Silica sulfuric acid-catalyzed five-component efficient synthesis of five-substituted tetrahydropyridines

Article abstract of DOI:10.1002/jhet.1744

A highly atom-economic one-pot synthesis of five-substituted tetrahydropyridines via a five-component condensation of two equivalents of aromatic aldehyde, two equivalents of aromatic aniline, and one equivalent of β-keto ester catalyzed by silica sulfuric acid is reported. In this reaction, up to five new bonds and one new ring were formed in one pot with water as the only one by-product.

Full text of DOI:10.1002/jhet.1744

442
Silica Sulfuric Acid-Catalyzed Five-component Efficient Synthesis of
Vol 51
Five-Substituted Tetrahydropyridines
Xiao-xiao Zhang,a Yu Wan,b Li-ling Pang,a Hai-ying Wang,a Ling-ling Zhao,a,c Chao Wang,a
Shu Ying Hang,a Gui Xiang Liu,a Liang-Feng Chen,a and Hui Wua,b
*
aSchool of Chemistry and Chemical Engineering, Jiangsu Normal University, Xuzhou 221116, China
bKey Laboratory of Biotechnology on Medical Plant of Jiangsu Province, Xuzhou, 221116, China
cKey Laboratory of Green Synthesis of Functional Material of Jiangsu Province, Xuzhou, 221116, China
*
E-mail: wuhui72@126.com
Received March 15, 2012
DOI 10.1002/jhet.1744
Published online 19 November 2013 in Wiley Online Library (wileyonlinelibrary.com).
A highly atom-economic one-pot synthesis of five-substituted tetrahydropyridines via a five-component
condensation of two equivalents of aromatic aldehyde, two equivalents of aromatic aniline, and one
equivalent of b-keto ester catalyzed by silica sulfuric acid is reported. In this reaction, up to five new bonds
and one new ring were formed in one pot with water as the only one by-product.
J. Heterocyclic Chem., 51, 442 (2014).
INTRODUCTION
tetrahydropyridines include aza Diels–Alder reaction [14],
intramolecular Michael addition [15], Dieckmann conden-
sation [16], photochemical reaction [17], ring-closing
metathesis[18], and ene reaction [19]. However, most
methods have their limitations such as complex material
(Brassard’s diene) [20], low yields, expensive catalyst
(InCl3, L-proline/TFA, ZrOCl2ꢀ8H2O) [21], long reaction
time (50 h) [22], and requirement of toxic solvents (such
as MeCN) [23].
Silica sulfuric acid (SSA) has been proven as a very useful
reagent in organic synthesis [24–26]. To investigate its new
application, herein, we report an interesting five-component
efficient synthesis of five-substituted tetrahydropyridines
via the reaction of aromatic aldehyde (1), aromatic aniline
(2), and b-keto ester (3) catalyzed by SSA (Scheme 1).
Diversity-oriented synthesis is a useful tool at the inter-
face of the fields of organic synthesis and chemical biology
[1]. At the heart of diversity-oriented synthesis are the
synthetic means needed for the generation of collections
of functionally and regiochemically diverse small mole-
cules, particularly those possessing skeletons resembling
those naturally found products or drug-like molecules [2].
An efficient method for generating these collections of mole-
cules is multicomponent reactions (MCRs) with subsequent
transformations that further increase molecular complexity and
diversity, requiring a minimum of time, labor, cost, and waste
production [3]. Therefore, the design of novel MCRs for the
synthesis of diverse groups of compounds, especially the ones
that are biologically active, has commanded great attention [4].
Recently, the researches on MCRs in which more than four
components were used have already become a trend. Bonfield
et al. reported a six-compound to prepare isoindoline via
tandem double A3-coupling and [2 + 2 + 2]-cyclo-addition
reaction [5]. Brauch et al. have extended MCRs to seven
components by taking advantage of the different chemoselec-
tivities of the Ugi-Mumm and the Ugi-Smiles reaction [6].
The Orru group developed a one-pot reaction of up to eight
components that involves nine new bond formations and 11
points of diversity [7].
RESULTS AND DISCUSSION
Using the conversion of benzaldehyde (1d, 2.0 mmol),
paraiodoaniline (2d, 2.0 mmol), and ethyl acetoacetate
(3, 1 mmol) as a model reaction, we tested different
reaction conditions to optimize the conditions at first. A
summary of the optimization experiment is provided in
Table 1. It was found that this transformation could not
run smoothly except in the presence of SSA (Table 1,
entries 1–6). Other acids such as L-proline, camphorsulfo-
nic acid, and TsOH could not be employed as promoters
in this reaction. The important role of SSA in this interest-
ing reaction may be attributed to its suitable acidity and
supporting function. The combination between SSA and
reactants made it act as phase transfer catalysis and en-
hanced the solubility of reactant in solvent. SSA could be
easy separated and recycled five times without significant
The framework of five-substituted tetrahydropyridines is
widely found in biologically active natural products and
pharmaceuticals [8]. They are also an important class of
heterocyclic compounds, and structural units have many
functions such as antibacterial [9], anti-inflammation [10],
antineoplastic [11,12], and they are used to treat the
mental disorders [13]. Some methods for the syntheses of
© 2013 HeteroCorporation

March 2014
Silica Sulfuric Acid-Catalyzed Five-component Efficient Synthesis of
443
Five-Substituted Tetrahydropyridines
deactivation. Ethanol is superior to [BmIm][BF4] as the
solvent (Table 1, entries 4 andꢁ6). It maybe because the
basicity of [BmIm][BF4] (pKa [BF4] = 0.5) is too strong to
meet this reaction. When 0.1 g of SSA was used, the
reaction proceeded in good yield (Table 1, entries 6–8).
Finally, when the temperature was increased to 60ꢂC with
EtOH as the solvent, the reaction proceeded smoothly
(Table 1, entries 7 and 9–11).
To explore the application of this method, the scope of
the substrates was evaluated with a variety of aromatic
aldehydes and aromatic anilines (Table 2). It appeared that
the electronic nature of the substituted groups in the
aromatic ring had slightly influence on the yield. It is
noteworthy that no remarkable steric hindrance on the
reaction was observed, for example, the desired products
were obtained in moderate to good yields when the ortho
substituent on the benzaldehyde were used (Table 2,
Entries 7–11).
The possible reaction mechanism was proposed in
Scheme 2. SSA can serve as an acidic catalyst for this
reaction. We presume that the reaction proceeds via initial
formation of 5 through condensation of aryl aldehyde 1 and
aromatic aniline 2. Meanwhile, b-keto ester 3 condensed with
another aromatic aniline 2 to give enamine 6. Subsequently,
the enamine 6 reacted with another aromatic aldehyde 1 to
give intermediate 7 by the Knoevenagel reaction. Interme-
diate 7 turned to provide 8 via tautomerization, and then
8 cyclized with 5 to give the expected tetrahydropyridines
4 by an [4 + 2]-aza Diels–Alder reaction. We supposed
that the important role of SSA in this reaction is attributed
to its apropos acidity and supporting function.
In summary, we have developed a novel and simple
SSA-catalyzed five-component condensation for the
construction of five-substituted tetrahydropyridines from
commercially available starting materials. SSA showed
its important role in this interesting reaction. Six bonds
were cleaved, and five new bonds (two C-N single bonds,
one C═N double bond, one C═C double bond, one C-C
single bond) were constructed in the formation of 4,
whereas only three H2O molecules were removed. One
ring of the fused-ring framework was constructed in one
pot. This method offers several advantages including
inexpensive starting materials, low catalyst loading, and
no formation of by-products such as aldol or deamination
products. In addition, there are several modifiable and
coordinate sites in this one new interesting type of
framework, so the subsequent step of the combinatorial
development process, namely, structural optimization,
should be possible. Future efforts to explore the coordina-
tion effect of products and the synthetic utility of the
reaction are underway.
EXPERIMENTAL
General information. IR spectra were recorded with a Varian
FTIR-Tensor-27 spectrophotometer (Bruker Daltonic Inc., USA)
1
using KBr optics. H NMR spectra were recorded at 400 MHz
on a Bruker DPX 400 spectrometer (Hitachi, Japan) using TMS
as an internal standard and DMSO-d6 as solvent. Mass was
determined by using a Bruker TOF-MS high resolution mass
spectrometer (USA). All reagents were obtained from commercial
suppliers and used without further purification unless otherwise
stated. SSA was prepared in our lab. Organic solvents were dried
and distilled prior to use.
Scheme 1
The synthesis of SSA was followed according to the method
described in the literature [27].
Table 1
Optimization of reaction conditionsa.
Entry
Catalyst
L-proline
Camphorsulfonic acid
—
SSA
TsOH
SSA
SSA
SSA
SSA
Amount (g)
Solvent
T(ꢂC)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
0.2
0.2
—
EtOH
EtOH
[Bmim][BF4]
[Bmim][BF4]
EtOH
EtOH
EtOH
EtOH
EtOH
60
60
60
60
60
60
60
60
50
55
65
15
15
15
15
14
7
7
7
7
7
Nrc
Nrc
Nrc
Nrc
<5
80
86
78
70
78
0.2
0.2
0.2
0.1
0.05
0.1
0.1
0.1
9
10
11
SSA
SSA
EtOH
EtOH
7
85
aReactions were performed in 2:2:1 (benzaldehyde: paraiodoaniline: ethyl acetoacetate) in different conditions.
bYield of pure product after crystallization.
cNo reaction.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

444
X.-x Zhang, Y. Wan, L.-l. Pang, H.-y. Wang, L.-l. Zhao,
C. Wang, S. Y. Hang, G. X. Liu, L-F. Chen, and H. Wu
Vol 51
Table 2
Synthesis of 4 under optimum conditiona.
Mp (ꢂC)
Time
(h)
Yields
(%)b
Entry
Product
Ar
Ar0
Found
Reported
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
2-OCH3C6H4
2-OCH3C6H4
2-OCH3C6H4
2-OCH3C6H4
2-OCH3C6H4
4-FC6H4
4-FC6H4
9
9
8
7
8
74
78
80
86
82
77
55
68
75
76
78
64
70
74
74
72
67
72
68
66
72
70
64
66
71
73
80
72
70
74
58
67
70
68
76
73
77
75
78
74
80
181.2–182.3
222.0–222.9
226.9–228.5
243.4–244.9
195.2–196.7
190.9–192.1
166.3–167.2
178.2–179.2
197.2–198.6
168.4–169.8
227.1–228.0
196.7–198.9
205.9–206.6
167.4–169.1
195.3–197.8
196.9–198.1
140.0–141.4
236.9–238.4
216.2–218.6
199.9–202.1
160.0–162.3
180.4–181.5
188.2–189.1
185.0–186.5
208.7–210.2
206.7–207.8
246.5–247.4
221.3–222.6
254.7–255.2
239.0–240.1
237.6–238.3
178.3–180.5
178.4–179.8
148.8–149.3
186.4–186.9
192.2–193.4
179.8–180.4
181.5–182.5
177.2–179.3
158.5–160.1
165.7–166.2
4-ClC6H4
4-BrC6H4
4-IC6H4
4-CH3C6H4
4-OCH3C6H4
4-CH3C6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-IC6H4
4-CH3C6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-IC6H4
3-Cl-4-FC6H3
4-FC6H4
4-ClC6H4
4-BrC6H4
4-IC6H4
3-Cl-4-FC6H3
4-CH3C6H4
4-OCH3C6H4
4-FC6H4
3-Cl-4-FC6H3
4-OCH3C6H4
4-FC6H4
4-ClC6H4
4- BrC6H4
4-IC6H4
4-CH3C6H4
4-OCH3C6H4
4-CH3C6H4
4-ClC6H4
4-BrC6H4
4-IC6H4
220.0–221.5 [22]
172.4–173.9 [22]
9
14
12
10
9
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
8
12
11
9
10
10
13
9
12
13
10
14
11
10
12
10
8
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-IC6H4
4-IC6H4
4-IC6H4
4-IC6H4
4-IC6H4
4-IC6H4
4-CNC6H4
3-FC6H4
3-FC6H4
3-FC6H4
3-FC6H4
3-FC6H4
3-BrC6H4
4-OCH3C6H4
4-OCH3C6H4
3,4,5-(OCH3)3C6H2
4s
4t
4u
4v
4w
4x
4y
4z
4aa
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
4aj
4ak
4al
4am
4an
4ao
10
9
9
12
13
12
12
10
10
9
10
10
8
4-FC6H4
4-BrC6H4
4-OCH3C6H4
4-ClC6H4
7
aAll reactions were carried out in the scale of aromatic aldehyde (2.0 mmol), aromatic aniline (2.0 mmol), ethyl acetoacetate (1 mmol), and SSA (0.1 g).
bIsolated yields.
The procedure for the synthesis of five-substituted
tetrahydropyridines derivatives 4. A mixture of aldehyde
2.67 (dd, J = 14.0 and 1.2 Hz, 1H, H5a), 2.91 (dd, J = 15.6 and
5.6 Hz, 1H, H5b), 4.24–4.44 (m, 2H, OCH2), 5.34 (br s, 1H, H6),
6.27 (s, 1H, H2), 6.36–6.41 (m, 4H, ArH), 6.87 (t, J = 8.8 Hz, 2H,
ArH), 6.99 (t, J = 8.8 Hz, 2H, ArH), 7.14–7.34 (m, 10H, ArH),
10.13 (s, 1H, NH); HRMS (ESI) m/z: Calcd for [M+ H]+ found
(expected): 511.2160 (511.2197).
Ethyl 4-(4-bromophenylamino)-1-(4-bromophenyl)-1,2,5,6-
tetrahydro-2,6-diphenylpyridine-3-carboxylate (4c):. White solid.
IR (KBr, n, cmꢁ1): 3242, 3060, 2973, 1645, 1602, 1580; 1H
NMR (400 MHz, DMSO-d6) d: 1.37 (t, J = 7.2 Hz, 3H, CH3),
2.75 (dd, J = 15.6 and 2.4 Hz, 1H, H5a), 2.97 (dd, J = 16.0
and 5.6 Hz, 1H, H5b), 4.24–4.43 (m, 2H, OCH2), 5.40 (br s,
1H, H6), 6.23 (s, 1H, H2), 6.38 (d, J = 8.8 Hz, 2H, ArH), 6.55
(d, J = 8.8 Hz, 2H, ArH), 7.07–7.18 (m, 10H, ArH), 7.25 (d,
(2.0 mmol), aniline (2.0mmol), b-keto ester (1.0 mmol), SSA
(0.1 g), and EtOH (2.0 mL) was stirred at 60ꢂC for 7 to 14h until
complete consumption of the starting material as monitored by
TLC. After completion of the reaction, the mixture was diluted
with water; the crude solid was filtered and washed with 95%
EtOH. The solid residue was then recrystallized (95% EtOH/
DMF, 1:4) to provide the pure product 4.
The spectral data of new products are given next.
Ethyl 4-(4-fluorophenylamino)-1-(4-fluorophenyl)-1,2,5,6-
tetrahydro-2,6-diphenylpyridine-3-carboxylate (4a):. White solid.
IR (KBr, n, cmꢁ1): 3247, 3012, 2983, 1650, 1605, 1508; 1H
NMR (400 MHz, DMSO-d6) d: 1.37 (t, J = 7.2 Hz, 3H, CH3),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2014
Silica Sulfuric Acid-Catalyzed Five-component Efficient Synthesis of
445
Five-Substituted Tetrahydropyridines
1654, 1613, 1485; 1H NMR (400 MHz, DMSO-d6) d: 1.42
(t, J = 7.2 Hz, 3H, CH3), 2.08 (d, J = 4.0 Hz, 2H, CH2), 3.66
(s, 3H, OCH3), 3.81 (s, 3H, OCH3), 4.25–4.43 (m, 2H,
OCH2), 5.36 (br s, 1H, H6), 6.19–6.22 (m, 2H, ArH and H2),
6.29–6.33 (m, 2H, ArH), 6.37 (s, 1H, ArH), 6.72–6.85 (m, 7H,
ArH), 6.91 (d, J = 8.4 Hz, 1H, ArH), 6.98 (d, J = 7.6 Hz, 1H,
ArH), 7.12 (dd, J = 8.0 and 1.6 Hz, 1H, ArH), 7.19–7.25
(m, 2H, ArH), 9.66 (s, 1H, NH); HRMS (ESI) m/z: Calcd for
[M + H]+ found (expected): 571.2414 (571.2408).
Scheme 2
Ethyl 4-(4-chlorophenylamino)-1-(4-chlorophenyl)-1,2,5,6-
tetrahydro-2,6-bis(2-methoxyphenyl)pyridine-3-carboxylate
(4i):.
White solid. IR (KBr, n, cmꢁ1): 3247, 2979, 2898,
1656, 1612, 1504; 1H NMR (400 MHz, DMSO-d6) d: 1.43
(t, J = 7.2 Hz, 3H, CH3), 2.81 (dd, J = 15.6 and 5.6 Hz, 1H, H5a),
2.91 (dd, J = 15.6 and 2.4Hz, 1H, H5b), 3.67 (s, 3H, OCH3), 3.83
(s, 3H, OCH3), 4.24–4.44 (m, 2H, OCH2), 5.38 (br s, 1H, H6),
6.16 (d, J = 8.8 Hz, 2H, ArH and H2), 6.32 (d, J = 9.2 Hz, 2H,
ArH), 6.39 (s, 1H, ArH), 6.79–6.85 (m, 3H, ArH), 6.91–7.09
(m, 7H, ArH), 7.19–7.25 (m, 2H, ArH), 9.66 (s, 1H, NH);
HRMS (ESI) m/z: Calcd for [M + H]+ found (expected):
603.1861 (603.1817).
Ethyl 4-(4-bromophenylamino)-1-(4-bromophenyl)-1,2,5,6-
tetrahydro-2,6-bis(2-methoxyphenyl)pyridine-3-carboxylate
(4j):.
White solid. IR (KBr, n, cmꢁ1): 3250, 2978, 2876,
1656, 1611, 1585; 1H NMR (400 MHz, DMSO-d6) d: 1.34
(t, J = 7.2 Hz, 3H, CH3), 2.80 (dd, J = 16.0 and 5.6 Hz, 1H, H5a),
2.90 (dd, J = 16.0 and 1.6Hz, 1H, H5b), 3.69 (s, 3H, OCH3), 3.79
(s, 3H, OCH3), 4.19–4.39 (m, 2H, OCH2), 5.42 (br s, 1H, H6),
6.17–6.22 (m, 4H, ArH and H2), 6.29 (s, 1H, ArH), 6.80–6.88
(m, 3H, ArH), 6.97–7.07 (m, 3H, ArH), 7.16–7.32 (m, 6H, ArH),
9.54 (s, 1H, NH); HRMS (ESI) m/z: Calcd for [M+ H]+ found
(expected): 691.0876 (691.0807).
J = 8.8 Hz, 2H, ArH), 7.33–7.37 (m, 2H, ArH), 10.20 (s, 1H,
NH); HRMS (ESI) m/z: Calcd for [M + H]+ found (expected):
631.0546 (631.0596).
Ethyl 4-(4-iodophenylamino)-1,2,5,6-tetrahydro-1-(4-
iodophenyl)-2,6-diphenylpyridine-3-carboxylate (4d):. White
solid. IR (KBr, n, cmꢁ1): 3243, 2981, 1647, 1600, 1578; 1H
NMR (400 MHz, DMSO-d6) d: 1.38 (t, J = 7.2Hz, 3H, CH3),
2.77 (dd, J = 15.6 and 0.8 Hz, 1H, H5a), 2.96 (dd, J = 16.0 and
6.0 Hz, 1H, H5b), 4.25–4.44 (m, 2H, OCH2), 5.38 (br s, 1H, H6),
6.21–6.27 (m, 5H, ArH and H2), 7.12 (d, J = 7.2Hz, 2H, ArH),
7.23–7.33 (m, 10H, ArH), 7.47 (d, J = 8.4 Hz, 2H, ArH), 10.15
(s, 1H, NH); HRMS (ESI) m/z: Calcd for [M+ H]+ found
(expected): 727.0284 (727.0318).
Ethyl 4-(4-tolylamino)-1,2,5,6-tetrahydro-2,6-diphenyl-1-
(4-tolylpyridine)-3-carboxylate (4e):. White solid. IR (KBr, n,
cmꢁ1): 3245, 3024, 2984, 1649, 1593; 1H NMR (400 MHz,
DMSO-d6) d: 1.39 (t, J =7.2 Hz, 3H, CH3), 2.07 (s, 3H, ArCH3),
2.22 (s, 3H, ArCH3), 2.75 (dd, J =12.8 and 0.8Hz, 1H, H5a), 2.88
(dd, J = 12.8 and 5.6 Hz, 1H, H5b), 4.24–4.44 (m, 2H, OCH2),
5.33 (br s, 1H, H6), 6.24–6.33 (m, 5H, ArH and H2), 6.81
(d, J = 8.8Hz, 2H, ArH), 6.95 (d, J = 8.0 Hz, 2H, ArH), 7.14–7.32
(m, 10H, ArH), 10.18 (s, 1H, NH); HRMS (ESI) m/z: Calcd for
[M + H]+ found (expected): 503.2663 (503.2699).
Ethyl 4-(4-tolylamino)-1,2,5,6-tetrahydro-2,6-bis(2-
methoxyphenyl)-1-(4-tolylpyridine)-3-carboxylate (4g):. White
solid. IR (KBr, n, cmꢁ1): 3253, 2920, 2834, 1655, 1517; 1H
NMR (400 MHz, DMSO-d6) d: 1.41 (t, J = 7.2 Hz, 3H, CH3),
2.14 (s, 3H, ArCH3), 2.25 (s, 3H, ArCH3), 2.79 (dd, J = 15.6
and 5.6 Hz, 1H, H5a), 2.95 (dd, J = 15.6 and 2.0 Hz, 1H, H5b),
3.61 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 4.22–4.43 (m, 2H,
OCH2), 5.39 (br s, 1H, H6), 6.14–6.16 (m, 2H, ArH and H2),
6.32 (d, J = 8.4 Hz, 2H, ArH), 6.42 (s, 1H, ArH), 6.77–6.92
(m, 8H, ArH), 7.02 (d, J = 6.8 Hz, 1H, ArH), 7.13–7.24 (m, 3H,
ArH), 9.68 (s, 1H, NH); HRMS (ESI) m/z: Calcd for [M + H]+
found (expected): 563.2931 (563.2910).
Ethyl 4-(4-iodophenylamino)-1,2,5,6-tetrahydro-1-(4-
iodophenyl)-2,6-bis(2-methoxyphenyl)pyridine-3-carboxylate
(4k):.
White solid. IR (KBr, n, cmꢁ1): 3246, 3030, 2976,
1654, 1606, 1581; 1H NMR (400 MHz, DMSO-d6) d: 1.33
(t, J = 7.2 Hz, 3H, CH3), 2.79 (dd, J = 12.0 and 5.6 Hz, 1H, H5a),
2.92 (dd, J = 14.8 and 1.6Hz, 1H, H5b), 3.68 (s, 3H, OCH3), 3.78
(s, 3H, OCH3), 4.19–4.39 (m, 2H, OCH2), 5.40 (br s, 1H, H6),
6.07 (d, J = 8.4 Hz, 4H, ArH and H2), 6.28 (s, 1H, ArH), 6.79–
6.87 (m, 3H, ArH), 6.96–7.06 (m, 3H, ArH), 7.20–7.31
(m, 4H, ArH), 7.45 (d, J = 8.4 Hz, 2H, ArH), 9.53 (s, 1H, NH);
HRMS (ESI) m/z: Calcd for [M + H]+ found (expected):
787.0514 (787.0530).
Ethyl 4-(4-tolylamino)-2,6-bis(4-fluorophenyl)-1,2,5,6-
tetrahydro-1-(4-tolylpyridine)-3-carboxylate 4l:. White solid.
IR (KBr, n, cmꢁ1): 3236, 2998, 2869, 1650, 1596, 1516; 1H
NMR (400 MHz, DMSO-d6) d: 1.37 (t, J = 7.2 Hz, 3H, CH3),
2.07 (s, 3H, ArCH3), 2.23 (s, 3H, ArCH3), 2.73 (dd, J = 14.4
and 2.0 Hz, 1H, H5a), 2.88 (dd, J = 16.0 and 5.6 Hz, 1H, H5b),
4.22–4.42 (m, 2H, OCH2), 5.33 (br s, 1H, H6), 6.22 (s, 1H, H2),
6.30 (d, J = 8.8 Hz, 2H, ArH), 6.37 (d, J = 8.4 Hz, 2H, ArH), 6.83
(d, J = 8.4Hz, 2H, ArH), 7.00 (d, J = 8.0Hz, 2H, ArH), 7.11–7.15
(m, 6H, ArH), 7.30–7.34 (m, 2H, ArH), 10.20 (s, 1H, NH);
HRMS (ESI) m/z: Calcd for [M + H]+ found (expected):
539.2563 (539.2510).
Ethyl 4-(4-fluorophenylamino)-1,2,6-tris(4-fluorophenyl)-
1,2,5,6-tetrahydropyridine-3-carboxylate (4m):. White solid.
IR (KBr, n, cmꢁ1): 3243, 2986, 2889, 1649, 1605, 1507; 1H
NMR (400 MHz, DMSO-d6) d: 1.37 (t, J = 7.2 Hz, 3H, CH3), 2.67
(dd, J = 15.6 and 2.0Hz, 1H, H5a), 2.90 (dd, J = 16.0 and 5.6Hz,
1H, H5b), 4.22–4.42 (m, 2H, OCH2), 5.34 (br s, 1H, H6),
Ethyl 4-(4-fluorophenylamino)-1-(4-fluorophenyl)-1,2,5,6-
tetrahydro-2,6-bis(2-methoxyphenyl)pyridine-3-carboxylate
(4h):.
White solid. IR (KBr, n, cmꢁ1): 3240, 3020, 2978,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

446
X.-x Zhang, Y. Wan, L.-l. Pang, H.-y. Wang, L.-l. Zhao,
C. Wang, S. Y. Hang, G. X. Liu, L-F. Chen, and H. Wu
Vol 51
6.20 (s, 1H, H2), 6.33–6.37 (m, 2H, ArH), 6.53–6.56 (m, 2H,
ArH), 6.89 (t, J = 8.8 Hz, 2H, ArH), 7.05 (t, J = 8.8 Hz, 2H,
ArH), 7.12–7.17 (m, 6H, ArH), 7.32–7.35 (m, 2H, ArH),
10.16 (s, 1H, NH); HRMS (ESI) m/z: Calcd for [M + H]+
found (expected): 547.2017 (547.2009).
NMR (400 MHz, DMSO-d6) d: 1.44 (t, J = 7.2 Hz, 3H, CH3),
2.68 (dd, J = 15.2 and 2.4 Hz, 1H, H5a), 2.81 (dd, J = 15.2 and
6.0 Hz, 1H, H5b), 4.29–4.49 (m, 2H, OCH2), 5.05 (br s, 1H,
H6), 6.28–6.37 (m, 5H, ArH and H2), 7.02 (t, J = 8.6 Hz, 4H,
ArH), 7.12 (d, J = 8.4 Hz, 2H, ArH), 7.19–7.25 (m, 6H, ArH),
10.25 (s, 1H, NH); HRMS (ESI) m/z: Calcd for [M + H]+ found
(expected): 611.0846 (611.0827).
Ethyl 4-(4-chlorophenylamino)-1-(4-chlorophenyl)-2,6-bis
(4-fluorophenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate
(4n):. White solid. IR (KBr, n, cmꢁ1): 3237, 3068, 2978, 1649,
Ethyl 4-(4-bromophenylamino)-1-(4-bromophenyl)-2,6-bis
(4-chlorophenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate
1
1495; H NMR (400MHz, DMSO-d6) d: 1.38 (t, J = 7.2 Hz, 3H,
CH3), 2.75 (dd, J =15.6 and 2.4 Hz, 1H, H5a), 2.97 (dd, J = 16.0
and 5.6 Hz, 1H, H5b), 4.24–4.43 (m, 2H, OCH2), 5.40 (br s,
1H, H6), 6.23 (s, 1H, H2), 6.38 (d, J = 8.8 Hz, 2H, ArH), 6.55
(d, J = 8.8 Hz, 2H, ArH), 7.07–7.18 (m, 8H, ArH), 7.25
(d, J = 8.8 Hz, 2H, ArH), 7.33–7.37 (m, 2H, ArH), 10.20
(s, 1H, NH); HRMS (ESI) m/z: Calcd for [M + H]+ found
(expected): 579.1483 (579.1418).
Ethyl 4-(4-bromophenylamino)-1-(4-bromophenyl)-2,6-bis
(4-fluorophenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate
(4o):. White solid. IR (KBr, n, cmꢁ1): 3240, 3032, 2978, 1649,
1592, 1492; 1H NMR (400 MHz, DMSO-d6) d: 1.37 (t, J = 7.2Hz,
3H, CH3), 2.76 (dd, J = 14.4 and 1.2 Hz, 1H, H5a), 2.97 (dd,
J = 15.6 and 5.6 Hz, 1H, H5b), 4.23–4.43 (m, 2H, OCH2), 5.39
(br s, 1H, H6), 6.22 (s, 1H, H2), 6.34 (d, J = 9.2 Hz, 2H, ArH),
6.50 (d, J = 8.8 Hz, 2H, ArH), 7.12–7.21(m, 8H, ArH), 7.32–7.39
(m, 4H, ArH), 10.18 (s, 1H, NH); HRMS (ESI) m/z: Calcd for
[M + H]+ found (expected): 667.0434 (667.0407).
(4t):.
White solid. IR (KBr, n, cmꢁ1): 3241, 3063, 2981,
1650, 1609, 1513; 1H NMR (400 MHz, DMSO-d6) d: 1.37
(t, J = 7.2 Hz, 3H, CH3), 2.77 (dd, J = 14.4 and 1.2 Hz, 1H, H5a),
2.91 (dd, J = 16.0 and 5.6 Hz, 1H, H5b), 4.23–4.42 (m, 2H,
OCH2), 5.39 (br s, 1H, H6), 6.20 (s, 1H, H2), 6.32 (d, J = 8.8Hz,
2H, ArH), 6.34 (d, J = 8.8 Hz, 2H, ArH), 7.10 (d, J = 8.4 Hz, 2H,
ArH), 7.20 (d, J = 8.8 Hz, 2H, ArH), 7.33–7.41 (m, 8H, ArH),
10.19 (s, 1H, NH); HRMS (ESI) m/z: Calcd for [M+ H]+ found
(expected): 698.9826 (698.9816).
Ethyl 4-(4-iodophenylamino)-2,6-bis(4-chlorophenyl)-
1,2,5,6-tetrahydro-1-(4-iodophenyl)pyridine-3-carboxylate
(4u):. White solid. IR (KBr, n, cmꢁ1): 3243, 2982, 1652, 1612,
1
1503; H NMR (400 MHz, DMSO-d6) d: 1.45 (t, J = 7.2Hz, 3H,
CH3), 2.71 (dd, J = 15.2 and 2.4 Hz, 1H, H5a), 2.81 (dd, J = 15.2
and 5.6Hz, 1H, H5b), 4.29–4.49 (m, 2H, OCH2), 5.04 (br s, 1H,
H6), 6.14 (d, J = 8.4 Hz, 2H, ArH and H2), 6.24 (t, J = 11.0Hz,
3H, ArH), 7.02 (d, J = 8.4Hz, 2H, ArH), 7.19–7.25 (m, 6H,
ArH), 7.31 (d, J = 9.2Hz, 2H, ArH), 7.46 (d, J = 8.8Hz, 2H,
ArH), 10.25 (s, 1H, NH); HRMS (ESI) m/z: Calcd for [M+ H]+
found (expected): 794.9508 (794.9539).
Ethyl 4-(4-iodophenylamino)-2,6-bis(4-fluorophenyl)-
1,2,5,6-tetrahydro-1-(4-iodophenyl)pyridine-3-carboxylate
(4p):.
White solid. IR (KBr, n, cmꢁ1): 3246, 3021, 2963,
1654, 1604, 1578; 1H NMR (400 MHz, DMSO-d6) d: 1.37
(t, J = 7.2 Hz, 3H, CH3), 2.77 (dd, J = 15.6 and 2.0 Hz, 1H, H5a),
2.96 (dd, J = 15.6 and 5.2 Hz, 1H, H5b), 4.23–4.42 (m, 2H,
OCH2), 5.38 (br s, 1H, H6), 6.22 (t, J = 8.2Hz, 3H, ArH and H2),
6.35 (d, J = 8.2Hz, 2H, ArH), 7.11–7.17 (m, 6H, ArH), 7.31–
7.35 (m, 4H, ArH), 7.52 (d, J = 8.2Hz, 2H, ArH), 10.17 (s, 1H,
NH); HRMS (ESI) m/z: Calcd for [M + H]+ found (expected):
763.0107 (763.0130).
Ethyl 4-(3-chloro-4-fluorophenylamino)-1-(3-chloro-4-
fluorophenyl)-2,6-bis(4-chlorophenyl)-1,2,5,6-tetrahydropyridine-
3-carboxylate (4v):.
White solid. IR (KBr, n, cmꢁ1): 3240,
1
3030, 2978, 1654, 1618, 1517; H NMR (400MHz, DMSO-d6)
d: 1.37 (t, J = 7.2 Hz, 3H, CH3), 2.65 (dd, J = 14.4 and 1.2 Hz,
1H, H5a), 2.96 (dd, J = 16.0 and 5.6 Hz, 1H, H5b), 4.23–4.43 (m,
2H, OCH2), 5.40 (br s, 1H, H6), 6.18 (s, 1H, H2), 6.32–6.36 (m,
1H, ArH), 6.38–6.40 (m, 1H, ArH), 6.57 (dd, J =8.4 and 2.4Hz,
1H, ArH), 6.66–6.70 (m, 1H, ArH), 7.11–7.15 (m, 3H, ArH),
7.28 (t, J = 9.2Hz, 1H, ArH), 7.33–7.42 (m, 6H, ArH), 10.09
(s, 1H, NH); HRMS (ESI) m/z: Calcd for [M + H]+ found
(expected): 647.0621 (647.0638).
Ethyl 4-(3-chloro-4-fluorophenylamino)-1-(3-chloro-4-
fluorophenyl)-2,6-bis(4-fluorophenyl)-1,2,5,6-tetrahydropyridine-
3-carboxylate (4q):.
White solid. IR (KBr, n, cmꢁ1): 3243,
1
2998, 2876, 1649, 1581; H NMR (400 MHz, DMSO-d6) d: 1.47
(t, J= 7.2 Hz, 3H, CH3), 2.60 (dd, J= 15.2 and 1.2 Hz, 1H, H5a),
2.78 (dd, J= 15.2 and 5.6 Hz, 1H, H5b), 4.30–4.52 (m, 2H,
OCH2), 5.03 (br s, 1H, H6), 6.24 (s, 1H, H2), 6.26–6.34 (m, 3H,
ArH), 6.43–6.45 (m, 1H, ArH), 6.84 (t, J = 9.0 Hz, 1H, ArH),
6.91–7.05 (m, 5H, ArH), 7.08–7.12 (m, 2H, ArH), 7.19–7.22 (m,
2H, ArH), 10.21 (s, 1H, NH); HRMS (ESI) m/z: Calcd for
[M + H]+ found (expected): 615.1237 (615.1229).
Ethyl 4-(4-tolylamino)-2,6-bis(4-chlorophenyl)-1,2,5,6-
tetrahydro-1-(4-tolylpyridine)-3-carboxylate (4w):. White solid.
IR (KBr, n, cmꢁ1): 3243, 3047, 2988, 1659, 1610, 1504; 1H
NMR (400 MHz, DMSO-d6) d: 1.36 (t, J = 7.2 Hz, 3H, CH3),
2.06 (s, 3H, ArCH3), 2.23 (s, 3H, ArCH3), 2.74 (dd, J = 14.0
and 1.6 Hz, 1H, H5a), 2.91 (dd, J = 15.6 and 5.6 Hz, 1H, H5b),
4.21–4.40 (m, 2H, OCH2), 5.33 (br s, 1H, H6), 6.20 (s, 1H, H2),
6.28 (d, J = 8.8 Hz, 2H, ArH), 6.39 (d, J = 8.0 Hz, 2H, ArH), 6.82
(d, J = 8.4 Hz, 2H, ArH), 7.00 (d, J = 8.4Hz, 2H, ArH), 7.11
(d, J = 8.4 Hz, 2H, ArH), 7.32–7.37 (m, 6H, ArH), 10.20 (s, 1H,
NH); HRMS (ESI) m/z: Calcd for [M+ H]+ found (expected):
571.1984 (571.1919).
Ethyl 4-(4-methoxyphenylamino)-2,6-bis(4-chlorophenyl)-
1,2,5,6-tetrahydro-1-(4-methoxyphenyl)pyridine-3-carboxylate
(4x):. White solid. IR (KBr, n, cmꢁ1): 3244, 3047, 2978, 1654,
1618, 1517; 1H NMR (400 MHz, DMSO-d6) d: 1.34 (t, J = 7.2 Hz,
3H, CH3), 2.66 (dd, J = 15.6 and 2.0 Hz, 1H, H5a), 2.86
(dd, J = 16.0 and 5.2 Hz, 1H, H5b), 3.56 (s, 3H, OCH3), 3.72 (s,
3H, OCH3), 4.19–4.38 (m, 2H, OCH2), 5.26 (br s, 1H, H6),
6.12 (s, 1H, H2), 6.31 (d, J = 9.2 Hz, 2H, ArH), 6.47 (d,
J = 8.8 Hz, 2H, ArH), 6.66 (d, J = 9.2 Hz, 2H, ArH), 6.76 (d,
Ethyl 4-(4-fluorophenylamino)-2,6-bis(4-chlorophenyl)-1-
(4-fluorophenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate
(4r):.
White solid. IR (KBr, n, cmꢁ1): 3247, 3012, 2871,
1651, 1612, 1505; 1H NMR (400 MHz, DMSO-d6) d: 1.44
(t, J = 7.2 Hz, 3H, CH3), 2.61 (dd, J = 15.6 and 2.8Hz, 1H, H5a),
2.77 (dd, J = 15.2 and 5.6 Hz, 1H, H5b), 4.27–4.48 (m, 2H, OCH2),
5.01 (br s, 1H, H6), 6.25 (s, 1H, H2), 6.34–6.38 (m, 4H, ArH),
6.78 (t, J = 8.8 Hz, 2H, ArH), 6.85 (t, J = 8.4 Hz, 2H, ArH), 7.05
(d, J = 8.4Hz, 2H, ArH), 7.19–7.25 (m, 6H, ArH), 10.19 (s, 1H,
NH); HRMS (ESI) m/z: Calcd for [M + H]+ found (expected):
579.1494 (579.1418).
Ethyl 4-(4-chlorophenylamino)-1,2,6-tris(4-chlorophenyl)-
1,2,5,6-tetrahydropyridine-3-carboxylate (4s):. White solid.
IR (KBr, n, cmꢁ1): 3246, 2996, 2867, 1652, 1600, 1493; 1H
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2014
Silica Sulfuric Acid-Catalyzed Five-component Efficient Synthesis of
447
Five-Substituted Tetrahydropyridines
J = 8.8 Hz, 2H, ArH), 7.11 (d, J = 8.4 Hz, 2H, ArH), 7.30–7.37
(m, 6H, ArH), 10.13 (s, 1H, NH); HRMS (ESI) m/z: Calcd for
[M + H]+ found (expected): 603.1848 (603.1817).
(t, J = 7.2 Hz, 3H, CH3), 2.75 (dd, J = 16.0 and 1.2 Hz, 1H, H5a),
2.99 (dd, J = 15.8 and 5.6 Hz, 1H, H5b), 4.22–4.41 (m, 2H,
OCH2), 5.33 (br s, 1H, H6), 6.15 (s, 1H, H2), 6.31 (d, J = 8.8Hz,
2H, ArH), 6.52 (d, J = 8.8 Hz, 2H, ArH), 6.89 (d, J = 8.4 Hz, 2H,
ArH), 7.13 (d, J = 8.0Hz, 2H, ArH), 7.19 (d, J = 9.2Hz, 2H,
ArH), 7.37 (d, J = 8.8 Hz, 2H, ArH), 7.63–7.69 (m, 4H, ArH),
10.16 (s, 1H, NH); HRMS (ESI) m/z: Calcd for [M+ H]+ found
(expected): 882.8526 (882.8529).
Ethyl 4-(4-fluorophenylamino)-2,6-bis(4-bromophenyl)-1-
(4-fluorophenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate
(4y):. White solid. IR (KBr, n, cmꢁ1): 3248, 3020, 1652, 1614,
1
1497; H NMR (400MHz, DMSO-d6) d: 1.36 (t, J = 7.2 Hz, 3H,
CH3), 2.68 (dd, J =16.0 and 1.2 Hz, 1H, H5a), 2.89 (dd, J = 15.2
and 5.6 Hz, 1H, H5b), 4.21–4.41 (m, 2H, OCH2), 5.32 (br s, 1H,
H6), 6.15 (s, 1H, H2), 6.32–6.35 (m, 2H, ArH), 6.73–6.76
(m, 2H, ArH), 7.03–7.07 (m, 4H, ArH), 7.22–7.29 (m, 6H, ArH),
7.39 (d, J = 8.4Hz, 2H, ArH), 10.14 (s, 1H, NH); HRMS (ESI)
m/z: Calcd for [M+ H]+ found (expected): 667.0389 (667.0407).
Ethyl 4-(3-chloro-4-fluorophenylamino)-1-(3-chloro-4-
fluorophenyl)-1,2,5,6-tetrahydro-2,6-bis(4-iodophenyl)pyridine-
3-carboxylate (4z):. Yellow solid. IR (KBr, n, cmꢁ1): 3236, 2968,
2855, 1653, 1501; 1H NMR(400MHz, DMSO-d6)d:1.37(t, J=7.2Hz,
3H, CH3), 2.62 (dd, J= 14.4 and 0.8 Hz, 1H, H5a), 2.93 (dd, J= 16.0 and
5.6 Hz, 1H, H5b), 4.22–4.42 (m, 2H, OCH2), 5.35 (br s, 1H, H6), 6.14 (s,
1H, H2), 6.32–6.35 (m, 1H, ArH), 6.38–6.40 (m, 1H, ArH), 6.47 (dd,
J= 6.4 and 1.6 Hz, 1H, Ar), 6.66–6.70 (m, 1H, ArH), 6.93 (d,
J= 8.0 Hz, 2H, ArH), 7.10–7.15 (m, 3H, ArH), 7.28 (t, J= 9.2 Hz, 1H,
ArH), 7.67–7.71 (m, 4H, ArH), 10.07 (s, 1H, NH); HRMS (ESI) m/z:
Calcd for [M + H]+ found (expected): 830.9391 (830.9351).
Ethyl 4-(4-methoxyphenylamino)-1,2,5,6-tetrahydro-2,6-bis
(4-iodophenyl)-1-(4-methoxyphenyl)pyridine-3-carboxylate
(4aa):. Yellow solid. IR (KBr, n, cmꢁ1): 3244, 2996, 2857,
1659, 1617, 1586; 1H NMR (400 MHz, DMSO-d6) d: 1.34
(t, J = 7.2Hz, 3H, CH3), 2.80 (dd, J = 16.0 and 5.6Hz, 1H, H5a),
2.91 (dd, J = 16.0 and 1.6Hz, 1H, H5b), 3.69 (s, 3H, OCH3), 3.79
(s, 3H, OCH3), 4.19–4.39 (m, 2H, OCH2), 5.42 (br s, 1H, H6),
6.17–6.22 (m, 4H, ArH and H2), 6.29 (s, 1H, ArH), 6.80–6.88
(m, 3H, ArH), 6.97–7.07 (m, 3H, ArH), 7.16–7.32 (m, 6H, ArH),
9.54 (s, 1H, NH); HRMS (ESI) m/z: Calcd for [M+ H]+ found
(expected): 755.0616 (755.0631).
Ethyl 4-(4-iodophenylamino)-1,2,5,6-tetrahydro-1,2,6-tris
(4-iodophenyl) pyridine-3-carboxylate (4ae):.
Yellow solid.
IR (KBr, n, cmꢁ1): 3245, 2987, 2871, 1650, 1609, 1515; 1H
NMR (400 MHz, DMSO-d6) d: 1.36 (t, J = 7.2 Hz, 3H, CH3), 2.76
(dd, J = 16.0 and 2.4 Hz, 1H, H5a), 2.98 (dd, J = 16.0 and
5.6 Hz, 1H, H5b), 4.22–4.41 (m, 2H, OCH2), 5.33 (br s, 1H,
H6), 6.14 (s, 1H, H2), 6.21 (d, J = 9.2 Hz, 2H, ArH),
6.38 (d, J = 8.4 Hz, 2H, ArH), 6.68 (d, J = 8.4 Hz, 2H, ArH), 7.12
(d, J = 8.4 Hz, 2H, ArH), 7.32 (d, J = 8.8Hz, 2H, ArH), 7.52
(d, J = 8.4 Hz, 2H, ArH), 7.62–7.69 (m, 4H, ArH), 10.16 (s, 1H,
NH); HRMS (ESI) m/z: Calcd for [M+ H]+ found (expected):
978.8213 (978.8180).
Ethyl 4-(4-tolylamino)-2,6-bis(4-cyanophenyl)-1,2,5,6-
tetrahydro-1-(4-tolyl pyridine)-3-carboxylate (4af):. White solid.
IR (KBr, n, cmꢁ1): 3246, 3010, 2976, 2230, 1653, 1573; 1H
NMR (400 MHz, DMSO-d6) d: 1.38 (t, J = 7.2 Hz, 3H, CH3),
2.07 (s, 3H, ArCH3), 2.24 (s, 3H, ArCH3), 2.78 (dd, J = 16.0
and 2.4 Hz, 1H, H5a), 2.95 (dd, J = 15.6 and 5.6 Hz, 1H, H5b),
4.24–4.44 (m, 2H, OCH2), 5.47 (br s, 1H, H6), 6.27
(t, J = 7.6 Hz, 2H, ArH and H2), 6.41 (d, J = 8.0 Hz, 2H, ArH),
6.84 (d, J = 8.4 Hz, 3H, ArH), 7.02 (d, J = 8.0 Hz, 2H,
ArH), 7.28 (d, J = 8.4 Hz, 2H, ArH), 7.51 (d, J = 8.4 Hz, 2H,
ArH), 7.75–7.81 (m, 4H, ArH), 10.18 (s, 1H, NH); HRMS (ESI)
m/z: Calcd for [M+ H]+ found (expected): 553.2632 (553.2604).
Ethyl 4-(4-methoxyphenylamino)-2,6-bis(3-fluorophenyl)-
1,2,5,6-tetrahydro-1-(4-methoxyphenyl)pyridine-3-carboxylate
(4ag):.
White solid. IR (KBr, n, cmꢁ1): 3247, 2987, 2836,
Ethyl 4-(4-fluorophenylamino)-1-(4-fluorophenyl)-1,2,5,6-
tetrahydro-2,6-bis(4-iodophenyl)pyridine-3-carboxylate
(4ab):. Yellow solid. IR (KBr, n, cmꢁ1): 3241, 3050, 2954,
1650, 1590, 1513; 1H NMR (400 MHz, DMSO-d6) d: 1.36
(t, J = 7.2 Hz, 3H, CH3), 2.66 (dd, J = 15.6 and 1.6 Hz, 1H, H5a),
2.93 (dd, J = 15.6 and 5.6 Hz, 1H, H5b), 4.20–4.40 (m, 2H,
OCH2), 5.29 (br s, 1H, H6), 6.13 (s, 1H, H2), 6.31–6.35 (m, 2H,
ArH), 6.55–6.58 (m, 2H, ArH), 6.87–6.91 (m, 4H, ArH), 7.04
(t, J = 8.6 Hz, 2H, ArH), 7.13 (d, J = 8.4 Hz, 2H, ArH), 7.64–7.68
(m, 4H, ArH), 10.14 (s, 1H, NH); HRMS (ESI) m/z: Calcd for
[M + H]+ found (expected): 763.0190 (763.0130).
1646; 1H NMR (400 MHz, DMSO-d6) d: 1.35 (t, J = 7.2 Hz,
3H, CH3), 2.67 (dd, J = 15.2 and 2.0 Hz, 1H, H5a), 2.89 (dd,
J = 16.0 and 6.0 Hz, 1H, H5b), 3.59 (s, 3H, OCH3), 3.71
(s, 3H, OCH3), 4.22–4.41 (m, 2H, OCH2), 5.33 (br s, 1H, H6),
6.18 (s, 1H, H2), 6.35 (d, J = 8.8 Hz, 2H, ArH), 6.43
(d, J = 8.8 Hz, 2H, ArH), 6.63–6.71 (m, 2H, ArH), 6.75 (d,
J = 8.8 Hz, 2H, ArH), 6.89 (t, J = 8.0 Hz, 1H, ArH), 6.96
(d, J = 7.6 Hz, 1H, ArH), 7.02–7.09 (m, 3H, ArH), 7.14–7.18
(m, 1H, ArH), 7.31–7.39 (m, 2H, ArH), 10.13 (s, 1H, NH);
HRMS (ESI) m/z: Calcd for [M + H]+ found (expected):
571.2455 (571.2408).
Ethyl 4-(4-chlorophenylamino)-1-(4-chlorophenyl)-1,2,5,6-
tetrahydro-2,6-bis(4-iodophenyl)pyridine-3-carboxylate
(4ac):. Yellow solid. IR (KBr, n, cmꢁ1): 3243, 2975, 2894,
1649, 1602, 1590, 1492; 1H NMR (400 MHz, DMSO-d6) d:
1.37 (t, J = 7.2 Hz, 3H, CH3), 2.75 (dd, J = 12.0 and 1.6 Hz,
1H, H5a), 3.00 (dd, J = 16.0 and 5.6 Hz, 1H, H5b), 4.22–4.42
(m, 2H, OCH2), 5.35 (br s, 1H, H6), 6.16 (s, 1H, H2), 6.36
(d, J = 9.2 Hz, 2H, ArH), 6.58 (d, J = 8.8 Hz, 2H, ArH), 6.90
(d, J = 8.4 Hz, 2H, ArH), 7.08 (d, J = 8.8 Hz, 2H, ArH), 7.14 (d,
J = 8.4Hz, 2H, ArH), 7.25 (d, J = 8.8 Hz, 2H, ArH), 7.63–7.70
(m, 4H, ArH), 10.19 (s, 1H, NH); HRMS (ESI) m/z: Calcd for
[M + H]+ found (expected): 794.9599 (794.9539).
Ethyl 4-(4-tolylamino)-2,6-bis(3-fluorophenyl)-1,2,5,6-
tetrahydro-1-(4-tolylpyridine)-3-carboxylate (4ah):.
White
solid. IR (KBr, n, cmꢁ1): 3243, 2976, 2834, 1659, 1607, 1572;
1H NMR (400MHz, DMSO-d6) d: 1.38 (t, J = 7.2Hz, 3H, CH3),
2.08 (s, 3H, ArCH3), 2.24 (s, 3H, ArCH3), 2.76 (dd, J = 15.6 and
1.2 Hz, 1H, H5a), 2.93 (dd, J = 15.6 and 6.8 Hz, 1H, H5b), 4.24–
4.44 (m, 2H, OCH2), 5.39 (br s, 1H, H6), 6.25 (s, 1H, H2), 6.32
(d, J = 8.4Hz, 2H, ArH), 6.38 (d, J = 8.0Hz, 2H, ArH), 8.85–8.89
(m, 3H, ArH), 6.95–7.07 (m, 6H, ArH), 7.18 (d, J = 8.0Hz, 1H,
ArH), 7.31–7.40 (m, 2H, ArH), 10.21 (s, 1H, NH); HRMS (ESI)
m/z: Calcd for [M + H]+ found (expected): 539.2551 (539.2510).
Ethyl 4-(4-chlorophenylamino)-1-(4-chlorophenyl)-2,6-bis
(3-fluorophenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate
(4ai):. Yellow solid. IR (KBr, n, cmꢁ1): 3244, 3019, 2926,
1651; 1H NMR (400 MHz, DMSO-d6) d: 1.38 (t, J = 7.2 Hz,
3H, CH3), 2.78 (dd, J = 16.4 and 1.6 Hz, 1H, H5a), 3.03 (dd,
Ethyl 4-(4-bromophenylamino)-1-(4-bromophenyl)-1,2,5,6-
tetrahydro-2,6-bis(4-iodophenyl)pyridine-3-carboxylate
(4ad):. Yellow solid. IR (KBr, n, cmꢁ1): 3246, 3027, 2988,
1647, 1602, 1486; 1H NMR (400 MHz, DMSO-d6) d: 1.36
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

448
X.-x Zhang, Y. Wan, L.-l. Pang, H.-y. Wang, L.-l. Zhao,
C. Wang, S. Y. Hang, G. X. Liu, L-F. Chen, and H. Wu
Vol 51
J = 16.0 and 2.0 Hz, 1H, H5b), 4.25–4.45 (m, 2H, OCH2), 5.45
(br s, 1H, H6), 6.25 (s, 1H, H2), 6.40 (d, J = 8.8 Hz, 2H, ArH),
6.57 (d, J = 8.8 Hz, 2H, ArH), 6.86 (d, J = 10.0 Hz, 1H, ArH),
6.94 (d, J = 8.0 Hz, 1H, ArH), 7.06–7.11 (m, 5H, ArH), 7.19
(d, J = 7.6 Hz, 1H, ArH), 7.25 (d, J = 8.4 Hz, 2H, ArH), 7.32–
7.42 (m, 2H, ArH), 10.20 (s, 1H, NH); HRMS (ESI) m/z:
Calcd for [M + H]+ found (expected): 579.1478 (579.1418).
Ethyl 4-(4-bromophenylamino)-1-(4-bromophenyl)-2,6-bis
(3-fluorophenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate
(s, 3H, OCH3), 3.82 (s, 3H, OCH3), 4.22–4.43(m, 2H, OCH2),
5.39 (br s, 1H, H6), 6.14–6.16 (m, 2H, ArH and H2), 6.32
(d, J = 8.4Hz, 2H, ArH), 6.42 (s, 1H, ArH), 6.77–6.92 (m, 8H,
ArH), 7.02 (d, J = 6.8 Hz, 1H, ArH), 7.13–7.24 (m, 3H, ArH),
9.68 (s, 1H, NH); HRMS (ESI) m/z: Calcd for [M+ H]+ found
(expected): 594.2781 (594.2730).
Ethyl 4-(4-chlorophenylamino)-1-(4-chlorophenyl)-1,2,5,6-
tetrahydro-2,6-bis(3,4,5-trimethoxyphenyl)pyridine-3-carboxylate
(4ao):. White solid. IR (KBr, n, cmꢁ1): 3248, 2998, 2876, 1651,
1606, 1589; 1H NMR (400 MHz, DMSO-d6) d: 1.36 (t, J = 7.2Hz,
3H, CH3), 2.74 (dd, J = 13.6 and 1.2 Hz, 1H, H5a), 3.04
(dd, J = 16.0 and 5.6 Hz, 1H, H5b), 3.59 (s, 6H, OCH3), 3.64
(s, 6H, OCH3), 3.69 (s, 6H, OCH3), 4.23–4.46 (m, 2H, OCH2),
5.33 (br s, 1H, H6), 6.19 (s, 1H, H2), 6.41 (s, 2H, ArH), 6.45–6.51
(m, 4H, ArH), 6.56 (s, 2H, ArH), 7.12 (d, J = 9.2Hz, 2H, ArH),
7.22 (d, J= 8.8 Hz, 2H, ArH), 10.20 (s, 1H, NH); HRMS (ESI) m/z:
Calcd for [M+ H]+ found (expected): 723.2267 (723.2240).
(4aj):.
Yellow solid. IR (KBr, n, cmꢁ1): 3243, 2978, 2886,
1649, 1589; 1H NMR (400 MHz, DMSO-d6) d: 1.37
(t, J = 7.2 Hz, 3H, CH3), 2.78 (dd, J = 16.4 and 2.0 Hz, 1H,
H5a), 3.03 (dd, J = 16.0 and 5.2 Hz, 1H, H5b), 4.25–4.45
(m, 2H, OCH2), 5.44 (br s, 1H, H6), 6.24 (s, 1H, H2), 6.36
(d, J = 9.2 Hz, 2H, ArH), 6.51 (d, J = 8.4 Hz, 2H, ArH), 6.87 (d,
J = 10.0 Hz, 1H, ArH), 6.94 (d, J = 7.6 Hz, 1H, ArH), 7.06–7.10
(m, 3H, ArH), 7.20 (t, J = 8.8 Hz, 3H, ArH), 7.31–7.42 (m, 4H,
ArH), 10.19 (s, 1H, NH); HRMS (ESI) m/z: Calcd for [M + H]+
found (expected): 667.0472 (667.0407).
Ethyl 4-(4-iodophenylamino)-2,6-bis(3-fluorophenyl)-
1,2,5,6-tetrahydro-1-(4-iodophenyl)pyridine-3-carboxylate
(4ak):.
Acknowledgments. We are grateful to the foundation of the
“Priority Academic Program Development of Jiangsu Higher
Education Institutions”, “Qing Lan Project in Jiangsu Province”
(No.08QL001T), “Key Basic Research Project in Jiangsu
University” (No. 10KJA430050, 11KJB150017), the “Postgraduate
Innovation Project in Jiangsu Province” (No. CXZZ11_0904), and
“The Project of Outstanding Scientific and Technological
Innovation Team for Higher Education Institutions in Jiangsu
Province (Predevelopment of medicinal microbial resources)” for
financial support.
Yellow solid. IR (KBr, n, cmꢁ1): 3246, 3012, 2986,
1649, 1606, 1573; 1H NMR (400 MHz, DMSO-d6) d: 1.37
(t, J = 7.2 Hz, 3H, CH3), 2.79 (dd, J = 16.0 and 1.6Hz, 1H, H5a),
3.02 (dd, J = 15.6 and 6.0 Hz, 1H, H5b), 4.25–4.45 (m, 2H,
OCH2), 5.43 (br s, 1H, H6), 6.23–6.27 (m, 3H, ArH and H2),
6.37 (d, J = 8.8 Hz, 2H, ArH), 6.85–6.88 (m, 1H, ArH), 6.93
(d, J = 8.0Hz, 1H, ArH), 7.05–7.10 (m, 3H, ArH), 7.18
(d, J = 7.6 Hz, 1H, ArH), 7.31–7.40 (m, 4H, ArH), 7.53 (d,
J = 8.4Hz, 2H, ArH), 10.18 (s, 1H, NH); HRMS (ESI) m/z:
Calcd for [M + H]+ found (expected): 763.0142 (763.0130).
Ethyl 4-(4-fluorophenylamino)-2,6-bis(3-bromophenyl)-1-
(4-fluorophenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate
REFERENCES AND NOTES
[1] (a) Burke, M. D.; Schreiber, S. L. Angew Chem Int Ed 2004,
43, 46; (b) Spring, D. R. Org Biomol Chem 2003, 1, 3867; (c) Strausberg,
R. L.; Schreiber, S. L. Science 2003, 300, 294.
(4al):.
White solid. IR (KBr, n, cmꢁ1): 3245, 3020, 2986,
1659; 1H NMR (400 MHz, DMSO-d6) d: 1.38 (t, J = 7.2 Hz,
3H, CH3), 2.67 (dd, J = 16.0 and 2.0 Hz, 1H, H5a), 2.89
(dd, J = 16.0 and 5.6 Hz, 1H, H5b), 4.23–4.46 (m, 2H, OCH2),
5.38 (br s, 1H, H6), 6.20 (s, 1H, H2), 6.35–6.38 (m, 2H, ArH),
6.50–6.54 (m, 2H, ArH), 6.93 (t, J = 8.8 Hz, 2H, ArH), 7.04
(t, J = 8.8 Hz, 3H, ArH), 7.24–7.32 (m, 4H, ArH), 7.42–7.46
(m, 2H, ArH), 7.51(s, 1H, ArH), 10.11 (s, 1H, NH); HRMS (ESI)
m/z: Calcd for [M + H]+ found (expected): 667.0358 (667.0401).
