Synthesis of new 7-alkylmethylene derivatives of 2-(thio)oxo-2,5,6,7- tetrahydro-1H-pyridine-3-carbonitriles

Article abstract of DOI:10.1134/S1070363210100245

Alkylmethyleneamines of cyclic ketones were used for the synthesis of earlier unknown 7-alkylmethylene-2-(thio)oxo-2,5,6,7-tetrahydro-1H-pyridine-3- carbonitriles.

Full text of DOI:10.1134/S1070363210100245

ISSN 1070-3632, Russian Journal of General Chemistry, 2010, Vol. 80, No. 10, pp. 2032–2036. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © V.D. Dyachenko, E.N. Karpov, V.V. Dyakonenko, O.V. Shishkin, 2010, published in Zhurnal Obshchei Khimii, 2010, Vol. 80,
No. 10, pp. 1723–1727.
Synthesis of New 7-Alkylmethylene Derivatives
of 2-(Thio)oxo-2,5,6,7-tetrahydro-1H-pyridine-3-carbonitriles
V. D. Dyachenkoa, E. N. Karpova, V. V. Dyakonenkob, and O. V. Shishkinb
aTaras Shevchenko Lugansk National University,
ul. Oboronnaya 2, Lugansk, 91011 Ukraine
fax: (0642)530008
е-mail: dvd_lug@online.lg.ua
b Scientific-Technological Concern “Institute of Monocrystals,”
National Academy of Sciences of Ukraine, Kharkov, Ukraine
Received November 24, 2009
Abstract—Alkylmethyleneamines of cyclic ketones were used for the synthesis of earlier unknown 7-alkyl-
methylene-2-(thio)oxo-2,5,6,7-tetrahydro-1Н-pyridine-3-carbonitriles.
DOI: 10.1134/S1070363210100245
The cyclic ketone enamnes are convenient building
blocks in organic chemistry. Earlier the behavior of
these compounds have beeen studied in electrophile
addition reactions [1] and their reactions with various
reagents [2]. The analysis of published data showed
that the accessible α-alkylmethylene substituted enamines
have not been considered in these types reactions.
Moreover, although the synthesis of the cyclic ketone
alkyl-methyleneamines has been reported [2], such
promising derivatives as enamines of aliphatic al-
dehydes were not isolated in pure state promising.
Main synthetic difficulty lies in the preparation of
starting α-alkylmethyleneamines Ia–Ic. These com-
pounds are oils, which are purified by distillation
under reduced pressure. They are unstable in air and
polymerize to lose the activity. α-Alkylmethylene-
amines can be obtained by reaction of aliphatic
aldehydes
IIa–IIc with N-(cyclopent-1-enyl)mor-
pholine III (method А) or by reaction of morpholine
IV with alkylmethylenecycloketones V, which are in
turn synthesized from cycloalkanone VI and aldehydes
IIa–IIc in the presence of alkali aqueous solution
(method B). As in the case of synthesis of arylmethyl-
enecycloketone enamines [4], the use of method A
leads to increase in the target products yield. It is
probably connected with cross aldol condensations
with formation of compound V by method B.
Therefore all the alkylmethyleneamines Ia–Ic were
obtained through enamine III by method A.
The activity of α-methylene substituted enamines
was established to depend on the electronic nature of
the methylene moiety [3]. The incorporation of an
acceptor benzylidene substituent into the enamine
system decreases the reactivity of the latter in addition
reactions at the double bond. On the contrary, alkyl-
methylene substituents increase their efficiency. A
number of previously not characterized alkylme-
thylene derivatives Ia–Ic was chosen for investigation
of reactivity of this type enamines.
In the present work we use new compounds Ia–Ic
to obtain partially hydrogenated functionalized pyri-
dine-2-chalcogenones through their reaction with ac-
O
O
O
N
O
N
HN
O
R
R
O
O
IIа_IIc
IIа_IIc
IV
method B
OH_
R
method A
R
Iа_Ic
V
III
VI
R = i-Pr (a), Et (b), s-Bu (c).
2032

SYNTHESIS OF NEW 7-ALKYLMETHYLENE DERIVATIVES
2033
tivated alkenes VIIa, VIIb. Indeed, the use of α-alkyl-
methyleneamines in this reaction opens the way to
obtain earlier unknown 7-alkylmethylene-2-(thio)oxo-
2,5,6,7-tetrahydro-1Н-pyridine-3-carbonitriles, and the
latter are easily isolated single reaction product. The intro-
duction of different alkyl substituents allows varying lipo-
philicity of molecule as a whole, and a double bond in
С8-position gives additional possibility for function-
alization. Use of alkenes VII with the others aryl sub-
stituents does not lead to the target products formation.
