Meglumine: An efficient, biodegradable, and recyclable green catalyst for one-pot synthesis of functionalized dihydropyridines

Article abstract of DOI:10.1007/s00706-015-1416-9

A green and efficient one-pot synthesis of functionalized dihydropyridines by four-component reaction of aldehydes, amine, malononitrile, and dimethyl acetylenedicarboxylate in presence of meglumine has been developed. The main advantages of this new meth

Full text of DOI:10.1007/s00706-015-1416-9

Monatsh Chem
DOI 10.1007/s00706-015-1416-9
ORIGINAL PAPER
Meglumine: an efficient, biodegradable, and recyclable green
catalyst for one-pot synthesis of functionalized dihydropyridines
•
Hong-Shuo Chen Rui-Yun Guo
Received: 22 November 2014 / Accepted: 5 January 2015
Ó Springer-Verlag Wien 2015
Abstract A green and efficient one-pot synthesis of
functionalized dihydropyridines by four-component reac-
tion of aldehydes, amine, malononitrile, and dimethyl
acetylenedicarboxylate in presence of meglumine has been
developed. The main advantages of this new methodology
are reusability of catalyst, simplicity of the starting mate-
rials, short reaction time, one-pot and high yields of
products.
Functionalized dihydropyridines are an important class of
biologically active heterocycles [4–7]. Dihydropyridine
derivatives have attracted considerable attention because of
their wide variety of biological activities, including anti-
hypertension [8], antioxidant [9], anticancer [10], and
antitumor activity [11]. Functionalized dihydropyridines
are also potential calcium channel antagonists, which are
structurally similar to biologically active 4H-pyran deriv-
atives [12]. Consequently, various methods have been
developed for the synthesis of these compounds [13–17].
Yan et al. [18] have synthesized poly-substituted dihydro-
pyridine derivatives using triethylamine as a base, as well
as solvent and catalyst. Pal and coworkers [19, 20] have
reported the synthesis of functionalized dihydropyridines
used KF/Al2O3 or NaOH as catalysts. Pal [21] also has
synthesized them with the use of PEG as solvent without
catalyst. Kumar and coworker [22] have synthesized the
functionalized dihydropyridines under grinding condition
without catalyst and solvent. Although these procedures
worked nicely in many cases, sometimes, however, some
of these procedures are associated with one or more
shortcomings such as long reaction time [19–21], toxic
solvent and catalyst [18], unsatisfactory yield [19–21], or
the lack of generality [22]. Due to the importance of
functionalized dihydropyridines from pharmaceutical,
industrial, and synthetic points of view, the development of
a more practical and economical method for the prepara-
tion of these compounds is still highly desirable.
Graphical abstract
O
O
R3
O
OR3
R1
CN
CN
O
O
O
CHO
R1
NH2
R2
Meglumine
EtOH/H2O
+
+
+
R2
N
R3
OR3
H2N
CN
Keywords Multicomponent reaction ꢀ
Functionalized dihydropyridines ꢀ Meglumine ꢀ
Recyclable catalyst
Introduction
In medicinal chemistry, the synthesis of biologically active
molecules is one of the main challenges. Heterocycles
constitute the largest diversity of organic molecules of
chemical, biomedical, and industrial significance [1–3].
In recent years, the target of science and technology has
been shifting more towards environmentally friendly, sus-
tainable resources and reusable catalysts. Some biological
catalysts such as chitosan [23–25], cellulose sulfate [26–
30], xanthan sulfuric acid [31–35], and starch sulfuric acid
[36–38] have been widely used in organic synthesis.
However, the number of biological catalyst is still limited
H.-S. Chen (&)
Beijing General Research Institute of Mining and Metallurgy,
Beijing 100160, China
e-mail: chenhongshuo2011@163.com
R.-Y. Guo
The College of Chemistry and Material Science, Hebei Normal
University, Shijiazhuang 050024, China
123

H.-S. Chen, R.-Y. Guo
at this stage. More recently, meglumine as a biological
catalyst has been introduced in organic synthesis [39–42].
Meglumine is an amino sugar derived from sorbitol with
the IUPAC name of (2R,3R,4R,5S)-6-(methylamino)hex-
ane-1,2,3,4,5-pentol. It contains an amino group, primary
and secondary hydroxyl groups that can activate the
nucleophilic as well as electrophilic components of the
reactions by hydrogen bonding and donation of a lone pair
of electrons, respectively. Meglumine possesses environ-
mentally benign properties such as bio-degradability,
physiological inertness, inexpensiveness, non-corrosivity,
stability to air and moisture, and largely available in the
market.
NaOH, and choline chloride were also tested, in which the
product was obtained in low yields. Meglumine was found
to be the most effective catalyst for this transformation
since it gave the highest yield of product. The efficiency of
the catalyst was found to be affected the quantity of the
catalyst used in the reaction. It was also found that the use
of 10 mmol% meglumine is sufficient to promote the
reaction (Table 1, entry 14).
Next, the effects of solvents were evaluated for this
model reaction, and the results are summarized in Table 2.
As shown in Table 2, the results showed that the efficiency
and the yield of the reaction in aqueous ethanol solution
were higher than those obtained in other solvents such as
H2O, MeOH, EtOH, and PEG400 or under solvent-free
conditions.
