Reactions of 2-chloro-4-methylquinolines with sulfur nucleophiles and of 4-methylquinoline-2(1H)-thiones with substituted benzyl chlorides

Full text of DOI:10.1134/S1070428014030257

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 3, pp. 442–444. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © I.L. Aleksanyan, L.P. Hambardzumyan, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 3, pp. 421–423.
SHORT
COMMUNICATIONS
Reactions of 2-Chloro-4-methylquinolines with Sulfur
Nucleophiles and of 4-Methylquinoline-2(1H)-thiones
with Substituted Benzyl Chlorides
I. L. Aleksanyan and L. P. Hambardzumyan
Yerevan State University, ul. Aleka Manukyana 1, Yerevan, 0025 Armenia
e-mail: ialeksanyan@ysu.am
Received August 9, 2013
DOI: 10.1134/S1070428014030257
Among functionally substituted quinoline deriva-
tives, those containing sulfur occupy a particular place
due to their antitumor, analgesic, antimicrobial, and
other kinds of biological activity [1]. They also exhibit
good antioxidant properties and are used in anti-stress
therapy [2]. Sulfur-containing compounds comprising
more than one heterocyclic fragment attract increased
interest as fluorophores [3] and play an important role
in studying various biological systems [4]. Quinoline
derivatives are also promising as fluorophores [5],
antioxidants, and radioprotectors [6].
zole-2-thiol, biphenyl-4,4′-diyldimethanethiol, (oxydi-
benzene-4,1-diyl)dimethanethiol, and benzene-1,4-di-
yldimethanethiol. Optimal reaction conditions were
found. Bis-quinoline derivatives were mainly formed
at different reactant ratios. The reactions ensured high
yields when mixtures of 2-chloroquinolines Ia–Ic [7]
with the corresponding binucleophiles at a ratio of 2:1
(1:1 in the reaction with 1,3-benzothiazole-2-thiol)
were heated in boiling ethanol over a period of 3–5 h.
As a result, we isolated substituted 4,4′-bis(quinolin-2-
ylsulfanyl)biphenyls IIa–IIc, bis[4-(quinolin-2-yl)phe-
nyl] sulfides IIIa–IIIc, 4,4′-bis(quinolin-2-ylsulfanyl-
methyl)biphenyls IVa–IVc, 2,2′-[oxybis(benzene-4,1-
diylsulfanediyl)]bis(4-methylquinolines) Va–Vc,
1,4-bis(quinolin-2-ylsulfanyl)benzenes VIa–VIc, and
With a view to synthesize new quinoline deriva-
tives, in the present work we examined reactions of
2-chloro-4-methylquinolines Ia–Ic with biphenyl-4,4′-
dithiol, 4,4′-sulfanediyldibenzenethiol, 1,3-benzothia-
Scheme 1.
Me
Me
HS
X
SH
R
R
X
Me
N
N
S
S
N
IIa–IIc, IIIa–IIIc, IVa–IVc, Va–Vc, VIa–VIc
R
N
Me
Cl
SH
Ia–Ic
S
N
R
S
N
S
VIIa–VIIc
S
R = H (a), 6-Me (b), 8-Me (c); II, X =
; III, X =
;
O
IV, X =
; V, X =
; VI, X =
.
442

REACTIONS OF 2-CHLORO-4-METHYLQUINOLINES WITH SULFUR NUCLEOPHILES
443
Scheme 2.
C32H24N2S3. Calculated, %: C 72.14; H 4.54; N 5.26;
S 18.06.
Me
2,2′-[Sulfanediylbis(benzene-4,1-diylsulfanedi-
yl)]bis(4,6-dimethylquinoline) (IIIb). Yield 5.10 g
(91%), mp 167–168°C, Rf 0.53 (ethanol–toluene,
1:50). Found, %: C 72.74; H 5.16; N 4.89; S 17.28.
C34H28N2S3. Calculated, %: C 72.82; H 5.03; N 5.00;
S 17.15.
Cl
X
Cl, NaOH
IVa–IVc, Va–Vc
VIa–VIc
R
N
H
S
VIIIa–VIIIc
R = H (a), 6-Me (b), 8-Me (c).
2,2′-[Sulfanediylbis(benzene-4,1-diylsulfanedi-
yl)]bis(4,8-dimethylquinoline) (IIIc). Yield 5.38 g
(96%), mp 126–127°C, Rf 0.59 (ethanol–toluene,
1:50). Found, %: C 72.97; H 5.17; N 5.12; S 17.03.
