N-Protection of amines using pyridinium 2,2,2-trifluoroacetate ionic liquid as an efficient and reusable catalyst

Article abstract of DOI:10.1016/j.cclet.2013.11.052

A simple, green, and efficient method for the N-tert-butoxycarbonylation of amines by pyridinium 2,2,2-trifluoroacetate ([Py][OTf]) as an efficient and reusable catalyst is reported. In general, electron donating groups on aryl group give rise to the higher yields than electron withdrawing groups. Clean reaction, short reaction times, high yields, reusability of catalyst, and easy preparation of it are some advantages of this work.

Full text of DOI:10.1016/j.cclet.2013.11.052

Chinese Chemical Letters 25 (2014) 218–220
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
N-Protection of amines using pyridinium 2,2,2-trifluoroacetate ionic
liquid as an efficient and reusable catalyst
a,b
Somaye Karimian a, , Hassan Tajik
*
a Department of Chemistry, Persian Gulf University, Bushehr 75169, Iran
b Department of Chemistry, University of Guilan, Rasht 41335/1914, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
A simple, green, and efficient method for the N-tert-butoxycarbonylation of amines by pyridinium 2,2,2-
trifluoroacetate ([Py][OTf]) as an efficient and reusable catalyst is reported. In general, electron donating
groups on aryl group give rise to the higher yields than electron withdrawing groups. Clean reaction,
short reaction times, high yields, reusability of catalyst, and easy preparation of it are some advantages of
this work.
Received 13 August 2013
Received in revised form 24 October 2013
Accepted 19 November 2013
Available online 2 December 2013
ß 2013 Somaye Karimian. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Keywords:
Ionic liquid
Pyridinium 2,2,2-trifluoroacetate
N-Boc protection
Tert-butoxycarbonylation
Amine
1. Introduction
Ionic liquids are extensively being used as green solvents and
efficient catalysts for the preparation of organic compounds
Functional group protection and deprotection methods are
important in the synthesis of the organic compounds. The N-amine
protecting groups have been used extensively across a wide range
of chemical fields, such as peptide, nucleotide, polymer, and ligand
preparations. Several methods and reagents have been reported for
the protection of amine and amino groups [1–5]. Among them, N-
tert-butoxycarbonylation has received the greatest attention
because of the stability of the N-Boc group against nucleophilic
attack or alkali media and catalytic hydrogenation [6,7].
Some catalytic systems such as indium (III) halides [6], DMAP
[8], NaHMDS [9], Zn(ClO4)2Á6H2O [10], ZrCl4 [11], LiClO4 [12],
yttria–zirconia [13], copper tetrafluoroborate [14], ionic liquid
[(HMIm) BF4] [15], 1-alkyl-3-methylimidazolium cation [16],
HClO4–SiO2 [17], sulfamic acid [18], sulfonic acid-functionalized
because of their unique properties such as excellent chemical and
thermal stability, good solvating capability, wide liquid range,
variable polarity, low vapor pressure, and recyclability. As
mentioned above, ionic liquids have already been used for this
important reaction and satisfactory results have been achieved.
Given the importance of these compounds in order to meet the
demands of green chemistry, development of synthetic methods in
ionic liquids as solvents or as catalysts has been of interest to
researchers. In this regard, we introduce [Py][OTf] as an acidic ionic
liquid in the N-protection of amines. The simple preparation and
the ability to be recycled up to seven runs are salient features of
this catalytic system.
2. Experimental
silica [19],
b-cyclodextrine [20], thiourea [21], iodine CsF [22],
General procedure for the N-Boc protection of amines: To a
magnetically stirred mixture of amine (1 mmol) and (Boc)2O
(1 mmol) a catalytic amount of ionic liquid (0.2 mmol) was added
under solvent-free conditions at room temperature for the
specified period of time. The progress of the reaction was
monitored by TLC and GC–MS. The mixture extraction was carried
out using ethyl acetate (2 Â 5 mL). The organic layer was washed
with water (2 Â 10 mL) and dried over anhydrous Na2SO4. The
solvent was evaporated under vacuum to yield highly pure N-Boc
derivatives. In some cases, the purification was done by column
chromatography using silica gel (60–120) by hexane-ethyl acetate
as eluent to get a pure product.
H3PW12O40 [23], montmorillonite K10 and KSF [24], indion 190
resin [25], ionic liquid [TMG][Ac] [26] and 1,3-disulfonic acid
imidazolium hydrogen sulfate [27], and NH2OH [28] have been
used for N-tert-butoxycarbonylation of amines. However, these
proposed methods have limits such as the use of toxic, hazardous
and expensive reagents, long reaction times, low yields, adverse
reactions that produce a mixture of products, and multiple stages.
*
Corresponding author.
E-mail address: karimian.somaye@yahoo.com (S. Karimian).
1001-8417/$ – see front matter ß 2013 Somaye Karimian. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.11.052

