Studies on chemoselective synthesis of 1,4- And 1,2-dihydropyridine derivatives by a Hantzsch-like reaction: A combined experimental and DFT study

Article abstract of DOI:10.1039/d0ob02289f

In the experimental process of preparing diethyl 3,5-dicarboxylate-1,4-dihydropyridine (1,4-DHP) by a Hantzsch-like reaction, it was found that a by-product named diethyl 3,5-dicarboxylate-1,2-dihydropyridine (1,2-DHP) was produced in the reaction. To discuss this phenomenon, the effects of the reaction conditions on the yield ratio of 1,4-DHP and 1,2-DHP were studied by using aromatic amines, aromatic aldehydes and ethyl propiolate as raw materials. The mechanisms for the formation of 1,4-DHP and 1,2-DHP were proposed based on the isolated intermediate named diethyl 4-((phenylamino)methylene)pent-2-enedioate generated by the Michael addition of aniline and ethyl propiolate. The transition state structures were optimized and the reaction energy barriers of intermediates in the speculated mechanisms were calculated by DFT calculations at the M062X/def2TZVP//B3LYP-D3/def-SVP level. It was found that the reaction energy barriers and dominant configurations of intermediates IM2 and IM3′ are the determinants for the chemoselectivity. Together, these results demonstrate a high chemoselectivity in the synthesis of 1,4-DHPs and 1,2-DHPs by a Hantzsch-like reaction and that 1,4-DHPs and 1,2-DHPs can be easily obtained under different conditions. This journal is

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Studies on chemoselective synthesis of 1,4- and
1,2-dihydropyridine derivatives by a Hantzsch-like
reaction: a combined experimental and DFT study†
Cite this: Org. Biomol. Chem., 2021,
19, 3882
Peng Li, Shijie Wang, Nana Tian, Hong Yan, * Juan Wang* and Xiuqing Song
In the experimental process of preparing diethyl 3,5-dicarboxylate-1,4-dihydropyridine (1,4-DHP) by a
Hantzsch-like reaction, it was found that a by-product named diethyl 3,5-dicarboxylate-1,2-dihydropyri-
dine (1,2-DHP) was produced in the reaction. To discuss this phenomenon, the effects of the reaction
conditions on the yield ratio of 1,4-DHP and 1,2-DHP were studied by using aromatic amines, aromatic
aldehydes and ethyl propiolate as raw materials. The mechanisms for the formation of 1,4-DHP and 1,2-
DHP were proposed based on the isolated intermediate named diethyl 4-((phenylamino)methylene)pent-
2-enedioate generated by the Michael addition of aniline and ethyl propiolate. The transition state struc-
tures were optimized and the reaction energy barriers of intermediates in the speculated mechanisms
were calculated by DFT calculations at the M062X/def2TZVP//B3LYP-D3/def-SVP level. It was found that
the reaction energy barriers and dominant configurations of intermediates IM2 and IM3’ are the determi-
nants for the chemoselectivity. Together, these results demonstrate a high chemoselectivity in the syn-
thesis of 1,4-DHPs and 1,2-DHPs by a Hantzsch-like reaction and that 1,4-DHPs and 1,2-DHPs can be
easily obtained under different conditions.
Received 18th November 2020,
Accepted 29th March 2021
DOI: 10.1039/d0ob02289f
rsc.li/obc
The synthesis of 1,4-DHPs was first reported by Hantzsch in
the 1880s, which was performed by one-pot condensation of
Introduction
There are five possible isomers in dihydropyridines (DHPs) aldehydes with ethyl acetoacetate and ammonia either in
due to the position difference of double bonds; among them, acetic acid or by refluxing in alcohols.10 Since then, there has
1,4-dihydropyridines (1,4-DHPs) and 1,2-dihydropyridines (1,2- been continuous research on the improvement of the
DHPs) are the two most common isomers.1,2 1,4-DHPs have Hantzsch reaction. The application of simple multifunctional
widely been used as a critical scaffold for the synthesis of synthetic building blocks based on α,β-unsaturated ketenes,
calcium channel inhibitors. Clinically, 1,4-DHPs represented aldehydes and amines has greatly promoted the development
by nifedipine have developed into an important class of drugs of new methods for the synthesis of 1,4-DHPs. To date, multi-
for treating cardiovascular and cerebrovascular diseases.3,4 1,4- component synthesis based on the Hantzsch reaction, also
DHPs also have important applications in the fields of anti- called a Hantzsch-like reaction, has become the main way to
tumor drugs and antibacterial drugs.3,5–7 Unlike 1,4-DHPs, 1,2- synthesize 1,4-DHPs.11–15 The synthesis of 1,2-DHPs was first
DHPs cannot directly show biological pharmacological activi- reported by Fowler, which was performed by sodium boro-
ties, but they have served as important raw materials for the hydride reduction of N-acylpyridinium salts.16 Since then, the
synthesis of many natural alkaloids and drugs with biological reduction method of pyridinium salts has been widely used in
activities.1,8 For example, 1,2-DHPs were used as the lead com- the synthesis of 1,2-DHPs.17–21 In addition, the annulation
pounds for the synthesis of 2-azabicyclo[2.2.2]octane, which is reaction between unsaturated imines and alkynes has also
an important skeleton for the synthesis of iberg base, potato been used for the formation of 1,2-DHPs.22–27
base and oseltamivir.9
When diethyl 3,5-dicarboxylate-1,4-dihydropyridine (1,4-
DHP) was synthesized by a Hantzsch-like reaction with ethyl
propiolate as the synthetic block, it was found that a by-
product named diethyl 3,5-dicarboxylate-1,2-dihydropyridine
(1,2-DHP) appeared in the reaction (Scheme 1). The similarity
of polarity between the two DHPs increased the difficulty of
separation and purification. By exploring the reaction con-
ditions, and according to the guidance of the possible mecha-
Beijing Key Laboratory of Environmental and Viral Oncology, Faculty of Environment
and Life, Beijing University of Technology, Beijing 100124, P. R. China.
E-mail: hongyan@bjut.edu.cn, juanwang@bjut.edu.cn
†Electronic supplementary information (ESI) available: 1H NMR and 13C NMR
spectra of new compounds. See DOI: 10.1039/d0ob02289f
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Scheme 1 Synthesis of 1,4-DHPs 4 and 1,2-DHPs 5 by a Hantzsch-like reaction.
