An efficient and highly chemoselective N-Boc protection of amines, amino acids, and peptides under heterogeneous conditions

Article abstract of DOI:10.1007/s00706-011-0534-2

A simple and efficient procedure for chemoselective mono-N-Boc protection of various structurally diverse amines, amino acids, and peptides with di-tert-butyl dicarbonate using Amberlyst-15 as catalyst in ethanol is described. The catalyst can be readily separated from the reaction products with simple filtration and recovered for direct reuse. No competitive side-reactions such as formation of isocyanate, urea, oxazolidinone, and N,N-di-Boc derivatives were observed.

Full text of DOI:10.1007/s00706-011-0534-2

Monatsh Chem (2011) 142:1035–1043
DOI 10.1007/s00706-011-0534-2
ORIGINAL PAPER
An efficient and highly chemoselective N-Boc protection of amines,
amino acids, and peptides under heterogeneous conditions
Fatemeh Jahani
Samad Khaksar
•
•
Mahmood Tajbakhsh
Mohamad Reza Azizi
•
Received: 2 October 2010 / Accepted: 30 May 2011 / Published online: 19 July 2011
Ó Springer-Verlag 2011
Abstract A simple and efficient procedure for chemo-
selective mono-N-Boc protection of various structurally
diverse amines, amino acids, and peptides with di-tert-
butyl dicarbonate using Amberlyst-15 as catalyst in ethanol
is described. The catalyst can be readily separated from the
reaction products with simple filtration and recovered for
direct reuse. No competitive side-reactions such as for-
mation of isocyanate, urea, oxazolidinone, and N,N-di-Boc
derivatives were observed.
well as readily removed under a variety of conditions
[4, 5]. Besides, protection of amino groups in amino acids as
N-Boc derivatives is an important strategy in peptide syn-
thesis, as they can be easily converted into the free amines,
and is also useful in Merrifield solid-phase peptide syn-
thesis [6]. Furthermore, N-tert-butoxycarbonyl amino acids
are resistant to racemization during peptide synthesis,
making this protocol more applicable in multistep reactions
[6–12]. A vast array of acidic, neutral, and basic reagents
such as NaOH [13], K CO [14], Me NOHꢀ5H O [15],
2
3
4
2
Keywords Amberlyst-15 ꢀ Di-tert-butyl dicarbonate ꢀ
Protection ꢀ Amine ꢀ Amino acid
NaHCO [16], hexamethyldizilazane sodium salt [17],
3
dimethylaminopyridine [18–21], yttria-zirconia [22], ZrCl4
[
[
23], Zn(ClO ) ꢀ6H O [24], LiClO [25], Cu(BF ) [26], I
4
2
2
4
4 2
2
27], H PW O [28], montmorillonite K10 or KSF [29],
3 12 40
Introduction
sulfonic acid-functionalized silica [30], La(NO3)3 [31],
thiourea [32], hexafluoroisopropanol [33], and guanidine
hydrochloride [34] have been applied as catalysts for this
transformation.
Chemical manipulation of complex polyfunctional mole-
cules often requiressequential protectionand deprotectionof
various functionalities. The presence of the amine moiety in
a wide range of biomolecules makes protection of amines
one of the most fundamental and useful transformations in
organic synthesis, especially in peptide chemistry [1, 2].
Due to the stability of tert-butylcarbamates towards a
wide range of nucleophilic reagents and alkaline reaction
Some of these methodologies, although effective, have
several drawbacks such as long reaction times, formation of
side-products during the catalyzed reactions [19, 20],
potential hazards (e.g., the high toxicity of DMAP and
reagents derived from it), excess reagents in the case of
Lewis acid-catalyzed reactions [36], and the problem of
catalyst recovery and limited applicabilities (e.g., the use of
H SO at 500 °C to prepare yttria-zirconia; ZrCl is highly
conditions, di-tert-butyl pyrocarbonate [(Boc) O] has
2
become an important and popular protective group for
2
4
4
amines [3]. Tert-butylcarbamates are easily introduced as
moisture sensitive and liberates HCl fumes; perchlorate
reagents are strong oxidants and explosive in nature).
Moreover, many of the N-Boc protection reactions do not
show generality for amines; especially when amino acids
are used as the amine moiety, the protection fails. There-
fore, to overcome these problems, a new and more efficient
protocol for synthesis of N-Boc amines, amino acids, and
peptides, which can be applied to a number of substrates in a
catalytic process, is still required.
