Imidazole-catalyzed three-component cascade reaction for the facile synthesis of highly substituted 3,4-dihydropyridin-2-one derivatives

Article abstract of DOI:10.1002/cjoc.201200500

A novel one-pot protocol for the synthesis of valuable 3,4-dihydropyridin- 2-ones from the condensation of aldehyde with cyanoacetamide and 1,3-dicarbonyl compounds in the presence of imidazole was developed. A series of aldehydes and 1,3-dicarbonyl compounds were employed to examine the scope of substrates for this protocol. This reaction proceeded through the formation of one ring and four new bonds (two Ci￡C, one Ci￡N, one Ci￡C) via the sequence involving Knoevenagel condensation, Michael addition and intramolecular cyclization with moderate to excellent yields. All new compounds were characterized by IR, ¹H NMR, ¹³C NMR and HRMS. Copyright

Full text of DOI:10.1002/cjoc.201200500

FULL PAPER
DOI: 10.1002/cjoc.201200500
Imidazole-catalyzed Three-component Cascade Reaction for
the Facile Synthesis of Highly Substituted
3,4-Dihydropyridin-2-one Derivatives
Liu, Zhiqiang(刘志强)
Tan, Lu(谭璐)
Wu, Qi(吴起)
Lin, Xianfu*(林贤福)
Department of Chemistry, Zhejiang University, Hangzhou, Zhejiang 310027, China
A novel one-pot protocol for the synthesis of valuable 3,4-dihydropyridin-2-ones from the condensation of al-
dehyde with cyanoacetamide and 1,3-dicarbonyl compounds in the presence of imidazole was developed. A series
of aldehydes and 1,3-dicarbonyl compounds were employed to examine the scope of substrates for this protocol.
This reaction proceeded through the formation of one ring and four new bonds (two C—C, one C—N, one C＝C)
via the sequence involving Knoevenagel condensation, Michael addition and intramolecular cyclization with
moderate to excellent yields. All new compounds were characterized by IR, 1H NMR, 13C NMR and HRMS.
Keywords multicomponent reactions, 3,4-dihydropyridin-2-one, cyanoacetamide, cyclization, imidazole
Introduction
ral products, lots of methods in exploring polysubsti-
tuted 3,4-dihydropyridin-2-ones have been developed.
Many involve 1-azadienes,[11] aza-annulation of ena-
mines,[12] carboxylic acid derivatives[13] or α-metallated
acetate derivatives.[14] Also the 3,4-dihydro-pyridin-2-
one could be gotten as the byproduct through the reac-
tion of hydrazone with methyl 3-aminocrotonate in hot
acetic acid.[15] However, developing a novel reaction, a
non-toxic and efficient catalyst for the construction of
this ring system from readily available components is
still highly desirable. Imidazole has emerged as a gen-
eralist which can act not only as reactant[16] but also as
catalyst[17] or additive.[18] Nevertheless, MCRs catalyzed
by imidazole were really rare,[19] Liu[20] reported the
imidazole-mediated cascade annulation reaction from
two units of (arylmethylidene) malononitriles and one
unit of nitroalkenes.
Multicomponent reactions (MCRs) have become an
efficient and powerful tool for the synthesis of biologi-
cally relevant or natural-like molecular framework due
to their convergence, atom economy and eco-friendli-
ness.[1] These reactions allow three or more reactants in
one pot to generate molecular complexity and diversity
through the facile formation of several bonds, such as
C—C, C—O or C—N. Furthermore, MCRs play the
key role in combinatorial synthesis and pharmaceutical
and drug discovery research.[2] Especially the construc-
tion of six-membered heterocyclic ring of biological
activity is facile and interesting.
Dihydropyridine (DHP) heterocyclic ring is well
known as a part of the fundamental skeleton of impor-
tant classes of drugs.[3] For example, 1,4-DHPs systems
are of great significance owing to their exceptional
properties as calcium antagonists.[4] Moreover, slight
structural modification on the DHP ring has been widely
studied which may bring about remarkable changes in
pharmacological effect.[5] Among them, 3,4-dihydro-
pyridin-2-one is an important moiety because of its ex-
tensive occurrence in a large number of natural products
which exhibits significant pharmacological activities
such as antibacterial,[6] antifungal[7] and antitumor,[8]
also served as HIV-1 specific reverse transcriptase in-
hibitors.[9] Also, 3,4-dihydropyridin-2-ones are the key
intermediates in the synthesis of the corresponding pyri-
dines.[10]
Here we will present a new one-pot method for the
synthesis of a set of 3,4-dihydropyridin-2-ones via the
condensation of aldehyde, cyanoacetamide and 1,3-di-
carbonyl compounds catalyzed by trace imidazole, in
which cyanoacetamide acted as ammonia source.
