Multicomponent reactions leading to symmetric and asymmetric multi-substituted 1,4-dihydropyridines on montmorillonite

Article abstract of DOI:10.1016/j.tet.2013.04.006

Highly functionalized multi-substituted symmetric and asymmetric 1,4-dihydropyridines were concisely synthesized in moderate to good yields via one-pot multicomponent reactions (MCRs) of β-dicarbonyl compounds, aldehydes and amines at room temperature on

Full text of DOI:10.1016/j.tet.2013.04.006

Accepted Manuscript
Multicomponent reactions leading to symmetric and asymmetric multi-substituted 1, 4-
dihydropyridines on montmorillonite
Yu-peng Liu, Jin-ming Liu, Xin Wang, Tie-ming Cheng, Run-tao Li
PII:
S0040-4020(13)00518-8
10.1016/j.tet.2013.04.006
TET 24206
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 30 January 2013
Revised Date: 25 March 2013
Accepted Date: 2 April 2013
Please cite this article as: Liu Y-p, Liu J-m, Wang X, Cheng T-m, Li R-t, Multicomponent reactions
leading to symmetric and asymmetric multi-substituted 1, 4-dihydropyridines on montmorillonite,
Tetrahedron (2013), doi: 10.1016/j.tet.2013.04.006.
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Multicomponent reactions leading to
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symmetric and asymmetric multi-substituted
1, 4-dihydropyridines on montmorillonite
Yu-peng Liu, Jin-ming Liu, Xin Wang*, Tie-ming Cheng, Run-tao Li*
No.38 Xueyuan Road, Haidian District, Beijing, PR China

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Tetrahedron
journal homepage: www.elsevier.com
Multicomponent reactions leading to symmetric and asymmetric multi-
substituted 1, 4-dihydropyridines on montmorillonite
Yu-peng Liu, Jin-ming Liu, Xin Wang , Tie-ming Cheng, Run-tao Li
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Highly functionalized multi-substituted symmetric and asymmetric 1,4-dihydropyridines were
concisely synthesized in moderate to good yields via one-pot multicomponent reactions (MCRs)
of β-dicarbonyl compounds, aldehydes and amines at room temperature on montmorillonite. The
merits of this method include the environmentally friendly reaction conditions, simple operation,
broad substrate, satisfied yields and the reuse of the montmorillonite.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
1.4-dihydropyridine
multicomponent reaction
solid media
montmorillonite
green chemistry
1. Introduction
The 1,4-dihydropyridine (DHP) scaffold is not only a very
useful reducing agent1,2 and synthetic intermediates,3,4 but also an
important pharmacophore found in a large number of biologically
active5,6 and potential therapeutic compounds.7 Their pharmaco-
logical activities include calcium channel blockers,8 multidrug-
resistance (MDR) reversing agents, 9 , 10 radioprotection, 11 HIV
protease inhibition,12 cocaine dependent regulator,13 TGFβ signal
inhibitors 14 etc. Based on the existed experimental and SAR
studies of DHP derivatives,15 most of the researches were focused
on N-unsubstituted DHPs. However, the N-substituted DHPs
with biological activity are attracted more attention recently. For
example, N-acyloxy DHPs (Fig. 1, a)16 and N-substituted cage
dimeric DHPs (Fig. 1, b)17 were synthesized as P-gloycoprotein-
mediated MDR-reversing agents, N-aryl substituted DHPs were
verified as sirtuin activators and inhibitors (Fig. 1, c),18 and 1-
phenyl-4-glycosyl-dihydropyridines were prepared as potent
antileishmanial agents (Fig. 1, d).19
Figure 1. Representative N-substituted DHPs with biological
activities
Hantzsch DHPs synthesis is one of the most broadly used
methods for the preparation of DHPs. In order to improve the
efficiency of Hantzsch DHPs synthesis, different catalysts have
been explored and many of them exhibited excellent catalytic
activity, 20 - 23 such as L-proline, 24 S-Valin, 25 Yb(OTf)3, 26 I2, 27
TBAHS,28 HOAc,29 Et3N,30 DBU,31 Py32 and so on. Furthermore,
along with the development of environmental consciousness in
chemical research and industry, solvent-free reaction, microwave
33
method,29,30,31 “grindstone chemistry” technique
and some
efficient attempts have been used to build dihydropyridine
scaffold.34,35 However, some drawbacks still exist, such as the use
———
Corresponding author. Tel.: +8610 82801504; fax: +8610 82716956; E-mail addresses: xinwang@bjmu.edu.cn.(X, Wang);
lirt@bjmu.edu.cn.( R.-T., Li); Postal address: No.38 Xueyuan Road, Haidian District, Beijing100191, PR China

