, 136.81,
139.32, 154.38, 160.23, 161.40, 187.99; MS: 736 (M+);
C42H36N6O7: Anal. Calcd: C, 68.47; H, 4.92; N, 11.41. Found: C,
68.40; H, 4.97; N, 11.36%.
General procedure for the synthesis of bis-(3-imino-2,3-
dihydropyridazine) derivatives 20a–f and bis-(ethyl 3-oxo-2,3-
dihydropyridazine-4-carboxylate) derivatives 22a,b.
Silent
reactions: To a suspension of the appropriate bis-arylhydrazonal
derivatives 6a,b (10 mmol) in pyridine (25 mL), active
methylene nitrile compounds 18a–c (20 mmol) or diethyl
malonate 21 (20 mmol), one drop of piperidine was added. The
reaction mixture was refluxed for the time indicated in Table 2.
After completion of the reaction as indicated by TLC, the
solvent was evaporated under reduced pressure, and the
products obtained were triturated with ethanol, collected by
filtration and crystallized from a mixture of DMF/EtOH (1:10)
to give the corresponding compounds 20a–f and 22a,b.
Sonicated reactions: These processes were performed on the same
scale described above for silent reactions. The mixture was irradi-
ated with ultrasound at 50°C for suitable time (Table 2). The ad-
dition or removal of water controlled the temperature of the water
bath. After completion of the reaction, as indicated by TLC mon-
itoring, the products were obtained and purified as described
above in silent reaction.
6,6′-(4,4′-Oxybis(benzoyl))bis(4-benzoyl-3-imino-2-(4-(tri-
fluoromethyl)phenyl)-2,3-dihydropyridazine) (20e).
Yellow
solid, m.p. 231–233°C; IR: ν 3340 (NH), 1658, 1622 (2CO)
cmꢀ1 1H NMR (DMSO-d6): δ 7.18 (d, 4H, ArH, J = 8.4 Hz),
;
7.36 (t, 2H, ArH, J = 8 Hz), 7.49 (t, 4H, ArH, J = 8 Hz), 7.80 (d,
4H, ArH, J = 8 Hz), 7.94 (s, 2H, pyridazine-5-CH), 8.01 (d, 4H,
ArH, J = 8.4 Hz), 8.08 (d, 4H, ArH, J = 8.4 Hz), 8.35 (d, 4H, ArH,
J = 8.4Hz), 8.74 (s, 2H, 2NH, D2O-exchangeable); 13C NMR
(DMSO-d6): δ 118.76, 122.63, 124.18, 125.21, 126.63, 126.76,
128.57, 129.48, 130.25, 131.54, 132.19, 136.97, 137.10, 139.03,
141.62, 159.83, 160.86, 187.60, 191.99; 19F NMR (DMSO-d6): δ
ꢀ67.76; MS: 908 (M+); C50H30F6N6O5: Anal. Calcd: C, 66.08;
H, 3.33; N, 9.25. Found: C, 66.19; H, 3.26; N, 9.19%.
6,6′-(4,4′-Oxybis(benzoyl))bis(4-benzoyl-3-imino-2-(4-methyl-
6,6′-(4,4′-Oxybis(benzoyl))bis(3-imino-2-(4-(trifluoromethyl)
phenyl)-2,3-dihydropyridazine) (20f).
Yellow solid, m.p.
252–254°C; IR: ν 3332 (NH), 1661, 1629 (2CO) cmꢀ1; 1H NMR
(DMSO-d6): δ 2.39 (s, 6H, 2CH3), 7.32 (t, 2H, ArH, J = 8 Hz),
7.40 (t, 4H, ArH, J = 8 Hz), 7.74 (d, 4H, ArH, J = 8.4 Hz), 7.82 (s,
2H, pyridazine-5-CH), 7.94–8.02 (m, 8H, ArH), 8.10 (d, 4H,
ArH, J = 8.4 Hz), 8.32 (d, 4H, ArH, J = 8.4 Hz), 8.69 (s, 2H, 2NH,
D2O-exchangeable); 13C NMR (DMSO-d6): δ 20.16, 118.20,
122.54, 125.11, 126.80, 128.35, 129.40, 129.89, 131.52, 132.03,
132.27, 137.04, 139.10, 140.17, 142.06, 159.73, 160.37, 187.55,
192.17; MS: 800 (M+); C50H36N6O5: Anal. Calcd: C, 74.99; H,
4.53; N, 10.49. Found: C, 74.89; H, 4.57; N, 10.54%.
phenyl)-2,3-dihydropyridazine-4-carbonitrile) (20a).
