Mild and eco-friendly chemoselective acylation of amines in aqueous medium using a green, superparamagnetic, recoverable nanocatalyst

Article abstract of DOI:10.1002/aoc.3744

Copper-grafted guanidine acetic acid-modified magnetite nanoparticles (Fe₃O₄@GAA-Cu(II)) as a green, superparamagnetic and recoverable nanocatalyst is found to promote quantitative N-acylation of various amines in a very short time with an equimolar amount of thioacetic acid in water at room temperature. This method is found to be highly selective for amines and not sensitive to other functional groups. Mild reaction condition, high selectivity, efficiency, simple workup and excellent yields are some of the major advantages of the procedure.

Full text of DOI:10.1002/aoc.3744

Received: 20 November 2016
DOI 10.1002/aoc.3744
Revised: 23 December 2016
Accepted: 31 December 2016
F U L L PA P E R
Mild and eco‐friendly chemoselective acylation of amines in
aqueous medium using a green, superparamagnetic, recoverable
†
nanocatalyst
Maryam Kazemi Miraki
| Elahe Yazdani | Leila Ghandi | Kobra Azizi | Akbar Heydari
Chemistry Department, Tarbiat Modares
University, PO Box 14155‐4838,
Tehran, Iran
Copper‐grafted guanidine acetic acid‐modified magnetite nanoparticles
(
Fe O @GAA‐Cu(II)) as a green, superparamagnetic and recoverable nanocatalyst
3
4
is found to promote quantitative N‐acylation of various amines in a very short time
with an equimolar amount of thioacetic acid in water at room temperature. This
method is found to be highly selective for amines and not sensitive to other func-
tional groups. Mild reaction condition, high selectivity, efficiency, simple workup
and excellent yields are some of the major advantages of the procedure.
Correspondence
Akbar Heydari, Chemistry Department,
Tarbiat Modares University, PO Box
1
4155‐4838, Tehran, Iran.
Email: heydar_a@modares.ac.ir
†This article is dedicated to memory of
Khalil Motaharniya
KEYWORDS
heterogeneous catalyst, magnetic nanoparticles, N‐acylation reaction, organocatalyst
1
| INTRODUCTION
anhydrides react rapidly with water and alcohols leading to
the corresponding acids and esters, respectively. The selec-
Acylation of amines is a basic and important reaction in
organic chemistry. Many pharmacological molecules possess
tive acylation of amines in the presence of other functional
groups is a rather difficult process. Numerous strategies
including the direct and metal‐mediated condensation of
[1]
at least one amide bond. N‐Acyl derivatives of amines are
used for the synthesis of amides and their derivatives, as
starting materials for various transformations and for
protecting ─NH and ─OH group functionality in multi‐step
[
7]
unactivated carboxylic acids and amines, acylation through
[
8]
N‐acyl DBN tetraphenyl borate salts, mercury‐ and ruthe-
[
9]
nium‐catalysed Beckman rearrangements,
oxidative
[
2]
[10]
syntheses. Several methods for acylation have been devel-
amidation,
triazole‐ and imidazole‐mediated acyl transfer
and acylation through acylbenzotriazoles
[
11]
[12]
oped including: (a) direct reaction of an amine and an acid,
reactions
(
b) reaction of a readily available acid derivative (e.g. simple
have been developed to circumvent the inherent problems.
These reactions suffer from some drawbacks such as the
requirement of more expensive reagents, relatively harsh
reaction conditions and long reaction times. Thus, there is
still a great need to find various alternative reagents for acyl-
ation of amines.
methyl ester) with an amine, (c) formation of an activated car-
bonyl compound (e.g. acid chloride, anhydride or active
ester) followed by condensation with an amine and (d) one‐
pot reaction of a carboxylic acid with an amine in which a
[
3]
coupling reagent activates the acid component in situ.
[4]
Among various synthetic protocols, N‐acylation reaction
is commonly carried out with acetic anhydride or acetyl chlo-
ride in the presence of either acidic or basic catalysts under
various conditions. However, there are a number of prob-
lems associated with N‐acylation reactions using acyl chlo-
rides and acid anhydrides. For example, anhydrides can
form imides as side products when reacted with primary
In contrast to carboxylic acids, thioacids have been of
considerable interest due to their unique reactivity and selec-
[
13–17]
tivity in amide bond formations. Various authors
have
[
5]
reported elegant methods for N‐acylation of amines in pep-
[
18]
tide synthesis. In 2013, Gopi and co‐workers
used
copper(II) acetate as a catalyst for acylation of amines. But
this methodology suffers from using a large amount of cata-
lyst and cumbersome procedures for separation of the
resulting product. Filtration and expensive ultracentrifugation
[
6]
amines, while reactions of acyl chlorides with amines can
be highly exothermic. In addition, many acid chlorides and
Appl Organometal Chem. 2017;e3744.
wileyonlinelibrary.com/journal/aoc
Copyright © 2017 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.3744

