FeCl3-catalyzed four-component nucleophilic addition/intermolecular cyclization yielding polysubstituted pyridine derivatives

Article abstract of DOI:10.1021/jo5014383

We report an efficient route to pyridine derivatives via an FeCl₃-catalyzed four-component nucleophilic addition/intermolecular cyclization. This simple fragment assembly strategy uses mild conditions and affords a broad range of polysubstituted pyridines in moderate to good yield from simple and readily available starting materials. A plausible mechanism for this process is proposed.

Full text of DOI:10.1021/jo5014383

Note
pubs.acs.org/joc
FeCl3‑Catalyzed Four-Component Nucleophilic Addition/
Intermolecular Cyclization Yielding Polysubstituted Pyridine
Derivatives
Xinwei He, Yongjia Shang,* Zhiyu Yu, Mei Fang, Yao Zhou, Guang Han, and Fuli Wu
Key Laboratory of Functional Molecular Solids, Ministry of Education, Anhui Key Laboratory of Molecule-Based Materials, College of
Chemistry and Materials Science, Anhui Normal University, Wuhu 241000, P.R. China
S
* Supporting Information
ABSTRACT: We report an efficient route to pyridine
derivatives via an FeCl3-catalyzed four-component nucleophilic
addition/intermolecular cyclization. This simple fragment
assembly strategy uses mild conditions and affords a broad
range of polysubstituted pyridines in moderate to good yield
from simple and readily available starting materials. A plausible
mechanism for this process is proposed.
yridine derivatives are among the most important classes of
Pnitrogen-containing heterocycles; they are found in many
natural products, pharmaceutical agents, and functionalized
materials.1−3 These derivatives possess activity against a wide
variety of pathogens and illnesses, such as prions,4 hepatitis B
virus,5 bacteria,6 and cancer.7 Recently, pyridine derivatives
have been proposed as potential therapies for Parkinson’s
disease, hypoxia, asthma, kidney disease, epilepsy, cancer, and
Creutzfeldt-Jakob disease.8−10 During recent decades, facile
During our ongoing studies on transition metal-mediated
synthesis of heterocyclic compounds, we found that pyridines
could be efficiently prepared using an iron catalyst under mild
reaction conditions. Herein, we report an efficient synthetic
pathway to polysubstituted pyridines involving nucleophilic
addition/intermolecular cyclization catalyzed by FeCl3 under
mild conditions in moderate to good yields (Scheme 1).
Scheme 1. Synthesis of Polysubstituted Pyridines via an
FeCl3-Catalyzed Four-Component Reaction
methods, such as the Chichibabin,11 Krohnke,12 Boger,13 and
̈
Hantzsch reactions,14 have been developed for constructing the
pyridine framework. In consideration of efficiency, novel
synthetic methods under mild conditions are not only of
fundamental interest but are also needed for practical
applications.15 To date, typical methods include reductive
cyclizations, such as transition metal catalyzed [2 + 2+2]
cycloadditions,16 copper-catalyzed C−N bond cleavage in
aromatic methylamines,17 synergistic copper/iminium-catalyzed
[3 + 3] condensations,18 and ZnO nanoparticle catalyzed
multicomponent reactions.19
Initially, 4-nitrobenzaldehyde (1b), malononitrile (2a), ethyl
acetoacetate (3a), and aniline (4a) served as model substrates
for optimization of the four-component reaction conditions;
results are given in Table 1. Transition metal catalysts, such as
FeCl3, NiCl2·6H2O, CuSO4, CuBr2, and AgNO3, were
examined first (Table 1, entries 2−6). Of these, FeCl3 (15
mol %) was found to be the best catalyst, giving 5b in 80% yield
(Table 1, entry 2). In the absence of catalyst, only 35% yield
was obtained, even after 24 h (Table 1, entry 1). Further
screening of solvents showed that ethanol gave the best result
in comparison to DMF, toluene, acetonitrile, H2O, DMSO,
THF, and methanol (Table 1, entries 7−14). Here, the yield
could not be improved by increasing the amount of catalyst
(Table 1, entries 16, 17). While decreasing the amount of
Multicomponent reactions (MCRs) have gained tremendous
attention from medicinal and organic chemists because they
offer highly convergent routes to complex molecules. These
methods offer rapid and convergent construction of complex
molecules without isolation and purification of intermediates,
minimizing waste, effort, time, and cost.20 Thus, they can satisfy
the need for high-throughput screening of new bioactive
molecules with diverse scaffolds.21 Owing to their abundance,
affordability, and environmental friendliness, Fe22-based cata-
lytic MCRs have achieved popularity in promoting a broad
range of organic transformations. We previously reported an
efficient synthesis of functionalized coumarin derivatives via an
FeCl3-catalyzed cascade reaction between salicylaldehydes and
activated methylene compounds.23 We expected this type of
MCR to be an effective route to pyridine derivatives; more
work should be conducted to test this possibility.
Received: June 27, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo5014383 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
Table 1. Optimization of Reaction Conditions
Table 2. FeCl3-Catalyzed Four-Component Reaction for the
Formation of Polysubstituted Pyridines
a
b
entry
catalyst (mol %)
solvent
temp./°C time/h yield/%
yield/
1

EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
DMF
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
rt
24
8
35
80
62
15
50
45
trace
50
10
60
trace
40
80
81
82
79
79
25
72
81
41
80
83
57
b
entry
R1
H (1a)
R2
R3
product
%
2
FeCl3 (15)
NiCl2·6H2O (15)
CuSO4 (15)
CuBr2 (15)
AgNO3 (15)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (5)
FeCl3 (20)
FeCl3 (30)
FeCl3 (5)
FeCl3 (5)
FeCl3 (5)
FeCl3 (5)
FeCl3 (5)
FeCl3 (5)
FeCl3 (2)
1
CN (2a)
H (4a)
5a
5b
5c
5d
5e
5f
75
82
83
76
75
75
62
70
68
60
78
86
85
83
82
81
80
72
52
46
45
47
48
39
38
3
8
2
4-NO2 (1b)
3-NO2 (1c)
4-Cl (1d)
2a
4a
4
8
3
2a
4a
5
8
4
2a
4a
6
8
5
4-Br (1e)
2a
4a
7
10
10
10
10
10
10
10
10
6
6
4-CH3 (1f)
4-OCH3 (1g)
2-NO2 (1h)
2-Br (1i)
2a
4a
8
Toluene
CH3CN
H2O
7
2a
4a
5g
5h
5i
9
8
2a
4a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
9
2a
4a
DMSO
THF
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
2-OCH3 (1j)
H (1a)
2a
4a
5j
CN (2a)
4-CH3 (4b)
5k
5l
CH3OH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
4-NO2 (1b)
3-NO2 (1c)
4-Cl (1d)
2a
4b
2a
4b
5m
5n
5o
5p
5q
5r
2a
4b
6
4-Br (1e)
2a
4b
6
4-CH3 (1f)
2-NO2 (1h)
2,4-Cl2 (1k)
3-NO2 (1c)
4-Cl (1d)
2a
4b
18
10
8
2a
4b
50
100
70
70
70
70
2a
4b
2a
3-NO2 (4c)
5s
5t
2
2a
3-NO2 (4c)
5
4-Br (1e)
2a
3-NO2 (4c)
5u
5v
5w
5x
5y
10
18
4-NO2 (1b)
3-NO2 (1c)
4-Cl (1d)
COOEt (2b)
4a
4a
4a
4a
2b
2b
2b
a
Reaction conditions: 4-nitrobenzaldehyde 1b (1.0 mmol), malononi-
trile 2a (1.0 mmol), ethyl acetoacetate 3a (1.0 mmol), aniline 4a (1.0
mmol), catalyst, solvent (3 mL). Isolated yield.
