Cascade heterocyclization in the synthesis of new Sulfur-containing 1,4-dihydropyridines and 1,4,5,6,7,8-hexahydroquinolines

Full text of DOI:10.1023/A:1019205013304

Doklady Chemistry, Vol. 377, Nos. 4–6, 2001, pp. 94–100. Translated from Doklady Akademii Nauk, Vol. 377, No. 4, 2001, pp. 493–500.
Original Russian Text Copyright © 2001 by Litvinov, Krivokolysko, Rusanov.
CHEMISTRY
Cascade Heterocyclization in the Synthesis
of New Sulfur-Containing 1,4-Dihydropyridines
and 1,4,5,6,7,8-Hexahydroquinolines
V. P. Litvinov*, S. G. Krivokolysko**, and E. B. Rusanov***
Presented by Academician N.K. Kochetkov December 26, 2000
Received December 27, 2000
Among active calcium antagonists, 1,4-dihydropy- CH acids according to the cascade heterocyclization
pattern [3]. Multistep processes of this type do not
require preliminary preparation of α,β-unsaturated
compounds, which is often difficult, and they afford the
final products in high yields.
Aldehydes Ia, Ib, cyanothioacetamide (II), and 1,3-
cyclohexanedione (III) were shown to react in ethanol
in the presence of piperidine to give substituted
hexahydroquinolines IV and V. The regioselectivity of
this reaction is determined by the unstable intermediate
VI, which undergoes subsequent transformations under
the reaction conditions, giving rise to compounds VII,
IV, or V. This scheme is consistent with the latest pub-
lished data for the isostructural analog of diketone III,
ridine derivatives occupy a prominent place [1]. The
most widely used methods for the synthesis of these
compounds are based on the Hanzsch synthesis and
some of its modifications [2]. Sulfur-containing
1,4-dihydropyridines and their fused analogs still
remain a poorly studied group of organic compounds.
The range of methods used to prepare these compounds
is rather narrow; this is due to the small assortment and
poor availability of the initial reactants and to the insta-
bility of some hydrated systems against oxidation dur-
ing the reactions. In view of these circumstances, we
developed convenient methods for the synthesis of new
sulfur-containing 3-cyano-1,4-dihydropyridines and
3-cyano-1,4,5,6,7,8-hexahydroquinolines, based on namely, dimedone [4]. Alkylation of compounds IV
reactions of aldehydes, cyanothioacetamide, and some and V by halides VIII yielded organic sulfides IX.
H
O
N
O
R
O
R
CN
S–
CN
CN
S–
RCHO +
+
O
HN
CSNH2
N
H
(Ia, Ib)
OH
(VI)
HO
(II)
(III)
(VII)
HCl
Cl
Hal
(VIIIa–VIIId)
R1
Cl
CN
O
O
R
O
CN
CN
SH
VIIIa, VIIIb,
KOH
N+H2
KOH
S–
S
R1
N+H2
N
H
N
N
H
H
(IV)
(IXa–IXf)
Scheme 1.
(V)
I: R = 2-ClC6H4 (a), R = 4-ClC6H4 (b).
* Zelinskii Institute of Organic Chemistry, Russian Academy
of Sciences, Leninskii pr. 47, Moscow, 117334 Russia
** East Ukrainian State University, Lugansk, Ukraine
*** Institute of Organic Chemistry, National Academy
of Sciences of Ukraine, ul. Murmanskaya 5, Kiev,
253660 Ukraine
VIII: Hal = I, R1 = H (a); Hal = I, R1 = Me (b);
Hal = Cl, R1 = CONH2 (c); Hal = Cl, R1 =
4-BrC6H4NHCO (d).
IX: R = 2-ClC6H4, R1 = H (a); R = 2-ClC6H4,
0012-5008/01/0004-0094$25.00 © 2001 åÄIä “Nauka /Interperiodica”

CASCADE HETEROCYCLIZATION IN THE SYNTHESIS
95
R1 = Me (b); R = 2-ClC6H4, R1 = CONH2 (c); R = corresponding
3,4,5,6,7,8-hexahydroxyquinoline-
2-ClC6H4, R1 = 4-BrC6H4NHCO (d); R = 4-ClC6H4,
2(1H)-thione.
