[TPA][Pro] ionic liquid as efficient reaction medium for N-tert-Boc protection of amines

Article abstract of DOI:10.14233/ajchem.2017.20479

A facile and efficient N-tert-Boc protection of amines is described by the reaction of various primary, secondary, benzylic and aryl amines with di-tert-butyl dicarbonate in the ionic liquid [TPA][Pro] at room temperature. All the N-tert-butylcarbamates are afforded in excellent yields. A catalyst-free method was developed and the ionic liquid [TPA][Pro] can be recovered and reused for several times without loss of its activity.

Full text of DOI:10.14233/ajchem.2017.20479

Asian Journal of Chemistry; Vol. 29, No. 6 (2017), 1313-1316
ASIAN JOURNAL OF CHEMISTRY
https://doi.org/10.14233/ajchem.2017.20479
[TPA][Pro] Ionic Liquid as Efficient Reaction Medium for N-tert-Boc Protection of Amines
*
T. VIJAYA DURGA, A. RAMBABU, M. SRINIVASA REDDY and B. HARI BABU
Department of Chemistry, Acharya Nagarjuna University, Nagarjunanagar-522 510, India
*Corresponding author: Tel: +91 863 2346575; E-mail: dr.b.haribabu@gmail.com
Received: 27 December 2016;
Accepted: 17 February 2017;
Published online: 10 April 2017;
AJC-18345
A facile and efficient N-tert-Boc protection of amines is described by the reaction of various primary, secondary, benzylic and aryl amines
with di-tert-butyl dicarbonate in the ionic liquid [TPA][Pro] at room temperature. All the N-tert-butylcarbamates are afforded in excellent
yields. A catalyst-free method was developed and the ionic liquid [TPA][Pro] can be recovered and reused for several times without loss
of its activity.
Keywords: Ionic liquid [TPA][Pro], Amines, N-tert-butylcarbamates, N-tert-butoxycarbonylation.
transfer reactions using tert-Boc-imidazole [16] or tert-butoxy-
INTRODUCTION
carbonyl-1,2-dihydroisoquinoline [17].Although, various base
mediated methods are available for the preparation of N-tert-
butylcabamates using di-tert-butyl dicarbonate and also few
Notwithstanding the unique advantages of ionic liquids
(IL’s) as reaction media and catalysts including biological
systems, currently they have not been widely applied in indus-
reports on acid-mediated reactionYttria-Zirconia [18], Cu(BF4)2
try. The reason for this is probably related to the high cost of
[19], InBr3 [20], HClO4-SiO2 [21], La(NO3)3·6H2O [22],
ionic liquids, the difficulty in separation or recycling, the
H3PW12O40 [23],LiClO4 [24] and I2 [25] as Lewis acids catalysts
paucity of data with regard to their toxicity and biodegrada-
and also in water [26], sulfonic-acid-functionalized silica [27]
bility, etc. [1-5]. To overcome these disadvantages, recently
as a catalyst for N-tert-butoxycarbonylation of amines. The
some new ionic liquids have been prepared via simple and
catalyst free ionic liquid mediated N-tert-butoxycarbonylation
economic acid-base neutralizations. For example the prepa-
of amines is not investigated so far. The selected ionic liquid,
ration and application of the Brönsted acid-base ionic liquids
tetrapropylammonium L-prolinate [TPA][Pro] was reported
from imidazole and bis(trifluoromethanesulfonyl)amide [6],
as an efficient reaction medium for the synthesis of β-keto-
a new class of ionic liquids by neutralization of 1,1,3,3-tetra-
sulfones, β-hydroxysulfones, N-benzyloxycarbonylation of
methylguanidine with different acids have been reported [7].
amines [28,29]. We reported number of studies on molecular
Similarly, the synthesis of ionic liquids using quaternary
interactions between various ionic liquid’s[30-33] and organic
ammonium hydroxide and chiral carboxylic acids have also
solvents, but in the present investigation an attempt was made
been reported [8]. Although there are several reports on ionic
to utilize ionic liquid [TPA][Pro] as an efficient reaction medium
liquids, the preparation of chiral ionic liquids using inexpensive
for N-tert-butoxycarbonylation of amines with di-tert-butyl
starting materials is very limited.
dicarbonate.
Among carbonic acid derivatives used as protecting
groups, tert-butylcarbonates and tert-butylcarbamates are of
EXPERIMENTAL
great importance in organic chemistry [9], because they are
stable to wide range of nucleophiles in alkaline conditions
and are very liable under moderately acidic conditions to give
the parent alcohols and amines. Classically, introduction of
tert-Boc group to an amine is generally achieved by reaction
of amine with di-tert-butyl dicarbonate in the presence
triethylamine in dry dichloromethane [10-14]. It has been
reported that this can be promoted by di-tert-butyl dicarbonate
in the presence of dimethylaminopyridine [15], tert-Boc
All the chemicals used were ofAR grade, purchased from
Merck manufactures Pvt. Ltd. and were used as such. The melting
points were calculated on Remi melting point apparatus. All
the reactions were monitored by TLC and the yields refer to
isolated products. The IR spectra were recorded on Shimadzu
spectrophotometer using KBr pellet method, proton NMR
spectra were recorded in CDCl3 on Bruker instrument at 300
MHz and 13C NMR spectra were recorded in CDCl3 on a Bruker

