A magnetically recoverable copper–salen complex as a nano-catalytic system for amine protection via acetylation using thioacetic acid

Article abstract of DOI:10.1007/s11164-018-3702-8

A novel copper(II)–salen complex was immobilized on the surface of magnetite nanoparticles using chitosan as a linker. This system exhibits superior catalytic activity in acetyl protection of various amines with thioacetic acid as the acetylating reagent. The method has advantages over others in high selectivity, simple work-up, green reaction medium and the application of an easily recoverable heterogeneous catalyst.

Full text of DOI:10.1007/s11164-018-3702-8

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-018-3702-8
A magnetically recoverable copper–salen complex
as a nano‑catalytic system for amine protection
via acetylation using thioacetic acid
1
1
1
Elahe Yazdani · Maryam Kazemi Miraki · Arefe Salamatmanesh ·
1
1
1
1
Jamshid Azarnia · Kobra Azizi · Leila Ghandi · Akbar Heydari
Received: 20 August 2018 / Accepted: 5 December 2018
©
Springer Nature B.V. 2019
Abstract
A novel copper(II)–salen complex was immobilized on the surface of magnetite nan-
oparticles using chitosan as a linker. This system exhibits superior catalytic activity
in acetyl protection of various amines with thioacetic acid as the acetylating reagent.
The method has advantages over others in high selectivity, simple work-up, green
reaction medium and the application of an easily recoverable heterogeneous catalyst.
Keywords Thioacetic acid · Copper–salen complex · Magnetite · Nano catalyst ·
N-Acetylation
Introduction
Amines are a beneꢀcial class of compounds which are used as bioactive com-
pounds, dyes and especially synthetic intermediates in the manufacture of many
pharmaceutically active ingredients [1–4]. Due to the presence of a lone elec-
tron pair, amines can act as both nucleophiles and bases. Alkylation, the Schot-
ten–Baumann reaction, imine/enamine formation and oxidation are mentioned
examples in the literature [5–11]. Hence, because of their signiꢀcant nucleo-
philicity, it is unavoidable to protect amine functional groups in the presence of
other nucleophilic functionalities (e.g., OH, S, P, etc.) to exclude side reactions
[
12–15]. Generally, the protecting groups are electron-withdrawing substituents,
This article is dedicated to memory of Hasan Rahimi.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s1116
4
-018-3702-8) contains supplementary material, which is available to authorized users.
*
Akbar Heydari
heydar_a@modares.ac.ir
1
Chemistry Department, Tarbiat Modares University, P.O. Box 14155-4838, Tehran, Iran
Vol.:(012
1
3456789)
3

E. Yazdani et al.
intended to decrease the nucleophilicity of the nitrogen atom. Thus, classically,
the amino group is protected with (1) carboxylic acid-derived groups such as for-
myl, triꢁuoroacetyl, phthaloyl, acetoacetyl, maleoyl, chloroacetyl and 2-nitroben-
zoyl, and (2) urethane-type protecting groups like benzyloxycarbonyl (Cz, Bz),
furfuryloxycarbonyl (Foc), pyridine-4-methoxycarbonyl (Inc) and tert-butyloxy-
carbonyl (Boc) [16]. Among various methods for the protection of amines, the
acetyl moiety is one of the most employed ones [17]. Acetyl chloride and acetic
anhydride are widely applied reagents for the acetyl protection of amines. The
protocols normally comprise either basic or acidic catalysts [18–28]. In spite of
the popularity of these reagents in classical organic synthesis, there are inherited
problems associated with the mentioned reagents, such as sensitivity to moisture,
the possibility of side reactions and violent reactivity [29].
Thioacetic acid is an organosulfur analogue of acetic acid. It is usually
employed for the introduction of a thiol group in molecules. The compound is
a yellow liquid which is readily soluble in water [30]. Recently, thioacids have
attracted considerable interest in peptide science, as well as in native chemical
ligiation [31–40]. Moreover, Gopi et al. [41] reported selective acetyl protection
of amines using thioacetic acid in the presence of copper(II) acetate as catalyst.
However, recycling of the catalyst in this system is quite cumbersome. Further-
more, there is a possibility for product contamination with metal ions, which
might be hazardous in pharmaceutical and natural product syntheses. Although
there are more recent reports of using thioacetic acid [42] (or its potassium salt
[
43]), a more eꢂcient protocol is still required, because this method suꢃers from
the use of various reagents, long reaction times and not being economically
viable.
Magnetic nanoparticles are considered as valuable supports for the embedding of
various organocatalysts and metals due to their high eꢂciency and easy separation
from the reaction mixture by applying an external magnet, which eliminates tedious
and time-consuming ꢀltration or centrifugation [44].
Schiꢃ bases have been intensively explored as ligands and have played impor-
tant roles in the development of coordination chemistry and catalysis. Schiꢃ bases
are typically prepared via the condensation of a primary amine with an aldehyde
or ketone [45]. Schiꢃ base–metal complexes have been used as catalysts in many
organic transformations such as epoxidation of oleꢀns [46], hydrogenation of
organic substrates [47], asymmetric ring opening of terminal epoxides [48] conver-
sion of epoxides into halohydrins [49], oxidation reactions [50], synthesis of pyri-
dopyrazine and quinoxaline derivatives, and cross-coupling reactions [51].
Chitosan, a linear polysaccharide of glucosamine, is the product of deacetylation
of chitin in alkaline media. The natural source of chitin is the exoskeleton of shrimps
and crabs [52]. Therefore, chitosan is highly biodegradable and environmentally
benign [53].
As the progress of our recent researches on environmentally friendly catalytic
systems [54–58], we devised a nanocatalyst, taking advantage of the easy separation
of magnetic nano-catalysts, the powerful complexing nature of Schiꢃ bases, and the
green character of chitosan, to heterogenize copper(II) ion to be applied in the acetyl
protection of amines using thioacetic acid.
1
3