S. Karimian, H. Tajik / Chinese Chemical Letters 25 (2014) 218–220
219
Table 3
[Py][CF3COO]
Solvent free, r.t
A comparison of the efficiency of [Py][OTf] with several reported procedures in the
RNH2 + ( Boc)2O
RNH-Boc
preparation of tert-butyl phenyl carbamate 3a.
1
2
3a-p
Entry Catalyst/reaction conditions
Time Yield (%) Reference
Scheme 1. N-Boc protection of amines.
1
2
3
4
5
6
7
Sulfonic acid/functionalized silica/CH2Cl2, r.t. 45 min 83
[20]
I2/Solvent-free, r.t.
30 min 94
14 h 90
12 h 92
2.5 h 75
40 min 95
25 min 95
[30]
Yttria-Zirconia/CH3CN, r.t.
Zn(ClO4)2.6H2O/CH2Cl2, r.t.
Cyclodextrin/H2O, r.t.
[14]
Table 1
The optimal reaction conditions for the model reactiona.
[11]
[21]
Thiourea/Toluene, 60–708C
[Py][OTf]/Solvent-free, r.t.
[22]
Entry Solvent
Catalyst amount (mmol) Time (min) Yield (%)b
this work
1
2
3
4
5
6
7
8
9
10
–
–
180
25
80
97
95
95
95
70
95
65
80
90
–
0.2
0.2
0.2
Acetonitrile
n-Hexane
75
120
110
100
100
25
Table 4
Dichloromethane 0.2
Reusability of the [Py][OTf] in the synthesis of compound 3a.
Ethyl acetate
0.2
Ethanol
0.2
Entry
Time (min)
Yield (%)a
–
–
–
0.05
0.15
0.3
25
1
2
3
4
5
6
7
8
25
25
25
25
25
25
25
25
95
94
92
94
94
95
90
55
25
a
Aniline (1 mmol), (Boc)2O (1 mmol), solvent (2 mL), room temperature.
All measured by GC.
b
3. Results and discussion
a
Isolated yield.
In continuing our interest on ionic liquid as a catalyst in the
synthesis of organic compounds [29], here we report the selective
tert-butoxycarbonylation of amines using (Boc)2O catalyzed by
pyridinium 2,2,2-trifluoroacetate [Py][OTf] ionic liquid as a novel
catalyst at room temperature with high yields and short reaction
times (Scheme 1).
To find the optimal conditions, the reaction between aniline and
(Boc)2O was chosen as a model reaction. Initially, the reaction was
performed under the solvent and catalyst free condition, and as can
be seen in Table 1, after 180 min of reaction time, the product was
obtained in 80% yield (Table 1, entry 1). By using 0.2 mmol of
[Py][OTf] ionic liquid as catalyst, 97% yield of product was obtained
in the period of 25 min (Table 1, entry 2). The effect of different
solvents on the reaction efficiency was tested but the reaction in
the solvent-free conditions had the best performance (Table 1,
entries 3–7). Finally, the amount of catalyst was studied and by
reducing it, the reaction yield was significantly reduced. (Table 1,
entries 8–9). Interestingly, by increasing the amount of catalyst to
0.3 mmol, the yield for unknown reasons was decreased to 90%
after 25 min of reaction time (Table 1, entry 10).
[Py][OTf] (0.2 mmol), room temperature. Various derivatives of
aniline and benzyl amine were taken under the reaction conditions
and the products were obtained with good yields (Table 2). In
general, benzyl amine derivatives reacted more quickly than
aniline derivatives due to their high nucleophilicity. As expected,
