One-pot multicomponent reactions for the efficient synthesis of highly functionalized dihydropyridines

Article abstract of DOI:10.1080/00397911.2011.618283

An efficient, atom-economic, one-pot protocol has been developed for the synthesis of highly functionalized dihydropyridines via four-component reactions of aromatic aldehydes, arylamines, malononitrile, and dimethylacetylenedicarboxylate in the presence

Full text of DOI:10.1080/00397911.2011.618283

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One-Pot Multicomponent Reactions
for the Efficient Synthesis of Highly
Functionalized Dihydropyridines
Suman Pal a , Lokman H. Choudhury a & Tasneem Parvin a
a Department of Chemistry, Indian Institute of Technology Patna,
Patna, India
Accepted author version posted online: 08 May 2012.Version of
record first published: 07 Jan 2013.
To cite this article: Suman Pal , Lokman H. Choudhury & Tasneem Parvin (2013): One-Pot
Multicomponent Reactions for the Efficient Synthesis of Highly Functionalized Dihydropyridines,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 43:7, 986-992
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Synthetic Communications1, 43: 986–992, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.618283
ONE-POT MULTICOMPONENT REACTIONS FOR THE
EFFICIENT SYNTHESIS OF HIGHLY FUNCTIONALIZED
DIHYDROPYRIDINES
Suman Pal, Lokman H. Choudhury, and Tasneem Parvin
Department of Chemistry, Indian Institute of Technology Patna, Patna, India
GRAPHICAL ABSTRACT
Abstract An efficient, atom-economic, one-pot protocol has been developed for the synthesis
of highly functionalized dihydropyridines via four-component reactions of aromatic alde-
hydes, arylamines, malononitrile, and dimethylacetylenedicarboxylate in the presence of
sodium hydroxide in ethanol. This domino reaction proceeded smoothly in good to excellent
yields and offered several advantages, including short reaction time, simple experimental
procedure, and applicability to a broad range of substrates.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Aldehydes; amines; dihydropyridines; dimethylacetylenedicarboxylate;
multicomponent reactions
INTRODUCTION
Synthesis of diverse heterocyclic molecules from the readily available starting
materials in a cost and time effective manner is an enduring challenge for organic
chemists.[1] Multicomponent reactions (MCRs), where three or more reactants are
combined together in a single reaction flask to generate a product incorporating
most of the atoms contained in the starting materials, are considered as an efficient
tool for this challenge.[2] MCRs are suitable both from Green Chemistry and econ-
omic point of view considering its virtue such as pot, atom and step economy, con-
sumption of less energy, less waste production and high selectivity. They allow rapid
access to combinatorial libraries of complex organic molecules in a very short time.
Thus MCRs have gained considerable interest in recent times.[3]
Dihydropyridines (DHPs) and their analogues represent an important class of
nitrogen heterocycles, which is abundant in various natural products, synthetic
Received June 22, 2011.
Address correspondence to Lokman H. Choudhury, Department of Chemistry, Indian Institute of
Technology Patna, Patna 800 013, India. E-mail: lokman@iitp.ac.in
986

