Cyclohexanecarbaldehyde in multicomponent syntheses of functionalized cyclohexyl-substituted acrylonitriles, 4H-chalcogenopyrans, 1,4- dihydropyridines, and pyridines

Article abstract of DOI:10.1134/S1070363206020216

Multicomponent condensations of cyclohexanecarbaldehyde with CH acids, malonodinitrile, cyanothio(seleno)acetamide, ethyl cyanoacetate, ethyl acetoacetate, thiobarbituric acid, dimedone, resorcinol, and 3-aminophenol, afforded functionalized cyclohexyl-substituted acrylonitriles, 4H-pyrans, 4H-thio(seleno)-pyrans, 1-benzopyrans, 1,4-dihydropyridines, and pyridines. Pleiades Publishing, Inc., 2006.

Full text of DOI:10.1134/S1070363206020216

ISSN 1070-3632, Russian Journal of General Chemistry, 2006, Vol. 76, No. 2, pp. 282 291.
Pleiades Publishing, Inc., 2006.
Original Russian Text V.D. Dyachenko, 2006, published in Zhurnal Obshchei Khimii, 2006, Vol. 76, No. 2, pp. 299 308.
Cyclohexanecarbaldehyde in Multicomponent Syntheses
of Functionalized Cyclohexyl-Substituted Acrylonitriles,
4H-Chalcogenopyrans, 1,4-Dihydropyridines, and Pyridines
V. D. Dyachenko
Taras Shevchenko National Pedagogical University, ul. Oboronnaya 2, Lugansk, 91011 Ukraine
fax: (0642) 530008; e-mail: dvd_lug@online.lg.ua
Received January 19, 2005
Abstract Multicomponent condensations of cyclohexanecarbaldehyde with CH acids, malonodinitrile,
cyanothio(seleno)acetamide, ethyl cyanoacetate, ethyl acetoacetate, thiobarbituric acid, dimedone, resorcinol,
and 3-aminophenol, afforded functionalized cyclohexyl-substituted acrylonitriles, 4H-pyrans, 4H-thio(seleno)-
pyrans, 1-benzopyrans, 1,4-dihydropyridines, and pyridines.
DOI: 10.1134/S1070363206020216
Synthesis of complex heterocyclic compounds
from several simple initial compounds is a promising
line in the design of substances possessing required
properties [1 3]. In continuation of our studies in the
field of synthesis of alkyl-substituted pyridines and
pyrans by multicomponent condensations [4 8], here
we report on the reactions of cyclohexanecarbalde-
hyde (I) with CH acids, 2-cyano(thioacetamide) (II),
2-cyano(selenoacetamide) (III), malonodinitrile (IV),
ethyl cyanoacetate (V), ethyl acetoacetate (VIa), ethyl
benzoylacetate (VIb), thiobarbituric acid (VII),
resorcinol (VIIIa), 3-aminophenol (VIIIb), aceto-
acetamide (IXa), acetoacetanilide (IXb), and di-
medone (X).
and DMSO-d6 exists as prototropic tautomer XIVB.
In the H NMR spectrum of this compound, signal
1
from the pyridine 1-H proton appeared as a broadened
singlet at 12.78 ppm, which is typical of such sys-
tems [9]. In addition, pyridine-2-thione XIVB showed
1
in the IR spectrum an absorption band at 1197 cm
due to stretching vibrations of the C=S group [10].
Salt XI was subjected to alkylation with alkyl
halides XV in dimethylformamide (DMF). The reac-
tion occurred regioselectively at the sulfur atom to
give the corresponding sulfides XVI (Scheme 1, a),
indicating negative charge localization in molecule XI
on the sulfur atom. Pyridine-2-thione XIV also readily
reacted with alkylating agents XV in alkaline medium
to afford sulfides XVI (Scheme 1, b), and cyano-
ethylation of XIV with acrylonitrile (XVII) gave
substituted 2-cyanoethylsulfanylpyridine XVIII.
Cyclohexanecarbaldehyde (I) reacted with cyano-
(thioacetamide) (II) in ethanol at 20 C in the presence
of morpholine to give morpholinium 6-amino-3,5-di-
cyano-4-cyclohexylpyridine-2-thiolate (XI) (Scheme 1,
a). Presumably, the initial reaction stage is Knoevena-
gel condensation leading to 2-cyano-2-cyclohexyli-
dene(thioacetamide) (XII) which takes up the second
cyano(thioacetamide) molecule according to Michael.
Adduct XIII thus formed undergoes regioselective
intramolecular ring closure to produce salt XI. The
maximal yield of XI was obtained when the initial
reactants were taken at a I:II ratio of 1:2, in keeping
with the proposed scheme.
