Ionic liquid (tetrachlorocobaltate(II) anion with a dicationic counterion) catalyzed N-Boc protection of amines

Article abstract of DOI:10.1039/c3ra40778k

Ionic liquid (1,1′-hexane-1,6-diylbis(3-methylpyridinium) tetrachlorocobaltate(II) ([C₆(mpy)₂][CoCl ₄]^2-)) catalyzed N-tert-butyloxycarbonylation (N-Boc) of various amines using (Boc)₂O is reported. Halogenated aniline and amino alcohols were converted efficiently to their corresponding N-Boc derivatives without any side products. The reported method is mild, solvent free, uses low amounts of ionic liquid, allows easy product separation and results in high yields of the products. The catalytic efficiency for N-Boc formation in IL is superior to previously reported catalysts.

Full text of DOI:10.1039/c3ra40778k

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Ionic liquid (tetrachlorocobaltate(II) anion with a
dicationic counterion) catalyzed N-Boc protection of
amines3
Cite this: RSC Advances, 2013, 3,
1
3324
Amutha Chinnappan, Dahye La and Hern Kim*
22
Ionic liquid (1,19-hexane-1,6-diylbis(3-methylpyridinium) tetrachlorocobaltate(II) ([C
6 2 4
(mpy) ][CoCl ]
))
catalyzed N-tert-butyloxycarbonylation (N-Boc) of various amines using (Boc)
2
O
is reported.
Received 14th February 2013,
Accepted 9th May 2013
Halogenated aniline and amino alcohols were converted efficiently to their corresponding N-Boc
derivatives without any side products. The reported method is mild, solvent free, uses low amounts of ionic
liquid, allows easy product separation and results in high yields of the products. The catalytic efficiency for
N-Boc formation in IL is superior to previously reported catalysts.
DOI: 10.1039/c3ra40778k
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reactions or process media in catalytic science. The non-
volatile ionic liquids have been already investigated in a wide
Introduction
The tert-butoxycarbonyl (Boc) group is of major importance for
25–29
range of reactions.
With increasing concern about
the protection and deprotection of amine and amine
environmental protection and sustainable development, in
1
–5
derivatives.
Acylation is an easy method for the protection
our previous work, we investigated an IL with metal complexes
of amine but it requires harsh reaction conditions, which are
not compatible with a multi-functional substrate to regenerate
30
for the reduction of aromatic nitro compounds.
This
prompted us to use the same kind of IL for the synthesis of
N-Boc protected amines. Herein we report that the ionic liquid
6
the amine. Numerous amine protecting groups are available
in the literature; among these the tert-butoxycarbonyl (Boc)
group is widely used due to its reactivity and stability towards a
variety of reagents and experimental conditions. Moreover it
can be easily converted to the parent amines under mild acidic
(
tetrachlorocobaltate(II) anion with a dicationic counterion)
serves as an excellent catalyst for the N-tert-butyloxycarbonyla-
tion of amines (Scheme 1).
7
–10
conditions.
(HMIm)BF
A few examples are: Brønsted acid ionic liquid
1
1
12
[
4
1
], 1-alkyl-3-methylimidazolium-derived RTILs,
Results and discussion
3
14
15
16
H
3
PW12
O
40
,
La(NO
3
)
3
18
?6H
2
O, ZrCl
4
,
DMAP,
sulfamic
water,
1
7
19
20
21
acid,
yttria-zirconia,
b-cyclodextrine,
Bu P,
Screening experiments were made with aniline and di-tert-
butyl dicarbonate as a model compound using different
amounts of ionic liquid (tetrachlorocobaltate(II) anion with a
dicationic counterion). It was found that the use of 100 mg of
IL gave the best yield, whereas 50 mg and 150 mg resulted in
82% and 88% yields, respectively. The results are listed in
Table 1. The model reaction could also be carried out in
dichloromethane as a solvent in the absence of an ionic liquid.
It is clear from Table 1, most prominently, that the ionic liquid
was found to be the best catalyst in terms of reaction times
and yields. Moreover the conversion of aniline to the
corresponding N-Boc derivative appears to be sluggish at
room temperature without an ionic liquid. On the basis of
these results we found that the standard condition for the N-
tert-butyloxycarbonylation of amines, using 100 mg of the IL as
a catalyst at room temperature, is sufficient to afford the
desired product in excellent yield.