4-Br (1e)
b
a
Reaction conditions: aromatic aldehyde 1 (1.0 mmol), activated
methylene compound 2 (1.0 mmol), ethyl acetoacetate 3a (1.0 mmol),
aromatic amine 4 (1.0 mmol), FeCl3 (5 mol %), ethanol (3 mL), 70
catalyst to 5 mol %, the desired compound was still obtained in
82% comparable yield (Table 1, entry 15). However, the
product yield dropped to 57% when further decreasing the
catalyst loading to 2 mol % (Table 1, entry 24) after 18 h.
Moreover, decreasing or increasing the reaction temperature
was detrimental to the yield (Table 1, entries 18−20).
Therefore, the optimum reaction conditions giving an 82%
yield of the polysubstituted pyridine (5b) were 5 mol % of
FeCl3, 6 h reaction time, and 70 °C reaction temperature.
After the reaction conditions were optimized, the substrate
scope was examined with various aromatic aldehydes 1,
activated methylene compounds 2, and aromatic amines 4.
The results are summarized in Table 2.
Among various aromatic aldehydes 1 investigated, electron-
withdrawing groups (-NO2, -Cl, -Br) generally gave higher
yields (Table 2, entries 2, 4, 5) than electron-donating groups
(-OCH3, -CH3) (Table 2, entries 6, 7). It should be noted that
the positions of these substituents had an obvious effect on the
reaction. When aromatic aldehydes bearing ortho electron-
withdrawing groups (-NO2, -Br, -OCH3) were used, lower
yields were obtained (Table 2, entries 8−10). When ethyl α-
cyanoacetate (2b) was used as substrate, the reaction appeared
to be quite general with respect to malononitrile (2a), and the
desired products 5v, 5w, 5x, and 5y were obtained in 47%, 48%,
39%, and 38% yields, respectively. Among various substituted
b
°C, 6 h. Isolated yield.
aromatic amines 4 investigated, electron-donating groups
(Table 2, entries 13−15) gave higher yields than electron-
withdrawing groups (Table 2, entries 19−21). The chemical
structure of compound 5f was unequivocally confirmed by
single-crystal X-ray analysis as shown in Figure 1 in the
Supporting Information (SI).
To test the versatility of this reaction, the optimized
conditions were applied to other nucleophiles, such as ethanol
(Scheme 2) and ammonium chloride (Scheme 3). In
comparison with aromatic amines, when ethanol was used
(Scheme 2), the desired products 7a, 7b, and 7c were obtained
in 75%, 73%, and 68% yield, respectively.
Initial mechanistic studies indicated that an intermediate
formed after 3 h and gradually transformed to the
polysubstituted pyridine product. We isolated this intermediate
and found it to be 1,4-dihydropyridine 6 (Scheme 4). The
structure of intermediate 6a was confirmed by X-ray analysis as
shown in Figure 2 in the SI. Treatment of 6a with 5 mol %
FeCl3 in ethanol afforded a polysubstituted pyridine in 85%
yield. However, ammonium chloride as substrate did not give
the desired product under these conditions (Scheme 2). In
B
dx.doi.org/10.1021/jo5014383 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
intermediate 6 results from intermolecular cycloaddition with
loss of H2O from intermediate E, which is derived in turn from
D. Finally, FeCl3-oxidized aromatization of intermediate 6
furnishes the final product 5.
Scheme 2. Synthesis of 2-Alkoxy Pyridines via an FeCl3-
Catalyzed Four-Component Reaction between Aromatic
Aldehydes, Malononitrile, β-Ketoesters, And Ethanol
In summary, we have developed a simple one-pot, four-
component nucleophilic addition/intermolecular cyclization
reaction using iron(III) chloride catalyst to give polysubstituted
pyridine derivatives. The advantages of this method include
mild conditions, environmentally friendly catalyst, and readily
available starting materials. No base or ligand is required, and
the reaction proceeds under air. This mild annulation strategy
may offer a protocol for synthesizing other N-heterocyclic
compounds of interest to medicinal chemists.
Scheme 3. Synthesis of 2-Amino-1,4-dihydropyridines via an
FeCl3-Catalyzed Four-Component Reaction between
Aromatic Aldehydes, Malononitrile, β-Ketoesters, And
Ammonium Chloride
EXPERIMENTAL SECTION
■
General Comments. Solvents were purified and dried by standard
procedures unless otherwise stated. Unless otherwise specified, all
reagents and starting materials were purchased from commercial
sources and used as received. Chromatography solvents were technical
grade, distilled prior to use. Flash chromatography was performed
using 200−300 mesh silica gel with the indicated solvent system using
1
standard techniques. H and 13C NMR spectra were recorded at 300
and 400 MHz unless otherwise specified. Chemical shifts (δ) in parts
per million are reported relative to the residual signals of chloroform
1
(7.26 ppm for H and 76.1 ppm for 13C). Multiplicities are described
as s (singlet), d (doublet), t (triplet), q (quartet), or m (multiplet);
coupling constants (J) are reported in Hz. HRMS analysis was
performed using a quadrupole time-of-flight mass spectrometer; mass/
charge (m/z) ratios are given in atomic mass units. IR spectra were
measured using dry films on KBr disks, and the peaks are reported in
wavenumber (cm−1).