Yellow
solid, m.p. 265–267°C; IR: ν 3370 (NH), 2220 (CN), 1622 (CO)
cmꢀ1; 1H NMR (DMSO-d6): δ 7.15 (d, 4H, ArH, J= 8.4 Hz), 7.74 (s,
2H, pyridazine-5-CH), 7.86 (d, 4H, ArH, J= 8.4 Hz), 7.99 (d, 4H,
ArH, J= 8.4 Hz), 8.14 (d, 4H, ArH, J= 8.4 Hz), 8.23 (s, 2H, 2NH,
D2O-exchangeable); 13C NMR (DMSO-d6): δ 108.88, 116.50, 118.78,
121.57, 124.87, 125.89, 126.65, 127.06, 129.95, 139.59, 141.62,
143.91, 155.33, 161.42, 188.07; 19F NMR (DMSO-d6): δ ꢀ67.61;
MS: 750 (M+); C38H20F6N8O3: Anal. Calcd: C, 60.80; H, 2.69; N,
14.93. Found: C, 60.69; H, 2.74; N, 14.99%.
Diethyl 6,6′-(4,4′-oxybis(benzoyl))bis(3-oxo-2-(4-(trifluorome-
6,6′-(4,4′-Oxybis(benzoyl))bis(3-imino-2-(4-methylphenyl)-
thyl)phenyl)-2,3-dihydropyridazine-4-carboxylate) (22a).
2,3-dihydropyridazine-4-carbonitrile) (20b).
Yellow solid, m.
p. 288–290°C; IR: ν 3378 (NH), 2231 (CN), 1629 (CO) cmꢀ1
;
Brown solid, mp 153–155°C; IR: ν 1710, 1649, 1630
1H NMR (DMSO-d6): δ 2.38 (s, 6H, 2CH3), 7.14 (d, 4H, ArH,
J = 8 Hz), 7.40 (d, 4H, ArH, J = 8.4 Hz), 7.74 (s, 2H, pyridazine-5-
CH), 7.87–7.90 (m, 8H, ArH), 8.26 (s, 2H, 2NH, D2O-exchange-
able); 13C NMR (DMSO-d6): δ 19.80, 108.84, 115.07, 117.36,
120.93, 127.16, 128.94, 129.07, 131.23, 136.83, 138.48, 143.95,
153.75, 160.87, 188.86; MS: 642 (M+); C38H26N8O3: Anal. Calcd:
C, 71.02; H, 4.08; N, 17.44. Found: C, 71.11; H, 4.04; N, 17.33%.
Diethyl 6,6′-(4,4′-oxybis(benzoyl))bis(3-imino-2-(4-(trifluo-
1
(3CO) cmꢀ1; H NMR (DMSO-d6): δ 1.13 (t, 6H, 2CH3,
J = 7 Hz), 4.19 (q, 4H, 2CH2, J = 7 Hz), 7.26 (d, 4H, ArH,
J = 8.4 Hz), 7.82 (s, 2H, pyridazine-5-CH), 7.94 (d, 4H,
ArH, J = 8.4 Hz), 8.00 (d, 4H, ArH, J = 8.4 Hz), 8.36 (d, 4H,
ArH, J = 8.4 Hz); 13C NMR (DMSO-d6): δ 13.82, 61.75,
118.02, 123.81, 124.36, 127.80, 128.22, 130.01, 131,52,
131.94, 139.51, 142.27, 143.65, 160.59, 161.42, 162.80,
187.46; 19F NMR (DMSO-d6): δ ꢀ67.54; MS: 846 (M+);
C42H28F6N4O9: Anal. Calcd: C, 59.58; H, 3.33; N, 6.62.
Found: C, 59.66; H, 3.27; N, 6.58%.
romethyl)phenyl)-2,3-dihydropyridazine-4-carboxylate) (20c).
Yellow solid, m.p. 178–180°C; IR: ν 3411 (NH), 1713, 1635
1
(2CO) cmꢀ1; H NMR (DMSO-d6): δ 1.04 (t, 6H, 2CH3,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2016
Ultrasound Assisted Synthesis of Some Novel Bis-Pyridazine Derivatives Using
Bis-Arylhydrazonopropanals
605
[2] Mason, T. J.; Peters, D. Practical Sonochemistry. Power Ultra-
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2012, 19, 999.
Diethyl 6,6′-(4,4′-oxybis(benzoyl))bis(3-oxo-2-(4-methylphenyl)-
2,3-dihydropyridazine-4-carboxylate) (22b).
