One-pot synthesis of 2-Oxo-1,2-dihydropyridine-3,4-dicarbonitriles

Full text of DOI:10.1134/S1070428015080242

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 8, pp. 1191–1193. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © S.V. Fedoseev, K.V. Lipin, O.V. Ershov, M.Yu. Belikov, A.S. Yatsko, O.E. Nasakin, 2015, published in Zhurnal Organicheskoi
Khimii, 2015, Vol. 51, No. 8, pp. 1210–1212.
SHORT
COMMUNICATIONS
One-Pot Synthesis of
2-Oxo-1,2-dihydropyridine-3,4-dicarbonitriles
S. V. Fedoseev, K. V. Lipin, O. V. Ershov, M. Yu. Belikov,
A. S. Yatsko, and O. E. Nasakin
I.N. Ul’yanov Chuvash State University, Moskovskii pr. 15, Cheboksary, 428015 Russia
e-mail: lipinkost@mail.ru
Received March 19, 2015
DOI: 10.1134/S1070428015080242
A pyridone fragment with a cyano group is present
in compounds with a wide range of biologic activity:
antiphlogistic [1], analgesic [1], anticancer [2, 3], and
cardiotonic [4] action. It is also known that pyridin-2-
one contained in the composition of 2-oxo-1,2-
dihydropyridine-3,4-dicarbonitriles is a fluorophore
[5–9]; it is stated in [5] that the presence of a cyano
group increases the fluorescence quantum yield. Up till
now a number of publications appeared describing the
synthesis of various 2-oxo-1,2-dihydropyridine-3,4-
dicarbonitriles [10–14]. The simplest procedure for the
preparation of these heterocycles is the synthesis from
4-oxoalkane-1,1,2,2-tetracarbonitriles with the help of
diverse acids [10–12].
thus increasing the overall yield of final compounds
and reducing the experiment duration.
2-Oxo-1,2-dihydropyridine-3,4-dicarbonitriles 1b,
1d, 1f, and 1g were obtained for the first time. The
1
structure of all compounds was confirmed with IR, Н
NMR, and mass spectra. IR spectra contain the
characteristic absorption bands of the carbonyl groups
in the region 1653–1671 cm–1, of conjugated cyano
groups at 2211–2226 cm–1, and of stretching vibrations
1
of the NH bonds at 3214-3288 cm–1. In the Н NMR
spectra signals are present of the protons of the NH
from the pyridine ring as a broadened singlet at 13.10–
13.58 ppm and of the protons of the alkyl groups. The
proton signals of alkyl substituents directly attached to
the pyridine ring shift to the region 2.15–2.78 ppm.
Alkyl-substituted 2-oxo-1,2-dihydropyridine-3,4-
dicarbonitriles were obtained along procedure [12] by
treating 4-oxoalkane-1,1,2,2-tetracarbonitriles А with
water in the presence of sulfuric acid in 1,4-dioxane.
The initial compounds for this synthesis were formed
by a reaction of tetracyanoethylene with ketones in the
presence of a catalytic quantity of hydrochloric acid
[15]. In this connection we developed a new one-pot
preparation method for 2-oxo-1,2-dihydropyridine-3,4-
dicarbonitriles 1a–1i without the isolation of
intermediate 4-oxoalkane-1,1,2,2-tetracarbonitriles А
In this procedure dioxane was used as the solvent
since it dissolves the initial tetracyanoethylene and 4-
oxoalkane-1,1,2,2-tetracarbonitriles and is chemically
inert toward them, and also forms solutions with conc.
sulfuric acid.
Application of other acids in this procedure did not
give good results. Thus hydrohalogenic acids in
catalytic quantities did not lead to the formation of
compounds 1а–1i, and at higher concentrations the
CN
NC CN
R2
R2
R1
CN
O
NC
NC
CN
CN
R2
R1
CN
conc. HCl
H2O, H2SO4
+
CN
R1
O
N
H
O
A
1a_1i
R1 = R2 = CH3 (а); R1 = CH3, R2 = C2H5 (b); R1 = CH3, R2 = C3H7 (c); R1 + R2 = (CH2)3 (d); R1 + R2 = (CH2)4 (e);
R1 + R2 = (CH2)5 (f); R1 + R2 = (CH2)6 (g); R1 + R2 = (СН2)2СН(СН3)СН2 (h); R1 + R2 = (СН2)2СН(t-Bu)СН2 (i).
1191

FEDOSEEV et al.