Results and Discussion
We started our research by carrying out the three-
component reaction of p-nitrobenzaldehyde (1), cyano-
acetamide (2) and acetyl acetone (3), in equimolecular
amounts of 0.5 mmol, using 5 mg imidazole as the base
and 1 mL ethylene glycol (EG) as the solvent. After 24
h at 50 ℃, the cascade reaction provided a considerable
Due to the important building blocks of many natu-
*
E-mail: llc123@zju.edu.cn; Tel.: 0086-0571-87953001; Fax: 0086-0571-87952618
Received May 22, 2012; accepted June 26, 2012; published online XXXX, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200500 or from the author.
Chin. J. Chem. 2012, XX, 1—6
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1

Liu et al.
FULL PAPER
64% yield of 5-acetyl-4-(4-chlorophenyl)-6-methyl-2-
oxo-1,2,3,4-tetrahydropyridine-3-carbonitrile (4) (Table
1, Eentry 7). Encouraged by this, the organic base
screening was developed. As shown in Table 1, the na-
ture of base had big influence on the yield. Morpholine
and 4-methylimidazole could also catalyze the reaction
to get the desired product though with the decrease in
the yield (Table 1, Entries 1 and 3). However, the reac-
tion became sluggish with yields below 20% when
2-methylimidazole, 4-dimethylamiopyridine (DMAP),
triethylamine and piperidine were used (Table 1, Entries
2, 4, 5, and 6). Maybe the moderate basicity of imida-
zole is just right for the reaction. While basicity of gen-
eral organic bases is strong, resulting in too many by-
products that cannot be confirmed. Considering the im-
portance of the reaction medium, a series of solvents
were used to examine the effect on the yield. Polar,
aprotic solvents like dioxane, N,N-dimethylformamide
(DMF), dimethyl sulfoxide (DMSO) and toluene were
used as solvents, the yields were low although the sub-
strates dissolved completely (Table 1, Entries 9, 10, 11
and 12). The three-component reaction could not pro-
ceed in other protic solvents involving glycerol and
1,4-butylene glycol (Table 1, Entries 13 and 14). Inter-
estingly, EG emerged as the best solvent and di-EG took
the second place (Table 1, Entries 7 and 8). It seemed
that EG played the vital role due to its good solubility
and double hydroxyl group. We also performed the re-
action in hexane and chloroform, but the cyanoacetam-
ide failed to dissolve in them.
So imidazole and EG acted as the choice of
base-solvent combination for the cascade reaction. Then
the amount of imidazole was established. From the data
listed in Figure 1, it could be seen that the reaction
hardly happened without imidazole. When just 0.1 mg
imidazole was applied, the yield of target molecular
could reach 30%. With further increase to 0.6 mg, we
obtained the product in 61% yield shown as the inflec-
tion point in Figure 1. However, the yield showed plat-
form trend when the mount exceeded 0.6 mg. That
meant trace imidazole had good catalytic activity to the
three-component cascade reaction.
Table 1 Catalyst and solvent screena
O2N
Figure 1 The influence of imidazole loading on the yield.
H
O
CN
In order to get better reaction conditions, we studied
the ratio of substrates and reaction temperature. The
best result of further screening on the ratio of three sub-
strates was aldehyde 0.5 mmol, cyanoacetamide 1 mmol
and 1,3-dicarbonyl compound 0.75 mmol, the yield of
the model reaction was 75% after 24 h at 50 ℃. Next,
as the increase of temperature from 50 to 70 ℃, the
yield increased by 22%.
With optimal reaction conditions in hand, the gener-
ality and limitation of the reaction were investigated by
changing aldehydes, cyanoacetamide and 1,3-dicarbonyl
compounds. The results were summarized in Table 2.
The reactions proceeded in good to excellent yields
though involving a number of individual steps. It
seemed that electronic nature had a little effect on the
yield. Strong electron-donating group (such as methoxy)
on the para of benzaldehyde diminished much com-
pared to electron-withdrawing group (Table 2, Entry 8
and Entries 4, 6). While meta-hydroxyl benzaldehyde
achieved high yield (Table 2, Entry 9). Aliphatic and
heterocyclic aldehyde could also build the correspond-
ing product successfully (Table 2, Entry 10 and Entries
11, 12). Nevertheless, the yield decreased as the carbon
chain lengthening (Entries 11 and 12). To our delight,
methyl acetoacetate and acetoacetanilide could substi-
tute acetyl acetone as 1,3-dicarbonyl compound, which
demonstrated the broad application of the reaction.
