Efficient, solventless N-Boc protection of amines carried out at room temperature using sulfamic acid as recyclable catalyst

Article abstract of DOI:10.1016/j.tetlet.2007.09.126

A simple, rapid, and efficient protocol for the chemoselective N-Boc protection of amines using sulfamic acid as catalyst is described. N-Boc protection of various structurally diverse aliphatic, aromatic, alicyclic, and heterocyclic amines (1°, 2°, 3°) was carried out with (Boc)₂O using sulfamic acid as catalyst (5 mol %) at room temperature under solventless conditions. The advantages of this method are simplicity, shorter reaction times (1-15 min), a cost-effective catalyst, and excellent isolated yields (90-100%); it is also environmentally benign. Moreover, the combined use of ultrasound and sulfamic acid achieves a synergic effect that is especially marked in the N-Boc protection of deactivated (sterically hindered and electron-deficient) amines. The catalyst possesses distinct advantages: ease of handling, cleaner reactions, high activity, and excellent chemoselectivity.

Full text of DOI:10.1016/j.tetlet.2007.09.126

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8318–8322
Efficient, solventless N-Boc protection of amines carried out at
room temperature using sulfamic acid as recyclable catalyst
Dharita J. Upadhyaya,a Alessandro Barge,a Rachele Stefaniab and Giancarlo Cravottoa,*
a
`
Dipartimento di Scienza e Tecnologia del Farmaco, Universita di Torino, Via Giuria 9, 10125-Torino, Italy
b
`
Dipartimento di Chimica I. F. M., Universita di Torino, Via Giuria 7, 10125-Torino, Italy
Received 4 July 2007; revised 15 September 2007; accepted 19 September 2007
Available online 22 September 2007
Abstract—A simple, rapid, and efficient protocol for the chemoselective N-Boc protection of amines using sulfamic acid as catalyst is
described. N-Boc protection of various structurally diverse aliphatic, aromatic, alicyclic, and heterocyclic amines (1ꢀ, 2ꢀ, 3ꢀ) was
carried out with (Boc)2O using sulfamic acid as catalyst (5 mol %) at room temperature under solventless conditions. The advan-
tages of this method are simplicity, shorter reaction times (1–15 min), a cost-effective catalyst, and excellent isolated yields (90–
100%); it is also environmentally benign. Moreover, the combined use of ultrasound and sulfamic acid achieves a synergic effect that
is especially marked in the N-Boc protection of deactivated (sterically hindered and electron-deficient) amines. The catalyst possesses
distinct advantages: ease of handling, cleaner reactions, high activity, and excellent chemoselectivity.
ꢁ 2007 Elsevier Ltd. All rights reserved.
Protection and deprotection of organic functions play
an essential role in the elegant art of multistep organic
synthesis.1 The choice of a suitable protecting group
often determines which method will be chosen, on
grounds of simplicity, highest yields of desired products,
and ease of workup/separation. This choice in turn
determines the overall cost of the process, especially at
the industrial level. The presence of an amine function
in so many biologically active compounds makes its pro-
tection a frequently needed exercise in synthetic/medici-
nal chemistry. Out of the vast array of available
methods, N-tert-butyloxycarbonylation has emerged as
the most commonly used strategy due to the ease of pro-
tection as well as deprotection and also due to the great-
er stability of the N-Boc group in the course of various
base-catalyzed nucleophilic substitutions and catalytic
hydrogenation reactions.2 The conventional procedure
employs di-tert-butyl dicarbonate (Boc)2O and base
catalysts such as DMAP,3 NaHMDS,4 K2CO3,5 and
Et3N,6 the last one being most commonly used. How-
ever the unpleasant smell, high toxicity, requirement in
large excess, and non-recyclability of these catalysts
makes the method objectionable, especially from the
standpoint of green chemistry.
Lately acid-catalyzed N-Boc protection of amines has
been widely studied with many homogeneous as well
as heterogeneous catalysts. Many of these procedures
involve the use of corrosive and moisture-sensitive
reagents like ZrCl4,7 LiClO4,8 HClO4,9 Cu(BF4)2,10
12
Zn(ClO4)2Æ6H2O,11 and La(NO3)3 to name a few.
The synthesis of heterogeneous catalysts often involves
long and tedious procedures (to prepare the silica-
sulfonic acid catalyst,13 3–4 days are required) or
calcinations at high temperatures (500 ꢀC for yttria–
zirconia.14) Moreover, most of the N-Boc protection
reactions are slow (1–24 h) especially with deactivated
(electron-deficient) amines.
Sulfamic acid (NH2SO3H) has emerged as a promising
substitute for conventional Bronsted- and Lewis acid
catalysts. It is relatively stable, non-volatile, non-hygro-
scopic, and non-corrosive. It possesses distinctive cata-
lytic features related to its zwitterionic nature and
displays an excellent activity over a vast array of acid-
catalyzed organic transformations, as witnessed by
numerous reports published in the past three years.15
These properties prompted us to investigate the use of
sulfamic acid for the N-Boc protection of amines
(Scheme 1).
Keywords: N-Boc protection; Sulfamic acid; Ultrasound; Solvent-free
reaction; Recyclable catalyst.
*
Corresponding author. Tel.: +39 011 6707684; fax: +39 011
6707687; e-mail: giancarlo.cravotto@unito.it
0040-4039/$ - see front matter ꢁ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.126

