Convenient synthetic route to 3-cyanopyridine-2(1H)-one derivatives with aromatic substituents

Article abstract of DOI:10.1515/hc-2012-0158

A new efficient method of synthesizing 3-cyanopyridine-2(1H)-ones containing variable substituents at position 4 and various aromatic substituents at position 1 of the pyridinone ring has been developed. The method is based on the reaction of ylidenecyanoacetic acid ethyl esters with dimethylformamide dimethyl acetal, the reamination of obtained derivatives with several aromatic amines in glacial acetic acid and the final cyclization of the intermediate products to targeted N -aryl-3-cyano-pyridine- 2(1H)-ones. The condensation reactions of some of the synthesized compounds with several aldehydes have been investigated.

Full text of DOI:10.1515/hc-2012-0158

ꢁꢁꢁꢂ
DOI 10.1515/hc-2012-0158ꢀ ꢀHeterocycl. Commun. 2012; 18(5-6): 233–237
Aleksandr Piroyan* and Gagik Melikyan*
Convenient synthetic route to 3-cyanopyridine-
2(1H)-one derivatives with aromatic substituents
Abstract: A new efficient method of synthesizing 3-cyano- activity by replacing one alkyl group with another have
pyridine-2(1H)-ones containing variable substituents at been reported.
position 4 and various aromatic substituents at position
The routine method for the synthesis of 3-cyanopyri-
1 of the pyridinone ring has been developed. The method dine-2(1H)-ones is the condensation of β-enamino deriva-
is based on the reaction of ylidenecyanoacetic acid ethyl tives of carbonyl compounds with cyanoacetic acid amides
esters with dimethylformamide dimethyl acetal, the re- or malononitrile (Ratemi et al., 1993; Litvinov et al., 1999).
amination of obtained derivatives with several aromatic However, these approaches do not allow obtaining the
amines in glacial acetic acid and the final cyclization of variety of substituents at the pyridinone ring which could
the intermediate products to targeted N-aryl-3-cyano-pyri- be a tempting idea for the application in combinatorial
dine-2(1H)-ones. The condensation reactions of some of chemistry and drug design. Other methods allow obtain-
the synthesized compounds with several aldehydes have ing 4,5,6-substituted 3-cyanopyridinones with a large
been investigated.
variety of substituents, but they are not convenient for
introducing substituents at the nitrogen atom of the pyri-
Keywords: alkaloids; 3-cyano-pyridine-2(1H)-one; mil- dinone ring (Nalage et al., 2010; Elassar, 2011).
rinone; ricinine.
Some pyridinone derivatives containing aromatic sub-
stituents have valuable properties and display a variety
of biological activities (Litvinov et al., 1999). In our pre-
vious report, we described the synthesis of some substi-
tuted 3-cyanopyridine-2(1H)-ones with various aliphatic
substituents at positions 1 and 4 of the pyridinone ring
(Melikyan and Piroyan, 2006). Taking this into account,
we report herein a new and simple path for synthesizing
N-substituted 3-cyanopyridine-2(1H)-ones with aromatic
substituents.
Corresponding authors: Aleksandr Piroyan and Gagik Melikyan,
Department of Organic Chemistry, Yerevan State University,
Alex Manoogian 1, Yerevan, 0025, Armenia,
e-mail: aleksandrpiroyan@gmail.com; gold@ysu.am
Introduction
The development of new routes to substituted pyridines
with a wide variety of substituents continues to attract
considerable attention for application in heterocyclic Results and discussion
chemistry, natural product synthesis and medicinal
chemistry. Compounds have been associated with anti- We started from various ethyl ylidenecyanoacetates
tumor, antifungal, antibacterial, antiviral, antithrom- obtained by the condensation of methyl ketones with
botic, psychotherapeutic and anti-HIV properties (Cox ethyl cyanoacetate. These ylidene derivatives were con-
and O’Hagan, 1991; Curran and Liu, 1992; Kozikowski densed with dimethylformamide dimethyl acetal to yield
et al., 1996; Williams et al., 1997; Fraley et al., 2003). They the new dimethylaminovinyl derivatives 1 and 2 in good
are the structural basis of some natural alkaloids, e.g., yields. The reaction was carried out in anhydrous xylenes
ricinine and nudiflorine (Mukherjee and Chaterjee, 1966; under reflux for 3 h (Scheme 1).
