Nano-ferrous ferric oxide (nano-Fe3O4): Powerful, reusable, and stable catalyst for N-Boc protection of amines

Article abstract of DOI:10.1016/j.crci.2013.05.010

Nano-ferrous ferric oxide (nano-Fe₃O₄) efficiently catalyzed N-boc protection of amines in high yields and acceptable reaction times. Nano-Fe₃O₄ was applied as an efficient, green, heterogeneous and reusable magnetite catalyst. Clean reaction, simple purification, short reaction time and high yield were some other advantages of this compound.

Full text of DOI:10.1016/j.crci.2013.05.010

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Preliminary communication/Communication
Nano-ferrous ferric oxide (nano-Fe3O4): Powerful, reusable,
and stable catalyst for N-Boc protection of amines
b,
a,c
Mohammad Ali Zolfigol a, , Ahmad Reza Moosavi-Zare , Parvin Moosavi
,
*
*
Vahid Khakyzadeh a, Abdolkarim Zare c
a Faculty of Chemistry, Bu-Ali Sina University, Hamedan 6517838683, Iran
b Department of Chemistry, University of Sayyed Jamaleddin Asadabadi, Asadabad 6541835583, Iran
c Chemistry Department, Payame Noor University, Tehran, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
Nano-ferrous ferric oxide (nano-Fe3O4) efficiently catalyzed N-boc protection of amines in
high yields and acceptable reaction times. Nano-Fe3O4 was applied as an efficient, green,
heterogeneous and reusable magnetite catalyst. Clean reaction, simple purification, short
reaction time and high yield were some other advantages of this compound.
Received 30 November 2012
Accepted after revision 17 May 2013
Available online xxx
ß 2013 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Keywords:
Nano-Fe3O4
Magnetite
Heterogeneous catalyst
N-Boc protection
Amine
1. Introduction
a magnet for reusing it to prevent any loss of the catalyst.
Recently, the chemists have focused on the catalytic
Transition-metal catalyzed organic reactions are often
considered to follow the principles of ‘‘Green Chemistry’’
due to the use of minimum energy, cleaner reagents or
auxiliaries and minimization of waste. Nanocatalysts are
considered to be a bridge between heterogeneous and
homogeneous catalysis [1]. One of the attractive properties
of the nanomaterials is that the active component has a
high specific surface area, leading to an increase of the
contact with the reactants [2]. Also, a higher surface area
gives nanomaterials more active surface; they are hard to
be separated. Therefore, it is important to design a
recoverable and well-dispersed catalyst. Magnetite nano-
particles (MNPs) as catalysts are very promising due to
their large specific surface area and their magnetic
properties [3,4]. They can be collected very easily using
aspects of nano-Fe3O4 to improve the protocols of catalytic
activity [5–8].
Functional group protection and deprotection methods
are important in the synthesis of the target molecule. The
protection of amines is one of the most fundamental and
useful transformations in organic synthesis, especially in
peptide synthesis [9,10]. Several reagents and methods
have been used for N-tert-butoxycarbonylation of amines
[11–13]. Some of these methodologies suffer from a variety
of drawbacks, such as long reaction times, low yields, high
toxicity and the use of expensive reagents. Commercially
available di-tert-butyl dicarbonate (diboc) is an efficient
reagent for the clean and rapid introduction of the boc-
protecting group [13–15].
Having the above facts in mind, we have introduced the
nano-ferrous ferric oxide (nano-Fe3O4) as a highly efficient,
reusable and heterogeneous Lewis acid catalyst for the
selective N-tert-butoxycarbonylation of various amines,
using diboc, at room temperature (Scheme 1). Interest-
ingly, this method has none of the above-mentioned
*
Corresponding authors.
E-mail addresses: mzolfigol@yahoo.com (M.A. Zolfigol),
moosavizare@yahoo.com, moosavi-zare@sjau.ac.ir (A.R. Moosavi-Zare).
1631-0748/$ – see front matter ß 2013 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.crci.2013.05.010
Please cite this article in press as: Zolfigol MA, et al. Nano-ferrous ferric oxide (nano-Fe3O4): Powerful, reusable, and
stable catalyst for N-Boc protection of amines. C. R. Chimie (2013), http://dx.doi.org/10.1016/j.crci.2013.05.010

