Convenient removal of N-tert-butyl from amides with scandium triflate

Article abstract of DOI:10.1016/j.tetlet.2006.03.010

Scandium triflate has been used as a convenient and efficient catalyst for removal of N-tert-butyl from amide groups. A variety of N-tert-butyl aryl and alkyl amides under these conditions gave the corresponding primary amide in high yields. With the use of microwave heating the deprotection reaction could be completed within 1 h.

Full text of DOI:10.1016/j.tetlet.2006.03.010

Tetrahedron Letters 47 (2006) 3051–3053
Convenient removal of N-tert-butyl from amides
with scandium triflate
A. K. Mahalingam, Xiongyu Wu and Mathias Alterman*
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, BMC, Uppsala University, PO Box 574,
SE-751 23 Uppsala, Sweden
Received 1 December 2005; revised 23 February 2006; accepted 1 March 2006
Available online 20 March 2006
Abstract—Scandium triflate has been used as a convenient and efficient catalyst for removal of N-tert-butyl from amide groups. A
variety of N-tert-butyl aryl and alkyl amides under these conditions gave the corresponding primary amide in high yields. With the
use of microwave heating the deprotection reaction could be completed within 1 h.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Initially, N-tert-butyl-benzamide was treated with
20 mol % of scandium triflate in nitromethane at 50 °C
(Scheme 1). A substantial amount of benzamide 1 was
formed, although the reaction was incomplete after
24 h. We therefore applied 1 equiv of scandium triflate
and increased the temperature to 100 °C. This resulted
in full conversion after 4 h, and benzamide could be iso-
lated in 96% yield. To further decrease the time of the
reaction, microwave heating was applied. At 170 °C
the reaction was completed in 1 h and delivered an
equally high yield of the deprotected compound.
Acid labile protecting groups are important in organic
synthesis.1,2 Among them, the tert-butyl group is com-
monly used for protection of a large variety of func-
tional groups, for example, acids,3 alcohols,4,5
phenols,6,5 and sulfonamides.7 On the other hand, the
tert-butyl group is very rarely used for the protection
of amides8–10 probably due to the conditions required
for its removal. Most of the known methodologies
require harsh conditions such as sulfuric acid, trifluoro-
acetic acid, or hydrobromic acid.8–10 A mild and
efficient removal would be attractive and likely to in-
crease the use of tert-butyl as a protecting group for
amides. Additionally, a convenient removal of N-tert-
butyl groups from amides could be used as an alterna-
tive two-step procedure to obtain primary amides from
acid chlorides via the N-tert-butyl amide.
To examine the scope and limitations of the deprotec-
tion procedure, a series of electron-rich and electron-
poor aromatic amides, as well as aliphatic substrates,
were selected for evaluation. The preparative results
are shown in Table 1. All of the N-tert-butyl aryl amides
provided excellent yields with both thermal and micro-
wave heating. All the aliphatic substrates gave full con-
version and with N-tert-butyl-3-phenyl-propionamide
(entry 8) a good yield was obtained. However in the
cases of entries 9 and 10, a lower yield was obtained.
In the case of 3-(thiophen-2-yl)-propionamide 9 the
low yield was caused by formation of degradation prod-
ucts and for pentanamide 10 the volatile nature of the
Scandium triflate is an effective Lewis acid that, unlike
traditional Lewis acids, is water stable.11,12 Due to its
unique water stability scandium triflate could, in an
environmentally friendly manner, be recovered and re-
used for several reaction cycles.13 We wanted to explore
the possibility of using scandium triflate as a mild re-
agent for the removal of N-tert-butyl groups from pri-
mary amides, in combination with both conventional
and microwave heating.
O
O
Sc(OTf)3
CH3NO2
N
H
NH2
1
*
Scheme 1.
Corresponding author. E-mail: mathias@orgfarm.uu.se
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.010

3052
A. K. Mahalingam et al. / Tetrahedron Letters 47 (2006) 3051–3053
Table 1. Deprotection of tert-butyl amides with scandium triflatea
N
N
Entry
Product
Thermal
heating
Microwave
heating
N
N
yield (%)
yield (%)
O
Sc(OTf)3
CH NO
O
O
1
2
3
4
96
94
94
98
99
99
3
2
NH2
NH2
2 h, 170
70%
C
˚
N
H
NH2
1
S
S
11
O
2
Scheme 2.
Br
O
In summary, a high-yielding method for removal of
N-tert-butyl protecting groups from amides has been
developed. The use of scandium triflate provides, to
the best of our knowledge, the first fast and more
generally applicable route for deprotection of N-tert-
butyl amides.
NH2
NH2
3
F3C
O
93
95
4
O
O
2. General procedure
O
O
NH2
5
96
96
99
90
64
68
5
A process vial (5 mL) was charged with a tert-butyl
amide16 (0.5 mmol), scandium triflate (0.5 mmol), and
nitromethane (2.0 mL). The vessel was exposed to
microwave heating17 for 1 h at 170 °C (or 4 h at
100 °C with a heat block). The reaction tube was there-
after cooled to room temperature and the solvent was
removed under vacuum. The residue was dissolved in
dichloromethane, washed with water, dried over
MgSO4, and concentrated. The crude product was puri-
fied on a silica gel column (acetone/petroleum ether) to
give the pure compounds 1–11.18
O
O
6
NH2
NH2
NH2
NH2
NH2
6
O
7
86
S
7
O
8
8
Acknowledgments
O
We gratefully acknowledge financial support from the
Swedish foundation for Strategic Research (SSF). We
thank Biotage AB for providing the microwave
synthesizer.
9
S
9
O
10
10
Supplementary data
a 0.5 mmol tert-butyl amide, 0.5 mmol scandium triflate, 2.0 mL
nitromethane, microwave heating: 170 °C, 1 h or 100 °C.
NMR-data of compound 11 and its corresponding start-
ing material are provided in the supplementary data file.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.03.010.
product lowered the isolated yield during isolation of the
product. No carboxylic side product (derived from
cleavage of the amide bond) was detected in any of the
reactions, which can be a major concern when aqueous
acids are used for the deprotection of amides.10
References and notes
To verify the deprotection method on a more complex
molecule, an intermediate in an ongoing medicinal chem-
istry program14,15 was used as a test molecule (Scheme 2).
The tert-butyl protected compound was dissolved in
nitromethane and 1 equiv of scandium triflate was
added. The reaction was heated to 170 °C with micro-
wave irradiation. The reaction required double the time
(2 h) for completion but gave a good yield of the depro-
tected compound 11 (70%).
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A. K. Mahalingam et al. / Tetrahedron Letters 47 (2006) 3051–3053
3053
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butyl-4-trifluoromethylbenzylamide:
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cavity, Smith Synthesizer (Biotage AB, Uppsala, Sweden),
producing controlled irradiation at 2450 MHz.
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mercial material except for compound 11 (see Supplemen-
tary data).
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