Table 2 Effect of the catalyst on the yield and yield ratio of 4a and 5aa
nism, 1,4-DHP and 1,2-DHP derivatives were produced with
high chemoselectivity under different conditions, which is of
great significance in terms of chemical reaction efficiency and
atom economy. To the best of our knowledge, a theoretical
mechanistic study of the chemoselectivity of 1,4-DHPs and 1,2-
DHPs in a Hantzsch-like reaction has never been reported.
These study results will provide us with an in-depth under-
standing of the essential reasons for the simultaneous pro-
duction of 1,4-DHP and 1,2-DHP in a Hantzsch-like reaction
and provide experimental and theoretical foundations for the
following studies of chemical synthesis and drug development
based on these two types of DHP skeletons.
Yieldc (%)
Yield ratio
Entry
Catalyst
Timeb (h)
4a
5a
(4a : 5a)
1
2
3
4
5
6
AcOH
TFA
p-TsOH
AlCl3
TiCl4
—
12
12
8
12
12
48
56
59
63
53
51
Trace
12
15
15
13
4.7 : 1
3.9 : 1
4.2 : 1
4.1 : 1
6.4 : 1
—
8
Trace
a All reactions were carried out with 1 equivalent of both aldehyde and
amine and 2 equivalents of ethyl propiolate, with ethanol as the
solvent and heated to reflux until the reaction was complete. b The
reaction time was determined by complete conversion of aniline moni-
tored by TLC. c Isolated yields after column chromatography.
Results and discussion
Synthesis of 1,4-DHPs 4
It can be seen from Table 1 that the reaction solvent and
temperature have no obvious influence on the yields of 4a and
5a; the yields of 4a and 5a were about 50% and 10% respect-
ively except in DCM. The yields of 4a and 5a were 56% and
12% respectively in ethanol at a temperature of 78 °C, and they
were 37% and 18% in DMSO at a high temperature of 189 °C
in a relatively short reaction time. The reaction solvent and
temperature have no obvious influence on the yield ratio of 4a
and 5a; the ratio is about 5 : 1 except in DCM and DMSO. This
shows that too high or too low reaction temperature is not con-
ducive to the reaction.
As can be seen from Table 2, different catalysts have
medium impacts on the yield and production efficiency of 4a
and 5a. Generally speaking, the catalytic effect of a protonic
acid is the best, and the yield of 4a increases with the enhance-
ment of protonic acid acidity. When p-TsOH is used as the
catalyst, the reaction effect is the best, and the reaction time is
8 h. The catalysts had no obvious influence on the yield ratios
of 4a and 5a; the ratio was about 5 : 1.
At the beginning, our original intention was to synthesize 1,4-
DHPs. However, when 1,4-DHPs were synthesized by the multi-
component synthesis method with ethyl propiolate as the syn-
thetic block, it was found that a small amount of 1,2-DHPs
was produced in the reaction. In order to discuss this phenom-
enon, taking the synthesis of diethyl 1,4-diphenyl-1,4-dihydro-
pyridine-3,5-dicarboxylate (4a) as an example, the effects of the
reaction conditions on the yields and yield ratios of 4 and 5
were studied. The effects of the solvent, temperature and cata-
lyst on the yields and yield ratios of 4a and 5a were investigated
and are shown in Tables 1 and 2.
Table 1 Effect of the solvent and temperature on the yield and yield
ratio of 4a and 5aa
Yieldc (%)
T
(°C)
Timeb
(h)
Yield ratio
(4a : 5a)
Entry
Solvent
4a
5a
Referring to the above experimental results, ethanol was
used as the solvent and p-TsOH as the catalyst, and ten
different substituted 1,4-DHPs (4) were synthesized at the
reflux temperature; the yields and yield ratios of 4 and 5 are
shown in Table 3.
It can be seen from Table 3 that the substituents of alde-
hydes and amines have a certain influence on the yield of 4.
When the substituents of amines are the same, the yields of 4
with aromatic aldehydes were higher than those with aliphatic
aldehydes, which can been seen from the yields of 4a (63%,
R1 = Ph, R2 = Ph), 4j (55%, R1 = H, R2 = Ph), 4f (59%, R1 = 4-Cl-
1
2
3
4
5
6
7
8
EtOH
78
12
10
12
12
12
24
17
12
56
37
52
50
50
Trace
48
12
18
11
8
14
Trace
14
10
4.7 : 1
2.1 : 1
4.7 : 1
6.3 : 1
3.6 : 1
—
DMSO
1,4-Dioxane
CH3CN
DCE
DCM
THF
189
101
82
84
40
66
110
3.4 : 1
5.1 : 1
Toluene
51
a All reactions were carried out with 1 equivalent of both aldehyde and
amine and 2 equivalents of ethyl propiolate, with 10% equivalent of
glacial acetic acid as the catalyst. b The reaction time was determined
by complete conversion of aniline monitored by TLC. c Isolated yields
after column chromatography.
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Table 3 Yields and yield ratios of 4 and 5a
Yieldb (%)
Entry
R1
R2
4
5
Yield ratio (4 : 5)
1
2
3
4
5
6
7
8
9
10
Ph
4-Br-Ph
Ph
Ph
Ph
4-Br-Ph
H
H
H
H
H
H
Ph
4a, 63
4b, 65
4c, 61
4d, 56
4e, 50
4f, 59
4g, 55
4h, 53
4i, 54
4j, 55
5a, 15
5b, 10
5c, 12
5d, 11
5e, 13
5f, 9
4.2 : 1
6.5 : 1
5.1 : 1
5.1 : 1
3.8 : 1
6.6 : 1
6.9 : 1
5.3 : 1
4.2 : 1
3.7 : 1
Ph
Fig. 1 Stereochemistry determination of intermediate 6a.