Three-component condensation of cyclohexanecar-
baldehyde (I) with CH acid II and -halo ketones
XIXa and XIXb led to formation of the Hantzsch
reaction products, thiazolyl-substituted acrylonitriles
XXa and XXb, which attract interest as potential bio-
logically active compounds [11 14]. By analogous
condensation with enamine XXI instead of -halo
ketone XIX we obtained morpholinium 3-cyano-4-
cyclohexyl-5,6-pentamethylenepyridine-2-thiolate
(XXII) (Scheme 2). It is likely to be formed via Stork
alkylation [15] of enamine XXI with alkene XII to
give adduct XXIII which undergoes intramolecular
transamination and dehydrogenation (presumably on
exposure to atmospheric oxygen).
The structure of salt XI was confirmed by its
physical properties, spectral data (Tables 1, 2) and
chemical transformations. Treatment of a suspension
of XI in alcohol with 10% hydrochloric acid gave the
corresponding sulfanyl derivative XIVA which, ac-
cording to the spectral data (Table 2), in chloroform
Multicomponent condensation involving cyclo-
hexanecarbaldehyde (I), cyano(thioacetamide) (II),
282

CYCLOHEXANECARBALDEHYDE IN MULTICOMPONENT SYNTHESES
283
Scheme 1.
CN
S
II
B
NC
CN
S
CN
S
+
H2O
H2N
H2N
S
H2N
XII
II
H2N
CHO
I
XIII
R
Br
a
H2S,
2[H]
O
XIXa, XIXb
H2O,
HBr
CN
H+
CN
NC
NC
CN
S BH+
N
S
H2N
H2N
SH
N
N
R
XXa, XXb
XIVA
XI
Z
Hlg
a
XVa XVd
CN
NC
CN
S
NC
CN
S
NC
XVa XVd/KOH
XVII
CN
b
CN
H2N
H2N
H2N
N
N
N
S
Z
XVIII
XIVB
XVIa XVId
B = morpholine; XV, XVI, Hlg = Cl, Z = CONH2 (a); Hlg = Cl, Z = Ph (b); Hlg = Br, Z = 4-MeOC6H4CO (c); Hlg = Cl,
Z = CN (d); XIX, XX, R = 4-BrC6H4 (a), 6,8-dibromo-2-oxochromen-3-yl (b).
ethyl benzoylacetate (VIa), and 2-chloroacetamide
(XVa) resulted in formation of substituted 1,4-di-
hydropyridine XXIV. The reaction was carried out at
20 C in ethanol in the presence of an equimolar
amount of morpholine. It is reasonable to presume
that initially formed alkene XII takes up CH acid VIa
according to Michael; the Michael adduct undergoes
chemoselective intramolecular ring closure to substi-
tuted 1,4-dihydropyridine XXVI, and alkylation of
the latter with 2-chloroacetamide (XVa) yields sulfide
XXIV. When 1,4-dibromobutane (XXVII) was used
as alkylating agent in the same condensation, the
product was substituted 1,4-bis(1,4-dihydropyridin-2-
ylsulfanyl)butane XXVIII. It should be noted that
4-alkyl-1,4-dihydropyridines, as well as their de-
hydrogenated derivatives, are promising from the
viewpoint of design of agents for the treatment of
cardiovascular diseases [16 18] and antitumor [19],
antibacterial, and antifungal agents [20].
Cyclohexanecarbaldehyde (I) readily reacts with
malonodinitrile (IV) and cyano(thioacetamide) (II) in
ethanol at 20 C in the presence of morpholine. Pre-
sumably, in the first step cyclohexylidenemalonodi-
nitrile (XXIX) is formed, and it then acts as Michael
acceptor. Addition of CH acid (Michael donor) to
XXIX gives intermediate XXX, which undergoes
intramolecular ring closure to 2-iminothiopyran XXXI,
and the latter is stabilized as 2,6-diamino-3,5-dicyano-
4-cyclohexyl-4H-thiopyran (XXXIIa). Compound
XXXIIa is stable at room temperature, and it was
isolated and characterized (Table 1, 2). Heating of a
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284
DYACHENKO
Scheme 2.
N
O
CN
S
H, B
H2O
XXI
[XII]
I
N
O
H2N
O
O
OEt
R
XXIII
VIa, VIb
2[H]
O
R
O
CN
S BH+
CN
EtO
CN
S
EtO
H2O
N
S BH+
O
H2N
R
N
H
XXVI
XXV
XXII
XVa
Br
Br
XXVII
O
O
O
NC
S
CN
CN
OEt
EtO
EtO
Ph
NH2
N
H
Ph
N
Ph
N
H
S
S
O
H
XXIV
XXVIII
B = morpholine; VI, R = Me (a), Ph (b).
solution of XXXIIa in ethanol in the presence of
morpholine resulted in recyclization to salt XI
(Scheme 3, b), which is typical of such compounds
[21 23]. The condensation of I with malonodinitrile
(IV) and cyano(selenoacetamide) (III) followed the
same pattern, and the product was 2,6-diamino-3,5-
dicyano-4-cyclohexyl-4H-selenopyran (XXXIIb)
(Scheme 3).
above-described reactions. Presumably, the salt-like
Michael adduct was isolated due to its low solubility.