R1 = H (e); R = 4-ClC6H4, R1 = Me (f).
Similarly, the reaction of compounds Ib and II with
tert-butyl acetoacetate (X) in ethanol in the presence of
morpholine resulted in the synthesis of morpholinium
5-tert-butoxycarbonyl-4-(4-chlorophenyl)-3-cyano-6-
methyl-1,4-dihydropyridine-2-thiolate (XI).
1
The H NMR spectra of the resulting compounds
exhibit typical signals for protons of the aromatic
group, the piperidinium cation (in IV), and the alkylthio
group (in IX). The signals of the protons of the hexahy-
droquinoline nucleus are manifested as three multiplets
at δ 1.91–1.98, 2.13–2.23, and 2.54–2.62 ppm ((CH2)3),
singlets at 4.47–5.08 ppm (ë(4)ç), and 8.33–10.69 ppm
(NH). The IR spectra of compounds IV and IX contain
an intense absorption band in the region of 2175–
2203 cm–1 due to the conjugated C≡N group, in addi-
tion to the bands for the NH, NH2, and C=O groups
occurring in the characteristic regions. The low-inten-
sity signal at 2239 cm–1 for the non-conjugated nitrile
group in the IR spectrum of quinoline V indicates that
Treatment of salt XI with a dilute hydrochloric acid
affords compound XII. According to 1H NMR spectra,
this product exists as a tautomeric equilibrium of stere-
oisomers XIIa, XIIb and thiol XIIc. The values of the
vicinal spin–spin coupling constants at the C(3)H and
C(4)H protons in the stereoisomers XIIa and XIIb (8.1
and 4 Hz) suggest that the aryl substituent and the
cyano group in these isomers are pseudoaxially equato-
this compound exists in the crystalline state only as the rial and pseudodiaxial, respectively.
Cl
Cl
H
N
O
Me
Me
Me O
O
Me O
O
Me
Me
Me
CN
S–
CN
S
O
O
VIIIa–VIIId
Ib + II +
Me
Me
O
Me
Me
N+H2
N
H
Me
R
N
H
(X)
(XI)
(XIIIa–XIIId)
O
HCl
Cl
Cl
Cl
Me O
O
Me O
O
Me O
O
Me
Me
Me
Me
Me
Me
CN
S
CN
SH
CN
S
Me
Me
Me
N
H
N
H
N
H
(XIIa)
(XIIc)
(XIIb)
XIII: R = H (a), R = Me (b), R = CONH2 (c), R = 4-BrC6H4CONH (d).
Scheme 2.
The crystalline compound XII was also found to This salt was employed to prepare 4,6-dimethyl-1,4-
dihydropyridines XVII.
exist as an equilibrium mixture; its IR spectrum exhib-
its bands at 2190 and 2253 cm–1 for stretching vibra-
tions of the conjugated and non-conjugated cyano
groups, respectively. A short-term heating of salt XI
with halides VIII gave the corresponding 2-alkylthio-
1,4-dihydropyridines XIII.
When compounds II and XIV react with acetylace-
tone XVIII, the corresponding thiolate XIX cannot be
isolated because of its high solubility in ethanol. Mean-
while, the subsequent treatment of the reaction mixture
with α-chloroacetamide VIIIc gives rise to pyridine XX.
The molecular and crystal structures of XX were
studied by X-ray diffraction analysis. The general view
of molecule XX is shown in Fig. 1, and the main geo-
Condensation of acetaldehyde XIV with cyanothio-
acetamide II and benzoylacetone XV in ethanol in the
presence of N-methylmorpholine furnished salt XVI. metric parameters are listed in Table 1.
DOKLADY CHEMISTRY Vol. 377
Nos. 4–6 2001

96
LITVINOV et al.
Me
N
O
O
Me
O
Me
Ph
Me
CN
S–
CN
S
,
O
O
(XV)
Ph
Me
Ph
VIIIa, VIIIc
MeCHO + II
(XIV)
Me
N+H
Me
R
N
H
N
H
(XVI)
(XVIIa, XVIIb)
O
Me
O
N
O
Me
O
Me
Me
Me
Me (XVIII)
CN
CN
,
Me
Me
O
O
VIIIc
Me
NH2
S
S–
Me
N
H
N
H
N+H
O
(XIX)
(XX)
O
XVII: R = H (a), R = CONH2 (b).
