Synthesis and characterization of a novel and reusable Fe3O4@THAM-CH2CH2-SCH2CO2H magnetic nanocatalyst for highly efficient preparation of xanthenes and 3-aminoisoxazoles in green conditio

Article abstract of DOI:10.1007/s11164-021-04558-9

In the present study, the synthesis and catalytic application of a novel thioglycolic acid doped on Fe₃O₄ nanomagnetic particles coated with tris(hydroxymethyl)aminomethane (THAM) and 1,2-dichloroethane are described. The morphology,

Full text of DOI:10.1007/s11164-021-04558-9

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-021-04558-9
Synthesis and characterization of a novel and reusable
Fe3O4@THAM‑CH2CH2‑SCH2CO2H magnetic nanocatalyst
for highly efcient preparation of xanthenes
and 3‑aminoisoxazoles in green conditions
Mahboobeh Rezaie Kahkhaie1 · Nourallah Hazeri1 ·
Malek Taher Maghsoodlou1 · Afshin Yazdani‑Elah‑Abadi2
Received: 25 April 2021 / Accepted: 28 July 2021
© The Author(s), under exclusive licence to Springer Nature B.V. 2021
Abstract
In the present study, the synthesis and catalytic application of a novel thioglycolic
acid doped on Fe3O4 nanomagnetic particles coated with tris(hydroxymethyl)ami-
nomethane (THAM) and 1,2-dichloroethane are described. The morphology, struc-
ture, and physicochemical properties have elucidated by several analytical methods
like FT-IR, TEM, VSM, XRD, TGA, and FE-SEM. This nanocatalyst has success-
fully applied as a heterogeneous acid catalyst in the synthesis of diversely substi-
tuted biologically important xanthene and 3-aminoisoxazole derivatives. This cat-
alyst eliminates our need for long-time reaction and hard catalyst separation from
product, and it can be easily recovered with an external magnet for eight consecutive
times without a signifcant decrease in its catalytic properties.
Graphic abstract
CH3
O
O
H
3C
OH
Me
Me
O
N
Ar
O
N
H2N
1
+
3
O
5
Ar
NH
OH
Me
Me
MNPs-CO2H, 50 °C
Solvent- free
O
H
O
MNPs-CO2H, 80 °C
Solvent- free
6a-l
4a-l
2
Keywords Benzoxanthenes · Green chemistry · Magnetically recoverable
nanocatalyst · MNPs-CO2H · 3-Aminoisoxazole
*
Nourallah Hazeri
nhazeri@chem.usb.ac.ir; n_hazeri@yahoo.com
Extended author information available on the last page of the article
Vol.:(0123456789)
1 3

M. Rezaie Kahkhaie et al.
CH3
O
O
O
H
3C
OH
Me
Me
O
N
Ar
O
N
H2N
1
+
3
5
Ar
NH
OH
Me
Me
MNPs-CO2H, 50 °C
Solvent- free
O
6a-l
H
O
MNPs-CO2H, 80 °C
Solvent- free
4a-l
2
Scheme 1 One-pot, three-component synthesis of 3-aminoisoxazolmethylnaphthol and 12-aryl-
8,9,10,12-tetrahydrobenzo[a]xanthen-11-one derivatives in the presence of MNPs–CO2H as catalyst
Introduction
Recently, with regard to green chemistry, efcient, and economical chemical pro-
cesses using nanocatalysts for the production of fne chemical and pharmaceutical
products through multi-component reactions (MCRs) have become the subject of
much interest in universities and industry [1–3]. Nanomaterial applications as het-
erogeneous catalysts have played a critical role at the interface of these felds. Nano-
catalysts consist of an inner core material and an outer shell. Their properties can be
changed by loading the acidic or alkaline groups on the core [4, 5]. The separation
of nanocatalysts from the reaction medium limits their applications.
To solve this challenge, magnetic nanocatalysts (MNCs) have emerged as attrac-
tive candidates, which can be separated by an external magnetic feld [6–12]. In
addition to this, high surface area, high activity, surface modifcation ability, catalyst
recovery, excellent thermal and chemical stability, possibility of re-use of catalysts,
are ideal properties of “green catalysts”.
Therefore, the design of novel MCRs used by nanocatalysts for the synthesis of
complex organic compounds has remained an important topic for medicinal and
organic chemistry. Having xanthene and 3-aminoisoxazole moieties, Heterocycles
are signifcant targets in synthetic organic chemistry. Benzoxanthenes and isoxazole
derivatives are popular scafolds for the development of new agents with variable
biological activities, such as anti-microbial, anti-viral, anti-cancer, immunomodula-
tory, and anti-diabetic properties [13–17].
Here, we demonstrate an important fnding in which that isolated Fe3O4 nanopar-
ticles can be stabilized by THAM, which is inexpensive, readily available and has
many applications in medicine, biochemistry, and biology. Clearly, the production
of THAM-stabilized nanoparticles [18, 19] is environmentally friendly, and thiogly-
colic acid is used as a chemical depilatory especially in salt forms, including cal-
cium thioglycolate and sodium thioglycolate. This nanocatalyst is used as an acidity
indicator.
In continuation of our interest in the heterocyclic system and magnetic nanoparti-
cles [20–22], herein we report the preparation of a novel acidic nanocatalyst and its
application for the green synthesis of 3-amino isoxazolmethylnaphthol and 12-aryl-
8,9,10,12-tetrahydrobenzo[a]xanthen-11-one derivatives (Scheme 1).
1 3