Moreover, possible delocalization of the negative
charge over the pyrimidine fragment of molecule
XXXIII does not favor further transformations, in
particular pyran ring closure. On the other hand,
replacement of thiobarbituric acid (VII) by CH acid
VI, VIII, or IX ensures facile formation of the cor-
responding substituted 4H-pyrans XXXIV XXXVI
which are potential agents for the treatment of cardio-
vascular [24] and CNS diseases [24, 25]. Obviously,
the reaction scheme includes intermediate formation
of adducts XXXVII XXXIX.
When thiobarbituric acid (VII) was used as CH
acid component in the condensation of cyclohexane-
carbaldehyde (I) with malonodinitrile (IV) in the
presence of morpholine (ethanol, 20 C), salt XXXIII
was isolated (Scheme 3). This result supports the
formation of alkene XXIX as intermediate in the
It should be noted that 4-aryl-substituted analogs
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CYCLOHEXANECARBALDEHYDE IN MULTICOMPONENT SYNTHESES
285
Table 1. Yields, melting points, and elemental analyses of cyclohexyl-substituted pyridines XI, XIV, XVI, XVIII, and
XXII, acrylonitriles XX, 1,4-dihydropyridines XXIV and XXVIII, and 4H-chalcogenopyrans XXXII, XXXIV XXXVI,
and XL
Found, %
H
Calculated, %
Comp.
no.
Yield, %,
method A/B
mp, C (solvent)
Formula
C
N
C
H
N
XI
XIVB
XVIa
XVIb
XVIc
XVId
XVIII
XXa
XXb
84/74
80
190 192a
58.92
60.32
56.95
68.79
64.87
60.42
6.64
5.29
5.32
5.61
5.33
4.91
5.39
4.47
2.89
8.14
6.27
7.48
6.06
5.02
6.27
6.69
6.62
6.92
7.19
6.72
6.67
8.32
20.05 C17H23N5OS
21.50 C13H14N4S
22.04 C15H17N5OS
15.93 C20H20N4S
17.61 C22H22N4O2S
23.47 C15H15N5S
22.31 C16H17N5S
7.42 C18H17BrN2S
59.11 6.71
60.44 5.46
57.12 5.43
68.94 5.79
65.00 5.46
60.58 5.08
61.71 5.50
57.91 4.59
20.27
21.69
22.21
16.08
13.78
23.55
22.49
7.50
248 250 (EtOH)
173 175 (BuOH)
199 200 (AcOH)
210 212 (AcOH)
136 137b (EtOH)
66/72
88/73
74/69
75/77
89
70
72
80
67
77
86
78
71
88
81
86
79
176 179b (MeOH) 61.67
114 115 (EtOH)
199 200 (DMF)
208 212a
57.78
48.33
67.38
64.81
64.72
59.60
50.77
55.13
71.42
70.95
71.18
64.21
74.42
70.98
68.97
5.21 C21H16Br2N2O2S 48.48 3.10
5.39
11.25
9.87
XXII
XXIV
11.07 C21H31N3OS
9.76 C23H27N3O3S
8.33 C36H50N4O4S2
21.68 C13H16N4S
18.08 C13H16N4Se
17.74 C18H25N5O3S
7.81 C21H24N2O3
10.18 C16H18N2O2
15.44 C16H19N3O
15.88 C14H19N3O2
8.58 C20H22N2O2
12.31 C20H23N3O2
3.89 C20H29NO4
67.52 8.37
64.92 6.40
64.83 7.56
59.97 6.19
50.82 5.25
55.22 6.44
71.57 6.86
71.09 6.71
71.35 7.11
64.35 7.33
74.51 6.88
71.19 6.87
69.14 8.41
162 163 (BuOH)
218 220 (BuOH)
215 217 (EtOH)
176 178 (EtOH)
214 216 (EtOH)
164 165 (EtOH)
276 277c (PrOH)
250 252c (EtOH)
217 218 (EtOH)
189 191 (EtOH)
188 190 (EtOH)
105 106 (EtOH)
XXVIII
XXXIIa
XXXIIb
XXXIII
XXXIV
XXXVa
XXXVb
XXXVIa
XXXVIb
XXXVIc
XL
8.40
21.52
18.23
17.89
7.95
10.36
15.60
16.08
8.69
71
74
88
12.45
4.03
a
b
c
The substance was not recrystallized.
1
Fluoresces under UV irradiation.
Sublimes at 200 C.
Table 2. IR and H NMR spectra of cyclohexyl-substituted pyridines XI, XIV, XVI, XVIII, and XXII, acrylonitriles XX,
1,4-dihydropyridines XXIV and XXVIII, and 4H-chalcogenopyrans XXXII, XXXIV XXXVI, and XL
1
IR spectrum, cm
1H NMR spectrum, , ppm (J, Hz)
1-H, cyclo-
hexane, m,
and NH2,
br.s
Comp.
no.
(C N),
(C=O),
(NH2)
(NH2)
other protons
XIa
2210, 1648
3202, 3305, 2.81, 7.29
3412
1.25 m (4H, 2CH2), 1.72 m (2H, CH2), 1.84 m (2H, CH2),
2.06 m (2H, CH2), 3.12 t (4H, CH2NCH2, J 4.35), 3.79 t (4H,
CH2OCH2)
XIVB
2220 sh,
1638,
3210, 3308, 2.99, 7.82
3440
1.27 m (4H, 2CH2), 1.77 2.18 m (6H, 3CH2), 12.78 br.s (1H, N1H)
1197 [ (C=S)]
XVIa
XVIb
XVIc
2222 sh, 1640 3195, 3314, 2.95, 7.86
1.15 1.48 m (4H, 2CH2), 1.64 2.17 m (6H, 3CH2), 3.82 s (2H,
SCH2), 7.16 br.s and 7.41 br.s (1H each, CONH2)
1.22 1.57 m (4H, 2CH2), 1.62 2.18 m (6H, 3CH2), 4.40 s (2H,
SCH2), 7.14 7.45 m (5H, Ph)
1.24 1.45 m (3H, CH, cyclohexane), 1.68 m (3H, CH, cyclo-
hexane), 1.79 m (2H, CH2), 2.07 m (2H, CH2), 3.88 s (3H, Me),
4.86 s (2H, SCH2), 7.05 d and 8.02 d (2H each, C6H4, J 8.82)
1.29 1.48 m (3H, CH, cyclohexane), 1.68 2.12 m (7H, CH,
cyclohexane), 4.23 s (2H, SCH2)
3439
2218 sh, 1645 3203, 3300, 2.91, 7.61
3411
2223 sh,
1715, 1645
3211, 3305, 2.94, 7.58
3422
XVId
2248,
3187, 3302, 2.97, 7.90
2225 sh, 1649 3449
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DYACHENKO
Table 2. (Contd.)
1
IR spectrum, cm
1H NMR spectrum, , ppm (J, Hz)
1-H, cyclo-
hexane, m,
and NH2,
br.s
Comp.
no.
(C N),
(C=O),
(NH2)
(NH2)
other protons
XVIII
2249,
3177, 3245, 2.80, 7.81 1.32 m (3H, CH, cyclohexane), 1.61 1.80 m (3H, CH, cyclo-
2212 sh, 1638 3361
hexane), 1.85 2.17 m (4H, CH, cyclohexane), 2.91 t (2H, SCH2,
J 6.94), 3.35 t (2H, CH2CN)
XXa
XXb
2214
2.62
2.73
2.81
1.15 1.43 m (6H, 3CH2), 1.62 1.87 m (4H, 2CH2), 7.40 d (1H,
3-H, J 8.89), 7.63 d and 7.92 d (2H each, C6H4, J 8.48), 8.29 s
(1H, 5-H, coumarin)
1.21 1.48 m (6H, 3CH2), 1.72 1.98 m (4H, 2CH2), 7.41 d (1H,
3-H, J 9.99), 7.98 s (1H, 5-H, thiazole), 8.14 s (1H, 7-H, thiazole),
8.48 s (1H, 5-H, coumarin), 8.75 s (1H, 4-H, thiazole)
1.11 1.34 m (8H, 4CH2), 1.52 2.23 m (12H, 6CH2), 3.09 t (4H,
CH2NCH2, J 4.39), 3.75 t (4H, CH2OCH2)
2215, 1732
2206
XXIIa
XXIV
2190, 1710
3360
3300
1.77, 7.52, 0.77 t (3H, Me, J 6.15), 0.92 1.21 m (4H, 2CH2), 1.63 1.70 m
7.86
(6H, 3CH2), 3.52 3.99 m (5H, 4-H, pyridine; OCH2 and SCH2),
7.39 s (5H, Ph), 10.61 br.s (1H, N1H)
XXVIII 2192, 1708
1.95
0.81 1.02 m (12H, 6CH2), 1.29 t (6H, 2Me, J 6.14), 1.49 1.78 m
(12H, 6CH2), 2.25 s (6H, 2Me), 2.84 m (2H, SCH2), 3.09 m (2H,
SCH2), 3.38 d (2H, 24-H, pyridine, J 6.15), 4.11 m (4H, 2OCH2),
9.22 br.s (2H, 2NH)
XXXIIa 2190, 2200, 3300, 3390, 1.80, 6.80 0.92 1.24 m (4H, 2CH2), 1.62 1.72 m (6H, 3CH2), 2.71 d (1H, 4-H,
1640 3450 J 6.98)
XXXIIb 2195, 2202, 3214, 3385, 1.84, 6.86 0.88 1.13 m (4H, 2CH2), 1.60 1.75 m (6H, 3CH2), 2.68 d (1H,