3
2
2
23
24
indium(III) chloride, CsF, and thiourea. However, the
drawbacks associated with these reactions are the formation of
side products, the requirement for an expensive and/or a
moisture-sensitive reagent and an organic solvent, toxicity and
corrosiveness, and restrictions for large scale applications. In
these methods, there is little consideration given to the
environment, cost, safety, or simplicity of operation. Most of
the acid catalysts cannot be recycled since they are decom-
posed and/or deactivated by the amines and amine derivatives.
These kinds of catalysts are required in more than stoichio-
metric amounts because the acids are trapped by nitrogen
9
when the reaction proceeds. Ionic liquids play a vital role in
catalysis due to the growing awareness of developing greener
Energy and Environment Fusion Technology Center, Department of Environmental
Engineering and Energy, Myongji University, Yongin, Kyonggi-do 449-728, Republic
of Korea. E-mail: hernkim@mju.ac.kr; Fax: +82 31 336 6336; Tel: +82 31 330 6688
Also, for comparison, results that other authors have
reported for N-Boc protection of amines are summarized in
3
Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3ra40778k
1
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Scheme 1 N-tert-Butyloxycarbonylation of amines in ionic liquid (tetrachlorocobaltate(II) anion with a dicationic counterion).
(
Boc) O in the IL took 60 min and afforded the N-Boc
2
2 a
2
Table 1 N-tert-Butyloxycarbonylation of aniline in [C
6
(mpy)
2
][CoCl
4
]
derivatives in 98, 97 and 98% yield respectively (Table 3,
entries 5, 7 and 8). We have also performed the reaction on a
large scale. We observed that the conversion of aniline to the
corresponding N-Boc derivative was achieved without any
difficulty by using the same amount of the ionic liquid. The
2
2
b
6 2 4
Entry Amount of catalyst [C (mpy) ][CoCl ]
Time (min) Yield (%)
1
2
3
4
5
50 mg
75 mg
100 mg
150 mg
None
10
10
10
10
8 h
82
88
95
88
48
reaction of aniline (0.107 mol, 10 ml) and (Boc)
2
O (0.107 mol,
c
2
3.5 g) was investigated in the presence of the IL
a
b
Reaction conditions: Molar ratio:1 : 1 substrate : (Boc)
Isolated yield. The reaction was performed in DCM (2 mL) in the
2
O, rt.
22
[C (mpy) ][CoCl ]
(100 mg). The reaction was complete
c
6
2
4
within 10 min and gave 84% yield. The results of this present
absence of IL.
2
2
process show that the ionic liquid [C
6
(mpy)
2
][CoCl
4
]
is an
efficient catalyst for the N-Boc protection of amines, as is
evident from the shorter reaction times and yields.
From an economical point of view, as well as the principles
of green chemistry, recycling of the catalyst is essential so this
was examined. Recycling experiments were carried out with
benzylamine (similar to Table 3, entry 9). After completion of
the reaction, the mixture was diluted with ethyl acetate (EtOAc)
and the IL settled to the bottom. The filtrate was decanted off
and the IL was separated and washed with EtOAc several times
and dried in a vacuum at 80 uC for 5 h. The catalyst was further
reused four consecutive times without any significant loss of
catalytic activity. The catalyst is stable and reusable under the
used reaction conditions. Fig. 1 shows that the catalyst was not
deactivated after repeated use.
2 2
Table 2. Compared with organic solvents such as CH Cl ,
CH CN, etc., ionic liquid as catalyst could effectively increase
3
the reaction rate as shown in Table 2.
These initial results motivated us to perform the N-tert-
butyloxycarbonylation of various amines in the presence of the
2
2
ionic liquid [C
6
(mpy)
2
][CoCl
4
]
without using additives. The
corresponding N-Boc derivatives were obtained in high yields
as shown in Table 3. The reactions were monitored using thin
layer chromatography (TLC), IR spectroscopy, and could also
be followed up visually. The identification of N-tert-Boc
1
13
derivatives was confirmed using H NMR, C NMR and IR
7
,12,21
data by comparison with reported data.
a kind of semi-liquid was obtained after the addition of
Boc) O to the magnetically stirred suspension of the amine in
For solid amines,
(
2
Conclusion
the IL. It then becomes completely solidified. In liquid amines
such as benzylamine and 4-methylbenzylamine, commence-
ment of slow effervescence took place with a concomitant
formation of solid residue indicating the completion of the
reaction. The faster rates of reaction with benzylamine,
In conclusion, we have developed a mild, safe and exceedingly
efficient procedure for the N-Boc protection of amines. The
advantages of the method are the minimal amount of IL used,
solvent free conditions, and ease of product separation from
the reaction mixture. The catalyst was recovered by simple
filtration and was reused with consistent activity.
