Improved One-Pot, Four-Component Strategy to Access Functionalized Dihydropyridines by Using 4-(N, N-Dimethylamino)pyridine as a Catalyst

Article abstract of DOI:10.1055/s-0037-1609579

A convenient strategy has been developed for the synthesis of structurally diverse novel 1,4-dihydropyridine frameworks bearing a 3-nitrophenyl moiety through a one-pot, four-component reaction with 4-(N, N -dimethylamino)pyridine as a catalyst at room temperature. This tandem process proceeds more effectively than previous catalytic processes.

Full text of DOI:10.1055/s-0037-1609579

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
letter
A
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R. Ramesh et al.
Letter
Synlett
Improved One-Pot, Four-Component Strategy to Access
Functionalized Dihydropyridines by Using 4-(N,N-Dimethylamino)
pyridine as a Catalyst
Rathinam Ramesha
Mani Arivazhagana
NO2
Jan Grzegorz Maleckib
Appaswami Lalitha*a
O
CHO
DMAP
(10 mol%)
COOCH3
R
H3CO
H3CO
R
NH2
R'
+
+
+
EtOH, r.t.
15–60 min
a Department of Chemistry, Periyar University, Periyar Palkalai
Nagar, Salem-636011, Tamil Nadu, India
lalitha253@periyaruniversity.ac.in
b Department of Crystallography, University of Silesia, Szkolna 9,
40-007 Katowice, Poland
N
R'
NH2
CN
NO2
COOCH3
O
15 examples
1
2(a,b)
3
4(a–n)
5(a–o)
R = CN or COOEt
91–97% yield
Received: 18.04.2018
Accepted after revision: 15.06.2018
Published online: 20.07.2018
Considerable attention has focused on multicomponent
reactions (MCRs) because they can provide operational effi-
ciency, minimization of chemical waste, faster reaction
rates, and high degrees of atom economy.12–15 4-(N,N-Di-
methylamino)pyridine (DMAP) can promote a number of
organic transformations as a reusable catalyst,16–18 and the
combination of an MCR approach with organocatalysis has
proved to be a most effective strategy.19 In a continuation of
our current work devoted to the synthesis of medicinally
important heterocycles by using green solvents or cata-
lysts,20–30 we have developed an efficient method for the
DOI: 10.1055/s-0037-1609579; Art ID: st-2018-d0245-l
Abstract A convenient strategy has been developed for the synthesis
of structurally diverse novel 1,4-dihydropyridine frameworks bearing a
3-nitrophenyl moiety through a one-pot, four-component reaction
with 4-(N,N-dimethylamino)pyridine as a catalyst at room temperature.
This tandem process proceeds more effectively than previous catalytic
processes.
Key words dimethylaminopyridine, nitrophenyldihydropyridines, multi-
component reactions, nitriles, amines, organocatalysis
Table 1 Optimization of the Catalyst and Reaction Conditions for the
Synthesis of 5aa
The use of multicomponent reactions is an effective
strategy in organic synthesis,1 and is of particular use in
syntheses of heterocycles having pharmacological activi-
ties.2 Among the various N-heterocycles, functionalized di-
hydropyridines (DHPs) have been used as effective anti-
hypertensive,3 antioxidant,4,5 anticancer,6 calcium antago-
nist,7 and antidiabetic agents.8 They also find applications
in the field of materials science.9,10 Other DHP derivatives
show potent neuroprotective activity, platelet antiaggrega-
tion activity, cerebral antiischemic activity, or chemosensi-
tizing activity in tumor therapy.11
Entry Catalyst (mol%)
Solvent
Time (min) Yieldb (%)
1
2
Urea (20)
EtOH
150
120
180
120
15
41
59
46
79c
96
88
79
84
56
71
95
96
63
NH4OAc (20)
sodium alginate (20)
–
EtOH
3
EtOH
4
EtOH
5
DMAP (20)
DMAP (20)
DMAP (20)
DMAP (20)
DMAP (20)
DMAP (20)
DMAP (15)
DMAP (10)
DMAP (5)
EtOH
6
MeOH
i-PrOH
MeCN
H2O
25
7
30
8
30
NO2
9
60
O
10
11
12
13
EtOH–H2O (1:1)
EtOH
45
CHO
COOCH3
DMAP
R
(10 mol%)
R
H3CO
H3CO
NH2
15
+
+
+
R'
EtOH, r.t.
