Journal of Chemistry

Journal of Chemistry / 2013 / Article

Research Article | Open Access

Volume 2013 |Article ID 169695 | 9 pages | https://doi.org/10.1155/2013/169695

An Efficient One-Pot Multicomponent Synthesis of 4-Aza-Podophyllotoxin Derivatives in Ionic Liquid

Academic Editor: Andrea Penoni
Received06 May 2013
Accepted02 Sep 2013
Published24 Oct 2013

Abstract

A simple, green, and efficient procedure for the synthesis of 4-aza-podophyllotoxin derivatives by using a one-pot three-component reaction of benzaldehydes, 1,3-cyclohexanediones, and anilinolactones in the presence of catalytic amount of alum in 1-butyl-3-methylimidazolium triflate as green media is described. This reaction proceeded under mild conditions with the use of an inexpensive and readily available catalyst, high to excellent yields, and simple workup procedure.

1. Introduction

Multicomponent reactions (MCRs) are one-pot processes in which three or more reactants come together in a single reaction vessel to give a final product containing substantial elements of all the reactants [14], and in recent year much attention has been directed toward the one-pot multicomponent reactions, because of their wide range of applications in pharmaceutical chemistry for the production of structural scaffolds and combinatorial libraries for drug discovery [58]. The strategies of MCRs offer significant advantages over conventional linear-type syntheses because of high degree of atom economy, high selectivity, and procedural simplicity due to formation of carbon-carbon and carbon-heteroatom bonds in one-pot procedure [911]. MCRs, particularly those performed in green and eco-friendly media, have become increasingly useful tools for the synthesis of chemically and biologically important compounds because of their environmentally friendly atom economy and green characteristics, and the “greening” of global chemical processes has became a major issue in the chemical industry [12, 13].

Organic reactions in ionic liquid (IL) media have received the considerable attention of synthetic organic chemists in recent years; IL is an environmentally friendly solvent with unique properties such as high ionic conductivity, nonvolatility, high thermal stability, nonflammability, and miscibility with organic compounds, especially with the heterocyclic compounds [1417]. Because of these useful properties numerous works have been published in the last decades reporting the possibility to perform several organic reactions and catalyzed processes in these green media [1820].

1,4-Dihydropyridine compounds are molecules based upon pyridine and this nucleus is one of the significant core structures among the most extensively natural and unnatural heterocyclic compounds, have been recognized as vital drugs for the treatment of cardiovascular diseases, and are well known as calcium channel modulators [21, 22]. 1,4-Dihydropyridine derivatives exhibit a variety of biological properties such as antihypertensive, antianginal [2325], antitumor [26], anti-inflammatory [27, 28], antitubercular [29], analgesic [30], and antithrombotic [31, 32].

The biological activity of 1,4-dihydropyridine derivatives has led to extensive structural modifications resulting in several clinically useful compounds as a source of valuable drug candidates. Extensive structural modifications have been performed to obtain more potent and less toxic anticancer agents [3335]. Among these compounds, furo[3,4-b]quinoline-1,8(3H,4H)-dione (podophyllotoxin) derivatives, which were reported as powerful DNA topoisomerase inhibitors and inhibit microtubule assembly as an antitumor ligand [3638], have attracted attention in the recent decade [3942].

With the aim to develop efficient synthetic processes using green and eco-friendly methods and to reduce laborious multistep techniques and minimize by-products, we report herein a novel and clean synthesis of some 4-aza-podophyllotoxin derivatives in ionic liquid through a three-component condensation reaction of benzaldehydes 1, 1,3-cyclohexanediones 2, and anilinolactones 3 in the presence of catalytic amount of alum as catalyst.

2. Results and Discussion

In this study, firstly, the anilinolactones were prepared from the condensation reaction of tetronic acid with various anilines. As shown in Scheme 1, when tetronic acid reacted with an equimolar amount of various anilines in dioxane solution at room temperature, the corresponding products were obtained in excellent yields, appropriate reaction times, and high purity [43].