A magnetically recoverable copper–salen complex as a…
Experimental section
All chemicals and solvents were purchased from commercial suppliers and
used without further puriꢀcation. FT-IR spectra were obtained over the region
−
1
4
00–4000 cm with a Nicolet IR100 FT-IR with spectroscopic grade KBr. XRD
patterns were obtained at room temperature with a Philips X-pert 1710 diꢃrac-
tometer with Co Kα (λ = 1.78897 Å), 40 kV voltage, 40 mA current and in the
−
1
range 10°–90° (2θ) with a scan speed of 0.020 s . Scanning electron microscopy
(
Philips XL 30 and S-4160) was used to study the catalyst morphology and size.
Magnetic saturation of the catalyst was investigated using a vibrating magnetom-
eter/alternating gradient force magnetometer (VSM/AGFM; MDK, Iran). Ther-
mogravimetric analysis was conducted using a thermal analyser with a heating
−
1
rate of 20 °C min over a temperature range of 25–1100 °C underꢁowing nitro-
gen. 1H NMR spectra were recorded with a Bruker Advance (DRX 500 MHz,
DRX 250 MHz, DRX 400 MHz) in pure deuterated dimethylsulfoxide and chlo-
roform (Sigma) solvent with tetramethylsilane as internal standard.
Preparation of Cu(II)–salen complex
Preparation of chitosan‑TCT adduct (Cb1)
Amounts of 1 g of chitosan and 10 mmol of cyanuric chloride (TCT) were stirred
in toluene (10 mL) under reꢁux for 24 h [59]. The resulting product (2 g) was ꢀl-
tered and washed with ethanol and dried at 50–60 °C overnight.
Preparation of chitosan‑TCT‑En adduct (Cb2)
An amount of 0.5 g of Cb1 was dispersed in 2 mL of ethylene diamine and stirred
under reꢁux for 24 h [59]. The obtained solid (0.7 g) was separated by ꢀltration
with subsequent washing with ethanol. It was dried at 60 °C for 12 h to be used in
the next step.
Preparation of chitosan‑TCT‑salen ligand (Cb3)
An amount mof 10 mmol of salicylaldehyde was added to a suspension of 0.5 g
of Cb2 in 10 mL methanol and 10 mL glacial acetic acid. The resulting mixture
was reꢁuxed for 24 h. The product (Cb3, 1.1 g) was ꢀltered, washed with ethanol
and acetone, and then dried at 80 °C for 3 h.
Preparation of chitosan‑TCT‑salen–Cu(II) complex(Cb4)
An amount of 0.5 g of prepared ligand was dispersed in 20 mL of methanol fol-
lowed by stepwise addition of 2 mmol CuCl and 1 mmol KOH. The mixture
2
1
3

E. Yazdani et al.
was stirred under reꢁux for 6 h. Finally, the resultant solid (0.64 g) was ꢀltered,
washed with water and acetone, and dried at 80 °C for 3 h.
Preparation of magnetite nanoparticles
Magnetite nanoparticles were prepared according to the previously reported literature
[
65]. To a vigorously stirred solution of 10 mmol FeCl ·6H O and 5 mmol FeCl ·4H O
3 2 2 2
in 40 mL deionized water at 80 °C, 10 mL of aqueous ammonia solution (25%W/W)
was added in small portions. After 2 h, the resulting black solid was magnetically ꢀl-
tered and washed several times with water till reaching pH 7. Then, the nanoparticles
were washed twice with ethanol and dried at ambient temperature.
Preparation of γ‑Fe O nanoparticles
2
3
Magnetite nanoparticles, prepared according to the previous section, were calcined at
00 °C in a vacuum for 3 h to obtain γ-Fe O @SiO .
3
2
3
2
Preparation of Fe O @SiO nanoparticles
3
4
2
A coating of a layer of silica on the surface of the Fe O nanoparticles was achieved
3
4
through hydrolysis of tetraethyl orthosilicate (TEOS), 2 mL of which was added to the
reaction ꢁask containing the mixture of “Preparation of magnetite nanoparticles” sec-
tion and EtOH (40 mL), and the mixture was continuously stirred overnight at 40 °C.
After decanting by a permanent magnet, the silica-coated nanoparticles were washed
three times with hot EtOH and dried at room temperature overnight.
Preparation of γ‑Fe O @SiO nanoparticles
2
3
2
The silica-coated magnetic nanoparticles prepared according to the previous section
were calcined at 300 °C in a vacuum for 3 h to obtain γ-Fe O @SiO .
2
3
2
Preparation of Fe O @TiO nanoparticles
3
4
2
A TiO layer was deposited on the magnetite nanoparticles according to a same proce-
2
dure as in “Preparation of γ-Fe O nanoparticles” section, in which titanium(IV) iso-
2
3
propoxide was used instead of TEOS.
Preparation of γ‑Fe O @TiO nanoparticles
2
3
2
Titania-coated magnetic nanoparticles prepared according to the previous section were
calcined at 300 °C in a vacuum for 3 h to obtain γ-Fe O @TiO .
2
3
2
1
3

