A grinding-induced catalyst- and solvent-free synthesis of highly functionalized 1,4-dihydropyridines via a domino multicomponent reaction

Article abstract of DOI:10.1039/c1gc15223h

A grinding-induced catalyst- and solvent-free domino multicomponent reaction for the synthesis of 1,4-dihydropyridines has been developed using aldehydes, amines, DEAD (diethyl acetylenedicarboxylate), and malononitrile/ethyl cyanoacetate. The synthesized

Full text of DOI:10.1039/c1gc15223h

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A grinding-induced catalyst- and solvent-free synthesis of highly
functionalized 1,4-dihydropyridines via a domino multicomponent reaction†
Atul Kumar* and Siddharth Sharma
Received 2nd March 2011, Accepted 24th March 2011
DOI: 10.1039/c1gc15223h
A grinding-induced catalyst- and solvent-free domino
multicomponent reaction for the synthesis of 1,4-
dihydropyridines has been developed using aldehydes,
amines, DEAD (diethyl acetylenedicarboxylate), and
malononitrile/ethyl cyanoacetate. The synthesized 1,4-
dihydropyridines were efficiently converted into novel
tacrine analogs 7a–7e using micelle-promoted microwave
irradiation.
activities.8 Initially, these compounds were found to be calcium
channel modulators, and were developed as cardiovascular and
antihypertensive drugs, which include felodipine, amlodipine,
nifedipine and nicardipine (Fig. 1).9 Recently, tacrine analogs
were found to be potent acetylcholinesterase inhibitors, and even
stronger inhibitors of butyrylcholinesterase.10
Green chemistry has become a powerful tool in organic chem-
istry in the last decade,1 and current areas of interest are the
generation of complex molecular systems via multicomponent
reactions (atom economy), catalyst and solvent-free syntheses,2
and reactions in/on water.3 The avoidance of catalysts and
solvents in chemical processes, or the replacement of hazardous
solvents with more benign solvents, have become major concerns
in academia and industry, and the need for green reactions is now
globally accepted. Catalyst- and solvent-free multicomponent
syntheses are particularly attractive, because they incorporate
many green chemistry principles.
In recent years, multicomponent reactions have been much
utilized for the synthesis of diverse highly functionalized
molecules,4 via the formation of carbon–carbon and carbon–
heteroatom bonds in one pot; as a consequence, they have
emerged as a significant tool in organic synthesis.5 These re-
actions are straightforward one-step transformations involving
a pair of reactions in which the product of the first is a substrate
for the second. The development of several methods for the
generation of libraries of structurally complex and diverse small
molecules has provided new applications for the “chemical
genetic” approach,6 as well as playing an important part in drug
discovery, namely the rapid identification and optimization of
biologically active lead compounds.7
Fig. 1 Some biologically important dihydropyridines.
The vast biological importance of dihydropyridines and
tacrine analogs inspired us to develop a novel protocol for the
efficient synthesis of new 1,4-dihydropyridines via a domino
multicomponent synthesis of DEAD (diethyl acetylenedicar-
boxylate), aldehyde, aniline and malononitrile/ethyl cyanoac-
etate/cyanoacetamide. During the synthesis of dihydropy-
ridines, Yan and coworkers reported the same class of
compound11 using triethylamine as a base, but this required a
long reaction time, as well as solvent and catalyst.
Our experience in the area of multicomponent reactions12
and the success of our environmentally friendly synthesis of
tryptanthrin13 inspired us to search for environmentally friendly
conditions for the synthesis of 1,4-dihydropyridines under
catalyst- and solvent-free conditions.
Researchers have long been fascinated by the biological
activity of 1,4-dihydropyridines (1,4-DHPs) (I), tacrine (II) and
their derivatives. 1,4-Dihydropyridines are a very important
class of heterocyclic compounds due to a variety of biological
In our initial studies, we attempted to optimize the reaction
conditions for the domino multicomponent reaction between
benzaldehyde, aniline, DEAD, and malanonitrile as model
substrates (Scheme 1). Solvent-free syntheses14 and Knoevengel
condensation15 under solventless conditions have gathered much
interest, so we examined this reaction under solvent-free condi-
tions. The reaction proceeded successfully in a porcelain mortar
and pestle without any catalyst. Interestingly, 100% conversion
in the synthesis of 5a was found on grinding for 15 min, but no
reaction was observed in ethanol (in the absence of catalyst). An
Medicinal and Process Chemistry Division, Central Drug Research
Institute, CSIR, Lucknow, India. E-mail: dratulsax@gmail.com;
Fax: +91 522-26234051; Tel: +91 522-2612411
† Electronic supplementary information (ESI) available: Experimental
details and NMR spectra. See DOI: 10.1039/c1gc15223h
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Table 1 Solvent- and catalyst-free domino synthesis of 1,4-dihydropyridinesa
Entry
Ar
Ar¢
EWG
Product
Yield (%)
1
2
3
4
5
6
7
8
C6H5
C6H5
p-CH3OC6H4
p-ClC6H4
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
COOEt
COOEt
COOEt
COOEt
COONH2