15–60 min
N
NH2
EtOH
15
CN
NO2
COOCH3
O
R'
EtOH
25
1
2(a,b)
3
4(a–n)
5(a–o)
a Reaction conditions: 3-nitrobenzaldehyde (1; 2.5 mmol), malononitrile
Scheme 1 Synthesis of highly functionalized 1,4-dihydropyridines by
using DMAP as a catalyst
(2a; 2.5 mmol), DMAD (3; 2.5 mmol), p-anisidine (4a; 2.5 mmol), r.t.
b Isolated yield.
c The intermediate 2-(3-nitrobenzylidene)malononitrile was the sole prod-
uct.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
R. Ramesh et al.
Letter
Synlett
four-component synthesis of densely functionalized 1,4-di-
hydropyridines from activated alkynes by using DMAP as a
catalyst under ambient conditions (Scheme 1).
Entry
R
R’–NH2
Product
Time Yieldb
(min) (%)
NO2
We began our investigation by attempting to identify
the optimal catalyst for the four-component reaction of 3-
nitrobenzaldehyde (1), malononitrile (2a), dimethyl acety-
lenedicarboxylate (3), and p-anisidine (4a) in ethanol at
room temperature as a model system with such catalysts as
urea, ammonium acetate, and sodium alginate, but these
catalysts gave low yields of the desired product 5a (Table 1,
entries 1–3). Performing the reaction under catalyst-free
conditions resulted in the formation of 2-(3-nitroben-
zylidene)malononitrile as the exclusive final product (entry
4). However, DMAP as a catalyst provided an excellent 96%
yield of dimethyl 4-(3-nitrophenyl)-1,4-dihydropyridine-
2,3-dicarboxylate (5a) in a short reaction time of 15 min
(entry 5). We then examined the effects of various solvents
(methanol, propan-2-ol, acetonitrile, water, and 1:1 v/v
aqueous ethanol) on the model reaction (entries 6–10).
From those results, we selected ethanol as a suitable sol-
vent. We also examined the effect of the quantity of catalyst
(entries 11–13), and we found that the best yield was ob-
tained by using 10 mol% of DMAP. Therefore, the optimal
conditions involve reaction at room temperature in ethanol
with 10 mol% of DMAP as the catalyst.
O
O
CN
H3CO
H3CO
4-H2NC6H4Br
4c
3
CN
CN
CN
25
25
15
95
96
93c
N
NH2
Br
5c
NO2
O
O
CN
H3CO
H3CO
4-H2NC6H4F
4d
4
N
F
NH2
5d
NO2
O
O
CN
H3CO
H3CO
Table 2 Synthesis of 4-(3-Nitrophenyl)-1,4-dihydropyridine-2,3-di-
carboxylatesa
4-H2NC6H4CH3
4e
5
N
NH2
Entry
R
R’–NH2
Product
Time Yieldb
(min) (%)
CH3
NO2
5e
O
O
NO2
CN
H3CO
H3CO
O
O
4-H2NC6H4OCH3
4a
1
CN
15
96
N
NH2
CN
H3CO
H3CO
4-H2NC6H4-i-Pr
4f
6
CN
20
92
N
NH2
OCH3
5a
NO2
5f
O
O
NO2
CN
H3CO
H3CO
O
O
4-H2NC6H4Cl
4b
2
CN
30
97
N
NH2
CN
H3CO
H3CO
4-H2NC6H4CO2Et
4g
7
CN
30
93c
N
NH2
Cl
5b
COOEt
5g
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

