Aluminized polyborate: a novel catalyst for the multicomponent solvent-free synthesis of alkyl 1,2,6-trisubstituted-4-[(hetero)arylamino]-1,2,5,6-tetrahydropyridine-3-carboxylates

Article abstract of DOI:10.1007/s13738-018-1340-0

Abstract: An efficient and simple method for the one-pot three-component synthesis of alkyl 1,2,6-trisubstituted-4-[(hetero)arylamino]-1,2,5,6-tetrahydropyridine-3-carboxylates was developed using aromatic aldehyde, amine and β-ketoesters catalyzed by aluminized polyborate, an efficient reusable catalyst under solvent-free condition. Aluminized polyborate has advantageous of cost, ecologically benefits, accessible preparation and recyclability up to five cycles along with high product yield and simplicity. Graphical Abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s13738-018-1340-0

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-018-1340-0
ORIGINAL PAPER
Aluminized polyborate: a novel catalyst for the multicomponent
solvent‑free synthesis of alkyl 1,2,6‑trisubstituted‑4‑[(hetero)
arylamino]‑1,2,5,6‑tetrahydropyridine‑3‑carboxylates
Anil S. Mali1 · Chinmay S. Potnis2 · Ganesh U. Chaturbhuj1
Received: 27 October 2017 / Accepted: 27 February 2018
© Iranian Chemical Society 2018
Abstract
An efcient and simple method for the one-pot three-component synthesis of alkyl 1,2,6-trisubstituted-4-[(hetero)arylamino]-
1,2,5,6-tetrahydropyridine-3-carboxylates was developed using aromatic aldehyde, amine and β-ketoesters catalyzed by
aluminized polyborate, an efcient reusable catalyst under solvent-free condition. Aluminized polyborate has advantageous
of cost, ecologically benefts, accessible preparation and recyclability up to fve cycles along with high product yield and
simplicity.
Graphical Abstract
Keywords Multicomponent reaction · Aluminized polyborate · Tetrahydropyridine · Solvent-free
Introduction
The study of multicomponent reaction is an attractive topic
in organic chemistry because of their advantageous in drug
discovery and in the preparation of diverse heterocyclic mol-
Electronic supplementary material The online version of this
ecules [1]. The piperidine ring system is one of the most
article (https://doi.org/10.1007/s13738-018-1340-0) contains
found in numerous natural products such as alkaloids, drug
supplementary material, which is available to authorized users.
candidates and drugs [2–4]. Synthesis of heterocyclic com-
pounds with potential biological activity is one of the focal
challenges in medicinal chemistry and chemical biology [5].
Nitrogen heterocyclic tetrahydropyridine moiety is abundant
in synthetic bioactive molecules as well as in various natural
products. Tetrahydropyridine possesses broad-spectrum bio-
logical and pharmacological activities [6]. The compounds
* Ganesh U. Chaturbhuj
gu.chaturbhuj@gmail.com
1
Department of Pharmaceutical Sciences and Technology,
Institute of Chemical Technology, Mumbai 400019, India
2
V. G. Vaze College of Arts, Science, and Commerce,
Mumbai 400081, India
Vol.:(0123456789)
1 3

Journal of the Iranian Chemical Society
with tetrahydropyridine ring exhibit antibacterial [7], anti-
hypertensive [8], anticonvulsant and anti-infammatory [9,
10], neuroprotective [11, 12] and antimalarial activities [13].
Furthermore, these are intricately involved as a inhibitor
of dihydroorotate dehydrogenase and farnesyl transferase
[14] and are also efective in treating Parkinson’s disease
[15]. Also substituted piperidines have been identifed as
an important class of therapeutic agent in treating cancer
metastatic [16], infuenza infection [17], diabetes [18] and
viral infection including AIDS [19] (Fig. 1).
reagents. Therefore, the development of a more efcient,
convenient is a desirable catalytic method that addresses
these limitations.
A literature search revealed many organic transforma-
tions at a temperature above 100 °C which is catalyzed by
boric acid [53]. Boric acid converts to its polymeric forms
when it dehydrates above 100 °C for catalyzing the reac-
tion which presumably is the active species [53, 54]. How-
ever, dehydrative polymerization of boric acid liberates
water molecules that may hamper the progress of the reac-
tion. This prompted us to develop a polymeric boric acid
catalyst. To accomplish, this boric acid was dehydrated
at 200 °C to convert it into its polymeric Lewis acid form
and then supported with aluminum. Electron-windrowing
efect of adjacent boron enhances its Lewis acidity of alu-
minum and aluminum being an electron-defcient element;
hence, it has good Lewis acid characters (Scheme 1).
The development of novel synthetic procedures with
an objective of green chemistry and technology, the use
of recyclable catalysts for organic synthesis to maximize
efciency and minimize waste been currently in demand.
To accomplish this objective, our laboratory has developed
sulfated polyborate [55] and activated Fuller’s earth [56]
catalyst and their applications [55–71, 78], in the con-
tinuation of our eforts to develop and apply eco-friendly
catalyst for organic transformations; herein, this report
describes the application of aluminized polyborate as an
efcient and eco-friendly catalyst for the tetrahydropyri-
dine synthesis under a solvent-free condition. This cata-
lyst is environmentally benign due to its reusability and
non-toxic nature. The catalyst was prepared from boric
acid and aluminum trichloride which are a readily avail-
able and inexpensive starting materials. To the best of our
knowledge, this is the frst report on the preparation and
use of aluminized polyborate for the synthesis of highly
functionalized tetrahydropyridine (Scheme 1).
