Deprotection of a primary Boc group under basic conditions

Article abstract of DOI:10.1016/j.tetlet.2003.11.108

Treatment of a primary t-butyl carbamate (Boc) group with excess sodium t-butoxide in slightly wet tetrahydrofuran or 2-methyltetrahydrofuran provides the corresponding primary amine in excellent yield. We believe the reaction proceeds through an isocyanate intermediate.

Full text of DOI:10.1016/j.tetlet.2003.11.108

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 905–906
Deprotection of a primary Boc group under basic conditions
*
Norma J. Tom, Wendy M. Simon, Heather N. Frost and Marcus Ewing
Pfizer Global Research and Development, Chemical Research and Development, Eastern Point Road, Groton, CT 06340, USA
Received 6 November 2003; revised 21 November 2003; accepted 24 November 2003
Abstract—Treatment of a primary t-butyl carbamate (Boc) group with excess sodium t-butoxide in slightly wet tetrahydrofuran or
2-methyltetrahydrofuran provides the corresponding primary amine in excellent yield. We believe the reaction proceeds through an
isocyanate intermediate.
Ó 2003 Elsevier Ltd. All rights reserved.
1
. Introduction
under basic conditions. However, for an activated amine
such as a pyrrole or indole, the Boc group can be cleaved
under basic conditions. Thus, we believed basic
1
A t-butyl carbamate (Boc) group is a common protect-
ing group for amines. It is stable to hydrolysis under
basic conditions and to many other nucleophilic
reagents. Deprotection is generally achieved under
acidic conditions, as extensively described in Greene’s
Protective Groups in Organic Synthesis. Deprotection
can be obtained under basic conditions only in special
cases, where the amine is highly activated, such as a
deprotection conditions were worth investigating. We
are happy to report that treatment of the carba-
mate with excess sodium t-butoxide in tetrahydrofuran
or 2-methyltetrahydrofuran did in fact provide the
desired amine. It was found that addition of 1 equiv
of water increased the rate of the reaction. Further
experimentation showed that a strong base such as
sodium t-butoxide was necessary as sodium or potas-
sium hydroxide was not effective. Other strong bases
such as sodium methoxide or sodium ethoxide could
also be employed but for simplicity, all of our experi-
ments were conducted with sodium t-butoxide as the
base.
1
2
pyrrole. Thermal deprotections have also been
3;4
reported. A basic deprotection would be advanta-
geous if the molecule contains other acid-sensitive moi-
eties. Herein, we report that unactivated primary Boc
groups can be deprotected with sodium t-butoxide in
slightly wet tetrahydrofuran or 2-methyltetrahydrofuran
to provide the corresponding primary amines in excel-
lent yield. We believe that this reaction proceeds
through an isocyanate intermediate.
t-BuO
H
NaOtBu, H2O
N
O
R
NH2
R
2
-MeTHF, reflux
2. Discussions
O
As a part of an early pre-clinical program, we needed to
develop a non-acidic method to deprotect a primary Boc
group, due to the presence of an acid-sensitive moiety on
the compound. A thermal deprotection was not an
option and to the best of our knowledge, for a simple
Boc group, there are no reported cases of deprotection
OtBu
CO2
O
H
N
OH
C
R
N
R
Keywords: t-Butyl carbamate; Boc; Sodium t-butoxide; Amine; Iso-
cyanate.
O
HO
*
Corresponding author. Tel.: +1-860-715-5270; fax: +1-860-441-5540;
e-mail: norma_j_tom@groton.pfizer.com
Scheme 1.
0
040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.108

906
N. J. Tom et al. / Tetrahedron Letters 45 (2004) 905–906
Table 1
Entry Carbamate
isocyanate intermediate, carbamate 6, which cannot
form the isocyanate intermediate, was recovered
unchanged in 85% yield.
Amine
Yield (%)
100
H
N
OtBu
1
2
O
We have developed a method for deprotecting primary
Boc protected amines under basic conditions with
sodium t-butoxide in wet tetrahydrofuran or 2-methyl-
tetrahydrofuran in excellent yields. This method seems
general for primary Boc protected amines that are stable
to strongly basic conditions and provides a nice com-
plement to the standard acidic deprotections.
92
O
HN
OtBu
3
100
O
HN
OtBu
4
5
6
100
90
3. General procedures
O
Sodium t-butoxide (2–4 equiv) was added to a solution
of the Boc protected amine (1 equiv) in 2-methyl-
tetrahydrofuran or tetrahydrofuran (10 vol). Volumes is
defined as mL of solvent per gram of starting material.
Water (1 equiv) was added and the reaction was heated
at reflux for 2–12 h. The reaction was cooled to room
temperature and quenched with 10% citric acid solution
N
N
N
H
OtBu
O
OtBu
O
OtBu
85
(
N
recovered)
(
10 vol). The resulting solution was stirred at room
Based on these observations, we believe that the reaction
proceeds through an isocyanate intermediate. We
believe the carbamate is deprotonated by sodium
t-butoxide (Scheme 1). Elimination of t-butoxide then
provides the isocyanate intermediate, which is then
hydrolyzed by water or sodium hydroxide formed from
water and sodium t-butoxide to the carbamic acid.
Finally, decarboxylation affords the free amine. The
deprotection does not proceed with sodium or potas-
sium hydroxide, which is not a strong enough base to
deprotonate the carbamate. Additionally, the addition
of 1 equiv of water increases the rate of reaction, pre-
sumably by enhancing the rate of hydrolysis of the iso-
cyanate intermediate to the carbamic acid.
temperature for 30–60 min and then the pH was
adjusted to 10–12 with 6 N NaOH solution. The layers
were separated. The aqueous layer was further extracted
with ethyl acetate (10 vol). The combined organic layers
were dried and concentrated to afford the desired amine
in 90% to quantitative yield. The crude amine was
generally of excellent purity but the crude reaction can
be purified by column chromatography or recrystalli-
zation if necessary.
References and notes
1
2
3
. Greene, T. W.; Wuts, P. G. Protective Groups in Organic
Synthesis; John Wiley: New York, 1991; pp 309–405.
. Hasan, I.; Marinelli, E. R.; Lin, L.-C. C.; Fowler, F. W.;
Levy, A. B. J. Org. Chem. 1981, 46, 157.
We decided to explore the scope of this reaction. The six
Boc protected amines shown in Table 1 were obtained
from the corresponding commercially available amines
1
using standard conditions. Each was subjected to the
. Rawal, V. H.; Jones, R. J.; Cava, M. P. J. Org. Chem. 1987,
2, 19.
Boc deprotection conditions. Carbamates 1–5 were
deprotected cleanly to provide the corresponding amines
in 90% to quantitative yields. As further evidence of an
5
4. Wasserman, H. H.; Berger, G. D.; Cho, K. R. Tetrahedron
Lett. 1982, 23, 465.