Scholarly article on topic 'Melamine trisulfonic acid as an efficient catalyst for the synthesis of 2,6-dimethyl-4-substituted-1,4-dihydropyridine-3,5-diethyl/dimethylcarboxylate derivatives via Hantzsch reaction in solvent free condition'

Melamine trisulfonic acid as an efficient catalyst for the synthesis of 2,6-dimethyl-4-substituted-1,4-dihydropyridine-3,5-diethyl/dimethylcarboxylate derivatives via Hantzsch reaction in solvent free condition Academic research paper on "Chemical sciences"

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{"Melamine trisulfonic acid" / "1 / 4-Dihydropyridine" / "Hantzsch reaction" / "One-pot synthesis" / "Reusable catalyst"}

Abstract of research paper on Chemical sciences, author of scientific article — S. Sheik Mansoor, K. Aswin, K. Logaiya, S.P.N. Sudhan

Abstract A facile and highly efficient one-pot synthesis of 1,4-dihydropyridine derivatives (1,4-DHPs) is reported via three component condensation reaction of aldehydes, ethyl acetoacetate or methyl acetoacetate and ammonium acetate using environmentally benign melamine trisulfonic acid (MTSA) as a catalyst in solvent free condition at 60°C. The method presented here is applied to the tenets of green chemistry to the generation of biologically interesting products under solvent-free media that is less expensive and less toxic than those with organic solvents. Also, the catalyst is recyclable and could be reused without significant loss of activity. Even after three runs for the reaction, the catalytic activity of MTSA was almost the same as that of the freshly used catalyst. The method also offers several advantages including high yields and simple work-up procedure.

Academic research paper on topic "Melamine trisulfonic acid as an efficient catalyst for the synthesis of 2,6-dimethyl-4-substituted-1,4-dihydropyridine-3,5-diethyl/dimethylcarboxylate derivatives via Hantzsch reaction in solvent free condition"

Journal of King Saud University - Science (2013) xxx, xxx-xxx

King Saud University Journal of King Saud University -Science

www.ksu.edu.sa www.sciencedirect.com

■ Journal of H Kinç Saud University

H -Science

ORIGINAL ARTICLE

Melamine trisulfonic acid as an efficient catalyst for the synthesis of 2,6-dimethyl-4-substituted-1,4-dihydropyridine-3,5-diethyl/dimethylcarboxylate derivatives via Hantzsch reaction in solvent free condition

S. Sheik Mansoor *, K. Aswin, K. Logaiya, S.P.N. Sudhan

Department of Chemistry, Bioactive Organic Molecule Synthetic Unit, C. Abdul Hakeem College, Melvisharam 632 509, Tamil Nadu, India

Received 15 November 2012; accepted 2 February 2013

KEYWORDS

Melamine trisulfonic acid; 1,4-Dihydropyridine; Hantzsch reaction; One-pot synthesis; Reusable catalyst

Abstract A facile and highly efficient one-pot synthesis of 1,4-dihydropyridine derivatives (1,4-DHPs) is reported via three component condensation reaction of aldehydes, ethyl acetoacetate or methyl acetoacetate and ammonium acetate using environmentally benign melamine trisulfonic acid (MTSA) as a catalyst in solvent free condition at 60 °C. The method presented here is applied to the tenets of green chemistry to the generation of biologically interesting products under solvent-free media that is less expensive and less toxic than those with organic solvents. Also, the catalyst is recyclable and could be reused without significant loss of activity. Even after three runs for the reaction, the catalytic activity of MTSA was almost the same as that of the freshly used catalyst.

The method also offers several advantages including high yields and simple work-up procedure.

© 2013 Production and hosting by Elsevier B.V. on behalf of King Saud University.

1. Introduction

In recent years, an increasing interest has been focused on the synthesis of Hantzsch 1,4-dihydropyridines, a class of model compounds of NADH coenzyme, due to the biological perti-

nence of these compounds to NADH redox process (Miri et al., 2006; Tewari et al., 2004). 1,4-dihydropyridines have been reported as anticancer (Tsuruo et al., 1983), neurotropic (Krauze et al., 1999), glycoprotein inhibitors (Zhou et al., 2005), anticoagulant (Kumar et al., 2011a), antioxidant (Vijesh et al., 2011), anti-inflammatory and anti-microbial agents (Kumar et al., 2011b). Calcium entry into the cytosol is mediated by multiple types of calcium channel, each with a distinct physiological role. Dihydropyridines are commercially used as calcium channel blockers for the treatment of cardiovascular diseases, including hypertension (Zamponi, 1998). Recently, the synthesis of dihydropyridines with respect to multidrug resistance (MDR) reversal in tumour cell gave a new dimension to their applications (Tanabe et al., 1998; Tasaka et al.,

* Corresponding author. Tel.: +91 9944093020. E-mail address: smansoors2000@yahoo.co.in (S.S. Mansoor). Peer review under responsibility of King Saud University.

