Facile synthesis of tetrahydrobenzoxanthenones via a one-pot three-component reaction using an eco-friendly and magnetized biopolymer chitosan-based heterogeneous nanocatalyst

Article abstract of DOI:10.1002/aoc.3524

A chitosan-based magnetic nanocomposite was synthesized by an eco-friendly and simple procedure, and was characterized using scanning electron microscopy, energy-dispersive X-ray spectroscopy, X-ray diffraction and Fourier transform infrared spectroscopy.

Full text of DOI:10.1002/aoc.3524

Full paper
Received: 23 April 2016
Accepted: 1 May 2016
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/aoc.3524
Facile synthesis of tetrahydrobenzoxanthenones
via a one-pot three-component reaction using
an eco-friendly and magnetized biopolymer
chitosan-based heterogeneous
nanocatalyst
Ali Maleki*, Morteza Aghaei and Nakisa Ghamari
A chitosan-based magnetic nanocomposite was synthesized by an eco-friendly and simple procedure, and was characterized using
scanning electron microscopy, energy-dispersive X-ray spectroscopy, X-ray diffraction and Fourier transform infrared spectros-
copy. It was then used for the efficient synthesis of tetrahydrobenzoxanthen-11-one derivatives via a one-pot three-component
condensation of 2-naphthol, various aldehydes and dimedone in ethanol. The catalyst was recovered easily and reused several
times without significant loss of catalytic activity. Copyright © 2016 John Wiley & Sons, Ltd.
Additional supporting information may be found in the online version of this article at the publisher’s web site.
Keywords: magnetic nanoparticles; chitosan nanocomposite; tetrahydrobenzoxanthenones; multicomponent reaction; green synthesis
best reported approaches for the
tetrahydrobenzo[a]xanthene-11-ones is the one-pot MCR of 2-
preparation
of
Introduction
Chitosan as a natural, abundant and inexpensive biopolymer is
applied widely in several industrial and manufacturing processes
including wastewater treatment, pharmaceutical, medical and food
naphthol, aryl aldehydes and 5,5-dimethyl-1,3-cyclohexanedione
[
14]
(dimedone) using various catalysts such as sulfamic acid,
[
15]
NaHSO /ionic liquid ([bmim]BF ),
dodecatungstophosphoric
and p-toluenesulfonic acid/ionic
Most of those methods suffer from some
4
[16]
4
[1,2]
[17]
[18]
processes, agriculture and textile industries. It has not only been
extensively used as a catalyst for some reactions, but also been
used as a support for the preparation of heterogeneous catalysts.
The insertion of metals such as iron into the chitosan polymer ma-
trix may improve its capacity of interaction by complexation.
Chitosan-based composites are increasingly important as biochem-
acid,
iodine,
InCl /P O
3 2 5
[
19]
liquid ([bmim]BF4).
disadvantages such as harsh reaction conditions, tedious
workup procedures, expensive or toxic chemicals, stoichiomet-
ric amounts of catalysts, long reaction times and low yields.
Thus, it is still desirable to develop an efficient and convenient
method in terms of operational simplicity and economic viabil-
ity for the synthesis of tetrahydrobenzo[a]xanthen-11-one
derivatives.
[
3]
ical, antimicrobial and catalytic reagents.
Multicomponent reactions (MCRs) as an important organic
synthesis approach are one-pot processes in which three or
more accessible components react to form a single product that
incorporates essentially most or all atoms of the starting
In connection with our recent research on new catalytic proto-
[
31–39]
cols for MCRs,
herein, we report a highly efficient procedure
[4]
materials. MCR strategies have marked advantages over con-
ventional bimolecular reactions owing to their convergence,
atom-economy, operational simplicity, structural diversity and
for the preparation of 12-aryl-8,9,10,12-tetrahydro-11H-benzo[a]
xanthen-11-one derivatives (4) via a one-pot three-component
reaction of 2-naphthol (1), various aldehydes (2) and dimedone
(3) in the presence of Fe O @chitosan as a recyclable
3 4
superparamagnetic composite nanocatalyst under mild reaction
conditions (Scheme 1).
[
5]
shortness of synthetic pathway. MCRs have recently gained a
new dimension in the field of designing methods to produce
[
6]
elaborate libraries of biologically active compounds and new
molecular frameworks for potential drugs with diverse pharma-
[7]
cological activities.
Xanthenes, benzoxanthenes and benzoxanthenones are impor-
[
8]
tant bioactive heterocyclic compounds that possess analgesic,
* Correspondence to: Ali Maleki, Catalysts and Organic Synthesis Research
Laboratory, Department of Chemistry, Iran University of Science and
Technology, Tehran 16846-13114, Iran. Email: maleki@iust.ac.ir
[9]
[10]
[11]
antiviral, antibacterial,
and anti-inflammatory activities.
They are also potent nonpeptidic inhibitors of recombinant human
[
12]
[13]
calpain I, and CCR1 receptor antagonists. Therefore, a few syn-
Catalysts and Organic Synthesis Research Laboratory, Department of Chemistry,
Iran University of Science and Technology, Tehran 16846-13114, Iran
[
14–30]
thetic methods have been introduced for them.
One of the
Appl. Organometal. Chem. (2016)
Copyright © 2016 John Wiley & Sons, Ltd.

