Hydrated ferric sulfate catalyzed synthesis of 5,6-unsubstituted 1,4-dihydropyridines using three-component reaction

Article abstract of DOI:10.1016/j.tetlet.2014.08.067

A wide variety of 5,6-unsubstituted 1,4-dihydropyridines derivatives (4a-q) were synthesized through a one-pot three-component reaction from α,β-unsaturated aldehydes, amines, and 1,3-diketones at room temperature using hydrated ferric sulfate as a Lewis acid catalyst. The key features of the present protocol are mild and simple reaction procedure, good to excellent yields, and use of inexpensive, recyclable, and environmentally benign catalyst.

Full text of DOI:10.1016/j.tetlet.2014.08.067

Accepted Manuscript
Hydrated ferric sulfate catalyzed synthesis of 5,6-unsubstituted 1,4-dihydro-
pyridines using three-component reaction
Kobirul Islam, Deb K. Das, Abu T. Khan
PII:
S0040-4039(14)01410-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.08.067
TETL 45034
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 May 2014
15 August 2014
18 August 2014
Please cite this article as: Islam, K., Das, D.K., Khan, A.T., Hydrated ferric sulfate catalyzed synthesis of 5,6-
unsubstituted 1,4-dihydropyridines using three-component reaction, Tetrahedron Letters (2014), doi: http://
dx.doi.org/10.1016/j.tetlet.2014.08.067
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Graphical Abstract
Hydrated ferric sulfate catalyzed synthesis of 5,6-unsubstituted 1,4-dihydropyridines
using three-component reaction
Kobirul Islam, Deb K. Das and Abu T. Khan*
1

Hydrated ferric sulfate catalyzed synthesis of 5,6-unsubstituted 1,4-dihydropyridines
using three-component reaction
Kobirul Islam,a Deb K. Dasa and Abu T. Khana,b*
a Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781 039, India
b Vice-Chancellor, Aliah University, DN-18, 8th Floor, Sector V, Salt Lake, Kolkata-700 091,
West Bengal, India
Tel.: +91 361 2582305; fax: +91 361 2582349.
E-mail address: atk@iitg.ernet.in (A.T. Khan).
Keywords: 5,6-unsubstituted 1,4-dihydropyridines, α,β-unsaturated aldehydes, amines, 1,3-
diketones, hydrated ferric sulfate [Fe2(SO4)3.xH2O]
Abstract
A wide variety of 5,6-unsubstituted 1,4-dihydropyridines derivatives (4a–q) were synthesized
through a one-pot three-component reaction from α,β-unsaturated aldehydes, amines and 1,3-
diketones at room temperature using hydrated ferric sulfate as a Lewis acid catalyst. The key
features of the present protocol are mild and simple reaction procedure, good to excellent yields,
and use of inexpensive, recyclable and environmentally benign catalyst.
The design and efficient synthesis of bioactive compounds is one of the main objectives of
organic and medicinal chemistry.1 One of the most useful ways to achieve this goal is to
articulate a synthetic strategy that allows the formation of several bonds in a single pot. Among
the various synthetic approaches, multicomponent reactions2 (MCRs) have emerged as a
powerful tool in the preparation of structurally diverse chemical libraries of drug-like
heterocyclic compounds due to lesser number of reaction and purification steps, high selectivity
and atom economy, simplicity and good yields.3 Thus, development of new multicomponent
reactions and improving the known MCRs are an area of considerable current interest in
contemporary organic synthesis. 1,4-Dihydropyridines, important class of nitrogen heterocycles,
are found in numerous synthetic pharmaceutical agents.4 Various 1,4-dihydropyridine-based
drug molecules such as amlodipine, clevidipine, felodipine, nicardipine, etc. are already
2

