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Journal of the Iranian Chemical Society

, Volume 11, Issue 5, pp 1407–1419 | Cite as

Highly active magnetically separable CuFe2O4 nanocatalyst: an efficient catalyst for the green synthesis of tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H) dione derivatives

  • Ramin Ghahremanzadeh
  • Zahra Rashid
  • Amir-Hassan Zarnani
  • Hossein Naeimi
Open Access
Original Paper
First Online:
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Accepted:

Abstract

A facile and efficient procedure has been reported for the synthesis of tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-diones by the condensation reaction of benzaldehydes, 1,3-cyclohexanediones and anilinolactones in the presence of CuFe2O4 as a reusable nanocatalyst with high catalytic activity in water. The notable advantages of this method are excellent isolated yields, short reaction times, simple workup procedure and little environmental impact.

Graphical Abstract

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Keywords

Multicomponent reactions Water Magnetic nanoparticles Azapodophyllotoxin Tetronic acid 

Introduction

Multicomponent reactions (MCRs) have emerged as a versatile approach in organic synthesis for the construction of complex structures from simple building blocks, due to their advantages over the conventional multistep synthesis [1, 2]. Preparation of products in a single step and one-pot, operational simplicity, less time consuming, high atom economy, consuming expensive purification processes are the major advantages of multicomponent reactions [3, 4, 5]. Since Breslow has demonstrated that hydrophobic effects could strongly enhance the rate of some organic reactions and rediscovered the use of water as solvent in organic chemistry in 1980s [6, 7], much attention has been focused on organic reactions in water. The unique properties of water are a desirable solvent for chemical reactions and it is safe, non-toxic, environmentally friendly, high abundance, and cheap compared to organic solvents. The use of water as solvent in organic reactions is one of the current focuses today [8, 9, 10].

Tetronic acid (tetrahydrofuran-2,4-dione) is one of the important heterocyclic units, has a broad spectrum of biological properties such as antifungal [11], antibiotic [12, 13, 14, 15, 16], insecticidal [17], anticoagulant [18, 19, 20], antiepileptic [21], analgesic [22] and anti-inflammatory activities [23]. Podophyllotoxin (Fig. 1) is a non-alkaloid toxin lignan extracted from the roots and rhizomes of Podophyllum species [24] that inhibits microtubule assembly [25, 26, 27]. Although Podophyllotoxin and its derivatives have a long and fascinating history biological properties such as, purgative, antiviral, antihelminthic and antitumor [28, 29], but because of mostly unsuccessful attempts to use it for the treatment of human neoplasia, extensive structural modifications have been performed to obtain more potent and less toxic anticancer agents [30, 31, 32]. Among them, derivatives of 4-azapodophyllotoxin (Fig. 1), were reported as powerful DNA topoisomerase II inhibitors, substitution of carbon atom at position 4 of podophyllotoxin by nitrogen atom would bring about great changes in the biological profile working through a mechanism of action entirely different from that of the parent natural podophyllotoxin [33, 34, 35, 36].
Fig. 1

Structure of podophyllotoxin and 4-azapodophyllotoxin

Magnetic nanoparticles are a class of nanostructured materials of current interest, due to their numerous applications, such as magnetic resonance imaging [37], drug delivery [38, 39], biomolecular sensors [40, 41], bioseparation [42, 43] and magneto-thermal therapy [44, 45]. In addition, biological and medical applications, magnetic nanoparticles are efficient supports for catalysts in organic synthesis [46, 47], because of their extremely small size and large surface to volume ratio and can facilitate their separation effectively from the reaction media by magnetization with a permanent magnetic field [48, 49, 50, 51].

In view of the important biological properties of the azapodophyllotoxin derivatives, we report herein a novel and clean synthesis of tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione derivatives through a three-component condensation reaction of benzaldehydes, 1,3-cyclohexanediones and anilinolactones in the presence of CuFe2O4 nanoparticles as magnetically recyclable catalyst in water media.

Experimental

Chemicals and apparatus

The chemical used in this work were obtained from Fluka and Merck and were used without purification. Melting points were measured on an Electrothermal 9200 apparatus. IR spectra were recorded as KBr pellets on a Perkin-Elmer 781 spectrophotometer and an Impact 400 Nicolet FT-IR spectrophotometer. 1H NMR and 13C NMR spectra were recorded in d 6 -DMSO 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. XRD analysis was performed with an X-ray diffractometer (PAnalytical X’Pert-Pro) using a Cu-Ka monochromatic radiation source and a Ni filter. The nanocatalyst was determined using a KYKY EM-3200 scanning electron microscope (SEM) operated at a 26 kV accelerating voltage. The purity determination of the substrates and reaction monitoring were accomplished by TLC on silica-gel polygram SILG/UV 254 plates (from Merck Company).

