Saccharin sulfonic acid catalyzed N-Boc protection of amines and formation of tertbutyl ethers from alcohols

Article abstract of DOI:10.1007/BF03246047

Saccharin sulfonic acid (SaSA), as a stable reagent is easily prepared by the reaction of saccharin with neat chlorosulfonic acid at room temperature. This compound is able to catalyze conversion of amines to their corresponding N-Boc protected amines with (Boc)₂O. Alcohols were also converted to their corresponding tert-butyl ethers. All reactions took place under mild conditions giving the desired products in good to high yields.

Full text of DOI:10.1007/BF03246047

J. Iran. Chem. Soc., Vol. 7, No. 3, September 2010, pp. 603-607.
JOUIRrNaAnLiaOnF THE
Chemical Society
Saccharin Sulfonic Acid Catalyzed N-Boc Protection of Amines and Formation of tert-
Butyl Ethers from Alcohols
F. Shirinia,*, M.A. Zolfigolb and M. Abedinia
aDepartment of Chemistry, College of Science, University of Guilan, Rasht 41335,
I. R. Iran
bCollege of Chemistry, Bu-Ali Sina University, Hamadan, I. R. Iran
(Received 22 May 2009, Accepted 3 September 2009)
Saccharin sulfonic acid (SaSA), as a stable reagent is easily prepared by the reaction of saccharin with neat chlorosulfonic acid
at room temperature. This compound is able to catalyze conversion of amines to their corresponding N-Boc protected amines with
(Boc)2O. Alcohols were also converted to their corresponding tert-butyl ethers. All reactions took place under mild conditions
giving the desired products in good to high yields.
Keywords: Alcohols, Amines, Saccharin sulfonic acid, tert-Butyl ethers, (Boc)2O
INTRODUCTION
(Boc)2O using basic or acidic catalysts [7-20]. Although these
represent some improvement, most of them suffer from
disadvantages such as long reaction times, tedious work-up,
the use of corrosive or moisture sensitive reagents, formation
of side-products during base-catalyzed reactions, difficulty in
the preparation of the reagent, and using excess of reagent in
the case of Lewis acid catalyzed reactions.
Protection and deprotection of organic functions are
important processes during multi-step organic synthesis [1,2].
The choice of a method which is used for the functional group
transformations depends on its simplicity, high 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
great stability of the N-Boc group in the course of various
base-catalyzed nucleophilic substitutions and catalytic
EXPERIMENTAL
Preparation of Saccharin Sulfonic Acid (SaSA) [21]
A flask (500 ml) charged with saccharin (17.1 g, 0.1 mol)
was equipped with a constant pressure dropping funnel
containing chlorosulfonic acid (11.65 g, 0.1 mol) and a gas
outlet tube which was dipped into water to dissolve the
generated HCl gas during the reaction. The flask was put into
an ice bath and chlorosulfonic acid was added dropwise over a
period of 10 min and the resulting mixture was stirred slowly
for another 10 min. The temperature of the mixture was
brought up to the room temperature and was stirred for an
hydrogenation
reactions,
the
N-tetr-butyloxycarbonyl
protection (Boc) has attracted much attention of many organic
chemists [3,4]. Di-tert-butyldicarbonate [(Boc)2O] as a stable
and commercially available reagent is widely used for this
purpose [5,6]. Many methods have been reported which were
meant to improve the rate of the N-Boc protection with
*Corresponding author. E-mail: shirini@guilan.ac.ir

Shirini et al.
additional 30 min. The mixture was triturated with n-hexane
RESULTS AND DISCUSSION
(10 ml) and then filtered. The solid residue was washed with
n-hexane (10 ml) and dried under vacuum. Saccharin sulfonic
acid, mp.: 110-112 °C; IR: 3100, 2976, 1726, 1593, 1462,
1340, 1292, 1180, 1130, 1068, 1007, 885, 853, 760, 706, 584,
519, 455 cm-1.
In continuation of our ongoing research project on the
development of new methods for the functional group
transformations [22-26], we recently carried out a research
work for the preparation of saccharin sulfonic acid (SaSA), as
a stable derivative of saccharin and its application for the
promotion of chemoselective trimethylsilylation of alcohols
with hexamethyldisilazane [21]. Our investigation clarified
that saccharin sulfonic acid was a suitable catalyst for the
efficient conversion of amines to their corresponding N-Boc
derivatives with (Boc)2O (Scheme 1).
A variety of aromatic and aliphatic amines underwent the
protection reaction with (Boc)2O in the presence of catalytic
amounts of SaSA in n-hexane at room temperature or under
reflux conditions in good to high yields. The results are
tabulated in Table 1.
General Procedure
A mixture of the substrate (1 mmol), (Boc)2O (1 mmol,
0.218 g) and SaSA (0.2 mmol, 0.052 g) in n-hexane (3 ml) was
stirred at room temperature or under reflux conditions. (Tables
1 and 2). The progress of the reaction was monitored by TLC.
After completion, the mixture was filtered and the filtrate was
washed with n-hexane (3 ml). Evaporation of the solvent
followed by column chromatography (silica-gel) eluting with
n-hexane-EtOAc (1:1) gave the desired product in good to
high yields.
Table 1. Boc Protection of Aminesa, b
Entry
Product
Time (h)
Yield (%)
Ph-NHBoc
4-Me-Ph-NHBoc
2, 4-Me2-Ph-NHBoc
1
2
3
1
3
4
97
90
80
4
3c
60
3-Br-Ph-NHBoc
5
6
7
8
Ph-CH2NHBoc
2-MeO-Ph-CH2NHBoc
Ph-CH2CH2NHBoc
1
4
1
2
95
80
92
95
3, 4- (MeO)2-Ph-CH2CH2NHBoc
9
10
1
1.5
95
95
Ph-CH2CH2CH(Me)NHBoc
NHBoc
11
1
95
NHBoc
12
13
1
97
90
N(Me)Boc
O
4c
N Boc
O
14
4c
90
O
N Boc
O
aProducts were identified spectroscopically. Isolated yields. cReaction was performed under
b
reflux conditions.
604

