Fe3O4@SiO2-imid-PMAn magnetic porous nanosphere as recyclable catalyst for the green synthesis of quinoxaline derivatives at room temperature and study of their antifungal activities

Article abstract of DOI:10.1016/j.materresbull.2015.10.002

An efficient, simple, and green procedure for the synthesis of quinoxaline derivatives catalyzed by Fe₃O₄@SiO₂-imid-PMAⁿ nanoparticles at room temperature is described. This environmentally benign method provides several advantages such as mild reaction conditions, good to excellent yields, short reaction times, simple work-up and catalyst stability, easy preparation, heterogeneous nature and easy separation of the catalyst. Also, nanocatalyst can be easily recovered by a magnetic field and reused for the next reactions for at least 6 times without distinct deterioration in catalytic activity. SEM, BET, DLS and leaching of catalyst after each reaction cycle were investigated. Furthermore, antifungal activity of various derivatives against three phytopathogenic fungi (Alternaria alternata, Pyricularia oryzae, and Alternaria brassicae) was investigated.

Full text of DOI:10.1016/j.materresbull.2015.10.002

Accepted Manuscript
Title: Fe3O4@SiO2–imid–PMAn magnetic porous nanosphere
as recyclable catalyst for the green synthesis of quinoxaline
derivatives at room temperature and study of their antifungal
activities
Author: Jaber Javidi Mohsen Esmaeilpour
PII:
S0025-5408(15)30136-7
DOI:
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http://dx.doi.org/doi:10.1016/j.materresbull.2015.10.002
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1-9-2015
1-10-2015
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Fe3O4@SiO2–imid–PMAn magnetic porous nanosphere as
recyclable catalyst for the green synthesis of quinoxaline
derivatives at room temperature and study of their antifungal
activities
Jaber Javidi a,b* jaberjavidi@sbmu.ac.ir, Mohsen Esmaeilpourc
aDepartment of Pharmaceutics, School of Pharmacy, Shahid Beheshti University of Medical
Sciences, Tehran, Iran
bStudents Research Committee, School of Pharmacy, Shahid Beheshti University ofMedical
Sciences, Tehran, Iran
cChemistry Department, College of Science, Shiraz University, Shiraz, Iran
*Corresponding author. Tel.: +98 7116137738, fax: +98 7112286008.
1

Graphical Abstract
2

Highlights
1. We developed simple and green procedure for the synthesis of
quinoxaline derivatives.
2. BET and leaching of catalyst after each reaction cycle was investigated.
3. Antifungal activity of derivatives was investigated.
3

Abstract
An efficient, simple, and green procedure for the synthesis of quinoxaline derivatives
catalyzed by Fe3O4@SiO2-imid-PMAn nanoparticles at room temperature is described. This
environmentally benign method provides several advantages such as mild reaction
conditions, good to excellent yields, short reaction times, simple work-up and catalyst
stability, easy preparation, heterogeneous nature and easy separation of the catalyst. Also,
nanocatalyst can be easily recovered by a magnetic field and reused for the next reactions for
at least 6 times without distinct deterioration in catalytic activity. SEM, BET, DLS and
leaching of catalyst after each reaction cycle were investigated. Furthermore, antifungal
activity of various derivatives against three phytopathogenic fungi (A. alternata, P. oryzae,
and A. brassicae) was investigated.
Keywords: Quinoxalines; Green synthesis; Heterogeneous; Magnetic catalyst; Antifungal
activity
4

1. Introduction
Quinoxalines are very important compounds due to their wide spectrum of biological
activities behaving as anticancer [1], antiviral [2], antibacterial [3-5] and activity as
kinase inhibitors [6]. Also, quinoxaline moieties have found applications in macro
cyclic receptors [7], chemically controllable switches [8], building blocks in the
synthesis of organic semiconductors [9], electroluminescent materials [10], organic
semiconductors [11], dehydroannulenes [12], DNA cleaving agents [13], anti-
inflammatory, anti-protozoal and anti-HIV [14,15]. The quinoxaline ring is also found
in antibiotics such as echinomycin, leromycin and actinomycin [16-18].
Because of important applications of quinoxaline compounds in both medicinal and
industrial fields, a number of protocols have been developed for the synthesis of
quinoxaline derivatives. The condensation of amines with ketones has been used as a
useful protocol for the synthesis of quinoxalines. For this transformation, several
catalysts and reagents have been reported, including acetic acid [19], oxalic acid [20],
sulfamic acid [21], H6P2W18O62.24H2O [22], KHSO4 [23], Ni nanoparticles [24],
iodine [25], gallium(III)triflate [26], montmorillonite K10 [27], polyanilinesulfate salt
[28], ZrO2/Ga2O3/MCM-41[29] and ionic liquids [17].
In addition, solid phase synthesis [30], microwave [31], bicatalyzed (bismuth and
copper) oxidative coupling of peroxides and ene-1,2-diamines [32] were also reported.
However, the critical product isolation procedure, long reaction time and harsh
conditions of the above mentioned methods, non-recoverable catalysts, highly toxic
and hazardous catalyst, limit their use in sustainable chemistry. Thus, the development
of a new procedure for the synthesis of quinoxaline derivatives is still a desirable goal.
5

