A simple and efficient route to substituted 2-alkylsulfanyl-6-oxo-1,4,5,6- tetrahydropyridine-3-carbonitriles

Full text of DOI:10.1134/S1070428006120256

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2006, Vol. 42, No. 12, pp. 1877–1879. © Pleiades Publishing, Inc., 2006.
Original Russian Text © V.D. Dyachenko, 2006, published in Zhurnal Organicheskoi Khimii, 2006, Vol. 42, No. 5, pp. 791–792.
SHORT
COMMUNICATIONS
A Simple and Efficient Route to Substituted 2-Alkylsulfanyl-
6-oxo-1,4,5,6-tetrahydropyridine-3-carbonitriles
V. D. Dyachenko
Taras Shevchenko National Pedagogical University, ul. Oboronnaya 2, Lugansk, 91011 Ukraine
e-mail: dvd_lug@online.lg.ua
Received August 9, 2005
DOI: 10.1134/S1070428006120256
morpholine. The alkylation of salt IIIb with 1,2-di-
bromoethane afforded 2,2'-ethylenedisulfanylbis-
(6-oxo-4-phenyl-1,4,5,6-tetrahydropyridine-3-carbo-
nitrile) (VI).
Substituted 6-alkylsulfanyl-1,2,3,4-tetrahydropyri-
dines were synthesized previously by alkylation of
the corresponding ammonium tetrahydropyridine-6-
thiolates [1]. 2-Alkylsulfanyl-4-aryl(hetaryl)-6-oxo-
1,4,5,6-tetrahydropyridine-3-carbonitriles (I) are po-
tential intermediate products for the synthesis of dyes
[2]. The present communication reports for the first
time on the synthesis of compounds I by heating
chloroacetic acid derivatives II with Michael adducts
III in ethanol for a short time. Compounds III were
prepared in turn by reaction of 5-aryl(hetaryl)meth-
ylidene-2,2-dimethyl-1,3-dioxane-4,6-diones IV with
cyanothioacetamide (V) in the presence of N-methyl-
N-(4-Bromophenyl)-2-[3-cyano-6-oxo-4-(2-
thienyl)-1,4,5,6-tetrahydropyridin-2-ylsulfanyl]
acetamide (Ia). A mixture of 4.40 g (10 mmol) of salt
IIIa and 2.49 g (10 mmol) of N-(4-bromophenyl)-
chloroacetamide (IIa) in 30 ml of ethanol was heated
for 5 min under reflux. The mixture was filtered while
hot through a folded filter, the filtrate was cooled, and
the precipitate was filtered off and washed with
ethanol and hexane. Yield 3.22 g (72%), white powder,
NH
Me
NC
S–
N
O
O
O
Me
O
S
O
R
O
R
N
H
+
NC
NH2
Me
Me
Me
Me
O
O
O
OH
IVa–IVc
V
IIIa–IIIc
R
CN
S
ClCH2C(O)Z
Z
O
N
H
O
Ia, Ib
CN
O
Ph
H
N
S
BrCH2CH2Br
S
N
H
NC
Ph
O
VI
I, R = 2-thienyl, Z = 4-BrC6H4NH (a), R = 3-EtO-4-HOC6H3, Z = PhCH2O (b); II, Z = 4-BrC6H4NH (a), PhCH2O (b);
III, IV, R = 2-thienyl (a), Ph (b), 3-EtO-4-HOC6H3 (c).
1877

DYACHENKO
1878
mp 220–224°C (from AcOH). IR spectrum, ν, cm–1:
1671 (C=O), 2212 (C≡N). 1H NMR spectrum, δ, ppm:
2.70 d and 2.99 d (1H each, 5-H, J = 10.82 Hz), 3.89 s
(2H, SCH2), 4.21 m (1H, 4-H), 6.92 m (2H, 3'-H,
5'-H.), 7.24 d.d (1H, 4'-H, J = 5.94 Hz), 7.39 d and
7.56 d (2H each, C6H4, J = 7.53 Hz), 10.38 br.s (1H,
NH), 10.57 br.s (1H, NH). Mass spectrum, m/z
(Irel, %): 450 (9) [M + 2]+, 449 (8) [M + 1]+, 448 (4)
[M]+, 276 (11), 174 (49), 138 (63), 122 (14), 111 (40),
99 (100), 98 (27). Found, %: C 48.01; H 3.00; N 9.15.
