Synthesis and alkylation of new functionally substituted 4,4-dimethylpiperidin-2-ones

Article abstract of DOI:10.1134/S1070428011080161

The reaction of ethyl isopropylidenecyanoacetate with ethyl 3-amino-3-thioxopropanoate gave rise to ethyl 4,4-dimethyl-6-oxo-2-thioxo-5- cyanopiperidine-3-carboxylate whose alkylation provided ethyl 2-benzylsulfanyl-4,4-dimethyl-6-oxo-5-cyano-1,4,5,6-tetr

Full text of DOI:10.1134/S1070428011080161

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 8, pp. 1214−1221. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © V.D. Dyachenko, A.A. Nikishin, I.E. Dyachenko, 2011, published in Zhurnal Organicheskoi Khimii, 2011, Vol. 47, No. 8, pp. 1196−1203.
Synthesis and Alkylation of New Functionally Substituted
4,4-Dimethylpiperidin-2-ones
V. D. Dyachenko, A. A. Nikishin, and I. E. Dyachenko
Taras Shevchenko Lugansk State University, Lugansk, 91011 Ukraine
e-mail: dvd_lug@online.lg.ua
Received January 15, 2011
Abstract—The reaction of ethyl isopropylidenecyanoacetate with ethyl 3-amino-3-thioxopropanoate gave
rise to ethyl 4,4-dimethyl-6-oxo-2-thioxo-5-cyanopiperidine-3-carboxylate whose alkylation provided ethyl
2-benzylsulfanyl-4,4-dimethyl-6-oxo-5-cyano-1,4,5,6-tetrahydropyridine-3-carboxylate, ethyl 5-benzyl-2-
benzylsulfanyl-4,4-dimethyl-6-oxo-5-cyano-1,4,5,6-tetrahydropyridine-3-carboxylate, and ethyl 7,7-dimethyl-
5-oxo-6-cyano-3,5,6,7-tetrahydro-2H-thiazolo[3,2-a]pyridine-8-carboxylate.
DOI: 10.1134/S1070428011080161
4,4-Disubstituted partially hydrogenated pyridin-
2-ones and thiones, promising semiproducts in the
designing of drugs for treating antidepressant states [1],
we obtained by Michael reaction of ethyl isopropyli-
denecyanoacetate [2] or isopropylidenemalononitrile [3]
with cyanothioacetamide and by Knoevenagel reaction
in Cope version by acetone condensation with cyanoac-
etanilide [4].
the use as the alkylating agent of benzyl chloride under
the same conditions resulted in the formation of the cor-
responding ethyl 2-benzylsulfanyl-4,4-dimethyl-6-oxo-
5-cyano-1,4,5,6-tetrahydropyridine-3-carboxylate (VI).
Further alkylation of compound VI with benzyl chloride
did not give the expected N-benzyl derivatives, but the
C5-alcylation occurred of the tetrahydropyridine ring with
the formation of ethyl 5-benzyl-2-benzylsulfanyl-4,4-
dimethyl-6-oxo-5-cyano-1,4,5,6-tetrahydropyridine-3-
carboxylate (VII), which could be easily obtained in one
stage from ester III by alkylation with a double amount
of benzyl chloride.
In this study under the conditions of Michael reaction
we obtained new substances from the above mentioned
class of organic compounds. The reaction of ethyl
isopropylidenecyanoacetate (I) with ethyl 3-amino-3-
thioxopropanoate (II) in the presence of sodium ethylate
at 20°C furnished ethyl 4,4-dimethyl-6-oxo-2-thioxo-5-
cyanopiperidine-3-carboxylate (III) (Scheme 1). The
reaction pathway evidently includes the formation of
Michael adduct A, unstable under the reaction conditions
and suffering a regioselective cyclization into substituted
piperidine III.
Bringing into the reaction with ethyl isopropylidene-
cyanoacetate (I) as the CH-component 2-(4-phenylthia-
zol-2-yl)thioacetamide (VIII) in the presence of sodium
ethylate resulted in 4,4-dimethyl-2-oxo-5-(4-phenylthi-
azol-2-yl)-6-thioxopiperidine-3-carbonitrile (IX) via the
intramolecular cyclocondensation of the hypothetical
Michael adduct B.
The structure of compound III was confirmed by
spectral characteristics (see EXPERIMENTAL) and by
chemical reactions. Its alkylation with 1,2-dibromoethane
in DMF at alkaline reaction gave ethyl 7,7-dimethyl-
5-oxo-6-cyano-3,5,6,7-tetrahydro-2H-thiazolo[3,2-a]
pyridine-8-carboxylate (IV), potential peptidomimetic
[5]. The alkylation of compound III with propyl bromide
in DMF in the presence of alkali provided thioether V, and
Using as CH-acid monothioxopropanediamide (X)
in the reaction with Michael acceptor I we synthesized
4,4-dimethyl-6-oxo-2-thioxo-5-cyanopiperidine-3-car-
boxamide (substituted monothioxoglutarimide) (XI). It is
reasonable to assume that it formed as a result of the in-
tramolecular cyclization of Michael adduct C. The alkyla-
tion of compound XI with phenacyl bromide (XIIa) in
DMF in the presence of equimolar amount of KOH led to
1214

SYNTHESIS AND ALKYLATION
1215
Scheme 1.