Ethyl 4-(4-bromophenylamino)-1-(4-bromophenyl)-1,2,5,6-
tetrahydro-2,6-bis(4-methoxyphenyl)pyridine-3-carboxylate
(4am):. White solid. IR (KBr, n, cmꢁ1): 3244, 2986, 2834,
1646, 1606, 1573; 1H NMR (400 MHz, DMSO-d6) d: 1.35
(t, J = 7.2Hz, 3H, CH3), 2.67 (dd, J = 15.2 and 2.0 Hz, 1H, H5a),
2.89 (dd, J = 16.0 and 6.0 Hz, 1H, H5b), 3.60 (s, 3H, OCH3), 3.71
(s, 3H, OCH3), 4.23–4.43 (m, 2H, OCH2), 5.33 (br s, 1H, H6),
6.18 (s, 1H, H2), 6.35 (d, J = 8.8 Hz, 2H, ArH), 6.43
(d, J = 8.8 Hz, 2H, ArH), 6.63–6.71 (m, 2H, ArH), 6.75
(d, J = 8.8 Hz, 2H, ArH), 6.89 (t, J = 8.0 Hz, 1H, ArH),
6.96 (d, J = 7.6 Hz, 1H, ArH), 7.02–7.09 (m, 3H, ArH), 7.14–7.18
(m, 1H, ArH), 7.31–7.39 (m, 2H, ArH), 10.13 (s, 1H, NH);
HRMS (ESI) m/z: Calcd for [M + H]+ found (expected):
690.0678 (690.0729).
[2] Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem Rev 2003,
103, 893.
[3] (a) Marcaccini, S.; Torroba, T. Post-condensation modifica-
tions of the Passerini and Ugi reactions. Multicomponent Reactions Zhu,
J.; Bienayme, H., Eds; Wiley-VCH: Wienheim, Germany, 2005; p 33;
(b) Domling, A. Chem Rev 2006, 106, 17.
[4] (a) Orru, R. V. A.; De Greef, M. Synthesis 2003, 1471; (b)
Schreiber, S. L. Science 2000, 287, 1964; (c) Weber, L. Curr Med Chem
2002, 9, 2085; (d) Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P.
Chem Eur J 2000, 6, 3321; (e) Abboub, F.; Amari, M.; Kolli, B. J Soc
Alger Chim 2001, 11, 223.
[5] Bonfield, E. R.; Li, C. J. Adv Synth Catal 2008, 350, 370.
[6] Brauch, S.; Gabriel, L. Chem Commun 2010, 46, 3387.
[7] Elders, N.; Born, D.; Hendrickx, L. J. D.; Timmer, B. J. J.;
Krause, A.; Janssen, E.; Kanter, F. J. J.; Ruijter, E.; Orru, R. V. A. Angew
Chem Int Ed 2009, 48, 5856.
[8] (a) Matsubara, Y.; Yoneda, R.; Harusawa, S.; Kurihara, T.
Pharmaceutical Chemistry 1988, 36(4), 1597. (b) Gogfraid, T.; Miller,
R.; Wibo, M. Pharmacol Rev 1986, 38, 321.
[9] Li, Q. Med Res Rev 2000, 20, 231.
[10] Cox, R. J.; O’Hagan, D. J Chem Soc, Perkin Trans 1: Organic
and Bio-Organic Chemistry 1991, 10, 2537.
[11] Nagarajan, M.; Xiao, X. S.; Antony, S.; Kohlhagen, G.;
Pommier, Y. J Med Chem 2003, 46, 5712.
[12] Ziessel, R.; Lehn, J. M. Helv Chim Acta 1990, 73, 1149.
[13] Kozikowski, A. P.; Campiani, G.; Sun, L.; Wang, S.; Saxena,
A.; Doctor, B. P. J Am Chem Soc 1996, 118, 11357.
[14] (a) Jørgensen, K. A. Angew Chem Int Ed 2000, 39, 3558; (b)
Ali, T.; Chauhan, K. K.; Frost, C. G. Tetrahedron Lett 1999, 40, 5621; (c)
Yuan, Y.; Li, X.; Ding, K. Org Lett 2002, 4, 3309; (d) Loncaric, C.;
Manabe, K.; Kobayashi, S. Chem Commun 2003, 574; (e) Loncaric, C.;
Ethyl 4-(4-methoxyphenylamino)-1,2,5,6-tetrahydro-1,2,6-
tris(4-methoxy phenyl) pyridine-3-carboxylate (4an):. White
solid. IR (KBr, n, cmꢁ1): 3246, 2920, 2834, 1655, 1517;
1H NMR (400MHz, DMSO-d6) d: 1.40 (t, J = 7.2Hz, 3H, CH3),
2.79 (dd, J = 15.6 and 5.6 Hz, 1H, H5a), 2.95 (dd, J = 15.6 and
2.0 Hz, 1H, H5b), 3.68 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 3.79
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2014
Silica Sulfuric Acid-Catalyzed Five-component Efficient Synthesis of
449
Five-Substituted Tetrahydropyridines
[19] (a) Ruggeri, R. B.; Hansen, M. M.; Heathcock, C. H. J Am
Chem Soc 1988, 110, 8734; (b) Laschat, S.; Grehl, M. Angew Chem Int
Ed Engl 1994, 33, 458; (c) Tanner, D.; Hagberg, L. Tetrahedron 1998,
54, 7907.
[20] Xiao, D. J.; Wang, L. J.; Feng, X. M. Synlett 2005, 10, 1531.
[21] (a) Paul, A. C.; Andrey, V. Z.; Adrian, C. W. Tetrahedron Lett
2007, 48, 5209; (b) Mridul, M.; Swaroop, K. P.; Vivek, P. P.; Jyoti, P.;
Renu, T.; Rama, P. T. Bioorg Med Chem 2009, 17, 625.
[22] Hong, J. W.; Li, P. M.; Zhan, H. Z. ACS Comb Sci 2011,
13(2), 181.
Manabe, K.; Kobayashi, S. Adv Synth Catal 2003, 345, 475; (f)
Josephsohn, N. S.; Snapper, M. L.; Hoveyda, A. H. J Am Chem
ꢀ
Soc 2003, 125, 4018; (g) Mancheno, O. G.; Arrayás, R. G.; Carretero, J.
C. J Am Chem Soc 2004, 126, 456; (h) Di Bari, L.; Guillarme, S.;
Hermitage, S.; Howard, J. A. K.; Jay, D. A.; Pescitelli, G.; Whiting, A.;
Yufit, D. S. Synlett 2004, 4, 708; (i) Guillarme, S.; Whiting, A. Synlett
2004, 4, 711.
[15] (a) Knapp, S.; Hale, J. J. J Org Chem 1993, 58, 2650; (b)
Herdeis, C.; Kaschinski, C.; Karla, R.; Lotter, H. Tetrahedron: Asymme-
try 1996, 7, 867; (c) Bousquet, Y.; Anderson, P. C.; Bogri, T.; Duceppe,
J. S.; Grenier, L.; Guse, I. Tetrahedron 1997, 53, 15671; (d) Bonjoch, J.;
Sole, D.; Garcia, R. S.; Bosch, J. J Am Chem Soc 1997, 119, 7230; (e)
Billon, S. F.; Martens, T.; Royer, J. Tetrahedron Lett 1999, 40, 3731; (f)
Johnson, T. A.; Curtis, M. D.; Beak, P. J Am Chem Soc 2001, 123, 1004.
[23] Abu, T. K.; Tasneem, P.; Lokman, H. C. J Org Chem 2008,
73, 8398.
[24] Janis, R. A.; Silver, P. J.; Triggle, D. J. Adv Drug Res 1987,
16, 309.
[16] (a) Ma, D.; Sun, H. Tetrahedron Lett 1999, 40, 3609; (b)
Knight, D. W.; Lewis, N.; Share, A. C.; Haigh, D. J. Chem. Soc. Perkin
Trans 1: Organic and Bio-Organic Chemistry 1998, 22, 3673.
[17] (a) Lindemann, U.; Wulff, M. D.; Wessig, P. Tetrahedron:
Asymmetry 1998, 9, 4459; (b) Ferroud, C.; Cocquet, G.; Guy, A. Tetrahe-
dron Lett 1999, 40, 5005; (c) Pandey, G.; Das, P. Tetrahedron Lett 1997,
38, 9073.
[25] Bossert, F.; Mayers, H.; Wehinger, E. Angew Chem Int Ed
Engl 1981, 93, 756.
[26] (a) Wu, H.; Shen, Y.; Wan, Y.; Fan, L. Y.; Zhang, P.; Zhang,
F. R.; Wang, W. X. Tetrahedron 2007, 63, 2404; (b) Wu, H.; Shen,Y.;
Fan, L. Y.; Wan, Y.; Shi, D. Q. Tetrahedron 2006, 62, 7995; (c) Wu,
H.; Chen, X. M.; Wan, Y.; Xin, H. Q.; Xu, H. H.; Ma, R.; Yue, C. H.;
Pang, L. L. Lett Org Chem 2009, 6, 219.
[27] Zolfigol, M. A. Tetrahedron 2001, 57, 9509.
[18] Deiters, A.; Martin, S. F. Chem Rev 2004, 104, 2199.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet