Benzyltrimethylammoniumfluoride Hydrate: An Efficient Catalyst for One-Pot Synthesis of Hantzsch 1,4-Dihydropyridines and Their Aromatization

Article abstract of DOI:10.1002/hc.21308

An efficient, cost-effective and simple protocol has been developed for the synthesis of Hantzsch 1,4-dihydropyridines and their oxidation into pyridines using benzyltrimethylammonium fluoride hydrate as an excellent catalyst under solvent-free condition. All of the products synthesized by this method are characterized by various spectroscopic methods (IR, ¹H NMR, ¹³C NMR, and DEPT).

Full text of DOI:10.1002/hc.21308

Heteroatom Chemistry
Volume 27, Number 2, 2016
Benzyltrimethylammoniumfluoride Hydrate:
An Efficient Catalyst for One-Pot Synthesis
of Hantzsch 1,4-Dihydropyridines and Their
Aromatization
Anamika Khaskel and Pranjit Barman
Department of Chemistry, National Institute of Technology, Silchar 788 010, India
Received 4 September 2015; revised 2 December 2015; accepted 7 December 2015
blockers [4–6] and are used most frequently as
ABSTRACT: An efficient, cost-effective and sim-
cardiovascular agents for the treatment of hyper-
ple protocol has been developed for the synthesis of
tension [7,8].
Hantzsch 1,4-dihydropyridines and their oxidation
Moreover, extensive studies have shown that
into pyridines using benzyltrimethylammonium flu-
1,4-DHPs also exhibit diverse physiological func-
oride hydrate as an excellent catalyst under solvent-
tions and are used as neuroprotectants [9], platelet
free condition. All of the products synthesized by this
antiaggregators [10], chemosensitizer in tumor ther-
method are characterized by various spectroscopic
apy [11], and as antiischaemic agents in Alzheimer’s
methods (IR, 1H NMR, 13C NMR, and DEPT). 2016
ꢀC
disease [12]. 1,4-DHPs are used as drug resistance
modifiers [12], antioxidants [13], and also used for
the treatment of urinary urge incontinence [14]. The
use of 1,4-DHPs against congestive heart failure [15]
and angina pectoris [16] are also reported. In
organic synthesis, 1,4-DHPs are used as reducing
agents [17]. Additional interest in 1,4-DHPs is due
to their structural resemblance to NADH, a cofactor
used by many reductases in metabolism [13–15].
1,4-DHPs are commonly synthesized using the
Hantzsch reaction by intermolecular heterocycliza-
tion of aldehydes, 1,3-dicarbonyls, and ammonia.
Several methods that have been developed for the
synthesis of 1,4-DHPs, involved microwave [18, 19],
ionic liquid [20], metal triflates [21], TMSCl-
NaI [22], PPh3 [23], InCl3 [24], ammonium bicarbon-
ate [25], tetrabutylammonium hydrogensulfate [26],
CAN [27], HClO4/SiO2 [28], glycine nitrate [29],
Triton-X-100 [30], L-tyrosine loaded nanoparti-
cles [31], etc. However, the use of high-temperature,
harmful organic solvents, expensive metal precur-
sors, long reaction time, tedious workup procedure,
and poor yields are some of the limitations asso-
ciated with most of the cases. So the development
of a mild, simple yet an efficient method for the
Wiley Periodicals, Inc. Heteroatom Chem. 27:114–
120, 2016; View this article online at wileyonlineli-
brary.com. DOI 10.1002/hc.21308
INTRODUCTION
4-Substituted 1,4-dihydropyridines (1,4-DHPs)
belong to the class of biologically important or-
ganic molecules [1–3]. 1,4-DHP nucleus is a rich
source of biologically active compounds possessing
various important pharmacological properties
such as vasodilator, bronchodilator, antihyperten-
sive, hepatoprotective, antitumor, antimutagenic,
geroprotective, and antidiabetic agents [1–3].
1,4-DHP nucleus is present in many drugs such as
nifedipine, nicardipine, and amlodipine, which have
been found to be very useful as calcium channel
Correspondence to: Anamika Khaskel; e-mail: anamika.khaskel
@yahoo.com.
Supporting Information is available in the online issue at
www.wileyonlinelibrary.com.
ꢀC
2016 Wiley Periodicals, Inc.
114