O
S
O
O
S
NC
O
NC
O
NC
O
Cl
Ph
OEt
OEt
OEt
Ph
Ph
N
H
V
N
H
VI
S
Ph
N
H
VII
2Cl
Ph
Br
Ph
Cl
O
S
O
S
O
S
NC
NC
O
NC
O
OEt
OEt
Br
Br
OEt
_EtOH
O
N
N
H
III
OEt H2N
A
IV
O
Ph
OEt
N
Ph
Ph
H2N
S
S
II
N
S
N
NC
O
NC
NC
H2N
O
S
S
S
VIII
_EtOH
N
O
OEt
O
OEt H2N
S
H
B
IX
I
NH2
H2N
S
X
O
O
S
O
S
NC
O
NC
NC
O
KOH_DMF
NH2
S K
NH2
NH2
_EtOH
N
H
O
N
H
OEt H2N
C
D
XI
Br
O
O
O
S
O
NC
O
NC
O
NC
O
NH2
NH2
NH2
Ph
XIIa
_H2O
_KBr
N
N
H
S
N
S
O
HO
Ph
Ph
E
XIII
F
Ph
the formation of 7,7-dimethyl-5-oxo-3-phenyl-6-cyano-
6,7-dihydro-5H-thiazolo-[3,2-a]pyridine-8-carboxamide
(XIII). Apparently in the course of the reaction a potas-
sium salt of substituted tetrahydropyridine-2-thiolate D
first formed whose reaction with phenacyl bromide (XIIa)
did not stop at the stage of the formation of thioether E
but an intramolecular acylation occurred of the atom N1
of the pyridine ring with the benzoyl moiety followed
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 8 2011

DYACHENKO et al.
1216
Scheme 2.
S
S
S
S
MeN
O
NC
NC
HO
CN
S
NH2
NC
NH2
+
_H2S
COOEt
O
OEt H2N
N
H
H
H2N
EtO
_EtOH
G
XIV
I
N
O
Cl
NC
O
CN
NC
CN
NC
CN
SEt
I2_KOH_EtOH
O
XVI
O
I
N
_
N
H
XIX
S
O
N
S
O
N
H
H Me
H
O
XV
XV
N
O
XVIII
XXIV
Br
BrCH2COR
2
Br
Br
XVIII
а, XIIb
XII
CN
S
NC
O
NC
O
CN
NC
O
CN NC
CN
N
2
N
H
S
N
H
S
S
N
H
O
H
XX
XXI
O
2Br2
R
Br2
XXIIа, XXIIb
NC
O
CN
NC
Br
O
CN
S
NC
CN
S
,
Br2 hv
_HBr
N
S
N
Br
O
N
Br
H
H
R
Br
Br
HO
XXIIIа, XXIIIb
XXVI
XXV
R = Ph (a), coumarin-3-yl (b).
by the closure into dihydrothiazole F which under the
reaction conditions eliminated water to give heterocyclic
system XIII.
resulted in thioethers XIX–XXI. The use as alkylating
agents of α-bromocarbonyl compounds XIIa, XIIb led
to the formation of thioethers mixtures XXIIa, XXIIb,
XXIIIa, XXIIIb as showed the double set of signals from
We obtained unexpected result in the reaction of Mi-
chael acceptor I with Michael donor, malonic acid dithio-
diamide (XIV) (Scheme 2). In the course of the process
hydrogen sulfide liberated and N-methylmorpholinium
4,4-dimethyl-6-oxo-3,5-dicyano-1,4,5,6-tetrahydropyr-
idine-2-thiolate (XV) formed which we had described
earlier [6]. Its formation is preceded by the heterocy-
clization of Michael adduct G with H2S elimination
giving substituted piperidine-2-thione H that stabilized
as salt XV. Its alkylation with alkyl halides XVI–XVIII
1
CH3, SCH2, and C3H groups in their H NMR spectra
(see EXPERIMENTAL). This phenomenon we had also
previously observed by another example in the series of
partially hydrogenated 2-aroylmethylthiopyridines [6].
At the attempt to oxidize salt XV into the correspond-
ing disulfide by treating with iodine in ethanol in the
presence of KOH an unexpected iodination occurred
of the position C5 of the tetrahydropyridine ring and
apparently also the alkylation of sulfur atom with the
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 8 2011

SYNTHESIS AND ALKYLATION
1217
Scheme 3.
S
NH2
NC
S
S
H2N
O
NC
NH2
NH2
NC
X
H2N
O
CN
H2N
N
O
N
I
XXVII
XXVIII
Cl
Cl
Br
N
_HBr,
_H2O
O
S
Cl
O
XXX
H2N
Cl
Cl
O
N
N
NH
N
NC
S
H2O
H2N
H2N
S
S
HO
_H2O
N
O
N
J
H2N
O
H2N
N
K
O
XXIX
ethyl iodide arising in the reaction mixture. As a result
3-iodo-4,4-dimethyl-2-oxo-6-ethylsulfanyl-1,2,3,4-tetra-
hydropyridine-3,5-dicarbonitrile (XXIV) was obtained.
methyl groups, of alkyl substituents, and of atoms H3, H5,
and NH (see EXPERIMENTAL). Mass spectra of com-
pounds obtained contain peaks [M + 2]+ of low intensity
indicating the presence of sulfur in their molecules [7].
