First organocatalytic asymmetric synthesis of 1-Benzamido-1,4-Dihydropyridine Derivatives

Article abstract of DOI:10.3390/molecules23102692

Preliminary results concerning the first asymmetric synthesis of highly functionalized 1-benzamido-1,4-dihydropyridine derivatives via the reaction of hydrazones with alkylidenemalononitriles in the presence of β-isocupreidine catalyst are reported. The m

Full text of DOI:10.3390/molecules23102692

molecules
Communication
First Organocatalytic Asymmetric Synthesis of
1-Benzamido-1,4-Dihydropyridine Derivatives
Fernando Auria-Luna, Eugenia Marqués-López and Raquel P. Herrera *
Laboratorio de Organocatálisis Asimétrica, Departamento de Química Orgánica, Instituto de Síntesis Química y
Catálisis Homogénea (ISQCH) CSIC-Universidad de Zaragoza, C/Pedro Cerbuna 12, E-50009 Zaragoza, Spain;
ferauria@unizar.es (F.A.-L.); mmaamarq@unizar.es (E.M.-L.)
* Correspondence: raquelph@unizar.es; Tel.: +34-97676-1190
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 30 September 2018; Accepted: 17 October 2018; Published: 19 October 2018
Abstract:
functionalized 1-benzamido-1,4-dihydropyridine derivatives via the reaction of hydrazones
with alkylidenemalononitriles in the presence of -isocupreidine catalyst are reported. The moderate,
Preliminary results concerning the first asymmetric synthesis of highly
β
but promising, enantioselectivity observed (40–54% ee), opens the door to a new area of research for
the asymmetric construction of new chiral 1,4-dihydropyridine derivatives, whose enantioselective
catalytic preparation are still very limited. Moreover, the use of hydrazones for the enantioselective
construction of chiral 1,4-dihydropyridines has been overlooked in the literature so far. Therefore,
our research represents a pivotal example in this field which remains still unexplored.
Keywords: chiral base; 1,4-dihydropyridine; enantioselective; hydrazone; organocatalysis
1. Introduction
1,4-Dihydropyridine (1,4-DHP) [
1
–
5] ring is a challenging structural core in organic chemistry
due to its biological properties [ ], especially as calcium channel blockers (Figure 1) [10,
6
–
9
11]. It is
noteworthy that its range of application has been recently extended to other affections such as
antioxidant, antidiabetic and antitumor agents [12].
NO2
N
O
N
CF3
O
CO2tBu
BnN
MeO2C
H3C
NO2
iPrO2C
H3C
NO2
CO2Me
CH3
EtO2C
H3C
CO2Et
CH3
O
N
CH3
N
CH3
H3C
N
N
H
H
H
H
Barnidipine
Lacidipine
Bay K 8644
PN 202-791
Figure 1. 1,4-Dihydropyridine based drugs as calcium channel blockers.
Therefore, the potential of 1,4-dihydropyridines as valuable building blocks in organic synthesis
has attracted the attention of many scientists [13 14]. Moreover, it has been found that the
,
stereochemistry at C-4 can be related with both qualitative and quantitative differences in their
biological activity. Thus, the control of the stereoselectivity in this chiral center has become an inspiring
task of research and, therefore, there is a growing interest for the development of new enantioselective
methods. However, there are only a few examples of organocatalytic enantioselective syntheses to
obtain these compounds [15,16].
Recently, we have successfully contributed to this field with two pioneering works
(Scheme 1) [16,17]. In the first example, we used Takemoto’s thiourea to synthesize chiral
Molecules 2018, 23, 2692; doi:10.3390/molecules23102692
www.mdpi.com/journal/molecules

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2-oxospiro-[indole-3,40-(10,40-dihydropyridine)] derivatives
1
with good reactivity and promising
enantioselectivities (Scheme 1, route a) [17]. The most recent work has allowed us to obtain for the first
time a family of substituted chiral 1,4-dihydropyridines
derivative as organocatalyst (Scheme 1, route b) [16].
2 with very good results, using a bis-cinchona
Scheme 1. Synthesis of highly substituted chiral 1,4-DHPs 1 (route a) [17]) and 2 (route b) [16]).
Related to our work reported herein, we must remark that Yan and co-workers previously
published two interesting racemic versions using benzohydrazides 3, instead of anilines, in two
concomitant multicomponent processes to obtain 1-benzamidospiro[indoline-3,40-pyridines]
4 [18] or
benzamido-1,4-dihydropyridines 5 [19] (Scheme 2).
Based on this idea, we envisioned that the use of chiral amine-based catalysts could provide
the first asymmetric version of a related reaction. Moreover, to the best of our knowledge, the use
of hydrazones for the enantioselective construction of 1,4-dihydropyridines has been overlooked
in the literature so far. It is worth noting that the development of new asymmetric strategies to
obtain enantioenriched 1,4-DHPs is still desirable since there are only scarce examples in this field of
research [15,16].

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Scheme 2. Synthesis of highly substituted benzamidospiro[indoline-3,40-pyridines]
4 [18] and
benzamido-1,4-dihydropyridines 5 [19].
2. Results and Discussion
2.1. Synthesis of Starting Materials: Hydrazones 7 and Alkylidenemalononitriles 9
On the base of our recent works [16
hydrazones could provide the same reactivity as reported in Schemes 1 and 2. With this aim in mind,
we firstly synthesized six different hydrazones 7a–f as described below in Scheme 3.
,17], we hypothesized that the enamine generated from
7
Scheme 3. Preparation of hydrazones 7a–f.
Hydrazones
differently substituted benzohydrazides
(electron-withdrawing or electron-donating groups or none of them) (Scheme 3). In contrast to our
previous works [16 17], the reaction between alkynyl and hydrazide leads to pure hydrazones
instead of the corresponding enamine (shown in Scheme 1), as previously obtained by us in the
reaction between alkynyl 6 and an aniline.
The preparation of diverse alkylidenemalononitriles 9a
general procedure described in Scheme 4, in quantitative yields [17].
7
were prepared after 12 h at room temperature with quantitative yields from
3
, bearing different electronic properties in the aromatic ring
,
6
3
7
–
m was further performed, following the

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Scheme 4. Synthesis of alkylidenemalononitriles 9a–m.
2.2. Screening of the Reaction Conditions
To carry out the synthesis of the first chiral 1-benzamido-1,4-dihydropyridine derivatives 10
17], we foresaw that a chiral organic base catalyst could promote this reaction, starting directly from
the preformed intermediates: hydrazones and malononitriles , giving rise to the desired final
[16,
7
9
benzamido-1,4-dihydropyridines 10. To explore the viability of this hypothesis, the efficiency of
different chiral organocatalysts I-X, with a base moiety in their structure, was initially studied in a
model reaction between hydrazone 7a and malononitrile 9a (Scheme 5).
Scheme 5. Chiral organocatalysts I-X tested to synthesize chiral 1,4-DHPs 10aa. Rac. = racemic mixture.
N.d. = not determined.

