Cerium ammonium nitrate-catalyzed multicomponent reaction for efficient synthesis of functionalized tetrahydropyridines

Article abstract of DOI:10.1021/co100055x

A highly atom-economic one-pot synthesis of functionalized tetrahydropyridines by a multicomponent condensation reaction of β-keto ester, two equivalents of aromatic aldehyde, and two equivalents of amine in the presence of a catalytic amount of cerium ammonium nitrate (CAN) is reported. In this way, a series of pharmacologically interesting substituted piperidine derivatives were obtained in moderate to good yields at room temperature.

Full text of DOI:10.1021/co100055x

RESEARCH ARTICLE
pubs.acs.org/acscombsci
Cerium Ammonium Nitrate-Catalyzed Multicomponent Reaction for
Efficient Synthesis of Functionalized Tetrahydropyridines
Hong-Juan Wang, Li-Ping Mo, and Zhan-Hui Zhang*
The College of Chemistry & Material Science, Hebei Normal University, Shijiazhuang 050016, China
S Supporting Information
b
ABSTRACT: A highly atom-economic one-pot
synthesis of functionalized tetrahydropyridines
by a multicomponent condensation reaction
of β-keto ester, two equivalents of aromatic
aldehyde, and two equivalents of amine in the
presence of a catalytic amount of cerium ammo-
nium nitrate (CAN) is reported. In this way, a series of pharmacologically interesting substituted piperidine derivatives were obtained in
moderate to good yields at room temperature.
KEYWORDS: multicomponent reaction, one-pot, cerium ammonium nitrate, tetrahydropyridines, heterocycles
’ INTRODUCTION
allenyl iminium ion cyclizations,7 phosphine-promoted [3þ3]-
annulations of aziridines with allenoates,8 and radical cyclization
of N-allylamino-substituted Baylis-Hillman adducts.9
Multicomponent coupling reactions (MCRs) represent a
highly valuable synthetic tool for the construction of novel and
complex molecular structures with a minimum number of
synthetic steps. These types of reactions have some advantages
over conventional linear syntheses, including lower costs, shorter
reaction times, high degrees of atom economy, the possibility for
combinatorial surveying of structural variations, and environ-
mental friendliness. Among notable recent efforts to develop new
MCRs,1 Bonfield et al. recently reported an efficient method
for the preparation of the isoindoline framework via a six-
component, tandem double A3-coupling and [2þ2þ2]-cyclo-
addition reaction.2 Brauch et al. have extended MCRs to seven
components by taking advantage of the different chemoselectivities
of the Ugi-Mumm and the Ugi-Smiles reaction.3 Recently, the
Orru group developed a one-pot reaction of up to eight components
that involves nine new bond formations and eleven points of
diversity.4 In this content, MCRs that involve 1,3-dicarbonyl com-
pounds, aldehydes, and nucleophilic compounds have received much
attention in recent years because the formation of different con-
densation products can be expected depending on the specific
conditions and structures of the building blocks.
One-pot, multicomponent reactions offer potential advantages.10
Of the many approaches to the synthesis of tetrahydropyridines, the
atom and step economic (PASE)11 synthesis of functionalized
tetrahydropyridines from relatively simple starting materials is
especially attractive. Recently, one-pot syntheses of these hetero-
cyclic compounds by condensation reactions employing InCl3,12
L-proline/TFA,13 bromodimethylsulfonium bromide,14 and tetra-
butylammonium tribromide (TBATB)15 have been reported. How-
ever, in these limited cases high loadings (up to 33 mol %)12 of
expensive catalysts13 were necessary to achieve reasonably high
yields. The development of simple and environmentally benign
synthetic methods for efficient preparation of functionalized tetra-
hydropyridines is therefore a significant challenge.
In recent years, cerium ammonium nitrate (CAN) has been
employed as a multipurpose promotor of a wide range of
synthetically useful reactions.16 However, most examples require
stoichiometric quantities of CAN. We report herein a highly
atom-economic synthesis of functionalized tetrahydropyridines
by a one-pot, three (in situ five)-component reaction requiring
CAN in only 15 mol % (Scheme 1).
The tetrahydropyridine ring is an essential building block for
numerous natural products, synthetic pharmaceuticals, and a
wide variety of biologically active compounds.5 (See Supporting
Information for a list of activities and references.) As a conse-
quence, the development of general methods for the synthesis of
tetrahydropyridine derivatives has been the subject of consider-
able synthetic efforts and still requires attention. Most current
procedures either require advanced starting materials or involve
multistep and low-yielding reaction sequences. Among the
more successful are a proline-mediated cascade Mannich-type/
intramolecular cyclizations,6 a palladium-catalyzed alkynyl and
’ RESULTS AND DISCUSSION
Various potential catalysts were tested for the direct synthesis
of 4c by the model reaction of 4-methylbenzaldehyde (2 mmol),
aniline (2 mmol), and methyl acetoacetate (1 mmol) in acetoni-
trile at room temperature, with results listed in Table 1. CAN
Received: November 3, 2010
Revised:
November 18, 2010
Published: December 16, 2010
r
2010 American Chemical Society
181
dx.doi.org/10.1021/co100055x ACS Comb. Sci. 2011, 13, 181–185
|

ACS Combinatorial Science
RESEARCH ARTICLE
Scheme 1. CAN Catalyzed Synthesis of Tetrahydropyridines
Table 2. Investigation of the Amounts of Catalyst and Solvent
Effects on the Model Reaction of Table 1a
catalyst
entry
loading (mol %)
solvent
time (h)
yield (%)b
1
2
3
4
5
6
7
15
15
15
15
10
15
20
EtOAc
EtOH
THF
46
40
47
50
35
22
22
50
75
70
28
70
85
86
H2O
MeCN
MeCN
MeCN
Table 1. Effect of Different Catalysts on the Model Reaction
of 4-Methylbenzaldehyde, Aniline, and Methyl Acetoacetatea
a Experimental conditions: 4-methylbenzaldehyde (2 mmol), aniline
(2 mmol), methyl acetoacetate (1 mmol), and CAN in 5 mL of solvent at
room temperature. b Isolated yields.
and cyclohexanecarboxaldehyde did not provide the desired
products. Aromatic amines were found to be effective substrates
and afforded the corresponding tetrahydropyridine derivatives in
high yields. Aliphatic amines gave moderate yields (Table 3,
entries 44-47), presumably due to the higher basicity of
aliphatic amines compared to anilines. Lastly, other β-keto esters
such as ethyl acetoacetate, iso-butyl acetoacetate, tert-butyl
acetoacetate, allyl acetoacetate, and 2-methoxyethyl acetoacetate
were examined. The alkoxy (-OR3) moiety present had little
influence on the reaction, and generally good yields were
obtained. Benzoyl acetone (5) also proved to be an excellent
substrate, giving good yields of the corresponding products
(Scheme 2).
reaction
entry
catalyst
time (h)
yield (%)b
1
none
30
50
50
50
50
50
50
50
50
50
50
22
trace
60
58
65
41
40
35
45
72
68
42
85
2
HClO4/SiO2
3
p-toluenesulfonic acid
phosphotungstic acid
4
1
The products were characterized by IR, H NMR, and 13C
5
(NH4)3PMo12O40 6H2O
3
NMR spectra and by elemental analysis. The stereochemistry of
the products 4 with 2- and 6-substituents on the six-membered
ring of tetrahydropridine was determined as trans by single-
crystal X-ray analysis (see the Supporting Information, Figure 1).
A proposed reaction mechanism for this five-component
reaction is outlined in Scheme 3. CAN can serve as a Lewis
acidic catalyst for the reaction of aniline and methyl acetoacetate
or 4-chlorobenzaldehyde to give the β-enaminone17 or imine,16a
respectively. The intermolecular Mannich addition of the
β-enaminone (7) to the imine (8) affords the intermediate 9.
Subsequently, the reaction of activated aldehyde with the inter-
mediate 9 proceeds to afford the intermediate 10 by the
elimination of H2O. Intermediate 10 should tautomerize to
provide 11, stabilized by intramolecular hydrogen bonding.
Intramolecular Mannich addition gives intermediate 12, which
finally transformes to the expected piperidine tautomer 4c. CAN
may enhance the rates of several of these transformations. This
scheme is supported by two principal experimental observations:
(1) the reaction intermediates 7 and 8 could be isolated in the
course of reaction, and (2) the reaction of 7, 8, and 4-methyl-
benzaldehyde gave the same product as the reaction of methyl
acetoacetate, 4-methylbenzaldehyde, and aniline.
6
Mg(ClO4)2
7
LiClO4 3H2O
3
8
ZrOCl2 8H2O
3
9
ZrO(NO3)2
10
11
12
Co(NO3)2 6H2O
3
(NH4)4Ce(SO4)4 2H2O
3
CAN
a Experimental conditions: 4-methylbenzaldehyde (2 mmol), aniline
(2 mmol), methyl acetoacetate (1 mmol), and catalyst (0.15 mmol) in
5 mL of MeCN at room temperature. b Isolated yields.
proved to be superior, producing the best yield of 4c, only trace
amounts of which were formed in the absence of catalyst
(Table 1, entry 1).
A survey of solvents revealed acetonitrile to be the best choice,
used directly without rigorous drying. Low yields were obtained
when EtOAc or water was employed as the solvent. Some
dependence was also observed on the amount of CAN used. A
satisfactory result was obtained in the presence of 15 mol % CAN
(Table 2, entry 6), with no improvement upon increasing the
catalyst loading to 20 mol %.
The scope and limitations of this five-component reaction
under optimized conditions were explored using a variety of
aldehydes, amines, and β-keto esters, as summarized in Table 3.
In general, aromatic aldehydes bearing electron-donating or
electron-withdrawing functional groups at different positions
reacted with methyl acetoacetate smoothly in the presence of
aniline to generate the corresponding products in good to
excellent yields. In contrast, aliphatic aldehydes such as n-hexanal
In conclusion, we have developed an efficient synthesis
of functionalized tetrahydropyridines suitable for combina-
torial synthesis through a one-pot, five-component reaction
using a catalytic amount of CAN at room temperature.
The attractive features of this procedure are the mild reac-
tion conditions, high atom efficiency, clean reaction profiles,
inexpensive starting materials, and an environmentally friendly
catalyst.
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ACS Combinatorial Science
RESEARCH ARTICLE
Table 3. CAN-Catalyzed Synthesis of Functionalized Tetrahydropyridines
.
mp (°C)
entry
R1
R2
R3
products
time (h)
yield (%)a
found
reported
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
iBu
tBu
4a
20
23
22
30
16
30
20
24
15
16
20
19
18
45
20
18
17
17
17
17
16
22
23
23
24
23
23
23
24
20
35
23
23
24
20
28
28
21
21
22
22
20
25
40
40
40
40
82
84
85
80
83
73
81
75
86
84
75
80
78
80
82
81
75
82
80
75
83
80
62
81
56
85
80
78
60
82
68
78
81
66
75
67
69
65
68
75
81
83
82
52
51
53
55
194-195
131-134
215-216
248-251
182-183
156-158
161-162
220-221
225-226
245-246
232-234
181-182
240-241
140-142
224-225
193-194
226-227
204-205
162-163
214
19413
89.3-90.212
212-21414
2
3-CH3C6H4
4-CH3C6H4
2-OCH3C6H4
4-OCH3C6H5
3,4,5-(OMe)3C6H2
4-FC6H4
4b
3
4c
4
4d
5
4e
18013
153-15614
16013
6
4f
7
4g
8
3-ClC6H4
4-ClC6H4
4-BrC6H4
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
3-CF3C6H4
Ph
4h
22013
9
4i
225-22718
245-24713
217-21914
18013
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
42
43
44
45
46
47
4j
4k
4l
4m
4n
239-24114
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
Ph
4o
223.5-224.112
193.5-194.512
225-22614
20513
3-CH3C6H4
4-CH3C6H4
4-FC6H4
4p
4q
4r
3-ClC6H4
4-ClC6H4
4-BrC6H4
3-CF3C6H4
3-CH3C6H4
3-CH3C6H4
3-CH3C6H4
3-CH3C6H4
Ph
4s
16013
4t
4u
179-180
157-158
140-142
154-155
157-159
140-142
175-176
162-163
150-151
172-173
201-202
230-231
170-171
175-176
247-250
253-254
159-160
194-195
177-178
175-176
221-224
168-169
189-190
172-173
155-156
151-153
144-146
17913
156.2-157.212
4v
4w
4x
Ph
Ph
CH2CHdCH2
4y
Ph
CH2CH2OMe
4z
Ph
Et
tBu
4aa
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
4aj
4ak
4al
4am
4an
4ao
4ap
4aq
4ar
4as
4at
4au
174-17514
162-16314
149-15014
17313
Ph
Ph
Ph
Ph
CH2CHdCH2
Ph
4-OCH3C6H4
4-ClC6H4
Ph
Et
Ph
Et
20213
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-NO2C6H4
4-CH3C6H4
4-BrC6H4
4-OCH3C6H4
4-OCH3C6H4
4-FC6H4
Et
tBu
227-23014
171-17318
172-17414
Ph
Ph
CH2CHdCH2
Ph
Et
4-BrC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-ClC6H4
4-OCH3C6H4
4-OCH3C6H4
4-ClC6H4
PhCH2
Me
Me
Me
Me
Me
Et
253-25414
160-16313
19513
17813
17613
4-CH3C6H4
3-ClC6H4
3-ClC6H4
4-CH3C6H4
4-CH3C6H4
3-CH3C6H4
3-CH3C6H4
Et
167-17013
19013
172-17314
153-15414
Et
Me
Me
Me
Me
CH3(CH2)3
CH3(CH2)2
CH3(CH2)3
a Isolated yields.
’ EXPERIMENTAL PROCEDURES
aldehyde (2.0 mmol), amine (2 mmol), and CAN (0.15 mmol) in
5 mL of acetonitrile was stirred at room temperature for an appropriate
time (Table 3). After completion of the reaction, as indicated by TLC,
General Procedure for the Preparation of Functionalized
Tetrahydropyridines (4). A mixture of β-keto ester (1.0 mmol),
183
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RESEARCH ARTICLE
Scheme 2. Reaction of Aldehyde, Aniline, and Benzoyl Acetone Catalyzed by CAN
Scheme 3. Proposed Mechanistic Steps for the Multicomponent Synthesis of Tetrahydropyridines
the mixture was diluted with ethyl acetate (20 mL), washed with water
and then brine, and dried with anhydrous Na2SO4. The filtrate was
concentrated and purified by silica gel column chromatography.
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374.
’ ASSOCIATED CONTENT
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S
Supporting Information. Experimental procedure, spec-
b
troscopic characterization for compound 4, and the X-ray crystal-
lographic information for compound 4i. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
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Corresponding Author
*Phone: 86 311 86263124. Fax: 86 311 89632795. E-mail:
zhanhui@mail.nankai.edu.cn.
Funding Sources
We thank the National Natural Science Foundation of China
(20872025 and 21072042), the Nature Science Foundation of
Hebei Province (B2008000149), and Science Foundation of
Hebei Normal University for financial support.
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’ NOTE ADDED AFTER ASAP PUBLICATION
Structure 7 of Scheme 3 was modified in the version of this paper
published December 16, 2010. The correct version published
January 7, 2011.
185
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