Scheme 3.
The central six-membered N1C1–5 heterocycle is cycle (S = 0.34, θ = 68.5°, Ψ = 13.13°) can be described
by a heavily distorted twist boat. The N1 and N3 atoms
form a planar trigonal configuration of the valence
bonds. The orientation of the N(3)H2 group is rather
favorable for the conjugation between the lone pair of
N3 and the π-system of the C(12)–O(2) double bond.
Indeed, the N3–C12 bond (1.318(4) Å) is substantially
shortened with respect to the lengths normal for
N(sp2)–C(sp2) single bonds (1.43–1.45 Å) [6, 7]. The
distribution of the bond lengths in the N1ë1–5 heterocy-
cle (Table 1) points to the pronounced conjugation
between the N1 atom lone pair and the π-systems of the
ë1=ë2 and ë4=ë5 double bonds. The geometric param-
eters of the ë1–S1–C11 group (S1–C11 1.816(4), S1–C1
1.756(3) Å, the ë1–S1–C15 angle is 104.7(2)°) are nor-
mal. For example, the S–C(Me) (1.803(4) Å) and S–
C(Ph) (1.749(4) Å) distances in the methyl phenyl sul-
fide molecule [8] coincide with those found in XX to
within experimental error. An interesting structural fea-
ture of XX is a rather strong [9] intramolecular hydro-
gen bond, N1–H1N···é2, which closes the seven-mem-
bered N1C1S1C11C12O2H1N ring. The main geometric
parameters of this H-bond are as follows:
N1···O2 2.759(4) Å, N1–H1N 0.85(3), O2···H1N 1.93(3) Å,
the N1–H1N···O2 angle is 165(3)°.
markedly nonplanar. The N1C1C2C4C5 group is planar
to within 0.056 Å, whereas ë3 deviates from this plane
by 0.344 Å. Thus, the ë2ë3ë4 angle and the
N1C1C2C4C5 plane form a dihedral angle of 22.7(3)°.
The ëéëç3 group is rotated through 7.2° with respect
to this plane. According to the modified Kramer–Pople
parameters [5], the conformation of the N1C1–5 hetero-
O1
C7
C9
C3
N2
C2
C10
C6
C4
C1
C5
N1
S1
C8
In the crystal, the molecules of compound XX form
infinite chains via intermolecular N3−H32N···O1 hydro-
gen bonds (N3···O1 2.953(4) Å, N3–H32N 0.87(2) Å,
O1···H32N 2.13(2) Å, the N3–H32N···O1 angle is 158(3)°)
(Fig. 2).
C11
O2
C12
N3
EXPERIMENTAL
1H NMR spectra were recorded on a Bruker AM300
spectrometer (300 MHz) in DMSO-d6 using Me4Si as
Fig. 1. General view of the molecule of XX with the num-
bering of non-hydrogen atoms.
DOKLADY CHEMISTRY Vol. 377
Nos. 4–6 2001

CASCADE HETEROCYCLIZATION IN THE SYNTHESIS
97
Table 1. Selected bond lengths d and angles ω in the
molecule of XX
the internal standard. IR spectra were recorded as min-
eral oil mulls on an IKS-29 spectrophotometer. Mass
spectra were run on a Kratos MS-30 mass spectrometer
with direct sample injection into the ion source. The
elemental analysis for C, H, N was performed on a Per-
kin Elmer CHN analyzer. The course of the reaction
was monitored, and the purity of the compounds syn-
thesized was checked by TLC on Silufol UV-254 plates
in an acetone–hexane system (3 : 5) using iodine vapor
for visualization. Melting points were determined using
a Koefler hot stage.
