An excellent method for Cbz-protection of amines

Article abstract of DOI:10.1246/cl.2010.228

Cbz-protection of aliphatic and aromatic amines can be accomplished with benzylchloroformate using a catalytic amount of dodecatungstophosphoric acid hydrate (0.05 equiv). The reaction is simple, fast, does not require aqueous work-up and gives excellent yields.

Full text of DOI:10.1246/cl.2010.228

doi:10.1246/cl.2010.228
228
Published on the web February 6, 2010
An Excellent Method for Cbz-protection of Amines
Khiangte Vanlaldinpuia, H Atoholi Sema, Lalthazuala Rokhum, and Ghanashyam Bez*
Department of Chemistry, North Eastern Hill University, Shillong-793022, India
(Received November 17, 2009; CL-091019; E-mail: bez@nehu.ac.in)
R1
N
R1
PhCH2OCOCl
H3PW12O40•xH2O (0.05 equiv)
Cbz-protection of aliphatic and aromatic amines can be
accomplished with benzylchloroformate using
a
catalytic
N
H
O
Ph
R
CH2Cl2, rt
R
amount of dodecatungstophosphoric acid hydrate (0.05 equiv).
The reaction is simple, fast, does not require aqueous work-up
and gives excellent yields.
O
Scheme 1.
The inertness of Cbz-protected amine toward most basic
reaction conditions and aqueous acidic conditions1 coupled with
easy removal of the Cbz-group upon hydrogenation makes the
Cbz-protection of amines one of the most sought after protocols
amongst synthetic chemists. Even though a myriad of literature
procedures concerning Cbz-protection of amine are available,
many potential drawbacks could be encountered while pursuing
this protection. There are several methods for preparation of
Cbz-derivatives of amines, such as LiHMDS as a base in THF-
HMPA solvent,2 cyclodextrine in aqueous media,3 silica-
sulfuric acid,4 La(NO3)3¢6H2O under solvent free conditions,5
iodine,6 and use of miceller media.7
change in reaction time while lower catalytic loading (0.02
equiv) increased the reaction time to half an hour for complete
conversion.
Having optimized the solvent and catalyst ratio, we
generalized our reaction protocol (Scheme 1)10 with a diverse
set of substrates (Table 1) to explore the versatility of the same.
It was observed that our experiments with typical aliphatic and
aromatic amines gave excellent results in terms of reaction times
and yields. Aromatic amines bearing other reactive functional
groups such as -OMe (Entry 2, Table 1), -Cl (Entry 3, Table 1),
phenolic -OH (Entry 4, Table 1), -OAc (Entry 6, Table 1), and
1,3-dioxolanes (Entries 7 and 8, Table 1) gave excellent yields
suggesting the compatible nature of the catalysts toward these
functionalities. Aliphatic amines with alcoholic -OH (Entry 15,
Table 1) groups also gave excellent yield without any side
reaction. Even highly sterically demanding amine (Entry 20,
Table 1) derived from Shi’s ketone could be protected without
affecting the acetonide groups. To explore the chemoselectivity
of the reagent system toward aromatic/heteroaromatic amine
and aliphatic amine, we studied the reaction for 3-(2-amino-
ethyl)indole (Entry 21, Table 1) using 0.90 equivalent of
benzylchloroformate. The retention of the -NH peak at
10.7 ppm in 1H NMR in the Cbz-protected amine confirmed
that primary amine was selectively protected in the presence
of an indolyl -NH- group. Similar observation was made for
N-(3-aminobenzyl)hexadecylamine (Entry 22), wherein the
benzylic secondary amine was selectively protected in the
presence of the aromatic primary amine. Both these results led
us to conclude that the reaction is chemoselective toward
aliphatic amines in the presence of aromatic/heteroaromatic
amines. As for the mechanism, we proposed that the formation
of the ammonium salt may be necessary to activate the
benzylchloroformate for Cbz-protection of the amine via the
intermediate A (Scheme 2).
Recently heteropoly acids8 are finding enormous applica-
tions as one of the most viable alternatives for acid-catalyzed
reactions because of their noncorrosive and environmentally
compatible properties. In contrast to mineral acid catalyzed
reactions, they have high structural and thermal stability, well-
defined redox and acidic properties. Nevertheless, they give
fewer side reactions as compared to mineral acids, are recyclable
and can be equally effective both in homogeneous as well as
in heterogeneous systems. Here, we are reporting an efficient
protection of both aliphatic and aromatic amines as their Cbz-
derivatives by reacting with benzylchloroformate in the presence
of catalytic amounts of dodecatungstophosphoric acid hydrate.
Initially, a mixture of piperidine (0.170 g, 2.0 mmol) with
benzylchloroformate (0.341 g, 2.0 mmol) in THF (5 mL) in the
presence of H3PW12O40¢xH2O (288 mg, 0.1 mmol) was stirred
for 30 min at room temperature. The reaction gave 82% yield
leaving the remaining as unreacted starting material. Henceforth,
we decided to screen out other solvents like CH3CN, CHCI3,
Et2O, EtOH, and CH2C12 for the said reaction and optimum
yield was observed in dichloromethane (90%) within a very
short reaction time (10 min). We also tried to explore the
reactivity of the catalyst in the absence of any solvent. The
reaction took place immediately and was found exothermic. But
for solid substrates, the conversion was not complete partly
because of inhomogenity of the reaction mixture. Ironically,
catalyst recovery was also not possible as some gel-type
formation took place. But when the reaction was carried out in
dichloromethane, the catalyst9 used after tertiary recovery also
gave 88% yield of the product with a small amount of piperidine
left unreacted. The catalyst ratio was also studied for piperidine
as the substrate wherein use of 0.05 equiv of dodecatungsto-
phosphoric acid hydrate was found optimum. Higher catalytic
loading (0.1 equiv and 0.2 equiv) did not make any noticeable
In summary, we have developed an easy and straightforward
method for Cbz-protection of amines using reusable and cheap
catalyst in dodecatungstophosphoric acid. Compatibility of the
reaction conditions toward commonly used protecting groups
and its chemoselctivity toward aliphatic amines over aromatic/
heteroaromatic amines is an added advantage over existing
literature reports.
SAIF, NEHU is acknowledged for recording NMR, Mass,
and elemental analysis. Help and suggestions from Dr. Nabin C
Barua, NEIST, India are gratefully acknowledged.
Chem. Lett. 2010, 39, 228-229
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

