Synthesis and biological evaluation of new series 1,4-dihydropyridines

Article abstract of DOI:10.1007/s11164-015-2310-0

Abstract: N,N,N′,N′-Tetrachlorobenzene-1,3-disulfonamide and poly(N,N′-dichloro-N-ethyl-benzene-1,3-disulfonamide) are new catalysts promoted by one-pot, facile and four-component synthesis of new substituted 1,4-dihydropyridine derivatives from the react

Full text of DOI:10.1007/s11164-015-2310-0

Res Chem Intermed
DOI 10.1007/s11164-015-2310-0
Synthesis and biological evaluation of new series 1,4-
dihydropyridines
Ramin Ghorbani-Vaghei1 Seyedeh Mina Malaekehpoor1
•
•
Parisa Hasanein2 Roya Karamyan2 Mostafa Asadbegy2
•
•
Received: 5 August 2015 / Accepted: 28 September 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract N,N,N0,N0-Tetrachlorobenzene-1,3-disulfonamide and poly(N,N0-dichloro-
N-ethyl-benzene-1,3-disulfonamide) are new catalysts promoted by one-pot, facile and
four-component synthesis of new substituted 1,4-dihydropyridine derivatives from the
reaction of ammonium acetate, aldehydes and various 1,3-dicarbonyl compounds with
good to high yields at room temperature under mild conditions. All the synthesized
compounds were evaluated for antibacterial and anti-oxidant activities. Antibacterial
activity was determined against four Gram-positive and -negative bacteria, and anti-
oxidant activity was evaluated by 2,2-diphenyl-1-picrylhydrazyl free radical scavenging.
The bioassay results indicated that synthesized 1,4-dihydropyridine derivatives have
effective anti-oxidant and antibacterial functions.
Graphical Abstract Synthesis andbiological evaluation ofnewseries dihydropyridines.
Electronic supplementary material Theonlineversionofthisarticle(doi:10.1007/s11164-015-2310-0)
contains supplementary material, which is available to authorized users.
&
Ramin Ghorbani-Vaghei
rgvaghei@yahoo.com
1
2
Department of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University,
65174 Hamedan, Iran
Department of Biology, Faculty of Science, Bu-Ali Sina University, 65174 Hamedan, Iran
123

R. Ghorbani-Vaghei et al.
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Keywords 1,4-Dihydropyridine Á 1,3-Dicarbonyl compound Á TCBDA Á PCBS Á
Antibacterial activity Á Anti-oxidant activity
Introduction
Rare structures and diverse functional groups of heterocyclic systems are of great
importance in chemical and biological investigations [1]. Dihydropyridine (DHP)
nucleus comprises an important class of bioactive molecules in pharmaceutical
fields. Also, they are used as reducing agents and versatile synthetic intermediates
for the construction of libraries, poly-substituted systems and natural products [2–9].
Variations in structural models of dihydropyridine derivatives may create various
biological activities [10–12]. For example, they are analogues of hydrogenase
coenzymes [13] and could be used as calcium-channel blockers [14], anti-
inflammatory, anti-microbial [15], anti-oxidant, anti-ulcer [16], and anticoagulant
[17], and suitable for treatment of multidrug resistance (MDR) (Fig. 1) [18].
Considering the importance of dihydropyridine derivatives, recently a number of
methods via multicomponent reaction have been developed [19, 20], by the use of I2
[21], Yb(OTf)3 [22], Sc(OTf)3 [23], HClO4–SiO2 [24, 25], and CuSO4Á5H2O [26],
including microwave irradiation [27–29], ZnO [30], ZnCl2 [31], ionic liquids [32,
33], magnetic Fe3O4 nanoparticles [34], cobalt nanoparticles [35] and organocat-
alysts [36–38]. Therefore, the design and synthesis of new 1,4-dihydropyridine
derivatives using multicomponent reactions are nowadays structurally desirable.
Experimental
All commercially available chemicals were purchased from Merck and Fluka, and
used without further purification unless otherwise stated. Nuclear magnetic
1
resonance H and 13C-NMR spectra were recorded on Bruker Avance 500, 400,
300, MHz FT and Varian 90 MHz NMR instrumenta. Chemical shifts were
expressed in parts per million (ppm) and J in hertz (Hz). Infrared (IR) spectroscopy
was conducted on a Perkin Elmer GX FT-IR spectrometer. Mass spectra was
123