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Tetrahedron
of expensive or toxic catalyst, high reaction temperature, low
reaction yields significantly. For example, when para or meta
position of aniline was substituted, whatever it is electron-
withdrawing group or electron-donating group, the reaction were
performed smoothly (Table 2, entries 1-4). Whereas, ortho
substituted aniline wouldn’t occur the reaction (Table 2, entry 5).
Similarly, among all examined aromatic aldehydes (Table 2,
entries 7-12), para substituted aromatic aldehydes gained higher
yields compare to ortho substituted aromatic aldehydes. Also,
tert-butyl 3-oxobutanoate, which owned bulky ester group,
provided the lowest yield among the five tested esters (Table 2,
entry 16, yield 65%). Moreover, when acetylacetone was used to
replace β-carbonyl esters to react with ethyl glyoxalate and
different aromatic aldehydes (Table 2, entries 18-24), the
reactions were much easier to carry out, even aryl amine with
strong electron-withdrawing group could achieve the moderate
yield (Table 2, entry 24, yield 51%).
yields or finite scope of substrates. Especially, the research on the
synthesis of N-substituted DHPs is usually ignored.36 Recently,
Yan et al. reported an efficient multicomponent synthesis of N-
substituted DHPs in EtOH.37 As our continuing efforts to develop
reactions in solid media,38 we here report a practical synthesis of
highly functionalized multi-substituted symmetric and
asymmetric DHPs using montmorillonite K10 as solid-phase.
2. Results and discussion
Initially, the reaction of ethyl acetoacetate, ethyl glyoxalate
and 4-methoxyaniline was chosen as a model to examine the
effect of different solid media on the reaction (Table 1). To our
delight, montmorillonite K10, as the best one among the screened
six kinds of solid media, i.e. alkaline, acid and neutral Al2O3,
silica gel, bentonite and montmorillonite K10, could generate the
product in high yield (Table 1, entry 7, yield 82%) comparing to
the solvent free system (Table 1, entry 1, yield 48%).
Optimization for using amount of the montmorillonite K10
revealed that the best yield could be obtained when 0.75g
montmorillonite K10 was used under the experimental scale
(Table 1, entry 9, yield 86%) .
Next, based on the mechanism of DHPs synthesis, we
envisaged that this protocol should be applied in the synthesis of
asymmetric 1,4-dihydropyridines by choosing different β-
dicarbonyl compounds and tandem multicomponent reactions
(MCRs). Therefore, four-component tandem reactions of 1,3-
diacetone, β-carbonyl ester, ethyl glyoxalate and 4-
methoxyaniline were investigated under the optimized reaction
conditions and the results are shown in Table 3. As expected, all
asymmetric 1,4-dihydropyridine derivatives could be obtained in
moderate to good yields through mixing the starting materials
successively.
Table 1. Screening of the solid mediaa
Finally, recyclability of montmorillonite K10 was examined
through the reaction of ethyl acetoacetate, ethyl glyoxalate and 4-
methoxyaniline in montmorillonite K10. As showed in Table 4,
montmorillonite K10 can be easily recovered and reused at least
5 times without any significant loss of activity. Besides, the
satisfied result was also obtained when the reaction was
amplified to 5 times.
Entry
Media
Media loading
Yield (%)b
(g)
--
Table 4. Recycle of the montmorillonite
1
2
Solvent-free
Alkaline Al2O3
Acid Al2O3
48
41
28
33
52
72
82
74
86
85
1
Entry
Recycle times
Yield (%)
3
1
1
2
3
4
5
0
1
2
3
4
86
85
85
81
78
4
Neutral Al2O3
1
5
Silica gel
1
6
Bentonite
1
7
Montmorillonite K10
Montmorillonite K10
Montmorillonite K10
Montmorillonite K10
1
8
0.5
0.75
1.5
9
10
3. Conclusion
a The reaction was conducted with ethyl acetoacetate (1 mmol),
ethyl glyoxalate (0.5 mmol) and amine(0.5mmol) for 12h at r. t..
In conclusion, we have developed an efficient method for the
synthesis of both symmetric and asymmetric 1, 4-dihydro-
pyridine derivatives from the MCRs of β-dicarbonyl compounds
with aldehyde and amine at room temperature by utilizing
montmorillonite K10 as solid media. The advantages of this
method include the environmentally friendly reaction conditions,
simple operation, broad substrate scope, satisfied yields and
reused montmorillonite K10. Thus, this method will be widely
applied in the synthesis of diverse substituted 1, 4-
dihydropyridine derivatives.
b Isolated yields.
Having optimized the reaction conditions for the model
system (Table 1, entry 9), the structurally diverse substrates were
chosen to explore the scope and limitations of this protocol. As
shown in Table 2, most scanned reactants afforded the
corresponding DHPs in moderate to excellent yields. It was
found that the steric hindrance of substrates influenced the

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Table 2. Synthesis of the symmetric DHPsa
Entry
1
R1
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OEt
i-PrO
t-BuO
OBz
Me
R2
R3
Product
4a
Yield(%)b
71
78
77
70
0
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
4-NO2Ph
4-ClPh
Ph
4-CH3Ph
Ph
2
4b
4c
3
4-ClPh
4
3-ClPh
4d
4e
4f
5
2-ClPh
6
3,5-(CH3)2Ph
4-CH3OPh
4-CH3OPh
4-CH3OPh
4-CH3OPh
4-CH3OPh
4-CH3OPh
4-CH3OPh
4-CH3OPh
4-CH3OPh
4-CH3OPh
4-CH3OPh
4-CH3OPh
4-CH3Ph
Ph
70
82
76
74
75
65
85
89
86
81
65
76
90
86
90
83
80
77
51
83
7
4g
4h
4i
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
4-CH3Ph
2-CNPh
2-thienyl
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
4j
4k
4l
4m
4n
4o
4p
4q
4r
Me
4s
Me
4t
Me
4-ClPh
4u
4v
4w
4x
4y
Me
3-ClPh
Me
3,5-(CH3)2Ph
3-CF3Ph
4-CH3OPh
Me
Ph
a The reaction was conducted with one pot method.
b Isolated yields.