The usual method for the preparation of tetrahydropyri-
dine is through the multicomponent reaction of benzal-
dehyde, aniline and ethyl acetoacetate. Various catalytic
methods have been reported for the preparation of tetrahy-
dropyridine, such as l-proline/TFA [13], InCl3 [20, 21],
bromodimethyl sulfonium bromide (BDMS) [22], tetrabu-
tylammonium tribromide (TBATB) [23], iodine [24], cerium
ammonium nitrate [25], ZrOCl2•8H2O [26], BF3•SiO2 [27],
Bi(NO3)3•5H2O [28], picric acid [29], oxalic acid [30] and
AcOH6 [31] as catalyst.
Several methodologies for the preparation of 1,2,5,6-tet-
rahydropyridines are known. They have been synthesized
by the partial reduction of corresponding pyridinium salts
or 4-piperidones [32, 33]. Normally, substituted tetrahydro-
pyridine, especially the products possessing N-aryl func-
tion, is difcult to prepare [34]. However, some exciting
strategies for their synthesis have been developed. These
include the synthesis via iminium ion intermediate [35–40],
phosphine-catalyzed (4+2) π-electron electrocyclic annula-
tions [41], acid-catalyzed cyclization of ene derivatives [42],
Wittig rearrangements [43–47], aza-Diels–Alder reaction
[48–51], enyne cross-metathesis and intermolecular allyl
silane-nitrone cycloaddition reaction [52].
However, most of the methods have certain boundaries
regarding scope and reaction conditions, e.g., cost of syn-
thesis, harsher reaction conditions, longer reaction time,
lower yields and the use of expensive, explosive and toxic
Fig. 1 Pharmacologically active tetrahydropyridines
1 3

Journal of the Iranian Chemical Society
Dehydration
HO
Cl
200 oC
OH
Alumination
-HCl
HO
OH
Al
OH
O
O
O
O
B
B
B
B
B
OH
OH OH
-H2O
OH OH
2
2
Aluminized Polyborate
O
O
O
NH
O
O
Aluminized
polyborate
NH2
+
2
Solvent free, rt
CHO
N
2
Scheme 1 Schematic representation of aluminized polyborate catalyzed the synthesis of ethyl 1,2,6-triphenyl-4-(phenylamino)-1,2,5,6-tetrahy-
dropyridine-3-carboxylate
After the completion of the reaction, the mixture was quenched
by water; solid precipitated was fltered at vacuum, washed
with water (3×5 mL), dried under vacuum and recrystallized
from ethanol to aford the pure product. After the completion
of each reaction cycle, water was added, and the product was
fltered of. The catalyst being water soluble, the fltrate was
evaporated in vacuum rotary evaporator to recover catalyst.
Experimental
Melting points of the compounds were recorded by Analab
ThermoCal melting point apparatus in open capillary tube and
are uncorrected. The FTIR spectra (KBr) were recorded on
Shimadzu FTIR Afnity-1 Fourier Transform Infrared spec-
trophotometer. 1H NMR spectra were recorded on MR400
Agilent Technology NMR spectrometer using tetramethylsi-
lane (TMS) as an internal standard and CDCl3 as a solvent.
X-ray Difraction (XRD) of catalyst we rerecorded (Shimadzu
XRD-6100 using Cu Kα radiations=1.5405Å) with a scan-
ning rate of 20/min and 2θ angle ranging from 100 to 800
with a current 30 mA and voltage 40 kV. JEOL JSM-6380LA
instrument was used for scanning electron microscope (SEM)
and energy-dispersive X-ray spectrometer (EDAX) at difer-
ent magnifcations. Chemicals and solvents used were of
LR grade and purchased from SD fne, Avra Synthesis and
Spectrochem and used as received. The purity determina-
tion of the starting materials and the reaction monitoring was
accomplished by thin-layer chromatography (TLC) on Merck
silica gel G F254 plates. All the products were characterized
by melting points in comparison with the literature values,
FTIR and 1H NMR spectroscopy for structural identifcation.
Representative spectral data
1. Ethyl 1,2,6‑triphenyl‑4‑(phenylamino)‑1,2,5,6‑tetrahy-
dropyridine‑3‑carboxylate 1H NMR (400 MHz, CDCl3) δ
10.27 (s, 1H), 7.35–7.01 (m, 15H), 6.61–6.43 (m, 4H), 6.26
(dd, J=4.9, 2.6 Hz, 2H), 5.12 (s, 1H), 4.47–4.39 (m, 1H),
4.36–4.27 (m, 1H), 2.85 (dd, J=15.2, 5.2 Hz, 1H), 2.75 (d,
J=15.3 Hz, 1H), 1.45 (t, J=7.1 Hz, 3H).
2 . E t h y l 2 , 6 ‑ b i s ( 4 ‑ c h l o r o p h e n y l ) ‑ 1 ‑ p h e n y l ‑ 4 ‑
1
(phenylamino)‑1,2,5,6‑tetrahydropyridine‑3‑carboxylate H
NMR (500 MHz, CDCl3) δ 10.30 (s, 1H), 7.26–7.04 (m,
14H), 6.66 (t, J=7.2 Hz, 1H), 6.48–6.36 (m, 4H), 5.10 (s,
1H), 4.46 (dd, J = 10.8, 7.1 Hz, 1H), 4.33 (dd, J = 10.8,
7.1 Hz, 1H), 2.84 (dd, J = 15.2, 5.6 Hz, 1H), 2.76 (dd,
J=15.2, 2.5 Hz, 1H), 1.46 (t, J=7.1 Hz, 3H).