4-CH3-Ph
4-Cl-Ph
H
CH3
CH3CH2
H
5g, 8
5h, 10
5i, 13
5j, 15
H and the hydrogen of C2H/C3H; meanwhile, weak NOE cross-
peaks between NH and CH3 (1.40, 10.72 ppm) were observed
(Fig. 2). Moreover, if the s-cis conformation exists singly, the
NOE cross-peaks between C4′H and C2H (7.76, 6.19 ppm) will
be more intensive than those between C4′H and C3H (7.76,
a All reactions were carried out with 1 equivalent of both aldehyde and
amine and 2 equivalents of ethyl propiolate, with ethanol as the
solvent and 10% equivalent of p-TsOH as the catalyst and heated to
reflux until the reaction was complete. b Isolated yields after column 7.48 ppm) or the NOE cross-peaks between C4′H and C3H will
chromatography.
not be observed; if the s-trans conformation exists singly, only
the NOE cross-peaks between C4′H and C3H (7.76, 7.48 ppm)
can be observed. But in fact, two NOE cross-peaks were
Ph, R2 = H) and 4h (53%, R1 = CH3, R2 = H). The yield of 4 is
improved when the substituent on aromatic aldehyde is an
electron-withdrawing group, for example, the yield of 4f (R1 =
4-Cl-Ph, R2 = H) was 59% and those of 4d (R1 = Ph, R2 = H) and
4e (R1 = 4-CH3-Ph, R2 = H) were 56% and 50%, respectively.
When using the same aldehyde, the yields of 4 with aromatic
amines were higher than that of ammonium acetate, which
can be seen from the yields of 4a (63%, R1 = Ph, R2 = Ph), 4d
(56%, R1 = Ph, R2 = H), 4g (55%, R1 = H, R2 = H) and 4j (55%,
R1 = H, R2 = Ph). The different substituted aldehydes and
amines have no obvious influence on the yield of 5; the yield
of 5 was about 10%, and the yield ratio of 4 and 5 was about
5 : 1.
observed and the NOE cross-peaks between C4′H and C3H
(7.76, 7.48 ppm) are more intensive, indicating the presence of
s-trans/s-cis equilibrium and the dominant conformation is the
s-trans conformation. The results of stereochemistry are con-
sistent with the previous literature which reported the con-
struction of a functionalized conjugated diene motif using a
silica gel-promoted method.28
The discovery of 6a has great significance to explore the syn-
thetic conditions and speculate the reaction mechanism. It
can be seen from Tables 1–3 that a small amount of 1,2-DHPs
(5) is always produced in the reactions. This fact makes us
wonder why a small amount of 1,2-DHPs exists when 1,4-DHPs
are produced in this reaction. To clarify this phenomenon, a
mechanistic study of these reaction pathways was performed
by DFT calculations. Given the little effects of substituents on
the chemoselectivity of 1,4-DHPs and 1,2-DHPs, the synthesis
reaction of 4a and 5a was used as a model for theoretical calcu-
lations. Referring to the literature on the synthesis of DHPs
and the separation of intermediate 6a, mechanisms were pro-
posed for the formation of 1,4-DHP and 1,2-DHP
(Scheme 3).1,29,30 There are two paths for this process: path a
is the formation of 1,4-DHP 4a and path b is the formation of
1,2-DHP 5a. In path a, trans intermediate IM2 is first gener-
ated. Then, intermediate IM3 is produced through a nucleo-
philic substitution reaction between IM2 and benzaldehyde.
Later, after intramolecular H migration and a rearrangement
reaction and loss of a molecule of water, intermediate IM4 is
obtained. After that, an intermolecular [4 + 2] cyclization reac-
tion between intermediate IM4 and ethyl propiolate occurs
and finally 4a is obtained. Different from path a, in path b, cis
IM3′ is first generated by the Michael addition reaction of
ethyl propiolate and aniline. Subsequently, zwitterionic inter-
mediate IM4′ is formed by the Michael addition of IM3′ onto
ethyl propiolate. This zwitterionic intermediate is reactive and
can be stabilized by proton transfer to give intermediate 6a.
Then, 6a and a Schiff base intermediate produced by the
nucleophilic addition reaction of benzaldehyde and aniline
Theoretical calculation analysis
It’s worth mentioning that the major byproduct 6a was iso-
lated in about 8% yield during the synthesis of 1,4-DHP 4a,
which can continue reacting with an equivalent amount of
benzaldehyde and aniline, and finally a certain amount of 5a
was obtained (Scheme 2). The products 6a were isolated as
s-trans-(2E,4Z)-diethyl-4-((phenylamino)methylene)pent-2-ene-
dioate and s-cis-(2E,4Z)-diethyl-4-((phenylamino)methylene)
pent-2-enedioate (Fig. 1). The 2E stereochemistry was estab-
lished on the basis of the large JH,H value of 15.7 Hz between
the C2 hydrogen atom and the C3 hydrogen atom, while the
4Z stereochemistry was inferred on the basis of the fact that
the diagonal signals were observed, correlation at (7.76,
6.19 ppm) and (7.76, 7.48 ppm), assigned to the proton of C4′
Scheme 2 Synthesis of 1,2-DHPs 5a from byproduct 6a.
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Fig. 2 (a) NOESY spectrum of 6a and (b) local amplified NOESY spectrum of 6a.
Scheme 3 Possible mechanism of 1,4-DHPs 4 and 1,2-DHPs 5.
undergo an intermolecular [4 + 2] cyclization reaction to
obtain intermediate IM6′. Ultimately, 1,2-DHP 5a is generated
through proton transfer and elimination of aniline as well as a
rearrangement reaction.
In order to investigate the favorable paths shown in
Scheme 3, DFT calculations were carried out at the M062X/
def2TZVP//B3LYP-D3/def-SVP level, and the calculations
included the solvent effect. For the sake of simplicity, the cata-
lytic effect is not considered. The calculated free energies of
path a and path b are shown in Fig. 3. The optimized struc-
tures of the pivotal intermediate (IM) and transition states (TS)
are presented in the ESI.†
In the following discussion, the Gibbs free energies of ethyl
Fig. 3 Energy profile of path a for 4a and path b for 5a without consid-
ering the catalytic effect.
propiolate and aniline were set as the energy reference point.
All structures were optimized using one low energy confor-
mation throughout. For the sake of simplicity, a full confor-
mational search of those structures was not performed and
there may be other conformations with lower energy, but the verify this, the energies of the key intermediates and transition
energy differences between different conformations are likely states of other conformations (denoted “New”) were calculated
very small and therefore unlikely to affect our conclusions. To and the data are presented in the ESI.† In summary, for
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14-DHP, Original_IM2: −36.88 kcal mol−1 vs. New_IM2:
As shown in Fig. 4, there are three steps in the process of
−37.40 kcal mol−1, Original_TS3: −5.63 kcal mol−1 vs. New_TS3: 1,3-H migration to generate trans intermediate IM2; the barrier
−6.35 kcal mol−1, Original_IM3: −26.87 kcal mol−1 vs. New_IM3: can be lowered by using a water H-transfer shuttle. Compared
−26.90 kcal mol−1, Original_TS4: 21.04 kcal mol−1 vs. New_TS4: with direct 1,3-H migration, the barrier is reduced by 9.64 and
21.73 kcal mol−1. For 12-DHP, Original_6a: −71.56 kcal mol−1 vs. 13.14 kcal mol−1 respectively by using one water molecule and
New_6a: −71.27 kcal mol−1, Original_TS6′: −31.82 kcal mol−1 vs. two water molecules as the H-transfer shuttle. In the process
New_TS6′: −33.38 kcal mol−1
.
of the transformation from IM2 to IM4, when the catalysis of
As shown in Fig. 3, in the process of forming 1,4-DHP 4a, acetic acid and water is considered, the barrier is also reduced.
the rate-determining states are IM2 and TS4,31 which thus has
As shown in Fig. 5, a direct transformation from IM1′ to
a barrier of 57.92 kcal mol−1. In the process of forming 1,2- IM3′ was found with the help of a water proton-transfer
DHP 5a, the rate-determining states are 2 + 3a and TS2′, which shuttle. The transition state energy can be further lowered to
thus has a barrier of 69.35 kcal mol−1. The calculated barrier 49.42 (TS3′_W) and 37.28 kcal mol−1 (TS3′_2W), respectively.
is too high, so it is necessary to consider the influence of the During the conversion of IM4′ to 6a, the energy barrier was
catalyst on the reaction path. Specifically, in the process of the reduced by 8.86 kcal mol−1 using a water proton-transfer
hydrogen transfer reaction, it is necessary to consider the shuttle.
influence of some traces of water or solvent since those proton
The specific mechanism for theoretical calculations was
transfer processes might be facilitated by a proton-transfer speculated with the synthesis of 4a and 5a as a model
shuttle.32 In the nucleophilic addition reaction, the effect of (Scheme 4). The calculated free energies of path a and path b
traces of acid on the reaction should be considered.
are shown in Fig. 6.
Fig. 4 Energy profile from IM1 to IM2 (a) and IM2 to IM4 (b) facilitated by the proton-transfer shuttles.
Fig. 5 Energy profile from IM1’ to IM3’ (a) and IM4’ to 6a (b) facilitated by the proton-transfer shuttles.
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Scheme 4 Specific mechanism of 1,4-DHPs 4 and 1,2-DHPs 5.
Fig. 6 Energy profile of path a for 4a and path b for 5a catalyzed by water and HOAc.
As shown in Fig. 6, there are two steps in the process of the help of a water proton-transfer shuttle to form IM3′; the
Michael addition of aniline onto ethyl propiolate to generate barrier of these two steps is 37.28 kcal mol−1. IM3′ passed
trans intermediate IM2. First, the nitrogen atom of aniline through 4 transition states (TS4′, TS5′_W, TS6′, TS7′) and 3
attacked the terminal carbon atom of ethyl propiolate to form intermediates (IM4′, 6a, IM6′) to finally generate 5a. The rate-
intermediate IM1 through transition state TS1. Then IM1 determining states of the reaction are 6a and TS6′, which thus
underwent 1,3-H migration to form IM2; the barrier of these has a barrier of 39.74 kcal mol−1
two steps is 26.12 kcal mol−1. IM2 passed through 3 transition
.
The formation energy barrier of IM3′ is higher than that of
states (TS3_HOAc, TS4_W, TS5) and 2 intermediates (IM3, IM2 (37.28 kcal mol−1 vs. 26.12 kcal mol−1), and the same ten-
IM4) to finally generate 4a. The rate-determining states of the dency can also be noticed when comparing their free energies
reaction are IM2 and TS4_W, which thus has a barrier of (IM2: −36.88 kcal mol−1; IM3′: −29.62 kcal mol−1), suggesting
48.39 kcal mol−1
.
that the generation of IM2 is more favorable than that of IM3′
Similarly, the production of cis intermediate IM3′ also both kinetically and thermodynamically. Starting from IM2, 4a
needs two steps. Intermediate IM1′ was formed firstly through is finally obtained, and starting from IM3′, 5a is obtained, so
transition state TS1′. Then it underwent 1,3-H migration with the yield of 4a is greater than that of 5a in this reaction.
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Table 5 Effect of the material ratio on the yield of 5a
Synthesis of 1,2-DHPs 5
The reason why a small amount of 5a is always produced in
the synthesis reaction of 4a was found through a mechanistic
study of the reaction pathways by DFT calculations. Under the
guidance of this result, the synthesis process of 1,2-DHPs 5
was explored. It was found that the essential step in the syn-
thesis process of 5a is the intermolecular [4 + 2] cyclization
reaction between 6a and a Schiff base intermediate which
was produced by the nucleophilic addition reaction of benz-
aldehyde and aniline. In order to overcome the reaction
energy barriers, a microwave reaction experiment was con-
ducted. We noticed that 4a is the dominant product in the
one-pot experiment. In order to obtain the inferior product
5a instead of 4a, it seems feasible to design a stepwise one-
pot reaction, and the reaction design route is shown in
Scheme 5.
Material ratio
(1a : 2 : 3a)
Timea
(h)
Yield, 5ab
(%)
Yield, 4ab
(%)
Entry
1
2
3
4
5
6
7
1 : 2 : 2
1 : 2 : 1.5
1 : 2 : 3
2 : 2 : 2
1 : 4 : 2
1 : 6 : 2
1 : 8 : 2
3
3
3
3
3
3
3
22
14
20
20
28
46
46
Trace
Trace
Trace
Trace
Trace
Trace
Trace
a Total time for 3 steps. b Total yield of the three-step reaction, isolated
yields after column chromatography.
Then, under the conditions of ethanol as a solvent, a micro-
wave power of 120 W and a temperature of 78 °C, the influence
of the material ratio on the yield of 5a was investigated. The
results are presented in Table 5.
Firstly, using ethanol as a solvent to carry out the reaction
at the reflux temperature, the influence of the microwave
power on the yield of 5a was studied. The results are presented
in Table 4.
It can be seen from Table 5 that the yield of 5a was basi-
cally unchanged upon increasing the amount of benz-
aldehyde (1a) with the same amount of ethyl propiolate (2)
and aniline (3a). When the amounts of 2 and 1a were
unchanged, the yield of 5a increased with increasing amount
of 3a. The yield of 5a increased with increasing amount of 2
when the amounts of 3a and 1a were unchanged. When
1a : 2 : 3a = 1 : 6 : 2, the yield of 5a reached the maximum, and
4a was not produced in all reactions, thus realizing the selec-
tive synthesis of 5a.
Ten different substituted 1,2-DHPs (5) were synthesized at
the reflux temperature and under microwave irradiation using
ethanol as the solvent. The yields are shown in Table 6.
It can be seen from Table 6 that the substituents of alde-
hydes and amines have a certain influence on the yield of 5.
When the substituents of amines are the same, the yields of 5
It can be seen that the microwave power has significant
influence on the yield and production efficiency of 5a. When
the microwave power is 80 W, the yield of 5a is only 12% and
the reaction time is 4 h. When the microwave power is 120 W,
the reaction time decreases to 3 h and the yield of 5a increases
to 22%. Compared with 120 W, when the microwave power is
increased to 150 W, the yield shows only a slight increase, but
it can be clearly observed from TLC that the reaction system
becomes miscellaneous, which increases the difficulty of sep-
aration. This shows that too high or too low power is not con-
ducive to the reaction.
Table 6 The yields of 1,2-dihydropyridine-3,5-dicarboxylates 5a
Entry
R1
R2
5, yieldb (%)
1
2
3
4
5
6
7
8
9
Ph
4-Br-Ph
Ph
Ph
Ph
4-Br-Ph
H
H
H
H
H
H
Ph
5a, 46
5b, 49
5c, 39
5d, 41
5e, 38
5f, 44
5g, 27
5h, 37
5i, 35
5j, 31
Ph
Scheme 5 A stepwise one-pot synthesis of 1,2-DHPs 5 under micro-
wave irradiation.
4-CH3-Ph
4-Cl-Ph
H
CH3
CH3CH2
H
10
Table 4 Effect of the microwave power on the yield of 5a
a All reactions were carried out by a stepwise one-pot method. 3 equiva-
lents of ethyl propiolate and 1 equivalent of aniline were heated with
ethanol as the solvent under microwave irradiation with a power of 120
W; after 1 hour, mixture 1 was obtained. Meanwhile, 1 equivalent of
benzaldehyde and 1 equivalent of aniline were added into a round
bottom flask with ethanol as the solvent and 10% equivalent of
p-TsOH as the catalyst and heated to reflux under microwave
irradiation with a power of 120 W to obtain mixture 2. Then, mixture 2
was added to mixture 1 and heated for 1 hour at 120 W microwave
Microwave
power (W)
Timea
(h)
Yield, 5ab
(%)
Yield, 4ab
(%)
Entry
1
2
3
4
80
4
4
3
3
12
15
22
23
Trace
Trace
Trace
Trace
100
120
150
a Total time for 3 steps. b Total yield of the three-step reaction, isolated power. b Total yield of the three-step reaction, isolated yields after
yields after column chromatography.
column chromatography.
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with aromatic aldehydes were higher than those with aliphatic (TLC) was conducted on silica gel 60 F254 plates (Merck
aldehydes, which can be seen from the yields of 5a (46%, R1 = KGaA). The NMR experiments were performed on a Bruker
1
Ph, R2 = Ph) and 5j (41%, R1 = H, R2 = Ph). The yields of 5 (R1 Avance 400 spectrometer at 400 MHz for H NMR spectra and
= aryl) were improved by an electron-withdrawing group, for 100 MHz for 13C NMR spectra at ambient temperature (25 °C)
example, the yield of 5f (R1 = 4-C1-Ph, R2 = H) was 44% and using CDCl3 as the solvent and tetramethylsilane (TMS) as the
that of 5d (R1 = Ph, R2 = H) was 41%. When using the same internal standard. Electrospray ionization mass spectra
aldehyde, the yields of 5 with aromatic amines were higher (ESI-MS) were measured on a ZAB-HS & ESQUIRE6000 mass
than that of ammonium acetate, which can be seen from the spectrometer.
yields of 5a (46%, R1 = Ph, R2 = Ph) and 5d (41%, R1 = Ph, R2 =
H). When the substituent on the aromatic amine is an elec-
Computational details
tron-withdrawing group, the nucleophilic activity of the aro- The geometrical structures of all the stationary points along
matic amine is reduced, such as 5a (46%, R1 = Ph, R2 = Ph) the reaction paths were optimized at the B3LYP-D3/def-SVP
and 5c (39%, R1 = Ph, R2 = 4-Br-Ph). It was also worth mention- theoretical level.33–37 Frequency analysis calculations were
ing that 1,4-DHP derivatives 4 were not found in all reactions; carried out at the same level to classify the located stationary
the chemoselectivity is excellent in the case of the stepwise points as minima (no imaginary frequency) and transition
one-pot reaction.
states (only one imaginary frequency). The thermodynamic
correction data used in this paper were obtained at 298.15 K
and 1 atm. Intrinsic reaction coordinate (IRC) pathways have
also been calculated for all the transition states to determine
whether these transition states could connect the reactants,
Conclusion
A series of diethyl 3,5-dicarboxylate-1,4-dihydropyridines (1,4- intermediates or products.38 The single point energies of all
DHPs) were synthesized with moderate yields by a Hantzsch-like the optimized structures were calculated at the M062X/def2-
reaction using aromatic amines, aromatic aldehydes and ethyl TZVP level.39,40 The polarized continuum model (PCM) was
propiolate as raw materials. Unexpectedly, it was found that a used in a Self-Consistent Reaction Field (SCRF) for modelling
by-product named diethyl 3,5-dicarboxylate-1,2-dihydropyridine ethanol solvent.41,42 All of the quantum chemical calculations
(1,2-DHP) was produced in the reaction. Based on the results of were performed using the Gaussian 09 program package.43
the effects of the reaction conditions on the yield and yield ratio The diagrams of molecular structures were plotted using the
of 1,4-DHPs and 1,2-DHPs, especially on the separation of the CYLview program and the electrostatic potential (ESP) on the
intermediate named diethyl-4-((phenylamino)methylene)pent-2- molecular vdW surface was rendered using the VMD 1.9.2
enedioate, the possible mechanisms for the formation of 1,4- software.44,45 All other wavefunction analyses were performed
DHPs and 1,2-DHPs were speculated. DFT calculations were using Multiwfn 3.8.46
used to optimize the transition state structures and calculate
the energy barriers of the intermediates at the M062X/
General synthetic procedures
def2TZVP//B3LYP-D3/def-SVP level. In the paths of the synthesis
General procedure for the synthesis of 1,4-hydropyridines
of 1,4-DHPs and 1,2-DHPs, the reaction energy barriers and (4). 2 mmol ethyl propiolate, 1 mmol aniline and 1 mmol
dominant configurations of intermediates IM2 and IM3′ are the benzaldehyde were added into a round bottom flask with
determinants for the chemoselectivity. The trans intermediate ethanol as the solvent and 0.1 mmol p-TsOH as the catalyst.
IM2 was formed with an energy barrier of 26.12 kcal mol−1 and Under nitrogen protection, the reaction mixture was heated to
the cis intermediate IM3′ was formed with an energy barrier of reflux until the completion of the reaction (TLC detection).
37.28 kcal mol−1
. The free energies of IM2 and IM3′ After cooling to room temperature, the solvent was removed by
(−36.88 kcal mol−1 and −29.62 kcal mol−1) also suggest that the reduced pressure distillation, 10 mL of water was added, and
formation of 1,4-DHPs is more favorable than that of 1,2-DHPs the mixture was extracted with ethyl acetate (10 mL × 3). The
thermodynamically. Under the guidance of the theoretical cal- organic phase was dried over anhydrous sodium sulfate. The
culation results, the synthesis process of 1,2-DHPs was explored solvent was removed in vacuo and the residue was purified by
through a stepwise one-pot reaction. In order to overcome the flash chromatography on silica gel (petroleum ether/ethyl
reaction energy barriers and decrease the reaction time, a acetate = 20 : 1 to 8 : 1) to obtain a light yellow solid of 1,4-dihy-
microwave irradiation experiment was conducted. Finally, 1,4- dropyridines 4.
DHPs and 1,2-DHPs were obtained with high chemoselectivity
by a Hantzsch-like reaction under different conditions.
Diethyl
1,4-diphenyl-1,4-dihydropyridine-3,5-dicarboxylate
(4a).25 Yield 63%; H NMR (400 MHz, chloroform-d) δ: 7.67 (s,
2H), 7.47 (dd, J = 8.7, 7.2 Hz, 2H), 7.39–7.34 (m, 2H), 7.34–7.27
(m, 4H), 7.24 (s, 1H), 7.20–7.14 (m, 1H), 4.96 (s, 1H), 4.19–4.03
(m, 4H), 1.20 (t, J = 7.1 Hz, 6H). 13C NMR (100 MHz, chloro-
form-d) δ: 166.80, 146.10, 143.21, 135.55, 129.93, 128.40,
128.04, 126.58, 126.33, 120.75, 111.06, 60.27, 37.74, 14.24.
1
Experiments and methods
Physical measurements
All chemicals were purchased from commercial sources and
Diethyl
4-(4-bromophenyl)-1-phenyl-1,4-dihydropyridine-3,5-
used without further purification. Thin-layer chromatography dicarboxylate (4b).25 Yield 65%; 1H NMR (400 MHz, chloro-
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form-d) δ: 7.66 (s, 2H), 7.50–7.44 (m, 2H), 7.41–7.36 (m, 2H),
Diethyl 4-((phenylamino)methylene)pent-2-enedioate (6a).28
7.34–7.28 (m, 3H), 7.25 (d, J = 8.2 Hz, 2H), 4.94 (s, 1H), 4.11 Yield 8%; 1H NMR (400 MHz, chloroform-d) δ: 10.77 (d, J =
(m, 4H), 1.20 (t, J = 7.1 Hz, 6H). 13C NMR (100 MHz, chloro- 13.1 Hz, 1H), 7.76 (d, J = 13.1 Hz, 1H), 7.48 (d, J = 15.7 Hz, 1H),
form-d) δ 166.59, 145.19, 143.07, 135.74, 131.13, 130.18, 7.36 (dd, J = 8.5, 7.3 Hz, 2H), 7.18–7.03 (m, 3H), 6.19 (d, J =
129.98, 126.51, 120.79, 120.48, 110.55, 60.38, 37.38, 14.26.
Diethyl
15.7 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 4.22 (q, J = 7.1 Hz, 2H),
1-(4-bromophenyl)-4-phenyl-1,4-dihydropyridine-3,5- 1.40 (t, J = 7.2 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H). 13C NMR
dicarboxylate (4c).15 Yield 61%; 1H NMR (400 MHz, chloro- (100 MHz, chloroform-d) δ: 168.97, 168.42, 147.73, 142.29,
form-d) δ: 7.61 (s, 2H), 7.62–7.53 (m, 2H), 7.38–7.32 (m, 2H), 139.38, 129.88, 124.38, 116.60, 111.05, 98.59, 60.44, 59.91,
7.29–7.23 (m, 2H), 7.21–7.14 (m, 3H), 4.95 (s, 1H), 4.18–4.03 14.48, 14.42.
(m, 4H), 1.20 (t, J = 7.1 Hz, 6H). 13C NMR (100 MHz, chloro-
General procedure for the synthesis of 1,2-hydropyridines
form-d) δ 166.62, 145.77, 142.18, 134.94, 132.99, 128.39, (5). 3 mmol ethyl propiolate and 1 mmol aniline were heated
128.09, 126.68, 122.20, 119.44, 111.63, 60.40, 37.70, 14.22.
under microwave irradiation with a power of 120 W and at a
Diethyl 4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate (4d).47 temperature of 78 °C; after 1 hour, mixture 1 was obtained.
1
Yield 56%; H NMR (400 MHz, chloroform-d) δ: 7.38–7.31 (m, Meanwhile, 1 mmol benzaldehyde and 1 mmol aniline were
2H), 7.31–7.21 (m, 4H), 7.19–7.11 (m, 1H), 6.81 (brs, 1H), 4.89 added into a round bottom flask with ethanol as the solvent
(s, 1H), 4.16–3.98 (m, 4H), 1.19 (t, J = 7.1 Hz, 6H). 13C NMR and 0.1 mmol p-TsOH as the catalyst and heated to reflux
(100 MHz, chloroform-d) δ: 167.26, 146.97, 133.87, 128.29, under microwave irradiation with a power of 120 W until the
127.96, 126.41, 108.32, 60.04, 37.65, 14.19.
completion of the reaction (TLC detection) to obtain mixture
Diethyl 3,5-dicarboxylate-4-(p-tolyl)-1,4-dihydropyridine-3,5- 2. Then, mixture 2 was added to mixture 1 and heated for
dicarboxylate (4e).48 Yield 50%; 1H NMR (400 MHz, chloro- 1 hour at 120 W microwave power. After cooling to room temp-
form-d) δ: 7.29 (d, J = 5.3 Hz, 2H), 7.22 (d, J = 7.8 Hz, 2H), 7.05 erature, the solvent was removed by reduced pressure distilla-
(d, J = 7.7 Hz, 2H), 6.55–6.52 (m, 1H), 4.85 (s, 1H), 4.16–3.99 tion, 10 mL of water was added, and the mixture was extracted
(m, 4H), 2.28 (s, 3H), 1.20 (t, J = 7.1 Hz, 6H). 13C NMR with ethyl acetate (10 mL × 3). The organic phase was dried
(100 MHz, chloroform-d) δ 167.22, 144.12, 135.90, 133.61, over anhydrous sodium sulfate. The solvent was removed in
128.71, 128.16, 108.55, 60.05, 37.12, 21.12, 14.25.
vacuo and the residue was purified by flash chromatography
Diethyl 4-(4-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxy- on silica gel (petroleum ether/ethyl acetate = 20 : 1 to 8 : 1) to
late (4f).49 Yield 59%; 1H NMR (400 MHz, chloroform-d) δ: obtain a light yellow oil of 1,2-dihydropyridines 5.
7.33 (m, 2H), 7.30–7.26 (m, 2H), 7.23–7.18 (m, 2H), 6.41 (d, J =
Diethyl
1,2-diphenyl-1,2-dihydropyridine-3,5-dicarboxylate
1
13.0 Hz, 1H), 4.88 (s, 1H), 4.17–4.00 (m, 4H), 1.19 (t, J = 7.1 Hz, (5a).27 Yield 46%; H NMR (400 MHz, chloroform-d) δ: 8.11 (s,
6H). 13C NMR (101 MHz, chloroform-d) δ: 166.95, 145.44, 1H), 7.72 (s, 1H), 7.45–7.37 (m, 2H), 7.37–7.27 (m, 5H),
133.73, 132.10, 129.72, 128.10, 108.23, 60.18, 37.21, 14.23.
7.25–7.11 (m, 3H), 6.16 (s, 1H), 4.33–4.15 (m, 4H), 1.34 (t, J =
Diethyl 1,4-dihydropyridine-3,5-dicarboxylate (4g).47 Yield 7.2 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, chloro-
1
55%; H NMR (400 MHz, chloroform-d) δ: 7.10 (d, J = 5.0 Hz, form-d) δ: 165.84, 165.78, 144.87, 144.44, 141.47, 130.68,
2H), 6.60 (brs, 1H), 4.24–4.13 (m, 4H), 3.25 (s, 2H), 1.28 (t, J = 129.52, 128.76, 128.15, 126.19, 125.94, 121.06, 114.48, 103.43,
7.1 Hz, 6H). 13C NMR (100 MHz, chloroform-d) δ: 167.73, 61.22, 60.56, 60.08, 14.55, 14.36.
135.08, 104.15, 60.01, 21.71, 14.37.
Diethyl
2-(4-bromophenyl)-1-phenyl-1,2-dihydropyridine-
Diethyl 4-methyl-1,4-dihydropyridine-3,5-dicarboxylate (4h).50 3,5-dicarboxylate (5b). Yield 49%; H NMR (400 MHz, chloro-
Yield 53%; 1H NMR (400 MHz, chloroform-d) δ: 7.20 (d, J = 5.2 form-d) δ: 8.08 (t, J = 1.2 Hz, 1H), 7.72 (d, J = 1.1 Hz, 1H),
Hz, 2H), 6.63 (brs, 1H), 4.26–4.12 (m, 4H), 3.79 (q, J = 6.4 Hz, 7.43–7.39 (m, 2H), 7.38–7.31 (m, 2H), 7.31–7.20 (m, 3H),
1H), 1.32–1.26 (m, 6H), 1.11 (d, J = 6.4 Hz, 3H). 13C NMR 7.16–7.11 (m, 2H), 6.12 (d, J = 1.3 Hz, 1H), 4.30–4.25 (m, 2H),
(100 MHz, chloroform-d) δ: 167.54, 134.33, 108.98, 59.97, 4.25–4.12 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H), 1.29 (t, J = 7.1 Hz,
1
26.30, 23.31, 14.39.
3H). 13C NMR (100 MHz, chloroform-d) δ: 165.70, 165.65,
Diethyl 4-ethyl-1,4-dihydropyridine-3,5-dicarboxylate (4i). 144.84, 144.21, 140.39, 131.91, 130.88, 129.65, 127.77, 126.43,
Yield 54%; 1H NMR (400 MHz, chloroform-d) δ: 7.30 (d, J = 5.3 122.20, 121.07, 114.07, 103.41, 60.78, 60.69, 60.19, 14.55,
Hz, 2H), 6.35 (brs, 1H), 4.26–4.12 (m, 4H), 3.92 (t, J = 4.6 Hz, 14.37. HRMS (ESI), m/z calcd 456.0805 for C23H23BrNO4 [M +
1H), 1.49 (qd, J = 7.5, 4.4 Hz, 2H), 1.29 (t, J = 7.1 Hz, 6H), 0.79 H]+, found 456.0802.
(t, J = 7.5 Hz, 3H); 13C NMR (100 MHz, chloroform-d) δ:
167.61, 135.23, 106.68, 59.97, 31.78, 28.19, 14.40, 8.63. HRMS dicarboxylate (5c). Yield 39%; H NMR (400 MHz, chloroform-
(ESI), m/z calcd 254.1387 for C23H24NO4 [M + H]+, found d) δ: 8.04 (t, J = 1.3 Hz, 1H), 7.70 (d, J = 1.0 Hz, 1H), 7.47–7.41
Diethyl
1-(4-bromophenyl)-2-phenyl-1,2-dihydropyridine-3,5-
1
254.1385.
(m, 2H), 7.41–7.35 (m, 2H), 7.33–7.26 (m, 3H), 7.06–7.00 (m,
Diethyl 1-phenyl-1,4-dihydropyridine-3,5-dicarboxylate (4j).47 2H), 6.09 (d, J = 1.2 Hz, 1H), 4.32–4.06 (m, 4H), 1.34 (t, J = 7.1
Yield 55%; H NMR (400 MHz, chloroform-d) δ: 7.47–7.37 (m, Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, chloro-
1
4H), 7.26–7.16 (m, 3H), 4.23 (q, J = 7.1 Hz, 4H), 3.34 (s, 2H), form-d) δ: 165.72, 165.61, 144.11, 143.42, 141.06, 132.58,
1.30 (t, J = 7.1 Hz, 6H). 13C NMR (100 MHz, chloroform-d) δ: 130.39, 128.89, 128.35, 125.89, 122.40, 119.39, 115.12, 104.07,
167.31, 143.20, 136.95, 129.78, 125.91, 120.29, 107.08, 60.28, 61.12, 60.69, 60.24, 14.54, 14.36. HRMS (ESI), m/z calcd
21.98, 14.45.
456.0805 for C23H23BrNO4 [M + H]+, found 456.0806.
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Diethyl 2-phenyl-1,2-dihydropyridine-3,5-dicarboxylate (5d). 118.70, 110.81, 102.71, 60.43, 59.93, 47.42, 14.55, 14.41. HRMS
1
Yield 41%; H NMR (400 MHz, chloroform-d) δ: 7.74 (s, 1H), (ESI), m/z calcd 302.1387 for C17H20NO4 [M + H]+, found
7.63 (d, J = 7.0 Hz, 1H), 7.40 (d, J = 7.3 Hz, 2H), 7.31 (m, 3H), 302.1391.
5.75 (s, 1H), 5.66 (s, 1H), 4.21 (q, J = 7.3 Hz, 2H), 4.10 (m, 2H),
1.30 (t, J = 7.2 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz, chloroform-d) δ: 166.06, 166.01, 146.57, 143.56,
Conflicts of interest
132.83, 128.76, 128.30, 126.76, 112.90, 97.05, 60.23, 59.71,
55.45, 14.53, 14.23. HRMS (ESI), m/z calcd 302.1387 for There are no conflicts to declare.
C17H20NO4 [M + H]+, found 302.1391.
Diethyl 2-(p-tolyl)-1,2-dihydropyridine-3,5-dicarboxylate (5e).
1
Yield 38%; H NMR (400 MHz, chloroform-d) δ: 7.73 (s, 1H),
Acknowledgements
7.62 (d, J = 6.9 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 7.9
Hz, 2H), 5.73–5.66 (m, 1H), 5.62 (d, J = 2.7 Hz, 1H), 4.21 (q, J = This study was supported by the 2019 Beijing Natural Science
7.1 Hz, 2H), 4.15–4.02 (m, 2H), 2.32 (s, 3H), 1.30 (t, J = 7.1 Hz, Foundation (Grant No. 2192004).
3H), 1.22 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, chloroform-d)
δ: 165.92, 165.89, 146.07, 140.83, 138.24, 132.44, 129.48,
126.71, 113.52, 97.39, 60.21, 59.71, 55.27, 21.18, 14.57, 14.27.
Notes and references
HRMS (ESI), m/z calcd 316.1543 for C18H22NO4 [M + H]+,
found 316.1541.
Diethyl 2-(4-chlorophenyl)-1,2-dihydropyridine-3,5-dicarboxy-
late (5f). Yield 44%; H NMR (400 MHz, chloroform-d) δ: 7.72
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1
(d, J = 1.5 Hz, 1H), 7.62 (dd, J = 6.9, 1.5 Hz, 1H), 7.34–7.26 (m,
4H), 6.07 (dd, J = 7.4, 3.0 Hz, 1H), 5.63 (d, J = 2.9 Hz, 1H), 4.19
(q, J = 7.1 Hz, 2H), 4.15–4.03 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H),
1.22 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, chloroform-d) δ:
165.89, 165.81, 146.28, 142.01, 134.18, 132.80, 128.94, 128.19,
112.93, 97.42, 60.38, 59.85, 54.85, 14.54, 14.26. HRMS (ESI),
m/z calcd 336.0997 for C17H19ClNO4 [M + H]+, found 336.1002.
Diethyl 1,2-dihydropyridine-3,5-dicarboxylate (5g). Yield 27%;
1H NMR (400 MHz, chloroform-d) δ: 7.58 (dd, J = 7.2, 1.5 Hz,
1H), 7.49 (d, J = 1.4 Hz, 1H), 5.88 (s, 1H), 4.42–4.36 (m, 2H),
4.18 (p, J = 7.1 Hz, 4H), 1.29 (td, J = 7.1, 5.3 Hz, 6H). 13C NMR
(100 MHz, chloroform-d) δ: 166.12, 165.88, 149.35, 134.10,
108.38, 97.42, 60.25, 59.58, 41.86, 14.54, 14.38. HRMS (ESI),
m/z calcd 226.1074 for C11H16NO4 [M + H]+, found 226.1071.
Diethyl 2-methyl-1,2-dihydropyridine-3,5-dicarboxylate (5h).
3 S. Valente, P. Mellini, F. Spallotta, V. Carafa, A. Nebbioso,
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1
Yield 37%; H NMR (400 MHz, chloroform-d) δ: 7.62–7.56 (m,
2H), 5.64 (s, 1H), 4.69 (qd, J = 6.3, 3.4 Hz, 1H), 4.20 (qd, J = 7.1,
3.8 Hz, 4H), 1.30 (td, J = 7.1, 3.6 Hz, 6H), 1.21 (d, J = 6.3 Hz,
3H). 13C NMR (100 MHz, chloroform-d) δ: 166.06, 165.97, 10 A. Hantzsch, Ber. Dtsch. Chem. Ges., 1881, 14, 1637–1638.
146.60, 132.44, 113.79, 98.03, 60.18, 59.65, 47.22, 22.59, 14.56, 11 M. Maheswara, V. Siddaiah, Y. K. Rao, Y.-M. Tzeng and
14.39. HRMS (ESI), m/z calcd 240.1230 for C12H18NO4 [M +
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H]+, found 240.1235.
Diethyl 2-ethyl-1,2-dihydropyridine-3,5-dicarboxylate (5i). Yield
1
35%; H NMR (400 MHz, chloroform-d) δ: 7.67–7.59 (m, 2H), 13 S. Maiti, P. T. Perumal and J. C. Menéndez, Tetrahedron,
5.85 (s, 1H), 4.56 (dt, J = 7.6, 3.8 Hz, 1H), 4.27–4.14 (m, 4H),
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