Compound XX easily underwent bromination at the
double bond of the allylfragment with bromine in the gla-
cial acetic acid giving the corresponding dibromo deriva-
tive XXV. Further bromination of the latter with bromine
resulted in 3-bromo-6-(2,3-dibromopropylsulfanyl)-4,4-
dimethyl-2-oxo-1,2,3,4-tetrahydropyridine-3,5-dicarbo-
nitrile (XXVI). This compound can be obtained by treat-
ing allyl derivative XX with double excess of bromine.
Bringing into Michael reaction of isopropyliden-
emalononitrile (XXVII) and malonic acid monothio-
diamide (X) gave rise evidently through the formation
of adduct I to 6-amino-4,4-dimethyl-2-oxo-5-cyano-
2,3,4,5-tetrahydropyridine-3-carbothioamide (XXVIII)
(Scheme 3). Its reaction with 4-chlorophenacyl bromide
afforded Hantzsch thiazole. Under the reaction conditions
the cyano group hydrolyzed into amide giving as a re-
sult 2-amino-4,4-dimethyl-6-oxo-5-[4-(4-chlorophenyl)
thiazol-2-yl]-3,4,5,6-tetrahydropyridine-3-carboxamide
(XXIX).
The characteristic feature of IR specra of compounds
synthesized is the presence of absorption bands of the
stretching vibrations of conjugated and nonconjugated cy-
ano groups in the region 2248–2256 and 1190–2200 cm–1
respectively, and also the absorption bands of the stretch-
ing vibrations of the amide moiety at 1665–1678 cm–1.
This compound was also obtained by the reaction of
isopropylidenemalononitrile (XXVII) with 2-[4-(4-chlo-
rophenyl)thiazol-2-yl]acetamide (XXX) in ethanol in the
1
Their H NMR spectra contain proton signals of two
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 8 2011

DYACHENKO et al.
1218
presence of sodium ethylate. The reaction pathway appar-
ently included the formation of substituted tetrahydropyr-
idin-2-ones J, K, where the cyano group hydrolyzed into
amide with the formation of compound XXIX.
Spectral characteristics confirm the structure of
compounds XXVIII, XXIX. Characteristic feature of
1H NMR spectra is the appearance alongside the proton
signals of the substituents the signals of H3 and H5 protons
of the tetrahydropyridine ring at δ 4.28 and 3.73 ppm
respectively. The IR spectra contained the characteristic
absorption bands of stretching vibrations of the functional
groups (see EXPERIMENTAL).
dro-2H-thiazolo[3,2-a]pyridine-8-carboxylate (IV). To
a solution of 2.54 g(10 mmol) of substituted piperidine
III in 10 ml of DMF while stirring was added in succes-
sion 5.6 ml (10 mmol) of 10% aqueous KOH and 0.9 ml
(10 mmol) of 1,2-dibromoethane, the mixture was stirred
for 3 h and was left standing for 24 h. To the reaction
mixture at stirring was again added 5.6 ml (10 mmol) of
10% aqueous KOH, the stirring was continued for 30 min,
the solution was diluted with the same volume of water
and left standing for 48 h. The separated precipitate was
filtered off, washed in succession with water, ethanol,
and hexane. Yield 2.13 g (76%), colorless crystals, mp
163–164°C (EtOH). IR spectrum, ν, cm–1: 2248 (C≡N),
1704, 1666 (C=O). 1H NMR spectrum, δ, ppm: 1.26 s (3H,
Me), 1.34 t (3H, Me, J 6.18 Hz), 1.49 s (3H, Me), 3.17 t
(2H, SCH2, J 7.3 Hz), 3.96 m (2H, NCH2), 4.21–4.26 m
(3H, NCH2, OCH2), 4.28 s (1H, H of pyridine). Mass
spectrum, m/z (Irel, %): 282 (4) [M + 2]+, 281 (7) [M + 1]+,
280 (47) [M]+, 265 (87) [M – Me]+, 235 (24), 219 (52),
207 (100), 126 (9), 61 (39), 45 (14). Found, %: C 55.59;
H 5.64; N 9.85. C13H16N2O3S. Calculated, %: C 55.70;
H 5.72; N 9.99.
EXPERIMENTAL
IR spectra of compounds synthesized were recorded
on a spectrophotometer IKS-40 from mulls in mineral
oil. 1H NMR spectra were registered on a spectrometer
Gemini-200 (199.975 MHz) in DMSO-d6, internal ref-
erence TMS. Mass spectra were taken on instruments
Kratos MS-890 (70 eV) with a direct admission of the
sample into ion source (compounds III–VII, IX, XI,
XXV, XXVI, XXVIII, XXIX) and Chrommas GC/MC
Hewlett Packard 5890/5972, column HP-5 MS (70 eV)
in CH2Cl2 (compounds XIX, XXIIa). Melting points
were measured on a Koeffler heating block. The reaction
progress was monitored and the purity of compounds
obtained was checked by TLC on Silufol UV-254 plates,
eluent acetone–hexane, 3:5, development in iodine vapor
and under UV irradiation.