Synthesis and characterization of a novel and reusable…
The reaction involves one-pot, three-components coupling of 2-naphthol 1,
benzaldehyde 2, and 3-amino-5-methylisoxazole 3 or dimedone 5 in the presence
of Fe3O4@THAM-CH2CH2-SCH2CO2H as a new, efcient, and non-toxic cata-
lyst under solvent-free condition. All reactions proceeded with good to excellent
yields in a short time, and the catalyst could be used up to eight times without
signifcant loss of its activity.
Result and discussion
Preparation and characterization of THAM‑CH2CH2‑SCH2CO2H coated core–shell
magnetic nanocatalyst
In this study, Fe3O4 MNPs were prepared through a common precipitation method
in r.t., for hosting THAM active species and forming Fe3O4@THAM NPs. To
immobilize thio glycolic acid on to the magnetic core, frst, the Fe3O4 NPs have
modifed with THAM magnetic NPs. In the next step, the interaction between the
1,2-dicholoro ethane and the surface OH groups of the MNP derived efective
attachment Fe3O4@THAM-CH2CH2Cl and then thio glycolic acid was coated
(Scheme 2).
Synthesized pure Fe3O4 MNPs and Fe3O4@THAM-CH2CH2-SCH2CO2H
nanocatalyst were characterized using powder XRD, FE-SEM, TEM, FT-IR,
VSM. Elemental analysis results indicate the presence of sulfur and nitrogen con-
frming the THAM coating on the surface Fe3O4.
OH
N
O
I
T
U
OH
HO
L
O
E
S
R
E
H
P
room temp.
60 min
A
S
O
O
O
O
I
M
THAM
24 h
O
N
T
A
O
Fe
3O4
OH
N2
OH
OH
NH2
Fe
3O4
M
HO
HO
M
A
Cl
Cl
CH3CN
.6H
FeCl
O
h
3.4H2
4
FeCl2
2O
2
HO
O
O
Cl
SH
S
OH
Ethanol , 24 h
Fe
3O4
NH
Fe
3O4
NH
Scheme 2 Preparation of THAM-CH2CH2-SCH2CO2H coated core–shell magnetic nanocatalyst
1 3

M. Rezaie Kahkhaie et al.
FT‑IR
FT-IR spectra of the prepared Fe3O4 MNPs and MNPs-CO2H are shown in Fig. 1.
There are several vibrational peaks in the spectrum of the Fe3O4 NPs that verify the
Fe3O4 structure. These peaks include the 1618 and 3374 cm−1 broad bands, which
refer to the surface-adsorbed water molecules and hydroxyl groups, and the 582 and
631 cm−1 peaks associated with the octahedral bending and tetrahedral stretching
modes of the Fe–O functional group. Based on Fig. 1, the FT-IR peaks of C–Cl and
CH–Cl are positioned at 780, 1200 cm−1. On the other hand, the absorption peak
around 2923 indicated C–H stretching vibrations in the aliphatic group [18]. Finally,
the presence of thioglycolic acid is confrmed by 3392, 1601, 1411, 1035 peaks.
With respect to the FT-IR spectra, the surface of Fe3O4 NPs is successfully coated
by THAM, 1,2-dicholoroethane and thioglycolic acid.
XRD
XRD difraction patterns of undoped Fe3O4 and thioglycolic acid doped Fe3O4
nanocatalyst are shown in Fig. 2. The powder XRD patterns of Fe3O4 and Fe3O4@
THAM-CH2CH2@SCH2CO2H MNPs exhibited difraction peaks at 2θ = 30.34°,
35.65°, 36.99°, 43.12°, 53.56°, 57.11°, and 62.56°, which are associated with cor-
responding indicants of (2 2 0), (3 1 1), (2 2 2), (4 0 0), (4 2 2), (5 1 1), and (4
4 0), respectively [18]. The XRD pattern of Fe3O4@THAM-CH2CH2@SCH2CO2H
MNPs showed a broad band less than 20° that can be related to the amorphous layer
Fig. 1 FT-IR spectra of Fe3O4 (a) Fe3O4@THAM-Cl (b), and MNPs–CO2H (c)
1 3