Nanoparticles (NPs) have been a topic of intense research mainly because of their
unique physical and chemical properties compared with their bulk counterparts [33].
Metal oxide nanoparticles, with their potential applications in the fields of physics,
chemistry, biology, and medicine have attracted increasing research attention from the
past decades because of their interesting physical and chemical properties [34].
Magnetic nanoparticles have been widely used in the immobilization of enzymes [35],
bio-separation [36], biosensor [37], immunoassay [38], targeted drug delivery and
hyperthermia [39], environmental analysis [40] and catalysis [41-46].
In the field of catalysis, superparamagnetic nanoparticles have been utilized as catalyst
supports for organic transformations such as alcohol hydrogenation [47], olefin
hydrogenation [48], olefin hydroformylation [49], Sonogashira and Carbonyla- tive
Sonogashira reactions [50], Suzuki and Heck cross-coupling reactions [51], oxidation
[52], dehalogenation [53], ring-opening polymerization of epsilon-caprolactone [54],
asymmetric hydrogenation [55], as well as supports for biocatalysts [56,57] with high
activity and selectivity. Recently, a number of functionalized Fe3O4 nanoparticles
have been employed in a range of organic transformations, and the studies on
immobiliztation of metal and organo catalysts on silica coated iron oxide
nanoparticles have been reported [58-61].
In recent years, heteropoly acids (HPAs) especially Keggin type have attracted
increasing interest due to their high acidity, low toxicity and tunable redox properties
[62]. Although HPAs are versatile compounds in their acidic form, their main
disadvantages are high solubility in polar solvents and low surface area (<10 m2/g).
Therefore, in a homogeneous reaction the isolation of the products and the reuse of the
6

catalyst after reaction become difficult [63]. Therefore, in order to overcome this
problem, these materials disperse on supports (such as silica, acidic ion-exchange
resins, active carbon and etc.) which possess large surface area. The use of support
allows the heteropolyacids to be dispersed over a large surface area and increases
theirs catalytic activity [64].
Therefore, as part of our researches to develop efficient and environmentally benign
synthetic methods in organic chemistry [65], we report here an efficient, mild, green,
and simple method for the preparation of quinoxalines from aryl/alkyl amines and
different ketones using Fe3O4@SiO2-imid-PMAn as magnetic catalyst in EtOH.
2. Experimental
2.1. General methods
All chemicals were purchased from Merck or Fluka Chemical Companies. The
progress of the reactions was followed by TLC using silica gel SILG/UV 254 plates
and purification was achieved by silica gel column chromatography. Fourier transform
infrared (FT-IR) spectra were recorded on a Shimadzu FT-IR 8300 spectrophotometer
The NMR spectra were recorded on a Bruker avance DMX 400MHz spectrometer in
chloroform (CDCl3) using tetramethylsilane (TMS) as an internal reference. Scanning
electron microscopy (SEM) image was obtained on Philips XL-30ESEM. Magnetic
characterization was carried out on a vibrating sample magnetometer (Meghnatis
Daghigh Kavir Co., Iran) at room temperature. Molybdenum contents in the
functionalized sample before and after catalytic reactions were estimated by
inductively coupled plasma-atomic emission spectroscopy (ICP-AES). Melting points
were recorded on a Buchi B-545 apparatus in open capillary tubes. Elemental analysis
7