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Scheme 1. Selective tert-butoxycarbonylation of various amines using diboc catalyzed by nano-Fe3O4.
drawbacks for the N-boc protection of amines at all. The
catalyst can be easily collected by a magnet and recovered
without significant loss in the catalytic activity.
The magnetic properties of the catalyst were also
calculated by VSM at 298 K. The magnetization curves
reveal that the magnetization was saturated up to 60 emu/
g at an applied field of 7000 Oe and confirm the super
paramagnetic behavior of the catalyst at room tempera-
ture (Fig. 1b).
2. Results and discussion
Finally, to further prove the composition of the catalyst,
an FTIR spectrum of Fe3O4 was examined as shown in
Fig. 1c, the peak at 582 cmꢁ1 being related to the
interactions of Fe–O bonds in the structure of nano-
Fe3O4 (Fig. 1c).
After the preparation and characterization of the
catalysts, to optimize the reaction conditions, the reaction
of 4-methoxyaniline with diboc was tested as a model in
the presence of 3 mol% of nano-Fe3O4 in various solvents,
such as EtOH, H2O, CHCl3, CH2Cl2, CH3OH, CH3CN, n-
hexane and EtOAc at room temperature. The results are
summarized in Table 1. Diboc was soluble in all the tested
solvents, except H2O. As it can be seen in Table 1, ethanol
was the best solvent in this reaction.
The model reaction was then carried out with different
amounts of the catalyst (Table 2) and a higher yield and
shorter reaction times were observed using 3 mol% of
nano-Fe3O4 in ethanol at room temperature.
To assess the efficiency and scope of the catalyst, the
reaction of diboc with various amines was studied under
At first, in this research project, the catalyst {nano-
Fe3O4} was synthesized according to the previous
literature [16,17]. The synthesized powder was studied
by X-ray diffractometry (XRD), vibrating sample magne-
tometry (VSM), Fourier transform infrared spectroscopy
(FTIR) and transmission electron microscopy (TEM). In
order to prove that the magnetite was correctly
synthesized, initially, its XRD pattern was recorded. As
shown in Fig. 1a, the XRD patterns of magnetite Fe3O4
nanoparticles reveal peaks at 2
53.638, 57.298 and 62.808, respectively, which was
u
ꢀ 30.248, 35.628, 43.338,
confirmed by the reported value (JCPDS 01-1111). The
average crystallite size
Debye–Scherrer formula: D ¼ k
X-ray wavelength, K is the Scherrer constant,
maximum peak width, and
D was calculated using the
l
=ðbcosu
Þ,
l
b
being the
is the half-
u
is the Bragg diffraction
angle. The average size of the catalyst, thus, obtained
from this equation was found to be about 9 nm, which is
basically in accordance with the transmission electron
micrographs (Fig. 2).
Fig. 1. (a) XRD pattern of the nano-Fe3O4. (b) Vibrating sample magnetometry (VSM) spectrum of the nano-Fe3O4. (c) FTIR spectrum of the nano-Fe3O4.
Please cite this article in press as: Zolfigol MA, et al. Nano-ferrous ferric oxide (nano-Fe3O4): Powerful, reusable, and
stable catalyst for N-Boc protection of amines. C. R. Chimie (2013), http://dx.doi.org/10.1016/j.crci.2013.05.010

