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

Article abstract of DOI:10.1007/s13738-014-0422-x

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: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s13738-014-0422-x

J IRAN CHEM SOC
DOI 10.1007/s13738-014-0422-x
ORIGINAL PAPER
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
Received: 4 April 2013 / Accepted: 3 January 2014
Ó The Author(s) 2014. This article is published with open access at Springerlink.com
Abstract A facile and efficient procedure has been
reported for the synthesis of tetrahydrofuro[3,4-b]quino-
line-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.
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 [3–5].
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 abun-
dance, and cheap compared to organic solvents. The use of
water as solvent in organic reactions is one of the current
focuses today [8–10].
Keywords Multicomponent reactions Á Water Á Magnetic
nanoparticles Á Azapodophyllotoxin Á Tetronic acid
Introduction
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
[12–16], insecticidal [17], anticoagulant [18–20], antiepi-
leptic [21], analgesic [22] and anti-inflammatory activities
[23]. Podophyllotoxin (Fig. 1) is a non-alkaloid toxin lig-
nan extracted from the roots and rhizomes of Podophyllum
species [24] that inhibits microtubule assembly [25–27].
Although Podophyllotoxin and its derivatives have a long
and fascinating history biological properties such as, pur-
gative, antiviral, antihelminthic and antitumor [28, 29], but
because of mostly unsuccessful attempts to use it for the
treatment of human neoplasia, extensive structural modi-
fications have been performed to obtain more potent and
less toxic anticancer agents [30–32]. Among them, deriv-
atives 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
Multicomponent reactions (MCRs) have emerged as a
versatile approach in organic synthesis for the construction
of complex structures from simple building blocks, due to
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-014-0422-x) contains supplementary
material, which is available to authorized users.
R. Ghahremanzadeh
Nanobiotechnology Research Center, Avicenna Research
Institute, (ACECR), Tehran, Islamic Republic of Iran
Z. Rashid Á H. Naeimi (&)
Department of Organic Chemistry, Faculty of Chemistry,
University of Kashan, 87317 Kashan, Islamic Republic of Iran
e-mail: naeimi@kashanu.ac.ir
A.-H. Zarnani
Reproductive Immunology Research Center, Avicenna Research
Institute, (ACECR), Tehran, Islamic Republic of Iran
123

J IRAN CHEM SOC
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).
H
N
OH
H
O
O
O
O
O
O
H
O
O
Typical experimental procedure for the preparation
of magnetic nanocatalyst
H3CO
OCH3
H3CO
OCH3
OCH3
OCH3
CuFe2O4 nanoparticles were prepared by co-precipitation
of Cu(NO3)2 and Fe(NO3)3 in water in the presence of
Fig. 1 Structure of podophyllotoxin and 4-azapodophyllotoxin
sodium hydroxide. Briefly, to
Fe(NO3)3Á9H2O (0.05 mol) and
a
solution of
Cu(NO3)2Á3H2O
different from that of the parent natural podophyllotoxin
[33–36].
(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 separa-
tor. 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].
Magnetic nanoparticles are a class of nanostructured
materials of current interest, due to their numerous appli-
cations, such as magnetic resonance imaging [37], drug
delivery [38, 39], biomolecular sensors [40, 41], biosepa-
ration [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 magne-
tization with a permanent magnetic field [48–51].
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-cyclohexan-
ediones and anilinolactones in the presence of CuFe2O4
nanoparticles as magnetically recyclable catalyst in water
media.
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.
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 appara-
tus. IR spectra were recorded as KBr pellets on a Perkin-
Elmer 781 spectrophotometer and an Impact 400 Nicolet
9-(4-Methoxyphenyl)-4-p-tolyl-5,6,7,9-tetrahydrofuro[3,4-
1
FT-IR spectrophotometer. H NMR and 13C NMR spectra
b]quinoline-1,8(3H,4H)-dione(4c)
were recorded in d6-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
Yield 95 %; mp: 255–257 °C; 1H NMR (DMSO-d6): d
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.
123