Ethyl 4,4-dimethyl-6-oxo-2-propylsulfanyl-5-
cyano-1,4,5,6-tetrahydropyridine-3-carboxylate (V).
To a solution of 2.54 g (10 mmol) of compound III in
10 ml of ethanol while stirring was added in succession
5.6 ml (10 mmol) of 10% aqueous KOH and 0.91 ml
(10 mmol) of 1-bromopropane, the mixture was stirred
for 4 h and was left standing for 24 h. The separated pre-
cipitate was filtered off, washed in succession with water,
ethanol, and hexane. Yield 2.31 g (78%), yellow powder,
mp 158–159°C (EtOH). IR spectrum, ν, cm–1: 3422 (NH),
2251 (C≡N), 1721, 1698 (C=O). 1H NMR spectrum, δ,
ppm: 0.91 t (3H, Me, J 7.21 Hz), 1.17 s (3H, Me), 1.19 s
(3H, Me), 1.24 t (3H, Me, J 7.22 Hz), 1.50 m (2H, CH2),
2.76 m (2H, CH2), 4.17 q (2H, OCH2, J 7.22 Hz), 4.50 s
(1H, H3), 10.44 br.s (1H, NH). Mass spectrum, m/z (Irel,
%): 298 (2) [M + 2]+, 297 (4) [M + 1]+, 296 (29) [M]+,
281 (28), [M – Me]+ 254 (34), 251 (38), 235 (55), 223
(100), 207 (29), 193 (75), 182 (36), 154 (27), 109 (27),
83 (22), 55 (16). Found, %: C 56.65; H 6.71; N 9.32.
C14H20N2O3S. Calculated, %: C 56.74; H 6.80; N 9.45.
Ethyl 4,4-dimethyl-6-oxo-2-thioxo-5-cyano-
piperidine-3-carboxylate (III). To a solution of 1.53 g
(10 mmol) of ethyl isopropylidenecyanoacetate (I) and
1.47 g (10 mmol) of malonic acid monothiodiamide (II)
in 15 ml of anhydrous ethanol at 20°C while stirring
was added a solution of 0.23 g of sodium in 10 ml of
anhydrous ethanol, the mixture was stirred for 15 min
and left standing for 24 h. The separated precipitate
was filtered off, washed with cold ethanol and hexane.
Yield 1.58 g (62%), yellow powder, mp 221–223°C.
IR spectrum, ν, cm–1: 3445 (NH), 2259 (C≡N), 1687
(C=O), 1667 (NHC=O), 1286 (C=S). 1H NMR spectrum,
δ, ppm: 1.01 s (6H, 2Me), 1.16 t (3H, Me, J 6.18 Hz),
3.37 s (1H, H3), 4.05 m (3H, CH2, H5), 10.88 br.s (1H,
NH). Mass spectrum, m/z (Irel, %): 256 (3) [M + 2]+, 255
(7) [M + 1]+, 254 (49) [M]+, 182 (85), 167 (63), 98 (72),
44 (100) [C=S]+. Found, %: C 51.84; H 5.42; N 10.93.
C11H14N2O3S. Calculated, %: C 51.95; H 5.55; N 11.02.
Ethyl 2-benzylsulfanyl-4,4-dimethyl-6-oxo-5-
cyano-1,4,5,6-tetrahydropyridine-3-carboxylate (VI)
was obtained using 1.15 ml (10 mmol) of benzyl chloride.
Yield 1.86 g (54%), colorless crystals, mp 122–124°C
(EtOH). IR spectrum, ν, cm–1: 3451 (NH), 2251 (C≡N),
1
Ethyl 7,7-dimethyl-5-oxo-6-cyano-3,5,6,7-tetrahy-
1688 (C=O), 1669 (CONH). H NMR spectrum, δ,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 8 2011

SYNTHESIS AND ALKYLATION
1219
ppm: 0.78 s (3H, Me), 1.11 s (3H, Me), 1.28 t (3H, Me,
J 6.14 Hz), 4.08 d (1H, SCH2, 2J 14.75 Hz), 4.11 d (1H,
SCH2, 2J 14.75 Hz), 4.22 q (2H, OCH2, J 6.14 Hz), 4.38 s
(1H, H3 of pyridine), 7.14–7.48 m (5H, Ph), 10.62 br.s
(1H, NH). Mass spectrum, m/z (Irel, %): 343 (8) [M – 1]+,
297 (4), 253 (3), 181 (2), 91 (100) [PhCH2]+. Found, %:
C 62.69; H 5.73; N 7.98. C18H20N2O3S. Calculated, %:
C 62.77; H 5.85; N 8.13.
(3H, Me), 4.00 s (1H, H3 of piperidine), 4.81 (1H, H5
of piperidine), 7.48 br.s (1H, NH2), 7.96 br.s (1H, NH2),
12.95 br.s (1H, NH). Mass spectrum, m/z (Irel, %): 227
(6) [M + 2]+, 226 (12) [M + 1]+, 225 (100) [M]+, 208 (52)
[M – NH3]+, 193 (9), 181 (16), 167 (66), 159 (9), 124
(15), 108 (21), 99 (57), 82 (25), 73 (8), 67 (23), 53 (33),
44 (84) [CONH2]+. Found, %: 47.85; H 4.78; N 18.51.