Meanwhile, multicomponent reactions (MCRs) repre-
sent a highly valuable synthetic tool for the construction of
novel and complex molecular structures because of their
environmentally friendly, atom economy, and high
throughput generation of organic compounds. Multicom-
ponent reactions take significant advantages over
conventional stepwise strategies by reducing waste pro-
duction, saving energy, shortening reaction periods, and
avoiding protection and deprotection of functional groups;
thus resulting in both economical and environmental ben-
efits [43–60]. Therefore, the development of MCRs using
meglumine as catalyst has been considered in our research
work. Herein, we report a novel, efficient, and environ-
mentally benign procedure for the synthesis of
functionalized dihydropyridines by a one-pot, four-com-
ponent reaction of aldehydes, amine, malononitrile, and
dimethyl acetylenedicarboxylate in the presence of meg-
lumine in aqueous ethanol solution (Scheme 1).
To examine the efficiency of this multicomponent reac-
tion, a series of different aldehydes was employed. As shown
in Table 3, this protocol can be applied to aromatic aldehydes
either with electron-withdrawing groups or electron-donating
groups. Furthermore, a series of different substituted alde-
hydes gave excellent yields. It has been observed that the
benzaldehyde with electron-withdrawing groups led to pro-
ducts in shorter reaction time. Para-substituted and meta-
substituted benzaldehyde needed shorter reaction time than
those with ortho-substituted benzaldehyde. To our disap-
pointment, when aliphatic aldehyde instead of aromatic
aldehyde, such as pelargonic aldehyde was subjected to the
reaction system in 24 h, no reaction was observed.
Aliphatic amines show less reactivity than aromatic
amines for this reaction, for example cyclopropylamine
gave the corresponding product in 80 % yield (Table 3,
entry 19), whereas 4-methylaniline provided 93 % yield
(Table 3, entry 20). Aromatic amines with stronger elec-
tron-donor groups showed less reactivity, and more
reaction time was required than electron-withdrawing
substituents. Para-substituted as well as meta-substituted
amines were found to react well to give the corresponding
product in high yields, however, ortho-substituted cannot
get the products.
Results and discussion
To optimize the reaction conditions, we conducted the
reaction of 4-chlorobenzaldehyde, 4-methylaniline, mal-
ononitrile, and dimethyl acetylenedicarboxylate at room
temperature in various conditions. As shown in Table 1, in
the absence of catalyst, no product was formed. Some
commercially available catalysts including DMU, urea,
Al2O3, Et3N, CuO, ZnO, CH3COONa, NaHCO3, K2CO3,
Dimethyl and diethyl acetylenedicarboxylate were also
tested. As revealed in Table 3, these reactants worked well
and furnished the desired products in high yields. To extend
Scheme 1
O O
R3
O
OR3
R1
CN
CN
O
O
O
CHO
R1
NH2
R2
Meglumine
EtOH/H2O
+
+
+
R2
N
OR3
R3
H2N
CN
1
2
3
4
5
123

Meglumine for one-pot synthesis of dihydropyridines
In conclusion, we have developed a new, one-pot synthesis
of functionalized dihydropyridines by the reaction of aldehydes,
amine, malononitrile, and dimethyl acetylenedicarboxylate
using meglumine as an efficient, eco-friendly, reusable, and
biodegradable catalyst. This method is found to be more
advantageous than the previously reported methods. This cat-
alyst could be directly reused at least three additional times.
Table 1 Influence of different catalysts for the reaction of 4-chlo-
robenzaldehyde, 4-methylaniline, malononitrile, and dimethyl
acetylenedicarboxylate
Entry Catalyst
Catalyst loading/mol% Time/h Yield/%a
1
No [21]
CeO2
10
10
10
10
10
10
10
10
10
10
10
10
10
4.5
4.5
4.5
0
40
35
80
50
50
35
85
50
60
85
10
15
94
90
94
2
10
10
10
10
10
10
3
DMU
4
K2CO3
CH3COONa
NaHCO3
Urea
5
Experimental
6
7
Melting points were determined using an X-4 apparatus. IR
spectra were taken as KBr discs using a Bruker-TENSOR
27 spectrometer instrument. NMR spectra were taken with
a Bruker DRX-500 spectrometer, using CDCl3 or DMSO-
d6 as the solvent and TMS as an internal standard.
8
Choline chloride 10
9
ZnO
10
10
10
10
10
10
5
10
11
12
13
14
15
16
CuO
NaOH [20]
Al2O3 [19]
Et3N [18]
Meglumine
Meglumine
Meglumine
Representative procedure for the synthesis of dimethyl
6-amino-5-cyano-1-(p-tolyl)-4-(4-chlorophenyl)-1,4-
dihydropyridine-2,3-dicarboxylate
15
A solution of 140 mg 4-chlorobenzaldehyde (1.0 mmol),
66 mg malononitrile (1.0 mmol), and meglumine (0.1 mmol)
were stirred in 1 cm3 of aqueous ethanol solution at room
temperature. Then, a solution of 107 mg 4-methylaniline
(1.0 mmol) and 142 mg dimethyl acetylenedicarboxylate
(1.0 mmol) in 2 cm3 aqueous ethanol solution was added.
