Cyclohexene-4-carbaldehyde in the synthesis of 4-(cyclohex-3-enyl)- substituted 4H-chromenes, 4H-thiopyrans, 1,4,5,6,7,8-hexahydroquinolines, 1,4-dihydropyridines, pyridines, and 6,7-dihydro-5H-[1]pyrindines

Article abstract of DOI:10.1007/s11176-005-0463-z

Cyclocondensation of cyclohexene-4-carbaldehyde in the presence of morpholine with CH acids [malonodinitrile, dimedone, 1,3-cyclohexanedione, ethyl acetoacetate, cyanothioacetamide, β-aminophenol, resorcinol, and 4-(cyclopent-1-enyl)morpholine] yields the corresponding 4-(cyclohex-3-enyl)- substituted 4H-chromenes, 4H-thiopyrans, 1,4,5,6,7,8-hexahydroquinolines, 1,4-dihydropyridines, and 6,7-dihydro-5H-[1]pyrindines. 2005 Pleiades Publishing, Inc.

Full text of DOI:10.1007/s11176-005-0463-z

Russian Journal of General Chemistry, Vol. 75, No. 10, 2005, pp. 1537 1544. Translated from Zhurnal Obshchei Khimii, Vol. 75, No. 10, 2005,
pp. 1612 1619.
Original Russian Text Copyright
2005 by Dyachenko.
Cyclohexene-4-carbaldehyde in the Synthesis
of 4-(Cyclohex-3-enyl)-Substituted 4H-Chromenes,
4H-Thiopyrans, 1,4,5,6,7,8-Hexahydroquinolines,
1,4-Dihydropyridines, Pyridines,
and 6,7-Dihydro-5H-[1]pyrindines
V. D. Dyachenko
Shevchenko National Pedagogical University, Lugansk, Ukraine
Received September 21, 2004
Abstract Cyclocondensation of cyclohexene-4-carbaldehyde in the presence of morpholine with CH acids
[malonodinitrile, dimedone, 1,3-cyclohexanedione, ethyl acetoacetate, cyanothioacetamide, -aminophenol,
resorcinol, and 4-(cyclopent-1-enyl)morpholine] yields the corresponding 4-(cyclohex-3-enyl)-substituted
4H-chromenes, 4H-thiopyrans, 1,4,5,6,7,8-hexahydroquinolines, 1,4-dihydropyridines, and 6,7-dihydro-5H-
[1]pyrindines.
A promising strategy of the modern organic syn-
thesis is performing a sequence of reactions without
isolating intermediates (one-pot process). In this case,
complex molecules can be assembled under mild
conditions, often regio- and stereoselectively [1 6].
and chemical transformations. In particular, alkylation
of pyrindine-2-thione IV with VIIa VIIj in DMF in
a basic medium yields the corresponding organic
sulfides VIIIa VIIIj. The subsequent treatment of
VIIIa with an aqueous alkali is accompanied by the
intramolecular Thorpe reaction with the formation of
imino derivative IX stabilized in the form of 3-amino-
6,7-dihydro-4-(cyclohex-3-enyl)-8-aza-5H-thiainda-
cene-2-carbonitrile X, which is in agreement with the
known chemical properties of 3-cyanopyridine-2-
(1H)-thiones and their 2-alkylthio-substituted analogs
[15, 16]. Note that compound X shows promise in
synthesis of polycondensed heterocycles [17] and in
development of substances with antibacterial [18 22]
and antitumor [23] activity, telomerase inhibitors [24],
and compounds with other kinds of biological activity
[25].
Proceeding with studies on the synthesis of hetero-
cyclic compounds by multicomponent condensation
[1 7], we studied the reaction of cyclohexene-4-carb-
aldehyde I with various CH acids under the conditions
of the Knoevenagel reaction. Aliphatic aldehydes are
used in the synthesis or carbo- and heterocycles to a
lesser extent than their aromatic analogs, which may
be associated with their higher toxicity, inflammabil-
ity, and tendency to readily polymerize [12].
Here we report that aldehyde I, which was success-
fully used previously for preparing compounds with
selective juvenile activity [13], enters into condensa-
tion with cyanothioacetamide II and 4-(cyclopent-1-
enyl)morpholine III in the presence of a base B. The
reaction occurs at 20 C in ethanol and yields 2-thi-
oxo-4-(cyclohex-3-enyl)-2,5,6,7-tetrahydro-1H-[1]-
pyrindine-3-carbonitrile IV as final product. The reac-
tion apparently occurs via formation of Knoevenagel
reaction product V, which subsequently undergoes
regioselective Stork alkylation [14] with cyclopen-
tanone enamine III to the corresponding derivative VI.
