Copper(II) triflate-catalyzed highly efficient synthesis of N-substituted 1,4-dihydropyridine derivatives via three-component cyclizations of alkynes, amines, and α,β-unsaturated aldehydes

Article abstract of DOI:10.1016/j.tetlet.2016.08.085

A copper(II) triflate-catalyzed three-component cyclization of alkynes, amines, and α,β-unsaturated aldehydes was developed to give various 1,4-dihydropyridines in good to high yields. In addition, this efficient and practical protocol proceeded smoothly in gram scale even when the catalytic loading was reduced to 1?mol?%.

Full text of DOI:10.1016/j.tetlet.2016.08.085

Tetrahedron Letters 57 (2016) 4500–4504
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper(II) triflate-catalyzed highly efficient synthesis of
N-substituted 1,4-dihydropyridine derivatives via three-component
cyclizations of alkynes, amines, and a,b-unsaturated aldehydes
⇑
Sifeng Li, Qingjing Yang, Jun Wang
Department of Chemistry, South University of Science and Technology of China, Shenzhen, Guangdong 518055, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 July 2016
Revised 22 August 2016
Accepted 29 August 2016
Available online 30 August 2016
A copper(II) triflate-catalyzed three-component cyclization of alkynes, amines, and a,b-unsaturated alde-
hydes was developed to give various 1,4-dihydropyridines in good to high yields. In addition, this effi-
cient and practical protocol proceeded smoothly in gram scale even when the catalytic loading was
reduced to 1 mol %.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Copper(II) triflate
1,4-Dihydropyridine
Three-component
a,b-Unsaturated aldehydes
Cyclization
Introduction
Recently, Wan reported a three-component reaction of terminal
alkynes, amines, and a
,b-unsaturated aldehydes (Scheme 1c).8y In
Among numerous bioactive compounds in the pharmaceutical
and medicinal chemistry, 1,4-dihydropyridines (1,4-DHPs) are
one of the most common and privileged skeletons in many antihy-
pertension drugs,1 calcium-channel-modulating agents,2 MDR-
modulators,3 HIV-1 protease inhibitors,4 chemosensitizers in
tumor therapy,5 and compounds with many other activities.6 Due
to their high frequency in small molecular drugs, 1,4-DHPs have
attracted more and more chemists in this area to synthesize vari-
ous functional 1,4-dihydropyridines. Since the report of the
Hantzsch reaction with an amine, an aldehyde, and two 1,3-dicar-
bonyl compounds, various strategies involving different substrates
and catalysts have been developed for the synthesis of these useful
compounds,7 and most of them are based on the multicomponent
reactions (MCRs).8
the presence of 30 mol % of piperazine and 80 mol % of p-
tolsulfonic acid (p-TSA), 1,4-DHPs were obtained with 57–85%
yields. It encourages us to develop a more efficient catalyst
system to approach the synthesis of 1,4-dihydropyridines.
Herein, we report
catalyzed three-component reaction of alkynes, amines, and
a
highly efficient and practical Cu(OTf)2-
,b-
a
unsaturated aldehydes to afford 1,4-DHPs with good yields
(Scheme 1d). In order to show the synthetic utility of this
protocol, a large scale experiment (6 mmol) with only 1 mol % Cu
(OTf)2 catalyst was also performed to give the expected 1,4-DHPs
in 94% yield (1.78 g).
Results and discussion
In 2008, Sambri and co-workers reported a multicomponent
domino reaction for synthesis of substituted 1,4-dihydropyridines
from aryl amines, b-dicarbonyl compounds, and ethyl propiolate
that promoted by Mg(ClO4)2.8k Balalaie’s group found that 1,4-
dihydropyridine derivatives could be obtained from primary
amine, methyl (arylmethylide) pyruvates, and dialkyl
acetylenedicarboxylate in the presence of 40 mol % of ZnCl2.8t
In a prototype experiment, the three-component reaction of a-
methyl cinnamaldehyde 1a, aniline 2a, and ethyl propiolate 3a
were treated with 5 mol % Lewis acid in DCE at 70 °C. The reaction
parameters optimized included temperature, solvent, and Lewis
acid. As shown in Table 1, no product was formed in the absence
of Lewis acids. A wide range of commercially available triflates
including Fe(OTf)3, La(OTf)3, In(OTf)3, Yb(OTf)3, Y(OTf)3, Pr(OTf)3,
and Bi(OTf)3 were investigated, however only traces of the desired
product were formed. Then a variety of copper salts such as
2CuOTfÁtoluene, CuCl, Cu(MeCN)4BF4, Cu(OAc)2, Cu(ClO4)2Á6H2O,
⇑
Corresponding author. Tel.: +86 755 88018317; fax: +86 755 88018304.
E-mail address: wang.j@sustc.edu.cn (J. Wang).
http://dx.doi.org/10.1016/j.tetlet.2016.08.085
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

S. Li et al. / Tetrahedron Letters 57 (2016) 4500–4504
4501
a) Sambri's work
EtO2C
O
O
O
O
O
10 mol% Mg(ClO4)2
+ Ar'NH2
+
R2
R2
R2
R2=Me, OEt, OtBu
OEt
2
20 mol% MgSO4
50 °C, neat
N
Ar
45 - 95% yield
b) Balalaie's work
O
CO2R2
Ar
R2O2C
R2O2C
40 mol% ZnCl2
CO2R1
+ Ar'NH2
+
Ar
R1=Me, Et
DCE, reflux
N
Ar'
CO2R1
CO2R2
R2=Et, Me
42 - 87% yield
c) Wan's work
O
Ar
CO2R3
30 mol% piperazine R1
80 mol% p-TSA
DCE, reflux
O
R2 NH2
+
OR3
+
Ar
H
R1
R1=H, Me,
N
R2= Ar
Alkyl
R2
R3=Et, Me
57-85% yield
d) Our work
O
O
Ar
Ar
Ar
H
R1
CO2Et
CO2Et
OR3
R1
CO2R3
or
R1
1-5 mol% Cu(OTf)2
toluene, 70 °C
CO2Et
+
R1=H, Me
or
N
N
EtO2C
R3=Et, Me
R2 NH2
R2
R2
R2= Ar, Alkyl
Scheme 1. Three-component reaction for synthesis of 1,4-DHPs.
Table 1
Optimization of the reaction conditionsa
Ph
NH2
O
CO2Et
Me
O
5 mol% Catalyst
Solvent, 70 °C
H
+
+
OEt
N
Me
1a
Ph
4aaa
3a
2a
Entry
Triflate
Solvent
Time (h)
Yield (%)b
1c
2c
3c
4c
5c
6
None
DCE
DCE
DCE
DCE
DCE
DCE
DCE
72
72
72
72
72
12
2
NR
57
NR
Trace
NR
81
2CuOTfÁtoluene
CuCl
Cu(MeCN)4BF4
Cu(OAc)2
Cu(ClO4)2Á6H2O
Cu(OTf)2
7
87
8
Cu(OTf)2
THF
6
86
9
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
DMF
Dioxane
DME
Toluene
Toluene
Toluene
12
24
12
2
1
12
82
79
72
92
89
80
10
11
12
13d
14e
a
Reaction conditions: 1a (0.3 mmol), 1a/2a/3a/catalyst (1.0:1.2:2.0:0.05), all the reagents were intermediately added to 2 mL of solvent under Ar, then stirring at 70 °C for
indicated period of time.
b
Yield of isolated product after column chromatography.
The reaction was not completed.
The reaction was stirred at 90 °C.
The reaction was stirred at 50 °C.
c
d
e
and Cu(OTf)2 were also applied to this reaction (Table 1, entries 2–
7). To our delight, the expected product 4aaa was obtained with
87% yield when the reaction was catalyzed with Cu(OTf)2. Further
solvent screening revealed that the efficiency and the yield of the
product in toluene were higher than those obtained in other sol-
vents such as DCE, THF, DMF, Dioxane, and DME (Table 1, entries
7–12). In addition, lowering or raising the reaction temperature
would not help to improve the yield (Table 1, entries 13 and 14).
Optimal condition was obtained when
a-methyl cinnamaldehyde
1a, aniline 2a, and ethyl propiolate 3a in the ratio of 1:1.2:2 were