Bond
d, Å
Angle
ω, deg
S1–C1
1.756(3)
1.816(4)
1.225(4)
1.227(4)
1.366(4)
1.382(4)
0.85(3)
C1S1C11
C1N1C5
C1N1H1N
C5N1H1N
C12N3H31N
C12N3H32N
H31NN3H32N
C2C1N1
C2C1S1
104.7(2)
122.5(3)
117(2)
S1–C11
O1–C9
O2–C12
N1–C1
N1–C5
N1–H1N
N2–C6
N3–C12
N3–H31N
N3–H32N
C1–C2
C2–C6
C2–C3
C3–C4
C3–C7
C3–H3
C4–C5
C4–C9
C5–C8
C9–C10
C11–C12
119(2)
120(3)
116(2)
The X-ray diffraction study of a single crystal of XX
was carried out at room temperature on an Enraf-Non-
ius CAD4 four-circle automated diffractometer
(λMoäα radiation, graphite monochromator, ratio of
scanning velocities ω/2θ 1.2, θmax 24°, sphere segment
0 ≤ h ≤ 9, –10 ≤ k ≤ 10, –10 ≤ l ≤ 10). The unit cell
parameters and the orientation matrix for a 0.34 ×
0.31 × 0.25 mm crystal of XX were determined using
22 reflections with 12° < θ < 13°. A total of 2267 reflec-
tions were collected, of which 2105 reflections were
independent (the averaging R factor was 0.028). The crys-
tals of XX are triclinic, ‡ = 8.677(3) Å, b = 9.324(4) Å, c =
9.484(4) Å, α = 101.52(3)°, β = 107.64(4)°, γ =
106.19(4)°, V = 672.4(5) Å3, Z = 2, dcalcd = 1.311 g/cm3,
µ = 0.239 mm–1, F(000) 280, space group ê1 (no. 2).
The structure was solved by direct methods and refined
by least-squares calculation in the full-matrix anisotro-
pic approximation using the SHELXS86 and
SHELXL93 program packages [10, 11]. The refine-
ment included 1499 reflections with I > 2σ(I) (223
refined parameters, 6.72 reflections per parameter; the
weighting scheme ω = 1/[σ2(Fo2) + (0.0808P)2 +
0.1070ê] was used, where ê = (Fo2 + 2Fc2)/3, and the
ratio of the maximum (average) shift to the error in the
last cycle was 0.124(0.008)). A correction for abnormal
scattering was applied, and no absorption correction
was used. All the hydrogen atoms were located objec-
tively and refined isotropically. The final residual fac-
tors were R1(F) 0.0455 and RW(F2) 0.1189, GOF 1.001.
The residual electron densities found from a difference
Fourier synthesis after the last refinement cycle were
0.18 and –0.20 Â/Å3. The structural calculations were
carried out using a PC. The atomic coordinates are
deposited in CSDB.
125(3)
1.141(4)
1.318(4)
0.88(2)
120.2(3)
120.5(2)
119.2(2)
121.0(3)
120.7(3)
118.2(3)
110.4(2)
110.7(3)
112.1(3)
125.2(3)
120.6(3)
114.2(3)
119.6(3)
128.9(3)
111.6(3)
176.4(4)
118.2(3)
117.0(3)
124.7(3)
113.5(2)
122.6(3)
121.2(3)
116.2(3)
N1C1S1
0.87(2)
C1C2C6
1.347(4)
1.418(5)
1.514(4)
1.517(4)
1.528(5)
1.01(2)
C1C2C3
C6C2C3
C2C3C4
C2C3C7
C4C3C7
C5C4C9
1.360(4)
1.471(4)
1.500(5)
1.488(5)
1.508(5)
C5C4C3
C9C4C3
C4C5N1
C4C5C8
N1C5C8
N2C6C2
O1C9C4
O1C9C10
C4C9C10
C12C11S1
O2C12N3
O2C12C11
N3C12C11
(2 g, 20 mmol), 1,3-cyclohexanedione III (2.24 g,
20 mmol), and piperidine (2.47 ml, 25 mmol) were
added at 20°C to a stirred mixture of 4-chlorobenzalde-
hyde Ib (2.81 g, 20 mmol) and 3 drops of piperidine in
30 ml of ethanol. After 6 h, 10% hydrochloric acid was
added to the resulting solution to pH 5. The precipitate
was filtered off after 12 h and washed with ethanol and
hexane (Tables 2, 3).
Piperidinium 4-(2-chlorophenyl)-3-cyano-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-2-thiolate
(IV).