The resulting mixture was stirred until the reaction was
completed as indicated by thin-layer chromatography (TLC).
The resulting precipitates were collected by filtration and
washed with ethanol. The crude product was purified via
recrystallization from ethanol to give pure product.
Reaction condition: 4-chlorobenzaldehyde (1 mmol), 4-methylaniline
(1 mmol), malononitrile (1 mmol), dimethyl acetylenedicarboxylate
(1 mmol), catalyst (0.01 mmol)
a
Yield refers to isolated pure product
Table 2 Optimization of reaction conditions
Entry
Solvent
Time/h
Yield/%a
1
2
3
4
5
6
No
10
10
10
10
10
4.5
0
0
H2O
EtOH
90
50
80
94
PEG400
MeOH
Dimethyl 6-amino-5-cyano-1-(p-tolyl)-4-[3-(trifluoro
methyl)phenyl]-1,4-dihydropyridine-2,3-dicarboxylate
(5d, C24H20F3N3O4)
EtOH:H2O = 9:1
White solid; m.p.: 117–118 °C; IR (KBr): v = 3,473,
Reaction condition: 4-chlorobenzaldehyde (1 mmol), 4-methylaniline
(1 mmol), malononitrile (1 mmol), dimethyl acetylenedicarboxylate
(1 mmol), meglumine (0.01 mmol), solvent (3 cm3)
3,322, 2,188, 1,743, 1,654, 1,225 cm-1
;
1H NMR
(500 MHz, CDCl3): d = 2.42 (s, 3H), 3.47 (s, 3H), 3.61
(s, 3H), 4.15 (s, 2H), 4.74 (s, 1H), 7.21 (d, J = 8.5 Hz,
2H), 7.30 (d, J = 8.0 Hz, 2H), 7.48–7.54 (m, 2H), 7.57 (d,
J = 7.5 Hz, 1H), 7.62 (s, 1H) ppm; 13C NMR (125 MHz,
CDCl3): d = 21.3, 38.6, 52.1, 52.7, 61.7, 104.6, 120.3,
124.1 (3JCF = 3.75 Hz), 125.3, 127.4 (1JCF = 270.8 Hz),
129.3, 129.8, 130.6, 130.7, 130.9, 131.1 (2JCF = 31.6 Hz),
132.1, 141.1, 142.3, 145.8, 150.3, 163.3, 165.5 ppm.
a
Yield refers to isolated pure product
the utility and generality of this method, ethyl cyanocaetate
was also explored, only 60 % product was observed.
To explain the mechanism of this multicomponent
reaction, we proposed
a plausible reaction course
(Scheme 2). Arylamine was added to acetylenedicarbox-
ylate to give the 1,3-dipole intermediate (A). Knoevenagel
condensation of aldehyde with malononitrile and meglu-
mine as base catalyst yielded arylidene malononitrile (B),
and Michael addition of A and B to give intermediate C,
followed by migration of the hydrogen atom, intramole-
cular addition, and tautomerization to give D.
Dimethyl 6-amino-5-cyano-4-(3-phenoxyphenyl)-1-
(p-tolyl)-1,4-dihydropyridine-2,3-dicarboxylate
(5e, C29H25N3O5)
Light green solid; m.p.: 83–85 °C; IR (KBr): v = 3,467,
3,341, 2,182, 1,710, 1,648, 1,227 cm-1
;
1H NMR
(500 MHz, CDCl3): d = 2.40 (s, 3H), 3.44 (s, 3H), 3.61
(s, 3H), 4.08 (s, 2H), 4.62 (s, 1H), 6.91 (dd, J = 8.0,
123

H.-S. Chen, R.-Y. Guo
Table 3 Preparation of functionalized dihydropyridines catalyzed by meglumine
Compounds Aldehyde
Amine
R3
Time/h Yielda/% m.p./°C
Found
Reported
5a
5b
5c
5d
5e
5f
4-ClC6H4CHO
4-CH3C6H4NH2
4-CH3C6H4NH2
4-CH3C6H4NH2
4-CH3C6H4NH2
4-CH3C6H4NH2
4-CH3C6H4NH2
4-CH3C6H4NH2
4-CH3C6H4NH2
4-CH3C6H4NH2
