Synthesis of tetrahydropyridines by one-pot multicomponent reaction using nano-sphere silica sulfuric acid

Article abstract of DOI:10.1007/s13738-014-0548-x

A highly efficient protocol for the synthesis of 1,2,3,4-tetrahydropyridines in the presence of nano-sphere silica sulfuric acid (NS-SSA) was used for good yields by one-pot multicomponent reaction (MCRs). The reagent nano-sphere silica sulfuric acid (NS-SSA) has several advantages, such as easy workup, nontoxicity, convenience and high yields of products.

Full text of DOI:10.1007/s13738-014-0548-x

J IRAN CHEM SOC
DOI 10.1007/s13738-014-0548-x
ORIGINAL PAPER
Synthesis of tetrahydropyridines by one‑pot multicomponent
reaction using nano‑sphere silica sulfuric acid
Masoume Daraei · Mohammad Ali Zolfigol ·
Fateme Derakhshan‑Panah · Morteza Shiri ·
Hendrik G. Kruger · Mohammad Mokhlesi
Received: 29 January 2014 / Accepted: 18 October 2014
© Iranian Chemical Society 2014
Abstract A highly efficient protocol for the synthesis of
1,2,3,4-tetrahydropyridines in the presence of nano-sphere
silica sulfuric acid (NS-SSA) was used for good yields
by one-pot multicomponent reaction (MCRs). The rea-
gent nano-sphere silica sulfuric acid (NS-SSA) has several
advantages, such as easy workup, nontoxicity, convenience
and high yields of products.
compounds [1–7]. They have high biological activities
associated with antiparasitic, antimicrobial, antiviral, anti-
malarial, anticancer, herbicidal and antihypertensive prop-
erties [8–25]. In addition, some of the derivatives of these
compounds are used in a drug administered for the cause of
permanent Parkinson’s disease [26–28]..
In recent decades, the use of solid-supported catalysts
such as silica, alumina and titania has gained considerable
attention both in industrial and academia research due to
their unique properties, such as selectivity, efficiency and
straightforward workup [29–36]. Considering the above
points and along the line of our studies in design and appli-
cation of new heterogeneous catalysts in chemical transfor-
mations [37–44], we report the synthesis, characterization
and catalytic application of nano-sphere silica sulfuric acid
(NS-SSA) that can be easily prepared from commercially
available materials, for the synthesis of tetrahydropyridines
by the one-pot multi-component reactions. This method
shows high atom economy and high selectivity and is envi-
ronmentally friendly as it reduces the number of synthesis
steps [45, 46]. (Scheme 1).
Keywords Tetrahydropyridines · Nano-sphere silica
sulfuric acid · Multicomponent reaction
Introduction
One of the basic and essential heterocycles are tetrahy-
dropyridines that have used to synthesize pharmaceutical
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-014-0548-x) contains supplementary
material, which is available to authorized users.
M. Daraei · M. A. Zolfigol · F. Derakhshan-Panah
Faculty of Chemistry, Bu-Ali Sina University, P.O. Box
6517838683, Hamedan, Iran
Results and discussion
M. Shiri
Initially, the nano-sphere silica was prepared according to
the reported procedures.43 Then, the catalyst was synthe-
sized by the reaction of nano-sphere silica with chlorosul-
fonic acid in excellent yield (Scheme 2).
Nano-sphere silica sulfuric acid was characterized by
transmission electron microscopy (TEM), FT-IR, XRD,
EDS, N2 adsorption–desorption techniques and thermal
analysis [43].
Department of Chemistry Faculty of Science, Alzahra University,
1993893973 Vanak, Tehran, Iran
H. G. Kruger
Catalysis and Peptide Research Unit, School of Health Sciences,
University of KwaZulu-Natal, Durban 4001, South Africa
M. Mokhlesi (*)
Pishro Parsian Company, 11th floor, No. 1917, Amir Bldg,
above the four way the Jalal alahmad, North Kargar Ave,
1439713134 Tehran, Iran
To optimize the reaction conditions for the synthe-
sis of tetrahydropyridine compounds, the reaction of
e-mail: mmokhlesi313@gmail.com
1 3

J IRAN CHEM SOC
Table 3 The effect of various solvents on the synthesis of tetrahydro-
pyridines
O
O
R1
NH
N
O
NH2
H
R
O
3C
O
2
Entry
Solvent
Time (h)
Yield (%)
gr
C
(
)
-
NS SSA 0.05
O
R
2
+
2
1
2
3
4
5
6
7
8
CH3CN
EtOH
2
4
86
46
48
0
H
C
N
6
,
5°
3C
H
C
R1
2
R
R
MeOH
(CH3)2CO
Ethyl acetate
CH2Cl2
H2O
1
R
R1
24
18
12
–
6
Scheme 1 Synthesis of tetrahydropyridines using nano-sphere silica
sulfuric acid (NS-SSA)
44
0
THF
–
0
H
OSO3
H
OSO3
H
O
H
H
O
H
O
O
O3SO
l
H
C SO3
H
-
H
H
H
OSO3
O
O3SO
N
i
-
N i
S S O2
S S O2
H
OSO3
(Table 2). As it can be seen in Table 2, the best amount of
the catalyst was 0.05 g. Moreover, the product yield was
not changed by increasing the amount of the catalyst. The
best results were obtained when the reaction was per-
formed at 65 °C. Increasing the reaction temperature did
not improve the results (Table 2).