Synthesis and biological evaluation of new series…
Fig. 1 Chemical structures of bioactive DHPs derivatives
recorded on a Shimadzu QP 1100 BX Mass Spectrometer. Elemental analyses were
performed with CHNS-932, Leco, USA.
A sample experimental procedure for the synthesis of ethyl-4-(4-
chlorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-
carboxylate (1)
A mixture of ammonium acetate (0.077 g, 1 mmol), 4-chlorobenzaldehyde
(0.140 g, 1 mmol), dimedone (0.140 g, 1 mmol), ethyl acetoacetate (0.130 g,
1 mmol) and TCBDA (0.06 g, 0.16 mmol) or PCBS (0.05 g), ethanol (2 mL) was
stirred at room temperature for 4 h. The progress of the reaction was monitored by
TLC (9:3, n-hexane/acetone). After completion of the reaction, ethanol (10 mL)
was added. The crude product was filtered, washed with ethanol and dried. The
crude product was recrystallized from methanol to give the pure product.
Evaporation of the solvent was followed by the addition of CH2Cl2 (10 mL)
recycling the catalysts. Yield 0.2 g (70 %); white powder; m.p.: 236–238 °C; IR
(KBr, mmax/cm-1): 3290, 3082, 2963, 2930, 1698, 1644, 1611, 1484, 1381, 1280,
1
1072, 697 cm-1; H NMR spectrum (90 MHz, CDCl3): dH = 0.80 (s, 3H, CH3),
0.97 (s, 3H, CH3), 1.08–1.16 (t, J = 7.2 Hz, 3H, CH3), 2.30–2.07 (m, 7H),
4.04–3.80 (q, J = 6.9 Hz, 2H, OCH2), 4.81 (s, 1H, CH), 7.11 (s, 4H, H Ar), 9.04 (s,
1H, NH) ppm.
Ethyl-4-(2-methoxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate (2)
Yield 0.33 g (91 %); white powder; m.p.: 240–242 °C; IR (KBr, mmax/cm-1): 3285,
3070, 2964, 1689, 1610, 1488, 1381, 1281, 1215, 1028, 752 cm-1 1H NMR
;
spectrum (300 MHz, CDCl3): dH = 0.93 (s, 3H, CH3), 1.06 (s, 3H, CH3), 1.16–1.20
(t, J = 7.1 Hz, 3H, CH3), 2.34–2.11 (m, 7H), 3.80 (s, 3H, CH3), 4.05–3.97 (q,
J = 9.6 Hz, 2H, OCH2), 5.25 (s, 1H, CH), 5.98 (s, 1H, NH), 6.84–6.77 (m, 2H, H
Ar), 7.08–7.05 (m, 3H, H Ar), 7.31–7.29 (m, 1H, H Ar) ppm; 13C NMR (75 MHz,
CDCl3): dC = 14.11 (CH3), 19.31 (CH3), 26.84 (CH3), 29.48 (CH3), 32.55 (CH2),
33.47 (CH2), 41.24 (CH), 50.72 (OCH3), 55.34 (C), 59.56 (OCH2), 105.09, 110.79,
111.02, 119.9 (C Ar), 127.2 (C Ar), 131.2 (C Ar), 134.4, 143.03, 148.37, 157.48,
167.90 (CO2), 195.29 (C=O) ppm; MS m/z = 369 [M]? (80), 340 (60), 262 (100),
234 (55), 178 (10); Anal. Calcd. for C22H27NO4: C, 71.54; H, 7.31; N, 3.79 %.
Found: C, 71.42; H, 7.60; N, 3.81 %.
123

R. Ghorbani-Vaghei et al.
Ethyl-4-(3-nitrophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate (3)
Yield 0.33 g (88 %); yellow powder. m.p.: 169–171 °C. IR (KBr, mmax/cm-1):
3285, 3076, 2958, 2872, 1705, 1642, 1606, 1534, 1487, 1380, 1352, 1281, 1211,
1
1072, 682 cm-1; H NMR spectrum (300 MHz, CDCl3): dH = 0.93 (s, 3H, CH3),
1.08 (s, 3H, CH3), 1.22–1.17 (t, J = 7.2 Hz, 3H, CH3), 2.41–2.11 (m, 7H),
4.09–4.02 (q, J = 6.9 Hz, 2H, OCH2), 5.15 (s, 1H, CH), 6.34 (s, 1H, NH),
7.40–7.35 (t, J = 7.8 Hz, 1H, H Ar), 7.74–7.71 (d, J = 7.8 Hz, 1H, H Ar),
7.99–7.96 (d, J = 6.0 Hz, 1H, H Ar), 8.11 (s, 1H, H Ar) ppm; 13C NMR (75 MHz,
CDCl3): dC = 14.16 (CH3), 19.47 (CH3), 27.07 (CH3), 29.35 (CH3), 32.75 (CH2),
36.94 (CH2), 40.95 (CH), 50.54 (C), 60.05 (OCH2), 105.1, 111.2, 121.2 (C Ar),
122.8 (C Ar), 128.5, 134.8, 144.3, 148.2, 148.7, 149.1 (C Ar), 166.8 (CO2), 195.4
(C=O) ppm; MS m/z = 384 [M]? (12), 367 (24), 262 (100), 234 (74), 178 (24).
Anal. Calcd. for C21H24N2O5: C, 65.62; H, 6.25; N, 7.29 %. Found: C, 64.58; H,
6.48; N, 7.18 %.
3-Acetyl-4-(2-methoxyphenyl)-2,7,7-trimethyl-1,4,5,6,7,8-
hexahydroquinoline-5-one (4)
Yield 0.29 g (88 %); yellow powder. m.p.: 210–212 °C. IR (KBr, mmax/cm-1):
3289, 3300, 2960, 2930, 1666, 1611, 1473, 1379, 1220, 1142, 762; 1H NMR
spectrum (300 MHz, CDCl3): dH = 0.93 (s, 3H, CH3), 1.04 (s, 3H, CH3), 2.33–2.09
(m, 10 H), 3.84 (s, 3H, OCH3), 5.36 (s, 1H, CH), 6.64 (s, 1H, NH), 6.83-6.78 (t,
J = 6.6 Hz, 2H, H Ar), 7.18–7.06 (m, 2H, H Ar) ppm; 13C NMR (75 MHz, CDCl3):
dC = 19.60 (CH3), 27.04 (CH3), 29.19 (CH3), 29.46 (CH3), 31.95 (CH2), 32.56
(CH2), 40.96 (CH), 50.78 (OCH3), 55.46 (C), 111.1, 111.5, 114.5, 120.6, 127.6 (C
Ar), 129.8, 134.6, 141.0, 148.8, 155.9 (C Ar), 195.4 (C=O), 200.9 (C=O) ppm; MS
m/z = 339 [M]? (10), 309 (56), 232 (100), 190 (10), 77 (18); Anal. Calcd. for
C21H25NO3: C, 74.33; H, 7.37; N, 4.12 %. Found: C, 74.36; H, 7.83; N, 4.15 %.
A sample experimental procedure for the synthesis of ethyl-2-methyl-4-
(3-methylphenyl)-5-oxo-4,6,7,8-tetrahydro-1H-quinoline-3-carboxylate (5)
A mixture of ammonium acetate (0.077 g, 1 mmol), 3-methylbenzaldehyde
(0.120 g, 1 mmol), 1,3-cyclohexanedione (0.112 g, 1 mmol), ethyl acetoacetate
(0.130 g, 1 mmol) and TCBDA (0.06 g, 0.16 mmol) or PCBS (0.05 g), ethanol
(2 mL) was stirred at room temperature for the appropriate time. The progress of the
reaction was monitored by TLC (9:2, n-hexane/acetone). After completion of the
reaction, ethanol (10 mL) was added. The crude product was filtered, washed with
ethanol and dried. The crude product was recrystallized from methanol to give the
pure product. Evaporation of the solvent was followed by the addition of CH2Cl2
(10 mL) recycling the catalysts. Yield 0.22 g (70 %); white powder; m.p.:
195–197 °C; IR (KBr, mmax/cm-1): 3373, 3295, 3075, 2960, 2940, 1722, 1693,
1608, 1485, 1377, 1219, 1181, 1073 cm-1; 1H NMR spectrum (400 MHz, CDCl3):
dH = 1.20–1.23 (t, J = 6.0 Hz, 3H, CH3), 1.89–2.05 (m, 2H, CH2), 2.29 (s, 3H,
123