Benzyltrimethylammoniumfluoride Hydrate: An Efficient Catalyst for One-Pot Synthesis of Hantzsch 1,4-DHPs 115
Cl
Cl
Cl
EtO2C
CO2Et
Me
EtOOC
Me
COOEt
Me
EtOOC
O
COOCH3
Me
N
H
H2NH2CH2C
N
H
Me
N
H
Felodipine
Diludine
Amlodipine
FIGURE 1 Some bioactive 1,4-dihydropyridines.
TABLE 1 BTMAFH-Catalyzed Synthesis of 1,4-DHPs (3a) in
Different Solvents and under Solvent-Free Condition at 70ºC
Temperature
synthesis of 1,4-DHPs is an area of interest for the
synthetic chemists. For increasing environmental
and economic concerns in recent years, search for
environmentally benign catalytic reactions is highly
desirable. Recently, Ghosh and his co-workers
reported the synthesis of Hantzsch 1,4-DHPs in
aqueous ethanol by visible light [32]. Safari and
Jarnegar recently reported a solvent-free method
for the synthesis of 1,4-DHPs using a magnetic
nanoparticle-supported ionic liquid [33]. In aque-
ous medium, synthesis of 1,4-DHPs using a phase
transfer catalyst has been reported [34] but this
method requires a lengthy and complex workup
procedure involving column chromatography and
use of some hazardous chemicals such as ethyl
acetate, petroleum ether, magnesium sulfate, etc.
An inherent problem associated with the Hantzsch
synthesis is a slow rate of reaction [35,36]. However,
the search for the new, readily available and green
catalyst is still being actively pursued due to their
vast biological activities.
In this paper, we report a new protocol for
fast and efficient synthesis of biologically active
1,4-DHPs under solvent-free condition and oxi-
dation of 1,4-DHPs to corresponding pyridines at
room temperature both in good yields using ben-
zyltrimethylammonium fluoride hydrate (BTMAFH)
as a catalyst in ethanol as a solvent. BTMAFH gener-
ally used as a source of organic soluble fluoride ion
to remove silyl ether protecting groups. In case of
intramolecular cross-coupling reaction, tetrabuty-
lammonium fluoride hydrate has been used as an
Yield
(%)a
Catalyst Load
(mmol%)
Solvent
Time (min)
Ethanol
Methanol
Chloroform
Acetonitrile
Solvent free
30
30
40
40–50
15
72
62
65
50
89
10
10
10
10
10
aPure isolated yields.
activator. To the best of our knowledge, no report on
BTMAFH in catalysis has been published until now.
RESULTS AND DISCUSSION
With an aim to establish a new protocol for a facile
and efficient synthesis of 1,4-DHPs, we have chosen
BTMAFH as the catalyst (see Scheme 1). The use
of 10 mmol% of the catalyst in the reaction of 4-
methoxybenzaldehyde (1 mmol), ethyl acetoacetate
(2 mmol), and ammonium acetate (2 mmol) under
solvent-free condition at 70 ºC produced the expected
1,4-DHP (Table 3; 3a) in good yield. In comparison,
the same reaction carried out in various organic sol-
vents gave poorer yields at a slower rate (Table 1).
It was also observed that under solvent-free con-
dition the catalytic efficiency of BTMAFH in the
synthesis of Hantzsch 1,4-DHPs (Table 3; entry 3a)
OMe
OMe
COOEt
EtOOC
O
O
10 mmol % BTMAFH
+
NH4OAC
+
OEt
N
H
CHO
Scheme 1 Synthesis of Hantzsch 1,4-dihydropyridines.
Heteroatom Chemistry DOI 10.1002/hc