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3
Table 3
Protection of amines (1 mmol) with diboc (1 mmol) using nano-Fe3O4
(3 mol %) as catalyst in ethanol (5 mL) at room temperature.
Entry Amine
Time
(min)/Yielda (%)
Reference
1a
Ph-NH2
20/99
180/99
120/80
15/99
20/99
30/95
120/80
100/85
200/95
10/95
60/80
[13a,d]
[13b]
[13b]
[13c]
[13c]
[13b]
[13b]
[13b,d]
[13a]
[13a]
[13a]
[13c]
[13a]
[13a]
[13c]
[13a]
[13a]
[13a]
1b
1c
4-Cl-Ph-NH2
4-Br-Ph-NH2
1d
1e
4-OMe-Ph-NH2
4-OH-Ph-NH2
2-OH-Ph-NH2
2-Me-Ph-NH2
3-Me-Ph-NH2
3-Br-Ph-NH2
1f
1g
1h
1i
1j
(PhCH2)2NH
1kb
1l
(4-NH2Ph)2CH2
Ph-CH2NH2
200/95
60/95
45/99
180/99
20/95
25/95
15/99
1mb
1nb
1o
1p
1qb
1rb
Benzene-1,2-diamine
4-Methylbenzene-1,2-diamine
Naphthalen-1-amine
Azepane
Piperazine
Cyclohexane-1,2-diamine
a
Isolated yield
b
This reaction was performed using 2 mmol of diboc.
Fig. 2. Transmission electron microscopy (TEM) of the nano-Fe3O4.
Furthermore, we compared the turnover number (TON)
value of our catalyst with some reported catalysts in the
reaction (1 mmol) of aniline with diboc (1 mmol) (Table 4).
As shown in Table 4, nano-Fe3O4 was better than the
reported catalysts in terms of TON.
In a plausible mechanism shown in Scheme 2, carbonyl
groups of diboc would be activated by nano-Fe3O4 as a
Lewis acid. Fe3O4 was clearly considered as a Lewis acid
and studied in the previous literature [18]. Then, the
nucleophilic nitrogen of amine would attack the carbonyl
optimal conditions (Section 4.3). The results were sum-
marized in Table 3. All amines, including aromatic and
aliphatic, as well as halogens on their aromatic rings
afforded the desired tert-butoxycarbonylated products in
high to excellent yields (80–99%) in acceptable reaction
times (10–200 min). As shown in Table 3, when diboc
reacted with aromatic amines with the electron-releasing
substituents, the yield was increased and the reaction time
was decreased in accordance with the effect of the
electron-withdrawing substituents.
group. After opening and closing the
p bond of the
carbonyl group in diboc, the amine was protected and one
molecule of CO2 and tert-butyl alcohol were obtained as
the side products.
Table 1
In another study, the recyclability of the catalyst was
examined in the reaction of 4-methoxyaniline with diboc.
After completion of the reaction, the catalyst was collected
by a magnet and separated from the product and from the
remaining starting materials. The recovered catalyst was
washed with ethanol, dried and reused for the next run.
The catalyst was recovered and reused for six times
The effect of various solvents on the reaction of 4-methoxyaniline
(1 mmol) with diboc (1 mmol) catalyzed by 3 mol% of nano-Fe3O4 at room
temperature.
Entry
Solvent
Time (min)/Yielda (%)
1
2
3
4
5
6
7
9
EtOH
15/99
130/95
135/85
60/95
85/70
30/90
60/95
30/90
H2O
CHCl3
CH2Cl2
CH3OH
CH3CN
n-Hexane
EtOAc
Table 4
Comparison of the results of the reaction of aniline (1 mmol) with diboc
(1 mmol) catalyzed by nano-Fe3O4 with those obtained by the reported
catalysts.
a
Isolated yield
Catalyst/condition
Catalyst Time
TON Reference
amount (min)/Yielda
(mol%) (%)
Table 2
Effect of different amounts of the catalyst on the reaction of 4-
methoxyaniline (1 mmol) with diboc (1 mmol) at room temperature.
b
Nano-Fe3O4/EtOH/rt
Thiourea/toluene/60 8C
NH2SO3H/solvent-free/rtc
La (NO3)3 6H2O/solvent-
free/35 8C
3
10
5
20/99
40/95
10/96
2/100
33
–
9.5 11
Time (min)/Yielda (%)
19.2 12
Entry
Mol% of catalyst
5
20
16
1
2
3
4
1
3
60/70
15/99
15/99
15/99
TON: turn-over number; rt: room temperature.
6
a
Isolated yield.
10
b
Our work.
a
c
Isolated yield
In this reaction, 5 mmol of aniline were reacted with 5 mmol of diboc.
Please cite this article in press as: Zolfigol MA, et al. Nano-ferrous ferric oxide (nano-Fe3O4): Powerful, reusable, and
stable catalyst for N-Boc protection of amines. C. R. Chimie (2013), http://dx.doi.org/10.1016/j.crci.2013.05.010