Synthesis and characterization of a novel and reusable…
Fig. 2 XRD pattern of Fe3O4 (a) and MNPs–CO2H (b)
including thioglycolic acid. The crystallite sizes of nanocatalyst can be calculated by
the Scherrer’s formula. Therefore, the average crystallite sizes of nanocatalyst were
calculated to be 13.70382, and lattice constants were a (Å):8.3100, b (Å): 8.3100, c
(Å): 8.3100, Alpha (°): 90.0000, Beta (°):90.0000, Gamma (°): 90.0000 with Ref-
erence code:01-075-0449 in Crystal system:Cubic. D-spacing can be calculated
by Bragg law. The results are summarized in Table 1.
TGA
Thermogravimetry indicates that the mass loss at 160 °C is the mass of the molecu-
lar water in the catalyst. The organic moiety grafted on the Fe3O4 NPs decomposed
in the temperature range of 180–600 °C (5.38%). In accordance with this mass loss,
the amount of 53.8 mg (0.22 mmol) of the organic layer was loaded on 1 g of Fe3O4
Table1 d-spacing of
Entry
h
k
l
d [A]
2Theta [°]
I [%]
nanocatalyst
1
2
3
4
5
6
7
8
9
1
2
3
2
4
3
4
5
4
5
1
2
1
2
0
3
2
1
4
3
1
0
1
2
0
1
2
1
0
1
4.79778
2.93803
2.50556
2.39889
2.07750
1.90644
1.69627
1.59926
1.46901
1.40465
18.478
30.399
35.810
37.460
43.528
47.663
54.016
57.588
63.251
66.514
6.9
28.7
100.0
7.5
19.8
1.1
7.8
23.7
32.9
0.6
10
1 3

M. Rezaie Kahkhaie et al.
Fig. 3 Thermogravimetry (TGA) of Synthesized MNPs-CO2H
Fig. 4 Comparison of pure magnetic properties of synthesized Fe3O4 MNPs (a) and MNPs-CO2H (b)
nanoparticles. Furthermore, the DTG curve indicates that the nanocatalyst has good
thermal stability before 230 °C (Fig. 3).
VSM
Variation of pure magnetic properties of synthesized Fe3O4 MNPs and MNPs-
CO2H was investigated using VSM at room temperature with an applied feld of
15,000 Oe. As VSM indicates, both samples exhibit the typical behavior of super-
paramagnetic materials and give nearly zero coercivity and remanence. Moreover,
according to Fig. 4, the nonmagnetic coating including THAM and thioglycolic acid
1 3

Synthesis and characterization of a novel and reusable…
species decreases the amount of saturation magnetization (Ms) of the fnal MNPs
(about 55 emu g−1) than magnetization value of bulk (about 116 emu g−1).
TEM, FE‑SEM, and EDS
TEM and SEM images were performed to examine the morphology, size distribu-
tion, and physical properties of synthesized nanoparticles. As can be seen in Fig. 5,
the MNPs have nano-size with spherical morphology. In addition, the EDS study
was used to confrm the presence of thioglycolic acid and shell extract on the surface
of the species Fe3O4NPs (Fig. 6).
Synthesis of 3‑aminoisoxazolmethylnaphthols
In order to investigate the optimizing reaction conditions for the synthesis of func-
tionalized 3-aminoisoxazole, we carried out the multi-component reaction between
2-naphthol (1.0 mmol), banzaldehyde (1.0 mmol) and 3-amino-5-methylisoxazole
(1.0 mmol) as a model (Scheme 3). For caracterization of solvents, initially, the
model reaction was studied using various green solvents and solvent-free conditions.
All of the results are registered in Table 2. Among the investigated solvents (EtOH,
H2O, and AcOH with yileds including 56, 66, and 54%), the solvent-free condi-
tion showed the strongest efect and the highest yield (95%) on the model reaction
(Table 2, entry 1). Then, the efect of amount of catalyst was investigated, and the
highest yield of target product was obtained using 0.01 g of catalyst (Table 3, entry
1). Finally, the efect of temperature was studied. Based on our experimental results
(Table 3), the best conversion was obtained at 80 °C in the presence of 0.01 g of
MNPs-CO2 H, which is an efcient condition (Table 3, entry 1). Also,
Fig. 5 TEM (a) and SEM (b) images of MNPs-CO2H
1 3

M. Rezaie Kahkhaie et al.
Fig. 6 EDS for MNPs-CO2H
H
3C
O
N
H
O
CH3
O
OH
NH
OH
MNPs-CO2H
Various conditions
N
H2N
Scheme 3 Synthesis of 1-(((5-methylisoxazol-3-yl) amino) (phenyl)methyl) naphthalen-2-ol under vari-
ous conditions as a model reaction
Table 2 Investigation of solvent
Entry
Solvent
Temp. (°C)
Time (min)
Yield%
efects on the reaction
1
2
3
4
Solvent-free
Ethanol
ACOH
80
80
80
80
5
40
55
40
95
56
54
66
H2O
Table 3 Optimization of the
catalyst value and reaction
temperature in the desired
reaction
Entry
Amount of
catalyst (gr)
Temp. (°C)
Time (min)
Yield (%)
1
2
3
4
5
6
0.01
0.02
0.01
0.01
0.01
0.01
80
80
25
50
70
90
5
4
60
55
15
3
95
89
Trace
52
78
86
1 3