SYNTHESIS OF FUNCTIONALIZED DIHYDROPYRIDINES
987
Scheme 1. Synthesis of highly substituted dihydropyridines. (Figure is provided in color online.)
pharmaceuticals, and a wide variety of biologically active compounds.[4] Substituted
dihydropyridines exhibit diverse range of biological activities like antihyperten-
sion,[5] antioxidant,[6,7] anticancer[8] and antitumor activity.[9] The remarkable drug
activity of these compounds not only attracted many chemists to synthesize this het-
erocyclic nucleus but also became an active research area of continuing interest.
1,4-DHPs can be synthesized by various ways. The conventional way is the
Hantzsch method from the cyclocondensation of an aldehyde, a b-ketoester and
ammonia.[10] Regioselective [4 þ 2] cycloaddition of 1-aryl-4-phenyl-1-azadienes
and allenic esters for the synthesis of N-aryl-1,4-DHPs[11] and a multicomponent
reaction of alkyl amines, ethyl propiolate, and benzaldehydes for the construction
of N-alkyl-1,4-DHPs[12] are known in the literature. In continuation of our ongoing
research to develop new synthetic methodologies for the synthesis of diverse hetero-
cycles using multicomponent reactions, herein we report an efficient and practical
synthesis of highly substituted dihydropyridines via the four-component reactions
of aromatic aldehydes, arylamines, dimethylacetylenedicarboxylate, and malononi-
trile or its derivatives using sodium hydroxide as catalyst in ethanol as solvent at
room temperature (Scheme 1).
RESULTS AND DISCUSSION
Dimethylacetylenedicarboxylate (DMAD) is a versatile substrate for the syn-
thesis of diverse N-heterocycles by multicomponent reactions.[13a–d] Most interest-
ingly, the outcomes of the final products from the MCRs involving DMAD are
substrate dependent. Therefore, we were interested to explore the virtue of this
electron-deficient alkyne for the synthesis of highly substituted 1,4-DHPs using a
very cheap and readily available catalyst. Initially, the reaction of 4-chlorobenzalde-
hyde (1.0 equiv.), 4-methylaniline (1.0 equiv.), malononitrile (1.0 equiv.), and
dimethylacetylenedicarboxylate (1.0 equiv.) was tested in the presence of K2CO3
(10 mol%) in ethanol at room temperature. Interestingly, after 12 h, we ended with
a four-component product 1c in 50% yield. The compound was fully characterized
1
by infrared (IR), H and 13C NMR, and elemental analysis. Encouraged by this
result we were interested in optimizing the reaction condition by taking the same
set of substrates in ethanol and changing the catalysts. Different base catalysts such
as LiOH, Ln2O3, KOH, NaOH, PPh3, Na2CO3, and NaHCO3 were screened under
the similar reaction conditions to find the optimum condition. The results are sum-
marized in Table 1 (entries 2–9). Surprisingly, the LiOH provided a trace amount of
the desired product, whereas NaOH was the most efficient catalyst of choice among
all the screened catalysts for this transformation in terms of reaction time and yield
obtained. In the absence of any catalyst, even after 24 h of stirring the desired

988
S. PAL, L. H. CHOUDHURY, AND T. PARVIN
Table 1. Optimization of reaction conditionsa
Entry
Catalyst
Solvent
Time (h)
Yield (%)b
1
2
—
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
CH3CN
DMF
CH2Cl2
THF
24
12
16
16
8
0
50
K2CO3
LiOH
Ln2O3
KOH
3
Trace
Trace
66
4
5
6
PPh3
16
8
Trace
68
70
7
Na2CO3
NaHCO3
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
8
8
9
8
85
68
10
11
12
13
14
8
8
64
8
Trace
63
20
8
H2O
8
aAll the reactions were carried out using 4-chlorobenzaldehyde, 4-methylaniline, malononitrile, and
dimethylacetylenedicarboxylate in 1:1:1:1 ratio.
bIsolated yield.
product was not observed (Table 1, entry 1). To find the best solvent for this trans-
formation, the four-component reaction in the presence of 10 mol% NaOH was also
screened in various solvents such as CH3CN, dimethylformamide (DMF), CH2Cl2,
tetrahydrofuran (THF), and H2O (Table 1, entries 10–14). Among all these solvents,
EtOH was found to be the best solvent for this transformation, and dichloromethane
was found to be an unsuitable solvent for this multicomponent reaction.
Under the optimized reaction conditions, a study on the substrate scope was
carried out and the results are summarized in Table 2. It can be found from the
results that a wide range of aromatic aldehydes and aromatic amines are suitable
for this multicomponent reaction. Aromatic aldehydes tethered with both
electron-donating and electron-withdrawing substituents afforded the desired pro-
ducts in very good yields. Similarly, arylamines with various substituents gave the
expected dihydropyridines in very good yields. To extend the utility and generality
of this method, malononitrile derivatives such as ethyl cyanoacetate and cyanoace-
tamide were also explored, and the corresponding highly substituted dihydropyri-
dines 1o–1r were obtained in good yields (Table 2, entries 15–18). Similarly,
benzoylacetonitrile also afforded the corresponding four-component product 1s in
good yields.
Next we realized that this protocol is not so useful for aliphatic amines such as
butyl amine, and in the case of benzylamine the reaction took longer time with mod-
erate yield (1t, 50% in 24 h). Bulky amines such as a-naphthyl amine and b-naphthyl
amine also underwent four-component reactions smoothly to provide 1u and 1v in
good yields (Fig. 1).