Synthesis and biological evaluation of new series…
CH3), 2.31–2.37 (m, 2H, CH2), 2.38 (s, 3H, CH3), 2.46–2.42 (m, 2H, CH2)
4.10–4.04 (q, J = 8.1 Hz, 2H, CH2), 5.07 (s, 1H, CH), 6.14 (s, 1H, NH), 6.93–6.94
(t, J = 2.7 Hz, 1H, H Ar), 7.12–7.09 (m, 3H, H Ar) ppm; 13C NMR (100 MHz,
CDCl3): dC = 14.20 (CH3), 19.41 (CH3), 21.02 (CH3), 21.57 (CH2), 27.48 (CH2),
36.28 (CH2), 37.05 (CH), 59.80 (OCH2), 106.1, 113.4, 125.0, 126.8, 127.8, 128.8,
137.2 (C Ar), 143.2 (C Ar), 147.0, 149.6, 167.5 (CO2), 195.7 (C=O) ppm; MS
m/z = 325 [M]? (33), 295 (16), 234 (100), 205 (77), 160 (16); Anal. Calcd. for
C19H21NO2: C, 73.84; H, 7.07; N, 4.30 %. Found: C, 73.67; H, 7.32; N, 3.71 %.
3-Acetyl-4-(2-hydroxy-5-bromophenyl)-2-methyl-4,6,7,8-tetrahydro-
1H-quinoline-5-one (6)
Yield 0.32 g (85 %); white powder; m.p.: 209–211 °C; IR (KBr, mmax/cm-1): 3420,
3281, 3088, 2951, 2900, 1714, 1580, 1511, 1472, 1378, 1237, 1195, 1027 cm-1; 1H
NMR spectrum (300 MHz, DMSO-d6): dH = 1.62–1.58 (m, 1H, CH2), 1.98–1.93
(d, J = 12.9 Hz, 1H, CH2), 2.03 (s, 3H, CH3), 2.23 (s, 3H, CH3), 2.40–2.30 (m, 2H,
CH2), 3.02 (s, 1H, NH), 4.42 (s, 1H, CH), 6.75-6.72 (d, J = 8.7 Hz, 1H, H Ar),
7.17–7.14 (d, J = 7.8 Hz, 1H, H Ar), 7.36 (s, 1H, H Ar), 7.68 (s, 1H, OH) ppm; 13
C
NMR (75 MHz, DMSO-d6): dC = 20.07 (CH3), 20.74 (CH3), 28.74 (CH2), 30.54
(CH2), 32.99 (CH2), 47.34 (CH), 84.45, 109.1, 111.4, 118.0, 129.4, 130.4 (C Ar),
131.0, 150.0, 150.7, 192.7 (C=O), 204.4 (C=O) ppm; MS m/z = 378 [M]? (50), 360
(66), 332 (31), 204 (100), 162 (53); Anal. Calcd. for C20H22BrNO: C, 57.6; H, 4.80;
N, 3.73 %. Found: C, 56.98; H, 4.83; N, 3.69 %.
A sample experimental procedure for the synthesis of ethyl-4-
(3-methylphenyl)-2-methyl-5-oxo-4,5-dihydro-1H-indeno-
[1,2-b]pyridine-3-carboxylate (7)
A mixture of ammonium acetate (0.077 g, 1 mmol), 3-methylbenzaldehyde
(0.120 g, 1 mmol), 1,3-indandione (0.146 g, 1 mmol), ethyl acetoacetate
(0.130 g, 1 mmol) and TCBDA (0.06 g, 0.16 mmol) or PCBS (0.05 g), ethanol
(2 mL) was stirred at room temperature for the appropriate time. The progress of the
reaction was monitored by TLC (9:3, n-hexane/acetone). After completion of the
reaction, ethanol (10 mL) was added. The crude product was filtered, washed with
ethanol and dried. The crude product was recrystallized from methanol to give the
pure product. Evaporation of the solvent was followed by the addition of CH2Cl2
(10 mL) recycling the catalysts. Yield 0.33 g (92 %); red powder; m.p.:
256–258 °C; IR (KBr, mmax/cm-1): 3436, 3274, 3192, 3083, 2984, 1670, 1637,
1512, 1189, 1085 cm-1 1H NMR spectrum (500 MHz, CDCl3): dH = 1.17 (t,
;
J = 7.0 Hz, 3H, CH3), 2.3 (s, 3H, CH3), 2.51 (s, 3H, CH3), 4.08 (q, 2H, CH2), 6.86
(s, 1H, NH), 6.96 (d, J = 3.5 Hz, 1H, H Ar), 7.15–7.11 (m, 4H, H Ar), 7.29 (s, 1H,
H Ar), 7.38–7.37 (d, J = 6.0 Hz, 2H, H Ar) ppm; 13C NMR (100 MHz, CDCl3):
dC = 14.01 (CH3), 19.66 (CH3), 21.47 (CH3), 37.24 (CH), 60.01 (OCH2), 108.2,
110.6, 117.1, 121.3, 125.0, 127.2, 128.0, 128.6, 130.0 (C Ar), 131.2, 134.0, 136.1,
137.5, 143.2 (C Ar), 145.6, 153.2, 167.4 (CO2), 192.4 (C=O) ppm; MS m/z = 359
123

