Magnetic nanoparticles catalyzed N-tert-butoxycarbonylation of Amines and amine derivatives

Article abstract of DOI:10.2174/157017812800167510

A simple and efficient protocol for the chemoselective mono-N-Boc protection of various structurally diverse amines with di-tert-butyl dicarbonate using magnetically recoverable γ-Fe₂O₃@SiO ₂ nanoparticles is reported. The catalyst can be easily recovered and recycled without a significant loss in the catalytic activity. No competitive side reactions, such as formation of isocyanate, urea, oxazolidinone, and N,N-di-Boc derivatives were obsereved.

Full text of DOI:10.2174/157017812800167510

Letters in Organic Chemistry, 2012, 9, 165-168
165
Magnetic Nanoparticles Catalyzed N-Tert-Butoxycarbonylation of Amines
and Amine Derivatives
,a
b
b
c
Jafar Akbari* , Soghra B. Sajirani , Jafar M. Nezhad and Akbar Heydari
a
Chemistry Department, Buinzahra Branch, Islamic Azad University, Buinzahra, P. O. Box: 3451686799, Iran
Chemistry Department, Shahr-e-Qods Branch, Islamic Azad University, Tehran, Iran
b
c
Research center for organic chemical synthesis, No. 10. First-Kosar St. Tohid St, Tehran, Iran
Received June 30, 2011: Revised October 12, 2011: Accepted October 12, 2011
Abstract: A simple and efficient protocol for the chemoselective mono-N-Boc protection of various structurally diverse
amines with di-tert-butyl dicarbonate using magnetically recoverable ꢀ-Fe O @SiO nanoparticles is reported. The
2 3 2
catalyst can be easily recovered and recycled without a significant loss in the catalytic activity. No competitive side
reactions, such as formation of isocyanate, urea, oxazolidinone, and N,N-di-Boc derivatives were obsereved.
Keywords: (Boc)
2
O, chemoselective, magnetic nanoparticles, protection, recycling.
INTRODUCTION
formation of side-products, the use of corrosive and
moisture-sensitive reagents, limited applicabilities, and
tedious work-up procedures. Moreover, many of these
methods fail when amino acids or peptides are involved.
Because of increasing environmental concerns, the
development of a clean synthetic procedure has become a
crucial and demanding research. In this sense, heterogeneous
organic reactions have many advantages, such as ease of
handling, separation, recycling, and environmentally safe
disposal [1]. Nanoparticles as heterogeneous catalysts have
attracted a great deal of attention in recent years because of
their interesting structure and high catalytic activities [2]. In
this context, magnetic particles, in particular, have emerged
as one of the most useful heterogeneous catalysts because of
their numerous applications in nanocatalysis, biotechnology,
and medicine [3]. Additionally, the magnetic properties
make possible the complete recovery of the catalyst by
means of an external magnetic field [4].
As a part of our ongoing research projects to develop
new synthetic methodologies, particularly with a potential
for using metal oxides [18], we have been interested in
magnetic nanoparticles as an inexpensive, high corrosion
resistive and as a potential reaction catalyst. ꢀ-Fe
Nanoparticles were synthesized by chemical co-
precipitation technique of ferric and ferrous ions in alkali
solution [19]. SEM and TEM images of ꢀ-Fe
Nanoparticles are shown in Fig. (1). Herein, we roport ꢀ-
Fe as an efficient, heterogeneous and recyclable catalyst
2 3
O
a
2
O
3
2
O
3
for the selective tertbutoxycarbonylation of various amines
and amine derivatives. The general applicability of the
method for the synthesis of a wide variety of diverse N-Boc-
amines is demonstrated (Table 1).
The choice of the protection strategy is of high
importance in synthetic chemistry of multifunctional
molecules including the total synthesis of natural products.
Amines protection continues to attach a great deal of
attention in a wide range of chemical fields, such as peptides,
nucleoside, polymer and catalyst ligand synthesis [5]. A
large variety of protective groups have been developed.
Among them, the tert-butoxycarbonyl (t-Boc) group is
frequently used as a protecting group for amine in synthetic
organic/peptide chemistry due to its stability towards
catalytic hydrogenolysis and extreme resistance to basic and
nucleophilic conditions. Various reagents and methods have
been reported for the N-tertbutoxycarbonylation of amines.
N-tert-butyl carbamates using di-tert-butyl dicarbonate
RESULTS AND DISCUSSION
Initially, Aniline reacted with (Boc)
room temperature in the presence of 5 mol% ꢀ- Fe
2
O instantaneously at
@SiO
2
2
O
3
under solvent free condition and a white precipitate of tert-
butyl-N-phenyl carbamate is formed. No competitive side
reactions leading to the formation of isocyanate, urea, or
N,N-di-Boc derivatives were detected. The chosen amount of
catalyst (5 mol %) was found to be sufficient for an optimal
result, but increasing the quantity of catayst brought no
substantial improvement. In the absence of catalyst, longer
reaction time (90 min) was observed with lower isolated
yield of tert-butyl-N-phenyl carbamate [20].
(
Boc)
2
O have been carried out either in the presence of a
base (DMAP [6] or inoeganic bases [7]) or more recently
acid catalysts [8-17] and miscellaneous reagents. Some of
the above procedures have certain drawbacks such as
This study was extended to a wide range of structurally
diverse amines including open-chain, cyclic, aromatic and
heteroaromatic, as well as b-amino alcohols and a-amino
acid esters which underwent the reaction smoothly with
*
Address correspondence to this author at the Chemistry Department,
Buinzahra Branch, Islamic Azad University, Buinzahra, P. O. Box:
451686799, Iran; Tel: 00982182884452; Fax: 00982182883455;
E-mail: j_akbari@modares.ac.ir
(
2
Boc) O. The method can be applied for the conversion of
3
poorly reactive amines, such as chloroaniline and
1
875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