C9H11N3O2S. Calculated, %: C 47.99; H 4.92; N 18.65.
Ethyl 5-benzyl-2-benzylsulfanyl-4,4-dimethyl-6-
oxo-5-cyano-1,4,5,6-tetrahydropyridine-3-carboxylate
(VII). a. It was obtained similarly to compound VI using
as initial compounds thioether VI and benzyl chloride.
Yield 3.39 g (78%), colorless crystals, mp 175–176°C
(AcOH). IR spectrum, ν, cm–1: 3395 (NH), 2248 (C≡N),
1702, 1673 (C=O). 1H NMR spectrum, δ, ppm: 1.25 s (3H,
Me), 1.31 s (3H, Me), 1.38 t (3H, Me, J 6.14 Hz), 2.84 d
(1H, CH2, J 17.4 Hz), 2.89 d (1H, CH2, J 17.4 Hz),
4.19 s (2H, SCH2), 4.24 q (2H, OCH3, J 6.14 Hz), 6.99 m
(2H, Ph), 7.14–7.29m (6Harom), 7.38 d (2H, Ph, J 7.26 Hz),
10.59 br.s (1H, NH). Mass spectrum, m/z (Irel, %): 436
(2) [M + 2]+, 435 (5) [M + 1]+, 434 (24) [M]+, 343 (45)
[M – PhCH2]+, 306 (27), 297 (31), 91 (100) [PhCH2]+, 65
(14). Found, %: C 68.95; H 5.91; N 6.33. C25H26N2O3S.
Calculated, %: C 69.10; H 6.03; N 6.45.
7,7-Dimethyl-5-oxo-3-phenyl-6-cyano-6,7-dihydro-
5H-thiazolo[3,2-a]pyridine-8-carboxamide (XIII). To
solution of 2.25 g (10 mmol) of compound XI in 10 ml of
DMF DMF while stirring was added in succession 5.6 ml
(10 mmol) of 10% aqueous KOH and 2.0 g (10 mmol)
of phenacyl bromide (XIIa), the mixture was stirred for
2 h and left standing for 24 h. The reaction mixture was
diluted with the same volume of water, the separated
precipitate was filtered off, washed in succession with
water, ethanol, and hexane. Yield 2.6 g (80%), yellow
crystals, mp 275–276°C (AcOH). IR spectrum, ν, cm–1:
3411, 3295, 3115 (NH2), 2252 (C≡N), 1669 (CONH).
1H NMR spectrum, δ, ppm: 1.19 s (3H, Me), 1.29 s (3H,
Me), 3.50 s (1H, H6), 6.50 s (1H, =CH), 7.24–7.63m
(3H, Ph), 7.93–8.12 m (2H, Ph), 11.46 br.s (1H, NH2),
11.99 br.s (1H, NH). Found, %: C 62.63; H 4.59; N 12.88.
C17H15N3O2S. Calculated, %: C 62.75; H 4.65; N 12.91.
2
2
b. The method analogous to the preparation of com-
pound VI, only the benzyl chloride and alkali was taken
in the double amount. Yield 3.43 g (79%).
N-Methylmorpholinium 4,4-dimethyl-6-oxo-3,5-
dicyano-1,4,5,6-tetrahydropyridine-2-thiolate (XV).
A mixture of 1.53 g (10 mmol) of alkene I, 1.34 g
(10 mmol) of CH-acid XIV, and 1.1 ml (10 mmol) of
N-methylmorpholine in 15 ml of DMF was stirred for
4 h and left standing for 24 h. The reaction mixture was
diluted with 15 ml of anhydrous ethanol and left standing
for 48 h at 20°C. The separated precipitate was filtered off,
washed with anhydrous ethanol and hexane. Yield 2.0 g
(64%), the sample by mp, chromatogram, IR and 1H NMR
spectra was identical to the previously obtained [2].
4,4-Dimethyl-2-oxo-6-thioxo-5-(4-phenyl-thiazol-2-
yl)piperidine-3-carbonitrile (IX) was obtained similarly
to compound III using as CH-acid 2.34 g (10 mmol) of
thioacetamide (VIII). Yield 2.0 g (59%), yellow powder,
mp 217–219°C (ACOH). IR spectrum, ν, cm–1: 3195
(NH), 2248 (C≡N), 1672 (CONH). 1H NMR spectrum,
δ, ppm: 1.02 s (3H, Me), 1.27 s (3H, Me), 5.03 s (1H,
H5(3) of piperidine), 5.18 s (1H, H3(5) of piperidine), 7.34 t
(1H, Ph, J 6.95 Hz), 7.44 t (2H, Ph, J 6.95 Hz), 7.90 d
(2H, Ph, J 7.03 Hz), 8.11 s (1H, H5 of thiazole), 11.27 br.s
(1H, NH). Mass spectrum, m/z (Irel, %): 341 (91) [M]+,
309 (11), 217 (90), 175 (48), 134 (100), 89 (30). Found,
%: C 59.72; H 4.38; N 12.25. C17H15N3OS2. Calculated,
%: C 59.80; H 4.43; N 12.31.