F. Jahani ꢀ M. Tajbakhsh (&) ꢀ M. R. Azizi
Department of Chemistry, University of Mazandaran,
P.O. Box 453, Babolsar, Iran
e-mail: tajbaksh@umz.ac.ir
S. Khaksar
Chemistry Department, Islamic Azad University,
Ayatollah Amoli Branch, PO Box 678, Amol, Iran
123

1
036
F. Jahani et al.
On the other hand, organic synthesis using heteroge-
lack of generality towards different substrates in water and
the toxicity of methanol resulted in utilization of ethanol as
a convenient solvent in this method. An optimum catalytic
amount of 7–10% (w/w) of Amberlyst-15 was sufficient to
afford the desired product in excellent yield. An increase in
the amount of catalyst from 10% to 30% (w/w) did not
improve the reaction time, and a smaller amount (2–5%
w/w) led to a longer reaction time. In the absence of cat-
alyst, longer time (38 min) was required for completion of
the reaction (Table 1, entry 2).
neous acid catalysts has received much attention from the
standpoint of green and sustainable chemistry because of
the possibility of performing environmentally highly
acceptable chemical processes [37–39].
In this context, Amberlyst-15, a sulfonic acid-based ion
exchange resin, has been used as an acid catalyst in a wide
variety of processes [40–43]. It has unique properties such
as environmental compatibility, nontoxicity, reusability,
noncorrosiveness, selectivity, and chemical and physical
stability, and can be used over a prolonged period.
A very recent paper on the use of Amberlyst-15 as a
catalyst for N-Boc protection [44] and its previous use as a
catalyst for N-Boc deprotection [45] prompted us to report
our own independent results.
Recently, Pal et al. [44] published a paper for N-Boc
protection of amines in the presence of Amberlyst-15 under
solvent-free conditions. They claimed that, in all cases,
reactions were completed in 1–12 min. They have also
reported tert-butoxycarbonylation of aniline in CH Cl ,
2
2
toluene, and CH CN in 1–3 min (Table 1, footnote c), but
3
our effort to repeat the reaction under their reaction con-
ditions led to formation of tert-butyl-N-phenyl carbamate
in 72% yield after 6–7 min (Table 1, entry 10), and the
reaction mixture became a mass which was very difficult to
stir magnetically. Similarly, 4-chloro- and 4-bromoaniline
Results and discussion
Our initial experiments were carried out on aniline with
1
.1 equiv (Boc) O in the presence of Amberlyst-15 at room
2
temperature, in order to find the best reaction conditions.
The reaction was carried out in different organic solvents
and monitored by thin-layer chromatography (TLC)
with (Boc) O under solvent-free conditions gave only 68%
2
yield of the products after 30–35 min at 30–35 °C. Higher
yield of the products would be obtained if the solid reaction
masses were stirred manually or by mechanical stirrer for a
long time. In general, the solvent-free condition was not
effective. When other solid amines, especially amino acids
and peptides, were employed, only low yield of the desired
N-Boc products was obtained and excess amount of
(
Table 1).
It is clear from Table 1 that protic solvents exert bene-
ficial rate acceleration on the tert-butoxycarbonylation of
amines as reported previously [46] (Table 1, entries 1–3).
Reaction in other solvents needed longer time to give
reasonable yield of the product (Table 1, entries 4–9). The
(Boc) O was required to solve the stirring problem.
2
Table 1 Solvent screening
H
N
NH2
Amberlyst-15
Solvent
Boc
(
Boc) O
+
2
a
Entry
Solvent
Time/min
10
Yield/%
1
2
3
4
5
6
7
8
9
2
H O
98
b
EtOH
12 (38)
100
100
MeOH
12
c
c
CH
Cl
2 2
50 (3)
95 (95)
CHCl
3
90
45
95
90
Dioxane
Toluene
c
c
60 (1)
90 (80)
c
c
CH
3
CN
60 (1)
90 (92)
Tetrahydrofuran
–
60
95
c
c
1
a
0
6 (1 or 2)
72 (99)
Yield refers to isolated products
b
c
Without catalyst
Values in parentheses are from [44]
1
23

An efficient and highly chemoselective N-Boc protection of amines, amino acids, and peptides
1037
However, with the optimized reaction conditions in etha-
nol, we evaluated the efficacy, applicability, and better
potential of our protocol using a variety of structurally
diverse amines. Various aliphatic, heterocyclic, and aro-
matic amines underwent smooth conversion into the
corresponding mono-N-Boc products in excellent yields
As indicated in this table, diamines were protected under
reaction conditions in high yields. Clearly, when diamines
were treated with 1 equiv (Boc) O, mono-N-Boc-protected
2
diamines were formed, and with 2–2.5 equiv (Boc) O,
2
rapid formation of di-Boc derivatives occurred (30–35). In
the case of 3,4-diaminonitrobenzene, using 1 equiv
(
Table 2).