1
66 Letters in Organic Chemistry, 2012, Vol. 9, No. 3
Akbari et al.
a
b
Fig. (1). The SEM (a), TEM (b) images of ꢀ-Fe O .
2
3
Table 1. Magnetic Nanoparticles Catalyzed N-Boc Protection of Amines
R1
R1
N
3
2 3 2
nano Fe O @SiO
N
Boc O
+
H
2
R2
r.t
R2
Boc
1
2
Entry
Amine
Time (min)
Product
Yield 3 %
H
N
H
N
a
H
5
98
Boc
H
H
N
N
b
c
H
20
30
96
94
Boc
Cl
Cl
H
N
H
N
H
Boc
Cl
Cl
H
N
H
N
d
H
30
98
Boc
Br
Br
H
N
H
N
H
Boc
e
f
30
10
98
95
Br
Br
Cl
Cl
H
Boc
N
H
N
H

Magnetic Nanoparticles Catalyzed N-Tert-Butoxycarbonylation of Amines
Letters in Organic Chemistry, 2012, Vol. 9, No. 3
167
(
Table 1). Contd…..
Yield 3 %
Entry
Amine
Time (min)
Product
Boc
H
N
H
N
H
6
94
98
H
Boc
h
i
N
H
10
15
N
H
Boc
94
N
H
NH2
N
N
H
Ph
Ph
8
8
Ph
96
98
j
Ph
Boc
k
O
N
H
O
N
Boc
H
N
NH2
l
6
98
98
Boc
OH
OH
NH2
NHBoc
OH
m
10
OH
bromoaniline, as well as the sterically hindered tert-
butylamine, into the corresponding N-Boc derivatives. The
that proved the unusual properties and potential applications
of this magnetic material.
2 3
chemoselectivity of ꢀ- Fe O was assessed by performing
In conclusion, we have developed an efficient method for
N-tertbutoxycarbonylation of various electronically and
structurally diverse amines using ꢀ-Fe O in good-to-
2 3
NBoc protection of amines in bifunctional compounds.
Excellent chemoselectivity was observed in the cases of
aminoalcohols and aminophenols, where the corresponding
N-Boc protected compounds were formed as sole products
without competitive formation of O-Boc or oxazolidinone
excellent isolated yields. The catalyst can be readily
recovered by magnetic separation and reused. It is
noteworthy that this reaction has some advantages in
comparison with existing protocols. The rate of reaction for
all substrates is faster than when there is no catalyst.
Chemoselectivity of this reaction is the main advantage of
this nano catalyst that could not happened without catalyst.
In contrast to some existing methods using potentially
hazardous catalysts/additives, this new method offers the
following advantages: (i) short reaction times, (ii) ease of
product isolation/non-aqueous work-up, (iii) high
chemoselectivity, (iv) no side reactions, and (v) simple
processing and handling. The recovered nano catalyst can be
recycled.
2
derivatives, even using an excess of (Boc) O (Table 1).
The mechanistic rule of magnetic nanoparticles catalyzed
N-Boc protection of amines could be explained by the
electrophilic activation of (Boc)
group susceptible to nucleophilic attack by the amine.
Successive elimination of CO and tert-BuOH results in the
