A simple and convenient per-O-acylation of cyclodextrins catalyzed by molecular iodine

Article abstract of DOI:10.1055/s-0030-1258163

Per-O-acylated cyclodextrins with different alkyl chains were prepared in good to high yields by iodine-catalyzed acylation of all hydroxy groups of cyclodextrins with carboxylic anhydrides under solvent-free conditions. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258163

PAPER
3083
A Simple and Convenient Per-O-acylation of Cyclodextrins Catalyzed by
Molecular Iodine
C
Y
onvenient Proced
a
ur
e
for the
s
Per-O-acy
u
lation of Cy
h
clodextrins iro Ide, Yuji Hori, Soichi Kobayashi, Md. Delwar Hossain, Tsugio Kitamura*
Department of Chemistry and Applied Chemistry, Graduate School of Science and Engineering, Saga University, Honjo-machi,
Saga 840-8502, Japan
Fax +81(952)288550; E-mail: kitamura@cc.saga-u.ac.jp
Received 2 April 2010; revised 20 May 2010
3
a
any other solvent containing a tertiary amine as a base, a
simpler and more convenient procedure is desired.
Abstract: Per-O-acylated cyclodextrins with different alkyl chains
were prepared in good to high yields by iodine-catalyzed acylation
of all hydroxy groups of cyclodextrins with carboxylic anhydrides Molecular iodine is moderately reactive and a user-friend-
under solvent-free conditions.
ly reagent. Utilization of iodine in organic synthesis has
4
Key words: cyclodextrins, iodine catalyst, acylation, solvent-free
been reviewed recently. During the course of our studies
on application of molecular iodine in organic synthesis,
we have found that iodoarenes, (diacetoxyiodo)arenes,
and diaryliodonium salts can be prepared directly from
molecular iodine and arenes in the presence of potassium
Cyclodextrins are macrocyclic oligosaccharides com-
posed of six, seven, and eight a-(1–4)-D-glucopyranosyl
units, which are known as a, b-, and g-cyclodextrins, re-
spectively. These cyclodextrins have a truncated conical
shape, a hydrophilic exterior, and a hydrophobic cavity.1
This cavity enables to act as host to lipophilic molecules,
5
peroxodisulfate. Recently, it has been revealed that io-
dine can serve as a promoter for per-O-acetylation of un-
protected sugars.6 Encouraged by these reports, we
examined the per-O-acylation of cyclodextrins with car-
boxylic anhydrides in the presence of molecular iodine.
Here we report a simple and very convenient procedure
for synthesis of per-O-acylated cyclodextrins using mo-
lecular iodine as a catalyst.
2
allowing various pharmaceutical applications. Practical
use of cyclodextrins as drug carriers is restricted by their
low aqueous solubility. Effective recognition in organic
solvents is also difficult due to the low solubility in less
polar solvents. Chemical modifications of cyclodextrins
have been extensively studied to improve the solubility in
aqueous and organic solvents and to elaborate further their
First, the reaction of a-, b-, and g-cyclodextrins with ace-
tic anhydride in the presence of I at room temperature un-
2
der solvent-free conditions was conducted. The outline
and results are given in Scheme 1 and Table 1.
3
amphiphilicity and molecular recognition. All hydroxy
groups can be converted into ester functionalities by using
suitable reagents under appropriate conditions. Since es-
ters of cyclodextrins have been synthesized by a typical
ester synthesis using organic acid chlorides in pyridine or
The reaction of b-cyclodextrin with Ac O was carried out
2
in the presence of I at room temperature for 24 hours.
2
Workup of the reaction mixture gave a quantitative yield
(
1
96%) of per-O-acetylated b-cyclodextrin (Table 1, entry
). Since b-cyclodextrin has 21 hydroxy groups, 21 mmol
HO
OAc
AcO
OH
HO
AcO
O
O
O
O
O
O
OH
OAc
OH
OAc
O
O
OAc
OH
HO
Ac2O
AcO
O
O
OH
OAc
I2 (cat.)