169695.sch.001

In continuation of this research, investigation on the preparation of 4-aza-podophyllotoxin derivatives 4 by using a one-pot three-component condensation reaction of benzaldehydes 1, 1,3-cyclohexanediones 2, and anilinolactones 3 was surveyed (Scheme 2).

169695.sch.002

To achieve suitable conditions for the synthesis of tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione derivatives, the reaction of 4-bromobenzaldehyde 1d, dimedone 2b, and 4-(4-methylphenylamino)furan-2(3H)-one 3d was chosen as a model reaction (Scheme 3). This reaction was first performed in various solvents in the presence of a catalytic amount of p-toluene sulfonic acid (p-TSA) as an inexpensive and readily available catalyst at 90°C. The results are summarized in Table 1.


EntrySolventTime (min)Yield (%)b

1MeOH12072
2EtOH12075
31,4-Dioxane12060
4DMF12070
5Toluene12065
6[bmim][triflate]3090
7[bmim]OH3075
8[bmim]PF63088
9[bmim]BF43083
10[bmim]Br3080

Reaction conditions: 4-bromobenzaldehyde 1d (1 mmol), dimedone 2b (1 mmol), and 4-(4-methylphenylamino)furan-2(3H)-one 3d (1 mmol), p-TSA (20 mol%).
Isolated yields.
169695.sch.003

It was observed that, among all solvents and media, the best result was obtained when 1-butyl-3-methylimidazolium triflate was chosen in the presence of catalytic amount of p-TSA at 90°C. The desired product was obtained in excellent yield and high purity

The catalyst plays a crucial role in the success of the reaction in terms of rate of the reaction and yield. After determining the optimized conditions, we investigated the scope of the catalyst. To find the best catalyst, we screened the model reaction in the presence of different catalysts. The obtained results are outlined in Table 2.


EntryCatalyst (20 mol%)Yield (%)b

1Alum94
2p-TSA90
3K-1085
4S.S.A80
5AlCl355
6Et3N63

Reaction conditions: 4-bromobenzaldehyde 1d (1 mmol), dimedone 2b (1 mmol), and 4-(4-methylphenylamino)furan-2(3H)-one 3d (1 mmol), IL (0.2 mL).
Isolated yields.

These results indicate that, among all the catalyst systems tested, alum proved to be the most efficient since the reaction could be carried out and the desired product was obtained in excellent yield and high purity. In the absence of the catalyst, the model reaction could be carried out but the product was obtained in very low yield during 48 h and gives by TLC analysis only traces of the product.

In order to optimize the more suitable reaction conditions for the preparation of 4-aza-podophyllotoxin derivatives via this novel green chemical approach, quantity of the catalyst required was determined. It was found that, when the reaction was carried out in the presence of 5 mol% of catalyst, 51% of yield was obtained. As we increase the percentage of the catalyst to 5 mol%, 10 mol%, and 15 mol%, the yields were also found to be increased up to 65%, 81%, and 95%, respectively, but beyond 20 mol% there is no significant improvement of the rate as well as yield of the reaction, and further increase in the quantity of catalyst did not show appreciable improvement in the yield of product. Thus, 20 mol% of catalyst was chosen as maximum quantity of the catalyst for the reaction (Table 3).


EntryAlum (mol%)Yield (%)b

1551
21065
31581
42094
53096

Reaction conditions: 4-bromobenzaldehyde 1d (1 mmol), dimedone 2b (1 mmol), and 4-(4-methylphenylamino)furan-2(3H)-one 3d (1 mmol), IL (0.2 mL).
Isolated yields.

To optimize the reaction temperature, the reaction of dimedone 1, bromobenzaldehyde 2, and 4-(4-methylphenylamino)furan-2(3H)-one 3, as model substrates, was studied in the ionic liquid 1-butyl-3-methylimidazolium triflate in the presence of 20 mol% alum, at different temperatures such as room temperature, 70°C, 90°C, and 110°C, respectively. The results are summarized in Table 4.


