Aqueous phase mono-protection of amines and amino acids as N-benzyloxycarbonyl derivatives in the presence of β-cyclodextrin

Article abstract of DOI:10.1016/j.tetlet.2006.06.162

A simple and selective protection of amines/amino acids with Cbz-Cl has been achieved in aqueous phase with catalytic amounts of β-cyclodextrin in high yields at room temperature. This reaction proceeds without the formation of any by-products and has advantages over existing methods.

Full text of DOI:10.1016/j.tetlet.2006.06.162

Tetrahedron Letters 47 (2006) 6393–6396
Aqueous phase mono-protection of amines and amino acids as
N-benzyloxycarbonyl derivatives in the presence of b-cyclodextrinI
V. Pavan Kumar, M. Somi Reddy, M. Narender, K. Surendra,
Y. V. D. Nageswar and K. Rama Rao*
Organic Chemistry Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 17 April 2006; revised 16 June 2006; accepted 29 June 2006
Abstract—A simple and selective protection of amines/amino acids with Cbz-Cl has been achieved in aqueous phase with catalytic
amounts of b-cyclodextrin in high yields at room temperature. This reaction proceeds without the formation of any by-products and
has advantages over existing methods.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
as seen in enzymes. These attractive features of cyclo-
dextrins in the biomimetic modeling of organic reactions
and our earlier expertise developed in this field4
prompted us to attempt the protection of amines with
Cbz-Cl using b-cyclodextrin as the catalyst in water at
room temperature (Scheme 1).
Among the widely used protecting groups for amines
and amino acids, the benzyloxycarbonyl (Cbz) group1
is extensively used since it can be easily removed by cat-
alytic hydrogenation. The Cbz group is stable to basic
and most aqueous acidic conditions. The reported meth-
ods for the protection of amino groups with Cbz have
various limitations such as highly basic conditions,
organic solvents, the use of water–organic solvent
mixtures, elevated temperatures, extended reaction times,
tedious work-up, etc.2 Apart from these limitations, pro-
tection of amines in an aqueous medium is still
problematic.3
In general, the reactions were carried out by dissolving
b-cyclodextrin (CD) in water and then adding the amine
followed by the addition of Cbz-Cl at room temperature
and gave the corresponding carbamates in high yields
(89–98%, Table 1, entries 1–13). The reactions were ra-
pid with all the amines studied (1–4 min). This method
was also compatible with various types of primary and
secondary amines. No by-product formation was ob-
served. These reactions did not take place in the absence
of CD. All the products were isolated and characterized
by 1H NMR, mass and IR spectroscopy and by compar-
ison with known compounds. The CD can also be recov-
ered and reused.
Organic reactions in aqueous media have recently be-
come a topic of focus in organic synthesis since they
overcome the harmful effects of organic solvents and
are environmentally benign. These aqueous reactions
can be made more sophisticated if they can be per-
formed under supramolecular catalysis.
The successful protection of amino groups with
Cbz prompted us to attempt this reaction with amino
acids (Scheme 2) since Cbz protection of amino acids
is usually carried out under highly alkaline conditions
with long reaction times under controlled temperatures.2
Cyclodextrins which are cyclic oligosaccharides exert
microenvironmental effects and catalyze reactions by
supramolecular catalysis through noncovalent bonding
H
Keywords: Amino acids; Amines; Cbz-Cl; b-Cyclodextrin; Buffer;
NH2
N
Cbz-Cl/ 0.1 mol% β-CD
Cbz
Water.
q IICT Communication No. 060616.
rt, Water
R
R
*
Corresponding author. Tel.: +91 40 27193164; fax: +91 40
27160512; e-mail: drkrrao@yahoo.com
Scheme 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.162

6394
V. Pavan Kumar et al. / Tetrahedron Letters 47 (2006) 6393–6396
Table 1. Protection of amines/amino acids in water/buffer catalyzed by b-cyclodextrin
Entry
1
Substrate
Producta
Time (min)
1
Yieldb (%)
97
H
N
NH2
Cbz
Cbz
F
F
F
F
H
N
NH2
F
2
1
98
F
H
NH2
N
Cbz
3
4
2
4
96
85
Cl
Cl
H
NH2
N
Cbz
HOOC
HOOC
H
N
NH2
Cbz
Cbz
5
1
96
OMe
NH2
OMe
S
N
S
N
6
7
2
1
92
98
N
H
Cbz
NH
N
Cbz
NH2
NH2
HN
HN
8
9
1
1
97
96
Cbz
Cbz
NH
N
10
11
2
3
94
89
O
O
Cbz
HO
NH
HO
N
Cbz
12
13
2
2
92
94
NH2
N
H
Cbz
N
NH2
H
COOH
COOH
NH2
14
15
87
Cbz
N
H
COOH
COOH
NH2
15
16
12
8
90
92
Cbz
N
H
COOH
NH2
COOH
Cbz
N
H

V. Pavan Kumar et al. / Tetrahedron Letters 47 (2006) 6393–6396
6395
Table 1 (continued)
Entry
Substrate
COOH
Producta
COOH
Time (min)
Yieldb (%)
90
17
8
Cbz
N
H
NH2
COOH
NH2
COOH
18
19
Cbz
9
95
84
S
S
N
H
COOH
COOH
NH2
13
HOOC
Cbz
HOOC
N
H
COOH
NH2
COOH
Cbz
20
21
12
10
85
92
N
H
OH
OH
COOH
NH2
COOH
Cbz
N
H
HN
COOH
HN
COOH
NH2
22
23
7
7
96
97
Cbz
N
N
N
H
COOH
NH2
COOH
Cbz
HN
N
N
H
H
a All products were identified by IR, NMR and mass spectroscopy.
b Yields of products isolated after column chromatography.
was observed during these reactions. Selectivity was also
observed in the cases of entries 11, 20, 22 and 23 (Table
1) where Cbz-Cl only reacted with the amino group
without formation of a by-product. The reaction of
amines is very fast in water in the presence of b-CD
whereas in the absence of b-CD the reaction did not take
place unless a base was used. Here, b-CD appears to be
involved in intermolecular hydrogen bonding with the
guest to promote the reaction.
COOH
Cbz-Cl/ 0.1 mol% β-CD
COOH
HN
NH2
Cbz
rt, Buffer (pH = 8)
N
H
N
H
Scheme 2.
The reaction of amino acids with Cbz-Cl also takes
place in water in the presence of b-CD giving very low
yields after long reaction times (after 6 h, the yield was
only 16%). Next, these reactions were attempted at
pH 8 using a mild carbonate buffer (0.1 M) with b-CD
catalysis. Surprisingly, the reactions were complete in
7–15 min at room temperature in yields of 84–97%.
The reaction of amino acids with Cbz-Cl was also stud-
ied at various pH values (4, 7, 8 and 9) in the presence of
b-CD. Increasing the pH to basic decreased the reaction
time (for example in the case of tryptophan, the yields
and reaction times are shown in Table 2), but the reac-
tion did not proceed at acidic pH. No racemization
Thus, we have demonstrated an efficient and simple pro-
cedure under aqueous conditions for the mono-protec-
tion of amines/amino acids with Cbz-Cl using the
inexpensive and recyclable catalyst b-cyclodextrin at
room temperature. The notable features of this reaction
are high yields, short reaction times, clean reaction pro-
files and operational simplicity.
2. Experimental section
b-Cyclodextrin (0.1 mmol) was dissolved in water
(10 ml) or 0.1 M carbonate buffer (pH = 8) (10 mL) at
room temperature, then the amine or amino acid
(1 mmol) was added and the reaction mixture stirred
for 5 min. Cbz-Cl (1 mmol) was added and stirring
was continued at room temperature until the reaction
was complete (see Table 1). The reaction mixture was
extracted with ethyl acetate (the aqueous phase was
Table 2. Reaction of L-tryptophan with Cbz-Cl at various pH’s
Entry
pH
Time
Yield (%)
1
2
3
4
4
7
8
9
—
6 h
7 min
5 min
—
16
97
98

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V. Pavan Kumar et al. / Tetrahedron Letters 47 (2006) 6393–6396
109; (b) Berkowitz, D. B.; Pedersen, M. L. J. Org. Chem.
1994, 59, 5476–5478; (c) Maligres, P. E.; Houpis, I.; Rossen,
K.; Molina, A.; Sager, J.; Upadhyay, V.; Wells, K. M.;
Reamer, R. A.; Lynch, J. E.; Askin, D.; Volante, R. P.;
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3590–3592.
neutralized with 10% Na2CO3 in the case of water-based
reactions). The filtrate was cooled to 5 °C and precipi-
tated b-CD was removed by filtration. The organic layer
was dried over anhydrous Na2SO4 and the solvent was
removed under vacuum to yield the products. Although
seen as single compounds by TLC, they were further
purified by silica gel chromatography using ethyl ace-
tate–hexane as eluent.
2. Greene, T. W. Protective Groups in Organic Synthesis;
Wiley: New York, 1981; p 218.
3. For an interesting example, see: Kita, Y.; Haruta, J.;
Yasuda, H.; Fukunaga, K.; Shirouchi, Y.; Tamura, Y. J.
Org. Chem. 1982, 47, 2697–2700.
Acknowledgements
4. (a) Surendra, K.; Krishnaveni, N. S.; Rao, K. R. Chem.
Commun. 2005, 669; (b) Krishnaveni, N. S.; Surendra, K.;
Rao, K. R. Adv. Synth. Catal. 2004, 346, 346; (c) Surendra,
K.; Krishnaveni, N. S.; Reddy, M. A.; Nageswar, Y. V. D.;
Rao, K. R. J. Org. Chem. 2003, 68, 9119; (d) Surendra, K.;
Krishnaveni, N. S.; Nageswar, Y. V. D.; Rao, K. R. J. Org.
Chem. 2003, 68, 4994; (e) Surendra, K.; Krishnaveni, N. S.;
Reddy, M. A.; Nageswar, Y. V. D.; Rao, K. R. J. Org.
Chem. 2003, 68, 2058.
We thank CSIR, New Delhi, India, for fellowships to
V.P.K., M.S.R., M.N. and K.S.
References and notes
1. (a) Fieser, L. F.; Fieser, M. In Reagents for Organic
Synthesis; John Wiley & Sons: New York, 1967; Vol. 1, p