Synthesis and biological evaluation of 3-O-substituted 1-benzyl-6-oxo-1,6-dihydropyridazine derivatives

Article abstract of DOI:10.1177/1747519819866402

On the basis of 2-benzyl-6-hydroxypyridazin-3(2H)-one, a series of its novel O-substituted (including 6-(1,3,5-triazin-2-yl)oxy) derivatives is prepared. It is proven that the substitution reactions in the initial compound occur mainly at the oxygen atom of the hydroxy group. On the basis of the obtained oxy-aceto(propane)hydrazides, the corresponding azides and anilides are synthesized. A series of 2-[(1-benzyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]-N′-(substituted benzylidene)aceto(propane)hydrazides is obtained via the reaction of various aromatic aldehydes with the same hydrazides. Heterocyclization of the latter affords compounds with a combination of pyridazine and 1,3,4-oxadiazole rings in the molecule. The reaction of oxy-acetohydrazide with potassium thiocyanate and a mixture of CS₂/KOH leads to potassium salts of 2-{[(1-benzyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]methyl}hydrazine-1-carbothioamide and 2-{2-[(1-benzyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]acetyl}hydrazine-1-carbodithioic acid, respectively. Acid hydrolysis of the latter affords 2-benzyl-6-[(5-thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)methoxy]pyridazin-3(2H)-one.

Full text of DOI:10.1177/1747519819866402

866402CHL0010.1177/1747519819866402Journal of Chemical ResearchShainova et al.
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Research Paper
Journal of Chemical Research
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Synthesis and biological evaluation of
3-O-substituted 1-benzyl-6-oxo-1,6-
dihydropyridazine derivatives
https://doi.org/10.1177/1747519819866402
DOI: 10.1177/1747519819866402
journals.sagepub.com/home/chl
Roza S Shainova1,2 , Tiruhi A Gomktsyan2,
Armen V Karapetyan2 and Aleksandr P Yengoyan1,2
Abstract
On the basis of 2-benzyl-6-hydroxypyridazin-3(2H)-one, a series of its novel O-substituted (including 6-(1,3,5-triazin-2-
yl)oxy) derivatives is prepared. It is proven that the substitution reactions in the initial compound occur mainly at the
oxygen atom of the hydroxy group. On the basis of the obtained oxy-aceto(propane)hydrazides, the corresponding
azides and anilides are synthesized. A series of 2-[(1-benzyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]-N′-(substituted
benzylidene)aceto(propane)hydrazides is obtained via the reaction of various aromatic aldehydes with the same
hydrazides. Heterocyclization of the latter affords compounds with a combination of pyridazine and 1,3,4-oxadiazole
rings in the molecule. The reaction of oxy-acetohydrazide with potassium thiocyanate and a mixture of CS2/KOH
leads to potassium salts of 2-{[(1-benzyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]methyl}hydrazine-1-carbothioamide and
2-{2-[(1-benzyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]acetyl}hydrazine-1-carbodithioic acid, respectively. Acid hydrolysis
of the latter affords 2-benzyl-6-[(5-thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)methoxy]pyridazin-3(2H)-one.
Keywords
2-[(1-benzyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]-N'-(substituted benzylidene)aceto(propane)hydrazides, 2-benzyl-
6-[(1,3,5-triazin-2-yl)oxy]pyridazin-3(2H)-one, 2-benzyl-6-[(5-thioxo-4,5-dihydro-1,3,4-oxa(thia)diazol-2-yl)methoxy]
pyridazin-3(2H)-ones, 2-benzyl-6-hydroxypyridazin-3(2H)-one, heterocyclization, oxo-oxy-tautomerism, plant growth
stimulant activity
Date received: 13 Febrauary 2019; accepted: 21 June 2019
Introduction
In medical and agricultural practice, a range of medi-
cines and plant protection chemicals created on the basis
1Department of General and Pharmaceutical Chemistry, Russian-
Armenian University, Yerevan, Armenia
2Research Center of Pesticides Synthesis and Plant Protection,
Armenian National Agrarian University, Yerevan, Armenia
of azines and azoles are used. Pyridazine derivatives rep-
resent one of the most active classes of organic com-
pounds possessing a broad spectrum of biological
activity. Pyridazin-3-ones, a form of pyridazine with a
carbonyl group, also exhibit a diverse range of pharma-
ceutical properties. A variety of drugs (e.g. chloridazon,
Corresponding author:
Roza S Shainova, Department of General and Pharmaceutical Chemistry,
Russian-Armenian University, 123, H.Emin str., Yerevan 0051, Armenia.
Email: rozetta_11@mail.ru

2
Journal of Chemical Research 00(0)
Scheme 1. Synthesis and substitution reactions of 2-benzyl-6-hydroxypyridazin-3(2H)-one (1).
emorfazone, zardaverine, pyridaphenthion, minaprine, derivatives, as well as compounds in which the pyridazine
gabazine, hydralazine, levosimendan, amipizone, indoli- moiety is linked with azines or azoles, and to study their
dan, imazodan, pimobedan) are widely used in medical biological activity in terms of searching for new environ-
therapy.1 The arsenal of pesticides based on pyridazine mentally friendly pesticides or plant growth regulators.
and pyridazinone includes mainly herbicides (credazine,
pyridafol, pyridate, brompyrazon, chloridazon, dimida-
zon, flufenpyr, metflurazon, norflurazon, oxapyrazon,
Results and discussion
pydanon).2 Because of the significant interest in these The initial 2-benzyl-6-hydroxypyridazin-3(2H)-one (1)
heterocyclic derivatives, over the last decades, studies was obtained from benzylhydrazine and maleic anhydride
on pyridazine derivatives have continued to lead to new (Scheme 1). Compound 1 can exist in oxo and oxy tauto-
compounds with fungicidal,3–6 herbicidal,7,8 and insecti- meric forms, and the subsequent alkylation can proceed at
cidal9 activities.