R. Ghorbani-Vaghei et al.
[M]? (6.2), 298 (100), 268 (31), 206 (31), 178 (35); Anal. Calcd. for C23H21NO3: C,
76.86; H, 5.89; N, 3.90 %. Found: C, 76.53; H, 5.87; N, 3.69 %.
Ethyl-4-(2-hydroxy-5-bromophenyl)-2-methyl-5-oxo-4,5-dihydro-
1H-indeno-[1,2-b]pyridine-3-carboxylate (8)
Yield 0.38 g (88 %); orange powder; m.p.: 235–237 °C; IR (KBr, mmax/cm-1):
1
3430, 3210, 3080, 2985, 1738, 1659, 1548, 1460, 1093 cm-1; H NMR spectrum
(400 MHz, DMSO-d6): dH = 1.11–1.08 (t, J = 7.2 Hz, 3H, CH3), 1.94 (s, 3H,
CH3), 3.23–3.24 (d, J = 2.8 Hz, 1H, CH), 4.06–4.01 (q, J = 7.2 Hz, 2H, CH2),
4.13–4.12 (d, 1H, NH), 6.75–6.73 (d, J = 8.4 Hz, 1H, H Ar), 7.45–7.16 (m, 6H, H
Ar), 9.60 (br, 1H, OH) ppm; 13C NMR (100 MHz, DMSO-d6): dC = 14.33 (CH3),
24.63 (CH3), 30.36 (CH), 44.38 (OCH2), 60.96, 83.34, 107.65, 112.0, 118.6, 119.6,
120.6 (C Ar), 127.8 (C Ar), 130.1, 130.1, 131.0, 131.4, 135.9, 136.2, 151.5, 160.9
169.4 (CO2), 186.5 (C=O) ppm; MS m/z = 441 [M]? (31), 325 (17), 268 (100), 234
(89), 206 (19); Anal. Calcd. for C22H18BrNO4: C, 60.01; H, 4012; N, 3.18 %.
Found: C, 59.25; H, 3.94; N, 2.87 %.
A sample experimental procedure for the synthesis of ethyl-5-phenyl-2,2,7-
trimethyl-4-oxo-5,8-dihydro-4H-1,3-dioxa-8-aza-naphthalene-6-carboxylate
(9)
A mixture of ammonium acetate (0.077 g, 1 mmol), benzaldehyde (0.106 g,
1 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (0.144 g, 1 mmol), ethyl acetoacetate
(0.130 g, 1 mmol) and TCBDA (0.06 g, 0.16 mmol) or PCBS (0.05 g), ethanol
(2 mL) was stirred at room temperature for the appropriate time. The progress of the
reaction was monitored by TLC (8:2, n-hexane/acetone) until completion of the
reaction. Evaporation of the solvent under reduced pressure was followed by the
addition of methanol (2 mL) to give the pure product. Evaporation of methanol and
then the addition of CH2Cl2 (10 mL) recycling the catalysts. Yield 0.29 g (86 %);
white powder; m.p.: 158–160 °C. IR (KBr, mmax/cm-1): 3426, 2985, 2800, 1736,
1
1704, 1555, 1501, 1443, 1387, 1266, 1061 cm-1; H NMR spectrum (90 MHz,
DMSO-d6): dH = 1.18 (t, J = 4.8 Hz, 3H, CH3), 1.63 (s, 3H, CH3), 2.06 (s, 6H, 2
CH3), 3.46 (q, 2H, CH2), 5.96 (s, 1H, CH), 7.25–7.40 (m, 6H, H Ar, NH) ppm; 13
C
NMR (100 MHz, DMSO-d6): dC = 13.82 (CH3), 19.78 (CH3), 27.89 (CH3), 28.48
(CH3), 49.06 (CH), 58.10 (OCH2), 59.66 (C), 95.69, 105.6, 127.4, 128.6, 128.9,
129.2, 129.8 (C Ar), 130.0 (C Ar), 153.4, 160.8, 166.8 (CO2), 167.6 (CO2) ppm; MS
m/z = 343 [M]? (9), 341 (28), 208 (50), 104 (86), 77 (100); Anal. Calcd. for
C19H21NO5: C, 66.47; H, 6.12; N, 4.08 %. Found: C, 65.40; H, 6.10; N, 3.81 %.
Ethyl-5-(2,4-dichlorophenyl)-2,2,7-trimethyl-4-oxo-5,8-dihydro-4H-1,
3-dioxa-8-aza-naphthalene-6-carboxylate (10)
Yield 0.28 g (70 %); white powder; m.p.: 183–184 °C; IR (KBr, mmax/cm-1): 3369,
3077, 3001, 2928, 1769, 1740, 1587, 1470, 1384, 1277, 1102, 1024 cm-1; 1H NMR
spectrum (90 MHz, DMSO-d6): dH = 1.52 (t, J = 6.8 Hz, 3H, CH3), 2.08 (s, 9H,
123