General Procedure for the Synthesis of Polysubstituted
Pyridines 5. To a stirred solution of 4-nitrobenzaldehyde 1b (0.151 g,
1 mmol), malononitrile 2a (0.066 g, 1 mmol), ethyl acetoacetate 3a
(0.130 g, 1 mmol), and aniline 4a (0.093 g, 1 mmol) in ethanol (3
mL) was added anhydrous FeCl3 (0.080 g, 0.05 mmol). The mixture
was heated in an oil bath at 70 °C for 6 h and cooled to room
temperature. Solvent was removed under vacuum, and the residue was
purified by flash column chromatography on silica gel (200−300
mesh) with ethyl acetate and petroleum ether (1:10, v/v) as eluent to
afford the product 5b (0.329 g, 0.82 mmol) in 82% yield.
contrast, the reaction stopped at the 1,4-dihydropyridines,
giving 7d and 7e in 65% and 63% yield, respectively, illustrating
that the conjugation effect of the aromatic ring bearing amino
group can promote the aromatization of 1,4-dihydropyridines
based on the planar structure of the compound 5f.
On the basis of previous studies24 and our experimental
results, a possible reaction mechanism is proposed in Scheme 4.
First, the intermediate A is produced by the Knoevenagel
condensation between aromatic aldehydes 1 and malononitrile
2a. Then, intermediate B is produced from Michael addition of
ethyl acetoacetate 3 on intermediate A. Subsequently, aromatic
amine 4 attacks B to form C, which isomerizes to D. Then,
Scheme 4. Proposed Mechanism for the Formation of Pyridines via FeCl3-Catalyzed Four-Component Reactions
C
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The Journal of Organic Chemistry
Note
Ethyl 5-Cyano-2-methyl-4-phenyl-6-(phenylamino)nicotinate
3H), 0.95 (t, J = 7.5 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ
167.5, 160.6, 159.9, 155.4, 153.6, 138.3, 129.4, 128.9, 127.9, 123.9,
120.7, 120.6, 116.2, 114.0, 90.7, 61.4, 55.3, 23.8, 13.6 ppm; IR (KBr) v:
3317, 2220, 1712, 1598, 1554, 1521, 1442, 1363, 1276, 1253, 1176,
1083, 1028, 829 cm−1; HRMS (ESI) calcd for C23H21N3O3 ([M +
H]+) 388.1661, found 388.1661.
(5a). Petroleum ether/ethyl acetate 10:1, 75% yield (267 mg), white
1
solid; mp 205−206 °C. H NMR (300 MHz, CDCl3): δ 7.65 (d, J =
8.4 Hz, 2H), 7.43 (d, J = 6.6 Hz, 3H), 7.31−7.36 (m, 4H), 7.08−7.17
(m, 1H), 3.91 (q, J = 6.9 Hz, 2H), 2.55 (s, 3H), 0.82 (t, J = 6.9 Hz,
3H) ppm; 13C NMR (100 MHz, CDCl3): δ 167.2, 160.3, 155.4, 154.0,
138.4, 135.9, 129.5, 128.9, 128.6, 128.4, 127.9, 126.4, 124.1, 120.7,
120.5, 115.8, 90.8, 61.3, 23.8, 13.4 ppm; IR (KBr) v: 3344, 2222, 1707,
1552, 1498, 1442, 1365, 1271, 1180, 1070, 748, 707 cm−1; HRMS
(ESI) calcd for C22H19N3O2 ([M + H]+) 358.1555, found 358.1553.
Ethyl 5-Cyano-2-methyl-4-(4-nitrophenyl)-6-(phenylamino)-
nicotinate (5b). Petroleum ether/ethyl acetate 10:1, 82% yield (329
mg), pale yellow solid; mp 220−221 °C. 1H NMR (300 MHz,
CDCl3): δ 8.31 (d, J = 8.7 Hz, 2H), 7.63 (d, J = 8.1 Hz, 2H), 7.53 (d, J
= 8.7 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.12−7.19 (m, 1H), 3.95 (q, J
= 6.9 Hz, 2H), 2.58 (s, 3H), 0.89 (t, J = 6.9 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3): δ 166.3, 161.5, 155.3, 151.8, 148.4, 142.4, 137.9,
129.2, 129.0, 124.5, 123.8, 121.0, 119.6, 115.2, 90.3, 61.5, 24.2, 13.6
ppm; IR (KBr) v: 3327, 2222, 1712, 1606, 1556, 1514, 1496, 1444,
1350, 1278, 1184, 1008, 852, 748 cm−1; HRMS (ESI) calcd for
C22H18N4O4 ([M + H]+) 403.1406, found 403.1406.
Ethyl 5-Cyano-2-methyl-4-(2-nitrophenyl)-6-(phenylamino)-
nicotinate (5h). Petroleum ether/ethyl acetate 10:1, 70% yield (281
1
mg), brown solid; mp 187−189 °C. H NMR (300 MHz, CDCl3): δ
8.35 (d, J = 7.8 Hz, 1H), 7.71−7.81 (m, 4H), 7.44 (t, J = 7.8 Hz, 2H),
7.33 (t, J = 7.8 Hz, 1H), 7.19−7.23 (m, 1H), 4.00 (q, J = 7.2 Hz, 2H),
2.72 (s, 3H), 0.93 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ 165.6, 162.7, 155.0, 152.9, 147.3, 138.0, 133.7, 132.1, 130.3,
129.0, 124.9, 124.4, 121.0, 117.7, 115.0, 91.0, 61.2, 25.0, 13.5 ppm; IR
(KBr) v: 3361, 2216, 1708, 1610, 1558, 1521, 1496, 1444, 1377, 1348,
1276, 1176, 1068, 1018, 794 cm−1; HRMS (ESI) calcd for
C22H18N4O4 ([M + H]+) 403.1406, found 403.1402.
Ethyl 4-(2-Bromophenyl)-5-cyano-2-methyl-6-(phenylamino)-
nicotinate (5i). Petroleum ether/ethyl acetate 10:1, 68% yield (295
1
mg), white solid; mp 125−127 °C. H NMR (300 MHz, CDCl3): δ
7.68 (d, J = 7.5 Hz, 2H), 7.34−7.42 (m, 5H), 7.12−7.24 (m, 4H), 3.97
(q, J = 6.9 Hz, 2H), 2.66 (s, 3H), 0.86 (t, J = 6.6 Hz, 3H) ppm; 13C
NMR (75 MHz, CDCl3): δ 166.1, 162.0, 155.0, 153.6, 138.1, 137.4,
132.8, 130.5, 129.4, 129.0, 127.4, 126.3, 124.2, 121.9, 120.7, 115.1,
91.8, 61.1, 24.6, 13.4 ppm; IR (KBr) v: 3334, 2223, 1714, 1658, 1602,
1496, 1444, 1363, 1244, 1182, 1056, 1024, 752 cm−1; HRMS (ESI)
calcd for C22H18BrN3O2 ([M + H]+) 436.0660, found 436.0650.