the oxygen atom or the nitrogen atom of the pyridazine
Among the five-membered heterocycles with three heter- ring. Reaction of 2-benzyl-6-hydroxypyridazin-3(2H)-one
oatoms, one of the most applicable is 1,2,4-triazole deriva- (1) with azinyl-2-yl-trimethylammonium chloride and
tives, which are widely used in medicine, agriculture, and alkyl halides formed compounds 2 and 3, respectively. In
industry. Anumber of compounds synthesized on the basis of the IR spectra of compounds 2 and 3, just as in the case of
this heterocyclic ring are used in agriculture as plant protec- compound 1, only one absorption due to the carbonyl group
tion chemicals: herbicides (amitrole, cafenstrole, epronaz, C=O is observed, which indicates that the substitution
flupoxam, amicarbazone, bencarbazone, carfentrazone, flu- occurs at the oxygen atom of the hydroxy form. Otherwise,
carbazone, ipfencarbazone, propoxycarbazone, sulfentra- absorptions from two different carbonyl groups should
zone, thiencarbazone, and a series of triazolopyrimidines), have been observed.
fungicides (amisulbrom, bitertanol, fluotrimazole, triazbutil,
and a large number of conazole fungicides), and organothi- hydrazides 4 and 5 which were obtained by the reaction of
ophosphate insecticides (isazofos, triazophos).2
esters 3 with hydrazine hydrate (see “Safety warning” in
The spectrum of the pesticidal activity of 1,3,4-oxadia- the “Experimental” section).
Further syntheses were carried out on the basis of
zole derivatives is more limited. However, in the recent
The reactions of hydrazides 4 and 5 with sodium nitrite
years, derivatives of this heterocycle have been the subject in acetic acid afforded 2-[(1-benzyl-6-oxo-1,6-dihydro-
of many studies in terms of searching for new biologically pyridazin-3-yl)oxy]acetyl azides 6 and 7, which with
active compounds.
4-chloroaniline formed the corresponding amides 8 and 9
The increase of environmental requirements and the fact (Scheme 2). Reaction of the initial hydrazides with vari-
that harmful organisms сan acquire resistance against the ous aldehydes formed substituted benzylidene acetohy-
chemical means of plant protection make it necessary to drazides 10 and 11. The heterocyclization of the same
systematically replenish the arsenal of pesticides with new hydrazides (4 and 5) under the action of carbon disulfide
and more environmentally friendly preparations having dif- and an alcoholic solution of potassium hydroxide led to
ferent mechanisms of action. In this regard, the targeted 2-benzyl-6-[(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)
synthesis of new compounds with a combination of the alkyloxy]-3(2H)-ones 12 and 13. The corresponding
above mentioned pharmacophore heterocycles in the same S-substituted products 14 and 15 were obtained by alkyla-
molecule could lead to new biologically active derivatives, tion of the latter with alkyl halides. In this case, it was
with respect to which resistance has not yet emerged. The proved that derivatives 12 and 13 have the thione tauto-
purpose of this study was to develop accessible and effec- meric structure, but their alkylation proceeds at the sulfur
tive methods for the synthesis of novel pyridazine atom. In the 13C NMR spectra of compounds 12 and 13, a

Shainova et al.
3
Scheme 2. Transformations based on hydrazides (4,5).
Scheme 3. Synthesis and transformations of potassium salts of hydrazine-1-carbodithioic acid 16 and hydrazine-1-carbothioamide 18.
signal for the carbon atom of the exocyclic C=S double broken to form the initial 2-benzyl-6-hydroxypyridazin-
bond was observed at 177.7–177.9 ppm, and in the 13C 3(2H)-one (1) (Scheme 3).
NMR spectra of compounds 14 and 15 this signal disap-
peared and resonances corresponding to S-alkyl groups
were observed (Scheme 2).
Biological properties
In order to synthesize compounds with a combination of Preliminary screening of the pesticidal and growth regula-
pyridazine ring and other azoles (1,3,4-thiadiazole or 1,2,4-tri- tory activities of the novel synthesized compounds was
azole) in the molecule, potassium 2-{2-[(1-benzyl-6-oxo- studied. None of the preparations demonstrated any notice-
1,6-dihydropyridazin-3-yl)oxy]acetyl}hydrazine-1- able herbicidal or fungicidal properties, but they showed
carbodithioate (16) and potassium (2-{[(1-benzyl-6-oxo- pronounced growth stimulation activity.
1,6-dihydropyridazin-3-yl)oxy]methyl}hydrazine-1-carbon-
othioyl)amide (18) were first obtained (Scheme 3).
For the evaluation of growth regulatory properties, the
action of aqueous emulsions (25 and 50 mg L−1) of the com-
The acid hydrolysis of compound 16 afforded the pounds synthesized on the germination, growth, and surviva-
expected 2-benzyl-6-[(5-thioxo-4,5-dihydro-1,3,4-thiadia- bility of seeds and seedlings of dicotyledonous bean
zol-2-yl)methoxy]pyridazin-3(2H)-one (17), and boiling of (Phaseolus vulgaris L.) were studied and compared with that
the same salt in ethanol led to compound 12. At the same of heteroauxin (IAA). Two series of bean seeds were incu-
time, the reaction of compound 16 with hydrazine or alka- bated for 24 h in appropriate mediums in the dark at 25 °C.
line hydrolysis of compound 18 failed to yield the target Then, the seeds were transplanted into soil and watered daily.
6-[(4-amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl) The experimental data calculations were produced in 20–25
methoxy]-2-benzylpyridazin-3(2H)-one and 2-benzyl- days. The number of plant roots of each series, their length
6-[(5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methoxy] and weight in moist and dry forms, and their average values
pyridazin-3(2H)-one. In both reactions, the O–C bond was were calculated. The results were compared with similar data

4
Journal of Chemical Research 00(0)
of plants placed in IAA solutions, and the activities of prepa-
rations in comparison with IAA (in %) were determined.