1192
formation was observed of the known 2-halo-1,2-
dihydropyridine-3,4-dicarbonitriles [16, 17]. The use
of acetic acid retarded the process, and only after 48–
72 h 2-oxo-1,2-dihydropyridines formed in trace
amounts, and the increase in the temperature of the
process or in the acid concentration resulted in
significant tarring of the reaction mixture and in the
lower yield of the target product. This is apparently
due to the fact that acetic acid (рKа 4.8) is far less
strong than sulfuric acid (рKа1 –2.8). All attempts to
catalyze this reaction with nitric or phosphoric acid
(change of solvent, variation of acid concentration)
resulted only in the formation of tar which prevented
the isolation of individual compounds. This is
evidently due to side processes resulting in the
decomposition of tetracyanoalkanones.
13.29 s (1H, NH). Mass spectrum, m/z (Irel, %): 187
(67) [M]+. Found, %: C 64.20; H 4.89; N 22.35.
C10H9N3O. Calculated, %: C 64.16; H 4.85; N 22.45.
M 187.07.
6-Methyl-2-oxo-5-propyl-1,2-dihydropyridine-
3,4-dicarbonitrile (1с). Yield 0.40 g (79%), mp 243–
245°С (decomp.) (238–239°С [11]). IR spectrum, ν,
1
cm–1: 3271 (NН), 2223 (С≡N), 1659 (С=О). Н NMR
spectrum, δ, ppm: 0.93 t (3Н, СН3, J 7.3 Hz), 1.50
sextet (2Н, СН2, J 7.5 Hz), 2.38 s (3Н, СН3), 2.51 m
(2Н, СН2), 13.28 s (1H, NH). Mass spectrum, m/z (Irel,
%): 201 (69) [M]+. Found, %: C 65.59; H 5.48; N
20.96. C11H11N3O. Calculated, %: C 65.66; H 5.51; N
20.88. M 201.09.
2-Oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]-
pyridine-3,4-dicarbonitrile (1d). Yield 0.365 g (79%),
mp 227–229°С (decomp.). IR spectrum, ν, cm–1: 3264
(NН), 2220 (С≡N), 1667 (С=О). 1Н NMR spectrum, δ,
ppm: 2.11 quintet (2Н, СН2, J 7.5 Hz), 2.81 t (2Н,
СН2, J 7.5 Hz), 2.19 t (2Н, СН2, J 7.5 Hz), 13.58 s
(1H, NH). Mass spectrum, m/z (Irel, %): 185 (96) [M]+.
Found, %: C 64.89; H 3.79; N 22.77. C10H7N3O.
Calculated, %: C 64.86; H 3.81; N 22.69. M 185.06.
Hence we have developed a simple and rational
one-pot preparation method for 2-oxo-1,2-
dihydropyridine-3,4-dicarbonitriles 1а–1i providing a
possibility to raise the yields of final compounds and
to reduce the reaction time compared with the known
procedures.
5,6-Dimethyl-2-oxo-1,2-dihydropyridine-3,4-di-
carbonitrile (1а). To a solution of 0.32 g (2.5 mmol)
of tetracyanoethylene in 10 mL of 1,4-dioxane was
added 0.20 g (2.7 mmol) of butan-2-one, 1–2 drops of
conc. sulfuric acid, and the reaction mixture was
stirred till complete dissolution. After the
disappearance of tetracyanoethylene from the reaction
mixture (test with hydroquinone) 2 mL of 80% water
solution of sulfuric acid was added. The reaction
mixture was stirred at 40–50°С for 1.5–2 h, cooled,
and poured to 100 mL of brine. The separated
crystalline light-yellow precipitate was filtered off,
washed with cold water and cold 2-propanol. The
product was dried in a vacuum desiccator over CaCl2.
Yield 0.36 g (84%), mp 265°С [11]. IR spectrum, ν,
2-Oxo-1,2,5,6,7,8-hexahydroquinoline-3,4-dicar-
bonitrile (1e). Yield 0.44 g (88%), mp 266–267°С
(decomp.) [11]. IR spectrum, ν, cm–1: 3277 (NН), 2211
(С≡N), 1657 (С=О). 1Н NMR spectrum, δ, ppm: 1.69–
1.73 m (4Н, 2СН2), 2.51–2.58 m (4Н, 2СН2), 13.20 s
(1H, NH). Mass spectrum, m/z (Irel, %): 199 (100) [M]+.
Found, %: C 66.43; H 4.48; N 21.15. C11H9N3O. Cal-
culated, %: C 66.32; H 4.55; N 21.09. M 199.07.