Yuldashev, 2001; Leite et al., 2005). Substituted 3-cyan-
The key point of our investigation was the reaction
opyridine-2(1H)-ones are also effective cardiotonic (e.g., of dimethylaminovinyl derivatives 1 and 2 with aromatic
milrinone) agents (Hopkins, 1990; Kulnevich et al., 1990; amines in glacial acetic acid at 90°C to give new arylami-
Shiao et al., 1990; Litvinov et al., 1999; Saad et al., 2002; novinyl derivatives 3–10. Compounds 3–10 are brightly
El-Sayed et al., 2011). Some authors consider that biologi- colored (yellow, orange, red), which can be explained by
cal activity of 3-cyanopyridine-2(1H)-ones depends on the presence of a chromophorous moiety (the arylamino
the substituent at a nitrogen atom of the pyridinone ring group) conjugated through the system of double bonds
(Kulnevich et al., 1990). Serious changes in biological with the cyano group.
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234ꢀ
ꢀA. Piroyan and G. Melikyan: Synthesis of 3-cyanopyridine-2(1h)-one derivatives
R1
Me
Me
R2
NH
CN
O
N
Me
R1
CO2Et
CN
DMF/DMA
R2NH2
CO2Et
CO2Et
xylenes, Δ
AcOH, Δ
xylenes, Δ
N
R2
11-18
R1
R1
CN
CN
3-10
1,2
1: R1=Me
2: R1=Ph
7: R1=Ph, R2=4-EtO(O)C-Ph
8: R1=Ph, R2=4-HO-Ph
9: R1=R2=Ph
13: R1=Ph, R2=4-MeO-Ph
14: R1=Ph, R2=4-Me-C(O)-Ph
15: R1=Ph, R2=4-EtO2C-Ph
16: R1=Ph, R2=4-HO-Ph
17: R1=R2=Ph
3: R1=Me, R2=4-Br-Ph
4: R1=Me, R2=4-MeO-Ph
5: R1=Ph,R2=4-MeO-Ph
6: R1=Ph, R2=4-Me-C(O)-Ph
10: R1=Me, R2=Ph
11: R1=Me, R2=4-Br-Ph
12: R1=Me, R2=4-MeO-Ph
18: R1=Me, R2=Ph
Scheme 1
R1
O
O
CN
CN
R1CHO
O
O
O
12
N
O
N
O
EtOH, NaOH
AcOK, AcOAc
19-26
27
OMe
OMe
19: R1=2-thienyl
20: R1=2-pyridyl
21: R1=Ph
22: R1=1-Me-2-pyrrolyl
23: R1=4-F-Ph
24: R1=2-furyl
25: R1=4-Me2N-Ph
26: R1=4-piperonyl
Scheme 2
Compounds 3–10 undergo intramolecular cyclization of 12 with phthalic anhydride was carried out at 120–130°C
in refluxing xylenes. The products obtained in high yields for 2 h in acetic anhydride in the presence of potassium
are new derivatives of substituted 3-cyanopyridine-2(1H)- acetate catalytic amounts to give the expected product 27.
ones 11–18 containing variable substituents at position 4
of the pyridinone ring and several aromatic substituents
Conclusions
at the nitrogen atom of the ring.
It is important to note that refluxing compounds 1, 2
in acetic acid, as reported for the synthesis of condensed A new convenient synthesis of 3-cyano-pyridine-2(1H)-
pyridazinones (Abu-Shanab et al., 1995), did not result in ones with aromatic substituents was developed. Easy vari-
ring closure and the desired 3-cyanopyridine-2(1H)-ones ability of substituents allows using this method to be used
11–18 were not obtained. Instead, impure compounds in combinatorial chemistry and drug design. The avail-
3–10 with low yields were obtained.
ability of the substrates, efficient work-up and high yields
It has been previously shown that some vinyl-substi- make this route an attractive methodology.
tuted heterocycles are of practical interest (Melikyan
et al., 1993; Leite et al., 1999). Considering this, we carried
out condensation of 4-methyl-2-oxo-1,2-dihydropyridine
Experimental section
12 with a number of aromatic and heterocyclic aldehydes
Melting points were determined on a Kofler hot-stage microscope and
in dry ethyl alcohol media in the presence of catalytic
amount of sodium hydroxide. The resulting 3-cyano-4-
(substituted vinyl)pyridin-2(1H)-ones 19–26 were obtained
in high yields. It was estimated by the analysis of coupling
1
are uncorrected. H NMR (300 MHz) and 13C NMR (75 MHz) spectra
were obtained in DMSO-d6 or a mixture of DMSO-d6 and CCl4 on a
Varian Mercury 300 spectrometer at 303 K.
1
constants in the H NMR spectra that these products are
trans-isomers (Scheme 2).
Synthesis of compounds 1 and 2
The starting ethyl ylideneacetate (0.01 mol) in anhydrous xylenes
Taking into account a wide spectrum of the applica-
tions of phthalic acid derivatives, we extended the conden-
sation reactions on phthalic acid anhydride. Condensation (20 mL) was treated with dimethylformamide dimethyl acetal (0.011
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A. Piroyan and G. Melikyan: Synthesis of 3-cyanopyridine-2(1h)-one derivativesꢀ
ꢀ235
mol). The mixture was heated under reflux for 3 h, and then allowed
to cool to room temperature. Light petroleum (10 mL, bp 60–80°C)
was added to the mixture and the resultant solid product was col-
lected by filtration and crystallized from light petroleum.
3.69 (s, 3H), 3.88 (q, J = 7 Hz, 2H), 6.45 (d, J = 12 Hz, 1H), 6.59–6.93
(m, 5H), 7.06–7.14 (m, 2H), 7.32–7.40 (m, 3H), 10.44 (br s, 1H). Isomer
b: yield 76%; 1H NMR: δ 1.33 (t, J = 7 Hz, 3H), 3.69 (s, 3H), 4.21 (q, J =
7 Hz, 2H), 6.57–6.95 (m, 5H), 7.21–7.32 (m, 2H), 7.40–7.51 (m, 3H), 7.63
(d, J = 13 Hz, 1H), 10.49 (br s, 1H). Anal. Calcd for C21H20N2O3: C, 72.40;
H, 5.79; N, 8.04. Found: C, 72.24; H, 5.61; N, 8.11.
Ethyl 2-cyano-5-(dimethylamino)-3-methylpenta-2,4-dienoate
(1)ꢀYield 55%; mp 98–101°C; mixture of two stereoisomers a and b.
Isomer a: yield 66%; 1H NMR: δ 1.30 (t, J = 7 Hz, 3H), 2.25 (s, 3H), 3.00
(s, 3H), 3.22 (s, 3H), 4.12 (q, J = 7 Hz, 2H), 6.99 (d, J = 13 Hz, 1H), 7.58
(d, J = 13 Hz, 1H). Isomer b: yield 34%; 1H NMR: δ 1.29 (t, J = 7 Hz, 3H),
2.41 (s, 3H), 3.00 (s, 3H), 3.22 (s, 3H),4.11 (q, J = 7 Hz, 2H), 5.60 (d, J = 13
Hz, 1H), 7.58 (d, J=13 Hz, 1H). Anal. for mixture of isomers. Calcd for
C11H16N2O2: C, 63.44; H, 7.74; N, 13.45. Found: C, 63.21; H, 7.56; N, 14.11.
General procedure for synthesis
of compounds 11–18
A solution of an arylamino derivative 3–10 (0.01 mol) in anhydrous
xylenes (20 mL) was heated under reflux for 5–6 h and then allowed
to cool to room temperature. Light petroleum (10 mL, bp 60–80°C)
was added to the mixture and the resultant precipitate of 11–18 was
filtered and crystallized from xylenes.
Ethyl
2-cyano-5-dimethylamino-3-phenylpenta-2,4-dienoate
(2) ꢀYield 85%; mp 141–142°C; mixture of two stereoisomers a and b.
Isomer a: yield 75%; 1H NMR: δ 1.34 (t, J = 7 Hz, 3H), 3.04 (s, 6H), 4.19
(q, J = 7 Hz, 2H), 6.50 (d, J = 13 Hz, 1H), 7.14 (d, J = 13 Hz, 1H), 7.15–7.25
(m, 2H), 7.50–7.39 (m, 3H). Isomer b: yield 25%; 1H NMR: δ 1.03 (t, J =
7 Hz, 3H), 3.03 (s, 6H), 3.86 (q, J = 7 Hz, 2H), 5.79 (d, J = 12 Hz, 1H),
6.40 (d, J = 12 Hz, 1H), 7.10–7.00 (m, 2H), 7.38–7.30 (m, 3H). Anal. for
mixture of isomers. Calcd for C16H18N2O2: C, 71.09; H, 6.71; N, 10.36.
Found: C, 70.95; H, 6.63; N, 10.68.
1-(4-Bromophenyl)-4-methyl-2-oxo-1,2-dihydropyridine-3-car-
bonitrile (11)ꢀYield 65%; mp 220–225°C; 1H NMR: δ 2.48 (s, 3H), 6.37
(d, J = 7 Hz, 1H), 7.40–7.32 (m, 2H), 7.68–7.62 (m, 2H), 7.76 (d, J = 7 Hz,
1H); 13C NMR: δ 20.5, 104.0, 107.9, 114.2, 121.7, 128.0, 131.7, 138.2, 141.2,
158.2, 159.8. Anal. Calcd for C13H9BrN2O: C, 54.00; H, 3.14; N, 9.69.
Found: C, 53.86; H, 3.51; N, 9.84.
1-(4-Methoxyphenyl)-4-methyl-2-oxo-1,2-dihydropyridine-
General procedure for synthesis of
compounds 3–10
A mixture of dimethylamino derivative 1 or 2 (0.005 mol) and an
amine (0.0055 mol) in glacial acetic acid (10 mL) was heated at 90°C
for 4–5 h, then cooled to room temperature and treated with water (10
mL). The resultant solid product was filtered, washed with water (20
mL), dried and crystallized from light petroleum (bp 60–80°C). In the
case of compounds 6–10, the crude products were used in the next
step without further purification.
1
3-carbonitrile (12)ꢀYield 60%; mp 189–190°C; H NMR: δ 2.46
(s, 3H), 3.83 (s, 3H),6.25 (d, J = 7 Hz, 1H), 7.06–6.88 (m, 2H), 7.32–7.15
(m, 2H), 7.60 (d, J = 7 Hz, 1H); 13C NMR: δ 20.4, 54.8, 104.3, 107.2,
113.8, 114.2, 126.9, 131.8, 141.2, 158.5, 159.0, 159.1. Anal. Calcd for
C14H12N2O2: C, 69.99; H, 5.03; N, 11.66. Found: C, 70.28; H, 4.95; N,
11.12.
1-(4-Methoxyphenyl)-2-oxo-4-phenyl-1,2-dihydropyridine-3-car-
bonitrile (13)ꢀYield 65%; mp 195–196°C; 1H NMR: δ 3.82 (s, 3H), 6.58
(d, J = 7 Hz, 1H), 7.12–7.05 (m, 2H), 7.46–7.39 (m, 2H), 7.63–7.56 (m, 3H),
7.73–7.66 (m, 2H), 8.05 (d, J = 7 Hz, 1H); 13C NMR: δ 55.5, 101.1, 107.0,
114.4, 116.3, 127.8, 128.1, 129.0, 130.7, 132.3, 135.5, 144.0, 159.4, 159.9.
Anal. Calcd for C19H14N2O2: C, 75.48; H, 4.67; N, 9.27. Found: C, 75.24;
H, 4.61; N, 9.01.
Ethyl
5-(4-bromophenylamino)-2-cyano-3-methylpenta-2,4-
dienoate(3)ꢀYield95%;mp185–190°C;mixtureoftwostereoisomers
a and b. Isomer a: yield 47%; 1H NMR: δ 1.31 (t, J = 7 Hz, 3H), 2.51 (s,
3H), 4.16 (q, J = 7 Hz, 2H), 6.36 (d, J = 13 Hz, 1H), 7.09–7.14 (m, 2H),
7.30–7.40 (m, 2H), 7.90 (t, J = 13 Hz, 1H), 10.32 (s, 1H). Isomer b: yield
53%; 1H NMR: δ 1.32 (t, J = 7 Hz, 3H), 2.38 (s, 3H), 4.19 (q, J = 7 Hz, 2H),
7.10–7.19 (m, 2H), 7.29–7.40 (m, 2H), 7.54 (d, J = 13 Hz, 1H), 7.91 (t, J = 13
Hz, 1H), 10.28 (s, 1H). Anal. Calcd for C15H15BrN2O2: C, 53.75; H, 4.51; N,
8.36. Found: C, 53.41; H, 4.30; N, 8.11.
1-(4-Acetylphenyl)-2-oxo-4-phenyl-1,2-dihydropyridine-3-car-
bonitrile (14)ꢀYield 61%; mp 203–205°C; 1H NMR: δ 2.65 (s, 3H), 6.66
(d, J = 7 Hz, 1H), 7.54–7.78 (m, 7H), 8.05–8.19 (m, 3H); 13C NMR: δ 26.9,
39.5, 101.4, 107.4, 116.1, 127.1, 128.1, 129.0, 129.2, 130.9, 135.4, 137.0, 143.1,
159.6, 160.3, 197.4. Anal. Calcd for C20H14N2O2: C, 76.42; H, 4.49; N, 8.91.
Found: C, 76.44; H, 4.59; N, 8.72.
Ethyl 2-cyano-5-(4-methoxyphenylamino)-3-methylpenta-2,4-di-
enoate (4)ꢀYield 94%; mp 172–173°C; mixture of two stereoisomers a
and b. Isomer a: yield 46%; 1H NMR: δ 1.30 (t, J = 7 Hz, 3H), 2.48 (s, 3H),
3.74 (s, 3H), 4.14 (q, J = 7 Hz, 2H), 6.31 (d, J = 13 Hz, 1H), 6.73–6.81 (m,
2H), 7.01–7.09 (m, 2H), 7.77 (d, J = 13 Hz, 1H), 10.11 (br s, 1H). Isomer b:
yield 54%; 1H NMR: δ 1.30 (t, J = 7 Hz, 3H), 2.34 (s, 3H), 3.74 (s, 3H), 4.15
(q, J = 7 Hz, 2H), 6.73–6.81 (m, 2H), 6.98–7.05 (m, 2H), 7.51 (d, J = 13 Hz,
1H), 7.72 (d, J = 13 Hz, 1H), 10.15 (br s, 1H). Anal. Calcd for C16H18N2O3: C,
67.12; H, 6.34; N, 9.78. Found: C, 67.32; H, 6.21; N, 10.08.
Ethyl 4-(3-cyano-2-oxo-4-phenylpyridin-1(2H)-yl)benzoate (15)
1
Yield 60%, mp 221–223°C; H NMR: δ 1.35 (t, J = 7 Hz, 3H), 4.36 (q,
J = 7 Hz, 2H), 6.66 (d, J = 7 Hz, 1H), 7.56–7.77 (m, 7H), 8.07–8.19 (m,
3H); 13C NMR: δ 14.2, 61.2, 101.4, 107.4, 116.0, 127.2, 128.1, 129.0, 130.1,
130.3, 130.9, 135.3, 143.1, 143.2, 159.5, 160.3, 165.0. Anal. Calcd for
C21H16N2O3: C, 73.24; H, 4.68; N, 8.13. Found: C, 73.59; H, 4.61; N, 7.93.
1-(4-Hydroxyphenyl)-2-oxo-4-phenyl-1,2-dihydropyridine-
1
3-carbonitrile (16)ꢀYield 63%; mp >250°C; H NMR: δ 6.55 (d, J =
Ethyl 2-cyano-5-(4-methoxyphenylamino)-3-phenylpenta-2,4-
7 Hz, 1H), 6.90 (m, 2H), 7.28 (m, 2H), 7.63–7.50 (m, 3H), 7.75–7.63 (m,
2H), 8.02 (d, J = 7 Hz, 1H), 9.95 (s, 1H); 13C NMR: δ 101.0, 106.9, 115.6,
116.3, 127.7, 128.1, 129.0, 130.7, 130.9, 135.5, 144.1, 157.7, 159.8, 159.9.
dienoate (5)ꢀYield 90%; mp 137–139°C; mixture of two stereoiso-
1
mers a and b. Isomer a: yield 24%; H NMR: δ 1.03 (t, J = 7 Hz, 3H),
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236ꢀ ꢀA. Piroyan and G. Melikyan: Synthesis of 3-cyanopyridine-2(1h)-one derivatives
1H), 7.83 (d, J = 8 Hz, 1H); 13C NMR: δ 34.0, 55.5, 97.9, 101.8, 109.8, 111.8,
114.3, 116.0, 125.9, 127.9, 128.5, 129.3, 130.2, 132.5, 142.0, 155.5, 159.2,
160.0. Anal. Calcd for C20H17N3O2: C, 72.49; H, 5.17; N, 12.68. Found: C,
72.31; H, 5.21; N, 12.46.
Anal. Calcd for C18H12N2O2: C, 74.99; H, 4.20; N, 9.72. Found: C, 75.89;
H, 4.51; N, 9.54.
1,4-Diphenyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (17)ꢀYield
70%; mp 190–192°C; 1H NMR: δ 6.61 (d, J = 7 Hz, 1H), 7.55 (m, 8H), 7.71
(m, 2H), 8.09 (d, J = 7 Hz, 1H); 13C NMR: δ 101.3, 107.1, 116.2, 126.7, 128.1,
129.0, 129.0, 129.3, 130.8, 135.4, 139.5, 143.7, 159.7, 160.1. Anal. Calcd for
C18H12N2O: C, 79.39; H, 4.44; N, 10.29. Found: C, 79.07; H, 4.32; N, 9.98.
4-(4-Fluorostyryl)-1-(4-methoxyphenyl)-2-oxo-1,2-dihydropyri-
1
dine-3-carbonitrile (23)ꢀYield 55%; mp 247–249°C; H NMR: δ 3.82
(s, 3H), 6.96 (d, J = 7 Hz, 1H), 7.03–7.12 (m, 2H), 7.19 (d, J = 16 Hz, 1H),
7.24–7.46 (m, 4H), 7.73–7.83 (m, 2H), 7.87 (d, J = 16 Hz, 1H), 7.96 (d, J =
7 Hz, 1H); 13C NMR: δ 55.5, 100.5, 102.1, 114.3, 116.1, 116.4, 121.5, 127.8,
130.3, 130.4, 131.7, 132.3, 139.3, 143.0, 154.7, 159.3, 159.8. Anal. Calcd for
C21H15FN2O2: C, 72.82; H, 4.37; N, 8.09. Found: C, 72.77; H, 4.26; N, 8.24.
4-Methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carbonitrile
1
(18)ꢀYield 55.5%; mp = 197–199°C; H NMR: δ 2.48 (s, 3H), 6.37 (d,
J = 7 Hz, 1H), 7.59–7.31 (m, 5H), 7.77 (d, J = 7 Hz, 1H); 13C NMR: δ 19.7,
102.8, 107.2, 109.67, 124.1, 128.1, 129.5, 137.3, 140.8, 149.5, 163.3. Anal.
Calcd for C13H10N2O: C, 74.27; H, 4.79; N, 13.33. Found: C, 74.08; H,
4.76; N, 13.21.
4-[2-(2-Furyl)vinyl]-1-(4-methoxyphenyl)-2-oxo-1,2-dihydro-
1
pyridine-3-carbonitrile (24)ꢀYield 62%; mp 249–252°C; H NMR:
δ 3.81 (s, 3H), 6.68 (dd, J = 4 Hz and 2 Hz, 1H), 6.92 (d, J = 8 Hz,
1H), 6.92 (d, J = 4 Hz, 1H), 7.03 (d, J = 16 Hz, 1H), 7.03–7.13 (m, 2H)
7.32–7.44 (m, 2H), 7.74 (d, J = 16 Hz, 1H), 7.91 (d, J = 8 Hz, 1H), 7.91
(d, J = 2 Hz, 1H); 13C NMR: δ 55.5, 99.9, 101.6, 113.1, 114.3, 115.7, 116.1,
118.7, 127.4, 127.8, 132.4, 142.9, 146.3, 151.1, 154.4, 158.3, 159.2. Anal.
Calcd for C19H14N2O3: C, 71.69; H, 4.43; N, 8.80. Found: C, 71.71; H,
4.33; N, 8.59.
General procedure for synthesis of
compounds 19–26
A mixture of compound 12 (0.005 mol), an aldehyde (0.006 mol) and
a catalytic amount of sodium hydroxide in anhydrous ethanol (10
mL) was heated under reflux for 5–6 h. Then the mixture was cooled
slowly to room temperature which caused crystallization of product
19–26. The product was filtered, washed with water (20 mL) and crys-
tallized from ethanol.
4-[4-(Dimethylamino)styryl]-1-(4-methoxyphenyl)-2-oxo-1,2-
dihydropyridine-3-carbonitrile (25)ꢀYield 76%; mp 238–241°C;
1H NMR: δ 3.01 (s, 6H), 3.81 (s, 3H), 6.74–6.82 (m, 2H), 6.92 (d, J = 7
Hz, 1H), 6.96 (d, J = 16 Hz, 1H), 7.02–7.10 (m, 2H), 7.33–7.40 (m, 2H),
7.52–7.60 (m, 2H), 7.76 (d, J = 16 Hz, 1H), 7.83 (d, J = 7 Hz, 1H): 13C
NMR: δ 55.5, 67.2, 101.7, 105.1, 108.8, 112.0, 114.3, 115.5, 116.1, 122.3,
127.8, 129.9, 134.8, 141.6, 142.1, 151.9, 155.5, 159.1. Anal. Calcd for
C23H21N3O2: C, 74.37; H, 5.70; N, 11.31. Found: C, 74.61; H, 5.54; N,
11.28.
1-(4-Methoxyphenyl)-2-oxo-4-(2-(thiophen-2-yl)vinyl)-1,2-dihy-
dropyridine-3-carbonitrile (19)ꢀYield 77%; mp 248–252°C; 1H NMR:
δ 3.86 (s, 3H), 6.86 (d, J = 7 Hz, 1H), 7.01 (d, J = 15 Hz, 1H), 6.94–7.07 (m,
2H), 7.12 (dd, J = 5 Hz and 4 Hz, 1H), 7.26–7.37 (m, 2H), 7.43 (d, J = 4 Hz,
1H), 7.56 (d, J = 5 Hz, 1H), 7.74 (d, J = 7 Hz, 1H), 7.93 (d, J = 15 Hz, 1H);
13C NMR: δ 55.5, 96.0, 103.5, 111.0, 116.9, 119.0, 126.8, 126.9, 127.4, 128.3,
130.7, 132.8, 135.3, 143.2, 147.6, 159.2, 160.1. Anal. Calcd for C19H14N2O2S:
C, 68.24; H, 4.22; N, 8.38. Found: C, 68.02; H, 4.56; N, 8.10.
4-[2-(Benzo[d][1,3]dioxol-5-yl)vinyl]-1-(4-methoxyphenyl)-
2-oxo-1,2-dihydropyridine-3-carbonitrile
(26)ꢀYield
62%;
1
mp >250°C; H NMR: δ 3.81 (s, 3H), 6.10 (s, 2H), 6.86–6.96 (m, 1H),
6.97–7.14 (m, 4H), 7.24 (dd, J = 8 Hz and 1.7 Hz, 1H), 7.31–7.42 (m, 3H),
7.78 (d, J = 16 Hz, 1H), 7.92 (d, J = 7 Hz, 1H); 13C NMR: δ 55.5, 67.2, 101.8,
102.0, 106.5, 108.8, 108.9, 114.3, 119.7, 124.5, 127.8, 127.8, 129.5, 132.4,
140.5, 142.8, 148.2, 149.4, 155.0, 159.2. Anal. Calcd for C22H16N2O4: C,
70.96; H, 4.33; N, 7.52. Found: C, 71.02; H, 4.11; N, 7.27.