2-Benzyl-6-{[4,6-bis(dimethylamino)-1,3,5-triazin-
2-yl]oxy}pyridazin-3(2H)-one (2b): White crystals; yield
Twelve of the obtained compounds (2b, 5, 7, 10a–c, 2.8 g (78%); m.p. 142–144 °C; IR ν (cm−1): 1664 (C=O);
11a–c, 12, 13, 18), which have shown activity higher than 1H NMR: δ 3.00 and 3.11 (12H, s, 4×NCH3), 5.15 (2H, s,
70%, are being prepared for more detailed studies and fur- NCH2), 6.91 (1H, d, J = 9.7 Hz, = CH pyrid.), 7.19–7.37
ther field trials.
(m, 6H, = CH pyrid. and C6H5); 13C NMR: δ 35.4, 35.6,
53.8, 127.0, 127.8, 127.9, 129.8, 130.6, 136.0, 147.6, 158.1,
165.6, 169.0. Anal. Calcd for C18H21N7O2: C, 58.84; H,
5.76; N, 26.69. Found: C, 58.72; H, 5.67; N, 26.41.
Experimental
IR spectra were obtained on an Avatar 330FT-IR (Thermo
Nicolet) spectrometer, using the attenuated total reflectance
Synthesis of compounds 3a–c; general
procedure
1
(ATP) method. H and 13C NMR spectra were recorded at
30 °C on a Varian Mercury-300 (300 and 75 MHz appropri-
ately) spectrometer with standard pulse sequences operat-
ing in a mixture of solvents (DMSO-d6 and CCl4 (1:3)),
using tetramethylsilane (0.0 ppm) as internal standard. The
NMR multiplicities br s, s, d, t, q, and m stand for broad
singlet, singlet, doublet, triplet, quartet, and multiplet,
respectively. The reaction progress and purity of the
obtained substances was checked by thin-layer chromatog-
raphy (TLC) on “Silufol UV-254” plates with acetone/hex-
ane mixture (2:1) as the eluent. Elemental analysis was
carried out on a Eurovector EA3000 elemental CHNS-O
analyzer. All melting points were determined in open capil-
laries and are uncorrected.
To a mixture of the potassium salt of compound 1 (10 mmol)
in dimethylformamide (DMF; 10 mL), NaI (10 mmol) and
an appropriate alkyl halide (10 mmol) were added. The mix-
ture was stirred at room temperature for 5 h and then allowed
to stand overnight. After stirring at 65–70 °C for 5–6 h, the
solvent was evaporated at normal pressure, the residue was
washed with aqueous Na2S2O3 solution, and the precipitate
was filtered off and dried.
2-[(1-Benzyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]aceta-
mide (3a): White crystals; yield 1.1 g (42%); m.p. 157–158
°C; 1H NMR: δ 4.46 (2H, s, OCH2), 5.06 (2H, s, NCH2), 6.87
(1H, d, J = 9.7 Hz, = CH pyrid.), 7.13 (1H, d, J = 9.7 Hz, =
CH pyrid.), 7.13–7.37 (7H, m, NH2 and C6H5); 13C NMR: δ
53.4, 64.5, 126.4, 127.0, 127.8, 128.1, 132.4, 136.2, 150.7,
157.5, 168.3. Anal. Calcd for C13H13N3O3: C, 60.23; H, 5.05;
N, 16.21. Found: C, 60.38; H, 5.18; N, 16.50.
Methyl 2-[(1-benzyl-6-oxo-1,6-dihydropyridazin-3-yl)
oxy]acetate (3b): White crystals; yield 2.4 g (88%); m.p.
90–92 °C; IR ν (cm−1): 1757, 1663 (C=O). 1H NMR: δ 3.62
(3H, s, OCH3), 4.68 (2H, s, OCH2), 5.04 (2H, s, NCH2),
6.93 (1H, d, J = 9.8 Hz, = CH pyrid.), 7.12 (1H, d, J = 9.8
Hz, = CH pyrid.), 7.20–7.32 (5H, m, C6H5); 13C NMR: δ
51.1, 53.1, 62.5, 125.6, 127.0, 127.8, 127.9, 133.0, 136.1,
150.2, 157.3, 167.1. Anal. Calcd for C14H14N2O4: C, 61.31;
H, 5.15; N, 10.21. Found: C, 61.22; H, 5.10; N, 10.02.
Methyl 2-[(1-benzyl-6-oxo-1,6-dihydropyridazin-3-yl)
oxy]propanoate (3c): White crystals; yield 1.9 g (67%);
m.p. 86–88 °C; 1H NMR: δ 1.52 (3H, d, J = 7.0 Hz, CH3),
3.55 (3H, s, OCH3), 4.93 (1H, q, J = 7.0 Hz, OCH), 4.89
and 5.14 (2H, d, d, J = 13.8 Hz, NCH2), 6.92 (1H, d, J =
9.7 Hz, = CH pyrid), 7.07 (1H, d, J = 9.7 Hz, = CH pyrid),
7.20–7.32 (5H, m, C6H5); 13C NMR: δ 16.9, 51.2, 51.2,
53.0, 70.1, 125.6, 126.9, 127.8, 127.9, 132.9, 136.1, 150.2,
157.2, 170.2. Anal. Calcd for C15H16N2O4: C, 62.49; H,
5.59; N, 9.72. Found: C, 62.31; H, 5.45; N, 9.55.