C18H14BrN3O2S2. Calculated, %: C 48.22; H 3.15;
N 9.37. M 448.36.
CH2NCH2), 3.78 m (4H, CH2OCH2), 4.40 d and 4.61 d
(1H, 2-H, J = 12.05 Hz), 5.32 d and 5.48 d (1H, 3-H,
J = 12.05 Hz), 6.99–7.21 m (3H, Harom), 7.42–7.54 m
(2H, Harom), 9.02 br.s and 9.76 br.s (1H, OH), 9.49 br.s
and 9.54 br.s (1H, C=NH); no N+H signal was ob-
served, presumably due to fast exchange with water
present in the solvent. Some signals are doubled, for
compound IIIb is a mixture of stereoisomers. Found,
%: C 57.96; H 6.02; N 9.50. C21H27N3O5S. Calculated,
%: C 58.18; H 6.28; N 9.69.
N-Methylmorpholinium 2-cyano-3-(3-ethoxy-4-
hydroxyphenyl)-3-(4-hydroxy-2,2-dimethyl-6-oxo-
6H-1,3-dioxin-5-yl)propanimidothioate (IIIc) was
synthesized in a similar way from 2.93 g (10 mmol) of
compound IVc. Yield 4.24 g (86%), yellow powder,
mp 130–132°C. IR spectrum, ν, cm–1: 1650 (C=O),
Benzyl 2-[3-cyano-4-(3-ethoxy-4-hydroxyphen-
yl)-6-oxo-1,4,5,6-tetrahydropyridin-2-ylsulfanyl]-
acetate (Ib) was synthesized in a similar way from
4.33 g (10 mmol) of salt IIIb and 1.52 ml (10 mmol)
of benzyl chloroacetate (IIb). Yield 2.80 g (64%),
colorless needles, mp 133–135°C (from EtOH). IR
spectrum, ν, cm–1: 1682 (C6=O), 1744 (C=O, ester),
2204 (C≡N), 3416 (OH). 1H NMR spectrum, δ, ppm:
1.31 t (3H, CH3CH2, J = 6.19 Hz), 2.49 d.d and
2.61 d.d (1H each, 5-H, J = 10.99 Hz), 3.80 m (1H,
4-H), 3.95 q (2H, OCH2CH3, J = 6.19 Hz), 4.00 d and
1
2256 (C≡N), 3177–3380 (OH, NH). H NMR spec-
trum, δ, ppm: 1.23 t (3H, CH2CH3, J = 6.17 Hz), 1.39 s
(3H, Me), 1.44 s (3H, Me), 2.62 s (3H, NMe), 2.95 m
(4H, CH2NCH2), 3.70 m (4H, CH2OCH2), 4.08 q (2H,
CH2CH3, J = 6.17 Hz), 4.22 d and 4.49 d (1H, 2-H, J =
12.14 Hz), 5.25 d and 5.38 d (1H, 3-H, J = 12.14 Hz),
6.48 d and 6.59 d (1H, Harom, J = 6.99 Hz), 6.72 d and
6.95 d (1H, Harom, J = 7.00 Hz), 7.14 s and 7.66 s
(1H, Harom), 8.03 br.s (1H, NH), 8.40 br.s (1H, OH),
9.42 br.s and 9.93 br.s (1H, OH). Found, %: C 56.11;
H 6.25; N 8.40. C23H31N3O7S. Calculated, %: C 55.97;
H 6.33; N 8.51.
2
4.11 d (1H each, SCH2, J = 18.09 Hz), 5.10 d and
5.18 d (1H each, OCH2Ph, 2J = 17.16 Hz), 6.52 d (1H,
Harom, J = 7.12 Hz), 6.71 m (2H, Harom), 7.32-7.41 m
(5H, Harom), 8.95 br.s (1H, NH), 11.58 br.s (1H, OH).
