A Regioselective Approach to Synthesize Indolyl Diketone Derivatives via Magnetic Polymeric Copper-Catalyst

Article abstract of DOI:10.1007/s10562-021-03697-3

Abstract: In the present paper, an efficient Cu-catalyzed regioselective acylation of indoles with phenylglyoxals was developed which is the first example of indolyl diketones synthesis by a heterogeneous catalyst. The magnetic polyacrylonitrile was synth

Full text of DOI:10.1007/s10562-021-03697-3

Catalysis Letters
https://doi.org/10.1007/s10562-021-03697-3
A Regioselective Approach to Synthesize Indolyl Diketone Derivatives
via Magnetic Polymeric Copper‑Catalyst
Firouz Matloubi Moghaddam1 · Atefeh Jarahiyan1 · Ali Pourjavadi2
Received: 1 January 2021 / Accepted: 4 June 2021
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021
Abstract
In the present paper, an efcient Cu-catalyzed regioselective acylation of indoles with phenylglyoxals was developed which is
the frst example of indolyl diketones synthesis by a heterogeneous catalyst. The magnetic polyacrylonitrile was synthesized
through anchoring acrylonitrile monomers on Fe3O4 nanoparticles surface and then modifed with 2-aminopyridine. At the
fnal step, copper nanoparticles were immobilized onto the polymeric support containing stable ligands from functionalized
nitrile groups of polyacrylonitrile. The diferent techniques such as Fourier transmission infrared spectroscopy, X-ray dif-
fraction, Field emission scanning electron microscopy, Transmission electron microscopy, and Thermogravimetric analysis
were used to prove the structure of the polymeric catalyst. Finally, the activity of the magnetic PAN Cu-catalyst was investi-
gated as an efcient magnetic heterogeneous catalytic system to synthesize 3-acylated indoles with good to high yields. The
synthesis of a variety of 3-acylated indoles derivatives was illustrated ready access to this important building blocks class.
Graphic Abstract
Keywords Acylation · C–H functionalization · Heterogeneous catalysis · Indole moieties · Nitrogen heterocycles
1 Introduction
* Firouz Matloubi Moghaddam
matloubi@sharif.edu
Indole moieties have been known as important building
1
blocks in biologically active compounds, natural products,
pharmaceuticals and ubiquitous intermediates in organic
synthesis [1–3]. For instance, these heterocyclic com-
pounds are fundamental scafolds in a large number of anti-
cancer, anti-HIV and type 2 diabetes’ treatment drugs [4].
Laboratory of Organic Synthesis and Natural Products,
Department of Chemistry, Sharif University of Technology,
Azadi Street, PO Box 111559516, Tehran, Iran
2
Polymer Research Laboratory, Department of Chemistry,
Sharif University of Technology, Azadi Street, PO
Box 111559516, Tehran, Iran
Vol.:(0123456789)
1 3