J IRAN CHEM SOC
9-(4-Methoxyphenyl)-6,6-dimethyl-4-p-tolyl-5,6,7,9-
9-(4-Bromophenyl)-4-(4-fluorophenyl)-6,6-dimethyl-
5,6,7,9-tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione
(4q)
tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione(4h)
1
Yield 96 %; mp: 257 °C; H NMR (DMSO-d6): d 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.
Yield 90 %; mp: 284–285 °C; 1H NMR (DMSO-d6): d
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)
9-(4-Methoxyphenyl)-6,6-dimethyl-4-phenyl-5,6,7,9-
tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione (4l)
1
Yield 94 %; mp: 260 °C; H NMR (DMSO-d6): d 0.84
1
Yield 94 %; mp: 268 °C; H NMR (DMSO-d6): d 0.88
(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.
(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.
4,9-bis(4-Chlorophenyl)-6,6-dimethyl-5,6,7,9-
6,6-Dimethyl-9-(4-nitrophenyl)-4-phenyl-5,6,7,9-
tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione (4n)
tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione (4s)
1
Yield 93 %; mp: [300 °C; H NMR (DMSO-d6): d 0.83
Yield 92 %; mp: 296–298 °C; 1H NMR (DMSO-d6): d
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-d6, 100 MHz): d: 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.
(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)
9-(3-Chlorophenyl)-6,6-dimethyl-4-p-tolyl-5,6,7,9-
Yield 93 %; mp: 282–283 °C; 1H NMR (DMSO-d6): d
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.
tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione (4t)
Yield 91 %; mp: 268–270 °C; 1H NMR (DMSO-d6): d
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-d6, 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.
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-d6): d
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.
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-d6): d
0.82 (3H, s, CH3),0.90 (3H, s, CH3), 2.02–2.06 (2H, m,
123

J IRAN CHEM SOC
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-d6, 100 MHz): d: 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.
through a three-component condensation reaction in the
presence of CuFe2O4 nanoparticles as magnetically recy-
clable catalyst in water (Scheme 1). In this reaction, the
tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione deriva-
tives were obtained as pure products in high yields.
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].
4-(4-Methoxyphenyl)-6,6-dimethyl-9-(3-
nitrophenyl)furo[3,4-b]quinoline-1,8(3H,4H)-dione (4v)
1
Yield 95 %; mp: [300 °C; H NMR (DMSO-d6): d 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-d6, 100 MHz): d: 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.
To optimize the reaction conditions for the synthesis of
tetrahydrofuro[3,4 b]quinoline-1,8(3H,4H)-dione deriva-
tives, 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).
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.
4-(4-Bromophenyl)-6,7-dihydro-6,6-dimethyl-9-(3-
nitrophenyl)furo[3,4-b]quinoline- 1,8(3H,4H)-dione (4w)
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 sol-
vent of this reaction (Table 1, entry 5).
1
Yield 91 %; mp: [300 °C; H NMR (DMSO-d6): d 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-
d6, 100 MHz): d: 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.
Catalytic reaction for synthesis of tetrahydrofuro[3,4-
b]quinoline-1,8(3H,4H)-diones
Catalyst plays an important role in the formation of tetra-
hydrofuro[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 condi-
tions, the same reaction was carried out in refluxing water
using different catalysts. The obtained results are outlined
in Table 2.
4-(4-bromophenyl)-6,7-dihydro-6,6-dimethyl-9-(4-
nitrophenyl)furo[3,4-b]quinoline-1,8(3H,4H)-dione (4x)
1
Yield 93 %; mp: [300 °C; H NMR (DMSO-d6): d 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-
d6, 100 MHz): d: 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.
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 tremen-
dous 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 facil-
itates their easy and quantitative removal from the reac-
tion medium in the presence of an external magnetic field
for further uses.
Results and discussion
In this research, benzaldehydes, 1, 1,3-cyclohexanediones
2 and anilinolactones 3 with initial moles were reacted
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J IRAN CHEM SOC
Scheme 1 The reaction leading to the synthesis of tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)dione derivatives 4a-x
Br
O
H2N
O
O
O
O
H
O
+
O
O
N
1,4-dioxane
H3C
H
CH3
+
O
r.t.
H3C
O
+
O
HN
N
Br
O
O
CH3
R2
1d
2b
3d
4i
R2
CH3
CH3
Scheme 2 Synthetic route of anilinolactones
Scheme 3 Screening of solvents and catalysts for the synthesis of 4i
Table 1 Screening of solvents for the synthesis of 4i
Table 2 Diverse used catalyst in a model reaction
Entry
Solvent
Time (h)
Yield (%)a
Entry
Catalyst
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
MeOH
EtOH
3
3
3
3
3
3
3
3
65
68
1
2
3
4
5
6
7
8
9
10
Alum
3
3
5
5
5
3
3
3
5
5
67
70
p-TSA
DMF
55
K-10
57
CH3CN
Water
THF
60
S.S.A
55
70
Nano MgO
Nano CuFe2O4
Nano Fe3O4
Nano TiO2
Nano ZnO
Nano SnO2
\50
93
\50
73
HOAc
Toluene
75
55
55
The reaction was carried out using 4-bromobenzaldehyde 1d, dime-
done 2b and 4-(4-methylphenylamino)furan-2(3H)-one 3d, in the
presence of p-TSA (20 mol%) and solvent (5 mL)
\50
\50
a
Reaction conditions: 4-bromobenzaldehyde 1d, dimedon 2b and 4-(4-
methylphenylamino)furan-2(3H)-one 3d, CuFe2O4 (5 mol%), H2O
(5 mL), 90 °C
Isolated yield of the pure compound
a
Characterization of the catalyst
Isolated yields
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 struc-
ture. The copper ferrite calcined at 800 °C presents a
particle size of 35 nm, calculated from the broadening of
the peak at 2h = 35.31 using the Scherrer equation
(Fig. 2). The SEM image shows that copper ferrite nano-
particles have a mean diameter of about 30–35 nm and a
nearly spherical shape in Fig. 3. The magnetization curve
123