4-CH3C6H4NH2
4-CH3C6H4NH2
4-CH3C6H4NH2
4-CH3C6H4NH2
4-CH3OC6H4NH2
4-BrC6H4NH2
Me 4.5
Me 5.5
94
93
90
93
90
93
95
95
90
93
90
92
90
90
90
91
92
90
80
93
90
92
93
90
87
90
92
91
93
197–198 188–189 [16]
182–183 168–169 [16]
180–182 181–182 [16]
117–118
4-CH3OC6H4CHO
3-ClC6H4CHO
Me
4
3-CF3C6H4CHO
Me 3.5
3-PhOC6H4CHO
Furan-2-carbaldehyde
Thiophen-2-carbaldehyde
Pyridin-4-carbaldehyde
Naphthalene-1-carbaldehyde
2-ClC6H4CHO
Me
Me
Me
6
4
4
83–85
186–188
5g
5h
5i
164–166
Me 3.5
Me 6.5
151–152
260–262
5j
Me
Me
Me
5
6
8
213–215
5k
5l
2-CH3OC6H4CHO
2,4-Cl2C6H3CHO
2,3,4-(MeO)3C6H2CHO
4-ClC6H4CHO
192–194
288–290
5m
5n
5o
5p
5q
5r
5s
Me 8.5
Me
Me 3.5
210–212
5
185–187 173–174 [16]
181–183
4-ClC6H4CHO
4-ClC6H4CHO
3-CH3OC6H4NH2
3-ClC6H4NH2
Me
Me
5
4
173–175
4-ClC6H4CHO
122–123 120–121 [16]
192–193
4-ClC6H4CHO
1-Naphthylamine
Cyclopropylamine
4-CH3C6H4NH2
4-CH3C6H4NH2
4-CH3C6H4NH2
4-CH3C6H4NH2
4-CH3C6H4NH2
Me 4.5
Me
Me 4.5
4-ClC6H4CHO
3
154–156
5t
3-NO2C6H4CHO
4-CH3(CH2)4OC6H4CHO
3-FC6H4CHO
210–212 213–214 [16]
148–149
5u
5v
5w
5x
5y
5z
5aa
5ab
5ac
a
Et
Et
Et
Et
Et
Et
Et
5
4
101–102
3-CF3C6H4CHO
3.5
4
215–216
4-(CH3)3CC6H5CHO
112–113
6-Nitrobenzo[d] [1, 3] dioxol-5-carbaldehyde 4-CH3C6H4NH2
6
229–231
4-ClC6H4CHO
4-PhOC6H4NH2
3-CH3C6H4NH2
6
161–163
4-ClC6H4CHO
5
76–78
4-ClC6H4CHO
9H-Fluoren-2-amine Me 6.5
4-CH3OC6H4NH2 Me 4.5
288–289
4-(CH3)3CC6H5CHO
240–242
Yields refer to isolated products
1.5 Hz, 1H), 7.02 (s, 1H), 7.07–7.15 (m, 6H), 7.23 (d,
J = 8.0 Hz, 2H), 7.32 (t, J = 8.0 Hz, 1H), 7.36 (t,
J = 8.0 Hz, 2H) ppm; 13C NMR (125 MHz, CDCl3):
d = 21.3, 38.5, 52.0, 52.6, 62.0, 104.9, 117.1, 117.4, 119.3,
120.6, 121.9, 123.6, 129.8, 129.9, 130.0, 130.5, 132.2,
140.9, 141.9, 147.0, 150.1, 156.9, 157.8, 163.5, 165.7 ppm.
Dimethyl 6-amino-5-cyano-4-(thiophen-2-yl)-1-(p-tolyl)-
1,4-dihydropyridine-2,3-dicarboxylate
(5g, C21H19N3O4S)
White solid; m.p.: 164–166 °C; IR (KBr): v = 3,422,
3,336, 2,187, 1,751, 1,573, 1,230 cm-1
;
1H NMR
(500 MHz, CDCl3): d = 2.40 (s, 3H), 3.46 (s, 3H), 3.71
(s, 3H), 4.17 (s, 2H), 4.98 (s, 1H), 6.95–6.97 (m, 1H), 6.99
(d, J = 3.5 Hz, 1H), 7.20–7.24 (m, 3H), 7.28 (s, 2H) ppm;
13C NMR (125 MHz, CDCl3): d = 21.3, 33.6, 52.1, 52.6,
62.2, 105.5, 120.4, 123.8, 124.5, 127.2, 129.9, 130.6,
132.3, 141.0, 141.4, 149.6, 150.4, 163.4, 165.5 ppm.
Dimethyl 6-amino-5-cyano-4-(furan-2-yl)-1-(p-tolyl)-1,4-
dihydropyridine-2,3-dicarboxylate (5f, C21H19N3O5)
Red solid; m.p.: 186–188 °C; IR (KBr): v = 3,472, 3,341,
2,178, 1,743, 1,642, 1,250 cm-1 1H NMR (500 MHz,
;
CDCl3): d = 2.40 (s, 3H), 3.47 (s, 3H), 3.69 (s, 3H), 4.15
(s, 2H), 4.78 (s, 1H), 6.17 (s, 1H), 6.32 (s, 1H), 7.22–7.25
(m, 4H), 7.38 (s, 1H) ppm; 13C NMR (CDCl3, 125 MHz):
d = 21.3, 32.3, 52.1, 52.6, 59.1, 103.0, 105.4, 110.4, 120.5,
129.9, 130.6, 132.5, 140.9, 142.2, 142.2, 151.2, 156.0,
163.5, 165.6 ppm.