Typical experimental procedure for the preparation of magnetic nanocatalyst

CuFe2O4 nanoparticles were prepared by co-precipitation of Cu(NO3)2 and Fe(NO3)3 in water in the presence of sodium hydroxide. Briefly, to a solution of Fe(NO3)3·9H2O (0.05 mol) and Cu(NO3)2·3H2O (0.025 mol) in 100 mL of distilled water, 75 mL of NaOH 4 M was added at room temperature over a period of 10 min to form reddish-black precipitate. Then the reaction mixture was warmed to 90 °C and stirred. After 2 h, it was cooled to room temperature and the formed magnetic particles were separated by a magnetic separator. The catalyst was washed with water and kept in air oven over night at 80 °C. Then the catalyst was ground in a mortar–pestle and kept in a furnace at 800 °C at a heating rate of (2 °C/min) and cooled to 100 °C at (5 °C/min) in air. [52].

Typical procedure for the preparation of tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione derivatives

To prepare tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione derivatives, to a mixture of benzaldehyde (1 mmol), 1,3-cyclohexanedione (1 mmol), anilinolactone (1 mmol) in water, nano CuFe2O4 (5 mol%) was added and heated under reflux condition. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled at room temperature. The nanoparticles were easily separated from the reaction mixture with an external magnet and reutilized four times for the same reaction. The crude solids were filtered off and washed with water. The pure products were obtained by recrystallization from methanol and were 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 95 %; mp: 255–257 °C; 1H NMR (DMSO-d 6 ): 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 96 %; mp: 257 °C; 1H NMR (DMSO-d 6 ): 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-Methoxyphenyl)-6,6-dimethyl-4-phenyl-5,6,7,9-tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione (4l)

Yield 94 %; mp: 260 °C; 1H NMR (DMSO-d 6 ): 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-d 6 ): 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: 282–283 °C; 1H NMR (DMSO-d 6 ): 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; 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 91 %; mp: 298–300 °C; 1H NMR (DMSO-d 6 ): 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 90 %; mp: 284–285 °C; 1H NMR (DMSO-d 6 ): 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, 2.86.

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 94 %; mp: 268 °C; 1H NMR (DMSO-d 6 ): 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, 3.28.

6,6-Dimethyl-9-(4-nitrophenyl)-4-phenyl-5,6,7,9-tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione (4s)

Yield 92 %; mp: 296–298 °C; 1H NMR (DMSO-d 6 ): δ 0.85 (3H, s, CH3),0.92 (3H, s, CH3), 2.04–2.10 (2H, m, CH2), 2.21–2.30 (2H, m, CH2), 4.50–4.63 (2H, m, CH2), 4.94 (1H, s, CH), 7.59–8.15 (9H, m, ArH); 13C NMR (DMSO-d 6 , 100 MHz): δ: 27.4, 29.3, 34.5, 36.2, 49.1, 51.2, 65.8, 112.3, 120.9, 121.3, 124.0, 127.5, 129.0, 131.2, 133.0, 140.9, 147.1, 159.4, 160.3, 178.0, 195.6; Anal. Calcd for C25H22N2O5: C, 69.76; H, 5.15; N, 6.51. Found C, 69.71; H, 5.20; N, 6.47.

9-(3-Chlorophenyl)-6,6-dimethyl-4-p-tolyl-5,6,7,9-tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione (4t)

Yield 91 %; mp: 268–270 °C; 1H NMR (DMSO-d 6 ): δ 0.83 (3H, s, CH3),0.91 (3H, s, CH3), 2.03–2.08 (2H, m, CH2), 2.19–2.21 (2H, m, CH2), 2.39 (3H, s, CH3), 4.52–4.57 (2H, m, CH2), 4.90 (1H, s, CH), 7.40–8.16 (8H, m, ArH); 13C NMR (DMSO-d 6 , 100 MHz): 21.2, 27.4, 29.3, 34.4, 36.2, 49.1, 51.2, 65.8, 112.2, 120.8, 121.4, 124.0, 127.9, 129.0, 131.3, 137.1, 138.9, 143.2, 156.3, 161.2, 178.1, 195.5; Anal. Calcd for C26H24ClNO3: C, 71.97; H, 5.57; N, 3.23. Found C, 71.93; H, 5.63; N, 3.28.