(Boc) O afforded only 65% of the mono-N-Boc product
2
No competitive side-reactions leading to formation of
and introduction of 2.5 equiv (Boc) O did not result in the
2
isocyanate, urea or N,N-di-Boc derivatives were detected
1
by TLC or H nuclear magnetic resonance (NMR) analyses
di-Boc derivative as expected, but only the mono-N-Boc
0
product in nearly quantitative yield (36). 4,4 -Diaminodi-
0
of the crude products.
phenylether and 4,4 -diaminodiphenylmethane with 1 equiv
Reaction rates and yields are governed by the nucleo-
philicity of the amines. Primary and secondary aliphatic
amines reacted instantaneously to give the N-Boc products
in excellent yields (1–6). Sterically hindered tert-butyl-
amine also underwent rapid and quantitative conversion
(Boc) O under the reaction condition afforded di-Boc
2
derivatives as the sole products (5 min, 45%), but stepwise
addition of (Boc) O in 1.5 h selectively gave mono-N-Boc-
2
protected products in moderate yields (32, 37, and 39).
However, when 2 equiv (Boc) O was employed, the corre-
2
(
6). Similarly, aniline and electron-rich aromatic amines
gave their N-Boc-derivatives under reaction conditions
7–10). In contrast, the presence of electron-withdrawing
sponding di-Boc derivatives were formed in excellent yields
(33, 38, and 40).
(
Since protection of the a-amino functionality of amino
acids is one of the most important issues in peptide
chemistry and is mandatory to prevent polymerization of
the amino acid once it is activated, the utility of this pro-
tocol in reactions with amino acids and peptides was
studied. In the initial experiments, we treated L-proline
substituent groups, such as Cl, Br, CO H, COMe, and CN,
2
decreased the nucleophilicity of the amines, and the cor-
responding conversion became quite slow (11–15), but in
comparison with other catalysts reported in the literature,
electron-deficient aromatic amines undergo N-Boc protec-
tion at much faster rates and in higher yields; for example,
with 1.5–2.5 equiv (Boc) O in the presence of Amberlyst-
2
4
-chloroaniline using this method (11) required 80 min to
15 (7–10% w/w) in ethanol at 40–45 °C, and after only
5 min a quantitative yield of the N-Boc-L-proline was
obtained. Measurement of the optical rotation value of the
product and comparison with the literature [53, 54] showed
that the configuration of the chiral center is not affected
during the course of the reaction.
form the corresponding N-Boc product (100%), which can
be compared with 6 h required for the same conversion
without catalyst in EtOH [46], 2.5 h (90%) in the presence
of I (10 mol%) under solvent-free conditions [27], and 6 h
2
(
96%) under solvent- and catalyst-free conditions [47]. A
more interesting example is N-tert-butoxycarbonylation of
-acetylaniline. Cu(BF ) ꢀxH O (1 mol%) catalyzed the
Encouraged by these results, N-Boc protections of
amino acids and peptides were examined. Various amino
4
4
2
2
reaction under neat conditions to generate N-Boc-4-acety-
laniline in 60% yield after 24 h [26], whereas the desired
product was obtained in 97% yield after 6 h when the
reaction was carried out in the presence of Amberlyst-15 in
ethanol (15). A notable feature of this method is the
excellent chemoselectivity in the case of aminoalcohols,
aminophenols, and aminothiophenol, where the N-Boc-
protected compounds were formed as sole products without
competitive formation of O-Boc or oxazolidinone deriva-
acids and peptides were treated with (Boc) O using the
2
same approach, and the results are summarized in
Table 4.
As seen in Table 4, amino acids, dipeptides (41–50), and
glycylglycylglycine as a tripeptide (51) were efficiently
protected with (Boc) O. Chemoselective protection of the
2
a-amino group of DL-lysine was achieved in 85% under
reaction conditions after 5.5 h (47). An interesting feature
of this procedure was that the protection reactions of amino
acids (but not L-proline) and peptides depicted in Table 4
could be followed visually. This is due to the poor solu-
bility of the starting materials and solubility of the
corresponding N-Boc derivatives in EtOH. Dissolution of
the reaction mixture indicates completion of the reaction.
This observation demonstrates the practical utility of this
protocol, particularly in peptide synthesis.
tives, even using excess amount of (Boc) O (16–21).
2
Similarly, heteroaromatic amines underwent Boc protec-
tion in excellent yields (21–26). Moreover, the mildness of
the protocol was exemplified by the conversion of a chiral
amine (29) and a-amino acid esters (27 and 28) to their
optically pure N-Boc derivatives as confirmed by mea-
surement of their optical rotation values and comparison
with those reported in the literature [22, 34, 48, 51, 52].
With these results, we decided to extend this method for
protection of diamines. The results are tabulated in
Table 3.
After completion of the reaction, Amberlyst-15 can be
easily separated from the product by filtration and reused
without any decrease in its activity; for example, the
reaction of 4-chloroaniline (11) and (Boc) O afforded the
2
123

1
038
F. Jahani et al.
Table 2 Amberlyst-15-catalyzed protection of amines
a
Comp.