Saccharin Sulfonic Acid Catalyzed N-Boc Protection of Amines
SaSA, (Boc)2O
R1R2NH
R1R2N-Boc
n-Hexane, r.t. or reflux
R1= H, Me
R2= Ph, 4-Me-Ph, 2,4-Me2-Ph, 3-Br-Ph, PhCH2, 2-MeO-PhCH2, Ph-CH2CH2, 3,4-(MeO)2-Ph-CH2CH2,
Ph-CH2CH2CH(Me), Cyclohexyl, Cycloheptyl,
O
O
,
O
O
Scheme 1
SaSA, (Boc)2O
ROH
ROCMe3
n-Hexane, reflux
R= 4-Cl-Ph-CH2, 2-Cl-Ph-CH2, 2-Br-Ph-CH2, 2-Me-Ph-CH2, 4-Me3C-Ph-CH2,
2-MeO-Ph-CH2, 3-MeO-Ph-CH2, 2-NO2-Ph-CH2, Cyclohexyl, (-)-Menthyl,
Ph-CH2CH2, 1-Adamantanyl
Scheme 2
Table 2. Protection of Alcohols as tert-Butyl Ethersa, b
Entry
Product
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
2
4
6
3
2
2
2
4
2
90
90
90
80
80
90
90
50
80
4-Cl-Ph-CH2OCMe3
2-Cl-Ph-CH2OCMe3
2-Br-Ph-CH2OCMe3
2-Me-Ph-CH2OCMe3
4-Me3C-Ph-CH2OCMe3
2-MeO-Ph-CH2OCMe3
3-MeO-Ph-CH2OCMe3
2-NO2-Ph-CH2OCMe3
OCMe3
10
4
70
Me3CO
11
12
1
1
90
-
Ph-CH2CH2OCMe3
OCMe3
c
aProducts were identified spectroscopically. bIsolated yields. cMixture of products.
We further found out that under similar reaction conditions
alcohols are protected as their corresponding tert-butyl ethers
(Scheme 2).
to high yields (Table 2). Because of the formation of mixture
of the products, the method is not suitable for the protection of
tertiary alcohols (Table 2, entry 12).
Different types of alcohols, including benzylic, primary
and secondary aliphatic ones, underwent etherification with
(Boc)2O in the presence of SaSA in refluxing n-hexane in good
In order to show the merit of this method, in Table 3, we
have compared the results obtained from the N-Boc protection
of aniline by our method with some of those reported in the
605

Shirini et al.
Table 3. Comparison of the Effect of Different Catalysts in N-Boc Protection of Aniline with (Boc)2O at
Room Temperature
Entry Catalyst
Time (h)
Solvent
Isolate yield
Ref.
1
2
3
4
5
FeCl3
Yttria-zirconia
Zn(ClO4)2.6H2O
1
14
Neat
89
90
92
75
83
[20]
[18]
[16]
[19]
[7]
CH3CN
CH2Cl2
H2O
12
ꢀ-Cyclodextrin
Sulfonic acid-
2.5
0.75
CH2Cl2
functionalized silica
6
7
Uncatalyzed
SaSA
48
1
Neat
n-Hexane
60
97
[20]
Present method
literature.
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[6]
[7]
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CONCLUSIONS
In conclusion, saccharin sulfonic acid, can be used as an
efficient catalyst for the N-Boc protection of amines using
(Boc)2O. This compound is also a suitable catalyst for the
formation of tert-butyl ethers from the related alcohols. The
method has several advantages such as mild reaction
conditions, high yields of the products, heterogeneous nature
of the reaction, easy work-up, which make this procedure a
useful and significant addition to the currently available
methods.
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