4-methylbenzylamine and 4-methoxyanisidine were due to
their better nucleophilicity. Most of the reactions were
completed within a short time. However, the reactions of
4-aminophenol, 3-chloroaniline and 4-bromoaniline with
Table 2 Comparison of various catalysts in the N-Boc protection of aniline with (Boc)
2
O at room temperature
Entry
Catalyst
Solvent
Time
Yield (%)
Reference
1
2
3
4
5
6
7
b-cyclodextrin
Sulfonic acid-functionalized silica
Yttria-zirconia
H
2
O
2.5 h
45 min
14 h
75
83
90
92
94
95
95
19
9
18
31
32
24
CH
CH
CH
CH
Toluene
Neat
2
3
2
2
Cl
CN
2
Zn(ClO
ZnCl
Thiourea
[C (mpy)
4
)
2
?6H
2
O
Cl
Cl
2
12 h
2
2
20 min
40 min
10 min
2
2
6
2
][CoCl
4
]
This work
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Table 3 N-tert-Butyloxycarbonylation of amines in [C
6 2 4
(mpy) ][CoCl ]
Table 3 (Continued)
b
Entry Substrate
1
Product
Time (min) Yield (%)
b
Entry Substrate
8
Product
Time (min) Yield (%)
10
35
95
90
60
98
2
3
9
10
96
97
30
86
10
4
4
5
94
a
Reaction conditions: Molar ratio: 1 : 1 substrate : (Boc)
2
O, IL
2
b
6 2 4
[C (mpy) ][CoCl ] (100 mg), rt. Isolated yield.
Experimental section
5
6
7
60
30
60
98
98
97
General information
All chemicals were purchased from Sigma Aldrich and used as
received. The spectral data of the compounds were in perfect
agreement with those reported in the literature.
7
,12,21
Preparation of 1,19-hexane-1,6-diylbis(3-methylpyridinium)
2
2
tetrachlorocobaltate(II) (C
6
(mpy)
2
][CoCl
4
]
)
The dicationic IL was synthesized (Fig. 2) according to our
previously reported procedure. 3-Methyl pyridine (0.04 mol,
3
3
2
2
Fig. 1 Recycling of [C
6
(mpy)
2
][CoCl
4
]
.
1
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2
p-Tolyl-carbamic acid tert-butyl ester. IR: 1696.1 cm . H
1 1
NMR (CDCl , 400 MHz) d: 1.50 (s, 9H), 2.28 (s, 3H), 6.54 (bs,
3
1H), 7.08 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8 Hz, 2H).
4
-Methoxy-phenyl-carbamic acid tert-butyl ester. IR: 1692.8
2
1 1
cm . H NMR (CDCl , 400 MHz) d: 1.52 (s, 9H), 3.76 (s, 3H),
3
6
.44 (bs, 1H), 6.81–6.83 (d, J = 8.8 Hz, 2H), 7.25–7.27 (d, J = 8.4
Hz, 2H).
-Hydroxy-phenyl-carbamic acid tert-butyl ester. IR: 1697.5
Fig. 2 Tetrachlorocobaltate(II) anion with dicationic counterion
2
2
(
[C
6
(mpy)
2
][CoCl
4
]
).
4
2
1 1
cm . H NMR (CDCl , 400 MHz) d: 1.5 (s, 9H), 5.69 (bs, 1H),
3
6
.54 (bs, 1H), 6.72–6.74 (d, J = 10 Hz, 2H), 7.07–7.09 (d, J = 9.2
Hz, 2H).
-Mercapto-phenyl-carbamic acid tert-butyl ester. IR: 1699.5
3
.89 mL) was dissolved in 25 mL toluene at RT. 1,6-
Dibromohexane (0.02 mol, 3.07 mL) was added slowly into
the flask in an ice bath over 30 min. The stirring was
continued at this temperature for 30 min before elevating the
temperature to 110 uC for 12 h. An off-white solid was formed.