F. M. Moghaddam et al.
3-Acylindoles are among the most value-added structures
because they are not only privileged structures in medicinal
chemistry and drug design but also ideal intermediates for
the preparation of versatile indole derivatives (Fig. 1) [5–7].
Owing to their carbonyl groups, acylindoles have attracted
synthetic organic chemists’ interest for versatile transfor-
mations such as carbon–carbon and carbon-heteroatom
coupling reactions and also polyheterocyclic compounds
fabrication as efcient probes for Hg2+ and Fe3+ [1–3, 8].
The 3-acylindole has proven successful for the heteroannu-
lated 3-(2-aminophenyl)-pyridines synthesis, a signifcant
structure in drug discovery and drug design, using electron-
donating aminoheterocycles with 3-acylindoles [9]. It is also
used for the synthesis of SB-216763, selective glycogen syn-
thase kinase-3 inhibitor, containing condensation of (aryl or
indolyl)glyoxyl esters with (aryl or indolyl)acetamides [10].
Thereupon, the new preparation methods for the synthe-
sis of 3-acylindoles have received intense attention and to
date, the carbo-acylation of indoles synthesis with transi-
tion-metal-catalyst were disclosed in the literature reports
[11–14]. For instance, Xiang and Li’s group illustrated a
new method to synthesize 3-acylation indole derivatives by
oxidative cross coupling of indoles and α-amino carbonyl
compounds with aim of Pd-catalyst (Scheme 1a) [1]. Yang
and Ji’s group reported copper-catalyzed the construction
of 3-acylated indoles using α-carbonyl aldehydes in good
to excellent yields (Scheme 1b) [15]. In addition, Zhang
and Duan et al. provided an expedient synthetic method
for 3-acylindoles with the aid of α-carbonyl aldehydes and
Cu(OAc)2 as a homogeneouse catalyst. A broad substrate
scope and moderate to good yields were some advantages
of their method [16]. In 2017, the synthesis of 3-acylindoles
was developed by Yi et al., they applied iron as a catalyst and
indoles with α-amino carbonyl compounds as easily avail-
able starting materials (Scheme 1c) [17]. The high atom
economy synthesis of dicarbonyl indoles investigated by
Guo and his co-workers. They applied styrenes and indoles
as starting materials under metal-free conditions [18].
Despite of such eforts, there are some restrictions, such
as the need for expensive palladium, side reactions, reus-
ability and separation problems of catalysts, and the more
important poor selectivity.
To the best of our knowledge, no examples of heteroge-
neous catalysts have been disclosed to synthesize indolyl
diketone derivatives before. Inspired by our aforemen-
tioned background, we decided to apply a heterogeneous
catalyst involving stable ligands for the immobilization of
copper to improve the reaction conditions [19]. Among dif-
ferent catalyst supports, polyacrylonitrile (PAN) has been
attractive with broad properties such as superior catalytic
activity, superior thermal stability, low cost, and accessibil-
ity [20–22]. Since, PAN has plentiful cyano groups, it is
the main precursor for a series of functional groups such
as tetrazoles, amidines, amines, aldehydes, amides and
Fig. 1 Examples of biologically
active compounds based on
OCH3
CO2H
O
O
N
O
3-acylated indoles
NH
N
H
HO
O
N
O
N
F3OC
O
N
N
O
O
HN
HO
H
N
N
H
MK-0533
F
AM-2201
O
O
MeO
Cyclomarin C
H
O
N
O
N
H
N
O
O
N
H
N
O
OEt
N
H
H3CO
O
N
H
Cl
Inhibitor for the enzyme h-15-LOX-1
Fumitremorgin C
Echiniulin
Me
O
O
N
N
Ph
O
N
H
GPRC6A
1 3

A Regioselective Approach to Synthesize Indolyl Diketone Derivatives via Magnetic Polymeric…
Scheme 1 Synthesis of
O
R
O
a
Xiang 's work, 2013
3-acylindoles
R3
R4
R3
Pd(OAC)2, Cu(OAC)2, air
HOAc, MeCN, 80°C
N
R
N
R5
O
R1
N
R1
R2
R2
R2= H, Me
O
O
b Yang 's work, 2015
O
H
R3
CuBr, Pyridine, air
Toluene, 90°C
R
O
N
O
N
R1
R1
R3
R2
R2
O
c Yi 's work, 2017
R3
R3
Fe(OTf)3, TBHP
PhHN
PivOH, DMSO, 50°C
N
N
O
R1
R1
R2
R2
O
O
d Our work
O
Magnetic PAN-based
Cu-catalyst (5 mol% )
H
R2
CH3CN/HOAC, 80°C
O
N
N
R1
R2
R1
carboxyl derivatives which makes it an excellent candidate
to immobilize various transition metals [23, 24].
On the other hand, incorporation of Fe3O4 nanoparticles
with the polymeric chains can enhance nanocomposite prop-
erties like its chemical, thermal, and mechanical stability
compared to the pure polymer. In addition, homogeneous
dispersibility, fast and easy separation, excellent stability,
and high surface area are some advantages of magnetic cata-
lysts under diferent conditions [25].
polymerization. Afterwards, the acrylonitrile monomers and
initiators were added to the fask equipped with a condenser
and heated which led to complete the reaction. In the fol-
lowing step, the magnetic PAN support was modifed with
2-aminopyridine (2-AP). Finally, the immobilization of cop-
per nanoparticles on the magnetic PAN/2-AP support was
performed by dispersion of the magnetic PAN/2-AP sup-
port in a CuCl2 solution. In this step, the copper ions were
coordinated with various functional groups in the prepared
support (Scheme 2). After proving the catalyst structure, our
investigation was initiated using indole and arylglyoxal as
coupling partners in the presence of 5 mol% of the magnetic
PAN-based Cu catalyst to provide a variety of corresponding
products. The activity of the catalyst was examined through
C3 functionalized indoles which sufers from competing
reactions between N1, C2 and double acylated at N1 and C3
positions because the aromatic system has intrinsic reactiv-
ity [26, 27].
Thus, the preparation of viable catalytic system including
magnetic PAN as a catalyst support and copper nanoparticles
can be useful to construct the 3-acylated indoles regiose-
lectively in mild reaction conditions with excellent yields
(Scheme 1d).
2 Results and Discussion
2.1 Synthesis of the Catalyst
2.2 Characterization of the Catalyst
The magnetic PAN support was synthesized through a
several-step procedure, including the synthesis of Fe3O4
nanoparticles modified with 3-(trimethoxysilyl)propyl-
methacrylate (MPS) to prepare the magnetite surface for
According to FT-IR spectroscopy, all spectra with demon-
strated bands at 576, 1100, 1412 and 1718 cm−1 have been
identifed as Fe–O, Si–O, C=C (for MPS) and C=O (for
1 3