Synthesis of 2-Benzyl-6-hydroxypyridazin-3(2H)-one
(1): To a mixture of benzylhydrazine (10 mmol), water
(100 mL), and hydrochloric acid (10 mmol), maleic anhy-
dride was added (10 mmol). The mixture was stirred at
110–120 °C for 6 h, cooled, and the precipitate was filtered
off and dried to give product 1. Brown crystals; yield 1.2 g
1
(62%); m.p. 204–206 °C; IR ν (cm−1): 1660 (C=O); H
NMR: δ 5.06 (2H, s, NCH2), 6.82 (1H, d, J = 9.7 Hz, = CH
pyrid.), 6.94 (1H, d, J = 9.7 Hz, = CH pyrid.), 7.19–7.35
(5H, m, C6H5), 10.76 (1H, s, OH); 13C NMR: δ 52.9, 126.6,
126.8, 127.6, 127.8, 132.4, 136.9, 152.2, 157.5. Anal. Calcd
for C11H10N2O2: C, 65.34; H, 4.98; N, 13.85. Found: C,
65.18; H, 4.79; N, 13.66.
Synthesis of compounds 2a,b; general
procedure
To a mixture of potassium salt of compound 1 (10 mmol) in
anhydrous acetone (10 mL) at 0–5 °C, substituted 1,3,5-tri-
azinyl-trimethyl ammonium chloride (10 mmol) was added
in portions. The mixture was stirred at room temperature for
5–6 h and then at 45–50 °C until the amine had been evapo-
rated. The solvent was evaporated off at normal pressure and
the residue was treated with ice-cold water and filtered off.
6-{[4-Amino-6-(dimethylamino)-1,3,5-triazin-2-yl]
oxy}-2-benzylpyridazin-3(2H)-one (2a): White crystals;
yield 2.9 g (85%); m.p. 184–186 °C; IR ν (cm−1): 1663
Synthesis of compounds 4, 5; general
procedure
(C=O); 1H NMR: δ 2.99 (3H, s, NCH3), 3.09 (3H, s, NCH3), Safety warning: Appropriate precautions must be taken
5.14 (2H, s, NCH2), 6.43 and 6.71 (2H, br s, NH2), 6.92 when using hydrazine hydrate or hydrazines due to their
(1H, d, J = 9.8 Hz, = CH pyrid.), 7.20–7.38 (6H, m, = CH toxicity and possible explosive nature.
pyrid. and C6H5); 13C NMR: δ 35.5, 35.7, 53.8, 127.1,
To compound 3b or 3c (10 mmol) in isopropanol (10
127.9, 128.0, 130.1, 130.7, 136.0, 147.6, 158.3, 166.0, mL), 63% hydrazine hydrate (15 mmol) was added slowly
167.6, 169.3. Anal. Calcd for C16H17N7O2: C, 56.63; H, at 0 °C. The reaction mixture was stirred at room tempera-
5.05; N, 28.89. Found: C, 56.50; H, 5.14; N, 28.61.
ture for 4–5 h and allowed to stand overnight. Water

Shainova et al.
5
(20–25 mL) was added and the precipitate was filtered 5.03 (2H, s, NCH2), 6.90 (1H, d, J = 9.8 Hz, = CH pyrid.),
off, washed with water, and dried. 7.18 (1H, d, J = 9.8 Hz, = CH pyrid.), 7.10–7.62 (9H,
2-[(1-Benzyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]ace- C6H5, C6H4), 9.96 (1H, s, NH). Anal. Calcd for
tohydrazide (4): White crystals; yield 2.3 g (83%); m.p. C19H16ClN3O3: C, 61.71; H, 4.36; N, 11.36. Found: C,
138–140 °C; 1H NMR: δ 3.94 (2H, brs, NH2), 4.53 (2H, s, 61.63; H, 4.27; N, 11.18.
OCH2), 5.05 (2H, s, NCH2), 6.86 (1H, d, J = 9.8 Hz, = CH
2-[(1-Benzyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]-N-
pyrid.), 7.13 (1H, d, J = 9.8 Hz, = CH pyrid.), 7.20–7.36 (4-chlorophenyl)propanamide (9): Brown crystals; yield
(5H, m, C6H5), 9.21 (1H, brs, NH); 13C NMR: δ 53.3, 64.0, 2.3 g (60%); m.p. 170–172 °C; 1H NMR: δ 1.56 (3H, d, J =
126.5, 127.0, 127.8, 128.1, 132.3, 136.2, 150.6, 157.5, 6.7 Hz, CH3), 5.03 (1H, q, J = 6.7 Hz, OCH), 4.90 and 5.04
165.7. Anal. Calcd for C13H14N4O3: C, 56.93; H, 5.15; N, (2H, d,d, J = 13.7 Hz, NCH2), 6.82 (1H, d, J = 9.7 Hz, =
20.43. Found: C, 56.79; H, 5.07; N, 20.28.
CH pyrid.), 6.93 (1H, d, J = 9.8 Hz, = CH pyrid.), 6.87–
2-[(1-Benzyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]pro- 7.63 (9H, C6H5, C6H4), 9.94 (1H, s, NH). Anal. Calcd for
panehydrazide (5): White crystals; yield 1.9 g (67%); m.p. C20H18ClN3O3: C, 62.58; H, 4.73; N, 10.95. Found: C,
160–162 °C; 1H NMR: δ 1.45 (3H, d, J = 6.7 Hz, CH3), 3.88 62.62; H, 4.62; N, 10.71.
(2H, br s, NH2), 4.97 (1H, q, J = 6.7 Hz, OCH), 4.99 and
5.07 (2H, d, d, J = 13.8 Hz, NCH2), 6.84 (1H, d, J = 9.7 Hz,
Synthesis of compounds 10a–c, 11a–c;
= CH pyrid.), 7.08 (1H, d, J = 9.7 Hz, = CH pyrid.), 7.20–
general procedure
7.37 (5H, m, C6H5), 9.17 (1H, br s, NH); 13C NMR: δ 17.6,
53.2, 71.1, 126.6, 126.9, 127.8, 128.2, 132.1, 136.3, 150.3, To compounds 4 or 5 (10 mmol), water (10 mL) and HCl
157.3, 169.3. Anal. Calcd for C14H16N4O3: C, 58.32; H, 5.59; (36%, 1.5 mL) were added. The appropriate aldehyde (10
N, 19.43. Found: C, 58.19; H, 5.44; N, 19.27.
mmol) was added to the reaction mixture, which was stirred
at 20 °C for 24 h. After the addition of water (10–15 mL),
the precipitate was filtered off and dried.