D. J. Upadhyaya et al. / Tetrahedron Letters 48 (2007) 8318–8322
8319
sulfamic acid
(5 mol %)
Under solventless conditions aniline reacts instanta-
neously at room temperature and a white precipitate
of tert-butyl-N-phenyl carbamate is formed. No compe-
titive side reactions leading to formation of isocyanate,
urea, or N,N-di-Boc derivatives were detected by TLC,
MS, and 1H NMR analyses of crude product. The
(R) ArNH2
(R) ArNHBoc
85-100%
+
(Boc)2O
RT, 1 - 30 min
(((( solvent-free
Scheme 1. N-Boc protection catalyzed by sulfamic acid.
Table 1. Compared performances of various catalysts in the N-Boc protection of aniline with (Boc)2O at room temperature
Entry
Catalyst
Time
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
Iodine
30 min
14 h
12 h
5 min
2.5 h
48 h
30 min
30 min
45 min
5 min
5 min
Neat
CH3CN
CH2Cl2
Neat
H2O
—
H2O
—
CH2Cl2
H2O
9519
90
Yttria–zirconia
Zn(ClO4)2Æ6H2O
HClO4–silica
b-Cyclodextrin
Uncatalyzed
Uncatalyzed
Uncatalyzed
Sulfonic acid-functionalized silica
Sulfamic acid
Sulfamic acid
92
100
7520
6019
9521
9516
83
10
11
99
98
Neat
Table 2. N-Boc protection of amines catalyzed by sulfamic acida
Entry
Amine
Product
Time (min)
Yieldb,c (%)
1
2
NH2
3
3
99
99
NHBoc
NH2
NHBoc
HO
HO
3
4
5
5
5
5
100
97
NH2
NHBoc
H2N
BocHN
OH
OH
NH2
NH2
NHBoc
OH
100
HO
OH
HO
6
7
3
3
3
3
3
3
3
3
100d
97
H2N
H2N
H2N
H2N
NH
BocHN
NHBoc
NHCbz
NHCbz
NH2
BocHN
H2N
NHBoc
8
91
100d
99
NH2
NHBoc
9
BocHN
NBoc
10
11
12
13
100
99
NH
NBoc
O
NH
O
NBoc
97d
HN
NH
BocN
NBoc
NHBoc
NH2
NH2
14
3
93
NH2
NH2
NH2
NHBoc
NHBoc
15
16
3
5
100d
95
N
NH2
N
NHBoc
(continued on next page)