Synthesis and biological evaluation of new series…
3CH3), 3.52 (q, 2H, CH2), 4.02 (s, 1H, CH), 6.54 (s, 1H, NH), 7.11–7.68 (m, 3H, H
Ar) ppm; 13C NMR 100 MHz, DMSO-d6): dC = 14.4 (CH3), 18.6 (CH3), 35.0
(2CH3), 36.5 (CH) 59.9 (OCH2), 103 (C), 128.1 (C Ar), 129.1, 129.7, 132.5, 133.6,
138.8, 150.2, 166.4, 169.3 (2CO2) ppm; MS m/z = 412 [M]? (45), 376 (9), 295
(16), 262 (100), 179 (33), 149 (66); Anal. Calcd. for C19H19Cl2NO5: C, 55.33; H,
4.65; N, 3.40 %. Found: C, 54.32; H, 4.43; N, 2.91 %.
6-Acetyl-5-(2,4-dichlorophenyl)-2,2,7-trimethyl-5,8-dihydro-4H-1,3-dioxa-
8-aza-naphthalene-4-one (11)
Yield 0.30 g (80 %); white powder.; m.p.: 189–191 °C; IR (KBr, mmax/cm-1): 3175,
3001, 3001, 2928, 1660, 1565, 1454, 1347, 1260, 1203, 1058, 756 cm-1; 1H NMR
spectrum (300 MHz, DMSO-d6): dH = 1.80 (s, 3H, CH3), 1.88 (s, 3H, CH3), 2.07
(s, 6H, CH3), 4.86 (s, 1H, CH), 7.12-7.09 (d, J = 8.4 Hz, 1H, H Ar), 7.47-7.43 (d,
J = 8.4 Hz, 1H, H Ar), 7.73 (s, 1H, H Ar) ppm; 13C NMR (75 MHz, DMSO-d6):
dC = 26.58 (CH3), 27.44 (CH3), 30.69 (CH), 41.88 (C), 106.9, 127.3 (C Ar), 127.5,
128.6, 129.2, 133.5, 136.1, 158.7, 160.2 (CO2), 206.4 (C=O) ppm; MS m/z = 381
[M]? (2.7), 296 (61), 282 (16), 241 (16), 199 (100) ppm; Anal. Calcd. for
C18H17Cl2NO4: C, 56.56; H, 4.48; N, 3.66 %. Found: C, 55.56; H, 4.13; N, 3.59 %.
A sample experimental procedure for the synthesis of 9-(phenyl)-3,3,6,6-
tetra-methyl-1,2,3,4,5,6,7,8-octahydro-acridine-1,8-dione (16)
A mixture of ammonium acetate (0.077 g, 1 mmol), benzaldehyde (0.106 g,
1 mmol), dimedone (0.280 g, 2.1 mmol) and TCBDA (0.06 g, 0.16 mmol) or PCBS
(0.05 g), ethanol (2 mL) was stirred at room temperature for the appropriate time.
The progress of the reaction was monitored by TLC (9:3, n-hexane/acetone). After
completion of the reaction, ethanol (10 mL) was added. The crude product was
filtered, washed with ethanol and dried. Evaporation of the solvent was followed by
the addition of CH2Cl2 (10 mL) recycling the catalysts.
9-(2,4-dichlorophenyl)-3,3,6,6-tetra-methyl-2,4,5,7-tetraoxa-1,3,6,8-
tetrahydro-acridine-1,8-dione (17)
Yield 0.34 g (80 %); white powder; m.p.: 168–170 °C; IR (KBr, mmax/cm-1): 3129,
3077, 3001, 2882, 1779, 1743, 1589, 1477, 1395, 1320, 1273, 1201, 1020 cm-1; 1H
NMR spectrum (400 MHz, DMSO-d6): dH = 1.81 (s, 6H, 6H, 2CH3), 1.89 (s, 6H,
2CH3), 4.88 (s, 1H, CH), 7.10–7.13 (t, J = 8.4 Hz, 1H, H Ar), 7.45–7.48 (q,
J = 8.4 Hz, 1H, H Ar), 7.74–7.75 (d, J = 2.0 Hz, 1H, H Ar) ppm; 13C NMR
(100 MHz, DMSO-d6): dC = 27.0 (CH3), 27.9 (CH3), 42.3 (CH), 107.4, 127.8,
128.0 (C Ar), 129.0, 129.6, 133.9, 136.5, 159.1, 160.6 ppm.
Screening of DPPH radical scavenging activity
Free radical scavenging activity of the new synthesized compounds was evaluated
by the stable radical DPPH. Thrn, 0.3 mmol DMSO solution of DPPH (1 mL) was
123