Ethyl 5-Cyano-4-(2-methoxyphenyl)-2-methyl-6-(phenylamino)-
nicotinate (5j). Petroleum ether/ethyl acetate 10:1, 60% yield (232
Ethyl 5-Cyano-2-methyl-4-(3-nitrophenyl)-6-(phenylamino)-
nicotinate (5c). Petroleum ether/ethyl acetate 8:1, 83% yield (332
1
mg), yellow solid; mp 198−200 °C. H NMR (300 MHz, CDCl3): δ
8.35 (d, J = 7.2 Hz, 1H), 8.26 (s, 1H), 7.64−7.73 (m, 4H), 7.39 (t, J =
7.8 Hz, 2H), 7.14−7.23 (m, 1H), 4.01 (q, J = 6.9 Hz, 2H), 2.62 (s,
3H), 0.95 (t, J = 6.9 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ
166.4, 162.7, 155.4, 151.4, 148.2, 137.9, 134.1, 129.8, 124.5, 124.2,
123.2, 121.1, 119.9, 115.2, 90.5, 61.6, 24.2, 13.6 ppm; IR (KBr) v:
3361, 2218, 1714, 1624, 1531, 1442, 1348, 1271, 1186, 898 cm−1;
HRMS (ESI) calcd for C22H18N4O4 ([M + H]+) 403.1406, found
403.1404.
1
mg), white solid; mp 151−153 °C. H NMR (300 MHz, CDCl3): δ
7.68 (d, J = 8.1 Hz, 2H), 7.34−7.45 (m, 3H), 7.10−7.18 (m, 2H),
6.98−7.05 (m, 2H), 3.96 (q, J = 6.9 Hz, 2H), 3.82 (s, 3H), 2.62 (s,
3H), 0.86 (t, J = 7.5 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ
166.9, 160.8, 156.0, 155.2, 151.8, 138.4, 130.9, 129.3, 128.9, 125.1,
123.8, 120.7, 120.6, 120.5, 115.9, 111.1, 92.2, 61.0, 55.6, 24.2, 13.4
ppm; IR (KBr) v: 3340, 2222, 1726, 1606, 1558, 1494, 1442, 1377,
1267, 1242, 1163, 1066, 1022, 759 cm−1. HRMS (ESI) calcd for
C23H21N3O3 ([M + H]+) 388.1661, found 388.1662.
Ethyl 4-(4-Chlorophenyl)-5-cyano-2-methyl-6-(phenylamino)-
nicotinate (5d). Petroleum ether/ethyl acetate 10:1, 76% yield (297
1
mg), yellow solid; mp 192−194 °C. H NMR (400 MHz, CDCl3): δ
7.65 (d, J = 7.6 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.37 (t, J = 8.0 Hz,
2H), 7.32 (d, J = 8.4 Hz, 2H), 7.23 (s, 1H), 7.14 (t, J = 7.2 Hz, 1H)
ppm; 13C NMR (100 MHz, CDCl3): δ 167.0, 160.6, 155.4, 152.7,
138.2, 135.8, 134.3, 129.4, 129.0, 128.9, 124.2, 120.8, 120.3, 115.9,
90.6, 61.4, 23.9, 13.6 ppm; IR (KBr) v: 3331, 2216, 1714, 1598, 1556,
1442, 1365, 1278, 1180, 1089, 1016, 827 cm−1; HRMS (ESI) calcd for
C22H18ClN3O2 ([M + H]+) 392.1165, found 392.1165.
Ethyl 5-Cyano-2-methyl-4-phenyl-6-(p-tolylamino)nicotinate
(5k). Petroleum ether/ethyl acetate 12:1, 78% yield (289 mg), white
1
solid; mp 141−142 °C. H NMR (300 MHz, CDCl3): δ 7.54 (d, J =
9.0 Hz, 2H), 7.45−7.47 (m, 3H), 7.35 (d, J = 9.6 Hz, 2H), 7.16 (d, J =
8.1 Hz, 2H), 3.96 (q, J = 7.5 Hz, 2H), 2.57 (s, 3H), 2.35 (s, 3H), 0.85
(t, J = 7.8 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 167.3, 160.4,
155.5, 153.9, 136.0, 135.6, 133.8, 129.9, 129.5, 129.4, 128.6, 127.9,
126.1, 121.0, 120.1, 116.0, 90.4, 61.3, 23.9, 20.9, 13.4 ppm; IR (KBr) v:
3331, 2220, 1712, 1604, 1556, 1516, 1452, 1365, 1278, 1180, 1082,
813 cm−1; HRMS (ESI) calcd for C23H21N3O2 ([M + H]+) 372.1712,
found 372.1709.
Ethyl 4-(4-Bromophenyl)-5-cyano-2-methyl-6-(phenylamino)-
1,4-dihydropyridine-3-carboxylate (5e). Petroleum ether/ethyl ac-
etate 10:1, 75% yield (326 mg), pale yellow solid; mp 176−178 °C. 1H
NMR (300 MHz, CDCl3): δ 7.55 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 8.7
Hz, 2H), 7.25 (t, J = 5.4 Hz, 2H), 7.07−7.18 (m, 3H), 4.75 (s, 1H),
4.00 (q, J = 6.9 Hz, 2H), 2.33 (s, 3H), 1.00 (t, J = 6.9 Hz, 3H) ppm;
13C NMR (75 MHz, CDCl3): δ 168.4, 155.3, 137.0, 136.8, 135.2,
134.7, 132.4, 131.7, 131.5, 130.1, 129.8, 126.6, 123.5, 122.9, 114.6,
113.3, 89.8, 60.0, 47.7, 43.6, 39.5, 30.9, 21.0, 14.0 ppm; IR (KBr) v:
3329, 2216, 1714, 1651, 1593, 1490, 1440, 1180, 1072, 1047, 1010,
906, 825, 732, 698 cm−1; HRMS (ESI) calcd for C22H21BrN3O2 ([M +
H]+) 438.0817, found 438.0812.
Ethyl 5-Cyano-2-methyl-4-(4-nitrophenyl)-6-(p-tolylamino)-
nicotinate (5l). Petroleum ether/ethyl acetate 16:1, 86% yield (357
1
mg), brown solid; mp 163−164 °C. H NMR (300 MHz, CDCl3): δ
8.36 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 9.0 Hz, 2H), 7.53 (d, J = 8.4 Hz,
2H,), 7.21 (d, J = 8.4 Hz, 2H), 4.01 (q, J = 6.9 Hz, 2H), 2.61 (s, 3H),
2.36 (s, 3H), 0.93 (t, J = 7.5 Hz, 3H) ppm; 13C NMR (75 MHz,
CDCl3): δ 166.3, 153.1, 147.0, 146.7, 144.0, 136.1, 133.7, 130.7, 127.9,
123.9, 123.5, 120.1, 102.5, 60.2, 20.8, 19.6, 14.1 ppm; IR (KBr) v:
3273, 2181, 1654, 1608, 1508, 1479, 1344, 1267, 1186, 1109, 1068,
1006, 848, 827 cm−1; HRMS (ESI) calcd for C23H20NaN4O4 ([M +
Na]+) 439.1388, found 439.1382.