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Tetrahedron
Table 3. The tandem process leading to asymmetric DHPsa
Entry
R4
Me
Me
Me
Me
Ph
R5
OMe
OEt
Productb
Yield(%)c
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
78
76
76
69
85
78
78
i-PrO
t-BuO
Me
Ph
OMe
OEt
Ph
5g
a The reaction is conducted with tandem MCRs.
b These products are mixture of enantiomers.
c Isolated yields.
173.88, 167.56, 149.01, 138.67, 137.48, 130.08, 129.97, 100.98,
60.60, 60.10, 40.06, 21.15, 18.20, 14.33, 14.25. HRMS (ESI):
m/z calcd for C23H30NO6 [M+H]+: 416.20676. Found: 416.20722.
4. Experimental section
4.1. General experimental
4.2.2. Triethyl 2,6-dimethyl-1-phenyl-1,4-dihydro-
pyridine-3,4,5-tricarboxylate(4b).
Unless otherwise stated, all reagents were purchased from
commercial suppliers (Aladdin) and were used without further
purification. Melting point data were recorded on an X-4 micro-
melting point instrument. NMR spectra were recorded on a
Yellow oil, 1H NMR (400 MHz, CDCl3) δ 7.42 (t, J = 7.2 Hz,
3H), 7.20 (dd, J = 7.8, 1.5 Hz, 2H), 4.88 (s, 1H), 4.23 (dt, J =
10.8, 3.7 Hz, 4H), 4.15 (m, 2H), 2.05 (s, 6H), 1.31 (t, J = 7.1 Hz,
6H), 1.26 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
173.84, 167.52, 148.76, 140.21, 130.46, 129.37, 128.69, 101.20,
60.63, 60.14, 40.10, 18.21, 14.32, 14.24. HRMS (ESI): m/z calcd
for C22H27NO6 [M+H]+: 402.19111. Found: 402.19084.
1
Bruker ACF 500 (400MHz H, 100MHz 13C), the spectra were
recorded in CDCl3 as a solvent at room temperature. HRMS was
performed on a Bruker-APEX IV. Column chromatography was
performed on silica gel (200-300 mesh).
4.2. General procedure for the synthesis of symmetric DHPs
4.2.3. Triethyl 1-(4-chlorophenyl)-2,6-dimethyl-
1,4-dihydropyridine-3,4,5-tricarboxylate(4c).
A mixture of β-dicarbonyl compound 1 (1 mmol), amine 3
(0.5 mmol), aldehyde 2 (0.5 mmol) and the montmorillonite K-10
(0.75 g) was added into a small test tube and magnetically stirred
at room temperature until the reaction was completed (TLC, 4-
18h). The mixture was added ethyl acetate (5 mL), stirred and
filtered. The filtrate was concentrated and the residue was
recrystallized in ethyl acetate/petroleum ether or purified by
silica gel column chromatography (ethyl acetate/petroleum ether)
to give the corresponding products. The filter (montmorillonite
K10) could be reused after dried and ground.
Yellow oil, 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.6 Hz,
2H), 7.16 (d, J = 8.6 Hz, 2H), 4.86 (s, 1H), 4.23 (m, 4H), 4.15
(dd, J = 14.0, 6.9 Hz, 2H), 2.05 (s, 6H), 1.31 (t, J = 7.1 Hz, 6H),
1.26 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 173.80,
167.34, 148.35, 138.76, 134.75, 131.82, 129.66, 101.81, 60.72,
60.24, 40.11, 18.14, 14.30, 14.23. HRMS (ESI): m/z calcd for
C22H26ClNNaO6 [M+Na]+: 458.13409. Found: 458.13408.
4.2.4. Triethyl 1-(3-chlorophenyl)-2,6-dimethyl-
1,4-dihydropyridine-3,4,5-tricarboxylate(4d).
4.2.1. Triethyl 2,6-dimethyl-1-p-tolyl-1,4-dihydro-
pyridine-3,4,5-tricarboxylate(4a).
Yellow oil, 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 7.8 Hz,
2H), 7.05 (d, J = 7.9 Hz, 2H), 4.87 (s, 1H), 4.22 (dd, J = 13.9, 7.0
Hz, 4H), 4.14 (m, 2H), 2.39 (s, 3H), 2.05 (s, 6H), 1.30 (t, J = 7.2
Hz, 6H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
Yellow oil, 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 7.1 Hz,
2H), 7.25 (s, 1H), 7.13 (d, J = 7.1 Hz, 1H), 4.86 (s, 1H), 4.22 (m,
4H), 4.15 (m, 2H), 2.06 (s, 6H), 1.31 (t, J = 7.1 Hz, 6H), 1.26 (t,
J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 173.68, 167.32,
148.15, 141.40, 135.04, 130.77, 130.26, 129.15, 128.93, 101.92,