r. .
l
2C 2
30 min
H
t
,
C
H
H
H
O
O
O3SO
H
O
H
OSO3
Nano-sphere silica
Nano-sphere silica sulfuric acid
( )
N
SS
-
(
N
)
A
S SS
Scheme 2 Synthesis of nano-sphere silica sulfuric acid
In another study, we studied the synthesis of tetrahydro-
pyridines in a variety of solvents. The results showed that
acetonitrile is the best solvent in terms of time and product
yield (Table 3).
Table 1 Synthesis of compound 2c using different catalysts
Entry
Catalyst
Yeild (%)
In the next part, the generality and efficiency of nano-
sphere silica sulfuric acid in the synthesis of tetrahydro-
pyridines were explored under the optimized reaction
conditions by the reaction of various anilines and arylalde-
hydes with a broad range of electron-releasing substituents,
electron-withdrawing substituents and halogens on their
aromatic rings, and different β-ketoester in the acetonitrile.
As it can be seen in Table 4, all benzaldehyde derivatives,
anilines and different β-ketoester afforded the desired tet-
rahydropyridines in high to excellent yields. All the target
compounds were completely characterized by IR, 1HNMR,
13CNMR.
In summary, we have developed a method for the synthe-
sis of nano-sphere silica sulfuric acid (NS-SSA) as an effi-
cient and heterogeneous catalyst via the reaction of nano-
sphere silica with chlorosulfonic acid. NS-SSA showed
powerful activity in the one-pot multicomponent reaction
leading to tetrahydropyridines in good to high yield.
1
2
3
4
5
6
Citric acid
SSA
55
57
65
63
86
50
FeCl3
[Msim]Cl
NS-SSA
I2
Table 2 Optimization of reaction conditions
Entry Amount of Catalyst (g) Temp. (°C) Time (h) Yield (%)
1
2
3
4
5
–
65
65
65
65
65
6
3
–
0.005
0.01
0.03
0.05
46
62
68
86
4
4
3:20
4-bromoaniline, benzaldehyde and methyl acetoacetate
was selected as a model reaction to provide compound 2c
(Table 4, entry 3).
Experimental section
At first, the reaction was examined in the presence of
20 mol % of different catalysts during 2 h. Higher yield of
product was obtained when nano-sphere silica sulfuric acid
was utilized as catalyst (Table 1, entry 5). The results are
summarized in Table 1.
General procedure for the synthesis of tetrahydropyridines
β-ketoester (1.0 mmol), aniline (2 mmol) and 0.05 g nano-
sphere silica sulfuric acid (NS-SSA) in 10 ml CH3CN was
stirred at 65 °C for 20 min, aldehyde (2.0 mmol) was then
added and stirring was continued until the formation of a
solid. Then the reaction mixture was filtered and the solid
In the next step, the model reaction was tested using
different amounts of NS-SSA at the same temperature
1 3

J IRAN CHEM SOC
Table 4 The synthesis of tetrahydropyridines using nano-sphere silica sulfuric acid (NS-SSA)
Product
number
Time
(h)
Yield
(%)
M.P. (°C)
Entry
R
R1
R2
Product
(Found)[ref.]