A magnetically recoverable copper–salen complex as a…
Immobilization of chitosan‑TCT‑Salen–Cu(II) complex on magnetite nanoparticles
An amount of 1 g of freshly prepared magnetite nanoparticles was dispersed
in 20 mL slightly acidiꢀed water (10% w/w AcOH). Then, 0.5 g of the Cu(II)
complex was added to the mixture and stirred for 12 h at room temperature. The
resulting nanoparticles were washed with methanol, water and diethyl ether and
dried at room temperature overnight.
General procedure for N‑acetylation reaction
To a mixture of amine (1.0 mmol, 0.093 for aniline) and thioacetic acid
(
1.0 mmol, 0.076 g) in water (1 mL), the catalyst (40 mg) was added. The sus-
pension was stirred for 5 min at ambient temperature, and the reaction progress
was monitored using thin layer chromatography. After the reaction was consid-
ered complete, when the starting material was totally consumed, the catalyst
was removed from the reaction mixture with a permanent magnet. The reaction
vessel was washed several times with water and methanol. The reaction mixture
was extracted from the aqueous mixture with EtOAc (3 × 10 mL) and dried with
Na SO . After evaporation of the solvent under vacuum, the crude product was
2
4
obtained which could be further puriꢀed with recrystallization from ethanol.
Selected spectra of the products
N-phenylacetamide (Table 1, 3a, see later): White solid; Isolated yield = 85%;
−
1
mp: 110–112 °C; IR (KBr) ν (cm ) = 3293, 2924, 2855, 1662, 1603, 1549, 1495,
1
1
7
3
433, 1317, 1259, 753. H NMR (500 MHz, DMSO-d ): δ (ppm) = 9.92 (s, 1H),
6
H
.57 (d, J = 7.5 Hz, 2H), 7.27 (t, J = 7.5 Hz, 2H), 7.00 (t, J = 7.5 Hz, 1H), 2.03 (s,
H).
N-(2-mercaptophenyl)acetamide (Table 1, 3b, see later): Yellow solid; 93%
−
1 1
yield; IR (KBr) ν 3275, 2925, 2857, 1664, 1575, 1515, 1431, 1290, 752 cm
H
NMR (500 MHz, CDCl ): δ (ppm)=1.68 (s, 1H), 2.25 (s, 3H), 7.07 (t, 1H), 7.31
3
H
(
dd, J=16.9–7.2 Hz, 1H), 7.70 (dd, J=20.1–6.3 Hz, 1H), 8.27 (s, 1H), 8.28 (d,
J=7.4 Hz, 1H).
N-(4-hydroxyphenyl)acetamide (Table 1, 3c, see later): Dark brown solid; 92%
yield; IR (KBr): ν 3322, 3161, 1654, 1614, 1562, 1507, 1437, 1369, 1231, 1108,
−1 1
8
02, 682 cm . H NMR (250 MHz, DMSO): δ (ppm)=1.82 (s, 3H), 6.57 (d,
H
J=7.7 Hz, 2H), 7.24 (d, J=8.0 Hz, 2H), 8.99 (s, 1H), 9.53 (s, 1H).
-acetamidobenzoic acid (Table 1, 3d, see later): White solid; 95% yield; IR
3
−
1 1
(
KBr) ν 3339, 2927, 1706, 1639, 1559, 1486, 1256, 725 cm . H NMR (250 MHz,
DMSO): δ (ppm)=2.10 (s, 3H), 7.34 (t, J=7.7 Hz, 1H), 7.64 (d, J=7.5 Hz, 1H),
H
7
.87 (d, J=7.7 Hz, 1H), 7.98 (s, 1H), 8.17 (s, 1H), 9.97 (s, 1H).
N-benzylacetamide (Table 1, 3e, see later): White solid; 92% yield; mp 58–60 °C;
IR (KBr): ν 3291, 3084, 2926, 2855, 1641, 1550, 1442, 1366, 1287, 1080, 1025,
1
3

E. Yazdani et al.
Table 1 Fe O @Chitosan-TCT-Salen–Cu(II) catalyzed acylation of amines
3
4
O
R
NH
Cat.(40 mg, 0.86 mol%)
R-NH2
+
SH
O
H O,r.t.,5 min
2
HS
1a-m
2
3
a-m
H
N
H
N
H
N
O
O
O
SH
HO
3
a, 97%
3
b,99%
3c,92%
H
N
HOOC
O
3
d,97%
O
NH
N
H
NH
Cl
O
3
e,98%
O
f,92%
3
g,98%
3
O
H
N
N
NH
NH
NH
O
3
i,94%
O
3j,91%
3
h,90%
O
O
O
NH
NH
O N
2
I
MeO
3k,81%
3
m,95%
3
l,93%
a
Reaction conditions: amine (1 mmol), thioacetic acid (1 mmol), catalyst (40 mg), water (1 mL), room
temperature, 5 min
b
Isolated yield
1
3

