Sustainable and chemoselective N-Boc protection of amines in biodegradable deep eutectic solvent

Article abstract of DOI:10.1007/s00706-016-1856-x

Abstract: A green and practical approach for the chemoselective N-tert-butyloxycarbonylation of structurally diverse amines with di-tert-butyl dicarbonate (Boc₂O) is described. Selective N-Boc protection was achieved in excellent yields in urea-choline chloride deep eutectic solvent (DES) as the most promising environmentally benign and cost-effective solvent under mild reaction condition. DES can protect various aromatic and aliphatic amines using Boc₂O in good to excellent yields in short reaction times without any side products. Graphical abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s00706-016-1856-x

Monatsh Chem
DOI 10.1007/s00706-016-1856-x
ORIGINAL PAPER
Sustainable and chemoselective N-Boc protection of amines
in biodegradable deep eutectic solvent
Najmedin Azizi1 Fatemeh Shirdel1
•
Received: 5 July 2016 / Accepted: 10 October 2016
Ó Springer-Verlag Wien 2016
Abstract A green and practical approach for the
chemoselective N-tert-butyloxycarbonylation of struc-
turally diverse amines with di-tert-butyl dicarbonate
(Boc2O) is described. Selective N-Boc protection was
achieved in excellent yields in urea-choline chloride deep
eutectic solvent (DES) as the most promising environ-
mentally benign and cost-effective solvent under mild
reaction condition. DES can protect various aromatic and
aliphatic amines using Boc2O in good to excellent yields in
short reaction times without any side products.
One of the most common methods of protecting amines as
well as amino acids in peptide chemistry involves the
formation of N-Boc functionality due to their ease of for-
mation and cleavage [2]. The stability of the tert-butyl
carbamates towards basic and nucleophilic attacks make
them the most frequently protective groups used in com-
plex structure where the selectivity is a prime issue [3–5].
Furthermore, several mild methods are available for the
removal of the Boc protecting group which mostly utilizes
acidic condition at room temperature [6–8]. A vast array of
catalyst and promoter have been used for N-tert-butoxy-
carbonylation of amines in the literature that some of them
using di-tert-butyl dicarbonate Boc2O a more eco-sustain-
able reagent [9–19].
Graphical abstract
Green Chemistry has emerged as a research area with
the aim of providing sustainable materials and environ-
mentally preferable products to achieve an upstanding
sustainable environment maintaining the health and safety
of animal and people [20]. The most common pollutants in
the academic and industrial process are volatile organic
solvents, especially halogenated solvents that used in large
quantities due to a wide range of application from analysis
to synthesis [21]. In this context, four main alternatives to
organic solvents have been developed [22]: (1) water is
really green solvent regarding the aforementioned consid-
erations and unconventional properties, yet the negligible
solubility of carbon compounds in water and the reaction of
some organometallic compounds with water limits its
applications [23–25], (2) use of ‘‘bio-solvents’’, i.e., sol-
vents produced with renewable resources or solvent-free
processes [26], (3) supercritical fluids and fluorous biphasic
systems have been reported as recyclable, environmentally
benign reaction media [27], (4) ionic liquids (ILs) are
molten salts with a melting point below 100 °C, came into
the spotlight during the last decade, is an excellent green
Keywords Green chemistry Á Deep eutectic solvent Á
tert-Butyloxycarbonylation Á Amines Á Boc2O
Introduction
Protecting groups play a pivotal role in organic synthesis,
particularly in the multi-step synthesis of multifunctional
targets and structurally complicated natural products [1].
& Najmedin Azizi
azizi@ccerci.ac.ir
1
Chemistry and Chemical Engineering Research Center of
Iran, P.O. Box 14335-186, Tehran, Iran
123