4,4-Dimethyl-6-[(2-morpholin-1-yl-2-oxo)-
ethylsulfanyl]-2-oxo-1,2,3,4-tetrahydropyridine-3,5-
dicarbonitrile (XIX). A mixture of 3.1 g (10 mmol)
of salt XV and 1.5 g (10 mmol) of amide XVI in 15 ml
of DMF was stirred for 5 h and diluted with an equal
volume of water. The separated precipitate was filtered
off, washed with water, ethanol, and hexane. Yield 2.2 g
(66%), colorless crystals, mp 160–162°C (AcOH). IR
spectrum, ν, cm–1: 3211 (NH), 2246, 2193 (C≡N), 1672,
1666 (C=O). 1H NMR spectrum, δ, ppm: 1.19 s (3H, Me),
1.38 s (3H, Me), 3.41–3.74 m (8H, H of morpholine),
3.88 s (2H, SCH2), 4.26 s (1H, H3), 11.14 br.s (1H, NH).
4,4-Dimethyl-6-oxo-2-thioxo-5-cyanopiperidine-3-
carboxamide (XI) was obtained similarly to compound
III using as CH-acid 1.18 g (10 mmol) of malonic acid
monothiodiamide (X). Yield 1.53 g (68%), yellow crys-
tals, mp 210–211°C (EtOH). IR spectrum, ν, cm–1: 3410,
3332, 3111 (NH, NH2), 2249 (C≡N), 1677 (CONH).
1H NMR spectrum, δ, ppm: 1.20 s (3H, Me), 1.34 s
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DYACHENKO et al.
1220
Mass spectrum, m/z (Irel, %): 333 (100) [M – 1]+. Found,
%: C 53.72; H 5.29; N 16.61. C15H18N4O3S. Calculated,
%: C 53.88; H 5.43; N 16.75.
7.23–7.42m (2H, Harom), 7.63 t (1H, Harom, J 7.62 Hz),
7.82 t (1H, Harom, J 7.72 Hz), 8.02 s, 8.15 s (1H,
H4coumarin), 8.31 br.s, 8.37 br.s (1H, NH and OH). Found,
%: C 60.92; H 3.72; N 10.55. C20H15N3O4S. Calculated,
%: C 61.06; H 3.84; N 10.68.
6-Allylsulfanyl-4,4-dimethyl-2-oxo-1,2,3,4-tetra-
hydropyridine-3,5-dicarbonitrile (XX) was obtained
similarly to compound XIX using as alkylating agent 1 g
(0.85 ml, 10 mmol) of allyl bromide (XVII). Yield 2.0 g
3-Iodo-4,4-dimethyl-2-oxo-6-ethylsulfanyl-1,2,3,4-
tetrahydropyridine-3,5-dicarbonitrile (XXIV). To
a dispersion of 3.1 g (10 mmol) of salt XV in 15 ml of
ethanol was added at stirring 5.6 ml (10 mmol) of 10%
aqueous KOH and then was added dropwise a solution
of 2.53 g (10 mmol) of iodine in 20 ml of ethanol. The
reaction mxture was left standing for 48 h. The separated
precipitate was filtered off, washed with ethanol and hex-
ane. Yield 1.7 g (47%), yellow powder, mp 199–201°C
(EtOH). IR spectrum, ν, cm–1: 3198 (NH), 2246, 2195
(C≡N), 1666 (CONH). 1H NMR spectrum, δ, ppm: 1.26 t
(3H, Me, J 7.22 Hz), 2.33 s (3H, Me), 2.39 s (3H, Me),
4.22 q (2H, CH2, J 7.22 Hz), 7.04 br.s (1H, NH). Found,
%: C 36.41; H 3.22; N 11.55. C11H12IN3OS. Calculated,
%: C 36.58; H 3.35; N 11.63.
1
(81%), mp, chromatogram and H NMR spectrum of
the sample were identical to the previously obtained [2].
6,6′-[Ethane-1,2-diylbis(sulfanyl)]bis(4,4-dimeth-
yl-2-oxo-1,2,3,4-tetrahydropyridine-3,5-dicarboni-
trile) (XXI). To a solution of 3.1 g (10 mmol) of salt XV
in 15 ml of DMF was added at stirring 0.45 ml (5 mmol)
of 1,2-dibromoethane (XVIII), the mixture was stirred for
4 h, diluted with an equal volume of water, the separated
precipitate was filtered off, washed with water, ethanol,
and hexane. Yield 3.2 g (72%), yellow powder, mp 258–
260°C (AcOH). IR spectrum, ν, cm–1: 3150 (NH), 2244,
2190 (C≡N), 1677 (CONH). 1H NMR spectrum, δ, ppm:
1.15 s, 1.37 s (6H each, 4Me), 2.64–3.28 m (4H, 2CH2),
4.61 s, 4.69 s (1H each, 2H3), 11.23 br.s and 11.28 br.s
(1H each, 2NH). Found, %: C 54.41; H 4.44; N 18.95.
C20H20N6O2S2. Calculated, %: C 54.53; H 4.58; N 19.08.