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MIRAKI ET AL.
−
1
are available methods to recover heterogeneous catalysts, but
these routes can result in loss of catalyst. Magnetic nanopar-
ticle‐supported catalysts have been successfully deployed in a
variety of important organic reactions due to their high stabil-
ity and the easy separation of the catalyst from the reaction
mixture using an external magnet. Recently, magnetic nano-
particles have served as highly promising supports of
in the FT‐IR spectrum of Fe O @GAA at 1400 cm with
3
4
−
1
that of Fe O @GAA‐Cu(II) at 1408 cm confirms forma-
3
4
tion of the complex.
The morphology of Fe O @GAA and Fe O @GAA‐
3
4
3 4
Cu(II) was investigated using scanning electron microscopy
(SEM). The SEM images confirm that the synthesized
Fe O @GAA and Fe O @GAA‐Cu(II) present uniform
nanoparticles. Regarding the incorporation of Cu(II), the
image obtained (Figure 2b) does not reveal significant
changes in the Fe O @GAA morphology (Figure 2a).
As illustrated in Figure 3, the magnetic properties of the
catalyst were investigated at room temperature using a
vibrating sample magnetometer. The magnetic hysteresis
loop of Fe O @GAA‐Cu(II) was measured in an applied
3
4
3 4
[
19]
organocatalysts.
Guanidine acetic acid (GAA) is the essential precursor of
creatine, and belongs to the class of guanidino compounds
that are characterized by the presence of a basic guanidine
group. GAA has a carboxylic acid group that facilitates the
easy linkage of the compound to a magnetite support and
the guanidino group renders it suitable to serve as a
complexing agent for most transition metal ions. Herein, we
report the rapid and highly selective N‐acylation of amines
using thioacids in water at room temperature mediated by
copper‐grafted GAA‐modified magnetite nanoparticles
3
4
3
4
magnetic field of 15 000 Oe at 298 K. The hysteresis loop
of the Fe O @GAA‐Cu (II) nanoparticles shows
superparamagnetic behaviour with its redispersion stability
in solution, without aggregation.
a
3
4
(
Fe O @GAA‐Cu(II)). Studies with amines containing vari-
3
4
ous other functional groups such as thiols, carboxylic acids
and alcohols suggest that the reactions are highly selective
for amines, and other functional groups are unaffected.
(
a)
2
| RESULTS AND DISCUSSION
Some spectroscopic and microscopic techniques were used
for characterization of the catalyst structure. The organic
moieties anchored on the surface of Fe O were investigated
3
4
using Fourier transform infrared (FT‐IR) spectroscopy.
Figure 1 shows FT‐IR spectra of GAA, bare Fe O ,
3
4
Fe O @GAA and Fe O @GAA‐Cu(II). Typical band
3
4
3 4
ascribed to the Fe─O stretching vibration appears at
61 cm− for the bare magnetic nanoparticles. Immobiliza-
1
5
tion of GAA on the surface of the magnetic nanoparticles
is proved with the appearance of peaks at 1626 and
−
1
1
400 cm , assigned to the stretching vibration of C═O
(b)
and C─N respectively. Comparison of the C─N vibration
3 4
FIGURE 2 SEM images of (a) Fe O @GAA nanoparticles and (b)
FIGURE 1 FT‐IR spectra of catalyst and its components
3 4
Fe O @GAA‐Cu(II) nanoparticles