N. Azizi, F. Shirdel
solvent due to their unique properties, such as low vapor
pressure, high thermal stability, recyclability, non-
flammability, and wide liquid range [28–32]. Furthermore,
the IL characteristics can be controlled by many combi-
nations of cations and anions and allow the design of ionic
liquids with unique properties and special application [33].
In addition, by incorporating a functional group it was
possible to make task-specific ionic liquids that have dual
properties [34–36]. The main disadvantages of ionic liquids
such as non-biodegradable, toxic, and commercially
expensive enforced the scientists to discover environmen-
tally friendly reaction media. Alternative sustainable to
traditional solvents and ionic liquids is deep eutectic sol-
vents (DESs), that they are usually obtained by the
complexation of a quaternary ammonium salt such as
choline chloride with a metal salt or hydrogen bond donor
like urea, carboxylic acid, sugar and amide [30, 37–39].
DESs as an alternative to ILs, not only have similar char-
acteristics to traditional imidazolium based ILs, but also
have several advantages such as ease of preparation, and
available from bulk renewable resources [40–44]. Prepa-
ration of DESs involves the simple mixing of their
components under gently heating or freeze drying method
without any further modification [45]. Furthermore, choline
chloride (ChCl) and urea are both a naturally occurring
biocompatible sustainable building block of DESs that are
not hazardous if they release back into the nature [46].
Besides, they are cheap and the processes which use these
DESs are economically viable and green [47].
Results and discussion
In the past few years, our research group has explored
applicability of an abundant and nontoxic urea-choline
chloride based DES as new alternative renewable solvents
for various organic transformations while adopting a more
eco-sustainable approach [48–50]. For the first time, we
here report a convenient protocol for the N-Boc protection
of amines using DES as a solvent under catalyst-free
conditions.
Urea-choline chloride DES was synthesized by mixing
urea with choline chloride at 60 °C for 2 h until the clear,
transparent, homogeneous DES appears. First, aniline
(0.5 mmol) and di-tert-butyl dicarbonate (0.5 mmol) was
chosen as model compound using different amounts of
DES at room temperature (Table 1). It was found the use of
0.5 cm3 of DES gave the optimum yield (84%), at room
temperature within 1 h, whereas 0.1 cm3 and 0.3 cm3
resulted in 67 and 74% yields, respectively. The results are
shown in Table 1. Prolonged reaction times (4 h) or excess
of DES (3 cm3) could not improve the yields. Next, we
attempted to improve the yields by increasing the reaction
temperature. It was found that the temperature plays key
factor and the reaction completed within 20 min at 50 °C
leading to excellent yields of the protected aniline. The
protection reaction was quantitative, and no product other
than Boc-protected aniline was present in the reaction
mixture. Importantly, the isolation and purification steps
are very simple and easy that involves the addition of a
Table 1 Optimization of the model reaction
O
Boc2O
Ph
N
H
O
Ph-NH2
DES
Entry
DES/cm3
Time/min
Temp./°C
Yield/%a,b
1
0.1
0.2
0.3
0.4
0.5
1.0
3.0
0.5
0.5
0.5
0.5
60
60
60
60
60
60
240
10
10
10
10
rt
67
67
74
82
84
84
88
90
97
97
97
2
rt
3
rt
4
rt
5
rt
6
rt
7
rt
8
40
50
60
80
9
10
11
a
Isolated yields
b
Reaction conditions: aniline (0.5 mmol), Boc2O (0.5 mmol), and DES
123