6-(2,3-Dibromopropylsulfanyl)-4,4-dimethyl-2-
oxo-1,2,3,4-tetrahydropyridine-3,5-dicarbonitrile
(XXV). To a solution of 2.5 g (10 mmol) of thioether XX
in 15 ml of glacial acetic acid at stirring was added drop-
wise a solution of 0.51 ml (10 mmol) of bromine in 10 ml
of glacial acetic acid monitoring the rate by decolorizing
of the solution. Then the reaction mixture was diluted
with an equal volume of water, the separated precipitate
was filtered off, washed with water, ethanol, and hexane.
Yield 2.9 g (71%), colorless crystals, mp 203–205°C. IR
spectrum, ν, cm–1: 3194 (NH), 2250, 2199 (C≡N), 1665
(CONH). 1H NMR spectrum, δ, ppm: 1.19 s (3H, Me),
1.37 s (3H, Me), 3.40–3.89 m (2H, SCH2), 4.29, 4.33 s
(1H, H5), 5.03–5.22 m (2H, CH2Br), 5.63–5.98 m (1H,
CHBr), 11.06 br.s (1H, NH). Mass spectrum, m/z (Irel, %):
407 (3) [M]+, 325 (24), 310 (100), 246 (31), 230 (82),
204 (11), 179 (65), 119 (17), 82 (70), 73 (76). Found, %:
C 35.29; H 3.14; N 10.29. C12H13Br2N3OS. Calculated,
%: C 35.40; H 3.22; N 10.32.
6-Benzoylmethylsulfanyl-4,4-dimethyl-2-oxo-
1,2,3,4-tetrahydropyridine-3,5-dicarbonitrile (XXIIa)
was obtained analogously to compound XIX using 2.0 g
(10 mmol) of phenacyl bromide (XIIa). Yield 2.4 g
(74%), colorless crystals, mp 172–174°C (AcOH). IR
spectrum, ν, cm–1: 3198 (NH), 2254, 2196 (C≡N), 1715
(C=O), 1663 (CONH). 1H NMR spectrum, δ, ppm: 1.21 s,
1.25 s (3H, Me), 1.42 s, 1.44 s (3H, Me), 3.44 s, 3.53 s
(1H, H3), 4.34 s, 4.75 s (2H, CH2), 7.31–7.57 m (2H, Ph),
7.60 t (2H, Ph, J 7.14 Hz), 7.98 d (1H, Ph, J 7.14 Hz),
11.03 br.s (1H, NH). The signal of OH proton was not
observed evidently due to the fast deuteroexchange with
the residual heavy water in the solvent. Mass spectrum,
m/z (Irel, %): 324 (100) [M – 1]+. Found, %: C 62.69;
H 4.58; N 12.85. C17H15N3O2S. Calculated, %: C 62.75;
H 4.65; N 12.91.
3-Bromo-6-(2,3-dibromopropylsulfanyl)-4,4-
dimethyl-2-oxo-1,2,3,4-tetrahydropyridine-3,5-dicar-
bonitrile (XXVI). a. To a solution of 4.07 g (10 mmol) of
dibromide XXV in 20 ml of glacial acetic acid was added
dropwise 0.51 ml (10 mmol) of bromine under a bright
light, the mixture was stirred for 2 h and diluted with an
equal volume of water. The separated precipitate was
filtered off, washed with ethanol and hexane. Yield 3.0 g
(62%), colorless crystals, mp 123–125°C. IR spectrum,
ν, cm–1: 3211 (NH), 2255, 2195 (C≡N), 1671 (CONH).
4,4-Dimethyl-2-oxo-6-[2-oxo-2-(2-oxo-2H-chro-
men-3-yl)ethylsulfanyl]-1,2,3,4-tetrahydro-pyridine-
3,5-dicarbonitrile (XXIIb) was obtained analogously
to compound XIX using 2.7 g (10 mmol) of substituted
coumarin XIIb. Yield 3.1 g (79%), white powder, mp
193–195°C. IR spectrum, ν, cm–1: 3212 (NH), 2249, 2201
(C≡N), 1722 (C=O), 1670 (CONH). 1H NMR spectrum,
δ, ppm: 1.23 s, 1.28 s (3H, Me), 1.39 s, 1.42 s (3H, Me),
3.25m, 3.76m (1H each, CH2), 4.51 s, 4.59 s (1H, H3),
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SYNTHESIS AND ALKYLATION
1221
1H NMR spectrum, δ, ppm: 1.35 s (3H, Me), 1.52 s
(3H, Me), 3.41–3.72 m (2H, SCH2), 3.89–4.25 m (2H,
BrCH2), 4.27–4.52 m (1H, BrCH), 7.19 br.s (1H, NH).
Mass spectrum, m/z (Irel, %): 488 (6) [M + 2]+, 487 (22)
[M + 1]+, 486 (22) [M]+, 472 (8) [M – Me]+, 406 (35)
[M – Br]+, 398 (31), 326 (64), 311 (69), 284 (37), 272
(14), 246 (15), 230 (55), 201 (100), 179 (92), 119 (94),
108 (52), 73 (34), 41 (56). Found, %: C 29.58; H 2.35;
N 8.58. C12H12Br3N3OS. Calculated, %: C 29.66;
H 2.49; N 8.65.
