An efficient and chemoselective Br?nsted acidic ionic liquid-catalyzed N-Boc protection of amines

Article abstract of DOI:10.1016/j.tetlet.2008.02.126

The first report of a Br?nsted acidic ionic liquid, 1-methylimidazolium tetrafluoroborate [(HMIm)BF₄], catalyzed efficient and chemoselective N-Boc protection of various amines using (Boc)₂O is presented. Optically pure amino alcohols and amino acid esters were converted efficiently to their corresponding optically pure N-Boc derivatives. The reported method is mild, solvent-free and has the advantages of both homogeneous and heterogeneous catalysis with high product yields, selectivity and ease of product separation.

Full text of DOI:10.1016/j.tetlet.2008.02.126

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2527–2532
An efficient and chemoselective Brønsted acidic ionic
liquid-catalyzed N-Boc protection of amines
Sadula Sunitha, Sanjit Kanjilal, P. Srinivasa Reddy, Rachapudi B. N. Prasad *
Lipid Science and Technology Division, Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500 007, India
Received 7 December 2007; revised 19 February 2008; accepted 22 February 2008
Available online 4 March 2008
Abstract
The first report of a Brønsted acidic ionic liquid, 1-methylimidazolium tetrafluoroborate [(HMIm)BF4], catalyzed efficient and
chemoselective N-Boc protection of various amines using (Boc)2O is presented. Optically pure amino alcohols and amino acid esters were
converted efficiently to their corresponding optically pure N-Boc derivatives. The reported method is mild, solvent-free and has the
advantages of both homogeneous and heterogeneous catalysis with high product yields, selectivity and ease of product separation.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Amines; Brønsted acidic ionic liquid; Chiral aminols; Chiral amino acid esters; Di-tert-butyl pyrocarbonate; N-Boc protection
Sequential protection and deprotection of any polyfunc-
tional molecule often needs a selective and efficient protect-
ing reagent together with mild reaction conditions. The
protection of an amine is an important step in synthetic
organic chemistry. Even though a variety of amine protect-
ing groups are available in the literature, the tert-butyl car-
bonyl group (abbreviated as Boc or t-Boc) is one of the
most widely studied.1–5 Commercially available di-tert-
butyl pyrocarbonate, (Boc)2O, is an efficient reagent for
N-Boc protection. There are a variety of N-Boc protection
strategies available in the literature.6,7 However, these
methods have several drawbacks such as long reaction
times, formation of side-products during base-catalyzed
reaction,6 excess reagents in the case of Lewis acid-cata-
lyzed reactions,8 and difficulty in the preparation of solid
acid catalysts in some cases during solid acid-catalyzed
reactions.
catalysts have been employed for the preparation of N-
Boc derivatives, reports of using a Brønsted acid catalyst
are scanty in the literature.9 A Brønsted acidic ionic liquid
(IL) could be an ideal alternate system, which has all the
characteristics of solid catalysts and a greener outlook at
the same time.
In recent years, ILs have attracted significant attention
as green solvents for many chemical and biochemical trans-
formations.10,11 1-Methylimidazolium tetrafluoroborate,
[(HMIm)BF4], has been exploited as an efficient Brønsted
acid IL in various organic transformations.12–14 This IL
is much simple to prepare without the use of organic sol-
vents as compared to other imidazolium based ILs, which
thus makes it an ideal IL for exploration. In the present
work, we report a Brønsted acidic ionic liquid, [(HMIm)-
BF4], catalyzed synthetic protocol for the efficient and
selective tert-butoxy carbonylation of amines. The protec-
tion protocol is conducted at room temperature under
solvent-free conditions.
The challenge of designing a protocol for efficient Boc
protection of amines, which is mild as well as environ-
ment-friendly and which has the advantages of solid cata-
lysts, continues to draw attention. Though various
Various aromatic, heteroaromatic, aliphatic (cyclic and
acyclic) and heterocyclic amines were treated with (Boc)2O
(1:1 mol/mol) under solvent-free conditions at ambient
temperature (ꢀ30–35 °C) in [(HMIm)BF4] (10 mol %) and
the results are summarized in Table 1. Nearly all the
*
Corresponding author. Tel.: +91 40 27193179; fax: +91 40 27193370.
E-mail address: rbnprasad@iict.res.in (R. B. N. Prasad).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.126

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S. Sunitha et al. / Tetrahedron Letters 49 (2008) 2527–2532
Table 1
[(HMIm)BF4]-catalyzed Boc protection of various amines
Entry
1
Substrate
Product
Time (min)
5
Isolated yield (%)
100
NH2
NH-Boc
NH2
NH-Boc
2
3
4
5
6
7
8
20
10
2
100
100
100
100
100
100
100
NH2
NHBoc
NH
N-Boc
5
N-Boc
NH
2
NH
N-Boc
2
N
N
NH
NBoc
5
O
O
NH
N-Boc
9
30
92
NH
NBoc
10
11
12
15
10
5
100
98
NH2
NH-Boc
NH2
Me
Me
NH-Boc
NH-Boc
100
NH2
MeO
MeO
13
14
15
60
60
90
68
78
25
NH2
O2N
O2N
NH-Boc
NH2
NO2
NH-Boc
NO2
NHBoc
NH2
NO2
NO2

S. Sunitha et al. / Tetrahedron Letters 49 (2008) 2527–2532
2529
Isolated yield (%)
55
Table 1 (continued)
Entry
Substrate
Product
Time (min)
60
MeO
MeO
16
NH2
OMe
NHBoc
OMe
17
18
20
30
82
88
NH2
NHBoc
NH-Boc
HS
HS
HO
NH2
HO
NH2
NH-Boc
19
20
2
5
100
100
HO
HO
Boc
N
H
N
OH
OH
NHBoc
NH2
21
22
5
100
96
(PhCH2)2NH
(PhCH2)2NBoc
10
NH
NBoc
23
30
55
24
25
(Ph)2NH
(Ph)2NBoc
120
2
72
96
NH2
NH2
H2N
BocHN
26
2
98
HN
NH
HN
N-Boc
NH2
NH2
NH-Boc
NH2
27
28
29
5
5
90
100
75
N
N
NH
N-Boc
120
N
H
N-Boc
N
N
30
31
30
60
96
N
N
H
Boc
N
N
NBoc
78
NH
N
N
(continued on next page)

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S. Sunitha et al. / Tetrahedron Letters 49 (2008) 2527–2532
Table 1 (continued)
Entry
Substrate
Product
Time (min)
15
Isolated yield (%)
95
32
33
N
NH2
N
NHBoc
NH.NHBoc
NH.NH2
90
120
90
86
72
85
O
O
NH.NH2
NH.NHBoc
34
35
O
O
Cl
Cl
O
S
O
S
NHBoc
NH2
O
O
amines reacted efficiently affording the corresponding Boc
protected amines in good to excellent yields in 2–120 min.
In most cases, the products were obtained in quantitative
conversion. All the products were characterized by using
IR, NMR and mass spectroscopy and by elemental
analysis.
an equimolar amount of aniline, benzyl amine and (Boc)2O
in [(HMIm)BF4] afforded the corresponding N-Boc-benzyl
amine in 90% conversion and N-Boc-aniline only in 10%
conversion after 15 min according to GC. A competitive
reaction was also conducted taking an equimolar amount
of aniline, N-methyl aniline and (Boc)2O in [(HMIm)BF4].
The GC results obtained after 40 min showed exclusive for-
mation of N-Boc-aniline.
The IL-catalyzed N-Boc protection strategy was also
studied for the protection of some selected chiral amino
acid alcohols and esters and the results are summarized
in Table 2. Chiral aminols and amino acid esters were con-
verted efficiently to their corresponding optically active
products as determined by optical rotation measurements
and by comparison with literature values under similar
conditions.6,7,17
The feasibility of any catalytic process depends on the
reusability of the catalyst. In the present work, the reusabil-
ity of [(HMIm)BF4] was assessed by conducting N-tert-but-
oxy carbonylation of aniline over four successive cycles
without any pre-treatment of the IL. The results shown
in Table 3 indicate no significant loss of activity of the
Brønsted acidic IL.
The Brønsted acidic promoting nature of [(HMIm)BF4]
is quite apparent from the IR and NMR study to under-
stand the mechanistic aspects (See Supplementary data).
In the IR spectrum of an equimolar mixture of [(HMIm)-
BF4] and (Boc)2O, the doublet frequency bands of
the C@O stretching vibration of free (Boc)2O appearing
at 1808 and 1761 cmꢁ1 shifted to 1786 cmꢁ1 on complex-
ation with [(HMIm)BF4]. This indicates that the b-dike-
tone moiety of (Boc)2O disappeared in TS-1. Moreover,
the appearance of a new band at 1326 cmꢁ1 could be
due to the C–O–H in plane bending vibrations of TS-1
(Scheme 1).
Aliphatic (cyclic and acyclic) primary and secondary
amines (Table 1; entries 1–9) gave the corresponding N-
Boc products in 92–100% yields in 2–30 min. Aniline
undergoes quantitative Boc protection at a much faster rate
(15 min) in [(HMIm)BF4] (Table 1; entry 10) compared to
those methods using other Lewis acid/solid acid-catalyzed
protection strategies.6,7,9,15 N-Boc protection of indole
(Table 1; entry 29) was moderate.16 Moreover, the reported
protection strategy yields mono-protected amines exclu-
sively in 2–5 min when diamines were subjected to Boc pro-
tection (Table 1; entries 25–27). Even aromatic amines
containing an electron-withdrawing group and a sulfon-
amide undergo N-Boc protection at a faster rate and in
good yields compared to other catalysts reported in the lit-
erature.6,7,9,15 From these results, it is evident that the stud-
ied IL, [(HMIm)BF4], is a mild, highly efficient and a green
catalyst for N-Boc protection of amines. The chemoselec-
tivity of the IL was also assessed by performing N-Boc pro-
tection of amines in bifunctional compounds (Table 1;
entries 17–20). Excellent chemoselectivity was observed
for substrates with OH and SH functionalities providing
N-Boc derivatives as the major products, and no significant
O/S-tert butoxy carbonylation took place.
The results obtained highlight the influence of electronic
environment on controlling the rate of the protection of the
amine group.7 This encouraged us to study the competitive
N-Boc protection of an aromatic amines in the presence of
an aliphatic amine and a primary aromatic amine in the
presence of a secondary aromatic amine. The reaction of

S. Sunitha et al. / Tetrahedron Letters 49 (2008) 2527–2532
2531
Table 2
[(HMIm)BF4]-catalyzed Boc protection of amino acid derivatives
25
Entry
Amine
Product
Time (min)
15
Isolated yield (%)
90
½aꢂD
OH
OH
NHBoc
1
ꢁ26.5 (c 1, CHCl3)
ꢁ4.4 (c 1, CH3OH)
NH2
O
O
2
45
88
OEt
OEt
NH2
NHBoc
OMe
OMe
3
4
10
30
96
82
ꢁ54.7 (c 1, CHCl3)
ꢁ17.4 (c 1, CH3OH)
N
N
H
O
O
Boc
O
O
HO
OMe
HO
OMe
NH2
NH - Boc
spectrum of the mixture showed a new broad peak at d
3.9–4.2 indicating the presence of an OH functionality in
TS-1 (confirmed by D2O exchange). The NH peak of free
[(HMIm)BF4] appearing at d 6.9–7.1 disappeared on com-
plexation with (Boc)2O supporting TS-1 formation. Fur-
thermore, three types of methyl protons of the tert-butyl
group were observed: one peak at d 1.55 being the same
as in free (Boc)2O and the other two appearing at d 1.08
and d 1.58 are due to two different tert-butyl protons in
TS-1. Thus, the mechanistic pathway involved the initial
activation of the carbonyl oxygen atoms of (Boc)2O by
[(HMIm)BF4] followed by the nucleophilic attack at the
carbonyl group by the amine in one-pot resulting in the
Table 3
Recycling of [(HMIm)BF4] in the synthesis of N-Boc-anilinea
Cycle
Isolated yield (%)
1
2
3
4
a
98
98
95
90
Reaction time: 15 min.
The proposed mechanistic pathway was further con-
firmed by recording the H NMR spectrum of an equimo-
lar mixture of [(HMIm)BF4] and (Boc)2O in DMSO. The
1
N
H
+
N
H
-
O
O
N
BF4
+
O
O
O
O
O
-
N
O
O
O
δ+
TS-1
BF4
R-NH2
H
N
O
+
N
-
O
BF4
N
R
OH
CO
2
+
+
+
O
N
N
H
H
O
O
O
O
NH2-R
+
-
BF4
Scheme 1. Proposed mechanism for the [(HMIm)BF4]-catalyzed N-Boc protection of amines.

2532
S. Sunitha et al. / Tetrahedron Letters 49 (2008) 2527–2532
formation of the N-Boc protected amine. This is accompa-
nied by the generation of tert-butanol and carbon dioxide
(Scheme 1).
Supplementary data
Spectra based on IR and NMR of an equimolar mixture
of [(HMIm)BF4] and (Boc)2O for establishing the mecha-
nistic pathway of the [(HMIm)BF4]-catalyzed Boc protec-
tion of amines are available. Supplementary data
associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2008.02.126.
In conclusion, we have described here the first example
of a Brønsted acidic ionic liquid-catalyzed N-tert-butoxy
carbonylation of amines. The reported protocol is efficient,
inexpensive, chemoselective and the IL is reusable. The
advantages of the present method are (i) the use of a green
and easy to handle catalyst; (ii) the ease of preparation of
[(HMIm)BF4]; (iii) mild and solvent-free reaction condi-
tions; (iv) the ease of extraction of the product/substrate
from ionic liquid; (v) [(HMIm)BF4] could be directly
reused after drying without any significant loss of activity
and (vii) excellent chemoselectivity.
References and notes
1. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; John Wiley and Sons: New York, 1999.
2. Theodoridis, G. Tetrahedron 2000, 56, 2339.
3. Sartori, G.; Ballani, R.; Bigi, F.; Bosica, G.; Maggi, R.; Righi, P.
Chem. Rev. 2004, 104, 199.
4. Agami, C.; Couty, F. Tetrahedron 2002, 58, 2701.
5. Lutz, C.; Lutz, V.; Knochel, P. Tetrahedron 1998, 54, 6385.
6. Chankeshwara, S. V.; Chakraborti, A. K. Synthesis 2006, 2784 and
references cited therein.
7. Varala, R.; Sreelatha, N.; Adapa, S. R. J. Org. Chem. 2006, 71, 8283.
and references cited therein.
8. Ishihara, K.; Hasegama, A.; Yamamoto, H. Angew. Chem., Int. Ed.
2001, 40, 4077.
9. Das, B.; Venkateswarlu, K.; Krishnaiah, M.; Harish, H. Tetrahedron
Lett. 2006, 47, 7551.
10. Jain, N.; Kumar, A.; Chauhan, S.; Chauhan, S. M. S. Tetrahedron
2005, 61, 1015.
11. Park, S.; Kazlauskas, J. Curr. Opin. Biotechnol. 2003, 14, 432.
12. Zhu, H.-P.; Yang, F.; Tang, J.; He, M.-Y. Green Chem. 2003, 5, 38.
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2004, 45, 4963.
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3985.
The Brønsted acidic ionic liquid, 1-methylimidazolium
tetrafluoroborate [(HMIm)BF4], was prepared according
to the reported procedure.11
General procedure for the Boc protection of amines: To a
magnetically stirred mixture of (Boc)2O (1.5 mmol) and
[(HMIm)BF4] (0.015 mmol), amine (1.5 mmol) was added
and the mixture was stirred at ambient temperature
(ꢀ30–35 °C) for the specified period of time. The progress
of the reaction was monitored by TLC and GC–MS. The
mixture was diluted with Et2O and the IL settled at the bot-
tom. The supernatant was decanted off and the IL was
washed with Et2O (2 mL) and the combined ethereal solu-
tion concentrated under vacuum. In some cases, the Boc
protected product was found to be sufficiently pure (GC–
MS and NMR) and did not require any further purifica-
tion. In most cases, the product was purified by silica gel
column chromatography (5–15% EtOAc in hexane). The
ionic liquid was recovered, dried under vacuum for
10 min at 80 °C and reused.
15. Chankeshwara, S. V.; Chakraborti, A. K. Org. Lett. 2006, 8,
3259.
16. Grehn, L.; Ragnarsson, U. Angew. Chem., Int. Ed. 1984, 23, 296.
17. Aldrich Handbook of Fine Chemicals and Laboratory Equipments;
Aldrich: India, 2006, p 410.
All products were characterized by IR, NMR, mass
spectrometry and elemental analysis and by comparison
with those reported in the literature.6,7,15,16,18
´
´
´
18. Alıas, M.; Cativiela, C.; Dıaz-de-Villegas, M. D.; Galvez, J. A.;
Lapenˇa, Y. Tetrahedron 1998, 54, 14963.