Dimethyl
6-amino-5-cyano-1-(p-tolyl)-1,4-dihydro-4,40-
bipyridine-2,3-dicarboxylate (5h, C22H20N4O4)
White solid; m.p.: 151–152 °C; IR (KBr): v = 3,568,
3,463, 2,180, 1,747, 1,649, 1,226 cm-1
;
1H NMR
(500 MHz, CDCl3): d = 2.42 (s, 3H), 3.48 (s, 3H), 3.60
123

Meglumine for one-pot synthesis of dihydropyridines
Scheme 2
Ar'NH2
CO2Me
CO2Me
Ar'NH2
+
MeO2C
CO2Me
A
Ar
NC
CO2Me
CN
CN
NC
Ar
Meglumine
Ar
+
ArCHO
C
CN
B
N H2N
Me
CO2
Ar'
C
Migration of the
hydrogen atom
Ar
Ar
Intramolecular
addition
NC
CO2Me
NC
CO2Me
Me
NC
C
CO2Me
Tautomerization
H2N
N
Ar'
D
Me
HN
N
Ar'
N
HN
Ar'
CO2
CO2
CO2
Me
(s, 3H), 4.16 (s, 2H), 4.68 (s, 1H), 7.02–7.21 (m, 2H),
7.29–7.30 (m, 4H), 8.61–8.63 (m, 2H) ppm; 13C NMR
(125 MHz, CDCl3): d = 21.3, 38.1, 52.2, 52.7, 60.5,
103.4, 120.2, 122.0, 129.8, 130.6, 132.0, 141.2, 143.0,
150.3, 150.5, 153.1, 163.2, 165.5 ppm.
Dimethyl 6-amino-5-cyano-4-(2-methoxyphenyl)-1-
(p-tolyl)-1,4-dihydropyridine-2,3-dicarboxylate
(5k, C24H23N3O5)
White solid; m.p.: 192–194 °C; IR (KBr):v = 3,441,
3,319, 2,188, 1,747, 1,701, 1,251 cm-1
;
1H NMR
(500 MHz, CDCl3): d = 2.40 (s, 3H), 3.50 (s, 3H), 3.56
(s, 3H), 3.92 (s, 3H), 4.00 (s, 2H), 5.11 (s, 1H), 6.93 (d,
J = 8.0 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H),7.20–7.27 (m,
6H) ppm; 13C NMR (125 MHz, CDCl3): d = 21.3, 32.2,
51.9, 52.6, 55.8, 62.2, 104.2, 111.4, 120.9, 127.9, 128.2,
129.9, 130.5, 132.7, 132.9, 140.7, 142.9, 150.4, 156.8,
163.9, 166.0 ppm.
Dimethyl 6-amino-5-cyano-4-(naphthalene-2-yl)-1-
(p-tolyl)-1,4-dihydropyridine-2,3-dicarboxylate
(5i, C27H20N3O4)
White solid; m.p.: 260–262 °C; IR (KBr): v = 3,457,
3,366, 2,183, 1,745, 1,705, 1,644, 1,572, 1,202 cm-1; H
1
NMR (500 MHz, CDCl3): d = 2.42 (s, 3H), 3.42 (s, 3H),
3.51 (s, 3H), 4.03 (s, 2H), 5.60 (s, 1H), 7.27–7.32 (m, 4H),
7.49–7.56 (m, 2H), 7.56 (d, J = 6.0 Hz, 1H), 7.61 (t,
J = 8.0 Hz, 1H), 7.77 (d, J = 7.5 Hz, 1H), 7.87 (d,
J = 8.5 Hz, 1H), 8.47 (d, J = 8.5 Hz, 1H) ppm; 13C
NMR (125 MHz, CDCl3): d = 21.3, 33.2, 51.9, 52.7, 62.9,
105.5, 120.7, 123.5, 125.5, 125.8, 125.9, 126.3, 127.9,
128.6, 130.0, 130.6, 130.8, 132.4, 134.0, 141.0, 141.8,
142.4, 150.0, 163.7, 165.9 ppm.
Dimethyl 6-amino-5-cyano-4-(2,4-dichlorophenyl)-1-
(p-tolyl)-1,4-dihydropyridine-2,3-dicarboxylate
(5l, C23H19Cl2N3O4)
White solid; m.p.: 288–290 °C; IR (KBr): v = 3,467,
3,367, 2,182, 1,740, 1,648, 1,253 cm-1
;
1H NMR
(500 MHz, CDCl3): d = 2.42 (s, 3H), 3.47 (s, 3H), 3.56
(s, 3H), 4.08 (s, 2H), 5.24 (s, 1H), 7.23 (d, J = 8.0 Hz,
2H), 7.28–7.30 (m, 3H), 7.35 (d, J = 8.0 Hz, 1H), 7.40 (s,
1H) ppm; 13C NMR (125 MHz, DMSO-d6): d = 21.3,
35.6, 52.1, 52.7, 61.3, 103.7, 119.9, 127.8, 129.7, 130.0,
130.6, 130.8, 132.1, 133.3, 140.9, 141.2, 142.9, 150.0,
163.3, 165.4 ppm.
Dimethyl 6-amino-4-(2-chlorophenyl)-5-cyano-1-(p-tolyl)-
1,4-dihydropyridine-2,3-dicarboxylate
(5j, C23H20ClN3O4)
White solid; m.p.: 213–215 °C; IR (KBr): v = 3,473,
3,377, 2,180, 1,745, 1,645, 1,251 cm-1
;
1H NMR
(500 MHz, CDCl3): d = 2.42 (s, 3H), 3.45 (s, 3H), 3.55
(s, 3H), 4.07 (s, 2H), 5.29 (s, 1H), 7.17–7.20 (m, 1H), 7.24
(m, 2H), 7.28–7.31 (m, 3H), 7.38 (d, J = 8.0 Hz, 1H), 7.42
(dd, J = 7.5, 1.0 Hz, 1H) ppm; 13C NMR (125 MHz,
CDCl3): d = 21.3, 35.7, 51.9, 52.6, 61.2, 104.0, 120.3,
127.5, 128.3, 129.9, 130.0, 130.7, 132.2, 132.7, 141.0,
142.4, 142.8, 150.3, 163.5, 165.7 ppm.