A magnetically recoverable copper–salen complex as a…
−
1 1
7
42, 693 cm . H NMR (400 MHz, CDCl ): δ (ppm)=7.30–7.37 (m, 5H), 5.83
3 H
(
br s, 1H), 4.45 (s, 2H), 2.05 (s, 3H).
N-(1-phenylethyl)acetamide (Table 1, 3f, see later): White solid; 90% yield; IR
−
1
−1 1
(
KBr): ν (cm ) 3279, 3044, 2978, 2865, 1668, 1530, 1382, 1262, 1088; cm . H
NMR (500 MHz, Chloroform-d): δ (ppm)=7.43–7.28 (m, 5H), 5.93 (s, 1H), 5.14
H
(
p, J=7.0 Hz, 1H), 1.99 (s, 3H), 1.50 (d, J=6.9 Hz, 3H).
N-(4-chlorobenzyl)acetamide (Table 1, 3g, see later): White solid; 95% yield; IR
KBr): ν 3277, 3079, 2927, 1640, 1551, 1488, 1455, 1374, 1286, 1090, 1015, 811,
(
−1 1
5
7
98 cm . H NMR (500 MHz, Chloroform-d): δ (ppm)=7.28 (d, J=7.9 Hz, 2H),
H
.18 (s, 2H), 6.28 (s, 1H), 4.35 (d, J=5.9 Hz, 2H), 2.00 (s, 3H).
N-isopropyl-N-phenylacetamide (Table 1, 3h, see later): Yellow oil, 91% yield; IR
−
1 1
(
KBr) ν 3437, 2926, 2856, 1642, 1420, 1263, 1202, 722 cm . H NMR (500 MHz,
Chloroform-d): δ (ppm)=7.31–7.22 (m, 6H), 4.49 (s, 2H), 4.15 (hept, J=6.7 Hz,
H
1
H), 2.04 (s, 3H), 1.12 (d, J=6.8 Hz, 6H).
N-butylacetamide (Table 1, 3i, see later): Yellow oil, 92% yield; IR (KBr): ν
−
1 1
3
295, 2933, 2869, 1649, 1555, 1445, 1372, 1295, 735 cm . H NMR (500 MHz,
Chloroform-d): δ (ppm)=5.97 (s, 1H), 3.21 (td, J=7.2, 5.7 Hz, 2H), 1.95 (s, 3H),
H
1
.46 (p, J=7.3 Hz, 2H), 1.33 (h, J=7.3 Hz, 2H), 0.90 (t, J=7.4 Hz, 3H).
N′-phenylacetohydrazide (Table 1, 3j, see later): Pale brown solid;89% yield; mp
−
1 1
1
29–132 °C; IR (KBr): ν 3287, 3234, 3031, 2928, 1665, 1643, 1597 cm . H NMR
(
500 MHz, DMSO): δ (ppm)=2.02 (s, 3H), 7.00 (t, J=7.4, 7.3 Hz, 1H), 7.26 (t,
H
J=7.5, 8.3 Hz, 2H), 7.56 (d, J=7.6 Hz, 2H), 9.94 (s, 1 H).
N-(4-nitrophenyl)acetamide (Table 1, 3k, see later): Yellow solid; 80% yield;
mp 101–103 °C; IR (KBr) ν 3358, 2960, 2925, 1628, 1596, 1477, 1304, 1261,
−1 1
8
04 cm . H NMR (500 MHz, Chloroform-d): δ (ppm)=8.24 (d, J=8.7 Hz, 2H),
H
7
.72 (d, J=8.7 Hz, 2H), 7.53 (s, 1H), 2.27 (s, 3H).
N-(4-iodophenyl)acetamide (Table 1, 3l, see later): White solid; 92% yield;
mp 182–187 °C; IR (KBr) ν 3293, 2923, 2855, 1662, 1602, 1546, 1437, 1375,
−1 1
1
317, 1260, 752 cm . H NMR (500 MHz, Chloroform-d): δ (ppm)=7.64 (d,
H
J=10.0 Hz, 2H), 7.30 (d, J=10.0 Hz, 2H), 7.16 (s, 1H), 2.20 (s, 3H).
N-(4-methoxyphenyl)acetamide (Table 1, 3m, see later): White solid; 94% yield;
−
1 1
IR (KBr) ν 3445, 2925, 2855, 1647, 1512, 1455, 1250, 1023, 817 cm . H NMR
(
500 MHz, DMSO): δ (ppm)=1.99 (s, 3H), 3.69 (s, 3H), 6.84 (d, J=9.0 Hz, 2H),
H
7
.46 (d, J=8.9 Hz, 2H), 9.74 (s, 1H).
Results and discussion
Schematic pathway for preparation of Fe O @Chit-TCT-Salen–Cu(II) is illus-
3
4
trated in Scheme 1. Every intermediate in the synthetic pathway was characterized
using FT-IR spectroscopy (Fig. 1). Characteristic peaks of chitosan are observed in
−1
Fig. 1a. Absorption at 3436 cm is ascribed to the OH stretching frequency, which
overlaps the NH stretching ones [54–58]. The carbonyl stretching vibration of
2
amide groups and C=N stretching of bonded cyanuric chloride appears in about the
−
1
1
600–1700 cm region [59]. The FT-IR spectrum of ethylenediamine-grafted Cht-
−
1
−1
TCT depicted in Fig. 1b shows an enlargement of peaks at 1590 cm and 3400 cm
1
3

E. Yazdani et al.
OH
OH
Cl
N
*
O
*
O
N
N
O
O
+
Cl
HO
OH
Toluene, 1000C, 24 h
HO
OH
Cl
NH
2
NH
n
n
N
N
Cl
N
Cl
Cb1
reflux
4 h
NH
2
2
H N
2
OH
OH
CHO
OH
*
O
*
O
O
O
HO
OH
HO
OH
NH
NH
N
N
N
n
MeOH, reflux,24 h
N
N
n
H
2
N
NH
2
NH
N
N
NH
N
N
H
N
H
OH
HO
Cb 3
Cb 2
1
2
.CuCl , MeOH, r.t., 10 min
2
. KOH,MeOH, reflux, 6h
OH
OH
3 4
Fe O , 10%AcOH/Water, 12 h , r.t.
*
O
O
Fe
3
O
4
*
O
HO
OH
O
NH
HO
OH
NH
N
N
n
N
N
n
NH
N
N
NH
NH
N
NH
N
O
N
O
Cu
N
Cu
O
O
Cb 4
3 4
Fe O @Chitosan-TCT-Salen-Cu(II)
Scheme 1 Pathway to the synthesis of Fe O @Chitosan-TCT-Salen–Cu(II) nanoparticles
3
4
due to addition of pendant groups bearing NH functionality [54–58]. The Schiꢃ
2
−
1
−1
base absorption bands are shown in Fig. 1c. Peaks at 1634 cm and 1412 cm can
be attributed to C=N stretching of the azomethine group and C=C stretching of the
aromatic ring, respectively [59]. Coordination of the prepared ligand to Cu(II) ions
1
3