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60.75, 60.25, 40.15, 18.14, 14.29, 14.22. HRMS (ESI): m/z calcd
60.17, 55.54, 39.30, 29.69, 18.70, 14.27. HRMS (ESI): m/z
calcd for C27H29N2O5 [M+H]+: 461.20710. Found: 461.20733.
for C22H26ClNNaO6 [M+Na]+: 458.13409. Found: 458.13404.
4.2.5. Triethyl 1-(3,5-dimethylphenyl)-2,6-dimethyl
-1,4-dihydropyridine-3,4,5-tricarboxylate(4f).
4.2.11. Diethyl 4-(furan-2-yl)-1-(4-methoxyphenyl)
-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxy-
late(4l).
1
Yellow oil, H NMR (400 MHz, CDCl3) δ 7.03 (s, 1H), 6.79
1
Yellow oil, H NMR (400 MHz, CDCl3) δ 7.31 (s, 1H), 7.10
(s, 2H), 4.88 (s, 1H), 4.23 (dd, J = 14.1, 7.1 Hz, 4H), 4.16 (m,
2H), 2.34 (s, 6H), 2.07 (s, 6H), 1.32 (t, J = 7.1 Hz, 6H), 1.27 (t, J
= 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 173.96, 167.64,
148.94, 139.92, 139.12, 130.26, 127.90, 100.79, 60.60, 60.08,
58.45, 40.11, 21.15, 18.26, 14.34. HRMS (ESI): m/z calcd for
C24H32NO6 [M+H]+: 430.22241. Found: 430.22355; m/z calcd
for C24H31NNaO6 [M+Na]+: 452.20436. Found: 452.20513.
(d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 6.28 (m, 1H), 6.04
(d, J = 3.0 Hz, 1H), 5.27 (s, 1H), 4.20 (m, 4H), 3.85 (s, 3H), 2.09
(s, 6H), 1.30 (t, J = 7.2Hz, 6H). 13C NMR (100 MHz, CDCl3) δ
167.75, 159.37, 158.68, 149.17, 140.95, 133.01, 131.31, 114.39,
110.05, 104.27, 102.86, 59.98, 55.48, 32.93, 18.29, 14.31.HRMS
(ESI): m/z calcd for C24H28NO6 [M+H]+: 426.19111. Found:
426.19063.
4.2.6. Diethyl 1-(4-methoxyphenyl)-2,6-dimethyl-4-
(4-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxy-
late(4g).
4.2.12. 4-Ethyl 3,5-dimethyl 1-(4-methoxyphenyl)-
2,6-dimethyl-1,4-dihydropyridine-3,4,5-tricarboxy-
late(4m).
Yellow oil, 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.8 Hz,
2H), 7.56 (d, J = 8.8 Hz, 2H), 7.00 (dd, J = 21.9, 8.8 Hz, 4H),
5.24 (s, 1H), 4.17 (q, J = 7.2 Hz, 4H), 3.88 (s, 3H), 2.10 (s, 6H),
1.26 (t, J = 7.2 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 167.60,
159.57, 154.60, 148.68, 132.54, 130.92, 129.98, 128.32, 123.45,
114.68, 104.66, 60.22, 55.55, 39.18, 18.73, 14.28. HRMS (ESI):
m/z calcd for C26H29N2O7 [M+H]+: 481.19693. Found: 481.19664.
Yellow crystal, mp: 101.6-103.1℃, 1H NMR (400 MHz,
CDCl3) δ 7.08 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 4.87
(s, 1H), 4.14 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 3.75 (s, 6H), 2.07
(s, 6H), 1.25 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
173.59, 167.91, 159.47, 149.68, 132.61, 131.26, 114.45, 100.70,
60.68, 55.48, 51.40, 39.91, 18.15, 14.20. HRMS (ESI): m/z calcd
for C21H26NO7 [M+H]+: 404.10738. Found: 404.17082.
4.2.7. Diethyl 4-(4-chlorophenyl)-1-(4-methoxy-
phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylate(4h).
4.2.13. Triethyl 1-(4-methoxyphenyl)-2,6-dimethyl-
1,4-dihydropyridine-3,4,5-tricarboxylate(4n).
Yellow oil, 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.8 Hz,
2H), 7.56 (d, J = 8.8 Hz, 2H), 7.00 (dd, J = 23.5, 8.7 Hz, 4H),
5.24 (s, 1H), 4.16 (q, J = 7.2 Hz, 4H), 3.87 (s, 3H), 2.10 (s, 6H),
1.26 (t, J = 7.2 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 167.60,
159.58, 154.63, 148.70, 146.43, 132.54, 130.94, 128.34, 123.46,
114.69, 104.66, 60.22, 55.55, 39.19, 18.74, 14.28. HRMS (ESI):
m/z calcd for C26H29ClNO5 [M+H]+: 470.17288. Found:
470.17336.
Yellow crystal, mp: 108.2-109.5℃, 1H NMR (400 MHz,
CDCl3) δ 7.10 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 4.87
(s, 1H), 4.23 (q, J = 7.2 Hz, 4H), 4.15 (q, J = 7.2Hz, 2H), 3.85 (s,