2-[(1-Benzyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]-N′-
(4-methoxybenzylidene)acetohydrazide (10a): White crys-
Synthesis of compounds 6, 7; general
procedure
To a mixture of compound 4 or 5 (20 mmol) in water (10 mL), tals; yield 3.6 g (93%); m.p. 78–80 °C; 1H NMR: δ (E/Z =
NaNO2 (56 mmol) was added. Then, at 0 °C, acetic acid (56 80:20%) 3.83 (3H, s, OCH3), 4.65 (Z) and 5.13 (E) (2H, s,
mmol) was added dropwise. The reaction mixture was stirred OCH2), 5.02 (E) and 5.05 (Z) (2H, s, NCH2), 6.86–7.67
at room temperature for 3–4 h, washed with water, the pre- (11H, m, CH=CH, C6H5 and C6H4), 7.91 (E) and 8.22 (Z)
cipitate filtered off, washed with water, and dried.
(1H, s, CH=N), 11.15 (Z) and 11.37 (E) (s, 1H, NH); 13C
2-[(1-Benzyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]acetyl NMR: δ 53.4, 54.7, 63.1, 113.6, 126.1, 126.5, 126.9, 127.8,
azide (6): White crystals; yield 2.5 g (88%); m.p. 96–98 °C; 128.2, 132.5, 136.1, 143.4, 150.9, 157.5, 160.4, 162.4,
1H NMR: δ 4.73 (2H, s, OCH2), 5.05 (2H, s, NCH2), 6.94 167.2. Anal. Calcd for C21H20N4O4: C, 64.28; H, 5.14; N,
(1H, d, J = 9.8 Hz,= CH pyrid.), 7.13 (1H, d, J = 9.8 Hz, = 14.28. Found: C, 64.40; H, 5.29; N, 14.44.
CH pyrid.), 7.22–7.31 (5H, m, C6H5); 13C NMR: δ 53.0,
2-[(1-Benzyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]-N′-(4-
64.5, 125.4, 127.1, 127.8, 128.0, 133.2, 136.0, 149.9, 157.3, hydroxy-3-methoxybenzylidene)acetohydrazide (10b): White
1
174.2. Anal. Calcd for C13H11N5O3: C, 54.74; H, 3.89; N, crystals; yield 3.6 g (89%); m.p. 135–137 °C; H NMR: δ
24.55. Found: C, 54.88; H, 3.96; N, 24.72.
3.82 (E) and 3.84 (Z) (3H, s, OCH3), 4.65 (Z) and 5.14 (E)
2-[(1-Benzyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]pro- (2H, s, OCH2), 5.01 (E) and 5.03 (Z) (2H, s, NCH2), 6.89 (E)
panoyl azide (7): White crystals; yield 2.5 g (85%); m.p. (0.8H, d, J = 9.8 Hz, = CH pyrid.), 7.13 (E) (0.8H, d, J = 9.8
92–94 °C; 1H NMR: δ 1.54 (3H, d, J = 6.9 Hz, CH3), 4.89 Hz, = CH pyrid.), 6.74–7.35 (8H, m, C6H5 and C6H3); 7.86
(1H, q, J = 6.9 Hz, OCH), 4.85 and 5.21 (2H, d,d, J = 13.9 (E) and 8.15 (Z) (1H, s, CH=N), 8.98 (E) and 9.01 (Z) (1H, s,
Hz, NCH2), 6.96 (1H, d, J = 9.8 Hz, = CH pyrid.), 7.07 OH), 11.11 (Z) and 11.30 (E) (1H, s, NH); 13C NMR: δ 53.4
(1H, d, J = 9.8 Hz, = CH pyrid.), 7.20 and 7.38 (5H, m, (E), 53.5 (Z), 55.27 (E), 55.33 (Z), 63.1 (E), 64.4 (Z) 108.8
C6H5); 13C NMR: δ 16.7, 52.9, 71.7, 125.3, 127.1, 127.8, (Z), 109.2 (E), 115.0 (Z), 115.1 (E), 121.2 (E), 121.8 (Z),
128.0, 133.2, 136.0, 149.9, 157.2, 177.4. Anal. Calcd for 125.2 (E), 125.3 (Z), 126.1 (E), 126.3 (Z), 126.97 (E), 127.02
C14H13N5O3: C, 56.18; H, 4.38; N, 23.40. Found: C, 56.02; (Z), 127.8 (E), 127.9 (Z), 128.1, 132.5, 136.1, 144.1, 147.6
H, 4.23; N, 23.21.
(E), 147.7, 148.2, 148.8 (E), 149.0 (Z), 150.9, 157.5, 162.4
(Z), 167.1. Anal. Calcd for C21H20N4O5: C, 61.76; H, 4.94; N,
13.72. Found: C, 61.90; H, 4.99; N, 13.97.
Synthesis of compounds 8, 9; general
procedure
2-[(1-Benzyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]-N′-
(3-nitrobenzylidene)acetohydrazide (10c): White crystals;
1
To compound 6 or 7 (10 mmol) in dry toluene medium, yield 3.1 g (77%); m.p. 245–247 °C; H NMR: δ (E/Z =
4-chloroaniline (11 mmol) and two drops of pyridine were 80:20%) 4.69 (Z) and 5.18 (E) (2H, s, OCH2), 5.02 (E) and
added. The mixture was stirred at 120 °C for 4 h, the toluene 5.05 (Z) (2H, s, NCH2), 6.90 (E) (0.8H, d, J = 9.8 Hz, =
was evaporated at normal pressure, the residue was washed CH pyrid.), 7.14 (E) (0.8H, d, J = 9.8 Hz, = CH pyrid.),
with hexane, and the precipitate was filtered off and dried.