Cl
N
1
H
4-Cl
CH3
4
88
(217-220)[9]
2a
O
NH
O
Cl
Cl
H
3C
CH3
N
2
4-CH3
4-Cl
CH3
3:30
80
(211-213)[4]
2b
OCH3
NH
O
Cl
Br
N
3
H
4-Br
CH3
2
86
(245-248)[9]
2c
OCH3
NH
Br
O
Br
3C
H
CH3
N
OCH3
4
5
4-CH3
4-Br
CH3
3:30
80
(226-229)[9]
2d
NH
O
Br
r
B
r
r
B
B
N
4-Br
4-Br
CH3
4:30
74
(226-229)[9]
2e
OCH3
NH
O
r
B
r
B
F
F
N
6
4-F
4-Br
CH3
4
75
(239-241)[18]
2f
e
OM
NH
r
O
r
B
B
N
r
B
r
B
7
3-Br
4-Br
CH3
6
75
(223-226)[9]
2g
e
OM
NH
O
r
B
1 3

J IRAN CHEM SOC
Table 4 continued
e
OM
N
8
H
4-OCH3
CH3
3
78
(292-294)[2]
2h
OCH3
NH
O
MeO
3C
l
C
H
H
C
3
N
(228-231)[4]
OCH2CH3
9
4-CH3
4-Cl
CH2CH3
1
92
2i
NH
O
l
C
F
F
N
OCH2CH3
10
4-F
H
CH2CH3
3
78
(215-218)[28]
2j
NH
O
r
B
H
3C
H
C
3
N
11 4-CH3
4-Br
CH2CH3
4:30
76
(239-241)[9]
2k
OCH2CH3
NH
O
r
B
r
B
N
OCH2CH3
12
13
H
4-Br
CH2CH3
5:30
89
(227-230)[18]
2l
NH
O
r
B
H
C
3
N
H
4-CH3
CH2CH3
6
75
(223-226)[28]
2m
OCH2CH3
NH
O
H
3C
so obtained was washed with acetonitrile. Since the solid
does not solve in chloroform, it was separated from nano-
sphere silica sulfuric acid (NS-SSA) by the addition of
CHCl3. Finally, a colorless powder resulted with filtering of
solution and evaporation.
Methyl 1-(4-chlorophenyl)-4-((4-chlorophenyl)amino)-
2,6-diphenyl-1,2,5,6-tetrahydropyridine-3-carboxylate
(2a): White powder, mp 217–220 °C; IR(KBr): υ = 3325,
3086, 3063, 2949, 2868, 1651, 1600, 1504, 626 cm−1
.
1HNMR (600 MHz; CDCl3) = 2.709–2.665 (1H, m,
J = 18 Hz), 2.87–2.82 (1H, m, J = 3 Hz), 3.937 (3H,
s), 5.1–5.09 (1H, d, J = 6 MHz), 6.176–6.154 (2H, d,
J = 12 Hz), 6.434-6.412 (2H, t, j = 12 Hz), 10.185 (S, 1H).
13CNMR (150 MHz; CDCl3) = 33.4, 51.2, 55.27, 58.3,
98.4, 114, 121.1, 126.2, 127, 128.7, 129, 131.4, 136, 142,
143.2, 145.4, 168.4.
1 3

J IRAN CHEM SOC
Methyl
1-(4-chlorophenyl)-4-((4-chlorophenyl)amino)-
methyl
2,6-bis(3-bromophenyl)-1-(4-bromophenyl)-
2,6-di-p-tolyl-1,2,5,6-tetrahydropyridine-3-carboxylate
(2b): White powder, mp 211–213 °C; IR(KBr): υ = 3248,
4-((4-bromophenyl)amino)-1,2,5,6-tetrahydropyridine-
3-carboxylate (2 g): white powder, mp 223–226 °C;
1
3087, 3023, 2950, 2857, 1651, 1605, 1585 cm−1. HNMR
IR(KBr): υ = 3233, 3200, 2989, 1714, 1655, 1582 cm−1
.
(600 MHz; CDCl3) = 2.34–2.31(6H, d, j = 18 Hz), 2.69–2.6
(1H, m, j = 18 Hz), 3.92 (3H, s), 5.06–5.05 (1H, d, J = 6 Hz),
6.19–6.17 (2H, d, j = 12 Hz), 6.43–6.41 (2H, d, j = 12 Hz),
10.18 (1H, s). 13CNMR (600 MHz; CDCl3) = 20.99, 33.47,
51.1, 55, 58, 98.1, 113, 121, 126.2, 127, 128, 131, 136, 137,
139, 140.1, 168.4.
1HNMR (600 MHz; CDCl3) = 1.56 (4H, s), 2.71-2.66 (1H,
m, j = 3 Hz), 2.83–2.78 (1H, m, j = 3 Hz), 3.93 (3H, s),
5.05–5.04 (1H, d, j = 6 Hz), 6.31–6.28 (2H, d, j = 18 Hz),
7.16–7.13 (5H, m, j = 18 Hz), 10.17 (1H, s). 13CNMR
(600 MHz; CDCl3) = 33.3, 51.3, 55, 57.7, 97.6, 109.2,
114.6, 119.8, 122.7, 125, 127.7, 129.2, 130, 131, 132,
136.5, 144.2, 145.2, 155.2, 168.1.