Cyanothioacetamide II (2 g, 20 mmol), 1,3-cyclohex-
anedione III (2.24 g, 20 mmol), and piperidine (2.47 ml,
25 mmol) were added at 20°C to a stirred mixture of 2-
chlorobenzaldehyde Ia (2.25 ml, 20 mmol) and 3 drops
of piperidine in 30 ml of ethanol. After 6 h, the precip-
itate was filtered off and washed with acetone (Tab-
les 2, 3). MS (EI, 70 eV), m/z (most intense peak,
Irel, %): 41 (46); 56 (64); 70 (14); 84 (100); 198 (39);
281 (46); 316 (8).
4-R-2-(R1-Methylthio)-3-cyano-5-oxo-1,4,5,6,7,8-
hexahydroquinolines IXa–IXf. A 10% aqueous solu-
tion of KOH (2.8 ml, 5 mmol) and 5 mmol of halide
VIII were added to a stirred suspension of salt IV or
thiol V (5 mmol) in 25 ml of 85% ethanol. After 12 h,
the precipitate was filtered off and washed with ethanol
4-(4-Chlorophenyl)-3-cyano-5-oxo-1,4,5,6,7,8-hexa-
hydroquinoline-2-thiol (V). Cyanothioacetamide II and hexane (Tables 2, 3).
DOKLADY CHEMISTRY Vol. 377
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2001

98
LITVINOV et al.
Table 2. Yields and physicochemical characteristics of compounds IV, V, IX, XI, XII, XIII, XVI, XVII, and XX
Found
-------------------------
Calculated
, %
Compound
Yield (%)
Tm, °C
Molecular formula
C
H
N
62.55
------------
62.75
5.82
---------
6.02
10.16
------------
10.45
IV
78
66
77
82
67
92
92
59
92
68
72
56
66
89
71
73
82
63
180–183
187–189
238–240
252–254
256–258
249–251
241–243
182–184
195–197
181–183
197–199
147–149
237–239
245–247
200 (dec. onset)
169–171
227–229
196–198
C21H24ClN3OS
C16H13ClN2OS
C17H15ClN2OS
C18H17ClN2OS
C18H16ClN3O2S
C24H19BrClN3O2S
C17H15ClN2OS
C18H17ClN2OS
C22H28ClN3O3S
C18H19ClN2O2S
C19H21ClN2O2S
C20H23ClN2O2S
C20H22ClN3O3S
C26H25BrClN3O3S
C20H25N3O2S
60.52
------------
60.66
4.21
---------
4.14
8.63
---------
8.84
V
61.53
------------
61.72
4.51
---------
4.57
8.17
---------
8.47
IXa
62.48
------------
62.69
5.13
---------
4.97
8.25
---------
8.12
IXb
IXc
57.78
------------
57.83
4.11
---------
4.31
11.33
------------
11.24
54.33
------------
54.51
3.55
---------
3.62
8.08
---------
7.95
IXd
IXe
61.58
------------
61.72
4.44
---------
4.57
8.26
---------
8.47
62.53
------------
62.69
4.88
---------
4.97
8.04
---------
8.12
IXf
58.88
------------
58.72
6.13
---------
6.27
9.51
---------
9.34
XI
59.74
------------
59.58
5.41
---------
5.28
7.59
---------
7.72
XII
60.41
------------
60.55
5.81
---------
5.62
7.16
---------
7.43
XIIIa
XIIIb
XIIIc
XIIId
XVI
XVIIa
XVIIb
XX
61.62
------------
61.45
6.09
---------
5.93
7.05
---------
7.17
57.39
------------
57.20
5.12
---------
5.28
10.19
------------
10.01
54.55
------------
54.32
4.21
---------
4.38
7.28
---------
7.31
64.51
------------
64.66
6.64
---------
6.78
11.37
------------
11.31
67.31
------------
67.58
5.62
---------
5.67
9.79
---------
9.85
C16H16N2OS
62.22
------------
62.37
5.09
---------
5.23
12.76
------------
12.83
C17H17N3O2S
54.22
------------
54.32
5.65
---------
5.70
15.66
------------
15.84
C12H15N3O2S
Morpholinium 5-tert-butoxycarbonyl-4-(4-chlo- ethanol. After 3 h, the precipitate was filtered off and
washed with ethanol and acetone (Tables 2, 3). MS (EI,
70 eV), m/z (most intense peak, Irel, %): 41 (42); 57 (100);
87 (19); 163 (16); 261 (28); 279 (35); [M+] is absent.
