Synthesis of Novel Combined Heterocyclic Systems Derived from 2-[(2-Methylquinolin4-yl)sulfanyl]acetohydrazides Substituted in the Benzene Ring

Article abstract of DOI:10.1134/S1070428020020141

Abstract: New developments in the quinoline chemistry are considered, and previously unknown heterocyclic systems comprising of oxadiazole or dioxoisoindoline moieties combined with the quinoline core and Schiff base residues are synthesized on the basis

Full text of DOI:10.1134/S1070428020020141

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 2, pp. 265–268. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Organicheskoi Khimii, 2020, Vol. 56, No. 2, pp. 264–268.
Synthesis of Novel Combined Heterocyclic Systems
Derived from 2-[(2-Methylquinolin-
4-yl)sulfanyl]acetohydrazides Substituted in the Benzene Ring
I. L. Aleksanyana,* and L. P. Hambardzumyana
a Yerevan State University, Yerevan, 375025 Armenia
*e-mail: ialeksanyan@ysu.am
Received June 26, 2019; revised November 27, 2019; accepted November 27, 2019
Abstract—New developments in the quinoline chemistry are considered, and previously unknown heterocyclic
systems comprising of oxadiazole or dioxoisoindoline moieties combined with the quinoline core and and Schiff
base residues are synthesized on the basis of 2-[(2-methylquinolin-4-yl)sulfanyl]acetohydrazides substituted in
the benzene ring.
Keywords: quinoline, acetohydrazide, hydrazine hydrate, carbohydrazide, Schiff bases, dioxoisoindoline, carbon
disulfide, oxadiazole, phthalic anhydride, substituted benzaldehyde
DOI: 10.1134/S1070428020020141
Quinoline and its combined heterocyclic derivatives
represent a class of compounds quite important for the
development of new drugs with diverse pharmacological
activities [1]. Quinoline derivatives that exhibited
antitumor, antibacterial, antimicrobial, anticonvulsant,
anti-inflammatory, cardiovascular, and other activities
have been reported [2–8]. In this context, increased
attention is being paid to the synthesis of quinoline
derivatives as target structures. On the other hand, great
interest is presently attached to compounds with the
oxadiazole core due to their unique chemical structure
and a wide range of biological properties [9]. Hybrids
of these two groups of compounds can represent novel
interesting pharmacologically active heterocyclic
systems [10, 11].
Here we report the synthesis of previously unknown
derivatives of 1,3,4-oxadiazoles, 1,3-dioxoisoindolines,
and Schiff bases of the basis of benzene ring–substituted
2-[(2-methylquinolin-4-yl)sulfanyl]acetohydrazides
1a–1c.
Proceeding with our research into the synthesis
of biologically active compounds [12] and aimed at
preparing the target hetarylquinolines [13], we reacted
hydrazides 1a–1c with CS2 in the presence of KOH in
ethanol. The reaction involved oxadiazoline ring closure
and formed 5-[(2-methylquinolin-4-ylsulfanyl)methyl]-
1,3,4-oxadiazolo-2(3H)-thiones 2a–2c (Scheme 1).
The reaction of hydrazides 1a–1c with substituted
benzaldehydes in ethanol under reflux gave benzene
ring–substituted N'-(hydroxybenzylidene)-2-(2-methyl-
Scheme 1.
O
N
N
S
C
S
S
N
NH
S
O
O
HN
CS2/KOH
NH2
SH
R
R
R
N
Me
Me
N
Me
N
2a–2c
1a–1c
R = H (a), 6-Me (b), 8-Me (c).
265

266
ALEKSANYAN, HAMBARDZUMYAN
Scheme 2.
O
R'
N
S
N
H
H
O
R
R
R
C
N
S
Me
O
3a–3i
R'
N(Me)2
O
N
S
C
O
H
N
H
C
(Me)2N
HN
NH2
R
N
S
Me
O
O
O
N
Me
4a–4c
O
1a–1c
O
C
N
N
O
H
N
Me
5a–5c
R = H (a), 6-Me (b), 8-Me (c); R' = o-, m-, p-OH.
quinolin-4-ylsulfanyl)acetohydrazides
3a–3c
and
precipitate that formed was filtered off, washed with
water, and recrystallized from aqueous ethanol.
N'-[4-(dimethylamino)benzylidene)-2-(2-methylquino-
lin-4-ylsulfanyl)acetohydrazides 4a–c. Furthermore, the
reaction of hydrazides 1a–1c with phthalic anhydride in
dioxane under reflux resulted in the synthesis of N'-(1,3-
dioxoindolin-2-yl)-2-(2-methylquinolin-4-ylsulfanyl)-
acetamides 5a–5c (Scheme 2).