C34H28N2S3. Calculated, %: C 72.82; H 5.03; N 5.00;
S 17.15.
Compounds IVa–IVc, Va–Vc, and VIa–VIc (gen-
eral procedure). a. The reactions were carried out as
described above for IIa–IIc and IIIa–IIIc.
2-(1,3-benzothiazol-2-ylsulfanyl)quinolines VIIa–
VIIc (Scheme 1).
Compounds IVa–IVc, Va–Vc, and VIa–VIc were
also synthesized independently by reaction of 4-meth-
ylquinoline-2(1H)-thiones VIIIa–VIIIc [8] with
4,4′-bis(chloromethyl)biphenyl, 4,4′-oxybis(chloro-
methylbenzene), and 1,4-bis(chloromethyl)benzene at
a ratio of 2:1 in aqueous sodium hydroxide on stirring
for 2 h at room temperature (Scheme 2).
b. A mixture of 0.4 g (10 mmol) of sodium hydrox-
ide and 10 mmol of quinoline VIIIa–VIIIc [8] in
10 mL of water was stirred for 15 min at room tem-
perature. The corresponding bis(chloromethyl) deriva-
tive, 5 mmol, was then added, the mixture was stirred
for 2 h, and the precipitate was filtered off, washed
with water, and dried. The products showed no depres-
sion of the melting point on mixing with samples
prepared as described in a.
Compounds IIa–IIc and IIIa–IIIc (general proce-
dure). A mixture of 0.02 mol of 2-chloroquinoline Ia–
Ic [7] and 0.01 mol of the corresponding nucleophile
in 50 mL of ethanol was heated for 3–5 h under reflux
with stirring. After cooling, the precipitate was filtered
off, washed with ethanol, and dried.
2,2′-(Biphenyl-4,4′-diylbissulfanediyl)bis-
(4-methylquinoline) (IIa). Yield 4.80 g (96%),
mp 202–203°C, Rf 0.56 (ethanol–toluene, 1:50). Found,
%: C 76.92; H 4.71; N 5.73; S 12.94. C32H24N2S2. Cal-
culated, %: C 76.76; H 4.83; N 5.60; S 12.81.
2,2′-[Biphenyl-4,4′-diylbis(methylenesulfanedi-
yl)]bis(4-methylquinoline) (IVa). Yield 4.91 g (93%)
(a), 2.51 g (95%) (b); mp 186°C, Rf 0.53 (ethanol–
2,2′-(Biphenyl-4,4′-diylbissulfanediyl)bis(4,6-di-
1
toluene, 1:50). H NMR spectrum, δ, ppm: 2.59 s (6H,
methylquinoline) (IIb). Yield 5.17 g (98%), mp 255–
CH3), 4.59 s (4H, CH2), 7.26 s (2H, 3-H), 7.41–7.67 m
(10H, Harom), 7.72 t.d (2H, Harom, J = 7.54, 1.59 Hz),
7.96 d.d (4H, Harom, J = 17.85, 7.54 Hz). Found, %:
C 77.10; H 5.46; N 5.18; S 12.27. C34H28N2S2. Calcu-
lated, %: C 77.23; H 5.34; N 5.30; S 12.13.
1
256°C, Rf 0.50 (ethanol–toluene, 1:50). H NMR spec-
trum, δ, ppm: 2.50 s (6H, CH3) 2.56 s (6H, CH3),
7.07 s (2H, 3-H), 7.55 d.d (2H, Harom, J = 7.94,
1.59 Hz), 7.67–7.77 m (6H, Harom), 7.80 m (2H, Harom),
7.90 d (4H, Harom, J = 7.94 Hz). Found, %: C 77.35;
H 5.42; N 5.18; S 11.98. C34H28N2S2. Calculated, %:
C 77.23; H 5.34; N 5.30; S 12.13.
2,2′-[Biphenyl-4,4′-diylbis(methylenesulfanedi-
yl)]bis(4,6-dimethylquinoline) (IVb). Yield 5.17 g
(93%) (a), 2.69 g (97%) (b); mp 205–206°C, Rf 0.54
(ethanol–toluene, 1:50). Found, %: C 77.53; H 5.62;
N 5.19; S 11.68. C36H32N2S2. Calculated, %: C 77.66;
H 5.79; N 5.03; S 11.52.