7.10–8.75 (9H, m, C6H5 and C6H4), 8.09 (1H, s, CH=N),
2-[(1-Benzyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]-N- 11.55 (Z) and 11.78 (E) (1H, s, NH). Anal. Calcd for
(4-chlorophenyl)acetamide (8): Brown crystals; yield 1.9 g C20H17N5O5: C, 58.97; H, 4.21; N, 17.19. Found: C, 58.81;
(52%); m.p. 146–148 °C; 1H NMR: δ 4.70 (2H, s, OCH2), H, 4.12; N, 16.91.

6
Journal of Chemical Research 00(0)
2-[(1-Benzyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]-N′-(4- filtered off. The filtrate was acidified with hydrochloric
methoxybenzylidene)propanehydrazide (11a): White crystals; acid (pH = 4), and the precipitate was filtered off, washed
1
yield 3.8 g (95%); m.p. 194–196 °C; H NMR: δ (E/Z = with water, and dried.
75:25%) 1.54 (Z) and 1.55 (E) (3H, t, J = 6.8 Hz, CH3), 3.84
2-Benzyl-6-[(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)
(3H, s, OCH3), 4.79 (E) and 5.07 (E) (1.5H, d, J = 13.5 Hz, methoxy]pyridazin-3(2H)-one (12): Yellow crystals; yield
1
NCH2), 5.00 (Z) and 5.81 (E) (1H, q, J = 6.8 Hz, OCH), 6.85 2.7 g (87%); m.p. 190–192 °C; H NMR: δ 5.04 (2H, s,
(E) and 7.05 (E) (1.5H, d, J = 9.7 Hz, = CH pyrid.), 6.87 (Z) NCH2), 5.20 (2H, s, OCH2), 6.92 (1H, d, J = 9.7 Hz, = CH
(0.25H, d, J = 9.7 Hz, = CH pyrid.), 6.87–7.66 (9H, m, pyrid.), 7.13 (1H, d, J = 9.7 Hz, = CH pyrid.), 7.20–7.37
C6H5, C6H4 and 0.25H, = CH pyrid.), 7.96 (E) and 8.25 (Z) (5H, m, C6H5), 14.18 (1H, br s, NH); 13C NMR: δ 53.4, 57.5,
(1H, s, CH=N), 11.10 (Z) and 11.26 (E) (1H, s, NH); 13C 125.6, 127.1, 127.9, 128.1, 133.2, 135.9, 149.9, 157.3, 157.9,
NMR: δ 16.4 (E), 17.6 (Z), 53.2 (Z), 54.6 (E), 68.9 (E), 72.0 177.9 (C=S). Anal. Calcd for C14H12N4O3S: C, 53.16; H,
(Z), 104.5 (Z), 113.6 (E), 125.8 (E), 126.3 (Z), 126.6 (Z), 3.82; N, 17.71. Found: C, 53.29; H, 3.94; N, 17.96.
126.9 (E), 127.7, 127.8, 128.21 (Z), 128.23 (Z), 128.5 (E),
2-Benzyl-6-[1-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-
132.4, 136.0, 142.9, 147.2 (Z), 150.4 (E), 157.2 (Z), 160.3 2-yl)ethoxy]pyridazin-3(2H)-one (13): Yellow crystals;
(E), 170.7 (E). Anal. Calcd for C22H22N4O4: C, 65.01; H, yield 2.9 g (87%); m.p. 168–170 °C; 1H NMR: δ 1.68 (3H,
5.46; N, 13.78. Found: C, 65.18; H, 5.55; N, 13.91.
d, J = 6.5 Hz, CH3), 4.99 and 5.07 (2H, d,d, J = 13.8 Hz,
2-((1-Benzyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-N′- NCH2), 5.78 (1H, q, J = 6.5 Hz, OCH), 6.91 (1H, d, J =
(4-hydroxy-3-methoxybenzylidene)propanehydrazide 9.7 Hz, = CH pyrid.), 7.08 (1H, d, J = 9.7 Hz, = CH
(11b): White crystals; yield 3.8 g (90%); m.p. 202–204 °C; pyrid.), 7.19–7.33 (5H, m, C6H5), 14.32 (1H, br s, NH); 13
C
1H NMR: δ (E/Z = 70:30%) 1.54 (Z) and 1.55 (E) (3H, t, J NMR: δ 17.4, 53.4, 64.8, 125.8, 127.2, 128.0, 128.2, 133.2,
= 6.8 Hz, CH3), 3.84 (E) and 3.88 (Z) (3H, s, OCH3), 4.76 135.9, 149.6, 157.3, 161.0, 177.7(C=S). Anal. Calcd for
(E) and 5.10 (E) (1.4H, d, J = 13.5 Hz, NCH2), 4.99 (Z) C15H14N4O3S: C, 54.54; H, 4.27; N, 16.96. Found: C, 54.42;
and 5.04 (Z) (0.6H, d, J = 13.5 Hz, NCH2), 5.00 (Z) and H, 4.19; N, 16.71.
5.80 (E) (1H, q, J = 6.8 Hz, OCH), 6.77–7.34 (10H, m,
C6H5, C6H3 and CH=CH), 7.90 (E) and 8.18 (Z) (1H, s,
Synthesis of compounds 14a,b, 15a,b;
CH=N), 8.94 (1H, s, OH), 11.06 (Z) and 11.20 (E) (s, 1H,
general procedure
NH); 13C NMR: δ 16.5 (E), 17.7 (Z), 53.3 (Z), 55.3 (E),
69.0 (E), 71.5 (Z), 108.8 (Z), 109.4 (E), 115.0 (Z), 115.2 To a mixture of compound 12 or 13 (10 mmol) and DMF
(E), 121.1 (E), 122.0 (Z), 125.4 (E), 125.5 (Z), 125.9 (E), (10 mL), the halogenated carboxylic acid or its derivative
126.4 (Z), 127.0, 127.7 (E), 127.9 (Z), 128.3 (Z), 128.6 (E), (11 mmol) was added. The mixture was stirred at room
132.5 136.1, 143.7, 147.6 (E), 147.7 (Z), 148.2, 148.8 (E), temperature for 1 h and then heated at 65–70 °C for 10–12
149.0 (Z), 150.5 (Z), 150.6 (E), 157.3 (E), 157.4 (Z), 166.0 h. The solvent was evaporated at low pressure, and the resi-
(Z), 170.7 (E). Anal. Calcd for C22H22N4O5: C, 62.55; H, due was washed with water, filtered off, washed with water,
5.25; N, 13.26. Found: C, 62.41; H, 5.12; N, 13.05.
and dried.