O
O
O
Catalyst
Solvent
O
NC
O
H2N
NO2
2
N
H
3
1
4
Entry Catalyst
Solvent
EG
Yieldb/%
1
Morpholine
42
11
52
10
12
9
2
2-Methylimidazole
4-Methylimidazole
DMAP
EG
3
EG
4
EG
5
Triethylamine
Piperidine
EG
6
EG
7
Imidazole
EG
64
46
10
2
8
Imidazole
Di-EG
Dioxane
DMF
DMSO
Toluene
Glycerol
9
Imidazole
10
11
12
13
14
Imidazole
Imidazole
22
15
＜1
4
Imidazole
Imidazole
Imidazole
1,4-Butylene glycol
a The reaction was carried out with 1 (0.5 mmol), 2 (0.5 mmol), 3
(0.5 mmol) and catalyst (5 mg) in 1 mL solvent at 50 ℃ for 24 h.
b determined by HPLC.
2
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Chin. J. Chem. 2012, XX, 1—6

Facile Synthesis of Highly Substituted 3,4-Dihydropyridin-2-one Derivatives
Table 2 Substrate scope of the imidazole catalyzed cascade
Scheme 1. Firstly, the Knoevenagel condensation prod-
reactiona
uct 1 was initially formed via the reaction of benzalde-
hyde and cyanoacetamide. Then intermediate 1 was
trapped by dicarbonyl compound to produce the Mi-
chael product 2, which was deprived one proton of
amino by imidazole. Finally, intermediate 2 underwent
intramolecular nucleophilic attack to generate com-
pound 3 which subsequently lost one molecular water
and regenerated imidazole at the same time.
R1
O
R1
H
CN
O
O
NC
O
Imidazole
EG
R2
O
+
+
O
N
H
H2N
R2
1
2
3
4
Entry R1
R2
Product Yieldb/%
1
Ph
Me
4a
4b
4c
4d
4e
4f
87
82
88
92
86
89
84
67
95
78
98
78
87
94
70
87
73
84
93
Conclusions
2
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
2-ClC6H4
4-ClC6H4
4-MeC6H4
4-OMeC6H4
3-OHC6H4
2-Furyl
Me
In summary, we have developed a novel three-
component cascade reaction to construct multisubsti-
tuted 3,4-dihydropyridin-2-ones in good to excellent
yield from the reaction of aldehyde, cyanoacetamide
and 1,3-dicarbonyl compound in the presence of trace
imidazole in ethylene glycol. This reaction had promi-
nent advantages of easy operation, convergence and
broad scope of applicability.
3
Me
4
Me
5
Me
6
Me
7
Me
4g
4h
4i
8
Me
9
Me
10
11
12
13
14
15
16
17
18
19
Me
4j
Experimental
CH3CH2
Me
4k
4l
Chemicals and solvents were either purchased from
commercial suppliers or purified by standard techniques.
Analytical thin-layer chromatography (TLC) was per-
formed on silica gel plates with iodine as an indicator
and compounds were visualized by irradiation with UV
light. Flash column chromatography was carried out
using silica gel (400 mesh). The 1H NMR and 13C NMR
spectra were recorded with TMS as internal standard
using a Bruker AMX-400 MHz spectrometer. Analyti-
cal HPLC was performed using an Agilent 1100 series
with a reversed-phase Shim-Pack VP-ODS column (150
×4.6 mm) and a UV detector (290 nm). IR spectra were
measured with a Nicolet Nexus FTIR 670 spectropho-
tometer. Melting points were determined using XT-4
apparatus and were not corrected. All the known prod-
ucts were characterized by comparing the 1H NMR data
CH3CH2CH2
3-NO2C6H4
4-ClC6H4
4-MeC6H4
CH3CH2
Me
OMe
OMe
OMe
OMe
4-NHC6H5
4-NHC6H5
4m
4n
4o
4p
4q
4r
4s
4-ClC6H4
4-MeC6H4
2-Furyl
4-NHC6H5
a The reaction was carried out with 1 (0.5 mmol), 2 (1.0 mmol), 3
(0.75 mmol) and catalyst (0.6 mg) in 1 mL EG at 70 ℃ for 24 h.
b Determined by HPLC.