General procedure for the synthesis
of alkyl 1,2,6‑trisubstituted‑4‑[(hetero)
arylamino]‑1,2,5,6‑tetrahydro
pyridine‑3‑carboxylates
3. Methyl 1,2,6‑triphenyl‑4‑(phenylamino)‑1,2,5,6‑tetrahydro-
1
pyridine‑3‑carboxylate H NMR (500 MHz, CDCl3) δ 11.96
(s, 1H), 7.53–6.90 (m, 15H), 6.88–6.33 (m, 4H), 6.01 (s,
2H), 5.13 (t, J=5.2 Hz, 1H), 3.89 (s, 3H), 3.10 (dd, J=16.4,
5.8 Hz, 1H), 2.74 (dd, J=16.4, 4.8 Hz, 1H).
To a mixture of ethyl acetoacetate (1 mmol), amine (2 mmol)
and aldehyde (2 mmol) was added aluminized polyborate (10%
by wt.). The reaction mixture was stirred at room temperature.
The reaction was monitored by thin-layer chromatography.
4. Ethyl 1‑(4‑nitrophenyl)‑4‑((4‑nitrophenyl)amino)‑2,6‑di-
phenyl‑1,2,5,6‑tetrahydropyridine‑3‑carboxylate 1H NMR
1 3

Journal of the Iranian Chemical Society
(400 MHz, CDCl3) δ 11.94 (s, 1H), 7.95 (d, J=9.5 Hz, 2H),
7.45–7.03 (m, 14H), 6.54 (d, J=9.5 Hz, 2H), 6.23 (s, 1H),
5.39 (s, 1H), 4.57–4.49 (m, 1H), 4.44–4.36 (m, 1H), 3.23
(dd, J=15.8, 6.2 Hz, 1H), 2.69 (dd, J=15.8, 2.1 Hz, 1H),
1.50 (t, J=7.1 Hz, 3H).
8 . E t h y l 1 ‑ b e n z y l ‑ 4 ‑ ( b e n z y l a m i n o ) ‑ 2 , 6 ‑ d i p h e -
nyl‑1,2,5,6‑tetrahydropyridine‑3‑carboxylate 1H NMR
(500 MHz, CDCl3) δ 8.03 (d, J = 7.7 Hz, 2H), 7.54 (t,
J=7.1 Hz, 2H), 7.42 (t, J=7.5 Hz, 4H), 7.38–7.20 (m, 12H),
6.20 (s, 1H), 4.53 (dd, J=55.5, 34.0 Hz, 2H), 3.99 (s, 2H),
3.12 (s, 1H), 2.88 (s, 3H), 2.02 (d, J=23.8 Hz, 1H), 1.81 (s,
1H), 1.26 (s, 3H).
5. Ethyl 1‑phenyl‑4‑(phenylamino)‑2,6‑di‑p‑tolyl‑1,2,5,6‑tet-
1
rahydropyridine‑3‑carboxylate H NMR (400 MHz, CDCl3)
δ 10.28 (s, 1H), 7.24–7.00 (m, 13H), 6.59 (t, J = 7.2 Hz,
1H), 6.52 (d, J=8.1 Hz, 2H), 6.40 (s, 1H), 6.30 (dd, J=7.6,
1.8 Hz, 2H), 5.11 (d, J = 3.3 Hz, 1H), 4.45 (dq, J = 10.8,
7.1 Hz, 1H), 4.32 (dq, J = 10.8, 7.1 Hz, 1H), 2.86 (dd,
J=15.1, 5.6 Hz, 1H), 2.76 (dd, J=15.1, 2.4 Hz, 1H), 2.31
(t, J=10.4 Hz, 6H), 1.46 (t, J=7.1 Hz, 3H).
Results and discussion
Preparation of Aluminized polyborate catalyst
In total, 30 gm of boric acid was heated in a petri dish at
200 °C for 4 h to convert it to the 20.05 gm of polyboric
acid; 2.25 gm of aluminum trichloride [77] was stirred with
70 ml of dried toluene in 250 ml of round-bottom fask,
added 10 g of polyboric acid; and the resulting slurry was
refuxed for 2 h. Residual HCl gas was eliminated by nitro-
gen fush, and the solvent was evaporated under vacuum at
room temperature to retrieve a fowable powder (Scheme 1).
The catalyst was characterized by techniques such as FTIR,
XRD, SEM and EDAX.
6. Ethyl 2,6‑diphenyl‑1‑(p‑tolyl)‑4‑(p‑tolylamino)‑1,2,5,6‑tet-
1
rahydropyridine‑3‑carboxylate H NMR (400 MHz, CDCl3)
δ 10.20 (s, 1H), 7.35–7.26 (m, 5H), 7.25–7.14 (m, 5H), 6.87
(d, J=3.6 Hz, 4H), 6.41 (s, 3H), 6.15 (d, J=8.2 Hz, 2H),
5.11 (s, 1H), 4.47–4.41 (m, 1H), 4.35–4.29 (m, 1H), 2.82
(dd, J=15.1, 5.7 Hz, 1H), 2.72 (dd, J=15.1, 2.5 Hz, 1H),
2.25 (s, 3H), 2.15 (s, 3H), 1.45 (t, J=7.1 Hz, 3H).