This is followed by intramolecular amine interchange
and dehydrogenation with the formation of IV. The
composition and structure of IV were confirmed by
elemental analysis (Table 1), spectroscopy (Table 2),
With malonodinitrile XI taken instead of III in the
condensation with aldehyde I and amide II, the reac-
tion yields 2,6-diamino-4-(cyclohex-3-enyl)-4H-thio-
pyran-3,5-dicarbonitrile XII as a result of the Michael
addition of CH acid XI to hypothetical alkene V. The
adduct XIII arising in the process regioselectively
cyclizes into compound XII. The latter, when refluxed
in ethanol in the presence of an equimolar amount of
morpholine, undergoes recyclization, similarly to
4-aryl-substituted analogs [26 29], into morpholinium
6-amino-3,5-dicyano-4-(cyclohex-3-enyl)pyridine-2-
thiolate XIV. Treatment of an ethanol solution of XIV
with a solution of hydrochloric acid in ethanol yields
6-amino-1,2-dihydro-2-thioxo-4-(cyclohex-3-enyl)py-
1070-3632/05/7510-1537 2005 Pleiades Publishing, Inc.

1538
DYACHENKO
Table 1. Yields, melting points, and elemental analyses of IV, VIIIa VIIIj, X, XII, XIV XVI, XVIIIa XVIIIc, XXII,
XXIV, XXVIa, XXVIb, and XXIX
Found, %
H
Calculated, %
H
mp,
(solvent for
crystallization)
C
Comp.
no.
Yield,
%
Formula
C
N
C
N
IV
86
85
79
81
88
87
92
73
90
85
94
70
81
80
77
72
76
79
76
68
70
95
80
76
262 265a (AcOH) 70.14
6.12
5.71
5.96
6.31
6.58
6.37
6.88
6.14
4.99
6.64
4.88
5.72
5.39
5.93
4.58
4.70
6.04
5.41
7.14
6.48
6.32
5.88
6.29
6.02
10.88
14.16
8.42
7.95
7.72
7.99
9.74
7.31
6.72
C15H16N2S
C17H17N3S
70.28
69.12
65.83
76.26
67.39
66.64
71.79
73.76
67.55
72.93
70.57
69.12
60.44
59.45
60.91
67.36
62.95
59.31
69.48
63.13
59.81
71.62
71.89
77.07
6.29
5.80
6.14
6.40
6.79
6.48
7.09
5.92
5.18
6.80
5.01
5.80
5.46
6.16
4.72
4.85
6.16
5.36
7.37
6.62
6.41
6.01
6.41
6.19
10.93
14.22
8.53
8.08
7.86
8.18
9.85
7.48
6.85
VIIIa
VIIIb
VIIIc
VIIId
VIIIe
VIIIf
VIIIg
VIIIh
VIIIi
VIIIj
X
XII
XIV
XVA
XVI
XVIIIa
XVIIIb
XVIIIc
XXII
XXIV
XXVIa
XXVIb
XXIX
133 134 (EtOH)
130 131 (EtOH)
111 113 (PrOH)
68.95
65.70
76.14
C18H20N2O2S
C22H22N2S
C20H24N2O2S
C19H22N2O2S
C17H20N2S
C23H22N2OS
C23H21ClN2OS
C18H20N2S
C26H22N2O3S
C17H17N3S
105 106 (i-PrOH) 67.22
109 110 (EtOH)
92 93 (EtOH)
121 122 (AcOH)
117 118 (AcOH)
85 86 (EtOH)
66.50
71.60
73.60
67.44
72.81
70.38
68.91
60.31
59.28
60.82
67.28
62.88
59.26
69.34
9.32
6.19
9.45
6.33
188 190 (BuOH)
173 175 (AcOH)
199 201 (EtOH)
174 176 (EtOH)
229 231 (AcOH)
235 237 (EtOH)
189 190 (BuOH)
233 235 (AcOH)
206 208 (AcOH)
14.03
21.50
20.22
21.70
15.11
12.32
8.14
8.42
9.15
11.50
10.33
15.64
7.74
14.22
21.69
20.39
21.86
14.96
12.24
7.98
8.53
9.20
11.63
10.44
15.72
7.82
C13H14N4S
C17H21N5OS
C13H12N4S
C21H18N4OS
C18H21N3O2S
C26H28BrN3O2S
C19H24N2OS
C16H20N2O2S
C18H23N3O3S
C16H16N2O2
C16H17N3O
228 230b (EtOH) 63.01
184 186 (EtOH)
227 229 (EtOH)
194 196 (EtOH)
177 179 (EtOH)
59.68
71.51
71.72
76.92
C23H22N2O2
a
b
Notes: Sublimation temperature, C:
220 and
110.
Table 2. IR and 1H NMR spectra of IV, VIIIa VIIIj, X, XII, XIV XVI, XVIIIa XVIIIc, XXII, XXIV, XXVIa, XXVIb,
and XXIX
Comp.
no.