EntryReaction temperature (°C)Reaction time (min)Yield (%)b

1r.t.120Trace
2706087
3903094
41103095

Reaction conditions: 4-bromobenzaldehyde 1d (1 mmol), dimedone 2b (1 mmol), and 4-(4-methylphenylamino)furan-2(3H)-one 3d (1 mmol), IL (0.2 mL), alum (20 mol%).
Isolated yields.

As shown in Table 4, the reaction at 90°C proceeded in the highest yield and shortest reaction time among four reaction temperatures tested. No significant increase in the yield of product was observed as the reaction temperature was raised from 70°C to 110°C. Therefore, 90°C was chosen for this reaction.

Although the detailed mechanism of the reaction remains to be unclear, a reasonable suggestion is offered in Scheme 4. Firstly, intermediate 5 was formed via the Knoevenagel condensation reaction between aldehyde 1 and cyclohexanediones 2 followed by Michael addition reaction between 5 and 3 furnished 6, which upon intermolecular cyclization and dehydration gave rise to 4.

169695.sch.004

With the optimized conditions, a variety of benzaldehydes possessing either electron-donating or -withdrawing substituents, 1,3-cyclohexanediones, and substituted anilinolactones were next explored to investigate the generality of this methodology; when this reaction was carried out with an aliphatic aldehyde such as propionaldehyde or butanaldehyde in the same conditions ([bmim][triflate]/alum), the TLC and 1H NMR spectra of the crude reaction mixture showed the presence of a combination of starting materials and numerous by-products that can be synthesized via some reactions such as autocondensation reactions, with the yield of the expected product being very poor. The detailed results were presented in Table 5.


EntryRR1R2ProductYield (%)bLit. Mp (°C)Found Mp (°C)

4a4-ClHp-CH3169695.tab.001a92274-275275-276

4bHHp-CH3169695.tab.001b91280-281281-282

4c4-CH3OHp-CH3169695.tab.001c93254-255255–257

4d4-BrHH169695.tab.001d89280-281281-282

4e4-CH3Hp-CH3169695.tab.001e93263-264264–266

4fHHH169695.tab.001f90275-276276-277

4g4-ClHp-Cl169695.tab.001g92227-228228–230

4h4-CH3OCH3p-CH3169695.tab.001h95256-257257-258

4i4-BrCH3p-CH3169695.tab.001i94269-270271–273

4j3-NO2CH3p-CH3169695.tab.001j92232-233232-233

4k4-ClCH3H169695.tab.001k94260-261262-263

4l4-CH3OCH3H169695.tab.001l92258-259260–262

4m3-NO2CH3H169695.tab.001m89293-294294-295

4n4-ClCH3p-Cl169695.tab.001n93>300>300

4o4-CH3CH3p-F169695.tab.001o93281–283283–285

4p4-ClCH3p-F169695.tab.001p92297–299299-300

4q4-BrCH3p-F169695.tab.001q88283–285285–287

4r4-OCH3CH3p-F169695.tab.001r92266–268268–270

Reaction conditions: benzaldehydes 1 (1 mmol), cyclohexanediones 2 (1 mmol), and anilinolactones 3 (1 mmol), IL (0.2 mL), alum (20 mol%), at 90°C.
Isolated yields.

In conclusion, we have developed an extremely efficient and green procedure for the synthesis of biologically active natural product 4-aza-podophyllotoxin derivatives. These products were synthesized previously by the condensation of benzaldehydes, enaminones, and tetronic acid [44, 45]. This is the first report of the synthesis of these compounds via a multicomponent condensation of various benzaldehydes, 1,3-cyclohexanediones, and anilinolactones in the presence of Alum as an inexpensive and available catalyst. The advantages of this new method are operational simplicity, high to excellent yields of products in short reaction times, and easy workup procedures.

2.1. Experimental Part

General. The chemicals used in this work were obtained from Fluka and Merck and were used without purification. Melting points were measured on an Electrothermal 9200 apparatus. 1H NMR spectra were recorded in DMSO-d6 solvents on a Bruker DRX-400 spectrometer with tetramethylsilane as internal reference. The elemental analyses (C.H.N) were obtained from a Carlo ERBA Model EA 1108 analyzer. The purity determination of the substrates and reaction monitoring were accomplished by TLC on silica-gel polygram SILG/UV 254 plates (from Merck company).