1018-3647 © 2013 Production and hosting by Elsevier B.V. on behalf of King Saud University. http://dx.doi.Org/10.1016/j.jksus.2013.02.001

2001). Tuberculosis (TB) is a common and often deadly infectious disease caused by various strains of mycobacterium, usually Mycobacterium tuberculosis. Tuberculosis has been considered to be a disease of poverty for many years with quite rare occurrences in the developed countries. Recently, studies showed that 3,5-dicarbamoyl derivatives of 1,4-dihydropyri-dine (DHP) with lipophilic groups have considerable antitubercular activity against M. tuberculosis H37Rv (Trivedi et al., 2011; Khoshneviszadeh et al., 2009).

Generally, the basic skeleton of DHP was first discovered by Hantzsch in 1882 (Hantzsch, 1882). Due to the biological importance of these compounds several methods have been reported for the improvement of 1,4-dihydropyridine ring and polyhydroquinoline derivatives. Different approaches for the syntheses of 1,4-dihydropyridine derivatives using various catalysts, such as cellulose sulphuric acid (Safari et al., 2011), triphenylphosphine (Debache et al., 2009), silica supported 12-tungstophosphoric acid (Rafiee et al., 2009), Iron (III) trifluoroacetate (Adibi et al., 2007), ionic liquid [tbmim]Cl2/AlCl3 (Reddy et al., 2011), organo catalyst (Baghbanian et al., 2010), cerric ammonium nitrate (Reddy and Raghu, 2008), nickel nanoparticle (Saikia et al., 2012), aluminium phosphate (Purandhar et al., 2012), bismuth nitrate (Bandyopadhyay et al., 2012), gadolinium triflate (Mansoor et al., 2012a), titanium dioxide nanoparticles (Tajbakhsh et al., 2012), ferric fluoride (Surasani et al., 2012) and silica sulphuric acid (Kolvari et al., 2011), MgO nanoparticles (Mirzaei and Davoodnia, 2012), visible light (Ghosh et al., 2013) and protic pyridinium ionic liquid (Tajbakhsh et al., 2013) have been reported. Many of these reported methods involve the use of expensive reagents, hazardous solvents, long reaction times and tedious workup procedures. Thus, the search for new reagents and methods is still of growing importance.

Melamine trisulfonic acid is effectively used as a catalyst in organic reactions, such as regioselective nitration of aromatic compounds (Albadi et al., 2012), N-formylation of amines (Yang and Zhang, 2012), aryldithienylmethanes (Wu et al., 2012), spiro[pyrazolo[3,4-b]pyridine-4,3'-indoline] derivatives (Yang et al., 2012), acetylation of alcohols, phenols and amines (Shirini et al., 2010a), trimethylsilylation of alcohols and phenols (Wu et al., 2011), solvent free synthesis of couma-rins (Shirini et al., 2010b), chemoselective methoxymethylation of alcohols (Shirini et al., 2010c), synthesis of chromen-6-ones (Ma et al., 2011) and synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones (Shirini et al., 2011).

To the best of our knowledge, there are no examples on the use of melamine trisulfonic acid as a catalyst for the synthesis of 1,4-dihydropyridine derivatives. In continuation of our investigation with the one-pot synthesis of biologically active molecules, such as 3,4-dihydropyrimidin-2(1H)-ones/-thiones/ imines (Mansoor et al., 2011), b-amino ketone compounds (Mansoor et al., 2012b), amidoalkyl naphthols (Mansoor et al., 2012c), 2-amino-4,6-diphenylpyridine-3-carbonitrile derivatives (Mansoor et al., 2012d) and a-amino nitriles (Mansoor et al., 2012e), herein, we wish to report the one-pot condensation of aldehydes, ethyl/methyl acetoacetate and ammonium acetate under solvent free conditions at 60 0C using melamine trisulfonic acid as a reusable catalyst for the synthesis of 1,4-dihydropyridine derivatives via Hantzsch reaction. Melamine trisulfonic acid is safe, easy to handle and environmentally benign.

