N-boc protection of amines with di-tert-butyldicarbonate in water under neutral conditions in the presence of β-cyclodextrin

Article abstract of DOI:10.1055/s-2006-939689

A new protocol for protection of aryl and aliphatic amines was developed with (Boc)₂O in the presence of β-cyclodextrin in water. A catalytic amount of β-cyclodextrin is specific for activation of amines. This procedure works well on a wide variety of both electron-rich and electron-deficient amines. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-939689

1
110
LETTER
N-Boc Protection of Amines with Di-tert-butyldicarbonate in Water under
Neutral Conditions in the Presence of b-Cyclodextrin1
N
M
-Boc Protectionof
A
.
mines Somi Reddy, M. Narender, Y. V. D. Nageswar, K. Rama Rao*
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160512; E-mail: drkrrao@yahoo.com
Received 20 December 2005
b-CD, H2O
Abstract: A new protocol for protection of aryl and aliphatic
RNH2
RNHBoc
(
Boc)2O, r.t.
amines was developed with (Boc) O in the presence of b-cyclodex-
2
trin in water. A catalytic amount of b-cyclodextrin is specific for
activation of amines. This procedure works well on a wide variety
of both electron-rich and electron-deficient amines.
R = aryl, alkyl
Scheme 1
Key words: b-cyclodextrin, amines, Boc-anhydride, Boc-deriva-
Cyclodextrins are cyclic oligosaccharides, which exert
micro environmental effect. They catalyze reactions by
supramolecular catalysis through non-covalent bonding
as in enzymes. The attractive features of cyclodextrins in
the modeling of chemical reactions prompted us to inves-
tigate the Boc protection of a variety of amines in the pres-
tives, water
Protection of amino groups is often required during the
synthesis of peptides, amino acids and other natural prod-
2
ucts. Among the most widely used protecting groups, the
ence of b-cyclodextrin with Boc O in water. b-CD was
2
tert-butoxy carbonyl (Boc) has been recognized as the
used as a catalyst since it is inexpensive and could also be
recovered and reused. In the absence of cyclodextrin un-
der the same conditions, even under extended reaction
times, the yields obtained were only to the extent of 20%
method of choice due to easy installation, removal, stabil-
3
ity towards nucleophiles and strong basic conditions. Di-
tert-butyldicarbonate [Boc O] is widely applied to intro-
2
4
duce the tert-butoxy carbonyl (Boc) protecting group.
(
e.g., entry 3, Table 1: 9 h).
Boc-protected aryl amines are important intermediates in
organic synthesis and have been used for the directed These reactions are efficiently carried with catalytic
lithiation of aromatic ring and preparation of unsymmetri- amount of b-cyclodextrin (0.1 mmol) in water followed
5
,6
15
cal ureas amongst others.
by the addition of amines/amino acid esters and Boc O.
2
These reactions take place at room temperature without
generation of any toxic waste products. All the products
were characterized by H NMR and IR spectroscopy,
However, various reagents and methodologies developed
over the years to introduce this group using Boc O have
2
1
7
been carried out either in the presence of a base (DMAP,
8
9
mass spectrometry, and by the comparison with the
aq NaOH, NaHMDS ) or Lewis acid catalysts such as
known compounds.1
0,11
1
0
11
Zr(ClO ) ·6H O, ZrCl4, etc. These reports have de-
4
2
2
monstrated that the reaction of Boc O requires acidic or Reaction rates and yields are governed by the nucleophi-
2
1
2
basic catalysts, extended reaction times, elevated tem- licity of the amines. In particular, anilines with fluoro and
1
3
peratures, tedious work-up, and anhydrous organic sol- COMe groups give the protected derivative with lower
vents. Keeping in view of the various limitations in the yields considering their low reactivity (Table 1, entry 4
introduction of Boc group, we felt the need to develop a and 5), whereas the yields are comparatively better with
cleaner synthetic methodology under neutral conditions.
the aliphatic amines (Table 1). In the case of amino acid
esters the yields are in the range of 82–92% (Table 2).
Recently, organic reactions in aqueous media have ac-
quired significance as they overcome the harmful effects In conclusion, we have developed a simple and efficient
of organic solvents and are environmentally benign. procedure for the direct protection of amines with Boc
These reactions will be more sophisticated if they can be under mild conditions with an inexpensive and reusable
performed under supramolecular catalysis. In our efforts catalyst (b-CD) at room temperature. This method works
to develop chemical reactions under supramolecular well with different substrates. The notable features of this
1
4
catalysis involving cyclodextrins in water, we report methodology are cleaner reaction profiles, high yields,
herein an efficient method for the preparation of N-Boc shorter reaction times and operational simplicity.
derivatives from amines using catalytic amount of b-cy-
clodextrin as a catalyst in water at room temperature
under neutral conditions (Scheme 1).
Acknowledgment
M.S.R. and M.N. thank CSIR, New Delhi India, for the award of
fellowships.
SYNLETT 2006, No. 7, pp 1110–1112
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Advanced online publication: 24.04.2006
DOI: 10.1055/s-2006-939689; Art ID: D37905ST
©
Georg Thieme Verlag Stuttgart · New York

