Succinimide sulfonic acid (SuSA): An efficient and recyclable catalyst for the chemoselective N-Boc protection of amines

Article abstract of DOI:10.1007/s00706-011-0612-5

Succinimide sulfonic acid (SuSA) as a stable reagent is easily prepared by the reaction of succinimide with neat chlorosulfonic acid. This compound is able to catalyze the chemoselective conversion of amines to their corresponding N-Boc protected derivatives with (Boc)₂O. All reactions were performed under mild conditions, giving the desired products in good to high yields. Springer-Verlag 2011.

Full text of DOI:10.1007/s00706-011-0612-5

Monatsh Chem (2012) 143:631–635
DOI 10.1007/s00706-011-0612-5
ORIGINAL PAPER
Succinimide sulfonic acid (SuSA): an efficient and recyclable
catalyst for the chemoselective N-Boc protection of amines
•
Farhad Shirini Nader Ghaffari Khaligh
Received: 21 May 2010 / Accepted: 5 August 2011 / Published online: 10 December 2011
Ó Springer-Verlag 2011
Abstract Succinimide sulfonic acid (SuSA) as a stable
reagent is easily prepared by the reaction of succinimide
with neat chlorosulfonic acid. This compound is able to
catalyze the chemoselective conversion of amines to their
corresponding N-Boc protected derivatives with (Boc)2O.
All reactions were performed under mild conditions, giving
the desired products in good to high yields.
used for this purpose [5, 6]. Many methods have been
reported to improve the rate of the N-Boc protection with
(Boc)2O using basic or acidic catalysts [7–20]. Although
these procedures provide an improvement, most of them
suffer from disadvantages such as long reaction times,
tedious work-up, the use of corrosive or moisture-sensitive
reagents, the formation of side-products during base-cata-
lyzed reactions, difficulty in the preparation of the reagent,
and using an excess of reagent in the case of Lewis acid-
catalyzed reactions.
Keywords Succinimide Amine Á
Di-tert-butyl dicarbonate Á N-tert-butoxycarbonylation Á
Solvent-free reaction conditions
Results and discussion
Introduction
In recent years, the introduction of new methods and
reagents for the functional group transformations became
an important part of our research program [21–24]. In
continuation of these studies, we have found that succini-
mide (1), as a cheap and commercially available reagent,
reacts with neat chlorosulfonic acid to give succinimide
sulfonic acid (SuSA, 2) at room temperature. The reaction
is easy and clean, and needs no special work-up procedure
(Scheme 1).
The protection and deprotection of organic functions are
important processes during multi-step organic synthesis
[1, 2]. The choice of the method which is used for the
functional group transformations depends on its simpli-
city, highest yields of the desired products, short reaction
times, low cost of the process, and ease of the work-up
procedures.
Because of its applicability in peptide and nucleoside
syntheses, as well as heterocyclic chemistry, and also due to
the great stability of the N-Boc group in the course of
various base-catalyzed nucleophilic substitutions and cata-
lytic hydrogenation reactions, the N-tert-butoxycarbonyl
(Boc) protection has attracted much attention of many
organic chemists [3, 4]. Di-tert-butyl dicarbonate [(Boc)2O]
as a stable and commercially available reagent is widely
The structure of SuSA assured us to accept that this
reagent can act as an efficient catalyst in reactions that need
acidic reagents in order to speed up. Our investigations
clarified that this prediction is correct and the conversion
of amines to their corresponding N-Boc derivatives is
efficiently promoted in the presence of SuSA (Table 1;
Scheme 2). All reactions were performed in the absence
of solvent at room temperature in good to high yields.
No competitive side reactions leading to the formation
of isocyanates, urea, and N,N-di-Boc derivatives were
observed at all. Alcohols, phenols, and thiols remain intact
under the same reaction conditions. Therefore, the method
F. Shirini (&) Á N. G. Khaligh
Department of Chemistry, College of Science,
University of Guilan, 41335 Rasht, Iran
e-mail: shirini@guilan.ac.ir
123

632
F. Shirini, N. G. Khaligh
We have found that SuSA is a reusable catalyst and,
even after four runs for the N-Boc protection of amines
with (Boc)2O, the catalytic activity of SuSA was almost the
same as that of the freshly used catalyst.
O
O
ClSO3H, CH2Cl2
NH
N SO3H + HCl
o
0 C-r.t., 2 h
O
O
Although the actual role of SuSA is not clear, the
mechanism that is shown in Scheme 3 is selected as a most
probable one.
1
2
In order to show the merit of this method, Table 2
compares the results obtained from the N-Boc protection of
aniline by our method with some of those reported in the
literature.
Scheme 1
can be useful for the chemoselective N-tert-butoxycarb-
onylation of amines in the presence of alcohols, phenols,
and thiols (Table 1, entries 2, 3, 14, and 15).
In conclusion, the N-tert-butoxycarbonylation of amines
with (Boc)2O is efficiently catalyzed in the presence of
Table 1 N-Boc protection of amines catalyzed by SuSA
Entry
Substrate
Product
Time/min
Yield/%a
1
2
3
4
5
6
7
8
9
Ph–NH2
Ph–NH–Boc
2 (2, 2, 2, 2)b
98 (98, 98, 95, 92)b
2–HO–Ph–NH2
2–HS–Ph–NH2
3–Cl–Ph–NH2
4–Br–Ph–NH2
4–Et–Ph–NH2
4–Me–Ph–NH2
3–MeO–Ph–NH2
2–HO–Ph–NH–Boc
2–HS–Ph–NH–Boc
3–Cl–Ph–NH–Boc
4–Br–Ph–NH–Boc
4–Et–Ph–NH–Boc
4–Me–Ph–NH–Boc
3–MeO–Ph–NH–Boc
8
92
14
92
32
94
30
96
45
94
12
95
74
12 (12, 14, 14, 15)b
91
94 (90, 90, 87, 84)b
NH2
NH-Boc
10
1
92
H
N
H
N
NH2
NH-Boc
N
N
11
12
1
1
92
91
NH-Boc
NH2
NH-Boc
NH2
13
1
94
NH2
NH-Boc
MeO
MeO
OMe
OMe
123