was done on a 2400 series Perkin-Elmer analyzer. Therefore, all of the products were
characterized by FT-IR, 1H NMR and 13C NMR, and also by comparison with
authentic samples.
2.2. General procedure
2.2.1. Preparation of Fe3O4@SiO2 Core-Shell
The core–shell Fe3O4@SiO2 nanospheres were prepared by a modified Stober method
in our previous work [65]. In a typical procedure, the mixture of FeCl3.6H2O (1.3 g,
4.8 mmol) in water (15 ml) was added to the solution of polyvinyl alcohol (PVA
15000), as a surfactant, and FeCl2.4H2O (0.9 g, 4.5 mmol) in water (15 ml), which
was prepared by completely dissolving PVA in water followed by addition of
FeCl2.4H2O. The resultant solution was left to be stirred for 30 min in 80 oC. Then,
hexamethylen tetraamine (HMTA) (1.0 mol/l) was added drop by drop with vigorous
stirring to produce a black solid product when the reaction media reaches pH 10. The
resultant mixture was heated on water bath for 2 h at 60 oC and the black magnetite
solid product was filtered and washed with ethanol three times and was then dried at
80oC for 10h. Then Fe3O4 nanoparticle (0.5 g, 2.1 mmol) was dispersed in the mixture
of ethanol (50 mL), deionized water (5 mL) and tetraethoxysilane (TEOS) (0.20 mL),
followed by the addition of 5.0mL of NaOH (10 wt%). This solution was stirred
mechanically for 30 min at room temperature. Then the product, Fe3O4@SiO2, was
separated by an external magnet, and was washed with deionized water and ethanol
three times and dried at 80 oC for 10 h.
8

2.2.2. Preparation of H3PMo12O40 nanoparticles (PMAn)
PMAn nanoparticles were prepared in our previous work [66]. In a typical procedure,
5 mmol of bulk H3PMo12O40 (PMAb) was dispersed in 50 mL n-Octane and the
resulting dispersion was stirred vigorously for 30 min at room temperature to form a
homogeneous dispersion. This dispersion was transferred into a Teflon-lined stainless
autoclave filling 80 % of the total volume. The autoclave was sealed and maintained
at 150 oC for 12 h. The autoclave was then cooled to room temperature. Finally, the
resulted powder was filtered and washed for several times by Octane, and dried in a
vacuum at 80 oC for 12 h.
2.2.3. Preparation of Fe3O4@SiO2-imid-PMAn
Fe3O4@SiO2 (1 g) was added to the solution of 3-chlorotriethoxypropylsilane (1
mmol, 0.241 g) and imidazole (1 mmol, 0.0680 g) in p-xylene (20 mL) and the
resultant mixture was under reflux for 24 h under nitrogen atmosphere. After refluxing
for about 24 h, the mixture was cooled to room temperature, filtered by an external
magnet and the product was washed with xylene to remove no reacted species and
dried at 70 oC for 6 h. Fe3O4@SiO2-imid (1.0 g) was added to an acetonitrile solution
of PMAn (1.0 mmol) in 20 mL was taken in a round-bottom flask. The mixture was
refluxed for 24h under nitrogen atmosphere. After 24 h, the mixture was filtered by an
external magnet, washed with acetonitrile and dichloromethane, and dried at 70 oC for
6h. Also, the same method was used for the synthesis of Fe3O4@SiO2-imid-PMAb
(PMAn = nano H3PMo12O40, PMAb= H3PMo12O40) (Scheme1) [67].
9

2.2.4. General procedure for the preparation of quinoxaline derivatives
To a stirred solution of amine (1 mmol) and carbonyl compounds (1 mmol) in EtOH
(5 mL) were added Fe3O4@SiO2-imid-PMAn (0.03g, 0.5 mol%). The progress of the
reaction was followed by thin-layer chromatography (TLC). After completion of the
reaction, ethyl acetate was added to the solidified mixture and the insoluble catalyst
was separated by magnetic field. The filtrate was dried and organic medium was
removed with a rotary evaporator under reduced pressure. The crude products were
crystallized from ethanol to afford pure products for analytical measurements.
2.3. Biological assay
Several derivatives of quinoxaline (Entry 26 to 35 from Table 2) were investigated for
their antifungal activities against three phytopathogenic fungi (A. alternata, P. oryzae,
and A. brassicae).
Potato dextrose agar (PDA) medium was prepared in the flasks. Selected compounds
were dissolved in acetone, and the concentration of these compounds was fixed at 60
mg/mL. The medium was then poured into sterilized Petri dishes. All types of fungi
were incubated in PDA at 30 oC for five day to get new mycelium for the antifungal
assays, and a mycelia disk of approximately 5 mm diameter cut from culture medium
was picked up with a sterilized inoculation needle and inoculated in the center of the
PDA Petri dishes. Acetone mixed with PDA The control sample was prepared by
mixing Acetone mixed with PDA, without any compounds.
The growths of the fungal colonies were measured and the inhibitory effects of the
compounds on these fungi in vitro were calculated by the formula:
10