R. Ghorbani-Vaghei et al.
added to samples (2.5 mL) containing different synthesized 1,4-DHPs. The samples
were first kept in a dark place at room temperature and their absorbance was read at
517 nm after 30 min. The anti-oxidant activity (AA) was determined using the
following formula:
AA % ¼ 1 À ððAsÀAbÞ=AcÞ Â 100
Blank samples contained (1 mL) DMSO ? (2.5 mL) from various concentra-
tions of synthesized compounds; the control sample contained (1 mL) of
(0.3 mmol) DPPH ? (2.5 mL) DMSO. The optic density of the samples, the
control and the empty samples were measured in comparison with DMSO. Ascorbic
acid was used as a positive control and experiments were carried out in triplicate.
The discoloration was plotted against the sample concentration in order to calculate
the IC50 value, which is the amount of sample necessary to decrease the absorbance
of DPPH by 50 % (Table 3).
Screening of antimicrobial activity
Synthesized 1,4-dihydropyridine derivatives were tested by the disc diffusion
method against a panel of microorganisms including two Gram-positive bacteria,
namely Bacillus cereus (PTCC 1247) and Staphylococcus aureus (Wild) and two
Gram-negative bacteria, namely Escherichia coli (Wild) and Serratia marcescens
(PTCC 1111). The complexes were dissolved in hexane to a final concentration of
1 mg/mL then sterilized by filtration (0.45 lm; Millipore). All tests were carried out
with 10 mL of suspension containing 1.5 9 108 bacteria/mL and spread on nutrient
agar medium. A negative control was prepared by DMSO. Gentamicin, Penicillin,
Streptomycin and Cephalexin were used as positive standard discs for the
comparison of antibacterial activity. Positive and negative controls are shown in
Table 5 (below).
Statistical analysis
The evaluation of antibacterial and anti-oxidant assays was carried out in triplicate
and recorded as mean standard deviation. Analysis of variance was performed by
Excel and SPSS procedures. p value \0.05 was regarded as significant.
Results and discussion
As a part of our research into the application of N-halosulfunamides in organic
synthesis [39–43], we report one-pot, four-component synthesis of 1,4-dihydropy-
ridine derivatives from ammonium acetate, cyclic and acyclic 1,3-dicarbonyl
compounds and various aldehydes in the presence of N,N,N0,N0-tetrachlorobenzene-
1,3-disulfonamid (TCBDA) and poly(N,N0-dichloro-N-ethyl-benzene-1,3-disulfon-
amide) (PCBS) [44, 45] as catalyst at room temperature and under mild conditions
(Scheme 1).
123

Synthesis and biological evaluation of new series…
Scheme 1 Synthesis of various multisubstituted 1,4-dihydropyridine derivatives
Scheme 2 Structure of TCBDA and PCBS
Providing the TCBDA and PCBS are easy and stable under atmospheric
conditions for 2 months, after the completion of the reaction, the catalyst can be
recovered and can be reused several times without significant decrease of the yield
(Scheme 2).
In order to optimize the reaction conditions, we first examined the effect of
TCBDA and/or PCBS for the synthesis of 1,4-DHPs under Hantzsch condensation
from 4-chlorobenzaldehyde (1.0 mmol), ethyl acetoacetate (1.0 mmol), ammonium
acetate (1.0 mmol) and dimedone (1.0 mmol) as a model reaction. It was observed
that, in the absence of the catalyst, only a trace of ethyl-4-(4-chlorophenyl)-2,7,7-
trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate was formed, even
after prolonged reaction times (Table 1, entry 8). So, the effect of the catalyst
was also investigated in various conditions and the results are summarized in
Table 1. It was determined that TCBDA (0.06 g, 0.16 mmol) or PCBS (0.05 g) and
ethanol were optimal to this reaction (Table 1, entries 1, 2).
Therefore, in order to determine the scope and generality of this reaction,
cyclocondensation of a number of various cyclic and acyclic 1,3-dicarbonyl
compounds, aromatic, heteroaromatic and aliphatic aldehydes and ammonium
acetate as a source of nitrogen was applied and the corresponding 1,4-dihydropy-
ridine derivatives were synthesized in good to high yields. The results are
summarized in Table 2.
Furthermore, under optimized reaction conditions, we selected dimedone and
2,2-dimethyl-1,3-dioxane-4,6-dione for the synthesis of structurally symmetrical
1,4-DHPs, and, as shown in Table 2, the desired products were achieved in good to
high yields (Table 2, entries 16, 17).
123