A magnetically recoverable copper–salen complex as a…
Fig. 1 FT-IR spectra of (a) Cb1, (b) Cb 2, (c) Cb3, (d) Cb4, (e) Fe O @Chitosan-TCT-Salen–Cu(II)
3
4
−
1
shifts the peak related to C=N to a lower frequency, i.e., 1621 cm as compared
to the free ligand (Fig. 1d) [60]. The FT-IR spectra of the ꢀnal target nanoparticles
are depicted in Fig. 1e, showing good accordance with the free complex absorption
−
1
−1
peaks, although intrinsic bands of magnetite at 580 cm and overlapped 3400 cm
are also observed [61].
The crystalline structure of the magnetite core of the nanoparticles was veriꢀed
by X-ray diꢃraction (XRD) patterns as shown in Fig. 2. The diꢃraction peaks of
2
1.38, 35.27, 41.62, 50.71, 63.28, 67.64 and 74.6 are related to the crystal faces
(
111), (220), (311), (400), (422), (511) and (440), respectively. These peaks are
in acceptable agreement with those of JCPDS card no. 75-0033 which conꢀrms
no alteration of the spinel structure after modiꢀcation of the magnetite nanoparti-
cles with the metal complex. Furthermore, the XRD patterns of chitosan and every
1
3

E. Yazdani et al.
Fig. 2 XRD patterns of (a) Fe O and (b) Fe O @Chitosan-TCT-Salen–Cu(II)
3
4
3
4
intermediate in the synthetic pathway are illustrated in Fig. 3. Chitosan exhibited
low crystallinity as indicated by a broad band at about 20. The intermediates, Cb1,
Cb2, Cb3 and Cb4, which are chemically modiꢀed chitosan, show sn even greater
decrease in crystallinity [62].
Thermogravimetric analysis was conducted to determine the organic moieties
content of the nanoparticles (Fig. 4). For this purpose, the nanoparticles were heated
at a rate of 10 °C/min within the range of 25–800 °C under a ꢁow of compressed N
2
gas. The ꢀrst weight loss below 200 °C is due to evaporation of chemisorbed materi-
als, presumably moisture. As the sample temperature is increased to over 400 °C,
disintegration of the organic ligands of the immobilized complex on the surface of
nanoparticels occurs which contributes to about 15% (W/W) of the total sample size
[
63].
The magnetic properties of the prepared nanoparticles were measured by vibrat-
ing sample magnetometry (Fig. 5). The magnetization curve of the nanoparticles
−1
(
emug ) as a function of the applied magnetic ꢀeld between −10,000 and +10,000
−
1
Oe shows a magnetic saturation of about 30 emu g . The superparamangetic nature
of the nanoparticles is demonstrated by the zero remanence and coercivity of the
magnetization curve, which facilitate its easy separation from the reaction mixture
with an external magnet [64].
The transmission electron microscopy micrograph of the prepared nanoparticles
shows almost spherical particles (Fig. 6). The size of the particles is in the range of
5
–16 nm. The average particle size was calculated using Scherrer’s formula [66]:
1
3

A magnetically recoverable copper–salen complex as a…
Fig. 3 XRD patterns of (a) Chitosan, (b) Cb1, (c) Cb2, (d) Cb3, (e) Cb4
Ʈ=Kλ/βcosθ, where Ʈ is the mean size of crystalline phase, K is a dimensionless
shape factor, which is close to unity. λ is the X-ray wavelength, β is the FWHM of
diꢃraction peak and θ is the diꢃraction angle. The resulting mean particle size from
this equation is 16.5 nm.
A scanning electron microscopy image of the synthesized nanoparticles is shown
in Fig. 7, and indicates uniform nanoparticles.
1
3

E. Yazdani et al.
Fig. 4 Thermogravimetric analysis of Fe O @Chitosan-TCT-Salen–Cu(II)
3
4
Fig. 5 Vibrating sample magnetometry of Fe O @Chitosan-TCT-Salen–Cu(II)
3
4
1
3

A magnetically recoverable copper–salen complex as a…
Fig. 6 Transmission electron microscopy micrograph of Fe O @Chitosan-TCT-Salen–Cu(II)
3
4
Fig. 7 Scanning electron microscopy image of Fe O @Chitosan-TCT-Salen–Cu(II)
3
4
The presence of the expected elements in the prepared nanoparticles was deduced
using EDS which is outlined in Fig. 8. The presence of Fe, C, N, O and Cu elements
on the surface of the nanoparticles conꢀrms the successful synthesis and immobili-
zation of the copper complex. Furthermore, the precise amount of the copper con-
tent of the nanoparticles was determined using ICP analysis as 0.216 mmol per g.
The catalytic activity of the prepared nanoparticles was tested in the N-acetylation
of amines with thioacetic acid. To achieve the best reaction condition, N-acetylation
of aniline was chosen as the probe reaction (Scheme 2). Then, the reaction was car-
ried out under various conditions of solvent and catalyst loadings (Table 2). As most
of the organic materials are soluble in dichloromethane, the ꢀrst run was performed
1
3