All the products 4(ar) are known compounds and were characterized by comparison of their 1H NMR spectrum, physical properties, and elemental analyses data with previous synthetic products [44, 45].

Typical Procedure for the Preparation of 4-Aza-Podophyllotoxin Derivatives. To a mixture of benzaldehyde (1 mmol), dimedone (1 mmol), anilinolactone (1 mmol), and alum (20 mol%), [bmim][triflate] (0.2 mL) was added. The resulting mixture was stirred at 90°C for an appropriate time. After completion of the reaction as indicated by TLC, water (5 mL) was added and the product was extracted. The reaction mixture was filtered and the precipitate washed with water and recrystallized by EtOH to afford the pure product and was identified by physical and spectroscopic data.

9-(4-Methoxyphenyl)-4-p-tolyl-5,6,7,9-tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione (4c). Yield 93%; mp: 255–257°C; 1H NMR (DMSO- ): δ 1.67–1.95 (2H, m, CH2), 2.12–2.20 (2H, m, CH2), 2.21–2.30 (2H, m, CH2), 2.38 (3H, s, CH3), 3.75 (3H, s, CH3), 4.39–4.55 (2H, m, CH2), 4.79 (1H, s, CH), 6.80–747 (8H, m, ArH). Anal. Calcd for C25H23NO4:C, 74.79; H, 5.77; N, 3.49. Found C, 74.72; H, 5.71; N, 3.55.

9-(4-Methoxyphenyl)-6,6-dimethyl-4-p-tolyl-5,6,7,9-tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione (4h). Yield 95%; mp: 257-258°C; 1H NMR (DMSO- ): δ 0.85 (3H, s,CH3), 0.95 (3H, s, CH3), 1.95–2.10 (2H, m, CH2), 2.20–2.28 (2H, m, CH2), 2.44 (3H, s, CH3), 3.75 (3H, s, OCH3), 4.51–4.58 (2H, m, CH2), 4.73 (1H, s, CH), 6.81–7.45 (8H, m, ArH). Anal. Calcd for C27H27NO4: C, 75.50; H, 6.34; N, 3.26. Found C, 75.45; H, 6.41; N, 3.20.

9-(4-Bromophenyl)-6,6-dimethyl-4-p-tolyl-5,6,7,9-tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione (4i). Yield 94%; mp: 271–273°C; 1H NMR (DMSO- ): δ 0.87 (3H, s, CH3), 0.95 (3H, s, CH3), 2.04–2.11 (2H, m, CH2), 2.18–2.23 (2H, m, CH2), 2.42 (3H, s, CH3), 4.50–4.54 (2H, m, CH2), 4.71 (1H, s, CH), 7.27–7.50 (8H, m, ArH). Anal. Calcd for C26H24BrNO3: C, 65.28; H, 5.06; N, 2.93. Found C, 65.30; H, 5.04; N, 2.88.

9-(4-Methoxyphenyl)-6,6-dimethyl-4-phenyl-5,6,7,9-tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione (4l). Yield 92%; mp: 260–262°C; 1H NMR (DMSO- ): δ 0.84 (3H, s, CH3), 0.95 (3H, s, CH3), 2.02–2.11 (2H, m, CH2), 2.18–2.25 (2H, m, CH2), 3.74 (3H, s, CH3), 4.45–4.61 (2H, m, CH2), 4.75 (1H, s, CH), 6.83–7.58 (9H, m, ArH). Anal. Calcd for C26H25NO4: C, 75.16; H, 6.06; N, 3.37. Found C, 75.11; H, 6.10; N, 3.43.

4,9-Bis(4-chlorophenyl)-6,6-dimethyl-5,6,7,9-tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione (4n). Yield 93%; mp: >300°C; 1H NMR (DMSO- ): δ 0.83 (3H, s, CH3), 0.96 (3H, s, CH3), 2.02–2.11 (2H, m, CH2), 2.18–2.27 (2H, m, CH2), 4.50–4.63 (2H, m, CH2), 4.74 (1H, s, CH), 7.35–7.62 (8H, m, ArH). Anal. Calcd for C25H21Cl2NO3: C, 66.09; H, 4.66; N, 3.08. Found C, 66.14; H, 4.71; N, 3.05.

4-(4-Fluorophenyl)-6,6-dimethyl-9-p-tolyl-5,6,7,9-tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione (4o). Yield 93%; mp: 283–285°C; 1H NMR (DMSO- ): δ 0.84 (3H, s, CH3), 0.91 (3H, s, CH3), 1.97–2.10 (2H, m, CH2), 2.15–2.24 (2H, m, CH2), 2.26 (3H, s, CH3), 4.53–4.60 (2H, m, CH2), 4.75 (1H, s, CH), 7.06–7.66 (8H, m, ArH). Anal. Calcd for C26H24FNO3: C, 74.80; H, 5.79; F, 4.55; N, 3.36. Found C, 74.85; H, 5.75; N, 3.40.

9-(4-Chlorophenyl)-4-(4-fluorophenyl)-6,6-dimethyl-5,6,7,9-tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione (4p). Yield 92%; mp: 299-300°C; 1H NMR (DMSO- ): δ 0.84 (3H, s, CH3), 0.96 (3H, s, CH3), 2.01–2.11 (2H, m, CH2), 2.16–2.22 (2H, m, CH2), 4.50–4.62 (2H, m, CH2), 4.76 (1H, s, CH), 7.32–7.62 (8H, m, ArH). Anal. Calcd for C25H21ClFNO3: C, 68.57; H, 4.83; N, 3.20. Found C, 68.63; H, 4.78; N, 3.22.

9-(4-Bromophenyl)-4-(4-fluorophenyl)-6,6-dimethyl-5,6,7,9-tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione (4q). Yield 88%; mp: 285–287°C; 1H NMR (DMSO- ): δ 0.85 (3H, s, CH3), 0.97 (3H, s, CH3), 2.00–2.11 (2H, m, CH2), 2.15–2.20 (2H, m, CH2), 4.49–4.58 (2H, m, CH2), 4.74 (1H, s, CH), 7.28–7.61 (8H, m, ArH). Anal. Calcd for C25H21BrFNO3: C, 62.25; H, 4.39; N, 2.90. Found C, 62.19; H, 4.44; N, 2.88.

4-(4-Fluorophenyl)-9-(4-methoxyphenyl)-6,6-dimethyl-5,6,7,9-tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione (4r). Yield 92%; mp: 268–270°C; 1H NMR (DMSO- ): δ 0.88 (3H, s, CH3), 0.94 (3H, s, CH3), 1.98–2.04 (2H, m, CH2), 2.15–2.22 (2H, m, CH2), 3.74 (3H, s, OCH3), 4.48–4.60 (2H, m, CH2), 4.75 (1H, s, CH), 6.88–7.60 (8H, m, ArH). Anal. Calcd for C26H24FNO4: C, 72.04; H, 5.58; N, 3.23. Found C, 72.10; H, 5.52; N, 3.25.

Acknowledgments

The authors are thankful to the University of Kashan for supporting this work by Grant no. 159148/15 and also gratefully acknowledge the financial support from the Avicenna Research Institute.

References

  1. A. Dömling, “Recent developments in isocyanide based multicomponent reactions in applied chemistry,” Chemical Reviews, vol. 106, pp. 17–89, 2006. View at: Publisher Site | Google Scholar
  2. R. V. A. Orru and M. de Greef, “Recent advances in solution-phase multicomponent methodology for the synthesis of heterocyclic compounds,” Synthesis, no. 10, pp. 1471–1499, 2003. View at: Google Scholar
  3. C. Hulme and V. Gore, “Multi-component reactions: emerging chemistry in drug discovery from Xylocain to Crixivan,” Current Medicinal Chemistry, vol. 10, no. 1, pp. 51–80, 2003. View at: Publisher Site | Google Scholar
  4. C. Montagne, J. J. Shiers, and M. Shipman, “Rapid generation of molecular complexity using “sequenced” multi-component reactions: one-pot synthesis of 5,5′-disubstituted hydantoins from methyleneaziridines,” Tetrahedron Letters, vol. 47, no. 52, pp. 9207–9209, 2006. View at: Publisher Site | Google Scholar
  5. A. Dömling and I. Ugi, “Multicomponent reactions with isocyanides,” Angewandte Chemie, vol. 39, no. 18, pp. 3169–3210, 2000. View at: Google Scholar
  6. I. Ugi, “Recent progress in the chemistry of multicomponent reactions,” Pure and Applied Chemistry, vol. 73, no. 1, pp. 187–191, 2001. View at: Google Scholar
  7. B. B. Touré and D. G. Hall, “Natural product synthesis using multicomponent reaction strategies,” Chemical Reviews, vol. 109, no. 9, pp. 4439–4486, 2009. View at: Publisher Site | Google Scholar
  8. J. D. Sunderhaus and S. F. Martin, “Applications of multicomponent reactions to the synthesis of diverse heterocyclic scaffolds,” Chemistry, vol. 15, no. 6, pp. 1300–1308, 2009. View at: Publisher Site | Google Scholar
  9. I. Devi and P. J. Bhuyan, “Sodium bromide catalysed one-pot synthesis of tetrahydrobenzo[b]pyrans via a three-component cyclocondensation under microwave irradiation and solvent free conditions,” Tetrahedron Letters, vol. 45, no. 47, pp. 8625–8627, 2004. View at: Publisher Site | Google Scholar
  10. D. M. D'Souza and T. J. Mueller, “Multi-component syntheses of heterocycles by transition-metal catalysis,” Chemical Society Reviews, vol. 36, no. 7, pp. 1095–1108, 2007. View at: Google Scholar
  11. C. C. A. Cariou, G. J. Clarkson, and M. Shipman, “Rapid synthesis of 1,3,4,4-tetrasubstituted β-lactams from methyleneaziridines using a four-component reaction,” Journal of Organic Chemistry, vol. 73, no. 24, pp. 9762–9764, 2008. View at: Publisher Site | Google Scholar
  12. K. Kumaravel and G. Vasuki, “Four-component catalyst-free reaction in water: combinatorial library synthesis of novel 2-amino-4-(5-hydroxy-3-methyl-1H-pyrazol-4-yl)-4H-chromene-3- carbonitrile derivatives,” Green Chemistry, vol. 11, no. 12, pp. 1945–1947, 2009. View at: Publisher Site | Google Scholar
  13. S. L. Jain, S. Singhal, and B. Sain, “PEG-assisted solvent and catalyst free synthesis of 3,4-dihydropyrimidinones under mild reaction conditions,” Green Chemistry, vol. 9, no. 7, pp. 740–741, 2007. View at: Publisher Site | Google Scholar
  14. R. Hagiwara and Y. Ito, “Room temperature ionic liquids of alkylimidazolium cations and fluoroanions,” Journal of Fluorine Chemistry, vol. 105, no. 2, pp. 221–227, 2000. View at: Google Scholar
  15. T. Welton, “Room-temperature ionic liquids: solvents for synthesis and catalysis,” Chemical Reviews, vol. 99, no. 8, pp. 2071–2083, 1999. View at: Google Scholar
  16. M. J. Earle and K. R. Seddon, “Ionic liquids: green solvents for the future,” Pure and Applied Chemistry, vol. 72, no. 7, pp. 1391–1398, 2000. View at: Google Scholar
  17. H. Olivier, “Recent developments in the use of non-aqueous ionic liquids for two-phase catalysis,” Journal of Molecular Catalysis A, vol. 146, no. 1-2, pp. 285–289, 1999. View at: Publisher Site | Google Scholar
  18. J. S. Yadav, B. V. S. Reddy, P. Sreedhar et al., “Three compounent coupling reactions in ionic liquids: one-pot synthesis of isoxazolidines,” Journal of Molecular Catalysis A, vol. 270, pp. 160–163, 2007. View at: Google Scholar
  19. R. Sheldon, “Catalytic reactions in ionic liquids,” Chemical Communications, no. 23, pp. 2399–2407, 2001. View at: Google Scholar
  20. J. Dupont, R. F. De Souza, and P. A. Z. Suarez, “Ionic liquid (molten salt) phase organometallic catalysis,” Chemical Reviews, vol. 102, no. 10, pp. 3667–3692, 2002. View at: Publisher Site | Google Scholar
  21. F. Bossert, H. Meyer, and E. Wehinger, “4-Aryldihydropyridines, a new class of highly active calcium antagonists,” Angewandte Chemie, vol. 20, no. 9, pp. 762–769, 1981. View at: Google Scholar
  22. H. Nakayama and Y. Kasoaka, “Chemical identification of binding sites for calcium channel antagonists,” Heterocycles, vol. 42, no. 2, pp. 901–909, 1996. View at: Google Scholar
  23. B. Loev, M. M. Goodman, K. M. Snader, R. Tedeschi, and E. Macko, “‘Hantzsch-type’ dihydropyridine hypotensive agents. 3,” Journal of Medicinal Chemistry, vol. 17, no. 9, pp. 956–965, 1974. View at: Google Scholar
  24. F. Bossert, H. Meyer, and E. Wehinger, “4-Aryldihydropyridines, a new class of highly active calcium antagonists,” Angewandte Chemie, vol. 20, no. 9, pp. 762–769, 1981. View at: Google Scholar
  25. J. G. Breitenbucher and G. Figliozzi, “Solid-phase synthesis of 4-aryl-1,4-dihydropyridines via the Hantzsch three component condensation,” Tetrahedron Letters, vol. 41, no. 22, pp. 4311–4315, 2000. View at: Google Scholar
  26. R. Boer and V. Gekeler, “Chemosensitizers in tumor therapy: new compounds promise better efficacy,” Drugs of the Future, vol. 20, no. 5, pp. 499–509, 1995. View at: Google Scholar
  27. V. M. Briukhanov, “The effect of Ca antagonist on the development of inflammatory edema in rats,” Clinical and Experimental Pharmacology, vol. 57, pp. 47–49, 1994. View at: Google Scholar
  28. S. Bahekar and D. Shinde, “Synthesis and anti-inflammatory activity of 1-4-dihydropyridines,” Acta Pharmaceutica, vol. 52, no. 4, pp. 281–287, 2002. View at: Google Scholar
  29. G. A. Wachter, M. C. Davis, A. R. Martin, and S. G. Franzblau, “Antimycobacterial activity of substituted isosteres of pyridine- and pyrazinecarboxylic acids,” Journal of Medicinal Chemistry, vol. 41, no. 13, pp. 2436–2438, 1998. View at: Publisher Site | Google Scholar
  30. S. Gullapalli and P. Ramarao, “L-type Ca2+ channel modulation by dihydropyridines potentiates κ-opioid receptor agonist induced acute analgesia and inhibits development of tolerance in rats,” Neuropharmacology, vol. 42, no. 4, pp. 467–475, 2002. View at: Publisher Site | Google Scholar
  31. C. E. Sunkel, M. Fau de Casa-Juana, L. Santos et al., “4-Alkyl-1,4-dihydropyridines derivatives as specific PAF-acether antagonists,” Journal of Medicinal Chemistry, vol. 33, no. 12, pp. 3205–3210, 1990. View at: Google Scholar
  32. M. Ono Handkinura, “Effect of Ca+2 antagonist, vasodilators, diltizem, nifedipine, perhexiline and verapamil on platelet aggregation invitro. Arzneim-forsch,” Drug Research, vol. 3, pp. 1131–1134, 1981. View at: Google Scholar
  33. K. Tomioka, Y. Kubota, and K. Koga, “Design, synthesis, and antitumor activity-absolute configuration relationships of podophyllotoxin aza-analogues,” Tetrahedron, vol. 49, no. 9, pp. 1891–1900, 1993. View at: Publisher Site | Google Scholar
  34. P. Lienard, J. Royer, J.-C. Quirion, and H.-P. Husson, “Asymmetric synthesis XXIV1: benzoquinolizidine analogues of podophyllotoxin via the CN(R, S) method,” Tetrahedron Letters, vol. 32, no. 22, pp. 2489–2492, 1991. View at: Publisher Site | Google Scholar
  35. G. Poli and G. Giambastiani, “An epiisopicropodophyllin aza analogue via palladium-catalyzed pseudo-domino cyclization,” Journal of Organic Chemistry, vol. 67, no. 26, pp. 9456–9459, 2002. View at: Publisher Site | Google Scholar
  36. J. van der Eycken, J.-P. Bosmans, D. van Haver et al., “The synthesis of 4-desoxy-2-azapodophyllotoxins,” Tetrahedron Letters, vol. 30, no. 29, pp. 3873–3876, 1989. View at: Google Scholar
  37. K. Tomioka, Y. Kubota, and K. Koga, “Synthesis and antitumor activity of podophyllotoxin aza-analogues,” Tetrahedron Letters, vol. 30, no. 22, pp. 2953–2954, 1989. View at: Google Scholar
  38. J.-P. Bosmans, J. Van der Eycken, M. Vandewalle, A. Hulkenberg, R. Van Hes, and W. Veerman, “The synthesis of 2-azapodophyllotoxins,” Tetrahedron Letters, vol. 30, no. 29, pp. 3877–3880, 1989. View at: Google Scholar
  39. Y. Hitotsuyanagi, M. Kobayashi, M. Fukuyo, K. Takeya, and H. Itokawa, “A facile synthesis of the 4-aza-analogs of 1-arylnaphthalene lignans chinensin, justicidin B, and Taiwanin C,” Tetrahedron Letters, vol. 38, no. 48, pp. 8295–8296, 1997. View at: Google Scholar
  40. Y. Hitotsuyanagi, M. Kobayashi, H. Morita, H. Itokawa, and K. Takeya, “Synthesis of (-)-4-aza-4-deoxypodophyllotoxin from (-)-podophyllotoxin,” Tetrahedron Letters, vol. 40, no. 51, pp. 9107–9110, 1999. View at: Google Scholar
  41. C. Tratrat, S. Giorgi-Renault, and H.-P. Husson, “A multicomponent reaction for the one-pot synthesis of 4-aza-2,3-didehydropodophyllotoxin and derivatives,” Organic Letters, vol. 4, no. 19, pp. 3187–3189, 2002. View at: Publisher Site | Google Scholar
  42. S. Tu, Y. Zhang, J. Zhang et al., “A simple procedure for the synthesis of 4-aza-podophyllotoxin derivatives in water under microwave irradiation conditions,” Synlett, no. 17, pp. 2785–2790, 2006. View at: Publisher Site | Google Scholar
  43. Y. Hitotsuyanagi, M. Kobayashi, M. Fukuyo, K. Takeya, and H. Itokawa, “A facile synthesis of the 4-aza-analogs of 1-arylnaphthalene lignans chinensin, justicidin B, and Taiwanin C,” Tetrahedron Letters, vol. 38, no. 48, pp. 8295–8296, 1997. View at: Google Scholar
  44. S. Tu, Y. Zhang, R. Jia, B. Jiang, J. Zhang, and S. Ji, “A multi-component reaction for the synthesis of N-substituted furo[3,4-b]quinoline derivatives under microwave irradiation,” Tetrahedron Letters, vol. 47, no. 37, pp. 6521–6525, 2006. View at: Publisher Site | Google Scholar
  45. C.-L. Shi, H. Chen, and D. Shi, “An efficient one-pot three-component synthesis of tetrahydrofuro[3,4-b] quinoline-1,8(3H,4H)-dione derivatives catalyzed by L-proline,” Journal of Heterocyclic Chemistry, vol. 49, no. 1, pp. 125–129, 2012. View at: Publisher Site | Google Scholar

Copyright © 2013 Hossein Naeimi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1492 Views | 1073 Downloads | 2 Citations
 PDF  Download Citation  Citation
 Download other formatsMore
 Order printed copiesOrder