F. M. Moghaddam et al.
stretching vibrations, which its intensity decreased after
modifcation by 2-AP in the next step (Fig. 2c). As can be
seen in Fig. 2d, the fnal catalyst showed pyridine-related
peaks at 1671 cm−1 (N-sp2 stretching vibration), 1176 cm−1
(N-sp3 C bond), and 641 cm−1 (C‒H bending vibration of
pyridine) [29, 30].
CN
+ AIBN
Reflux, DI water
60 °C, 24h
The XRD pattern indicates that the crystalline nature of
Fe3O4 nanoparticles has preserved during catalyst synthe-
sis; based on comparing data with JCPDS Card (No.98-011-
1284) [19]. Also, no sharp difraction peaks are detected for
PAN which shows the amorphous structure of this polymer
[31].
CN
O
CN
O
CN
O
O
O
O
O
O
O
1.
O
O
O
O
O
O
i
i
i
S
S
S
N
NH2
O
O
O
O
O
O
O
O
O
i
i
i
S
S
S
O
O
O
O
O
O
Magnetic Nanoparticles
Reflux, DI water
Magnetic Nanoparticles
Fe3O4@SiO2@MPS
FE-SEM and TEM analyses of the catalyst are given in
two magnifcations that confrm the catalyst morphology.
The FE-SEM images show that the nanoparticles are small
and well-dispersed within the polymeric support material
(Fig. 3a and b). Based on the TEM image, the average nano-
particles size of the catalyst is 37 nm with a core–shell struc-
ture which is related to surface modifcation of magnetite
with PAN polymer and other organic layers. Therefore, they
can confrm the proposed structure of the resulting catalyst
(Fig. 4a and b).
2.
CuCl2
RT, DI water
Cu2+
N
N
N
Cu2+
O
Cu2+
HNC
HNC
O
HNC
O
O
O
O
Cu2+
O
O
O
Cu2+
Cu2+
O
O
O
O
i
i
S
S
S i
O
O
O
O
O
Magnetic Nanoparticles
In addition, the EDX analysis was taken to show the con-
tents of various components in the catalyst (Fig. 5).
TGA spectrum for the fnal catalyst is provided as a ref-
erence for the investigation of ligand amounts anchored to
the inorganic core at a temperature range of 25–750 °C. It
can confrm the presence of PAN and 2-AP and the thermo-
gram shows good thermal stability of the catalyst, which
is an important property. The frst step (100 °C region) is
assigned to water molecules [32] and the whole organic
phase is burned in the next steps (Fig. 6).
Scheme 2 Preparation procedure of the magnetic PAN Cu-catalyst
2.3 Catalytic Activity
With the new magnetic PAN-based Cu-catalyst in hand, a
series of experiments were performed to obtain optimized
conditions for the acylation of indoles. It commenced with
indole 1 and arylglyoxal 2 to investigate diferent solvents
such as toluene, 1,2-dichloroethane (DCE), dimethyl sulfox-
ide (DMSO), acetonitrile (MeCN) and 1,4-dioxane under
an air atmosphere in which the yield was higher in MeCN
(Table 1, entry 1–5). After solvent optimization, we found
that, reducing the amount of catalyst from 5 to 3 mol%
decreased the yield of the product from 92 to 87% (Table 1,
entry 4 and 6) and increasing the catalyst amount from 5
to 10 mol% did not drastically improve the product yield
(Table 1, entry 4 and 7). No product was produced without
the catalyst even though time and temperature of reaction
were increased (Table 1, entry 8 and 9). Also, the use of
higher temperature did not enhance the yield (Table 1, entry
10). In the next step, the treatment of indole 1 with arygly-
oxal hydrate 2 at room temperature provided only 20% of the
Fig. 2 FT-IR spectra of a Fe3O4@SiO2, b Fe3O4@SiO2@MPS, c
Fe3O4@PAN, d Final Cu-catalyst
MPS) stretching vibrations which ensures the successful
coating of MPS on the Fe3O4 surface (Fig. 2b) [28]. The
presence of PAN on the Fe3O4 core–shell was proved by
the characteristic peak at 2375 cm−1 assigned to cyano
1 3