2-Oxo-2,5,6,7,8,9-hexahydro-1H-cyclohepta[b]-
pyridine-3,4-dicarbonitrile (1f). Yield 0.46 g (86%),
mp 252–254°С (decomp.). IR spectrum, ν, cm–1: 3214
(NН), 2223 (С≡N), 1668 (С=О). 1Н NMR spectrum δ,
ppm: 1.56–1.64 m (4Н, 2CH2), 1.74–1.78 m (2Н,
CH2), 2.69–2.73 m (2Н, CH2), 2.76–2.80 m (2Н, CH2),
13.31 s (1H, NH). Mass spectrum, m/z (Irel, %): 213
(100) [M]+. Found, %: C 67.43; H 5.16; N 19.82.
C12H11N3O. Calculated, %: C 67.59; H 5.20; N 19.71.
M 213.09.
1
cm–1: 3242 (NН), 2224 (С≡N), 1656 (С=О). Н NMR
spectrum, δ, ppm: 2.15 s (3Н, СН3), 2.35 s (3Н, СН3),
13.31 s (1H, NH). Mass spectrum, m/z (Irel, %): 173
(81) [M]+. Found, %: C 62.37; H 4.02; N 24.35.
C9H7N3O. Calculated, %: C 62.42; H 4.07; N 24.27. M
173.06.
2-Oxo-1,2,5,6,7,8,9,10-octahydrocyclocta[b]pyri-
dine-3,4-dicarbonitrile (1g). Yield 0.45 g (80%), mp
289–291°С (decomp.). IR spectrum, ν, cm–1: 3222
(NH), 2226 (С≡N), 1662 (С=О). 1Н NMR spectrum, δ,
ppm: 1.34–1.42 m (4Н, 2CH2), 1.58–1.69 m (4Н,
2CH2), 2.74–2.78 m (2Н, CH2), 2.83–2.87 m (2Н,
CH2), 13.25 s (1H, NH). Mass spectrum, m/z (Irel, %):
Compounds 1b–1i were prepared similarly.
6-Methyl-2-oxo-5-ethyl-1,2-dihydropyridine-3,4-
dicarbonitrile (1b). Yield 0.38 g (81%), mp 254–255°С.
IR spectrum, ν, cm–1: 3288 (NН), 2214 (С≡N), 1655
1
(С=О). Н NMR spectrum, δ, ppm: 1.08 t (3Н, СН3, J
6.5 Hz), 2.61 q (2Н, СН2, J 6.5 Hz), 2.36 s (3Н, СН3),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 8 2015

ONE-POT SYNTHESIS OF 2-OXO-1,2-DIHYDROPYRIDINE-3,4-DICARBONITRILES
227 (100) [M]+. Found, %: C 68.63; H 5.81; N 18.45.
1193
REFERENCES
C13H13N3O. Calculated, %: C 68.70; H 5.77; N 18.49.
M 227.11.
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6-Methyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-
3,4-dicarbonitrile (1h). Yield 0.43 g (81%), mp 203–
205°С (decomp.) (205–207°С (decomp.) [12]). IR
spectrum, ν, cm–1: 3216 (NН), 2212 (С≡N), 1653
1
(С=О). Н NMR spectrum, δ, ppm: 1.03 d (3Н, СH3,
J 6.5 Hz), 1.28–1.37 m (1H, CHCH3), 1.76–1.83
m (2H, CH2), 2.12–2.18 d.d (1H, CH2, J 10.4,
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153–154°С (decomp.) [12]. IR spectrum, ν, cm–1: 3253
(NН), 2215 (С≡N), 1671 (С=О). 1Н NMR spectrum, δ,
ppm: 0.92 s (9Н, t-Bu), 1.23–1.27 m (1Н, CH2), 1.37–
1.41 m (1Н, CH2), 1.93–1.97 m (1Н, t-BuCH), 2.26–
2.32 d.d (1Н, CH2, J 12.1, 15.5 Hz), 2.60–2.69 m (2Н,
CH2), 2.72–2.78 m (1Н, CH2), 13.10 br.s (1H, NH).
Mass spectrum, m/z (Irel, %): 255 (16) [M]+. Found, %:
C 70.66; H 6.79; N 16.36. C15H17N3O. Calculated, %:
C 70.56; H 6.71; N 16.46. M 255.14.
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The purity of synthesized compounds was checked
by TLC on Silufol UV-254 plates, development at UV
irradiation, in iodine vapor, or by thermal
decomposition. IR spectra were recorded on an IR
Fourier spectrophotometer FSM-1202 from thin films
or mulls in mineral oil. 1Н NMR spectra were register-
red on a spectrometer Bruker DRX-500, operating
frequency 500.13 MHz, solvent DMSO-d6, internal
reference TMS. Mass spectra were measured on an
instrument Finnigan MAT INCOS-50 (EI, 70 eV).
The study was carried out under a financial support
of the grant of the President of the Russian Federation
for young scientists and post-graduate students SP-
2782.2015.4.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 8 2015