2,2′-[Biphenyl-4,4′-diylbis(methylenesulfanedi-
yl)]bis(4,8-dimethylquinoline) (IVc). Yield 5.28 g
(95%) (a), 2.69 g (97%) (b); mp 202–203°C, Rf 0.61
(ethanol–toluene, 1:50). Found, %: C 77.79; H 5.88;
N 5.17; S 11.39. C36H32N2S2. Calculated, %: C 77.66;
H 5.79; N 5.03; S 11.52.
2,2′-(Biphenyl-4,4′-diylbissulfanediyl)bis(4,8-di-
methylquinoline) (IIc). Yield 5.02 g (95%), mp 226–
227°C, Rf 0.69 (ethanol–toluene, 1:50). Found, %:
C 77.10; H 5.48; N 5.18; S 12.26. C34H28N2S2. Calcu-
lated, %: C 77.23; H 5.34; N 5.30; S 12.13.
2,2′-[Sulfanediylbis(benzene-4,1-diylsulfanedi-
yl)]bis(4-methylquinoline) (IIIa). Yield 4.42 g (83%),
mp 144–145°C, Rf 0.55 (ethanol–toluene, 1:50).
1H NMR spectrum, δ, ppm: 2.57 s (6H, CH3), 6.98 s
(2H, 3-H), 7.35 d.d (4H, Harom, J = 17.85, 7.54 Hz),
7.52–7.71 m (10H, Harom), 7.82 t.d (2H, Harom, J = 7.54,
1.59 Hz). Found, %: C 71.26; H 4.68; N 5.11; S 18.23.
2,2′-[Oxybis(benzene-4,1-diylmethylenesulfane-
diyl)]bis(4-methylquinoline) (Va). Yield 4.95 g (91%)
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 3 2014

ALEKSANYAN, HAMBARDZUMYAN
444
(a), 2.36 g (87%) (b); mp 111–112°C, Rf 0.58
(heptane–toluene, 1:25). Found, %: C 74.85; H 5.32;
N 5.38; S 11.94. C34H28N2OS2. Calculated, %:
C 74.97; H 5.18; N 5.14; S 11.77.
Rf 0.62 (ethanol–toluene, 1:50). Found, %: C 66.32;
H 3.78; N 9.28; S 20.66. C17H12N2S2. Calculated, %:
C 66.20; H 3.92; N 9.08; S 20.79.
2-(1,3-Benzothiazol-2-ylsulfanyl)-4,6-dimethyl-
quinoline (VIIb). Yield 3.03 g (94%), mp 149–151°C,
Rf 0.59 (ethanol–toluene, 1:50). Found, %: C 66.92;
H 4.23; N 8.86; S 19.99: C18H14N2S2. Calculated, %:
C 67.05; H 4.38; N 8.69; S 19.89.
2,2′-[Oxybis(benzene-4,1-diylmethylenesulfane-
diyl)]bis(4,6-dimethylquinoline) (Vb). Yield 5.49 g
(96%) (a), 2.80 g (98%) (b); mp 145–146°C, Rf 0.53
1
(heptane–toluene, 1:25). H NMR spectrum, δ, ppm:
2.50 s (6H, CH3), 2.56 s (6H, CH3), 4.59 s (4H, CH2),
2-(1,3-Benzothiazol-2-ylsulfanyl)-4,8-dimethyl-
7.07 s (2H, 3-H), 7.55 d.d (2H, Harom, J = 7.94,
quinoline (VIIc). Yield 2.87 g (89%), mp 147–148°C,
1.59 Hz), 7.67–7.77 m (6H, Harom), 7.80 s (2H, Harom
)
1
Rf 0.63 (ethanol–toluene, 1:50). H NMR spectrum, δ,
7.90 d (4H, Harom, J = 7.94 Hz). Found, %: C 75.64;
H 5.48; N 5.02; S 11.33: C36H32N2OS2. Calculated, %:
C 75.49; H 5.63; N 4.89; S 11.20.
ppm: 2.72 s (3H, CH3), 2.85 s (3H, CH3), 7.33–7.53 m
(4H, Harom), 7.61 d (1H, Harom, J = 6.35 Hz) 7.88 d (1H,
H
arom, J = 7.94 Hz), 7.95 d.d (2H, Harom, J = 17.46,
2,2′-[Oxybis(benzene-4,1-diylmethylenesulfane-
diyl)]bis(4,6-dimethylquinoline) (Vc). Yield 5.38 g
(94%) (a), 2.63 g (92%) (b); mp 126–127°C, Rf 0.49
(heptane–toluene, 1:25). Found, %: C 75.36; H 5.78;
N 5.14; S 11.02. C36H32N2OS2. Calculated, %:
C 75.49; H 5.63; N 4.89; S 11.20.