5-[(2-Methylquinolin-4-ylsulfanyl)methyl]-1,3,4-
oxadiazolo-2(3H)-thione (2a). Yield 0.24 g (83%),
mp 260–261°C, Rf 0.56 (ethanol–toluene, 1 : 4). IR
spectrum, ν, cm–1: 1175 (C=S). Found, %: C 53.74; H
3.98; N 14.31; S 22.20. C13H11N3OS2. Calculated, %: C
53.98; H 3.80; N 14.53; S 22.14.
EXPERIMENTAL
5-[(2,6-Dimethylquinolin-4-ylsulfanyl)methyl]-
1,3,4-oxadiazolo-2(3H)-thione(2b).Yield0.26g(86%),
mp230–231°C,Rf0.55(ethanol–toluene,1:4).Found,%:
C 55.60; H 4.18; N 13.78; S 21.20. C14H13N3OS2.
Calculated, %: C 55.44; H 4.29; N 13.86; S 21.12.
The IR spectra were run on a Nicolet Nexus FTIR
spectrometer. The 1H NMR spectra were registered on a
VarianMercury-300spectrometerinDMSO-d6–CCl4,1:3.
The reaction progress and the purity of the isolated
compounds were monitored by TLC on AlUGRAM
XtraSIL G UV254 plates; spots were visualized by
treatment with iodine vapor. All reactions were
performed in freshly distilled solvents, and reagents
were purchased from Merck.
5-[(2,8-Dimethylquinolin-4-ylsulfanyl)methyl]-
1,3,4-oxadiazolo-2(3H)-thione (2c). Yield 0.27 g
(89%), mp 201–202°C, Rf 0.69 (ethanol–toluene, 1 : 4).
1H NMR spectrum, δ, ppm: 2.69 s (3H, CH3), 2.72 br.s
(3H, CH3), 4.49 s (2H, SCH2), 7.35 d.d (1Harom, J 8.3,
7.1 Hz), 7.43 br.s (1Harom), 7.49 d (1Harom, J 7.1 Hz),
7.86 d (1Harom, J 8.3 Hz), 14.00 br.s (1H, SH). Found, %:
C 55.50; H 4.38; N 13.98; S 21.00. C14H13N3OS2.
Calculated, %: C 55.44; H 4.29; N 13.86; S 21.12.
Compounds 2a–2c (general procedure). A mixture
of 1 mmol of compound 1a–1c [13], 20 mL of ethanol,
and 0.8 mL of CS2 was stirred at room temperature for
30 min and, after 0.014 g (2.5 mmol) of KOH had been
added, another 30 min and then refluxed for 10 h. After
cooling, 20 mL of water was added, the mixture was
filtered, the filtrate was acidified to pH 4.5–5.0, and the
Compounds 3a–3i (general procedure). A mixture
of 1 mmol of compound 1a–1c [13], 6 mL of ethanol,
and 0.122 g (1 mmol) of ortho-, meta-, or para-
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SYNTHESIS OF NOVEL COMBINED HETEROCYCLIC SYSTEMS
267
N'-(3-Hydroxybenzylidene)-2-(2,8-dimethyl-
quinolin-4-ylsulfanyl)acetohydrazide(3f).Yield0.32g
(88%), mp 207–208°C, Rf 0.52 (ethanol–toluene, 1 : 4).
Found, %: C 65.72; H 5.91; N 11.40; S 8.63.
C20H21N3O2S. Calculated, %: C 65.75; H 5.75; N 11.51;
S 8.77.
hydroxybenzaldehyde was refluxed with stirring for
5–6 h. After cooling, the precipitate was filtered off,
washed with ethanol, and dissolved in dilute alkali. The
solution was acidified to pH 5.5–6, and the precipitate
that formed was filtered off and washed with water.
N'-(2-Hydroxybenzylidene)-2-(2-methylquinolin-
4-ylsulfanyl)acetohydrazide (3a). Yield 0.33 g (95%),
mp 201–202°C. Rf 0.55 (ethanol–toluene, 1 : 6). 1H NMR
spectrum, δ, ppm: (1 : 1 syn/anti mixture) 2.63 and 2.67 s
(1.5H and 1.5H, CH3), 3.95 and 4.26 s (1H and 1H,
SCH2), 6.80–6.91 m (2Harom), 7.16–7.25 m (1Harom),
7.34–7.38 m (0.5Harom), 7.41 s (1Harom), 7.42–7.51 m
(1Harom), 7.55–7.68 m (1.5Harom), 7.83–7.90 m (1Harom),
8.03–8.08 m (1Harom), 8.29 and 8.37 s (0.5H and 0.5H,
N=CH), 9.86 and 11.05 br.s (0.5H and 0.5H, OH), 11.59
and 11.83 br.s (0.5H and 0.5H, NH). Found, %: C 65.10;
H 4.78; N 11.78; S 9.01. C19H17N3O2S. Calculated, %:
C 64.96; H 4.84; N 11.97; S 9.12.