Synthesis and characterization of a novel and reusable…
Further enlarge the scope of these conditions, we conducted reaction with a
variety of substituted aldehydes under the optimized condition for the synthesis of
3-aminoisoxazolmethylnaphthols (4a-l). There is smooth progression in reaction for
various substituents to aford the products in high yields. The obtained results are
summarized in (Table 4).
Nanocatalysts are attractive alternatives to conventional catalysts because when
the size of the material is decreased to the nanometer scale, the surface area is sig-
nifcantly increased, and the catalyst can be equally dispersed in solution, to form a
homogenous emulsion. A possible mechanism for the synthesis of 3-aminoisoxa-
zolmethylnaphthol derivatives 4 using MNPs–CO2H outlined in Scheme 4 acts as
a heterogeneous catalysis in all steps. In this mechanism, MNPs–CO2H is an ef-
cient catalyst to form the olefn A, which readily prepares in situ from Knoevenagel
condensation of aromatic aldehyde 2 with 2-naphthol 1. The Michael addition of
3-amino-5-methyl isoxazole 3 with olefn A in the presence of MNPs–CO2H then
causes the inner molecular ring to be formed after a tautomeric proton shift to pro-
duce the corresponding products 4a-l .
Produce of 12‑aryl‑8,9,10,12‑tetrahydrobenzo[a]xanthen‑11‑one derivatives
The catalytic performance of MNPs-CO2H was tested in one-pot, three-compo-
nent reaction of 2-naphthol 1 (1.0 mmol), benzaldehyde 2 (1.0 mmol) dimedone 5
(1.0 mmol) as a model reaction (Scheme 5). At the outset, a test reaction was accom-
plished in the presence of 0.005 g of catalyst at 50 °C and ofered 94% yield of the
desired product, as shown in (Table 5, entry1). Then, for caracterization of solvents,
a brief screening of diverse green solvents (EtOH, H2O, and AcOH) was aforded
(Table 5). These studies revealed that the rate solvent-free is better than other rates.
Finally, to investigate the efcacy of reaction temperature, the model reaction was
Table 4 Synthesis of 3-aminoisoxazolmethylnaphthols in the presence of MNPs– MNPs-CO2H under
solvent-free conditions at 80 °C
Entry
Derivatives
Time (min)
Yield (%)
Product
m.p. obs. (°C)
m.p lit. (°C)
1
2
3
4
5
6
7
8
H
5
10
13
6
4
6
4
5
6
95
89
86
93
90
89
96
95
90
91
92
86
4a
4b
4c
4d
4e
4f
4g
4h
4i
212–213
202–203
193–194
192–193
192–193
186–187
198–199
193–194
192–193
149–150
146–147
147–148
212–214 [22]
202–203 [23]
194–195 [23]
194–195 [23]
193–195 [23]
185–186 [23]
200–201 [23]
195–196 [23]
193–194 [23]
150–151 [23]
148–150 [23]
149–150 [23]
4-Me
4-OMe
4-Cl
3-Cl
2-Cl
4- Br
3-Br
4-F
4-NO2
3-NO2
2-NO2
9
10
11
12
11
13
14
4j
4k
4l
1 3

M. Rezaie Kahkhaie et al.
HO
Ar
H
O
S
O
O
A
O
S
1
OH
O
H
O
Ar
H
Ar
2
H2N
O
N
O
OH
O
CH3
H
3C
3
O
N
S
Ar
NH
OH
4a-l
HO
O
O
S
S
OH
NH
Fe
3O4
Scheme 4 Possible mechanism for the synthesis of 3-aminoisoxazolmethylnaphthol in the presence of
MNP-CO2H
done at diferent temperatures. The yield growth to 94% when the reaction was car-
ried out at 50 °C temperature (Table 6, entry 1).
After broad screening, we found the best optimized yields and time profles with
0.005 g of MNPs-CO2H at 50 °C under solvent–free conditions, which furnished the
corresponding 9,9-dimethyl-12-phenyl-9,10-dihydro-8H-benzo[a]xanthen-11(12H)-
one 6a in 94% yield within 4 min proceed efciently. The results are summarized in
Tables 5, 6, and 7.
Using these optimized reaction conditions, the scope and efciency of the
reaction were explored for the synthesis of a wide variety of 12-aryl-8,9,10,12-
tetrahydrobenzo[a]xanthen-11-one derivatives. The results are summarized in
Table 7.
A proposed mechanism for the synthesis of 12-aryl-8,9,10,12-tetrahydrobenzo[a]
xanthen-11-one derivatives is illustrated in Scheme 6. We suggest that intermediate
1 3

Synthesis and characterization of a novel and reusable…
Fig. 7 Recovery of MNPs– CO2H in the synthesis of 3-aminoisoxazolmethylnaphthols (a) and 12-aryl-
8,9,10,12-tetrahydrobenzo[a]xanthen-11-one (b)
H
O
O
O
O
OH
MNPs-CO2H
Various conditions
O
6a-l
1
5
2
Scheme 5 Production of 9,9-dimethyl-12-phenyl-9,10-dihydro-8H-benzo[a]xanthen-11(12H)-one
Table 5 Investigation of solvent
Entry
Solvent
Temp. (°C)
Time (min)
Yield (%)
efects on the reaction
1
2
3
4
Solvent-free
Ethanol
ACOH
50
50
50
50
4
20
40
45
94
75
65
60
THF
Table 6 Optimization of the
catalyst value and reaction
temperature for the desired
reaction
Entry
Amount of
catalyst (g)
Temp. (°C)
Time (min)
Yield (%)
1
2
3
4
5
6
0.005
0.01
0.005
0.005
0.005
0.005
50
50
r.t
60
80
90
4
3
50
5
5
4
94
85
78
80
83
85
1 3