2,2′-[Benzene-1,4-diylbis(methylenesulfanedi-
yl)]bis(4-methylquinoline) (VIa). Yield 4.29 g (95%)
(a), 2.10 g (93%) (b); mp 155–156°C, Rf 0.60
(ethanol–toluene, 1:50). Found, %: C 74.46; H 5.17;
N 6.38; S 14.03. C28H24N2S2. Calculated, %: C 74.30;
H 5.34; N 6.19; S 14.17.
7.94 Hz). Found, %: C 67.19; H 4.21; N 9.42; S 19.75.
C17H14N2S2. Calculated, %: C 67.05; H 4.38; N 8.69;
S 19.89.
1
The H NMR spectra were recorded on a Varian
Mercury-300 spectrometer from solutions in
DMSO-d6. The purity of the isolated compounds was
checked by TLC on Silufol UV-254 plates; spots were
visualized by treatment with iodine vapor.
REFERENCES
1. Okada, E. and Tsukushi, N., Heterocycles, 2000, vol. 53,
p. 709; Skrzypek, L. and Suwinska, K., Heterocycles,
2002, vol. 57, p. 2035.
2,2′-[Benzene-1,4-diylbis(methylenesulfanedi-
yl)]bis(4,6-dimethylquinoline) (VIb). Yield 4.46 g
(93%) (a), 2.35 g (98%) (b); mp 221–222°C, Rf 0.52
2. Brazhko, A.A., Visn. Zapor. Nats. Univ., 2002, no. 2, p. 1.
1
(ethanol–toluene, 1:50. H NMR spectrum, δ, ppm:
3. Sharath, N., Bhojya Naik, H.S., Vinai Kumar, B., and
Hoskeri, J., Brit. J. Pharm. Res., 2011, vol. 1, no. 3, p. 46;
Sharath, N., Bhojya Naik, H.S., Vinai Kumar, B., and
Hoskeri, J., Pharm. Sinica, 2012, vol. 3, p. 254;
Toche, R.B., Kazi, M.A., Patil, S.P., Kanawade, S.B., and
Jachak, M.N., J. Fluorescence, 2010, vol. 20, p. 1129.
2.49 s (6H, CH3), 2.63 s (6H, CH3), 4.49 s (4H, CH2),
7.20–7.32 m (8H, Harom), 7.51 d.d (4H, Harom, J = 7.94,
1.59 Hz). Found, %: C 74.84; H 5.73; N 5.99; S 13.48.
C30H28N2S2. Calculated, %: C 74.96; H 5.87; N 5.83;
S 13.34.
2,2′-[Benzene-1,4-diylbis(methylenesulfanedi-
yl)]bis(4,6-dimethylquinoline) (VIc). Yield 4.56 g
(95%) (a), 2.30 g (96%) (b); mp 187–188°C, Rf 0.52
(ethanol–toluene, 1:50). Found, %: C 75.11; H 6.01;
N 5.98; S 13.21. C30H28N2S2. Calculated, %: C 74.96;
H 5.87; N 5.83; S 13.34.
Compounds VIIa–VIIc were synthesized as de-
scribed above for IIa–IIc and IIIa–IIIc from 1,3-ben-
zothiazole-2-thiol; the products were recrystallized
from aqueous ethanol.
4. Shanker, R.M., Arkivoc, 2012, part (i), p. 1.
5. Avetisyan, A.A., Aleksanyan, I.L., and Ambartsu-
myan, L.P., Russ. J. Org. Chem., 2007, vol. 43, p. 1052.
6. Malakyan, M.G., Badzhinyan, S.A., Vardevanyan, L.A.,
Grigoryan, D.S., Egiazaryan, D.E., Avetisyan, A.A.,
Aleksanyan, I.L., Ambartsumyan, L.P., and Sarg-
syan, K.S., Khim.-Farm. Zh., 2009, no. 1, p. 8.
7. Beilsteins Handbuch der organischen Chemie, vol. H20,
p. 392.
8. Sintezy geterotsiklicheskikh soedinenii (Syntheses of
Heterocyclic Compounds), Mndzhoyan, A.L., Ed.,
Yerevan, Akad. Nauk Arm. SSR, 1966, vol. 7, p. 41.
2-(1,3-Benzothiazol-2-ylsulfanyl)-4-methylquino-
line (VIIa). Yield 2.83 g (92%), mp 153–155°C,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 3 2014