7. Ethyl 2,6‑diphenyl‑1‑(thiazol‑2‑yl)‑4‑(thiazol‑2‑yla-
mino)‑1,2,5,6‑tetrahydropyridine‑3‑carboxylate 1H NMR
(500 MHz, CDCl3) δ 9.05 (s, 1H), 8.00 (s, 1H), 7.98 (s,
1H), 7.69 (s, 1H), 7.69 (s, 1H), 7.56–7.55 (m, 1H), 7.54
(d, J=1.3 Hz, 1H), 7.52 (s, 1H), 7.50 (s, 1H), 7.49 (s, 1H),
7.25 (s, 1H), 7.24 (s, 1H), 7.08 (d, J=3.6 Hz, 2H), 6.80 (s,
1H), 6.54 (d, J=3.7 Hz, 1H), 5.01 (s, 3H), 4.07 (dd, J=9.5,
7.1 Hz, 1H), 3.47 (d, J=27.5 Hz, 1H), 1.17 (t, J=7.1 Hz,
3H).
The FTIR spectrum showed OH stretching band at
3402 cm−1. O–H stretching of B–O–H corresponds to the
band at 3224 cm−1. The band displayed at 1627 cm−1 showed
bending of the Al–OH group, and the peak at 1465 cm−1
showed the B–O stretching. The peaks at 648 cm−1 were
for the B–O–B stretching (Fig. 2) [72, 73]. The catalyst for-
mation was also confrmed by XRD analysis. The peak at
2θ = 28.7° is shown in the powder XRD, which confrms
the presence of B–O bonds in the catalyst (Fig. 3) [74]. The
XRD pattern of boron particles matched well with the XRD
Fig. 2 FTIR spectrum of the
catalyst
1 3

Journal of the Iranian Chemical Society
(Fig. 5). We recycle the catalyst, the recovered catalyst was
characterized, and their result shows that no change in the
physical nature, details (Figs. 6, 7 and 8) is included in sup-
plementary information of this article.
H+ ion concentration of precursor polyboric acid was
determined by potentiometric titration using the following
procedure.
Accurately weighed polyboric acid (0.1 g) was dis-
solved in a mixture of water and glycerin (2:1) and titrated
against standard 0.1 N NaOH solution. The titration data of
∆mV/∆V were plotted against the volume of NaOH. The
concentration of H+ was found to be 23 mmol/g at equiva-
lence point due to H+ associated with B–O–H (Figure 9).
10
20
30
40
50
60
2
Application of Aluminized
Polyborate for the synthesis of alkyl
1,2,6‑trisubstituted‑4‑[(hetero)
arylamino]‑1,2,5,6‑tetrahydro
pyridine‑3‑carboxylates
Fig. 3 XRD pattern of the catalyst
Initially, our study was aimed to determine the suitability
for the synthesis of the catalyst under diferent reaction
conditions. For the preliminary experiment, benzaldehyde
(2 mmol), aniline (2 mmol) and ethyl acetoacetate (1 mmol)
were used to synthesize alkyl 1,2,6-trisubstituted-4-[(hetero)
arylamino]-1,2,5,6-tetrahydropyridine-3-carboxylates.
Efect of the catalyst loading on time and yields of the
reaction was assessed (Table 1, entries 3–5). The reaction
does not proceed in the absence of a catalyst at room temper-
ature as well as 90 °C (Table 1, entries 1 and 2). An increase
in the catalyst loading at rt increased the product yield with a
signifcant reduction in reaction time (Table 1, entries 3–5).
The catalyst loading beyond 10 wt% was not advantageous
(Table 1, entries 5 and 6); hence, a 10 wt% catalyst loading
was chosen for further study.
Fig. 4 SEM image of the catalyst
The temperature played an important role in the synthe-
sis of tetrahydropyridine (Table 1, entries 5, 7 and 8). The
temperature efect was examined at ambient, 60 and 90 °C
under the solvent-free condition with aluminized polybo-
rate as a catalyst. The reaction proceeded with good yield
at room temperature (Table 1, entry 5), while the increase
in temperature resulted in decreased yield probably due
to non-selective reaction or degradation of products and
intermediates. The further increasing temperature to 90 °C
resulted in further decreased product yield. Therefore, room
temperature was the optimum temperature for performing
the reaction.
patterns of crystalline cubic (JCPDS 6-0297); the major
peak at 2θ=28° is assigned to the (310) plane of the cubic
phase [75]. Displayed in Fig. 3 are characteristic results from
X-ray difraction (XRD) analysis performed on selected syn-
thesized powder samples. The Miller indices of aluminum
corresponding to each of the two peaks identifed in the pat-
terns are (111) (JCPDS Card No: 00-004-0787) [76]. The
surface morphology of aluminized polyborate catalyst in the
SEM image clearly indicated that the catalysts are crystal-
line in nature with various shapes and sizes of the particles
in the range of 5–8 μm (Fig. 4). The EDAX analysis of the
catalyst showed aluminum/oxygen/chlorine signal in the
ratio of 50.45: 44.87: 4.69% over diferent areas. Boron was
not detected on the surface as it formed a core for aluminum
The effect of various solvents in model reaction on
time and yield of the reaction was ascertained (Table 2,
entries 2–7). None of the solvents presented the advantage
of time and yield over solvent-free condition. Hence, the
1 3

Journal of the Iranian Chemical Society
Fig. 5 EDAX analysis of the
001
180
160
140
120
100
80
catalyst
60
40
20
0
0.00
1.00
2.00
3.00
4.00
5.00
keV
6.00
7.00
8.00
9.00
10.00
Fig. 6 IR data of recycled
catalyst
solvent-free condition was regarded as the best for the cost
and environmental acceptability. In all the experiments, the
products were isolated by aqueous quenching followed by
fltration and washing the products with water.
catalyst was recycled for four times with no signifcant loss
in catalytic activity (Fig. 10).