E. Yazdani et al.
Fig. 8 EDS analysis of Fe O @Chitosan-TCT-Salen–Cu(II)
3
4
O
NH2
HN
O
Cat.(40 mg, 0.86 mol%)
+
SH
H O,r.t.,5 min
2
Scheme 2 Acetylation of aniline
Table 2 Optimization of
reaction conditions of aniline
acetylation
Yield (%)a
Entry
Catalyst (mg)
Solvent
1
2
3
4
5
6
7
8
40
40
40
40
40
–
CH Cl2
48
68
85
96
97
–
2
CH CN
3
EtOH
MeOH
H O
2
H O
2
b
40
H O
50
99
2
80
H O
2
Reaction conditions: aniline (1 mmol), thioacetic acid (1 mmol), sol-
vent (1 mL)
a
Isolated yield
b
Fe O nanoparticles
3
4
in this solvent; however, the practical yield was moderately low (entry 1). The result
of the ꢀrst test implied that a more polar solvent is needed to enhance the catalyst
eꢂciency. Thus, the eꢃects of common laboratory polar solvents like acetonitrile,
ethanol, methanol and water were examined (entries 2–5). It is evident that the more
polar the solvent, the more the yield of the desired product. Therefore, water was
1
3

A magnetically recoverable copper–salen complex as a…
selected as the reaction medium, due to the higher product yield and also because
it is a sustainable solvent. The requirement of catalyst presence for the reaction to
proceed was veriꢀed, as no product was detected in the absence of the catalyst (entry
6
). In order to ensure that the copper(II) ion has a necessary role in the catalytic pro-
cess, the reaction was conducted with bare magnetite nanoparticles, which resulted
in a much lower yield (entry 7). Furthermore, it was observed that increasing the
amount of catalyst had a negligible eꢃect on the obtained yield (entry 8).
As mentioned earlier, chemoselective protection of amino groups is a rather dif-
ꢀ
cult process when other nucleophilic functionalities are present. To prove chem-
oselectivity of the copper-catalyzed acetylation method, S, OH and carboxylic sub-
stituted anilines were examined (3b–d). The desired N-acetylated products were
formed and no O or S acetylation or sulꢀde dimerization was observed. The protocol
is also applicable to benzyl amines and to secondary and aliphatic ones (3e–i). Fur-
thermore, regioselectivity of the method under investigation was checked. Phenyl
hydrazine was reacted under similar reaction conditions and only the primary amino
group was protected (3j).
To understand the tolerance of the protocol to electronic eꢃects of the substitu-
ents, both electron-withdrawing (nitro and halogen) and electron-donating (meth-
oxy) groups were undertaken as the reaction substrates (3 k m). It can be concluded
that groups with a resonance electron-withdrawing character e.g. –NO will decrease
2
the product yield due to diminishing the nucleoophilic power of the amino group.
The model reaction (Scheme 2) was carried out under the optimized conditions.
After the reaction was completed, the catalyst was removed from the medium using
an external magnet, washed twice with water and dichloromethane, and dried at
ambient temperature for reuse in the next run. This process was repeated 6 times
until unsatisfactory results were obtained (Fig. 9). A hot ꢀltration test was used to
check the heterogeneity of the catalyst. After 2 min from the beginning of the reac-
tion, the catalyst was removed and the reaction mixture was left being stirred for
another 2 h, but no more product was formed during this period. Moreover, leach-
ing of copper ions was studied using ICP analysis of the reaction mixture. The
result showed no detection of the Cu element. Additionally, the obtained acylation
Fig. 9 Recycling of Fe O @Chitosan-TCT-Salen–Cu(II) in the N-acetylation of aniline
3
4
1
3

E. Yazdani et al.
Fig. 10 Recycling of diꢃerent complex magnetic supports in the N-acetylation of aniline
products were dissolved in ethyl acetate, and, after extraction with water, no residual
Cu content was detected in the aqeuoeus layer using ICP analysis.
Furthermore, the eꢃect of variations in the magnetic core and shell of the nano-
particles as the complex support was studied (Fig. 10). γ-F O showed the great-
2
3
est yields as compared to the others, which may be attributed to its low molecular
weight; hence, more Cu content is present in the reaction when the same catalyst
amount is used. However, catalysts with maghemite as the core showed further
decrease in their activity which is due to more loss of the catalyst in every step of
magnetic decanting. Hence, the choice of bare magnetic nanoparticles was reason-
able due to their eꢂcient recyclability and straightforward synthetic procedure.
The eꢂciency of the prepared nanocatalyst was compared to the reported catalyst
in our groups or others for the acetylation of aniline using thioacetic acid and acetic
acid as the acetylating agent (Table 3). It is clear that the amount of copper loading
needed for catalysis is considerably diminished in the reported protocol. Also, thio-
acetic acid is a considerably more eꢂcient agent for amine acetylation.
Scheme 3 presents a proposed mechanism of the N-acetylation reaction. First, the
C–S bond of thioacetic acid is weakened through chelation to copper ions. More-
over, the carbonyl group electrophilic character is enhanced as it is complexed to
Table 3 Fe O @Chitosan-TCT-Salen–Cu(II)-catalyzed acylation of amines
3
4
Entry
Catalyst (mg)
Solvent
Yield (%)
1
2
3
4
5
6
7
CuSO (30%) [41]
MNP-GAA-Cu(II) (2.2%) [62]
MeOH
92
95
96
97
99
97
20
4
H O
2
Fe O @SiO /Salen–Cu(II) (40 mg)
H O
3
4
2
2
Fe O @SiO @Mo–Schiꢃ base (40 mg)
H O
3
4
2
2
Chitosan-TCT-Salen–Cu(II) (40 mg)
MNP-Chit-Salen–Cu(II) (0.86%)
MNP-Chit-Salen–Cu(II) (0.8%)
H O
2
H O
2
a
H O
2
aAcetic acid as acetylating agent
1
3