Percent of inhibition rate=(C-T)×100/C
where C represents the diameter of fungi for the control sample, and T represents the
diameter of fungi on treated PDA. Results were shown in Fig. 1.
3. Results and discussion
In our previous work [67], the Fe3O4, Fe3O4@SiO2 and Fe3O4@SiO2–imid–PMAn
nano catalysts were characterized by various methods such as transmission electron
microscopy (TEM), scanning electron microscopy (SEM), dynamic light scattering
(DLS), Fourier transform infrared (FT-IR), vibrating sample magnetometer (VSM)
and etc. As shown in Scheme.1 Fe3O4@SiO2–imid–PMAn nanoparticles have
spherical shapes with approximately 50 nm diameters. The size distribution of these is
centered at a value of 55 nm. The magnetic properties of Fe3O4, Fe3O4@SiO2,
Fe3O4@SiO2-imid-PMAn nanoparticles were measured by VSM at room temperature.
All the samples show a typical superparamagnetic behavior. The saturation
magnetization of samples is 63.4, 39.7, 33.2 emu/g, respectively. Hysteresis
phenomenon was not found and the magnetization and demagnetization curves were
coincident.
XPS is an important method to distinguish Fe3O4 and Fe2O3 since their same
crystalline structure but different valence state of iron ions. For the Fe 2p spectrum of
Fe3O4@SiO2-imid-PMAn two peaks at 711 and 725 eV correspond to Fe 2p3/2 and Fe
2p1/2 of Fe3O4, respectively. Moreover, the absence of shakeup satellite peak situated
at ~719 eV, which is the fingerprint of the electronic structure of Fe2O3 also confirms
the Fe3O4 species rather than Fe2O3.
11

Mo ion has two valence state, +5 or +6 and show two distinct couple peaks at (231.4
and 234.3 eV) or (232.4 and 235.5 eV) respectively in the Mo 3d spectrum. In the Mo
3d XPS spectrum of Fe3O4@SiO2-imid-PMAn to peaks at 232.5 and 235.5 eV which
correspond to Mo 3d5/2 and 3d3/2 respectively were observed. Therefore the Mo ion in
Fe3O4@SiO2-imid-PMAn has +5 valence states.
Also, in this article, determination of molybdenum content was performed by
inductively coupled plasma-atomic emission spectroscopy (ICP-AES). According to
the ICP-AES analysis, the Mo content in the magnetic nanocatalyst was determined
which revealed the presence of 218 and 196 ppm for Fe3O4@SiO2-imid-PMAn and
Fe3O4@SiO2-imid-PMAb catalyst. The amounts of PMAn and PMAb immobilized on
Fe3O4@SiO2-imid-PMAn and Fe3O4@SiO2-imid-PMAb were found to be 36.1 wt%
(0.19 mmol/g) and 31.3 wt% (0.17 mmol), respectively.
In order to optimize this condensation reaction conditions such as, solvents, amount of
the nanocatalyst and also to check the versatility of this method with substituted
amines, the reaction was carried out under various conditions.
In a model condensation reaction, o-phenylenediamine (1 mmol) and benzil (1 mmol)
were stirred at room temperature in the presence of catalytic amount of Fe3O4@SiO2-
imid-PMAn (0.5 mol%) in ethanolic medium (Scheme2). The reaction was completed
in 5 min.
In order to evaluate the optimum amount of catalyst required for this condensation, the
reaction was carried out in the presence varying amount of the catalysts and the results
are presented in Table 1. The best result was achieved by carrying out the reaction
12

with (0.5 mol%, 1 mmol, 1 mmol) ratio of Fe3O4@SiO2-imid-PMAn catalyst, o-
phenylene diamine and benzil in EtOH (Table 1, entry1). The results show clearly that
catalyst is effective for this transformation and in the absence of catalyst; the reaction
did not take place even after higher reaction time (Table 1, entry 14). Use of a higher
amount of catalysts did not improve the yield (Table 1, entries 13) while a decrease in
the amount of catalysts decreases the yield (Table 1, entries 11, 12).
The effect of solvent was studied by carrying out the model reaction at different
solvents (Table 1, entries 1-10). Among the solvents examined, ethanol was found to
be the most effective solvent (Table 1, entry 1). Furthermore, the reaction also
proceeded comparatively well in methanol, acetonitrile and ethyl acetate (Table 1,
entries 2,4,6). For this reaction a protic solvent whit high dielectric constant such as
water and ethanol show better reaction yield, but organic substrate have less solubility
in water than ethanol. Therefore the yield of reaction in water is less than ethanol and
we selected ethanol as reaction medium.
The scope and generality of the present method was then further demonstrated by the
condensation at room temperature of various ketones with amine derivatives using the
optimized conditions and the results are presented in Table 2. The yields of products
were highly dependent on the electronic demands of the substrate used. Results show
that electron-donating groups at the phenyl ring of amine favored the formation of
product (Table 2, entries 7-11, 28-32). In contrast, electron-withdrawing groups such
as nitro, benzoyl and chloro, gave slightly lower yields (Table 2, entries 12-23). On
the other hand, electron donating substituents associated with aromatic ketone
13