LETTER
N-Boc Protection of Amines
1111
Table 1 Protection of Amines as Boc Derivatives
Entry
Starting material
Producta
Time
min
Yield (%)b
h
1
2
3
4
5
6
7
8
9
Ph-NH2
Ph-NHBoc
2.5
3.0
1.5
4.0
4.0
75c
76c
78c
60c
50c
96
o-MeO-C H -NH
o-MeO-C H -NHBoc
6
4
2
2
6
4
p-MeO-C H -NH
p-MeO-C H -NHBoc
6 4
6
4
p-F-C H -NH
p-F-C H -NHBoc
6 4
6
4
2
p-COMe-C H -NH
p-COMe-C H -NHBoc
6 4
6
4
2
Bn-NH2
Bn-NHBoc
7
8
NH2
NHBoc
NHBoc
NHBoc
94
Ph
Ph
NH2
NH2
NH2
NH2
5
96
MeO
MeO
10
4
91
1
1
1
0
1
2
90
NHBoc
NHBoc
5
94
12
90
Ph
Ph
N
Ph
Ph
N
H
Boc
1
3
10
91
N
H
N
Boc
1
1
4
5
NMe
NMe
Boc
5
4
93
89
H
N
O
N
O
NH
NBoc
1
1
1
6
7
8
8
7
92
NH
NH
NBoc
NBoc
90
NH2
CN
NHBoc
CN
2.5
73c
a
b
c
1
All products were characterized by H NMR and IR spectroscopy, and mass spectrometry.
Isolated yields after purification.
Remainder is starting material.
References and Notes
(7) (a) Basel, Y.; Hashers, A. J. Org. Chem. 2000, 65, 6368.
b) Grehn, L.; Ragnarsson, U. Angew. Chem., Int. Ed. Engl.
985, 510. (c) Knolker, T.; Braxmeier, H.-J. Tetrahedron
(
1
(
(
1) IICT Communication no. 060204.
2) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 2nd ed.; Wiley: New York, 1991, Chap.
Lett. 1996, 37, 5861.
(
8) For examples, see: (a) Lutz, C.; Lutz, V.; Knochel, P.
Tetrahedron 1998, 54, 6385. (b) Bailey, S. W.;
Chandrasekaran, R. Y.; Ayling, J. E. J. Org. Chem. 1992, 57,
7, 309. (b) Kocienski, P. J. Protecting Groups; Thieme:
Stuttgart, 1994, Chap. 6, 185.
(3) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; J. Wiley and Sons: New York,
4
470.
9) Kelly, T. A.; McNeil, D. W. Tetrahedron Lett. 1994, 35,
003.
(
1999. (b) Kocienski, P. J. Protecting Groups; Thieme:
9
Stuttgart, New York, 2000.
(
(
10) Boger, D. L.; McKie, J. A. J. Org. Chem. 1995, 60, 1271.
11) Muchowski, J. M.; Venuti, M. C. J. Org. Chem. 1980, 45,
(
4) (a) Houlihan, F.; Bouchrad, F.; Frechet, J. M. J.; Willson, C.
G. Can. J. Chem. 1985, 63, 153. (b) Losse, G.; Splits, G.
Synthesis 1990, 1035.
4798.
(
12) Bartoli, G.; Bosco, M.; Locatelli, M.; Marcantoni, E.;
(
(
5) Snieckus, V. Chem. Rev. 1990, 295.
6) Lamothe, M.; Perez, M.; Colovray-Gotteland, V.; Halazy, S.
Synlett 1996, 1823.
Massaccesi, M.; Melchiorre, P.; Sambri, L. Synlett 2004,
1794.
Synlett 2006, No. 7, 1110–1112 © Thieme Stuttgart · New York

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M. Somi Reddy et al.
LETTER
Table 2 b-CD-Catalyzed Protection of Amino Acid Esters
Entry
1
Substrate
Producta
Time (min)
20
Yield (%)b
NH2
NHBoc
92
90
MeO2C
NH2
MeO2C
NHBoc
2
3
4
15
20
10
CO2Me
NH2
CO Me
2
NHBoc
88
87
HS
HS
CO2Me
CO2Me
NHBoc
NH2
CO2Me
CO Me
2
5
6
CO Me
CO Me
25
20
82
90
2
2
Ph
Ph
NH2
NHBoc
OMOM
OMOM
NHBoc
MeO
NH2
MeO
O
O
a
1
All products were characterized by H NMR and IR spectroscopy, and mass spectrometry.
Isolated yields after purification.
b
(
13) Sharma, G. V. M.; Reddy, J. J.; Lakshmi, P. S.; Krishna, P.
R. Tetrahedron Lett. 2004, 45, 6963.
14) (a) Reddy, M. A.; Bhanumathi, N.; Rao, K. R. Chem.
Commun. 2001, 1974. (b) Reddy, L. R.; Bhanumathi, N.;
Rao, K. R. Chem. Commun. 2000, 2321. (c) Somi Reddy,
M.; Narender, M.; Rao, K. R. Synlett 2005, 489.
(15) General Procedure.
b-Cyclodextrin (0.1 mmol of b-CD) was dissolved in H O
(15 mL) at r.t. and the amine (1 mmol) dissolved in acetone–
MeOH (1 mL) was added with stirring. Then (Boc) O
2
(
2
(1 mmol) was added and the reaction was stirred at r.t. for
specific reaction times (Table 1). The reaction mixture was
extracted with EtOAc and washed with brine. The organic
phase was dried (Na SO ), filtered and the solvent was
(
d) Krishnaveni, N. S.; Surendra, K.; Somi Reddy, M.;
Nageswar, Y. V. D.; Rao, K. R. Adv. Synth. Catal. 2004,
46, 395. (e) Surendra, K.; Krishnaveni, N. S.; Reddy, M.
A.; Nageswar, Y. V. D.; Rao, K. R. J. Org. Chem. 2003, 68,
119. (f) Somi Reddy, M.; Narender, M.; Rao, K. R.
Tetrahedron Lett. 2005, 46, 1299.
2
4
3
removed under vacuum. The crude product was purified by
silica gel column chromatography with EtOAc–hexane (1:9)
as eluent. b-Cyclodextrin was recovered (95%) after
lyophilization of the aqueous phase.
9
Synlett 2006, No. 7, 1110–1112 © Thieme Stuttgart · New York