Synthesis and Antibacterial Activity of Novel (4-Methoxyphenyl)-tetrahydropyranyl-substituted 1,3,4-Oxadiazoles

Article abstract of DOI:10.1134/S1070428020020177

Abstract: Condensation of 4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-carbonyl chloride with hydrazine hydrate, furan-2- and 2,5-dimethylfuran-2carbohydrazides gave disubstituted hydrazides, whose cyclization formed symmetrical and unsymmetrical 2,5-disubstituted 1,3,4-oxadiazoles. Ethyl 4-[4-(4-methoxyphenyl)-tetrahydro-2H-pyran-4-carboxamido]benzoate was reacted with hydrazine to obtain N-[4-(hydrazinocarbonyl)-phenyl]-4-(4-methoxphenyl)tetrahydro-2H-pyran-4-carboxamide. Treatment of the latter with triethyl orthoformate gave a monosubstituted 1,3,4-oxadiazole, and with carbon disulfide, a 5-sulfanyl-1,3,4-oxadiazole derivative was obtained. The subsequent alkylation of this derivative with 5-metoxyfuran-2-methyl and benzylaminocarbonylmethyl chlorides substituted chlorides resulted in the synthesis of the corresponding novel S-substituted oxadiazole derivatives. The synthesized compounds were tested for antibacterial activity.

Full text of DOI:10.1134/S1070428020020177

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 2, pp. 281–286. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Organicheskoi Khimii, 2020, Vol. 56, No. 2, pp. 283–289.
Synthesis and Antibacterial Activity of Novel (4-Methoxyphenyl)-
tetrahydropyranyl-substituted 1,3,4-Oxadiazoles
А. А. Aghekyana,*, G. G. Mkryana, H. A. Panosyana, A. S. Safaryana,
A. G. Arakelyana, and H. M. Stepanyana
a Scientific Technological Center for Organic and Pharmaceutical Chemistry, NAS of Armenia, Yerevan, 0014, Armenia
*е-mail: aaghekyan@mail.ru
Received September 12, 2019; revised October 14, 2019; accepted December 2, 2019
Abstract—Condensation of 4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-carbonyl chloride with hydrazine
hydrate, furan-2- and 2,5-dimethylfuran-2carbohydrazides gave disubstituted hydrazides, whose cyclization
formed symmetrical and unsymmetrical 2,5-disubstituted 1,3,4-oxadiazoles. Ethyl 4-[4-(4-methoxyphenyl)-
tetrahydro-2H-pyran-4-carboxamido]benzoate was reacted with hydrazine to obtain N-[4-(hydrazinocarbonyl)-
phenyl]-4-(4-methoxphenyl)tetrahydro-2H-pyran-4-carboxamide. Treatment of the latter with triethyl orthofor-
mate gave a monosubstituted 1,3,4-oxadiazole, and with carbon disulfide, a 5-sulfanyl-1,3,4-oxadiazole derivative
was obtained. The subsequent alkylation of this derivative with 5-metoxyfuran-2-methyl and benzylaminocarbon-
ylmethyl chlorides substituted chlorides resulted in the synthesis of the corresponding novel S-substituted oxadia-
zole derivatives. The synthesized compounds were tested for antibacterial activity.
Keywords: furan-2-carboxylic acid, 4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-carboxylic acid, hydrazine hy-
drate, 1,3,4-oxadiazole, 4-[4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-carboxamido]benzoic acid
DOI: 10.1134/S1070428020020177
The 1,3,4-oxadiazole ring is an important structural
fragment of many biologically active compounds
that exhibit antibacterial [1], anti-inflammatory [2],
anticonvulsive [3], antitumor [4], antihypertensive [5],
and other properties. Therefore, the interest in such
structures remains in the focus of attention of synthetic
chemists [6, 7].
of ethyl ester of the mentioned acid by passing dry HCl
through a solution of its nitrile followed by hydrolysis
of the resulting imino ester, as well as by ethanolysis of
the acid itself in the presence of a catalyst (H2SO4), were
unsuccessful. Ethyl ester 2 could be prepared in a high
yield by reacting 4-(4-methoxyphenyl)tetrahydro-2H-
pyran-4-carbonyl chloride (1) with ethanol in pyridine.