4502
S. Li et al. / Tetrahedron Letters 57 (2016) 4500–4504
stirred in toluene with 5 mol % of Cu(OTf)2 at 70 °C, resulting dihy-
dropyridine 4aaa in 92% isolated yield (Table 1, entry 12).
With the optimized conditions in hands, a range of aromatic
and aliphatic amines was investigated. As shown in Table 2, the
electronic factor of anilines showed no obvious influence on the
yields of products and the rate of the reactions, but the reactions
of more sterically hindered ortho-substituted anilines proceeded
sluggishly to give the desired 1,4-DHPs in a lower yields (entries
6 and 16). Moreover, this catalytic system is still fit for aliphatic
amines (Table 2, entries 18 and 19), though moderate yields were
resulted. The configuration of the product was confirmed by X-ray
crystal structure analysis (3aja, Fig. 1).9
To further broaden the substrate scope of this three-component
Figure 1. ORTEP drawing of 3aja.
cyclization, a variety of
a- or b-substituted enals were explored
under the optimal reaction conditions. We are happy to find that
all the substituted enals reacted smoothly as well, and afforded
the expected product with 71–92% yields (Table 3, entries 1–10).
When ethyl propiolate 3b was used instead of methyl propiolate
3a, the yield of 4aab was obtained in 87% (Table 3, entry 11).
Encouraged by these results, we turned our attention to study
this three-component cyclization with internal alkyne acetylenedi-
carboxylate 5 (Scheme 2). Fortunately, the reaction proceeded
smoothly in standard conditions, and gave the product 6 with
82% yield.
In order to show the synthetic utility of this protocol, we per-
formed large scale experiments (20 fold example of Table 2, entries
1 and 11) with only 1 mol % Cu(OTf)2 catalyst. Products 4aaa and
4aka were obtained with excellent yields (1.78 g, 94% and 1.87 g,
91% respectively) which were even better with the yields obtained
in usual scale with 5 mol % catalyst loading. It is strongly demon-
strated that this type of 1,4-dihydropyridines was easily prepared
in large scale under this catalytic system (Scheme 3).
for this cyclization. One is [4+2] cyclization of imine 7 and alkyne
3a, and another is [3+3] cyclization of enamine 8 and enal 1a. In
the presence of 5 mol % of Cu(OTf)2,
a-methyl cinnamaldehyde
1a reacted with 4-methoxyl aniline 2k smoothly and gave corre-
sponding imine 7 equivalently. The imine 7 also can be formed
from 1a and 2k even without any catalyst with longer time. Inter-
estingly, no expected enamine 8 was detected (acetate functional-
ized 1,4-dihydropyridine 9 was obtained with 56% of yield10) by
the reaction of 4-methoxyl aniline 2k and ethyl propiolate 3a with
5 mol % of Cu(OTf)2, while enamine 8 could be obtained with 12%
yield without any catalyst. Therefore, imine 7 is more stable and
possible intermediate than enamine 8 under this reaction condi-
tion. Further experiments showed that both the pre-generated
imine 7 and enamine 8 could be activated by Cu(OTf)2 catalyst
and react with ethyl propiolate 3a and aldehyde 1a respectively
to give the desired 1,4-DHP 4aka.
To study the mechanism, a series of control experiments are
conducted and shown in Scheme 4. There are two possible routes
According to the control experiments, we proposed a plausible
mechanism for this three-component cyclization with two
Table 2
Synthesis of N-substituted 1,4-dihydropyridines with various aminesa
NH2
R
Ph
2a-s
CO2Et
Me
O
O
5 mol% Cu(OTf)2
toluene, 70 °C
+
OEt
H
N
R
Me
1a
3a
4aaa-4asa
Entry
R
Time (h)
Product
Yieldb
1
2
3
4
C6H5 2a
2
2
2
6
12
72
6
6
2
72
2
2
2
6
12
72
6
72
72
4aaa
4aba
4aca
4ada
4aea
4afa
4aga
4aha
4aia
4aja
4aka
4ala
4ama
4ana
4aoa
4apa
4aqa
4ara
4asa
92
91
90
84
79
61
86
82
89
71
88
85
87
82
78
60
85
64
68
4-FC6H4 2b
4-ClC6H4 2c
3-ClC6H4 2d
3,5-ClC6H3 2e
2-ClC6H4 2f
4-BrC6H4 2g
4-IC6H4 2h
4-CF3C6H4 2i
4-NO2C6H4 2j
4-OMeC6H4 2k
4-OCF3C6H4 2l
4-MeC6H4 2m
3-MeC6H4 2n
3,5-MeC6H3 2o
2-MeC6H4 2p
4-iPrC6H4 2q
Bn 2r
5
6d
7
8
9
10
11
12
13
14
15
16d
17
18d
19d
Cy 2s
a
Reaction conditions: 1a (0.3 mmol), 1a/2/3a/Cu(OTf)2 (1.0:1.2:2.0:0.05), all the reagents were intermediately added to toluene (2 mL) under Ar, then stirring at 70 °C for
indicated period of time.
b
Yield of isolated product after column chromatography.
The reaction was not completed.
d