In comparison with the literature reported other catalysts
used for the synthesis of 1,2,6-trisubstituted 1,2,5,6-tetrahy-
dropyridine-3-carboxylate, aluminized polyborate catalyst
showed an advantage in many cases with respect to reaction
condition, workup procedure, time and yields (Table 3).
To investigate the substrate scope, optimized reaction
condition was applied to substituted aromatic/heterocyclic
The reusability of the catalyst in the model reaction under
optimized reaction condition was evaluated. In this study,
after the completion of each reaction cycle, water was added,
and the product was fltered of. The fltrate was evaporated
in vacuum rotary evaporator to recover catalyst. Recovered
1 3

Journal of the Iranian Chemical Society
Table 1 Catalyst loading and temperature optimization study for the
synthesis of ethyl 1,2,6-triphenyl-4-(phenylamino)-1,2,5,6-tetrahydro-
pyridine-3-carboxylate
Entry
Catalyst (wt%)
Tempera-
ture (°C)
Time (min)
Yielda (%)
1
2
3
4
5
6
7
8
0
0
rt
90
rt
rt
rt
rt
60
90
120
120
120
120
45
45
120
120
NRb
NRb
85
88
92
92
58
52
2.5
5
10
15
10
10
10
20
30
40
2
50
60
70
Benzaldehyde (2.0 mmol), aniline (2.0 mmol), ethyl acetoacetate
(1.0 mmol) and 10 wt% catalyst at room temperature
aIsolated yield. bNo reaction
Fig. 7 XRD data of recycled catalyst
aldehydes, β-ketoesters and amines variants. All the sub-
strate variants reacted well and aforded higher yields of
the corresponding alkyl 1,2,6-trisubstituted-4-[(hetero)
arylamino]-1,2,5,6-tetrahydropyridine-3-carboxylates within
short reaction time (Table 4). Several electron-releasing or
electron-withdrawing substituents at the ortho, para and meta
positions of aromatic aldehydes/amines have been examined.
The nature of substitution has no signifcant efect on reac-
tion time and yields. On the other hand, methyl ester vari-
ation in β-ketoesters was also adaptable (Table 4, entry 6).
Moreover, the amine varients (Table 4, entries 3, 7–9, 11 and
12) also reacted well to aford good to excellent yields. This
protocol tolerates a variety of substituents on aromatic alde-
hydes and also applicable to heteroaromatic aldehydes along
with methyl/ethyl ester variants of β-ketoesters and substi-
tuted amines for the synthesis of alkyl 1,2,6-trisubstituted-
4-[(hetero)arylamino]-1,2,5,6-tetrahydropyridine-3-carbox-
ylates under optimized conditions.
Fig. 8 SEM data of recycled catalyst
Fig. 9 Potentiometric titration
of polyboric acid
Polyboric acid
180
160
140
120
100
80
60
40
20
0
0
5
10
15
20
25
Volume of NaOH
1 3

Journal of the Iranian Chemical Society
Table 2 Efect of solvent
on the synthesis of
ethyl 1,2,6-triphenyl-4-
(phenylamino)-1,2,5,6-
tetrahydropyridine-3-
carboxylate
Entry
Catalyst (wt%)
Solvent
Temperature (°C)
Time (min)
Yielda (%)
1
2
3
4
5
6
7
10
10
10
10
10
10
10
Solvent-free
EtOH
DMF
rt
45
60
60
60
60
60
60
92
57
63
40
refux
refux
refux
refux
refux
refux
H2O
MeCN
Toluene
THF
Traces
61
NRb
Benzaldehyde (2.0 mmol), aniline (2.0 mmol), ethyl acetoacetate (1.0 mmol) and 10 wt% catalyst at room
temperature
aIsolated yield. bNo reaction
The plausible mechanism for the reaction for the syn-
thesis of ethyl 1,2,6-triphenyl-4-(phenylamino)-1,2,5,6-
tetrahydropyridine-3-carboxylate is proposed (Fig. 11).
The aluminized polyborate might be activating both ethyl
acetoacetate and benzaldehyde to react with aniline to give
β-enaminone (I) and imine (II), respectively. The interme-
diate (III) is produced by an intermolecular Mannich reac-
tion between β-enaminone (I) and imine (II). Intermediate
III reacts with one more molecule of benzaldehyde to give
intermediate (IV). Finally, tautomerization and intramo-
lecular cyclization of intermediate (IV) give the desired
ethyl 1,2,6-triphenyl-4-(phenylamino)-1,2,5,6-tetrahydro-
100
90
80
70
60
50
40
30
20
10
0
1
2
3
4
5
pyridine-3-carboxylate.