Substrate
Product
Time/min
Yield/%
100
M.p./°C found/reported
1
\1
Colorless oil [19, 48, 49]
NH
NBoc
NBoc
2
3
4
\1
\1
\1
100
100
100
Colorless oil [48, 49]
57–60/56–58 [19, 25, 48]
52–54/55–57 [46, 48]
NH
O
NH
O
NBoc
NH
2
NHBoc
5
6
\1
\1
100
100
Colorless oil [25, 27]
(
PhCH
2
)
2
NH
2 2
(PhCH ) NBoc
b
42–45/– [25]
NH
2
NHBoc
7
8
9
12
15
7
100
100
100
100
100
100
65
132/132 [29, 48]
NH
2
NHBoc
84–85/86–87 [46, 48]
94–96/94–96 [27, 46]
110–112/110–112 [34]
102–104/102–103 [46]
100–103/102 [48]
Me
MeO
EtO
Cl
NH
2
Me
MeO
EtO
Cl
NHBoc
NH
2
NHBoc
NHBoc
NHBoc
NHBoc
NHBoc
1
1
1
1
0
1
2
3
6
NH
2
80
45
6 h
NH
2
Br
NH
2
Br
112/113–114 [26]
NC
NH
2
NC
1
23

An efficient and highly chemoselective N-Boc protection of amines, amino acids, and peptides
Table 2 continued
1039
a
Comp.
Substrate
Product
Time/min
6 h
Yield/%
100
M.p./°C found/reported
14
15
16
17
179–181/180–183 [50]
HO
2
C
NH
2
HO
2
C
NHBoc
NHBoc
NHBoc
6 h
97
100
100
135–138/137 [26]
MeOC
HO
NH
2
MeOC
HO
3
146/146 [48]
NH
2
50
140–143/142 [33, 46, 48]
NH
2
NHBoc
OH
OH
1
1
8
9
5
100
95
135–138/135–137 [28]
HO
HO
OH
NH2
HO
HO
OH
NHBoc
60
Oil [34]
OH
OH
NH
2
NHBoc
b
20
21
60
83
93
83–84/– [27]
SH
SH
NH
2
NHBoc
2.5 h
129–132/–
OH
NH
OH
N
2
N
NHBoc
2
2
3
\1
100
95
46–48/42–45 [23, 24]
139–142/141–143 [34]
N
N
NH
NBoc
2
17
N
NH
2
N
NHBoc
2
4
5
2
100
90–91/90–92 [34]
NH
2
NHBoc
N
H
N
H
2
4 h
75
[240/–
N
S
N
S
NH
2
NHBoc
123

1
040
F. Jahani et al.
Table 2 continued
Comp. Substrate
a
Product
Time/min
5.5 h
Yield/%
100
M.p./°C found/reported
[240/–
2
6
N
S
N
S
NH
2
NHBoc
MeO
MeO
c
27
28
29
19
16
93
107–109/110–111 [48]
35–39/37–38 [48]
CO
2
Me
CO
2
Me
Ph
NH
2
Ph
NHBoc
d
95
NH
2
NHBoc
CO Me
Ph
Ph
CO Me
2
2
e
\1
100
85–87/87–88 [25, 27, 46]
Ph
NH
2
Ph
NHBoc
Me
Me
a
b
c
d
e
Yield refers to isolated products
Reference to NMR data
27
D
2
-1
[
a]
= ?134.0° cm g (c = 0.8, CHCl
3
)
27
D
2
-1
[
a]
= -4.0° cm g (c = 2, CH
3
OH)
27
D
2
-1
[
a]
= -51.6° cm g (c = 1, CHCl
3
)
corresponding N-Boc product in nearly 100% isolated yield
over three cycles.
General procedure for preparation of N-Boc amines
and amine derivatives
In conclusion, we describe herein an efficient method-
ology for N-tert-butoxycarbonylation of various electronically
and structurally divergent amines in good to excellent
isolated yields. The method proceeds at ambient tempera-
ture in a convenient solvent, ethanol, with an easily
recovered acid catalyst which can be used immediately
without any activation.
The amine or diamine (1 mmol) was added to a mag-
netically stirred mixture of Amberlyst-15 (7–10% w/w)
3
and di-tert-butyl dicarbonate (1.1–2.5 mmol) in 1 cm
EtOH at room temperature. After completion of the
reaction (followed by TLC), the catalyst was separated
by filtration. The filtrate was concentrated on a rotary
evaporator to afford the corresponding pure product. If
necessary, the product was further purified either by
recrystallization or silica gel column chromatography
with EtOAc-hexane (1:6) as eluent. In the cases where
Experimental
1
13
H and C NMR spectra were recorded on 300 and
00 MHz Bruker spectrometers in CDCl and dimethyl
excess (Boc) O was used, the crude products were
2
4
washed with n-hexane or petroleum ether before further
purification.