Methyl 1-(4-bromophenyl)-4-((4-bromophenyl)amino)-
2,6-diphenyl-1,2,5,6-tetrahydropyridine-3-carboxylate
(2c): White powder, mp 245-248 °C; IR(KBr): υ = 3256,
Methyl 1-(4-methoxyphenyl)-4-((4-methoxyphenyl)amino)-
2,6-diphenyl-1,2,5,6-tetrahydropyridine-3-carboxylate
(2 h): white powder, mp 292-294 °C; IR(KBr): υ = 3233,
1
3084, 2948, 1651, 1599, 1578 cm−1. HNMR (600 MHz;
1
CDCl3) = 2.72–2.67 (1H, m, j = 3 Hz), 2.87–2.82 (1H, m,
j = 3 Hz), 3.93 (3H, s), 5.1–5.09 (1H, d, j = 6 Hz), 6.11–
6.09 (2H, d, j = 12 Hz), 6.39–6.37 (3H, d, j = 12 Hz),
10.17 (1H, s). 13CNMR (600 MHz; CDCl3) = 33.4, 51.2,
55.2, 58.2, 98.5, 108.4, 114.5, 119, 126.2, 127, 128.8,
131.5, 132, 136.8, 142.1, 143, 145.8, 168.4.
3200, 2989, 1714, 1655, 1582 cm−1. HNMR (400 MHz;
CDCl3) = 1.99 (3H, s), 2.14 (3H, s), 2.68–2.65 (1H, m,
j = 12 Hz), 2.68–2.65 (3H, d, J = 12 Hz), 3.78 (3H, S),
5.25–5.24 (1H, d, J = 4 Hz), 6.18–6.15 (2H, d, j = 12 Hz),
6.25–6.21(3H, t, J = 12 Hz), 6.74–6.72 (2H, d, J = 8 Hz),
6.89–6.87 (2H, d, J = 8 Hz), 7.09–7.07(3H, d, J = 8 Hz),
7.22–7.21(7H, d, J = 4 Hz), 10.01(1H,s). 13CNMR
(600 MHz; CDCl3) = 19.6, 20.33, 33.2, 50.9, 54, 56, 97,
112, 124, 124.9, 126, 126.2, 126.26, 128, 128.3, 129,
129.4, 134, 143, 144, 144.2, 155, 167.
Methyl
1-(4-bromophenyl)-4-((4-bromophenyl)
amino)-2,6-di-p-tolyl-1,2,5,6-tetrahydropyridine-3-car-
boxylate (2d): White powder, mp 226-229 °C; IR(KBr):
υ = 3240, 3091, 2951, 2861, 1650, 1603, 1586 cm−1
.
1HNMR (600 MHz; CDCl3) = 2.33–2.31 (6H, d,
j = 12 Hz), 2.71–2.67 (1H, m, j = 24 Hz), 3.92 (3H, s),
5.06–5.04 (1H, d, j = 6 Hz), 6.13–6.11 (2H, d, j = 12 Hz),
6.39–6.36 (2H, d, j = 18 Hz), 10.17 (1H, s). 13CNMR
(600 MHz; CDCl3) = 21, 33.4, 51.1, 55, 57.9, 98.6, 108.2,
114.5, 119, 126.2, 127.2, 129, 131, 136.1, 137, 139, 140,
145.9, 155.4, 168.4.
Ethyl 1-(4-chlorophenyl)-4-((4-chlorophenyl)amino)-2,6-
di-p-tolyl-1,2,5,6-tetrahydropyridine-3-carboxylate
(2i):
white powder, mp 228-231 °C; IR(KBr): υ = 3230, 3173,
1
2979, 2864, 1646, 1604, 1504 cm−1. HNMR (600 MHz;
CDCl3) = 1.47–1.43 (3H, t, j = 24 Hz), 2.7–2.67 (1H, m,
j = 18 Hz), 2.86–2.81 (1H, m, J = 3 Hz), 2.33–2.31 (6H,
d, j = 12 Hz), 4.34–4.29 (1H, m, j = 3 Hz), 5.06–5.05
(1H, d, j = 6 Hz), 6.43–6.4 (5H, m, j = 18 Hz). 13CNMR
(600 MHz; CDCl3) = 14.7, 20.9, 21.1, 33.4, 55.5, 59.8,
98.8, 114, 121, 126, 128.9, 129, 131, 136, 137, 139, 140.2,
145, 155.3, 168.1.
Methyl
1,2,6-tris(4-bromophenyl)-4-((4-bromophenyl)
(2e):
amino)-1,2,5,6-tetrahydropyridine-3-carboxylate
White powder, mp 226–229 °C; IR(KBr): υ = 3233,
1
3200, 2989, 1714, 1655, 1582 cm−1. HNMR (600 MHz;
CDCl3) = 2.1 (5H, s), 2.7–2.65 (1H, m, j = 3 Hz), 2.81–
2.79 (1H, m, j = 18 Hz), 3.92 (3H, s), 5.03–5.02 (1H,
d, j = 6 Hz), 6.30–6.26 (5H, m, j = 24 Hz), 7.13–7.11
(4H, m, j = 12 Hz), 10.18 (1H, s). 13CNMR (600 MHz;
CDCl3) = 30.93, 33.4, 51.3, 54.9, 57.4, 98, 109, 114.5,
117.6, 119, 120.5, 121.3, 128, 131.8, 132, 136.5, 140.7,
142, 145, 155.1, 168.1.