M. Rezaie Kahkhaie et al.
Table 7 Production of 12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-one derivatives in the presence
MNPs-CO2H under solvent-free conditions at 50 °C
Entry
Derivatives
Time (min)
Yield %
Product
m.p. (°C)
m.p. ref. (°C)
1
2
3
4
5
6
7
8
H
4-Me
4-OMe
4-Cl
2,4-Di Cl
2-Cl
3-OH
2-OH 5-Br
4-F
4-NO2
3-NO2
2-NO2
4
9
11
6
9
7
13
10
5
8
9
94
91
89
94
92
91
94
92
91
90
89
88
6a
6b
6c
6d
6e
6f
6g
6h
6i
148–149
174–175
200–201
172–173
173–174
171–172
239–240
265–266
175–176
176–177
166–167
218–219
149–151 [24]
176–177 [24]
203–205 [24]
173–174 [25]
175–176 [26]
173–174 [26]
240–241 [27]
266–268 [27]
177–180 [25]
176–178 [24]
168–169 [24]
218–220 [24]
9
10
11
12
6j
6k
6l
14
(A) be created by the nucleophilic addition of 2- naphthol to the activated benzal-
dehyde, facilitated by proton of MNP-CO2H. Intermediate (A) react with dimedone
via Michael addition and then eliminate one molecule of H2O to close the ring and
obtain the products 6a-l. The role of the catalyst depends on CO2H-functionalized
active sites, which might exhibit excellent catalytic activity in rapid transfer of
protons.
Recycling experiments of the nanocatalyst
After completion of the reaction, the resulting product was dissolved with hot
ethanol, and the catalyst was easily separated by an external magnet. To eliminate
impurities, the product was crystallized in ethanol. The catalyst was separated from
the reaction mixture using an external magnet, and it was washed with ethanol
(2×5 mL) to remove any unreacted organic compound. The washed catalyst was
dried in an oven at 70 °C for the cycle of reaction. The same purifcation procedure
of the catalyst was carried out after each catalytic cycle. Interestingly, for up to fve
cycles of reaction, no loss of activity of the catalyst was observed. The catalytic
activity was found to decrease to a small extent from the sixth cycle, and after the
eighth cycle, the yield was 80% that may be due to little weight loss of catalyst dur-
ing each recovery process (Fig. 7).
Comparison between present reaction methodology and previously reported meth‑
ods
Many methods have been reported for the synthesis of 12-aryl-8,9,10,12-
tetrahydrobenzo[a]xanthen-11-one and 3-aminoisoxazolmethylnaphthol derivatives
from the reaction of banzaldehyde, 2-naphthol, and dimedone or and 3-amino-5-meth-
ylisoxazole (Table 8). This methods ofer disadvantages such as high temperature
1 3

Synthesis and characterization of a novel and reusable…
5
H
O
O
Ar
HO
S
O
O
A
O
Ar
O
OH
HO
Ar
Ar
S
HO
S
O
O
H
O
O
H
1
2
O
Ar
O
H
O
O
OH
6a-l
H
2O
HO
O
O
S
S
OH
NH
Fe
3O4
Scheme 6 Synthesis of 12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-one derivatives with using
MNP-CO2H
(entry 1, 3, 6, 7, 8), long reaction times (entry 5, 10), hard reaction conditions (entry
10), but in present work, the Fe3O4 nanoparticles (NPs) was synthesized easily by
chemical coprecipitation method at room temperature. The synthesis of Fe3O4 NPs at
room temperature has some advantage such as better magnetic properties and avoids
Fe3O4 to γ-Fe2O3 conversion. This method ofers some advantages in terms of solvent-
free condition, short reaction times, mild reaction conditions and excellent yields and
utilization of a reusable catalyst, eco-friendly nature that make it sustainable, attractive
and economic in agreement with some green chemistry protocols.
Conclusion
A mild and efcient method has been developed to promote the synthesis of 3-amino
isoxazolmethylnaphthol and 12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-one
1 3

M. Rezaie Kahkhaie et al.
Table 8 Comparison between this work and previously reported methods
Entry
Product
Catalyst
Time (min)
Temp (°C)
Yield (%)
Ref.
1
2
3
4
5
6
7
8
4a
4a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
Oxalic acid
Fe3O4–NHPhSO3H
SrFe12O19
γ-Fe2O3[Fe2O3@HAp]
Fe3O4@chitosan
AIL@MNP
Fe3O4/CS-Ag NPs
LAIL@MNP
Iodine
8
8
15
4
180
40
30
30
60
90
70
80
60
40
90
80
80
60
92
93
98
96
90
91
95
96
90
87
95
89
[23]
[38]
[36]
[35]
[37]
[33]
[32]
[34]
[29]
[30]
[31]
[28]
9
10
11
12
NaHSO4·SiO2
Lactic Acid
Trityl chloride
300
30–40
40–70
Refux
50
110
derivatives employing a magnetically separable core–shell Fe3O4@THAM-
CH2CH2-SCH2 CO2H nanocatalyst under solvent-free conditions. Several useful
favorites, such as short time reaction, easy workup, good to excellent yields of prod-
ucts, and use of a magnetically separable and recyclable nano catalyst, make this
method attractive. To the best of our knowledge, this is the frst report of the synthe-
sis of a core–shell structured MNPs-CO2H nanocatalyst and its successful applica-
tion as an efcient heterogeneous acid catalyst.
Experimental
General
Solvents and chemicals were purchased from commercial suppliers and used with-
out further purifcation. Melting points were measured in open capillary tubes and
were uncorrected. Melting points and IR spectra of all compounds were determined
by using an Electrothermal 9100 apparatus and a PerkinElmer plus a spectrome-
ter. The 1H and 13C NMR spectra of known compounds were recorded on a Bruker
DRX-400 Avance instrument in CDCl3 and DMSO at 300 and 400 MHz. MNPs-
CO2H nanocatalyst was characterized by methods like this: FT-IR, TEM, VSM,
XRD, TGA, FE-SEM, and EDS.
Catalyst preparation
Synthesis of Fe3O4 magnetite nanoparticles
MNPs-CO2H nanocatalyst was synthesized using a four-step approach. At the frst,
the mixture of FeCl3.6H2O (10.0 mmol) and FeCl2.4H2O (5.0 mmol) was dissolved
1 3