2.67 g (71%), yellow powder, mp 179–180°C (EtOH). IR
spectrum, ν, cm–1: 3394, 3210, 3102 (NH2), 1677 (C=O),
1647 [δ(NH2)]. 1H NMR spectrum, δ, ppm: 1.23 s (3H,
Me), 1.31 s (3H, Me), 3.73 s (1H, H5of pyridine ), 4.28 C (1H,
H3of pyridine), 7.33 d (2H, C6H4, J 7.9 Hz), 7.59 br.s (1H,
NH2), 7.86–7.99m (5H, NH2, 2Harom, Hof thiazole), 8.22 br.s
(1H, NH2). Mass spectrum, m/z (Irel, %): 376 (8) [M]+, 359
(7), 293 (14), 276 (12), 252 (61), 235 (9), 209 (100), 174
(28), 168 (53), 133 (32), 124 (51), 108 (13), 96 (25), 89
(37), 84 (28), 75 (13), 66 (47), 53 (39), 44 (62), 39 (32).
Found, %: C 54.05; H 4.39; N 14.75. C17H17ClN4O2S.
Calculated, %: C 54.18; H 4.55; N 14.87.
b. To a solution of 5 g (10 mmol) of thioether XX in
15 ml of glacial acetic acid at stirring under bright light
was added dropwise 1.02 ml (20 mmol) of bromine
monitoring the rate by decolorizing of the solution. Then
the reaction mixture was diluted with an equal volume of
water. The separated precipitate was filtered off, washed
with ethanol and hexane. Yield 3.1 g (64%).
b. To a solution of 1.06 g (10 mmol) of alkene XXVII
in 15 ml of DMF was added at stirring 2.52 g (10 mmol)
of thiazole XXX and a solution of 0.23 g (10 mmol) of
sodium in 10 ml of anhydrous ethanol, the mixture was
stirred for 1 h, diluted with an equal volume of water,
and left standing for 48 h. The separated precipitate was
filtered off, washed with ethanol and hexane. Yield 2.6 g
(69%).
6-Amino-4,4-dimethyl-2-oxo-5-cyano-2,3,4,5-
tetrahydropyridine-3-carbothioamide (XXVIII) was
obtained similarly to compound III using as initial re-
agents 1.06 g (10 mmol) of isopropylidenemalononitrile
XXVII and 1.18 g (10 mmol) of CH-acid X. Yield 1.48 g
(66%), colorless crystals, mp 275–277°C (MeOH). IR
spectrum, ν, cm–1: 3411, 3332, 2115 (NH2), 2251 (C≡N),
1672 (C=O), 1646 [δ(NH2)]. 1H NMR spectrum, δ, ppm:
1.31 s (6H, 2Me), 3.97 s (2H, H3 and H5), 7.01 br.s (2H,
NH2), 7.42 br.s (2H, NH2). Mass spectrum, m/z (Irel, %):
207 (100) [M – NH3]+, 192 (18), 137 (8), 105 (6), 78
(6), 66 (12), 53 (7), 39 (8). Found, %: C 48.12; H 5.26;
N 24.79. C9H12N4OS. Calculated, %: C 48.20; H 5.39;
N 24.98.
REFERENCES
1. Gittos, M.W., UK Inventor’s Certificate 2379216, 2003;
Ref. Zh. Khim., 2003, 03.18-19O.226P.
2. Dyachenko, V.D., Nikishin,A.A., and Litvinov, V.P., Khim.
Geterotsikl. Soedin., 1997, p. 996.
3. Dyachenko, V.D. and Litvinov, V.P., Zh. Org. Khim., 1998,
vol. 34, p. 589.
4. Nikishin, A.A., Dyachenko, V.D., and Chernega, A.N., Zh.
Org. Khim., 2009, vol. 45, p. 1544.
5. Dragovich, P.S., Prins, T.J., Zhon, R., Johnson, T.O.,
Brown, E.L., Maldonado, F.C., Fuhrman, S.A., Zalman, L.S.,
Patick, A.K., Matthews, D.A., Hou, X., Meador, J.W.,
Ferre, R.A., and Worland, S.T., Bioorg. Med. Chem. Lett.,
2002, p. 733.
6. Dyachenko, V.D., Nikishin, A.A., and Chernega, A.N.,
Khim. Geterotsikl. Soedin., 2003, p. 1316.
7. Pretsch, E., Buhlmann, P., and Affolter, C., Structure
Determination of Organic Compounds, Springer-Verlag,
2000.
2-Amino-4,4-dimethyl-6-oxo-5-[4-(4-chlorophenyl)
thiazol-2-yl]-3,4,5,6-tetrahydropyridine-3-carbox-
amide (XXIX). a. To a solution of 2.24 g (10 mmol) of
thioamide XXVIII in 15 ml of DMF was added at stirring
2.33 g (10 mmol) of 4-chlorophenacyl bromide, the mix-
ture was stirred for 1 h, diluted with an equal volume of
water, and left standing for 48 h. The separated precipitate
was filtered off, washed with ethanol and hexane. Yield
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 8 2011