A Regioselective Approach to Synthesize Indolyl Diketone Derivatives via Magnetic Polymeric…
Fig. 3 FE-SEM images of the
magnetic PAN Cu-catalyst in
two magnifcations a 1 µm and
b 200 nm
Fig. 4 TEM images of the
magnetic PAN Cu-catalyst in
two magnifcations a 40 nm and
b 80 nm
Fig. 5 EDX of the magnetic
PAN Cu-catalyst
1 3

F. M. Moghaddam et al.
entry 13 and 14; respectively). The trace amount of desired
product was provided by 5 mol% of Fe3O4 nanoparticles
after 12 h and Cu nanoparticles decorated Fe3O4 could pro-
duce only 38% of the product after 24 h. It is worth to note;
the present polymeric catalyst was prepared as a nitrogen-
rich support to immobilize high amounts of Cu nanoparti-
cles into it. Also, such polymeric support could reduce the
leaching of Cu nanoparticles by trapping them into the poly-
meric chains [25]. This property led to high loading of Cu
nanoparticles without signifcant leaching and therefore, the
lower amounts of the catalyst provided more active sites to
complete the reaction. Hence, the present catalyst provided
higher activity than the Cu/Fe3O4 catalyst with similar cata-
lyst loading.
Fig. 6 TGA thermogram of the catalyst
After screening the reaction parameters and inspired by
the results, diverse products were synthesized under an air
atmosphere at 80 °C for 4 h using 5 mol% of Cu-catalyst,
and combination of MeCN/acetic acid (HOAC) as the sol-
vent (2 mL), then the results were collected in Table 2. A
series of arylglyoxal hydrates with para-position substituted
were compatible under the reaction conditions, and the
desired products were isolated in good yields. All methoxy,
desired product 3 whereas the amount of catalyst and time
of reaction were evaluated (Table 1, entry 11). when the
reaction was done under a nitrogen atmosphere, the lower
yield was observed that is confrmed the reaction atmosphere
plays an important role in this reaction (Table 1, entry 12). In
the following, Fe3O4 nanoparticles (5 mol%) and Fe3O4@Cu
nanoparticles (5 mol%) were applied as the catalyst (Table 1,
Table 1 Screening of reaction condition for Copper@Magnetic PAN/2-AP catalyst on 3-acylated indoles
Entry
Solvent
Catalyst (mol%)
T (°C)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
Toluene
DCE
5
5
5
5
5
3
10
–
–
5
10
80
80
80
80
80
80
80
80
120
100
rt
4
4
4
4
4
4
4
12
12
4
24
4
59
47
Trace
92
71
87
92
Trace
Trace
92
20
77
Trace
38
DMSO
MeCN
1,4-Dioxane
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
9
10
11
12b
13
14
5
80
80
80
Fe3O4 (5 mol%)
Fe3O4@Cu NPs (5 mol%)
12
24
Indole (0.25 mmol), arylglyoxal hydrate (0.3 mmol), catalyst, solvent (2 mL) under an air atmosphere
aIsolated yields are given
bUnder N2 atmosphere
1 3