3H), 2.06 (s, 6H), 1.31 (t, J = 7.2 Hz, 6H), 1.26 (t, J = 7.2 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ 173.90, 167.56, 159.42,
149.27, 132.77, 131.32, 114.41, 101.10, 60.60, 60.11, 55.49,
40.08, 18.17, 14.32, 14.24. HRMS (ESI): m/z calcd for
C23H30NO7 [M+H]+: 432.20168. Found: 432.20124.
4.2.8. Diethyl 1-(4-methoxyphenyl)-2,6-dimethyl-4-
phenyl-1,4-dihydropyridine-3,5-dicarboxylate(4i).
4.2.14. 4-Ethyl 3,5-diisopropyl 1-(4-methoxyphen-
yl)-2,6-dimethyl-1,4-dihydropyridine-3,4,5-tricar-
boxylate(4o).
Yellow oil, 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 7.4 Hz,
2H), 7.31 (d, J = 7.5 Hz, 2H), 7.19 (t, J = 7.2 Hz, 1H), 7.05 (d, J
= 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 5.16 (s, 1H), 4.16 (q, J =
7.2 Hz, 4H), 3.86 (s, 3H), 2.08 (s, 6H), 1.27 (t, J = 7.2 Hz, 6H).
13C NMR (100 MHz, CDCl3) δ 168.18, 159.37, 147.78, 147.17,
133.03, 129.53, 128.85, 128.02, 127.51, 126.14, 114.48, 105.80,
59.94, 55.50, 38.77, 18.58, 14.26. HRMS (ESI): m/z calcd for
C26H30NO5 [M+H]+: 436.21185. Found: 436.21189.
Yellow oil, 1H NMR (400 MHz, CDCl3) δ 7.10 (d, J = 8.8 Hz,
2H), 6.92 (d, J = 8.8 Hz, 2H), 5.15 – 5.02 (m, 2H), 4.86 (s, 1H),
4.15 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 2.05 (s, 6H), 1.32 – 1.26
(m, 15H). 13C NMR (100 MHz, CDCl3) δ 174.06, 167.12, 159.38,
148.87, 132.86, 131.37, 114.37, 101.45, 67.37, 60.55, 55.48,
40.23, 22.01, 21.87, 18.13, 14.29. HRMS (ESI): m/z calcd for
C25H34NO7 [M+H]+:460.23298. Found:460.23410.
4.2.15. 3,5-Di-tert-butyl 4-ethyl 1-(4-methoxyphen-
yl)-2,6-dimethyl-1,4-dihydropyridine-3,4,5-tricar-
boxylate(4p).
4.2.9. Diethyl 1-(4-methoxyphenyl)-2,6-dimethyl-4-
p-tolyl-1,4-dihydropyridine-3,5-dicarboxylate(4j).
Yellow oil, 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.0 Hz,
2H), 7.12 (d, J = 7.9 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 6.96 (d, J
= 8.8 Hz, 2H), 5.11 (s, 1H), 4.16 (q, J = 7.2 Hz, 4H), 3.87 (s, 3H),
2.34 (s, 3H), 2.08 (s, 6H), 1.28 (t, J = 7.2 Hz, 6H). 13C NMR (100
MHz, CDCl3) δ 168.21, 159.33, 147.69, 144.28, 135.58, 133.07,
130.98, 128.78, 127.39, 114.46, 105.87, 59.94, 55.52, 38.32,
21.10, 18.64, 14.30. HRMS (ESI): m/z calcd for C27H32NO5
[M+H]+: 450.22750. Found: 450.22849.
Yellow oil, 1H NMR (400 MHz, CDCl3) δ 7.09 (d, J = 8.8 Hz,
2H), 6.91 (d, J = 8.8 Hz, 2H), 4.80 (s, 1H), 4.15 (q, J = 7.2 Hz,
2H), 3.84 (s, 3H), 2.02 (s, 6H), 1.51 (s, 18H), 1.28 (t, J = 7.2 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ 174.15, 166.94, 159.30,
148.28, 133.01, 131.44, 114.31, 102.42, 79.94, 60.47, 55.46,
40.86, 28.23, 17.99, 14.37. HRMS (ESI): m/z calcd for
C27H38NO7 [M+H]+: 488.26428. Found: 488.26451
4.2.16. 3,5-Dibenzyl 4-ethyl 1-(4-methoxyphenyl)-
2,6-dimethyl-1,4-dihydropyridine-3,4,5-tricarboxy-
late(4q).
Yellow oil, 1H NMR (400 MHz, CDCl3) δ 7.44 – 7.38 (m, 4H),
7.37 – 7.30 (m, 6H), 7.11 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz,
2H), 5.22 (dd, J = 29.4, 12.8 Hz, 4H), 5.04 (s, 1H), 4.08 (q, J =
7.2 Hz, 2H), 3.86 (s, 3H), 2.10 (s, 6H), 1.13 (t, J = 7.2 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ 173.79, 167.09, 159.49, 150.16,
136.60, 132.58, 131.24, 128.38, 127.75, 127.67, 114.47, 100.72,
4.2.10. Diethyl 4-(2-cyanophenyl)-1-(4-methoxy-
phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylate(4k).
Yellow oil, 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.3 Hz,
2H), 7.50 (d, J = 8.3 Hz, 2H), 6.99 (m, 4H), 5.19 (s, 1H), 4.16 (q,
J = 7.2 Hz, 4H), 3.88 (s, 3H), 2.09 (s, 6H), 1.26 (t, J = 7.2 Hz,
6H). 13C NMR (100 MHz, CDCl3) δ 167.66, 159.55, 152.55,
148.53, 132.59, 131.98, 128.32, 119.24, 114.65, 109.88, 104.75,