rophenyl)-3-cyano-6-methyl-1,4-dihydropyridine-2-
thiolate XI. Morpholine (2.18 ml, 25 mmol) was added
at 20°C to a stirred mixture of 4-chlorobenzaldehyde Ib
(2.81 g, 20 mmol), cyanothioacetamide II (2 g, 20 mmol),
5-tert-Butoxycarbonyl-4-(4-chlorophenyl)-3-cyano-
and tert-butyl acetoacetate (3.29 ml, 20 mmol) in 30 ml of 6-methyl-3,4-dihydropyridine-2(1H)-thione XII. A
DOKLADY CHEMISTRY Vol. 377
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CASCADE HETEROCYCLIZATION IN THE SYNTHESIS
99
Table 3. IR spectra and 1H NMR spectra of compounds IV, V, IX, XI, XII, XIII, XVI, XVII, and XX
IR spectrum, ν, cm–1
1H NMR, δ, ppm (J/Hz)
Compound
3185 (NH, N+H2);
IV
1.62, 1.85, 2.13, 2.53 (four m, 12H, (CH2)6); 3.02 (m, 4H, N(CH2)2);
2175 (C≡N); 1620 (C=O) 4.84 (s, 1H, C(4)H); 7.12 (m, 3H, H-Ar); 7.21 (d, 1H, H-Ar, 3J = 8.2); 8.33 (s, 1H, NH)
3214 (NH); 2239 (C≡N); 1.95, 2.23, 2.62 (three m, 6H, (CH2)3); 4.59 (s, 1H, C(4)H); 7.16, 7.25
V
(both d, 4H, H-Ar, 3J = 8.1); 10.09 (s, 1H, NH)
1622 (C=O)
IXa
IXb
3155 (NH); 2194 (C≡N); 1.96, 2.22, 2.59 (three m, 6H, (CH2)3); 2.52 (s, 3H, SMe); 5.04 (s, 1H, C(4)H);
7.22 (m, 3H, H-Ar); 7.33 (d, 1H, H-Ar, 3J = 8.2); 9.57 (s, 1H, NH)
1625 (C=O)
1.25 (t, 3H, Me, 3J = 6.5); 1.97, 2.23, 2.58 (three m, 6H, (CH2)3); 2.98 (m, 2H,
3213 (NH); 2203 (C≡N);
1620 (C=O)
SCH2); 5.07 (s, 1H, C(4)H); 7.23 (m, 3H, H-Ar); 7.34 (d, 1H, H-Ar, 3J = 8.2);
9.62 (s, 1H, NH)
1.98, 2.23, 2.59 (three m, 6H, (CH2)3); 3.59, 3.68 (both d, 2H, SCH2, 2J = 14.1);
IXc
IXd
3159, 3308 (NH, NH2);
2193 (C≡N); 1622,
1648 (2C=O)
5.07 (s, 1H, C(4)H); 7.22 (m, 3H, H-Ar); 7.32 (d, 1H, H-Ar, 3J = 8.3); 7.53, 7.88
(both br s, 2H, NH2); 10.69 (s, 1H, NH)
1.96, 2.22, 2.58 (three m, 6H, (CH2)3); 3.81, 3.95 (both d, 2H, SCH2, 2J = 16.2);
5.07 (s, 1H, C(4)H); 7.21 (m, 3H, H-Ar); 7.31 (d, 1H, H-Ar, 3J = 8.2); 7.43, 7.54
(both d, 4H, H-Ar, 3J = 8.3); 10.03, 10.42 (both s, 2H, 2NH)
3154–3318 (2NH);
2192 (C≡N); 1605,
1616, 1624 (2C=O)
IXe
IXf
3390 (NH); 2198
1.92, 2.23, 2.55 (three m, 6H, (CH2)3); 2.51 (s, 3H, SMe); 4.51 (s, 1H, C(4)H);
7.16, 7.28 (both d, 4H, H-Ar, 3J = 8.1); 9.56 (s, 1H, NH)
(C≡N); 1823 (C=O)
1.26 (t, 3H, Me, 3J = 6.7); 1.93, 2.22, 2.57 (three m, 6H, (CH2)3); 2.99 (m, 2H, SCH2);
3214 (NH); 2201 (C≡N);
1638 (C=O)
4.53 (s, 1H, C(4)H); 7.17, 7.28 (both d, 4H, H-Ar, 3J = 8.1); 9.64 (s, 1H, NH)
1.33 (s, 9H, Me3C); 2.31 (s, 3H, Me); 2.51 (m, 4H, CH2NCH2);
3.82 (m, 4H, CH2OCH2); 4.39 [s, 1H, C(4)H]; 7.35, 7.55
(both d, 4H, Ar, 3J = 8.7); 9.45 (br s, 1H, NH)