AcO
HO
O
O
O
O
O
r.t., 24 h
OH
OAc
O
HO
AcO
O
OAc
OH
HO
O
AcO
O
O
HO
AcO
HO
AcO
O
O
O
O
OH
OAc
n
OH
HO
n
OAc
AcO
α-CD: n = 1; β-CD: n = 2; γ-CD: n = 3
Scheme 1 Iodine-catalyzed synthesis of per-O-acetylcyclodextrins
SYNTHESIS 2010, No. 18, pp 3083–3086
x
x.
x
x
.
2
0
1
0
Advanced online publication: 07.07.2010
DOI: 10.1055/s-0030-1258163; Art ID: F05910SS
Georg Thieme Verlag Stuttgart · New York
©

3
084
Y. Ide et al.
PAPER
Table 1 Iodine-Catalyzed Per-O-acetylation of Cyclodextrins with
Acetic Anhydride
Butyric and valeric anhydrides also underwent the per-O-
acylation reaction with a- and b-cyclodextrins to afford
the corresponding per-O-acylated cyclodextrins in high
yields (entries 3–5). Longer alkyl-chained carboxylic an-
hydrides (decanoic and lauric anhydrides) showed some-
what low reactivity and needed a higher loading of
catalyst (1–2 mol%) to obtain a reasonable yield of the
product (entries 6–9).
a
Entry CD (mmol) Ac O
I2 (mmol, mol%)b
Temp Yield
2
(%)c
(
mmol)
1
2
3
4
5
6
b-CD (0.5) 21
b-CD (0.5) 21
b-CD (0.5) 10.5
b-CD (5.0) 210
a-CD (0.5) 18
g-CD (0.5) 24
0.1 (0.95 mol%)
0.05 (0.49 mol%)
0.05 (0.49 mol%)
0.1 (0.01 mol%)
0.1 (1.1 mol%)
r.t.
r.t.
r.t.
r.t.
r.t.
96
~100
59
Table 2 Iodine-Catalyzed Per-O-acylation of Cyclodextrins with
Other Carboxylic Anhydridesa
95
~100
Entry CD (mmol) (RCO) O (mmol) I2 (mmol, mol%)b Yield
2
(
%)c
0.005 (0.08 mol%) 80 °C 92
a
b
c
1
2
3
4
5
6
b-CD (0.5) (EtCO)
2
O (21)
0.025 (0.23 mol%) 92
The reaction was carried out for 24 h.
Based on one OH group of CD.
Isolated yield.
a-CD (0.5) (EtCO) O (13.5) 0.005 (0.11 mol%) 99
2
b-CD (0.5) (PrCO) O (21)
0.05 (0.48 mol%) 89
2
of Ac O are equal to two-fold moles of the hydroxy
groups in b-cyclodextrin (0.5 mmol) and 1 mmol of I cor-
responds to 0.95 mol% of catalyst. Even in the case of the
reaction using 0.49 mol% of I , any decrease of the yield
was not observed (entry 2), but the use of stoichiometric
amounts of Ac O reduced the yield to 59% (entry 3). A
larger-scale reaction using 5 mmol of b-CD gave a satis-
factory result (entry 4). Under the same conditions, a-cy-
clodextrin was per-O-acetylated to give the product
quantitatively (entry 5). The reaction of g-cyclodextrin at
room temperature did not proceed completely under the
same conditions. However, the reaction at 80 °C was
found to cause a partial transformation of the structure.
Eventually, the decrease of the catalyst amount to 0.08
2
a-CD (0.5) (PrCO) O (13.5) 0.01 (0.22 mol%) 98
2
2
b-CD (0.5) (BuCO)
O (21)
0.05 (0.48 mol%) 91
0.05 (0.48 mol%) 24
2
2
b-CD (0.5) (n-C H CO) O
9
19
2
(
21)
2
7
8
9
b-CD (0.5) (n-C H CO) O
0.1 (0.95 mol%)
93
9
19
2
(
21)
b-CD (0.05) (n-C H CO) O 0.01 (0.95 mol%) 32
1
1
23
2
(2.1)
b-CD (0.05) (n-C H CO) O 0.02 (1.9 mol%)
61
1
1
23
2
(
2.1)
a
b
c
The reaction was carried out at 80 °C for 24 h.