However, treatment neither with hydrazine hydrate
nor with 80% hydrazine (in ethanol and butanol)
allowed us to convert ester 2 into the corresponding acid
hydrazide.
Aryltetrahydropyran derivatives, too, show diverse
biological properties: among them, compounds
that act as α- and β-adrenoreceptors, as well as
antimonoaminooxidase, antibacterial, and antihistamine
agents were found [8–10].
Therefore, oxadiazoles, in which the tetrahydro-
pyran ring is directly attached to the oxadiazole ring,
were synthesized starting with furan- and 4,5-dimethyl-
furancarboxydrazides (3а and 3b, respectively)
prepared, in their turn, from the corresponsing ethyl
furancarboxylates. The condensation of chloride 1
with hydrazides 3a and 3b resulted in the isolation
of disubstituted hydrazides 4а and 4b, respectively.
The latters were cyclized by phosphorus oxychloride
to obtain the target unsymmetrical 2,5-disubstituted
1,3,4-oxadiazoles 5а and 5b (Scheme 1).
In the present work we set ourselves the goal
to synthesize previously unknown compounds, in
which the 1,3,4-oxadiazole ring is linked to the
aryltetrahydropyran fragment, both directly and via an
amidobenzyl linker. To this end, we had first to prepare
4-(4-methoxyphenyl)tetrahydro-2Н-pyrancarboxylic
and 4-[4-(4-methoxyphenyl)tetrahydro-2Н-pyran-4-car-
boxamido]benzoic acid hydrazides through the
corresponding esters.
In the first case, the nitrile of 4-(4-methoxyphenyl)-
tetrahydro-2Н-pyran-4-carboxylic acid was used as the
starting compound [11]. However, attempted synthesis
To synthesized a symmetrical 2,5-disubstituted
oxadiazole, where the tetrahydropyran rings are directly
281

282
AGHEKYAN et al.
Scheme 1.
O
O
O
O
O
O
O
NH2NH2
O
SOCl2
C2H5OH
Py
OH
Cl
NHNH2
OC2H5
H3CO
H3CO
H3CO
H3CO
1
2
R
R
CONHNH2
O
3a, 3b
O
O
O
R
O
R
H
O
O
POCl3
N
N
H
N
O
R
N
R
H3CO
H3CO
5a, 5b
4a, 4b
R = H (a), R = CH3 (b).
linked to the five-membered hetericycle, we reacted
chloride1withhydrazinehydratetopreparedisubstituted
hydrazide 6. The latter was subjected to intramolecular
cyclization under the action of phosphorus oxychloride
to form oxadiazole 7 in a yield of 83% (Scheme 2).
N-phenyltetrahydro-2Н-pyran-4-carboxamido]phenyl
substituents on C2 and C5 from hydrazide 14 prepared by
the condensation of 4-[(4-methoxyphenyl)-N-phenyl-
tetrahydro-2Н-pyran-4-carboxamido]benzoyl chloride
(13) with hydrazine hydrate failed because of bond
cleavage during cyclization in the presence of
phosphorus oxychloride (Scheme 4).
The synthesis of 1,3,4-oxadiazoles containing a
4-(4-methoxyphenyl)-N-phenyltetrahydro-2Н-pyran-
4-carboxamide fragment was performed starting from
the previously prepared ethyl 4-[4-(4-methoxyphenyl)-
tetrahydro-2H-pyran-4-caroxamido]benzoate (8) pre-
pared [11]. The condensation of compound 8 with
hydrazine hydrate gave hydrazide 9. The latter was
reacted with CS2 to obtain 5-sulfanyl derivative 10,
which was used in further syntheses, in particular,
alkylation reactions. Thus, the reactions of thiol 10
with methyl 5-(chloromethyl)furan-2-carboxylate and
N-benzyl-2-chloroacetamide gave compounds 11a
and 11b, respectively. Hydrazide 9 was reacted with
triethyl orthoformate to prepare monosubstituted
1,3,4-oxadiazole 12 containing a 4-[(4-methoxyphenyl)-
N-phenyltetrahydro-2Н-pyran-4-carboxamido]phenyl
substituent in the 2-position (Scheme 3).