MIRAKI ET AL.
3 of 7
FIGURE 5 TGA curves of catalyst
FIGURE
3
3 4
Magnetization curve of Fe O @GAA‐Cu(II)
nanoparticles
The hydrodynamic diameter of the nanoparticles was
measured using dynamic light scattering (DLS), with the
nanoparticles being sonicated in water before the measure-
ment (Figure 6). DLS characterization shows that the average
sizes of nanoparticles are about 65.8 and 114 nm before and
after the reaction, respectively.
X‐ray diffraction (XRD) was applied to determine the
crystal structure of the superparamagnetic nanoparticles.
The obtained lattice parameters of Fe O @GAA and
3
4
Fe O @GAA‐Cu(II) coincide with the standard parameters
3
4
of magnetite. Comparison of the patterns of Fe O @GAA
3
4
and Fe O @GAA‐Cu(II) indicates retention of the crystalline
cubic spinel structure during functionalization of the
Acylation of amines was chosen to evaluate the catalytic
behaviour of the Fe O @GAA‐Cu(II) nanoparticles. Initially,
3
4
3
4
magnetic nanoparticles (Figure 4).
The amount of GAA supported on the surface of Fe O4
was determined using thermogravimetric analysis (TGA) of
acylation of aniline (1.0 mmol) with thioacetic acid
(1.0 mmol) was studied as a model reaction in the presence
of 40 mg of Fe O @GAA‐Cu(II) nanoparticles at room tem-
3
3
4
Fe O @GAA‐Cu(II). As depicted in Figure 5, the TGA
perature in water (Scheme 1).
3
4
curve of Fe O @GAA‐Cu(II) shows a weight loss of 2%
When the reaction is carried out using these conditions,
the desired product is obtained in 95% isolated yield. Based
on these findings, we further investigated other reaction
parameters, such as acylation agent, solvent and amount of
catalyst in order to achieve a better chemoselectivity and a
higher chemical yield. It should be noted that the use of com-
mon organic solvents, such as ethanol, methanol and CH Cl ,
3
4
below 200 °C, which is due to the loss of adsorbed water
in the sample. The mass loss of about 3.3% by weight in
the range 200–400 °C is attributed to the thermal decompo-
sition of GAA, which is estimated to be about 0.28 mmol
of GAA per gram of catalyst. The TGA curve indicates
the successful supporting of the GAA complex onto the
magnetic surface. The copper content of the catalyst was
2
2
results in low to moderate yields. In the absence of any cata-
lyst, no reaction is observed even after prolonged reaction
time. The acylation of amines proceeds smoothly in the pres-
ence of unsupported Fe O (Table 1, entry 8). It is found that
−
1
determined as 0.55 mmol g using inductively coupled
plasma (ICP) analysis.
3
4
4
0 mg of Fe O @GAA is enough to progress the reaction.
3 4
When acetic acid is used as acylation agent, no product is
observed. Under these optimized conditions, the acylation
of various amines was examined using Fe O @GAA‐Cu(II)
3
4
nanoparticles in water at room temperature. The obtained
results are summarized in Table 1.
The selective acylation of amines in the presence of other
functional groups is a rather difficult process. In order to
understand the selectivity and the reactivity of the protocol
under investigation, we subjected 2‐aminothiophenol
(Table 2, entry 5) and p‐aminophenol (Table 2, entry 6) to
N‐acetylation (Scheme 2). The reaction proceeds with the
same rate as that of aniline. When 2‐aminothiophenol and
p‐aminophenol are treated with one equivalent of thioacetic
FIGURE 4 XRD pattern of catalyst