N'-(4-Hydroxybenzylidene)-2-(2-methylquinolin-
4-ylsulfanyl)acetohydrazide (3g). Yield 0.33 g (93%),
mp251–252°C.Rf0.67(ethanol–toluene,1:2).Found,%:
C 65.11; H 4.77; N 11.78; S 9.22. C19H17N3O2S. Cal-
culated, %: C 64.96; H 4.84; N 11.97; S 9.12.
N'-(4-Hydroxybenzylidene)-2-(2,6-dimethyl-
quinolin-4-ylsulfanyl)acetohydrazide(3h).Yield0.36g
(99%), mp 274–275°C, Rf 0.56 (ethanol–toluene, 1 : 3).
1H NMR spectrum, δ, ppm (1 : 4 syn/anti mixture): 2.54
and 2.55 br.s (0.6H and 2.4H, CH3), 2.57 and 2.63 s
(0.6H and 2.4H, CH3), 3.88 and 4.25 s (0.4H and 1.6H,
SCH2), 6.74–6.81 m (2Harom), 7.33 and 7.38 s (0.8H and
3.2H, 4Harom), 7.41–7.53 m (3Harom), 7.75 and 7.79 d
(0.2H and 0.8H, 1Harom, J 8.6 Hz), 7.79 br.s (1Harom),
7.92 and 8.10 s (0.2H and 0,8H, 1H, N=CH), 9.50 and
9.51 br.s (0.2H and 0.8H, 1H, OH), 11.32 and 11.37 br.s
(0.2H and 0,8H, 1H, NH). Found, %: C 65.62; H 5.88;
N 11.54; S 8.89. C20H21N3O2S. Calculated, %: C 65.75;
H 5.75; N 11.51; S 8.77.
N'-(2-Hydroxybenzylidene)-2-(2,6-dimethyl-
quinolin-4-ylsulfanyl)acetohydrazide(3b).Yield0.34g
(94%), mp 207–208°C, Rf 0.52 (ethanol–toluene,
1 : 3). Found, %: C 65.82; H 5.51; N 11.76; S 8.59.
C20H21N3O2S. Calculated, %: C 65.75; H 5.75; N 11.51;
S 8.77.
N'-(2-Hydroxybenzylidene)-2-(2,8-dimethyl-
quinolin-4-ylsulfanyl)acetohydrazide(3c).Yield0.33g
(92%), mp 198–199°C, Rf 0.55 (ethanol–toluene,
1 : 3). Found, %: C 65.62; H 5.91; N 11.39; S 8.89.
C20H21N3O2S. Calculated, %: C 65.75; H 5.75; N 11.51;
S 8.77.
N'-(4-Hydroxybenzylidene)-2-(2,8-dimethyl-
quinolin-4-ylsulfanyl)acetohydrazide(3i).Yield0.31g
(85%), mp 248–249°C, Rf 0.65 (ethanol–toluene, 1 : 1.5).
Found, %: C 65.83; H 5.61; N 11.69; S 8.63.
C20H21N3O2S. Calculated, %: C 65.75; H 5.75; N 11.51;
S 8.77.
N'-(3-Hydroxybenzylidene)-2-(2-methylquinolin-
4-ylsulfanyl)acetohydrazide (3d). Yield 0.34 g (96%),
mp250–251°C,Rf0.52(ethanol–toluene,1:3).Found,%:
C 65.12; H 4.76; N 12.11; S 9.21. C19H17N3O2S.
Calculated, %: C 64.96; H 4.84; N 11.97; S 9.12.
Compounds 4a–4c (general procedure). A mixture
of 1 mmol of compound 1a–1c [13], 6 mLof ethanol, and
0.149 g (1 mmol) of 4-(dimethylamino)benzaldehyde
was refluxed for 6 h with stirring. After cooling, the
precipitate was filtered off, washed with ethanol, and
dissolved in dilute acid. The solution was alkalinized to
pH 8–8.5, and the precipitate that formed was filtered
off and washed with water.
N'-(3-Hydroxybenzylidene)-2-(2,6-dimethyl-
quinolin-4-ylsulfanyl)acetohydrazide(3е).Yield0.33g
(90%), mp 274–275°C, Rf 0.43 (ethanol–toluene, 1 : 4).
1H NMR spectrum, δ, ppm (2 : 3 syn/anti mixture): 2.43–
2.56 m (5H, CH3), 2.56–2.62 m (1H, CH3), 4.05 and
4.43 s (0.80H and 1.20H, SCH2), 6.78–6.88 m (1Harom),
7.04–7.18 m (2Harom), 7.19–7.28 m (1Harom), 7.31–
7.42 m (1Harom), 7.52–7.59 m (1Harom), 7.74–7.83 m
(2Harom), 7.98 and 8.13 s (0.6H and 0.4H, N=CH),
9.55–9.62 m (1H, OH), 11.61 and 11.74 s (0.6H and
0.4H, NH). Found, %: C 65.62; H 5.53; N 11.74; S 8.60.