A Regioselective Approach to Synthesize Indolyl Diketone Derivatives via Magnetic Polymeric…
Table 2 Scope of Indoles and
arylglyoxals toward 3-acylated
indole synthesis
Entry
1
Indoles
Arylglyoxal hydrates
Products/Yield (%)a
3aa, 93%
2
3
4
5
6
7
3ab, 89%
3ac, 91%
3ad, 86%
3ae, 87%
3af, Trace
3ba, Trace
8
3cb, 82%
3cc, 80%
3cd, 81%
3ce, 84%
9
10
11
12
3da, 83%
3dd,81%
13
1 3

F. M. Moghaddam et al.
Table 2 (continued)
14
15
16
3de, 83%
3dc, 82%
3ea, 82%
3ed, 80%
3ee, 81%
3eb, 81%
3ec, 82%
17
18
19
20
21
3fd, 82%
3ge, 81%
3ha, 80%
3hd, 76%
22
23
24
25
3he, 79%
Indole (0.25 mmol), arylglyoxal hydrates (0.3 mmol), 5 mol% of cata-
lyst, MeCN (2 mL) under an air atmosphere
aIsolated yields are given
1 3

A Regioselective Approach to Synthesize Indolyl Diketone Derivatives via Magnetic Polymeric…
methyl, bromo- and chloro-substituted arylglyoxals exhib-
ited the desired products in moderate to good yields. The
free (N–H) indoles provided high reactivities and gave the
corresponding products in good yields (3aa-ae). The aryg-
lyoxals with electron-donating groups such as p-CH3 and
p-OCH3 showed the high efciency and the desired products
were generated in excellent yields (3ab:89% and 3ac:91%).
The arylglyoxals with electron-defcient substitutions (p-Cl
and p-Br) reacted with free (N–H) indole and the yields of
reaction were obtained in 87% and 86%, respectively (3ad
and 3ae). However, the reaction of strong electron-defcient
nitro-substituted arylglyoxal did not give the dicarbonyl
indole product because the electron density was decreased
(3af). And also, 2-methyl indole could not react with aryl-
glyoaxal and it furnishes the favorite product 3ba only in
trace amount.
fnal step, the product 3 was formed by aerobic oxidation
of intermediate II leading to the release of the Cu-catalyst.
To demonstrate the reusability of the prepared Cu-cata-
lyst, the catalyst was applied to several model reactions and
the reactions were monitored by thin layer choromatograghy
(TLC). When each reaction was completed, it was separated,
washed with methanol (5 × 5 mL), dried at 50 °C to 24 h
and used for the next run to confrm the recyclability of the
prepared Cu-catalyst. It is worth mentioning that no signif-
cant metal leaching and reduction product yield was detected
and the recovered catalyst was reused in nine cycles with no
signifcant loss of activity (Table 3).
Based on the ICP-OES results, the loading amounts of
Cu2+ were calculated 0.77 and 0.71 mmol g−1 for fresh cata-
lyst and the recovered catalyst after ninth cycle; respectively,
which is high loading of copper ions per 1 g of the catalyst.
Compared to the previous literature, the reported works
sufer from some restrictions such as the use of expensive
palladium nanoparticles, stoichiometric amounts of iodine
and copper, and complex ligands as well as by-products gen-
eration, long reaction time, and low yield (Table 4, entry
1–6). To overcome these limitations, the magnetic PAN
Cu-catalyst was synthesized and used in the synthesis of
indolyl diketones (Table 4, entry 7). The worthwhile char-
acteristics of the presented method are summarized below:
(a) The use of an inexpensive catalyst with high-loading
copper through stable ligands; (b) Mild reaction conditions
(higher yield versus lower reaction time); (c) The use of low
catalyst weight percentages for acylation of indoles due to its
high catalytic efciency; (d) Having high catalyst reusability
because the prepared catalyst can be easily separated via an
external magnet and applied to several runs, making it useful
for industrial applications.
Subsequently, the diacylation of a series N-substituted
indoles were tested with arylglyoxals bearing p–H, p-CH3,
p-OCH3, p-Cl, and p-Br groups. The results showed they
worked well under the optimal reaction conditions to pro-
vide the favorite products. As presented in Table 2, N-methyl
(3cb-ce), N-ethyl (3da-dc), N-isopropyl (3ea-ec), N-propyl
(3fd), N-butyl (3ga), and N-benzyl (3 ha-he) indole sub-
strates could proceed to give the corresponding products in
good yields. But, the indoles with bulkier N-substitutions
such as N-benzyl group produced the products in lower
yields. According to the above results, it is clear that the
reaction could tolerate diferent functional groups with vari-
ous electronic properties (1H and 13C NMR spectral data of
compounds can be found in Supplementary data).
To confrm the potential of this catalytic system, the prod-
uct 3ad was successfully synthesized from free (N–H) indole
and para-bromoarylglyoxal under the optimal conditions in
a gram scale. It is noteworthy, the reaction time increased
slightly and the desired product was detected in 81% yield
(Scheme 3).
3 Conclusion
On the basis of the experimental results and previous lit-
erature reports [16, 18, 33], a plausible reaction mechanism
is demonstrated in Scheme 4. Initially, arylglyoxal 2 was
activated by the Cu-catalyst system to provide intermediate
I; Subsequently, indole 1 attacked by the C3 position through
Friedel–Crafts type reaction and gave intermediate II. At the
In summary, we have demonstrated a simple, scalable and
regioselective Cu-catalyzed acylation of indoles with phe-
nylglyoxals. In this work, indole moieties were selected
because they are important scafolds for natural products,
biologically active and pharmaceutical compounds. On the
other hand, it is a new method to construct magnetic PAN
Cu-catalyst as an efcient magnetic heterogeneous catalyst
with a several-step procedure. The high ability of the poly-
meric support to hold Cu ions which is resulted from its
diferent functional groups accompanied by its stability and
easy recyclability plays a crucial role in improving the cata-
lyst activity. Finally, a wide range of starting materials were
studied, and the desired indolyl diketone derivatives were
synthesized in excellent yields as common intermediates.
Moreover, a gram scale experiment was performed in good
yield suited for further derivatization.
O
O
O
Magnetic PAN-based
Cu-catalyst (5 mol% )
H
CH3CN/HOAC, 80°C
N
H
Br
O
N
H
Br
1a
2d
3ad
3 mmol, 352 mg
3.6 mmol, 831 mg
81%, 891 mg
Scheme 3 Reaction carried out on
a
large scale of
1-(4-bromophenyl)-2-(1H-indol-3-yl) ethane-1,2-dione
1 3

