An organocatalytic multi-molecular cascade reaction for the synthesis of acetate functionalized 1,4-dihydropyridines

Article abstract of DOI:10.1016/j.tet.2015.06.101

Abstract An organocatalytic cascade reaction involving the incorporation of alkyl propiolates and primary amines has been realized for the facile synthesis of 1,4-dihydropyridines (1,4-DHPs) bearing a C4 acetate fragment. This method allows rapid and atom economical generation of N-aryl, N-alkyl, and NH 1,4-DHPs with moderate to excellent yields.

Full text of DOI:10.1016/j.tet.2015.06.101

Tetrahedron 71 (2015) 6094e6098
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An organocatalytic multi-molecular cascade reaction for the
synthesis of acetate functionalized 1,4-dihydropyridines
*
Deqing Hu, Yunyun Liu, Jie-Ping Wan
Key Laboratory of Functional Small Organic Molecules, Ministry of Education, College of Chemistry and Chemical Engineering, Jiangxi Normal
University, Nanchang 330022, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 June 2015
Received in revised form 28 June 2015
Accepted 29 June 2015
Available online 3 July 2015
An organocatalytic cascade reaction involving the incorporation of alkyl propiolates and primary amines
has been realized for the facile synthesis of 1,4-dihydropyridines (1,4-DHPs) bearing a C4 acetate frag-
ment. This method allows rapid and atom economical generation of N-aryl, N-alkyl, and NH 1,4-DHPs
with moderate to excellent yields.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Multi-molecular
Cascade reaction
Organocatalysis
1,4-Dihydropyrdines
Propiolates
1. Introduction
must be used to donate the formyl group. Such kind of synthetic
methods result in the consequence of limited product diversity
Heterocycles are central backbones of numerous natural prod-
ucts, pharmaceutically active molecules and biologically relevant
compounds. As one of the most well-known privileged heterocyclic
structures, the 1,4-DHP has showed up ubiquitously in clinic drugs
and biologically active lead compounds.1 In addition, new bi-
ological functions on 1,4-DHPs scaffolds have continuously been
discovered in recent years along with the daily increasing avail-
ability of new synthetic strategies.2 More over, 1,4-DHPs are also
known as useful reactants in the synthesis of complex organic
molecules by acting as the cyclic backbone donors.3 The versatile
known utilities as well as the high application of 1,4-DHPs in dif-
ferent research areas have accordingly stimulated the everlasting
research interest in the synthesis of 1,4-DHPs, especially in the
manner of diversity-oriented synthesis.4
As the first authentic diversity-oriented method toward 1,4-
DHPs synthesis, the Hantzsch multicomponent reaction has tre-
mendously contributed to the chemistry of 1,4-DHPs,5 which also
inspired the splendid research advances in 1,4-DHPs synthesis with
new approaches. During the past decades, a large number of out-
standing works have been reported allowing the synthesis of 1,4-
DHPs in great span of structural diversity, especially in the fash-
ion of multicomponent reactions.6 A common feature of most
known multicomponent methods, however, is that an aldehyde
since most known multicomponent 1,4-DHPs syntheses provide 4-
aryl or 4-alkyl 1,4-DHPs by relying on the aldehyde as the donor of
C4 fragment of the ring. In this regard, discovering new electro-
philic component to alternate aldehyde constitutes a main current
challenge in the synthesis of diverse 1,4-DHPs libraries.
One interesting example using unconventional electrophile to
enable the multi-molecular synthesis of 1,4-DHPs is the reactions of
alkyl propiolates and amines. Ajavakom et al. have7 developed the
stepwise method for the synthesis of 4-acetate functionalized 1,4-
DHPs by using the prior prepared enamino ester as the key build-
ing block in the presence of TiCl4 (Eq 1 in Scheme 1). The em-
ployment of metal catalyst, however, is usually not favored,
especially in the efforts of preparing biologically relevant products.
To avoid the reliance on metal catalyst, finding alternative metal-
free approach for the synthesis of these products is therefore of
high significance.
We have recently developed an efficient secondary amine-based
organocatalytic strategy to activate propiolates by forming reactive
N,N-disubstituted enamino ester intermediate and have success-
fully established a series of novel cascade reactions for diversity-
oriented synthesis by making use of this key activation protocol.8
As our ongoing efforts in disclosing the application of this cata-
lytic method, we wish to report herein the organocatalytic synthesis
of 4-acetate 1,4-DHPs via the multi-molecular reactions of propio-
lates and primary amines in aqueous media (Eq 2 in Scheme 1).
* Corresponding author. E-mail address: wanjieping@jxnu.edu.cn (J.-P. Wan).
http://dx.doi.org/10.1016/j.tet.2015.06.101
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

D. Hu et al. / Tetrahedron 71 (2015) 6094e6098
6095
Table 1). Subsequent optimization on reaction temperature proved
that 120 ꢀC was more proper (entries 16e17, Table 1) than other
screened temperatures. Finally, the examination on the loading of
piperazine was able to further increase the yield of 3a when 20 mol
% piperazine was subjected (entries 18e19, Table 1).
Based on the results from optimization experiment, the scope of
this organocatalytic synthesis toward 1,4-DHPs was examined. As
shown by the results in Table 2, the present synthetic method
displayed excellent tolerance to the synthesis of 4-acetate 1,4-DHPs
by employing different propiolates and primary amines. The
products were generally obtained with moderate to excellent yield.
Notably, not only the aryl amines containing different substituents
such as alkyl, alkoxyl etc. were generally applicable for the syn-
thesis, the alkyl primary amines, including those conventional ones
and the one containing sensitive substituent such as 2-hydroxyl
ethylamine (3p) could also be smoothly transformed to corre-
sponding products. A tendency suggested by the results was that
electron deficient amines such as those anilines containing electron
withdrawing group provided corresponding 1,4-DHPs with evi-
dently lower yield (3c, 3d, 3f, 3r), and the ortho-substitution on the
aniline also hindered the formation of corresponding products to
some extent (3g, 3h, 3i, 3j, 3t, 3u). Interestingly, the alkyl amines,
both linear ones with and without branched structure participated
the reaction to afford N-alkyl 1,4-DHPs with high yield probably
because of their higher nucleophilicity (3le3o). No expect product
was observed when 4-nitroaniline was employed, and the result
could be attributed to the much weaker nucleophilicity of the
amino group resulted by the strong electron withdrawing effect of
the nitro substituent.
Scheme 1. Metal-catalyzed and organocatalytic multi-molecular synthesis of 1,4-
DHPs.
2. Results and discussion
To start the investigation, the model reaction of ethyl propiolate
1a and p-methylaniline 2a was tentatively run under either the
presence of only TMSCl or piperazine, which were found both un-
able to produce target product 3a (entries 1e2, Table 1). On the
other hand, the simultaneous employment of TMSCl and piperazine
in the reaction allowed smooth production of 3a (entry 3, Table 1).
Systematic optimization on the reaction medium suggested that
the aqueous DMSO could provide much higher yield of 3a than all
other examined solvents (entries 4e10, Table 1). In addition, the
variation in the acidic catalyst or the secondary amine species
didn’t lead to the occurrence of improved result (entries 11e15,
In order to probe more comprehensively the application of the
present method in 1,4-DHPs synthesis, the reaction between ethyl
propiolate 1a and ammonium acetate 4 was executed under the
standard reaction. To our delight, the reaction was found to provide
Table 1
Optimization on reaction conditionsa
Table 2
Scope of the organocatalytic multi-molecular 1,4-DHPs synthesisa
Entry
Solvent(v/v)
Catalyst
Amine
Yield(%)b
R1
R2
Product
Yieldb (%)b
1
2
3
4
5
6
7
8
DMSO
DMSO
DMSO
DMF
i-PrOH
H2O
Toluene
DMSO/H2O(1.5/0.5)
DMSO/H2O(0.5/1.5)
DMSO/H2O(1/1)
DMSO/H2O(1/1)
DMSO/H2O(1/1)
DMSO/H2O(1/1)
DMSO/H2O(1/1)
DMSO/H2O(1/1)
DMSO/H2O(1/1)
DMSO/H2O(1/1)
DMSO/H2O(1/1)
DMSO/H2O(1/1)
TMSCl
No
No
Trace
Trace
20
15
27
Trace
37
40
45
65
Trace
Trace
Trace
26
38
57
50
83
42
Piperazine
Piperazine
Piperazine
Piperazine
Piperazine
Piperazine
Piperazine
Piperazine
Piperazine
Piperazine
Piperazine
Piperazine
Morpholine
Dimethylamine
Piperazine
Piperazine
Piperazine
Piperazine
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
4-MeC6H4
4-MeOC6H4
4-BrC6H4
4-ClC6H4
3-OHC6H4
3-ClC6H4
2-MeC6H4
2-ClC6H4
2-MeOC6H4
2,4-Me2C6H4
C6H5
i-Propyl
n-Butyl
i-Butyl
Benzyl
CH2CH2OH
4-MeC6H4
4-BrC6H4
4-MeOC6H4
2-ClC6H4
2,4-Me2C6H4
4-NO2C6H4
3a
3b
3c
3d
3e
3f
3g
3h
3i
83
77
61
69
45
60
53
63
49
51
75
81
78
77
84
83
62
54
61
53
52
nr
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
P-TSA
AcOH
FeCl3
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
9
10
11
12
13
14
15
16c
17d
18e
19f
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
Me
Me
Me
Me
Me
Et
a
General conditions: ethyl propiolate (0.9 mmol), 4-methylaniline (0.3 mmol),
catalyst (0.06 mmol), secondary amine (0.12 mmol) were stirred for 12 h by heating
at 120 ꢀC in 2.0 mL solvent(s).
3u
d
b
Yield of isolated products base on 0.3 mmol.
c
a
The temperature was 110 ꢀC.
General conditions: 1 (0.9 mmol), 2 (0.3 mmol), TMSCl (0.06 mmol), piperazine
(0.06 mmol) were stirred for 12 h by heating at 120 ꢀC in mixed DMSO/water (1 mL/
1 mL).
d
The temperature was 130 ꢀC.
The piperazine was 0.06 mmol.
The piperazine was 0.03 mmol.
e
f
b
Yield of isolated product.

6096
D. Hu et al. / Tetrahedron 71 (2015) 6094e6098
NH-containing 1,4-DHP 3v with excellent yield (Eq 3), demon-
strating the highly broad application scope of this organocatalytic
procedure.
X-4A instrument without correcting temperature, and the HRMS
were obtained under ESI model.
3.2. General procedure for the synthesis of 1,4-DHPs 3
To a 25 mL round-bottom flask was added alkyl propiolate 1
(0.9 mmol), primary amine 2 (0.3 mmol), piperazine (0.06 mmol),
TMSCl (0.06 mmol) and DMSO/water (1 mL/1 mL). The resulting
mixture was heated to 120 ꢀC, and reacted at the same temperature
for 12 h. After completion of the reaction, the resulting solution was
mixed with water (10 mL), and then extracted with ethyl acetate
(3ꢁ10 mL). The combined organic phase was dried over anhydrous
Na2SO4. The solid was filtered away and the solvent was removed at
reduced pressure. Target products were acquired by the purifica-
tion of the residue via silica gel flash column chromatography
(VEtOAc:VPET¼1:10).
According to the results from the present work and our previous
investigation on secondary amine-catalyzed multi-molecular syn-
thesis involving propiolates, the mechanism of the present reaction
has been proposed and outlined in Scheme 2. The reaction has
firstly been initiated via the rapid formation of enamino ester in-
termediate 5 via the addition of secondary amine to propiolate 1.
The easy transamination9 of 5 with primary amine leads to the
occurrence of NH-containing enamino ester 6 in the presence of
3. 2.1. Diethyl-4-(2-ethoxy-2-oxoethyl)-1-p-tolyl-1, 4-
dihydropyridine-3,5-dicarboxylate (3a). Brown liquid; 1H NMR
acidic catalyst. The Michael addition of the nucleophilic a-carbon to
(400 MHz, CDCl3):
d
7.55 (s, 2H), 7.22 (d, 2H, J¼7.2 Hz), 7.12 (d, 2H,
another propiolate molecule provides intermediate 7, which un-
dergoes a further Michael addition by intermediate 5 to afford bis-
enaminoesters 8. The intramolecular transamination on 8 yields
the target 1,4-DHPs 3.
J¼7.6 Hz), 4.28e4.21 (m, 5H), 4.07e4.01 (m, 2H), 2.59 (d, 2H,
J¼4.8 Hz), 2.37 (s, 3H), 1.31 (t, 6H, J¼6.4 Hz), 1.18 (t, 3H, J¼6.8 Hz);
13C NMR (100 MHz, CDCl3):
d 171.7, 166.8, 140.7, 137.9, 136.3, 130.3,
120.9, 107.8, 60.3, 60.1, 40.6, 29.6, 20.8, 14.4, 14.2; ESI-HRMS: Calcd
for C22H27NO6Na [MþNa]þ: 424.1731; Found: 424,1777.
3.2.2. Diethyl-4-(2-ethoxy-2-oxoethyl)-1-(4-methoxyphenyl)-1,4-
dihydropyridine-3,5-dicarboxylat (3b).7 Yellow liquid; 1H NMR
(400 MHz, CDCl3):
d
7.47 (s, 2H), 7.16 (d, 2H, J¼7.6 Hz), 6.93 (d, 2H,
J¼8.0 Hz), 4.26e4.20 (m, 5H), 4.07e4.02 (m, 2H), 3.83 (s, 3H), 2.58
(d, 2H, J¼7.6 Hz), 1.30 (t, 6H, J¼6.4 Hz), 1.19 (t, 3H, J¼6.4 Hz); 13C
NMR (100 MHz, CDCl3):
d 171.7, 166.8, 158.2, 138.4, 136.6, 123.0,
114.9, 107.5, 60.3, 60.0, 55.6, 40.6, 29.5, 14.4, 14.2.
3.2.3. Diethyl-1-(4-bromophenyl)-4-(2-ethoxy-2-oxoethyl)-1,4-
dihydropyridine-3,5-dicarboxylate (3c). Green liquid; 1H NMR
(400 MHz, CDCl3):
d
7.53 (d, 2H, J¼7.2 Hz), 7.12 (d, 2H, J¼8.4 Hz),
4.26e4.22 (m, 5H), 4.05e4.00 (m, 2H), 2.60 (d, 2H, J¼4.4 Hz),1.31 (t,
6H, J¼7.2 Hz), 1.18 (t, 3H, J¼7.2 Hz); 13C NMR (100 MHz, CDCl3):
d
172.0, 166.9, 142.4, 137.5, 133.3, 122.7, 119.9, 109.2, 60.9, 60.5, 40.7,
29.9, 14.8, 14.6; ESI-HRMS: Calcd for C21H24NO6BrNa [MþNa]þ:
488.0679; Found: 488.0704.
3.2.4. Diethyl-1-(4-chlorophenyl)-4-(2-ethoxy-2-oxoethyl)-1,4-
dihydropyridine-3,5-dicarboxylate
(3d). Brown
solid;
mp
101e102 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.52 (s, 2H), 7.39 (d, 2H,
Scheme 2. The proposed reaction mechanism.
J¼8.8 Hz), 7.17 (d, 2H, J¼8.4 Hz), 4.26e4.22 (m, 5H), 4.06e4.00 (m,
2H), 2.60 (d, 2H, J¼4.8 Hz), 1.31 (t, 6H, J¼6.8 Hz), 1.18 (t, 3H,
In conclusion, by employing a secondary amine-based organo-
catalytic strategy, we have successfully developed
a
multi-
J¼6.8 Hz); 13C NMR (100 MHz, CDCl3):
d 171.6, 166.6, 141.6, 137.2,
molecular protocol for the synthesis of 1,4-DHPs bearing 4-
acetate substructure. This method doesn’t require any metal cata-
lyst and has exhibited excellent tolerance to the synthesis of N-aryl,
N-alkyl, and NH 1,4-DHPs, which will reasonably be a useful route
to complement those known methods on 1,4-DHPs synthesis.
131.9, 129.9, 122.0, 108.7, 60.4, 60.1, 40.3, 29.5, 14.4, 14.2; ESI-HRMS:
Calcd for C21H24NO6ClNa [MþNa]þ: 444.1184; Found: 444.1208.
3.2.5. Diethyl-4-(2-ethoxy-2-oxoethyl)-1-(3-hydroxyphenyl)-1,4-
dihydropyridine-3,5-dicarboxylate (3e). Brown solid; mp 93e94 ꢀC;
1H NMR (400 MHz, CDCl3):
d
7.59 (s, 2H), 7.20 (t, 1H, J¼8.0 Hz),
3. Experimental section
6.76e6.69 (m, 3H), 4.28e4.22 (m, 5H), 4.09e4.03 (m, 2H), 2.60 (d,
2H, J¼4.4 Hz), 1.31 (t, 6H, J¼6.8 Hz), 1.19 (t, 3H, J¼6.8 Hz); 13C NMR
3.1. General experimental information
(100 MHz, CDCl3): d 172.3, 167.1, 157.5, 144.1, 137.8, 130.6, 113.5,
112.0, 108.1, 108.0, 60.6, 60.4, 40.7, 29.7, 14.4, 14.1; ESI-HRMS: Calcd
All experiments were carried out at open atmosphere. All
chemicals and solvents used in the experiments were obtained
from commercial sources and used directly without further treat-
ment. 1H and 13C NMR were recorded in 400 MHz apparatus in
CDCl3. The frequencies for 1H NMR and 13C NMR test are 400 MHz
and 100 MHz, respectively. The chemical shifts were reported in
ppm with TMS as internal standard. Melting points were tested in
for C21H25NO7Na [MþNa]þ: 426.1523; Found: 426.1518.
3.2.6. Diethyl-1-(3-chlorophenyl)-4-(2-ethoxy-2-oxoethyl)-1,4-
dihydropyridine-3,5-dicarboxylate (3f). Brown liquid; 1H NMR
(400 MHz, CDCl3):
d
7.55 (s, 2H), 7.36 (t, 1H, J¼8.0 Hz), 7.24 (s, 2H),
7.13 (d, 1H, J¼7.6 Hz), 4.27e4.25 (m, 5H), 4.07e4.01 (m, 2H), 2.61 (d,
2H, J¼3.2 Hz), 1.32 (t, 6H, J¼6.0 Hz), 1.18 (t, 3H, J¼6.8 Hz); 13C NMR

D. Hu et al. / Tetrahedron 71 (2015) 6094e6098
6097
(100 MHz, CDCl3):
d
171.6, 166.5, 144.0, 137.0, 135.5, 130.9, 126.4,
J¼6.4 Hz), 0.95 (t, 3H, J¼6.4 Hz); 13C NMR (100 MHz, CDCl3):
d
171.6,
120.9, 118.7, 109.1, 60.5, 60.1, 40.3, 29.6, 14.4, 14.2; ESI-HRMS: Calcd
166.8, 139.3, 105.7, 60.0, 59.8, 54.6, 40.9, 32.2, 29.5, 19.4, 14.3, 14.1,
13.6.
for C21H25NO6Cl [MþH]þ: 422.1365; Found: 422.1373.
3. 2. 7. Diethyl-4-(2-ethoxy-2-oxoethyl)-1-o-tolyl-1, 4-
3.2.14. Diethyl-4-(2-ethoxy-2-oxoethyl)-1-isobutyl-1,4-
dihydropyridine-3,5-dicarboxylate (3g). Yellow solid; mp 80e81 ꢀC;
dihydropyridine-3,5-dicarboxylate (3n). Yellow liquid; 1H NMR
1H NMR (400 MHz, CDCl3):
d
7.29 (d, 3H, J¼5.2 Hz), 7.26 (s, 2H), 7.18
(400 MHz, CDCl3): d 7.11 (s, 2H), 4.21e4.19 (m, 5H), 4.06e4.01 (m,
(d,1H, J¼6.4 Hz), 4.31 (t,1H, J¼4.4 Hz), 4.24e4.19 (m, 4H), 4.11e4.06
2H), 3.12 (d, 2H, J¼6.8 Hz), 2.46 (d, 2H, J¼3.2 Hz), 1.93e1.90 (m, 1H),
(m, 2H), 2.63 (d, 2H, J¼4.4 Hz), 2.32 (s, 3H), 1.28 (t, 6H, J¼6.4 Hz),
1.30 (t, 6H, J¼6.4 Hz), 1.21 (t, 3H, J¼7.2 Hz), 0.95 (d, 6H, J¼5.2 Hz);
1.22 (t, 3H, J¼6.8 Hz); 13C NMR (100 MHz, CDCl3):
d
172.1, 167.2,
13C NMR (100 MHz, CDCl3):
d 171.6, 166.9, 139.6, 105.5, 62.5, 60.0,
142.8, 139.8, 134.6, 132.1, 128.7, 127.7, 126.5, 106.9, 60.6, 60.4, 40.8,
29.9, 18.1, 14.8, 14.6; ESI-HRMS: Calcd for C22H27NO6Na [MþNa]þ:
424.1731; Found: 424.1759.
59.8, 41.0, 29.5, 29.4, 19.5, 14.3, 14.1; ESI-HRMS: Calcd for
C
20H23NO6Na [MþNa]þ: 390.1887; Found: 390.1885.
3.2.15. Diethyl-1-benzyl-4-(2-ethoxy-2-oxoethyl)-1,4-
3.2.8. Diethyl-1-(2-chlorophenyl)-4-(2-ethoxy-2-oxoethyl)-1,4-
dihydropyridine-3,5-dicarboxylate (3o).7 Yellow liquid; 1H NMR
dihydropyridine-3,5-dicarboxylate (3h). Yellow solid; mp 94e95 ꢀC;
(400 MHz, CDCl3):
d
7.40e7.30 (m, 3H), 7.24 (d, 2H, J¼7.6 Hz), 7.20
1H NMR (400 MHz, CDCl3):
d
7.50 (d, 2H, J¼7.2 Hz), 7.35 (s, 2H), 7.30
(s, 2H), 4.50 (s, 2H), 4.24 (t, 1H, J¼4.4 Hz), 4.21e4.16 (m, 4H),
4.02e3.97 (m, 2H), 2.51 (d, 2H, J¼4.4 Hz), 1.27 (t, 6H, J¼7.2 Hz), 1.16
(s, 2H), 7.29 (s, 1H), 4.29 (t, 1H, J¼4.8 Hz), 4.25e4.20 (m, 4H),
4.11e4.06 (m, 2H), 2.62 (d, 2H, J¼4.8 Hz), 1.29 (t, 6H, J¼7.2 Hz), 1.22
(t, 3H, J¼7.2 Hz); 13C NMR (100 MHz, CDCl3):
d 171.7, 166.7, 139.5,
(t, 3H, J¼7.2 Hz); 13C NMR (100 MHz, CDCl3):
d
171.6, 166.6, 140.5,
136.0, 129.0, 128.2, 127.1, 106.4, 60.1, 59.9, 58.0, 40.8, 29.6, 14.3, 14.1.
138.9, 131.0, 130.5, 129.3, 128.2, 127.6, 107.4, 60.3, 60.1, 40.5, 29.4,
14.4,14.2; ESI-HRMS: Calcd for C21H24NO6ClNa [MþNa]þ: 444.1184;
Found: 444.1185.
3.2.16. Diethyl-4-(2-ethoxy-2-oxoethyl)-1-(2-hydroxyethyl)-1,4-
dihydropyridine-3,5-dicarboxylate
(3p).7 Yellow
solid;
mp
72e74 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.19 (s, 2H), 4.22e4.18 (m,
3.2.9. Diethyl-4-(2-ethoxy-2-oxoethyl)-1-(2-methoxyphenyl)-1,4-
4H), 4.09 (s, 1H), 4.06e4.01 (m, 2H), 3.88 (s,1H), 3.76 (s, 2H), 3.45 (s,
2H), 2.62 (s, 2H), 1.29 (t, 6H, J¼6.8 Hz), 1.20 (t, 3H, J¼6.8 Hz); 13C
dihydropyridine-3,5-dicarboxylate (3i). Yellow liquid; 1H NMR
(400 MHz, CDCl3):
d
7.36 (s, 2H), 7.32 (d, 1H, J¼7.2 Hz), 7.21 (d, 1H,
NMR (100 MHz, CDCl3): d 173.6, 166.8, 140.2, 105.3, 61.6, 60.2, 60.0,
J¼7.2 Hz), 7.02 (d, 2H, J¼5.2 Hz), 4.30 (t, 1H, J¼4.8 Hz), 4.25e4.20
(m, 4H), 4.12e4.06 (m, 2H), 3.88 (s, 3H), 2.61 (d, 2H, J¼4.8 Hz), 1.30
(t, 6H, J¼7.2 Hz), 1.23 (t, 3H, J¼7.2 Hz); 13C NMR (100 MHz, CDCl3):
57.5, 39.3, 28.7, 14.3, 14.0.
3.2.17. Dimethyl-4-(2-methoxy-2-oxoethyl)-1-p-tolyl-1,4-
d
171.7, 166.8, 153.5, 139.8, 131.8, 128.9, 126.1, 121.0, 112.2, 106.6,
dihydropyridine-3,5-dicarboxylate (3q). Yellow liquid; 1H NMR
60.0, 59.9, 55.8, 40.7, 29.4, 14.3, 14.1; ESI-HRMS: Calcd for
C
(400 MHz, CDCl3):
d
7.56 (s, 2H), 7.21 (d, 2H, J¼3.2 Hz), 7.11 (d,
22H27NO7Na [MþNa]þ: 440.1680; Found: 440.1706.
2H,J¼8.0 Hz), 4.26 (t, 3H, J¼4.8 Hz), 3.76 (s, 6H), 3.59 (s, 3H), 2.59 (d,
2H, J¼4.4 Hz), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 172.0,
3.2.10. Diethyl-1-(2,4-dimethylphenyl)-4-(2-ethoxy-2-oxoethyl)-1,4-
167.2, 140.6, 138.1, 136.5, 130.3, 120.8, 107.5, 51.6, 51.4, 40.6, 29.5,
20.9; ESI-HRMS: Calcd for C19H21NO6Na [MþNa]þ: 382.1261;
Found: 382.1262.
dihydropyridine-3,5-dicarboxylate (3j). Yellow solid; mp 76e77 ꢀC;
1H NMR (400 MHz, CDCl3):
d 7.23 (s, 2H), 7.10 (s, 1H), 7.06 (s, 2H),
4.30 (t, 1H, J¼4.8 Hz), 4.24e4.18 (m, 4H), 4.11e4.05 (m, 2H), 2.61 (d,
2H, J¼4.8 Hz), 2.35 (s, 3H), 2.27 (s, 3H), 1.28 (t, 6H, J¼7.6 Hz), 1.22 (t,
3.2.18. Dimethyl-1-(4-bromophenyl)-4-(2-methoxy-2-oxoethyl)-1,4-
3H, J¼7.2 Hz); 13C NMR (100 MHz, CDCl3):
d
170.3, 165.3, 138.5,
dihydropyridine-3,5-dicarboxylate (3r). Yellow liquid; 1H NMR
138.1, 136.8, 132.4, 130.7, 126.3, 124.4, 104.8, 58.6, 58.5, 39.0, 28.0,
19.5, 16.0, 12.8, 12.7; ESI-HRMS: Calcd for C23H29NO6Na [MþNa]þ:
438.1887; Found: 438.1891.
(400 MHz, CDCl3):
d
7.55 (d, 4H, J¼2.4 Hz), 7.13 (s, 2H), 4.23 (t, 1H,
J¼4.4 Hz), 3.78 (s, 6H), 3.59 (s, 3H), 2.61 (d, 2H, J¼4.4 Hz); 13C NMR
(100 MHz, CDCl3):
d 171.9, 166.9, 141.9, 137.4, 132.9, 122.3, 119.7,
108.5, 51.7, 51.4, 40.3, 29.4; ESI-HRMS: Calcd for C18H18NO6BrNa
3.2.11. Diethyl-4-(2-ethoxy-2-oxoethyl)-1-phenyl-1,4-
[MþNa]þ: 446.0210; Found: 446.0235.
dihydropyridine-3,5-dicarboxylate (3k).7 Yellow liquid; 1H NMR
(400 MHz, CDCl3):
d
7.59 (s, 2H), 7.43 (t, 1H, J¼7.6 Hz), 7.27 (s, 1H),
3.2.19. Dimethyl-4-(2-methoxy-2-oxoethyl)-1-(4-methoxyphenyl)-
7.23 (d, 2H, J¼7.2 Hz), 4.28e4.22 (m, 5H), 4.05e4.01 (m, 2H), 2.60
1,4-dihydropyridine-3,5-dicarboxylate (3s). Yellow solid; mp
(d, 2H, J¼4.8 Hz), 1.31 (t, 6H, J¼6.8 Hz), 1.18 (t, 3H, J¼7.2 Hz); 13C
95e96 ꢀC; 1H NMR (400 MHz, CDCl3):
d 7.49 (s, 2H), 7.16 (d, 2H,
NMR (100 MHz, CDCl3):
d
171.7, 166.8, 143.1, 137.7, 129.8, 126.4,
J¼9.2 Hz), 6.93 (d, 2H, J¼8.8 Hz), 4.25 (t, 1H, J¼4.8 Hz), 3.82 (s, 3H),
120.8, 108.3, 60.4, 60.1, 40.5, 29.6, 14.4, 14.2.
3.76 (s, 6H), 3.60 (s, 3H), 2.59 (d, 2H, J¼4.8 Hz); 13C NMR (100 MHz,
CDCl3):
d 172.0, 167.2, 158.2, 138.6, 136.5, 122.9, 114.9, 107.1, 55.6,
3.2.12. Diethyl-4-(2-ethoxy-2-oxoethyl)-1-isopropyl-1,4-
51.5, 51.4, 40.6, 29.4; ESI-HRMS: Calcd for C19H21NO7Na [MþNa]þ:
dihydropyridine-3,5-dicarboxylate (3l). Yellow liquid; 1H NMR
398.1210; Found: 398.1209.
(400 MHz, CDCl3):
d 7.23 (s, 2H), 4.22e4.18 (m, 5H), 4.06e4.00 (m,
2H), 3.66e3.62 (m, 1H), 2.45 (d, 2H, J¼4.8 Hz), 1.30 (t, 12H,
3.2.20. Dimethyl-1-(2-chlorophenyl)-4-(2-methoxy-2-oxoethyl)-1,4-
J¼6.4 Hz), 1.21 (t, 3H, J¼7.2 Hz); 13C NMR (100 MHz, CDCl3):
d
171.6,
dihydropyridine-3,5-dicarboxylate (3t). Yellow liquid; 1H NMR
166.9, 137.2, 105.8, 59.9, 59.8, 55.4, 40.8, 30.0, 21.9, 14.3, 14.1; ESI-
(400 MHz, CDCl3):
d
7.50 (d, 1H, J¼7.6 Hz), 7.34 (d, 3H, J¼2.0 Hz),
HRMS: Calcd for
376.1727.
C
18H27NO6Na [MþNa]þ: 376.1731; Found:
7.32 (s, 2H), 4.28 (t, 1H, J¼4.8 Hz), 3.75 (s, 6H), 3.64 (s, 3H), 2.63 (d,
2H, J¼5.2 Hz); 13C NMR (100 MHz, CDCl3):
d 171.9, 167.0, 140.4,
139.1,131.0,130.5,129.4,128.2,127.4,107.1, 51.6, 51.4, 40.5, 29.3; ESI-
HRMS: Calcd for C18H18NO6ClNa [MþNa]þ: 402.0715; Found:
402.0725.
3. 2.13. Diethyl-1-butyl-4-(2-ethoxy-2-oxoethyl)-1, 4-
dihydropyridine-3,5-dicarboxylate (3m).7 Yellow liquid; 1H NMR
(400 MHz, CDCl3):
d 7.13 (s, 2H), 4.21e4.19 (m, 5H), 4.06e4.01 (m,
2H), 3.31 (t, 2H, J¼6.4 Hz), 2.46 (d, 2H, J¼2.8 Hz), 1.61 (t, 2H,
3.2.21. Dimethyl-1-(2,4-dimethylphenyl)-4-(2-methoxy-2-oxoethyl)-
J¼6.8 Hz), 1.37 (t, 2H, J¼6.8 Hz), 1.29 (t, 6H, J¼6.4 Hz), 1.21 (t, 3H,
1,4-dihydropyridine-3,5-dicarboxylate (3u). Yellow liquid; 1H NMR

6098
D. Hu et al. / Tetrahedron 71 (2015) 6094e6098
F.; Gruciani, G.; Zhorov, B. S.; Chiarini, A.; Budriesi, R. Curr. Med. Chem. 2012, 19,
(400 MHz, CDCl3): d 7.26 (s, 2H), 7.10 (s, 2H), 7.06 (s, 2H), 4.30 (t, 1H,
4306.
J¼4.8 Hz), 3.74 (s, 3H), 3.64 (s, 3H), 2.62 (d, 2H, J¼4.8 Hz), 2.35 (s,
2. (a) Singh, R. K.; Prasad, D. N.; Bhardwaj, T. R. Med. Chem. Res. 2015, 24, 1534; (b)
Shekari, F.; Sadeghpour, H.; Javidnia, K.; Saso, L.; Nazari, F.; Firuzi, O.; Min, R. Eur.
J. Pharmacol. 2015, 746, 233; (c) Hilgeroth, A.; Baumert, C.; Coburger, C.; Seifert,
M.; Krawczyk, S.; Hempel, C.; Neubauer, F.; Krug, M.; Molnar, J.; Lage, H. Med.
Chem. 2013, 9, 487; (d) Locatelli, A.; Cosconati, S.; Micucci, M.; Leoni, A.; Ma-
rinelli, L.; Bedini, A.; Ioan, P.; Spampinato, S. M.; Novellino, E.; Chiarini, A.; Bu-
driesi, R. J. Med. Chem. 2013, 56, 3966; (e) Sirisha, K.; Bikshapathi, D.; Achaiah, G.;
3H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
172.0, 167.2, 139.9,
139.8, 138.4, 133.7, 132.2, 127.9, 125.8, 106.0, 51.4, 52.3, 40.5, 29.4,
20.9, 17.5; ESI-HRMS: Calcd for C20H23NO6Na [MþNa]þ: 396.1418;
Found: 396.1415.
~
Reddy, V. M. Eur. J. Med. Chem. 2011, 46, 1564; (f) Reimao, J. Q.; Scotti, M. T.;
3.2.22. Diethyl-4-(2-ethoxy-2-oxoethyl)-1,4-dihydropyridine-3,5-
Tempone, A. G. Bioorg. Med. Chem. 2010, 18, 8044.
dicarboxylate (3v). Yellow liquid; 1H NMR (400 MHz, CDCl3):
d 7.55
3. (a) Rudler, H.; Parlier, A.; Hamon, L.; Herson, P.; Daran, J. C. Chem. Commun. 2008,
4150; (b) Schmaunz, C. E.; Mayer, P.; Wanner, K. T. Synthesis 2014, 46, 1630.
4. For reviews on 1,4-DHPs synthesis, see: (a) Stout, D. M.; Meyers, A. I. Chem. Rev.
1982, 82, 223; (b) Wan, J.-P.; Liu, Y. RSC Adv. 2012, 2, 9763.
(s, 1H), 7.32 (d, 2H, J¼5.2 Hz), 4.22e4.19 (m, 5H), 4.08e4.03 (m, 2H),
2.49 (d, 2H, J¼3.2 Hz), 1.30 (t, 6H, J¼6.8 Hz), 1.24 (t, 3H, J¼8.4 Hz);
13C NMR (100 MHz, CDCl3):
d 172.4, 167.2, 136.1, 105.3, 60.2, 60.1,
5. Hantzsch, A. Justus Liebigs Ann. Chem. 1882, 215, 1.
41.0, 29.7, 14.3, 14.0; ESI-HRMS: Calcd for C15H21NO6Na [MþNa]þ:
6. (a) Liu, L.; Sarkisian, R.; Deng, Y.; Wang, H. J. Org. Chem. 2013, 78, 5751; (b) Wen,
L.-R.; Liu, C.; Li, M.; Wang, L.-J. J. Org. Chem. 2010, 75, 7605; (c) Wan, J.-P.; Zhou,
R.; Liu, Y.; Cai, M. RSC Adv. 2013, 3, 2477; (d) Kumar, R.; Andhare, N. H.; Shard, A.;
Richa; Sinha, A. K. RSC Adv. 2014, 4, 19111; (e) Safari, J.; Zarnegar, Z. RSC Adv. 2013,
3, 26094; (f) Gati, W.; Rammah, M. M.; Rammah, M. B.; Evano, G. Beilstein J. Org.
Chem. 2012, 8, 2214; (g) Liu, Y.-p.; Liu, J.-m.; Wang, X.; Cheng, T.-m.; Li, R.-t.
Tetrahedron 2013, 69, 5242; (h) Sun, J.; Sun, Y.; Gao, H.; Yan, C.-G. Eur. J. Org.
Chem. 2011, 6952; (i) Yan, S.-H.; Zhao, F.-Y.; Liu, H.-Y.; Deng, J.; Zhang, Z.-H. J.
Heterocycl. Chem. 2012, 49, 1126; (j) Yang, J.; Wang, C.; Xie, X.; Li, H.; Li, Y. Eur. J.
Org. Chem. 2010, 4189; (k) Jiang, H.; Mai, R.; Cao, H.; Zhu, Q.; Liu, X. Org. Biomol.
Chem. 2009, 7, 4943.
334.1261; Found: 334.1264.
Acknowledgements
The work is financially supported by the Natural Science Foun-
dation of Jiangxi Province (20151BAB203008) and Jiangxi Normal
University.
7. Sirijindalert, T.; Hansuthirakul, K.; Rashatasakhon, P.; Sukwattanasinitt, M.;
Ajavakom, A. Tetrahedron 2010, 66, 5161.
Supplementary data
8. (a) Wan, J.-P.; Lin, Y.; Huang, Q.; Liu, Y. J. Org. Chem. 2014, 79, 7232; (b) Wan, J.-P.;
Lin, Y.; Hu, K.; Liu, Y. Beilstein J. Org. Chem. 2014, 10, 287; (c) Wan, J.; Zhou, Y.; Liu,
Y.; Fang, Z.; Wen, C. Chin. J. Chem. 2014, 32, 219; (d) Wan, J.-P.; Lin, Y.; Jing, Y.; Xu,
M.; Liu, Y. Tetrahedron 2014, 70, 7874; (e) Wan, J.-P.; Zhou, Y.; Jiang, K.; Ye, H.
Synthesis 2014, 46, 3256.
Supplementary data (1H and 13C NMR spectra of all products)
related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2015.06.101.
9. For reaction based-on this kind of transamination, see: (a) Wan, J.-P.; Zhou, Y.;
Cao, S. J. Org. Chem. 2014, 79, 9872; (b) Cao, S.; Xin, L.; Liu, Y.; Wan, J.-P.; Wen, C.
RSC Adv. 2015, 5, 27372; (c) Wan, J.-P.; Wang, C.; Pan, Y. Tetrahedron 2011, 67, 922;
(d) Liu, Y.; Zhou, R.; Wan, J.-P. Synth. Commun. 2013, 43, 2475; (e) Muthusar-
avanan, S.; Sasikumar, C.; Bala, B. D.; Perumal, S. Green. Chem. 2014, 16, 1297; (f)
Cao, S.; Jing, Y.; Liu, Y.; Wan, J.-P. Chin. J. Org. Chem. 2014, 34, 876.
References and notes
1. (a) Hilgeroth, A. Mini-Rev. Med. Chem. 2002, 2, 235; (b) Ioan, P.; Carosati, E.;
Micucci, M.; Gruciani, G.; Broccatelli, F.; Zhorov, B. S.; Chiarini, A.; Budriesi, R.
Curr. Med. Chem. 2011, 18, 4901; (c) Carosati, E.; Ioan, P.; Micucci, M.; Broccatelli,