A magnetically recoverable copper–salen complex as a…
O
HN
O
SH
Linker
Fe O
3
H O
2
4
Cu
SH
H
Fe O
3
4
Li
nk
er
Cu
O
H
H O
N
O
2
S
H
HS
H
Cu
r
e
k
NH2
in
L
Fe O
3
4
H
H
N
O
HS
H O
3
H O
2
Cu
r
e
k
in
L
Fe O
3
4
Scheme 3 Proposed mechanism for amine acylation
Cu(II). In the next step, the amino group attaches to the carbonyl group. Finally, the
N-acetylated product is released with the simultaneous evolution of hydrogen sulꢀde
gas.
Conclusions
In summary, a copper(II)–salen complex was supported on the surface of magnet-
ite nanoparticles. These nanoparticles were applied in the N-acetylation of anilines
using thioacetic acid as the acetylating agent. The protocol is highly chemo- and
region-selective. Furthermore, it is an environmentally benign method, as it is per-
formed in water. The catalyst is magnetically recoverable for 6 consecutive cycles
1
3

E. Yazdani et al.
with no signiꢀcant decrease in catalytic activity. Moreover, the puriꢀcation process
contains simple work-up with no need for chromatographic separations.
Acknowledgement We acknowledge Tarbiat Modares University for partial support of this work.
References
1
2
.
.
P.R. Sultane, T.B. Mete, R.G. Bhat, Org. Biomol. Chem. 12, 261 (2014)
P.M. Dewick, Medicinal Natural Products: A Biosynthetic Approach (Wiley, West Sussex, 2009), p.
3
11
3
4
5
6
7
.
.
.
.
.
M. Nasrollahzadeh, New J. Chem. 38, 5544 (2014)
D. Chusov, B. List, Angew. Chem. Int. Ed. 53, 5199 (2014)
D. Seildel, Acc. Chem. Res. 48, 317 (2015)
A. Peeters, R. Ameloot, D.E. De Vos, Green Chem. 15, 1550 (2013)
J. Li, M.J. Lear, Y. Kawamoto, S. Umemiya, A.R. Wong, E. Kwon, I. Sato, Y. Hayashi, Angew.
Chem. Int. Ed. 54, 12986 (2015)
8
.
J.T. Reeves, M.D. Visco, M.A. Marsini, N. Grinberg, C.A. Busacca, A.E. Mattson, C.H. Senanay-
ake, Org. Lett. 17, 2442 (2015)
9
.
R. Villano, M.R. Acocella, G. Guerra, ChemistrySelect 2, 10559 (2017)
1
1
0. A. Leoncini, J. Huskens, W. Verboom, Synlett 27, 2463 (2016)
1. S.L. Montgomery, J.M. Sanchez, M.P. Thompson, G.A. Aleku, B. Dominguez, N.J. Turner, Angew.
Chem. Int. Ed. 56, 10491 (2017)
1
1
1
1
1
2. R.M. McFadden, B.M. Stoltz, J. Am. Chem. Soc. 128, 7738 (2006)
3. I.S. Young, P.S. Baran, Nat. Chem 1, 193 (2009)
4. W.R. Gutekunst, P.S. Baran, Chem. Soc. Rev. 40, 1976 (2011)
5. V. Hickmann, M. Alcarazo, A. Furstner, J. Am. Chem. Soc. 132, 11042 (2010)
6. P.G.M. Wuts, T.W. Greene, Green’s Protective Groups in Organic Synthesis (Wiley, Hookben,
2
007), p. 773
1
1
1
2
2
2
2
7. R.C. Larock, Comprehensive Organic Transformations (Wiley, Weinheim, 1989), p. 150
8. K. Phukan, M. Ganguly, N. Devi, Synth. Commun. 39, 2694 (2009)
9. C.L. Allen, J.M. Williams, Chem. Soc. Rev. 40, 3405 (2011)
0. N.O. Sonntag, Chem. Rev. 52, 237 (1953)
1. R. Murugan, E.F. Scriven, ChemInform. 35, e3744 (2004)
2. R.P. Wurz, Chem. Rev. 107, 5570 (2007)
3. M. Sato, K. Matsushima, H. Kawanami, M. Chatterjee, T. Yokoyama, Y. Ikuhsima, T.M. Suzuki,
Lab Chip 9, 2877 (2009)
2
4. A. Vogel, Practical Organic Chemistry (Langman Scientiꢀc & Technical and Wiley, New York,
1
989), p. 708
2
2
2
5. J. March, Advanced Organic Chemistry (Wiley, New York, 1992), p. 416
6. G. Hoꢁe, W. Steglich, H. Vorbruggen, Angew. Chem. Int. Ed. Engl. 17, 569 (1978)
7. E. Vedejs, N.S. Bennett, L.M. Conn, S.T. Diver, K. Gingras, S. Lin, P.A. Oliver, M.J. Peterson, J.
Org. Chem. 58, 7286 (1993)
2
2
3
8. R. Murugan, E.F.V. Scriven, Aldrichimica Acta 36, 23 (2003)
9. A.R. Katritzky, H.Y. He, K. Suzuki, J. Org. Chem. 65, 8210 (2000)
0. J.R. Phillips, Thiolacetic Acid. e-EROS Encyclopedia of Reagents for Organic Synthesis (Wiley-
VCH, Weinheim, 2001)
3
3
1. P. Wang, S.J. Danishefsky, J. Am. Chem. Soc. 132, 17045 (2010)
2. P. Wang, X. Li, J. Zhu, J. Chen, Y. Yuan, X. Wu, S.J. Danishefsky, J. Am. Chem. Soc. 133, 1597
(
2011)
3
3
3
3
3
3
3. W. Wu, Z. Zhang, L.S. Liebeskind, J. Am. Chem. Soc. 133, 14256 (2011)
4. N. Shangguan, S. Katukojvala, R. Greenberg, L.J. Williams, J. Am. Chem. Soc. 125, 7754 (2003)
5. Y. Rao, X. Li, S.J. Danishefsky, J. Am. Chem. Soc. 131, 12924 (2009)
6. D. Crich, I. Sharma, Angew. Chem. Int. Ed. 48, 2355 (2009)
7. D. Crich, K. Sana, S. Guo, Org. Lett. 9, 4423 (2007)
8. J. Pan, N.O. Devarie-Baez, M. Xian, Org. Lett. 13, 1092 (2011)
1
3