The structure and purity of all the synthesized
compounds were confirmed by physicochemical
methods and TLC.
The antibacterial activity of the synthesized
compounds was evaluated by the agar diffusion assay
[13] at the microbial load 2 × 106/mL medium. Gram-
positive (Staphylococcus aureus 209 p and Bacilus
subtilis) and gram-negative bacilli (Shigella flexneri
6858 and E. coli 0–55) were used in the experiments.
The test compounds were dissolved in DMSO (1 : 20).
Hydrazide 4a and thiol 11 showed a moderate
antibacterial activity: the inhibition zone diameters (d)
were 15–16 mm. The other compounds exhibited a
weak activity (d 10–11 mm). The test compounds all
were much less active that the control drug Furadonin
(d 23–26 mm) [14].
Attempted synthesis of symmetrical disubstituted
1,3,4-oxadiazole 15 with the 4-[(4-methoxyphenyl)-
Scheme 2.
O
O
O
OCH3
O
H
O
N
NH2NH2
POCl3
N
1
H
N
N
OCH3
O
H3CO
H3CO
O
6
7
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SYNTHESIS AND ANTIBACTERIAL ACTIVITY
283
Scheme 3.
O
O
O
O
H
N
H
N
NH2NH2
O
O
O
O
H3CO
H3CO
H3CO
H3CO
NHNH2
OC2H5
8
9
CS2
(C2H5O)3CH
O
H
N
H
N
O
O
SH
O
O
H3CO
N
N
N
N
10
12
R
Cl
H
H
N
N
COOCH3 (a),
(b).
R =
O
S
O
R
O
O
N
N
11a, 11b
EXPERIMENTAL
on a Boёtius hot stage. Thin-layer chromatography was
performed on Silufol UV-254, visualization by exposure
to iodine vapor.
The IR spectra were run on a Nicolet Avatar 330
FTIR spectrometer in mineral oil. The 1Н NMR spectra
were obtained on a Varian Mercury-300 spectrometer
in DMSO-d6, operating frequency 300 MHz, internal
reference TMS. The melting points were determined
4-(4-Methoxyphenyl)tetrahydro-2Н-pyran-4-car-
boxylic acid and ethyl ester and chloride of
4-(4-methoxyphenyl)tetrahydro-2Н-pyran-4-carbo-
xamido]benzoic acid were prepared as described in [11].
Scheme 4.
O
H
O
N
O
H3CO
H
N
H
N
O
O
N
H
OCH3
O
COCl
O
N
O
H
H3CO
13
O
14
POCl3
O
H
O
N
O
N
N
O
H
H3CO
N
O
OCH3
15
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284
AGHEKYAN et al.
4-(4-Methoxyphenyl)tetra-2Н-pyran-4-carbonyl
[4-(4-Methoxyphenyl)tetrahydro-2Н-pyran]-N-
(4,5-dimethylfuran-2-carbonyl)-4-carbohydrazide
(4b) was prepared in a similar way from 1.0 g (4 mmol)
of chloride 1 and 0.6 g (4 mmol) of 4,5-dimethylfuran-
2-carbohydrazide (3b). Yield 0.9 g (61%), mp 168–
170°C, Rf 0.52 (benzene–acetone, 2 : 1). IR spectrum,
ν, cm–1: 3310 s (NH), 1696 s and 1655 s (NCO). 1Н NMR
spectrum, δ, ppm: 1.84 d.d.d (2Н, CН2, J 13.4, 10.6,
4.6 Hz), 1.99 s (3Н, CН3), 2.28 s (3Н, CН3), 2.56 br.d
(2Н, CН2, J 13.4 Hz), 3.63–3.79 m [4Н, (CН2)2О], 3.78 s
(3Н, ОCН3), 6.81–6.86 m (2Н, C6Н4), 6.90 br.s (1Н,
Н4fur), 7.31–7.36 m (2Н, C6Н4), 9.47 br.d (1Н, NН, J
1.5 Hz), 9.59 br.s (1Н, NН). Found, %: C 64.23; Н 6.70;
N 7.67. C20Н24N2О5. Calculated, %: C 64.50; Н 6.50;
N 7.52.
chloride (1). A mixture of 14.2 g (0.06 mol) of
4-(4-methoxyphenyl)tetrahydro-2Н-pyran-4-carboxylic
acid and 9.0 g (0.75 mol) of thionyl chloride in 60 mL
of benzene was heated under reflux for 6 h. The solvent
was removed by distillation. The residue was dissolved
in 20 mL of benzene, which was then evaporated to
dryness. The residue was distilled in a vacuum. Yield
12.3 g (80%), bp 170–175°C (2 mmHg).