2. Experimental

Chemicals were purchased from Merck, Fluka and Aldrich Chemical Companies. The benzaldehydes used were with sub-stituents H, p-OCH3, p-CH3, p-Cl, p-NO2, p-Br, p-OH, m-Cl, m-NO2 and m-OH. Heterocyclic aldehydes like Furfural and 2-Thienal were also used for the synthesis. The solid aldehydes were used as such and the liquid aldehydes were used after vacuum distillation. Ethyl acetoacetate and methyl acetoacetate were used as 1,3-dicarbonyl compounds. Ammonium acetate was used as the nitrogen source. Solvents like THF, methanol, ethanol, dichloromethane, acetonitrile, cyclohexane and benzene were used. Melamine and chlorosulfonic acid were used for the preparation of MTSA. All yields refer to isolated products unless otherwise stated.

2.1. Preparation of melamine trisulfonic acid (MTSA)

Melamine trisulfonic acid was prepared from melamine and chlorosulfonic acid as reported previously in the literature by Shirini et al. (2010a) Scheme 1.

2.2. General experimental procedure for the synthesis (compounds 4a-p)

A mixture of aldehyde 1 (1 mmol), ethyl acetoacetate 2 (2 mmol), ammonium acetate 3 (1.5 mmol) and MTSA (5 mol%) was taken in a 50 ml flask and heated at 60 0C under solvent-free condition for the appropriate time monitored by TLC. The reaction mixture, after being cooled to room temperature was poured into cold water and extracted with ethyl acetate. The organic layer was washed with brine and water and dried over Na2SO4. The crude products were purified by crystallization from ethanol to afford 1,4-dihydropyridines. The catalyst was filtered and washed with methanol for reuse (see Scheme 2).

2.3. Spectral data for the synthesized compounds

2.3.1. 2,6-Dimethyl-4-phenyl-1,4-dihydropyridine-3,5-diethylcarboxylate (4a)

White solid; mp 157-159 0C; IR (KBr, cm"1): 3342, 1691, 1643, 1489, 1210, 779.

*H NMR (500 MHz, DMSO-d6) d: 1.19 (t, J = 7.2 Hz, 6H, 2CH3CH2), 2.33 (s, 6H, 2CH3), 4.08 (q, J = 7.0 Hz, 4H, 2CH3CH2), 4.96 (s, 1H, CH), 5.97 (s, 1H, NH), 7.16-7.33 (m, 5H, Ar-H) ppm; 13C NMR (125 MHz, DMSO-d6) d: 14.0, 19.4, 39.6, 59.5, 104.0, 121.8, 129.0, 131.0, 144.4, 146.5, 166.8 ppm; MS (ESI): m/z 330 (M + H)+. Anal. Calcd. for C19H23NO4 (%): C, 69.30; H, 6.99; N, 4.25. Found: C, 69.22; H, 6.94; N, 4.23.

2.3.2. 2,6-Dimethyl-4-(4-methylphenyl)-1,4-dihydropyridine-3,5-diethylcarboxylate (4b)

Yellow solid; mp 135-137 0C; IR (KBr, cm"1): 3338, 1698, 1653, 1480, 1200, 789.

*H NMR (500 MHz, DMSO-d6) d: 1.24 (t, J = 7.4 Hz, 6H, 2CH3CH2), 2.28 (s, 6H, 2CH3), 4.09 (q, J = 7.2 Hz, 4H, 2CH3CH2), 5.00 (s, 1H, CH), 5.90 (s, 1H, NH), 7.10-7.43 (m, 4H, Ar-H), 2.22 (s, 3H, CH3) ppm; 13C NMR (125 MHz, DMSO-d6) d: 14.3, 19.5, 38.9, 60.0, 103.5, 119.3,

N N Neat

+ OSO3H (3 eq.) -^ 3HCl

NH(SO3H)

H2N n nh2 (HO3S)HN' "N' "NH(SO3H)

Melamine Melamine trisulfonic acid (MTSA)

Scheme 1 Preparation of melamine trisulfonic acid.

ArCHO + H3C

R = CH3 Or C2H5

VOR + NH4OAc

5 mol % RO -►

Solvent-free

60oC H3C'

1 2 3 4a - 4p

Scheme 2 The reaction of aromatic aldehyde, ethyl/methyl acetoacetate and ammonium acetate in the presence of MTSA as catalyst at 60 °C under solvent free condition.

129.8, 131.0, 144.0, 146.4, 167.5 ppm; MS (ESI): m/z 344 (M + H) + . Anal. Calcd. for C20H25NO4 (%): C, 69.97; H, 7.29; N, 4.08. Found: C, 69.91; H, 7.28; N, 4.07.

2.3.3. 2,6-Dimethyl-4-(4-methoxyphenyl)-1,4-dihydropyridine-3,5-diethylcarboxylate (4c)

Yellow solid; mp 156-158 °C; IR (KBr, cm"1): 3329, 1700, 1633, 1494, 1214, 783.

NMR (500 MHz, DMSO-d6) d: 1.21 (t, J = 7.4 Hz, 6H, 2CH3CH2), 2.29 (s, 6H, 2CH3), 4.10 (q, J = 7.0 Hz, 4H, 2CH3CH2), 4.99 (s, 1H, CH), 6.07 (s, 1H, NH), 6.96-7.12 (m, 4H, Ar-H), 3.62 (s, 3H, OCH3) ppm; 13C NMR (125 MHz, DMSO-d6) d: 15.0, 20.0, 40.3, 59.5, 104.4, 118.8, 131.0, 131.5, 144.4, 147.3, 166.5 ppm; MS (ESI): m/z 360 (M + H) + . Anal. Calcd. for C20H25NO5 (%): C, 66.85; H, 6.96; N, 3.90. Found: C, 66.77; H, 6.97; N, 3.88.

2.3.4. 2,6-Dimethyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3,5-diethylcarboxylate (4d)

Yellow solid; mp 132-134 °C; IR (KBr, cm"1): 3348, 1688,

1644, 1481, 1207, 782.

NMR (500 MHz, DMSO-d6) d: 1.24 (t, J = 7.4 Hz, 6H, 2CH3CH2), 2.31 (s, 6H, 2CH3), 4.08 (q, J = 7.2 Hz, 4H, 2CH3CH2), 5.06 (s, 1H, CH), 6.00 (s, 1H, NH), 7.14-7.54 (m, 4H, Ar-H) ppm; 13C NMR (125 MHz, DMSO-d6) d: 15.1, 19.6, 39.8, 59.5, 103.9, 119.0, 129.5, 131.4, 143.9, 146.5, 167.0 ppm; MS (ESI): m/z 375 (M + H) + . Anal. Calcd. for C19H22N2O6 (%): C, 60.96; H, 5.88; N, 7.49. Found: C, 60.93; H, 5.86; N, 7.48.

2.3.5. 2,6-Dimethyl-4-(4-chlorophenyl)-1,4-dihydropyridine-3,5-diethylcarboxylate (4e)

White solid; mp 144-146 °C; IR (KBr, cm"1): 3335, 1695,

1645, 1499, 1219, 789.

NMR (500 MHz, DMSO-d6) d: 1.19 (t, J = 7.2 Hz, 6H, 2CH3CH2), 2.34 (s, 6H, 2CH3), 4.10 (q, J = 7.2 Hz, 4H, 2CH3CH2), 5.09 (s, 1H, CH), 5.94 (s, 1H, NH), 7.22-7.48 (m, 4H, Ar-H) ppm; 13C NMR (125 MHz, DMSO-d6) d: 14.6, 19.4, 39.8, 59.4, 103.6, 119.0, 130.4, 131.4, 144.5, 146.6, 166.8 ppm; MS (ESI): m/z 364.45 (M + H) + . Anal. Calcd. for C19H22ClNO4 (%): C, 62.73; H, 6.05; N, 3.85. Found: C, 62.64; H, 6.01; N, 3.80.

2.3.6. 2,6-Dimethyl-4-(4-bromophenyl)-1,4-dihydropyridine-3,5-diethylcarboxylate (4f)

White solid; mp 160-162 °C; IR (KBr, cm"1): 3332, 1692, 1649, 1491, 1213, 772.

NMR (500 MHz, DMSO-d6) d: 1.25 (t, J = 7.2 Hz, 6H, 2CH3CH2), 2.31 (s, 6H, 2CH3), 4.14 (q, J = 7.2 Hz, 4H, 2CH3CH2), 4.97 (s, 1H, CH), 6.02 (s, 1H, NH), 7.12-7.53 (m, 4H, Ar-H) ppm; 13C NMR (125 MHz, DMSO-d6) d: 14.4, 18.9, 39.7, 59.6, 103.7, 119.5, 130.2, 131.2, 143.9, 145.7, 165.3 ppm; MS (ESI): m/z 408.9 (M + H) + . Anal. Calcd. for C19H22BrNO4 (%): C, 55.90; H, 5.39; N, 3.43. Found: C, 55.82; H, 5.36; N, 3.40.

2.3.7. 2,6-Dimethyl-4-(3-chlorophenyl)-1,4-dihydropyridine-3,5-diethylcarboxylate (4g)

White solid; mp 140-142 °C; IR (KBr, cm"1): 3340, 1689, 1652, 1480, 1200, 770.

1H NMR (500 MHz, DMSO-d6) d: 1.20 (t, J = 7.2 Hz, 6H, 2CH3CH2), 2.29 (s, 6H, 2CH3), 4.09 (q, J = 7.0 Hz, 4H, 2CH3CH2), 5.02 (s, 1H, CH), 5.96 (s, 1H, NH), 7.26-7.61 (m, 4H, Ar-H) ppm; 13C NMR (125 MHz, DMSO-d6) d: 15.1, 19.3, 39.7, 60.1, 104.0, 119.4, 130.0, 131.1, 144.4, 146.4, 165.2 ppm; MS (ESI): m/z 364.45 (M + H) + . Anal. Calcd. for C19H22ClNO4 (%): C, 62.73; H, 6.05; N, 3.85. Found: C, 62.66; H, 6.03; N, 3.84.

2.3.8. 2,6-Dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-diethylcarboxylate (4h)

Yellow solid; mp 162-164 0C; IR (KBr, cm"1): 3344, 1701, 1643, 1487, 1217, 777.

1H NMR (500 MHz, DMSO-d6) d: 1.21 (t, J = 7.2 Hz, 6H, 2CH3CH2), 2.32 (s, 6H, 2CH3), 4.16 (q, J =7.2 Hz, 4H, 2CH3CH2), 4.96 (s, 1H, CH), 6.04 (s, 1H, NH), 7.06-7.42 (m, 4H, Ar-H) ppm; 13C NMR (125 MHz, DMSO-d6) d: 14.6, 19.7, 39.8, 59.5, 102.9, 119.5, 130.3, 131.3, 143.9, 146.4, 166.6 ppm; MS (ESI): m/z 375 (M + H) + . Anal. Calcd. for C19H22N2O6 (%): C, 60.96; H, 5.88; N, 7.49. Found: C, 60.88; H, 5.88; N, 7.47.

2.3.9. 2,6-Dimethyl-4-(4-hydroxyphenyl)-1,4-dihydropyridine-3,5-diethylcarboxylate (4i)

White solid; mp 228-230 0C; IR (KBr, cm"1): 3443, 3341, 1698, 1640, 1493, 1213, 778.

1H NMR (500 MHz, DMSO-d6) d: 1.23 (t, J = 7.2 Hz, 6H, 2CH3CH2), 2.33 (s, 6H, 2CH3), 4.09 (q, J = 7.0 Hz, 4H, 2CH3CH2), 5.11 (s, 1H, CH), 6.10 (s, 1H, NH), 7.12-7.43 (m, 4H, Ar-H), 9.96 (s, 1H, OH) ppm; 13C NMR (125 MHz, DMSO-d6) d: 14.9, 19.6, 38.9, 59.7, 103.6, 119.9, 129.9, 130.5, 144.0, 146.5, 166.8 ppm; MS (ESI): m/z 346 (M + H) + . Anal. Calcd. for C19H23NO5 (%): C, 66.09; H, 6.67; N, 4.06. Found: C, 66.01; H, 6.65; N, 4.04.

2.3.10. 2,6-Dimethyl-4-(3-hydroxyphenyl)-1,4-dihydropyridine-3,5-diethylcarboxylate (4j)

White solid; mp 172-174 0C; IR (KBr, cm"1): 3429, 3336, 1687, 1633, 1487, 1215, 781.

1H NMR (500 MHz, DMSO-d6) d: 1.25 (t, J = 7.4 Hz, 6H, 2CH3CH2), 2.27 (s, 6H, 2CH3), 4.08 (q, J = 7.2 Hz, 4H, 2CH3CH2), 4.98 (s, 1H, CH), 5.99 (s, 1H, NH), 6.96-7.23 (m, 4H, Ar-H) 9.88 (s, 1H, OH) ppm; 13C NMR (125 MHz, DMSO-d6) d: 15.0, 19.6, 39.6, 59.7, 103.6, 119.7, 130.0, 130.7, 144.6, 147.0, 167.2 ppm; MS (ESI): m/z 346 (M + H) + . Anal. Calcd. for C19H23NO5 (%): C, 66.09; H, 6.67; N, 4.06. Found: C, 66.05; H, 6.66; N, 4.05.

2.3.11. 2,6-Dimethyl-4-(2furyl)-1,4-dihydropyridine-3,5-diethylcarboxylate (4k)

Yellow solid; mp 160-162 0C; IR (KBr, cm"1): 3333, 1704, 1635, 1499, 1213, 772.

1H NMR (500 MHz, DMSO-d6) d: 1.22 (t, J = 7.4 Hz, 6H, 2CH3CH2), 2.29 (s, 6H, 2CH3), 4.10 (q, J =7.1 Hz, 4H, 2CH3CH2), 4.96 (s, 1H, CH), 6.03 (s, 1H, NH), 6.32-6.41 (m, 2H, Furyl-H), 7.13 (m, 1H, Furyl-H) ppm; 13C NMR (125 MHz, DMSO-d6) d: 14.3, 19.4, 37.3, 59.8, 103.6, 118.8, 132.0, 133.8, 144.5, 147.9, 167.5 ppm; MS (ESI): m/z 320 (M + H) + . Anal. Calcd. for C17H21NO5 (%): C, 63.95; H, 6.58; N, 4.39. Found: C, 63.88; H, 6.55; N, 4.36.

2.3.12. 2,6-Dimethyl-4-(2-thienyl)-1,4-dihydropyridine-3,5-diethylcarboxylate (4l)

Yellow solid; mp 172-174 0C; IR (KBr, cm"1): 3347, 1700, 1630, 1486, 1215, 766.

1H NMR (500 MHz, DMSO-d6) d: 1.19 (t, J = 7.4 Hz, 6H, 2CH3CH2), 2.28 (s, 6H, 2CH3), 4.08 (q, J = 7.2 Hz, 4H, 2CH3CH2), 5.04 (s, 1H, CH), 6.07 (s, 1H, NH), 6.08-6.13 (m, 2H, Thienyl-H), 6.89 (m, 1H, Thienyl-H) ppm; 13C

NMR (125 MHz, DMSO-d6) d: 14.5, 19.5, 39.4, 59.6, 103.7, 118.9, 131.1, 131.8, 144.6, 146.5, 167.3 ppm; MS (ESI): m/z 336 (M + H) + . Anal. Calcd. for C17H21NO4S (%): C, 60.89; H, 6.27; N, 4.18. Found: C, 60.80; H, 6.28; N, 4.17.

2.3.13. 2,6-Dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dimethylcarboxylate (4m)

White solid; mp 116-118 0C; IR (KBr, cm"1): 3317, 1692, 1648, 1477, 1205, 765.

1H NMR (500 MHz, DMSO-d6) d: 3.72 (s, 6H, 2OCH3), 2.27 (s, 6H, 2CH3), 4.96 (s, 1H, CH), 6.08 (s, 1H, NH), 6.91-7.22 (m, 5H, Ar-H) ppm; 13C NMR (125 MHz, DMSO-d6) d: 20.2, 41.3, 56.8,105.4,129.0,130.8,143.5,148.9,167.6 ppm; MS (ESI): m/z 302 (M + H) + . Anal. Calcd. for C17H19NO4 (%): C, 67.77; H, 6.31; N, 4.65. Found: C, 67.66; H, 6.28; N, 4.62.

2.3.14. 2,6-Dimethyl-4-(4-chlorophenyl)-1,4-dihydropyridine-3,5-dimethylcarboxylate (4n)

Yellow solid; mp 194-196 0C; IR (KBr, cm"1): 3315, 1698,

1653, 1487, 1212, 772.

1H NMR (500 MHz, DMSO-d6) d: 3.72 (s, 6H, 2OCH3), 2.27 (s, 6H, 2CH3), 5.05 (s, 1H, CH), 5.94 (s, 1H, Nh), 7.01-7.34 (m, 4H, Ar-H) ppm; 13C NMR (125 MHz, DMSO-d6) d: 20.4, 41.4, 56.5, 105.6, 129.0, 130.4, 143.6, 149.1, 167.4 ppm; MS (ESI): m/z 336.45 (M + H) + . Anal. Calcd. for C17H18ClNO4 (%): C, 60.81; H, 5.36; N, 4.17. Found: C, 60.70; H, 5.34; N, 4.15.

2.3.15. 2,6-Dimethyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3,5-dimethylcarboxylate (4o)

Yellow solid; mp 152-154 0C; IR (KBr, cm"1): 3322, 1690, 1650, 1479, 1207, 771.

1H NMR (500 MHz, DMSO-d6) d: 3.72 (s, 6H, 2OCH3), 2.27 (s, 6H, 2CH3), 4.99 (s, 1H, CH), 6.00 (s, 1H, NH), 7.09-7.47 (m, 4H, Ar-H) ppm; 13C NMR (125 MHz, DMSO-d6) d: 20.1, 41.0, 56.3,105.7,129.7,131.3,144.0,149.3,167.2 ppm; MS (ESI): m/z 347 (M + H) + . Anal. Calcd. for C17H18N2O6 (%): C, 58.96; H, 5.20; N, 8.09. Found: C, 58.90; H, 5.18; N, 8.06.

2.3.16. 2,6-Dimethyl-4-(2furyl)-1,4-dihydropyridine-3,5-dimethylcarboxylate (4p)

Yellow solid; mp 148-150 0C; IR (KBr, cm"1): 3324, 1694,

1654, 1481, 1211, 773.

1H NMR (500 MHz, DMSO-d6) d: 3.66 (s, 6H, 2OCH3), 2.19 (s, 6H, 2CH3), 4.93 (s, 1H, CH), 6.07 (s, 1H, Nh), 6.22-6.34 (m, 2H, Furyl-H), 7.22 (m, 1H, Furyl-H) ppm; 13C NMR (125 MHz, DMSO-d6) d: 19.8, 41.0, 56.4, 105.7, 129.3, 130.7, 143.6, 149.0, 167.1 ppm; MS (ESI): m/z 292 (M + H) + . Anal. Calcd. for C15H17NO5 (%): C, 61.85; H, 5.84; N, 4.81. Found: C, 61.75; H, 5.82; N, 4.79.

3. Results and discussion

Initially, 4-nitro benzaldehyde has been used to react with ethyl acetoacetate and ammonium acetate in the presence of 5 mol% melamine trisulfonic acid under various solvents like THF, methanol, ethanol, dichloromethane, acetonitrile, cyclo-hexane and benzene at 60 0C in order to optimize the reaction conditions (Table 1, entries 1-7). The reaction was studied under solvent-free conditions also. It was found that the best

Table 1 Synthesis of 2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihy-dropyridine-3,5-diethylcarboxylate from 4-nitrobenzaldehyde, ethyl acetoacetate and ammonium acetate catalysed by MTSA under various conditionsa.

Entry Solvent Amount of Time (h) Yield (%)b

catalyst (mol %)

1 THF 5 6 68

2 Methanol 5 5 78

3 Ethanol 5 5 80

4 Dichloromethane 5 6 73

5 Acetonitrile 5 6 65

6 Cyclohexane 5 6 70

7 Benzene 5 6 55

8 None 5 4 92

a Reaction conditions: 4-nitrobenzaldehyde (1 mmol), ethyl acetoacetate (2 mmol) and ammonium acetate (1.5 mmol), the amount of solvent used for entries 1-7 was 5 mL. b Isolated yields.

Table 2 Optimisation of temperature using MTSA (5 mol%) as catalysta.

Entry Temperature (°C) Time (h) Yield (%)b

1 r.t 6.5 65

2 40 6.0 74

3 50 5.0 83

4 60 4.0 92

5 70 3.5 86

6 80 3.0 80

a Reaction conditions: 4-nitrobenzaldehyde (1 mmol), ethyl acetoacetate (2mmol) and ammonium aceate (1.5 mmol), under solvent-free condition. b Isolated yields.

Table 3 Synthesis of 2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihy-dropyridine-3,5-diethylcarboxylate from 4-nitrobenzaldehyde, ethyl acetoacetate and ammonium acetate catalysed by MTSA (5 mol%) under solvent-free conditiona.

Entry Cycle Time (h) Yield (%)b

1 0 4.0 92

2 1 4.0 90

3 2 4.0 89

4 3 4.0 87

a Reaction conditions: 4-nitrobenzaldehyde (1 mmol), ethyl ace-toacetate (2 mmol) and ammonium aceate (1.5 mmol), under solvent-free condition at 60 °C. b Isolated yields.

results were obtained with 5mol% MTSA under solvent-free condition. (Table 1, entry 8). The reaction was completed within 4 h and the expected product was obtained in a 92% yield.

Next, we have studied the effect of temperature for the model reaction. The reaction has been studied at various temperatures like room temperature, 40, 50, 60, 70 and 80 0C. The yield of the product increased up to 60 0C. After 60 0C, increasing temperature leads to a decrease in yields. Therefore, our optimized condition is 5 mol% of MTSA under solvent free condition at 60 0C Table 2.

The reusability of the catalyst is one of the most important benefits and makes it useful for commercial applications. Thus the recovery and reusability of melamine trisulfonic acid were investigated. The reusability of the catalyst was checked by separating the melamine trisulfonic acid from the reaction mixture and drying in a vacuum oven at 60 0C for 5 h prior to reuse in subsequent reactions. The recovered catalyst can be reused at least three additional times in subsequent reactions without significant loss in product yield Fig. 1 Table 3.

A series of 1,4-dihydropyridines were synthesized by using diverse aldehydes, 1,3-diketo compounds and ammonium acetate in the presence of MTSA (5 mol%) as catalyst under solvent-free conditions. As shown in Table 4, the reaction proceeded equally well irrespective of the nature of the car-bonyl compounds (aromatic, heteroaromatic) to afford the corresponding products in excellent yield (86-94%). The catalytic system worked well. It is noteworthy to mention that, the effect of the nature of the substituents on the aromatic ring

Number of Runs

Figure 1 Recyclability of melamine trisulfonic acid for the synthesis of 2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3,5-diethylcarboxylate.