No. of cycles
Fig. 10 Reusability of the aluminized polyborate
Table 3 Comparison of
aluminized polyborate with
the literature reported other
catalysts used for the synthesis
of ethyl 1,2,6-triphenyl-
4-(phenylamino)-1,2,5,6-
tetrahydropyridine-3-
Entry
Catalyst (wt%)
Condition/(°C)
Time
Yielda (%)
References
1
2
3
4
5
6
7
8
Aluminized polyborate
CoCl2.6H2O
FeCl3.6H2O
CoO powder
Fe3O4 powder
NiFeO4@SiO2-FHS
ZrOCl2·8H2O
BF3·SiO2
Fe(NO3)3·9H2O
Bi(NO3)3·5H2O
TBATB
l-Proline/TFA
InCl3
Solvent-free/rt
aq. EtOH/120
aq. EtOH/120
aq. EtOH/120
aq. EtOH/120
Solvent free/100
EtOH/refux
MeOH/65
Solvent free/rt
EtOH/rt
EtOH/rt
MeCN/rt
MeCN/rt
45 min
3 h
3 h
3 h
3 h
4 h
4 h
7 h
16 h
16 h
24 h
24 h
48 h
92
23
30
32
57
51
91
81
37
79
74
72
60
This work
[2]
[2]
[2]
[2]
[3]
[4]
[5]
[6]
[7]
carboxylate
9
10
11
12
13
[8]
[96]
[10, 11]
Benzaldehyde (2.0 mmol), aniline (2.0 mmol), ethyl acetoacetate (1.0 mmol) and 10 wt % catalyst at room
temperature
aIsolated yield
1 3

Journal of the Iranian Chemical Society
Table 4 Aluminized polyborate-catalyzed synthesis of alkyl 1,2,6-trisubstituted-4-[(hetero)arylamino]-1,2,5,6-tetrahydropyridine-3-carboxylates
Entry
Aldehyde (R1)
Amine (R2)
β-Ketoesters (R3)
Time (min.)
Yielda (%)
M.P. °C
(Obs.)
(Lit.)
1
2
3
4
5
6
7
8
H
4-Br
H
4-Cl
4-CH3
H
H
H
H
H
4-Br
H
4-CN
4-Cl
4-Cl
H
C6H5
C6H5
4-F-C6H4
C6H5
C6H5
C2H5
C2H5
C2H5
C2H5
C2H5
CH3
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
45
50
50
50
45
45
45
50
45
55
45
45
45
45
55
45
65
92
91
90
89
88
91
89
89
90
87
91
92
90
87
90
86
85
171–173
241–242
180–181
207–209
230–231
193–195
213–215
134–136
198–200
249–251
287–289
228–230
191–193
201–203
237–239
195–197
121–123
172–175
242
181–182
206–208
229–231
192–195
212–215
135–137
197–200
250–252
288
C6H5
2-CH3-C6H4
3-Cl-C6H4
4-CH3-C6H4
4-NO2-C6H4
4-F-C6H4
4-Br-C6H4
H
4-Br-C6H4
4-CH3-C6H4
Thiazol-2-yl
C6H6CH2
9
10
11
12
13
14
15
16
17
227–230
190–193
200–202
236–238
NAb
H
NAb
Benzaldehyde (2.0 mmol), aniline (2.0 mmol), ethyl acetoacetate (1.0 mmol) and 10 wt% catalyst at room temperature
aIsolated yield. bNot available in the literature
aldehydes, β-ketoesters and amines under optimal condi-
tions. Mild reaction conditions, shorter reaction time, higher
yield, ease of workup and recyclability of the catalyst are
the key features of this procedure. Moreover, this method
also has the ability to tolerate a wide variety of substituents.
Conclusions
In conclusion, the present procedure is an efcient and eco-
friendly protocol for the synthesis of alkyl 1,2,6-trisubsti-
tuted-4-[(hetero)arylamino]-1,2,5,6-tetrahydropyridine-
3-carboxylates by multicomponent reaction of various
1 3

Journal of the Iranian Chemical Society
O
O
O
H
NH
O
OEt
N
OEt
NH2
(I)
(II)
O
N
N
O
H
N
O
H3C
OEt
Inter-molecular
Mannich reaction
OEt
(I)+(II)
HN
(IV)
(III)
H
N
O
N
N
O
H
NH
N
O
Intra-molecular
Mannich reaction
OEt
H2C
OEt
OEt
N
(V)
(VI)
= Aluminized polyborate
Fig. 11 A plausible mechanism for the synthesis of ethyl 1,2,6-triphenyl-4-(phenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate
9. R. Gitto, L. De Luca, S. Ferro, F. Occhiuto, S. Samperi, G. De
Sarro, E. Russo, L. Ciranna, L. Costa, A. Chimirri, Chem. Med.
Chem. 3, 1539 (2008)
Acknowledgements Authors are grateful to University Grant Commis-
sion, India, for their fnancial support.