formation of N-Boc derivatives and regenerates ꢀ-Fe
2
O, making the carbonyl
2
2
3
O .
The ease of reusability is one of the important properties
of this catalyst. The insolubility of catalyst in CH Cl allows
2
2
an easy separation of product by simple filtration. The
catalyst was absorbed onto the external magnet. The catalyst
2 2
was then washed with CH Cl , air-dried, and used directly
with fresh substrates under identical conditions without
further purification. It was shown that the catalyst could be
used for five runs without noticeable drop in the product
yield and its catalytic activity. A transmission electron
EXPERIMENTAL SECTION
General Procedure for the N-Tert-Butoxycarbonylation
of Amines
microscopy (TEM) image of Fe
size and distribution of the Fe
altered, in good agreement with previously reported results
2
O
3
showed that the average
Amine (2 mmol) was added to a magnetically stirred
2
O
3
were not significantly
mixture of (Boc)
2 3 2
O (2 mmol) and ꢀ-Fe O @SiO nano (5
2
mol%), and the mixture was stirred at room temperature. The

1
68 Letters in Organic Chemistry, 2012, Vol. 9, No. 3
Akbari et al.
Handy, S.T.; Sabatini, J.J.; Zhang, Y.; Vulfora, I. Protection of
poorly nucleophilic pyrroles. Tetrahedron Lett. 2004, 45(26), 5057-
reaction was monitored by TLC. After the completion of
reaction, the N-Boc product was separated from the reaction
5
4 2
060; Me NOH-5H O in MeCN: (c) Khalil, E. M.; Subasinghe, N.
mixture by extraction with CH
the products were identified by using NMR in CDCl
Fe nanocatalyst was separated by external magnet and
2
Cl
2
and vacuum dried. Then
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3
. The ꢀ-
2
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o
1
N-Boc products: (3c) White solid, mp: 102–104 C; HNMR
500 MHz, CDCl ): d 1.53 (s, 9H), 6.59 (br s, 1H, NH),
[8]
(
3
1
3
7
8
1
.23–7.33 (m, 4H); C NMR (125 MHz, CDCl
0.8, 119.7, 127.9, 128.9, 136.9, 152.6. (3l) White solid, mp
42 C, H NMR (500 MHz, CDCl ): d 1.57 (s, 9H), 6.69 (br
3
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[9]
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o
1
3
13
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004, 2004(10), 1794-1798.
s, 1H, NH), 6.88–7.30 (m, 4H), 8.17 (br s, 1H, OH);
NMR (125 MHz, CDCl ): d 28.6, 82.4, 119.0, 121.1, 121.7,
25.8, 126.0, 147.3, 155.3.
C
[
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ACKNOWLEDGEMENTS
This research is supported by the Islamic Azad
University, Buinzahra branch and Shahre-Qods branch.
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