1314 Durga et al.
Asian J. Chem.
spectrometer at 100 MHz. Mass spectra were recorded on
Elegant LC-1100 series instrument.
The combined organic layer was washed with brine solution
and concentrated under reduced pressure to give crude product,
which was purified over silica gel column to afford corres-
ponding N-tert-butylcarbamate. The ionic liquid [TPA][Pro]
in aqueous solution was recovered by removing water under
reduced pressure and dried. The recovered ionic liquid was
reused for five times without loss of its activity. Finally, all the
compounds confirmed by their m.p.’s, IR, 1H NMR, 13C NMR,
mass spectral data and elemental analysis wherever needed.
General procedure for preparation of N-tert-butyl-
carbamates: To the ionic liquid [TPA][Pro] (1 mL) was added
amine (1-14; Table-1) (1 mmol) and di-tert-butyl dicarbonate
(1.2 mmol). The reaction was stirred 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).
TABLE-1
N-tert-BUTOXYCARBONYLATION OF AMINES USING IONIC LIQUID [TPA][Pro] CONDITIONS
Entry
Substrate
Product
Time (min)
Yield (%)a
H
N
NH2
O
R3
O
R1
R3
R1
R2
R2
R1 = H, R2 = H, R3 = H
R1 = CH3, R2 = H, R3 = H
R1 = OH, R2 = H, R3 = H
R1 = H, R2 = NO2, R3 = H
R1 = H, R2 = H, R3 = NO2
R1 = H, R2 = H, R3 = F
R1 = H, R2 = H, R3 = H
10
25
13
15
10
30
100
95
99
95
98
96
1
2
3
4
5
6
R1 = CH3, R2 = H, R3 = H
R1 = OH, R2 = H, R3 = H
R1 = H, R2 = NO2, R3 = H
R1 = H, R2 = H, R3 = NO2
R1 = H, R2 = H, R3 = F
OH
OH
N
7
8
9
15
20
05
95
N
H
O
O
O
O
O
NH
N
O
100
100
N
Me
N
Me
O
NH
N
O
H
N
O
O
10
10
100
N
O
NH
N
O
11
12
10
20
99
95
O
O
H
N
NH2
O
O
N
N
ts
ts
H
NH2
NH2
N
O
13
14
10
10
98
99
O
HO
HO
H
N
O
O
AcO
AcO
aIsolated yields after silica gel chromatography.