5a
5b
5c
5d
5e
5f
5g
5h
5i
92
88
84
92
99
84
86
93
92
95
91
94
84
82
88
92
93
98
95
96
0
p-CH3OC6H4
p-CH3OC6H4
p-CH3OC6H4
3,4,5-(CH3O)3C6H2
3,4,5-(CH3O)3C6H2
3,4,5-(CH3O)3C6H2
3,4,5-(CH3O)3C6H2
3,4,5-(CH3O)3C6H2
3,4,5-(CH3O)3C6H2
3,4,5-(CH3O)3C6H2
3,4-(CH3O)2C6H3
3,4-(CH3O)2C6H3
3,4-(CH3O)2C6H3
p-CH3OC6H4
p-CH3OC6H4
p-ClC6H4
p-CH3C6H4
p-CH3OC6H4
p-ClC6H4
3,4,5-(CH3O)3C6H2
p-CH3C6H4
2,4-(CH3)2C6H4
p-BrC6H4
C6H5
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
5j
5k
5l
p-BrC6H4
p-ClC6H4
5m
5n
5o
5p
5q
5r
5s
5t
5u
5v
6a
6b
6c
6d
6e
p-CH3OC6H4
p-BrC6H4
p-C2H5OC6H4
p-BrC6H4
p-BrC6H4
p-BrC6H4
p-CH3C6H4
C6H5
2,4-Cl2C6H4
p-(C6H5CH2O)C6H4
p-NO2C6H4
Isatin
Cyclohexanone
3,4,5-(CH3O)3C6H2
p-ClC6H4
C6H5
0
p-CH3OC6H4
p-BrC6H4
p-CH3C6H4
p-ClC6H4
91
93
91
84
79
p-NO2C6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
a Reagents and conditions: Aniline (1 mmol), aldehyde (1 mmol), malanonitrile/ethyl cyanoacetate (1 mmol), DEAD (1 mmol), grinding, 5–20 min.
Scheme 1 Synthesis of 1,4-dihydropyridines.
Scheme 2 Possible mechanistic pathway for the synthesis of 1,4-
dihydropyridines.
exothermic reaction started immediately after grinding started,
with liquification of the mixture, followed by solidification of
the product 5a, as explained by Scott and coworkers.16 The
purity of the product was high enough for spectroscopic analysis
without any further purification, but all the compounds were
nevertheless crystallized from ethanol.
hydroamination or Knoevenagel products were isolated. This
indicates the fast rate of the aza-Michael reaction compared to
the other possible reactions.
In order to demonstrate the efficiency and the applicability
of our method, we performed the reaction with a variety of
arylaldehydes and aryl amines under solvent-free conditions
(Table 1), without using any catalyst. No obvious electronic
effects of the aldehyde or amine were observed, and the products
were obtained in excellent yields. A limitation of the reaction is
that complex mixtures of products were observed when ketones
such as isatin and cyclohexanone were used in place of aldehydes.
Using malononitrile instead of cyanoacetamide gave the desired
product in very good yield (Scheme 1).
In order to synthesize tacrine analogs, the synthesized di-
hydropyridines were used in the micelle-promoted coupling of
cyclohexanone, to yield hexahydrobenzo[b][1,8]naphthyridine
derivatives in the presence of SDS (sodium dodecyl sulfate) as
a catalyst in water (Scheme 3). We also tested sodium lauryl
sulfate, Triton X-100 and dodecylsulfonic acid, to optimize the
reaction conditions. The reaction of dihydropyridine 5m and
cyclohexanone using these catalysts gave 7a in 43, 48 and 32%
yields respectively (Scheme 3, Table 2).
A possible mechanistic pathway is shown in Scheme 2, using
5a as an example. Initially, coupling of the aldehyde with the
active methylene compound, and the aza-Michael reaction of
DEAD and aniline occur (and are known to take place under
catalyst-free conditions). Rearrangement of the intermediates
then generates the product 5a. We observed the aza-Michael
product as an oily compound after 1 min of grinding, but no
Scheme 3 Synthesis of novel hexahydrobenzo[b][1,8]naphthyridines.
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Table 2 Synthesis of hexahydrobenzo[b][1,8]naphthyridine derivatives
via SDS-promoted reaction of dihydropyridines
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Entry Ar
Ar ¢
Product Yield (%)
7a
65, 43a, 48b, 32c
1
2
3
4
5
3,4-(CH3O)2C6H3
p-ClC6H4
p-C2H5OC6H4 7b
p-BrC6H4
p-BrC6H4
p-CH3OC6H4
52
68
79
61
p-ClC6H4
7c
7d
7e
2,4-Cl2C6H4
p-(C6H5CH2O)C6H4 p-BrC6H4
a Sodium lauryl sulfate (30 mol%) used as a catalyst. b Triton X-100 used
as a catalyst. c Dodecylsulfonic acid (30 mol%) used as a catalyst.
Conclusions
In conclusion, a domino multicomponent reaction for the
synthesis of dihydropyridines has been developed using solvent-
and catalyst-free conditions. The features of this procedure
are mild conditions, high yields, operational simplicity, and
the environmental friendliness. In addition, the synthesized
dihydropyridines could be efficiently converted into polyhydron-
aphthyridines in water.
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General procedure for synthesis of compounds 5a–v and 6a–e
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An oven-dried microwave vial was charged with dihydropyridine
5 (1 mmol), cyclohexanone (3 mmol) and SDS (30 mol% solution
in water, 3 ml), and irradiated in a microwave (power input
140 W) at 150 ◦C with stirring for 15 min. After completion of
the reaction, the mixture was diluted with 5 ml ethyl acetate and
washed with saturated aqueous NH4Cl solution. The aqueous
layer was extracted with ether, and the combined organic layers
washed with brine and dried over Na2SO4. The solvent was
evaporated to yield a crude residue, which was purified by silica
gel column chromatography using EtOAc–hexane to give the
pure product 7.
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Acknowledgements
S.S. is thankful to CSIR New Delhi for financial support.
The authors also acknowledge SAIF-CDRI for providing
the spectral and analytical data. CDRI communication No.
8078.
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