Succinimide sulfonic acid
633
Table 1 continued
Entry
Substrate
Product
Time/min
Yield/%a
14
15
HO–CH2–CH2–NH2
HO–CH2–CH2–NH–Boc
1
2
82
95
OH
OH
N
H
N
Boc
16
17
2
2
88
92
N
NH
NH
N
N-Boc
N-Boc
18
19
2
6
89
86
NH
N-Boc
N-Boc
NH
20
21
a
Ph–CH2–NH2
Ph–CH2–NH–Boc
1
1
98
96
4–Me–Ph–CH2–NH2
4–Me–Ph–CH2–NH–Boc
Isolated yield
b
Results obtained using recycled catalyst
SuSA, as a newly prepared succinimide-based reagent.
High yields of the products, relatively short reaction times,
ease of the preparation, stability and reusability of the
reagent, solvent-free reaction conditions, and easy work-up
are among the other advantages of this new method which
(Boc)2O (1 equiv.)
R1R2NH
R1R2N-Boc
SuSA (5 mg), neat, r.t.
Scheme 2
R1R2NH
(Boc)2O
Scheme 3
O
O
O
N SO3 + R1R2NH2
N SO3H
O
R1R2NCO2CMe3
+ CO2 + Me3COH
O
O
O3S N
O3S N
O
H
O
O
H
R1R2NH
O
O
O
O
O
O
O
O
O
NR1R2
H
123

634
F. Shirini, N. G. Khaligh
Table 2 Comparison of the effect of catalysis in the N-Boc protection of aniline with (Boc)2O at room temperature
Entry
Catalyst
Time/h
Solvent
Isolated yield/%
Reference
1
2
3
4
5
6
7
FeCl3
1
Neat
89
90
92
75
83
60
98
[20]
Yttria-zirconia
Zn(ClO4)2Á6H2O
b-Cyclodextrin
Sulfonic acid-functionalized silica
Uncatalyzed
14
Acetonitrile
Dichloromethane
Water
[18]
12
[16]
2.5
0.75
48
[19]
Dichloromethane
Neat
[7]
[20]
SuSA
2 min
Neat
Present method
General procedure for the N-Boc protection of amines
mixture of 1 mmol substrate, 0.218 g (Boc)2O
make this procedure a useful and attractive addition to the
available methods. We are exploring further applications of
SuSA for the other types of functional group transforma-
tions in our laboratory.
A
(1 mmol), and 5 mg SuSA (0.03 mmol) was stirred at
room temperature in the absence of solvent. The progress
of the reaction was monitored by TLC. After completion
of the reaction, the mixture was triturated with 5 cm3
ethyl acetate and filtered. Then, the solid residue was
washed with 5 cm3 ethyl acetate and dried. The recovered
catalyst can be used for four reactions again. Evaporation
of the solvent followed by column chromatography (silica
gel) eluting with petroleum ether-EtOAc (8:2) followed by
evaporation of the solvent gave the desired product in
good to high yields.
Experimental
Chemicals were purchased from Fluka, Merck, and Aldrich
Chemical Companies. All yields refer to the isolated
products. The purity determination of the substrate and
reaction monitoring were accompanied by thin-layer
chromatography (TLC) on silica-gel polygram SILG/UV
254 plates.
Products were characterized by the comparison of their
physical and spectral data with authentic samples [10, 16,
17, 20, 25–31].
Succinimide sulfonic acid (2, C4H5NO5S)
A 25-cm3 suction flask charged with a solution of 0.99 g
succinimide (10 mmol) in 5 cm3 dry CH2Cl2 was equipped
with a constant pressure-dropping funnel containing
1.165 g chlorosulfonic acid (10 mmol) and a gas inlet
tube for conducting HCl gas over an adsorbing solution,
i.e., water. Chlorosulfonic acid was added dropwise over a
period of 15 min while the reaction mixture was stirred
slowly in an ice bath. The mixture was then heated to room
temperature and stirred for an additional 2 h. The mixture
was filtered and the solid residue was washed with
2 9 5 cm3 ether and dried under vacuum. Succinimide
sulfonic acid was obtained as a cream solid (1.74 g, 97%).
Acknowledgments We are thankful to the University of Guilan
Research Council for the partial support of this work.
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