Probably, the mechanism of formation of com-
pounds IIa–IId includes nucleophilic attack of enami-
nes Ia–Ic on the activated double bond of alkenes
VIIа and VIIb followed by intramolecular nucleo-
philic vinyl substitution in the intermediate А to form
hydropyridine ring in compound B, which is oxidized
to pyridine ring under the reaction conditions.
Cl
Cl
Cl
Cl
CN
Iа_Ic
+
CN
CN
X
CN
X
X
_2[H]
_O
H2N
NH
X
N
N
H
N
H
R
H2N
R
R
O
А
VIIа, VIIb
VIIIа_VIIId
B
X = O, R = i-Pr (a), Et (b), s-Bu (c); X = S, R = s-Bu (d).
The structure of the products was established by
means of 1Н NMR and mass spectrometry. We
performed X-ray diffraction study of compound VIIIа
to confirm the direction of the considered condensation
(Figs. 1, 2, Tables 1, 2).
1.389(2) Å and С4–С8 to 1.370(2) Å in comparison
with their average values 1.455 and 1.331 Å [5]
respectively. Similar arrangement of bond length was
earlier observed in compounds IX and X [6, 7].
According to X-ray diffraction analysis data, in the
molecule of VIIIа the bicyclic fragment is plane with
in the accuracy of 0.02 Å. In the fragment С4–С8–С7–С6
of the pyridine ring a strong delocalization of electron
density is observed. It leads to equalization of С–С
bond lengths through shortening of the bond С7–С8 to
1.405(2) Å and lengthening of the bonds С6–С7 to
CN
O
O
N
H
N
O
H
IX
X
С18
С2
Сl1
С19
С17
С16
С11
С13
С1
С8
С12
С10
С7
С3
С14
С4
С15
N1
С6
С9
С5
N2
O1
Fig. 1. Structure of compound VIIIa by X-ray diffraction data.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 10 2010

2034
DYACHENKO et al.
Fig. 2. Molecular packing of VIIIa in crystal.
The chlorophenyl substituent is appreciably turned
EXPERIMENTAL
relative to the bicycle plane [torsion angle С15–С14–
С7–С6 –50.4(2)°] due to repulsion of these fragments
as indicated by shortened intramolecular contacts
Н1А···Н19 [2.25 Å] (the sum of Van der Waals radii
2.32 Å [8]), С1···С19 3.20 Å (3.42 Å), С19···С15 3.02 Å
(3.42 Å), С9···Н15 [2.70 Å (2.87 Å)]. The isopropyl
substituent is in the sp-conformation relative to double
bond С10–С3 [torsion angle С3–С10–С11–Н11 10°] in
spite of ap-pearance of short intramolecular contact
Н10···Н1 [2.24 Å (2.32 Å)].
X-Ray diffraction analysis of compound VIIIa was
performed on a Xcalibur-3 diffractometer (MoKα irradia-
tion, ССD-detector, graphite monochromator, ω-scan-
ning, 2θmax =50°). Crystals are triclinic, the unit cell param-
eters at 21°С are as follows: a 8.992(3) Å, b 9.092(3) Å,
c 10.634(2) Å, α 81.73(3)°, β 83.60(2)°, γ 75.91(2)°,
V 831.8(4) Å3, M 324.8, Z 2, space group P1, dcalc
1.297 g cm–3, μ(MoKα) 0.235 mm–1, F(000) 340.
Intensities of 6608 reflections were measured (2883 in-
dependent, Rint 0.013).
In the crystal the VIIIа molecules form centro-
symmetrical dimers due to intramolecular hydrogen
bonds N1–H1···O1' (x, 2 – y, 1 – z) H···O 1.88 Å N–
H···O 172°. These dimers form stacks along
crystallographic direction [100] (Fig. 2) and they are
connected between themselves through intermolecular
hydrogen bond С–Н···π: С19–Н19···С9' (–1 – x, 3 – y,
1 – z) Н···С 2.89 Å, С–Н···С 115°. The formation of
hydrogen bond N–H···O leads also to the bond О1–С5
lengthening to 1.242(2) Å (average value 1.210 Å).