Ethyl 4-(4-methoxyphenyl)tetrahydro-2Н-pyran-
4-carboxylate (2). Chloride 1, 2.5 g (0.01 mol), was
added dropwise to an ice-cooled mixture of 20 mL of
absolute ethanol and 10 mL of pyridine. The resulting
mixture was left to stand overnight at room temperature
and then poured into ice water and acidified with 10%
HCl under cooling with ice with water. The solution
was extracted with benzene (2 × 30 mL), the extract was
washed with a soda solution, and dried. The solvent
was distilled off, and the residue was recrystallized
from hexane. Yield 1.8 g (70%), mp 58–60°C, Rf 0.55
(benzene–ether, 5 : 1). IR spectrum, ν, cm–1: 1720 s
5-[4-(4-Methoxyphenyl)tetrahydro-2Н-pyran-4-
yl]-2-(furan-2-yl)-1,3,4-oxadiazole (5а). A solution of
0.7 g (2 mmol) of N,N'-diacylhydrazine 4а and 6 mL of
POCl3 in 15 mL of absolute toluene was heated under
reflux for 2 h. After cooling, the mixture was poured into
water, extracted with benzene, the organic layer was
washed with water and dried over MgSO4, the solvent
was distilled off, and the residue was recrystallized
from hexane. Yield 0.5 g (75%), mp 90–91°C, Rf 0.52
1
(CO). Н NMR spectrum, δ, ppm: 1.18 t (3Н, CН3, J
7.1 Hz), 1.80–1.90 m (2Н) and 2.38–2.45 m (2Н, CН2),
3.42 d.d.d (2Н, ОCН2, J 11.8, 11.2, 2.2 Hz), 3.77 s
(3Н, ОCН3), 3.77–3.84 m (2Н, ОCН2), 4.08 q (2Н,
ОCН2CН3, J 7.1 Hz), 6.79–6.84 m (2Н) and 7.19–7.25 m
(2Н, C6Н4). 13C NMR spectrum, δ, ppm: 13.6, 33.9,
47.0, 54.4, 59.8, 64.5, 113.3, 126.0, 134.0, 157.9, 172.8.
Found, %: C 68.34; Н 7.45. C15Н20О4. Calculated, %:
C 68.16; Н 7.63.
1
(benzene–acetone, 5 : 1). Н NMR spectrum, δ, ppm:
2.23 d.d.d (2Н, CН2, J 13.7, 10.9, 4.2 Hz), 2.58–2.66 m
(2Н, CН2), 3.49–3.58 m (2Н, CН2О), 3.76 s (3Н,
ОCН3), 3.84–3.91 m (2Н, CН2О), 6.62 d.d (1Н, Н4fur,
J 3.5, 1.8 Hz), 6.82–6.87 m (2Н, C6Н4), 7.13 d.d (1Н,
Н3fur, J 3.5, 0.8 Hz), 7.22–7.27 m (2Н, C6Н4), 7.76 d.d
(1Н, Н5fur, J 1.8, 0.8 Hz). 13C NMR spectrum, δ, ppm:
34.5, 40.5, 54.4, 63.7, 111.6, 113.4, 113.7, 126.2, 134.2,
138.7, 145.3, 156.8, 158.7, 167.7. Found, %: C 66.52;
Н 5.43; N 8.44. C18Н18N2О4. Calculated, %: C 66.25;
Н 5.56; N 8.58.