ACCEPTED MANUSCRIPT
6
Tetrahedron
65.91, 60.71, 55.50, 39.90, 18.25, 14.10. HRMS (ESI): m/z
Yellow oil, 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 7.8 Hz,
1H), 7.63 (t, J = 7.8 Hz, 1H), 7.48 (s, 1H), 7.44 (d, J = 7.9 Hz,
1H), 4.74 (s, 1H), 4.19 (q, J = 7.1 Hz, 2H), 2.43 (s, 6H), 2.00 (s,
6H), 1.28 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
198.00, 172.73, 147.07, 140.54, 133.92, 132.41, 130.29, 127.34,
127.30, 127.27, 127.23, 125.96, 125.92, 125.89, 125.85, 111.03,
61.34, 41.12, 30.13, 18.87, 14.15. HRMS (ESI): m/z calcd for
C21H23F3NO4 [M+H]+: 410.15737. Found: 410.15811.
calcd for C33H34NO7 [M+H]+: 556.23298. Found: 556.23300.
4.2.17. Ethyl 3,5-diacetyl-1-(4-methoxyphenyl)-
2,6-dimethyl-1,4-dihydropyridine-4-carboxylate
(4r).
Yellow oil, 1H NMR (400 MHz, CDCl3) δ 7.06 (d, J = 8.8 Hz,
2H), 6.92 (d, J = 8.8 Hz, 2H), 4.72 (s, 1H), 4.14 (q, J = 7.2 Hz,
2H), 3.83 (s, 3H), 2.40 (s, 6H), 2.01 (s, 6H), 1.25 (t, J = 7.2 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ 197.97, 172.98, 159.57,
148.49, 132.29, 131.08, 114.55, 110.25, 61.09, 55.50, 40.97,
30.14, 18.88, 14.18. HRMS (ESI): m/z calcd for C21H26NO5
[M+H]+: 372.18055. Found: 372.18063.
4.2.24. Ethyl 3,5-dibenzoyl-1-(4-methoxyphenyl)-
2,6-dimethyl-1,4-dihydropyridine-4-carboxylate
(4y).
Yellow oil, 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 7.1 Hz,
4H), 7.50 (t, J = 7.3 Hz, 2H), 7.43 (t, J = 7.4 Hz, 4H), 7.18 (d, J =
8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 4.67 (s, 1H), 4.08 (q, J =
7.2 Hz, 2H), 3.84 (s, 3H), 1.67 (s, 6H), 1.14 (t, J = 7.2 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ 197.06, 172.66, 159.50, 145.46,
139.82, 132.50, 131.95, 131.17, 128.82, 128.53, 114.48, 109.29,
60.96, 55.50, 44.03, 19.69, 14.02. HRMS (ESI): m/z calcd for
C31H30NO5 [M+H]+: 496.21185. Found: 496.21119.
4.2.18. Ethyl 3,5-diacetyl-2,6-dimethyl-1-p-tolyl-
1,4-dihydropyridine-4-carboxylate(4s).
Yellow oil, 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 7.9 Hz,
2H), 7.02 (d, J = 8.0 Hz, 2H), 4.72 (s, 1H), 4.14 (q, J = 7.1 Hz,
2H), 2.40 (s, 6H), 2.38 (s, 3H), 2.00 (s, 6H), 1.24 (t, J = 7.1 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ 197.96, 172.95, 148.21,
138.95, 137.06, 130.09, 129.81, 110.15, 61.07, 40.97, 30.15,
21.14, 18.92, 14.18. HRMS (ESI): m/z calcd for C21H26NO4
[M+H]+: 356.18563. Found: 356.18629.
4.3. General procedure for the synthesis of asymmetric DHPs
A mixture of β-dicarbonyl compound 1a (0.5mmol), amine 3a
(0.5mmol) and the montmorillonite K-10 (0.75g) was added into
a small test tube and magnetically stirred at room temperature for
6h, then the other β-dicarbonyl compound 1a’ (0.5mmol) and
aldehyde 2a (0.5mmol) was added and stirred overnight. The
mixture was added ethyl acetate (5 mL), stirred and filtered. The
filtrate was concentrated and the residue was recrystallized in
ethyl acetate/petroleum ether or purified by silica gel column
chromatography (ethyl acetate/petroleum ether) to give the
corresponding product. The filter (montmorillonite K10) could be
reused after dried and ground.
4.2.19. Ethyl 3,5-diacetyl-2,6-dimethyl-1-phenyl-
1,4-dihydropyridine-4-carboxylate(4t).
Yellow solid, mp: 77.2-79.9℃, 1H NMR (400 MHz, CDCl3) δ
7.43 (t, J = 6.6 Hz, 3H), 7.17 (d, J = 7.7 Hz, 2H), 4.74 (s, 1H),
4.16 (q, J = 7.1 Hz, 2H), 2.41 (s, 6H), 2.01 (s, 6H), 1.26 (t, J =
7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 197.95, 172.92,
147.95, 139.79, 130.20, 129.51, 128.93, 110.27, 61.12, 41.00,