3
sulfoxide (DMSO)-d using SiMe as an internal standard.
6
4
Chemical shifts are reported in ppm, and coupling con-
stants (J values) are reported in Hz. Reactions were
monitored by TLC (Merck) or gas chromatography (GC).
Evaporation of solvents was performed at reduced pres-
sure, using a rotary evaporator. Melting points were
measured using the capillary tube method with a Bamstead
Electrothermal 9200 apparatus. Infrared (IR) spectra were
recorded from KBr disks on a Bruker Tensor 27 FT-IR
spectrophotometer. All solvents and reagents were pur-
chased from Aldrich or Merck with high-grade quality and
used without any purification.
General procedure for preparation of N-Boc amino
acids and peptides
Amino acid or peptide (1 mmol) was added to a mag-
netically stirred mixture of Amberlyst-15 (7–10% w/w)
3
and di-tert-butyl dicarbonate (2.5 mmol) in 1 cm EtOH
at 40–45 °C. The reaction mixture was stirred until a
clear solution was obtained. After completion of the
reaction (followed by TLC or visually), the catalyst was
separated by filtration. The filtrate was evaporated under
1
23

An efficient and highly chemoselective N-Boc protection of amines, amino acids, and peptides
Table 3 Amberlyst-15-catalyzed Boc protection of diamines
1041
a
b
Comp.
(Boc) O (equiv)
2
Product
Time/min
20
Yield/%
90
M.p./ °C
Ref.
3
0
1
110–113
[34]
NH
2
NHBoc
3
1
2
60
100
104–106
[34]
NHBoc
NHBoc
3
3
3
2
3
4
1
2
1
30
80
100
70
112–114
189 (dec.)
190–192
[34]
[34]
–
H
2
N
NHBoc
12
BocHN
NHBoc
NHBoc
2 h
HO
HO
2
C
NH
2
3
3
5
6
2.5
4.5 h
95
195–197
190–192
–
2
C
NHBoc
NHBoc
1
6 h
8 h
65
97
[34]
O
2
N
NHBoc
2
.5
NH
2
3
3
3
4
7
8
9
0
1
90
70
90
60
60
100
60
126–129
191–194
188 (dec.)
208–210
–
–
–
–
H
2
N
CH
NHBoc
NHBoc
NHBoc
NHBoc
2
2
1
2
BocHN
CH
2
H
2
N
O
100
BocHN
O
a
Yield refers to isolated products
Reference to NMR data
b
1
13
vacuum, and the residue was washed with hexane
3
2 9 5 cm ) to afford the pure product. If necessary, the
The physical data (m.p.), H, and C NMR spectra of
known compounds were found to be identical to those
reported in the literature.
(
crude product was further purified by recrystallization.
123

1
042
F. Jahani et al.
Table 4 Amberlyst-15-
catalyzed Boc protection of
amino acids and peptides
a
Comp.
Product
Time/h
Yield/%
M.p./ °C found/reported
41
42
43
44
45
46
47
48
49
50
51
N-Boc-D-phenylalanine
N-Boc-L-proline
20
93
100
91
Oil [55]
5 min
5
132–134/135–137 [54, 56]
82–85/85–87 [34]
137–140/136–140 [54]
85–88/89 [54, 56]
121–124/–
N-Boc-L-leucine
N-Boc-L-tryptophan
N-Boc-glycine
10
93
24
100
87
N-Boc-L-arginine
35
a
N -Boc-DL-lysine
5.5
85
198–200/201–202 [35]
72–75/76–78 [57]
106–108/107–108 [34]
126–130/128–131 [34]
125–127/125–127 [34]
N-Boc-L-valine
40 min
50 min
19
97
N-Boc-glycylvaline
N-Boc-glycylglycine
N-Boc-glycylglycylglycine
93
95
a
Yield refers to isolated
products
10
91
2
-(tert-Butoxycarbonylamino)-3-pyridinol
21, C H N O )
3,4-Bis(tert-Butoxycarbonylamino)benzoic acid
(35, C H N O )
(
1
0
14
2
3
17 24 2 6
1
1
Off-white solid, m.p.: 129–132 °C; H NMR (300 MHz,
Off-white solid, m.p.: 195–197 °C; H NMR (300 MHz,
CDCl ): d = 1.54 (s, 9H), 7.00 (dd, J = 8.0, 4.7 Hz, 1H),
DMSO-d ): d = 1.47 (s, 9H), 7.62 (dd, J = 8.5, 1.8 Hz,
3
6
7
.32 (dd, J = 8.0, 1.5 Hz, 1H), 7.91 (dd, J = 4.7, 1.5 Hz,
1H), 7.70 (d, J = 8.5 Hz, 1H), 8.07 (br s, 1H), 8.70 (br s,
1H, NH), 8.75 (br s, 1H, NH), 12.8 (br s, 1H, CO H) ppm;
1
3
H), 9.31 (s, 1H, OH), 9.96 (br s, 1H, NH) ppm; C NMR
1
2
1
3
(
75 MHz, CDCl ): d = 28.2 (CH ), 83.2 (C), 121.2 (CH),
C NMR (75 MHz, DMSO-d ): d = 28.0 (CH ), 28.1
6
3
3
3
1
27.8 (CH), 138.8 (CH), 140.3 (C), 143.8 (C), 156.1 (C=O)
(CH ), 79.6 (C), 80.0 (C), 122.0 (CH), 125.1 (CH), 125.3
3
ppm.