94 -92 -

90 -g -

2 88-ÏÏ

Table 4 Synthesis of 1,4-dihydropyridine derivatives using aldehyde, ethyl/methyl acetoacetate and ammonium acetate in the presence of MTSA (5 mol%) under solvent-free conditiona.

Entry Aldehyde Ar

1,3-dicarbonyl compound Ammonia source Product Time (h) Yieldb (%)

NH4OAc

NH4OAc

NH4OAc

■OC2H5

NH4OAc

NH4OAc

NH4OAc

■OC2H5

NH4OAc

NH4OAc

NH4OAc

(continued on next page)

Table 4 (continued)

Entry Aldehyde Ar

1,3-dicarbonyl compound Ammonia source Product Time (h) Yieldb (%)

NH4OAc

NH4OAc

NH4OAc

NH4OAc

NH4OAc

NH4OAc

NH4OAc

a Reaction conditions: aldehyde (1 mmol), ethyl/methyl acetoacetate (2 mmol) and ammonium aceate (1.5 mmol), under solvent-free condition at 60 °C. b Isolated yields.

showed no obvious effect on this conversion, because they were obtained in high yields in relatively short reaction times.

In order to show the merit of MTSA in comparison with other catalysts, we summarized some of the results for the preparation of 2,6-Dimethyl-4-(4-nitrophenyl)-1,4-dihydro-pyridine-3,5-diethylcarboxylate (4d) in Table 5. A number of Lewis acid catalysts such as ZnCl2, AlCl3, FeCl3, BiCl3,

Bi(OTf)3 and BiBr3 have been screened using the model reaction under solvent-free conditions at 60 0C (Table 5, entry 2-7). The results showed that MTSA (5 mol%) is a more efficient catalyst with respect to reaction temperature, catalyst load, reaction time and yield than other catalysts (Table 5, entry 9). It was found that the reaction without catalyst produced low yield (Table 5, entry 1).

Table 5 Synthesis of 2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihy-dropyridine-3,5-diethylcarboxylate from 4-nitrobenzaldehyde, ethyl acetoacetate and ammonium acetate using various catalysts under solvent-free conditiona.

Entry Catalyst (h) Amount of Time Yieldb (%)

catalyst (mol%)

1 None - 6 32

2 ZnCl2 50 6 42

3 AlCl3 50 64 8

4 FeCl3 50 6 40

5 BiCl3 10 6 70

6 Bi(OTf)3 10 6 76

7 BiBr3 20 6 60

8 MTSA 10 4 88

9 MTSA 5 4 92

10 MTSA 3 4 72

11 MTSA 2 4 66

a Reaction conditions: 4-nitrobenzaldehyde (1 mmol), ethyl ace-toacetate (2 mmol) and ammonium aceate (1.5 mmol), under solvent-free condition at 60 oc. b Isolated yields.

Recently Debache et al., reported the synthesis of 1,4-dihy-dropyridines using triphenylphosphine (20 mol%) as a Lewis base in ethanol (Debache et al., 2009). In our method we have synthesized 1,4-dihydropyridines using MTSA (5 mol%) under solvent-free conditions. We have described the reusability of the catalyst also.

4. Conclusions

In conclusion, MTSA was found to be an efficient catalyst in one-pot reaction of aldehydes, ethyl/methyl acetoacetate and ammonium acetate to afford 1,4-dihydropyridines. Synthesis of biologically significant heterocyclic molecules under solvent-free conditions is very promising and challenging. The ultimate aim, of course, is to use no solvent at all and to conduct the reactions under solvent-free conditions. Development of cleaner technologies is a major emphasis in green chemistry. Solventfree reaction condition is used as an eco-friendly approach for the synthesis of a variety of products and this generally leads to large reductions in reaction times and enhancements of conversions. There is a growing interest in the one-pot three component synthesis of 1,4-dihydropyridines because of the significant importance of this scaffold in preparing a wide variety of biologically and pharmacologically active molecules. On this basis we have developed an extremely rapid, convenient and environmentally benign route for the one-step synthesis of 1,4-dihydro-pyridines. The present methodology offers attractive features such as shorter reaction times, milder conditions, and simplicity of the reaction as well as excellent yield of the products. This reaction will be applicable to the synthesis of various organic compounds of medicinal interest. Also the catalyst could be successfully recovered and recycled at least for four runs without significant loss in activity. The one-pot nature and the use of reusable and an eco-friendly catalyst make it an interesting alternative to multi-step approaches.

Acknowledgement

The authors gratefully acknowledge the University Grants

Commission, Government of India, New Delhi for the financial support (Major Research Project: F. No. 40-44/2011(SR)).

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