4-(4-Bromophenyl)-6,6-dimethyl-9-p-tolyl-5,6,7,9-tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione (4u)

Yield 90 %; mp: 288–290 °C; 1H NMR (DMSO-d 6 ): δ 0.82 (3H, s, CH3),0.90 (3H, s, CH3), 2.02–2.06 (2H, m, CH2), 2.18–2.20 (2H, m, CH2), 2.38 (3H, s, CH3), 4.47–4.60 (2H, m, CH2), 4.89 (1H, s, CH), 7.39–8.26 (8H, m, ArH); 13C NMR (DMSO-d 6 , 100 MHz): δ: 27.1, 28.7, 34.8, 35.7, 50.0, 51.4, 66.5, 111.9, 121.4, 123.8, 128.1, 129.6, 130.4, 130.9, 133.2, 134.0, 137.8, 160.1, 162.0, 177.9, 195.2; Anal. Calcd for C26H24BrNO3: C, 65.28; H, 5.06; N, 2.93. Found C, 65.34; H, 5.11; N, 2.96.

4-(4-Methoxyphenyl)-6,6-dimethyl-9-(3-nitrophenyl)furo[3,4-b]quinoline-1,8(3H,4H)-dione (4v)

Yield 95 %; mp: >300 °C; 1H NMR (DMSO-d 6 ): δ 0.84 (3H, s, CH3),0.91 (3H, s, CH3), 2.03–2.07 (2H, m, CH2), 2.19–2.28 (2H, m, CH2), 3.82 (3H, s, OCH3), 4.54–4.60 (2H, m, CH2), 4.91 (1H, s, CH), 7.10–8.10 (8H, m, ArH); 13C NMR (DMSO-d 6 , 100 MHz): δ: 27.4, 29.1, 34.5, 36.1, 49.0, 50.9, 55.9, 66.1, 115.3, 112.7, 120.6, 122.0, 123.4, 125.3, 136.0, 139.2, 143.1, 143.2, 148.9, 159.1, 159.9, 161.8, 178.1, 195.6; Anal. Calcd for C26H24N2O6: C, 67.82; H, 5.25; N, 6.08. Found C, 67.87; H, 5.31; N, 6.13.

4-(4-Bromophenyl)-6,7-dihydro-6,6-dimethyl-9-(3-nitrophenyl)furo[3,4-b]quinoline- 1,8(3H,4H)-dione (4w)

Yield 91 %; mp: >300 °C; 1H NMR (DMSO-d 6 ): δ 0.70 (3H, s, CH3),0.89 (3H, s, CH3), 1.99–2.03 (2H, m, CH2), 2.19–2.24 (2H, m, CH2), 4.54–4.58 (2H, m, CH2), 4.92 (1H, s, CH), 7.07–8.11 (8H, m, ArH); 13C NMR (DMSO-d 6 , 100 MHz): δ: 27.3, 29.3, 34.5, 36.1, 49.2, 51.2, 65.9, 112.8, 120.7, 122.0, 125.4, 127.3, 130.7, 133.6, 139.3, 140.1, 143.1, 144.2, 148.8, 159.1, 161.6, 178.2, 195.6; Anal. Calcd for C25H21BrN2O5: C, 58.95; H, 4.16; N, 5.50. Found C, 58.99; H, 4.11; N, 5.56.

4-(4-bromophenyl)-6,7-dihydro-6,6-dimethyl-9-(4-nitrophenyl)furo[3,4-b]quinoline-1,8(3H,4H)-dione (4x)

Yield 93 %; mp: >300 °C; 1H NMR (DMSO-d 6 ): δ 0.69 (3H, s, CH3),0.88 (3H, s, CH3), 1.97–2.01 (2H, m, CH2), 2.17–2.21 (2H, m, CH2), 4.56–4.89 (2H, m, CH2), 5.11 (1H, s, CH), 7.46–8.16 (8H, m, ArH); 13C NMR (DMSO-d 6 , 100 MHz): δ: 27.0, 28.8, 34.8, 35.7, 50.0, 51.4, 66.5, 112.9, 121.8, 122.4, 130.2, 133.1, 134.6, 138.9, 140.2, 144.0, 147.8, 152.1, 160.9, 179.7, 195.5; Anal. Calcd for C25H21BrN2O5: C, 58.95; H, 4.16; N, 5.50. Found C, 58.89; H, 4. 21; N, 5.55.

