Ytterbium-catalyzed synthesis of dihydropyridines

Article abstract of DOI:10.1016/j.tetlet.2011.06.070

The reaction of anilines, benzaldehydes, and ethyl 3,3-diethoxypropionate in the presence of Yb(OTf)₃ proceeded under mild reaction conditions to give dihydropyridines (DHPs). We have found that the reaction depended on the solvent and the DHPs

Full text of DOI:10.1016/j.tetlet.2011.06.070

Tetrahedron Letters 52 (2011) 4473–4477
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Tetrahedron Letters
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Ytterbium-catalyzed synthesis of dihydropyridines
⇑
Shunsuke Sueki, Ryo Takei, Junya Abe, Isao Shimizu
Department of Applied Chemistry, School of Advanced Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 169-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of anilines, benzaldehydes, and ethyl 3,3-diethoxypropionate in the presence of Yb(OTf)3
proceeded under mild reaction conditions to give dihydropyridines (DHPs). We have found that the reac-
tion depended on the solvent and the DHPs were obtained selectively in 1,4-dioxane as a solvent. Various
2,6-unsubstituted DHPs were synthesized in one pot in satisfactory yields.
Received 29 April 2011
Revised 14 June 2011
Accepted 17 June 2011
Available online 23 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
2,6-Unsubstituted dihydropyridine
DHP
Ytterbium catalyst
Multi-component coupling reaction
Introduction
Fukuzawa and co-workers succeeded the synthesis of 2,6-unsub-
stituted DHPs from propargyl esters and imines using Sc catalyst.6b
Dihydropyridines (DHPs) are important nitrogen-containing
heterocycles, and have some interesting biological activities,1 such
as widely used calcium channel blockers.2 In 1998, Hilgeroth et al.
reported that several DHP dimers showed the inhibition of HIV-1
protease.1d–f DHPs are also useful as synthetic intermediates.3 So
far various DHP syntheses4 have been reported, and among them
Hantzsch method4a using 1,3-dicarbonyl compounds is one of the
most useful general synthetic methods for DHPs, which gives
2,6-disubstituted DHP known as the Hantzsch ester. Although nor-
mal Hantzsch esters do not show any fluorescence, 2,6-unsubsti-
tuted DHPs are known to show strong blue fluorescence.5
However, photo-electronic property of DHPs is not studied much
despite potential usefulness since synthesis of 2,6-unsubstituted
DHPs6 having various functional groups is not easy by Hantzsch
method. Eisner method6a using highly reactive propargyl esters in-
stead of 2-formylacetates is one of the few methods for 2,6-unsub-
stituted DHPs. Recently, the Eisner method has been improved by
the use of imines or enamines as sources of amines and aldehydes.
Li and co-workers also reported DHP synthesis using enaminone
and aldehyde.6c However, development of simple chemistry for
various 2,6-unsubstituted DHPs starting with amines, aldehydes,
and esters directly is expected in view of the practical science.
Previously, we reported the Yb- or Ir-catalyzed multi-substi-
tuted quinoline syntheses.7 In the course of our studies to develop
various heterocycles, we have found that the reaction with ani-
lines, ethyl glyoxylate and ethyl 3,3-diethoxypropionate proceeded
unexpectedly to yield DHPs (Scheme 1). Herein, we describe the
novel and versatile 2,6-unsubstituted DHP synthesis catalyzed by
Lewis acids using ethyl 3,3-diethoxypropionate, which is stable en-
ough to be handled easily and is a readily available useful starting
material for organic synthesis.8
Results and discussions
At first the reactions with p-anisidine (1a), ethyl glyoxylate (2a)
and ethyl 3,3-diethoxypropionate (3a) were carried out using
O
CO2Et
OEt
R3
R2
NH2
CO2Et
H
EtO
R3
R2
O
[IrCl2(H)(cod)]2
N
Yb(OTf)3
R1
CO2Et
+
R2
H
DMSO, 90 °C,
1,4-Dioxane, 90 °C
R1
N
R1
Dihydropyridine
O
2 (1 atm)
Quinoline
Scheme 1. Ir- or Yb-catalyzed one-pot synthesis of quinolines and dihydropyridines.
⇑
Corresponding author.
E-mail address: shimizui@waseda.jp (I. Shimizu).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.070

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S. Sueki et al. / Tetrahedron Letters 52 (2011) 4473–4477
Table 1
One-pot synthesis of DHPs under various reaction conditions
NH2
CO2Et
CO2Et
O
+
H
OEt
O
catalyst
+
1,4-Dioxane, Temp.
CO2Et
2a
EtO
OEt
N
PMP
CO2Et
OMe
1a
3a
4a
Entry
Catalyst (mol %)
Temp. (°C)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Blank
90
50
90
120
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
Trace
N.R.
73
Yb(OTf)3 (2.5)
42
[IrCl2(H)(cod)]2 (2.5)
[IrCl(cod)]2 (2.5)
Ir(acac)3 (2.5)
[RhCl(cod)]2 (2.5)
Ru(acac)3 (2.5)
Fe(acac)3 (2.5)
ZnCl2 (2.5)
28b
Trace
Trace
Trace
Trace
Trace
21
TiCl4 (2.5)
61
57
53
62
64
51
31
48
Sc(OTf)3 (2.5)
La(OTf)3 (2.5)
Sm(OTf)3 (2.5)
Eu(OTf)3 (2.5)
Pr(OTf)3 (2.5)
PTSA monohydrate (2.5)
DOWEXÒ (2.5)
4 M HCl in 1,4-dioxane (5.0)
TfOH (7.5)
67
50
a
Isolated yields based on p-anisidine (1a).
DMSO was used as a solvent.
b
various Brønsted and Lewis acids and the results are summarized
in Table 1. When the reaction was carried out without catalyst at
90 °C, the DHP 4a was scarcely obtained (entry 1). In the reaction
at 50 °C in the presence of Yb(OTf)3 as a catalyst, the reaction did
not proceed, but the reaction at 90 °C gave 4a in 73% yield (entries
2 and 3). However in the reaction at 120 °C, the yield of 4a was
decreased to 42% (entry 4). Transition metal salts and complexes
were less effective or inactive (entries 5–10). The reaction with
the Lewis acids, ZnCl2 and TiCl4, gave 4a in 21% and 61% yields (en-
tries 11 and 12). Sc(OTf)3 was not so effective in this reaction
system as the synthesis from imines and propargyl ester as Fuku-
zawa et al. reported (entry 13). Other lanthanoid triflates, La(OTf)3,
Sm(OTf)3, Eu(OTf)3 and Pr(OTf)3, gave similar activities as Sc(OTf)3
in this reaction (entries 14–17). When Brønsted acids, such as PTSA
monohydrate and DOWEXÒ, were used, 4a was obtained in low
yields (entries 18 and 19). However, when a catalytic amount of
4 M HCl in 1,4-dioxane or TfOH was used, the reaction proceeded
to give 4a in moderate yields, 67% and 57%, respectively (entries
20 and 21). As above Yb(OTf)3 was the best catalyst for the synthe-
sis of the DHP 4a and used for further studies of DHP synthesis.
Various solvents in this reaction under oxygen were studied,
and the results are shown in Table 2. The selectivity of the DHP
4a and the quinaldate 5 depends upon the solvents. The reaction
of p-anisidine (1a), ethyl glyoxylate (2a) and ethyl 3,3-diethoxy-
Table 2
One-pot synthesis of DHPs under various solvents
NH2
CO2Et
MeO
CO2Et
CO2Et
O
OEt
O
Yb(OTf)3 (2.5 mol%)
Solvent, 90 °C
CO2Et
+
+
+
H
CO2Et
2a
EtO
OEt
N
N
O2 (1 atm)
PMP
CO2Et
OMe
1a
3a
4a
5
Entry
Solvent
Yielda (%)
4a
5
1
2
3
4
5
6
7
8
9
DMSO
CH3CN
DMF
1,4-Dioxane
Toluene
THF
Benzene
CH2Cl2
Ethanol
NMP
51
58
72
74
58
20
18
3
20
Trace
14
Trace
21
16
16
11
0
0
10
Trace
Trace
a
Isolated yields based on p-anisidine (1a).

S. Sueki et al. / Tetrahedron Letters 52 (2011) 4473–4477
4475
Table 3
Yb-catalyzed one-pot synthesis of various DHPs
CO2Et
R2
NH2
OEt
O
O
Yb(OTf)3 (2.5 mol%)
1,4-Dioxane, 90 °C
+
+
N
R2
H
CO2Et
EtO
OEt
R1
R1
1
2
3a
4
Product (yielda)
CO2Et
CO2Et
EtO2C
N
EtO2C
N
EtO2C
N
NO2
CO2Et
Cl
N
PMP
CO2Et
PMP
CO2Et
PMP
PMP
CO2Et
4a (73 %)
4b (31 %)
4c (o-, 32 %)
4d (m-, 71 %)
4e (p- , 73 %)
4f (o-, 55 %)
4g (m-, 60 %)
4h (p- , 50 %)
Br
CN
CO2H
EtO2C
EtO2C
N
EtO2C
EtO2C
N
N
N
N
PMP
CO2Et
PMP
CO2Et
CO2Et
PMP
CO2Et
4k (82 %)
NO2
PMP
CO2Et
4l (21 %)
4i (65 %)
4i (57 %)
OMe
CO2Me
CF3
EtO2C
EtO2C
EtO2C
N
EtO2C
OMe
N
NO2
N
PMP
PMP
CO2Et
4p (66 %)
N
PMP
CO2Et
PMP
Cl
CO2Et
4o (62 %)
4n (69 %)
4m (57 %)
Me
Cl
EtO2C
EtO2C
EtO2C
EtO2C
N
Ph
NO2
NO2
NO2
N
N
CO2Et
N
Ph
CO2Et
4t (66 %)
PMP
CO2Et
PMP
CO2Et
4q (62 %)
4r (67 %)
4s(49 %)
EtO2C
EtO2C
EtO2C
EtO2C
Ph
CO2Et
Ph
Ph
CO2Et
OH
N
N
N
N
CO2Et
PMP
CO2Et
HO
O2N
X
4w (27 %)
4u (63 %)
4x (X = F, 53 %)
4y (X = Br, 32 %)
4z (X = I , 51 %)
4v (29 %)
a
Isolated yields based on arylamine 1.
NH2
CO2Et
CO2Et
MeO
CO2Et
CO2Et
O
+
OR
O
Yb(OTf)3 (2.5 mol%)
DMSO, 90 °C
+
+
H
CO2Et
RO
OEt
N
N
O2 (1 atm)
PMP
CO2Et
OMe
1a
2a
3
4a
5
51 %
40 %
0 %
20 %
35 %
0 %
3a (R = Et)
3b (R = Pr)
3c (R = -CH2CH2-)
Scheme 2. The effect of acetal moiety for Yb-catalyzed one-pot DHP synthesis.
propionate (3a) with Yb catalyst in DMSO at 90 °C, 4a and 5 were
obtained in 51% and 20% yields, respectively (entry 1). The reaction
in acetonitrile gave 4a in 58% yield, but formation of 5 was scarcely
observed by TLC analysis (entry 2). Although DMF as an aprotic po-
lar solvent was used, the yield of 4a increased (72%) and the unde-
sired 5 was also obtained in 14% yield (entry 3). The most
satisfactory result was obtained when the reaction in 1,4-dioxane
was carried out and 4a was obtained in a good yield (74%) without
formation of 5 even under oxygen atmosphere (entry 4). The reac-
tion in aprotic non-polar solvent, such as toluene gave 4a and 5 in
58% and 21% yields (entry 5). In this reaction, THF, benzene, CH2Cl2,
ethanol and NMP were less effective or inactive (entries 6–10).