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As reported in Scheme 5, the most promising value of enantioselectivity was achieved with
-isocupreidine (32% ee), while the best reactivity was found with (DHQ)2Phal VI (81% yield).
β
X
These results encouraged us to continue with both catalysts VI and
X in the subsequent screening of
different parameters to optimize this process (Table 1).
Table 1.
Screening of the reaction conditions for the synthesis of chiral
1-benzamido-1,4-dihydropyridine 10aa a.
Yield (%) b
Entry
Solvent (mL)
7a (mmol)
9a (mmol)
Cat. (mol%)
ee (%) c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
MeCN (0.5)
MeCN (0.5)
AcOEt (0.5)
AcOEt (0.5)
CH2Cl2 (0.5)
CH2Cl2 (0.5)
CHCl3 (0.5)
CHCl3 (0.5)
Et2O (0.5)
Et2O (0.5)
THF (0.5)
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.15
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.15
0.1
0.15
0.15
0.15
0.15
VI (20%)
X (20%)
VI (20%)
X (20%)
VI (20%)
X (20%)
VI (20%)
X (20%)
VI (20%)
X (20%)
VI (20%)
X (20%)
VI (20%)
X (20%)
X (20%)
X (20%)
X (20%)
X (20%)
X (10%)
X (30%)
>95
56
72
54
67
35
44
49
26
39
54
54
>95
77
61
51
58
48
57
61
7
10
20
40
15
d
Rac.
24
33
25
40
17
50
THF (0.5)
d
MeOH (0.5)
MeOH (0.5)
THF (0.5)
THF (0.5)
THF (0.25)
THF (1)
Rac.
Rac.
d
50
49
46
52
48
46
THF (0.5)
THF (0.5)
a Otherwise indicated: To a mixture of catalyst VI or
X
(20 mol%) and hydrazone 7a (0.1 mmol), in the corresponding
b
solvent (0.5 mL), alkylidenemalononitrile 9a (0.1 mmol) was added. Isolated yield after column chromatography
c
(SiO2, Hex:Et2O 20:80 to Hex:Et2O 0:100). Determined by chiral HPLC analysis (Daicel Chiralpak IC, Hex:iPrOH
d
70:30, 1 mL/min). Racemic mixture.
As shown in Table 1, parameters such as solvent, concentration of the reaction, amount of each
reagent and catalyst were analyzed. In general, catalyst VI still provided better reactivity in some
reactions media, such as MeCN, AcOEt, CH2Cl2 or MeOH (entries 1, 3, 5 and 13), in comparison with
catalyst
in almost all solvents (except in CH2Cl2, entry 6). The best compromise in terms of reactivity and
enantioselectivity was achieved in THF (entries 12, 15–20) using catalyst . Concentration of the
X (entries 2, 4, 6 and 14). However, better enantioselectivities were found with catalyst X
X
reaction medium led to a slight decrease in the enantioselectivity of the process with a smooth increase
of the reactivity (entry 17). The opposite behavior is true when the reaction was diluted (entry 18).
Variations in the amount of catalyst did not provide an appreciable improvement of the process (entries
19 and 20). Increasing the amount of reagents 7a or 9a gave rise to similar results in both cases (entries
15 and 16), although the use of 1.5 equivalent of 9a led to slightly better reactivity (entry 15). Therefore,
we continue to the ensuing exploration of the scope of the reaction with these conditions (entry 15),
as they are the best ones at this stage.

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2.3. Scope of the Reaction
Once the reaction conditions were optimized, a series of 1-benzamido-1,4-dihydropyridine
derivatives 10 were synthesized as shown in Scheme 6.
The final products 10 were isolated with high yields (up to 99%) and with moderate but
promising enantioselectivities (up to 54% ee) since this work represents the first chiral version to
obtain enantioenriched 1-benzamido-1,4-dihydropyridines. The results suggest a dependence of the
reactivity of the process on the electronic properties of the aromatic ring in the alkylidenemalononitriles
9
, since electron-withdrawing groups (4-NO2, 3-NO2, 3-Cl, 4-Cl, 4-Br or 4-CN) or heteroaromatic rings
(2-furyl, 2-thienyl, 3-pyridyl) afforded better results in comparison with electrondonating substituents
(4-Me and 4-MeO) or in the absence of substituents (1-naphthyl or phenyl). On the other hand,
the enantioselectivity of the process does not have a clear correlation with the electronic properties of
the aromatic ring in the alkylidenemalononitriles
1-benzamido-1,4-dihydropyridines 10 changing the substituent in the aromatic ring of the hydrazone
7b ), achieving more similar results in terms of enantioselectivity and reactivity than those obtained
with hydrazone 7a.
Based on our previously reported works for the obtainment of chiral 1,4-dihydropyridine
derivatives [16 17], in the field of cinchona alkaloids and in our own experience using this kind
of organocatalysts [20 22], we think that the same mechanism could be operating in this case [16 17].
Thus, a first Michael addition reaction between the enamine generated in situ from hydrazones and
the alkylidenemalononitriles , followed by an intramolecular nucleophilic cyclization and a final
tautomerization would yield 1-benzamido-1,4-dihydropyridines 10. However, in order to really know
if -isocupreidine is acting as a bifunctional catalyst [23 25] and to better understand the role of this
structure, more studies are ongoing in our lab.
9. Interestingly, we were able to obtain the desired
(
–f
,
–
,
7
9
β
X
–

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R
NC
CN
O
N
R1
NC H2N
N
O
R
X (20 mol%)
NH
CO2Me
NH
+
R1
THF
r.t., 120 h
MeO2C
7a-f
7a R = H
MeO2C
CO2Me
9a-m
9a R1 = H
9b R1 = 4-NO2Ph 9i R1 = 4-MePh
9c R1 = 3-NO2Ph 9j R1 = 4-MeOPh
9d R1 = 3-ClPh
9e R1 = 4-ClPh
9f R1 = 4-BrPh
9g R1 = 4-CNPh
10
9h R1 = 1-naphthyl
7b R = NO2
7c R = Cl
7d R = Br
8k R1 = 2-furyl
7e R = t-Bu
7f R = OMe
9l R1 = 2-thienyl
9m R1 = 3-pyridyl
NC H2N
O
NC H2N
O
NC H2N
N
O
NO2
Cl
Br
N
NH
N
NH
NH
MeO2C
CO2Me
MeO2C
CO2Me
MeO2C
10da
CO2Me
10ba
56% yield
45% ee
10ca
75% yield
43% ee
60% yield
44% ee
NC H2N
N
O
NC H2N
N
O
tBu
OMe
NH
NH
MeO2C
10ea
CO2Me
MeO2C
10fa
CO2Me
58% yield
48% ee
55% yield
42% ee
O2N
NC H2N
N
O
Cl
NC H2N
NC H2N
O
O
NH
O2N
N
NH
N
NH
MeO2C
10ac
CO2Me
MeO2C
10ab
CO2Me
MeO2C
CO2Me
10ad
70% yield
52% ee
89% yield
51% ee
95% yield
46% ee
NC H2N
N
O
NC H2N
N
O
NC H2N
N
O
NC
NH
Br
Cl
NH
NH
MeO2C
10ag
CO2Me
MeO2C
10af
CO2Me
MeO2C
10ae
CO2Me
70% yield
50% ee
61% yield
52% ee
99% yield
50% ee
H2N
N
O
NC H2N
N
O
NC
NC H2N
N
O
OMe
NH
NH
Me
NH
MeO2C
CO2Me
MeO2C
CO2Me
MeO2C
CO2Me
10ah
51% yield
50% ee
10ai
44% yield
50% ee
10aj
44% yield
40% ee
NC H2N
N
O
NC H2N
O
NC H2N
O
NH
N
NH
N
NH
O
S
N
MeO2C
CO2Me
MeO2C
CO2Me
MeO2C
CO2Me
10ak
70% yield
54% ee
10al
76% yield
43% ee
10am
92% yield
40% ee
Scheme 6. Scope of the reaction to obtain 1-benzamido-1,4-dihydropyridine derivatives 10.

