Reaction of 5,5-dialkyl-2-halo-6-hydroxy-5,6-dihydro-1H-pyridine-3,4,4- tricarbonitriles with alcohols

Full text of DOI:10.1134/S107042800909022X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 9, pp. 1423–1425. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © A.V. Eremkin, K.V. Lipin, O.V. Ershov, Ya.S. Kayukov, O.E. Nasakin, V.A. Tafeenko, 2009, published in Zhurnal Organicheskoi
Khimii, 2009, Vol. 45, No. 9, pp. 1436–1437.
SHORT
COMMUNICATIONS
Reaction of 5,5-Dialkyl-2-halo-6-hydroxy-5,6-dihydro-
1H-pyridine-3,4,4-tricarbonitriles with Alcohols
A. V. Eremkina, K. V. Lipina, O. V. Ershova, Ya. S. Kayukova,
O. E. Nasakina, and V. A. Tafeenkob
a I.N. Ul’yanov Chuvash State University, Moskovskii pr. 15, Cheboksary, 428015 Russia
e-mail: oleg.ershov@mail.ru
b Faculty of Chemistry, Moscow State University, Vorob’evy gory 1, Moscow, 119992 Russia
Received July 4, 2008
DOI: 10.1134/S107042800909022X
We previously reported that 2-halo-6-hydroxy-5,5-
dimethyl-5,6-dihydro-1H-pyridine-3,4,4-tricarboni-
triles I in methanol undergo transformation involving
replacement of the hydroxy group and mild intramo-
lecular hydrolysis of one cyano group [1]. It was also
noted that such transformation is determined by struc-
tural specificity of the substrates which possess a hemi-
aminal fragment and spatially close axial hydroxy and
cyano groups [1, 2]. While continuing studies in this
line we found that tetrahydropyridines Ia and Ib react
with methanol in anhydrous acetonitrile in a similar
way, leading to 6-halo-4,5-dicyano-3,3-diethyl-2-me-
thoxy-1,2,3,4-tetrahydropyridine-4-carboxamides IIa
and IIb (Scheme 1).
hydrolysis of cyano group owing to higher acidity of
the hydroxy group in α-diols as compared to methanol
(by an order of magnitude). In fact, the reactions of
tetrahydropyridines Ia–Ic with methanol in the pres-
ence of concentrated sulfuric acid afforded 85–95% of
5,5-dialkyl-2-halo-6-methoxy-1,4,5,6-tetrahydropyri-
dine-3,4,4-tricarbonitriles IVa–IVc (Scheme 3).
The structure of compounds II–IV was confirmed
1
by the IR, H NMR, and mass spectra. The molecular
Scheme 2.
NC
CN
Me
CN
Me
+
HOCH2CH2OH
HO
N
H
Hlg
Scheme 1.
Ic, Id
NC
NC
CN
CONH2
CN
NC
CN
Et
Et
Et
Et
Me
CN
Hlg
CN
MeOH
Me
HO
HO
N
MeO
N
Hlg
O
N
Hlg
H
H
H
Ia, Ib
IIa, IIb
IIIa, IIIb
Hlg = Cl (a), Br (b).
Ic, IIIa, Hlg = Cl (a); Id, IIIb, Hlg = Br (b).
Scheme 3.
The reactions of tetrahydropyridines Ic and Id with
ethylene glycol required a longer time and resulted in
replacement of the hydroxy group, whereas the cyano
groups remained intact (Scheme 2). The yield of
2-halo-6-(2-hydroxyethoxy)-5,5-dimethyl-1,4,5,6-
tetrahydropyridine-3,4,4-tricarbonitriles IIIa and IIIb
was 62–64%. We presumed that in this case replace-
ment of the hydroxy group is not accompanied by
NC
NC
CN
CN
R
R
CN
Hlg
CN
Hlg
MeOH, H+
R
R
HO
N
MeO
N
H
H
Ia–Ic
IVa–IVc
R = Et, Hlg = Cl (a), Br (b), R = Me, Hlg = Cl (c).
1423

EREMKIN et al.
1424
structure of IIIa and IVb was determined by X-ray
analysis.
4.61 d (1H, 2-H), 4.5 t (1H, OH), 3.6 m (1H,
OCH2CH2O), 3.5 m (3H, OCH2CH2O), 1.4 s and 1.1 s
(3H each, Me). Mass spectrum: m/z 326 (Irel = 5%)
[M]+ (80Br). Found, %: C 44.34; H 4.13; N 17.20.
C12H13BrN4O2. Calculated, %: C 44.33; H 4.03;
N 17.23.
6-Chloro-4,5-dicyano-3,3-diethyl-2-methoxy-
1,2,3,4-tetrahydropyridine-4-carboxamide (IIa).
Methanol, 0.1 ml, was added to 0.066 g (0.25 mmol)
of 2-chloro-5,5-diethyl-6-hydroxy-1,4,5,6-tetrahydro-
pyridine-3,4,4-tricarbonitrile (Ia) in 0.5 ml of anhy-
drous acetonitrile. After 2 h, the precipitate was filtered
off and washed with acetone. An additional small
amount of the product way be isolated by diluting the
reaction mixture with water. Yield 0.066 g (85%),
mp 194–195°C. IR spectrum, ν, cm–1: 3380, 3250 (NH,
NH2); 2250, 2210 (C≡N); 1685 (C=O). 1H NMR spec-
trum, δ, ppm: 0.90 t and 1.08 t (3H each, Me), 1.25 m
and 1.50 m (1H each, CH2CH3), 1.80 m (2H, CH2CH3),
3.30 s (3H, OMe), 4.18 d (1H, 2-H), 7.42 s and 7.58 s
(1H each, NH2), 9.50 d (1H, NH). Mass spectrum:
m/z 296 (Irel = 0.2%). Found, %: C 52.60; H 5.81;
N 18.85. C13H17ClN4O2. Calculated, %: C 52.62;
H 5.77; N 18.88.
2-Chloro-6-methoxy-5,5-dimethyl-1,4,5,6-tetra-
hydropyridine-3,4,4-tricarbonitrile (IVc). Methanol,
0.1 ml, and one drop of concentrated sulfuric acid were
added in succession to 0.118 g (0.5 mmol) of 2-chloro-
6-hydroxy-5,5-dimethyl-1,4,5,6-tetrahydropyridine-
3,4,4-tricarbonitrile (Ic) in 0.5 ml of 1,4-dioxane. The
mixture was kept for 24 h, and the precipitate was
filtered off and washed with acetone. An additional
amount of the product may be isolated by diluting the
reaction mixture with water. Yield 0.1 g (85%),
mp 208–209°C. IR spectrum, ν, cm–1: 3250 (NH);
1
2251, 2211 (C≡N). H NMR spectrum, δ, ppm: 1.1 s
and 1.45 s (3H each, Me), 3.35 s (3H, OMe), 4.5 d
(1H, 2-H), 10.3 d (1H, NH). Found, %: C 52.73;
H 4.48; N 22.32. C11H11ClN4O. Calculated, %:
C 52.70; H 4.42; N 22.35.
Compounds IVa and IVb were synthesized in
a similar way from nitriles Ia and Ib, respectively.
6-Bromo-4,5-dicyano-3,3-diethyl-2-methoxy-
1,2,3,4-tetrahydropyridine-4-carboxamide (IIb) was
obtained in a similar way from compound Ib. Yield
0.080 g (94%), mp 194–195°C. IR spectrum, ν, cm–1:
3380, 3250 (NH, NH2); 2250, 2210 (C≡N); 1685
2-Chloro-5,5-diethyl-6-methoxy-1,4,5,6-tetrahy-
dropyridine-3,4,4-tricarbonitrile (IVa). Yield 0.13 g
(94%), mp 198–199°C. IR spectrum, ν, cm–1: 3260
1
(C=O). H NMR spectrum, δ, ppm: 0.90 t (3H, Me),
1.08 t (3H, Me), 1.25 m and 1.50 m (1H each,
CH2CH3), 1.80 m (2H, CH2CH3), 3.30 s (3H, OMe),
4.20 d (1H, 2-H), 7.30 s and 7.45 s (1H each, NH2),
1
(NH); 2260, 2220 (C≡N). H NMR spectrum, δ, ppm:
0.92 t and 1.08 t (3H each, CH2CH3); 1.3 m and
1.77 m, 1.9 m, and 2.08 m (1H each, CH2CH3); 3.35 s
(3H, OMe); 4.5 d (1H, 2-H); 10.3 d (1H, NH). Mass
spectrum: m/z 278 (Irel = 10%) [M]+. Found, %:
C 56.11; H 5.46; N 20.07. C13H15ClN4O. Calculated,
%: C 56.02; H 5.42; N 20.10.
9.45 d (1H, NH). Mass spectrum: m/z 342/340 (Irel
=
10%) [M]+. Found, %: C 45.71; H 5.09; N 16.36.
C13H17BrN4O2. Calculated, %: C 45.76; H 5.02;
N 16.42.
2-Chloro-6-(2-hydroxyethoxy)-5,5-dimethyl-
1,4,5,6-tetrahydropyridine-3,4,4-tricarbonitrile
(IIIa). A solution of 0.118 g (0.5 mmol) of 2-chloro-6-
hydroxy-5,5-dimethyl-1,4,5,6-tetrahydropyridine-
3,4,4-tricarbonitrile (Ic) in 0.3 ml of ethylene glycol
was kept for 24 h. The precipitate was filtered off and
washed with acetone. Yield 0.087 g (62%), mp 225–
226°C. IR spectrum, ν, cm–1: 3500, 3250 (OH, NH);
2260, 2220 (C≡N). Mass spectrum: m/z 280 (Irel = 1%)
[M]+. Found, %: C 51.37; H 4.62; N 19.92.
C12H13ClN4O2. Calculated, %: C 51.34; H 4.67;
N 19.96.
2-Bromo-5,5-diethyl-6-methoxy-1,4,5,6-tetrahy-
dropyridine-3,4,4-tricarbonitrile (IVb). Yield 0.15 g
(95%), mp 205–206°C. IR spectrum, ν, cm–1: 3245
1
(NH); 2260, 2220 (C≡N). H NMR spectrum, δ, ppm:
0.92 t and 1.07 t (3H each, CH2CH3); 1.25 m, 1.75 m,
1.87 m, and 2.02 m (1H each, CH2CH3); 3.32 s (3H,
OMe); 4.4 d (1H, 2-H); 10.2 d (1H, NH). Mass spec-
trum: m/z 322 (Irel = 8%) [M]+. Found, %: C 48.27;
H 4.64; N 17.38. C13H15BrN4O. Calculated, %:
C 48.31; H 4.68; N 17.34.
The IR spectra were recorded on an FSM 1202
instrument from samples dispersed in mineral oil. The
1H NMR spectra were measured on a Bruker DRX-500
spectrometer at 500.13 MHz using DMSO-d6 as sol-
vent. The mass spectra (electron impact, 70 eV) were
obtained on a Finnigan MAT INCOS-50 spectrometer.
Single crystals of IIIa and IVb were examined using
2-Bromo-6-(2-hydroxyethoxy)-5,5-dimethyl-
1,4,5,6-tetrahydropyridine-3,4,4-tricarbonitrile
(IIIb) was synthesized in a similar way from com-
pound Id. Yield 0.1 g (64%), mp 210–211°C. IR spec-
trum, ν, cm–1: 3520, 3250 (OH, NH); 2260, 2220
1
(C≡N). H NMR spectrum, δ, ppm: 10.05 d (1H, NH),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 9 2009

REACTION OF 5,5-DIALKYL-2-HALO-6-HYDROXY-5,6-DIHYDRO-1H-PYRIDINE-...
an Enraf–Nonius CAD-4 four-circle automatic diffrac-
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REFERENCES
tometer (CuKα-irradiation, graphite monochromator,
ω scanning).
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 08-03-97015r-povolzh’e-a). The authors thank the
Nanotechnology Collective Use Center of the Chuvash
Republic for recording the IR and mass spectra.
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kov, Ya.S., Nasakin, O.E, and Tafeenko, V.A., Russ. J.
Org. Chem., 2007, vol. 43, p. 938.
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kov, Ya.S., Nasakin, O.E., Tafeenko, V.A., and Nurie-
va, E.V., Mendeleev Commun., 2006, vol. 16, p. 115.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 9 2009