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S. Sueki et al. / Tetrahedron Letters 52 (2011) 4473–4477
OEt
O
NH2
CO2Et
CO2Et
EtO
EtO
OEt
OEt
MeO
CO2Et
CO2Et
O
Yb(OTf)3 (2.5 mol%)
+
+
3a
3d
+
DMSO, 90 °C
O2 (1 atm)
H
CO2Et
2a
N
N
O
PMP
CO2Et
OMe
1a
4a
5
3a
3d
51 %
19 %
6 %
20 %
72 %
41 %
44 %
trans- 3d
cis- 3d
17 %
Scheme 3. The comparison of acetal and vinyl ether in Yb-catalyzed one-pot DHP synthesis.
[Yb]
R2
OEt
O
O
EtO2C
EtO2C
EtO2C
R2
H
OH
EtO
OEt
R1NH2
N
NH
R1
NH
R1
[Yb]
imine-enamine
R1 tautomerization
A
B
C
R2
O
R2
R2
EtO2C
OEt
EtO2C
CO2Et
NHR1
EtO2C
CO2Et
- R1NH2
- H2O
N
R1
NH
R1
N
R1
N
R1
F
D
B
E
Scheme 4. The plausible reaction mechanism of Yb-catalyzed one-pot DHP synthesis.
These solvents have lower boiling points, indicating that the higher
temperature is necessary for this reaction. This is in accordance
with the results of entry 2 in Table 1.
the a,b-unsaturated imine D. The Michael-type annulation with
the intermediate D and the intermediate B proceeds to give the
tetrahydropyridine E. Finally elimination of amine from E affords
the DHP F.
From these results, Yb(OTf)3 and 1,4-dioxane were chosen as a
suitable catalysis system and applied to synthesis of various DHPs
4. Thus, the reactions of anilines 1, aldehyde 2 and ethyl 3,3-dieth-
oxypropionate (3a) in the presence of Yb(OTf)3 at 90 °C were car-
ried out to synthesize the corresponding N-aryl-3,5-
diethoxycarbonyl-DHPs 4. As shown in Table 3, the reactions with
various electron deficient aldehydes gave the corresponding DHPs
in good yields (4d–4j and 4k–4r). On the other hand, DHPs such as
4m and 4w bearing electron donating group in 4-aryl moiety were
obtained in moderate yields. The DHP 4c, which was obtained from
reaction with o-nitrobenzaldehyde, was obtained in 32% yield be-
cause of the steric hindrance of the o-nitro substituent in aryl moi-
ety at 4-position of DHP. The reaction with various functionalized
anilines also gave DHPs in good yields.
When ethyl 3,3-dipropylpropionate (3b) was used instead of 3a,
4a and 5 were obtained in 40% and 35% yields. The reaction with
cyclic acetal 3c did not proceed to give any 4a and 5 (Scheme 2).
The ethyl vinyl ether 3d was considered as an intermediate for
the reaction and used for the synthesis of 4a, however the selectiv-
ity of the reaction was very different from that with the reaction of
ethyl 3,3-diethoxypropionate (3a). Thus the reaction with the ethyl
vinyl ether 3d (cis- and trans-isomers mixture) gave 4a and 5 in
19% and 72% yields. Although cis- or trans-isomer of 3d was used
separately, the quinaldate 5 was obtained as a major product in
each reaction (Scheme 3).
Conclusion
We have found that Yb(OTf)3 is a suitable catalyst for one-pot
DHP synthesis, and 2,6-unsubstituted DHPs tolerated various func-
tional groups were synthesized easily, which is expected to provide
a useful tool for medicinal chemistry and materials science.
Acknowledgments
This work is financially supported in part by the Global COE
program ‘Center for Practical Chemical Wisdom’ by MEXT and is
also a part of the outcome of research performed under a Waseda
University Grant for Special Research Projects (Project number:
2010A-874).
Supplementary data
Supplementary data (general experimental procedure and spec-
tral data for all compounds) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2011.06.070.
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and activated ethyl 3,3-diethoxypropionate formed imine A. This
imine intermediate A can easily tautomerize enamine intermediate
B, and reacts with Yb-activated aldehyde to form enaminoalcohol
C. Subsequent dehydration proceeds via intermediate X to give
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