marketed to reduce systemic vascular resistance and arterial pressure.5 In addition, they exhibit a
diverse range of biological properties such as calcium channel blockers,6a HIV protease
inhibition,6b inhibition of topoisomerase I,6c MDR reversal,6d neuroprotection,6e
radioprotection,6f cocaine dependent regulator,6g and TGFβ signal inhibitors.6h They are also
useful synthetic precursors specially in the preparation of libraries of alkaloid-like compounds
and variety of nitrogen-containing heterocycles such as piperidines or pyridines.7 The synthesis
of these heterocycles has long been an area of immense interest resulting in the development of
efficient synthetic approaches for 1,4-dihydropyridines. Among them, the direct condensation of
α,β-unsaturated aldehydes with amines and 1,3-carbonyl compounds in presence of suitable
catalyst for the synthesis of 5,6-unsubstituted 1,4-dihydropyridines is well documented in
literature. Over the last few years, several reagents have been explored as catalysts to access
these compounds, such as sulfated mixed metal oxides,8a perchloric acid adsorbed on magnetic
Fe3O4 nanoparticles coated with silica,8b Brønsted acid–thiourea co-catalyst,8c InCl3, iodine,8e
8d
nano CuO,8f L-Proline,8g chiral binol-derived phosphoric acid derivatives,8h Mg(ClO4)2,8i
8j
Sc(OTf)3 and cerium ammonium nitrate (CAN).8k Other synthetic methods developed for the
construction of 5,6-unsubstituted 1,4-dihydropyridines are as follows: PdCl2 catalyzed 1,4-
conjugated addition of enamines and cinnamaldehyde,9a Michael addition of β-enaminocarbonyl
compounds with α,β-unsaturated aldehyde,9b three-component reaction using amines, and α,β-
unsaturated aldehyde and dimethyl acetylenedicarboxylate (DMAD)9b or enaminones9c and
microwave assisted [4+2] cycloadditions of 1-azadienes with allenic esters.9d,e Some of these
methods are associated with certain limitations such as use of excess8a,9c and expensive
catalyst,8a-d,8h,8j,9a low yields,8i-j,9b-c requirement of multistep sequences9b and harsh reaction
conditions.8d,9e-f Consequently, there is still a need to find out greener reusable catalyst, which
provides better yields at room temperature. Recently, ferric sulfate [Fe2(SO4)3.xH2O] has
received considerable attention as a mild, inexpensive, and reusable catalyst for various organic
transformations, such as tetrahydropyranylation of alcohols,10a preparation of acylals from
aldehydes,10b 2,3-unsaturated glycosides via Ferrier rearrangement,10c and per- O-acetylation of
sugars,10d synthesis of tetrahydroquinoline,10e tetrahydropyrido[2,3-c]-coumarin derivatives,10f
1H-pyrazole-4-carbodithioate10g and 3-[(alkyl/arylthio)(aryl)methyl]-1H-indole derivatives.10h
The unique solubility of the catalyst in acetonitrile/methanol and insolubility in DCM enables us
3

to use it as both homogenous and heterogeneous catalyst. Moreover, it can also be easily
recovered at the end of reaction by adding DCM. Due to its wide applicability as a catalyst, we
presume that it would be an efficient catalyst for the one-pot three-component reaction for the
synthesis of the 5,6-unsubstituted 1,4-dihydropyridines derivatives. In this letter, we would like
to disclose our successful results for the one-pot synthesis of 5,6-unsubstituted 1,4-
dihydropyridines from α,β-unsaturated aldehydes, amines and acyclic 1,3-carbonyl compounds
as shown in Scheme 1.
(Scheme 1)
For the present study, the mixture of cinnamaldehyde (1 mmol), benzylamine (1 mmol) and
methyl acetoacetate (1 mmol) was stirred in presence of 5 mol % of Fe2(SO4)3.xH2O in methanol
(3 mL) for 2 h at room temperature. The product 5,6-unsubstituted 1,4-dihydropyridines (4a) was
isolated in 92% yield after chromatographic purification (entry 1, Table 1) and it was
1
characterized from H NMR, 13C NMR and mass spectra. The same set of reactions were also
carried out using 10 and 15 mol% of Fe2(SO4)3.xH2O in methanol under identical reaction
condition and it provided the desired product 4a (entry 2 and 3, Table 1) in 89%, and 82% yields,
respectively.
(Table 1)
From these observations, it is clear that the yield of the product 4a reduces slowly with
increasing the amount of catalyst from 5% to 15%. To find out a suitable solvent system, the
similar reactions were conducted in ethanol, iso-propanol, n-BuOH, DCM, acetonitrile, 1,4-
dioxane, THF, DMF and DMSO under identical reaction conditions (entries 4–12, Table 1). The
best yield was obtained in methanol using 5 mol% catalyst with the shortest reaction time, which
are summarized in Table 1. It was also observed that no desired product was obtained in absence
of catalyst even after 12 h of stirring at room temperature and only the starting substrates were
recovered (entry 13, Table 1). After optimizing the reaction condition, various amines such as 4-
methylbenzylamine, methoxybenzylamine and α-methylbenzylamine were examined with
cinnamaldehyde and methyl acetoacetate under identical reaction conditions and the desired
products 4b-d were isolated in good yields (entries 2-4, Table 2). Similarly, a wide variety of
aliphatic amines such as n-butylamine, sec-butylamine, n-heptylamine, 1-hexadecylamine and
4