Ethyl 5-Cyano-2-methyl-6-(phenylamino)-4-(p-tolyl)nicotinate
(5f). Petroleum ether/ethyl acetate 10:1, 75% yield (278 mg), white
1
solid; mp 211−212 °C. H NMR (300 MHz, CDCl3): δ 7.64 (d, J =
7.8 Hz, 2H), 7.33 (t, J = 7.8 Hz, 2H), 7.17−7.23 (m, 4H), 7.07−7.12
(m, 1H), 3.97 (q, J = 7.2 Hz, 2H), 2.53 (s, 3H), 2.36 (s, 3H), 0.87 (t, J
= 7.5 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 167.4, 160.0,
159.7, 155.4, 154.1, 146.3, 139.6, 138.4, 132.9, 130.9, 130.3, 129.3,
128.9, 128.5, 127.9, 124.0, 120.7, 116.0, 90.9, 23.8, 21.3, 13.5 ppm; IR
(KBr) v: 3342, 2222, 1707, 1664, 1620, 1498, 1442, 1365, 1246, 1188,
815, 752 cm−1; HRMS (ESI) calcd for C23H21N3O2 ([M + H]+)
372.1712, found 372.1709.
Ethyl 5-Cyano-2-methyl-4-(3-nitrophenyl)-6-(p-tolylamino)-
nicotinate (5m). Petroleum ether/ethyl acetate 16:1, 85% yield (353
1
mg), white solid; mp 181−182 °C. H NMR (300 MHz, CDCl3): δ
8.32−8.36 (m, 1H), 8.25 (s, 1H), 7.49−7.72 (m, 2H), 7.49 (d, J = 8.4
Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 4.02 (q, J = 6.9 Hz, 2H), 2.60 (s,
3H), 2.35 (s, 3H), 0.95 (t, J = 6.6 Hz, 3H) ppm; 13C NMR (75 MHz,
CDCl3): δ 166.4, 161.5, 155.5, 151.4, 148.1, 137.6, 135.2, 134.3, 134.1,
129.8, 129.5, 124.2, 123.2, 121.3, 119.6, 115.3, 90.2, 61.5, 24.3, 20.9,
13.6 ppm; IR (KBr) v: 3332, 2214, 1714, 1560, 1535, 1348, 1273,
Ethyl 5-Cyano-4-(4-methoxyphenyl)-2-methyl-6-(phenylamino)-
nicotinate (5g). Petroleum ether/ethyl acetate 10:1, 62% yield (239
1
mg), white solid; mp 179−180 °C. H NMR (300 MHz, CDCl3): δ
7.67 (d, J = 7.5 Hz, 2H), 7.30−7.39 (m, 4H), 7.10−7.19 (m, 1H), 6.99
(d, J = 8.1 Hz, 2H), 4.03 (q, J = 7.5 Hz, 2H), 3.85 (s, 3H), 2.56 (s,
D
dx.doi.org/10.1021/jo5014383 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1022, 813, 713 cm−1; HRMS (ESI) calcd for C23H20N4O4 ([M + H]+)
417.1563, found 417.1561.
Ethyl 4-(4-Chlorophenyl)-5-cyano-2-methyl-6-((3-nitrophenyl)-
amino)nicotinate (5t). Petroleum ether/ethyl acetate 8:1, 46% yield
(200 mg), yellow solid; mp 145−146 °C. 1H NMR (300 MHz,
CDCl3): δ 8.87 (s, 1H), 7.96−7.99 (m, 1H), 7.81−7.84 (m, 1H),
7.43−7.54 (m, 3H), 7.33 (d, J = 8.7 Hz, 2H), 4.05 (q, J = 7.5 Hz, 2H),
2.63 (s, 3H), 0.97 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (75 MHz,
CDCl3): δ 166.6, 160.5, 154.7, 152.8, 148.7, 139.5, 136.1, 133.8, 129.6,
129.5, 129.3, 129.0, 125.8, 121.6, 118.4, 115.3, 115.2, 91.4, 61.6, 23.8,
13.5 ppm; IR (KBr) v: 3346, 2220, 1716, 1612, 1552, 1523, 1483,
1348, 1282, 1182, 1095, 879, 819 cm−1; HRMS (ESI) calcd for
C22H17ClN4O4 ([M + H]+) 437.1016, found 437.1017.
Ethyl 4-(4-Bromophenyl)-5-cyano-2-methyl-6-((3-nitrophenyl)-
amino)nicotinate (5u). Petroleum ether/ethyl acetate 8:1, 45% yield
(216 mg), yellow solid; mp 188−190 °C. 1H NMR (300 MHz,
CDCl3): δ 8.88 (s, 1H), 7.96−8.00 (m, 1H), 7.80−7.84 (m, 1H),
7.61−7.64 (m, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H),
4.05 (q, J = 7.2 Hz, 2H), 2.64 (s, 3H), 0.97 (t, J = 7.2 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl3): δ 166.6, 160.6, 154.8, 152.9, 148.7,
139.5, 134.3, 132.5, 132.0, 131.8, 131.4, 131.3, 129.6, 125.8, 124.3,
121.6, 118.5, 115.4, 91.4, 61.7, 23.8, 13.6 ppm; IR (KBr) v: 3344, 2220,
1716, 1612, 1550, 1523, 1483, 1350, 1282, 1182, 1074, 1014, 879, 819
cm−1; HRMS (ESI) calcd for C22H17BrN4O4 ([M + H]+) 481.0511,
found 481.0510.
Diethyl 2-Methyl-4-(4-nitrophenyl)-6-(phenylamino)pyridine-3,5-
dicarboxylate (5v). Petroleum ether/ethyl acetate 10:1, 47% yield
(211 mg), white solid; mp 165−166 °C. 1H NMR (300 MHz,
CDCl3): δ 8.17 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 9.0 Hz, 2H), 7.43−
7.47 (m, 3H), 7.12 (d, J = 6.6 Hz, 2H), 4.14 (q, J = 7.2 Hz, 4H), 2.05
(s, 3H), 1.23 (t, J = 6.9 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ
167.5, 154.5, 148.1, 146.6, 140.0, 130.0, 129.6, 129.0, 128.9, 128.3,
124.4, 123.4, 115.2, 104.7, 85.9, 60.2, 18.8, 14.2, 14.0 ppm; IR (KBr) v:
2981, 1702, 1648, 1583, 1556, 1348, 1282, 1182, 1153, 1078, 1044,
845 cm−1; HRMS (ESI) calcd for C24H23N3O6 ([M + H]+) 450.1665,
found 450.1667.