A plausible mechanism to rationalize the formation
of 3,4-dihydropyridin-2-one derivatives is outlined in
Scheme 1 A proposed mechanism of the imidazole-mediated reaction
O
NC
O2N
O
NH2
H2O
H
N
O
O
H2N
NC
N
H
O
H
H2N
NO2
H
CN
N
O
1
HN
N
O
O2N
O
N
H
H
N
NC
NH
H2O
O2N
O
H
NH
O
2
O
N
Product
NH
NH
NC
O
3
Chin. J. Chem. 2012, XX, 1—6
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3

Liu et al.
FULL PAPER
with those reported in the literature. The structures of
new compounds were confirmed by 1H NMR, 13C NMR
and HRMS.
C15H13N3O4 299.0906, found 299.0909.
5-Acetyl-4-(2-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-
tetrahydropyridine-3-carbonitrile (4e)
White solid; m.p. 220—221 ℃; 1H NMR (400 MHz,
DMSO-d6) δ: 2.02 (d, J＝6.8 Hz, 3H, CH3C＝O), 2.30
(d, J＝49.6 Hz, 3H, CH3C＝C), 4.83 (d, J＝6.8 Hz, 1H,
CHC＝C), 4.99 (d, J＝6.8 Hz, 1H, CHCN), 7.11—7.52
(m, 4H, ArH), 10.58 (d, J＝58.0 Hz, 1H, NH); 13C
NMR (100 MHz, DMSO-d6) δ: 19.1, 30.0, 37.4, 40.3,
114.8, 115.5, 128.5, 128.6, 130.4, 130.4, 133.8, 135.5,
147.8, 162.7, 196.9; IR (neat) ν: 3221, 3134, 2251, 1716,
General experimental procedure
A mixture of aldehyde (0.5 mmol), cyanoacetamide
(84 mg, 1 mmol), 1,3-dicarbonyl compound (0.75
mmol), and a catalytic amount of imidazole (0.6 mg) in
1 mL EG was stirred at 70 ℃ for 24 h. After comple-
tion of the reaction detected by TLC, the solution was
directly separated by column chromatography using
about 50 mL petroleum ether firstly, then the eluent was
changed into petroleum ether/ethyl acetate mixture (1∶
1, V∶V). Finally the product was obtained after rotation
under reduced pressure.
－
1
1675 cm . HRMS calcd for C15H13N2O2Cl 288.0666,
found 288.0664.
5-Acetyl-4-(4-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-
tetrahydropyridine-3-carbonitrile (4f)
5-Acetyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahy-
dropyridine-3-carbonitrile (4a)[21]
1
Light yellow solid; m.p. 173—174 ℃; H NMR
1
(400 MHz, DMSO-d6) δ: 2.12 (d, J＝10.0 Hz, 3H,
CH3C＝O), 2.38 (d, J＝10.4 Hz, 3H, CH3C＝C), 3.94
(q, J＝6.8 Hz, 1H, CHC＝C), 4.42 (q, J＝6.8 Hz, 1H,
CHCN), 7.12—7.36 (m, 4H, ArH), 8.76 (d, J＝11.2 Hz,
1H, NH); 13C NMR (100 MHz, DMSO-d6) δ: 19.0, 30.1,
40.7, 41.4, 114.7, 116.0, 129.2, 130.2, 133.3, 136.2,
147.3, 162.9, 197.1; IR (neat) ν: 3255, 3167, 2257, 1712,
Light yellow solid; m.p. 152—153 ℃; H NMR
(400 MHz, CDCl3) δ: 2.10 (d, J＝11.6 Hz, 3H, CH3C＝
O), 2.39 (d, J＝10.4 Hz, 3H, CH3C＝C), 3.95 (q, J＝6.4
Hz, 1H, CHC＝C), 4.40 (q, J＝6.4 Hz, 1H, CHCN),
7.17—7.40 (m, 4H, ArH), 8.51—8.59 (m, 1H, NH); IR
－
1
(neat) ν: 3224, 3139, 2257, 1713, 1668 cm .
－
1
5-Acetyl-6-methyl-4-(2-nitrophenyl)-2-oxo-1,2,3,4-
tetrahydropyridine-3-carbonitrile (4b)
1675 cm . HRMS calcd for C15H13N2O2Cl 288.0661,
found 288.0660.