10. B. Ho, A.M. Crider, J.P. Stables, Eur. J. Med. Chem. 36, 265
(2001)
References
11. I. Borza, G. Domany, Curr. Top. Med. Chem. 6, 687 (2006)
12. L. Mony, J.N. Kew, M.J. Gunthorpe, P. Paoletti, Br. J. Pharmacol.
157, 1301 (2009)
1. T.R. Bastami, M.H. Entezari, Ultrason. Sonochem. 19, 830 (2012)
2. F.X. Felpin, J. Lebreton, Curr. Org. Synth. 1, 83 (2004)
3. N. Howard, C. Abell, W. Blakemore, G. Chessari, M. Congreve, S.
Howard, H. Jhoti, C.W. Murray, L.C. Seavers, R.L. Van Montfort,
J. Med. Chem. 49, 1346 (2006)
13. M. Misra, S.K. Pandey, V.P. Pandey, J. Pandey, R. Tripathi, R.P.
Tripathi, Bioorg. Med. Chem. 17, 625 (2009)
14. S.L. Gwaltney, S.J. O’Connor, L.T. Nelson, G.M. Sullivan, H.
Imade, W. Wang, L. Hasvold, Q. Li, J. Cohen, W.Z. Gu, Bioorg.
Med. Chem. Lett. 13, 1359 (2003)
4. P.S. Watson, B. Jiang, B. Scott, Org. Lett. 2, 3679 (2000)
5. M. Rudrapal, B. De, Int. Res. J. Pure Appl. Chem. 3, 232 (2013)
6. D. O’Hagan, Nat. Prod. Rep. 17, 435 (2000)
15. N.H. Hazeri, M.T. Maghsoodlou, S.M. Habibi-Khorassani, J.
Aboonajmi, S.S. Sajadikhah, J. Chin. Chem. Soc. 60, 355 (2013)
16. P.E. Goss, M.A. Baker, J.P. Carver, J.W. Dennis, Clin. Cancer Res.
1, 935 (1995)
7. Y. Zhou, V.E. Gregor, B.K. Ayida, G.C. Winters, Z. Sun, D. Mur-
phy, G. Haley, D. Bailey, J.M. Froelich, S. Fish, Bioorg. Med.
Chem. Lett. 17, 1206 (2007)
17. P. Chand, P.L. Kotian, A. Dehghani, Y. El Kattan, T.H. Lin, T.L.
Hutchison, Y.S. Babu, S. Bantia, A.J. Elliott, J.A. Montgomery,
J. Med. Chem. 44, 4379 (2001)
8. S. Petit, J. Nallet, M. Guillard, J. Dreux, R. Chermat, M. Poncelet,
C. Bulach, P. Simon, C. Fontaine, M. Barthelmebs, Eur. J. Med.
Chem. 26, 19 (1991)
1 3

Journal of the Iranian Chemical Society
51. T. Hamada, T. Zenkoh, H. Sato, O. Yonemitsu, Tetrahedron Lett.
32, 1649 (1991)
18. J.L. Treadway, P. Mendys, D.J. Hoover, Expert Opin. Investig.
Drugs 10, 439 (2001)
52. S.C. Schürer, S. Blechert, Tetrahedron Lett. 40, 1877–1880 (1999)
53. G. Arce, G. Carrau, A. Bellomo, D. Gonzalez, World J. Chem.
Edu. 3, 27 (2015)
19. G. Karlsson, T.D. Butters, R.A. Dwek, F.M. Platt, J. Biol. Chem.
268, 570 (1993)
20. P.A. Clarke, A.V. Zaytsev, A.C. Whitwood, Synthesis 2008, 3530
(2008)
54. S. Chandrasekhar, K. Gopalaiah, Tetrahedron Lett. 43, 2455
(2002)
21. P.A. Clarke, A.V. Zaytzev, A.C. Whitwood, Tetrahedron Lett. 48,
5209 (2007)
55. C.K. Khatri, D.S. Rekunge, G.U. Chaturbhuj, New J. Chem. 40,
10412 (2016)
22. A.T. Khan, T. Parvin, L.H. Choudhury, J. Org. Chem. 73, 8398
(2008)
56. D.S. Rekunge, K.S. Indalkar, G.U. Chaturbhuj, Tetrahedron Lett.
57, 5815 (2016)
23. A.T. Khan, M. Lal, M.M. Khan, Tetrahedron Lett. 51, 4419 (2010)
24. A.T. Khan, M.M. Khan, K.K. Bannuru, Tetrahedron 66, 7762
(2010)
57. K.S. Indalkar, C.K. Khatri, G.U. Chaturbhuj, J. Chem. Sci. 129,
141 (2017)
58. K.S. Indalkar, C.K. Khatri, G.U. Chaturbhuj, J. Chem. Sci. 129,
415 (2017)
25. H.J. Wang, L.P. Mo, Z.H. Zhang, ACS. Comb. Sci. 13, 181 (2010)
26. S. Mishra, R. Ghosh, Tetrahedron Lett. 52, 2857 (2011)
27. R. Ramachandran, S. Jayanthi, Y.T. Jeong, Tetrahedron 68, 363
(2012)
59. K.S. Indalkar, C.K. Khatri, G.U. Chaturbhuj, Tetrahedron Lett.
58, 2144 (2017)
60. C.K. Khatri, A.S. Mali, G.U. Chaturbhuj, Monatsh. Chem. 148,
1463 (2017)
28. G. Brahmachari, S. Das, Tetrahedron Lett. 53, 1479 (2012)
29. C. Mukhopadhyay, S. Rana, R.J. Butcher, A.M. Schmiedekamp,
Tetrahedron Lett. 52, 5835 (2011)
61. C.K. Khatri, M.S. Patil, G.U. Chaturbhuj, J. Iran. Chem. Soc. 8,
1683 (2017)
30. S.S. Sajadikhah, M.T. Maghsoodlou, N. Hazeri, S.M. Habibi-
Khorassani, A.C. Willis, Chin. Chem. Lett. 23, 569 (2012)
31. M. Lashkari, M.T. Maghsoodlou, N. Hazeri, S.M. Habibi-Khoras-
sani, S.S. Sajadikhah, R. Doostmohamadi, Synth. Commun. 43,
635 (2013)
62. C.K. Khatri, S.M. Potadar, G.U. Chaturbhuj, Tetrahedron Lett. 58,
1778 (2017)