C
R. Ramesh et al.
Letter
Synlett
Table 2 (continued)
Entry
R
R’–NH2
Product
Time Yieldb
(min) (%)
Entry
R
R’–NH2
Product
Time Yieldb
(min) (%)
NO2
NO2
O
O
O
CN
CN
H3CO
H3CO
H3CO
BnNH2
4m
13
CN
60
91c
3-H2NC6H4OCH3
4h
8
CN
30
91c
H3CO
N
NH2
N
NH2
O
OCH3
NO2
5m
5h
n-PrNH2
4n
NO2
O
O
O
CN
CN
H3CO
H3CO
H3CO
14
CN
60
94
3-H2NC6H4CH3
4i
9
CN
25
93c
H3CO
N
N
NH2
NH2
O
5n
CH3
NO2
5i
NO2
O
O
O
O
H3CO
H3CO
OEt
NH2
CN
4-H2NC6H4F
4d
H3CO
15
CO2Et
30
96
3-H2NC6H4Cl
4j
N
F
10
11
12
CN
CN
CN
20
30
20
95c
90c
93
H3CO
N
NH2
O
Cl
5o
5j
a Reaction conditions: 3-nitrobenzaldehyde (1; 2.5 mmol), nitrile 2 (2.5
mmol), DMAD 3 (2.5 mmol), amine 4 (2.5 mmol), DMAP (10 mol%), EtOH
NO2
(10 mL), stirring, r.t.
b Isolated yield.
O
c Novel compound.
CN
H3CO
2-H2NC6H4OCH3
4k
H3CO
N
NH2
O
OCH3
Having determined the optimized conditions, we
turned our attention to exploring the versatility of this pro-
tocol with various amines 4b–n.31,32 Anilines bearing either
electron-donating (methoxy, methyl or isopropyl) or electron-
withdrawing (chloro, bromo, fluoro, or ethoxycarbonyl)
substituents, all furnished the desired DHPs efficiently
(Table 2, entries 1–11), with those possessing electron-
donating substituents requiring shorter times than those
with electron-withdrawing substituents, presumably due
to the lower nucleophilicity of the latter. The parent aniline
4l provided the desired product 5l in 93% yield (Table 2,
entry 12). Aliphatic amines, such as benzylamine (4m) and
propylamine (4n) also gave the desired products in excel-
lent yields (Table 2, entries 13 and 14). However, reactions
involving aliphatic amines proceeded comparatively slowly
compared to those of the aromatic amines 4a–l.
5k
NO2
O
CN
H3CO
PhNH2
4l
H3CO
N
NH2
O
5l
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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R. Ramesh et al.
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Synlett
We then examined the optimized protocol with ethyl
cyanoacetate (2b) instead of malononitrile (2a). In this case,
the expected tricarboxylate 5o was obtained in good yield
(Table 2, entry 15). Note that the workup procedure was
simple in all cases; once the reaction was complete, the
solid produced was collected by filtration and crystallized
from ethanol.
Table 3 Comparison of the Efficiency of DMAP as a Catalyst with
Previously Reported Protocols
Entry Catalyst
Solvent
Time (h) Yield (%)
Ref.
34
1
2
Fe3O4@SiO2–NH2
EtOH
4.0
2.0
94
84
82
85
85
81
94
95
80
87
97
35
The 1H NMR spectrum of compound 5a showed two
sharp singlets at δ = 3.40 and 3.55 ppm, demonstrating the
presence of two methyl ester groups. A singlet at δ = 3.83
ppm was assigned to the methoxy protons of the anisidine
moiety. The benzylic methine was observed as a singlet at
δ = 4.71 ppm. A singlet at δ = 5.81 ppm signified the pres-
ence of the –NH2 protons, and the aromatic protons
appeared as multiplets at δ = 7.05–8.20 ppm. The 13C NMR
spectrum showed a peak at δ = 164 ppm corresponding to
the ester carbonyl carbon and a peak at δ = 120 ppm corre-
sponding to the nitrile carbon (–CN).