Mass spectrum, m/z (Irel, %): 439 (8) [M + 1]+, 438 (6)
[M]+, 424 (5), 333 (14), 245 (12), 175 (16), 154 (27),
138 (84), 122 (25), 111 (30), 99 (100). Found, %:
C 62.81; H 4.97; N 6.20. C23H22N2O5S. Calculated, %:
C 63.00; H 5.06; N 6.39. M 438.51.
2,2'-Ethylenedisulfanylbis(6-oxo-4-phenyl-
1,4,5,6-tetrahydropyridine-3-carbonitrile) (VI) was
synthesized as described above for compound Ia from
4.33 g (10 mmol) of salt IIIa and 0.45 ml (5 mmol) of
1,2-dibromoethane. Yield 3.60 g (74%), white powder,
mp 272–274°C (from AcOH). IR spectrum, ν, cm–1:
N-Methylmorpholinium 2-cyano-3-(4-hydroxy-
2,2-dimethyl-6-oxo-6H-1,3-dioxin-5-yl)-3-(2-thi-
enyl)propanimidothioate (IIIa). Cyanothioacetamide
(V), 1.0 g (10 mmol), was dispersed in 25 ml of
ethanol, 1.10 ml (10 mmol) of N-methylmorpholine
was added under stirring, the mixture was stirred for
15 min until it became homogeneous, 2.38 g (10 mmol)
of compound IVa was added, and the mixture was
stirred for 20 min and was left to stand for 24 h. The
precipitate was filtered off and washed with ethanol
and hexane. Yield 3.47 g (79%), white powder,
mp 140–142°C; published data [1]: mp 139–141°C.
1
1680 (C=O), 2184, 2206 (C≡N), 3176 (NH). H NMR
spectrum, δ, ppm: 2.62–2.71 m (2H, 5-H), 2.93–
3.04 m (2H, 5-H), 3.22–3.38 m (4H, SCH2), 4.03 t
(2H, 4-H, J = 6.90 Hz), 7.23–7.40 m (10H, Harom),
10.62 br.s (2H, 2NH). Mass spectrum, m/z (Irel, %):
489 (5) [M + 2]+, 488 (21) [M + 1]+, 487 (100) [M]+,
257 (33), 138 (12), 111 (8), 99 (13). Found, %:
C 64.00; H 4.31; N 11.42. C26H22N4O2S2. Calculated,
%: C 64.18; H 4.56; N 11.51.
The IR spectra were recorded on an IKS-40 spec-
trometer from samples dispersed in mineral oil. The
1H NMR spectra were measured in DMSO-d6 on
a Varian Mercury-400 instrument (400.397 MHz) using
TMS as internal reference. The mass spectra (electron
impact, 70 eV) were obtained on a Hewlett–Packard
5890/5972 GC–MS system (HP-5MS column; samples
were injected as solutions in methylene chloride). The
melting points were determined on a Kofler melting
N-Methylmorpholinium 2-cyano-3-(4-hydroxy-
2,2-dimethyl-6-oxo-6H-1,3-dioxin-5-yl)-3-phenyl-
propanimidothioate (IIIb) was synthesized in a simi-
lar way from 2.32 g (10 mmol) of compound IVb.
Yield 3.51 g (81%), yellow powder, mp 152–154°C.
IR spectrum, ν, cm–1: 1650 (C=O), 2253 (C≡N), 3410
1
(OH, NH). H NMR spectrum, δ, ppm: 1.39 s (3H,
Me), 1.42 s (3H, Me), 2.75 s (3H, NMe), 3.11 m (4H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 12 2006

A SIMPLE AND EFFICIENT ROUTE TO SUBSTITUTED 2-ALKYLSULFANYL-...
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point apparatus. The progress of reactions was moni-
tored by TLC on Silufol UV-254 plates using acetone–
hexane (3:5) as eluent; spots were visualized by treat-
ment with iodine vapor or under UV light.
REFERENCES
1. Dyachenko, V.D., Krivokolysko, S.G., and Litvinov, V.P.,
Izv. Ross. Akad. Nauk, Ser. Khim., 1997, p. 1852.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 12 2006