Ethyl2,6-bis(4-fluorophenyl)-1-phenyl-4-(phenylamino)-
1,2,5,6-tetrahydropyridine-3-carboxylate (2j): white pow-
der, mp 215-218 °C; IR(KBr): υ = 3242, 3090, 3061, 3027,
1
2909, 1647, 1603, 1585, 1451 cm−1. HNMR (600 MHz;
CDCl3) = 1.485–1.45 (3H, t, j = 18 Hz), 2.71–2.67 (1H,
m, j = 18 Hz), 2.87–2.82 (1H, m, J = 3 Hz), 4.49–4.44
(1H, m, J = 3 Hz), 5.1–5.09 (1H, d, j = 6 Hz), 6.43–6.38
(1H, t, j = 3 Hz), 10.23 (1H, s). 13CNMR (600 MHz;
CDCl3) = 14.7, 33.48, 51.14, 55.07, 58.01, 98.58, 113,
121, 126, 127, 128, 129, 131, 136.1, 137, 139, 140, 145,
155, 168.4.
Ethyl 1-(4-bromophenyl)-4-((4-bromophenyl)amino)-2,6-
di-p-tolyl-1,2,5,6-tetrahydropyridine-3-carboxylate (2 k):
white powder, mp 239–241 °C; IR(KBr): υ = 3234, 2922,
1647, 1603 cm−1. 1HNMR (600 MHz; CDCl3) = 1.47–1.43
(3H, d, j = 3 Hz), 2.33–2.31 (6H, d, j = 12 Hz), 2.71–2.67
(1H, t, j = 24 Hz), 2.85–2.83 (1H, m, j = 3 Hz), 4.34–4.29
Methyl 1-(4-bromophenyl)-4-((4-bromophenyl)amino)-
2,6-bis(4-fluorophenyl)-1,2,5,6-tetrahydropyridine-3-car-
boxylate (2f): white powder, mp 239-241 °C; IR(KBr):
1
υ = 3233, 3200, 2989, 1714, 1655, 1582 cm−1. HNMR
(600 MHz; CDCl3) = 2.68 (2H, s), 2.82–2.64 (1H, m,
j = 18 Hz), 3.82 (3H, s), 5.03–52.02 (3H, d, J = 6 Hz),
6.25 (1H, S), 6.32-6.30 (4H, m, j = 12 Hz), 10.18 (1H,s).
13CNMR (600 MHz; CDCl3) = 30.9, 33.5, 51.3, 54.9, 57.4,
97.9, 114, 120, 121.2, 126.9, 128, 129, 131.5, 136, 140.8,
142.9, 144.1, 155, 168.16.
1 3

J IRAN CHEM SOC
7. X. Li, Y. Zhao, H. Qu, Z. Mao, X. Lin, Organocatalytic asymmet-
ric multicomponent reactions of aromatic aldehydes and anilines
with β-ketoesters: facile and atom-economical access to chiral
tetrahydropyridines. Chem. Commun. 49, 1401–1403 (2013)
8. D.F. Yu, Y. Wang, P.F. Xu, Organocatalytic enantioselective mul-
ticomponent cascade reaction: facile access to tetrahydropyri-
dines with C3 all-carbon quaternary stereocenters. Tetrahedron
67, 3273–3277 (2011)
9. R. Ramachandran, S. Jayanthi, Y.T. Jeong, One-pot synthesis of
highly diversified tetrahydropyridines by tandem condensation
of aldehydes, amines, and β-ketoesters. Tetrahedron 68, 363–369
(2012)
10. A.T. Khan, M.M. Khan, K.K.R. Bannuru, Iodine catalyzed one-
pot five-component reactions for direct synthesis of densely func-
tionalized piperidines. Tetrahedron 66, 7762–7772 (2010)
11. A.T. Khan, M. Lal, M.M. Khan, Synthesis of highly function-
alized piperidines by one-pot multicomponent reaction using
tetrabutylammonium tribromide (TBATB). Tetrahedron Lett. 51,
4419–4424 (2010)
(1H, m, j = 3 Hz), 5.06–5.05 (1H, d, j = 6 Hz), 6.14–6.12
(2H, d, j = 12 Hz), 6.39–6.37 (3H, m, j = 12 Hz), 10.22
(1H, s). 13CNMR (600 MHz; CDCl3) = 14.7, 20.9, 21.1,
33.4, 55, 58, 59.9, 98.9, 108.2, 114.5, 118.9, 126, 127.2,
129, 131.5, 136.1, 137, 139, 140, 145, 155, 168.1.
