Published on the web September 18, 2010
1127
PEG-mediated Facile Protocol for N-Boc Protection of Amines
V. Siddaiah,* G. M. Basha, G. Padma Rao, U. Viplava Prasad, and R. Suryachendra Rao
Department of Organic Chemistry & FDW, Andhra University, Visakhapatnam 530 003, India
(Received July 12, 2010; CL-100622)
Table 1. N-Boc protection of aniline with PEG-400 in various
conditions at room temperature (Entry 3 gives the optimum
conditions)
We have reported an efficient and eco-friendly protocol for
the protection of various structurally and electronically divergent
aryl and aliphatic amines using (Boc)2O in the presence of PEG-
400 at room temperature. The reaction gave excellent yields with
low as well as high molecular weight PEGs.
PEG-400
Solvent
/mL
Time
/min
Isolated
yield/%
Entry
/mL
1
2
3
4
5
7
8
9
®
®
®
®
®
120
30
5
70
80
100
100
75
95
88
90
0.1
0.5
1.0
0.5
0.5
0.5
0.5
In recent years eco-friendly chemical processes have gained
considerable interest in synthetic organic chemistry.1 Hazardous,
toxic, and volatile organic solvents are being continuously
replaced either by the use of solvent-free techniques,2 or by
using water,3 phase-transfer catalysts,4 or ionic liquids.5 The use
of PEG as a reaction medium is highly beneficial as the system
remains neutral, which helps insure a number of acid- and base-
sensitive functional groups remain unchanged.6
5
DCM (5)
EtOH (5)
THF (5)
CH3CN (5)
10
10
10
10
Protection and deprotection of functional groups are
important and frequently needed in modern organic chemistry.
Particularly protection of amines is very important due to their
high nucleophilicity and basicity. Among the widely used
protecting groups for amines the tert-butoxycarbonyl (Boc)7
group is extensively used since it can be easily removed by
using an acid like TFA or HCl.7a Furthermore the Boc group is
stable toward catalytic hydrogenation and extremely resistant to
basic and nucleophilic reactions.7c,8 Generally N-Boc protection
of amines is carried out by the treatment of amines with di-tert-
butoxypyrocarbonate ((Boc)2O) in the presence of DMAP,9
organic/inorganic bases,10 or Lewis acids.11 Other procedures
have also been developed by the reaction of amines with tert-
butyl-1-chloroalkyl carbonates in the presence of K2CO3 in
H2O-THF,12 4-dimethylamino-1-tert-butoxycarbonylpyridinium
chloride/tetrafluoroborate in aqueous NaOH,13 tert-butyl-2-
pyridyl carbonate in the presence of Et3N in H2O-DMF,14
or 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile in the
presence of Et3N in H2O-dioxane.15
Poly(ethylene glycol) (PEG) is commercially available,
inexpensive, and nontoxic, possesses high thermal stability, and
helps in maintaining a neutral reaction medium. Organic
synthesis in PEG is an area of great significance in modern
organic synthesis.17
In order to optimize the reaction conditions, we investigated
the reaction with aniline (3 mmol), di-tert-butoxypyrocarbonate
((Boc)2O) (3 mmol) and different quantities of PEG-400.18
Further we also studied this reaction using various solvents.
The optimized results are summarized in Table 1. We found that
the best result was obtained with 0.5 mL of PEG-400 for 3 mmol
of aniline in the absence of any solvent at room temperature
within 5 min (Table 1, Entry 3). Using more than 0.5 mL of
PEG-400 did not improve the yield of the product, and at the
same time, low yield of the product was obtained in the absence
of PEG-400 (Table 1, Entry 1). Thus in this reaction 0.5 mL of
PEG-400 acted as a solvent and as a good promoter. We
investigated our protocol with various PEGs with molecular
weights 200, 400, 600, 4000, and 6000 (0.05 mol % each) for
our model reaction with aniline (3 mmol) and di-tert-butoxy-
pyrocarbonate ((Boc)2O) (3 mmol). The reaction gave excellent
yields with low as well as high molecular weight PEGs.
With the above result in hand, aliphatic, heterocyclic, and
aromatic amines possessing both electron-donating and electron-
withdrawing groups were employed for N-Boc protection and in
all the cases, the yields were excellent (Table 2). This protocol is
highly chemoselective as only the amine group is protected even
in the presence of OH/SH groups and mono-N-Boc-protected
products were obtained in excellent yields.
However, these methods have various drawbacks such as
requirement of anhydrous solvents, use of toxic reagents, and
formation of side products. These drawbacks necessitate the
development of efficient new synthetic methodologies.
In continuation16 of our efforts in the development of new
synthetic methodologies for carbon-heteroatom bond formation,
herein we report an efficient and eco-friendly protocol for the
protection of amines using (Boc)2O in the presence of PEG-400
at room temperature (Scheme 1).
After successful completion of N-Boc protection of various
amines in excellent yields under the above optimized conditions,
we planned to evaluate the effectiveness of this protocol for
N-Boc protection of chiral amines, ¡-amino acid esters, and ¢-
amino alcohols (Table 3). In all cases, the corresponding
optically pure19 (as determined by the optical rotation and
comparison with literature values) N-Boc products were ob-
PEG-400
RT
R
R
Boc
N
NH
(Boc)2O
+
R1
R1
R, R1
= H, alkyl, aryl
Scheme 1.
Chem. Lett. 2010, 39, 1127-1129
© 2010 The Chemical Society of Japan
Siddaiah