[4-(4-Methoxyphenyl)tetrahydro-2Н-pyran]-N-
(furan-2-carbonyl)-4-carbohydrazide (4a). A solution
of 1.0 g (4 mmol) of chloride 1 in 10 mL of dioxane
was added to a solution of 0.5 g (4 mmol) of furan-2-
carbohydrazide (3а) and 0.4 g (4 mmol) of triethylamine
in 20 mL of dioxane. The reaction mixture was heated
under reflux for 10 h, poured into water, and filtered to
remove suspended matter. The filtrate was extracted
with benzene (2 × 50 mL), the extract was dried over
MgSO4, the solvent was distilled off, and the residue
was crystallized from ether and recrystallized from
toluene. Yield 0.8 g (59%), mp 162–164°C, Rf 0.55
(benzene–acetone, 2 : 1). IR spectrum, ν, cm–1: 3308 s
5-[4-(4-Methoxyphenyl)-2-(4,5-dimethylfuran-2-
yl)tetrahydro-2Н-pyran-4-yl]-1,3,4-oxadiazole (5b)
was prepared in a similar way from 0.75 g (2 mmol)
of N,N'-diacyhydrazine 4b and 6 mL of POCl3. Yield
0.6 g (84%), mp 110–111°C, Rf 0.56 (benzene–acetone,
5 : 1). 1Н NMR spectrum, δ, ppm: 2.01 br.s (3Н, CН3),
2.21 d.d.d (2Н, CН2, J 13.8, 11.0, 4.3 Hz), 2.32 br.s (3Н,
CН3), 2.56–2.63 m (2Н, CН2), 3.52 d.d.d (2Н, ОCН2, J
11.9, 11.0, 2.0 Hz), 3.76 s (3Н, ОCН3), 3.83–3.91 m (2Н,
CН2О), 6.81–6.86 m (2Н, C6Н4), 6.90 br.s (1Н, Н4fur),
7.19–7.25m(2Н,C6Н4).13CNMRspectrum,δ,ppm:9.1,
11.0, 34.5, 40.5, 54.4, 63.7, 113.7, 116.3, 116.6, 126.2,
134.4, 135.8, 150.7, 156.9, 158.1, 167.2. Found, %:
C 67.50; Н 6.41; N 8.03. C20Н22N2О4. Calculated, %:
C 67.78; Н 6.26; N 7.90.
1
(NH), 1693 s and 1652 s (NCO). Н NMR spectrum,
δ, ppm: 1.85 d.d.d (2Н, CН2, J 13.3, 11.0, 4.4 Hz),
2.57 br.d (2Н, CН2, J 13.3 Hz), 3.64–3.80 m [4Н,
(CН2)2О], 3.78 s (3Н, ОCН3), 6.52 br.s (1Н, Н4fur),
6.81–6.86 m (2Н, C6Н4), 7.16 br.d (1Н, Н3fur, J 3.2 Hz),
7.32–7.37 m (2Н, C6Н4), 7.66 br.s (1Н, Н5fur), 9.52 br.s
(1Н, NН), 9.90 br.s (1Н, NН). Found, %: C 62.59;
Н 5.94; N 8.25. C18Н20N2О5. Calculated, %: C 62.78;
Н 5.85; N 8.13.
N-[4-(4-Methoxyphenyl)tetrahydro-2Н-pyran-
4-carbonyl]-[4-(4-methoxyphenyl)-tetrahydro-2Н-
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SYNTHESIS AND ANTIBACTERIAL ACTIVITY
285
pyran]-4-carbohydrazide (6). A mixture of 1.5 g
(6 mmol) of chloride 1 and 10 mL of hydrazine hydrate
20 mL of ethanol was heated under reflux for 2 h. The
crystals that formed after cooling were filtered off,
washed with water, dried, and recrystallized from
isopropanol. Yield 1.2 g (85%), mp 188–190°C, Rf 0.47
(benzene–acetone, 2 : 1). IR spectrum, ν, cm–1: 3280 s
for 30 h. The solvent was distilled off, the residue was
dissolved in water, filtered, and the filtrate was acidified
with dilute HCl (1 : 1). The crystals were filtered off
and recrystallized from ethanol. Yield 1.1 g (66%), mp
140–142°C, Rf 0.49 (benzene–acetone, 1 : 1). 1Н NMR
spectrum, δ, ppm: 1.90–2.01 m (2Н) and 2.53–2.62 m
(2Н, CН2), 3.53–3.62 m (2Н) and 3.72–3.81 m (2Н,
ОCН2), 3.76 s (3Н, ОCН3), 6.82–6.87 m (2Н) and 7.29–
7.35 m (2Н, C6Н4О), 7.75–7.85 m (4Н, C6Н4N), 9.21 s
(1Н, NН), 14.29 br.s (1Н, SН). Found, %: C 61.48;
Н 5.38; N 10.35. C21Н21N3О4S. Calculated, %: C 61.30;
Н 5.14; N 10.21.