J IRAN CHEM SOC
Fig. 2 The X-ray diffraction patterns of calcinated CuFe2O4
Table 3 Different amounts of the CuFe2O4 nanoparticles as catalyst
in model reaction
Entry
CuFe2O4 nanoparticles (mol%)
Time (h)
Yield (%)a
1
2
3
4
1
2
6
5
3
3
55
80
93
94
5
10
Reaction conditions: 4-bromobenzaldehyde 1d, dimedone 2b and
4-(4-methylphenylamino)furan-2(3H)-one 3d, H2O (5 mL), 90 oC
a
Isolated yields
Fig. 3 The SEM image of nano CuFe2O4
40
30
20
10
0
Fig. 5 Recovery and reuse of CuFe2O4 nanoparticle in model
reaction
-10
-20
-30
-40
for CuFe2O4 nanoparticles is shown in Fig. 4. It is of great
importance that a catalyst should possess sufficient mag-
netic 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
-10000 -8000 -6000 -4000 -2000
0
2000 4000 6000 8000 10000
Applied Field(Oe)
Fig. 4 The vibrating sample magnetometer curve of synthesized
CuFe2O4 nanoparticles
123

J IRAN CHEM SOC
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. [53–55] Mp
(°C)
Found Mp
(°C)
1
4-Cl
H
CH3
2.5
93
274–275
275–276
Cl
O
O
H
H
O
N
CH3
4a
2
H
H
CH3
3
92
280–281
281–282
O
O
H
H
O
N
CH3
4b
OCH3
3
4-OCH3
H
CH3
3
95
254–255
255–257
O
O
H
H
O
N
CH3
Br
4c
4
4-Br
H
H
3
92
280–281
281–282
O
O
H
H
O
N
4d
CH3
5
4-CH3
H
CH3
2.5
90
257–258
258–259
O
O
H
H
O
N
CH3
4e
6
H
H
H
3
91
275–276
276–277
O
O
H
H
O
N
4f
123

J IRAN CHEM SOC
Table 4 continued
Entry
R
R1
H
R2
Cl
Time
(h)
Yield
(%)a
Product
Lit. [53–55] Mp
(°C)
Found Mp
(°C)
7
4-Cl
2.5
92
Cl
227–228
228–229
O
O
H
H
O
N
Cl
4g
8
4-OCH3
CH3
CH3
3
96
OCH3
256–257
257–259
O
O
O
H3C
N
CH3
CH3
Br
4h
9
4-Br
CH3
CH3
3
93
269–270
270–271
O
O
O
H3C
N
CH3
CH3
4i
10
3-NO2
CH3
CH3
2
93
232–233
232–233
NO2
O
O
O
H3C
N
CH3
CH3
Cl
4j
11
4-Cl
CH3
H
2.5
93
260–261
262–263
O
O
O
H3C
N
CH3
4k
123

J IRAN CHEM SOC
Table 4 continued
Entry
R
R1
R2
H
Time
(h)
Yield
(%)a
Product
Lit. [53–55] Mp
(°C)
Found Mp
(°C)
12
4-OCH3
CH3
3
94
258–259
260–262
OCH3
O
O
H3C
O
N
CH3
4l
13
3-NO2
CH3
H
2
90
NO2
293–294
294–295
O
O
O
H3C
N
CH3
4m
14
4-Cl
CH3
Cl
2.5
93
Cl
[300
[300
O
O
O
H3C
N
CH3
Cl
4n
4o
4p
15
4-CH3
CH3
F
3
93
CH3
281–283
282–283
O
O
O
H3C
N
CH3
F
16
4-Cl
CH3
F
2.5
91
Cl
297–299
298–300
O
O
O
H3C
N
F
CH3
123

J IRAN CHEM SOC
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. [53–55] Mp
(°C)
Found Mp
(°C)
17
4-Br
CH3
F
2.5
90
94
92
Br
N
283–285
284–285
268–270
296–298
O
O
H3C
O
CH3
F
4q
18
4-OCH3
CH3
F
3
OCH3
266–268
O
O
H3C
O
N
F
CH3
4r
19
4-NO2
CH3
H
2
–
NO2
O
O
O
H3C
N
CH3
4s
20
3-Cl
CH3
CH3
2.5
91
–
268–270
Cl
O
O
O
H3C
N
CH3
CH3
Cl
4t
21
4-CH3
CH3
Br
2.5
90
–
288–290
O
O
O
H3C
N
CH3
Br
4u
123

J IRAN CHEM SOC
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. [53–55] Mp
(°C)
Found Mp
(°C)
22
3-NO2
CH3
OCH3
2
95
–
[300
NO2
O
O
O
H3C
N
CH3
OCH3
NO2
4v
23
3-NO2
CH3
Br
2
91
–
[300
O
O
H3C
O
N
CH3
Br
4w
24
4-NO2
CH3
Br
2
93
–
[300
NO2
O
O
H3C
O
N
CH3
Br
4x
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)
a
Isolated yields
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).
4-bromobenzaldehyde 1d, dimedone 2b, and 4-(4-methyl-
phenylamino)-furan-2(3H)-one 3d, as model substrates. It
is important to highlight that the catalyst could be mag-
netically 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).
Subsequently to verify the general procedure of reac-
tion, various benzaldehydes possessing either electron-
donating or withdrawing substituents, 1,3-cyclohexanedi-
ones 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.
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 opti-
mization 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).
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
Herein, the comparison of our work with the previously
reported methods [53–55] has been done (Table 5). As can be
seen in this Table, compared to alternative reports for the
123

J IRAN CHEM SOC
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 conden-
sation. Then, 5 is attacked via Michael addition of anili-
nolactone 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 coordina-
tion of oxygen lone electron pairs with metal ions in
CuFe2O4.
Table 5 Comparing reported methods with our work for the syn-
thesis of 4h
Entry Solvent Catalyst
Conditions Yield References
(%)a
1
2
HOAc
EtOH
–
MW
97
96
[54, 55]
[53]
L-Proline
(10 mol%)
Reflux
3
H2O
Nano CuFe2O4 Reflux
(5 mol%)
96
–
a
Isolated yields
synthesis of 4h, in the present method, water as a unique sol-
vent, environmentally accepted, safest, and most abundant
solventwas 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.
Conclusions
Also, this methodology is very simple and without any
usage of specific instrument such as microwave. Further-
more, this is the first report for the synthesis of azapodo-
phyllotoxines using anilinolactones as an efficient
enaminone. Anilinolactones and associated compounds
possessing this structural unit are versatile synthetic inter-
mediates in organic chemistry that combine the ambient
nucleophilicity of enamine and the electrophilicity of
enones. To the best of our knowledge, there are very lim-
ited examples of heterocyclic compounds synthesized from
anilinolactones.
In
this
research,
tetrahydrofuro[3,4-b]quinoline-
1,8(3H,4H)-dione derivatives have been synthesized via a
simple multicomponent condensation of various benzal-
dehydes, 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.
Scheme 4 Proposed
mechanism
123

J IRAN CHEM SOC
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 sup-
porting this work by Grant Number 159148/11, and also gratefully
acknowledge financial support from the Avicenna Research Institute.
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