1
Light yellow solid; m.p. 106—107 ℃; H NMR
5-Acetyl-6-methyl-2-oxo-4-p-tolyl-1,2,3,4-tetrahy-
(400 MHz, DMSO-d6) δ: 1.65 (d, J＝12.8 Hz, 3H,
CH3C＝O), 1.87 (d, J＝16.8 Hz, 3H, CH3C＝C), 4.13
(q, J＝7.6 Hz, 1H, CHC＝C), 4.71 (q, J＝7.2 Hz, 1H,
CHCN), 6.82—7.61 (m, 4H, ArH), 10.20 (d, J＝69.6
Hz, 1H, NH); 13C NMR (100 MHz, DMSO-d6) δ: 19.4,
30.8, 35.4, 115.1, 115.6, 125.8, 128.9, 130.0, 133.0,
134.8, 148.2, 149.1, 162.8, 196.6; IR (neat) ν: 3237,
3139, 2254, 1712, 1686 cm － 1. HRMS calcd for
C15H13N3O4 299.0906, found 299.0910.
dropyridine-3-carbonitrile (4g)[21]
1
Light yellow solid; m.p. 212—213 ℃; H NMR
(400 MHz, DMSO-d6) δ: 2.00 (s, 3H, ArCH3), 2.22 (d,
J＝6.8 Hz, 3H, CH3C＝O), 2.27 (s, 3H, CH3C＝C),
4.21 (q, J＝4.0 Hz, 1H, CHC＝C), 4.62 (q, J＝4.0 Hz,
1H, CHCN), 7.07—7.15 (m, 4H, ArH), 10.45 (d, J＝
48.8 Hz, 1H, NH); IR (neat) ν: 3234, 3139, 2260, 1702,
－
1
1678 cm .
5-Acetyl-4-(4-methoxyphenyl)-6-methyl-2-oxo-1,2,3,
4-tetrahydropyridine-3-carbonitrile (4h)[21]
5-Acetyl-6-methyl-4-(3-nitrophenyl)-2-oxo-1,2,3,4-
tetrahydropyridine-3-carbonitrile (4c)[22]
1
1
Light yellow solid; m.p. 157—158 ℃; H NMR
Light yellow solid; m.p. 183—184 ℃; H NMR
(400 MHz, DMSO-d6) δ: 2.00 (s, 3H, CH3C＝), 2.27 (d,
J＝5.2 Hz, 3H, CH3C＝C), 3.68 (d, J＝5.2 Hz, 3H,
OCH3), 4.37 (d, J＝6.4 Hz, 1H, CHC＝), 4.60 (q, J＝
6.8 Hz, 1H, CHCN), 6.87—7.14 (m, 4H, ArH), 10.46 (d,
J＝1.2 Hz, 1H, NH); IR (neat) ν: 3257, 3172, 2210,
(400 MHz, DMSO-d6) δ: 2.04 (d, J＝6.0 Hz, 3H,
CH3C＝O), 2.29 (d, J＝4.4 Hz, 3H, CH3C＝C), 4.43 (q,
J＝6.4 Hz, 1H, CHC＝C), 4.89 (q, J＝6.8 Hz, 1H,
CHCN), 7.60—8.15 (m, 4H, ArH), 10.60 (d, J＝30.0
Hz, 1H, NH); IR (neat) ν: 3261, 3167, 2257, 1717, 1679
－
－
1
1
1713, 1608 cm .
cm .