Ethyl 1-(4-bromophenyl)-4-((4-bromophenyl)amino)-2,6-
diphenyl-1,2,5,6-tetrahydropyridine-3-carboxylate (2 l):
white powder, mp 227-230 °C; IR(KBr): υ = 3256,
1
3084, 2948, 1651, 1599, 1578 cm−1. HNMR (600 MHz;
CDCl3) = 2.686–2.681 (1H, d, j = 0.3 Hz), 2.84–2.82 (1H,
d, j = 12 Hz), 4.33–4.31(1H, m, j = 12 Hz), 5.1–5.09 (1H,
d, j = 12 Hz), 7.29–7.27 (7H, m, j = 12 Hz), 10.2 (1H,
s). 13CNMR (600 MHz; CDCl3) = 14.7, 33.4, 55.2, 58.2,
59.9, 98.8, 108.4, 114.5, 119.1, 126.4, 127.2, 128.3, 131.6,
136.9, 142.1, 143.1, 145.5, 155.2, 168.1.
Ethyl 2,6-diphenyl-1-(p-tolyl)-4-(p-tolylamino)-1,2,5,6-
tetrahydropyridine-3-carboxylate (2 m): white powder, mp
223-226 °C; IR(KBr): υ = 3239, 3024, 2919, 2854, 1617,
12. S. Mishra, R. Ghosh, Efficient one-pot synthesis of functional-
ized piperidine scaffolds via ZrOCl
2.8H2O catalyzed tandem
reactions of aromatic aldehydes with amines and acetoacetic
esters. Tetrahedron Lett. 52, 2857–2861 (2011)
1
1649, 15942 cm−1. HNMR (600 MHz; CDCl3) = 1.44
13. W.B. Liu, H.F. Jiang, Z. Shi-Fa, W. Wang, Hydroalkylation lead-
ing to heterocyclic compounds (Part 2): practical synthesis of
polysubstituted 1,2,3,4-tetrahydropyridines through multicompo-
nent reactions (MCRs). Tetrahedron 65, 7985–7988 (2009)
14. A. Sambyal, R.K. Bamezai, T.K. Razdan, V.K. Gupta, Syn-
thesis and Crystal Structure of (2S,6R) Ethyl 1,2,6-triphenyl-
(3H, s), 2.25 (3H, S), 2.14 (3H, S), 2.74–2.7 (1H, m,
J = 24 Hz), 4.32–4.31 (1H, m, j = 6 Hz), 4.44–4.43 (1H,
m, J = 6 Hz), 6.16–6.14 (2H, d, j = 12 Hz), 6.88–6.85
(4H, m, j = 18 Hz), 10.19 (1H, s). 13CNMR (600 MHz;
CDCl3) = 14.8, 20.1, 33.5, 55.1, 58.2, 59.5, 97.7, 112, 125,
126.1, 127, 128, 129.3, 135, 143, 144, 156.4, 168.2.
4-(phenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate.
J.
Chem. Crystallogr. 41, 868–873 (2011)
15. G. Harichandran, S.D. Amalraj, P. Shanmugam, A Facile and
Efficient Solid Supported, One-Pot Synthesis of Functionalized
Piperidine Derivatives Catalyzed by Amberlite IRA400-Cl Resin/
I2/KI via Multicomponent Reaction. J. Heterocycl. Chem. 50,
539–543 (2013)
Acknowledgments The authors acknowledge the Bu-Ali Sina
University Research Council and Center of Excellence in Develop-
ment of Environmentally Friendly Methods for Chemical Synthesis
(CEDEFMCS) for providing support to this work.
16. P.A. Clarke, A.V. Zaytzev, A.C. Whitwood, Pot, atom and step eco-
nomic (PASE) synthesis of highly functionalized piperidines: a five-
component condensation. Tetrahedron Lett. 48, 5209–5212 (2007)
17. G. Brahmachari, S. Das, Bismuth nitrate-catalyzed multicompo-
nent reaction for efficient and one-pot synthesis of densely func-
tionalized piperidine scaffolds at room temperature. Tetrahedron
Lett. 53, 1479–1484 (2012)
References
1. H.F. Jiang, J.H. Li, Z.W. Chen, L-Proline-catalyzed five-compo-
nent domino reaction leading to multifunctionalized 1,2,3,4-tet-
rahydropyridines. Tetrahedron 66, 9721–9728 (2010)
2. H.J. Wang, L.P. Mo, Z.H. Zhang, Cerium Ammonium Nitrate-
Catalyzed Multicomponent Reaction for Efficient Synthesis of
Functionalized Tetrahydropyridines. ACS. Comb. Sci. 13, 181–
185 (2011)
3. J. Safaei-Ghomi, A. Ziarati, An efficient FeCl3/SiO2 NPs as a
reusable heterogeneous catalyzed five-component reactions of
tetrahydropyridines under mild conditions. J. Iran. Chem. Soc.