SYNTHESIS OF FUNCTIONALIZED DIHYDROPYRIDINES
989
Table 2. Synthesis of highly substituted dihydropyridines
Entry
R1
R2
R3
CN
Product
Time (h)
Yield (%)a
Mpb (ꢀC)
1
2
H
H
H
1a
1b
1c
1d
1e
1f
10
8
78
80
85
89
90
90
78
89
83
82
92
91
80
90
90
88
79
55
70
161–163
4-Me
4-Me
4-Me
4-Me
4-Me
4-OMe
4-Cl
CN
CN
165–167[13c]
186–188[13c]
185–187[13c]
180–182[13c]
212–214[13c]
159–161
3
4-Cl
4-Br
8
4
CN
CN
7.5
7
5
3-Cl
6
3-NO2
4-OMe
4-Cl
CN
CN
6.5
8
7
1g
1h
1i
8
CN
CN
8
130–132[13c]
168–170[13c]
184–186
9
4-OMe
3-NO2
3-NO2
4-Br
4-Me
4-OMe
4-Cl
8
10
11
12
13
14
15
16
17
18
19
CN
CN
1j
8
1k
1l
8
195–197
163–165
165–167
4-Cl
CN
CN
8
4-Br
3-NO2
4-Cl
4-OMe
H
4-Cl
1m
1n
1o
1p
1q
1r
1s
9
CN
7
217–219
COOEt
COOEt
COOEt
CONH2
COPh
6
179–181[13c]
186–188[13c]
181–183[13c]
221–223[13c]
184–186
3-NO2
4-Br
4-Cl
4-Cl
4-Cl
8
8
4-OMe
4-Me
24
10
4-Cl
aIsolated yields.
bLiterature reference.
We believe the mechanism of the reaction goes via the Knoevenagel
condensation of aldehyde and malononitrile in the presence of NaOH catalyst to
yield arylidene malononitrile I (Fig. 2). Simultaneously aryl amine reacts with
dimethylacetylenedicarboxylate to give the 1,3-dipole intermediate II. The next step
Figure 1. Highly substituted dihydropyridines obtained from benzyl and naphthyl amines.

990
S. PAL, L. H. CHOUDHURY, AND T. PARVIN
Figure 2. Proposed mechanism for the four component reaction.
is the Michael addition of II to arylidene malononitrile I to yield the adduct III.
The migration of the hydrogen atom will provide the intermediate IV and sub-
sequent intramolecular addition of the amino group to the C-N triple bond gave
the cyclic intermediate (V), which tautomerizes to yield the final product N-aryl
dihydropyridine.
CONCLUSION
In conclusion, we have developed a facile and efficient one-pot, four-
component protocol for the synthesis of highly substituted dihydropyridines at room
temperature in high yields. This domino reaction proceeded smoothly in good to
excellent yields and offered several advantages including short reaction time, simple
experimental procedure, and no toxic by-product. Due to the presence of NH2 and
CN functionality in ortho position of the molecules, further functionalization of
these molecules is feasible, and work in this direction is ongoing in our laboratory
and will be reported in due course.
EXPERIMENTAL
All reagents were purchased from commercial sources and used without further
1
purification. IR spectra were recorded in Shimadzu FTIR spectrophotometer. H
NMR spectra and 13C NMR spectra were recorded on Jeol=Bruker 500 and Brucker
400 MHz spectrometer in CDCl3 using TMS as internal reference. Elemental
analyses were carried out in a Perkin Elmer 2400 automatic carbon, hydrogen,
and nitrogen analyzer. All unknown compounds were characterized by usual spec-
troscopic techniques and known compounds data were compared with the literature
data and melting points.

SYNTHESIS OF FUNCTIONALIZED DIHYDROPYRIDINES
991
General Procedure for the Preparation of Highly Functionalized
Dihydropyridines
A solution of 4-chlorobenzaldehyde (1.0 mmol), malononitrile (1.0 mmol) and
NaOH (0.1 mmol) were stirred in 3 mL of ethanol at room temperature. Then a sol-
ution of 4-methyl aniline (1.0 mmol) and dimethyl acetylenedicarboxylate (1.0 mmol)
in 2 mL ethanol was added to it. The resulting mixture was stirred until the reaction
was completed as indicated by thin-layer chromatography (TLC). The resulting pre-
cipitates were collected by filtration and washed with ethanol. The crude product was
purified via recrystallization from hot ethanol=acetonitrile to give pure products.
Complete experimental details are available online in the Supplementary Materials
for this article.
ACKNOWLEDGMENTS
L. H. C. and T. P. gratefully acknowledge financial support from the Depart-
ment of Science and Technology India, with Sanction No. SR=FT=CS-042=2009 and
SR=FT=CS-008=2010 respectively. S. P. is thankful to the University Grants Com-
mission for his junior research fellowship. Authors are also grateful to SAIF, CDRI
Lucknow and SAIF, Indian Institute of Technology Madras, for providing NMR
facilities for characterization of the compounds.
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