Ethyl 4-(4-Chlorophenyl)-5-cyano-2-methyl-6-(p-tolylamino)-
nicotinate (5n). Petroleum ether/ethyl acetate 16:1, 83% yield (336
mg), pale yellow solid; mp 198−200 °C. 1H NMR (300 MHz,
CDCl3): δ 7.52 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.32 (d, J
= 6.6 Hz, 2H), 7.19 (d, J = 8.1 Hz, 2H), 4.01 (q, J = 6.9 Hz, 2H), 2.56
(s, 3H), 2.35 (s, 3H), 0.94 (t, J = 6.9 Hz, 3H) ppm; 13C NMR (75
MHz, CDCl3): δ 167.0, 160.7, 155.5, 152.7, 135.7, 135.5, 134.3, 134.0,
129.5, 129.3, 128.9, 121.1, 119.9, 115.7, 90.2, 61.4, 23.9, 20.8, 13.5
ppm; IR (KBr) v: 3325, 2222, 1710, 1610, 1573, 1552, 1514, 1452,
1373, 1280, 1182, 1082, 1018, 835, 815 cm−1; HRMS (ESI) calcd for
C23H20ClN3O2 ([M + H]+) 406.1322, found 406.1322.
Ethyl 4-(4-Bromophenyl)-5-cyano-2-methyl-6-(p-tolylamino)-
nicotinate (5o). Petroleum ether/ethyl acetate 16:1, 82% yield (368
mg), pale yellow solid; mp 166−168 °C. 1H NMR (300 MHz,
CDCl3): δ 7.61 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 7.15−
7.24 (m, 5H), 4.01 (q, J = 7.2 Hz, 2H), 2.56 (s, 3H), 2.35 (s, 3H), 0.94
(t, J = 6.9 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 167.0, 160.7,
155.5, 152.7, 135.4, 134.8, 134.0, 132.4, 132.0, 131.8, 131.3, 129.9,
129.6, 129.5, 123.9, 121.1, 119.8, 115.8, 90.1, 61.4, 24.0, 20.9, 13.5
ppm; IR (KBr) v: 3323, 2222, 1708, 1662, 1610, 1552, 1512, 1490,
1454, 1367, 1282, 1219, 1182, 1012, 817 cm−1; HRMS (ESI) calcd for
C23H20BrN3O2 ([M + H]+) 450.0817, found 450.0819.
Ethyl 5-Cyano-2-methyl-4-(p-tolyl)-6-(p-tolylamino)nicotinate
(5p). Petroleum ether/ethyl acetate 16:1, 81% yield (311 mg), pale
1
yellow solid; mp 163−165 °C. H NMR (300 MHz, CDCl3): δ 7.53
(d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H),
7.15 (d, J = 6.6 Hz, 2H), 4.00 (q, J = 6.9 Hz, 2H), 2.55 (s, 3H), 2.40
(s, 3H), 2.34 (s, 3H), 0.91 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (75
MHz, CDCl3): δ 167.4, 160.1, 155.6, 154.0, 139.5, 135.7, 133.7, 133.0,
129.4, 129.2, 127.8, 126.0, 121.0, 120.3, 119.7, 116.1, 90.5, 61.2, 23.8,
21.3, 20.8, 13.5 ppm; IR (KBr) v: 3327, 2222, 1718, 1614, 1556, 1512,
1456, 1413, 1375, 1271, 1176, 1072, 815 cm−1; HRMS (ESI) calcd for
C24H23N3O2 ([M + H]+) 386.1868, found 386.1869.
Diethyl 2-Methyl-4-(3-nitrophenyl)-6-(phenylamino)pyridine-3,5-
dicarboxylate (5w). Petroleum ether/ethyl acetate 10:1, 48% yield
(215 mg), white solid; mp 161−162 °C. 1H NMR (300 MHz,
CDCl3): δ 8.32 (s, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 7.5 Hz,
1H), 7.43−7.51 (m, 5H), 7.23 (d, J = 6.6 Hz, 2H), 5.17 (s, 1H), 4.13
(q, J = 7.2 Hz, 4H), 2.07 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H) ppm; 13C
NMR (75 MHz, CDCl3): δ 167.5, 149.5, 148.2, 140.0, 134.0, 130.1,
129.7, 129.4, 129.1, 128.9, 128.6, 124.2, 122.7, 121.4, 117.8, 105.0,
60.2, 39.1, 18.8, 14.2 ppm; IR (KBr) v: 2976, 1693, 1637, 1573, 1521,
1346, 1278, 1201, 1143, 1083, 1024, 810 cm−1; HRMS (ESI) calcd for
C24H23N3O6 ([M + H]+) 450.1665, found 450.1665.
Ethyl 5-Cyano-2-methyl-4-(2-nitrophenyl)-6-(p-tolylamino)-
nicotinate (5q). Petroleum ether/ethyl acetate 16:1, 80% yield (333
1
mg), brown solid; mp 162−164 °C. H NMR (300 MHz, CDCl3): δ
8.27−8.30 (m, 1H), 7.63−7.76 (m, 2H), 7.52 (d, J = 8.4 Hz, 2H),
7.28−7.31 (m, 1H), 7.21 (d, J = 8.1 Hz, 2H), 3.94 (q, J = 7.2 Hz, 2H),
2.65 (s, 3H), 2.36 (s, 3H), 0.88 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (75
MHz, CDCl3): δ 165.8, 162.8, 155.1, 153.0, 147.4, 135.3, 134.2, 133.7,
132.2, 130.2, 129.5, 124.8, 121.3, 117.7, 115.0, 90.6, 61.2, 25.1, 20.9,
13.4 ppm; IR (KBr) v: 3406, 2216, 1710, 1606, 1556, 1512, 1450,
1342, 1278, 1261, 1178, 817, 796 cm−1; HRMS (ESI) calcd for
C23H20N4O4 ([M + H]+) 417.1563, found 417.1559.