1
(NH) and 1646 s (NCO). Н NMR spectrum, δ, ppm:
1.74–1.87 m (4Н, CН2), 2.58 br.d (4Н, CН2, J 13.4 Hz),
3.67–3.78 m [8Н, (CН2)2О], 3.77 s (6Н, ОCН3), 6.80–
6.85 m (4Н) and 7.31–7.36 m (4Н, C6Н4), 9.24 s (2Н,
NН). 13C NMR spectrum, δ, ppm: 34.1, 46.4, 54.5, 64.3,
113.0, 126.7, 135.7, 157.7, 172.3. Found, %: C 66.89;
Н 6.72; N 5.81. C26Н32N2О6. Calculated, %: C 66.65;
Н 6.88; N 5.98.
Methyl 5-[(5-{4-[4-(4-methoxyphenyl)tetrahydro-
2Н-pyran-4-carboxamido]phenyl}-1,3.4-oxadiazol-
2-ylsulfanyl)methyl]furan-2-carboxylate (11a). Po-
tassium hydroxide, 0.07 g (1.2 mmol), was added to a
suspension of 0.5 g (1.2 mmol) of thiol 11 in 10 mL
of water. Methyl 5-(chloromethyl)furan-2-carboxylate,
0.21 g (1.2 mmol), was added to the resulting potassium
salt solution, and the mixture was left to stand overnight
at room temperature. The crystals that formed were
filtered off, washed with water, dried, and recrystallized
from ethanol. Yield 0.4 g (60%), mp 130–132°C, Rf 0.55
2,5-Bis[4-(4-methoxyphenyl)tetrahydro-2Н-
pyran-4-yl]-1,3,4-oxadiazole (7). A mixture of 1.2 g
(2.6 mmol) of dihydrazide 6 and 12 mL of POCl3 in
20 mL of toluene was heated under reflux for 2 h. After
cooling, ice water was added, and the crystals that formed
(insoluble in both toluene and water) were filtered off,
washed with water, and recrystallized from isopropanol.
Yield 0.96 g (83%), mp 178–180°C, Rf 0.51 (benzene–
acetone, 5 : 1). 1Н NMR spectrum, δ, ppm: 2.14 br.d.d.d
(4Н, CН2, J 13.3, 11.4, 4.1 Hz), 2.44 br.d (4Н, CН2, J
13.3 Hz), 3.37 br.t (4Н, ОCН2, J 11.4 Hz), 3.75 s (6Н,
ОCН3), 3.81 br.d.t (4Н, ОCН2, J 11.8, 4.0 Hz), 6.75–
6.80 m (4Н) and 7.03–7.08 m (4Н, C6Н4). 13C NMR
spectrum, δ, ppm: 34.5, 40.8, 54.4, 63.7, 113.5, 125.9,
134.7, 158.0, 168.6. Found, %: C 69.59; Н 6.60; N 6.04.
C26Н30N2О5. Calculated, %: C 69.31; Н 6.71; N 6.22.
1
(benzene–acetone, 2 : 1). Н NMR spectrum, δ, ppm:
1.90–2.02 m (2Н) and 2.53–2.63 m (2Н, CН2), 3.53–
3.64 m (2Н) and 3.74–3.82 m (2Н, ОCН2), 3.76 s (3Н,
ОCН3), 3.80 s (3Н, ОCН3), 4.62 s (2Н, SCН2), 6.59 d
(1Н, Н4fur, J 3.4 Hz), 6.82–6.87 m (2Н, C6Н4О), 7.08 d
(1Н, Н3fur, J 3.4 Hz), 7.30–7.35 m (2Н, C6Н4О), 7.83 s
(4Н, C6Н4N), 9.20 br.s (1Н, NН). Found,%: C 61.37;
Н 4.78; N 7.52. C28Н27N3О7S. Calculated, %: C 61.19;
Н 4.95; N 7.65.