C20H21N3O2S. Calculated, %: C 65.75; H 5.75; N 11.51;
S 8.77.
N'-[4-(Dimehtylamino)benzylidene]-2-(2-methyl-
quinolin-4-ylsulfanyl)acetohydrazide(4a).Yield0.34g
(90%), mp 203–204°C, Rf 0.62 (ethanol–toluene, 1 : 3).
Found,%:C66.83;H5.63;N14.69;S8.63.C21H22N4OS.
Calculated, %: C 66.67; H 5.82; N 14.8; S 8.46.
N'-[4-(Dimehtylamino)benzylidene]-2-(2,6-
dimethylquinolin-4-ylsulfanyl)acetohydrazide (4b).
Yield 0.35 g (93%), mp 206–207°C, Rf 0.61 (ethanol–
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 2 2020

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ALEKSANYAN, HAMBARDZUMYAN
toluene, 1 : 3). Found, %: C 67.51; H 6.00; N 14.49;
S 8.33. C22H24N4OS. Calculated, %: C 67.35; H 6.12;
N 14.28; S 8.16.
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N'-[4-(Dimethylamino)benzylidene]-2-(2,8-
dimethylquinolin-4-ylsulfanyl)acetohydrazide (4c).
Yield 0.36 g (95%), mp 216–217°C, Rf 0.67 (ethanol–
toluene, 1 : 3). 1H NMR spectrum, δ, ppm (2 : 3 syn/anti
mixture):2.56s(2H,CH3),2.63s(1H,CH3),2.65–2.70m
(3H, N=C–CH3), 2.93–3.00 m (6H, NCH3), 4.01 and
4.40 s (0.80H and 1.20 H, SCH2), 6.74 d (2Harom, J
8.8 Hz), 7.38–7.63 m (5Harom), 7.85–7.92 m (1Harom),
7.93 and 8.07 s (0.6H and 0.4H, CH=N), 11.38 and
11.48 s (0.4H and 0.6H, NH). Found, %: C 67.28;
H 6.41; N 14.13; S 8.02. C22H24N4OS. Calculated, %:
C 67.35; H 6.12; N 14.28; S 8.16.
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Compounds 5a–5c (general procedure). A mixture
of 1 mmol of compound 1a–1c [13], 15 mL of dioxane,
and 0.18 g (1.2 mmol) of phthalic anhydride was refluxed
for 7 h with stirring. After cooling, rhe precipitate was
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N'-(1,3-Dioxoindolin-2-yl)-2-(2-methylquinolin-
4-ylsulfanyl)acetamide (5a). Yield 0.34 g (90%), mp
220–221°C, Rf 0.54 (ethanol–toluene, 1 : 1). H NMR
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spectrum, δ, ppm: 2.72 s (3H, CH3), 4.11 s (2H,
SCH2), 6.49 s (1Harom), 7.39 m (8Harom), 10.5 br.s (1H,
NH). Found, %: C 63.83; H 3.73; N 11.31; S 8.63.
C20H15N3O3S. Calculated, %: C 63.66; H 3.98; N 11.14;
S 8.49.
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N'-(1,3-Dioxoindolin-2-yl)-2-(2,6-dimethylqui-
nolin-4-ylsulfanyl)acetamide (5b). Yield 0.34 g (87%),
1
mp 228–229°C, Rf 0.52 (ethanol–toluene, 1 : 1). H
NMR spectrum, δ, ppm: 2.49 s (3H, CH3), 2.53 s (3H,
N=C–CH3), 4.16 s (2H, SCH2), 7.42 s (1Harom), 7.46–
7.64 m (3Harom), 7.75–7.98 m (4Harom), 12.99 br.s (1H,
NH). Found, %: C 64.23; H 4.51; N 13.53; S 8.02.
C21H17N3O3S. Calculated, %: C 64.45; H 4.35; N 13.30;
S 8.18.
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N'-(1,3-Dioxoindolin-2-yl)-2-(2,8-dimethylqui-
nolin-4-ylsulfanyl)acetamide (5c). Yield 0.36 g (92%),
mp210–211°C,Rf0.58(ethanol–toluene,1:1).Found,%:
C 64.63; H 4.51; N 13.19; S 8.41. C21H17N3O3S. Cal-
culated, %: C 64.45; H 4.35; N 13.30; S 8.18.
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CONFLICT OF INTEREST
The authors declare no conflict of interest.
https://doi.org/10.1134/ S1070428017020142
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 2 2020