Synthesis and characterization of a novel and reusable…
in 100 mL deionized water at room temperature. Then, a solution of ammonia was
added dropwise to medium reaction until pH=11. The black suspension was stirred
for 1 h in nitrogen atmosphere. Finally, nanoparticles (MNPs) were isolated by an
external magnet. MNPs were washed with water and ethanol and dried in an oven
for 2 h at 80 °C.
Synthesis of Fe3O4@THAM
In the next step, Fe3O4@THAM MNPs was prepared by dispersing Fe3O4 MNPs
(1.0 g) in the presence of 40 mL water and 60 mL ethanol for 30 min, then 2.0 g of
tris(hydroxymethyl) aminomethane was added in N2 atmosphere and refux condi-
tion for 24 h. Similar to the previous step, MNPs were gathered, washed, and dried
at 80 °C.
Synthesis of Fe3O4@THAM‑CH2CH2Cl
Next, Fe3O4@THAM was dispersed in 50 mL of acetonitrile. Then, 1 mL of dichlo-
roethane and 0.1 mL of triethylamine were added to the mixture of reaction under
refux condition, and the resulting mixture was refuxed under N2 atmosphere for
24 h to produce Fe3O4@THAM-CH2CH2Cl MNPs. These nanoparticles were
cooled to room temperature, washed with water/ethanol, separated using an external
magnet, and dried at 80 °C.
Synthesis of Fe3O4@THAM‑CH2CH2‑SCH2CO2H
Finally, MNP levels of Fe3O4@THAM-CH2CH2Cl were functionalized by dispers-
ing them in 100 mL of ethanol using an ultrasonic bath for 30 min and reacting
with 1.5 mL thioglycolic acid. The mixture was mechanically stirred under refux
condition and N2 atmosphere for 24 h, it was cooled at room temperature and was
washed with water/ethanol and dried at 80 °C for 8 h for desired Fe3O4@THAM-
CH2CH2-SCH2CO2H preparation. Synthesized MNPs-CO2H was characterized by
infrared spectroscopy (FT-IR), feld emission scanning electron microscopy (FE-
SEM), energy dispersive X-ray spectroscopy (EDS), transmission electron micros-
copy (TEM), and vibrating sample magnetometry (VSM).
General experimental procedure for the preparation of 3‑aminoisoxazolmethyl‑
naphthols
Initially, the reactants of benzaldehyde (1.0 mmol) and 2-naphthol (1.0 mmol),
3-amino-5-methylisoxazole (1.0 mmol), and 0.01 g of MNPs-CO2H were stired at
80 °C under solvent-free conditions. After completion of the reaction mentioned by
TLC, the reaction mixture was cooled to room temperature and washed with 5 mL
of water to separate the product. The resulting mixture was diluted with hot ethanol,
and the catalyst was easily separated by an external magnet. To eliminate impurities,
the product was crystallized in ethanol.
1 3

