Environmentally benign one-pot multicomponent synthesis of 1,4-dihydropyridine derivatives applying montmorillonite K10 as reusable catalyst

Article abstract of DOI:10.1007/s10593-019-02419-3

[Figure not available: see fulltext.] Environmentally benign one-pot multicomponent synthesis of different 1,4-dihydropyridine derivatives using montmorillonite K10 has been achieved. The montmorillonite K10-catalyzed reaction of aromatic aldehyde, malono

Full text of DOI:10.1007/s10593-019-02419-3

DOI 10.1007/s10593-019-02419-3
Chemistry of Heterocyclic Compounds 2019, 55(1), 60–65
Environmentally benign one-pot multicomponent synthesis
of 1,4-dihydropyridine derivatives applying montmorillonite K10
as reusable catalyst
Vemulapati Hanuman Reddy1,2*, Avula Krishna Kumari1, Guda Mallikarjuna Reddy3,4,
Yellala Venkata Rami Reddy2, Jarem Raul Garcia4*, Grigory V. Zyryanov3,5,
Nemallapudi Bakthavatchala Reddy3, Aluru Rammohan3
1
Natural Product Chemistry, Indian Institute of Chemical Technology,
Tarnaka 500007, Hyderabad, Telangana, India; e-mail: vemulapati.hanuman@gmail.com
2
Department of Chemistry, Sri Venkateswara University,
Tirupati 517502, Andhra Pradesh, India
3
Institute of Chemical Engineering, Ural Federal University
named after the first President of Russia B. N. Yeltsin,
28 Mira St., Yekaterinburg 620002, Russia; e-mail: susreddy.organic@gmail.com
4
Department of Chemistry, State University of Ponta Grossa,
General Carlos Cavalcanti Ave., 4748 – CEP 84030-900, Ponta Grossa, Paraná, Brazil;
e-mail: nagareddy.organic@gmail.com
5
I. Ya. Postovsky Institute of Organic Synthesis,
Ural Branch of the Russian Academy of Sciences,
22 S. Kovalevskoi / 20 Akademicheskaya St., Yekaterinburg 620219, Russia
Submitted August 3, 2018
Accepted after revision December 17, 2018
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2019, 55(1), 60–65
Environmentally benign one-pot multicomponent synthesis of different 1,4-dihydropyridine derivatives using montmorillonite K10 has
been achieved. The montmorillonite K10-catalyzed reaction of aromatic aldehyde, malononitrile, substituted aniline, and diethyl
acetylenedicarboxylate in H2O–EtOH allows to obtain structurally diverse 1,4-dihydropyridines in high yields. Possibility to recover and
reuse the acidic catalyst in up to five catalytic cycles has been demonstrated. Short reaction times, suppressed formation of side products,
inexpensive and nontoxic solvent system, catalyst recovery, and simple workup procedure are the main advantages of the developed
synthetic method.
Keywords: 1,4-dihydropyridine, montmorillonite K10, water–ethanol, atom economy, environmentally benign synthesis, one-pot synthesis.
Application of less hazardous reactants, reagents, and
solvents, reusable catalysts, and one-pot strategy as well as
reduction of reaction time and amounts of side products are the
key tools for environmentally benign organic synthesis. Hence,
multicomponent reactions (MCRs) and chemical transfor-
mations performed in H2O fit several of these criteria.1
Since 1,4-dihydropyridine (1,4-DHP) core is incorpo-
rated in many pharmaceuticals, natural biologically active
products, and reactants or reagents exploited in organic
synthesis, preparation of 1,4-DHP derivatives under
environmentally benign conditions is of high importance.
Compounds containing this broadly used motif have a wide
range of biological activities2 and have been applied for
treatment of hypertension, cardiovascular diseases,
Alzheimer's disease, and angina pectoris.3 Numerous
studies regarding drug molecules with 1,4-DHP fragment,
0009-3122/19/55(1)-0060©2019 Springer Science+Business Media, LLC
60

Chemistry of Heterocyclic Compounds 2019, 55(1), 60–65
Scheme 1
such as nifedipine, nicardipine, and amlodipine,4 have been
conducted. Many 1,4-DHPs exhibit anti-inflammatory,2b
antitubercular,5 and analgesic6 properties. Moreover, a
number of 1,4-DHP derivatives containing ester groups at
the C-3 and C-5 atoms of the ring have been used as
bronchodilator and antihypertensive agents.7 Over last two
decades, 1,4-DHPs have thereby attracted increased interest
and led to challenge of developing new synthetic methods.
Since the first studies of 1,4-DHPs performed by
Hantzsch,8 many synthetic paths have been demonstrated to
obtain these compounds. For example, Vilsmeier–Haack
reaction,9 chemical transformations using chiral
auxiliaries,10 asymmetric organocatalytic11 and chemo-
enzymatic synthesis,12 reactions with (NH4)2CO3 as source
of ammonia,13 nano-tungsten trioxide-supported sulfonic
acid (n-WSA)14 and sulfated boric acid nanoparticle-
catalyzed15 reactions, and other methods16 have been
successfully applied. However, many of the reported
synthetic methods with improved reaction conditions still
have several drawbacks, such as exploitation of high
temperature, low yields of products, and increased level of
chemical waste.
MCR in H2O–EtOH media. Possibility to recover and reuse
montmorillonite K10 up to five catalytic cycles has been
demonstrated.
Based on the knowledge in environmentally friendly
synthesis and diverse biological activities of 1,4-DHPs, a series
of unique and highly promising 1,4-DHPs via one-pot
MCR in H2O–EtOH medium were obtained. The reaction
of aromatic aldehyde 1a–l, malononitrile (2), substituted
aniline 3a–h, and diethyl acetylenedicarboxylate (4) in the
presence of montmorillonite K10 in H2O–EtOH allowed to
obtain compounds 5a–l in high yields (Scheme 1). The
structure of compound 5a as a representative was confirmed by
single crystal X-ray crystallographic analysis (Fig. 1).
To evaluate the efficiency of montmorillonite K10 in the
investigated reaction, compound 5a was also synthesized
using different catalysts and solvents and yields of product
5a as well as catalyst reusability were compared (Table 1).
When 4-bromobenzaldehyde (1a) was treated with malono-
nitrile (2), 4-methoxyaniline (3a), and diethyl acetylene-
dicarboxylate (4) in the presence of triethylamine in EtOH,
1,4-DHP 5a was obtained in 70% yield (Table 1, entry 1).
Performing SnCl2-catalyzed reaction in MeCN allowed to
isolate product 5a in 56% yield (entry 2). Comparatively
low yields of 1,4-DHP 5a were also obtained when the
MCR was conducted in MeCN using ZnCl2 or InCl3 as
catalysts (entries 3 and 5). Furthermore, PEG 400-cata-
In continuation of our multifaceted research regarding
environmentally benign synthesis of novel pyrrole, thiazole,
and pyranopyrazole derivatives,17 herein we present the
synthesis of 1,4-DHPs by montmorillonite K10-catalyzed
61

Chemistry of Heterocyclic Compounds 2019, 55(1), 60–65
Figure 2. Recovery of montmorillonite K10 in the synthesis of
1,4-DHP 5a.
Scheme 2
H
CN
CN
Ar2
6
CO2Et
CO2Et
Ar1NH2
+
Figure 1. The molecular structure of 1,4-DHP 5a with atoms
represented by thermal vibration ellipsoids of 30% probability.
Ar1-H2N
CO2Et
CO2Et
7
4
Ar2
Ar2
Table 1. Effects of various catalysts and solvents
on the yield of 1,4-DHP 5a*
NC
NC
C
CO2Et
CO2Et
C
CO2Et
CO2Et
C
C
N
HN
Entry
Catalyst**
Solvent
Yield, %
H
H
H
N
N
1
2
3
4
5
6
Et3N
SnCl2·2H2O
ZnCl2
EtOH
MeCN
MeCN
–
70
Ar1
Ar1
8
56
Ar2
52
65
NC
H2N
CO2Et
CO2Et
PEG 400
InCl3
MeCN
H2O–EtOH
60
N
Ar1
Montmorillonite K10
85 (80)***
* Reaction conditions: 4-bromobenzaldehyde (1a) (185 mg, 1 mmol),
malononitrile (2) (66 mg, 1 mmol), 4-methoxyaniline (3a) (123 mg,
1 mmol), diethyl acetylenedicarboxylate (4) (160 μl, 1 mmol), catalyst,
solvent (5 ml), 60°C, 6–8 h.
In conclusion, one-pot four-component synthesis of
1,4-DHP derivatives has been accomplished in H2O–EtOH
using montmorillonite K10 as catalyst. The acidic
properties of montmorillonite K10 promote the formation
of products, and the catalyst may be recovered and reused
in up to five catalytic cycles. The developed environ-
mentally benign and cost-effective synthetic approach
exhibits several advantages – short reaction times,
suppressed formation of side products, inexpensive and
nontoxic solvent system, simple workup procedure, and
catalyst reusability. Therefore, the presented method may
be further exploited to obtain novel 1,4-DHP derivatives
with promising biological activities.
** Catalyst was used in an amount of 50% by mass relative to 4-bromo-
benzaldehyde (1a).
*** Recovered montmorillonite K10 was used.
lyzed reaction under solvent-free conditions afforded
product 5a in 65% yield (entry 4).
The catalysts tested so far provided low to moderate
yield of 1,4-DHP 5a, and recovery of catalyst could not be
achieved. However, montmorillonite K10 in environ-
mentally benign H2O–EtOH medium was more efficient
and allowed to obtain product 5a in 85% yield (Table 1,
entry 6). Furthermore, montmorillonite K10 could be
successfully recovered and reused without significant
decrease in the yield of compound 5a. Encouraged by these
results, we applied such environmentally friendly reaction
conditions for the synthesis of other 1,4-DHPs affording
final products 5b–l in 80–89% yield. Moreover, the
catalyst could be reused up to five catalytic cycles, as
demonstrated for the synthesis of compound 5a (Fig. 2).
A plausible mechanism of the investigated MCR has
been proposed (Scheme 2). The Knoevenagel condensation
of aromatic aldehyde and malononitrile (2) catalyzed by
acidic montmorillonite K10 yields arylidene compound 6.
In addition, arylamine reacts with diethyl acetylene-
dicarboxylate (4) to give 1,3-dipole 7 that may further
interact with intermediate 6. Subsequent cyclization of
zwitterion 8 leads to the formation of target 1,4-DHP.
Experimental
IR spectra were recorded on a Bruker Alpha FTIR
1
spectrometer in KBr pellets. H NMR (500 and 300 MHz
for compounds 5a,b,d–l and 5c, respectively) and 13C
NMR spectra (125 and 75 MHz for compounds 5a,b,d–l
and 5c, respectively) were acquired on a Bruker Avance
500 spectrometer in CDCl3 solutions. TMS was used as
1
internal standard for H NMR spectra, and solvent carbon
atom served as internal standard for 13C NMR spectra
(CDCl3 77.27 ppm). Low-resolution mass spectra were
recorded on a Finnigan MAT 1020 mass spectrometer (ESI
method). HRMS data were obtained using a Thermo
Scientific Obitrap mass spectrometer (ESI method).
Melting points were measured on a Buchi R-535 micro
melting point apparatus. Reaction progress was monitored
62

Chemistry of Heterocyclic Compounds 2019, 55(1), 60–65
1
by analytical HPLC on a Waters HPLC system equipped
with a Waters Atlantis dc18 column (4.6 × 150 mm, 5 μm)
and by TLC on pre-coated silica gel GF254 plates
(visualization by UV light at 254 nm).
1300, 1215, 1176, 1108, 1031. H NMR spectrum, δ, ppm
(J, Hz): 7.30–7.27 (4H, m, H Ar); 6.96 (2H, d, J = 8.9,
H Ar); 6.90 (2H, d, J = 8.7, H Ar); 4.62 (1H, s, 4-CH); 4.06
(2H, s, NH2); 3.84 (3H, s, OCH3); 4.03–3.82 (4H, m,
2CH2CH3); 3.81 (3H, s, OCH3); 1.13 (3H, t, J = 14.1,
CH2CH3); 1.00 (3H, t, J = 14.3, CH2CH3). 13C NMR
spectrum, δ, ppm: 165.3; 163.2; 160.8; 158.6; 149.9; 141.7;
137.6; 131.7 (2C); 128.3 (2C); 127.4 (2C); 120.8; 114.9;
114.1; 105.4; 62.8; 61.9; 60.8; 55.7; 55.3; 37.9; 14.0; 13.6.
Found, m/z: 478.1977 [M+H]+. C26H28N3O6. Calculated, m/z:
478.1972.
Synthesis of 1,4-DHP derivatives 5a–l (General
method). Diethyl acetylenedicarboxylate (4) (160 μl, 1 mmol)
was added to a mixture of aromatic aldehyde 1a–l (1 mmol),
aromatic amine 3a–h (1 mmol), malononitrile (2) (66 mg,
1 mmol), and montmorillonite K10 (50% by mass relative
to aldehyde 1a–l) in H2O–EtOH, 4:1 (5 ml). The mixture
was stirred at 60°C for 6–8 h, and completion of the
reaction was confirmed by TLC (eluent hexane–EtOAc,
3:2) and analytical HPLC. EtOAc (6 ml) was then added
and the obtained suspension was filtered through a plug of
cotton. The filtrate was concentrated under reduced
pressure, and crude product was recrystallized from EtOH.
The cotton plug containing montmorillonite K10 was
soaked in EtOAc (5–7 ml) until the catalyst settled down to
the bottom of the beaker. The cotton was removed, EtOAc
was decanted, and the obtained powder was dried in oven
at 50°C. The recovered montmorillonite K10 could be
reused in up to five catalytic cycles.
Diethyl 6-amino-5-cyano-4-(4-cyanophenyl)-1-(3-fluoro-
phenyl)-1,4-dihydropyridine-2,3-dicarboxylate (5d). Yield
368 mg (80%), light-brown solid, mp 148–150°C.
IR spectrum, ν, cm–1: 3452 (NH2), 3329, 3019, 2928, 2855,
2230, 2186 (C≡N), 1736 (C=O), 1708, 1653, 1576, 1488,
1
1417, 1371, 1215, 1108, 1019. H NMR spectrum, δ, ppm
(J, Hz): 7.68 (2H, dd, J = 11.3, J = 2.6, H Ar); 7.70–7.66
(3H, m, H Ar); 7.53–7.49 (1H, m, H Ar); 7.47 (1H, d,
J = 8.2, H Ar); 7.18 (1H, d, J = 8.2, H Ar); 4.74 (1H, s,
4-CH); 4.29 (2H, s, NH2); 4.05–3.89 (4H, m, 2CH2CH3);
1.07 (3H, t, J = 14.3, CH2CH3); 0.99 (3H, t, J = 14.3,
CH2CH3). 13C NMR spectrum, δ, ppm (J, Hz): 164.4;
Diethyl 6-amino-4-(4-bromophenyl)-5-cyano-1-(4-methoxy-
phenyl)-1,4-dihydropyridine-2,3-dicarboxylate (5a). Yield
447 mg (85%), yellow solid, mp 150–152°C. IR spectrum,
ν, cm–1: 3466 (NH2), 3341, 3218, 2981, 2183 (C≡N),
1739 (C=O), 1703, 1648, 1570, 1509, 1416, 1369, 1300,
1
163.6; 162.4; 161.6 (d, J = 246); 149.7; 141.8; 136.1 (d,
3J = 8); 132.7 (2C); 131.2; 127.9 (d, J = 3.0); 126.3 (2C);
4
2
119.8; 118.7; 118.2; 118.0 (d, J = 22.0); 110.9; 104.6;
62.3; 61.7; 61.1; 38.9; 13.8; 13.4. Found, m/z: 461.1627
1
1217, 1107. H NMR spectrum, δ, ppm (J, Hz): 7.49 (2H,
[M+H]+. C25H22FN4O4. Calculated, m/z: 461.1619.
d, J = 8.8, H Ar); 7.27–7.24 (4H, m, H Ar); 6.96 (2H, d,
J = 8.8, H Ar); 4.65 (1H, s, 4-CH); 4.12 (2H, s, NH2);
4.06–3.87 (4H, m, 2CH2CH3); 3.85 (3H, s, OCH3); 1.10
(3H, t, J = 7.1, CH2CH3); 0.99 (3H, t, J = 7.1, CH2CH3).
13C NMR spectrum, δ, ppm: 165.0; 163.0; 160.9; 150.3;
144.2; 142.2; 131.8 (2C); 131.7 (2C); 129.0 (2C); 127.1;
120.9; 120.6; 114.9 (2C); 104.6; 62.0; 60.9 (2C); 55.7; 38.3;
13.9; 13.6. Found, m/z: 526.0946 [M+H]+. C25H25BrN3O5.
Calculated, m/z: 526.0972.
Diethyl 6-amino-1-(3-chlorophenyl)-5-cyano-4-(4-fluoro-
phenyl)-1,4-dihydropyridine-2,3-dicarboxylate (5e). Yield
409 mg (87%), yellow solid, mp 181–183°C. IR spectrum,
ν, cm–1: 3486 (NH2), 3358, 3017, 2186 (C≡N), 2134, 1736
(C=O), 1705, 1652, 1578, 1507, 1474, 1415, 1370, 1298,
1218, 1157, 1097, 1017. 1H NMR spectrum, δ, ppm
(J, Hz): 7.52–7.38 (3H, m, H Ar); 7.34–7.23 (3H, m,
H Ar); 7.05 (2H, dd, J = 14.2, J = 2.8, H Ar); 4.66 (1H, s,
4-CH); 4.17 (2H, s, NH2); 4.06–3.85 (4H, m, 2CH2CH3);
1.10 (3H, t, J = 14.3, CH2CH3); 1.00 (3H, t, J = 14.3,
CH2CH3). 13C NMR spectrum, δ, ppm (J, Hz): 164.8;
162.7; 162.6; 160.8 (d, 1J = 246.0); 149.3; 140.9; 140.5 (d,
Diethyl 6-amino-4-(3-chlorophenyl)-5-cyano-1-(4-methoxy-
phenyl)-1,4-dihydropyridine-2,3-dicarboxylate (5b). Yield
395 mg (82%), light-brown solid, mp 172–174°C.
IR spectrum, ν, cm–1: 3482 (NH2), 3350, 3278, 3018,
2930, 2184 (C≡N), 1737 (C=O), 1704, 1651, 1571,
3
4J = 2.0); 136.1; 135.2; 130.7 (2C); 130.6 (d, J = 5.0);
128.7 (2C); 120.2; 115.5; 115.3 (d, 2J = 23.0); 105.6; 62.6;
62.0; 60.9; 38.0; 13.7; 13.3. Found, m/z: 470.1277 [M+H]+.
C24H22ClFN3O4. Calculated, m/z: 470.1271.
1
1510, 1416, 1370, 1215, 1109, 1031. H NMR spectrum,
δ, ppm (J, Hz): 7.44 (1H, dd, J = 7.7, J = 1.3, H Ar); 7.37
(1H, d, J = 7.9, H Ar); 7.32–7.27 (3H, m, H Ar); 7.19
(1H, t, J = 7.8, H Ar); 6.94 (2H, d, J = 8.6, H Ar); 5.30
(1H, s, 4-CH); 4.09 (2H, s, NH2); 3.99–3.89 (4H, m,
2CH2CH3); 3.85 (3H, s, OCH3); 1.06–1.00 (6H, m,
2CH2CH3). 13C NMR spectrum, δ, ppm: 165.0; 163.1;
160.9; 150.3; 142.9; 142.6; 132.7; 131.8; 130.0; 129.8;
129.0; 128.2; 127.4; 127.2; 120.4; 114.9 (2C); 104.2;
62.0; 61.5; 60.8; 55.7; 35.8; 13.8; 13.6. Found, m/z:
482.1472 [M+H]+. C25H25ClN3O5. Calculated, m/z:
482.1477.
Diethyl 6-amino-5-cyano-1-(3-nitrophenyl)-4-phenyl-
1,4-dihydropyridine-2,3-dicarboxylate (5f). Yield 374 mg
(81%), yellow solid, mp 175–177°C. IR spectrum, ν, cm–1:
3473 (NH2), 3384, 3019, 2988, 2179 (C≡N), 1739 (C=O),
1699, 1649, 1577, 1534, 1448, 1415, 1354, 1244, 1216,
1
1108, 1015. H NMR spectrum, δ, ppm (J, Hz): 8.37 (1H,
d, J = 7.7, H Ar); 8.26 (1H, d, J = 7.8, H Ar); 7.76–7.69
(2H, m, H Ar); 7.41–7.30 (5H, m, H Ar); 4.70 (1H, s, 4-CH);
4.07 (2H, s, NH2); 4.02–3.88 (4H, m, 2CH2CH3); 1.10 (3H,
t, J = 14.3, CH2CH3); 1.01 (3H, t, J = 14.1, CH2CH3).
13C NMR spectrum, δ, ppm: 164.9; 162.9; 144.2; 140.6;
136.8; 136.7; 130.9; 130.1; 128.9; 128.5; 127.4; 127.2;
125.6; 125.3; 119.9; 107.0 (2C); 64.9; 62.4; 61.2; 38.7;
13.9; 13.5. Found, m/z: 463.1610 [M+H]+. C24H23N4O6.
Calculated, m/z: 463.1612.
Diethyl 6-amino-5-cyano-1,4-bis(4-methoxyphenyl)-
1,4-dihydropyridine-2,3-dicarboxylate (5c). Yield 411 mg
(86%), light-brown solid, mp 156–158°C (mp 168–170°C18).
IR spectrum, ν, cm–1: 3470 (NH2), 3348, 3225, 3018, 2978,
2183 (C≡N), 1738 (C=O), 1703, 1650, 1609, 1572, 1414,
63

Chemistry of Heterocyclic Compounds 2019, 55(1), 60–65
Diethyl 6-amino-5-cyano-1-(2-fluorophenyl)-4-(p-tolyl)-
CH2CH3); 1.14 (3H, t, J = 14.3, CH2CH3); 0.93 (3H, t,
J = 14.3, CH2CH3). 13C NMR spectrum, δ, ppm (J, Hz):
164.7; 162.7; 157.0; 154.9 (dd, 1J = 247.0, 3J = 9.0); 150.6
(dd, 1J = 247.0, 3J = 9.0); 148.0 (ddd, 1J = 245.0, 2J = 13.0,
4J = 2.0); 145.8; 142.6; 134.9; 130.7 (2C); 129.9 (2C);
1,4-dihydropyridine-2,3-dicarboxylate (5g). Yield 377 mg
(84%), dark-brown solid, mp 168–170°C. IR spectrum,
ν, cm–1: 3466 (NH2), 3376, 3018, 2978, 2186 (C≡N), 1736
(C=O), 1704, 1653, 1579, 1500, 1416, 1370, 1302, 1215,
1
2
3
1107, 1019. H NMR spectrum, δ, ppm (J, Hz): 7.52–7.50
128.4; 120.2; 117.5 (dd, J = 19.0, J = 5.0); 105.9; 102.7
2
(1H, m, H Ar); 7.39 (1H, t, J = 14.6, H Ar); 7.30–7.24 (4H,
m, H Ar); 7.17 (2H, d, J = 7.6, H Ar); 4.61 (1H, s, 4-CH);
4.05 (2H, s, NH2); 4.01–3.83 (4H, m, 2CH2CH3); 2.32 (3H,
s, CH3); 1.11 (3H, t, J = 14.1, CH2CH3); 0.92 (3H, t,
J = 14.3, CH2CH3). 13C NMR spectrum, δ, ppm (J, Hz):
(dd, J = 28.0, 2J = 21.0); 62.1; 61.1; 59.8; 34.0; 13.8; 13.4.
Found, m/z: 472.1458 [M+H]+. C24H21F3N3O4. Calculated, m/z:
472.1478.
Diethyl 6-amino-5-cyano-1-(3-fluorophenyl)-4-(1-methyl-
1H-indol-2-yl)-1,4-dihydropyridine-2,3-dicarboxylate (5k).
Yield 451 mg (89%), brown solid, mp 145–147°C.
IR spectrum, ν, cm–1: 3478 (NH2), 3365, 3018, 2928, 2864,
2182 (C≡N), 1736 (C=O), 1707, 1654, 1575, 1467, 1416,
1
164.9; 162.9; 161.0 (d, J = 245.0); 149.1; 141.7; 140.8;
2
136.6 (d, J = 22.0); 132.7; 132.6; 132.1; 129.2; 127.3;
3
4
124.8 (d, J = 7.0); 123.1 (d, J = 3.0); 120.3; 117.1;
117.0; 106.4; 63.6; 61.9; 60.8; 38.4; 21.0; 13.8; 13.3.
Found, m/z: 450.1799 [M+H]+. C25H25FN3O4. Calculated, m/z:
450.1823.
1
1370, 1317, 1215, 1135, 1104, 1018. H NMR spectrum,
δ, ppm (J, Hz): 7.55 (1H, d, J = 7.9, H Ar); 7.47–7.43 (1H,
m, H Ar); 7.34 (1H, d, J = 7.9, H Ar); 7.24–7.17 (3H, m,
H Ar); 7.14–7.07 (2H, m, H Ar); 6.41 (1H, s, H-3'); 4.94
(1H, s, 4-CH); 4.16 (2H, s, NH2); 4.08–3.94 (4H, m,
2CH2CH3); 3.91 (3H, s, NCH3); 1.07 (3H, t, J = 14.1,
CH2CH3); 0.99 (3H, t, J = 14.1, CH2CH3). 13C NMR
spectrum, δ, ppm (J, Hz): 164.6; 163.6; 162.7; 161.6;
149.9; 143.6; 141.0; 137.7; 136.4; 131.1; 127.6; 126.3;
121.3; 120.3; 119.5; 118.0 (d, J = 9.1); 117.8; 109.4;
104.7; 99.9; 62.1; 61.3; 61.1; 30.2; 29.9; 13.8; 13.4. Found,
m/z: 489.1905 [M+H]+. C27H26FN4O4. Calculated, m/z:
489.1902.
Diethyl 6-amino-1-(4-bromophenyl)-5-cyano-4-(2-hydroxy-
phenyl)-1,4-dihydropyridine-2,3-dicarboxylate (5h). Yield
456 mg (89%), light-brown solid, mp 204–206°C.
IR spectrum, ν, cm–1: 3469 (NH2), 3361, 3018, 2984, 2184
(C≡N), 1736 (C=O), 1699, 1650, 1574, 1485, 1455, 1417,
1
1394, 1371, 1325, 1215, 1109, 1013. H NMR spectrum,
δ, ppm (J, Hz): 7.57 (2H, d, J = 8.6, H Ar); 7.25–7.21 (3H,
m, H Ar); 7.11 (1H, t, J = 14.1, H Ar); 6.92 (1H, t, J = 14.1,
H Ar); 6.82 (1H, d, J = 7.9, H Ar); 4.88 (1H, s, 4-CH); 4.24
(2H, s, NH2); 4.11–3.80 (4H, m, 2CH2CH3); 1.11 (3H, t,
J = 14.1, CH2CH3); 0.97 (3H, t, J = 14.3, CH2CH3). 13C NMR
spectrum, δ, ppm: 166.4; 163.0; 153.8; 150.6; 141.6; 134.4;
133.1 (2C); 132.2 (2C); 131.0; 129.2; 128.6; 124.9; 121.0;
120.7; 117.4; 105.1; 62.2; 61.7; 61.6; 33.1; 13.8; 13.4.
Found, m/z: 512.0815 [M+H]+. C24H23BrN3O5. Calculated,
m/z: 512.0833.
Diethyl 6-amino-1-(4-bromophenyl)-4-(2-chloro-7-methoxy-
quinolin-3-yl)-5-cyano-1,4-dihydropyridine-2,3-dicarboxylate
(5l). Yield 536 mg (85%), brown solid, mp 209–211°C.
IR spectrum, ν, cm–1: 3468 (NH2), 3339, 3018, 2929, 2853,
2184 (C≡N), 1738 (C=O), 1706, 1651, 1622, 1572, 1493,
1
1418, 1370, 1342, 1216, 1171, 1112, 1036, 1015. H NMR
Diethyl 6'-amino-5'-cyano-1'-(4-iodophenyl)-1',4'-di-
hydro-[3,4'-bipyridine]-2',3'-dicarboxylate (5i). Yield
466 mg (83%), pale-yellow solid, mp 191–193°C.
IR spectrum, ν, cm–1: 3475 (NH2), 3368, 3019, 2976, 2150
(C≡N), 1737 (C=O), 1709, 1655, 1577, 1467, 1416, 1371,
1215, 1110, 1023. 1H NMR spectrum, δ, ppm (J, Hz): 8.89
(1H, s, H-6); 8.49 (1H, d, J = 7.6, H-2); 7.95 (2H, dd,
J = 7.5, J = 1.4, H Ar); 7.54–7.48 (2H, m, H-5, H Ar); 7.30
(1H, d, J = 7.4, H Ar); 7.26 (1H, d, J = 8.5, H-4); 4.81 (1H,
s, 4'-CH); 4.06 (2H, s, NH2); 4.04–3.83 (4H, m,
2CH2CH3); 1.08 (3H, t, J = 14.1, CH2CH3); 0.97 (3H, t,
J = 14.3, CH2CH3). 13C NMR spectrum, δ, ppm: 164.7;
162.3; 149.8; 148.1; 141.2; 140.0; 137.4; 135.9; 135.2;
132.7; 132.0; 129.6; 129.5; 123.6; 123.4; 120.1; 102.5;
62.0; 61.8; 61.0; 37.2; 13.8; 13.4. Found, m/z: 545.0678
[M+H]+. C23H22IN4O4. Calculated, m/z: 545.0680.
Diethyl 6-amino-5-cyano-1-phenyl-4-(2,4,5-trifluoro-
phenyl)-1,4-dihydropyridine-2,3-dicarboxylate (5j). Yield
386 mg (82%), light-brown solid, mp 166–168°C.
IR spectrum, ν, cm–1: 3482 (NH2), 3351, 3018, 2980, 2185
(C≡N), 2170, 1739 (C=O), 1705, 1651, 1573, 1515, 1421,
1371, 1321, 1215, 1146, 1117, 1088, 1018. 1H NMR
spectrum, δ, ppm (J, Hz): 7.54–7.50 (3H, m, H Ar); 7.37
(2H, dd, J = 9.6, J = 3.2, H Ar); 7.19–7.14 (1H, m, H Ar);
6.98–6.92 (1H, m, H Ar); 4.87 (1H, s, 4-CH); 4.18 (2H, s,
NH2); 4.09–4.01 (2H, m, CH2CH3); 3.96–3.78 (2H, m,
spectrum, δ, ppm (J, Hz): 8.04 (1H, s, H-4'); 7.91 (1H, d,
J = 9.1, H-5'); 7.67 (2H, d, J = 8.1, H Ar); 7.37 (1H, dd,
J = 9.2, J = 2.7, H-6'); 7.31 (2H, d, J = 8.6, H Ar); 7.09
(1H, d, J = 2.7, H-8'); 5.34 (1H, s, 4-CH); 4.15 (2H, s, NH2);
4.01–3.91 (7H, m, 2CH2CH3, OCH3); 1.00 (6H, t, J = 14.6,
2CH2CH3). 13C NMR spectrum, δ, ppm: 164.7; 162.8;
158.2; 150.0; 147.2; 142.8; 142.5; 137.7; 136.4; 133.9
(2C); 133.2 (2C); 132.3; 129.6; 128.7; 125.2; 123.2; 119.9;
105.1; 103.8; 62.4; 61.2; 61.0; 55.7; 36.9; 13.8; 13.5.
Found, m/z: 611.0694 [M+H]+. C28H25BrClN4O5.
Calculated, m/z: 611.0691.
X-ray structural analysis of compound 5a. Crystals
were obtained by crystallization from EtOH. Single crystal
X-ray crystallographic data were collected at room tempe-
rature on a Bruker Smart Apex CCD diffractometer with
graphite monochromatic MoKα radiation (λ 0.71073 Å)
using ω-scan method.19 Preliminary lattice parameters and
orientation matrices were obtained from four sets of
frames. Integration and reduction of data were accomp-
lished using SAINT19 and SMART20 programs. The
structure was solved by direct method, and all non-hydro-
gen atoms were refined by full-matrix least-squares
technique on F2 using SHELXS97.21 Anisotropic displace-
ment parameters were included for all non-hydrogen atoms.
Atoms C(14) and C(15) were disordered over two sites
(C(14)/C(14)' and C(15)/C(15)') and refined with equal site-
64

Chemistry of Heterocyclic Compounds 2019, 55(1), 60–65
5. Khoshneviszadeh, M.; Edraki, N.; Javidnia, K.; Alborzi, A.;
occupancy factor of 0.5. DFIX, SIMU, and SADI
constraints were applied to the disordered atoms. H atoms
were positioned geometrically and treated as riding on their
parent C atoms (C–H 0.93–0.97 Å and Uiso(H) = 1.5Ueq(C)
for methyl group H or 1.2Ueq(C) for other H atoms). The
methyl groups were allowed to rotate. Crystal data for
compound 5a: C25H24BrN3O5, Mr 526.38, triclinic space
group P1¯; a 7.6737(8), b 13.4179(13), c 13.5891(13) Å;
α 112.882(2), β 90.562(2), γ 104.086(2)°; V 1241.8(2) Å3;
T 294 K; Z 2; dcalc 1.408 g/cm3; μ 1.695 mm–1; 11955
reflections measured (3.42 ≤ 2Θ ≤ 50), 4354 unique
(Rint 0.0202), which were used in all calculations. The final
R1 was 0.0551 (>2σ(I)), and wR2 was 0.1566 (all data). The
complete crystallogrpahic dataset was deposited at the
Cambridge Crystallographic Data Center (deposit CCDC
1419160).
Pourabbas, B.; Mardaneh, J.; Miri, R. Bioorg. Med. Chem.
2009, 17, 1579.
6. Gullapalli, S.; Ramarao, P. Neuropharmacology 2002, 42, 467.
7. (a) Pattan, S. R.; Rasal, V. P.; Venkatramana, N. V.;
Khade, A. B.; Butle, S. R.; Jadhav, S. G.; Desai, B. G.;
Manvi, F. V. Indian J. Chem., Sect. B.: Org. Chem. Incl. Med. Chem.
2007, 46B, 698. (b) Suresh, T.; Swamy, S. K.; Reddy, V. M.
Indian J. Chem., Sect. B.: Org. Chem. Incl. Med. Chem. 2007,
46B, 115. (c) Desai, B.; Sureja, D.; Naliapara, Y.; Shah, A.;
Saxena, A. K. Bioorg. Med. Chem. 2001, 9, 1993.
8. Dondoni, A.; Massi, A.; Minghini, E.; Bertolasi, V.
Tetrahedron 2004, 60, 2311.
9. Torres, S. Y.; Verdecia, Y.; Rebolledo, F. Tetrahedron 2015,
71, 3976.
10. Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B.
Chem. Rev. 2012, 112, 2642.
11. (a) Franke, P. T.; Johansen, R. L.; Bertelsen, S.; Jørgensen, K. A.
Chem. Asian J. 2008, 3, 216. (b) Molleti, N.; Allu, S.; Ray, S. K.;
Singh, V. K. Tetrahedron Lett. 2013, 54, 3241.
1
The Supplementary information file containing H and
13C NMR spectral data of compounds 5a–l is available at
12. (a) Sobolev, A.; Franssen, M. C. R.; Duburs, G.; De Groot, Ae.
Biocatal. Biotransform. 2004, 22, 231. (b) Marchalín, S.;
Chudík, M.; Mastihuba, V.; Decroix, B. Heterocycles 1998,
48, 1943.
the journal website at http://link.springer.com/journal/10593.
The author Guda Mallikarjuna Reddy is grateful to
Brazilian Higher Education Personnel Training Coordina-
tion (CAPES: Coordenação de Aperfeiçoamento de
Pessoal de Nível Superior) for the fellowship under the
PNPD program.
13. Rekunge, D. S.; Khatri, C. K.; Chaturbhuj, G. U. Tetrahedron
Lett. 2017, 58, 1240.
14. Bitaraf, M.; Amoozadeh, A.; Otokesh, S. J. Chin. Chem. Soc.
2016, 63, 336.
15. Azizi, K.; Azarnia, J.; Karimi, M; Yazdani, E.; Heydari, A.
Synlett 2016, 1810.
References
16. (a) Pajuste, K.; Plotniece, A. Chem. Heterocycl. Compd.
2016, 52, 538. [Khim. Geterotsikl. Soedin. 2016, 52, 538.]
(b) Petrichenko, O.; Plotniece, A.; Pajuste, K.; Ose, V.; Cēbers, A.
Chem. Heterocycl. Compd. 2015, 51, 672. [Khim. Geterotsikl.
Soedin. 2015, 51, 672.] (c) Baumane, L.; Krauze, A.;
Krasnova, L.; Belyakov, S.; Duburs, G.; Stradiņš, J. Chem.
Heterocycl. Compd. 2013, 49, 1623. [Khim. Geterotsikl.
Soedin. 2013, 1752.] (d) Andzans, Z.; Krauze, A.; Adlere, I.;
Krasnova, L.; Duburs, G. Chem. Heterocycl. Compd. 2013, 49,
421. [Khim. Geterotsikl. Soedin. 2013, 454.] (e) Kulakov, I. V.;
Turdybekov, D. M. Chem. Heterocycl. Compd. 2010, 46, 839.
[Khim. Geterotsikl. Soedin. 2010, 1039.]
1. (a) DeSimone, J. M. Science 2002, 297, 799. (b) Green
Chemistry: Frontiers in Benign Chemical Syntheses and
Processes; Anastas, P. T.; Williamson, T. C., Eds.; Oxford
University Press: New York, 1998.
2. (a) Avendaño, C.; Menéndez, J. C. Med. Res. Rev. 2004, 1,
419. (b) Bahekar, S.; Shinde, D. Acta Pharm. 2002, 52, 281.
(c) Hilgeroth, A.; Lilie, H. Eur. J. Med. Chem. 2003, 38, 495.
(d) Triggle, D. J. Biochem. Pharmacol. 2007, 74, 1.
(e) Hilgeroth, A. Mini-Rev. Med. Chem. 2002, 2, 235.
3. (a) Triggle, D. J.; Langs, D. A.; Janis, R. A. Med. Res. Rev.
1989, 9, 123. (b) Marco-Contelles, J.; León, R.; de los Ríos, C.;
Samadi, A.; Bartolini, M.; Andrisano, V.; Huertas, O.; Barril, X.;
Luque, F. J.; Rodríguez-Franco, M. I.; López, B.; López, M. G.;
García, A. G.; do Carmo Carreiras, M.; Villarroya, M. J. Med.
Chem. 2009, 52, 2724. (c) Edraki, N.; Mehdipour, A. R.;
Khoshneviszadeh, M.; Miri, R. Drug Discovery Today 2009,
14, 1058.
17. (a) Reddy, V. H.; Reddy, G. M.; Reddy, M. T.; Reddy, Y. V. R.
Res. Chem. Intermed. 2015, 41, 9805. (b) Reddy, G. M.;
Garcia, J. R.; Reddy, V. H.; de Andrade, A. M.; Camilo, A., Jr.;
Pontes Ribeiro, R. A.; de Lazaro, S. R. Eur. J. Med. Chem.
2016, 123, 508. (c) Reddy, G. M.; Garcia, J. R. J. Heterocycl.
Chem. 2017, 54, 89.
4. (a) Kappe, C. O.; Fabian, W. M. F.; Semones, M. A.
Tetrahedron 1997, 53, 2803. (b) Rovnyak, G. C.; Kimball, S. D.;
Beyer, B.; Cucinotta, G.; DiMarco, J. D.; Gougoutas, J.;
Hedberg, A.; Malley, M.; McCarthy, J. P.; Zhang, R.;
Moreland, S. J. Med. Chem. 1995, 38, 119.
18. Kumar, A.; Sharma, S. Green Chem. 2011, 13, 2017.
19. Bruker, SAINT, v6.28A. Bruker AXS, Inc.: Madison, 2001.
20. Bruker, SMART, v5.625. Bruker AXS, Inc.: Madison, 2001.
21. Sheldrick, G. M. Acta Crystallogr., Sect. C: Struct. Chem.
2015, C71, 3.
65