1
IR spectrum, , cm
1H NMR spectrum, , ppm (J, Hz)
IV
1218 (C=S), 2219 (C N) 1.79 m (1H, CH), 2.04 m (6H, 3CH2), 2.41 m (1H, CH), 2.85 m (4H, CH), 3.10 m
(1H, CH), 5.79 m (2H, CH=CH), 14.16 br.s (1H, NH)
VIIIa
VIIIb
VIIIc
2224, 2253 (C N)
1.78 m (1H, CH), 2.05 2.23 m (6H, 3CH2), 2.40 m (1H, CH), 3.02 m (4H, CH),
3.14 m (1H, CH), 4.32 s (2H, SCH2), 5.77 m (2H, CH=CH)
1740 (C=O), 2223 (C N) 1.80 m (1H, CH), 2.06 2.19 m (6H, 3CH2), 2.42 m (1H, CH), 2.91 3.09 m (5H,
CH), 3.66 s (3H, Me), 4.11 s (2H, SCH2), 5.78 m (2H, CH=CH)
2218 (C N)
1.79 m (1H, CH), 2.01 2.18 m (6H, 3CH2), 2.37 m (1H, CH), 2.99 m (4H, CH),
3.14 m (1H, CH), 4.46 s (2H, SCH2), 5.76 m (2H, CH=CH), 7.22 t (1H, Ph, J 7.14),
7.29 t (2H, Ph), 7.38 d (2H, Ph, J 7.54)
VIIId
1722 (C=O), 2215 (C N) 1.21 d (6H, 2Me, J 5.02), 1.78 m (1H, CH), 2.02 2.23 m (6H, 3CH2), 2.44 m (1H,
CH), 3.91 t (2H, CH2, J 6.15), 2.99 t (2H, CH2, J 6.13), 3.07 m (1H, CH), 3.97 s
(2H, SCH2), 4.92 m (1H, OCH), 5.76 m (2H, CH=CH)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 10 2005

CYCLOHEXENE-4-CARBALDEHYDE IN THE SYNTHESIS
1539
Table 2. (Contd.)
Comp.
no.
1
IR spectrum, , cm
1H NMR spectrum, , ppm (J, Hz)
VIIIe
VIIIf
VIIIg
VIIIh
VIIIi
VIIIj
1733 (C=O), 2217 (C N) 1.26 t (3H, Me, J 7.21), 1.81 m (1H, CH), 2.08 2.19 m (6H, 3CH2), 2.42 m (1H,
CH), 2.93 t (2H, CH2, J 8.01), 2.30 t (2H, CH2, J 7.21), 3.10 m (1H, CH), 3.99 s
(2H, SCH2), 4.15 q (2H, OCH2, J 7.21), 5.77 m (2H, CH=CH)
2220 (C N)
1.32 t (3H, Me, J 6.04), 1.76 m (1H, CH), 2.01 2.23 m (6H, 3CH2), 2.44 t (2H,
CH2, J 7.22), 2.95 m (3H, CH), 3.01 m (1H, CH), 3.23 t (2H, SCH2, J 6.04),
5.77 m (2H, CH=CH)
1694 (C=O), 2219 (C N) 1.77 m (1H, CH), 1.95 2.24 m (6H, 3CH2), 2.42 m (1H, CH), 2.73 t (2H, CH2, J
7.61), 2.95 t (2H, CH2, J 8.41), 3.01 m (1H, CH), 4.74 s (2H, SCH2), 5.77 m (2H,
CH=CH), 7.54 t (2H, Ph, J 6.95), 7.63 t (1H, Ph, J 6.95), 8.02 d (2H, Ph, J 7.03)
1688 (C=O), 2215 (C N) 1.79 m (1H, CH), 1.94 2.22 m (6H, 3CH2), 2.39 m (1H, CH), 2.72 t (2H, CH2,
J 8.41), 2.95 t (2H, CH2, J 7.61), 3.08 m (1H, CH), 4.70 s (2H, SCH2), 5.77 m (2H,
CH=CH), 7.57 d and 8.04 d (2H each, C6H4, J 8.41)
2226 (C N)
1.78 m (1H, CH), 2.03 2.19 m (6H, 3CH2), 2.37 m (1H, CH), 2.96 m (4H, 2CH2),
3.07 m (1H, CH), 3.92 d (2H, SCH2, J 6.58), 5.12 d (1H, =CH2, Jcis 9.54), 5.34 d
(1H, =CH2, Jtrans 17.49), 5.79 m (2H, CH=CH), 5.96 m (1H, CH=)
1.76 m (1H, CH), 1.93 2.18 m (6H, 3CH2), 2.37 m (1H, CH), 2.74 t (2H, CH2,
J 8.42), 2.99 t (2H, CH2, J 8.38), 3.06 m (1H, CH), 4.74 s (2H, SCH2), 5.76 m (2H,
CH=CH), 7.44 t (1H, H arom., J 7.85), 7.51 d (1H, H arom.), 7.78 t (1H, H arom.,
J 7.94), 7.99 d (1H, H arom.), 8.71 s (1H, C4H of coumarin)
1685, 1726 (C=O),
2218 (C N)
X
1648 [ (NH2)], 2194 (C N), 1.84 m (1H, CH), 2.02 2.19 m (4H, 2CH2), 2.25 m (2H, CH2), 2.36 m (1H, CH),
3182, 3330, 3445 (NH2) 2.94 m (2H, CH2), 3.11 t (2H, CH2, J 7.54), 3.90 m (1H, CH), 5.79 m (2H,
CH=CH), 5.97 br.s (2H, NH2)
XII
1645 [ (NH2)], 2195 (C N), 1.24 m (1H, CH), 1.63 2.18 m (6H, 3CH2), 2.82 d (1H, C4H, J 13.14), 5.64 m (2H,