Maleki A., Aghaei M. and Ghamari N.
only trace amounts of product were detected after 15 h (Table 1,
entry 1). The obtained results showed that the reaction using 30
mg of the catalyst at 40°C proceeded in the highest yield (Table 1,
entry 4). Using greater amounts of Fe O @chitosan nanocomposite
3 4
did not improve the reaction yields and lower amounts of the cat-
alyst gave lower yields.
Then, the model reaction was examined using various solvents
(Table 2). The reaction yield was moderate under solvent-free
conditions after (entry 1). In CH CN, toluene and
4
h
3
dimethylformamide (DMF) low yields were afforded (entries 2–4).
In water, only a trace amount of the product was detected (entry
Scheme 1. One-pot synthesis of tetrahydrobenzoxanthen-11-ones 4a–k.
5). When EtOH was used, the yield of the reaction was increased
Results and discussion
up to 90% in shorter reaction time (entry 6).
The effect of temperature on the model reaction was also
investigated in the presence of the optimized amount of
Fe O @chitosan nanocatalyst in EtOH. It was found that the best
The Fe
using a sol–gel method.
electron microscopy (SEM). As shown in Fig. 1, the particle size
was studied using SEM and the identification of Fe @chitosan
morphology was based on the analysis of SEM images. The ob-
tained SEM images of nanoparticles clearly showed that Fe
nanoparticles were properly supported on chitosan.
To optimize the reaction parameters, initially a model reaction
was studied in the presence of various amounts of Fe @chitosan
3 4
O @chitosan composite nanocatalyst was first prepared
[
38–40]
It was characterized using scanning
3
4
yield of the reaction was obtained at 40°C. The yield of the reaction
at room temperature was 75% after 8 h. While at 80°C, the isolated
yield of the same reaction was 91%. So, it was not so much greater
than the 90% yield that was obtained at 40°C.
To generalize the suitability of the protocol, the reaction was
extended to various substituted aromatic aldehydes (Table 3). The
reactions proceeded smoothly with excellent yields (75–93%)
for substituted aldehydes with both electron-withdrawing
and electron-donating groups. Aldehydes bearing electron-
3 4
O
3 4
O
3 4
O
composite nanocatalyst (Table 1). The activity of the catalyst was
tested in a one-pot three-component condensation of 1 (1 mmol),
3
(1 mmol) and 4-chlorobenzaldehyde (1 mmol) as a model reac-
tion with stirring at 40°C in EtOH. Without the addition of catalyst,
a
Table 2. Optimization of solvent
b
Entry
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
Neat
4
9
62
43
3
CH CN
Toluene
DMF
12
5
10
50
2
H O
5
Trace
90
EtOH
3
a
Reaction conditions: 1 (1 mmol), 4-chlorobenzaldehyde (1 mmol), 3 (1
@chitosan (30 mg), 40°C.
Isolated yield.
3 4
mmol), Fe O
b
Table 3. Fe
3 4
O @chitosan-catalysed three-component reaction for the
a
preparation of tetrahydrobenzo[a]xanthen-11-one derivatives 4a–k
b
Entry
R
Product
Time (h)
Yield (%)
Figure 1. SEM image of Fe
3 4
O
@chitosan composite nanocatalyst.
1
4-ClC
2-ClC
2,4-(Cl)
4-BrC6H4
4-FC
4-NO
3-NO
4-OMeC
4-OHC
2-HOC
4-N,N′-(CH
6
H
4
4a
4b
4c
4d
4e
4f
3
90
86
90
80
85
92
93
75
79
77
85
2
6 4
H
2
3
2
C
6
H
3
3
a
Table 1. Optimization of amount of catalyst
4
4
b
5
6
H
4
4
Entry
Catalyst (mg)
Time (h)
Yield (%)
6
2
6
C H
4
2
1
2
3
4
5
0
10
20
30
40
15
10
6
20
25
50
90
90
7
2
6
C H
4
4g
4h
4i
2.5
3.5
5
8
6 4
H
9
6 4
H
3
10
11
6
H
4
4j
3
3
3 2
)
C
6
H
4
4k
5
a
a
Reaction conditions: 1 (1 mmol), 4-chlorobenzaldehyde 2 (1 mmol), 3 (1
@chitosan, EtOH (2 ml).
Isolated yield.
Reaction conditions:
@chitosan (30 mg), 40°C, EtOH (2 ml).
Isolated yield.
1
(1 mmol),
2
(1 mmol), 3 (1 mmol),
mmol), Fe
b
3 4
O
3 4
Fe O
b
wileyonlinelibrary.com/journal/aoc
Copyright © 2016 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. (2016)