116 Khaskel and Barman
TABLE 2 Hantzsch Synthesis of 1,4-DHP:a Effect of Cata-
The above optimized conditions for the synthe-
sis of 1,4-DHPs under solvent-free condition were
then extended to other aldehydes. The generality
of the reaction for the synthesis of 4-substituted
1,4-DHPs established by the results is shown in
Table 3.
lysts
Time
Entry
Catalystb
(min) Yield (%)c
1
2
3
4
5
6
Benzyltriethylammonium iodide
Benzyltrimethylammonium bromide 90
Benzyltrimethylammonium chloride 120
Benzyltrimethylammonium fluoride
Tetra-n-butylammonium fluoride
Tetraethylammonium fluoride
120
30
32
70
89
56
71
The significant aspects of the method described
are good yields of 1,4-DHPs and the mildness of the
reaction, which is reflected in its near insensitivity
to the polar effects of the substituents present in the
aromatic rings of the aldehydes used in the reaction.
The acid-sensitive functional groups such as olefin
(Table 3, entry 3l, yield 90 %), ether (Table 3, entry
3a, yield 89% and entry 3b, yield 92 %), and cyano
(Table 3, entry 3j, yield 85 %) remain unaffected due
to the mild reaction condition. Another striking ob-
servation of this procedure is that the bulky aromatic
aldehydes (Table 3, entries 3e and 3f) are found to
produce the corresponding 1,4-DHPs in high yield
within 10 min. In contrast, the uncatalyzed reactions
either failed (for entry 3c) or gave poor yields (for
entry 3j) of 1,4-DHPs.
15
60
50
a4-Methoxybenzaldehyde – ethyl acetoacetate – NH4OAC = 1:2:2,
reaction temperature 70ºC,
b10 mmol% used for each reaction,
cPure isolated yields.
was better than that of the corresponding chlo-
ride, bromide, and iodide (Table 2). We also com-
pare the catalytic activity of BTMAFH with tetra-n-
butylammonium fluoride and tetraethylammonium
fluoride for the model reaction in Table 2.
As the fluoride ion has smaller size and higher
elctronegativity, so its ability to abstract the active
hydrogen from β-ketoester is much higher than io-
dide, bromide, or chloride. So, the reaction follow-
ing the above-mentioned mechanism will be much
easier using BTMAFH than its chloride, bromide, or
iodide counterparts (see Scheme 2).
The scope of our study was extended to the oxi-
dation of 1,4-DHPs (see Scheme 3) using ethanol as
a solvent. A mixture of 1,4-DHP (1 mmol), K2S2O8
(1 mmol), and BTMAFH (10 mmol %) in ethanol
was taken in a round bottom flask, and stirring af-
ter 20–30 min of the mixture at room temperature a
_
+
[F] [PhCH2NMe3]
O
H
H
O
O
R
O
EtO
O
O
H
R
H
-H2O
EtO
OH
O
R
O
EtO
OEt
NH3
O
O
OEt
1
+
NMe3
H2N
PhH2C
-H2O
2
OEt
O
R
O
R
EtOOC
COOEt
O
EtO
HN
N
H
H
_
1
2
+
F
3
NMe3
PhH2C
Scheme 2 Plausible mechanism for the synthesis of 1,4-DHPs using BTMAFH as a catalyst.
Heteroatom Chemistry DOI 10.1002/hc

Benzyltrimethylammoniumfluoride Hydrate: An Efficient Catalyst for One-Pot Synthesis of Hantzsch 1,4-DHPs 117
TABLE 3 BTMAFH-Catalyzed Synthesis of Hantzsch 1,4-DHPs under Solvent-Free Condition
Entry
Aldehydes
1,3-Diketone
Time (min)
Product
Yield (%)
1
15
3a
89
OMe
O
O
Me
Me
OEt
CHO
OMe
2
15
3b
92
O
O
OMe
CHO
O
O
O
O
3
4
12
15
3c
3d
83
90
Me
Me
OMe
OEt
CHO
OH
CHO
CHO
O
O
O
O
5
6
10
10
3e
3f
91
93
Me
Me
OEt
OEt
CHO
NMe2
O
O
7
8
15
10
3g
3h
92
91
Me
Me
OEt
CHO
Me
O
O
O
O
OEt
CHO
9
13
10
3i
3j
88
85
Me
Me
OMe
NO2
CHO
CN
O
O
10
OMe
CHO
S
O
O
O
O
11
12
15
15
3k
3l
89
90
Me
Me
OEt
OEt
CHO
CHO
(Continued)
Heteroatom Chemistry DOI 10.1002/hc