Vol. 29, No. 6 (2017)
[TPA][Pro] Ionic Liquid as Efficient Reaction Medium for N-tert-Boc Protection of Amines 1315
Spectral data of the compounds (Table-1) Entry 1:
Solid, m.p.: 134 °C. FTIR (KBr, νmax, cm–1): 3314 NH, 1689
C=O.1H NMR (300 MHz, CDCl3) δ = 1.50 (s, 9H, Boc), 6.35
(bs, BocNH), 7.0 (t, J = 7.2 Hz, 1 Ar-H), 7.35 (m, 4 Ar-H);
13C NMR (75 MHz, CDCl3): δ = 28.2 (CH3), 80.3 (C), 118.5
(CH), 123 (CH), 128.9 (CH), 138.2 (C), 152.7 (C=O). EIMS:
NH
O
NH2
Boc
[TPA][Pro]
O
R
R
Scheme-I
1
m/z 194 (M+); Entry 2: Solid, m.p.: 82 °C. H NMR (300
the ionic liquid [TPA][Pro]. The present method is simple and
no special care to exclude the moisture from the reaction medium
and no by-products were observed. Further, the reaction medium
i.e. the ionic liquid [TPA][Pro] was recovered and reused several
times. We have prepared [28,29] the ionic liquid tetrapropyl-
ammonium prolinate [TPA][Pro] from readily available tetra-
propyl ammonium hydroxide and proline in aqueous medium
at 60 °C. Initially we have carried out the reaction of aniline
(1 mmol) with di-tert-butyl dicarbonate (1.2 mmol) in the ionic
liquid [TPA][Pro] at room temperature to give very rapidly
the corresponding N-tert-butylcarbamate in good yield (Table-1,
Entry 1). This achievement has encouraged us to extend the
reaction on various primary, secondary and benzylic and aryl
amines (Table-1) to yield the corresponding N-tert-butylcarba-
mates in a facile manner. From the foregoing results (Table-1)
it is evident that ionic liquid [TPA][Pro] is an excellent reaction
medium for N-tert-butoxycarbonylation of amines under very
mild conditions.
MHz, CDCl3) δ = 1.50 (s, 9H, Boc), 2.25 (s, 3H, CH3), 6.20
(bs, 1 BocNH), 6.9 (m, 1Ar-H), 7.0-7.24 (m, 2Ar-H), 7.80 (d,
1 Ar-H); EIMS: m/z 207 (M+); Entry 3: solid, m.p.: 142 °C.
FTIR (KBr, νmax, cm–1): 3322 NH, 1691 C=O. 1H NMR (300
MHz, CDCl3) δ = 1.56 (s, 9H, Boc), 6.63 (b s, 1H, OH), 6.81
(t, J = 7.5 Hz, 1 Ar-H), 7.0 (d, J = 9.5 Hz, 1 Ar-H), 7.03-7.09
(m, 2Ar-H) 8.12 (bs, 1 BocNH); 13C NMR (75 MHz, CDCl3):
δ = 28.6 (CH3), 82.4 (C), 121.17 (CH), 121.7 (CH), 125.85
(CH), 26.1 (CH), 147.78 (C), 155.38 (C=O). EIMS: m/z 209
(M+); Anal. calcd. for C11H15NO3; C, 63.13; H, 7.23; N, 6.70.
Found: C, 63.21; H, 7.31; N, 6.73. Entry 4: Solid, m.p.: 95
°C. 1H NMR (300 MHz, CDCl3) δ =1.50 (s, 9H, Boc), 7.5 (t, J
= 7.2 Hz, 1 Ar-H, ), 7.8-7.95 (m, 2 Ar-H), 8.66 (m, 1 Ar-H),
EIMS: m/z 238 (M+); Entry 5: Solid, m.p.: 110 °C. 1H NMR
(300 MHz, CDCl3) δ = 1.50 (s, 9H, Boc), 7.5 (d, J = 6.5Hz, 2
Ar-H) 8.1 (d, J = 6.5 Hz, 2Ar-H); EIMS: m/z 238 (M+). Entry
6: Solid, m.p.: 125 °C. δ = 1.50 (s, 9H, Boc), 5.6 (brs 1 BocNH),
7.1 (m, 2 Ar-H), 7.4 (m, 2Ar-H); Entry 7: Solid, m.p.: 123 °C.
1H NMR (300 MHz, CDCl3) δ = 1.40 (s, 9H, Boc), 2.1 (m, 4
Pyrldn-H), 3.4 (m, 2 Pyrldn-H), 4.4 (m, 1 Pyrldn-H), 9.0 (brs
1H BocNH); EIMS: m/z 215 (M+); Entry 8: 1H NMR (300
MHz, CDCl3) δ = 1.45 (s, 9H, Boc), 2.2 (s, 3H, CH3), 3.1 (m,
4H, Pip), 3.5 (m, 4H, Pip). EIMS: m/z 200 (M+); Entry 9: 1H
NMR (300 MHz, CDCl3):δ = 1.40 (m, 2H, Pip), 1.45 (m, 4H,
Pip), 1.45 (s, 9H, Boc) 2.8 (m, 4H, Pip); EIMS: m/z 185 (M+);
Entry 10: Solid, m.p.: 75 °C. FTIR (KBr, νmax, cm–1): 3090
NH, 1680 C=O. 1H NMR (300 MHz, CDCl3): δ = 1.04-1.79
ACKNOWLEDGEMENTS
The authors are highly thankful to Acharya Nagarjuna
University, Nagarjunanagar, India for constant encouragement
and Laila Impex R&D Center, Vijayawada for their help in
spectral data.
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