1643
3436
4-H, J 6.88)
XXXIII 2248
3311
1.90
0.84 1.22 m (4H, 2CH2), 1.62 1.84 m (6H, 3CH2), 3.10 t (4H,
CH2NCH2, J 4.40), 3.25 m (1H, 1-H), 3.76 t (4H, CH2OCH2,
J 4.40), 5.45 d (1H, 2-H, J 8.92), 8.70 br.s (2H, NH2), 10.58 br.s
+
(2H, 2NH)
XXXIV
2195, 1702, 3214, 3330, 1.83, 6.67 0.91 t (3H, Me, J 6.19), 1.15 1.42 m (4H, 2CH2), 1.52 1.73 m
1643
3404
(6H, 3CH2), 3.19 d (1H, 4-H, J 8.14), 3.96 q (2H, OCH2), 7.42 s
(5H, Ph)
XXXVa 2180, 1647
XXXVb 2188, 1645
3182, 3319, 1.77, 6.65 0.84 1.26 m (4H, 2CH2), 1.40 m (2H, CH2), 1.52 1.63 m (4H,
3495
2CH2), 3.28 d (1H, 4-H, J 8.93), 6.35 s (1H, 8-H), 6.51 d (1H, 5-H,
J 7.94), 6.96 d (1H, 6-H), 9.48 br.s (1H, OH)
3210, 3314, 1.79, 4.85, 0.89 1.28 m (4H, 2CH2), 1.40 m (2H, CH2), 1.55 1.69 m (4H,
3428
6.39
2CH2), 3.12 d (1H, 4-H, J 7.24), 6.19 s (1H, 8-H), 6.28 d (1H, 5-H,
J 7.95), 6.72 d (1H, 6-H)
XXXVIa 2186, 1694, 3175, 3248, 1.90, 6.24 0.92 1.14 m (4H, 2CH2), 1.43 1.67 m (6H, 3CH2), 2.00 s (3H, Me)
1653 3366 3.44 d (1H, 4-H, J 6.98), 6.87 br.s and 7.32 br.s (1H each, CONH2)
XXXVIb 2175, 1699, 3192, 3387, 1.71, 6.92 0.98 1.22 m (4H, 2CH2), 1.37 1.65 m (6H, 3CH2), 1.78 s (3H,
1645 3465 Me), 3.17 d (1H, 4-H, J 6.95), 7.49 s (5H, Ph)
XXXVIc 2178, 1722, 3210, 3307, 2.68, 5.49 1.02 1.48 m (6H, 3CH2), 1.80 m (4H, 2CH2), 2.29 s (3H, Me),
1670
3444
3.75 d (1H, 4-H, J 5.42), 7.14 d (2H, Ph, J 7.02), 7.48 m (3H, Ph),
13.61 br.s (1H, NH)
XL
1702, 1688, 3211, 3297, 1.65, 7.31 0.78 m (1H, CH, cyclohexane), 0.98 1.14 m (6H, 3CH2), 1.07 s
1635
3406
(3H, Me), 1.09 s (3H, Me), 1.25 t (3H, Me, J 6.47), 1.44 d (1H,
CH, cyclohexane, J 8.01), 1.56 t (2H, CH2, J 13.61), 2.17 d and
2.22 d (1H each, C8H2, 2J 16.01), 2.38 d and 2.44 d (1H each,
2
C6H2, J 17.62), 3.49 d (1H, 4-H, J 4.00), 4.06 q (2H, OCH2)
a
+
Signals of the NH protons were not observed, presumably due to fast H D exchange.
2
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CYCLOHEXANECARBALDEHYDE IN MULTICOMPONENT SYNTHESES
287
Scheme 3.
NC
CN
NC
CN
NH
I
C
N
H2N
S
H2N
X
XXX
XXXI
CN
CN
Se
H2O
CN, B
IV
H2N
II
III
O
N
HN
S
O
O
N
H
CN
CN
NC
CN
, B
VII
HN
S
CN
XI
b
BH+
O
NH2
XXIIa, XXIIb
X
H2N
CN
XXXIII
XXIX
O
O
VIb
R
Me
OH
VIIIa, VIIIb
R
IXa IXc
O
O
CN
CN
CN
R
EtO
C
C
N
C
N
R
OH
OH
Ph
Me
OH
N
XXXVII
XXXVIII
XXXIX
O
O
CN
CN
CN
R
EtO
NH2
NH2
O
Ph
NH2
R
O
Me
O
XXXIV
XXXVa, XXXVb
XXXVIa XXXVIc
B = morpholine; VIII, XXXV, R = OH (a), NH2 (b); IX, XXXVI, R = NH2 (a), Ph (b), NHPh (c); XXXII, X = S (a), Se (b).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 2 2006

288
DYACHENKO
of 1-benzopyrans XXXV were synthesized previously
by reaction of arylmethylidenemalonodinitrile with
phenol derivatives [26 28], as well as by three-com-
ponent condensation of aromatic aldehydes with
malonodinitrile or ethyl cyanoacetate and phenol
derivatives [29].
