Facile N-tert-butoxycarbonylation of amines using La(NO3)3·6H2O as a mild and efficient catalyst under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2006.09.081

Facile N-tert-butoxycarbonylation of amines is described by the treatment of various primary, secondary, benzylic and aryl amines with di-tert-butyl dicarbonate in the presence of catalytic amounts of La(NO₃)₃·6H₂O under solvent-free conditions at room temperature to afford N-tert-butylcarbamates in excellent yields.

Full text of DOI:10.1016/j.tetlet.2006.09.081

Tetrahedron Letters 47 (2006) 8039–8042
Facile N-tert-butoxycarbonylation of amines
using La(NO3)3Æ6H2O as a mild and efficient catalyst
under solvent-free conditionsI;II
N. Suryakiran, P. Prabhakar, T. Srikanth Reddy, K. Rajesh and Y. Venkateswarlu*
Natural Products Laboratory, Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 3 August 2006; revised 6 September 2006; accepted 15 September 2006
Available online 4 October 2006
Abstract—Facile N-tert-butoxycarbonylation of amines is described by the treatment of various primary, secondary, benzylic and
aryl amines with di-tert-butyl dicarbonate in the presence of catalytic amounts of La(NO3)3Æ6H2O under solvent-free conditions at
room temperature to afford N-tert-butylcarbamates in excellent yields.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Functional group protection/deprotection strategies are
central to target molecule synthesis. The protection of
amines is one of the most fundamental and useful trans-
formations in organic synthesis, especially in peptide
synthesis.1 Among the protecting groups for amines,
N-tert-butoxycarbonylation2 is used frequently, because
N-tert-butylcarbamates are stable in the presence of a
wide range of nucleophiles under alkaline conditions
and are very labile under mild acidic conditions liberat-
ing the parent amine.1a Although, various base mediated
methods are available for the preparation of N-tert-
butylcarbamates using di-tert-butyl dicarbonate,3–11
there are only a few reports on the Lewis acid catalyzed
reactions such as, ‘Yttria–Zirconia’ which needs long
reaction times 3–48 h12 and, very recently, ZrCl4, cop-
per(II) tetrafluoroborate, InBr3 and HClO4–SiO2
(Scheme 1).13
O
NH2
HN
O
La(NO3)3.6H2O
O
O
O
O
(Boc)2O
MeO
MeO
rt, 2-20 min
Scheme 1.
of alcohols, phenols and amines with acetic anhydride.17
It has been observed that substrates containing other
acid labile functional groups such as acetonides,
TBDMS ethers, isopropylidene protected diols and
N-tert-butylcarbamates were intact in the presence of
La(NO3)3Æ6H2O. Further, we report here that
La(NO3)3Æ6H2O is a mild and efficient catalyst for
N-tert-butoxycarbonylation of amines using di-tert-
butyl dicarbonate under solvent-free conditions.
In the course of our on-going search for chemoselective
reagents, our group has identified La(NO3)3Æ6H2O as a
mild and efficient catalyst for the chemoselective tetra-
hydropyranylation of primary alcohols,14 chemo-
selective deprotection of acetonides,15 synthesis of
quinazolinones16 and the mild and efficient acetylation
The reaction of aniline (1 mmol) with di-tert-butyl dicar-
bonate (1.2 mmol) using La(NO3)3Æ6H2O (5 mol %) at
room temperature rapidly gave the corresponding N-
tert-butylcarbamate in a 100% yield (Table 1, entry 1).
This success encouraged us to extend the generality of
the reaction. In order to establish the scope of the cata-
lytic activity of La(NO3)3Æ6H2O, we carried out the reac-
tion of various primary, secondary, benzylic and aryl
amines (Table 1) with di-tert-butyl dicarbonate, which
gave the corresponding N-tert-butylcarbamates in excel-
lent yields. Furthermore, it was observed that when the
Keywords: La(NO3)3Æ6H2O; Amines; N-tert-Butoxycarbonylation; Sol-
vent-free conditions.
q Reactions using lanthanum(III) nitrate hexahydrate paper 5.
qq IICT Communication No. 060904.
*
Corresponding author. Tel.: +91 40 27193167; fax: +91 40
27160512; e-mail: luchem@iict.res.in
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.081

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N. Suryakiran et al. / Tetrahedron Letters 47 (2006) 8039–8042
Table 1. N-tert-Butoxycarbonylation of amines in the presence of La(NO3)3Æ6H2O under solvent-free conditions
Entry
1
Substrate
NH2
Producta
Time (min)
2
Yieldb (%)
100
H
N
O
O
O
NH2
2
3
2
3
98
95
N
H
O
O
Ph
N
Ph
N
N
O
NH2
H
O
NH
4
5
2
3
100
95
O
N
O
O
H
N
NH2
O
O
O2N
O2N
H
N
NH2
O
6
7
3
3
98
98
O
NO2
NO2
H
N
NH2
O
O
H3C
O2N
CH3
CH3
H
N
NH2
O
8
9
2
3
100
98
O
H
NH2
N
O
O
HO
HN
HO
O
N
O
HN
O
80%
N
NH
10
3
98
O
O
N
20%
O
O
NH
11
12
3
98
N
O
Ph
N
Ph
N
HS
HS
N
O
N
S
S
N
N
O
N
NH2
H

N. Suryakiran et al. / Tetrahedron Letters 47 (2006) 8039–8042
8041
Table 1 (continued)
Entry
Substrate
Producta
Time (min)
3
Yieldb (%)
99
OH
N
OH
13
N
H
O
O
O
O
H2N
O
H
N
O
[ ]5
80%
O
NH2
14
2
98
H2N
H
N
O
[ ]5
O
N
H
O
20%
H
N
NH2
O
15
16
10
11
98
95
O
N
N
Ts
Ts
O
O
OMe
O
OMe
NH2
HN
N
N
O
Ts
Ts
O
NH2
HN
O
17
5
99
O
O
O
MeO
H2N
O
MeO
Ph
Ph
O
N
N
O
N
H
N
N
18
20
95
COOH
Ph
COOH
Ph
O
N
N
H2N
O
N
H
N
N
19
20
96
COOH
Ph
COOH
Ph
O
O
N
N
H2N
O
O
N
N
H
N
20
21
15
15
98
99
O
O
O
N
O
N
Ph
Ph
H2N
N
N
N
S
COMe
S
COMe
(continued on next page)

8042
N. Suryakiran et al. / Tetrahedron Letters 47 (2006) 8039–8042
Table 1 (continued)
Entry
Substrate
Producta
Time (min)
Yieldb (%)
99
22
23
24
25
10
05
05
05
N
N
H
O
O
O
NH2
98
99
99
N
O
H
HO
HO
F
H
NH2
N
O
O
F
COOMe
COOMe
H
NH2
N
O
O
a All compounds were characterized by 1H NMR and EIMS spectral data.
b Isolated yields after column chromatography.
(b) Raghavendra, N. S.; Kumar, B. P.; Longquin, H.
Tetrahedron Lett. 2006, 47, 389.
diamines were subjected to N-tert-butoxycarbonylation,
a mono-N-tert-butylcarbamate was formed in a very
good yield (entries 10 and 14). The N-tert-butylcarb-
amate is stable under the reaction conditions for 3–6 h
at room temperature. From these results (Table 1) it is
evident that La(NO3)3Æ6H2O is an excellent catalyst for
N-tert-butoxycarbonylation of amines under solvent-
free conditions.
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Typical experimental procedure: To a mixture of amine
(1 mmol) and di-tert-butyl dicarbonate (1.2 mmol) was
added finely powdered La(NO3)3Æ6H2O (5 mol %) and
the reaction mixture was stirred under solvent-free con-
ditions at room temperature for an appropriate time
(Table 1). After completion of the reaction as monitored
by TLC, water was added to the reaction mixture and
the product was extracted into ethyl acetate
(3 · 20 mL). The combined organic layer was washed
with brine, dried over anhydrous sodium sulfate and
concentrated under reduced pressure to give a crude
product, which was purified by silica gel column chro-
matography to afford the corresponding N-tert-
butylcarbamate.
Acknowledgements
14. Reddy, T. S.; Ravinder, K.; Suryakiran, N.; Narasimhulu,
M.; Chinni Mahesh, K.; Venkateswarlu, Y. Tetrahedron
Lett. 2006, 47, 2341.
15. Reddy, S. M.; Reddy, Y. V.; Venkateswarlu, Y. Tetra-
hedron Lett. 2005, 46, 7439.
The authors are thankful to the CSIR, DOD and DBT,
New Delhi, India, respectively, for the financial support
and to the Director of Indian Institute of Chemical
Technology, for his encouragement.
16. Narasimhulu, M.; Chinni Mahesh, K.; Reddy, T. S.;
Rajesh, K.; Venkateswarlu, Y. Tetrahedron Lett. 2006, 47,
4381.
References and notes
17. Reddy, T. S.; Narasimhulu, M.; Suryakiran, N.; Chinni
Mahesh, K.; Venkateswarlu, Y. Tetrahedron Lett. 2006,
47, 6825.
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