Synthesis and performance of a new magnetic bionanocomposite
Experimental
General
All solvents, chemicals and reagents were purchased from Merck,
Fluka or Aldrich. Melting points were measured with an Electrother-
mal 9100 apparatus and are uncorrected. Infrared (IR) spectra were
recorded with a Shimadzu IR-470 spectrometer. Mass spectra were
recorded with a Finnigan-MAT 8430 mass spectrometer operating
1
13
at an ionization potential of 70 eV. The H NMR and C NMR spec-
tra were recorded with a Bruker DRX-300 Avance spectrometer at
300 and 75 MHz, respectively. The magnetic property of the
nanocatalyst was measured on VSM-AGFM (Meghnatis Daghigh
Kavir Co., Iran) vibrating sample magnetometer at room tempera-
ture. Some reactions and products were confirmed by a gas
chromatography manufactured by Teif Gostar Faraz Co., Iran. SEM
images were obtained with a Seron AIS 2100. Elemental analyses
were performed with a VarioEL (Elementar Analysensysteme
GmbH).
Figure 2. Reusability of the nanocatalyst in the synthesis of 4a.
All products were identified by comparison of their spectroscopic
and analytical data with those of authentic samples.
Preparation of Fe O @chitosan nanocomposite
3
4
First, 1 g of chitosan powder was added into 100 ml of 0.1 M acetic
acid and the mixture was stirred to form a 1% (w/v) clear chitosan
solution. Then, the homogeneous solution was filtered through a
synthetic cloth to remove any undissolved materials and degassed
by keeping the solution in a vacuum oven for 3 h to remove the
trapped air bubbles. After that, 2 ml of glycolic acid and calculated
3 4
amount of Fe O nanoparticles (black powder, average particle
size 30 nm (transmission electron microscopy), purity 99% and
Scheme 2. A proposed mechanism for the synthesis of 4a–k.
2
À1
specific surface area 55 m g ) were dispersed in the chitosan
solution by stirring at room temperature followed by sonication
for 1 h. The resulting solution was stirred overnight at room
temperature. After that, the resulting gel was separated from
the reaction mixture using a permanent magnet, washed several
times with EtOH and dried on a ceramic plate at room tempera-
ture during 48 h to afford the chitosan-supported magnetite
nanoparticles.
withdrawing groups gave tetrahydrobenzo[a]xanthen-11-ones 4f
and 4g in higher yields than the corresponding electron-donating
ones (giving products 4h–k).
We also studied the catalytic activity of the recycled catalyst for
3 4
the synthesis of 4a. As shown in Fig. 2, Fe O @chitosan was simply
recovered from the reaction mixture, and reused in subsequent