Diethyl 4-(4-Chlorophenyl)-2-cyano-6-(phenylamino)pyridine-
3,5-dicarboxylate (5x). Petroleum ether/ethyl acetate 10:1, 39%
1
Ethyl 5-Cyano-4-(2,4-dichlorophenyl)-2-methyl-6-(p-tolylamino)-
nicotinate (5r). Petroleum ether/ethyl acetate 16:1, 72% yield (316
mg), pale yellow solid; mp 135−137 °C. 1H NMR (300 MHz,
CDCl3): δ 7.51−7.54 (m, 2H), 7.33−7.37 (m, 1H), 7.15−7.20 (m,
4H), 4.02 (q, J = 7.2 Hz, 2H), 2.64 (s, 3H), 2.36 (s, 3H), 0.95 (t, J =
7.2 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 165.9, 162.3, 155.3,
151.2, 135.8, 135.3, 134.1, 134.0, 133.3, 130.3, 130.1, 129.6, 129.5,
127.2, 121.2, 115.0, 91.3, 61.2, 24.7, 20.9, 13.5 ppm; IR (KBr) v: 3329,
2225, 1720, 1618, 1562, 1510, 1454, 1363, 1273, 1176, 1083, 1055,
812 cm−1; HRMS (ESI) calcd for C23H19Cl2N3O2 ([M + H]+)
440.0932, found 440.0930.
Ethyl 5-Cyano-2-methyl-4-(3-nitrophenyl)-6-((3-nitrophenyl)-
amino)nicotinate (5s). Petroleum ether/ethyl acetate 8:1, 52% yield
(243 mg), yellow solid; mp 191−193 °C. 1H NMR (300 MHz,
CDCl3): δ 8.87 (s, 1H), 8.36 (s, 1H), 8.26 (s, 1H), 7.99−8.02 (m,
1H), 7.83−7.85 (m, 1H), 7.70−7.72 (m, 1H), 7.47−7.56 (m, 2H),
4.06 (q, J = 6.9 Hz, 2H), 2.67 (s, 3H), 0.98 (t, J = 7.5 Hz, 3H) ppm;
13C NMR (75 MHz, CDCl3): δ 166.0, 161.3, 154.7, 151.5, 148.7,
yield (175 mg), white solid; mp 189−190 °C. H NMR (300 MHz,
CDCl3): δ 7.35 (d, J = 8.1 Hz, 2H), 7.18−7.22 (m, 2H), 7.18−7.32
(m, 5H), 7.13 (d, J = 8.4 Hz, 2H), 4.27 (q, J = 8.1 Hz, 2H), 3.96 (q, J
= 7.2 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H), 0.95 (t, J = 6.9 Hz, 3H) ppm;
13C NMR (75 MHz, CDCl3): δ 168.8, 166.3, 156.6, 138.8, 138.5,
135.7, 134.2, 133.6, 131.0, 130.5, 129.3, 128.7, 128.3, 126.4, 126.1,
117.4, 91.1, 62.9, 59.6, 13.9 ppm; IR (KBr) v: 2928, 1746, 1662, 1608,
1593, 1562, 1493, 1444, 1241, 1128, 10626, 1014, 842 cm−1; HRMS
(ESI) calcd for C24H21ClN3O4 ([M + H]+) 450.1220, found 450.1218.
Diethyl 4-(4-Bromophenyl)-2-methyl-6-(phenylamino)pyridine-
3,5-dicarboxylate (5y). Petroleum ether/ethyl acetate 10:1, 38%
1
yield (183 mg), white solid; mp 246−247 °C. H NMR (300 MHz,
CDCl3): δ 7.51 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 6.6 Hz, 2H), 7.18−
7.32 (m, 3H), 7.07 (d, J = 8.4 Hz, 2H), 4.62 (s, 1H, NH), 4.29 (q, J =
7.5 Hz, 2H), 3.97 (q, J = 6.9 Hz, 2H), 2.16 (s, 3H), 1.28 (t, J = 6.6 Hz,
3H), 0.95 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ
168.8, 166.2, 156.6, 139.3, 138.5, 136.2, 131.6, 131.4, 131.2, 130.9,
129.3, 126.4, 126.1, 122.4, 121.9, 117.4, 91.0, 62.9, 59.6, 30.5, 13.9
ppm; IR (KBr) v: 2924, 1745, 1651, 1606, 1593, 1579, 1492, 1433,
1240, 1122, 1056, 1010, 840 cm−1; HRMS (ESI) calcd for
C24H23BrN2O4 ([M + H]+) 483.0919, found 483.0922.
148.1, 139.2, 137.0, 134.0, 129.9, 129.6, 126.0, 124.4, 123.2, 121.5,
118.7, 115.6, 114.8, 91.3, 61.8, 24.1, 13.6 ppm; IR (KBr) v: 3350, 2233,
1732, 1612, 1556, 1525, 1479, 1438, 1348, 1273, 1184, 815, 738 cm−1;
HRMS (ESI) calcd for C22H17N5O6 ([M + Na]+) 470.1076, found
470.1074.
Ethyl 5-Cyano-2-methyl-4-(4-nitrophenyl)-6-(phenylamino)-1,4-
dihydropyridine-3-carboxylate (6a). Petroleum ether/ethyl acetate
E
dx.doi.org/10.1021/jo5014383 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1
10:1, 85% yield (343 mg), pale yellow solid; mp 198−200 °C. H
NMR (300 MHz, CDCl3): δ 8.18 (d, J = 8.7 Hz, 2H), 7.38−7.44 (m,
4H), 7.07 (d, J = 7.8 Hz, 2H), 6.33−6.36 (m, 1H), 6.01 (s, 1H), 4.81
(s, 1H), 4.06 (q, J = 7.2 Hz, 2H), 2.35 (s, 3H), 1.14 (t, J = 7.2 Hz, 3H)
ppm; 13C NMR (75 MHz, CDCl3): δ 165.3, 152.0, 145.9, 145.5, 143.1,
135.9, 129.3, 127.0, 124.9, 123.1, 121.8, 118.9, 101.7, 64.0, 59.4, 39.7,
18.7, 13.2 ppm; IR (KBr) v: 3284, 3220, 2185, 1651, 1598, 1475, 1346,
1271, 1238, 1105, 1064, 825 cm−1; HRMS (ESI) calcd for
C22H20N4O4 ([M + H]+) 405.1563, found 405.1562.
cm−1; HRMS (ESI) calcd for C16H16N4O4 ([M + H]+) 329.1249,
found 329.1251.
ASSOCIATED CONTENT
■
S
* Supporting Information
Spectral data for all compounds and crystallographic data of
compound 5f and 6a. This material is available free of charge
via the Internet at http://pubs.acs.org.