cyclohexylamine were also scrutinized with cinnamaldehyde and methyl acetoacetate under
similar reaction conditions and the desired 5,6-unsubstituted 1,4-dihydropyridines (4e-i) were
obtained in excellent yields (entries 5-9, Table 2). Likewise, numerous β-keto esters such as
ethyl acetoacetate, tert-butyl acetoacetate and ethyl butyrylacetate on reaction with
cinnamaldehyde and benzyl amine provided desired 5,6-unsubstituted 1,4-dihydropyridines (4j-
4l) in good to excellent yields under identical reaction condition (entries 10-12, Table 2).
Furthermore, various acyclic 1,3-diketones such as acetylacetone, benzoylacetone and
dibenzoylmethane on reaction with benzylamine, cinnamaldehyde afforded the desired
dihydropyridines (4m-4o) in good yields (entries 13–15, Table 2). When the similar reactions
were examined with cyclic 1,3-diketone such as 1,3-cyclohexanedione and dimedone,
cinnamaldehyde and benzylamine, it gave complicated reaction mixture and no desired products
were isolated. It is worthwhile to mention that β-keto esters react faster as compared to acyclic
1,3-diketones in the present reaction.
(Table 2)
To expand the scope of the present protocol, reactions were carried out with other α,β-
unsaturated aldehyde such as crotonaldehyde with benzylamine and methyl acetoacetate/ethyl
acetoacetate under similar reaction conditions and the desired dihydropyridines (4p-4q) were
obtained in good yields (entries 16 and 17, Table 2). Unfortunately, the reaction with aromatic
amine such as aniline gave inseparable complex reaction mixture under identical reaction
condition.
All the products 4a–q was characterized by recording IR, 1H NMR, 13C NMR spectra, and mass
spectra. On the basis of the reported literature,8a,8c,8g, 8l-m a plausible mechanism for the formation
of substituted 5,6-unsubstituted 1,4-dihydropyridines 4 is depicted in Scheme 2. There are two
possible mechanistic pathways. In Pathway A, we believe that a condensation reaction between
α,β-unsaturated aldehydes (1) and amine (2) gives α,β-unsaturated imine intermediate A in the
presence of catalyst Fe2(SO4)3.xH2O. Then the enolize form of β-keto ester or 1,3-diketone reacts
with α,β-unsaturated imine intermediate A to provide intermediate B, which undergoes
cyclization followed by dehydration to give the desired 5,6-unsubstituted 1,4-dihydropyridine (4)
(Scheme 2). In Pathway B, there is also another possibility that activated β-keto ester or 1,3-
5

diketone (3) reacts with amine 2 to form β-enaminones D as an intermediate in the initial step.
The second step involves Michael addition of an α,β-unsaturated aldehyde (1) to the β-
enaminone D to form intermediate E, which undergoes intramolecular cyclization to form
hydroxytetrahydropyridine F. Finally, the desired 5,6-unsubstituted 1,4-dihydropyridine 4 is
obtained after dehydration as shown in Scheme 2.
(Scheme 2)
Finally, the structure of one of the representative compounds such as 4a was confirmed
unambiguously by single crystal X-ray diffraction analysis (see the Supplementary data) (Fig. 1).
A racemic mixture was obtained and that the structure of 4a in Fig. 1 represents only one
enantiomer (S configuration) present in the Unit Cell. Otherwise there is no congruence between
a racemic mixture (both enantiomers in equal amounts) obtained in Scheme 2 and the single
crystal X-ray structure of a single enantiomer.
(Figure 1)
The efficient recovery of the catalyst at the end of the reaction is highly desirable. The
reusability test of the catalyst was performed as follows: a mixture of cinnamaldehyde (10
mmol), benzylamine (10 mmol), methyl acetoacetate (10 mmol) and Fe2(SO4)3.xH2O (0.5 mmol,
0.205 g) was taken in 30 mL of methanol and it was stirred for 2 h at room temperature. After
completion of the reaction, methanol was removed in a rotatory evaporator and the crude residue
was dissolved in 25 mL of dichloromethane. On adding dichloromethane, the catalyst separated
out and it was filtered off through a Büchner funnel, washed with another 5 mL of DCM and
dried. The recovered catalyst was used for a similar set of reactions for three more consecutive
cycles. Each reaction with recovered catalyst was carried out for 2 h using the same reaction
procedure. The yields and the number of experiments conducted are shown in the bar diagram in
Figure 2. The required product 4a was isolated in 86% yield after concentrating dichloromethane
followed by purification through a silica gel column chromatography. The yield of the reaction
decreased relatively in the fourth cycle which may be due to weight loss of the catalyst during
handling in each cycle.
(Figure 2)
6