Brown solid,
1
m.p. 141–143°C; IR: ν 1716, 1653, 1641 (3CO) cmꢀ1; H NMR
(DMSO-d6): 1.12 (t, 6H, 2CH3, J = 7 Hz), 2.38 (s, 6H, 2CH3),
4.21 (q, 4H, 2CH2, J = 7 Hz), 7.20 (d, 4H, ArH, J = 8 Hz), 7.41 (d,
4H, ArH, J = 8 Hz), 7.76 (s, 2H, pyridazine-5-CH), 8.00–8.09 (m,
8H, ArH); 13C NMR (DMSO-d6): δ 14.10, 21.05, 61.65, 118.10,
125.60, 126.34, 129.11, 129.18, 131.29, 132,17, 139.14, 141.98,
143.09, 160.38, 161.26, 162.42, 188.09; MS: 738 (M+);
C42H34N4O9: Anal. Calcd: C, 68.29; H, 4.64; N, 7.58. Found: C,
68.35; H, 4.60; N, 7.52%.
[9] Zbancioc, G.; Florea, O.; Jones, P.; Mangalagiu, I. I. Ultrason
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General procedure for the of synthesis bis(4-benzamido-3-
oxo-2,3-dihydropyridazine) derivatives 25a,b. Silent reactions:
A mixture of the bis-arylhydrazonal derivatives 6a,b (10 mmol),
hippuric acid (20 mmol), and acetic anhydride (25mL) was heated
under reflux for 8 h. The excess solvent was evaporated under
reduced pressure in vacuum. The pasty residue obtained was
triturated with ethanol (25 mL), and the solidified material was
collected by filtration, washed thoroughly with diethyl ether
(25 mL) and crystallized from acetic acid to give the
corresponding compounds 25a,b.
Sonicated reactions: These processes were performed on the same
scale described above for silent reactions. The mixture was irradi-
ated with ultrasound at 50°C for suitable time (Table 2). The
addition or removal of water controlled the temperature of the
water bath. After completion of the reaction, as indicated by
TLC monitoring, the products were obtained and purified as
described above in silent reaction.
[10] Bejan, V.; Moldoveanu, C.; Mangalagiu, I. I. Ultrason
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6,6′-(4,4′-Oxybis(benzoyl))bis(4-benzamido-3-oxo-2-(4-(tri-
fluoromethyl)phenyl)-2,3-dihydropyridazine) (25a).
Brown
solid, m.p. 168–170°C; IR: ν 3340 (NH), 1675, 1643, 1620
(3CO) cmꢀ1 1H NMR (DMSO-d6): δ 7.26 (d, 4H, ArH,
;
J = 8.4 Hz), 7.41 (t, 2H, ArH, J = 8 Hz), 7.63–7.68 (m, 8H, ArH),
7.73 (s, 2H, pyridazine-5-CH), 8.00–8.05 (m, 8H, ArH), 8.41 (d,
4H, ArH, J = 8.4Hz), 9.97 (s, 2H, 2NH, D2O-exchangeable); 13C
NMR (DMSO-d6): δ 120.14, 121.54, 124.11, 125.17, 126.24,
126.67, 128.53, 129.34, 130.21, 130.50, 132.11, 136.90, 138.03,
139.10, 141.62, 156.37, 160.83, 162.90, 188.07; 19F NMR (DMSO-
d6): δ ꢀ67.70; MS: 940 (M+); C50H30F6N6O7: Anal. Calcd: C, 63.83;
H, 3.21; N, 8.93. Found: C, 63.89; H, 3.16; N, 8.87%.
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6,6′-(4,4′-Oxybis(benzoyl))bis(4-benzamido-3-oxo-2-(4-methyl-
phenyl)-2,3-dihydropyridazine) (25b).
Brown solid, m.p.
199–201°C; IR: ν 3348 (NH), 1682, 1633, 1617 (3CO) cmꢀ1; H
NMR (DMSO-d6): δ 2.38 (s, 6H, 2CH3), 7.35 (d, 4H, ArH,
J= 8.4 Hz), 7.46 (t, 2H, ArH, J=8Hz), 7.71–7.79 (m, 10H, ArH,
pyridazine-5-CH), 7.96–8.03 (m, 8H, ArH), 8.36 (d, 4H, ArH,
J= 8.4 Hz), 9.91 (s, 2H, 2NH, D2O-exchangeable); 13C NMR
(DMSO-d6): δ 20.13, 120.19, 121.74, 125.10, 126.73, 128.70, 129.34,
130.05, 131.50, 131.88, 133.42, 137.13, 138.76, 140.11, 141.87,
156.24, 160.31, 163.11, 188.15; MS: 832 (M+); C50H36N6O7: Anal.
Calcd: C, 72.11; H, 4.36; N, 10.09. Found: C, 72.16; H, 4.29; N, 10.02%.
1
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[1] Dong, C.; Sanjay, K.; Ackmez, M. Handbook on Applications
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet