Multicomponent reaction for the synthesis of highly functionalized piperidine scaffolds catalyzed by TMSI

Article abstract of DOI:10.1007/s11164-020-04208-6

An efficient method for the synthesis of highly functionalized piperidines via one-pot domino reaction of β-ketoesters, aromatic aldehydes, and aromatic amines was reported. This multicomponent coupling was catalyzed by TMSI in methanol at room temperature, giving desired substituted pyridines in moderate to good yields.

Full text of DOI:10.1007/s11164-020-04208-6

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-020-04208-6
Multicomponent reaction for the synthesis of highly
functionalized piperidine scafolds catalyzed by TMSI
Lisha Wu1 · Shiqiang Yan2,3 · Wensheng Wang2 · Yinta Li1
Received: 23 January 2020 / Accepted: 29 June 2020
© Springer Nature B.V. 2020
Abstract
An efcient method for the synthesis of highly functionalized piperidines via one-
pot domino reaction of β-ketoesters, aromatic aldehydes, and aromatic amines was
reported. This multicomponent coupling was catalyzed by TMSI in methanol at
room temperature, giving desired substituted pyridines in moderate to good yields.
Keywords TMSI · Highly functionalized piperidines · Multicomponent reactions ·
Heterocycles
Introduction
The piperidine ring system is one of the most regular motifs found in many natu-
rally occurring alkaloids [1–5], synthetic pharmaceuticals, and biologically active
compounds [6]. For example, 1,4-disubstituted piperidine scafolds have been used
as established drugs [7–9] because of their wide range of biological activities such
as anti-bacterial [10], antimalarial [11], anti-infammatory [12], anticonvulsant [13],
and antihypertensive activities [14]. Furthermore, substituted piperidines have been
identifed as an important class of therapeutic agents in the treatment of cancer
metastasis [15, 16], schizophrenia [17, 18], Parkinson’s disease [19, 20], infuenza
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s1116
4-020-04208-6) contains supplementary material, which is available to authorized users.
* Shiqiang Yan
ysqiang@fudan.edu.cn
* Yinta Li
liyinta123@163.com
1
Weihai Ocean Vocational College, Weihai 264300, China
2
Shandong Dyne Marine Biopharmaceutical Co., Ltd., Weihai 264300, China
3
Colledge of Chemistry and Molecular Engineering, Qingdao University of Science
and Technology, Qingdao 266042, China
Vol.:(0123456789)
1 3

L. Wu et al.
infection [21–23], viral infections including AIDS [24, 25], obesity, and diabetes
[26, 27].
In the perspective of green chemistry, the main challenge for organic chemists is
to develop synthetic routes to selectively prepare molecular scafolds with structural
diversity under eco-benign conditions. On this account, multicomponent reactions
(MCRs) have already emerged as a useful tool for the construction of complex and
novel molecular structures due to their advantages over conventional multistep syn-
thesis [28–33]. These reactions constitute an especially remarkable synthetic proto-
col since they provide rapid and easy access to large libraries of organic compounds
with diverse substitution patterns. Furthermore, MCRs are more environmentally
benign and atom economic as they avoid time-consuming and protection–deprotec-
tion steps, as well as costly purifcation processes [34]. In recent years, the synthesis
of highly functionalized piperidines has been reported via fve-component reaction
involving one molecule of β-ketoester, two molecules of aldehyde, and two mol-
ecules of substituted aniline in the presence of various catalysts. Ionic liquids are
good catalyst to synthesis of these compounds, and many diferent kinds of ionic
liquid-mediated reactions for synthesizing highly functionalized piperidines have
already been described [35–39]. Organic acids including picric acid [40], tartaric
acid [41], citric acid [42], PSSA [43], oxalic acid dehydrate [44], and ( )-CSA
[45]; Lewis acids such as Bi(NO3)3.5H2O [46], ZrOCl2.8H2O [47], SbI3 [48], InCl3
[6], Ce(OTf)4 [49], LaCl3.7H2O [50], TiCl2.2H2O [51], NiCl2.6H2O [52], and
Fe(NO3)3.9H2O [53] are efcient catalysts for the synthesis of highly functional-
ized piperidines according to literatures. In addition, nanopowder [54–62] and gra-
phene oxide [63] also can be used to promote the formation of highly functional-
ized piperidines. Although the reported catalysts have been used in the synthesis of
functionalized piperidines widely, they still sufer from disadvantages such as the
need of commercially unavailable reactants or catalysts, overuse of reagent, toxic
solvents, relatively harsh conditions, and tedious work-up procedures. Hence, the
development of a facile, high-yielding, and environmental benign protocol for the
one-pot multicomponent synthesis of densely functionalized piperidine scafolds is
still necessary.
As the catalytic efect of TMSI in organic synthesis is well established [64],
we applied TMSI to promote the formation of highly functionalized piperidines
in this work. In continuation of our interests in organic synthesis [65–70], herein,
we describe the construction of densely functionalized piperidines via one-pot
multicomponent reactions of β-ketoester, aldehyde and aniline catalyzed by TMSI
(Scheme 1). The desired compounds were crystallized directly from methanol and
isolated through simple fltration followed with methanol washing.
Results and discussion
Readily available commercial reagents aniline, methyl acetoacetate, and 2-fuoroben-
zaldehyde were used for model reaction. Methylacetoacetate 3a (MAA, 1 mmol) and
aniline 2a (2 mmol) were stirred at room temperature for 30 min to form the enam-
ine intermediate followed by the addition of 2-fuorobenzaldehyde 1d (2 mmol).
1 3

Multicomponent reaction for the synthesis of highly…
Scheme 1 Synthesis of highly functionalized piperidines catalyzed by TMSI
Then, the reaction mixture was further stirred till the complete formation of product
4d.
Firstly, we focused on the screening of catalysts. No desired product was obtained
in the blank experiment in methanol (Table 1, entry 1). When 0.2 equiv. of tri-
methylsiylchloride (TMSCl) was added, piperidine 4d was isolated in the yield of
85% (Table 1, entry 2). Next, other catalysts such as tert-butyldimethylsiyl chloride
(TBSCl), acetyl chloride, chloroacetyl chloride, benzoyl chloride, and acetyl bro-
mide were tested, and they all gave good results (Table 1, entries 3–7). A better
result was obtained when using 0.2 equiv. of TMSI, which produced compound 4d
in the yield of 91%. We found that the yield was not afected by gradually reducing
the amount of catalyst (from 0.2 to 0.1 and then to 0.05 equiv.) (Table 1, entries
8–10). But too less loading of TMSI (0.02 equiv.) caused a sharp drop of yield
(Table 1, entry 11). We also examined other solvents including ethanol, iso-pro-
panol, tert-butanol, ethylene glycol, glycerol, acetonitrile, and tetrahydrofuran under
same conditions (Table 1, entries 12–18). The experiment results showed that meth-
anol was the best choice for the reaction.
With the optimal reaction conditions in hand, we then examined the generality
and scope of this fve-component reaction using a variety of aromaticaldehydes, aro-
maticamines, and β-ketoesters, and the outputs are summarized in Table 2. The mix-
ture of 4-methoxybenzaldehyde and aniline reacted with MAA under the standard
conditions, giving highly functionalized piperidine 4a in the yield of 74% (Table 2,
entry 1). In general, aromatic aldehydes bearing electron-donating or electron-with-
drawing functional groups at diferent positions can react with methyl acetoacetate
smoothly in the presence of aniline and the yields of corresponding products in
good to excellent yields (Table 2, entries 2–4). Besides substituted benzaldehyde,
aromatic heterocyclic aldehyde was also suitable for this reaction and the yield of
corresponding product was satisfactory (Table 2, entry 5). In contrast, aliphatic
aldehydes such as n-hexanal and isobutyraldehyde did not give their corresponding
functionalized piperidines (not shown in the table).
4-Chloroaniline and p-anisidine were also tolerated, which gave corresponding tet-
rahydropyridine derivatives in moderate to good yields (Table 2, entries 6–12). Finally,
other β-ketoester such as ethyl acetoacetate was tested. The alkoxy moiety presents
small or no infuence on the reaction, and the yields obtained were generally good
(Table 2, entries 13–18). All the known synthesized compounds and their relative
1 3

L. Wu et al.
Table 1 Screening of optimal reaction conditions
Entry
Catalyst (equiv.)
Solvent
Temperature Time (h)
(°C)
Isolated yield (%)
1
2
3
4
5
6
7
8
–
methanol
methanol
methanol
methanol
methanol
methanol
methanol
methanol
methanol
methanol
methanol
thanol
iso-propanol
tert-butanol
Ethylene glycol
glycerol
acetonitrile
tetrahydrofuran
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
–
TMSCl (0.20)
TBSCl (0.20)
AcCl (0.20)
ClAcCl (0.20)
BzCl (0.20)
AcBr (0.20)
TMSI (0.20)
TMSI (0.10)
TMSI (0.05)
TMSI (0.02)
TMSI (0.05)
TMSI (0.05)
TMSI (0.05)
TMSI (0.05)
TMSI (0.05)
TMSI (0.05)
TMSI (0.05)
85
86
78
81
88
89
91
93
94
76
91
89
43
24
trace
62
49
9
10
11
12
13
14
15
16
17
18
stereochemistry were confrmed by carefully comparing their spectral data and physical
properties with the reported literature.
The same excellent results were also obtained when this method was performed at
a gram scale using 4-fuorobenzaldehyde, aniline and EAA as substrates (Scheme 2).
This example clearly demonstrates the preparative utility of this newly developed
method.
1 3

Multicomponent reaction for the synthesis of highly…
Table 2 Synthesis of 4 under optimum conditionsa
Entry
R1
R2
R3
Product
Yield (%)b
1
2
3
4
5
6
7
8
4-MeOC6H4
C6H5
C6H5
C6H5
C6H5
C6H5
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
74
87
84
94
80
80
87
94
82
72
81
48
75
89
73
95
85
76
4-MeC6H4
2-FC6H4
2-Thenyl
4-MeOC6H4
C6H5
4-FC6H4
2-Thenyl
C6H5
2-FC6H4
2-Thenyl
4-MeOC6H4
4-MeC6H4
C6H5
4-FC6H4
4-ClC6H4
4-FC6H4
C6H5
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
C6H5
C6H5
C6H5
C6H5
C6H5
9
10
11
12
13
14
15
16
17
18
Et
Et
Et
Et
4-MeOC6H4
Et
areaction conditions: 1 (4 mmol), 2 (4 mmol), 3 (2 mmol), methanol (10 mL), TMSI (0.1 mmol) at room
temperature. bisolated yield.
Scheme 2 Synthesis of 4t on gram scale
1 3

L. Wu et al.
Experimental
General information
All reagents were purchased from Adamas (China) and were used without further
purifcation. Reactions were magnetically stirred and monitored by thin-layer chro-
matography (TLC) with silica gel plates (60F-254) using UV light. Yields refer to
pure compounds. Melting points were measured on an electrothermal 9100 appa-
ratus. Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker
400 MHz or 600 MHz spectrometer as indicated in the data list. Chemical shifts for
proton nuclear magnetic resonance (1H NMR) spectra are reported in parts per mil-
lion relative to the signal residual (CDCl3 at7.26 ppm) or TMS. Chemical shifts for
carbon nuclear magnetic resonance (13C NMR) spectra are reported in parts per mil-
lion relative to the center line of the CDCl3 triplet at 77.06 ppm. The abbreviations
s, d, dd, t, q, br, and m stand for the resonance multiplicity singlet, doublet, doublet
of doublets, triplet, quartet, broad, and multiplet, respectively.
General procedure for the synthesis ofpiperidines (4a‑4r)
A mixture of β-ketoester (2 mmol) and aromatic aniline (4 mmol) in methanol
(10 ml) in the presence of TMSI (0.1 mmol) was stirred for 30 min at room tempera-
ture, followed by the addition of aromatic aldehyde (4 mmol). The resulting mixture
was continuously stirred until the completion of reaction. Then, the reaction mixture
was concentrated and the precipitate was fltered of. Finally, the solids were washed
with methanol (5 mL) to give pure products.
Methyl
2,6-bis(4-methoxyphenyl)-1-phenyl-4-(phenylamino)-1,2,5,6-tetrahydropyr-
1
idine-3-carboxylate (4a) white solid. Mp: 188–189 °C; H NMR (400 MHz, CDCl3) δ
10.27 (s, 1H, NH), 7.21 (d, J=8.5 Hz, 2H), 7.14 – 7.02 (m, 7H), 6.81 (d, J=8.5 Hz, 4H),
6.60 (t, J=7.2 Hz, 1H), 6.52 (d, J=8.2 Hz, 2H), 6.35 (m, 3H), 5.08 (d, J=3.3 Hz, 1H),
3.92 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 2.85 (dd, J=15.0, 5.5 Hz, 1H), 2.75 (dd, J=15.0,
2.4 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 167.97, 158.08, 157.45, 155.73, 146.39,
137.32, 135.25, 134.02, 128.24, 127.07, 126.82, 125.15, 125.04, 115.44, 113.37, 112.95,
112.35, 97.51, 56.87, 54.67, 54.60, 53.95, 50.35, 33.11.
Methyl 1,2,6-triphenyl-4-(phenylamino)-1,2,5,6-tetrahydropyridine-3-carboxy-
late (4b) white solid. Mp: 170–172 °C; 1H NMR (400 MHz, CDCl3) δ 10.25 (s, 1H),
7.34–7.24 (m, 8H), 7.20–7.15 (m, 2H), 7.11–7.04 (m, 5H), 6.60 (t, J=7.2 Hz, 1H),
6.52 (d, J=8.2 Hz, 2H), 6.45 (s, 1H), 6.31–6.23 (m, 2H), 5.15 (d, J=4.2 Hz, 1H),
3.93 (s, 3H), 2.87 (dd, J=15.1, 5.7 Hz, 1H), 2.76 (dd, J=15.1, 2.3 Hz, 1H); 13C
NMR (150 MHz, CDCl3) δ 167.94, 155.64, 146.32, 143.30, 142.10, 137.20, 128.25,
128.21, 128.00, 127.61, 126.51, 126.01, 125.76, 125.68, 125.24, 125.14, 115.54,
112.30, 97.32, 57.57, 54.49, 50.38, 32.99.
Methyl 2,6-bis(4-methphenyl)-1-phenyl-4-(phenylamino)-1,2,5,6-tetrahydropyridine-
3-carboxylate (4c) white solid. Mp: 210–212 °C; 1H NMR (400 MHz, CDCl3) δ 10.25
(s, 1H), 7.19 (d, J=7.9 Hz, 2H), 7.12–7.02 (m, 11H), 6.59 (t, J=7.3 Hz, 1H), 6.52 (d,
1 3

Multicomponent reaction for the synthesis of highly…
J=8.3 Hz, 2H), 6.39 (s, 1H), 6.33–6.25 (m, 2H), 5.11 (d, J=3.9 Hz, 1H), 3.92 (s, 3H),
2.86 (dd, J=15.0, 5.6 Hz, 1H), 2.75 (dd, J=15.1, 2.2 Hz, 1H), 2.33 (s, 3H), 2.32 (s,
3H); 13C NMR (150 MHz, CDCl3) δ 167.97, 155.64, 146.44, 140.33, 139.06, 137.33,
135.97, 135.14, 128.63, 128.30, 128.21, 128.17, 126.12, 125.92, 125.69, 125.18,
124.99, 115.37, 112.28, 97.49, 57.29, 54.30, 50.34, 33.02, 20.46, 20.38.
Methyl 2,6-bis(2-fuorophenyl)-1-phenyl-4-(phenylamino)-1,2,5,6-tetrahydropyri-
dine-3-carboxylate (4d) white solid. Mp: 178–180 °C; 1H NMR (400 MHz, CDCl3)
δ 10.15 (s, 1H), 7.266.95 (m, 13H), 6.65 (t, J=7.3 Hz, 1H), 6.55 (s, 1H), 6.48 (d,
J=8.2 Hz, 2H), 6.38–6.36 (m, 2H), 5.45 (s, 2H), 3.89 (s, 3H), 2.932.87 (m, 2H); 13
C
NMR (150 MHz, CDCl3) δ 167.85, 160.86, 160.19, 159.22, 158.57, 154.93, 145.69,
137.27, 129.16, 129.07, 128.41, 128.32, 128.26, 128.21, 127.72, 127.67, 125.25,
125.15, 123.75, 122.76, 116.30, 115.86, 115.71, 114.60, 114.45, 112.34, 96.07,
51.65, 51.47, 50.42, 30.41.
Methyl 2,6-bis(2-thenyl)-1-phenyl-4-(phenylamino)-1,2,5,6-tetrahydropyridine-
1
3-carboxylate (4e) white solid. Mp: 220–222 °C; H NMR (400 MHz, CDCl3) δ
10.61 (s, 1H), 7.31 (t, J=7.8 Hz, 2H), 7.27–7.11 (m, 5H), 7.08–7.02 (m, 2H), 6.98
(t, J=8.8 Hz, 5H), 6.85–6.75 (m, 2H), 6.16 (s, 1H), 4.90 (dd, J=11.3, 4.4 Hz, 1H),
3.75 (s, 3H), 3.04–2.75 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 167.54, 156.66,
152.06, 149.30, 147.73, 137.68, 128.72, 128.42, 128.23, 128.10, 126.47, 125.85,
125.02, 124.51, 123.94, 123.47, 123.42, 123.38, 12,331, 118.64, 115.75, 112.75,
97.85, 58.90, 55.36, 50.42, 36.33.
Methyl
2,6-bis(4-methoxyphenyl)-1-(4-chlorophenyl)-4-((4-chlorophenyl)
amino)-1,2,5,6-tetrahydropyridine-3-carboxylate (4f) white solid. Mp:199–200 °C;
1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 7.16 (d, J=8.6 Hz, 2H), 7.06 (m,
4H), 6.99 (d, J=9.0 Hz, 2H), 6.86–6.78 (m, 4H), 6.42 (d, J=9.1 Hz, 2H), 6.28 (s,
1H), 6.25 (d, J=8.5 Hz, 2H), 5.04 (d, J=3.8 Hz, 1H), 3.93 (s, 3H), 3.80 (s, 3H),
3.78 (s, 3H), 2.83 (dd, J=15.1, 5.6 Hz, 1H), 2.68 (dd, J=15.0, 2.2 Hz, 1H); 13C
NMR (150 MHz, CDCl3) δ 167.86, 158.31, 157.63, 155.03, 144.91, 135.84, 134.44,
133.43, 130.72, 128.41, 128.04, 126.94, 126.75, 126.35, 120.52, 113.52, 113.45,
113.07, 98.02, 56.98, 54.70, 54.61, 54.13, 50.51, 32.97.
Methyl
2,6-bisphenyl-1-(4-chlorophenyl)-4-((4-chlorophenyl)amino)-1,2,5,6-
1
tetrahydropyridine-3-carboxylate (4g) white solid. Mp: 200–202 °C; H NMR
(400 MHz, CDCl3) δ 10.19 (s, 1H), 7.32–7.21 (m, 8H), 7.17–7.12 (m, 2H), 7.05 (d,
J=8.6 Hz, 2H), 6.99 (d, J=9.0 Hz, 2H), 6.43 (t, J=6.2 Hz, 2H), 6.38 (s, 1H), 6.16
(d, J=8.5 Hz, 2H), 5.11 (d, J=4.6 Hz, 1H), 3.94 (s, 3H), 2.85 (dd, J=15.1, 5.8 Hz,
1H), 2.69 (dd, J=15.1, 2.0 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 167.84, 154.96,
144.85, 142.54, 141.62, 135.74, 130.85, 128.62, 128.41, 128.10, 127.76, 126.85,
126.47, 125.97, 125.88, 125.67, 120.64, 113.40, 97.85, 57.68, 54.67, 50.56, 32.85.
Methyl 2,6-bis(4-fuorophenyl)-1-(4-chlorophenyl)-4-((4-chlorophenyl)amino)-
1,2,5,6-tetrahydropyridine-3-carboxylate (4h) white solid. Mp: 175–177 °C;
1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 7.21 (dd, J = 8.3, 5.4 Hz, 2H),
7.15–7.04 (m, 4H), 6.98 (m, 6H), 6.38 (d, J = 9.1 Hz, 2H), 6.32–6.26 (m, 3H),
5.07 (d, J = 3.7 Hz, 1H), 3.93 (s, 3H), 2.82 (dd, J = 15.2, 5.6 Hz, 1H), 2.68 (dd,
J = 15.1, 2.1 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 167.65, 162.28, 161.83,
160.65, 160.21, 154.77, 144.49, 138.02, 136.92, 135.58, 131.06, 128.55, 128.21,
1 3

L. Wu et al.
127.43, 127.24, 127.19, 126.27, 121.12, 115.13, 114.99, 114.68, 114.64, 114.45,
113.48, 97.66, 56.77, 54.18, 50.66, 33.03.
Methyl
2,6-bis(2-thenyl)-1-(4-chlorophenyl)-4-((4-chlorophenyl)amino)-
1
1,2,5,6-tetrahydropyridine-3-carboxylate (4i) white solid. Mp: 215–216 °C; H
NMR (400 MHz, CDCl3) δ 10.37 (s, 1H), 7.19–7.10 (m, 4H), 7.05 (t, J=6.5 Hz,
2H), 6.89 (m, 2H), 6.81 (s, 2H), 6.65 (d, J=9.1 Hz, 2H), 6.47 (d, J=8.5 Hz, 2H),
6.35 (s, 1H), 5.36 (s, 1H), 3.90 (s, 3H), 3.09 (dd, J=15.3, 5.3 Hz, 1H), 2.83 (dd,
J=15.3, 2.6 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 167.28, 154.90, 147.71,
146.02, 144.02, 135.86, 130.86, 128.61, 128.11, 126.25, 125.15, 125.95, 123.91,
123.79, 123.51, 123.15, 121.69, 113.88, 97.22, 53.11, 52.02, 50.51, 33.53.
Methyl 2,6-bisphenyl-1-(4-methoxyphenyl)-4-((4-methoxyphenyl)amino)-1,2,5,6-
1
tetrahydropyridine-3-carboxylate (4j) white solid. Mp: 223–225 °C; H NMR
(400 MHz, CDCl3) δ 10.10 (s, 1H), 7.40–7.08 (m, 10H), 6.63 (m, 4H), 6.43 (d,
J=9.0 Hz, 2H), 6.34 (s, 1H), 6.18 (d, J=8.6 Hz, 2H), 5.05 (d, J=3.2 Hz, 1H),
3.91 (s, 3H), 3.74 (s, 3H), 3.65 (s, 3H), 2.79 (dd, J=14.9, 5.4 Hz, 1H), 2.63 (d,
J=15.1 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 168.01, 157.20, 156.39, 150.29,
143.65, 142.62, 140.94, 130.04, 127.97, 127.51, 127.26, 126.44, 126.16, 125.89,
125.59, 113.89, 113.41, 113.33, 96.39, 57.62, 55.07, 55.02, 54.75, 50.25, 32.94.
Methyl 2,6-bis(2-fuorophenyl)-1-(4-methoxyphenyl)-4-((4-methoxyphenyl)amino)-
1
1,2,5,6-tetrahydropyridine-3-carboxylate (4k) white solid. Mp: 202–204 °C; H
NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 7.18 (m, 4H), 7.09–6.91 (m, 4H), 6.66
(m, 4H), 6.52–6.27 (m, 5H), 5.32 (t, J=4.3 Hz, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 3.66
(s, 3H), 2.87–2.69 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 167.97, 160.96, 160.27,
158.65, 157.25, 155.68, 151.32, 140.24, 130.20, 129.34, 129.25, 128.54, 128.43,
128.03, 127.54, 127.15, 123.68, 122.61, 115.57, 115.42, 114.95, 114.40, 113.80,
113.48, 94.87, 54.92, 54.77, 52.52, 50.89, 50.26, 30.85.
Methyl
2,6-bis(2-thenyl)-1-(4-methoxyphenyl)-4-((4-methoxyphenyl)amino)-
1,2,5,6-tetrahydropyridine-3-carboxylate (4l) white solid. Mp: 210–212 °C; 1H NMR
(400 MHz, CDCl3) δ 10.44 (s, 1H), 7.23 (d, J=5.0 Hz, 1H), 7.12 (d, J=3.3 Hz, 1H),
7.07 (d, J=5.0 Hz, 1H), 7.04–6.99 (m, 1H), 6.93 (t, J=6.4 Hz, 5H), 6.82 (m, 3H),
6.72 (d, J=9.0 Hz, 2H), 5.94 (s, 1H), 4.78 (t, J=7.8 Hz, 1H), 3.78 (s, 3H), 3.74 (s,
3H), 3.70 (s, 3H), 2.79 (d, J=7.9 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 167.71 (d,
J=18.6 Hz), 157.72, 157.25, 156.18, 153.25, 151.43, 149.02, 148.15, 146.94, 143.99,
139.98, 130.53, 130.21, 127.11, 126.39, 125.87, 125.77, 125.56, 123.80, 123.72,
123.55, 123.51, 123.24, 122.86, 122.77, 118.42, 115.23, 113.89, 113.67, 113.57,
113.45, 96.24, 95.54, 60.01 56.21, 54.90, 54.80, 53.08, 52.88, 50.23, 36.26, 33.39.
Ethyl 2,6-bis(4-methoxyphenyl)-1-phenyl-4-(phenylamino)-1,2,5,6-tetrahydropyr-
1
idine-3-carboxylate (4m) white solid. Mp: 166–168 °C; H NMR (400 MHz,
CDCl3) δ 10.31 (s, 1H), 7.23 (d, J=8.5 Hz, 2H), 7.15–7.04 (m, 7H), 6.81 (m, 4H),
6.60 (t, J=7.2 Hz, 1H), 6.53 (d, J=8.2 Hz, 2H), 6.38–6.35 (m, 2H), 6.34 (s, 1H),
5.08 (d, J=3.4 Hz, 1H), 4.44 (m, 1H), 4.32 (m, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 2.85
(dd, J=15.0, 5.5 Hz, 1H), 2.75 (dd, J=15.0, 2.4 Hz, 1H), 1.46 (t, J=7.1 Hz, 3H);
13C NMR (150 MHz, CDCl3) δ 167.64, 158.07, 157.42, 155.51, 146.43, 137.40,
135.38, 134.05, 128.21, 127.06, 126.83, 125.07, 124.92, 115.41, 113.36, 112.93,
112.37, 97.80, 58.99, 56.90, 54.67, 54.60, 53.93, 33.12, 14.18.
1 3

Multicomponent reaction for the synthesis of highly…
Ethyl
2,6-bis(4-methphenyl)-1-phenyl-4-(phenylamino)-1,2,5,6-tetrahy-
1
dropyridine-3-carboxylate (4n) white solid. Mp: 228–230 °C; H NMR (400 MHz,
CDCl3) δ 10.29 (s, 1H), 7.20 (m, 2H), 7.11–7.04 (m, 11H), 6.58 (dd, J=13.2, 5.9 Hz,
1H), 6.52 (d, J=8.3 Hz, 2H), 6.41 (s, 1H), 6.33–6.24 (m, 2H), 5.11 (d, J=4.2 Hz,
1H), 4.50–4.38 (m, 1H), 4.37–4.26 (m, 1H), 2.86 (dd, J=15.0, 5.6 Hz, 1H), 2.76
(dd, J=15.0, 2.3 Hz, 1H), 2.33 (s, 3H), 2.32 (s, 3H), 1.46 (t, J=7.1 Hz, 3H); 13C
NMR (150 MHz, CDCl3) δ 167.64, 155.43, 146.48, 140.45, 139.09, 137.40, 135.95,
135.10, 128.65, 128.62, 128.34, 128.28, 128.21, 128.14, 126.07, 125.92, 125.70,
125.10, 124.88, 115.52, 115.33, 112.29, 97.78, 58.98, 57.31, 54.27, 33.02, 20.46,
20.37, 14.16.
Ethyl 1,2,6-triphenyl-4-(phenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate
(4o) white solid. Mp: 172–173 °C; H NMR (400 MHz, CDCl3) δ 10.30 (s, 1H),
1
7.25 (m, 10H), 7.13–7.02 (m, 5H), 6.61 (t, J=7.2 Hz, 1H), 6.53 (d, J=8.3 Hz,
2H), 6.47 (s, 1H), 6.27 (dd, J=7.3, 1.9 Hz, 2H), 5.15 (d, J=3.8 Hz, 1H), 4.47 (dq,
J=10.8, 7.1 Hz, 1H), 4.33 (dq, J=10.8, 7.1 Hz, 1H), 2.88 (dd, J=15.1, 5.7 Hz,
1H), 2.77 (dd, J=15.1, 2.3 Hz, 1H), 1.47 (t, J=7.1 Hz, 3H); 13C NMR (150 MHz,
CDCl3) δ 167.63, 155.44, 146.37, 143.44, 142.15, 137.29, 128.27, 128.20, 128.00,
127.61, 126.51, 126.02, 125.78, 125.65, 125.17, 125.04, 115.52, 112.34, 97.62,
59.06, 57.61, 54.49, 33.00, 14.18.
Ethyl 2,6-bis(4-fuorophenyl)-1-phenyl-4-(phenylamino)-1,2,5,6-tetrahydropyri-
dine-3-carboxylate (4p) white solid. Mp: 204–208 °C; 1H NMR (500 MHz, CDCl3)
δ 10.31 (s, 1H), 7.27 (dd, J=8.4, 5.4 Hz, 2H), 7.17–7.05 (m, 7H), 6.95 (m, 4H),
6.63 (t, J=7.3 Hz, 1H), 6.48 (d, J=8.2 Hz, 2H), 6.39 (d, J=8.0 Hz, 3H), 5.11 (d,
J=3.1 Hz, 1H), 4.45 (m, 1H), 4.32 (m, 1H), 2.83 (dd, J=15.2, 5.6 Hz, 1H), 2.75
(dd, J=15.2, 2.6 Hz, 1H), 1.45 (t, J=7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 168.07, 162.98, 162.52, 161.03, 160.57, 155.88, 146.67, 139.53 (d, J=2.9 Hz),
138.14 (d, J=3.0 Hz), 137.81, 129.01, 128.98, 128.17, 128.11, 127.96, 127.90,
125.86, 125.65, 116.62, 115.55, 115.38, 115.10, 114.93, 113.07, 98.12, 59.81,
57.35, 54.68, 33.81, 14.80.
Ethyl 2,6-bis(4-chlorophenyl)-1-phenyl-4-(phenylamino)-1,2,5,6-tetrahydropyri-
dine-3-carboxylate (4q) white solid. Mp: 230–232 °C; 1H NMR (500 MHz, CDCl3)
δ 10.29 (s, 1H), 7.26–7.21 (m, 6H), 7.19–7.03 (m, 8H), 6.64 (t, J=7.3 Hz, 1H), 6.46
(d, J=8.2 Hz, 2H), 6.40 (d, J=7.3 Hz, 2H), 6.36 (s, 1H), 5.09 (d, J=3.2 Hz, 1H),
4.44 (dq, J=10.8, 7.1 Hz, 1H), 4.32 (dq, J=10.8, 7.1 Hz, 1H), 2.78 (ddd, J=17.8,
15.2, 4.1 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 168.00,
155.82, 146.57, 142.54, 141.01, 137.76, 132.92, 132.18, 129.09, 129.04, 128.80,
128.44, 128.08, 127.83, 125.97, 125.71, 116.81, 113.05, 97.90, 59.89, 57.42, 54.81,
33.74, 14.82.
Ethyl 2,6-bis(4-fuorophenyl)-1-(4-methoxyphenyl)-4-((4-methoxyphenyl)amino)-
1
1,2,5,6-tetrahydropyridine-3-carboxylate (4r) white solid. Mp: 224–228 °C; H
NMR (500 MHz, CDCl3) δ 10.16 (s, 1H), 7.25–7.22 (m, 1H), 7.12–7.06 (m, 2H),
6.99–6.90 (m, 4H), 6.67 (t, J=6.1 Hz, 4H), 6.42–6.38 (m, 2H), 6.35 (t, J=6.0 Hz,
2H), 6.23 (s, 1H), 5.02–4.93 (m, 1H), 4.40 (ddd, J=14.2, 9.0, 5.4 Hz, 1H),
4.33–4.23 (m, 1H), 3.75 (s, 3H), 3.67 (s, 3H), 2.73 (dd, J=15.3, 5.6 Hz, 1H), 2.62
(dd, J=15.3, 3.2 Hz, 1H), 1.41 (t, J=7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3)
δ 168.22, 162.52, 160.57, 157.97, 156.63, 151.49, 141.26, 139.83, 138.68, 130.72,
1 3

L. Wu et al.
128.42, 128.36, 128.20, 128.14, 127.75, 115.52, 115.35, 114.97, 114.88, 114.81,
114.60, 114.16, 97.03, 59.64, 57.30, 55.68, 55.47, 33.79, 14.81.
Conclusion
In summary, we have developed an efcient protocol to construct highly functional-
ized piperidines though employing catalytic amount of TMSI via one-pot multicom-
ponent reaction of β-ketoester, aromatic aldehydes, and aromatic amines in methanol
at room temperature. This novel method may have great potential in the synthesis
feld of highly functionalized piperidines because of the mild reaction conditions,
simple operation procedure, superior atom-economy, and eco-friendly catalyst.
Acknowledgements We gratefully acknowledge fnancial support from the National Natural Sci-
ence Foundation of China (Grant No. 51604207, 51674183), the Natural Science Foundation of Hubei
Province, China (Grant No. 2018CFB605), the Shandong Provincial Education Department, China
(Grant No. J18KB083), the Qingchuang Talent Incubation Program from Colleges and universities in
Shandong Province (Grant No. 2019) and the Funded by Ship Control Engineering and Intelligent Sys-
tems Engineering Technology Research Center of Shandong Province and Ship Motion Control and
Systems Engineering Technology Research center of Weihai, China (Grant No. SSCC-2018-0001 and
SSCC-2019-0005).
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