2-[(5-{[(1-Benzyl-6-oxo-1,6-dihydropyridazin-3-yl)
2-[(1-Benzyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]-N′-
(3-nitrobenzylidene)propanehydrazide (11c): White crys- oxy]methyl}-1,3,4-oxadiazol-2-yl)thio]acetamide (14a):
tals; yield 3.8 g (91%); m.p. 174–176 °C; 1H NMR: δ (E/Z Yellow crystals; yield 2.4 g (65%); m.p. 122–124 °C; IR ν
= 70:30%) 1.56 (Z) and 1.57 (E) (3H, t, J = 6.8 Hz, CH3), (cm−1): 1697, 1664 (C=O). 1H NMR: δ 4.00 (2H, s, SCH2),
4.80 (E) and 5.07 (E) (1.4H, d, J = 13.6 Hz, NCH2), 4.98 5.06 (2H, s, NCH2), 5.36 (2H, s, OCH2), 6.92 (1H, d, J =
(Z) and 5.06 (Z) (0.6H, d, J = 13.6 Hz, NCH2), 5.03 (Z) 9.8 Hz, = CH pyrid.), 7.14 (1H, d, J = 9.8 Hz, = CH
and 5.82 (E) (1H, q, J = 6.8 Hz, OCH), 6.87 (E) and 6.89 pyrid.), 7.11 and 7.57 (2H, brs, NH2), 7.20–7.38 (5H, m,
(Z) (1H, d,d, J = 9.7 Hz, = CH pyrid.), 7.06–8.50 (10H, m, C6H5); 13C NMR: δ 35.9, 53.4, 57.4, 125.6, 127.1, 127.9,
C6H5, C6H4 and = CH pyrid.), 8.13 (E) and 8.47 (Z) (1H, s, 128.0, 133.1, 136.0, 150.1, 157.4, 162.2, 164.5, 167.0.
CH=N), 11.55 (Z) and 11.67 (E) (1H, s, NH); 13C NMR: δ Anal. Calcd for C16H15N5O4S: C, 51.47; H, 4.05; N, 18.76.
16.5 (E), 17.5 (Z), 53.2 (E), 53.8 (Z), 68.8 (E), 71.7 (Z), Found: C, 51.28; H, 4.12; N, 18.51.
120.8 (E), 121.2 (Z), 123.4 (E), 123.5 (Z), 125.8 (E), 126.2
2-[(5-{[(1-Benzyl-6-oxo-1,6-dihydropyridazin-3-yl)
(Z), 126.88 (Z), 126.91 (E), 127.7 (E), 127.8 (Z), 128.16 oxy]methyl}-1,3,4-oxadiazol-2-yl)thio]acetic acid (14b):
1
(Z), 128.24 (E), 129.4 (Z), 129.5 (E), 131.8 (E), 132.3 (Z), Yellow crystals; yield 2.5 g (70%), m.p. 180–182 °C; H
132.6 (E), 135.9, 136.0, 136.3(Z), 140.7, 144.8, 148.0 (Z), NMR: δ 4.04 (2H, s, SCH2), 5.06 (2H, s, NCH2), 5.34 (2H,
148.1 (E), 150.3 (Z), 150.4 (E), 157.26 (E), 157.31 (Z), s, OCH2), 6.92 (1H, d, J = 9.7 Hz, = CH pyrid.), 7.13 (1H,
166.6 (Z), 171.2 (E). Anal. Calcd for C21H19N5O5: C, 62.55; d, J = 9.7 Hz, = CH pyrid.), 7.21–7.34 (5H, m, C6H5), 12.7
H, 5.25; N, 13.26. Found: C, 59.69; H, 4.48; N, 16.44.
(1H, br s, OH); 13C NMR: δ 34.0, 53.4, 57.4, 125.6, 127.1,
127.9, 128.1, 133.2, 136.0, 150.1, 157.4, 162.3, 163.9,
167.8. Anal. Calcd for C16H14N4O5S: C, 51.33; H, 3.77; N,
14.97. Found: C, 51.24; H, 3.67; N, 14.73.
Synthesis of compounds 12, 13; general
procedure
2-[(5-{1-[(1-Benzyl-6-oxo-1,6-dihydropyridazin-3-yl)
A mixture of compound 4 or 5 (10 mmol), KOH (10 mmol), oxy]ethyl}-1,3,4-oxadiazol-2-yl)thio]acetamide
(15a):
1
CS2 (10 mmol), and absolute ethanol (15 mL) was stirred at White crystals; yield 2.6 g (67%), m.p. 144–146 °C; H
75–80 °C for 10 h. The solvent was evaporated off at nor- NMR: δ 1.71 (3H, d, J = 6.5 Hz, CH3), 3.98 (2H, s, SCH2),
mal pressure, and the residue was treated with water and 5.02 (2H, s, NCH2), 5.94 (1H, q, J = 6.5 Hz, OCH), 6.91

Shainova et al.
7
amide (18): To compound 4 (10 mmol), ethanol (7–8 mL),
KNCS (25 mmol), and two to three drops of HCl were
added. The reaction mixture was heated at 80 °C for 6 h and
the obtained precipitate was filtered off and washed with
ethanol. Yellow crystals; yield 2.8 g (81%), m.p. >300 °C.