8320
D. J. Upadhyaya et al. / Tetrahedron Letters 48 (2007) 8318–8322
Table 2 (continued)
Entry
Amine
Product
Time (min)
3
Yieldb,c (%)
98e
17
18
N
NH2
N
NHBoc
NH2
NHBoc
10
88e
OH
HO
OH
19
20
5
5
95
94
NH2
NH2
HO
HS
NHBoc
HS
NHBoc
21
22
(Ph)2CHNH2
L-(+)-a-PhCH(CH3)NH2
(Ph)2CHNHBoc
L-(+)-a-PhCH(CH3)NHBoc
3
3
99
100
H2N
BocHN
23
24
3
3
100e
100
N Ts
Ts N
N Ts
Ts N
NHBoc
NH2
N
H
O
N
O
H
a The amine (5 mmol) was treated with (Boc)2O (1.1 equiv) in presence of sulfamic acid (5 mol %) under neat conditions.22
b Isolated yield of the corresponding N-Boc derivative.
c The products were characterized by IR, 1H NMR, and MS analyses.
d The reaction was carried out using 2 equiv of (Boc)2O.
e 1 ml/1 mmol distilled water was added as solvent during reaction.
chosen amount of catalyst (5 mol %) was found to
suffice for an optimal result, as increasing it brought no
substantial improvement. In absence of catalyst, longer
reaction time (90 min) was observed with lower isolated
yield of tert-butyl-N-phenyl carbamate (72%). Perfor-
mances of sulfamic acid and various previously used
catalysts are compared in Table 1.
protection of aryl amines under conventional conditions
and under US (Table 3). To our delight, the combina-
tion of sulfamic acid and US displayed a synergistic
effect that was more striking with electron-deficient
and sterically hindered amines. In case of o- and m-chlo-
roaniline reaction time was reduced from 3 h to 15 min
(Table 3, entries 4 and 5). Likewise with o-, m-, and p-bro-
moaniline and p-nitroaniline, a considerable shortening
of reaction time was observed (Table 3, entries 7–10).
Thus the accelerating effect of US can be an important
tool for the N-Boc protection of deactivated and steri-
cally hindered arylamines. It should be mentioned that
neither open-chain alkylamines nor aliphatic hetero-
cycles displayed the above-mentioned synergistic effect.
These substrates react very fast at room temperature
and comparable results were obtained in both conven-
tional as well as US assisted N-Boc protection of
open-chain alkylamines (Table 2, entries 1–9). The obvi-
ous reason for this outcome is the high nucleophilicity of
open-chain alkylamines, which makes them extremely
reactive even under conventional conditions. N-Boc pro-
tection catalyzed with sulfamic acid is highly chemo-
selective: the amino group is protected exclusively in
presence of alcoholic (Table 2, entries 3–5) or phenolic
–OH (Table 2, entries 18 and 19), thiophenol (Table 2,
entry 20), –Ts (Table 2, entry 23), and –Cbz groups (Ta-
ble 2, entry 7). In case of alkyl- and aryldiamine deriva-
tives, selective monoprotection could be achieved by
using 1 equiv of (Boc)2O (Table 2, entries 8 and 14),
even when two amino groups lay at a distance on an ali-
phatic chain. With 2 equiv of (Boc)2O, a rapid forma-
tion of di-Boc derivatives occurred (Table 2, entries 6,
9, and 15). The method then appears to be suitable for
the protection of a single amino group in a polyamino
compound. It is well known that monoprotection of
The efficacy of our protocol was evaluated using a
variety of structurally diverse amines. Various aliphatic,
heterocyclic, and aromatic amines reacted in 3–15 min,
leading to the corresponding N-Boc derivatives with
excellent yields (Tables 2 and 3).
With aryl amines (1ꢀ, 2ꢀ), the reaction rate was mainly
dependent on the nature of substituent groups as well
as their position on an aromatic ring. In case of anilines
with electron-rich substituents, for example, p-anisidine
(Table 3, entry 2), a very rapid reaction occurred yield-
ing an N-Boc derivative quantitatively. On the other
hand, reaction of o-anisidine was quite slow (Table 3,
entry 3) obviously because of the bulky o-substituent.
Sluggish reactions were also observed with arylamines
containing electron-deficient or bulky groups like –Cl,
–Br, and –NO2 (Table 3, entries 4–10). These results
are in accordance with many reports concerning N-
Boc protection of deactivated anilines, showing that
longer reaction times, higher temperatures, and excess
of catalysts were often required to achieve better
selectivities.16
It is now a well-established fact that power ultrasound
(US) accelerates organic reactions.17 Based on our previ-
ous experience in US-assisted organic synthesis,18 we
decided to carry out a comparative study of N-Boc