-(tert-Butoxycarbonylamino)benzothiazole
25, C H N O S)
(CH), 125.7 (C), 128.8 (C), 134.3 (C), 152.0 (C=O), 153.2
(C=O), 166.9 (CO H) ppm.
2
2
0
(
4 -(tert-Butoxycarbonylamino)diphenylmethan-4-amin
(37, C H N O )
1
2 14 2 2
1
White solid, m.p.:[240 °C; H NMR (400 MHz, CDCl ):
3
18 22 2 2
1
d = 1.61 (s, 9H), 7.03 (td, J = 8.0, 1.4 Hz, 1H), 7.42 (td,
J = 8.0, 1.2 Hz, 1H), 7.81 (dd, J = 8.0, 0.8 Hz, 1H), 7.92
White solid, m.p.: 126–129 °C; H NMR (400 MHz,
DMSO-d ): d = 1.52 (s, 9H), 3.65 (s, 2H), 4.83 (s, 2H,
6
1
d, J = 8.0 Hz, 1H) ppm; C NMR (100 MHz, CDCl3):
3
(
NH ), 6.47 (dd, J = 6.4, 2 Hz, 2H), 6.82 (d, J = 8.4 Hz,
2
d = 28.3 (CH ), 83.3 (C), 120.8 (CH), 121 (CH), 123.4
2H), 7.03 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H),
1
3
3
(
(
CH), 125.7 (CH), 131.5 (C), 148.6 (C), 156.4 (C), 161.3
C=O) ppm.
9.19 (br s, 1H, NH) ppm; C NMR (100 MHz, DMSO-d6):
d = 28.6 (CH ), 40.6 (CH ), 79.3 (C), 114.4 (CH), 118.7
3
2
(
CH), 129 (C), 129.1 (CH), 129.4 (CH), 136.4 (C), 137.6
2
-(tert-Butoxycarbonylamino)-6-methoxybenzothiazole
26, C H N O S)
(C), 147.0 (C), 153.3 (C=O) ppm.
(
1
3 16 2 3
1
0
White solid, m.p.:[240 °C; H NMR (300 MHz, CDCl ):
d = 1.59 (s, 9H), 3.87 (s, 3H), 6.98 (dd, J = 8.8, 2.4 Hz,
4,4 -Bis(tert-Butoxycarbonylamino)diphenylmethane
(38, C H N O )
3
2
3 30 2 4
1
1
H), 7.27 (d, J = 2.4 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H),
1
1.4 (br s, 1H, NH) ppm; C NMR (75 MHz, CDCl3):
White solid, m.p.: 191–194 °C; H NMR (300 MHz,
CDCl ): d = 1.52 (s, 9H), 3.90 (s, 1H), 6.50 (br s, 1H,
3
1
3
d = 28.3 (CH ), 55.8 (CH ), 83.0 (C), 104.0 (CH), 114.5
NH), 7.08 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H)
3
3
3
1
(
CH), 121.4 (CH), 132.7 (C), 142.9 (C), 152.8 (C), 156.4
ppm; C NMR (75 MHz, CDCl ): d = 28.4 (CH ), 40.5
3
3
(
C), 159.4 (C=O) ppm.
(CH ), 80.5 (C), 118.7 (CH), 129.4 (CH), 136 (C), 136.4
2
(
C), 152.9 (C=O) ppm.