decreased the product yields (Table 2, entries 2,3,8,13,17,18,22,26,29-31,33) and the
effect is contrary with electron withdrawing groups (Table 2 , entry 4-6,9-
11,14,15,19,20,23,27,32.34,35). Also, aliphatic 1,2-diamines afforded the
corresponding quinoxaline derivatives in slightly lower yields and longer reaction
times (Table 2, entries 24,25). Furthermore, it is to be noted that highly pure products
were obtained using this simple procedure and in most cases no further purification
was needed.
In order to show the merit of the present catalytic method for the synthesis of
quinoxalines, we have compared our results obtained using Fe3O4@SiO2-imid-PMAn,
Fe3O4@SiO2-imid-PMAb, Nano Fe3O4, Fe3O4@SiO2, Fe3O4@SiO2-imid, PMAb and
PMAn with some of those reported in the literature. These data, which are shown in
Table 3, revealed that Fe3O4@SiO2-imid- PMAn is a better catalyst than most of the
conventional catalysts mentioned with respect to reaction times and yields of the
obtained products.
Fe3O4@SiO2-imid-PMAn magnetic catalyst can be easily separated by external
magnetic field within several minutes without the need for a centrifugation or
filtration step or a tedious workup of the final reaction mixture (Fig. 1). However,
magnetic separation performance makes the nanoparticles more effective and
convenient in applications.
14

Several derivatives of quinoxaline (Entry 26 to 30 from Table 2) were investigated for
their antifungal activities against three phytopathogenic fungi (A. alternata, P. oryzae,
and A. brassicae).
The antifungal activities of several derivatives of quinoxaline (Entry 26 to 35 from
Table 2) were investigated against three phytopathogenic fungi (A. alternata, P.
oryzae, and A. brassicae). As shown in Fig. 2, compounds 26, 29 and 33 exhibited the
good and broad spectrum of antifungal activities against these fungi. Generally, when
the hydroxy group was introduced at the 4-position on the E-ring, derivatives showed
the potent activities. Moreover, addition of hydroxyl group at the 2-position on the E-
ring of compound 28 gave compound 31, the antifungal activities of which were
decreased as compared with compound 29 bearing hydroxyl group at the 4-position on
the E-ring.
An important advantage of employing magnetic catalysts is that they can be easily
recovered from the reaction media by means of an external magnetic field. The
activity of the recycle catalysts were also examined under the optimized conditions.
For this reason, the room temperature reaction of o-phenylenediamine and benzil was
studied in EtOH in the presence of Fe3O4@SiO2-imid-PMAn and Fe3O4@SiO2-imid-
PMAb catalysts. At the end of the reaction, the catalysts were recovered by external
magnetic field, followed by ethyl acetate washing and dried at ambient temperature.
The recycled catalysts were used for six reactions without observation of appreciable
loss in its catalytic activity (Fig. 3).
15

To determine the degree of leaching of the PMAn species from the heterogeneous
catalyst, the catalyst was removed by using a magnetic field and the molybdenum
amount in reaction medium after each reaction cycle was measured through
Inductively Coupled Plasma (ICP) analyzer. The analysis of the reaction mixture by
the ICP technique showed that the leaching of H3PMo12O40 was negligible (Fig.4a).
SEM image of the catalyst after the six recycle have been represented in Fig. 4b. As
shown in Fig. 4b, Fe3O4@SiO2-imid-PMAn nanoparticles had an average diameter of
80 nm. However, the SEM image illustrates that these particles are composed of some
smaller particles, which this indicates that some of the Fe3O4@SiO2-imid-PMAn NPs
agglomerate due to the magneto-dipole interactions between NPs.
Additionally, the size and surface area of catalysts after each reaction cycle was
investigated by DLS and nitrogen physisorption method (BET) respectively and
results are provided in Table 4. TEM image of Fe3O4@SiO2-imid-PMAn after sixth
cycle was shown in Scheme 1. As shown, the size of catalysts will be increased after
each cycle. Generally, leaching of nano H3PMo12O40, agglomeration and increasing of
Fe3O4@SiO2-imid-PMAn size and decrease of surface area led to a decrease in the
yield of reaction.
4. Conclusion
In summary, the present study confirms the applicability of immobilization of
phosphomolybdic acid nanoparticles on imidazole functionalized Fe3O4@SiO2 as an
effective and reusable catalyst for one-pot synthesis of quinoxaline derivatives. The
16