A magnetically recoverable copper–salen complex as a…
3
4
4
4
4
9. D. Crich, K. Sasaki, Org. Lett. 11, 3514 (2009)
0. R. Liu, L.E. Orgel, Nature 389, 52 (1997)
1. S.M. Mali, R.D. Bhaisare, H.N. Gopi, J. Org. Chem. 78, 5550 (2013)
2. H. Liu, Z. Liyun, Y. Yunfei, X. Zhifang, C. Kai, Q. Shengxiang, T. Haibo, ACS Catal. 6, 3 (2016)
3. W. Chen, S. Jiaan, H. Miao, Y. Wanwan, A.G. Marc, A.H. Richard, Y. Yongping, Chem. Sci. 4, 3
(
2013)
4
4
4
4
4
4. M. Munoz, Z.M. de Pedro, J.A. Casas, J.J. Rodriguez, Appl. Catal. B 176–177, 249 (2015)
5. S. Urus, S. Purtas, G. Ceyhan, F. Tumer, Chem. Eng. J. 220, 420 (2013)
6. B.S. Lane, K. Burgess, Chem. Rev. 103, 2457 (2003)
7. R. Skoda-Foldes, L. Kollar, A. Arcadi, J. Mol. Catal. 101, 37 (1995)
8. L.P.C. Nielson, C.P. Stevenson, D.G. Backmond, E.N. Jacobsen, J. Am. Chem. Soc. 126, 1360
(
2004)
4
5
5
5
5
5
5
5
5
9. G. Righi, C. Bonini, Synthesis 3, 225 (1994)
0. J. Lopez, S. Liang, X.R. Bu, Tetrahedron Lett. 39, 4199 (1998)
1. Y. He, C. Cai, Catal. Commun. 12, 678 (2011)
2. M.E.I. Badawy, E.I. Rabea, Int. J. Carbohydr. Chem. 2011, 29 (2011)
3. M. Rinaudo, Prog. Polym. Sci. 31, 603 (2006)
4. E. Yazdani, K. Azizi, A. Nakisa, A. Heydari, Org. Chem. Res. 1, 27 (2015)
5. K. Azizi, J. Azarnia, M. Karimi, E. Yazdani, A. Heydari, Synlett 27, 1810 (2016)
6. A. Nakisa, M. Karimi, E. Yazdani, A. Heydari, Appl. Organometal. Chem. 31, e3674 (2017)
7. M.K. Miraki, M. Areꢀ, E. Yazdani, S. Abbasi, M. Karimi, K. Azizi, A. Heydari, ChemistrySelect 1,
6
328 (2016)
5
5
6
6
6
8. L. Ghandi, M.K. Miraki, I. Radfar, E. Yazdani, A. Heydari, ChemistrySelect 3, 1787 (2018)
9. E.C.N. Lopez, K.S. Sousa, C. Airoldi, Thermochim. Acta 483, 21 (2009)
0. K. Abdollahi, F. Yazdani, R. Panahi, Int. J. Biol. Macromol. 94, 396 (2017)
1. M. Esmaeilpour, J. Javidi, F.N. Dodeji, M.M. Abarghou, Transit. Met. Chem. 39, 797 (2014)
2. M.K. Miraki, E. Yazdani, L. Ghandi, K. Azizi, A. Heydari, Appl. Organometal. Chem. 31, e3744
(
2017)
6
6
3. K. Azizi, N. Esfandiary, M. Karimi, E. Yazdani, A. Heydari, RSC Adv. 6, 89313 (2016)
4. E. Ghonchepour, E. Yazdani, D. Saberi, M. Areꢀ, A. Heydari, Appl. Organometal. Chem. 31, e3822
(
2017)
6
6
5. L. Liu, Y. Ai, D. Li, L. Qi, J. Zhou, Z. Tang, Z. Shao, Q. Liang, H.B. Sun, ChemCatChem. 9, 3131
2017)
6. A. Patterson, Phys. Rev. 56, 978 (1939)
(
1
3