1.32 (s, 9H, Me3C); 2.29*, 2.38**, 2.42*** (three s, Me); 4.19** (3J = 8.1),
4.28*** (3J = 4.0) (both d, C(4)H); 4.39*** (3J = 4.0), 4.91** (3J = 8.1)
(both d, C(3)H); 4.44* (s, C(4)H); 7.12–7.32 (m, 4H, Ar); 9.53*, 11.94**, 12.13***
(three br s, NH) (major stereoisomer : minor stereoisomer : thiol = 2 : 1 : 2)
3270–3330 (NH, +NH2);
2160 (C≡N); 1708 (C=O)
XI
XII
3240–3255 (NH);
2190, 2253 (C≡N);
1638 (C=O)
XIIIa
XIIIb
3300 (NH); 2194 (C≡N); 1.31 (s, 9H, Me3C); 2.28 (s, 3H, Me); 2.47 (s, 3H, SMe); 4.48 [s, 1H, C(4)H);
7.14, 7.31 (both d, 4H, Ar, 3J = 8.7); 9.15 (s, 1H, NH)
1706 (C=O)
1.24 (t, 3H, MeCH2, 3J = 7.3); 1.29 (s, 9H, Me3C); 2.28 (s, 3H, Me);
3240–3296 (NH);
2200 (C≡N); 1705 (C=O)
2.77, 3.06 (both m, 2H, SCH2); 4.46 (s, 1H, C(4)H); 7.15, 7.32
(both d, 4H, Ar, 3J = 8.6); 9.24 (s, 1H, NH)
1.31 (s, 9H, Me3C); 2.29 (s, 3H, Me); 3.56, 3.65 (both d, 2H, SCH2, 2J = 14.1);
XIIIc
XIIId
3274–3364 (NH, NH2);
2185 (C≡N);
1690–1706 (2C=O)
4.45 [s, 1H, C(4)H]; 7.17 and 7.32 (both d, 4H, Ar, 3J = 8.4); 7.53 and 7.88
(both br s, 2H, NH2); 10.39 (s, 1H, NH)
1.31 (s, 9H, Me3C); 2.31 (s, 3H, Me); 3.81, 3.89 (both d, 2H, SCH2, 2J = 15.4);
3210–3304 (2NH);
2193 (C≡N); 1620,
1684 (2C=O)
4.47 [s, 1H, C(4)H]; 7.16, 7.31 (both d, 4H, 4-ClC H , 3J = 8.5); 7.43, 7.53
6
4
(both d, 4H, 4-BrC H , 3J = 8.4); 9.68, 10.39 (both s, 2H, 2NH)
6
4
3348 (NH, N+H);
0.91 (d, 3H, C(4)Me, 3J = 6.1); 1.65 (s, 3H, C(6)Me); 2.65 (s, 3H, NMe);
XVI
2179 (C≡N); 1692 (C=O) 2.98, 3.74 (both m, 8H, morpholinium fragment); 3.19 (q, 1H, C(4)H,
3J = 6.1); 7.47–7.94 (m, 6H, Ph, N(1)H)
0.98 (d, 3H, C(4)Me, 3J = 6.2); 1.70 (s, 3H, C(6)Me); 2.65 (s, 1H, SMe);
3.39 (q, 1H, C(4)H, 3J = 6.2); 7.57–7.83 (m, 5H, Ph); 9.29 (s, 1H, NH)
1.02 (d, 3H, C(4)Me, 3J = 6.3); 1.73 (s, 3H, C(6)Me); 3.42 (q, 1H, C(4)H, 3J = 6.3);
3.54, 3.67 (both d, 2H, SCH2, 2J = 14.2); 7.43–7.63 (m, 6H, Ph, CONH2);
7.88 (s, 1H, CONH2); 10.31 (s, 1H, NH)
XVIIa
XVIIb
3222 (NH); 2197 (C≡N);
1680 (C=O)
3157–3390 (NH, NH2);
2196 (C≡N); 1695,
1620 (2C=O)
0.98 (d, 3H, C(4)Me, 3J = 6.4); 2.21 (br s, 6H, 2Me); 3.43 (q, 1H, C(4)H,
3J = 6.4); 3.51, 3.64 (both d, 2H, SCH2, 2J = 14.1); 7.52, 7.88
(both s, 2H, CONH2); 10.37 (s, 1H, NH)
XX
3180, 3421 (NH, NH2);
2195 (C≡N); 1708 (2C=O)
Note: An asterisk marks individual thiol signals, two asterisks mark the signals of the major stereoisomer, and three asterisks correspond
to the signals of the minor stereoisomer.
DOKLADY CHEMISTRY Vol. 377
Nos. 4–6
2001

100