Sustainable and chemoselective N-Boc protection of amines in biodegradable deep eutectic…
water and filtration of products and recrystallization from
EtOH.
Conclusion
Next, we examined the protection of a wide variety of
amines using this methodology, and the results are sum-
marized in Table 2. A range of commercially available
amines (aliphatic, aromatic, and heteroaromatic) under-
went the conversion efficiently. Under optimized
conditions aniline with both electron donating and electron
withdrawing substituents at various positions reacted
instantaneously and almost a white precipitate of tert-
butyl-N-aryl carbamates are formed after addition of water
to the reaction mixture. Anilines bearing electron-donating
groups had slightly higher yields than those with electron-
neutral and electron-withdrawing moieties. Good to
excellent yields were obtained when primary and sec-
ondary aliphatic amines, such as benzylamine,
4-methoxybenzylamine, 4-chlorobenzylamine, 1-naphthyl-
methylamine, and dihexylamine with Boc2O even at room
temperature. Importantly, the reaction also works with
sterically hindered amines like 2,6-dimethylaniline under
the same mild conditions. Benzo[d]thiazol-2-amine as
heteroaromatic amines gives moderated yields of product.
However, deactivated aromatic amines such as pyridin-2-
amine and 4-nitroaniline give only starting materials.
The chemoselectivity of the DES was also investigated
by the substrates with an OH/NH2 group. Reaction with
4-aminophenol (Table 2, entry 20) resulted in chemose-
lective formation of the N-Boc-aniline without
O-tertbutoxycarbonylation. Furthermore, chemoselective
mono-N-Boc protection of o-phenylenediamine was also
possible in DES.
In summary, efficient and recyclable DES was successfully
applied as a green solvent for N-tert-butyloxycarbonylation
of amines that is one of the most important functional
group protections in organic synthesis. A range of aromatic
and aliphatic amines with different functional groups were
successful protected in good to excellent yields under short
reaction times.
Experimental
Choline chloride, urea, and all substrates for the protec-
tion of amine derivatives are commercially available and
were purchased and used without further purification.
Solvents were purchased from commercial sources and
distilled from the relevant agents prior to use. All prod-
ucts were confirmed by melting point or boiling point,
1
FT-IR spectroscopy, and H NMR spectroscopy. All the
reactions are monitored by thin layer chromatography
(TLC) carried out on 0.25 mm silica gel with relevant
detecting agents. Melting points and boiling points were
recorded in Buchi 535 melting point apparatus. The FT-
IR spectra of the samples were obtained on a Bruk-
erVector-22 infrared spectrometer using KBr disks.1H
NMR spectra were recorded at r.t. on a FT-NMR Bruker
UltraShieldTM (500 MHz) instrument as CDCl3 as a sol-
vent, chemical shifts have been expressed in ppm
downfield from TMS.
Although the details of the reaction mechanism are not
clear at present, a possible mechanism for the N-Boc
protection of amines in deep eutectic solvent was shown in
Scheme 1. This reaction presumably occurs via activation
of the carbonyl group of Boc2O with the hydrogen bonding
ability of deep eutectic solvent to form a zwitterionic
species, making the carbonyl group susceptible to nucle-
ophilic attack by the amine. Successive elimination of CO2
and t-BuOH in the presence of DES to form the corre-
sponding N-Boc derivatives.
Deep eutectic solvent preparation
Choline chloride-urea based DES was prepared by mixing
of urea (200 mmol) and choline chloride (100 mmol) under
60 °C until a clear liquid was appeared [42]. The obtained
DES was used without any further purification.
General procedure
A dried test tube, equipped with a magnetic stir bar, was
charged with 0.5 cm3 DES, amine derivatives
(0.5 mmol), and Boc2O (0.5 mmol) and the mixture was
heated at 50 °C until the reaction was complete (moni-
tored by TLC and IR). After this time, 5 cm3 water was
added and in the most cases a white solid was obtained.
The solid product was collected by filtration and washed
successively with water and recrystallized from ethanol
to get the pure final product [51–60]. The viscous
products extracted with ethyl acetate and were purified
by column chromatography, using ethyl acetate–petro-
leum ether.
The recovery and reuse of DES was important which
helps address both economic and environmental viewpoints
in industrial and chemical process. The investigation of the
reusability of the DES using a model reaction of aniline
(5 mmol) and Boc2O (5 mmol) in 3 cm3 DES for the for-
mation of 2a was shown in Fig. 1. After completion,
10 cm3 water was added to the reaction mixture, shaken
vigorously and filter off the solid product, the deep eutectic
solvent was recovered from filtrate by evaporating the
water phase at 80 °C in vacuum and reused with minimal
loss of activity (Fig. 1).
123

N. Azizi, F. Shirdel
Table 2 N-Boc protection of
various amines in deep eutectic
solvent
Entry
Products 2
Yield / %a
M.p. / °C
Found
Reported
1
2
3
4
5
NHBoc
NHBoc
NHBoc
NHBoc
NHBoc
97
90
92
97
97
134-136
133-137 [52]
101-102 [53]
100-102 [53]
84-86 [53]
2a
2b
2c
2d
2e
Cl
Br
104-106
98-100
86-88
Me
MeO
92-93
92-93 [53]
Cl
Cl
6
92
60-62
63-64 [53]
2f
NHBoc
NHBoc
7
8
90
95
56-58
57-59 [54]
2g
2h
98-100
104-105 [55]
9
85
107-109
114-115 [56]
2i
Cl
NHBoc
NHBoc
10
11
O2N
0
0
-
-
-
-
2k
2l
12
90
88-89
86-87 [57]
NHBoc 2m
NHBoc
13b
14
95
90
95
54-56
74-75
52-54
55-57 [52]
75-76 [58]
50-50.5 [59]
2n
2o
NHBoc
15
2p
MeO
16
17
NHBoc
97
74
84-86
96-98
80-82 [18]
98-99 [57]
2q
2r
123

Sustainable and chemoselective N-Boc protection of amines in biodegradable deep eutectic…
Table 2 continued
Colorless
liquid
18
90
[59]
2s
19
20
62
82
99-101
98-100 [60]
146 [18]
2t
HO
NHBoc
NHBoc
2u
145-147
23c
24
90
85
112-112
104-106
110-113 [61]
105-106 [61]
2x
2y
NH2
NHBoc
NHBoc
Acknowledgements Financial support of this work by Chemistry and
Chemical Engineering Research Center of Iran is gratefully
appreciated.
Scheme 1
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