5-Acetyl-4-(3-hydroxyphenyl)-6-methyl-2-oxo-1,2,3,
4-tetrahydropyridine-3-carbonitrile (4i)
5-Acetyl-6-methyl-4-(4-nitrophenyl)-2-oxo-1,2,3,4-
tetrahydropyridine-3-carbonitrile (4d)
1
1
Yellow solid; m.p. 249—250 ℃; H NMR (400
Light yellow solid; m.p. 105—106 ℃; H NMR
MHz, DMSO-d6) δ: 1.99 (s, 3H, CH3C＝O), 2.23 (d,
J＝5.6 Hz, 3H, CH3C＝C), 4.30 (d, J＝6.4 Hz, 1H,
CHC＝C), 4.58 (q, J＝6.8 Hz, 1H, CHCN), 6.57—7.13
(m, 4H, ArH), 9.68 (d, J＝10.8 Hz, 1H, OH), 10.41 (d,
J＝52.8 Hz, 1H, NH); 13C NMR (100 MHz, DMSO-d6)
δ: 18.9, 30.1, 41.5, 115.0, 115.1, 115.5, 116.2, 119.1,
130.4, 138.8, 146.9, 157.8, 163.2, 197.4; IR (neat) ν:
(400 MHz, DMSO-d6) δ: 2.00 (d, J＝10.0 Hz, 3H,
CH3C＝O), 2.25 (d, J＝6.0 Hz, 3H, CH3C＝C), 4.56 (d,
J＝6.4 Hz, 1H, CHC＝C), 4.75 (q, J＝6.8 Hz, 1H,
CHCN), 7.42—8.13 (m, 4H, ArH), 10.52 (d, J＝44.4
Hz, 1H, NH); 13C NMR (100 MHz, DMSO-d6) δ: 19.1,
30.3, 40.0, 41.0, 114.4, 115.7, 124.3, 124.4, 129.3,
129.9, 145.1, 147.7, 148.0, 162.8, 196.8; IR (neat) ν:
－
－
1
1
3355, 3262, 2255, 1712, 1664 cm . HRMS calcd for
3266, 3165, 2257, 1719, 1677 cm . HRMS calcd for
4
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Chin. J. Chem. 2012, XX, 1—6

Facile Synthesis of Highly Substituted 3,4-Dihydropyridin-2-one Derivatives
Methyl-5-cyano-2-methyl-6-oxo-4-p-tolyl-1,4,5,6-
C15H14N2O3 270.1011, found 270.1004.
tetrahydropyridine-3-carboxylate (4o)[21]
5-Acetyl-4-(furan-2-yl)-6-methyl-2-oxo-1,2,3,4-tetra-
hydropyridine-3-carbonitrile (4j)[23]
White solid; m.p. 206—207 ℃; 1H NMR (400 MHz,
DMSO-d6) δ: 2.26 (d, J＝6.4 Hz, 3H, CH3Ph), 2.35 (d,
J＝22.2 Hz, 3H, CH3C＝C), 3.54 (d, J＝3.6 Hz, 3H,
OCH3), 4.29 (q, J＝6.8 Hz, 1H, CHC＝C), 4.66 (q, J＝
6.8 Hz, 1H, CHCN), 7.05—7.15 (m, 4H, ArH), 10.56 (d,
J＝48.4 Hz, 1H, NH); IR (neat) ν: 3283, 3181, 2265,
1
Yellow solid; m.p. 152—153 ℃; H NMR (400
MHz, DMSO-d6) δ: 1.72 (d, J＝8.8 Hz, 3H, CH3C＝O),
1.77 (d, J＝11.6 Hz, 3H, CH3C＝C), 3.94 (q, J＝6.0 Hz,
1H, CHC＝C), 4.23 (d, J＝6.4 Hz, 1H, CHCN), 5.90 (q,
J＝1.2 Hz, 1H, C＝CH), 5.93 (q, J＝2.0 Hz, 1H, OC＝
HC＝CH), 7.07 (d, J＝1.2, 1H, OCH＝), 10.04 (d, J＝
32.8 Hz, 1H, NH); IR (neat) ν: 3286, 3179, 2260, 1707,
－
1
1713, 1639 cm .
Methyl-5-cyano-4-ethyl-2-methyl-6-oxo-1,4,5,6-tetra-
hydropyridine-3-carboxylate (4p)
－
1
1663 cm .
White solid; m.p. 133—134 ℃; 1H NMR (400 MHz,
DMSO-d6) δ: 0.81 (t, J ＝ 8.0 Hz, 3H, CH2CH3),
1.29—1.68 (m, 2H, CH2CH3), 2.23 (d, J＝19.6 Hz, 3H,
CH3C＝C), 3.06—3.09, 3.15—3.19 (m, 1H, CHC＝C),
3.67 (d, J＝12.8 Hz, 3H, OCH3), 4.24 (q, J＝6.0 Hz, 1H,
CHCN), 10.40 (d, J＝78.8 Hz, 1H, NH); 13C NMR (100
MHz, DMSO-d6) δ: 10.6, 18.4, 23.7, 35.7, 36.0, 51.6,
105.3, 116.7, 147.4, 164.2, 166.8; IR (neat) ν: 3229,
3137, 2248, 1701, 1648 cm － 1. HRMS calcd for
C11H14N2O3 222.1004, found 222.1001.