M. Rezaie Kahkhaie et al.
General experimental procedure for the synthesis of 12‑aryl‑8,9,10,12‑tetrahyd‑
robenzo [a]xanthen‑11‑one derivatives
In a test tube, benzaldehyde (1.0 mmol), dimedone (1.0 mmol), 2-naphthol
(1.0 mmol), and MNPs-CO2H nanoparticles (0.005 g) were added at 50 °C for
the desired time. After completion of the reaction (the reaction mixture was
monitored using TLC), the reaction mixture was diluted with hot ethanol, and the
catalyst was easily separated from the reaction mixture by an external magnet,
washed with hot ethanol, dried and reused for a consecutive run under the same
reaction conditions. Then, the reaction mixture was cooled to room temperature,
and the obtained crude product was collected by fltration and recrystallized from
hot ethanol to give the pure solid 6a.
Spectral data for the selected compounds
1‑[(5‑Methyl‑isoxazol‑3‑ylamino)‑phenyl‑methyl]‑naphthalen‑2‑ol (4a)
1
IR (KBr ʋmax, cm−1): 3403, 3058, 2925,1628, 1600, 1581, 1541, 1516, 1493. H
NMR (300 MHz, DMSO-d6): 10.10 (1H, s, OH), 8.03 (1H, d, NH, J = 8.1 Hz),
7.76–7.83 (2H, m, Haromat), 7.14–7.41 (8H, m, Haromat), 6.79 (2H, dd, Haromat
J = 26.2 Hz, J = 7.5 Hz), 5.90 (1H, s, CHNH), 2.23 (3H, s, CH3).
,
1‑[(4‑Methoxy‑phenyl)‑(5‑methyl‑isoxazol‑3‑ylamino)‑methyl]‑naphthalen‑2‑ol (4c)
1H NMR (300 MHz, DMSO-d6): 10.06 (1H, s, OH), 8.00 (1H, d, NH), 7.73–7.81
(2H, m, Haromat), 7.20–7.39 (4H, m, Haromat), 6.76–6.85 (3H, m, Haromat), 6.64 (1H,
d, Haromat, J = 5.7 Hz), 5.86 (1H, s, CHNH), 3.69 (3H, s, OCH3), 2.21 (3H, s,
CH3).
1‑[(4‑Chloro‑phenyl)‑(5‑methyl‑isoxazol‑3‑ylamino)‑methyl]‑naphthalen‑2‑ol (4d)
1H NMR (300 MHz, DMSO-d6): 2.23 (3H, s, CH3), 5.88 (1H, s, CHNH), 6.79 (2H,
dd, Haromat, J=49.2 Hz, J=6.9 Hz), 7.25–7.42 (7H, m, Haromat), 7.80 (2H, t, Haromat
,
J=9 Hz), 7.97 (1H, d, NH, J=7.8 Hz), 10.16 (1H, s, OH); 13C NMR (75 MHz,
DMSO-d6): 167.8, 164.9, 153.2, 142.8, 132.5, 130.9, 129.8, 129.0, 128.5, 128.3,
126.8, 124.0, 122.9, 119.9, 118.8, 94.4, 52.5, 12.5.
1‑[(3‑Chloro‑phenyl)‑(5‑methyl‑isoxazol‑3‑ylamino)‑methyl]‑naphthalen‑2‑ol (4e)
1H NMR (300 MHz, DMSO-d6): 10.16 (1H, s, OH), 7.99 (1H, d, NH, J=8.1 Hz),
7.78–7.84 (1H, t, Haromat), 7.39–7.44 (1H, t, Haromat), 7.19–7.34 (6H, m, Haromat),
6.81 (2H, dd, Haromat, J=46.2 Hz, J=7.2 Hz), 5.88 (1H, s, CHNH), 2.23 (3H, s,
CH3); 13C NMR (75 MHz, DMSO-d6): 167.9, 164.8, 153.2, 146.5, 133.2, 132.4,
1 3