4
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MIRAKI ET AL.
FIGURE 6 DLS analysis of nanoparticles (a) before and (b) after reaction
acid under identical conditions, corresponding acetamides
are obtained in high yield and no O,S‐acylation and S─S
disulfide dimer product are observed in the reaction mixture.
Similar result is obtained with m‐aminobenzoic acid (Table 2,
entry 7), where exclusive N‐acetylation is achieved with
excellent yield. We also examined the tolerance of this
reaction to phenylhydrazine in the presence of the catalyst
No leaching of copper ion from the catalyst surface was
determined according to ICP analysis. Any possible change
in catalyst structure was studied using FT‐IR spectroscopy
and XRD (Figure 8). The FT‐IR spectrum shows no signifi-
cant changes compared to that of the fresh catalyst. The
XRD pattern shows the characteristics peaks of magnetite
and additional peaks of sulfur precipitated on the surface of
the catalyst in the course of the reaction.
(Table 2, entry 10). It is observed that only primary amino
group will undergo N‐acylation under this condition. This
method was applied for the formation of amide bond in
amino acids (Table 2, entry 14). Tryptophan is successfully
N‐acetylated with excellent yield in a short time.
Further, to understand the role of electron‐withdrawing
groups in the reaction, we subjected p‐nitroaniline (Table 2,
entry 3) and p‐iodoaniline (Table 2, entry 4) to N‐acetylation.
Except for p‐nitroaniline, all other N‐acetylated products are
isolated in excellent yields.
In order to establish the reusability of the catalyst for
N‐acylation, the model reaction was repeated under stan-
dard conditions. For this, after completion of the reaction,
the catalyst was recovered by magnetic decantation, washed
with deionized water, dried and used for the next cycle.
The catalytic activity does not decrease considerably after
six catalytic cycles (Figure 7).
a
TABLE 1 Optimization of reaction conditions
b
Entry
Catalyst (mg)
Solvent Yield (%)
1
2
3
4
5
6
7
8
9
40
40
40
40
35
30
25
CH
2
3
Cl
2
40
85
75
95
90
88
85
25
—
CH
OH
EtOH
H
H
H
H
H
H
2
2
2
2
2
2
O
O
O
O
O
O
c
40
—
a
Reaction conditions: thioacetic acid (1.0 mmol), amine (1.0 mmol) in solvent
1.0 ml).
(
b
Isolated yield.
c
SCHEME 1 N‐acylation of amine using thioacetic acid
3 4
40 mg of Fe O nanoparticles.

MIRAKI ET AL.
5 of 7
a
TABLE 2 Acetylation of amines with thioacetic acid
b
Entry
RNH
2
Product
Yield (%)
1
95
2
3
96
80
4
5
6
92
98
91
FIGURE 7 Recyclability of catalyst
7
8
95
93
consequently weakens the C─S bond. Following substitution
of amine to copper atom, hydrogen sulfide gas is released and
the acylated amine is liberated in the final step.
9
97
3
| EXPERIMENTAL
1
1
0
1
90
92
All chemicals and solvents were purchased from commercial
suppliers and used without further purification. FT‐IR spec-
−1
tra were obtained over the region 400–4000 cm with a
Nicolet IR100 FT‐IR with spectroscopic grade KBr. XRD
patterns were obtained at room temperature with a Philips
1
1
1
2
3
4
88
90
89
X‐pert 1710 diffractometer with Co K (λ = 1.78897 Å),
α
4
0 kV voltage, 40 mA current and in the range 10–90°
−1
(2θ) with a scan speed of 0.020° s . SEM (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 magnetometer/alternating gradient force
magnetometer (VSM/AGFM, MDK Co., Iran). TGA was
conducted using a thermal analyser with a heating rate of
2
0 °C min− over a temperature range of 25–1100 °C under
1
flowing nitrogen. The hydrodynamic diameter of the
nanoparticles was measured using a Zetasizer Nano‐
MAL1001767 (Malvern Instruments, Malvern, UK) by
DLS with the nanoparticles sonicated in water before the
a
Reaction conditions: thioacetic acid (1.0 mmol), amine (1.0 mmol) in solvent
1.0 ml).
(
b
Isolated yield.
1
measurement. H NMR spectra were recorded with a Bruker
The proposed mechanism is presented in Scheme 3.
Avance (DRX 500 MHz, DRX 250 MHz) in pure deuterated
dimethylsulfoxide solvent with tetramethylsilane as internal
standard.
Copper chelated to the guanidine moiety supported on the
magnetite nanoparticles interacts with thioacetic acid and
3
.1 | Preparation of GAA supported on Fe O
3
4
3
.1.1 | Preparation of Fe O @GAA
3
4
nanoparticles
SCHEME 2 Selective acylation of amines in the presence of other
Amounts of 5.0 mmol of FeCl ⋅6H O and 2.5 mmol of
3
2
functional groups
FeCl ⋅4H O salts were dissolved in 100 ml of deionized
2
2