229
Table 1. Protection of amines via Scheme 1a,b
Cl
Cl
R1
R1
R
HPA
HCl
O
O
Ph
Time
/min
Entry
Substrate
Yieldc/%
R
N
H
NH +
HO
O
A
Ph
Ph
H
R1
NHCbz
12
1
2
3
92
90
91
N
H
H
N
R1
R1
R
R
O
Ph
MeO
Cl
NHCbz
N
O
12
12
R
O
Cl
O
H
NHCbz
NHCbz
Scheme 2.
11
15
4
5
89
83
OH
References and Notes
1
a) L. F. Fieser, Reagents for Organic Synthesis, John Wiley &
Sons, New York, 1967, Vol. 1, p. 109. b) P. E. Maligres, I.
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Bergmann, L. Zervas, Ber. Dtsch. Chem. Ges. 1932, 65, 1192.
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6393. b) T. W. Green, Protecting Groups in Organic Synthesis,
Weily, New York, 1981, p. 218.
M. B. Gawande, V. Polshettiwar, R. S. Varma, R. V. Jayaram,
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R. Varala, R. Enugala, S. R. I. Adapa, J. Iran. Chem. Soc.
2007, 4, 370.
N
Cbz
NHCbz
10
10
6
7
89
88
OAc
O
O
NHCbz
2
3
O
NHCbz
NHCbz
O
12
8
85
THPO
4
5
6
7
12
10
9
83
89
TBSO
NHCbz
10
O
NCbz
7
11
12
92
90
a) T. H. Kim, J. C. Chun, Bull. Kor. Chem. Soc. 2003, 24, 157.
b) E. A. Papageorgiou, M. J. Gaunt, J.-Q. Yu, J. B. Spencer,
Org. Lett. 2000, 2, 1049.
NCbz
10
8
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8
13
14
92
91
N
Cbz
NHCbz
7
Cbz
N
7
8
9
15
16
17
18
89
94
88
91
HO
OH
NHCbz
Ph
PhCH2NHCbz
NHCbz
10
13
9
Catalyst was reused after washing with methanol followed by
heating at 100 °C overnight.
NHCbz
15
10
19
20
90
84
10 Typical procedure: To a mixture of dodecatungstophosphoric
acid hydrate (0.05 mmol) and benzylchloroformate (1.1 mmol)
was added a solution of piperidine (1.0 mmol) dissolved in
dichloromethane (4 mL). After stirring for 10 min, the reaction
mixture was filtered through ordinary filter paper and the
filtrate was concentrated by distillation under reduced pressure.
The resulting crude was then purified by column chromatog-
raphy to get the pure N-benzyloxycarbonyl derivative. IR
(KBr): 3030, 2940, 2860, 1685, 1435, 1268, 1150, 1085,
O
O
O
O
O
NHCbz
8
21
91
NHCbz
N
H
H2N
N
14
10
22
73
1
1024 cm¹1. H NMR (400 MHz, CDCl3): ¤ 1.51 (m, 6H), 3.36
Cbz
(t, J = 6.0 Hz, 4H), 5.05 (s, 2H), 7.24 (m, 5H); 13C NMR
(100 MHz, CDCl3): ¤ 22.48, 25.80, 44.98, 67.01, 127.91,
128.00, 128.57, 137.14, 155.47. MS (m/z): 219, 128, 108, 91,
77, 65.
aConditions: amine (1.0 mmol), benzyl chloroformate
(1.1 mmol), H3PW12O40¢xH2O (0.05 mmol), CH2Cl2 (4 mL),
rt. All reactions were carried out at rt. Isolated yield.
b
c
Chem. Lett. 2010, 39, 228-229
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/