30.16, 18.92, 14.19. HRMS (ESI): m/z calcd for C20H24NO4
[M+H]+: 342.16998. Found: 342.17043.
4.2.20. Ethyl 3,5-diacetyl-1-(4-chlorophenyl)-2,6-
dimethyl-1,4-dihydropyridine-4-carboxylate(4u).
4.3.1. 4-Ethyl 3-methyl 5-acetyl-1-(4-methoxy-
phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,4-
dicarboxylate(5a).
Yellow solid, mp: 79,5-81.1℃, 1H NMR (400 MHz, CDCl3) δ
7.41 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 8.6 Hz, 2H), 4.70 (s, 1H),
4.14 (q, J = 7.1 Hz, 2H), 2.39 (s, 6H), 1.99 (s, 6H), 1.24 (t, J =
7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 197.88, 172.81,
147.49, 138.31, 134.96, 131.59, 129.76, 110.64, 61.20, 40.99,
30.11, 18.81, 14.17. HRMS (ESI): m/z calcd for C20H23ClNO4
[M+H]+: 376.13101. Found: 376.13125.
Yellow oil, 1H NMR (400 MHz, CDCl3) δ 7.05 (d, J = 8.7 Hz,
2H), 6.91 (d, J = 8.8 Hz, 2H), 4.76 (s, 1H), 4.14 (qd, J = 7.1, 2.5
Hz, 2H), 3.82 (s, 3H), 3.74 (s, 3H), 2.41 (s, 3H), 2.08 (s, 3H),
1.97 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ198.89, 173.18, 167.66, 159.48, 150.14, 148.03, 132.38,
131.16, 114.47, 109.42, 100.59, 60.94, 55.48, 51.53, 40.71, 29.87,
18.68, 18.18, 14.19. HRMS (ESI): m/z calcd for C21H26NO6
[M+H]+: 388.17546. Found: 388.17661.
4.2.21. Ethyl 3,5-diacetyl-1-(3-chlorophenyl)-2,6-
dimethyl-1,4-dihydropyridine-4-carboxylate(4v).
1
Yellow oil. H NMR (400 MHz, CDCl3) δ 7.42 (m, 2H), 7.22
4.3.2. Diethyl 5-acetyl-1-(4-methoxyphenyl)-2,6-
dimethyl-1,4-dihydropyridine-3,4-dicarboxylate
(5b).
(s, 1H), 7.12 (d, J = 9.0 Hz, 1H), 4.72 (s, 1H), 4.17 (q, J = 7.1 Hz,
2H), 2.42 (s, 6H), 2.02 (s, 6H), 1.27 (t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ 197.96, 172.77, 147.31, 140.98, 135.19,
130.55, 130.40, 129.38, 128.71, 110.75, 61.27, 41.04, 30.15,
18.85, 14.18. HRMS (ESI): m/z calcd for C20H23ClNO4 [M+H]+:
376.13101. Found: 376.13143.
Yellow oil, 1H NMR (400 MHz, CDCl3) δ 7.06 (d, J = 8.3 Hz,
2H), 6.91 (d, J = 8.4 Hz, 2H), 4.78 (s, 1H), 4.17 (m, 4H), 3.83 (s,
3H), 2.41 (s, 3H), 2.08 (s, 3H), 1.98 (s, 3H), 1.29 (t, J = 7.1 Hz,
3H), 1.24 (t, J = 6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
198.88, 173.29, 167.23, 159.48, 149.71, 148.12, 132.47, 131.18,
114.46, 109.38, 101.06, 60.88, 60.23, 55.47, 40.81, 29.81, 18.67,
18.14, 14.32, 14.20. HRMS (ESI): m/z calcd for C22H28NO6
[M+H]+: 402.19111. Found: 402.19233.
4.2.22. Ethyl 3,5-diacetyl-1-(3,5-dimethylphenyl)-
2,6-dimethyl-1,4-dihydropyridine-4-carboxylate
(4w).
1
Yellow oil, H NMR (400 MHz, CDCl3) δ 7.05 (s, 1H), 6.77
(s, 2H), 4.75 (s, 1H), 4.18 (q, J = 7.1 Hz, 2H), 2.43 (s, 6H), 2.35
(s, 6H), 2.04 (s, 6H), 1.28 (t, J = 7.1 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 198.06, 173.04, 148.16, 139.54, 139.32, 130.51,
127.65, 110.01, 61.10, 41.01, 30.18, 21.17, 19.03, 14.20. HRMS
(ESI): m/z calcd for C22H28NO4 [M+H]+: 370.20128. Found:
370.20193.
4.3.3. 4-Ethyl 3-isopropyl 5-acetyl-1-(4-methoxy-
phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,4-
dicarboxylate(5c).
Yellow oil, 1H NMR (400 MHz, CDCl3) δ 7.07 (d, J = 8.8 Hz,
2H), 6.91 (d, J = 8.9 Hz, 2H), 5.08 (m, 1H), 4.76 (s, 1H), 4.14 (qd,
J = 7.1, 3.2 Hz, 2H), 3.83 (s, 3H), 2.41 (s, 3H), 2.07 (s, 3H), 1.98
(s, 3H), 1.26 (m, 9H). 13C NMR (100 MHz, CDCl3) δ 198.88,
173.37, 166.78, 159.45, 149.29, 148.25, 132.50, 131.20, 114.43,
109.27, 101.51, 67.58, 60.86, 55.48, 40.87, 29.84, 22.03, 21.91,
4.2.23. Ethyl 3,5-diacetyl-2,6-dimethyl-1-(3-(tri-
fluoromethyl)phenyl)-1,4-dihydropyridine-4-car-
boxylate(4x).