N-[4-(Hydrazinocarbonyl)phenyl]-4-(4-methoxy-
phenyl)tetrahydro-2Н-pyran-4-carboxamide (9). A
mixture of 3.8 g (0.01 mol) of amido ester 8 and 15 mLof
hydrazine hydrate in 30 mL of ethanol was heated under
reflux for 4 h. The crystals that formed after cooling
were filtered off, washed with water, and recrystallized
from ethanol. Yield 2.8 g (77%), mp 190–192°C, Rf 0.56
(methanol). IR spectrum, ν, cm–1: 3250–3300 s (NH,
N-(4-{5-[2-(Benzylamino)-2-oxoethylthio]-1,3,4-
oxadiazole-2-yl}phenyl)-4-(4-methoxyphenyl)
tetrahydro-2Н-pyran-4-carboxamide (11b). Potas-
sium hydroxide, 0.07 g (1.2 mmol), in 3 mL of absolute
ethanol was added to 0.5 g (1.2 mmol) of thiol 11 in
10 mL of absolute ethanol. The mixture was heated
for 30 min at 30–40°C, and, after addition of 0.22 g
(1.2 mmol) of N-benzyl-2-cloroacetamide, was heated
for an additional 4 h at 45–50°C. The solvent was
distilled off, the residue was poured with water, and the
precipitate that formed was filtered off, washed with
water and acetone, and recrystallized from isopropanol.
Yield 0.4 g (59%), mp 100–102°C, Rf 0.57 (benzene–
1
NH2), 1674 s and 1638 s (NCO). Н NMR spectrum,
δ, ppm: 1.89–2.01 m (2Н) and 2.53–2.62 m (2Н, CН2),
3.52–3.62 m (2Н) and 3.72–3.81 m (2Н, ОCН2), 3.76 s
(3Н, ОCН3), 4.17 br.s (2Н, NН2), 6.82–6.87 m (2Н) and
7.29–7.35 m (2Н, C6Н4О), 7.60–7.65 m (2Н) and 7.71–
7.76 m (2Н, C6Н4N), 9.05 s (1Н, NH), 9.48 br.s (1Н,
NН). Found, %: C 65.32; Н 6.14; N 11.23. C20Н23N3О4.
Calculated, %: C 65.03; Н 6.28; N 11.37.
1
acetone, 2 : 1). Н NMR spectrum, δ, ppm: 1.89–2.02
m (2Н, CН2), 2.57 br.d (2Н, CН2, J 13.5 Hz), 3.52–
3.63 m (2Н) and 3.73–3.81 m (2Н, ОCН2), 3.76 s (3Н,
ОCН3), 4.45 d (2Н, NCН2, J 5.8 Hz), 4.64 s (2Н, SCН2),
6.83–6.88 m (2Н) and 7.29–7.34 m (2Н, C6Н4О), 7.25–
7.30 m (5Н, C6Н5), 7.70–7.75 m (4Н, C6Н4), 8.04 br.t
(1Н, NH, J 5.8 Hz), 9.20 s (1Н, NН). Found, %: C 64.24;
N-[4-(5-Sulfanyl-1,3,4-oxadiazol-2-yl)phenyl]-
4-(4-methoxyphenyl)tetrahydro-2Н-pyran-4-
carboxamide (11). A mixture of 1.5 g (4 mmol) of
hydrazide 9, 0.3 g (5 mmol) of KOH, and 4 mL of CS2
in 5 mL of absolute ethanol was heated under reflux
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 2 2020

286
AGHEKYAN et al.
Egerland, U., and Rundfeldt, C., Eur. J. Med. Chem.,
2007, vol. 42, p. 873.