10, 135–139 (2013)
4. S.S. Sajadikhah, N. Hazeri, M.T. Maghsoodlou, S.M. Habibi-
Khorassani, A.C. Willis, Trityl chloride as an efficient organic
catalyst for one-pot, five-component and diastereoselective syn-
thesis of highly substituted piperidines. Res. Chem. Intermed. 40,
723–736 (2014)
5. S. Verma, S. Kumar, S.L. Jain, B. Sain, Thiourea dioxide pro-
moted efficient organocatalytic one-pot synthesis of a library of
novel heterocyclic compounds. Org. Biomol. Chem. 9, 6943–
6948 (2011)
18. X. Zhang, Y. Wan, L. Pang, H. Wang, L. Zhao, C. Wang, S.Y.
Hang, G.X. Liu, L.F. Chen, H. Wu, Silica Sulfuric Acid-Cata-
lyzed Five-component Efficient Synthesis of Five-Substituted
Tetrahydropyridines. J. Heterocycl. Chem. 51, 442–449 (2014)
19. S.S. Sajadikhah, M.T. Maghsoodlou, N. Hazeri, S.M. Habibi-
Khorassani, A.C. Willis, One-pot five-component synthesis of
highly functionalized piperidines using oxalic acid dihydrate as a
homogenous catalyst. Chin. Chem. Lett. 23, 569–572 (2012)
20. B. Umamahesh, V. Sathesh, G. Ramachandran, M. Sathishkumar,
K. Sathiyanarayanan, LaCl3.7H2O as an Efficient Catalyst for One-
Pot Synthesis of Highly Functionalized Piperidines via Multi-com-
ponent Organic Reactions. Catal. Lett. 142, 895–900 (2012)
21. P. Kar, B.G. Mishra, S.R. Pradhan, Polyphosphoric acid–zirconia
pillared clay composite catalytic system for efficient multicompo-
nent one pot synthesis of tetrahydropyridines under environmentally
benign conditions. J. Mol. Catal. A: Chem. 387, 103–111 (2014)
22. A. Javidan, A. Ziarati, J. Safaei-Ghomi, Simultaneous sonica-
tion assistance for the synthesis of tetrahydropyridines and its
efficient catalyst ZrP2O7 nanoparticles. Ultrason. Sonochem. 21,
1150–1154 (2014)
6. A.T. Khan, T. Parvin, L.H. Choudhury, Effects of Substituents in
the β-Position of 1,3-Dicarbonyl Compounds in Bromodimethyl-
sulfonium Bromide-Catalyzed Multicomponent Reactions: A
Facile Access to Functionalized Piperidines. J. Org. Chem. 73,
8398–8402 (2008)
23. R. Ghorbani-Vaghei, H. Shahbazi, Highly efficient one-pot syn-
thesis of tetrahydropyridines. C. R. Chimie. 16, 1047–1054
(2013)
1 3

J IRAN CHEM SOC
24. H.R. Shaterian, K. Azizi, Acidic ionic liquids catalyzed one-
pot, pseudo five-component, and diastereoselective synthesis of
highly functionalized piperidine derivatives. J. Mol. Liq. 180,
187–191 (2013)
36. B. Sreedhar, A. Suresh Kumar, P. Surendra Reddy, Magneti-
cally separable Fe3O4 nanoparticles: an efficient catalyst for the
synthesis of propargylamines. Tetrahedron Lett. 51, 1891–1895
(2010)
25. S.S. Sajadikhah, N. Hazeri, M.T. Maghsoodlou, S.M. Habibi-
Khorassani, A. Beigbabaei, A.C. Willis, Al(H2PO4)3 as an effi-
cient and reusable catalyst for the multi-component synthesis of
highly functionalized piperidines and dihydro-2-oxypyrroles. J.
Iran. Chem. Soc. 10, 863–871 (2013)
26. M. Misra, S.K. Pandey, V.P. Pandey, J. Pandey, R. Tripathi, R.P.
Tripathi, Organocatalyzed highly atom economic one pot synthe-
sis of tetrahydropyridines as antimalarials. Bioorg. Med. Chem.