4
-Amino-3-(tert-Butoxycarbonylamino)benzoic acid
34, C H N O )
0
(
4-Amino-4 -(tert-Butoxycarbonylamino)diphenylether
(39, C H N O )
1
2 16 2 4
1
Off-white solid, m.p.: 190–192 °C; H NMR (400 MHz,
DMSO-d ): d = 1.46 (s, 9H), 5.61 (s, 2H, NH ), 6.67 (d,
J = 8.4 Hz, 1H), 7.44 (dd, J = 8.4, 2.0 Hz, 1H), 7.84 (s,
1
7 20 2 3
1
White solid, m.p.: 192–194 °C (dec.); H NMR (400 MHz,
DMSO-d ): d = 1.45 (s, 9H), 4.90 (s, 2H, NH), 6.56 (d,
J = 8.0 Hz, 2H), 6.67 (d, J = 9.2 Hz, 2H), 6.78 (d,
J = 9.2 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 9.2 (br s, 1H,
6
2
6
1
3
1
H), 8.32 (br s, 1H, NH) ppm; C NMR (75 MHz, DMSO-
d ): d = 28.6 (CH ), 79.4 (C), 114.6 (CH), 118.0 (C),
1
6
3
1
3
22.8 (CH), 126.6 (C), 127.4 (CH), 146.2 (C), 154.1
NH) ppm; C NMR (100 MHz, DMSO-d ): d = 28.6
6
(
C=O), 167.8 (CO H) ppm.
2
(CH ), 79.2 (C), 115.3 (CH), 117.7 (CH), 120.2 (C), 120.6
3
1
23

An efficient and highly chemoselective N-Boc protection of amines, amino acids, and peptides
1043
(
(
CH), 134.4 (CH), 145.4 (C), 147.1 (C), 153.4 (C), 153.9
C=O) ppm.
18. Darnbrough S, Mervic M, Condon SM, Burns CJ (2001) Synth
Commun 31:3273
19. Basel Y, Hassner A (2000) J Org Chem 65:6368
20. Burk MJ, Allen JG (1997) J Org Chem 62:7054
0
4
,4 -Bis(tert-Butoxycarbonylamino)diphenylether
2
2
1. Grehn L, Ragnarsson U (1985) Angew Chem Int Ed 24:510
2. Pandey RK, Dagade SP, Upadhyay RK, Dongare MK, Kumar P
(
40, C H N O )
22 28 2 5
1
White solid, m.p.: 208–210 °C; H NMR (300 MHz,
(
2002) Arkivoc vii:28
CDCl ): d = 1.52 (s, 9H), 6.46 (br s, 1H, NH), 6.91 (d,
23. Sharma GVM, Reddy JJ, Lakshmi PS, Krishna PR (2004) Tet-
rahedron Lett 45:6963
3
1
J = 8.8 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H) ppm; C NMR
3
2
4. Bartoli G, Bosco M, Locatelli M, Marcantoni E, Massaccesi M,
Melchiorr P, Sambri L (2004) Synlett 10:1794
(
75 MHz, CDCl ): d = 28.3 (CH ), 80.5 (C), 119.1 (CH),
3
3
1
20.3 (CH), 133.6 (C), 153.0 (C), 153.03 (C=O) ppm.
2
2
5. Heydari A, Hosseini SE (2005) Adv Synth Catal 347:1929
6. Chankeshwara SV, Chakraborti AK (2006) Tetrahedron Lett
N-Boc-L-arginine (46, C H N O )
1
1 22 4 4
4
7:1087
1
White solid, m.p.: 121–124 °C; H NMR (400 MHz,
27. Varala R, Nuvula S, Adapa SR (2006) J Org Chem 71:8283
28. Heydari A, Kazem Shiroodi R, Hamadi H, Esfandyari M, Pou-
rayoubi M (2007) Tetrahedron Lett 48:5865
DMSO-d ): d = 1.35 (s, 9H), 1.46–1.61 (m, 4H), 3.03
6
(
m, 2H), 3.65 (m, 1H), 5.93 (d, J = 6.8 Hz, 1H, NH),
1
2
9. Chankeshwara SV, Chakraborti AK (2006) J Mol Catal A: Chem
53:198
3
7
.0–8.0 (br s, 4H, NH, NH ), 9.20 (br s, 1H) ppm;
2
C
2
NMR (100 MHz, DMSO-d ): d = 25.6 (CH ), 27.3 (CH ),
30. Das B, Verkateswarlu K, Krishnaiah M, Holla H (2006) Tetra-
hedron Lett 47:7551
6
2
2
2
8.6 (CH ), 31.7 (CH ), 55.0 (CH), 77.9 (C), 155.3
3 2
3
1. Suryakiran N, Prabhakar P, Srikanth Reddy T, Rajesh K,
Venkateswarlu Y (2006) Tetrahedron Lett 47:8039
2. Khaksar S, Heydari A, Tajbakhsh M, Vahdat SM (2008) Tetra-
hedron Lett 49:3527
3. Heydari A, Khaksar S, Tajbakhsh M (2008) Synthesis 19:3126
4. Jahani F, Tajbakhsh M, Golchoubian H, Khaksar S (2011)
Tetrahedron Lett 52:1260
(
C=NH), 157.7 (C=O), 176.1 (CO H) ppm.