significant advantages of our protocol are: mild reaction conditions, short reaction
times, excellent yields, nanocatalyat stability, simple work-up procedure and
involvement of an efficient and recyclable catalyst. Also, antifungal activity of various
derivatives against three phytopathogenic fungi was investigated and compounds 26,
29 and 33 exhibited the good antifungal activities against these fungi.
Spectral Data
6-(p-Hydroxyphenyl)-5,6-dihydro-indolo[1,2-a]quinoxaline (Table2, Entry 26). Pale
yellow solid, m.p. 147-149oC; 1H NMR (400 MHz, CDCl3) δ: 4.11 (1H, s, NH), 4.92 (1H, s,
OH), 5.42 (1H, s), 5.87 (1H, s), 6.80-6.88 (3H, m), 6.99-7.04 (2H, m), 7.11 (1H, t, J= 7.5
Hz), 7.22-7.28 (1H, m), 7.35 (2H, d, J= 8.7 Hz), 7.51 (1H, d, J= 7.5 Hz), 7.90-7.93 (1H, m),
7.98 (1H, d, J= 8.1 Hz); 13C NMR (125 MHz, CDCl3) δ: 56.6, 100.1, 111.6,
115.5,116.0,116.9,120.1, 120.8, 121.0, 122.5, 124.0, 127.3,129.6,129.8, 132.3, 134.2, 137.7,
139.6, 155.77; IR cm-1: 737, 746, 1230, 1454, 1509, 1598, 3309.
6-(p-Nitrophenyl)-5,6-dihydro-indolo[1,2-a]quinoxaline (Table2, Entry 27). Yellow solid,
m.p.168-169oC; 1H NMR (400 MHz, CDCl3) δ: 4.22 (1H, s, NH), 5.63 (1H, s), 5.85 (1H, s),
6.90-6.91 (1H,m), 7.04-7.06 (2H, m), 7.15 (1H, t, J= 7.6 Hz), 7.27 (1H, t, J= 7.2 Hz), 7.52
(1H, d, J= 7.6 Hz), 7.65-7.67 (2H, m), 7.93-8.02 (2H, m), 8.23 (2H, d, J= 8.4 Hz); 13C NMR
(125 MHz, CDCl3) δ: 56.7, 100.8, 112.0, 116.5, 117.3, 121.0, 121.4, 121.5, 123.3, 124.3,
124.6,127.5, 129.4, 129.7, 134.4, 136.9, 137.5, 147.6, 148.3; IR cm-1: 734, 747, 1353, 1455,
1511, 1598, 3330.
6-Phenyl-5,6-dihydro-8-methylindolo[1,2-a]quinoxaline (Table2, Entry 28). Pale yellow
solid, m.p. 159-161oC; 1H NMR (400 MHz, CDCl3) δ: 2.43 (3H, s, CH3), 4.16 (1H, s, NH),
17