ACCEPTED MANUSCRIPT
7
18.72, 18.14, 14.24. HRMS (ESI): m/z calcd for C23H30NO6
References and notes
[M+H]+: 416.20676. Found: 416.20738.
4.3.4. 3-tert-Butyl 4-ethyl 5-acetyl-1-(4-methoxy-
phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,4-
dicarboxylate(5d).
1. (a) Menche, D.; Hassfeld, J.; Li, J.; Menche, G.; Ritter, A.;
Rudolph, S. Org. Lett. 2006, 8, 741; (b) He, R.; Toy, P.H.; Lama,
Y. Adv. Synth. Catal. 2008, 350, 54; (c) Li,G.; Antilla, J. C. Org.
Lett. 2009, 11, 1075; (d) Itoht, T.; Anagata, K.; Miyazaki, M.;
Ishikawa, H.; Kurihara, A.; Ohsawa, A. Tetrahedron 2004, 60,
6649.
Yellow oil, 1H NMR (400 MHz, CDCl3) δ 7.08 (d, J = 8.7 Hz,
2H), 6.93 (d, J = 8.8 Hz, 2H), 4.75 (s, 1H), 4.17 (q, J = 7.1 Hz,
2H), 3.85 (s, 3H), 2.43 (s, 3H), 2.06 (s, 3H), 2.00 (s, 3H), 1.52 (s,
9H), 1.27 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
198.85, 173.45, 166.66, 159.43, 148.50, 148.40, 132.62, 131.26,
114.42, 109.03, 102.86, 80.42, 60.84, 55.48, 41.22, 29.80, 28.28,
18.74, 18.09, 14.27. HRMS (ESI): m/z calcd for C24H32NO6
[M+H]+: 430.22241. Found: 430.22320.
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M. Org. Lett. 2005, 7, 3781; (b) Rueping, M.; Theissmann, T.;
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135.
4.3.5. Ethyl 3-acetyl-5-benzoyl-1-(4-methoxy-
phenyl)-2,6-dimethyl-1,4-dihydropyridine-4-
carboxylate(5e).
Yellow oil, 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.0 Hz,
2H), 7.52 (t, J = 6.1 Hz, 1H), 7.44 (t, J = 7.4 Hz, 2H), 7.13 (d, J =
8.9 Hz, 2H), 6.94 (d, J = 8.9 Hz, 2H), 4.67 (s, 1H), 4.16 (qd, J =
7.1, 2.0 Hz, 2H), 3.85 (s, 3H), 2.38 (s, 3H), 2.11 (s, 3H), 1.60 (s,
3H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
198.47, 196.79, 172.87, 159.55, 149.20, 145.78, 139.79, 132.35,
132.08, 131.10, 128.89, 128.56, 114.52, 110.25, 108.46, 61.10,
55.51, 42.59, 29.97, 29.69, 19.81, 18.88, 14.15. HRMS (ESI):
m/z calcd for C26H28NO5 [M+H]+: 434.19620. Found: 434.19650.
4.3.6. 4-Ethyl 3-methyl 5-benzoyl-1-(4-methoxy-
phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,4-
dicarboxylate(5f).
Yellow oil, 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.1 Hz,
2H), 7.52 (t, J = 7.3 Hz, 1H), 7.44 (t, J = 7.4 Hz, 2H), 7.13 (d, J =
8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 4.74 (s, 1H), 4.09 (q, J =
7.1 Hz, 2H), 3.84 (s, 3H), 3.70 (s, 3H), 2.17 (s, 3H), 1.58 (s, 3H),
1.17 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 197.33,
173.01, 167.88, 159.47, 150.72, 143.67, 139.16, 132.58, 132.18,
131.22, 128.97, 128.53, 114.47, 110.14, 99.10, 60.82, 55.49,
51.42, 51.34, 42.33, 29.69, 19.24, 18.30, 18.17, 14.09. HRMS
(ESI): m/z calcd for C26H28NO6 [M+H]+: 450.19111. Found:
450.19231.
8. (a) Bretzel, R. G.; Bollen, C. C.; Maeser, E.; Federlin, K. F. Drugs
Fut. 1992, 17, 465; (b) Boer, R.; Gekeler, V. Drugs Fut. 1995, 20,
499.
4.3.7. Diethyl 5-benzoyl-1-(4-methoxyphenyl)-2,6-
dimethyl-1,4-dihydropyridine-3,4-dicarboxylate
(5g).
9. (a) Avendano, C.; Menendez, J. C.; Med. Chem. Rev. 2004, 1,
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Targets 2006, 7, 949; (e) Saponara, S.; Ferrara, A.; Gorelli, B.;
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Fusi, F. Eur. J. Pharmacol. 2007, 563, 160.
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A.; Naito, S.; Kuwano, M. Bioorg. Med. Chem. Lett. 2001, 11,
275.
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Bioorg. Med. Chem. 1998, 6, 563.
Yellow oil, 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.1 Hz,
2H), 7.51 (t, J = 7.3 Hz, 1H), 7.43 (t, J = 7.5 Hz, 2H), 7.13 (d, J =
8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 4.75 (s, 1H), 4.17 (qd, J =
7.1, 3.0 Hz, 2H), 4.08 (q, J = 6.7 Hz, 2H), 3.83 (s, 3H), 2.16 (s,
3H), 1.57 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ 197.31, 173.17, 167.40,
159.44, 150.38, 143.78, 139.19, 132.63, 132.16, 131.23, 128.98,
128.50, 114.45, 109.99, 99.53, 77.40, 77.08, 76.76, 60.76, 60.01,
55.48, 42.37, 19.32, 18.26, 14.30, 14.10. HRMS (ESI): m/z calcd
for C27H30NO6 [M+H]+: 463.20676. Found: 464.20783.
12. (a) Hilgeroth, A. Mini Rev. Med. Chem. 2002, 2, 235; (b)
Hilgeroth, A.; Lilie, H. Eur. J. Med. Chem. 2003, 38, 495.
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Vanree, J. M. Eur. J. Pharmacol. 1996, 295, 19.
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P.; Wahlquist, C.; Gilly,G.; Mercola, M.; Cashman, J.R. J. Med.
Chem. 2012, 55, 9946.
Acknowledgments
This work was supported by the funds of Natural Science
Foundation of China (20772009).
Supplementary Material
15. (a) Edraki, N.; Mehdipour, A.R.; Khoshneviszadeh, M.; Miri,R.
Drug Discovery Today 2009, 14, 1058; (b) Vo, D. Drug Des.
Discov. 1992, 9, 69; (c) Harrold, M. Foye’s Principles of
Medicinal Chemistry 2002, 533.
The original data of 1H NMR and 13C NMR of all products are
supplied. The supplementary data files are to be used as an aid
for the refereeing of the paper only.

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Supporting Information
Multicomponent reaction leading to symmetric and
asymmetric highly functionalized multi-substituted
1, 4-dihydropyridines on montmorillonite
Yu-peng Liu, Jin-ming Liu, Xin Wang , Tieming Cheng, Run-tao Li
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191,
PR China
Corresponding author. Tel.: +8610 82801504; fax: +8610 82716956; E-mail addresses:
xinwang@bjmu.edu.cn.(X, Wang); lirt@bjmu.edu.cn.( R.-T., Li); Postal address: No.38 Xueyuan Road, Haidian
District, Beijing100191, PR China
1

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NMR spectra for all compounds
4a
2

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3

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4c
4

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4d
5

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4f
6

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4g
7

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4h
8

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4i
9

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4j
10

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4k
11

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4l
12

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4m
13

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4n
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4o
15

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4p
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4q
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4r
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4s
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