Based on one OH group of CD.
Isolated yield.
mol% with three-fold excess of Ac O improved the reac-
tion to give the product in 92% yield (entry 6). According-
2
ly, it was found that I effectively acts as a catalyst in the
2
per-O-acetylation of cyclodextrins under the solvent-free In summary, we have demonstrated that cyclodextrins un-
conditions.
derwent easily per-O-acetylation in the presence of a cat-
alytic amount of iodine under solvent-free conditions.
This reaction was applied to higher acid anhydrides such
as propiolic, butyric, valeric, decanoic, and lauric anhy-
drides. The per-O-acylated cyclodextrins were obtained in
high yields. This procedure is synthetically valuable for
functionalization of cyclodextrins because of its simplici-
ty and convenience.
Next, the iodine-catalyzed reaction with other carboxylic
anhydrides was examined to explore the scope and limita-
tions, as shown in Scheme 2. The results are given in
Table 2. Propiolic anhydride reacted with b- and a-cyclo-
dextrins in the presence of a catalytic amount of iodine to
give the corresponding per-O-acylated cyclodextrins in
9
2 and 99% yield, respectively (Table 2, entries 1 and 2).
RCOO
OCOR
HO
OH
HO
RCOO
O
O
O
O
O
O
OH
OCOR
OH
OCOR
O
O
OCOR
OH
(
RCO)2O
RCOO
HO
O
O
OH
OCOR
I2 (cat.)
RCOO
HO
O
O
O
O
OH
80 °C, 24 h
OCOR
HO
RCOO
O
O
OCOR
OH
HO
O
RCOO
O
O
RCOO
O
HO
HO
RCOO
O
O
O
O
OH
OCOR
RCOO
OCOR
n
OH
HO
n
Scheme 2 Iodine-catalyzed synthesis of acylated cyclodextrins
Synthesis 2010, No. 18, 3083–3086 © Thieme Stuttgart · New York

PAPER
Convenient Procedure for the Per-O-acylation of Cyclodextrins
3085
1H NMR (300 MHz, CDCl
(m, CH ), 3.73 (dd, J = 9.3, 8.1 Hz, H-4), 3.94–3.98 (m, H-5), 4.31
2
(dd, J = 12.0, 3.9 Hz, H -6), 4.53 (d, J = 12.0 Hz, H -6), 4.79 (dd,
J = 9.3, 3.9 Hz, H-2), 5.06 (d, J = 3.9 Hz, H-1), 5.32 (dd, J = 9.3,
8.1 Hz, H-3).
): d = 1.07–1.16 (m, CH
), 2.11–2.42
All starting materials and reagents were used as purchased without
further purification. H NMR and C NMR were recorded on a Jeol
3
3
1
13
b
a
JNM-Al-300FT-NMR spectrometer in CDCl solution (TMS as an
3
internal standard). Melting points of the pure compounds were re-
corded on a Yanaco melting point apparatus and are uncorrected.
Column chromatographic separations were carried out using silica
13
C NMR (75 MHz, CDCl ): d = 8.39, 8.53, 8.67, 26.92, 27.00,
3
gel as the stationary phase. Precoated plates (silica gel 60 F254
,
27.20, 62.18, 69.38, 70.02, 70.37, 76.51, 96.43, 173.37, 173.64,
MERCK, on aluminum foils) were used for TLC examination.
1
73.77.
Iodine-Catalyzed Per-O-acetylation of Cyclodextrins; General
Procedure
Per-O-propionyl-a-cyclodextrin8
White crystals; yield: 0.981 g (99%); mp 99–101 °C (MeOH).