6
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MIRAKI ET AL.
FIGURE 8 FT‐IR spectrum and XRD pattern of catalyst (after sixth run)
water under vigorous stirring. Then 2.0 mmol of GAA and
3.2 | General procedure for acylation of
NH OH solution (25% w/w, 30 ml) were added to the mix-
amines
4
ture until the pH was raised to 11 at which a black suspension
was formed. This suspension was then refluxed at 100 °C for
To a mixture of catalyst (40 mg) and amine (1.0 mmol) in
water (1.0 ml) was added thioacetic acid (1.0 mmol). The
mixture was stirred at room temperature for 5 min. Comple-
tion of the reaction was confirmed by TLC. After completion
of the reaction, the nanoparticles were collected with a per-
manent magnet from the reaction mixture and washed with
distilled water and methanol repeatedly. Water (50 ml) was
added to the reaction mixture and extracted with EtOAc
(2 × 20 ml) and dried over Na SO . The solvent was removed
6
h, with vigorous stirring. Fe O @GAA nanoparticles were
3 4
separated from the aqueous solution by magnetic decanta-
tion, and washed with deionized water several times before
being dried in an oven overnight.
3
.1.2 | Preparation of Fe O @GAA‐Cu(II)
3
4
2
4
nanoparticles
under reduced pressure to give the crude product. The residue
was recrystallized from ethanol to afford the pure product.
An amount of 2.0 mmol of Cu(OAc) ⋅2H O in 50 ml of
2
2
water was added to Fe O @GAA nanoparticles and stirred
3
4
at room temperature for 2 h. The suspension was refluxed
for 2 h. Finally, the nanoparticles were separated from the
aqueous solution by magnetic decantation, and washed with
water, ethanol and diethyl ether several times before being
dried in an oven overnight.
4 | CONCLUSIONS
Robust and effective Fe O @GAA‐Cu(II) as
a
3
4
green, superparamagnetic and recoverable nanocatalyst for
N‐acylation of a variety of amines was synthesized and
studied. When thioacetic acid is used as the acylation
agent in water, N‐acylation can be carried out to afford
corresponding products in excellent yields and short time.
This method is found to be highly selective for amines
and not sensitive to other functional groups such as thiol,
phenol and amino acids. Mild reaction conditions, high
selectivity, efficiency, simple workup and excellent yields
are some of the major advantages of the procedure.
ACKNOWLEDGMENTS
We acknowledge Tarbiat Modares University for partial sup-
port of this work.
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How to cite this article: Miraki MK, Yazdani E,
Azizi K, Heydari A. Mild and eco‐friendly
chemoselective acylation of amines in aqueous
medium using a green, superparamagnetic,
recoverable nanocatalyst. Appl Organometal Chem.
2017;e3744. https://doi.org/10.1002/aoc.3744
3
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