Upon completion of the reaction, the solvent was removed by
decanting. The reaction mixture was extracted with ethyl
acetate (3 6 30 mL) and then dried under vacuum in oven at
4
21
1
cm . H NMR (CDCl
.55 (bs, 1H), 7.21–7.43 (m, 4H).
-Chloro-phenyl-carbamic acid tert-butyl ester. IR: 1729.5
3
, 400 MHz) d: 1.51 (s, 9H), 3.39 (bs, 1H),
6
3
21
1
cm . H NMR (CDCl
.55 (br s, 1H), 6.94 (d, 1H), 7.06–7.11 (m, 2H). C NMR
CDCl , 400 MHz) d: 28.17, 85.17, 116.41, 118.41, 122.70,
3
, 400 MHz) d: 1.48 (s, 9H), 6.88 (bs, 1H),
13
6
(
1
3
7
0 uC for 5 h.
29.75, 134.46, 139.77, 152.62.
1
,19-Hexane-1,6-diylbis(3-methylpyridinium)
dibromide
(
4-Bromophenyl)-carbamic acid tert-butyl ester. IR: 1695.3
1
[C
6
(mpy)
2
]?(Br)
2
: H NMR (400 MHz, DMSO-d
6
, d (ppm) relative
21 1
cm . H NMR (CDCl , 400 MHz) d: 1.51 (s, 9H), 6.50 (bs, 1H),
3
to TMS) 9.09 (s, 2H), 8.98 (d, 2H, J = 8 Hz), 8.43 (d, 2H, J = 8
Hz), 8.01 (dd, 2H, J = 6 Hz), 4.57 (t, 4H, J = 7.9 Hz), 3.49 (s, 6H),
7.265–7.269 (d, J = 1.6 Hz, 2H), 7.37–7.39 (d, J = 8.8 Hz, 2H)
2
1 1
Benzyl-carbamic acid tert-butyl ester. IR: 1677.1 cm . H
NMR (CDCl , 400 MHz) d: 1.45 (s, 9H), 4.29 (bs, 2H), 4.91 (bs,
1
1
3
1
(
2
.91 (m, 4H), 1.30 (m, 4H). C NMR (400 MHz, DMSO-d
ppm) 146.20, 144.76, 142.44, 139.08, 127.71, 60.55, 30.66,
5.04, 18.29.
,19-Hexane-1,6-diylbis(3-methylpyridinium)
(mpy) ]?Br ) (0.007 mol) and CoCl ?6H O (0.017 mol) were
6 H
): d
3
H), 7.22–7.34 (m, 5H).
4
-Methyl-benzyl-carbamic acid tert-butyl ester. IR: 1681.3
1
dibromide
2
1 1
cm . H NMR (CDCl
3
, 400 MHz) d:1.45 (s, 9H), 2.3 (s, 3H), 4.2
bs, 2H), 4.91 (bs, 1H), 7.09–7.11 (d, J = 8.4 Hz, 2H), 7.13–7.15
d, J = 8 Hz, 2H).
([C
6
2
2
2
2
(
(
dissolved in ethanol and stirred at room temperature for four
days. After completion of the reaction the solvent was
evaporated in a rotatory evaporator to give a blue color solid.
The obtained product was washed with ethyl acetate several
times and dried under vacuum at 80 uC for 5 h. LRMS (FAB+)
Acknowledgements
+
calcd for C H N Cl Co (M-[CoCl ]) 135.10 found 135.14.
1
8
26
2
4
4
This study was supported by the 2011 research fund of
Myongji University and by the Priority Research Centers
Program through the National Research Foundation of Korea
General procedure for the N-Boc protection of amines
Amine (0.01 mol) was added to a magnetically stirred mixture
of (Boc)
(NRF) funded by the Ministry of Education, Science and
2
2
2
O (0.01 mol) and [C
6
(mpy)
2
][CoCl
4
]
(100 mg), and
Technology, Republic of Korea (2012-0006693).
the mixture was stirred at room temperature for the specified
period of time. The progress of the reaction was monitored
using thin layer chromatography (TLC) using ethyl acetate and
hexane as the eluent (3 : 7). After completion of the reaction,
the reaction mixture was quenched with NaCl solution and the
product was extracted from the aqueous medium using EtOAc
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