L-proline
Et3N
–
36
3
EtOH
10.0
14.0
8.0
37
4
(NH4)2HPO4
NaOH
H2O–EtOH
EtOH
38
5
39
6
–
PEG-400
H2O–EtOH
EtOH
10.0
4.5
40
7
meglumine
piperidine
KF/Al2O3
CuI/sonication
DMAP
41
8
2.0
42
9
EtOH
10.0
0.5
43
10
11
H2O
EtOH
0.25
In addition, the structure of compound 5f was con-
firmed by single-crystal X-ray diffraction analysis (Figure 1)
33
;
its structural-refinement parameters and crystal-pack-
To check the reusability of the catalyst, after completion
of the first reaction the product was filtered and washed
with ethanol. The catalyst present in the filtrate was subse-
quently reused with the same scale of the same substrates,
and it was found to be highly active up to the fourth run
(Figure 2).
In conclusion, we have developed a convenient and
high-yielding protocol for the synthesis of polysubstituted
1,4-dihydropyridines through a one-pot, four-component
reaction using DMAP as a catalyst.
ing diagram are presented in the Supplementary Informa-
tion.
The efficiency of this DMAP-catalyzed method for the
preparation of various 1,4-dihydropyridines was compared
with that of previously reported catalytic methods (Table 3)
, and it was found to compare favorably with all previously
reported systems (Table 3, entry 11).
Funding Information
R.R. thanks the Department of Science and Technology, New Delhi,
India (Grant No: DST/INSPIRE Fellowship/2012/690) for financial sup-
port.
)(
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609579.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
Figure 1 ORTEP projection of compound 5f
Figure 2 Reusability of the catalyst
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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R. Ramesh et al.
Letter
Synlett
References and Notes
(24) Ramesh, R.; Lalitha, A. ChemistrySelect 2016, 1, 2085.
(25) Ramesh, R.; Nagasundaram, N.; Meignanasundar, D.; Lalitha, A.
Res. Chem. Intermed. 2017, 43, 1767.
(26) Ramesh, R.; Sankar, G.; Malecki, J. G.; Lalitha, A. J. Iran. Chem.
Soc. 2018, 15, 1.
(27) Ramesh, R.; Kalisamy, P.; Malecki, J. G.; Lalitha, A. Synlett 2018,
29, 203.
(28) Ramesh, R.; Maheswari, S.; Arivazhagan, M.; Malecki, J. G.;
Lalitha, A. Tetrahedron Lett. 2017, 58, 3905.
(29) Ramesh, R.; Meignanasundar, D.; Lalitha, A. ChemistrySelect
2017, 2, 10210.
(1) (a) Tang, S.; Si, Y.-Y.; Wang, Z.-P.; Mei, K.-R.; Chen, X.; Cheng, J.-Y.;
Zheng, J.-S.; Liu, L. Angew. Chem. Int. Ed. 2015, 54, 5713. (b)
Yatabe, T.; Jin, X.; Yamaguchi, K.; Mizuno, N. Angew. Chem. Int.
Ed. 2015, 54, 13302. (c) Deng, Y.; Gong, W.; He, J.; Yu, J.-Q.
Angew. Chem. Int. Ed. 2014, 53, 6692. (d) Yoshida, M.;
Mizuguchi, T.; Namba, K. Angew. Chem. Int. Ed. 2014, 53, 14550.
(2) (a) Singh, R. P.; Verma, R. D.; Meshri, D. T.; Shreeve, J. M. Angew.
Chem. Int. Ed. 2006, 45, 3584. (b) Winkler, M.; Houk, K. N. J. Am.
Chem. Soc. 2007, 129, 1805.
(3) Triggle, D. J.; Langs, D. D.; Janis, R. A. Med. Res. Rev. 1989, 9, 123.
