Heterocycl. Commun.

2018; 24(1): 27–29

Sepideh Ehsanifar and Masoud Mokhtary*

3-Carboxy-1-sulfopyridin-1-ium chloride
([CPySO3H]+Cl−): an efficient catalyst for one-pot
synthesis of hexahydroquinoline-3-carboxamides
https://doi.org/10.1515/hc-2017-0211 reaction of arylaldehydes, dimedone, acetoacetanilide and
Received September 28, 2017; accepted November 27, 2017; previously ammonium acetate in ethanol at 70°C to furnish a series
published online January 6, 2018
of hexahydroquinoline-3-carboxamides 5a–l in excellent
yields (Scheme 1). The catalyst was obtained by treatment
Abstract: 3-Carboxy-1-sulfopyridin-1-ium chloride
of nicotinic acid with chlorosulfonic acid (Scheme  2). The
([CPySO3H]+Cl−) was synthesized and evaluated as a recov-
structure of [CPySO3H]+Cl− was supported by infrared (IR),
erable catalyst for one-pot synthesis of hexahydroqui- 1
H nuclear magnetic resonance (NMR), 13C NMR, thermal
noline-3-carboxamide derivatives by a four-component
gravimetric analysis (TGA) and elemental analysis. In
reaction of an arylaldehyde, dimedone, acetoacetanilide
the IR spectrum, the stretching vibrations for O-H near
and ammonium acetate. The [CPySO3H]+Cl− catalyst was
3151 cm−1, for C=O at 1728 cm−1, for C=N at 1633 cm−1, for C=C
characterized by infrared (IR), 1H nuclear magnetic reso-
at 1600 cm−1 and 1537 cm−1 and the SO2 asymmetric and sym-
nance (NMR), 13C NMR, elemental analysis and thermal
metric stretching at 1272  cm−1 and 1172  cm−1, respectively,
gravimetric analysis (TGA).
were observed. These results provide evidence that sulfonic
Keywords: 3-carboxy-1-sulfopyridin-1-ium chloride; chlo- acid moiety is part of the molecular structure of the catalyst.
rosulfonic acid; hexahydroquinoline-3-carboxamide; nic- The thermal behavior of [CPySO3H]+Cl− was studied
otinic acid; one-pot reaction. by TGA. The thermal analysis indicated that the catalyst
was stable up to 250°C. A slow decomposition could be
observed starting around 300°C.
Introduction To optimize the reaction conditions, the four-­
component reaction of benzaldehyde, dimedone, ace-
Quinolines containing a 1,4-dihydropyridine (1,4-DHP) toacetanilide and ammonium acetate was examined as a
moiety show a variety of pharmacological properties [­ 1–8]. model reaction. The highest yield of 5a was obtained for
Acetoacetanilide is an important building block in the syn- the reaction conducted in ethanol at 70°C in the presence
thesis of heterocyclic compounds with antimicrobial [9, 10] of 20 mol% of [CPySO3H]+Cl−. Under these optimized con-
and analgesic activities [11]. The synthesis of hexahydro- ditions, the reaction furnished products 5b–l in the range
quinoline-3-carboxamides via a four-­component reaction of yields from 88% to 96%. The optimum reaction time
of acetoacetanilide, aromatic aldehyde, dimedone and was analyzed using thin-layer chromatography (TLC) and
ammonium acetate in the presence of p-toluenesulfonic was found to vary from 25 min to 45 min. The structure of
acid [12] and without catalyst under harsh conditions has all products was fully supported by IR, 1H NMR, 13C NMR
been reported [13]. Herein, we report that this reaction can and elemental analysis.
be conducted under much milder conditions in the pres- To study the recyclability of the catalyst, the synthesis
ence of another catalyst. of compound 5a was conducted 5 times. Upon comple-
tion of the reaction, the catalyst was filtered, washed with
dichloromethane (2 × 10 mL) and then reused in the subse-
Results and discussion quent preparation of 5a. It was found that the initial yield
of 5a of 95% decreased only to 90% in the fifth prepara-
In this study, 3-carboxy-1-sulfopyridin-1-ium chloride tion. Also, the catalyst retained its activity after several
([CPySO3H]+Cl−) was successfully used as a catalyst in the months of storage.

