Journal of Chemistry

Volume 2013 (2013), Article ID 169695, 9 pages

http://dx.doi.org/10.1155/2013/169695

Research Article

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

Hossein Naeimi,¹ Zahra Rashid,¹ Amir Hassan Zarnani,² and Ramin Ghahremanzadeh³

¹Department of Organic Chemistry, Faculty of Chemistry, University of Kashan, Kashan 87317, Iran

²Reproductive Immunology Research Center, Avicenna Research Institute, ACECR, Tehran 1936773493, Iran

³Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran 1936773493, Iran

Received 6 May 2013; Accepted 2 September 2013

Academic Editor: Andrea Penoni

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.

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 [1–4], 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 [5–8]. 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 [9–11]. 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 [14–17]. 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 [18–20].

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 [23–25], 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 [33–35]. 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 [36–38], have attracted attention in the recent decade [39–42].

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].

Scheme 1: Synthesis of anilinolactones.

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).

Scheme 2: Synthesis of 4-aza-podophyllotoxin.

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.

Table 1: Different polar and nonpolar used solvents, for the synthesis of 4i a under reflux conditions.

Entry
Solvent
Time (min)
Yield (%)b

1
MeOH
120
72

2
EtOH
120
75

3
1,4-Dioxane
120
60

4
DMF
120
70

5
Toluene
120
65

6
[bmim][triflate]
30
90

7
[bmim]OH
30
75

8
[bmim]PF₆
30
88

9
[bmim]BF₄
30
83

10
[bmim]Br
30
80

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.

Scheme 3: Model reaction.

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.

Table 2: Diverse used catalyst in a model reaction for the synthesis of 4i a in [bmim][triflate].

Entry
Catalyst (20 mol%)
Yield (%)b

1
Alum
94

2
p-TSA
90

3
K-10
85

4
S.S.A
80

5
AlCl₃
55

6
Et₃N
63

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).

Table 3: Different amounts of the alum as catalyst for the synthesis of 4i a.

Entry
Alum (mol%)
Yield (%)b

1
5
51

2
10
65

3
15
81

4
20
94

5
30
96

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.

Table 4: Different reaction temperatures in model reaction for the synthesis of 4i a.

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

1
r.t.
120
Trace

2
70
60
87

3
90
30
94

4
110
30
95

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.

Scheme 4: Proposed mechanism.

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.

Table 5: Synthesis of 4-aza-podophyllotoxin derivatives (4a–r) a.

Entry
R
R₁
R₂
Product
Yield (%)b
Lit. Mp (°C)
Found Mp (°C)

4a
4-Cl
H
p-CH₃

92
274-275
275-276

4b
H
H
p-CH₃

91
280-281
281-282

4c
4-CH₃O
H
p-CH₃

93
254-255
255–257

4d
4-Br
H
H

89
280-281
281-282

4e
4-CH₃
H
p-CH₃

93
263-264
264–266

4f
H
H
H

90
275-276
276-277

4g
4-Cl
H
p-Cl

92
227-228
228–230

4h
4-CH₃O
CH₃
p-CH₃

95
256-257
257-258

4i
4-Br
CH₃
p-CH₃

94
269-270
271–273

4j
3-NO₂
CH₃
p-CH₃

92
232-233
232-233

4k
4-Cl
CH₃
H

94
260-261
262-263

4l
4-CH₃O
CH₃
H

92
258-259
260–262

4m
3-NO₂
CH₃
H

89
293-294
294-295

4n
4-Cl
CH₃
p-Cl

93
>300
>300

4o
4-CH₃
CH₃
p-F

93
281–283
283–285

4p
4-Cl
CH₃
p-F

92
297–299
299-300

4q
4-Br
CH₃
p-F

88
283–285
285–287

4r
4-OCH₃
CH₃
p-F

92
266–268
268–270

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(a–r) 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.

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