3310, 3388, 3420 (NH2) CH=CH), 6.86 br.s (4H, 2NH2)
XIVa
XVA
1648 [ (NH2)], 2208 (C N), 1.68 m (1H, CH), 2.03 2.38 m (6H, 3CH2), 3.13 t (4H, CH2NCH2, J 4.37), 3.72 t
3211, 3340, 3442 (NH2) (4H, CH2OCH2), 5.75 m (2H, CH=CH), 7.48 br.s (2H, NH2)
1213 (C=S), 1640 [ (NH2)], 1.73 m (1H, CH), 2.01 2.33 m (6H, 3CH2), 5.78 m (2H, CH=CH), 7.82 br.s (2H,
2200 (C N), 3190, 3288, NH2), 12.91 br.s (1H, NH)
3350 (NH2)
XVI
1642 [ (NH2)],
1.80 m (1H, CH), 2.05 2.32 m (6H, 3CH2), 4.96 s (2H, SCH2), 5.78 m (2H,
1686 (C=O), 2200 (C N), CH=CH), 7.48 7.70 m (3H, Ph), 7.77 br.s (2H, NH2), 8.06 d (2H, Ph, J 7.12)
3205, 3321, 3466 (NH2)
XVIIIa 1668 (CONH), 1712 (C=O), 1.14 m (1H, CH), 1.33 2.34 m (12H, 6CH2), 3.61 d and 3.87 d (1H each, SCH2, 2J
2196 (C N), 3310 (NH) 14.76), 3.41 d (1H, C4H, J 7.20), 5.58 m (2H, CH=CH), 7.53 br.s and 7.85 br.s
(1H each, NH2), 10.47 br.s (1H, NH)
XVIIIb 1674 (CONH), 1695 (C=O), 1.02 s (6H, 2Me), 1.18 m (1H, CH), 1.42 1.95 m (6H, 3CH2), 2.18 s (2H, CH2),
2202 (C N), 3337 (NH) 2.38 s (2H, CH2), 3.44 d (1H, C4H, J 7.18), 3.99 s (2H, SCH2), 5.56 m (2H,
CH=CH), 7.49 d and 7.52 d (2H each, C6H4, J 7.52), 9.92 br.s (1H, NH),
10.46 br.s (1H, CONH)
XVIIIc 1688 (C=O), 2200 (C N), 0.95 s (3H, Me), 1.02 s (3H, Me), 1.48 m (1H, CH), 1.59 2.14 m (6H, 3CH2),
3325 (NH)
2.19 s (2H, CH2), 2.40 s (2H, CH2), 2.48 s (3H, SMe), 3.48 d (1H, C4H, J 7.04),
5.60 m (2H, CH=CH), 9.61 br.s (1H, NH)
XXII
1720 (C=O), 2247 (C N) 1.30 t (3H, CH2CH3, J 6.19), 1.58 m (1H, CH), 1.64 1.99 m (6H, 3CH2), 2.27 s
(3H, Me), 4.01 d (1H, C3H, J 4.13), 4.15 m (3H, C4H and OCH2), 5.51 m (2H,
CH=CH), 9.38 br.s (1H, NH)
XXIV
1668 (CONH), 1734 (C=O), 1.29 t (3H, CH2CH3, J 6.21), 1.52 m (1H, CH), 1.63 2.14 m (6H, 3CH2), 2.29 s
2205 (C N), 3302 (NH) (3H, Me), 3.42 d (1H, C4H, J 4.18), 3.48 d and 3.59 d (1H each, SCH2, 2J 15.14),
4.12 q (2H, OCH2), 5.58 m (2H, CH=CH), 7.41 br.s and 7.82 br.s (1H each, NH2),
10.43 br.s (1H, NH)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 10 2005

1540
DYACHENKO
Table 2. (Contd.)
Comp.
1
IR spectrum, , cm
1H NMR spectrum, , ppm (J, Hz)
no.
XXVIa 1648 [ (NH2)], 2200 (C N), 1.21 m (1H, CH), 1.62 2.17 m (6H, 3CH2), 3.36 d (1H, C4H, J 3.17), 5.61 m (2H,
3172, 3314, 3445 (NH2), CH=CH), 6.39 s (1H, C8H), 6.52 d (1H, C6H, J 8.46), 6.61 br.s (2H, NH2), 6.99 d
3496 (OH)
(1H, C5H), 9.47 br.s (1H, OH)
XXVIb 1647 [ (NH2)], 2195 (C N), 1.42 m (1H, CH), 1.64 m (4H, 2CH2), 1.96 m (2H, CH2), 3.44 d (1H, C4H, J 3.14),
3336, 3390, 3471 (NH2) 5.16 br.s (2H, C7NH2), 5.18 m (2H, CH=CH), 6.19 s (1H, C8H), 6.33 d (1H, C6H,
J 8.44), 6.65 br.s (2H, NH2), 6.82 d (1H, C5H)
XXIX
1649 [ (NH2)], 2193 (C N), 1.25 m (1H, CH), 1.72 2.15 m (6H, 3CH2), 3.36 d (1H, C4H, J 3.01), 5.04 s (2H,
3330, 3372, 3484 (NH2) OCH2), 5.55 m (2H, CH=CH), 6.46 br.s (2H, NH2), 6.57 s (1H, C8H), 6.71 d (1H,
C6H, J 8.43), 6.99 d (1H, C5H), 7.59 t (1H, Ph, J 6.91), 7.71 t (2H, Ph), 7.80 d
(2H, Ph, J 6.95)
a
+
The NH signals are not manifested, probably besause of deuterium exshange.
2
ridine-3,5-dicarbonitrile XVA. The corresponding pro-
totropic tautomer XVB is apparently unstable under
the conditions of recording the H NMR and IR spec-
will probably have structure XXIII. In alkylation of
XXII with chloroacetamide VIIk, we obtained ethyl
6-carbamoylmethylsulfanyl-2-methyl-5-cyano-4-(cy-
clohex-3-enyl)-1,4-dihydropyridine-3-carboxylate
XXIV, which, along with the spectroscopic data
(Table 2), additionally confirms the thione structure
of XXII.
1
tra. In particular, the IR spectrum of XV contains,
along with the characteristic absorption bands of the
cyano and amino groups (Table 2), also an absorption
band of the stretching vibrations of the C=S group at
1
1
2212 cm , in agreement with [30, 31]. The H NMR
spectrum of XV contains, along with proton signals
from the cyclohexenyl substituent and amino group
(Table 2), also an NH signal of the pyridine core in
the form of a broadened singlet at 12.91 ppm, typi-
cal of the related compounds [29]. The saltlike struc-
ture of XIV is readily confirmed by spectroscopic data
(Table 2) and by the fact that this compound reacts
with phenacyl bromide VIIg in DMF to form the ex-
pected organic sulfide XVI.
By using dinitrile XI and phenols XXVa and
XXVb as CH-acid components in the reaction with I
under mild conditions (20 C) in ethanol in the pres-
ence of morpholine, it is possible to prepare 4H-chro-
mene-3-carbonitriles XXVIa and XXVIb showing
promise in a search for new drugs [32 34]. Apparent-
ly, the reaction occurs via formation of cyclohex-3-
enylmethylenemalonodinitrile XXVII acting subse-
quently as substrate in the Michael addition of phen-
ols XXVa and XXVb. The subsequent intramolecular
cyclization of adducts XXVIIIa and XXVIIIb thus
formed gives as final products compounds XXVIa and
XXVIb in quantitative yield. In the presence of an
ethanol solution of sodium ethylate, product XXVIa
is smoothly alkylated with benzyl chloride VIIc to
2-amino-7-benzyloxy-4-(cyclohex-3-enyl)-4H-chrom-
ene-3-carbonitrile XXIX. The 1H NMR and IR spectra
of the product (Table 2) are well consistent with the
suggested structure.
Multicomponent condensation involving aldehyde
I, CH acid II, 1,3-dicarbonyl component XVII, mor-
pholine, and alkyl halides VIIk VIIm in ethanol at
20 C yields as final products substituted partially
hydrogenated 2-alkylsulfanylquinoline-3-carbonitriles
XVIIIa XVIIIc. Taking into account the structure of
XVIIIa XVIIIc, we can suggest the following con-
densation scheme: initially alkene V is formed, which
is followed by Michael addition of CH acid XVII.
Adduct XIX arising in the process undergoes regio-
selective cyclocondensation to salt XX. The latter
reacts with alkylating agents VIIk VIIm to form the
corresponding derivatives XVIIIa XVIIIc. Replace-
ment of diketones XVIIa and XVIIb in this reaction
by ethyl acetoacetate XXI and exclusion of alkyl
halides VIIk XIIm result in formation of substituted
ethyl 6-thioxo-5-cyano-1,4,5,6-tetrahydropyridine-3-
carboxylate XXII. The pathway of its formation is
similar to that of XX. The Michael adduct in this case
Thus, condensation of cyclohexene-4-carbaldehyde
with various CH acids under mild conditions is a
promising route to potentially bioactive substances.
EXPERIMENTAL
The IR spectra were recorded on an IKS-29 spec-
trometer from mulls in mineral oil and CHCl3 solu-
1
tions (compounds IV, XV). The H NMR spectra
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 10 2005

CYCLOHEXENE-4-CARBALDEHYDE IN THE SYNTHESIS
1541
CN
N
O
S, B
H2N
CN
S
III
II
CN
S
H2O
N H2N
H2N
CHO
I
V
O
VI
CH2(CN)2, B
B,
2[H]
XI
NC
CN
NH2
NC
CN
CN
C
N
S
H2N
N
H
IV
NH2
S
SH
XIII
XII
Z/KOH
Hlg
DMF
, B 2[H]
VIIa VIIj
H+
NC
CN
SH
CN
S BH+
NC
CN
CN
S
NC
H2N
Z
H2N
S
N
N
N
N
H
A
H2N
XIV
VIIIa VIIIj
B
XV
VIIg DMF
NH
KOH
NH2
S
VIIIa
NC
CN
DMFA
CN
CN
S
N
Ph
N
N
H2N
S
O
XVI
X
IX
VII, Hlg = Cl (a e), I (f), Br (g j); VII, VIII, Z = CN (a), CO2Me (b), Ph (c), CO2CH(Me)2 (d), CO2Et (e), Me (f),
PhCO (g), 4-ClC6H4CO (h), CH=CH2 (i), coumarin-1-ylcarbonyl (j); B = morpholine.
were taken on Bruker WP-100SY (100 MHz, com-
pounds XII, XV, XVI, XVIIIa, XVIIIc), Bruker WM-
250 (250.13 MHz, compounds XIV, XVIa), Bruker
AM-300 (300.13 MHz, compounds VIIIb, XVIb), and
Bruker DR-500 (500.13 MHz, compounds IV, VIIIa
VIIIj, X, XIX, XXII, XXIV) spectrometers in DMSO-
d6, internal reference TMS. The mass spectra were
recorded on a Kratos MS-890 mass spectrometer
(70 eV) with direct sample inlet.
The melting points were determined with a Koefler
device.
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1542
DYACHENKO
O
O
R
R
CN
S
O
XVIIa, XVIIb
R
II, B
[V]
I
O H2N
H2O
R
XIX
O
O
XI, B
H2O
OEt, B
Me
O
O
CN
CN
S
CN
S BH+
EtO
R
R
CN
H2N
O
Me
N
H
XXVII
XXIII
XX
OH
R
VIIk VIIm
H2O
XXVa, XXVb
O
O
CN
S
CN
CN
S
EtO
R
R
C
N
OH
N
H
N
H
R
Z
Me
XVIIIa XVIIIc
XXVIII
XXII
VIIk/KOH
DMF
O
VIIc/EtONa
CN
CN
CN
EtO
NH2
NH2
Me
N
H
XXIV
R
NH2
Ph
O
O
S
O
O
XXVIa, XXVIb
XXIX
VII, Hlg = I, Z = CONH2 (k); Hlg = Cl, 4-BrC6H4NHCO (l); Hlg = I, H (m). XVII, R = H (a), Me (b). XVIII, R = H,
Z = CONH2 (a); R = Me, Z = 4-BrC6H4NHCO (b); R = Me, Z = H (c). XXV, XXVI, R = OH (a), NH2 (b).
The reaction progress was monitored by TLC (Sil-
ufol UV-254, acetone hexane, 3 : 5; development
with iodine vapor).
10 mmol of aldehyde I and 10 mmol of amide II in
15 ml of absolute ethanol, we added three drops of
morpholine, and the mixture was stirred for 5 min at
20 C. Then 10 mmol of substituted morpholine III
was added, and the mixture was stirred for 40 min and
kept for 24 h at room temperature, after which it was
2-Thioxo-4-(cyclohex-3-enyl)-2,5,6,7-tetrahydro-
1H-[1]pyrindine-3-carbonitrile IV. To a mixture of
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CYCLOHEXENE-4-CARBALDEHYDE IN THE SYNTHESIS
1543
acidified with 10% HCl to pH 5 and allowed to stand
for 2 days. The precipitate thus formed was filtered
off and washed with water, ethanol, and hexane (in
the subsequent experiments the precipitates were
worked up similarly, unless otherwise indicated).
of 10 mmol of salt XIV and 10 mmol of phenacyl
bromide VIIg in 15 ml of DMF was stirred for 3 h
and diluted with an equal volume of water.
8-R-8-R-2-Z-Methylsulfanyl-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitriles XVIIIa
XVIIIc. To a mixture of 10 mmol of I and 10 mmol
of II in 15 ml of ethanol, we added three drops of
morpholine. After stirring for 5 min, we added
10 mmol of diketone XVII, stirred for 1 h, added
10 mmol of alkylating agent VIIk VIIm, and stirred
for 3 h. Then the mixture was diluted with an equal
volume of water and allowed to stand for 24 h at
room temperature.
2-Z-Methylsulfanyl-4-(cyclohex-3-enyl)pyrin-
dine-3-carbonitriles VIIIa VIIIj. To a solution of
10 mmol of IV in 12 ml of DMF we added succes-
sively 5.6 ml of 10% aqueous KOH (10 mmol) and
10 mmol of appropriate halide VIIa VIIj. The mixture
was stirred for 1 h and diluted with an equal volume
of water.
3-Amino-6,7-dihydro-4-(cyclohex-3-enyl)-8-aza-
5H-thiaindacene-2-carbonitrile X. To a solution of
10 mmol of VIIIa in 15 ml of DMF, we added with
stirring 5.6 ml of 10% aqueous KOH (10 mmol). The
stirring was continued for an additional 2 h, after
which the mixture was gradually diluted with an equal
volume of water. Mass spectrum, m/z (Irel, %): 297
(6) [M + 2]+, 296 (20) [M + 1]+, 295 (100) [M]+, 294
(14) [M 1]+, 278 (9), 266 (9), 254 (8), 253 (15), 252
(55), 241 (39), 240 (50), 226 (19), 213 (14), 186 (10),
140 (8), 115 (5), 77 (6), 54 (7), 39 (16).
Ethyl 2-methyl-6-thioxo-5-cyano-4-(cyclohex-3-
enyl)-1,4,5,6-tetrahydropyridine-3-carboxylate
XXII. To a mixture of 10 mmol of I and 10 mmol of
II in 15 ml of ethanol, we added three drops of mor-
pholine. After stirring for 5 min, we added 10 mmol
of ester XXI, stirred for 30 min, and left for 24 h at
room temperature. Mass spectrum, m/z (Irel, %): [M]+
absent, 277 (9) [M HCN]+, 262 (100), 234 (48), 216
(10), 188 (14), 161 (9), 149 (8), 79 (11), 65 (5), 53 (6),
44 (9).
2,6-Diamino-4-(cyclohex-3-enyl)-4H-thiopyran-
3,5-dicarbonitrile XII. To a mixture of 10 mmol of I
and 10 mmol of II in 15 ml of absolute ethanol, we
added three drops of morpholine, and the mixture was
stirred for 5 min. Then 10 mmol of dinitrile XI was
added, and the mixture was stirred for 10 min and
allowed to stand for 1 h at room temperature.
Ethyl 6-carbamoylmethylsulfanyl-2-methyl-5-
cyano-4-(cyclohex-3-enyl)-1,4-dihydropyridine-3-
carboxylate XXIV. To a solution of 10 mmol of
XXII in 15 ml of DMF, we added successively with
stirring 5.6 ml of 10% aqueous KOH (10 mmol) and
10 mmol of amide VIIk, stirred for 1 h, diluted with
an equal volume of water, and left for 24 h at room
temperature. Mass spectrum, m/z (Irel, %): 361 (5)
[M]+, 316 (19) [M HCONH2]+, 299 (10), 280 (100)
[M cyclohex-3-enyl]+, 263 (92), 235 (68), 223 (10),
207 (43), 177 (9), 163 (15), 79 (22) [Mcyclohex-3-enyl]+,
53 (18), 41 (17).
Morpholinium 6-amino-3,5-dicyano-4-(cyclo-
hex-3-enyl)pyridine-2-thiolate XIV. To a suspension
of 10 mmol of thiopyran XII in 15 ml of absolute
ethanol, we added 10 mmol of morpholine; the result-
ing solution was refluxed for 2 h. After cooling, the
precipitate was separated and washed with ethanol and
acetone. Salt XIV thus obtained was used in the sub-
sequent transformations without additional purifica-
2-Amino-4-(cyclohex-3-enyl)-7-R-4H-chromene-
3-carbonitriles XXVIa and XXVIb. To a solution of
10 mmol of I in 15 ml of ethanol, we added 10 mmol
of dinitrile XI and three drops of morpholine; the
mixture was stirred for 15 min. Then 10 mmol of sub-
stituted phenol XXVa or XXVb was added, and the
mixture was stirred for 1 h and allowed to stand at
room temperature for 3 days.
tion. Mass spectrum, m/z (Irel, %): 258 (12) [Manion
+
3]+, 257 (26) [Manion + 2]+, 256 (92) [Manion + 1]+,
255 (100) [Manion]+, 254 (19) [Manion 1]+, 241 (20),
227 (15), 203 (31), 177 (14), 169 (12), 158 (14), 115
(20), 88 (9) [Mcation]+, 87 (72) [Mcation 1]+, 81 (8)
[Mcyclohex-3-enyl]+, 79 (17), 67 (20), 58 (50), 57 (84).
2-Amino-7-benzyloxy-4-(cyclohex-3-enyl)-4H-
chromene-3-carbonitrile XXIX. To a suspension of
10 mmol of benzo[b]pyran XXVIa in 20 ml of abso-
lute ethanol, we successively added with stirring
a solution of 10 mmol of Na in 10 ml of absolute
ethanol and then 10 mmol of benzyl chloride VIIc.
The mixture was stirred for 4 h and allowed to stand
for 24 h at room temperature. Mass spectrum, m/z
(Irel, %): 358 (4) [M]+, 278 (19) [M cyclohex-3-
6-Amino-2-thioxo-4-(cyclohex-3-enyl)pyridine-
3,5-dicarbonitrile XV. A suspension of 10 mmol of
salt XIV in 15 ml of ethanol was acidified under
stirring with 10% HCl to pH 5. The solution was fil-
tered and allowed to stand for 24 h at room temper-
ature.
6-Amino-4-benzoylmethylsulfanyl-4-(cyclohex-
3-enyl)pyridine-3,5-dicarbonitrile XVI. A mixture
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 10 2005

1544
DYACHENKO
enyl]+, 277 (100), 187 (6), 186 (5), 158 (5), 92 (6), 91
(92) [PhCH2]+, 65 (7).
17. Kaigorodova, E.A., Vasilin, V.K., and Krapivin, G.D.,
Available from VINITI, Moscow, 2001, no. 1901-V;
Ref. Zh. Khim., 2002, 02.04-19Zh213Dep.
REFERENCES
18. Issac, Y.A., Ali, M.S., and Erian, A.W., Sci. Pharm.,
2000, vol. 68, no. 4, p. 389.
1. Tietze, L.F., Chem. Rev., 1996, vol. 96, no. 1, p. 115.
2. Litvinov, V.P., Usp. Khim., 2003, vol. 72, no. 1, p. 75.
19. El-Abadehan, M.M., Sabri, S.S., Al-Ashqar, A.,
Mion, P., Bompart, J., and Calas, M., Phosphorus,
Sulfur, Silicon, Relat. Elem., 1998, vols. 134 135,
no. 1, p. 21.
3. Dyachenko, V.D., Doctoral (Chem.) Dissertation,
Moscow, 1998.
4. Gorobets, E.V., Miftakhov, M.S., and Valeev, F.A.,
20. Attia, A., Abo-Ghalia, M.H., and El-Salem, O.I.A.,
Usp. Khim., 2000, vol. 69, no. 12, p. 1091.
Pharmazie, 1995, vol. 50, no. 7, p. 455.
5. Ugi, I., Abstracts of Papers, III Vserossiiskii simpo-
zium po organicheskoi khimii Strategiya i taktika
organicheskogo sinteza (III Russian Symp. Strategy
and Tactics of Organic Synthesis ), Yaroslavl, 2001,
p. 2.
21. Hussein, A.M., Abu-Shanal, F.A., and Ishak, E.A.,
Phosphorus, Sulfur, Silicon, Relat. Elem., 2000,
vol. 159, no. 1, p. 55.
22. Mohareb, R.M., Hoda, H.Z., Elkhoyly, Y.M., and
Rasha, R.A., Phosphorus, Sulfur, Silicon, Relat. Elem.,
1999, vol. 155, no. 1, p. 215.
6. Smith, W.A., Bochkov, A.F., and Caple, R., Organic
Synthesis: The Science behind the Art, London: Roy.
Soc. Chem., 1998.
23. US Patent 6329388, 2000, Ref. Zh. Khim., 2002,
02.20-19O73P.
7. Dyachenko, V.D., in Novye dostizheniya v khimii
karbonil’nykh soedinenii: Sbornik nauchnykh trudov
(New Achievements in Chemistry of Carbonyl Com-
pounds: Coll. of Scientific Papers), Saratov, 2000,
p. 60.
24. US Patent 5656638, 1997, Chem. Abstr., 1997,
vol. 127, no. 16, 220647x.
25. GDR Patent 275688, 1990, Ref. Zh. Khim., 1990,
22O60P.
8. Dyachenko, A.D., Desenko, S.M., and Dyachen-
ko, V.D., Khim. Geterotsikl. Soedin., 2002, no. 6,
p. 845.
26. Sharanin, Yu.A., Shestopalov, A.M., Nesterov, V.N.,
Melenchuk, S.N., Promonenkov, V.K., Shklover, V.E.,
Struchkov, Yu.T., and Litvinov, V.P., Zh. Org. Khim.,
1989, vol. 25, no. 6, p. 1323.
9. Dyachenko, V.D., Nesterov, V.N., Krivokolysko, S.G.,
and Litvinov, V.P., Izv. Ross. Akad. Nauk, Ser. Khim.,
1997, no. 1, p. 196.
27. Dyachenko, V.D., Krivokolysko, S.G., Sharanin, Yu.A.,
and Litvinov, V.P., Zh. Org. Khim., 1997, vol. 33,
no. 7, p. 1084.
10. Dyachenko, V.D., Krivokolysko, S.G., and Litvi-
nov, V.P., Khim. Geterotsikl. Soedin., 1998, no. 1,
p. 81.
28. Dyachenko, V.D. and Litvinov, V.P., Khim. Getero-
tsikl. Soedin., 1997, no. 7, p. 995.
11. Dyachenko, V.D., Nesterov, V.N., Krivokolysko, S.G.,
and Litvinov, V.P., Khim. Geterotsikl. Soedin., 1997,
no. 6, p. 785.
29. Dyachenko, V.D. and Litvinov, V.P., Zh. Org. Khim.,
1998, vol. 34, no. 4, p. 592.
30. Nakanishi, K., Infrared Absorption Spectroscopy,
12. Comprehensive Organic Chemistry. The Synthesis and
Reactions of Organic Compounds, Barton, D. and
Ollis, W.D., Eds., Oxford: Pergamon, 1979.
Tokyo: Nankido, 1962.
31. Sharanin, Yu.A., Shestopalov, A.M., Litvinov, V.P.,
Klokol, G.V., Mortikov, V.Yu., and Demerkov, A.S.,
Zh. Org. Khim., 1988, vol. 24, no. 4, p. 854.
13. Drabkina, A.A. and Tsizin, Yu.S., Zh. Obshch. Khim.,
1974, vol. 44, no. 2, p. 450.
32. RF Patent 2083572, 1997, Ref. Zh. Khim., 1998,
14. Stork, G. and Landesman, H.K., J. Am. Chem. Soc.,
6O50P.
1956, vol. 78, no. 19, p. 5128.
33. US Patent 5514706, 1996, Ref. Zh. Khim., 1998,
15. Litvinov, V.P., Promonenkov, V.K., Sharanin, Yu.A.,
and Shestopalov, A.M., Itogi Nauki Tekh., Ser.: Org.
Khim., 1989, vol. 17, p. 72.
13O40P.
34. Kartsev, V.G., in Izbrannye metody sinteza i modifi-
katsii geterotsiklov (Selected Methods for Synthesis
and Modification of Heterocycles), Moscow: IBS,
2003, p. 534.
16. Litvinov, V.P., Rodinovskaya, L.A., Sharanin, Yu.A.,
Schestopalov, A.M., and Senning, A., Sulfur Rep.,
1992, vol. 13, no. 1, p. 1.
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