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Scheme 2. Purposed mechanism for the protection of amines with diboc using nano-Fe3O4 as a catalyst.
Table 5
synthesized Fe3O4 (magnetite) was determined using an X-
ray diffractometer (Italstructure ADP2000 XRD diffract-
ometer) at ambient temperature. The magnetic measure-
ments were carried out in a vibrating sample magnetometer
(VSM-4 inch, Daghigh Meghnatis Kashan Co., Kashan, Iran)
at room temperature. TEM analyses were performed with a
Philips model CM 10 instrument.
Recovery and reuse of the nano-Fe3O4 as the catalyst in the reaction of 4-
methoxyaniline (1 mmol) with diboc (1 mmol) in EtOH at room
temperature.
Run
Time (min)
Yielda (%)
1
2
3
4
5
6
15
15
15
15
16
16
99
99
98
96
95
94
4.2. General procedure for the synthesis of nano-ferrous ferric
oxide (nano-Fe3O4)
a
Yield of the purified product.
First, 3 mL of FeCl3 (2 mol Lꢁ1 dissolved in 2 mol Lꢁ1 HCl)
were added to 10.33 mL of double distilled water, and 2 mL
of Na2SO3 (1 mol Lꢁ1) were added to the former solution
dropwise in 1 min under magnetic stirring. When the color
of the solution turned back from red to light yellow, the
solution was added to 80 mL NH3ꢂH2O solution
(0.85 mol Lꢁ1) under vigorous stirring. After 30 min, the
magnetite precipitates were washed to pH < 7.5 by distilled
water [16,17].
without any significant changes in the yield and the
reaction time (Table 5).
3. Conclusion
In summary, we have introduced nano-Fe3O4 as an
efficient, green and heterogeneous catalyst for the
chemoselective N-boc protection of amines at room
temperature in ethanol for the first time. The promising
points of this method are safety, low cost, ease of
separation and reusability of the catalyst, minimization
of chemical wastes, mild reaction conditions, high yields,
simple experimental procedure, short reaction times and
compliance with the green chemistry protocols.
4.3. General procedure for the N-boc protection of amines
A round-bottom flask (10 mL), which contains EtOH
(5 mL), was charged with a solution of diboc (1–2 mmol),
nano-Fe3O4 (3 mol%, 0.007 g) and the amine (1 mmol). The
mixture was stirred at room temperature for the appro-
priate time (Table 3). After completion of the reaction, the
catalyst was collected by a magnet and separated from the
solution of product and the remaining starting materials.
After drying and evaporation of the solvent, the resulting
solid was recrystallized from n-hexane or ethyl acetate
(5 mL) to give the pure product. The recovered catalyst was
washed with EtOH, dried and reused for the next run. The
catalyst was recovered and reused for six times without
any significant changes in the yield and the reaction time.
4. Experimental
4.1. General
All the chemicals were purchased from Merck, Fluka or
Acros Chemical Companies and used without any further
purification. The products were identified by comparison of
their 1H NMR, IR spectrum and TLC with those of authentic
samples.The progressofthereactionswasmonitoredbyTLC
using silica gel SIL G/UV 254 plates. The 1HNMR (90 MHz)
4.4. Selected spectral data of the products
was run on a Jeol FX90Q NMR spectrometer (
infrared spectrum of the compounds was recorded with a
PerkinElmer PE-1600-FTIR device. The crystal structure of
d
in ppm). The
4.4.1. tert-Butyl 4-chlorophenylcarbamate (1b) [13b]
IR(KBr): 3304, 2961, 1700, 1593 cmꢁ1; 1H NMR (90 MHz,
CDCl3),
d 1.49 (s, 9H), 6.49 (s, 1H), 7.19–7.35 (m, 4H).
Please cite this article in press as: Zolfigol MA, et al. Nano-ferrous ferric oxide (nano-Fe3O4): Powerful, reusable, and
stable catalyst for N-Boc protection of amines. C. R. Chimie (2013), http://dx.doi.org/10.1016/j.crci.2013.05.010

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The authors gratefully acknowledge the partial
support of this work by the Research Affairs Office of
Bu-Ali Sina University (Grant number 32-1716 entitled
‘‘Development of chemical methods, reagents and
molecules’’), and the Center of Excellence in Develop-
ment of Chemical Method (CEDCM), Hamedan, Islamic
Republic of Iran.
Please cite this article in press as: Zolfigol MA, et al. Nano-ferrous ferric oxide (nano-Fe3O4): Powerful, reusable, and
stable catalyst for N-Boc protection of amines. C. R. Chimie (2013), http://dx.doi.org/10.1016/j.crci.2013.05.010