Dimethyl 6-amino-5-cyano-1-(p-tolyl)-4-(2,3,4-trimethoxy
phenyl)-1,4-dihydropyridine-2,3-dicarboxylate
(5m, C26H27N3O7)
White solid; m.p.: 210–212 °C; IR (KBr): v = 3,423,
3,323, 2,188, 1,747, 1,654, 1,223 cm-1
;
1H NMR
(500 MHz, CDCl3): d = 2.41 (s, 3H), 3.47 (s, 3H), 3.57
(s, 3H), 3.86 (s, 3H), 3.90 (s, 3H), 3.99 (s, 2H), 4.01 (s,
123

H.-S. Chen, R.-Y. Guo
3H), 4.95 (s, 1H), 6.68 (d, J = 9.0 Hz, 1H), 6.98 (d,
J = 8.5 Hz, 1H), 7.24–7.29 (m, 4H) ppm; 13C NMR
(125 MHz, CDCl3): d = 21.3, 33.0, 51.9, 52.5, 55.9, 60.7,
61.5, 62.6, 104.7, 107.3, 120.9, 123.1, 129.9, 130.5, 130.8,
132.6, 140.7, 142.1, 142.2, 149.9, 151.5, 152.8, 163.8,
166.0 ppm.
(s, 3H), 4.47 (s, 1H), 4.70 (s, 2H), 7.09 (dd, J = 8.5,
2.5 Hz, 2H), 7.25–7.26 (m, 2H) ppm; 13C NMR (125 MHz,
CDCl3): d = 8.8, 9.8, 27.5, 37.4, 52.3, 53.2, 61.7, 107.7,
120.5, 127.8, 128.9, 132.8, 142.3, 143.4, 153.0, 164.0,
165.3 ppm.
Diethyl 6-amino-5-cyano-4-(4-pentyloxyphenyl)-
1-(p-tolyl)-1,4-dihydropyridine-2,3-dicarboxylate
(5u, C30H35N3O5)
Dimethyl 6-amino-1-(4-bromophenyl)-4-(4-chlorophenyl)-
5-cyano-1,4-dihydropyridine-2,3-dicarboxylate
(5o, C22H17BrClN3O4)
White solid; m.p.: 148–149 °C; IR (KBr): v = 3,465,
White solid; m.p.: 181–183 °C; IR (KBr): v = 3,470,
3,369, 2,185, 1,735, 1,643, 1,227 cm-1 1H NMR
;
3,336, 2,184, 1,717, 1,654, 1,224 cm-1
;
1H NMR
(500 MHz, CDCl3): d = 0.92–0.98 (m, 6H), 1.13 (t, 3H),
1.36–1.46 (m, 4H), 1.75–1.81 (m, 2H), 2.40 (s, 3H),
3.85–3.96 (m, 4H), 4.02–4.06 (m, 4H), 4.62 (s, 1H), 6.88
(d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.26–7.28
(m, 4H) ppm; 13C NMR (125 MHz, CDCl3): d = 13.5,
13.9, 14.1, 21.3, 22.5, 28.2, 29.0, 37.9, 60.8, 61.9, 68.0,
105.5, 114.6, 120.9, 128.3, 130.2, 130.4, 132.6, 137.3,
140.8, 141.4, 149.7, 158.2, 163.2, 165.3 ppm.
(500 MHz, CDCl3): d = 3.50 (s, 3H), 3.60 (s, 3H), 4.05
(s, 2H), 4.66 (s, 1H), 7.22 (d, J = 8.5 Hz, 2H), 7.28 (d,
J = 8.5 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 7.64 (d,
J = 8.5 Hz, 2H) ppm; 13C NMR (125 MHz, CDCl3):
d = 38.0, 52.2, 52.9, 63.2, 105.3, 119.9, 125.2, 128.4,
129.1, 131.8, 133.1, 133.4, 134.0, 141.5, 143.0, 149.2,
163.3, 165.4 ppm.
Dimethyl 6-amino-4-(4-chlorophenyl)-5-cyano-1-
(3-methoxyphenyl)-1,4-dihydropyridine-2,3-dicarboxylate
(5p, C23H20ClN3O5)
Diethyl 6-amino-5-cyano-4-(3-fluorophenyl)-
1-(p-tolyl)-1,4-dihydropyridine-2,3-dicarboxylate
(5v, C25H24FN3O4)
White solid; m.p.: 173–175 °C; IR (KBr): v = 3,475,
White solid; m.p.: 101–102 °C; IR (KBr): v = 3,406,
1
3,352, 2,179, 1,702, 1,647, 1,265 cm-1
;
1H NMR
3,329, 2,184, 1,716, 1,653, 1,418, 1,221 cm-1; H NMR
(500 MHz, CDCl3): d = 3.50 (s, 3H), 3.60 (s, 3H), 3.84
(s, 3H), 4.16 (s, 2H), 4.66 (s, 1H), 6.84 (s, 1H), 6.91 (d,
J = 7.5 Hz, 1H), 7.03 (dd, J = 8.5, 2.0 Hz, 1H), 7.29 (d,
J = 8.5 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 7.39 (t,
J = 8.0 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3):
d = 38.1, 52.1, 52.7, 55.7, 61.9, 104.8, 115.7, 116.3, 120.5,
122.0, 128.5, 128.9, 130.6, 132.9, 135.9, 141.9, 143.4,
149.9, 160.5, 163.4, 165.6 ppm.