(4) Mason, R. P.; Mak, I. T.; Trumbore, M. W.; Mason, P. E. Am. J. Car-
diol. 1999, 84, 16.
(30) Ramesh R., Jayamathi J., Karthika C., Malecki J. G., Lalitha A.;
Polycyclic Aromat. Compd.; DOI:10.1080/10406638.2018.
1454968.
(5) Aruoma, O.; Smith, C.; Cecchini, R.; Evans, P.; Halliwell, B. Bio-
chem. Pharmacol. 1991, 42, 735.
(6) Kawase, M.; Shah, A.; Gaveriya, H.; Motohashi, N.; Sakagami, H.;
Varga, A. J. Bioorg. Med. Chem. 2002, 10, 1051.
(7) Zamponi, G. W.; Stotz, S. C.; Staples, R. J.; Andro, T. M.; Nelson, J.
K.; Hulubei, V.; Blumenfeld, A.; Natale, N. R. J. Med. Chem. 2003,
46, 87.
(8) (a) Kharkar, P. S.; Desai, B.; Gaveria, H.; Varu, B.; Loriya, R.;
Naliapara, Y.; Shah, A.; Kulkarni, V. M. J. Med. Chem. 2002, 45,
4858. (b) McCormack, J. G.; Westergaard, N.; Kristiansen, M.;
Brand, C. L.; Lau, J. Curr. Pharm. Des. 2001, 7, 1457.
(9) (a) Guarna, A.; Belle, C.; Machetti, F.; Occhiato, E. G.; Payne, A. H.
J. Med. Chem. 1997, 40, 1112. (b) Li, Q.; Mitscher, L. A.; Shen, L. L.
Med. Res. Rev. 2000, 20, 231. (c) Stončius, S.; Orentas, E.; Butkus,
E.; Öhrström, L.; Wendt, O. F.; Wärnmark, K. W. J. Am. Chem. Soc.
2006, 128, 8272. (d) Mohler, M. L.; Bohl, C. E.; Jones, A.; Coss, C.
C.; Narayanan, R.; He, Y.; Hwang, D. J.; Dalton, J. T.; Miller, D. D.
J. Med. Chem. 2009, 52, 3597.
(10) (a) Simal, C.; Lebl, T.; Slawin, A. M. Z.; Smith, A. D. Angew. Chem.
2012, 124, 3713. (b) Jessen, H. J.; Schumacher, A.; Shaw, T.;
Pfaltz, A.; Gademann, K. Angew. Chem. Int. Ed. 2011, 50, 4222. (c)
Jiang, J.; Qing, J.; Gong, L.-Z. Chem. Eur. J. 2009, 15, 7031.
(11) (a) Klusa, V. Drugs Future 1995, 20, 135. (b) Boer, R.; Gekeler, V.
Drugs Future 1995, 20, 499.
(31) Dimethyl 6-Amino-5-cyano-4-(3-nitrophenyl)-1-phenyl-1,4-
dihydropyridine-2,3-dicarboxylate (5l); Typical Procedure
3-Nitrobenzaldehyde (2.5 mmol), malononitrile (2.5 mmol),
and DMAP (10 mol%) were dissolved in EtOH (5 mL), and the
mixture was stirred at r.t. for 2 min. A solution of DMAD (2.5
mmol) and aniline (2.5 mmol) in EtOH (5 mL) was added slowly,
and the resulting mixture was stirred at r.t. for 20 min. When
the reaction was complete (TLC; EtOAc–hexane), the solid that
formed was collected by filtration, dried, and crystallized from
EtOH.