*Corresponding author: Masoud Mokhtary, Department

of Chemistry, Rasht Branch, Islamic Azad University,
Conclusions
Rasht 4147654919, Iran, e-mail: [email protected]
Sepideh Ehsanifar: Department of Chemistry, Rasht Branch, Islamic A simple and efficient one-pot procedure for the synthe-
Azad University, Rasht, Iran sis of hexahydroquinolines using [CPySO3H]+Cl− as an
28      S. Ehsanifar and M. Mokhtary: 3-Carboxy-1-sulfopyridin-1-ium chloride ([CPySO3H] + Cl − )

O O Ph O R O
NH [CPySO3H]+Cl– Ph
+ RCHO + + NH4OAc N
Me EtOH, 70°C Me H
O Me
Me 2a–l 4 N Me
O Me H
1 3
5a–l
5a: R = Ph 5e: R = 3-NO2-C6H4 5i: R = 4-HO-C6H4
5b: R = 4-Cl-C6H4 5f: R = 4-NO2-C6H4 5j: R = 4-MeO-C6H4
5c: R = 2-Cl-C6H4 5g: R = 2-NO2-C6H4 5k: R = 4-N(Me)2-C6H4
5d: R = 3-Cl-C6H4 5h: R = 3-Br-C6H4 5l: R = CH(Me)2

Scheme 1 Synthesis of hexahydroquinoline-3-carboxamides 5a–l.

COOH COOH General procedure for synthesis of hexahydroquinoline-

Cl-SO3H
+ 3-carboxamides 5a–l
CH2Cl2, rt
N N Cl–
SO3H A mixture of aromatic aldehyde (1 mmol), dimedone (1 mmol, 0.14 g),
acetoacetanilide (1 mmol, 0.18 g) and ammonium acetate (1.2 mmol,
Scheme 2 Preparation of [CPySO3H]+Cl−. 0.09 g) in the presence of [CPySO3H]+Cl− (0.05 g, 0.2 mmol) was stirred
in ethanol (5 mL) at 70°C for 15–45 min. Completion of the reaction
was indicated by TLC monitoring. Then, the mixture was cooled
ionic organocatalyst in ethanol at 70°C was decribed. to ambient temperature, and the resultant precipitate of 5a–l was
Simplicity of the preparation, easy work-up, high yields crystallized from ethanol. All products were characterized by IR, 1H
NMR and 13C NMR, and the data for known compounds were com-
and recyclability of the catalyst are the advantages of
pared with those of the authentic samples reported in the literature.
this method. Yields for known compounds: 5a: 95%, reported: 78% [15], 89% [12];
5b: 96%, reported: 92% [12]; 5d: 93%, reported 74% [15]; 5e: 95%,
reported: 83% [12]; 5f: 94%, reported: 83% [12]; 5g: 92%, reported:

Experimental
84% [15]; 5i: 87%, reported: 76% [15]; 5j: 88%, reported: 94% [12].

