Catalyst-free water-mediated N-Boc deprotection

Article abstract of DOI:10.1016/j.tetlet.2009.01.056

A catalyst-free water-mediated N-Boc deprotection of N-Boc-amines is reported. In the absence of any additional reagents, the free amines were formed from a variety of aromatic and aliphatic N-Boc-amines as well as from some N-Boc-amino acid derivatives.

Full text of DOI:10.1016/j.tetlet.2009.01.056

Tetrahedron Letters 50 (2009) 1438–1440
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Tetrahedron Letters
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Catalyst-free water-mediated N-Boc deprotection
Gan Wang, Chunju Li, Jian Li, Xueshun Jia *
Department of Chemistry, Shanghai University, Shanghai 200444, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A catalyst-free water-mediated N-Boc deprotection of N-Boc-amines is reported. In the absence of any
additional reagents, the free amines were formed from a variety of aromatic and aliphatic N-Boc-amines
as well as from some N-Boc-amino acid derivatives.
Received 23 October 2008
Revised 26 November 2008
Accepted 13 January 2009
Available online 19 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
N-Boc-amine
Deprotection
Catalyst-free
Water-mediated reaction
The choice of the protection and deprotection strategy is of high
importance in synthetic chemistry of multifunctional molecules
including the total synthesis of natural products. A large variety
of protective groups have been developed along with numerous
methods for their removal. Among them, the tert-butoxycarbonyl
In the present work, we wish to report a catalyst-free water-
mediated N-Boc deprotection. In the absence of any additional re-
agents, the scope of this procedure is explored for the deprotection
of a series of N-Boc derivatives of aromatic and aliphatic amines.
Our initial experiments were carried out by using N-Boc-ani-
line14 as model substrate. As can be seen from Scheme 1 and
Table 1, the N-Boc deprotection performed on this model substrate
at 30 °C and 80 °C was not observed (Table 1, entries 1 and 2).
However, at 130 °C and 150 °C, the free aniline was afforded in
the yields of 39% and 86% after 4 h (Table 1, entries 4 and 6). We
also discovered that the shortening of reaction time resulted in
incomplete N-Boc deprotection (Table 1, entry 5). The critical
amount of water required was found to be 1 mL/mmol of the N-
Boc-amine. The use of a lesser amount of water led to incomplete
conversion, but the use of >1 mL/mmol did not have a significant
influence on the reaction rate and product yield. These results indi-
cated that the removal of N-Boc group from N-Boc-aniline could be
achieved in high performance in water without any additional
reagents.
(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. For these reasons, many methods for N-
Boc deprotection have been reported, in particular, under strong
1
2
3
4
5
acidic conditions (e.g., CF
3
COOH, HCl, HNO
3
,
and H
2
SO
4
,
etc. )
montmoril-
lonite K-10, etc. ). In some cases, basic conditions have also been
6
7
8
and Lewis acid (e.g., ZnBr
2
3 4 2 3 6
, BiCl , Ce(NH ) (NO ) ,
9
10
1
1
described. However, these methodologies have various draw-
backs such as the need for costly and cumbersome neutralization,
using more excessive amounts of catalysts, and auxiliary sub-
stances (e.g., solvents, acids, and Lewis acids). In addition, some
of these catalysts are more expensive and cannot be recovered
and used again. As a result, attempts to find alternative methodol-
ogies for this transformation which do not suffer from the severe
drawbacks of the conventional procedures are still very desirable.
In recent years, much attention has been focused on searching
more ‘green’ or environmentally friendly chemical processes.
Water is cheap, non-toxic, non-combustible, non-explosive, and
environmentally acceptable.12 Therefore, chemists have been
interested in investigating the possibility of using water as solvent
for organic reactions, sometimes with surprising and unforeseen
It is well known that subcritical water (150 < T < 370 °C,
+
À
0.4 < p < 22 MPa) can boast of a higher H and OH ion concentra-
tion than ambient water since the ion product in subcritical water
1
5
is much higher than in ambient water. Accordingly, subcritical
water can replace the catalysts in some acid- and base-catalyzed
13b,16
reactions.
The present hydrothermal reaction at 150 °C is
close to the subcritical water condition. So we deduce that hydro-
1
3
results.
Water
NHBoc
NH2
*
Corresponding author. Tel.: +86 21 66132408; fax: +86 21 66132797.
E-mail address: xsjia@mail.shu.edu.cn (X. Jia).
Scheme 1.
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.056