Synthesis and characterization of a novel and reusable…
130.3, 129.9, 129.0, 126.9, 126.4, 126.3, 125.4, 123.8, 122.9, 119.8, 118.8, 94.4,
52.6, 12.5.
1‑[(2–2.3.6.1‑[(3‑Chloro‑phenyl)‑(5‑methyl‑isoxazol‑3‑ylamino)‑methyl]‑naph‑
thalen‑2‑ol (4f)
1H NMR (300 MHz, DMSO-d6): 2.22 (3H, s, CH3), 5.78 (1H, s, CHNH), 6.83 (2H,
dd, Haromat, J=46.5, J=5.7), 7.16–7.42 (6H, m, Haromat), 7.69–7.82 (2H, m, Haromat),
8.06 (1H, d, NH, J=8.70 Hz), 9.94 (1H, s, OH); 13C NMR (75 MHz, DMSO-d6):
168.2, 163.6, 154.2, 146.5, 134.2, 132.4, 130.3, 129.9, 129.5, 129.2, 126.9, 126.4,
126.5, 125.4, 123.6, 122.9, 120.0, 118.6, 94.4, 52.5, 12.5.
1‑[(4‑Bromo‑phenyl)‑(5‑methyl‑isoxazol‑3‑ylamino)‑methyl]‑naphthalen‑2‑ol (4 g)
1H NMR (300 MHz, DMSO-d6): 10.16 (1H, s, OH), 7.97 (1H, d, NH, J=8.1 Hz),
7.77–7.83 (2H, t, Haromat), 7.23–7.48 (7H, m, Haromat), 6.77 (2H, dd, Haromat
,
J=6.6 Hz, J=48.9 Hz), 5.88 (1H, s, CHNH), 2.23 (3H, s, CH3); 13C NMR (75 MHz,
DMSO-d6): 167.8, 164.9, 153.2, 143.3, 132.9, 131.2, 129.8, 129.0, 128.9, 126.8,
124.0, 122.9, 119.9, 119.4, 118.8, 94.4, 52.6, 12.5.
1‑[(3‑Bromo‑phenyl)‑(5‑methyl‑isoxazol‑3‑ylamino)‑methyl]‑naphthalen‑2‑ol (4 h)
1H NMR (300 MHz, DMSO-d6): 10.14 (1H, s, OH), 7.99 (1H, d, NH, J=8.1 Hz),
7.78–7.84 (2H, t, Haromat), 7.19–7.49 (7H, m, Haromat), 6.81 (2H, dd, Haromat, J=47.7,
J=7.2 Hz), 5.88 (1H, s, CHNH), 2.23 (3H, s, CH3); 13C NMR (75 MHz, DMSOd6):
167.9, 164.8, 153.2, 146.7, 132.4, 130.6, 129.9, 129.3, 129.1, 129.0, 126.9, 125.8,
123.8, 122.9, 121.9, 119.8, 118.8, 94.4, 52.6, 12.5.
1‑[(4‑Fluoro‑phenyl)‑(5‑methyl‑isoxazol‑3‑ylamino)‑methyl]‑naphthalen‑2‑ol (4i)
1H NMR (300 MHz, DMSO-d6): 10.11 (1H, s, OH), 7.98 (1H, d, NH, J=8.1 Hz),
7.76–7.83 (2H, m, Haromat), 7.36–7.41 (1H, t, Haromat), 7.25–7.33 (4H, m, Haromat),
7.06–7012 (2H, t, Haromat), 6.77 (2H, dd, Haromat, J=7.5 Hz, J=39.6 Hz), 5.87 (1H,
s, CHNH), 2.23 (3H, s, CH3); 13C NMR (75 MHz, DMSO-d6): 167.8, 164.9, 162.7,
159.5, 153.1, 139.7, 132.5, 129.7, 129.0, 128.5, 128.4, 126.7, 124.0, 122.8, 120.1,
118.8, 115.1, 114.9, 94.4, 52.5, 12.5.
1‑[(5‑Methyl‑isoxazol‑3‑ylamino)‑(4‑nitro‑phenyl)‑methyl]‑naphthalen‑2‑ol (4j)
1H NMR (300 MHz, DMSO-d6): 10.25 (1H, s, OH), 8.17 (2H, d, Haromat
,
J=8.7 Hz), 7.95 (1H, d, NH, J=7.8 Hz), 7.80–7.85 (2H, m, Haromat), 7.54 (2H, d,
Haromat, J=8.7 Hz), 7.38–7.43 (1H, t, Haromat), 7.26–7.30 (2H, m, Haromat), 6.90 (2H,
dd, Haromat, J=6.6 Hz, J=50.1 Hz), 5.89 (1H, s, CHNH), 2.25 (3H, s, CH3); 13C
NMR (75 MHz, DMSOd6): 169.8, 168.0, 164.8, 153.3, 152.2, 146.3, 132.4, 130.2,
130.0, 129.1, 129.0, 128.9, 127.8, 127.7, 127.0, 124.4, 123.8, 123.6, 123.0, 119.4,
118.8, 118.4, 96.3, 94.4, 52.9, 12.5.
1 3

M. Rezaie Kahkhaie et al.
9,9‑Dimethyl‑12‑(phenyl)‑8,9,10,12‑tetrahydrobenzo[a]xanthen‑11‑one (6a)
1H NMR (400 MHz, CDCl3): 7.00–8.07 (m, 10H, Ar–H), 5.59 (s, 1H, CH),
2.62(s, 2H, CH2), 2.58 (d, J = 16.0 Hz, 1H, CH2), 2.35 (d, J = 16.0 Hz, 1H, CH2),
2.14 (s, 3H, CH3), 1.08 (s, 3H, CH3), 0.89 (s, 3H, CH3).
9,9‑Dimethyl‑12‑(4‑methyl phenyl)‑8,9,10,12‑tetrahydrobenzo[a]xanthen‑11‑one
(6b)
1H NMR (400 MHz, CDCl3): 7.00–8.07 (m, 10H, Ar–H), 5.71 (s, 1H, CH), 2.62
(s, 2H, CH2), 2.58 (d, J = 16.0 Hz, 1H, CH2), 2.35 (d, J = 16.0 Hz, 1H, CH2), 2.14
(s, 3H, CH3), 1.08 (s, 3H, CH3), 0.89 (s, 3H, CH3).
9,9‑Dimethyl‑12‑(4‑methoxy‑phenyl)‑8,9,10,12‑tetrahydrobenzo[a]xanthen‑11‑one
(6c)
1H NMR (400 MHz, CDCl3): 6.72–8.07 (m, 10H, Ar–H), 5.69 (s, 1H, CH),
3.72 (s, 3H, OCH3) 2.59 (s, 2H, CH2), 2.36 (d, J = 16.0 Hz, 1H, CH2), 2.30 (d,
J = 16.0 Hz, 1H, CH2), 2.25 (s, 3H, CH3), 1.15 (s, 3H, CH3), 1.00 (s, 3H, CH3).
Supplementary Information The online version contains supplementary material available at https://doi.
org/10.1007/s11164-021-04558-9.
Acknowledgements We gratefully acknowledge the fnancial support from the Research Council of the
University of Sistan and Baluchestan
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Authors and Afliations
Mahboobeh Rezaie Kahkhaie1 · Nourallah Hazeri1 ·
Malek Taher Maghsoodlou1 · Afshin Yazdani‑Elah‑Abadi2
1
Department of Chemistry, Faculty of Science, University of Sistan and Baluchestan,
P.O. Box 98135-674, Zahedan, Iran
2
Department of Biology, Science and Art University, Yazd, Iran
1 3