4-(2-Chlorophenyl)-2,7,7-trimethyl-5-oxo-N-phenyl-1,4,5,6,7,8-
Melting points were measured on an Electro-thermal 9100 apparatus hexahydroquinoline-3-carboxamide (5c) Reaction time 20  min;
and are uncorrected. Unless stated otherwise, 1H NMR (400 MHz) and yield 90%; white solid; mp 225–227°C; IR: 3265 (N-H stretch), 2956
13
C NMR (100 MHz) spectra were recorded in CDCl3 on a Bruker Avance (aliphatic C-H stretch), 1677 (C=O), 1645 (C=O), 1498 (C=C stretch),
DRX-400  spectrometer. Fourier-transform infrared (FT-IR) spectra 752 cm−1 (aromatic C-H out of plane bending); 1H NMR: δ 0.96 (s, 3H,
were obtained for potassium bromide pellets on a Shimadzu SP-1100 CH3), 1.06 (s, 3H, CH3), 1.95 (s, 3H, CH3), 1.98 (d, J = 13  Hz, 1H), 2.13
instrument. The TGA was conducted using a Mettler TGA instrument. (d, J = 16 Hz, 1H), 2.32 (d, J = 16 Hz, 1H), 2.41 (d, J = 16 Hz, 1H), 5.35 (s,
The thermograms were recorded at a heating rate of 10°C/min in the 1H, CH), 6.97–7.29 (m, 7H, Ar), 7.53 (d, J = 7.6 Hz, 2H, Ar), 8.74 (s, 1H,
range of temperature from 25°C to 600°C in an inert atmosphere. NH), 9.72 (s, 1H, NHCO); 13C NMR: δ 19.5, 27.1, 29.3, 32.6, 35.3, 41.2, 50.5,
­Elemental analyses were done on a Carlo-Erba EA1110 analyzer. 108.6, 110.9, 120.3, 124.0, 127.7, 128.3, 128.9, 129.7, 131.0, 131.6, 138.1,
140.4, 143.5, 148.6, 165.8, 194.9 (C=O). Anal. Calcd for C25H25ClN2O2: C,
71.33, H, 5.99, N, 6.66. Found: C, 71.13, H, 6.04, N, 6.59.

4-(3-Bromophenyl)-2,7,7-trimethyl-5-oxo-N-phenyl-1,4,5,6,7,8-
Catalyst preparation
hexahydroquinoline-3-carbox amide (5h) Reaction time 15 min;
yield 96%; yellow solid; mp 211–213°C; IR: 3276 (N-H stretch), 3062
The catalyst was synthesized according to the reported method for (aromatic C-H), 2956 (C-H stretch), 1674 (C=O stretch), 1643 (C=O
the preparation of a similar catalyst [14, 15]. A solution of chlorosul- stretch), 752 cm−1 (aromatic C-H out of plane bending); 1H NMR: δ 0.96
fonic acid (10 mmol) in CH2Cl2 (15 mL) was added dropwise to a solu- (s, 3H, CH3), 1.10 (s, 3H, CH3), 2.13 (s, 1H), 2.18–2.20 (m, 1H), 2.22–2.28
tion of nicotinic acid (10 mmol) in CH2Cl2 (25 mL), and the mixture (m, 2H), 2.36 (s, 3H, CH3), 5.40 (s, 1H, CH), 6.09 (s,1H, NH), 7.08 (m,
was stirred for 2  h at room temperature. The resulting precipitate 1H, Ar), 7.11–7.15 (m, 1H, Ar), 7.21–7.25 (m, 1H, Ar), 7.28–7.27 (m, 2H, Ar),
was filtered, washed with CH2Cl2 (2 × 10 mL) and dried in a desiccator 7.31–7.35 (m, 2H, Ar), 7.45–7.48 (m, 2H, Ar), 7.61 (s, 1H, NH); 13C NMR:
under reduced pressure to give [CPySO3H]+Cl− as a white stable pow- δ 19.0, 27.3, 29.5, 32.5, 36.6, 50.8, 108.2, 111.6, 119.9, 120.0, 123.2, 127.5,
der: Yield 94%; IR: 3157 (O-H stretch), 1731 (C=O stretch), 1631 (C=N 127.7, 128.8, 129.1, 131.2, 131.8, 133.9, 139.8, 139.9, 145.3, 151.4, 151.5,
stretch), 1621, 1533 (aromatic C=C stretch), 1176, 1107 cm−1 (SO2 asym- 167.3, 193.7 (C=O). Anal. Calcd for C25H25BrN2O2: C, 64.25, H, 5.41, N,
metric and symmetric stretch); 1H NMR (DMSO-d6): δ 11.74 (br s, 2H), 6.02. Found: C, 63.83, H, 5.64, N, 6.09.
9.27 (d, J = 1.6 Hz, 1H), 9.05 (dd, J = 6.0, 1.6 Hz, 1H), 8.82 (m, 1H), 8.06
(m, 1H); 13C NMR (DMSO-d6): δ 164.0, 147.5, 145.2, 144.4, 129.7 127.2. 4-(4-(Dimethylamino)phenyl)-2,7,7-trimethyl-5-oxo-N-phenyl-
Anal. Calcd C6H6NSO5Cl: C, 30.07; H, 2.52, N, 5.85. Found: C, 30.13; H, 1,4,5,6,7,8-hexahydroquinoline-3-carboxamide (5k) Reaction
2.64, N, 5.89. time 30 min; yield 92%; orange solid; mp 248–250°C: IR: 3269 (N-H
 S. Ehsanifar and M. Mokhtary: 3-Carboxy-1-sulfopyridin-1-ium chloride ([CPySO3H] + Cl − )      29

stretch), 3066 (aromatic C-H), 2952 (C-H stretch), 1674 (C=O stretch), [5] Sunkel, C. E.; de Casa-Juana, M. F.; Santos, L. 4-Alkyl-1,4-dihy-
1637 (C=O stretch), 754 cm−1 (aromatic C-H out of plane bending); 1H dropyridine derivatives as specific PAF-acether antagonists.
NMR: δ 0.87 (s, 3H, CH3), 1.03 (s, 3H, CH3), 2.11–2.26 (m, 4H), 2.37 (s, J. Med. Chem. 1990, 33, 3205–3210.
3H, CH3), 2.39 (s, 6H, 2CH3), 4.82 (s, 1H, CH), 6.72 (d, J = 8 Hz, 2H), [6] Gündüz, M. G.; Ragno, G.; Şimşek, R.; Deluca, M.; Şafak, C.;
6.94 (s, 1H, Ar), 7.04 (m, 1H, Ar), 7.23–7.34 (m, 4H, Ar), 7.36 (d, J = 4 Grande, F.; El-Khouly, A.; İşli, F.; Yildirim, Ş.; Fincan, G. S. Ö.;
Hz, 2H, Ar), 7.52 (s, 1H, NH), 9.72 (s, 1H, NHCO): 13C NMR: δ 18.0, 27.2, et al. Synthesis and photodegradation studies of analogues of
29.2, 32.5, 37.0, 40.1, 40.5, 50.7, 76.8, 77.1, 77.4, 108.3, 111.0, 111.05, 112.9, muscle relaxant 1,4-dihydropyridine compounds. Acta Pharm.
119.8, 123.8, 128.7, 128.8, 133.6, 138.3, 141.3, 149.1, 167.0, 195.0 (C=O). 2017, 67, 341–355.
Anal. Calcd for C27H31N3O2: C, 75.50, H, 7.27, N, 9.78. Found: C, 75.33, [7] Klusa, V. Cerebrocrast. Neuroprotectant, cognition enhancer.
H, 7.35, N, 9.69. Drugs Future 1995, 20, 135–138.
[8] Retzel, R. G.; Bollen, C. C.; Maeser, E.; Federlin, K. F.
4-Isopropyl-2,7,7-trimethyl-5-oxo-N-phenyl-1,4,5,6,7,8-hexa­ ­Trombodipine platelet aggregation inhibitor antithrombotic.
hydroquinoline-3-carboxamide (5l) Reaction time 45 min; yield Drugs Future 1992, 17, 465–468.
90%; yellow solid; mp 234–236°C, IR: 3296 (N-H stretch), 2956 [9] Gein, V. L.; Kholkin, I. V.; Zamaraeva, T. M.; Voronina, E. V.;
(aliphatic C-H stretch), 1664 (C=O), 1637 (C=O), 1490 (C=C stretch), Vakhrin, M. I. Synthesis and antimicrobial activity of N,6-diaryl-
752  cm−1 (aromatic C-H out of plane bending); 1H NMR: δ 0.74 (d, 4-methyl-2-thioxo-1,2,3,6-tetrahydropyrimidine-5-carboxam-
J = 4.4 Hz, 3H), 0.758 (d, J = 4.4 Hz, 3H, CH3), 1.05 (s, 6H, 2CH3), 1.64 ides. Pharm. Chem. J. 2012, 46, 49–51.
(m, 1H), 2.01 (s, 3H, CH3), 2.07 (d, J = 16 Hz, 1H), 2.16 (d, J = 16 Hz, 1H), [10] Gein, V. L.; Fedotov, A. Y.; Zamaraeva, T. M.; Bobyleva, A. A.;
2.22 (d, J = 2 Hz, 1H), 2.33 (d, J = 4.4 Hz, 1H), 3.81 (d, J = 2 Hz, CH), 7.00 Kasimova, N. N. ; Odegova, T. F. Synthesis and antimicrobial
(m, 1H, Ar), 7.26 (br s, 2H, Ar), 7.62 (m, 2H, Ar), 8.48 (s, 1H, NH), 9.62 activity of N,6-diaryl-4-methyl-2-oxo-1,2,3,6-tetrahydropyrimi-