5.51 (1H, s), 5.88 (1H, s), 6.84-6.86 (1H, m), 6.94 (1H, d, J= 7.2 Hz), 7.00-7.02 (2H, m), 7.15
(1H, t, J= 8.0 Hz), 7.41-7.45 (3H, m), 7.52-7.53 (2H, m), 7.84 (1H, d, J= 8.4 Hz), 7.92-7.94
(1H, m); 13C NMR (125 MHz, CDCl3) δ: 18.7, 57.3, 98.5, 109.3, 116.0, 116.9, 120.1, 121.2,
122.6, 123.9, 127.4, 128.4, 128.6, 128.8, 129.3, 130.4, 133.8, 137.6, 138.6, 140.1; IR cm-1:
628, 700, 738, 768, 1282, 1435, 1505, 1557, 1598, 3335.
6-(p-Hydroxyphenyl)-5,6-dihydro-8-methylindolo[1,2-a]quinoxaline (Table2, Entry 29).
Pale yellow solid, m.p. 178-179oC; 1H NMR (400 MHz, CDCl3) δ: 2.44 (3H, s, CH3), 4.10
(1H, s, NH), 4.98 (1H, s, OH), 5.43 (1H, s), 5.88 (1H, s), 6.84 (3H, d, J= 8.8 Hz), 6.94-7.02
(3H, m), 7.15 (1H, t, J= 8.0 Hz), 7.37 (2H, d, J= 8.4 Hz), 7.83 (1H, d, J= 8.4 Hz), 7.90-7.93
(1H, m); 13C NMR (125 MHz, CDCl3) δ: 18.7, 56.7, 98.4, 109.3, 115.5, 115.9, 116.9, 120.1,
121.1, 122.5, 123.9, 127.4, 129.3, 129.8, 130.4, 132.4, 133.8, 137.7, 139.0, 155.7; IR cm-1:
734, 766, 1221, 1276, 1427, 1508, 1568, 1597, 1610, 3308.
6-(p-Methoxyphenyl)-5,6-dihydro-8-methylindolo[1,2-a]quinoxaline (Table2, Entry 30).
Orange solid, m.p. 195-196oC; 1H NMR (400 MHz, CDCl3) δ: 2.44 (3H, s, CH3), 3.85 (3H, s,
OCH3), 4.12 (1H, s, NH), 5.45 (1H, s), 5.87 (1H, s), 6.84-6.86 (1H, m), 6.94 (3H, d, J= 8.8
Hz), 7.00-7.02 (2H, m), 7.15 (1H, t, J= 8.0 Hz), 7.44 (2H, d, J= 8.4 Hz), 7.83 (1H, d, J= 8.0
Hz), 7.91-7.94 (1H, m); 13C NMR (125 MHz, CDCl3) δ: 18.7, 55.3, 56.7, 98.4, 109.3, 114.0,
115.9, 116.9, 120.0, 121.1, 122.5, 123.9, 127.4, 129.3, 129.6, 130.4, 132.2, 133.9, 137.8,
139.0, 159.8; IR cm-1: 741, 764, 826, 1027, 1235, 1262, 1562, 1598, 3317, 3345.
6-(o-Hydroxyphenyl)-5,6-dihydro-8-methylindolo[1,2-a] quinoxaline (Table2, Entry 31).
White solid, m.p. 193-195oC; 1H NMR (400 MHz, CDCl3) δ: 2.42 (3H, s, CH3), 5.58 (1H, s),
5.93 (1H, s), 6.95-6.99 (4H, m), 7.05 (1H, t, J= 7.6 Hz), 7.13-7.21 (2H, m), 7.23-7.25 (1H,
18

m), 7.34-7.38 (1H, m), 7.81 (1H, d, J= 8.4 Hz), 7.94 (1H, d, J= 8.0 Hz); 13C NMR (125 MHz,
CDCl3) δ: 18.7, 57.5, 99.3, 109.2, 117.1, 117.4, 117.8, 119.8, 121.5, 122.1, 122.4, 123.0,
123.9, 128.4, 129.3, 129.9, 130.4, 130.8, 134.2, 135.7, 136.0, 156.7; IR cm-1: 731, 759, 824,
1245, 1278, 1490, 1510, 1561, 1592, 3298.
6-(p-Nitrophenyl)-5,6-dihydro-8-methylindolo[1,2-a]quinoxaline (Table2, Entry 32).
Yellow solid, m.p. 218-219oC; 1H NMR (400 MHz, CDCl3) δ: 2.44 (3H, s, CH3), 4.23 (1H, s,
NH), 5.67 (1H, s), 5.86 (1H, s), 6.90-6.92 (1H, m), 6.97 (1H, d, J= 7.6 Hz), 7.04-7.08 (2H,
m), 7.19 (1H, t, J= 7.6 Hz), 7.70 (2H, d, J= 8.4 Hz), 7.85 (1H, d, J= 8.8 Hz), 7.94-7.96 (1H,
m), 8.27 (2H, d, J= 8.4 Hz); 13C NMR (125 MHz, CDCl3) δ: 18.7, 56.5, 98.9, 109.4, 116.2,
117.0, 120.7, 121.5, 123.1, 124.0, 124.2, 127.3, 129.1, 129.2, 130.6, 133.8, 136.6, 136.7,
147.4, 148.1; IR cm-1: 730, 759, 1276, 1341, 1503, 1516, 1561, 1596, 3362.
6-(p-Hydroxyphenyl)-5,6-dihydro-7-methylindolo[1,2-a]quinoxaline (Table2, Entry 33).
Pale yellow solid, m.p. 205-206oC; 1H NMR (400 MHz, CDCl3) δ: 1.99 (3H, s, CH3), 5.59
(1H, s), 6.65 (2H, d, J= 8.0 Hz), 6.73-6.75 (1H, m), 6.93-6.95 (2H, m), 7.06 (2H, J= 8.4 Hz),
7.16-7.29 (2H, m), 7.54 (1H, d, J= 7.6 Hz), 7.86-7.89 (1H, m), 7.98 (1H, d, J= 8.8 Hz); 13C
NMR (125 MHz, CDCl3) δ: 8.3, 54.6, 107.2, 111.7, 115.5, 116.2, 116.4, 118.9, 119.8, 120.3,
122.5, 123.6, 127.4, 128.7, 130.7, 132.9, 133.3, 134.1, 135.7, 155.2. IR cm-1: 738, 752, 1172,
1220, 1453, 1507, 1596, 3302.
6-(p-Nitrophenyl)-5,6-dihydro-7-methylindolo[1,2-a]quinoxaline (Table2, Entry 34).
Yellow solid, m.p. 159-161oC; 1H NMR (400 MHz, CDCl3) δ: 2.12 (3H, s, CH3), 4.39 (1H, s,
NH), 5.78 (1H, s), 6.76 (1H, d, J= 6.8 Hz), 6.94-7.01 (2H, m), 7.21-7.25 (1H, m), 7.30-7.36
19