F. M. Moghaddam et al.
Scheme 4 Possible reaction
O
mechanism
OH
OH
R2
+H2O
O
O
N
NH
-H2O
R2
O
Cu2+
O
O
. H2O
N
R1
H
R2
air
N
NH
HN
O
O
Cu2+
. H2O
O
O
OH
N
O
Cu2+
Intermediate I
H
R2
R2
Intermediate II
N
R1
H2O
N
R1
Magnetic support
Cu2+
Table 3 The recyclability of the magnetic PAN Cu-catalyst in the synthesis of indolyl diketone under optimal conditions
Run
1
2
3
4
5
6
7
8
9
Yield%
93
93
93
91
90
89
86
86
85
Table 4 Comparison of catalysts activity in 3-acylated indole synthesis
Entry Catalyst(Loading) Reaction conditions
Time (h) Yield (%)
References
1
2
Pd(OAC)2 (5 mol%)
CuBr (10 mol %)
Indoles, α-amino carbonyl compounds, Cu(OAC)2 (2 mol%), CH3CN/ 12
64 (R=H)
[1]
HOAc, air, 80℃
N-methylindoles, ɑ-carbonyl aldehydes, pyridine (50 mol %), toluene,
6
70 (R=Me)
[15]
90 ℃
3
4
5
6
7
Fe(OTf)3 (10 mol%)
CuCl2 (10 mol%)
CuTC (10 mol %)
Indoles, α-amino carbonyl compounds, TBHP, PivOH, DMSO, 50℃
Indoles, α-amino carbonyl compounds, TBHP, CH2Cl2, air, RT
N-methylindoles, α-Hydroxy Ketones, Toluene, O2, 80℃
15
18
12
12
4
70 (R=H)
76 (R=H)
81 (R=Me)
84 (R=H)
[17]
[11]
[13]
[12]
Pyrrolidine (25 mol%) Indoles, acetophenone, I2, DMSO, 90℃
Copper@Magnetic
Indoles, ɑ-carbonyl aldehydes, CH3CN/HOAc, air, 80℃
91 (R=H)
This work
PAN/2-AP (5 mol%)
80 (R=Me)
1 3