R. Ghorbani-Vaghei et al.
Table 1 Optimization of reaction conditions for the synthesis of ethyl-4-(4-chlorophenyl)-2,7,7-tri-
methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate
Entry
Conditions
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
a
TCBDA (0.06 g), EtOH, rt
4
3
70
PCBS (0.05 g), EtOH, rt
90
TCBDA (0.056 g), EtOAc/acetone (8:2), rt
TCBDA (0.05 g), acetone, rt
4
38
5
Trace
25
TCBDA (0.05 g), EtOH/water (6:4), rt
TCBDA (0.05 g), solvent-free, rt
TCBDA (0.032 g), water, reflux
No catalyst, EtOH/CH3CN, rt
7
7
27
5
30
17
47
Experimental conditions: 4-chlorobenzaldehyde (1.0 mmol), ethyl acetoacetate (1.0 mmol), ammo-
nium acetate (1.0 mmol) and dimedone (1.0 mmol)
Also, our experiments determined that TCBDA is a reusable catalyst. Therefore,
it was applied for the synthesis of 3-acetyl-4-(2-hydroxy-5-bromophenyl)-2-methyl-
4,6,7,8-tetrahydro-1H-quinoline-5-one so that after three runs of reusing the
catalyst, its catalytic activity was almost the same as that of a fresh catalyst
(Table 2, entry 6). The results of catalytic activity of TCBDA for all three
consecutive runs are shown in Table 2.
All synthesized 1,4-dihydropyridine derivatives were screened for in vitro anti-
oxidant and antibacterial activities. Anti-oxidant properties, especially radical
scavenging activities, are very important due to the deleterious role of free radicals
in foods and biological systems [46]. The free radical scavenging activity of the
synthesized compounds (2–16) was assayed by 2,2-diphenyl-1-picrylhydrazyl
(DPPH) and comparison with ascorbic acid as a standard. Assessment of anti-
oxidant activity showed that all compounds have good free radical scavenging
activity but, in 1 mg/mL concentration, compounds 4, 6, 9, 11, 12, 4, 9, 11 and 17
show a remarkable amount of scavenging activity ([50 %) compared with standard
ascorbic acid (Table 3). The higher anti-oxidant activity is reflected in a lower IC50
(mg/mL). The effectiveness of anti-oxidants as DPPH radical scavengers ranged in
the following descending order: ascorbic acid [ 11 [ 4 [ 6 C 12 C 17 C 9 C
7 C 8 [ 16 C 15 C C3 C 10 [ 13 C C2 [ 14 C 5 (Table 3). The above results
indicate that the synthesized compounds may be used in the treatment of diseases
caused by free radicals.
The in vitro antibacterial activity of the synthesized compounds (2–16) were
assayed against four various bacterial strains like S. aureus (Gram-positive),
B.cereus (Gram-positive), E. coli (Gram-negative) and S. marcescens (Gram-
negative). The synthesized compounds were dissolved in dimethyl sulfoxide
(DMSO) at concentrations of 1, 0.1 and 0.01 mg/mL. Since dimethyl sulfoxide was
used as solvent control against all tested organisms, no activity was detected
(Table 5). Most of the studied compounds in this research represented antibacterial
activity especially on Gram-negative bacteria. It was observed that products of 3, 8,
10 and 15 have most antibacterial activity against E. coli (-) and S. marcescens (-)
123

Synthesis and biological evaluation of new series…
Table 2 Synthesis of various multifunctionalized 1,4-DHP derivatives
Entry
Aldehyde
R1
β-dicarbonyl
Product
TCBDA
PCBS
Ref.
Time (h) Yield (%)a
Time (h) Yield (%)a
Cl
a:
CHO
1
OEt
O
4
70
3
90
34
Cl
O
O
t
OE
O
N
H
a:
O
CHO
2
3
e
OM
O
O
O
OEt
OEt
4
91
88
3
3
90
78
34
34
e
OM
t
OE
O
N
H
a:
O
NO2
O
CHO
3
t
OE
NO2
O
N
H
a:
CHO
O
4
5
e
OM
O
CH3
4
2
88
80
5
3
87
76
-
O
e
OM
O
N
H
a:
CHO
O
OEt
OEt
O
O
O
O
22
t
OE
N
O
H
a:
a:
O
S
O
O
O
6
7
CHO
CHO
4
3
70
80
4
5
66
80
22
22
t
OE
N
H
O
O
S
OEt
OEt
O
O
O
O
t
OE
N
H
a:
8
9
O
O
3.5
4.5
65
70
2.5
2
60
75
22
-
t
OE
CHO
N
H
O
O
CHO
OEt
O
O
t
OE
b:
N
H
r
B
r
B
CHO
OH
O
OH
10
11
CH3
OEt
3
4
85,83,81 b
2
2
87
90
-
-
O
O
O
b:
N
H
c:
CHO
O
92
O
O
t
OE
O
N
H
c:
r
B
r
B
CHO
OH
O
12
OH
O
OEt
1.5
88
1
87
-
O
OEt
O
N
H
123

R. Ghorbani-Vaghei et al.
Table 2 continued
Entry
Aldehyde
R1
β-dicarbonyl
Product
TCBDA
PCBS
Ref.
Time (h) Yield (%)a Time (h) Yield (%)a
d:
CHO
O
O
13
O
O
O
OEt
3
6
86
70
4
5
78
60
-
O
O
t
OE
O
O
O
N
H
Cl
CHO
Cl
14
15
d:
O
O
OEt
-
-
Cl
O
Cl
O
O
t
OE
O
N
H
Cl
O
CHO
CH3
7
80
8
78
Cl
O
Cl
Cl
O
O
O
O
d:
O
O
N
H
a:
O
O
16
17
CHO
O
O
2.5
1
90
80
1.5
1.5
84
76
48
O
O
N
H
Cl
O
O
CHO
Cl
O
-
O
Cl
O
O
Cl
O
O
O
d:
O
O
O
O
N
H
O
a
Products were characterized from their physical properties, by comparison with authentic samples and
by spectroscopic methods
b
Isolated yield after three runs consecutively: 85, 83, 81
and products of 2, 4, 5, 6, 11 and 12 have low activity against most of the tested
organisms. In the tested organisms, S. aureus (?) is the most resistant bacterium.
Generally, antibacterial activity of compounds is attributed mainly to its major
components. However, today, it is known that the synergistic or antagonistic effect
of one compound in a minor percentage of mixtures has to be considered [47]. In the
synthesis of 1,4-DHPs 2–4, the introduction of -NO2 at the meta position of phenyl
(3) increased the antibacterial activity against the tested bacteria compared with the
2-OCH3 group on the benzene ring analogues (2, 4). Also, between analogues 9 and
10 of 1,4-DHPs, 10 enhanced activity against many of tested bacteria. The
introduction of -OH and -Br substituent on the benzene ring (8) showed a
decrease the antibacterial activity except against E. coli (-). 1,4-DHP (15) shows
significant activity against E. coli (-) and S. marcescens (-) bacteria compared
with unsubstituted phenyl analogues (13). 1,4-DHP (8) has a good antibacterial
activity against bacterial strains. Also, symmetrical 1,4-DHPs (16, 17) show
antibacterial activity against organisms except against S. aureus (?). All tested
organisms are resistant to Penicillin.
Our results indicated that the studied compounds can be used in the treatment of
diseases caused by the bacteria tested. However, further studies are needed to
evaluate the in vivo potential of these compounds in animal models. Inhibitory
123