(s, 1H, NHCO); 13C NMR: δ 17.3, 18.2, 19.7, 27.01, 30.1, 32.3, 35.3, 38.2, dine-5-carboxamides. Pharm.Chem. J. 2013, 46, 24–26.
51.2, 107.1, 109.0, 120.1, 123.3, 128.9, 136.2, 140.1, 152.1, 169.7, 194.6 [11] Gein, V. L.; Zamaraeva, T. M.; Buzmakova, N. A.; Syropyatov, B.
(C=O). Anal. Calcd for C22H27N2O2: C, 75.18, H, 7.74, N, 7.97. Found: C, Ya.; Alikina, N. V. Synthesis and analgesic activity of N,6-diaryl-
74.96, H, 7.85, N, 8.05. 4-methyl-2-thioxo-1,2,3,6-tetrahydropyrimidine-5-carboxam-
ides. Pharm. Chem. J. 2016, 50, 19–21.
[12] Ahmed, K.; Jain, A. K.; Dubey, B.; Shrivastava, B.; Sharma, P.;
Acknowledgments: Financial support provided by Rasht
Nadeem, S. p-TSA catalyzed synthesis of 4-aryl-2,7,7-trimethyl-
Branch, Islamic Azad University, under the Grant No. 5-oxo-N-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxam-
4.5830 is gratefully acknowledged. ides derivatives as CNS active agents. Der Pharma Chemica
2015, 7, 52–65.
[13] Gein, V. L.; Kazantseva, M. I.; Kurbatova, A. A.; Vahrin, M. I.
Synthesis of 4-aryl-2,7,7-trimethyl-5-oxo-n-phenyl-1,4,5,6,7,8-
References hexahydroquinoline-3-carboxamides. Chem. Heterocycl.
Compd. 2010, 46, 629–630.
[1] Bossert, F.; Meyer, H.; Wehinger, E. 4-Aryldihydropyridines, a [14] Moosavi-Zare, A. R.; Zolfigol, M. A.; Zarei, M.; Zare, A.;
new class of highly active calcium antagonists. Angew. Chem. ­Khakyzadeh, V.; Hasaninejad, A. Design, characterization and
Int. Ed. 1981, 20, 762–769. application of new ionic liquid 1-sulfopyridinium chloride as an
[2] Boer, R.; Gekeler, V. Chemosensitizers in tumor therapy: new com- efficient catalyst for tandem Knoevenagel-Michael reaction of
pounds promise better efficacy. Drugs Future 1995, 20, 499–509. 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one with aldehydes. Appl.
[3] Wachter, G. A.; Davis, M. C. Antimycobacterial activity of substi- Catal. A. 2013, 467, 61–68.
tuted isosteres of pyridine- and pyrazinecarboxylic acids. J. Med. [15] Moosavi-Zare, A. R.; Zolfigol, M. A.; Zarei, M.; Zare, A.;
Chem. 1998, 41, 2436–2438. Khakyzadeh, V. Preparation, characterization and application
[4] Gullapalli, S.; Ramarao, P. L-type Ca2+ channel modulation by of ionic liquid sulfonic acid functionalized pyridinium chloride
dihydropyridines potentiates κ-opioid receptor agonist induced as an efficient catalyst for the solvent-free synthesis of 12-aryl-
acute analgesia and inhibits development of tolerance in rats. 8,9,10,12-tetrahydrobenzo[a]-xanthen-11-ones. J. Mol. Liq.
Neuropharmacol. 2002, 42, 467–475. 2013, 186, 63–69.