(3H, m), 7.59 (1H, d, J= 8.0 Hz), 7.89 (1H, d, J= 6.8 Hz), 8.01 (1H, d, J= 8.0 Hz), 8.07-8.09
(2H, m); 13C NMR (125 MHz, CDCl3) δ: 8.4, 53.9, 107.9, 111.9, 116.50, 116.58, 119.2,
120.5, 120.7, 123.0, 124.0, 124.1, 127.3, 127.8, 130.4, 131.0, 133.5, 134.4, 147.4, 148.8; IR
cm-1: 707, 738, 1342, 1455, 1508, 1597, 3368.
6-(Furan-2-yl)-5,6-dihydro-7-methylindolo[1,2-a]quinoxaline (Table2, Entry 35). Pale
yellow solid, m.p. 44-46oC; 1H NMR (300 MHz, CDCl3) δ: 2.25 (3H, s, CH3), 4.52 (1H, s,
NH), 5.79-5.82 (2H, m), 6.15 (1H, s), 6.81-6.97 (3H, m), 7.21-7.30 (3H, m), 7.60 (1H, d, J=
7.5 Hz), 7.83-7.86 (1H, m), 7.97 (1H, d, J= 8.1 Hz); 13C NMR (125 MHz, CDCl3) δ: 8.0,
48.2, 107.2, 107.6, 110.3, 111.7, 116.4, 119.1, 120.2, 120.4, 122.6, 123.6, 127.3, 130.1,
130.3, 133.5, 135.2, 142.2,153.8; IR cm-1: 741, 750, 803, 1012, 1092, 1458, 1507, 1598,
2918, 3360.
Acknowledgements
Authors are grateful to the council of Iran National Science Foundation and University
of Shiraz for their unending effort to provide financial support to undertake this work.
20

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Figure Captions
Fig.1: Photo images of magnetic field-responsive of Fe3O4@SiO2-imid-PMAn nanoparticles
(before magnetic field (a) and under magnetic field (b)).
Fig. 2. Antifungal activities (inhibition %) of compounds 26-35 at 60 mg/mL.
Fig. 3: Recyclability of Fe3O4@SiO2-imid-PMAn and Fe3O4@SiO2-imid-PMAb in the
condensation reaction of o-phenylenediamine with benzyl at room temperature.a
(a) Reaction condition: benzil (1 mmol), o-phenylenediamine (1 mmol), Fe3O4@SiO2-imid-PMAn (0.5 mol%) or
Fe3O4@SiO2-imid-PMAb (0.7 mol%) and EtOH (5 mL), room temperature.
Fig.4: (a) PMAn leaching (%) in each reaction cycle; (b) SEM image of Fe3O4@SiO2-imid-
PMAn nanoparticles after six reaction cycles.a
(a) Reaction condition: benzil (1 mmol), o-phenylenediamine (1 mmol), Fe3O4@SiO2-imid-PMAn (0.5 mol%)
and EtOH (5 mL), room temperature.
Scheme 1 Process for preparation of immobilization of H3PMo12O40 nanoparticles on
imidazole functionalized Fe3O4@SiO2 nanoparticle.
Scheme.2: Preparation of quinoxaline derivatives catalyzed by Fe3O4@SiO2-imid-PMAn.
27

Fig.1
28

Fig. 2.
29