Synthesis and biological evaluation of new series…
123

R. Ghorbani-Vaghei et al.
Table 4 Antibacterial activity of 1,4-DHPs
Comp. no.
Inhibition zone (mm)
Concen. (mg/mL)
S. aureus (?)
E. coli (-)
B .cereus (?)
S. marcescens (-)
2
1
8
0.26
7
0.18a
0.15a
Na
Na
Na
7
7
0.33
0.1
0.01
1
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
7
7
Na
Na
9
Na
12 0.14a
10 0.12b
0.28
0.18
0.22a
0.15b
3
4
0.1
0.01
1
Na
Na
7
8
8
0.10c
Na
9
7
0.26
0.33a
0.25b
0.1
0.01
1
Na
Na
8
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
9
7
Na
7
0.33
0.26
0.24
5
6
0.1
0.01
1
Na
Na
7
Na
Na
8
0.11a
0.00a
0.1
0.01
1
7
Na
Na
8
Na
9
0.26a
0.13b
0.33a
0.54a
7
8
0.1
0.01
1
8
7
Na
13 0.12a
10 0.35b
Na
10 0.12a
0.16
0.54
0.28a
0.11b
0.1
0.01
1
Na
Na
7
7
8
0.16b
7
0.00c
10 0.28a
Na
Na
Na
Na
8
Na
7
0.44
9
0.1
0.01
1
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
7
8
0.13b
Na
Na
10 0.12a
Na
11 0.22a
10
0.28a
0.00b
0.1
0.01
1
9
0.15b
0.10c
0.26
7
8
0.16b
7
Na
7
Na
9
7
0.18
0.33a
0.25b
11
12
13
14
0.1
0.01
1
Na
Na
8
Na
Na
Na
Na
Na
8
7
Na
7
0.15a
0.24b
0.18
0.33
0.1
0.01
1
7
Na
Na
7
Na
9
0.22a
0.15b
0.36a
0.25b
0.1
0.01
1
8
7
Na
Na
8
Na
8
Na
Na
Na
Na
7
0.16
0.16a
0.00b
0.33a
0.24b
0.1
0.01
1
Na
Na
Na
7
7
Na
12 0.22a
Na
9
0.17
0.35a
123

Synthesis and biological evaluation of new series…
Table 4 continued
Comp. no.
Inhibition zone (mm)
Concen. (mg/mL)
S. aureus (?)
E. coli (-)
B .cereus (?)
S. marcescens (-)
15
16
17
0.1
0.01
1
Na
Na
Na
Na
Na
Na
Na
Na
11 0.18b
Na
Na
8
0.45b
0.21c
0.14
9
0.27c
10 0.22a
7
7
0.37
0.43
7
0.1
0.01
1
7
0.43b
Na
Na
8
Na
Na
7
Na
9
0.28a
0.65a
0.00
0.1
0.01
8
Na
Na
Na
Na
Na
Experiment was performed in triplicate and expressed as mean SD
Values with different superscripts within each column (for any bacteria in different concentrations) are
significantly different (p \ 0.05)
Na no activity
Table 5 Antibacterial activity of antibiotics as positive controls and DMSO solvent as negative control
Microorganism
Inhibition zone (mm)
Positive controls
Negative
control
DMSO
Gentamaicina
Penicillina
Streptomycina
Cephalexina
S. aureus (?)
E. coli (-)
30 0.14
Na
Na
Na
Na
Na
18 0.12
21 0.33
20 0.15
22 0.28
15 16
Na
Na
Na
Na
Na
B. cereus (?)
S. marcescens (-)
25 0.18
35 0.24
22 24
Na
Experiment was performed in triplicate and expressed as mean SD
a
Standard antibiotic disc
Na no activity
potency values of tested 1,4-DHPs and standard antibiotic discs are summarized in
Tables 4 and 5.
Conclusions
In summary, we have developed facile and one-pot four-component synthesis of
new substituted 1,4-dihydropyridine derivatives from various aldehydes, cyclic and
acyclic 1,3-dicarbonyl compounds and ammonium acetate in the presence of
TCBDA and PCBS as recoverable catalysts at room temperature under mild
conditions. A simple procedure, good to high yields, easy purification and
reusability of the catalyst are advantages of this process. All newly synthesized
multisubstituted 1,4-DHP derivatives were evaluated for in vitro antibacterial and
123

R. Ghorbani-Vaghei et al.
anti-oxidant activities. This might be helpful in preventing the progress of various
diseases and the development of new therapeutic agents.
Acknowledgment We are grateful to Bu-Ali Sina University, Center of Excellence and Development of
Chemical Methods (CEDCM) for financial support.
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