Results and discussion

In this research, benzaldehydes, 1, 1,3-cyclohexanediones 2 and anilinolactones 3 with initial moles were reacted through a three-component condensation reaction in the presence of CuFe2O4 nanoparticles as magnetically recyclable catalyst in water (Scheme 1). In this reaction, the tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione derivatives were obtained as pure products in high yields.
Scheme 1

The reaction leading to the synthesis of tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)dione derivatives 4a-x

Firstly, the anilinolactones were prepared from the condensation reaction of tetronic acid with various anilines. As shown in Scheme 2, when tetronic acid was reacted with an equimolar amount of various anilines in 1,4-dioxane solution at room temperature, the corresponding products were obtained in excellent yields, appropriate reaction times and high purity [33].
Scheme 2

Synthetic route of anilinolactones

To optimize the reaction 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).
Scheme 3

Screening of solvents and catalysts for the synthesis of 4i

The reaction was firstly carried out in the presence of p-toluenesulfonic acid (p-TSA) as an inexpensive and available catalyst in different polar and non-polar solvents, under reflux conditions. The results are summarized in Table 1.
Table 1

Screening of solvents for the synthesis of 4i

Entry

Solvent

Time (h)

Yield (%)a

1

MeOH

3

65

2

EtOH

3

68

3

DMF

3

55

4

CH3CN

3

60

5

Water

3

70

6

THF

3

<50

7

HOAc

3

73

8

Toluene

3

55

The reaction was carried out using 4-bromobenzaldehyde 1d, dimedone 2b and 4-(4-methylphenylamino)furan-2(3H)-one 3d, in the presence of p-TSA (20 mol%) and solvent (5 mL)

aIsolated yield of the pure compound

Upon screening of various solvents to find out the best choice, it was found that the reaction with water as solvent resulted in the most excellent yield and shortest reaction time. Therefore, water was applied as the appropriate solvent of this reaction (Table 1, entry 5).

Catalytic reaction for synthesis of tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-diones

Catalyst plays an important role in the formation of tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione derivatives. To compare the efficiency and effectiveness of the catalysts to improve the yield and to optimize the reaction conditions, the same reaction was carried out in refluxing water using different catalysts. The obtained results are outlined in Table 2.
Table 2

Diverse used catalyst in a model reaction

Entry

Catalyst

Time (h)

Yield (%)a

1

Alum

3

67

2

p-TSA

3

70

3

K-10

5

57

4

S.S.A

5

55

5

Nano MgO

5

<50

6

Nano CuFe2O4

3

93

7

Nano Fe3O4

3

75

8

Nano TiO2

3

55

9

Nano ZnO

5

<50

10

Nano SnO2

5

<50

Reaction conditions: 4-bromobenzaldehyde 1d, dimedon 2b and 4-(4-methylphenylamino)furan-2(3H)-one 3d, CuFe2O4 (5 mol%), H2O (5 mL), 90 °C

aIsolated yields

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 under reflux in water and gives by TLC analysis only trace of the product. Therefore, our efforts focused on the search for a suitable catalyst. A tremendous improvement was observed and the yield of this reaction was increased up to 93 % in the presence of CuFe2O4 nanoparticles with water as the selected solvent for the reaction. The desired product was obtained in excellent yield and high purity (entry 6, Table 2). The magnetic nature of the copper ferrite nanoparticles facilitates their easy and quantitative removal from the reaction medium in the presence of an external magnetic field for further uses.

Characterization of the catalyst

The synthesized CuFe2O4 was subjected to structural characterization with XRD, SEM, and VSM. The position and relative intensities of all peaks conform well with standard XRD pattern of CuFe2O4 (JCPDS card No. 34-0425) indicating characteristic of the tetragonal structure. The copper ferrite calcined at 800 °C presents a particle size of 35 nm, calculated from the broadening of the peak at 2θ = 35.31 using the Scherrer equation (Fig. 2). The SEM image shows that copper ferrite nanoparticles have a mean diameter of about 30–35 nm and a nearly spherical shape in Fig. 3. The magnetization curve for CuFe2O4 nanoparticles is shown in Fig. 4. It is of great importance that a catalyst should possess sufficient magnetic and super paramagnetic properties for its practical application. Magnetic hysteresis measurements on CuFe2O4 were conducted in an applied magnetic field at room temperature, with the field sweeping from −10,000 to +10,000 Oersted. As shown in Fig. 4, the hysteresis loop for the sample was completely reversible confirming its superparamagnetic nature. The catalyst showed high permeability in magnetization and high reversibility in the hysteresis loop (Fig. 4).
Fig. 2

The X-ray diffraction patterns of calcinated CuFe2O4

Fig. 3

The SEM image of nano CuFe2O4

Fig. 4

The vibrating sample magnetometer curve of synthesized CuFe2O4 nanoparticles

The next parameter needed to improve the reaction condition was the influence of the amount of the CuFe2O4 nanoparticles as catalyst. An increase in the quantity of CuFe2O4 nanoparticles from 2 to 5 mol% not only decreased the reaction time from 5 to 3 h but also increased the product yield from 80 to 93 %. This showed that the catalyst concentration plays an important role in the optimization of the product yield. Thus, using 5 mol% CuFe2O4 nanoparticles in water is sufficient and suitable choice to push this reaction forward. More amounts of the additive did not improve the yields of products (Table 3).
Table 3

Different amounts of the CuFe2O4 nanoparticles as catalyst in model reaction

Entry

CuFe2O4 nanoparticles (mol%)

Time (h)

Yield (%)a

1

1

6

55

2

2

5

80

3

5

3

93

4

10

3

94

Reaction conditions: 4-bromobenzaldehyde 1d, dimedone 2b and 4-(4-methylphenylamino)furan-2(3H)-one 3d, H2O (5 mL), 90 οC

aIsolated yields

The recovery and reuse of catalysts is highly preferable for a greener process. Finally, as shown in Fig. 5, the reusability of the catalyst was investigated using 4-bromobenzaldehyde 1d, dimedone 2b, and 4-(4-methylphenylamino)-furan-2(3H)-one 3d, as model substrates. It is important to highlight that the catalyst could be magnetically recovered by an external magnetic field and washed with acetone and EtOH. After being dried, it was subjected to another reaction. The procedure was repeated and the results indicated that the catalyst could be cycled four times without a significant loss of activity (Fig. 5).
Fig. 5

Recovery and reuse of CuFe2O4 nanoparticle in model reaction

Subsequently to verify the general procedure of reaction, various benzaldehydes possessing either electron-donating or withdrawing substituents, 1,3-cyclohexanediones and substituted anilinolactones were tested under these appropriate reaction conditions (5 mL of water, reflux, 5 mol% CuFe2O4 nanoparticles), and a series of 4-azapodophyllotoxin derivatives were synthesized. The results have been `summarized in Table 4.
Table 4

Synthesis of Tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione derivatives

Entry

R

R1

R2

Time (h)

Yield (%)a

Product

Lit. [53, 54, 55] Mp (°C)

Found Mp (°C)

1

4-Cl

H

CH3

2.5

93

Open image in new window

274–275

275–276

2

H

H

CH3

3

92

Open image in new window

280–281

281–282

3

4-OCH3

H

CH3

3

95

Open image in new window

254–255

255–257

4

4-Br

H

H

3

92

Open image in new window

280–281

281–282

5

4-CH3

H

CH3

2.5

90

Open image in new window

257–258

258–259

6

H

H

H

3

91

Open image in new window

275–276

276–277

7

4-Cl

H

Cl

2.5

92

Open image in new window

227–228

228–229

8

4-OCH3

CH3

CH3

3

96

Open image in new window

256–257

257–259

9

4-Br

CH3

CH3

3

93

Open image in new window

269–270

270–271

10

3-NO2

CH3

CH3

2

93

Open image in new window

232–233

232–233

11

4-Cl

CH3

H

2.5

93

Open image in new window

260–261

262–263

12

4-OCH3

CH3

H

3

94

Open image in new window

258–259

260–262

13

3-NO2

CH3

H

2

90

Open image in new window

293–294

294–295

14

4-Cl

CH3

Cl

2.5

93

Open image in new window

>300

>300

15

4-CH3

CH3

F

3

93

Open image in new window

281–283

282–283

16

4-Cl

CH3

F

2.5

91

Open image in new window

297–299

298–300

17

4-Br

CH3

F

2.5

90

Open image in new window

283–285

284–285

18

4-OCH3

CH3

F

3

94

Open image in new window

266–268

268–270

19

4-NO2

CH3

H

2

92

Open image in new window

–

296–298

20

3-Cl

CH3

CH3

2.5

91

Open image in new window

–

268–270

21

4-CH3

CH3

Br

2.5

90

Open image in new window

–

288–290

22

3-NO2

CH3

OCH3

2

95

Open image in new window

–

>300

23

3-NO2

CH3

Br

2

91

Open image in new window

–

>300

24

4-NO2

CH3

Br

2

93

Open image in new window

–

>300

Reaction conditions: 1(a–h) (1 mmol), 2(a–b) (1 mmol), 3(a–f) (1 mmol), CuFe2O4 (5 mol%), H2O (5 mL), 90 °C, reaction times (2–3 h)

aIsolated yields

Herein, the comparison of our work with the previously reported methods [53, 54, 55] has been done (Table 5). As can be seen in this Table, compared to alternative reports for the synthesis of 4 h, in the present method, water as a unique solvent, environmentally accepted, safest, and most abundant solvent was employed as the reaction media. In addition, in this research for the preparation of these molecules, nano CuFe2O4 was used as the heterogeneous catalyst that easily separated from the reaction via an external magnet. The advantages of this catalyst are such as; the easy synthesis, recoverability, reusability, non-toxicity, and inexpensive.
Table 5

Comparing reported methods with our work for the synthesis of 4h

Entry

Solvent

Catalyst

Conditions

Yield (%)a

References

1

HOAc

–

MW

97

[54, 55]

2

EtOH

l-Proline (10 mol%)

Reflux

96

[53]

3

H2O

Nano CuFe2O4 (5 mol%)

Reflux

96

–

aIsolated yields

Also, this methodology is very simple and without any usage of specific instrument such as microwave. Furthermore, this is the first report for the synthesis of azapodophyllotoxines using anilinolactones as an efficient enaminone. Anilinolactones and associated compounds possessing this structural unit are versatile synthetic intermediates in organic chemistry that combine the ambient nucleophilicity of enamine and the electrophilicity of enones. To the best of our knowledge, there are very limited examples of heterocyclic compounds synthesized from anilinolactones.

We have not established an exact mechanism for the formation of tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione derivatives, however, a reasonable possibility is shown in Scheme 4. In a first step, the carbonyl group benzaldehyde is activated by nano CuFe2O4. Then, reaction between 1 and 1,3-cyclohexanedione 2 gives intermediate 5. This step was regarded as a fast Knoevenagel condensation. Then, 5 is attacked via Michael addition of anilinolactone 3 to give the reactive intermediate 6. Followed intra-molecular cyclization occured in the presence of nano CuFe2O4, and the corresponding products were obtained. CuFe2O4 nanocatalyst as Lewis acid plays an important role in increasing the electrophilic character of the starting materials and activating the intermediate by the coordination of oxygen lone electron pairs with metal ions in CuFe2O4.
Scheme 4

Proposed mechanism

Conclusions

In this research, tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione derivatives have been synthesized via a simple multicomponent condensation of various benzaldehydes, 1,3-cyclohexanediones and anilinolactones in the presence of easy synthesized heterogeneous nano CuFe2O4 as an efficient, magnetically recoverable, commercially available, and powerful nanocatalyst in water as a unique, the most environmentally accepted, green, and abundant solvent. The operational simplicity of this method makes it more attractive for preparative applications.

Notes

Acknowledgments

This study is part of Zahra Rashid Ph.D. thesis entitled: “Synthesis, modification and functionalization of magnetic nanoparticles for catalytic application in the synthesis of heterocyclic compounds and biomedical applications” which has been conducted in the Nanobiotechnology Research Center, Avicenna Research Institute. Also, we are thankful from University of Kashan for supporting this work by Grant Number 159148/11, and also gratefully acknowledge financial support from the Avicenna Research Institute.

Supplementary material

13738_2014_422_MOESM1_ESM.doc (858 kb)
Supplementary material 1 (DOC 858 kb)

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Copyright information

© The Author(s) 2014

Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

Authors and Affiliations

  • Ramin Ghahremanzadeh
    • 1
  • Zahra Rashid
    • 2
  • Amir-Hassan Zarnani
    • 3
  • Hossein Naeimi
    • 2
  1. 1.Nanobiotechnology Research Center, Avicenna Research Institute(ACECR)TehranIslamic Republic of Iran
  2. 2.Department of Organic Chemistry, Faculty of ChemistryUniversity of KashanKashanIslamic Republic of Iran
  3. 3.Reproductive Immunology Research Center, Avicenna Research Institute(ACECR)TehranIslamic Republic of Iran

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