reactions at least five times without significant decrease in its
catalytic activity.
General procedure for synthesis of benzoxanthenones
A
possible mechanism of the synthesis of 8,9,10,12-
A mixture of 2-naphthol (1 mmol), aldehyde (1 mmol), dimedone (1
tetrahydrobenzo[a]xanthen-11-ones 4a–k is shown in Scheme 2.
It can be supposed that the reaction may proceed via the
o-quinone methide intermediate 5, which is formed by the nucleo-
philic addition of 1 to 2 catalysed by Fe O @chitosan. Subsequent
Michael addition reaction of 3 with 5′ gives the intermediate 6.
Then, an intramolecular condensation reaction of 6′ affords the
products 4a–k.
3 4
mmol) and Fe O @chitosan (30 mg) in EtOH (2 ml) was stirred at
40°C in a screw-cap vial in an oil bath for the appropriate time, as
indicated in Table 3. After completion of the reaction, the catalyst
was separated magnetically from the reaction mixture, washed
with ethanol and used for subsequent reactions after drying. Pure
benzoxanthenones were afforded by evaporation of the solvent,
followed by recrystallization from EtOH.
3
4
Spectral Data for 12-(4-Chlorophenyl)-9,9-dimethyl-8,9,10,12-
tetrahydrobenzo[a]xanthen-11-one (4a)
Conclusions
À1
In summary, we have described an efficient and mild protocol for
the preparation of 8,9,10,12-tetrahydrobenzo[a]xanthen-11-ones
from the reaction of 2-naphthol, various aldehydes and dimedone.
The promising points for the presented protocol are efficiency,
generality, high yields, clean reaction profile, reusability of the
nanocatalyst and simplicity, which make it a useful and attractive
process for the synthesis of chemically and biologically important
benzoxanthenone derivatives.
White solid; m.p. 190–193°C. IR (KBr, ν, cm ): 3060, 2961, 1605,
1
1515, 1370, 1207, 1158, 1029. H NMR (300 MHz, CDCl
3
, δ, ppm):
7.91 (d, J = 8.1 Hz, 1H), 7.78 (d, J = 6.3 Hz, 1H), 7.76 (d, J = 8.1 Hz,
1H), 7.38–7.42 (m, 1H), 7.33–7.36 (m, 1H), 7.20 (d, J = 8.1 Hz, 1H),
7.18 (s, 2H), 7.14 (d, J = 8.2 Hz, 2H), 4.50 (s, 1H), 2.34 (s, 2H), 2.25 (s,
2H), 2.20 (d, J = 16.1 Hz, 1H), 2.17 (d, J = 16.1 Hz, 1H), 1.08 (s, 3H),
0.97 (s, 3H). C NMR (75 MHz, CDCl , δ, ppm): 194.4, 164.5, 143.4,
3
142.5, 133.7, 132.4, 131.1, 129.4, 128.9, 128.6, 127.3, 125.7, 123.2,
13
Appl. Organometal. Chem. (2016)
Copyright © 2016 John Wiley & Sons, Ltd. wileyonlinelibrary.com/journal/aoc

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Supporting information
1
Additional supporting information may be found in the online ver-
sion of this article at the publisher’s web site.
2
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Appl. Organometal. Chem. (2016)