(500 MHz, CDCl3): d = 0.97 (t, J = 7.5 Hz, 3H), 1.11 (t,
J = 7.0 Hz, 3H), 2.41 (t, 3H), 3.88–4.06 (m, 4H), 4.09 (s,
2H), 4.69 (s, 1H), 6.96 (t, J = 8.0 Hz, 1H), 7.08 (dd,
J = 7.5, 1.5 Hz, 1H), 7.17 (d, J = 7.5 Hz, 1H), 7.23–7.25
(m, 1H), 7.28–7.33 (m, 4H) ppm; 13C NMR (125 MHz,
CDCl3): d = 13.4, 13.8, 21.2, 38.4, 60.9, 61.9, 62.1, 104.7,
113.9, 114.0, 114.1, 114.2 (3JCF = 9.0 Hz), 120.3, 122.9,
130.1, 130.5, 132.2, 141.0, 141.9, 147.5, 147.6, 149.8,
162.9, 162.1, 164.1(1JCF = 245.0 Hz), 164.9 ppm.
Dimethyl 6-amino-4-(4-chlorophenyl)-5-cyano-1-
(naphthalene-1-yl)-1,4-dihydropyridine-2,3-dicarboxylate
(5r, C26H20ClN3O4)
Diethyl 6-amino-5-cyano-1-(p-tolyl)-4-[3-(trifluoro-
methyl)phenyl]-1,4-dihydropyridine-2,3-dicarboxylate
(5w, C26H24F3N3O4)
White solid; m.p.: 192–193 °C; IR (KBr): v = 3,420,
1
3,324, 2,178, 1,747, 1,709, 1,644, 1,228 cm-1; H NMR
White solid; m.p.: 215–216 °C; IR (KBr): v = 3,469,
(500 MHz, CDCl3): d = 3.24 (s, 3H), 3.60 (s, 3H), 3.84 (s,
3H), 4.06 (s, 2H), 4.86 (s, 1H), 7.38–7.46 (m, 4H),
7.51–7.62 (m, 4H), 7.77 (dd, J = 9.0, 2.0 Hz, 1H, HAr),
7.93 (dd, J = 6.0, 2.0 Hz, 1H, HAr), 8.00 (dd, J = 7.0,
2.5 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3): d = 38.1,
52.1, 52.5, 61.9, 104.6, 120.6, 122.1, 125.0, 127.5, 128.3,
128.5, 128.6, 128.9, 129.1, 131.2, 131.4, 133.0, 134.3,
142.9, 143.3, 150.1, 163.3, 165.7 ppm.
3,309, 2,189, 1,740, 1,654, 1,222 cm-1 1H NMR
;
(500 MHz, CDCl3): d = 0.97 (t, J = 7.0 Hz, 3H), 1.11
(t, J = 7.0 Hz, 3H), 2.41 (s, 3H), 3.80–4.10 (m, 4H), 4.13
(s, 2H), 4.74 (s, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.28 (d,
J = 8.0 Hz, 2H), 7.41–7.53 (m, 2H), 7.57 (d, J = 7.5 Hz,
1H), 7.63 (s, 1H) ppm; 13C NMR (125 MHz, CDCl3):
d = 13.4, 13.8, 21.2, 38.7, 61.0, 61.3, 62.0, 104.6, 120.5,
124.0,
124.1
(3JCF = 4.0 Hz),
123.1,
125.3
(1JCF = 270.9 Hz), 129.3, 130.1, 130.6, 130.8, 132.1,
Dimethyl 6-amino-4-(4-chlorophenyl)-5-cyano-1-
cyclopropyl-1,4-dihydropyridine-2,3-dicarboxylate
(5s, C19H18ClN3O4)
141.1, 142.2, 146.1, 150.4, 162.8, 164.9 ppm.