The structure was solved by the direct method by
means of SHELXTL program package [9]. Hydrogen
atoms position were revealed from differential
synthesis of electron density and refined in a rider-
model with Uiso = nUequiv (n = 1.5 for methyl groups
and n = 1.2 for the remainder of hydrogen atoms) for
non-hydrogen atom connected with this hydrogen
atom. Hydrogen atom participating in the formation of
hydrogen bond N–H···O was refined in the isotropic
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 10 2010

SYNTHESIS OF NEW 7-ALKYLMETHYLENE DERIVATIVES
Table 1. Bond lengths (d, Å) for structure VIIIa
2035
Table 2. Bond angles (ω, deg) for structure VIIIa
Angle
C4N1C5
C8C1C2
C3C2C1
C10C3C4
C10C3C2
C4C3C2
N1C4C8
N1C4C3
C8C4C3
O1C5N1
O1C5C6
N1C5C6
C7C6C9
C7C6C5
C9C6C5
C6C7C8
C6C7C14
C8C7C14
ω
Angle
C4C8C7
C4C8C1
C7C8C1
N2C9C6
ω
Bond
Cl1–C17
d
Bond
C6–C9
d
122.8(2)
105.0(2)
106.7(2)
126.2(2)
127.8(2)
105.9(2)
121.6(2)
125.6(3)
112.8(2)
120.7(2)
123.5(3)
115.7(3)
123.2(3)
122.3(2)
114.4(2)
117.6(3)
121.2(2)
121.2(2)
119.8(2)
109.6(2)
130.5(2)
177.8(2)
126.9(2)
111.3(3)
109.3(2)
111.2(2)
118.8(3)
122.1(2)
119.1(2)
120.2(2)
119.5(2)
121.5(2)
119.2(2)
119.3(3)
118.9(2)
121.1(2)
1.741(2)
1.428(2)
O1–C5
N1–C4
N1–C5
N2–C9
C1–C8
C1–C2
C2–C3
C3–C10
C3–C4
C4–C8
C5–C6
C6–C7
1.244(2)
1.355(2)
1.365(2)
1.144(2)
1.506(2)
1.527(3)
1.515(2)
1.330(2)
1.453(2)
1.370(2)
1.444(2)
1.389(2)
C7–C8
1.405(2)
1.488(2)
1.495(2)
1.512(3)
1.516(3)
1.380(3)
1.392(3)
1.391(3)
1.367(3)
1.368(3)
1.381(3)
C7–C14
C10–C11
C11–C12
C11–C13
C14–C15
C14–C19
C15–C16
C16–C17
C17–C18
C18–C19
C3C10C11
C10C11C12
C10C11C13
C12C11C13
C15C14C19
C15C14C7
C19C14C7
C14C15C16
C17C16C15
C16C17C18
C16C17Cl1
C18C17Cl1
C17C18C19
C18C19C14
approximation. The structure was refined by means of
the full-matrix least-squares procedure on F2 in
anisotropic approximation for nonhydrogen atoms to
wR2 0.102 by 2856 reflexions [R1 0.039 by 2181
reflexions with F > 4σ(F), S 1.066]. The main
crystallographic data were deposited into the Cambridge
Crystallographic Data Center (CCDC 753380).
Method B. To 0.10 mol of cyclopentanone was
added 0.05 mol of aldehyde in 50 ml of 0.5% KOH
aqueous solution. The reaction mixture was stirred for
3 h and extracted with diethyl ether. The organic part
was dried with sodium sulfate, the solvent was re-
moved under a reduced pressure. Oily liquid was used
without further purification. It was refluxed with
morpholine in benzene in a flask equipped with the
Dean-Stark trap and reflux condenser in the presence
of catalytic amounts of p-toluenesolfonic acid (5 mol %).
This mixture was boiled to the water of water release
(6–8 h). Then benzene was distilled off under a re-
duced pressure. The product was isolated by a vacuum
distillation to yield yellow oil.
1
The Н NMR spectra were registered on a Varian
Mercury-500 (499.9601 MHz) (compounds Iа, VIIIа–
VIIId) and Varian Mercury VX-200 instruments (200
MHz) (Ib, Ic) in DMSO-d6 relative to internal TMS.
Mass spectra were recorded on a Crommas GC/MS-
Hewlett-Packard 5890/5972 device, column HP-5MS
(70 eV). Melting points were measured on a Koffler
apparatus. The reaction progress and the purity of the
compounds obtained were monitored by TLC method
on Silufol UV-254 plates in acetone-hexane system,
3:5 detecting with iodine vapors and UV irradiation.
General procedure of synthesis of compounds I.
Method А. A mixture of 200 ml of anhydrous benzene,
0.15 mol of freshly distilled enamine, 0.10 mol of
aldehyde and 5 mol % of p-toluenesulfonic acid was
placed into a flask equipped with Dean-Stark trap and
куадгч condenser. Dean-Stark trap was filled with
benzene. This mixture was stirred for 5–10 min at
room temperature and then refluxed to the end of water
release (5–8 h). The solvent was removed under a
reduced pressure and the product was distilled in high
vacuum to give yellow oily liquid.