The efficiency and generality of the present protocol can be realized at a glance by comparing
our results with those of some reported procedures as shown in Table 3. The results have been
compared with respect to the mole percent of the catalyst used, reaction time and yields. It can be
easily visualized that the reactions are considerably faster and give better product yields on using
only 5 mol % of Fe2(SO4)3.xH2O as compared to other catalyst as shown in Table 3.
(Table 3)
In short, we have achieved the synthesis of 5,6-unsubstituted 1,4-dihydropyridines derivatives
using α,β-unsaturated aldehydes, amines and 1,3-diketone in the presence of catalytic amount of
Fe2(SO4)3.xH2O in methanol. The reaction is compatible with variety of aliphatic amine and 1,3-
diketone compounds. In comparison to other Lewis acids catalyst, Fe2(SO4)3.xH2O has been
found to be effective, mild, and less expensive. Moreover, due to its recyclability, the present
method may open up a simple, mild and less expensive pathway for the synthesis of 5,6-
unsubstituted 1,4-dihydropyridines in good yields. The application of synthesized
dihydropyridines as dienophile in aza-Diels-Alder reaction is going on in our laboratory, and the
results will be reported in due course.
Acknowledgements
KI is thankful to UGC for his research fellowship. DKD acknowledges CSIR, New Delhi for
financial support for SRF. The authors are grateful to the Director, IIT Guwahati for providing
general facilities to carry out the research work. We are thankful to DST for providing XRD
facility under the FIST programme.
Supporting Information
Supplementary data (X-ray crystallographic data (CIF files) of 4a spectral data of all compounds
and copies of 1H and 13C NMR spectra of products) associated with this article can be found, in
the online version, at doi:
7

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11. General Procedure for the preparation of 5,6-unsubstituted 1,4-dihydropyridines: The
catalyst hydrated ferric sulfate (0.021g, 0.05 mmol) was added to a stirred mixture of α,β-
unsaturated aldehyde (1, 1 mmol) amine (2, 1 mmol) and 1,3-diketone (3, 1 mmol) in 3
mL of methanol and it was kept for stirring at room temperature. After completion of the
reaction as monitored by TLC, methanol was removed in a rotary evaporator and the
crude residue was extracted with ethyl acetate (2 x 10 mL). The organic layer was
washed with water followed by brine solution and finally it was dried over anhydrous
sodium sulfate. The organic extract was concentrated in a rotary evaporator and the crude
residue was purified through a silica gel (60-120 mesh) column chromatography. The
desired products (4a-4q) were eluted with a mixture of hexane/ethyl acetate (9:1).
Spectroscopic data of the 5,6-unsubstituted 1,4-dihydropyridine derivatives: Methyl 1-
benzyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-carboxylate (4a): Brown Solid, mp 74-
1
75 °C; Rf (10% ethyl acetate/hexane) 0.36; IR (KBr) 1685 cm-1; H NMR (CDCl3, 400
MHz) δ 7.39-7.32 (m, 2 H), 7.31-7.27 (m, 5 H), 7.21 (d, J = 7.6 Hz, 2 H), 7.19-7.14 (m, 1
H), 5.96 (d, J = 7.6 Hz, 1 H), 5.0 (dd, J = 5.6, 7.2 Hz, 1 H), 4.68-4.55 (m, 3 H), 3.53 (s, 3
H, OMe), 2.42 (s, 3 H, Me) ppm.13C NMR (100 MHz, CDCl3) δ 169.40, 149.13, 148.61,
131.04, 129.56, 128.86 (2 C), 128.29 (2 C), 127.47, 127.34 (2 C), 126.19(2 C), 126.03,
108.01, 100.02, 53.67, 50.64, 40.06, 16.01 ppm. HRMS (ESI) calcd for C21H21NO2 (M +
H+) 320.1651, found 320.1652. Ethyl 1-benzyl-2,4-dimethyl-1,4-dihydropyridine-3-
carboxylate (4q): Gummy liquid; Rf (10% ethyl acetate/hexane) 46; IR (KBr) 1677 cm-1;
10