electron donating groups on aryl groups give rise to higher yields
than electron withdrawing groups.
To see the advantages of [Py][OTf] as a catalyst in this reaction,
our obtained results and employed reaction conditions for
preparation of tert-butyl phenyl carbamate (3a) were compared
with previously reported data in Table 3. The results show the
proposed method with [Py][OTf], as catalyst is quite better than the
former methods in yields and reaction times.
To examine the reusability of [Py][OTf] in the model reaction
after completion the reaction mixture was extracted by ethyl
acetate and the catalyst was separated, washed with ethyl acetate
and EtOH, air-dried, and used directly for the next reaction without
further purification. The [Py][OTf] ionic liquid could be recovered
and reused seven times without any significant loss of the catalytic
activity (Table 4).
The following conditions were used for the preparation of
various amine carbamates: amine (1 mmol), (Boc)2O (1 mmol),
Table 2
Preparation of amine carbamates 3a–p in the presence of [Py][OTf] ionic liquid as catalyst.
Entry
Amine
Product
Time (min)
Yield (%)a
1
PhNH2
PhNH-Boc (3a)
25
9
95
96
96
95
94
94
93
95
93
92
92
94
93
94
95
78
2
4-(MeO)C6H4NH2
4-MeC6H4NH2
4-(MeO)C6H4NH-Boc (3b)
4-MeC6H4NH-Boc (3c)
3,4-(Me)2C6H3NH-Boc (3d)
4-BrC6H4NH-Boc (3e)
3
31
17
50
60
18
20
1
4
3,4-(Me)2C6H3NH2
4-BrC6H4NH2
5
6
4-ClC6H4NH2
4-BrC6H4NH-Boc (3f)
7
2,3-(Me)2C6H3NH2
3-EtC6H4NH2
2,3-(Me)2C6H3NH-Boc (3g)
3-EtC6H4NH-Boc (3h)
8
9
4-EtOC6H4NH2
2-CH3CH2CH(CH3)C6H4NH2
Naphthalen-1-NH2
PhCH2NH2
4-EtOC6H4NH-Boc (3i)
2-CH3CH2CH(CH3)C6H4NH-Boc (3j)
Naphthalen-1-NH-Boc (3k)
PhCH2NH-Boc (3l)
10
11
12
13
14
15
16
60
77
1
4-MeOC6H4CH2NH2
4-FC6H4CH2NH2
PhCH2CH2NH2
3-NO2C6H4NH2
4-MeOC6H4CH2NH-Boc (3m)
4-FC6H4CH2NH-Boc (3n)
PhCH2CH2NH-Boc (3o)
3-NO2C6H4NH-Boc (3p)
3
1
4
120
a
Isolated yield.

220
S. Karimian, H. Tajik / Chinese Chemical Letters 25 (2014) 218–220
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Scheme 2. Suggested mechanism for the formation of amine carbamates.
A suggested mechanism for the formation of amine carbamates
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group of (Boc)2O is activated by hydrogen bond formation with the
acidic hydrogen of [Py][OTf]. Then, the nitrogen of the amine
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In conclusion, we have developed a fast, simple, and efficient
procedure for N-protection of amines based on [Py][OTF]-
catalyzed reaction of amines and (Boc)2O, under solvent-free
conditions at room temperature. The short reaction times, easy
workup, clean reaction profiles, and high product yields make our
methodology a valid contribution to the existing processes in
amines protections.
Acknowledgment
The authors thank the Research Committee of Persian Gulf
University and Guilan University for financial support of this work.
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