1H NMR: δ 4.62 (2H, s, OCH2), 5.05 (2H, s, NCH2), 6.90
(1H, d, J = 9.7 Hz, = CH pyrid.), 7.18 (1H, d, J = 9.7 Hz,
= CH pyrid.), 7.20–7.40 (5H, m, C6H5), 7.68 (1H, brs,
NH), 9.10 (1H, brs, NH), 9.98 (1H, brs, NH). Anal. Calcd
for C14H14KN5O3S: C, 45.27; H, 3.80; N, 18.85. Found: C,
45.35; H, 4.03; N, 19.42.
(1H, d, J = 9.7 Hz, = CH pyrid.), 7.09 (d, J = 9.7 Hz, 1H,
CH), 7.20–7.37 (5H, m, C6H5), 7.13 and 7.57 (2H, br s,
NH2); 13C NMR: δ 17.8, 53.3, 64.9, 125.8, 127.1, 127.9,
128.0, 133.1, 136.0, 149.7, 157.3, 164.0, 165.3, 167.0.
Anal. Calcd for C17H17N5O4S: C, 52.71; H, 4.42; N, 18.08.
Found: C, 52.59; H, 4.31; N, 18.29.
2-[(5-{1-[(1-Benzyl-6-oxo-1,6-dihydropyridazin-3-yl)
oxy]ethyl}-1,3,4-oxadiazol-2-yl)thio]acetic acid (15b): Oil;
yield 2.4 g (63%), 1H NMR: δ 1.70 (3H, d, J = 6.5 Hz, CH3),
4.02 (2H, s, SCH2), 5.02 (2H, s, NCH2), 5.97 (1H, q, J = 6.5
Hz, OCH), 6.90 (1H, d, J = 9.7 Hz, = CH pyrid.), 7.10 (1H,
d, J = 9.7 Hz, = CH pyrid.), 7.20–7.38 (5H, m, C6H5), 10.0
(1H, brs, OH). Anal. Calcd for C17H16N4O5S: C, 52.57; H,
4.15; N, 14.43. Found: C, 52.44; H, 4.09; N, 14.29.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Synthesis of potassium 2-{2-[(1-benzyl-6-oxo-1,6-dihy-
dropyridazin-3-yl)oxy]acetyl}hydrazine-1-carbodithioate
(16): To compound 4 (10 mmol) at 0–5 °C, alcoholic solu-
tion of KOH (15 mmol) was added followed by CS2 (15
mmol). The reaction mixture was stirred at 20 °C for 24 h.
The obtained precipitate (salt) was washed with 5–7 mL of
ethanol and filtered off. White crystals; yield 3.8 g (97%),
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: This
research was supported by the Russian-Armenian University and
the Ministry of Education and Science of the Russian Federation.
1
m.p. 218–220 °C; H NMR: δ (D2O) 4.82 (2H, s, NCH2),
5.31 (2H, s, OCH2), 7.15 (1H, d, J = 9.7 Hz, = CH pyrid.),
7.28 (1H, d, J = 9.7 Hz, = CH pyrid.), 7.32–7.54 (5H, m,
C6H5); 13C NMR: δ 54.3, 65.4, 127.3, 127.5, 128.3, 131.7,
135.2, 152.9, 154.6, 160.1, 163.0, 165.4. Anal. Calcd for
C14H13KN4O3S2: C, 43.28; H, 3.37; N, 14.42, Found: C,
43.32; H, 3.44; N, 14.60.
ORCID iD
Roza S Shainova
https://orcid.org/0000-0003-0815-1041
Supplemental material
The ESI (1H and 13C NMR spectra of compounds 1-18) is
Synthesis of 2-benzyl-6-[(5-thioxo-4,5-dihydro-1,3,4- available.
thiadiazol-2-yl)methoxy]pyridazin-3(2H)-one (17): To
References
compound 16 (10 mmol), concentrated sulfuric acid (3 mL)
was added. The mixture was stirred at 20 °C for 6 h and
then carefully ice water was added. The mixture was neu-
tralized with a 10% solution of NaOH (until pH = 7), fil-
tered, and the precipitate was washed with water and dried.
1. Asif M. Cent Eur J Exp Biol 2017; 5: 1.
2. http://www.alanwood.net/pesticides/class_pesticides.html
(accessed 24 May 2019).
3. Zou X-J, Jin G-Y and Zhang Z-X. J Agr Food Chem 2002;
50: 1451.
4. Wu J, Song B, Chen H, et al. Molecules 2009; 14: 3676.
5. LamberthC,WendebornSV,TrahS,etal.US20100022526A1
Patent, 2010.
6. Trah S and Lamberth C. US8658644B2 Patent, 2014.
7. Xu H, Zou X-M, Zhu Y-Q, et al. Pest Manag Sci 2006; 62:
522.
1
Yellow crystals; yield 1.9 g (58%), m.p. 203–205 °C, H
NMR: δ 5.10 (2H, s, NCH2), 5.24 (2H, s, OCH2), 6.94 (1H,
d, J = 9.8 Hz, = CH pyrid.), 7.08 (1H, d, J = 9.8 Hz, = CH
pyrid.), 7.22–7.35 (5H, m, C6H5), 14.37 (1H, s, NH); 13C
NMR: δ 53.2, 62.1, 125.6, 127.2, 127.9, 128.1, 133.3,
135.9, 150.1, 156.5, 157.3, 188.8 (C=S). Anal. Calcd for
C14H12N4O2S2: C, 50.59; H, 3.64; N, 16.86. Found: C,
50.47; H, 3.52; N, 16.70.
8. Xu H, Hu X-H, Zou X-M, et al. J Agr Food Chem 2008; 56:
6567.
Synthesis of potassium (2-{2-[(1-benzyl-6-oxo-1,6-dihy-
dropyridazin-3-yl)oxy]acetyl}hydrazine-1-carbonothioyl)
9. Deeb A, Mourad E and Elenany D. Eur Chem Bull 2013; 2:
910.