Diethyl 6-amino-4-[4-(tert-butyl)phenyl]-5-cyano-1-
(p-tolyl)-1,4-dihydropyridine-2,3-dicarboxylate
(5x, C29H33N3O4)
White solid; m.p.: 154–156 °C; IR (KBr): v = 3,356,
3,284, 2,359, 1,669, 1,050 cm-1 1H NMR (500 MHz,
;
CDCl3): d = 0.79–0.82 (m, 1H), 0.90–0.96 (m, 2H),
1.03–1.07 (m, 1H), 2.83–2.86 (m, 1H), 3.67 (s, 3H), 3.92
White solid; m.p.: 112–113 °C; IR (KBr): v = 3,428,
3,328, 2,185, 1,742, 1,649, 1,226 cm-1 1H NMR
;
123

Meglumine for one-pot synthesis of dihydropyridines
(500 MHz, CDCl3): d = 0.97 (t, J = 7.0 Hz, 3H), 1.11 (t,
J = 7.0 Hz, 3H), 1.32 (s, 9H), 2.41 (s, 3H), 3.85–4.07 (m,
6H), 4.65 (s, 1H), 7.23–7.30 (m, 6H), 7.36 (d, J = 8.5 Hz,
2H) ppm; 13C NMR (125 MHz, CDCl3): d = 13.5, 13.9,
21.3, 31.4, 34.5, 38.1, 60.8, 61.9, 62.8, 105.5, 125.6, 126.8,
130.2, 130.4, 132.6, 131.5, 140.8, 141.5, 142.0, 149.7,
149.8, 163.2, 165.3 ppm.
7.50 (s, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.82–7.87 (m, 2H)
ppm; 13C NMR (125 MHz, DMSO-d6): d = 37.0, 38.7,
52.4, 52.9, 59.5, 104.3, 121.2, 121.4, 125.8, 127.5, 128.1,
129.1, 129.2, 129.3, 132.0, 134.0, 140.4, 142.8, 143.1,
144.2, 144.7, 145.0, 151.5, 163.4, 165.5 ppm.
Dimethyl 6-amino-4-[4-(tert-butyl)phenyl]-5-cyano-1-
(4-methoxyphenyl)-1,4-dihydropyridine-2,3-dicarboxylate
(5ac, C27H29N3O5)
Diethyl 6-amino-5-cyano-4-(6-nitrobenzo[d][1, 3]dioxol-
5-yl)-1-(p-tolyl)-1,4-dihydropyridine-2,3-dicarboxylate
(5y, C26H24N4O8)
White solid; m.p.: 240–242 °C; IR (KBr): v = 3,471,
3,309, 2,189, 1,654, 1,576, 1,223 cm-1
;
1H NMR
Brown solid; m.p.: 229–231 °C; IR (KBr): v = 3,441,
(500 MHz, CDCl3): d = 1.32 (s, 9H), 3.48 (s, 3H), 3.61
(s, 3H), 3.85 (s, 3H), 4.06 (s, 2H), 4.63 (s, 1H), 6.96 (d,
J = 8.5 Hz, 2H), 7.25–7.29 (m, 4H), 7.37 (d, J = 8.5 Hz,
2H) ppm; 13C NMR (125 MHz, CDCl3): d = 31.4, 34.5,
37.8, 52.0, 52.6, 55.6, 62.8, 105.2, 114.9, 120.8, 125.7,
126.6, 127.3, 131.5, 141.8, 142.0, 149.8, 150.0, 160.7,
163.7, 165.9 ppm.
3,327, 2,185, 1,727, 1,680, 1,222 cm-1
;
1H NMR
(500 MHz, CDCl3): d = 0.97 (t, J = 7.5 Hz, 3H), 1.03
(t, J = 7.0 Hz, 3H), 2.42 (s, 3H), 3.86–3.98 (m, 4H), 4.17
(s, 2H), 5.62 (s, 1H), 6.12 (s, 2H), 7.03 (s, 1H), 7.28–7.31
(m, 4H), 7.35 (s, 1H) ppm; 13C NMR (125 MHz, CDCl3):
d = 13.4, 13.7, 21.3, 33.5, 61.1, 62.1, 102.9, 104.5, 104.7,
109.4, 119.9, 130.2, 130.5, 131.9, 137.2, 141.2, 142.4,
142.5, 146.8, 150.5, 151.9, 162.7, 164.7 ppm.
Acknowledgments We thank the National Natural Science Foun-
dation of China (21272053) for financial support.
Diethyl 6-amino-4-(4-chlorophenyl)-5-cyano-1-
(4-phenoxyphenyl)-1,4-dihydropyridine-2,3-dicarboxylate
(5z, C30H26ClN3O5)
References
White solid; m.p.: 161–163 °C; IR (KBr): v = 3,457,
3,331, 2,192, 1,739, 1,651, 1,220 cm-1
;
1H NMR
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(500 MHz, CDCl3): d = 1.03 (t, J = 7.0 Hz, 3H), 1.11
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1,4-dihydropyridine-2,3-dicarboxylate
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3H), 2.43 (s, 3H), 3.87–3.98 (m, 2H), 4.06 (dd, J = 7.5,
7.0 Hz, 2H), 4.15 (s, 2H), 4.69 (s, 1H), 7.18 (s, 2H),
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d = 13.4, 13.9, 21.2, 29.7, 38.3, 60.9, 61.9, 104.8, 120.6,
127.3, 128.6, 128.8, 129.7, 130.9, 131.3, 132.8, 134.9,
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(5ab, C29H22ClN3O4)
White solid; m.p.: 288–289 °C; IR (KBr): v = 3,441,
3,327, 2,180, 1,749, 1,708, 1,654, 1,570, 1,254 cm-1; H
1
NMR (500 MHz, CDCl3): d = 3.44 (s, 3H), 3.61 (s, 3H),
3.97 (s, 2H), 4.16 (s, 2H), 4.67 (s, 1H), 7.32–7.44 (m, 7H),
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