5-Acetyl-4-ethyl-6-methyl-2-oxo-1,2,3,4-tetrahy-
dropyridine-3-carbonitrile (4k)
1
Yellow liquid; H NMR (400 MHz, DMSO-d6) δ:
0.96 (t, J＝7.6 Hz, 3H, CH2CH3), 1.39—1.87 (m, 2H,
CH2CH3), 2.32 (d, J＝5.6 Hz, 3H, CH3C＝O), 2.39 (d,
J＝6.0 Hz, 3H, CH3C＝C), 3.18—3.21, 3.32—3.37 (m,
1H, CHC＝C), 3.73 (q, J＝5.6 Hz, 1H, CHCN), 8.69 (d,
J＝60.4 Hz, 1H, NH); 13C NMR (100 MHz, DMSO-d6)
δ: 11.0, 11.1, 19.5, 19.6, 23.5, 24.6, 30.4, 30.5, 35.9,
36.7, 39.5, 39.6, 114.8, 115.4, 116.5, 117.0, 143.0,
143.7, 162.3, 163.9, 196.7, 196.8; IR (neat) ν: 3258,
3152, 2253, 1717, 1617 cm － 1. HRMS calcd for
C11H14N2O2 206.1055, found 206.1053.
4-(4-Chlorophenyl)-5-cyano-2-methyl-6-oxo-N-phe-
nyl-1,4,5,6-tetrahydropyridine-3-carboxamide (4q)
1
Yellow solid; m.p. 157—158 ℃; H NMR (400
MHz, DMSO-d6) δ: 2.03 (d, J＝37.2 Hz, 3H, CH3C＝
C), 4.34 (d, J＝7.2 Hz, 1H, CHC＝C), 4.78 (d, J＝6.8
Hz, 1H, CHCN), 6.99—7.49 (m, 9H, ArH), 9.89 (d, J＝
31.2 Hz, 1H, NH), 10.15 (s, 1H, NHPh); 13C NMR (100
MHz, DMSO-d6) δ: 17.7, 41.1, 41.3, 111.6, 116.2,
120.2, 124.4, 128.9, 129.1, 129.2, 130.2, 130.3, 133.3,
136.2, 136.9, 138.5, 138.5, 138.8, 162.5, 165.8; IR (neat)
5-Acetyl-6-methyl-2-oxo-4-propyl-1,2,3,4-tetrahy-
dropyridine-3-carbonitrile (4l)
1
Yellow solid; m.p. 138—139 ℃; H NMR (400
MHz, CDCl3) δ: 0.93 (t, J＝6.8 Hz, 3H, CH2CH3),
1.26—1.77 (m, 4H, CH2CH2), 2.29—2.33 (m, 3H,
CH3C＝O), 2.36—2.39 (m, 3H, CH3C＝C), 3.26—3.29,
3.37—3.41 (m, 1H, CHC＝C), 3.70 (q, J＝5.2 Hz, 1H,
CHCN), 8.68 (d, J＝1.2 Hz, 1H, NH); 13C NMR (100
MHz, CDCl3) δ: 13.7, 14.2, 19.5, 19.6, 19.8, 20.0, 30.4,
30.6, 32.7, 33.6, 35.5, 36.2, 37.7, 39.8, 114.8, 115.3,
116.8, 117.7, 142.8, 143.3, 162.4, 163.9, 196.6, 196.7;
－
1
ν: 3281, 3161, 2257, 1712, 1652 cm . HRMS calcd for
C20H16N3O2Cl 365.0935, found 365.0931.
5-Cyano-2-methyl-6-oxo-N-phenyl-4-p-tolyl-1,4,5,6-
tetrahydropyridine-3-carboxamide (4r)
White solid; m.p. 108—109 ℃; 1H NMR (400 MHz,
DMSO-d6) δ: 2.09 (d, J＝22.4 Hz, 3H, CH3Ph), 2.25 (d,
J＝17.2 Hz, 3H, CH3C＝C), 4.61 (q, J＝7.2 Hz, 1H,
CHC＝C), 4.32 (d, J＝7.2 Hz, 1H, CHCN), 6.97—7.58
(m, 9H, ArH), 9.70 (d, J＝12.0 Hz, 1H, NH), 10.21 (d,
J＝7.2 Hz, 1H, NHPh); 13C NMR (100 MHz, DMSO-d6)
δ: 17.8, 21.0, 41.1, 41.4, 112.2, 116.5, 120.0, 120.0,
123.9, 128.2, 128.9, 129.0, 129.5, 129.7, 134.4, 137.7,
138.4, 139.3, 162.7, 165.5; IR (neat) ν: 3278, 3140,
－
1
IR (neat) ν: 3221, 3134, 2251, 1716, 1675 cm . HRMS
calcd for C12H16N2O2 220.1212, found 220.1213.