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3. Materials and Methods
3.1. General Experimental Methods
Purification of reaction products was carried out by column chromatography using silical-gel
(0.063–0.200 mm). Analytical thin layer chromatography was performed on 0.25 mm silical gel 60-F
plates. ESI (Zaragoza, Spain) and MicroTof-Q Bruker mass analyzer (Zaragoza, Spain) were used for
HRMS measurements. HPLC was performed on analytical HPLC Waters (Delta 600 Separation Module,
2996 Photodiode Array Detector, Zaragoza, Spain). IR spectra have been registered in a PerkinElmer
Spectrum 100 FT-IR Spectrometer (Zaragoza, Spain). The optical rotation measurements were taken
on a JASCO Digital polarimeter DIP-370 (Zaragoza, Spain). NMR spectroscopy was conducted using
1
a Bruker AVANCE–II spectrometer (Zaragoza, Spain). H-NMR spectra were recorded at 300 and
400 MHz; 13C-APT-NMR spectra were recorded at 75 and 100 MHz; (min: minor isomer); DMSO-d6 was
used as the deuterated solvent. Chemical shifts were reported in the
δ scale relative to residual DMSO
(2.50 ppm) for 1H-NMR and to the central line of DMSO-d6 (39.52 ppm) for 13C-APT-NMR. Spectral
data for many of the synthesized compounds are consistent with values previously reported in the
literature: hydrazone 7a
[
26]; alkylidenemalononitriles 9a
[
27], 9b
[
27], 9c
[
28], 9d
[
28], 9e
[
27], 9f
[
[
29],
19],
9g
[
30], 9i
[
27], 9j
[
27], 9k
[
28], 9l 31] and 9m 31]; and 1,4-dihydropyridines 10ac [
[
[
19], 10ae
10af
[
19] and 10ai
[
19]. Melting points were recorded on a Gallenkamp MDP350 Variable Heater
32], II 32], VI 33], VII 34], VIII 33], IX 35
melting point apparatus without correction. Catalysts
I
[
[
[
[
[
[
]
and X [36] were commercially available and III [37], IV [38] and V [38] were synthesized as reported.
3.2. General Procedure for the Synthesis of Hydrazones 7
To a solution of the corresponding hydrazide
3 (5 mmol) in ethanol (15 mL), dimethyl
acetylenedicarboxylate (5 mmol, 615 L) was slowly added due to the exothermic characteristics
6
µ
of the reaction. The reaction mixture was stirred for 12 h at room temperature. Then, the solvent
was evaporated under vacuum, and the reaction crude was purified by filtration, washing the white
precipitate with small portions of ethanol (3
(Scheme 3).
×
3 mL) giving rise to the corresponding final adduct 7
(E)-Dimethyl 2-(2-(benzoyl)hydrazono)succinate (7a) [26]: Following the general procedure, compound 7a
was obtained as a white solid in a 98% yield.
(E)-Dimethyl 2-(2-(4-nitrobenzoyl)hydrazono)succinate
compound 7b was obtained as a white solid in a 98% yield. mp 146–148 C. H-NMR (300 MHz,
DMSO-d6) 3.65 (s, 3H), 3.76 (s, 3H), 3.90 (s, 2H), 8.06 (d, J = 8.1 Hz, 2H), 8.35 (d, J = 8.5 Hz, 2H),
11.70 (s, 1H). 13C-APT-NMR (75 MHz, DMSO-d6)
32.6 (1C), 52.2 (1C), 52.6 (1C), 123.3 (2C), 130.3 (2C),
138.8 (1C), 149.3 (1C), 164.4 (1C), 168.2 (3C). IR (neat) (cm–1)
3451, 3244, 3113, 1729, 1690, 1671, 1520,
(7b): Following the general procedure,
◦
1
δ
δ
ν
1349, 1241, 1124, 1005, 852, 719. HRMS (ESI+) calcd for C13H13N3NaO7 346.0646; found 346.0649
[M + Na].
(E)-Dimethyl 2-(2-(4-chlorobenzoyl)hydrazono)succinate (7c): Following the general procedure, compound
7c was obtained as a white solid in a 99% yield. mp 138–140 ◦C. 1H-NMR (300 MHz, DMSO-d6)
δ
3.64 (s, 3H), 3.76 (s, 3H), 3.89 (s, 2H), 7.60 (d, J = 8.6 Hz, 2H), 7.87 (d, J = 8.6 Hz, 2H), 11.47 (s, 1H).
13C-APT-NMR (75 MHz, DMSO-d6)
32.5 (1C), 52.2 (1C), 52.5 (1C), 128.4 (2C), 130.7 (2C), 131.7 (1C),
137.0 (1C), 164.5 (1C), 168.3 (3C). IR (neat) (cm–1)
3441, 3238, 2954, 1741, 1726, 1694, 1670, 1594,
δ
ν
1536, 1440, 1250, 1146, 1123, 1111, 1089, 1003, 889, 846, 756. HRMS (ESI+) calcd for C13H13ClN2NaO5
335.0405; found 335.0385 [M + Na].
(E)-Dimethyl 2-(2-(4-bromobenzoyl)hydrazono)succinate (7d): Following the general procedure,
◦
1
compound 7d was obtained as a white solid in a 99% yield. mp 114–116 C. H-NMR (300 MHz,
DMSO-d6)
δ
3.64 (s, 3H), 3.76 (s, 3H), 3.89 (s, 2H), 7.77 (q, J = 8.4 Hz, 4H), 11.48 (s, 1H). 13C-APT-NMR

Molecules 2018, 23, 2692
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(75 MHz, DMSO-d6)
δ
30.9 (3C), 32.5 (1C), 52.2 (1C), 52.6 (1C), 125.9 (1C), 130.9 (2C), 131.3 (2C),
132.1 (2C), 164.5 (1C), 168.3 (2C). IR (neat) (cm–1)
ν 3256, 2953, 1734, 1716, 1685, 1591, 1434, 1222, 1201,
1127, 1111, 1009, 889, 838, 752. HRMS (ESI+) calcd for C13H13BrN2NaO5 378.9900; found 378.9903
[M + Na].
(E)-Dimethyl 2-(2-(4-tert-butylbenzoyl)hydrazono)succinate (7e): Following the general procedure,
◦
1
compound 7e was obtained as a white solid in a 98% yield. mp 165–167 C. H-NMR (300 MHz,
DMSO-d6) 1.31(s, 9H), 3.64 (s, 3H), 3.77 (s, 3H), 3.89 (s, 2H), 7.54 (d, J = 8.6 Hz, 2H), 7.78 (d, J = 8.6 Hz
2H), 11.33 (s, 1H). 13C-APT-NMR (75 MHz, DMSO-d6)
30.9 (3C), 32.4 (1C), 34.8 (1C), 52.1 (1C),
52.5 (1C), 125.1 (2C), 128.6 (2C), 130.3 (1C), 155.2(1C), 164.6 (1C), 168.4 (3C). IR (neat) (cm–1)
3232,
δ
,
δ
ν
3201, 2964, 2949, 1741, 1721, 1671, 1609, 1536, 1432, 1246, 1205, 1150, 1126, 1118, 1021, 895, 857, 841, 707.
HRMS (ESI+) calcd for C17H22N2NaO5 357.1421; found 357.1419 [M + Na].
(E)-Dimethyl 2-(2-(4-methoxybenzoyl)hydrazono)succinate (7f): Following the general procedure,
◦
1
compound 7f was obtained as a white solid in a 98% yield. mp 144–146 C. H-NMR (300 MHz,
DMSO-d6) 3.64 (s, 3H), 3.76 (s, 3H), 3.84 (s, 3H), 3.89 (s, 2H), 7.06 (d, J = 8.9 Hz, 2H), 7.87 (d,
J = 8.9 Hz, 2H), 11.25 (s, 1H). 13C-APT-NMR (75 MHz, DMSO-d6)
32.4 (1C), 52.2 (1C), 52.5 (1C),
55.5 (1C), 113.6 (2C), 124.9 (1C), 130.9 (2C), 162.4 (1C), 164.6 (1C), 168.5 (3C). IR (neat) (cm–1)
3419,
δ
δ
ν
3223, 3189, 1737, 1715, 1659, 1601, 1541, 1508, 1436, 1319, 1256, 1205, 1170, 1143, 1109, 1027, 996, 889,
849, 762. HRMS (ESI+) calcd for C14H16N2NaO6 331.0901; found 331.0888 [M + Na].
3.3. General Procedure for the Synthesis of 1,4-Dihydropyridines 10
To a mixture of
benzylidenemalononitrile
β
-isocupreidine catalyst
X
(20 mol%, 6.21 mg) and the corresponding
(0.1 mmol) were
9
(0.15 mmol) in tetrahydrofuran (0.5 mL), hydrazones
7
added. The reaction mixture was stirred for 5 days at room temperature. Then, the reaction crude was
purified by column chromatography (SiO2, n-hexane:diethyl ether 20:80 to 0:100), giving rise to the
corresponding final chiral adducts 10 (Scheme 6).
Dimethyl 6-amino-1-benzamido-5-cyano-4-phenyl-1,4-dihydropyridine-2,3-dicarboxylate (10aa): Following
the general procedure, compound 10aa was obtained after 120 h of reaction at room temperature and
was purified by column chromatography (n-hexane:diethyl ether 20:80 to 0:100), as a white solid in
◦
61% yield (26.37 mg). mp 106–108 C. The ee of the product was determined to be 50% by HPLC
using a Daicel Chiralpak IC column (n-hexane/i-PrOH = 70:30, flow rate 1 mL min−1
,
λ
= 237.7 nm):
25.4 (c = 0.07, MeOH, 50% ee). H-NMR (400 MHz,
3.51 (s, 3H), 3.57 (s, 0.75H), 3.64 (s, 2.25H), 4.36 (s, 0.75H), 4.48 (s, 0.25H), 6.38 (s, 1.5H),
6.46 (s, 0.5H), 7.24 (t, J = 7.3 Hz, 1.5H), 7.35 (t, J = 7.4 Hz, 2H), 7.45–7.59 (m, 3.5H), 7.63 (t, J = 7.1 Hz,
1H), 7.79–7.91 (m, 2H), 11.21 (s, 0.75H), 11.32 (s, 0.25H). 13C-APT-NMR (100 MHz, DMSO-d6)
39.2
24
1
τmajor = 30.4 min
;
τminor = 11.1 min. [
α
]
=
−
D
DMSO-d6)
δ
δ
(1C), 51.8 (1C), 52.8 (1C), 58.6 (1C), 104.6 (1C), 120.9 (1C), 126.8 (2C), 127.7 (1C), 127.9 (2C), 128.3 (2C),
128.5 (2C), 131.3 (1C), 132.5 (1C), 142.6 (1C), 145.7 (1C), 151.1 (1C), 162.4 (1C), 164.7 (1C), 166.7 (1C).
IR (neat) (cm–1)
ν 3420, 3334, 3249, 3219, 2957, 2190, 1736, 1707, 1662, 1590, 1479, 1428, 1225, 1110, 717,
699, 689. HRMS (ESI+) calcd for C23H20N4NaO5 455.1326; found 455.1340 [M + Na].
Dimethyl 6-amino-5-cyano-1-(4-nitrobenzamido)-4-phenyl-1,4-dihydropyridine-2,3-dicarboxylate (10ba):
Following the general procedure, compound 10ba was obtained after 120 h of reaction at room
temperature and was purified by column chromatography (n-hexane:diethyl ether 20:80 to 0:100), as a
yellow solid in 56% yield (26.82 mg). mp 238–240 ◦C. The ee of the product was determined to be
45% by HPLC using a Daicel Chiralpak IC column (n-hexane/i-PrOH = 70:30, flow rate 1 mL min−1
,
24
1
λ = 249.6 nm)
:
τmajor = 47.0 min; τminor = 21.4 min. [
α
]
D
=
−
6.6 (c = 0.13, MeOH, 45% ee). H-NMR
(400 MHz, DMSO-d6)
δ
3.51 (s, 3H), 3.58 (s, 0.78H), 3.65 (s, 2.22H), 4.37 (s, 0.74H), 4.44 (s, 0.26H), 6.55 (s,
1.48H), 6.60 (s, 0.52H), 7.24 (t, J = 7.3 Hz, 1.48H), 7.35 (t, J = 7.5 Hz, 2H), 7.52 (d, J = 7.2 Hz, 1.52H),
8.04 (d, J = 8.8 Hz, 0.52H), 8.10 (d, J = 8.8 Hz, 1.48H), 8.38 (d, J = 8.8 Hz, 2H), 11.62 (s, 0.74H), 11.68 (s,

Molecules 2018, 23, 2692
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0.26H). 13C-APT-NMR (100 MHz, DMSO-d6)
δ
39.2 (1C), 51.8 (1C), 52.9 (1C), 58.1 (1C), 104.9 (1C),
120.8 (1C), 123.5 (min), 123.6 (2C), 126.9 (1C), 127.6 (2C), 128.3 (2C), 128.6 (min), 129.4 (min), 129.5 (2C),
137.0 (1C), 142.2 (1C), 145.6 (1C), 149.7 (1C), 151.0 (1C), 162.4 (1C), 164.6 (1C), 165.4 (1C). IR (neat)
(cm–1)
ν 3420, 3331, 3208, 2955, 2923, 2852, 2193, 1722, 1710, 1679, 1660, 1589, 1527, 1430, 1346, 1231,
1117, 1081, 697. HRMS (ESI+) calcd for C23H19N5NaO7 500.1177; found 500.1175 [M + Na].
Dimethyl 6-amino-1-(4-chlorobenzamido)-5-cyano-4-phenyl-1,4-dihydropyridine-2,3-dicarboxylate (10ca):
Following the general procedure, compound 10ca was obtained after 120 h of reaction at room
temperature and was purified by column chromatography (n-hexane:diethyl ether 20:80 to 0:100),
as a white solid in 75% yield (34.88 mg). mp 143–145 ◦C. The ee of the product was determined to be
43% by HPLC using a Daicel Chiralpak IC column (n-hexane/i-PrOH = 70:30, flow rate 1 mL min−1
,
24
1
λ = 254.0 nm)
:
τmajor = 24.2 min; τminor = 11.6 min. [
α
]
D
=
−
26.7 (c = 0.10, MeOH, 43% ee). H-NMR
(400 MHz, DMSO-d6)
δ
3.49 (s, 0.9H), 3.51 (s, 2.1H), 3.56 (s, 0.9H), 3.63 (s, 2.1H), 4.35 (s, 0.7H), 4.47 (s,
0.3H), 6.46 (s, 1.4H), 6.50 (s, 0.6H), 7.24 (t, J = 7 Hz, 1.4H), 7.30-7.38 (m, 2.2H), 7.53 (d, J = 7,1 Hz, 1.4H),
7.63 (d, J = 8.6 Hz, 2H), 7.83 (d, J = 8.6 Hz, 0.6H), 7.88 (d, J = 8.6 Hz, 1.4H), 11.33 (s, 0.7H), 11.42 (s,
0.3H). 13C-APT-NMR (100 MHz, DMSO-d6)
δ 39.1 (1C), 51.9 (1C), 52.8 (min), 52.9 (1C), 57.2 (min),
58.3 (1C), 104.7 (1C), 120.9 (1C), 121.0 (min), 126.9 (min), 127.0 (1C), 127.7 (2C), 128.4 (2C), 128.5 (min),
128.6 (2C), 129.9 (2C), 130.2 (1C), 130.3 (min), 137.2 (1C), 137.4 (1C), 142.5 (1C), 143.0 (1C), 145.7 (1C),
151.1 (1C), 151.6 (1C), 162.4 (1C), 164.7 (1C), 164.8 (1C), 165.3 (1C), 165.8 (1C). IR (neat) (cm–1)
ν 3413,
3331, 3251, 3025, 2956, 2192, 1727, 1715, 1664, 1590, 1432, 1335, 1230, 1093, 1014, 698. HRMS (ESI+)
calcd for C23H19ClN4NaO5 489.0912; found 489.0913 [M + Na].
Dimethyl 6-amino-1-(4-bromobenzamido)-5-cyano-4-phenyl-1,4-dihydropyridine-2,3-dicarboxylate (10da):
Following the general procedure, compound 10da was obtained after 120 h of reaction at room
temperature and was purified by column chromatography (n-hexane:diethyl ether 20:80 to 0:100),
◦
as a yellow solid in 60% yield (30.81 mg). mp 134–136 C. The ee of the product was determined
to be 44% by HPLC using a Daicel Chiralpak IC column (n-hexane/i-PrOH = 70:30, flow rate 1 mL
24
min−1
,
λ = 330.0 nm): τmajor = 24.6 min; τminor = 10.7 min. [
α
]
=
−
20.3 (c = 0.15, MeOH, 44% ee).
D
1H-NMR (400 MHz, DMSO-d6)
δ
3.49 (s, 0.75H), 3.51 (s, 2.25H), 3.56 (s, 0.75H), 3.63 (s, 2.25H), 4.35 (s,
0.75H), 4.47 (s, 0.25H), 6.45 (s, 1.5 H), 6.50 (s, 0.50H), 7.24 (t, J = 7.3 Hz, 1.5H), 7.34 (t, J = 7.5 Hz, 2H),
7.53 (d, J = 7.1 Hz, 1.5H), 7.73–7.84 (m, 4H), 11.33 (s, 0.75H), 11.42 (s, 0.25H). 13C-APT-NMR (100 MHz,
DMSO-d6)
(min), 127.6 (2C), 128.3 (2C), 128.6 (min), 130.0 (2C), 130.5 (min), 131.4 (2C), 131.5 (1C), 142.4 (1C),
145.6 (1C), 151.1 (1C), 162.4 (1C), 164.6 (1C), 165.9 (1C). IR (neat) (cm–1)
3417, 3331, 3240, 2955, 2190,
δ 39.2 (1C), 51.9 (1C), 52.8 (1C), 58.3 (1C), 104.7 (1C), 120.9 (1C), 126.3 (1C), 126.8 (1C), 126.9
ν
1716, 1663, 1588, 1431, 1230, 1079, 1010, 698. HRMS (ESI+) calcd for C23H19BrN4NaO5 533.0418; found
533.0418 [M + Na].
Dimethyl 6-amino-1-(4-(tert-butyl)benzamido)-5-cyano-4-phenyl-1,4-dihydropyridine-2,3-dicarboxylate (10ea):
Following the general procedure, compound 10ea was obtained after 120 h of reaction at room
temperature and was purified by column chromatography (n-hexane:diethyl ether 20:80 to 0:100), as a
yellow solid in 58% yield (28.33 mg). mp 141–143 ◦C. The ee of the product was determined to be
48% by HPLC using a Daicel Chiralpak IC column (n-hexane/i-PrOH = 70:30, flow rate 1 mL min−1
,
24
1
λ = 242.5 nm): τmajor = 13.2 min; τminor = 9.1 min. [
(400 MHz, DMSO-d6) 1.31 (s, 9H), 3.51 (s, 3H), 3.58 (s, 0.78H), 3.66 (s, 2.22H), 4.36 (s, 0.74H), 4.48 (s,
0.26H), 6.33 (s, 1.48H), 6.38 (s, 0.52H), 7.24 (t, J = 7.4 Hz, 1.48H), 7.35 (t, J = 7.4 Hz, 2H), 7.56 (d, J = 8.2 Hz
3.52H), 7.74–7.84 (m, 2H), 11.13 (s, 0.74H), 11.13 (s, 0.26H). 13C-APT-NMR (100 MHz, DMSO-d6)
30.9
α
]
D
=
−
24.7 (c = 0.15, MeOH, 48% ee). H-NMR
δ
,
δ
(1C), 34.8 (1C), 39.2 (1C), 51.9 (1C), 52.8 (1C), 58.7 (1C), 104.5 (1C), 120.9 (1C), 125.2 (min), 125.3 (2C),
126.8 (1C), 127.0 (min), 127.7 (2C), 127.8 (2C), 128.3 (2C), 128.5 (1C), 128.6 (min), 142.7 (1C), 145.7 (1C),
151.1 (1C), 155.6 (1C), 162.4 (1C), 164.7 (1C), 166.4 (1C). IR (neat) (cm–1)
ν 3261, 2958, 2192, 1731, 1638,
1608, 1438, 1270, 1238, 1118, 849, 698. HRMS (ESI+) calcd for C27H28N4NaO5 511.1948; found 511.1947
[M + Na].

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Dimethyl 6-amino-5-cyano-1-(4-methoxybenzamido)-4-phenyl-1,4-dihydropyridine-2,3-dicarboxylate (10fa):
Following the general procedure, compound 10fa was obtained after 120 h of reaction at room
temperature and was purified by column chromatography (n-hexane:diethyl ether 20:80 to 0:100), as a
yellow solid in 55% yield (25.24 mg). mp 113–115 ◦C. The ee of the product was determined to be
42% by HPLC using a Daicel Chiralpak IC column (n-hexane/i-PrOH = 70:30, flow rate 1 mL min−1
,
24
1
λ = 253.2 nm): τmajor = 32.7 min; τminor = 14.8 min. [
α
]
D
=
−
25.6 (c = 0.08, MeOH, 42% ee). H-NMR
(400 MHz, DMSO-d6) 3.51 (s, 3H), 3.55 (s, 0.75H), 3.62 (s, 2.25H), 3.84 (s, 3H), 4.35 (s, 0.75H), 4.47 (s,
δ
0.25H), 6.33 (s, 1.50H), 6.38 (s, 0.5H), 7.07 (d, J = 8.7 Hz, 2H), 7.24 (t, J = 7.1 Hz, 1.5H), 7.34 (t, J = 7.4 Hz,
2H), 7.55 (d, J = 7.5 Hz, 1.5H), 7.77–7.89 (m, 2H), 11.04 (s, 0.75H), 11.16 (s, 0.25H). 13C-APT-NMR (100
MHz, DMSO-d6)
120.9 (1C), 123.4 (1C), 126.8 (1C), 127.0 (min), 127.7 (2C), 128.3 (2C), 128.6 (min), 129.9 (2C), 142.8 (1C),
145.7 (1C), 151.2 (1C), 162.4 (1C), 162.6 (1C), 164.7 (1C), 166.0 (1C).IR (neat) (cm–1)
3409, 3334, 3247,
δ 39.3 (1C), 51.8 (1C), 52.7 (1C), 55.5 (1C), 58.6 (1C), 104.5 (1C), 113.6 (min), 113.8 (2C),
ν
3214, 2953, 2186, 1732, 1713, 1663, 1604, 1587, 1489, 1431, 1249, 1228, 1184, 1115, 1076, 1024, 841, 700.
HRMS (ESI+) calcd for C24H22N4NaO6 485.1426; found 485.1425 [M+Na].
Dimethyl 6-amino-1-benzamido-5-cyano-4-(4-nitrophenyl)-1,4-dihydropyridine-2,3-dicarboxylate (10ab):
Following the general procedure, compound 10ab was obtained after 120 h of reaction at room
temperature and was purified by column chromatography (n-hexane:diethyl ether 20:80 to 0:100),
as a white solid in 95% yield (45.3 mg). mp 158–160 ◦C. The ee of the product was determined to be
46% by HPLC using a Daicel Chiralpak IA column (n-hexane/i-PrOH = 70:30, flow rate 1 mL min−1
,
25
1
λ = 236.6 nm): τmajor = 26.1 min; τminor = 11.2 min. [
(400 MHz, DMSO-d6) 3.51 (s, 3H), 3.64 (s, 3H), 4.50 (s, 1H), 6.62 (s, 2H), 7.54 (t, J = 7.4 Hz, 2H),
7.59–7.83 (m, 3H), 7.87 (d, J = 7.3 Hz, 2H), 8.24 (d, J = 8.7 Hz, 2H), 11.31 (s, 1H). 13C-APT-NMR (100
MHz, DMSO-d6) 39.1 (1C), 45.7 (1C), 52.1 (1C), 52.9 (1C), 103.8 (1C), 120.5 (1C), 123.8 (2C), 128.0 (2C),
128.5 (2C), 128.7 (2C), 131.2 (1C), 132.6 (1C), 146.5 (1C), 151.6 (1C), 152.9 (1C), 162.2 (1C), 164.4 (1C),
166.8 (1C). IR (neat) (cm–1)
3330, 3200, 2953, 2185, 1743, 1708, 1652, 1579, 1516, 1428, 1344, 1225, 1110,
α
]
= +24.5 (c = 0.15, MeOH, 46% ee). H-NMR
D
δ
δ
ν
823, 694. HRMS (ESI+) calcd for C23H19N5NaO7 500.1181; found 500.1181 [M + Na].
Dimethyl 6-amino-1-benzamido-5-cyano-4-(3-nitrophenyl)-1,4-dihydropyridine-2,3-dicarboxylate (10ac) [19]:
Following the general procedure, compound 10ac was obtained after 120 h of reaction at room
temperature and was purified by column chromatography (n-hexane:diethyl ether 20:80 to 0:100),
as a white solid in 89% yield (42.4 mg). The ee of the product was determined to be 51% by HPLC
using a Daicel Chiralpak IC column (n-hexane/i-PrOH = 70:30, flow rate 1 mL min−1
τmajor = 18.6 min; τminor = 15.4 min. [α]D24 = −2.8 (c = 0.24, MeOH, 51% ee).
, λ = 238.9 nm):
Dimethyl 6-amino-1-benzamido-4-(3-chlorophenyl)-5-cyano-1,4-dihydropyridine-2,3-dicarboxylate (10ad):
Following the general procedure, compound 10ad was obtained after 120 h of reaction at room
temperature and was purified by column chromatography (n-hexane:diethyl ether 20:80 to 0:100),
as a white solid in 70% yield (32.6 mg). mp 134–136 ◦C. The ee of the product was determined to be
52% by HPLC using a Daicel Chiralpak IC column (n-hexane/i-PrOH = 80:20, flow rate 1 mL min−1
,
24
1
λ = 236.6 nm): τmajor = 32.3 min; τminor = 18.6 min. [
(400 MHz, DMSO-d6) 3.53 (s, 3H), 3.65 (s, 3H), 4.41 (s, 1H), 6.49 (s, 2H), 7.31 (d, J = 7.4 Hz, 1H),
7.39 (t, J = 7.7 Hz, 1H), 7.54 (t, J = 7.6 Hz, 3H), 7.60–7.68 (m, 2H), 7.86 (d, J = 7.3 Hz, 2H), 11.27 (s, 1H).
13C-APT-NMR (100 MHz, DMSO-d6)
39.0 (1C), 52.0 (1C), 52.9 (1C), 58.1 (1C), 104.3 (1C), 120.6 (1C),
126.4 (1C), 127.0 (1C), 127.6 (1C), 127.9 (2C), 128.5 (2C), 130.2 (1C), 131.3 (1C), 132.5 (1C), 133.2 (1C),
142.9 (1C), 148.1 (1C), 151.3 (1C), 162.3 (1C), 164.5 (1C), 166.8 (1C). IR (neat) (cm–1)
3330, 2953,
α
]
= +23.4 (c = 0.13, MeOH, 52% ee). H-NMR
D
δ
δ
ν
2922, 2850, 2184, 1736, 1707, 1654, 1578, 1430, 1227, 1115, 1079, 886, 781, 692. HRMS (ESI+) calcd for
C23H19ClN4NaO5 489.0942; found 489.0941 [M + Na].
Dimethyl 6-amino-1-benzamido-4-(4-chlorophenyl)-5-cyano-1,4-dihydropyridine-2,3-dicarboxylate (10ae) [19]:
Following the general procedure, compound 10ae was obtained after 120 h of reaction at room

Molecules 2018, 23, 2692
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temperature and was purified by column chromatography (n-hexane:diethyl ether 20:80 to 0:100),
as a white solid in 70% yield (32.7 mg). The ee of the product was determined to be 50% by HPLC
using a Daicel Chiralpak IC column (n-hexane/i-PrOH = 80:20, flow rate 1 mL min−1
τmajor = 22.5 min; τminor = 16.4 min. [α]D24 = −2.2 (c = 0.15, MeOH, 50% ee).
, λ = 237.7 nm):
Dimethyl 6-amino-1-benzamido-4-(4-bromophenyl)-5-cyano-1,4-dihydropyridine-2,3-dicarboxylate (10af) [19]:
Following the general procedure, compound 10af was obtained after 120 h of reaction at room
temperature and was purified by column chromatography (n-hexane:diethyl ether 20:80 to 0:100),
as a white solid in 61% yield (31.2 mg). The ee of the product was determined to be 52% by HPLC
using a Daicel Chiralpak IC column (n-hexane/i-PrOH = 80:20, flow rate 1 mL min−1
τmajor = 23.0 min; τminor = 18.0 min. [α]D24 = −19.5 (c = 0.05, MeOH, 52% ee).
, λ = 236.6 nm):
Dimethyl 6-amino-1-benzamido-5-cyano-4-(4-cyanophenyl)-1,4-dihydropyridine-2,3-dicarboxylate (10ag):
Following the general procedure, compound 10ag was obtained after 120 h of reaction at room
temperature and was purified by column chromatography (n-hexane:diethyl ether 20:80 to 0:100),
as a white solid in 99% yield (45.09 mg). mp 154–156 ◦C. The ee of the product was determined to be
50% by HPLC using a Daicel Chiralpak IC column (n-hexane/i-PrOH = 70:30, flow rate 1 mL min−1
,
1
λ = 234.2 nm): τmajor = 22.2 min; τminor = 18.5 min. [
(400 MHz, DMSO-d6)
(m, 5H), 11.30 (s, 1H). 13C-APT-NMR (100 MHz, DMSO-d6)
103.9 (1C), 109.8 (1C), 118.9 (1C), 120.5 (1C), 127.9 (3C), 128.5 (2C), 128.6 (2C), 131.2 (1C), 132.5 (2C),
143.3 (1C), 151.0 (1C), 151.4 (1C), 162.2 (1C), 164.4 (1C), 166.8 (1C). IR (neat) (cm–1)
3414, 3313, 3210,
α
]
D
24 = +4.0 (c = 0.07, MeOH, 50% ee). H-NMR
δ
3.51 (s, 3H), 3.65 (s, 3H), 4.49 (s, 1H), 6.55 (s, 2H), 7.35–7.69 (m,4H), 7.70–7.91
39.4 (1C), 52.0 (1C), 52.9 (1C), 57.5 (1C),
δ
ν
2947, 2231, 2192, 1750, 1704, 1682, 1665, 1590, 1433, 1360, 1272, 1253, 1222, 1115, 929, 846, 686. HRMS
(ESI+) calcd for C24H19N5NaO5 480.1258; found 480.1256 [M + Na].
Dimethyl 6-amino-1-benzamido-5-cyano-4-(naphthalen-1-yl)-1,4-dihydropyridine-2,3-dicarboxylate (10ah):
Following the general procedure, compound 10ah was obtained after 120 h of reaction at room
temperature and was purified by column chromatography (n-hexane:diethyl ether 20:80 to 0:100),
◦
as a yellow solid in 51% yield (24.61 mg). mp 122–124 C. The ee of the product was determined
to be 50% by HPLC using a Daicel Chiralpak IC column (n-hexane/i-PrOH = 70:30, flow rate 1 mL
24
min−1
,
λ = 221.2 nm): τmajor = 27.9 min; τminor = 16.5 min. [
1H-NMR (400 MHz, DMSO-d6)
0.25H), 6.33 (s, 1.5H), 6.38 (s, 0.5H), 7.41–7.70 (m, 6.25H), 7.78–7.97 (m, 4H), 8.09 (d, J = 6.7 Hz, 0.75H),
8.46 (d, J = 8.7 Hz, 1H), 11.27 (s, 0.75H), 11.39 (s, 0.25H). 13C-APT-NMR (100 MHz, DMSO-d6)
40.0
α
]
=
−
28.9 (c = 0.10, MeOH, 50% ee).
D
δ
3.33 (s, 3H), 3.60 (s, 0.75H), 3.67 (s, 2.25H), 5.42 (s, 0.75H), 5.47 (s,
δ
(1C), 51.7 (1C), 52.8 (1C), 59.2 (1C), 64.9 (1C), 105.4 (1C), 120.8 (1C), 123.5 (1C), 125.5 (1C), 125.7 (1C),
126.0 (1C), 127.0 (1C), 127.1 (1C), 127.9 (2C), 128.3 (1C), 128.5 (2C), 130.3 (1C), 131.4 (1C), 132.5 (1C),
133.1 (1C), 143.0 (1C), 151.1 (1C), 162.5 (1C), 164.8 (1C), 166.7 (1C). IR (neat) (cm–1)
ν 3202, 2951, 2194,
1715, 1704, 1661, 1592, 1510, 1426, 1334, 1232, 1070, 782. HRMS (ESI+) calcd for C27H22N4NaO5
505.1482; found 505.1454 [M + Na].
Dimethyl 6-amino-1-benzamido-5-cyano-4-(p-tolyl)-1,4-dihydropyridine-2,3-dicarboxylate
(10ai) [19]:
Following the general procedure, compound 10ai was obtained after 120 h of reaction at room
temperature and was purified by column chromatography (n-hexane:diethyl ether 20:80 to 0:100),
as a white solid in 44% yield (19.6 mg). The ee of the product was determined to be 50% by HPLC
using a Daicel Chiralpak IC column (n-hexane/i-PrOH = 70:30, flow rate 1 mL min−1
τmajor = 15.9 min; τminor = 9.6 min. [α]D24 = −19.4 (c = 0.12, MeOH, 50% ee).
, λ = 237.7 nm):
Dimethyl 6-amino-1-benzamido-5-cyano-4-(4-methoxyphenyl)-1,4-dihydropyridine-2,3-dicarboxylate (10aj):
Following the general procedure, compound 10aj was obtained after 120 h of reaction at room
temperature and was purified by column chromatography (n-hexane:diethyl ether 20:80 to 0:100),
as a white solid in 40% yield (18.57 mg). mp 137–139 ◦C. The ee of the product was determined to be

Molecules 2018, 23, 2692
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40% by HPLC using a Daicel Chiralpak IC column (n-hexane/i-PrOH = 70:30, flow rate 1 mL min−1
,
24
1
λ = 237.7 nm): τmajor = 48.4 min; τminor = 19.2 min. [
(400 MHz, DMSO-d6) 3.52 (s, 3H), 3.55 (s, 0.75H), 3.63 (s, 2.25H), 3.75 (s, 3H), 4.30 (s, 0.75H), 4.42 (s,
0.25H), 6.32 (s, 1.5H), 6.38 (s, 0.50H), 6.89 (d, J = 8.5 Hz, 2.25H), 7.10–7.22 (m, 0.75H), 7.43–7.68 (m,
α
]
=
−
24.0 (c = 0.05, MeOH, 40% ee). H-NMR
D
4H), 7.79–7.88 (m, 2H), 11.19 (s, 0.75H), 11.30 (s, 0.25H). 13C-APT-NMR (100 MHz, DMSO-d6)
δ 38.4
(1C), 51.8 (1C), 52.7 (1C), 55.0 (1C), 58.9 (1C), 104.9 (1C), 113.6 (2C), 113.9 (min), 120.9 (1C), 127.9 (2C),
128.5 (2C), 128.8 (2C), 131.3 (1C), 132.5 (1C), 137.9 (1C), 142.2 (1C), 151.0 (1C), 158.2 (1C), 162.5 (1C),
164.8 (1C), 166.7 (1C). IR (neat) (cm–1)
ν 3313, 3201, 2952, 2838, 2186, 1742, 1707, 1651, 1606, 1509,
1428, 1227, 1175, 1110, 1028, 833, 691. HRMS (ESI+) calcd for C24H22N4NaO6 485.1438; found 485.1435
[M + Na].
Dimethyl 6-amino-1-benzamido-5-cyano-4-(furan-2-yl)-1,4-dihydropyridine-2,3-dicarboxylate
(10ak):
Following the general procedure, compound 10ak was obtained after 120 h of reaction at room
temperature and was purified by column chromatography (n-hexane:diethyl ether 20:80 to 0:100),
as a white solid in 70% yield (29.77 mg). mp 151–153 ◦C. The ee of the product was determined to be
54% by HPLC using a Daicel Chiralpak IA column (n-hexane/i-PrOH = 80:20, flow rate 1 mL min−1
,
24
1
λ = 236.6 nm): τmajor = 16.4 min; τminor = 12.4 min. [
α
]
D
=
−
15.3 (c = 0.10, MeOH, 54% ee). H-NMR
(400 MHz, DMSO-d6) 3.55 (s, 1.35H), 3.58 (s, 1.35H), 3.59 (s, 1.65H), 3.65 (s, 1.65H), 4.51 (s, 0.55H),
δ
4.64 (s, 0.45H), 6.11 (d, J = 3.1 Hz, 0.45H), 6.33 (d, J = 3.1 Hz, 0.55H), 6.37–6.45 (m, 1H), 6.50 (s, 1.1H),
6.57 (s, 0.9H), 7.46–7.67 (m, 4H), 7.77–7.86 (m, 2H), 11.20 (s, 0.55H), 11.38 (s, 0.45H). 13C-APT-NMR
(100 MHz, DMSO-d6)
δ 32.4 (1C), 33.0 (min), 52.0 (min), 52.1 (1C), 52.7 (min), 52.9 (1C), 53.8 (min),
55.5 (1C), 101.8 (min), 102.3 (1C), 105.3 (min), 106.0 (1C), 110.6 (min), 110.8 (1C), 120.8 (1C), 120.9 (min),
127.8 (1C), 128.0 (min), 128.3 (min), 128.5 (1C), 131.3 (1C), 131.4 (min), 132.3 (min), 132.5 (1C), 141.6 (1C),
142.3 (min), 143.1 (1C), 143.7 (min), 152.0 (1C), 152.6 (min), 156.4 (min), 157.6 (1C), 162.1 (min),
162.2 (1C), 164.5 (1C), 164.7 (min), 166.1 (min), 166.2 (1C). IR (neat) (cm–1)
ν 3527, 3406, 3328, 2175,
1735, 1707, 1652, 1578, 1431, 1336, 1225, 1013, 939, 754, 705. HRMS (ESI+) calcd for C21H18N4NaO6
445.1125; found 445.1125 [M + Na].
Dimethyl 6-amino-1-benzamido-5-cyano-4-(thiophen-2-yl)-1,4-dihydropyridine-2,3-dicarboxylate
(10al):
Following the general procedure, compound 10al was obtained after 120 h of reaction at room
temperature and was purified by column chromatography (n-hexane:diethyl ether 20:80 to 0:100),
as a white solid in 76% yield (33.18 mg). mp 124–126 ◦C. The ee of the product was determined to be
43% by HPLC using a Daicel Chiralpak IC column (n-hexane/i-PrOH = 70:30, flow rate 1 mL min−1
,
24
1
λ = 236.6 nm): τmajor = 27.1 min; τminor = 16.1 min. [
α
]
D
=
−
12.6 (c = 0.10, MeOH, 43% ee). H-NMR
(400 MHz, DMSO-d6) 3.55 (s, 1.11H), 3.60 (s, 3H), 3.64 (s, 1.89H), 4.66 (s, 0.63H), 4.82 (s, 0.37H),
δ
6.50 (s, 1.26H), 6.57 (s, 0.74H), 6.88 (s, 0.37H), 7.00 (s, 1H), 7.19 (s, 0.63H), 7.39 (d, J = 4.7 Hz, 1H),
7.52 (t, J = 6.4 Hz, 2H), 7.62 (t, J = 6.7 Hz, 1H), 7.83 (d, J = 7.4 Hz, 2H), 11.21 (s, 0.63H), 11.38 (d, 0.37H).
13C-APT-NMR (100 MHz, DMSO-d6)
δ
33.7 (1C), 52.0 (1C), 52.8 (1C), 57.9 (1C), 104.3 (1C), 120.8 (1C),
124.5 (1C), 124.9 (1C), 127.1 (1C), 127.9 (2C), 128.3 (min), 128.5 (2C), 131.4 (1C), 132.4 (1C), 142.3 (1C),
148.7 (1C), 151.6 (1C), 162.2 (1C), 164.5 (1C), 166.2 (1C). IR (neat) (cm–1)
3415, 3332, 3248, 3213, 2954,
ν
2191, 1719, 1685, 1660, 1587, 1434, 1337, 1230, 941, 707, 687. HRMS (ESI+) calcd for C21H18N4NaO5S
461.0898; found 461.0897 [M + Na].
Dimethyl
60-amino-10-benzamido-50-cyano-10,40-dihydro-[3,40-bipyridine]-20,30-dicarboxylate
(10am):
Following the general procedure, compound 10am was obtained after 120 h of reaction at room
temperature and was purified by column chromatography (n-hexane:diet◦hyl ether 20:80 to 0:100 to
ethyl acetate 100), as a white solid in 92% yield (39.66 mg). mp 157–159 C. The ee of the product
was determined to be 40% by HPLC using a Daicel Chiralpak IC column (n-hexane/i-PrOH = 70:30,
24
flow rate 1 mL min−1
MeOH, 40% ee). H-NMR (400 MHz, DMSO-d6)
,
λ
= 336.0 nm): τmajor = 32.9 min; τminor = 50.6 min. [
α
]
=
−
12.6 (c = 0.17,
D
1
δ
3.52 (s, 3H), 3.64 (s, 3H), 4.44 (s, 1H), 6.53 (s, 2H),
7.42 (dd, J = 8 Hz, 5 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H), 7.63 (t, J = 7.3 Hz, 1H), 7.87 (d, J = 7.3 Hz, 2H),

Molecules 2018, 23, 2692
14 of 16
8.05 (s, 1H), 8.47 (dd, J = 4.7 Hz, 1.6 Hz, 1H), 8.67 (s, 1H), 11.31 (s, 1H). 13C-APT-NMR (100 MHz,
DMSO-d6) 36.9 (1C), 45.8 (1C), 52.0 (1C), 52.9 (1C), 104.1 (1C), 120.6 (1C), 123.8 (1C), 127.9 (2C),
128.5 (2C), 131.2 (1C), 132.6 (1C), 135.3 (1C), 141.0 (1C), 143.1 (1C), 148.2 (1C), 148.7 (1C), 151.5 (1C),
162.2 (1C), 164.4 (1C), 166.8 (1C). IR (neat) (cm–1)
3317, 3226, 2952, 2185, 1749, 1707, 1685, 1654, 1578,
δ
ν
1425, 1330, 1275, 1221, 1115, 1029, 703. HRMS (ESI+) calcd for C22H20N5O5 434.1468; found 434.1467
[M + H].
4. Conclusions
In summary, we have developed the first organocatalytic enantioselective approach for the
obtainment of chiral 1-benzamido-1,4-dihydropyridines. Final 1,4-dihydropyridines were reached with
high yields and showed promising results of enantioselectivity for the first time, using mild conditions
and following a simple approach. Further mechanistic studies are required in order to understand and
to prove the role of the β-isocupreidine catalyst in this process. Moreover, additional studies with the
aim of improving the enantioselectivity of the method are actively ongoing in our laboratory.
1
Supplementary Materials: The following are available online. Figures S1–S5: H and 13C-APT NMR spectra of
1
hydrazones
7
. Figures S6–S19: H and 13C-APT NMR spectra of 1,4-dihydropyridines 10 Figures S20–S57: HPLC
chromatograms of 1,4-dihydropyridines 10.
Author Contributions: All the authors designed the experiments and analyzed the data; F.A.-L. performed the
experiments; E.M.-L. and R.P.H. wrote the paper; all authors read and approved the final manuscript.
Funding: This research was funded by Ministerio de Economía, Industria y Competitividad [CTQ2017-88091-P],
Universidad de Zaragoza [JIUZ-2017-CIE-05] and Gobierno de Aragón-Fondo Social Europeo [Research
Group E07_17R]
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 7a–7f, 9a–9m and 10 are available from the authors.
2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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(CC BY) license (http://creativecommons.org/licenses/by/4.0/).