2
3
Acknowledgments Financial support of this work by the Research
Council of Mazandaran University is gratefully acknowledged.
3
3
References
35. Meienhofer J, Kuromizu K (1974) Tetrahedron Lett 15:3259
3
6. Ishihara K, Hasegama A, Yamamoto H (2001) Angew Chem Int
Ed 40:4077
7. Trost BM (1991) Science 254:1471
1
2
3
. Wuts PGM, Greene TW (2007) Greene’s protective group in
organic synthesis, 4th ed. Wiley, New York
. Raghavendra NS, Kumar BP, Longquin H (2006) Tetrahedron
Lett 47:389
. Pope BM, Yamamoto X, Tarbell DS (1988) Org Synth Coll
VI:418
3
3
3
8. Sheldon RA (1994) Chemtech 24:38
9. Anastas PT, Warner JC (1998) Green chemistry: theory and
practice. Oxford University Press, UK
0. Tajbakhsh M, Heydari A, Alinezhad H, Ghanei M, Khaksar S
4
4
4
(
2008) Synthesis 3:352
4
5
. Srinivasan N, Yurek-George AG (2005) Mol Diver 9:291
. Longenecker K, Hamilton GL, Stewart K, Lai C, Kopecka H, von
Geldern TW, Madar DJ, Pei Z, Lubben TH, Zinker BA, Tian Z,
Ballaron SJ, Stashko MA, Mika AK, Beno DWA, Kempf-Grote
AJ, Black-Schaefer C, Sham HL, Trevillyan JM (2007) Bioorg
Med Chem Lett 17:2005
1. Tajbakhsh M, Heydari A, Khalilzadeh MA, Lakouraj MM,
Zamenian B, Khaksar S (2007) Synlett 15:2347
2. Lakouraj MM, Tajbakhsh M, Tashakkorian H (2007) Monatsh
Chem 138:83
4
4
4
3. Tajbakhsh M, Hosseinzadeh R, Lasemi Z (2004) Synlett 4:635
4. Kumar KS, Iqbal J, Pal M (2009) Tetrahedron Lett 50:6244
5. Liu YS, Zhao C, Bergbreiter DE, Romo D (1998) J Org Chem
6
7
. Merrifield RB (1964) J Am Chem Soc 86:304
. Satori G, Ballini R, Bigi F, Bosica G, Maggi R, Righi P (2004)
Chem Rev 104:199
6
6. Vilaivan T (2006) Tetrahedron Lett 47:6739
7. Jia X, Huang Q, Li J, Li S, Yang Q (2007) Synlett 5:806
8. Chankeshwara SV, Chakraborti AK (2006) Org Lett 8:3259
9. Dieter RK, Li S (1997) J Org Chem 62:7726
3:3471
4
4
4
4
5
8
9
. Kocienski PJ (2000) Protecting groups. Georg Thieme Verlag,
Stuttgart
. Wuensch E (1974) Houben-Weyl, methods of organic chemistry,
4th edn. In: Mueller E, Bayer O, Meerwein H, Ziegler K (eds),
Georg Thieme Verlag, Stuttgart, vol 15/1, p 46
0. Norman MH, Rigdon GC, Hall WR, Navas F III (1996) J Med
Chem 39:1172
1
1
0. McOmie JFW (1973) Protective groups in organic chemistry.
Plenum Press, London
1. Gross E, Meienhofer J (1981) The peptides. Academic Press,
New York
5
5
1. Dondoni A, Perrone D, Semola T (1995) Synthesis 2:181
2. Green R, Taylor PJM, Bull SD, James TD, Mahon MF, Merritt
AT (2003) Tetrahedron: Asymmetry 14:2619
5
3. Marcantoni E, Massaccesi M, Torregiani E (2001) J Org Chem
6
1
1
1
2. Merrifield RB (1963) J Am Chem Soc 85:2149
3. Lutz C, Lutz V, Knochel P (1998) Tetrahedron 54:6385
4. Handy ST, Sabatini JJ, Zhang Y, Vulfova I (2004) Tetrahedron
Lett 45:5057
6:4430
5
5
4. Anderson GW, Mcgregor AC (1957) J Am Chem Soc 79:6180
5. Myers AG, Gleason JL, Yoon T, Kung DW (1997) J Am Chem
Soc 119:656
1
5. Khalil EM, Subasinghe NL, Johnson RL (1996) Tetrahedron Lett
3
5
5
6. Itoh M, Hagiwara D, Kamiya T (1975) Tetrahedron Lett 49:4393
7. Thaqi A, McCluskey A, Scott JL (2008) Tetrahedron Lett
7:3441
6. Eunhorn J, Einhorn C, Luche JL (1991) Synlett 1:37
7. Kelly TA, McNeil DW (1994) Tetrahedron Lett 35:9003
1
1
4
9:6962
123