Ethyl 5-Cyano-2-methyl-6-(phenylamino)-4-(p-tolyl)-1,4-dihy-
dropyridine-3-carboxylate (6b). Petroleum ether/ethyl acetate 16:1,
AUTHOR INFORMATION
1
■
78% yield (290 mg), white solid; mp 167−168 °C. H NMR (300
Corresponding Author
*Tel:+86-553-5910129. Fax: +86-553-5910126. E-mail: shyj@
mail.ahnu.edu.cn
MHz, CDCl3): δ 7.29−7.34 (m, 2H), 7.23 (d, J = 7.5 Hz, 2H), 7.17 (d,
J = 7.5 Hz, 2H), 7.05−7.13 (m, 3H), 4.73 (s, 1H), 3.96 (q, J = 7.2 Hz,
2H), 2.33 (s, 3H), 2.24 (s, 3H), 0.95 (t, J = 7.2 Hz, 3H) ppm; 13C
NMR (75 MHz, CDCl3): δ 167.8, 154.1, 138.2, 137.4, 134.0, 132.2,
128.9, 128.8, 128.5, 128.2, 127.1, 125.5, 125.4, 114.4, 112.9, 90.2, 58.9,
47.1, 38.5, 30.3, 20.3, 13.0 ppm; HRMS (ESI) calcd for C23H23N3O2
([M + H]+) 374.1868, found 374.1867.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Ethyl 5-Cyano-6-ethoxy-2-methyl-4-(4-nitrophenyl)nicotinate
■
(7a). Petroleum ether/ethyl acetate 10:1, 75% yield (266 mg), yellow
This work was supported by the National Natural Science
Foundation of China (No. 21172001, 21372008), the Program
for the NCET (NCET-10-0004), and the Anhui Provincial
Natural Science Foundation (No. 1308085QB39).
1
solid; mp 150−152 °C. H NMR (300 MHz, CDCl3): δ 8.38 (d, J =
8.7 Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H), 4.62 (q, J = 7.2 Hz, 2H), 4.06
(q, J = 7.5 Hz, 2H), 2.64 (s, 3H), 1.49 (t, J = 7.2 Hz, 3H), 0.98 (t, J =
7.2 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 166.3, 163.5, 160.3,
152.7, 148.3, 141.6, 129.3, 128.6, 123.8, 123.6, 122.1, 113.8, 93.7, 64.1,
61.8, 23.7, 14.3, 13.6 ppm; IR (KBr) v: 2216, 1716, 1656, 1564, 1456,
1298, 1269, 1043, 1004, 702 cm−1; HRMS (ESI) calcd for
C18H17N3O5 ([M + H]+) 356.1246, found 356.1244.
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Ethyl 5-Cyano-6-ethoxy-2-methyl-4-(3-nitrophenyl)nicotinate
(7b). Petroleum ether/ethyl acetate 10:1, 73% yield (259 mg), white
1
solid; mp 78−80 °C. H NMR (300 MHz, CDCl3): δ 8.31−8.35 (m,
1H), 8.23 (s, 1H), 7.64−7.72 (m, 2H), 4.59 (q, J = 7.2 Hz, 2H), 4.04
(q, J = 7.2 Hz, 2H), 2.60 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H), 0.97 (t, J =
7.5 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 166.3, 163.5, 160.2,
152.3, 148.1, 136.7, 134.2, 129.8, 124.3, 123.2, 122.4, 113.8, 94.1, 64.0,
61.8, 23.7, 14.3, 13.6 ppm; IR (KBr) v: 2233, 1720, 1556, 1512, 1444,
1350, 1273, 1157, 1095, 1022, 825, 740, 702 cm−1; HRMS (ESI) calcd
for C18H17N3O5 ([M + H]+) 356.1246, found 356.1244.
Ethyl 5-Cyano-6-ethoxy-4-(4-nitrophenyl)-2-phenylnicotinate
(7c). Petroleum ether/ethyl acetate 10:1, 68% yield (283 mg), pale
1
yellow solid; mp 162−163 °C. H NMR (300 MHz, CDCl3): δ 8.35
(d, J = 8.1 Hz, 2H), 7.62−7.64 (m, 2H), 7.57 (d, J = 8.4 Hz, 2H),
7.45−7.47 (m, 3H), 4.66 (q, J = 6.9 Hz, 2H), 3.88 (q, J = 7.2 Hz, 2H2),
1.49 (t, J = 6.9 Hz, 3H), 0.82 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (75
MHz, CDCl3): δ 166.5, 163.4, 158.9, 153.4, 148.5, 141.0, 138.0, 130.5,
130.2, 129.5, 129.0, 128.7, 128.5, 128.4, 123.8, 122.2, 113.7, 94.9, 64.3,
61.9, 14.3, 13.3 ppm; IR (KBr) v: 2229, 1720, 1550, 1519, 1350, 1247,
1141, 1014, 862, 690 cm−1; HRMS (ESI) calcd for C23H19N3O5 ([M +
H]+) 418.1403, found 418.1402.
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̈
(b) Krohnke, F.; Zecher, W. Angew. Chem. 1962, 74, 811−817.
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Ethyl 6-Amino-5-cyano-2-methyl-4-(4-nitrophenyl)-1,4-dihydro-
(13) Boger, D. L.; Panek, J. S. J. Org. Chem. 1981, 46, 2179−2182.
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pyridine-3-carboxylate (7d). Petroleum ether/ethyl acetate 10:1,
1
65% yield (213 mg), yellow solid; mp 151−153 °C. H NMR (300
MHz, CDCl3): δ 8.18 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H),
4.63 (s, 2H), 4.55 (s, 1H), 4.04 (q, J = 7.2 Hz, 2H), 2.40 (s, 3H), 1.09
(t, J = 6.9 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 165.2, 158.0,
157.6, 151.0, 147.0, 128.4, 124.0, 118.3, 106.7, 61.0, 38.7, 18.6, 13.9
ppm; IR (KBr) v: 3402, 3328, 2198, 1689, 1649, 1608, 1517, 1346,
1211, 1174, 1060, 858, 738 cm−1; HRMS (ESI) calcd for C16H16N4O4
([M + H]+) 329.1249, found 329.1250.
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Ethyl 6-Amino-5-cyano-2-methyl-4-(3-nitrophenyl)-1,4-dihydro-
pyridine-3-carboxylate (7e). Petroleum ether/ethyl acetate 10:1,
1
63% yield (206 mg), yellow solid; mp 158−159 °C. H NMR (300
MHz, CDCl3): δ 8.11 (d, J = 9.3 Hz, 1H), 8.04 (s, 1H), 7.59 (d, J = 7.8
Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 4.63 (s, 2H), 4.57 (s, 1H), 4.05 (q, J
= 6.9 Hz, 2H), 2.40 (s, 3H), 1.11 (t, J = 7.2 Hz, 3H) ppm; 13C NMR
(75 MHz, CDCl3): δ 165.2, 157.9, 157.7, 148.5, 146.0, 134.0, 133.9,
129.5, 122.5, 122.4, 106.9, 60.9, 38.7, 18.6, 13.9 ppm; IR (KBr) v:
3404, 3325, 2250, 1707, 1625, 1471, 1433, 1155, 1049, 1024, 842, 761
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