Under analogous conditions, the condensation of
cyclohexanecarbaldehyde (I) with ethyl cyanoacetate
(V) or dimedone (X) as CH acid led to formation of
substituted 4H-pyran XL (Scheme 4). Intermediate
ethyl 2-cyano-3-cyclohexylprop-2-enoate (XLI) could
not be isolated, for it undergoes fast further trans-
formations, primarily dimerization [30].
Scheme 4.
O
COOEt
CN
O
O
NH
O
X
V,
I
COOEt
NH2
H2O
COOEt
CN
XLI
O
XL
The structure of chalcogenopyrans XXXII,
XXXIV XXXVI, and XL is confirmed by their
physical properties and spectral parameters (Tables 1,
2; see Experimental). Their IR spectra characteristical-
ly contain absorption bands due to stretching and
bending vibrations of the amino group and stretching
vibrations of the conjugated cyano group (Table 2). In
DRX-500 instruments (500.13 MHz; XVIc, XVIII,
XXXVIc, XL) from solutions in DMSO-d6 using
tetramethylsilane as internal reference. The mass spec-
tra (70 eV) were run on a Kratos MS-890 mass spec-
trometer with direct sample inlet into the ion
source. The melting points were determined on a
Kofler melting point apparatus. The progress of re-
actions was monitored by TLC on Silufol UV-254
plates using acetone hexane (3:5) as eluent; de-
velopment with iodine vapor.
1
the H NMR spectra of 4-cyclohexyl-substituted 4H-
chalcogenopyrans, apart from signals from protons in
the substituents (Table 2), a signal from the pyran 4-H
proton appeared as a doublet at 3.15 3.50 ppm.
Morpholinium 6-amino-3,5-dicyano-4-cyclo-
hexylpyridine-2-thiolate (XI). a. Morpholine,
0.87 ml, was added to a mixture of 1.21 ml of cyclo-
hexanecarbaldehyde (I) and 2.0 g of cyano(thioacet-
amide) (II) in 15 ml of ethanol at 20 C. The mixture
was stirred for 30 min and was left to stand for 24 h at
room temperature. The precipitate was filtered off and
washed with acetone (Tables 1, 2).
To conclude, it should be emphasized that multi-
component Knoevenagel condensation involving
cyclohexanecarbaldehyde and various CH acids is a
convenient route to functionalized cyclohexyl-sub-
stituted acrylonitriles, 4H-chalcogenopyrans, 1,4-di-
hydropyridines, and pyridines.
EXPERIMENTAL
b. A mixture of 2.6 g of thiopyran XXXIIa and
0.87 ml of morpholine in 15 ml of anhydrous ethanol
was heated for 2 h under reflux and was then left to
stand for 24 h at room temperature. The precipitate
was filtered off and washed with acetone. The product
was identical to a sample prepared as described in a
in the melting point and IR spectrum (Tables 1, 2).
Mass spectrum, m/z (Irel, %): 259 (21) [Manion + 1]+,
258 (72) [Manion]+, 257 (64) [Manion 1]+, 230 (15),
229 (27), 217 (42), 204 (41), 203 (100), 190 (26), 178
(34), 165 (18), 143 (22), 87 (39) [Mcation]+, 80 (10),
77 (12), 67 (19).
The IR spectra were recorded on an IKS-29 spec-
trometer from samples dispersed in mineral oil (for
compound XVIb, from a solution in chloroform). The
1H NMR spectra were measured on Bruker WP-
100SY (100 MHz; XXII, XXIV, XXXIIa, XXXIIa,
XXXIII, XXXVb), Gemini-200 (199.975 MHz;
XIVB, XVIb, XXb), Bruker WM-250 (250.13 MHz;
XXXIV, XXXVa, XXXVb, XXXVIa), Bruker AM-
300 (300.13 MHz; XI, XVIa, XVId, XXVIII),
Varian Mercury-400 (400.397 MHz; XXa), and Bruker
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CYCLOHEXANECARBALDEHYDE IN MULTICOMPONENT SYNTHESES
289
6-Amino-4-cyclohexyl-2-thioxo-1,2-dihydro-
pyridine-3,5-dicarbonitrile (XIVB). Salt XI, 3.5 g,
was dispersed in 20 ml of ethanol, 10% hydrochloric
acid was added to pH 5 at 20 C, and the mixture was
stirred for 10 min, filtered, and left to stand for 48 h.