A Regioselective Approach to Synthesize Indolyl Diketone Derivatives via Magnetic Polymeric…
(monitored by TLC), then the mixture diluted with ethyl
4 Experimental Section
acetate and water and the layers were separated. The ethyl
acetate was used to extract aqueous layer (3 ×10 ml). The
combined organic layers were washed with saturated brine,
dried with Na2SO4 and after fltration, evaporated under
reduced pressure. The crude products were purifed by col-
umn chromatography on silica gel (n-hexan/ethyl acetate,
10/3, v/v) to provide the desired products 3.
4.1 General Procedure for the Synthesis
of Polyacrylonitrile‑Based Copper Catalyst
4.1.1 Immobilization of Acrylonitrile on Fe3O4@SiO2
Microspheres
The co-precipitation method was applied to synthesize
Fe3O4@SiO2 nanoparticles and then coated with MPS as
mentioned in the previous literature [34, 35]. In order to
polymerize polyacrylonitrile on the surface of Fe3O4@
SiO2@MPS, 3 mL of acrylonitrile was added to 0.30 g
of Fe3O4@SiO2@MPS in 20 mL of deionized water and
completely degassed under N2 atmosphere. Then, 10 mg of
azobisisobutyronitrile (AIBN) was added and refuxed for
24 h. After that, an external magnet was used to collect the
resulting magnetite nanoparticles and washed with deionized
water (DI water) and methanol three times, and fnally dried
in a vacuum oven at 50 °C for 12 h to provide the magnetic
PAN [19].
4.3 Spectroscopic Characterization of the Product
3ad
1-(4-bromophenyl)-2-(1H-indol-yl)ethane 1,2-dione: Ana-
lytical TLC on silica gel, (n-hexan/ethyl acetate, 10/3, v/v);
Yellow solid; 891 mg, yield 81%; mp 210–212 °C; 1H NMR
(500 MHz, DMSO-d6): δ 12.15 (s, 1H), 8.22 (s, 1H), 8.18
(s, 1H), 7.97 (d, J = 7.1 Hz, 2H), 7.61 (d, J= 6.9 Hz, 2H),
7.56 (d, J = 6.0 Hz, 1H), 7.32 (d, J = 3.4, 2H); 13C NMR
(125 MHz, DMSO-d6) δ 194.43, 188.99, 138.39, 137.46,
135.11, 133.45, 132.02, 130.17, 129.58, 129.11, 125.47,
124.29, 123.27, 121.61, 113.22, 113.04; FT-IR (neat) 3120,
3050, 1663, 1625, 1584, 1525, 1468, 1396, 1338, 1305,
1277, 1209, 1249, 1173, 1140, 1125, 1091, 1068, 991, 865,
843, 815, 776, 751, 736, 700, 624, 618, 579, 541, 504, 465,
423 cm−1.
4.1.2 Preparation of the Magnetic PAN/2‑Aminopyridine
(2‑AP) Cu‑Catalyst
In a round bottom fask, 0.50 g of magnetic PAN in DI
(30 mL) and 10 mmol of 2-aminopyridine were mixed and
refuxed. After 4 h, the magnetic PAN/2-AP was collected,
washed with DI water and methanol three times, and dried
in a vacuum oven at 50 °C for 12 h to provide the magnetic
PAN/2-AP. Finally, the saturated CuCl2 salt was added to the
mixture and stirred at room temperature for 24 h. The cata-
lyst was collected by an external magnet, washed with water
three times (3×20 mL) and dried under reduced pressure.
Supplementary Information The online version contains supplemen-
tary material available at https://doi.org/10.1007/s10562-021-03697-3.
Acknowledgements Authors thank the Research Afairs Division sha-
rif University of Technology (SUT) by the Islamic Republic of Iran for
fnsncisl support.
Declarations
Conflict of interest There are no confict to declare.
4.1.3 Preparation of the Fe3O4@Cu Nanoparticles Catalyst
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In a round bottom fask, the saturated CuCl2 salt was added
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at room temperature for 24 h. Then, the catalyst was col-
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(3×10 mL) and dried under reduced pressure.
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