63. C.K. Khatri, V.B. Satalkar, G.U. Chaturbhuj, Tetrahedron Lett.
58, 694 (2017)
64. M.S. Patil, A.V. Palav, C.K. Khatri, G.U. Chaturbhuj, Tetrahedron
Lett. 58, 2859 (2017)
32. Y.N. Bubnov, E.V. Klimkina, A.V. Ignatenko, I.D. Gridnev, Tet-
rahedron Lett. 37, 1317 (1996)
65. D.S. Rekunge, C.K. Khatri, G.U. Chaturbhuj, Tetrahedron Lett.
58, 1240 (2017)
33. Y. Genisson, C. Marazano, M. Mehmandoust, D. Gnecco, B.C.
Das, Synlett 1992, 431 (1992)
66. C.K. Khatri, G.U. Chaturbhuj, J. Iran. Chem. Soc. 14, 2513 (2017)
67. D.S. Rekunge, C.K. Khatri, G.U. Chaturbhuj, Monatsh. Chem.
148, 2019 (2017)
34. L. Overman, C. Flann, T. Malone, Org. Synth. 68, 188 (1990)
35. C. Agami, S. Comesse, C. Kadouri-Puchot, Tetrahedron Lett. 41,
6059 (2000)
68. D.S. Rekunge, C.K. Khatri, G.U. Chaturbhuj, Tetrahedron Lett.
58, 4304 (2017)
36. C. Agami, S. Comesse, C. Kadouri-Puchot, J. Org. Chem. 67,
1496 (2002)
69. M.S. Patil, C. Mudaliar, G.U. Chaturbhuj, Tetrahedron Lett. 58,
3256–3261 (2017)
37. G.W. Daub, D.A. Heerding, L.E. Overman, Tetrahedron 44, 3919
(1988)
70. K.S. Indalkar, M.S. Patil, G.U. Chaturbhuj, Tetrahedron Lett. 58,
4496 (2017)
38. H. Huang, T.F. Spande, J.S. Panek, J. Am. Chem. Soc. 125, 626
(2003)
71. M.S. Patil, C.K. Khatri, G.U. Chaturbhuj, Monatsh. Chem. (2018).
https://doi.org/10.1007/s00706-018-2169-z
72. R.L. Siqueira, I.V.P. Yoshida, L.C. Pardini, M.A. Schiavon, Mater.
Res. 10, 147 (2007)
39. Y. Yamakado, M. Ishiguro, N. Ikeda, H. Yamamoto, J. Am. Chem.
Soc. 103, 5568 (1981)
40. T.K. Yang, T.F. Teng, J.H. Lin, Y.Y. Lay, Tetrahedron Lett. 35,
3581 (1994)
73. J.S. Yeo, T.H. Park, S.H. Yoon, M.H. Seo, J. Miyawaki, I.
Mochida, Int. J. Electrochem. Sci. 8, 1308 (2013)
74. A. Khalaf-Nezhad, H. Ollah Foroughi, M.M. Doroodmand, F.
Panahi, J. Mater. Chem. 21, 12842 (2011)
75. H.J. Jung, Y. Sohn, H. G., H.S. Hyun, and W.G. Shin, 2015. Pow-
der Technol. 269, 548 (2015)
41. X.F. Zhu, J. Lan, O. Kwon, J. Am. Chem. Soc. 125, 4716 (2003)
42. Y. Chai, S.P. Hong, H.A. Lindsay, C. McFarland, M.C. McIntosh,
Tetrahedron 58, 2905 (2002)
43. J. Ahman, T. Jarevång, P. Somfai, J. Org. Chem. 61, 8148 (1996)
44. J. Ahman, P. Somfai, J. Am. Chem. Soc. 116, 9781 (1994)
45. J.C. Anderson, C.A. Roberts, Tetrahedron Lett. 39, 159 (1998)
46. T. Nakai, K. Tomooka, Pure Appl. Chem. 69, 595 (1997)
47. A. Sambyal, R. Bamezai, T. Razdan, V.K. Gupta, J. Chem. Crys-
tallogr. 41, 868 (2011)
76. C. Mandilas, E. Daskalos, G. Karagiannakis, A.G. Konstandopou-
los, Mater. Sci. Eng., B 178, 22 (2013)
77. J. Shorrock, J. Clark, K. Wilson, J. Chisem, Org. Process Res. Dev.
5, 249 (2001)
48. P.D. Bailey, G.R. Brown, P. Korber, A. Reed, R.D. Wilson, Tet-
rahedron Asymmetry 2, 1263 (1991)
78. V.P. Jejurkar, C.K. Khatri, G.U. Chaturbhuj, S. Saha, Chemis-
trySelect 2(35), 11693–11696 (2017)
49. P.D. Bailey, P.D. Smith, F. Pederson, W. Clegg, G.M. Rosair, S.J.
Teat, Tetrahedron Lett. 43, 1067 (2002)
50. T. Hamada, H. Sato, M. Hikota, O. Yonemitsu, Tetrahedron Lett.
30, 6405 (1989)
1 3