1H NMR (CDCl3, 400 MHz) δ 7.30-7.21 (m, 3 H), 7.15 (d, J = 7.6 Hz, 2 H), 6.54 (d, J =
9.2 Hz, 1 H), 4.98 (dd, J = 5.2, 9.2 Hz, 1 H), 4.77 (d, J = 16.8 Hz, 1 H), 4.30 (d, J = 17.2
Hz, 1 H), 4.08 (q, J = 7.2 Hz, 2 H), 3.90 (quin, J = 6.4 Hz, 1 H), 2.37 (s, 3 H, Me), 1.22
(t, J = 7.2 Hz, 3 H), 1.05 (d, J = 6.4 Hz, 3 H) ppm.13C NMR (100 MHz, CDCl3) δ 167.87,
155.28, 137.77, 129.09 (2C), 127.65, 126.37 (2 C), 124.12, 112.24, 98.58, 59.25, 55.71,
53.25, 19.69, 16.74, 14.82, ppm. HRMS (ESI) calcd for C17H21NO2 (M + H+) 272.1651,
found 272.1651.
11

Scheme 1. One-pot synthesis of 5,6-unsubstituted 1,4-dihydropyridine derivatives
Table 1. Effect of solvent and catalyst loading on the synthesis of 5,6-unsubstituted 1,4
dihydropyridine (4a)a
Entry
1
Catalyst (mol%)
Solvent
MeOH
Time
2
Yieldb%
92
5
10
15
5
2
MeOH
2
89
3
MeOH
2
82
4
EtOH
2
87
5
5
Isopropanol
n-BuOH
DCM
3
68
6
5
3
61
7
5
6
56
8
5
CH3CN
1,4-Dioxane
THF
6
41
9
5
6
28
10
11
12
13
5
6
trace
42
5
DMF
6
5
DMSO
6
45
None
MeOH
12
-
a All the reactions were performed with benzylamine (1.0 mmol), cinnamaldehyde (1.0 mmol), and
methyl acetoacetate (1.0 mmol) in the presence of Fe2(SO4)3.xH2O as catalyst in 3 mL of indicated
solvent at room temperature. bIsolated yields.
12

Table 2. Scope and yields of various 5,6-unsubstituted 1,4-dihydropyridinesa
Entry
1
R1
PhCH2
R2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
R3
R4
Product (4) Time (h) Yieldb (%)
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OEt
2
2
2
2
1
1
1
2
2
2
2
2
3
3
3
2
2
92
94
89
84
94
96
94
92
87
91
82
88
78
74
85
78
84
4a
4b
4c
4d
4e
4f
2
4-Me-PhCH2
4-MeO-PhCH2
PhCH(CH3)
Butyl
3
4
5
6
2-Butyl
7
Heptyl
4g
4h
4i
8
Me(CH2)15
Cyclohexyl
PhCH2
9
10
11
12
13
14
15
16
17
4j
PhCH2
OtBu
OEt
4k
4l
PhCH2
PhCH2
Me
Me
Ph
Me
4m
4n
4o
4p
4q
PhCH2
Ph
PhCH2
Ph
PhCH2
Me
Me
OMe
OEt
PhCH2
aThe reactions were carried out with amines (1.0 mmol), α,β-unsaturated aldehydes (1.0 mmol),
and 1,3-carbonyl compound (1.0 mmol) in the presence of 5 mol % of Fe2(SO4)3.xH2O in 3 mL
of MeOH at room temperature. bIsolated yields.
13

Scheme 2. Plausible mechanism for the formation of 5,6-unsubstituted 1,4-dihydropyridines (4)
14

Figure 1. Single crystal X-ray structure of compound 4a (CCDC 997063).
Figure 2. Reusability of the catalyst in methanol.
15

Table 3. Comparison of our result with other results using different catalystsa
Entry
Catalyst
SO42−/Ce0.07Zr0.93O2
Thiourea-Ammonium Salts
Binol-derived phosphoric acid
Sc(OTf)3
Amount
20 mol%
10 mol%
10 mol%
5 mol%
5 mol%
Time
1.5
12
--
Yieldb,c,%
848a
1
2
3
4
5
808c
548h
16
2
758j
Fe2(SO4)3.xH2O
91d
aAll reactions were carried out with cinnamaldehyde, benzylamine and ethyl acetoacetate (1:1:1 ratio)
at room temperatures. bIsolated Yields c Reported method with other catalysts. d The present protocol.
16