1-(N-Morpholino)-5-(2-methylpropylidene)-
cyclopent-1-ene (Iа). Yield 13 g (63%) by method A,
bp 107–109°С (2 mm Hg). Н NMR spectrum, δ,
ppm: 0.99 d (6Н, 2СН3, J 6 Hz), 1.92 m (1Н, СН),
2.34 m (2Н, СН2), 2.47 m (2Н, СН2), 2.85 m (4Н,
2СН2), 3.78 m (4Н, 2СН2), 5.05 m (1Н, СН), 5.16 m
(1Н, СН). Mass spectrum, m/z, Irel, %: 207 (50) [М]+;
164 (100) [М – С3Н7]+. Found, С 75.37; Н 10.27.
С13H21NO. Calculated, %: С 75.32; Н 10.21. M
207.16.
1
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 10 2010

2036
DYACHENKO et al.
1-(N-Morpholino)-5-propylidenecyclopent-1-ene
4-(4-Chlorophenyl)-7-(3-methylbutylidene)-2-
oxo-2,5,6,7-tetrahydro-1Н-pyrimidine-3-carbo-
nitrile (VIIIc). Yield 2.04 g (47%), white powder, mp
(Ib). Yield 11.6 (60%) by method А, 7.15 g (37%) by
method B. bp 92–95°С (2 mm Hg). 1Н NMR spectrum,
δ, ppm: 0.94 t (3Н, СН3, J 7.52 Hz), 2.02 m (2Н, СН2),
2.26 m (2Н, СН2), 2.37 m (2Н, СН2), 2.74 m (4Н,
2СН2), 3.61 m (4Н, 2СН2), 5.15 t (1Н, СН, J 2.34 Hz),
5.24 m (1Н, СН). Found, %: С 74.61; Н 9.94.
С12H19NO. Calculated, %: С 74.57; Н 9.91. M 193.15.
1
263–265°С (EtOH). Н NMR spectrum, δ, ppm: 0.93
m (6Н, 2СН3), 2.06 m (1Н, СН), 2.43–.61 m (6Н,
3СН2), 6.44 d (1Н, СН, J 10 Hz), 7.54 d (2Н, СНAr, J
8.5 Hz), 7.62 d (2Н, СНAr, J 8.5 Hz), 12.67 br.s (1Н,
NH). Mass spectrum, m/z, Irel, %: 339 (100) [М + 1]+;
340 (17) [М + 2]+; 227 (8) [М – 4-СlC6H4 ]+; 111 (11)
[4-СlC6H4]+. Found, %: С 70.82; Н 5.61; N 8.24.
С20H19ClN2O. Calculated, %: С 70.90; Н 5.65; N 8.27.
M 338.83.
1-(N-Morpholino)-5-(3-methylbutylidene)cyclo-
pent-1-ene (Ic). Yield 9.74 g (44%) by method А, bp
1
118–120°С (2 mm Hg). Н NMR spectrum, δ, ppm:
0.85 d (6Н, 2СН3, J 6.6 Hz), 1.62 m (1Н, СН), 1.91 t
(2Н, СН2, J 7.1 Hz), 2.27 m (2Н, СН2), 2.40 m (2Н,
СН2), 2.72 m (4Н, 2СН2), 3.63 m (4Н, 2СН2), 5.16 m
(1Н, СН), 5.25 m (1Н, СН). Found, %: С 75.93; Н
10.27. С14H23NO. Calculated, %: С 75.97; Н 10.47. M
221.18.
4-(4-Chlorophenyl)-7-(3-methylbutylidene)-2-thi-
oxo-2,5,6,7-tetrahydro-1Н-pyridine-3-carbonitrile
(VIIId). Yield 1.6 g (36%), dark green powder, mp
1
225-226°С (C6H6). Н NMR spectrum, δ, ppm: 0.9 d
(6Н, 2СН3, J 6 Hz), 1.02 m (1Н, СН), 1.64–1.81 m
(4Н, 2СН2), 2.07 t (2Н, СН2, J 6.36 Hz), 4.72 br.s (1Н,
NH), 6.66 s (1Н, СН), 7.36 d (2Н, СНAr, J 6.98 Hz),
7.51 d (2Н, СНAr, J 7.02 Hz). Mass spectrum, m/z, Irel,
%: 354 (62) [М]+; 356 (20) [М + 2]+; 311 (80)
[М – C3H7]+; 242 (25) [М – 4-СlC6H4]+; 41 (100)
[C3H5]+. Found, %: С 67.70; Н 5.43; N 7.83.