G. Wang et al. / Tetrahedron Letters 50 (2009) 1438–1440
1439
Table 1
Effect of temperature on the water-mediated deprotection of N-Boc-aniline
Table 2
a
a
Water-mediated deprotection of N-Boc-amines
Entry
Temp (°C)
Time (h)
Isolated yield (%)
Entry
N-Boc-amine
Time (h)
4
Isolated yield (%)
86
1
2
3
4
5
6
30
80
130
130
150
150
4
4
2
4
2
4
0
0
12
39
38
86
1
NHBoc
2
3
4
5
6
4
88
96
95
87
97
Me
NHBoc
a
Unless otherwise noted, all reactions proceeded with 1 mmol N-Boc-aniline and
1
mL distilled, deionized water. No additional reagents were added.
4
MeO
HO
Cl
NHBoc
nium ions formed by the dissociation of water may be a catalyst in
the present system. In the reference experiment, when the depro-
tection of N-Boc-aniline was performed under water-free condition
2
NHBoc
NHBoc
NHBoc
(
also heated for 4 h at 150 °C), no deprotection product was
observed and 90% unreacted N-Boc-aniline was recovered. Further-
more, we also isolated a byproduct (oxanilide, 8%), which was not
found under hydrothermal condition. These observations indicate
that water acts as the catalyst and plays crucial role in this
transformation.
6
O2N
10
Encouraged by these experimental results, a series of structur-
ally diverse aromatic and aliphatic N-Boc-amines were treated in
water at 150 °C (Scheme 2, Table 2). In most cases, the substrate
N-Boc-amines underwent smooth conversion to corresponding
free amino products in good to excellent yields. Moreover, behav-
ior of the present strategy is also quite dependent on the type of
substrate N-Boc-amines adopted. For the aromatic N-Boc-amines,
the deprotection processes were affected dramatically by the sub-
stituents on the aromatic ring. Electron-donating substituents such
as methyl, methoxy, and hydroxyl groups facilitate the reaction,
allowing shorter reaction times (Table 2, entries 2–4). While elec-
tron-withdrawing substitutents such as chloro and nitro groups
decrease the rate of the reaction (Table 2, entries 5 and 6). In par-
ticular, when nitro group was present in the aromatic ring, the
reaction time must be prolonged to 10 h. The method is also appli-
cable to the aliphatic N-Boc-amine, which could be converted to
deprotection compound within 4 h (Table 2, entry 8).
NHBoc
7
8
88
NHBoc
8
9
4
2
86
95
N
NBoc
Me
NHBoc
H
1
0
1
2
100
81b
HO C
2
NHBoc
1
16
In view of the importance of peptide synthesis, N-Boc-
N-Boc- -Phe-OMe were tested in this transformation (Table 2, en-
tries 10 and 11). As can be seen from Table 2, the deprotection pro-
cess for N-Boc- -Ala was quite satisfactory because it could be
quantitatively converted to its deprotection compound -alanine
within 2 h (entry 10). It is reasonable because the carboxyl group
L
-Ala and
MeO C
H
2
L
a
Unless otherwise noted, all reactions proceeded with 1 mmol N-Boc-amine and
mL distilled, deionized water at 150 °C. No additional reagents were added.
Both N-Boc and methyl ester groups were deprotected.
1
b
L
L
method will find its use in organic chemistry, especially in large-
scale industrial preparation.
+
in N-Boc-
L
-Ala can dissociate H in water and the resulting higher
H concentration facilitates this transformation. In contrast, when
N-Boc- -Phe-OMe was used as substrate, it is very interesting that
both N-Boc and methyl ester groups were deprotected, that is,
+
L
Acknowledgments
L
-
phenylalanine was achieved. The abilities of simultaneous cleavage
of N-Boc and ester groups could be used to decrease the reaction
steps in some instances and find applications in peptide synthesis.
The prolonged reaction time (16 h) indicated that the cleavage of
ester group was more difficult than that of N-Boc groups under
present conditions.
The authors thank the National Natural Science Foundation of
China (20572068, 20872087) and Innovation Fund of Shanghai
University for financial support.
References and notes
In conclusion, we have described a catalyst-free water-medi-
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ated deprotection of N-Boc-amines.17 Both aromatic and aliphatic
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Scheme 2.

1
440
G. Wang et al. / Tetrahedron Letters 50 (2009) 1438–1440
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cooled to room temperature. EtOAc (3 mL) was added and the mixture was
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007, 30, 5050.
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1
2
: (a) Bose, D. S.; Kumar, K. K.; Reddy, A. V. N.
4
:
(
3
2
3
3
1
2 4
anhydrous Na SO . The solvent was removed in vacuo and the residue was
1
2
3
purified by silica gel column chromatography to give corresponding amine.
Because amino acids were water-soluble and did not dissolve in common
organic solvents, the above purification strategy did not work when N-Boc
Guillaumet, G. Tetrahedron Lett. 2006, 47, 8575; t-BuONa: (b) Tom, N. J.; Simon,
W. M.; Frost, H. N.; Ewing, M. Tetrahedron Lett. 2004, 45, 905; NaOMe: (c)
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amino acid derivatives were the substrates. For
L-alanine, after the reaction
mixture was evaporated, the product was of sufficient purity (spectral data)
and did not require further efforts of purification. For
product was purified by recrystallization in EtOH/H
L
-phenylalanine, the
1
1
2. (a) Katritzky, A. R.; Allin, S. M.; Siskin, M. Acc. Chem. Res. 1996, 29, 399;
2
O. In addition, 4-
(
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971.
aminophenol was purified directly by drying in vacuo to afford pure product.
All the products are known and were characterized by comparison of their
spectral data with those of authentic samples.
1
1
Selected data of
L
-phenylalanine: IR (KBr): 3446, 3066, 3032, 2967, 1621, 1585,
À1
1
3. (a) Herreras, C. I.; Yao, X.; Li, Z.; Li, C.-J. Chem. Rev. 2007, 107, 2546; (b) Akiya,
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1501 cm
.
H NMR (500 MHz, D O): d = 7.40–7.28 (m, 5H), 3.96–3.94 (m, 1H),
2
13
3.27–3.06 (m, 2H). C NMR (125 MHz, D
129.06, 127.64, 55.98, 36.29.
2
O): d = 173.89, 135.02, 129.30,
2
002, 102, 2751.