D. J. Upadhyaya et al. / Tetrahedron Letters 48 (2007) 8318–8322
8321
Table 3. N-Boc protection of substituted anilines catalyzed by sulfamic acid: comparison of US-assisted and conventional proceduresa
Entry
Amine
Product
Conventional
Ultrasounda
Time (min)
Yieldb (%)
Time (min)
Yieldb (%)
99a
100
NH2
NHBoc
1
2
10
5
96
99
5
3
H3CO
NH2
H3CO
NHBoc
NH2
NHBoc
OCH3
3
4
90
82c
62c
10
15
95
OCH3
NH2
Cl
NHBoc
180
90d
Cl
NH2
NHBoc
5
6
120
60
80c
91
15
5
93d
98
Cl
Cl
Cl
Cl
NH2
NHBoc
NH2
NHBoc
7
8
180
180
67c
79c
15
15
87c
92d
Br
Br
NH2
NHBoc
Br
Br
Br
Br
9
60
90
85c
87c
5
93c
94c
NH2
NHBoc
10
10
O2N
NH2
O2N
NHBoc
a The amine (5 mmol) was treated with (Boc)2O (1.1 equiv) in the presence of sulfamic acid (5 mol %) at 25–28 ꢀC under neat conditions in an US
bath.23
b Isolated yield of the corresponding N-Boc derivative.
c The product was purified column chromatography using petroleum ether–ethyl acetate (8.2).
d 1 ml/1 mmol of distilled water was added as a solvent.
ethylenediamine can be easily achieved by appropriately
adjusting the pH of reaction mixture; this strategy how-
ever fails when two amino groups are separated by more
than two carbon atoms along the alkyl chain. In pres-
ence of sulfamic acid, acting as a mild catalyst, the selec-
tive monoprotection of 1,4-diamino butane can be
achieved with 1 equiv of (Boc)2O.
attack by the amine. Successive elimination of CO2
and t-BuOH results in the formation of N-Boc deriva-
tive and regenerates sulfamic acid in the reaction mix-
ture. This mechanism is supported by an experimental
observation: after tert-butyl-N-phenyl carbamate was
formed as a solid, when we added diethyl ether to dis-
solve it, the sulfamic acid separated out and could be
easily filtered off. It was washed with diethyl ether and
efficiently recycled. For example, when the recovered
catalyst was reused in a series of three cycles for the
reaction of aniline with (Boc)2O under sonication
(25 ꢀC, 5 min), the yields of tert-butyl-N-phenyl carba-
mate were 99%, 97%, and 96%, respectively.
A plausible mechanism for the N-Boc protection of
various amines is proposed in Scheme 2. Sulfamic acid
catalyzes the reaction by the electrophilic activation of
(Boc)2O to form a zwitterionic species (Scheme 1),
making the carbonyl group susceptible to nucleophilic
+
H3N
O
O
O
+ t-BuOH + CO2
+ NH2SO3H
O
R-NH
O
O
O
..
R-NH2
Scheme 2. Proposed mechanism for sulfamic-acid catalyzed N-Boc protection of amines.

8322
D. J. Upadhyaya et al. / Tetrahedron Letters 48 (2007) 8318–8322
15. (a) Jin, T. S.; Sun, G.; Li, Y. W.; Li, T. S. Green Chem.
2002, 4, 255–256; (b) Wang, B.; Yang, L.; Suo, J. Synth.
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In conclusion, sulfamic acid acts as a mild, regioselec-
tive, highly efficient, and recyclable catalyst for N-Boc
protection of various amines: open chain, cyclic, ali-
phatic, heterocyclic, aryl, and heteroaryl, 1,2-diaryl
amines besides aminoalcohols. The advantages of this
protocol are: (1) high activity and good chemoselectivity
(2) no side reactions (3) ease of handling and cost effi-
ciency of the catalyst, (4) wide substrate scope and gen-
erality in the presence of various other functions; (5)
effective reusability of catalyst, making the protocol
environmentally benign.
Acknowledgments
16. Jia, X.; Huang, J. L.; Li, S.; Yang, Q. Synlett 2007, 806–
808.
MIUR (FIRB 2003) is acknowledged for financial sup-
port. DJU acknowledges ASP (Associazione per lo Svi-
luppo Scientifico e Technologico del Piemonte), Torino
for the research fellowship.
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mic acid (5 mol %) were mixed together neat in 10 ml
round-bottom flask at 25–28 ꢀC. The amine (1 equiv) was
added and the resulting mixture was stirred at room
temperature. The progress of the reaction was monitored
by TLC analysis. The solid product was merely filtered off
and washed with excess cold water. If the product was a
liquid, its extraction was carried out using ethyl acetate.
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bottom flask at 25–28 ꢀC. The amine (1 equiv) was added
and the resulting mixture was sonicated at room temper-
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