(32) Dimethyl
6-Amino-5-cyano-1-(4-methoxyphenyl)-4-(3-
nitrophenyl)-1,4-dihydropyridine-2,3-dicarboxylate (5a)
Yellow crystals; yield: 1118 mg (96%); mp 194–196 °C. 1H NMR
(400 MHz, DMSO-d6): δ = 3.40 (s, 3 H, COOCH3), 3.55 (s, 3 H,
COOCH3), 3.83 (s, 3 H, OCH3), 4.71 (s, 1 H, CH), 5.81 (s, 2 H, NH2),
7.05 (d, J = 8.0 Hz, 2 H, ArH), 7.25 (d, J = 8.0 Hz, 2 H, ArH), 7.79
(d, J = 8.0 Hz, 2 H, ArH), 8.16 (d, J = 8.0 Hz, 2 H, ArH). 13C NMR
(100 MHz, DMSO-d6): δ = 38.2, 52.0, 52.4, 55.4, 58.4, 103.3,
114.7, 120.6, 121.0, 122.1, 127.2, 130.5, 131.3, 133.5, 142.8,
147.6, 148.0, 151.4, 160.0, 162.7, 164.7.
(33) CCDC 1561544 contains the supplementary crystallographic
data for compound 5f. The data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
(12) Rotstein, B. H.; Zaretsky, S.; Rai, V.; Yudin, A. K. Chem. Rev. 2014,
114, 8323.
(34) Ghasemzadeh, M. A.; Basir, M. H. A. Acta Chim. Slov. 2016, 63,
627.
(13) Cioc, R. C.; Ruijter, E.; Orru, R. V. A. Green Chem. 2014, 16, 2958.
(14) Langer, P. Chem. Eur. J. 2001, 7, 3858.
(15) Langer, P. Synthesis 2002, 2002, 441.
(16) Khan, A. T.; Lal, M.; Ali, S.; Khan, M. Tetrahedron Lett. 2011, 52,
5327.
(17) Xu, S.; Held, I.; Kempf, B.; Mayr, H.; Steglich, W.; Zipse, H. Chem.
Eur. J. 2005, 11, 4751.
(18) Octavio, R.; de Souza, M. A.; Vasconcellos, M. L. A. A. Synth.
Commun. 2003, 33, 1383.
(19) Misra, M.; Pandey, S.; Pandey, V. P.; Pandey, J.; Tripathi, R.;
Tripathi, R. P. Bioorg. Med. Chem. 2009, 17, 625.
(35) Kiruthika, S. E.; Perumal, P. T. RSC Adv. 2014, 4, 3758.
(36) Sun, J.; Xia, E.-Y.; Wu, Q.; Yan, C.-G. Org. Lett. 2010, 12, 3678.
(37) Hadjebia, M.; Hashtroudib, M. S.; Bijanzadeh, H. R.; Balalaie, S.
Helv. Chim. Acta 2011, 94, 382.
(38) Pal, S.; Choudhury, L. H.; Parvin, T. Synth. Commun. 2013, 43,
986.
(39) Pal, S.; Singh, V.; Das, P.; Choudhury, L. H. Bioorg. Chem. 2013,
48, 8.
(40) Chen, H.-S.; Guo, R.-Y. Monatsh. Chem. 2015, 146, 1355.
(41) Ramesh, R.; Madhesh, R.; Malecki, J. G.; Lalitha, A. ChemistrySe-
lect 2016, 1, 5196.
(20) Ramesh, R.; Lalitha, A. RSC Adv. 2015, 5, 51188.
(21) Ramesh, R.; Lalitha, A. Res. Chem. Intermed. 2015, 41, 8009.
(22) Ramesh, R.; Maheswari, S.; Murugesan, S.; Sandhiya, R.; Lalitha,
A. Res. Chem. Intermed. 2015, 41, 8233.
(23) Ramesh, R.; Vadivel, P.; Maheswari, S.; Lalitha, A. Res. Chem.
Intermed. 2016, 42, 7625.
(42) Pal, S.; Khan, N.; Choudhury, L. H. J. Heterocycl. Chem. 2014, 51,
E156.
(43) Tabassum, S.; Govindaraju, S.; Khan, R.-u.-R.; Pasha, M. A. RSC
Adv. 2016, 6, 29802.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E