A mixture of a cyclodextrin, I , and Ac O, using the amounts de-
2
2
1
H NMR (300 MHz, CDCl ): d = 1.07–1.21 (m, CH ), 2.17–2.50
scribed in Table 1, was stirred at r.t. for 24 h. In the case of g-cyclo-
dextrin, the mixture was heated with stirring at 80 °C for 24 h. After
the reaction, aq 1 M Na S O was added to the reaction mixture until
3
3
(
m, CH ), 3.86 (t, J = 8.7 Hz, H-4), 4.12 (d, J = 8.9 Hz, H-5), 4.46–
2
4
.49 (m, H-6), 4.77 (dd, J = 9.6, 3.3 Hz, H-2), 5.11 (d, J = 3.3 Hz,
2
2
3
H-1), 5.50 (dd, J = 9.6, 8.9 Hz, H-3).
the disappearance of the color of I . To the mixture was added H O
2
2
1
3
(
10 mL) and the product was extracted with CHCl (3 × 10 mL). The
C NMR (75 MHz, CDCl ): d = 8.51, 8.71, 8.74, 27.06, 27.13,
3
3
combined CHCl extracts were washed with aq 1 M Na CO (10
62.49, 69.53, 70.39, 70.51, 75.43, 95.83, 172.26, 173.68, 173.81.
3
2
3
mL) and dried (Na SO ). The solvent was evaporated on a rotary
2
4
Per-O-butyryl-b-cyclodextrin8
White crystals; yield: 1.16 g (89%); mp 62–65 °C (MeOH).
evaporator and finally in vacuo to give the product. The products
thus obtained were pure enough in most cases for use elsewhere di-
rectly. For further purification the products were submitted to col-
umn chromatography on silica gel and eluted with CH Cl –MeOH
1
H NMR (300 MHz, CDCl ): d = 0.85–0.91 (m, CH ), 1.54–1.60
3
3
2
2
(
m, CH ), 2.24–2.30 (m, CH ), 3.66 (dd, J = 9.2, 8.9 Hz, H-4),
2
2
(
50:1–25:1). Compounds were detected by dipping the TLC plates
b
4
.02–4.06 (m, H-5), 4.27 (dd, J = 12.0, 3.3 Hz, H -6), 4.47 (d,
in an ethanolic solution of H SO (4% v/v) and heating.
2
4
a
J = 12.0 Hz, H -6), 4.70 (dd, J = 9.2, 3.8 Hz, H-2), 5.00 (d, J = 3.8
Hz, H-1), 5.26 (t, J = 9.2 Hz, H-3).
Iodine-Catalyzed Per-O-acylation of Cyclodextrins with Car-
boxylic Anhydrides; General Procedure
A mixture of a cyclodextrin and a carboxylic anhydride in the pres-
13C NMR (75 MHz, CDCl
8.03, 35.43, 35.54, 35.69, 62.18, 69.53, 70.13, 70.23, 76.57, 96.47,
171.54, 172.69, 173.11.
): d = 13.36, 13.42, 13.46, 17.74, 17.77,
3
1
ence of I , using the amounts described in Table 2, was heated with
2
stirring at 80 °C for 24 h. The products were obtained by the workup
of the reaction mixture as described above.
Per-O-butyryl-a-cyclodextrin8
White crystals; yield: 1.09 g (98%); mp 60–62 °C (MeOH).
Per-O-acetyl-b-cyclodextrin7
White crystals; yield: 0.968 g (96%); mp 149–153 °C (EtOH).
1
H NMR (300 MHz, CDCl ): d = 0.90–0.98 (m, CH ), 1.57–1.73
3
3
(
(
m, CH ), 2.12–2.41 (m, CH ), 3.86 (dd, J = 9.2, 8.6 Hz, H-4), 4.09
2
2
1
d, J = 9.2 Hz, H-5), 4.43–4.47 (m, H-6), 4.74 (dd, J = 10.2, 3.5 Hz,
H NMR (300 MHz, CDCl ): d = 2.06 (s, CH ), 2.10 (s, CH ), 2.13
3
3
3
(
(
s, CH ), 3.71 (dd, J = 9.6, 8.1 Hz, H-4), 4.13–4.17 (m, H-5), 4.28
H-2), 5.04 (d, J = 3.5 Hz, H-1), 5.50 (dd, J = 10.2, 8.6 Hz, H-3).