С20H19ClN2S. Calculated, %: С 67.69; Н 5.40; N 7.89.
M 354.9.
General procedure for the synthesis of com-
pounds VIII. To a solution of alkene VII (10 mmol)
in a mixture of 20 ml of anhydrous ethanol and 10 ml
of DMF was added dropwise the corresponding
alkylmethyleneamine I under stirring within 3 min.
This mixture was kept for 1–3 days at room tem-
perature. The precipitate was filtered off, washed with
alcohol and hexane.
4-(N-Chlorophenyl)-7-sec-butylidene-2-oxo-2,5,6,7-
tetrahydro-1Н-pyridine-3-carbonitrile (VIIIa). Yield
1.06 g (26%), yellow powder, mp 310–311°С (EtOH).
1Н NMR spectrum, δ, ppm: 1.02 d (6Н, 2СН3, J 6.45 Hz),
2.45 m (1Н, СН), 2.55 m (2Н, СН2), 2.65 m (2Н,
СН2), 6.46 d (1Н, СН, J 9.15 Hz), 7.54 d (2Н, СНAr,
J 8.17 Hz), 7.62 d (2Н, СНAr, J 8.15 Hz), 12.62 br.s
(1Н, NH). Mass spectrum, m/z, Irel, %: 325 (100)
[М + 1]+; 323 (23) [М – 1]+; 213 (11) [М – 4-СlC6H4]+;
111 (11) [4-СlC6H4]+. Found, %: С 70.22; Н 5.21; N
8.64. С19H17ClN2O. Calculated, %: С 70.26; Н 5.28; N
8.62. M 324.8.
REFERENCES
1. Dyachenko, V.D. and Dyachenko, А.D. Zh. Org. Khim.,
2008, vol. 44, p. 415; Dyachenko, V.D., Krivokolys-
ko, S.G., and Litvinov, V.P., Khim. Geterotsykl.
Soedin., 1998, no. 1, p. 81; Dyachenko, V.D., and Cher-
nega, A.N., Khim. Geterotsykl. Soed., 2005, no. 7, p. 1053.
2. Kostyuk, A.N., Lysenko, N.V., Kuklya, A.S., Pin-
chuk, А.М., and Tolmachev, А.А., Ukr. Khim. Zh.,
2002, vol. 68, p. 31.
3. Kostyuk, A.N., Lysenko, N.V., and Karpus’, V.S., Ukr.
Khim. Zh., 1999, vol. 65, p. 27.
4. Cardia, M.C., Maccioni, E., and Bonsignore, L., J. Hetero-
cyclic Chem., 2003, vol. 40, p. 309.
4-(4-Chlorophenyl)-7-propylidene-2-oxo-2,5,6,7-
tetrahydro-1Н-pyridine-3-carbonitrile (VIIIb). Yield
0.87 g (43%), yellow powder, mp 290–291°С (EtOH).
1Н NMR spectrum, δ, ppm: 1.13 t (3Н, СН3, J 7.45 Hz),
2.54–2.65 m (6Н, 3СН2), 6.50 m (1Н, СН), 7.57 d
(2Н, CНAr, J 8.15 Hz), 7.65 d (2Н, СНAr, J 8.10 Hz),
12.72 br.s (1Н, NH). Mass spectrum, m/z, Irel, %:
310 (100) [М]+; 309 (33) [М – 1]+; 311 (22) [М + 1]+;
312 (27) [М + 2]+; 199 (7) [М – 4-СlC6H4]+; 111 (6)
[4-СlC6H4]+. Found, %: С 69.52; Н 4.85; N 4.89.
С18H15ClN2O. Calculated, %: С 69.57; Н 4.86; N 9.01.
M 310.78.
5. Burgi, H.-B. and Dunitz, J.D., Structure Correlation,
VCH: Weinheim, 1994, vol. 2, pp. 741–784.
6. Hongbin Li, Hua Yang, Petersen, J.L., and Kung K.
Wang, J. Org. Chem., 2004, vol. 69, p. 4500.
7. Fischer, C.B., Polborn, K., Steininger, H., and Zipse, H.,
Z. Naturforsch. B: Chem. Sci., 2004, vol. 59, p. 1121.
8. Zefirov, Yu.V., Kristallografiya, 1997, vol. 42, p. 936.
9. Sheldrick, G.M., SHELXTL PLUS. PC Version. A
System of Computer Programs for the Determination of
Crystal Structure from X-ray Diffraction Data, Rev.5.1,
1998.
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