118 Khaskel and Barman
TABLE 3 Continued
Entry
Aldehydes
1,3-Diketone
Time (min)
Product
Yield (%)
13
15
3m
87
NO2
O
O
Me
Me
OMe
OMe
CHO
S
14
10
3n
88
O
O
CHO
15
16
Ferrocene-3-carboxaldehyde
12
15
3o
3p
92
O
O
O
O
Me
Me
OMe
OEt
SMe
89 [31]
CHO
CHO
O
O
17
10
3q
83 [31]
Me
OMe
CHO
O
O
O
O
18
19
n-Propyl
15
15
3r
86 [30]
84 [30]
Me
Me
OEt
OEt
Isopropyl
3s
aAll products were characterized by IR, 1H NMR, 13C NMR, and DEPT spectroscopy and melting points.
bYields refer to isolated pure products.
TABLE 4 Oxidation of 1,4-DHPs to Pyridines
Ar
Ar
ROC
COR
ROC
COR
Entry
Ar
R
Product Time (min) Yield (%)
10 mmol % BTMAFH
K2S2O8, EtOH
1
2
3
4
5
4-MeOC6H4 OEt
C6H5 OEt
3-NO2C6H4 OEt
4a
4b
4c
4d
4e
30
30
25
20
20
91
90
90
93
90
N
N
H
H
OEt
OMe
Scheme 3 Oxidation of 1,4-DHPs.
4-CNC6H4
precipitate started to form. The results are summa-
rized in Table 4.
the reaction (confirmed by TLC), the product is fil-
tered. Then the filtrate was concentrated and cooled
in refrigerator. Then solid catalyst precipitated out
and after filtration the solid compound is dried over
silica gel. Then the catalyst was reused for four con-
secutive cycles to afford compound 3a. As shown in
Fig. 2. the catalyst can be recycled upto four times
without a significant decrease in catalytic activity;
the yields ranged from 89 to 85%.
In addition to the already stated findings, an-
other experiment was performed which showed that
pyridine derivatives could be directly synthesized
without 1,4-DHPs (see Scheme 4). To achieve that
4-methoxybenzaldehyde (1 mmol), ethyl acetoac-
etate (2 mmol), and ammonium acetate (2 mmol)
were refluxed at 70ºC in one pot, in the presence
of BTMAFH (10 mmol%) and K2S2O8 using ethanol
as a solvent for 2 h. The results are summarized in
Table 5.
CONCLUSIONS
Reusability of the Catalyst
We have successfully developed an efficient method-
ology for the synthesis of Hantzsch 1,4-DHPs, partic-
ularly under solvent-free conditions using BTMAFH
For green chemical synthesis, reusability of the cat-
alyst is a very important factor. After completion of
Heteroatom Chemistry DOI 10.1002/hc

Benzyltrimethylammoniumfluoride Hydrate: An Efficient Catalyst for One-Pot Synthesis of Hantzsch 1,4-DHPs 119
Ar
ROC
COR
O
O
10 mmol % BTMAFH
K2S2O8, EtOH
+
ArCHO
NH4OAC
+
R
N
Scheme 4 Synthesis of pyridines.
TABLE 5 Synthesis of Pyridines
100
80
60
40
20
0
Entry
Ar
R
Product Time (h) Yield (%)
1
2
3
4
5
4-MeOC6H4 OEt
5a
5b
5c
5d
5e
2
70
82
72
65
80
C6H5
OEt
OEt
OEt
OMe
2–3
2.5
1.5
2
3-NO2C6H4
H
4-CNC6H4
as a catalyst in relatively fast reaction under benign
conditions with good yields following a simple work-
up procedure. We have also developed a new and
easy to perform method for the efficient oxidation of
Hantzsch 1,4-DHPs.
1
2
3
4
Cycle
FIGURE 2 Recyclability of BTMAFH.
EXPERIMENTAL
General
20–30 min. Pale yellow solids were obtained and
filtered. The products thus obtained were recrystal-
lized from ethanol to get pure compounds as white
crystals.
Melting points were recorded on a Veego melting
point apparatus and were uncorrected. CHN anal-
yses were recorded on a Perkin-Elmer Series II
CHNS/O analyzer. IR spectra were recorded on the
IR-affinity-I FTIR spectrometer (Shimadzu) as KBr
pellet. 1H and 13C NMR spectra were recorded on the
Ultrasonic Bruker 300 MHz FT-NMR spectrometer,
using TMS as an internal standard and CDCl3 as a
solvent. All the chemicals used were obtained from
Merck.
ACKNOWLEDGMENTS
Authors thank the director of NIT, Silchar, India, for
laboratory facilities and financial support.
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