3
b
a
dd, J = 12.8,4.0 Hz, H -6), 4.57 (d, J = 12.8 Hz, H -6), 4.80 (dd,
13
C NMR (75 MHz, CDCl ): d = 13.39, 13.45, 17.92, 17.95, 18.15,
3
J = 9.9, 3.9 Hz, H-2), 5.09 (d, J = 3.9 Hz, H-1), 5.30 (dd, J = 9.9,
3
1
5.57, 35.73, 35.76, 62.46, 69.55, 70.12, 70.48, 75.16, 95.60,
71.31, 172.85, 173.00.
8
.1 Hz, H-3).
1
3
C NMR (75 MHz, CDCl ): d = 20.30, 20.33, 20.36, 62.16, 69.24,
3
Per-O-valeryl-b-cyclodextrin8
Colorless oil; yield: 1.32 g (91%).
7
0.10, 70.39, 76.40, 96.41, 169.25, 170.12, 170.34.
Per-O-acetyl-a-cyclodextrin8
White crystals; yield: 0.864 g (100%); mp 146–150 °C (EtOH).
1
H NMR (300 MHz, CDCl ): d = 0.89–0.95 (m, CH ), 1.28–1.43
3
3
(
m, CH ), 1.53–1.68 (m, CH ), 2.19–2.48 (m, CH ), 3.74 (t, J = 9.0
2 2 2
b
1
Hz, H-4), 4.08–4.12 (m, H-5), 4.31 (dd, J = 12.7, 3.3 Hz, H -6),
H NMR (300 MHz, CDCl ): d = 2.06 (s, CH ), 2.07 (s, CH ), 2.18
3
3
3
a
(
(
s, CH ), 3.79 (dd, J = 9.0, 8.4 Hz, H-4), 4.15–4.20 (m, H-5), 4.42
4.53 (d, J = 12.7 Hz, H -6), 4.76 (dd, J = 9.0, 3.6 Hz, H-2), 5.09 (d,
3
J = 3.6 Hz, H-1), 5.33 (t, J = 9.0 Hz, H-3).
d, J = 3.3 Hz, H-6), 4.77 (dd, J = 10.2, 3.3 Hz, H-2), 5.06 (d,
J = 3.3 Hz, H-1), 5.56 (dd, J = 10.2, 8.4 Hz, H-3).
13
C NMR (75 MHz, CDCl ): d = 13.62, 13.70, 22.14, 22.17, 22.27,
3
1
3
3
3.53, 33.62, 33.70, 62.18, 69.59, 70.33, 70.38, 76.20, 96.45,
C NMR (75 MHz, CDCl ): d = 20.76, 20.69, 20.83, 63.05, 69.39,
3
7
0.81, 70.84, 76.58, 96.45, 169.27, 170.58, 170.60.
171.67, 172.88, 173.36.
Per-O-decanoyl-b-cyclodextrin8
Colorless oil; yield: 2.03 g (93%).
Per-O-acetyl-g-cyclodextrin8
White crystals; yield: 1.06 g (92%); mp 146–149 °C (MeOH).