LITVINOV et al.
Z
Y
0
X
Fig. 2. Fragment of the crystal packing of XX. The dashed lines show hydrogen bonds.
suspension of salt XI (0.9 g, 2 mmol) in 10 ml of etha- acetamide VIIIc (0.93 g, 10 mmol) was added. The reac-
nol was diluted with 10% hydrochloric acid to pH 3 and tion mixture was heated to boiling and filtered through a
allowed to stand for 12 h. The resulting precipitate was fil- paper filter. The resulting crystalline precipitate was sep-
tered off and washed with ethanol and hexane (Tables 2, 3). arated and washed with ethanol and hexane (Tables 2, 3).
5-tert-Butoxycarbonyl-4-(4-chlorophenyl)-3-cyano-
6-methyl-2-(R-methylthio)-1,4-dihydropyridines
XIIIa–XIIId. A mixture of salt XI (0.9 g, 2 mmol) and
the corresponding halide VIII (2 mmol) in 10 ml of
85% ethanol was heated until the components dis-
solved and filtered through a paper filter. After 12 h, the
resulting precipitate was filtered off and washed with
ethanol and hexane (Tables 2, 3).
ACKNOWLEDGMENTS
The work was supported by the Russian Foundation
for Basic Research, project no. 99–03–32965.
REFERENCES
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dimethyl-1,4-dihydropyridine-2-thiolate
XVI.
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with stirring at 20°C to a mixture of acetaldehyde XIV
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10 mmol), and benzoylacetone XV (1.62 g, 10 mmol) in
15 ml of ethanol. After dissolution of the reactants, the
reaction mixture was heated to boiling and allowed to stand
for 24 h. The resulting precipitate was filtered off, washed
with acetone, and dried for 30 min at 80°C (Tables 2, 3).
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1,4-dihydropyridines XVIIa, XVIIb. A mixture of
salt XVI (1.86 g, 5 mmol) and the corresponding halide
VIII (5 mmol) in 20 ml of 80% ethanol was heated to
boiling, filtered through a paper filter, and allowed to
stand for 12 h. The resulting precipitate was separated
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11. Sheldrick, G.M., SHELXL93: Program for the Refine-
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gen, 1993.
5-Acetyl-2-carbamoylmethylthio-3-cyano-4,6-di-
methyl-1,4-dihydropyridine XX. A mixture of alde-
hyde XIV (0.56 ml, 10 mmol), cyanothioacetamide II
(1 g, 10 mmol), acetylacetone XVIII (1.03 ml,
10 mmol), and N-methylmorpholine (1.5 ml, 15 mmol)
in 20 ml of ethanol was stirred for 3 h at 20°C. α-Chloro-
DOKLADY CHEMISTRY Vol. 377
Nos. 4–6 2001