1-(4-Methoxyphenyl)-2-oxo-4-(2-(pyridin-3-yl)vinyl)-1,2-dihy-
dropyridine-3-carbonitrile (20)ꢀYield 57%; mp >255°C; 1H NMR:
δ 3.86 (s, 3H), 6.96 (d, J = 7 Hz, 1H), 7.00–7.10 (m, 2H), 7.28–7.40 (m,
3H), 7.45 (dd, J = 8 Hz and 5 Hz, 1H), 7.79–7.91 (m, 2H), 8.08–8.17
(m, 1H), 8.56 (dd, J = 5 Hz and 2 Hz, 1H), 8.81 (d, J = 2 Hz, 1H); 13C
NMR: δ 56.1, 98.9, 105.5, 112.4, 114.9, 124.0, 124.9, 126.9, 131.1, 132.8,
133.2, 134.8, 137.6, 146.8, 149.8, 151.3, 158.8, 162.3. Anal. Calcd for
C20H15N3O2: C, 72.94; H, 4.59; N, 12.76. Found: C, 72.74; H, 4.95; N,
12.91.
1-(4-Methoxyphenyl)-2-oxo-4-[(3-oxoisobenzofuran-1(3H)-
ylidene)methyl]-1,2-dihydropyridine-3-carbonitrile
(27)ꢀA
mixture of compound 12 (0.003 mol), phthalic anhydride (0.006
mol), acetic anhydride (0.45 mL) and a catalytic amount of potas-
sium acetate was stirred at 130–135°C for 2 h. Then the mixture
was cooled to room temperature. The solid product 27 was filtered,
washed with ethanol and aqueous sodium hydrocarbonate, dried
1-(4-Methoxyphenyl)-2-oxo-4-styryl-1,2-dihydropyridine-3-car-
bonitrile (21)ꢀYield 65%; mp 239–241°C; 1H NMR: δ 3.86 (s, 3H), 6.83
(d, J = 7 Hz, 1H), 7.00–7.06 (m, 2H), 7.52–7.29 (m, 6H), 7.81 (d, J = 7 Hz,
1H), 7.84–7.95 (m, 2H); 13C NMR: δ 56.1, 100.2, 104.4, 111.3, 114.6, 122.7,
127.0, 128.1, 128.6, 128.8, 132.8, 135.3, 136.1, 138.1, 145.8, 157.6, 162.3.
Anal. Calcd for C21H16N2O2: C, 76.81; H, 4.91; N, 8.53. Found: C, 76.58;
H, 4.83; N, 8.39.
1
and crystallized from xylenes. Yield 76%; mp >250°C; H NMR: δ
3.82 (s, 3H), 6.79 (s, 1H), 7.01–7.16 (m, 3H), 7.36–7.47 (m, 2H), 7.82 (t,
J = 8 Hz, 1H), 7.96 (t, J = 8 Hz, 1H), 8.05 (d, J = 8 Hz, 2H), 8.29 (d, J =
8 Hz, 1H); 13C NMR: δ 55.6, 99.5, 101.6, 105.8, 114.4, 115.6, 117.0, 122.4,
123.6, 125.8, 127.8, 132.3, 132.7, 135.8, 138.5, 143.7, 151.5, 151.7, 159.4,
165.2. Anal. Calcd for C22H14N2O4: C, 71.35; H, 3.81; N, 7.56. Found: C,
70.98; H, 4.02; N, 7.37.
1-(4-Methoxyphenyl)-4-[2-(1-methyl-1H-pyrrol-2-yl)vinyl]-
2-oxo-1,2-dihydropyridine-3-carbonitrile (22)ꢀYield 81%; mp
233–236°C; 1H NMR: δ 3.78 (s, 3H), 3.81 (s, 3H), 6.19 (dd, J = 4 Hz and 2
Hz, 1H), 6.81 (dd, J = 4.0 Hz and 2 Hz, 1H), 6.88 (d, J = 16 Hz, 1H), 7.03
(d, J = 8 Hz, 1H), 7.03–7.09 (m, 3H), 7.31–7.41 (m, 2H), 7.73 (d, J = 16 Hz,
Received October 26, 2012; accepted November 3, 2012
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ꢂꢁꢁꢁ
A. Piroyan and G. Melikyan: Synthesis of 3-cyanopyridine-2(1h)-one derivativesꢀ
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