1H NMR (300 MHz, CDCl
CH ), 1.59 (m, CH ), 2.13–2.42 (m, CH ), 3.74 (t, J = 9.0 Hz, H-4),
): d = 0.87–0.89 (m, CH ), 1.28 (m,
3
1
H NMR (300 MHz, CDCl ): d = 2.08 (s, CH ), 2.10 (s, CH ), 2.13
3
3
3
3
(
(
s, CH ), 3.71 (dd, J = 9.3, 8.9 Hz, H-4), 4.05–4.08 (m, H-5), 4.30
2
2
2
3
b
b
a
dd, J = 11.4, 3.8 Hz, H -6), 4.50 (d, J = 11.4 Hz, H -6), 4.73 (dd,
4.06–4.10 (m, H-5), 4.29 (dd, J = 12.0, 3.9 Hz, H -6), 4.53 (d,
a
J = 9.8, 3.9 Hz, H-2), 5.13 (d, J = 3.9 Hz, H-1), 5.36 (dd, J = 9.8,
8
J = 12.0 Hz, H -6), 4.72 (dd, J = 9.9, 3.7 Hz, H-2), 5.05 (d, J = 3.7
Hz, H-1), 5.32 (t, J = 9.0 Hz, H-3).
.9 Hz, H-3).
1
3
13
C NMR (75 MHz, CDCl ): d = 13.83, 22.46, 22.49, 24.60, 24.66,
C NMR (75 MHz, CDCl ): d = 20.51, 20.70, 20.78, 62.43, 69.67,
3
3
7
0.26, 70.85, 75.86, 96.23, 169.40, 170.32, 170.64.
28.62, 28.93, 29.00, 29.21, 31.55, 31.61, 31.67, 33.68, 33.84, 33.97,
6
1.99, 69.35, 70.28, 70.40, 75.91, 96.16, 171.47, 172.66, 173.17.
Per-O-propionyl-b-cyclodextrin8
White crystals; yield: 1.06 g (92%); mp 167–169 °C (MeOH).
Per-O-lauroyl-b-cyclodextrin8
Colorless oil; yield: 0.151 g (61%).
Synthesis 2010, No. 18, 3083–3086 © Thieme Stuttgart · New York

3
086
Y. Ide et al.
PAPER
(3) (a) Khan, A. R.; Forgo, P.; Stine, K. J.; D’Souza, V. T.
1
H NMR (300 MHz, CDCl ): d = 0.79–0.81 (m, CH ), 1.18 (m,
3
3
CH ), 1.52 (m, CH ), 1.99–2.29 (m, CH ), 3.66 (t, J = 9.0 Hz, H-4),
Chem. Rev. 1998, 98, 1977. (b) Gattuso, G.; Nepogodiev, S.
A.; Stoddart, J. F. Chem. Rev. 1998, 98, 1919. (c) Sallas, F.;
Darcy, R. Eur. J. Org. Chem. 2008, 957.
2
2
2
b
3
.98–4.02 (m, H-5), 4.21 (dd, J = 12.0, 3.6 Hz, H -6), 4.45 (d,
a
J = 12.0 Hz, H -6), 4.65 (dd, J = 9.0, 3.6 Hz, H-2), 4.98 (d, J = 3.6
Hz, H-1), 5.23 (t, J = 9.0 Hz, H-3).
(4) Togo, H.; Iida, S. Synlett 2006, 2159.
1
3
(5) (a) Hossain, M. D.; Ikegami, Y.; Kitamura, T. J. Org. Chem.
C NMR (75 MHz, CDCl ): d = 14.05, 22.67, 24.82, 29.19, 29.39,
3
2
006, 71, 9903. (b) Hossain, M. D.; Kitamura, T.
Tetrahedron Lett. 2006, 47, 7889. (c) Hossain, M. D.;
Kitamura, T. Bull. Chem. Soc. Jpn. 2007, 80, 2213.
2
6
9.44, 29.60, 29.66, 29.71, 29.75, 29.83, 31.93, 33.82, 33.99, 34.11,
2.12, 69.48, 70.38, 70.54, 75.61, 96.28, 171.63, 172.82, 173.32.
(
d) Hossain, M. D.; Oyamada, J.; Kitamura, T. Synthesis
008, 690.
6) (a) Kartha, K. P. R.; Field, R. A. Tetrahedron 1997, 53,
1753. (b) Mukhopadhyay, B.; Kartha, K. P.; Russell, D. A.;
2
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1
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(
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Synthesis 2010, No. 18, 3083–3086 © Thieme Stuttgart · New York