Н 5.56; N 10.22. C30Н30N4О5S. Calculated, %: C 64.50;
Н 5.41; N 10.03.
https://doi.org/10.1016/j.ejmech.2006.12.022
N-[4-(1,3,4-Oxadiazole-2-yl)phenyl]-4-(4-me
thoxy-phenyl)-tetrahydro-2Н-pyran-4-carboxamide
(12). A solution of 1.1 g (3 mmol) of hydrazide 9 in
20 mL of triethyl orthoformate was heated under reflux
for 24 h. The solvent was distilled off, the residue was
poured with methanol, and the crystals that formed were
filtered off and recrystallized from ethanol. Yield 0.8 g
(70%), mp 132–133°C, Rf 0.54 (benzene–acetone,
1 : 1). 1Н NMR spectrum, δ, ppm: 1.91–2.03 m (2Н) and
2.53–2.63 m (2Н, CН2), 3.54–3.64 m (2Н) and 3.73–
3.82 m (2Н, ОCН2), 3.77 s (3Н, ОCН3), 6.83–6.88 m
(2Н) and 7.30–7.36 m (2Н, C6Н4О), 7.82–7.93 m
(4Н, C6Н4N), 8.94 s (1Н, N=CH), 9.20 br.s (1Н, NН).
Found, %: C 66.71; Н 5.39; N 11.20. C21Н21N3О4.
Calculated, %: C 66.48; Н 5.58; N 11.08.
4. Liu, K., Lu, X., Zhang, H.J., Sun, J., and Zhu, H.L.,
Eur. J. Med. Chem., 2012, vol. 47, p. 473.
https://doi.org/10.1016/j.ejmech.2011.11.015
5. Bankar, G.R., Nampurath, G.K., Nayak, P.G., and
Bhattcharya, S., Chem. Biol. Interact., 2010, vol. 183,
p. 327.
https://doi.org/10.1016/j.cbi.2009.11.001
6. Friggeri, L., Hargrove, T.Y., Wawrzak, Z., Blobaum,A.L.,
Rachakonda, G., Lindsley, C.W., Villalta, F., Nes, W.D.,
Botta, M., Guengerich, F.P., and Lepesheva, G.I.,
J. Med. Chem., 2018, vol. 61, p. 5679.
https://doi.org/10.1021/acs.jmedchem.8b00641
7. Vosátka, R., Krátký, М., Švarcová, М., Janoušek, J.,
Stolaříková, J., Madacki, J., Huszár, S., Mikušová, K.,
Korduláková, J., Trejtnar, F., and Vinšová, J.,
Eur. J. Med. Chem., 2018, vol. 151, p. 824.
N,N'-[Hydrazinedicarbonylbis(4,1-phenylene)]-
bis[4-(4-methoxyphenyl)tetrahydro-2Н-pyran-4-
carboxamide] (14). A mixture of 0.5 g (1.2 mmol) of
chloride 13 and 5 mL of hydrazine hydrate in 10 mL of
ethanol was heated under reflux for 4 h. The crystals that
formed were filtered off, washed with water and ether,
and recrystallized from ethanol. Yield 0.35 g (79%), mp
256–258°C. Rf 0.53 (benzene–acetone, 1 : 1). 1Н NMR
spectrum, δ, ppm: 1.91–2.02 m (4Н) and 2.54–2.63 m
(4Н, CН2), 3.53–3.63 m (4Н) and 3.73–3.82 m (4Н,
ОCН2), 3.77 s (6Н, ОCН3), 6.83–6.88 m (4Н) and 7.31–
7.36 m (4Н, C6Н4О), 7.66–7.71 m (4Н) and 7.84–7.89 m
(4Н, C6Н4N), 9.13 br.s (2Н, NН), 10.16 br.s (2Н, NН).
Found, %: C 67.71; Н 5.69; N 7.81. C40Н42N4О8.
Calculated, %: C 67.97; Н 5.99; N 7.93.
https://doi.org/10.1016/j.ejmech.2018.04.017
8. Aghekyan,A.A., Pirdzhanov, L.Sh., and Markaryan, E.A.,
Khim. Zh. Arm., 2004, vol. 57, p. 85.
9. Aghekyan, A.A., Mkryan, G.G., Tsatinyan, A.S.,
Noravyan, O.S., and Gasparyan, G.V., Russ. J. Org.
Chem., 2016, vol. 52, p. 209.
https://doi.org/10.1134/S1070428016020081
10. Bernadelli, P., Cronin, A.M., Denis, A., Denton, S.M.,
Jacobelli, H., Kemp, M.I., Lorthiois, E., Rousseau, F.,
Serradeil-Civit, D., and Vergne, F. EU Patent no. 15.3679A1,
2005.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
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