Methyl-5-cyano-2-methyl-4-(3-nitrophenyl)-6-oxo-
1,4,5,6-tetrahydropyridine-3-carboxylate (4m)[24]
White solid; m.p. 207—208 ℃; 1H NMR (400 MHz,
DMSO-d6) δ: 2.35 (d, J＝13.6 Hz, 3H, CH3C＝C), 3.50
(d, J＝5.6 Hz, 3H, OCH3), 4.39 (q, J＝6.8 Hz, 1H,
CHC＝C), 4.79 (q, J＝7.6 Hz, 1H, CHCN), 7.60—8.16
(m, 4H, ArH), 10.70 (d, J＝46 Hz, 1H, NH); IR (neat) ν:
－
1
2257, 1709, 1654 cm . HRMS calcd for C21H19N3O2
345.1477, found 345.1476.
－
1
3272, 3182, 2268, 1709, 1639 cm .
5-Cyano-4-(furan-2-yl)-2-methyl-6-oxo-N-phenyl-1,4,
5,6-tetrahydropyridine-3-carboxamide (4s)
Methyl-4-(4-chlorophenyl)-5-cyano-2-methyl-6-oxo-
1,4,5,6-tetrahydropyridine-3-carboxylate (4n)[25]
1
Yellow solid. m.p. 98—99 ℃; H NMR (400 MHz,
White solid; m.p. 189—190 ℃; 1H NMR (400 MHz,
DMSO-d6) δ: 2.33 (d, J＝18.8 Hz, 3H, CH3C＝C), 3.51
(s, 3H, OCH3), 4.35 (d, J＝6.8 Hz, 1H, CHC＝C), 4.65
(q, J＝7.2 Hz, 1H, CHCN), 7.17—7.37 (m, 4H, ArH),
10.58 (d, J＝66.8 Hz, 1H, NH); IR (neat) ν: 3275, 3170,
DMSO-d6) δ: 2.07 (s, 3H, CH3C＝C), 4.63 (q, J＝6.4
Hz, 1H, CHC＝C), 4.62 (d, J＝6.8 Hz, 1H, CHCN),
6.30 (d, J＝2.8 Hz, 1H, CH＝C), 6.40 (s, 1H, OCH),
7.05 (t, J＝7.2 Hz, 1H, OCH＝CH), 7.27—7.62 (m, 5H,
ArH), 9.77 (d, J＝22.4 Hz, 1H, NH), 10.25 (d, J＝31.6
Hz, 1H, NHPh); 13C NMR (100 MHz, DMSO-d6) δ:
－
1
2254, 1711, 1637 cm .
Chin. J. Chem. 2012, XX, 1—6
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
5

Liu et al.
FULL PAPER
C.; Rooney, C. S.; Saari, W. S.; Thomas, C. M.; Goldman, M. E.;
Obrien, J. A.; Emini, E. A.; Nunberg, J. H.; Quintero, J. C.; Schleif,
W. A.; Anderson, P. S. J. Med. Chem. 1993, 36, 249.
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[11] (a) Palacios, F.; de Retana, A. M. O.; Pascual, S.; de Troconiz, G. F.;
Ezpeleta, J. M. Eur. J. Org. Chem. 2010, 6618; (b) Paravidino, M.;
Bon, R. S.; Scheffelaar, R.; Vugts, D. J.; Znabet, A.; Schmitz, R. F.;
de Kanter, F. J. J.; Lutz, M.; Spek, A. L.; Groen, M. B.; Orru, R. V.
A. Org. Lett. 2006, 8, 5369.
17.9, 30.0, 36.1, 108.1, 109.5, 110.9, 116.3, 120.1,
123.9, 129.0, 129.0, 129.2, 139.4, 139.6, 143.7, 151.2,
162.7, 165.1; IR (neat) ν: 3284, 3134, 2259, 1712, 1654
cm . HRMS calcd for C18H15N3O3 321.1113, found
321.1112.
－
1
Acknowledgement
The financial support from the National Natural
Science Foundation of China (No. 21072172) and the
Zhejiang Provincial Natural Science Foundation (No.
2010-Z4090225) is gratefully acknowledged.
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6
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Chin. J. Chem. 2012, XX, 1—6