S. Li et al. / Tetrahedron Letters 57 (2016) 4500–4504
4503
Table 3
Synthesis of N-substituted 1,4-dihydropyridines with various aldehydesa
R1
NH2
O
H
O
CO2R3
R2
5 mol% Cu(OTf)2
toluene, 70 °C
OR3
+
R1
+
R2
N
Ph
1a-j
3a-b
2a
4aaa-4jaa
Entry
R1
R2
R3
Time (h)
Product
Yieldb
1
2
3
4
5
6
7
8
H
H
H
H
Me 1a
H 1b
C5H11 1c
C6H13 1d
H 1e
H 1f
H 1g
H 1h
H 1i
Et 3a
Et 3a
Et 3a
Et 3a
Et 3a
Et 3a
Et 3a
Et 3a
Et 3a
Et 3a
Me 3b
2
2
6
6
6
6
6
6
6
6
2
4aaa
4baa
4caa
4daa
4eaa
4faa
4gaa
4haa
4iaa
4jaa
4aab
92
85
86
84
75
71
78
80
85
81
87
4-Me
4-OMe
4-Br
4-Cl
4-F
3-F
H
9
10
11
H 1j
Me 1a
a
Reaction conditions: 1 (0.3 mmol), 1/2a/3a/Cu(OTf)2 (1.0:1.2:2.0:0.05), all the reagents were intermediately added to toluene (2 mL) under Ar, then the mixture was
stirred at 70 °C for indicated period of time.
b
Yield of isolated product after column chromatography.
Ph
NH2
OMe
O
CO2Et
O
NH2
CO2Et
CO2Et
Me
toluene, 70 °C
5 mol% Cu(OTf)2
toluene, 70 °C
H
+
Ph
N
7
H
+
+
Me
N
Ph
Me
Me
1a
1a
OMe
2k
CO2Et
12 h, 98% yield with 5 mol % Cu(OTf)2
60 h, 92% yield without Cu(OTf)2
2a
5
6
24 h, 82% yield
EtO2C
NH2
MeO
toluene, 70 °C
O
Scheme 2. Acetylenedicarboxylate involved three-component reaction for 1,4-
DHPs.
EtO2C
CO2Et
O
OEt
N
H
OEt
+
N
PMP
9
3a
8
OMe
2k
9
12 h, trace with 5 mol % Cu(OTf)2, but 56% of was formed
60 h, 12% yield without Cu(OTf)2
O
NH2
Ar
Ph
5 mol% Cu(OTf)2
PMP
2a, 2k
decomposed, 30% yield of 9
O
N
H
OEt
CO2Et
toluene, 70 °C
Me
2k
was formed, trace of
remains
1 mol% Cu(OTf)2
toluene, 70 °C, 12h
O
8
H
+
Ph
N
Ar
Me
1a
OMe
+
OEt
O
Me
CO2Et
5 mol% Cu(OTf)2
OEt
3a
3a
Ph
N
toluene, 70 °C
6 mmol
4aaa
Ar= Ph, 1.78 g, 94% yield
4aka Ar=4-OMeC6H4, 1.87 g, 91% yield
N
Me
4aka
PMP
7
1 h, 98% yield
Ph
Scheme 3. Gram scale reaction.
O
O
CO2Et
Me
5 mol% Cu(OTf)2
toluene, 70 °C
PMP
Ph
H
+
OEt
N
H
Me
N
PMP
possible alternative reaction paths (Scheme 5). In the path A,
imine 7 was formed via dehydration reaction of -methyl cin-
4aka
8
1a
a
12 h, 82% yield, 12% 7 was obtained
namaldehyde 1a and 4-methoxyl aniline 2k in the presence of
catalyst before the desired product was obtained through aza-
Diels–Alder reaction. The aza Diels–Alder reaction showed high
regioselectivity that the most negatively charged nitrogen in
diene connected with the most positively charged carbon in
alkyne. As for path B, it looks more complicated and less possible
than the former one. Enamine 8 was generated slowly through
addition of 2k and 3a, and then intermediate I was produced
via nucleophilic attack of NH to formyl group of 1a. Conse-
quently, the dehydration led to the formation of 4aka via inter-
mediate II; at the same time enamine 8 would partly undergo
decomposition in the presence of Cu(OTf)2 catalyst which then
afforded imine 7 and 1,4-DHP same as path A.
Scheme 4. Control experiments for mechanism study.
Conclusions
In conclusion, we have successfully developed an efficient and
practical three-component protocol for synthesis of 1,4-dihydropy-
ridines in good to high yields. In addition, this reaction proceeded
smoothly in gram scale when the catalytic loading was reduced to
1 mol %. Further investigations on asymmetric synthesis method-
ology of 1,4-dihydropyridines and their biological activities evalu-
ation are ongoing in our laboratory.

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3a
N
O
Ph
Ph
H
7
OEt
Me
Me
PMP
1a
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N
2
-H2O
1a
)
f
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Path A
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+
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Path A
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NH2
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CO2Et
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Ph
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(
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(
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EtO
N
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-OH
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Me
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Scheme 5. Proposed mechanisms for the three-component reaction.
Acknowledgments
We gratefully thank the startup fund from South University of
Science and Technology of China and Shenzhen Basic Research Pro-
gram (JCYJ20150630145302229) for financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.08.
085.
References and notes
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