The precipitate was filtered off and washed with
water, ethanol, and hexane (Tables 1, 2). Mass spec-
trum, m/z (Irel, %): 260 (8) [M + 2]+, 261 (19) [M + 1]+,
258 (100) [M]+, 257 (76) [M 1]+, 240 (7), 230 (25),
217 (26), 203 (74), 178 (24), 158 (10), 142 (9), 116
(11), 89 (7), 77 (6), 55 (8), 41 (33).
10 ml of DMF. The mixture was stirred for 4 h, kept
for 24 h at room temperature, and diluted with an
equal volume of water. The precipitate was filtered
off and washed with water, ethanol, and hexane
(Tables 1, 2).
3-Cyclohexyl-2-[4-(6,8-dibromo-2-oxochromen-
3-yl)thiazol-2-yl]acrylonitrile (XXb) was synthesized
as described above for compound XXa using -halo
ketone XIXb (Tables 1, 2). Mass spectrum, m/z (Irel,
%): 523 (13) [M + 3]+ 522 (54) [M + 2]+, 521 (29)
[M + 1]+, 520 (100) [M]+, 519 (22) [M 1]+, 518 (50)
[M 2]+, 439 (48), 401 (20), 332 (41), 330 (32), 225
(48), 223 (52), 144 (65), 100 (20), 93 (28), 81 (30),
77 (20), 74 (13), 67 (67), 63 (11).
2-R-Methylsulfanyl-6-amino-4-cyclohexylpyri-
dine-3,5-dicarbonitriles XVIa XVId (general pro-
cedure). a. Salt XI, 10 mmol, was dissolved in 15 ml
of DMF, 10 mmol of the corresponding alkyl halide
XV was added, the mixture was stirred for 2 h and
diluted with an equal volume of water, and the pre-
cipitate was filtered off and washed with water, eth-
anol, and hexane (Tables 1, 2).
Morpholinium 3-cyano-4-cyclohexyl-5,6-penta-
methylenepyridine-2-thiolate (XXII). One drop of
morpholine was added to a mixture of 1.21 ml of
aldehyde I and 1.0 g of cyano(thioacetamide) (II) in
15 ml of anhydrous ethanol, and the mixture was
stirred for 10 min. Enamine XXI, 1.81 g, was then
added, and the mixture was stirred for 30 min and was
kept for 24 h at room temperature. The precipitate was
filtered off and washed with anhydrous ethanol and
hexane (Tables 1, 2).
b. Pyridinethione XIVB, 2.6 g, was dissolved in
10 ml of DMF, and 5.6 ml of 10% aqueous potassium
hydroxide and 10 mmol of alkyl halide were added in
succession. The mixture was stirred for 30 min and
diluted with an equal volume of water. The precipitate
was filtered off and washed with water, ethanol, and
hexane. Compounds XVIa XVId thus isolated were
identical to those prepared as described in a in the
melting points, IR spectra, and chromatographic data.
Mass spectrum, m/z (Irel, %): XVIa: 315 (5) [M]+, 272
(13), 271 (100), 270 (27), 269 (6), 265 (11), 258 (6),
257 (13), 243 (6), 216 (5), 215 (8); XVIb: 350 (4)
[M + 2]+, 349 (10) [M + 1]+, 348 (39) [M]+, 347 (13)
[M 1]+, 315 (32), 305 (12), 257 (21), 91 (100), 65
(14), 41 (9); XVId: 299 (4) [M + 2]+, 298 (11) [M +
1]+, 297 (58) [M]+, 296 (11) [M 1]+, 270 (17), 268
(19), 264 (44), 258 (17), 257 (100), 255 (15), 254 (27),
240 (19), 230 (27), 215 (17), 188 (10), 143 (21), 130
(16), 115 (17), 102 (11), 85 (13), 77 (14), 67 (21),
60 (9).
Ethyl 2-carbamoylmethylsulfanyl-3-cyano-4-
cyclohexyl-6-phenyl-1,4-dihydropyridine-5-carb-
oxylate (XXIV). Morpholine, 0.87 ml, was added to
a mixture of 1.21 ml of aldehyde I and 1.0 g of cyano-
(thioacetamide) (II) in 15 ml of ethanol, the mixture
was stirred for 5 min, 1.73 ml of ethyl benzoylacetate
(VIb) was added, and the mixture was kept for 24 h
at room temperature. 2-Chloroacetamide (XVa),
0.94 g, was added, the mixture was stirred for 2 h, left
to stand for 48 h, and diluted with an equal volume
of water, and the precipitate was filtered off and
washed with water, ethanol, and hexane (Tables 1, 2).
1,4-Bis(3-cyano-4-cyclohexyl-5-ethoxycarbonyl-
6-methyl-1,4-dihydropyridin-2-ylsulfanyl)butane
(XXVIII) was synthesized as described above for
compound XXIV using CH acid VIa and 0.59 ml of
1,4-dibromobutane (XXVII) (Tables 1, 2).
6-Amino-2-cyanoethylsulfanyl-4-cyclohexylpyri-
dine-3,5-dicarbonitrile (XVIII). A mixture of 2.6 g
of pyridinethione XIVB and 0.66 ml of acrylonitrile
(XVII) in 20 ml of methanol was heated for 2 h under
reflux, filtered while hot, and left to stand for 48 h.
The precipitate was filtered off and washed with
methanol and hexane (Tables 1, 2). Mass spectrum,
m/z (Irel, %): 313 (4) [M + 2]+, 312 (6) [M + 1]+, 311
(28) [M]+, 271 (100), 257 (27), 229 (8), 203 (12), 171
(9), 143 (7), 115 (9), 54 (8), 41 (9).
2,6-Diamino-4-cyclohexyl-4H-thiopyran-3,5-di-
carbonitrile (XXXIIa). One drop of morpholine was
added to a solution of 1.21 ml of cyclohexanecarbal-
dehyde (I) and 0.66 g of malonodinitrile (IV) in 15 ml
of ethanol under stirring at 20 C, the mixture was
stirred for 5 min, and 1.0 g of cyano(thioacetamide)
(II) was added. The mixture was stirred for 30 min
and was left to stand for 24 h. The precipitate was
filtered off and washed with ethanol and hexane
(Tables 1, 2).
2-[4-(4-Bromophenyl)thiazol-2-yl]-3-cyclohexyl-
acrylonitrile (XXa). 4-Bromophenacyl bromide
(XIXa), 2.78 g, was added to a solution of 1.21 ml of
aldehyde I and 1.0 g of cyano(thioacetamide) (II) in
2,6-Diamino-4-cyclohexyl-4H-selenopyran-3,5-
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290
DYACHENKO
dicarbonitrile (XXXIIb) was synthesized as described
above for compounds XXXIIa using 1.47 g of cyano-
(selenoacetamide) (III); the reaction was carried out
in anhydrous ethanol under argon.
thesized in a similar way using 1.77 g of acetoacet-
anilide (IXc) (Tables 1, 2). Mass spectrum, m/z (Irel,
%): 337 (5) [M]+, 294 (9), 254 (23) [M C6H11]+, 213
(16), 212 (100), 195 (8), 77 (7) [Ph]+.
Morpholinium 5-(2,2-dicyano-1-cyclohexyl-
ethyl)-6-oxo-2-thioxo-1,2,3,6-tetrahydropyrimidin-
4-olate (XXXIII). Malonodinitrile (IV), 0.66 g, and
morpholine, one drop, were added under stirring at
20 C to a solution of 1.21 ml of cyclohexanecarbal-
dehyde (I) in 15 ml of anhydrous ethanol. The mix-
ture was stirred at 5 min, 1.44 g of thiobarbituric acid
(VII) and 0.87 ml of morpholine were added, and the
mixture was stirred for 3 h and was left to stand for
24 h. The precipitate was filtered off and washed with
acetone (Tables 1, 2). Mass spectrum, m/z (Irel, %):
Ethyl 2-amino-4-cyclohexyl-7,7-dimethyl-5-oxo-
5,6,7,8-tetrahydro-4H-1-benzopyran-3-carboxylate
(XL). Ethyl cyanoacetate (V), 1.06 ml, and one drop
of morpholine were added to a solution of 1.21 ml of
cyclohexanecarbaldehyde (I) in 15 ml of ethanol
under stirring at 20 C. The mixture was stirred for
10 min, 1.4 g of dimedone (X) was added, and the
mixture was stirred for 1.5 h and was kept for 3 days
at room temperature. The precipitate was filtered off
and washed with ethanol and hexane (Tables 1, 2).
304 (5) [Manion]+, 238 (22) [Manion CH2(CN)2]+, 157
(56), 144 (12), 98 (17), 87 (36) [Mcation]+, 79 (15),
66 (39) [CH2(CN)2]+, 57 (100), 41 (56).
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mixture was stirred for 5 min, 1.73 ml of ethyl
benzoylacetate (VIb) was added, and the mixture was
stirred for 30 min and was left to stand for 48 h at
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pyran-5-carboxamide (XXXVIa) was synthesized in
a similar way using 1.0 g of acetoacetamide (IXa)
(Tables 1, 2). Mass spectrum, m/z (Irel, %): 261 (6)
[M]+, 178 (100) [M
C6H11]+, 161 (35), 134 (5),
105 (6), 83 (7) [C6H11]+, 55 (12), 43 (14).
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similar way using 1.62 g of benzoylacetone (IXb)
(Tables 1, 2).
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