17, 625–633 (2009)
27. M.R. Mousavi, J. Aboonajmi, M.T. Maghsoodlou, N. Hazeri,
S.M. Habibi-Khorassani, M. Safarzaei, La(NO3)3.6H2O Cata-
lyzed One-pot Highly Diastereoselective Synthesis of Functional-
ized Piperidines. Lett. Org. Chem. 10, 171–177 (2013)
28. S. Khaksar, S.M. Vahdat, M. Alipour, Cerium(IV) triflate-cata-
lyzed domino annulation approaches to the synthesis of highly
substituted piperidines. C. R. Chimie. 16, 1024–1028 (2013)
29. B.G. Trewyn, J.A. Nieweg, Y. Zhao, V.S.Y. Lin, Biocompat-
ible mesoporous silica nanoparticles with different morphologies
for animal cell membrane penetration. J. Chem. Eng. 137, 23–29
(2008)
30. B. Sreedhar, P. Radhika, B. Neelima, N. Hebalkar, Regioselective
ring opening of epoxides with amines using monodispersed silica
nanoparticles in water. J. Mol. Catal. A. 272, 159–163 (2007)
31. M. Najafi, Y. Yousefi, A.A. Rafati, Synthesis, characterization and
adsorption studies of several heavy metal ionson amino-function-
alized silica nano hollow sphere and silica gel. Sep. Pur. Tech. 85,
193–205 (2012)
37. M.A. Zolfigol, Silica sulfuric acid/NaNO2 as a novel heteroge-
neous system for production of thionitrites and disulfides under
mild conditions. Tetrahedron 57, 9509–9511 (2001)
38. N. Koukabi, E. Kolvari, A. Khazaei, M.A. Zolfigol, B. Shirmardi-
Shaghasemi, H. Khavasi, R. Chem, Hantzsch reaction on free
nano-Fe2O3 catalyst: excellent reactivity combined with facile cat-
alyst recovery and recyclability. Commun. 47, 9230–9232 (2011)
39. M.A. Zolfigol, A. Khazaei, A.R. Moosavi-Zare, A. Zare, V.
Khakyzadeh, Rapid synthesis of 1-amidoalkyl-2-naphthols over
sulfonic acid functionalized imidazolium salts. Appl. Catal. A:
General 400, 70–81 (2011)
40. P. Salehi, M.A. Zolfigol, F. Shirini, M. Baghbanzadeh, Silica Sul-
furic Acid and Silica Chloride as Efficient Reagents for Organic
Reactions. Curr. Org. Chem. 10, 2171–2189 (2006)
41. M.A. Zolfigol, P. Salehi, M. Shiri, A. Sayadi, A. Abdoli, H. Key-
pour, M. Rezaeivala, K. Niknam, E. Kolvari, A simple and effi-
cient route for the synthesis of di and tri(bis(indolyl) methanes)
as new triarylmethanes. Mol. Divers. 12, 203–207 (2008)
42. M.A. Zolfigol, A. Khazaei, M. Safaiee, M. Mokhlesi, R. Rosta-
mian, M. Bagheri, M. Shiri, H.G. Kruger, J. Mole, Application of
silica vanadic acid as a heterogeneous, selective and highly reus-
able catalyst for oxidation of sulfides at room temperature. Catal.
A: Chem. 370, 80–86 (2013)
43. M.A. Zolfigol, A. Khazaei, M. Mokhlesi, F. Derakhshan-Panah,
J. Mole, Synthesis, characterization and catalytic properties of
monodispersed nano-sphere silica sulfuric acid. Catal. A: Chem.
370, 111–116 (2013)
32. Z.Z. Li, L.X. Wen, L. Shao, J.F. Chen, J. Cont, Fabrication of
porous hollow silica nanoparticles and their applications in drug
release control. Release. 98, 245–254 (2004)
33. B. Sreedhar, D. Yada, P. Surendra Reddy, Nanocrystalline Tita-
nia-Supported Palladium(0) Nanoparticles for Suzuki–Miyaura
Cross-Coupling of Aryl and Heteroaryl Halides. Adv. Synth.
Catal. 353, 2823–2836 (2011)
34. B. Sreedhar, A. Suresh Kumar, D. Yada, CuFe2O4 nanoparticles:
a magnetically recoverable and reusable catalyst for the synthesis
of 5-substituted 1H-tetrazoles. Tetrahedron Lett. 52, 3565–3569
(2011)
44. A. Khazaei, M.A. Zolfigol, M. Mokhlesi, R. Rostamian, Nano-
sphere silica sulfuric acid: novel and efficient catalyst in the one-
pot multi-component synthesis. J. Iran. Chem. Soc. 10, 1297–
1301 (2013)
45. A. Khazaei, M.A. Zolfigol, M. Mokhlesi, A. Zare, F. Derakhshan-
Panah, M. Merajoddin, H. Keypour, A.A. Dehghani-Firouzabadi,
Pyrazinium Di(hydrogen sulfate) as a Novel, Highly Efficient
and Homogeneous Catalyst for the Condensation of Enolizable
Ketones with Aldehydes, Acetonitrile and Acetyl Chloride. J.
Chin. Chem. Soc. 58, 199–207 (2011)
46. J. Zhu, H. Bienayme, Multicomponent Reactions (Wiley-VCH,
35. L. He, A.F. Dexter, A.P.J. Middelberg, Biomolecular engineering
at interfaces. Chem. Eng. Sci. 61, 989–1003 (2006)
Weinheim, Germany, 2005)
1 3