Synthesis of functionalized β-cyclodextrins by "click chemistry"

Article abstract of DOI:10.3987/COM-08-S(N)16

Two new β-cyclodextrins (β-CDs) modified with chromophore were synthesized in high yields through Huisgen 1,3-dipolar cycloaddition. The amount of Cu catalyst was demonstrated to be a key factor that determines the yield of the 1,3-dipolar cycloaddition when applied to CD derivatization. While a catalytic amount of Cu-catalyst is commonly required in conventional click chemistry, more than a half equivalent of Cu catalyst was desirable for obtaining the modified CDs in satisfactory yields. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-08-S(N)16

HETEROCYCLES, Vol. 76, No. 1, 2008
155
HETEROCYCLES, Vol. 76, No. 1, 2008, pp. 155 - 160. © The Japan Institute of Heterocyclic Chemistry
Received, 31st January, 2008, Accepted, 5th March, 2008, Published online, 7th March, 2008. COM-08-S(N)16
SYNTHESIS OF FUNCTIONALIZED β-CYCLODEXTRINS BY “CLICK
CHEMISTRY”
Chenfeng Ke,1,2 Cheng Yang,2 Zixin Yang,1 Weijia Wu,1 Tadashi Mori,2*
Yoshihisa Inoue,2* and Yu Liu1*
1. Department of Chemistry, State Key Laboratory of Elemento-Organic
Chemistry, Nankai University, Tianjin 300071, P. R. China; 2. Department of
Applied Chemistry, Osaka University, 2-1 Yamada-oka, Suita 565-0871, Japan.
E-mail: tmori@chem.eng.osaka-u.ac.jp; yuliu@nankai.edu.cn
Abstract – Two new β-cyclodextrins (β-CDs) modified with chromophore were
synthesized in high yields through Huisgen 1,3-dipolar cycloaddition. The
amount of Cu catalyst was demonstrated to be a key factor that determines the
yield of the 1,3-dipolar cycloaddition when applied to CD derivatization. While a
catalytic amount of Cu-catalyst is commonly required in conventional click
chemistry, more than a half equivalent of Cu catalyst was desirable for obtaining
the modified CDs in satisfactory yields.
“Click chemistry” is a chemical philosophy introduced by Sharpless in 2001, which allows reactive
molecular building blocks to “click” together selectively and covalently.1 Among the several reaction
types that are regarded as “click chemistry,” the Cu-catalyzed 1,3-dipolar cycloaddition of azide to alkyne
is one of the most reliable reactions and therefore frequently used in various areas of science and
technology, such as organic chemistry,2 molecular biology,3 materials science,4 and biochemistry.5
Recently, this click reaction was employed as a convenient, efficient tool for constructing supramolecular
assemblies.6
Cyclodextrins (CDs), a series of cyclic oligosaccharides, have been widely used as supramolecular hosts
for molecular recognition,7 nano-sized reaction containers,8 and building blocks of supramolecular
assemblies.9 Especially interesting is the modified cyclodextrins with an appropriate light-absorbing
(chromophoric) group(s).10 However, in order to utilize their versatile functions in practical applications,

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chemical modifications of CDs are indispensable. Although a large number of modified CDs have already
been reported, efficient and selective derivatization of CDs still remains a difficult challenge for chemists.
In this context, click chemistry is expected to provide a promising route to the efficient modification of
CDs, in view of the ready access to 6-azido-6-deoxy-β-CD11 and the high reactivity and regioselectivity
of the azide-alkyne 1,3-dipolar cycloaddition. By using (Ph3P)3•CuBr and (EtO)3P•CuI as catalysts
soluble in organic solvent, a click reaction has been applied to CD peracetates,12 which are however
insoluble in water and has only limited application in supramolecular chemistry. No efforts other than our
recent work13 have been made to modify native CDs through a click chemical approach.
In this paper, we wish to show that click chemistry provides a convenient direct access to the preparation
of β-CD derivatives with aromatic chromophores, which are applicable to supramolecular sensing and
photosensitization. The factors affecting the Cu-catalyzed 1,3-dipolar cycloaddition of aryl alkynes to
6-azido-6-deoxy-β-CD were elucidated in detail and optimized.
6-Azido-6-deoxy-β-CD (Figure 1) was synthesized by reacting 6-TsO-β-CD with NaN3 in hot water, and
then purified by recrystallization from water. In the first attempt, commercially available phenylacetylene
was chosen as starting material for studying the 1,3-dipolar cycloaddition reaction with
6-azido-6-deoxy-β-CD. The 1,3-dipolar cycloaddition was conducted in a mixed solvent of H2O and THF
(1:1 v/v) in the presence of Cu(I) catalyst prepared in situ from CuSO4 and sodium ascorbate. However,
the reaction of phenylacetylene with 6-azido-6-deoxy-β-CD in the presence of 10 to 20 molar percent of
CuSO4 at room temperature did not give an appreciable amount of aimed adduct 1 after the typical
work-up procedures reported by Sharpless et al.1b Further efforts to promote the reaction by elongating
the reaction time up to several days, raising the temperature up to 60 °C, increasing the amount of CuSO4,
and replacing the solvent with DMF, DMSO, ethanol, methanol, and acetone proved unsuccessful. The
very rigid rod-like structure of phenylacetylene and the bulky size of CD may be jointly responsible for
the failure.
We consequently attempted to synthesize compound 2 by reacting propargyl bromide with
6-azido-6-deoxy-β-CD, because 2 is frequently used as a versatile intermediate that can be readily
converted to a variety of useful functionalities through nucleophilic substitution. Indeed, the addition
reaction did occur, when an equimolar amount of CuSO4 was used. After 2 days of reaction, no trace of
6-azido-6-deoxy-β-CD was detected in the reaction mixture by electrospray ionization (ESI) mass spectral
examinations. However, the ESI-MS also gave no signal that is assignable to the aimed adduct 2. Instead,
an intense molecular ion peak was observed at m/z 1338, which is tentatively assigned to the secondary
product 3 [+Na+] derived from the coupling of initially formed 2 with another propargyl bromide.

HETEROCYCLES, Vol. 76, No. 1, 2008
157
N3
TsO
NaN3
H2O
TsCl
NaOH
N
N
N
CuSO4
sodium ascorbate
1
Br
N
N
N
Br
2
N
N
N
Br
O
3
O
N
N
A1
N
4
O
O
N
N
N
A2
5
Figure 1. Syntheses of β-cyclodextrin derivatives 1-5
Based on the above results, we decided to use 1- and 2-naphthyl propargyl ethers A1 and A214 as
chromophoric alkynes that are feasible to cycloadd to 6-azido-6-deoxy-β-CD. A1 and A2 were prepared
by the reaction of propargyl bromide with 1- and 2-naphthol in acetone in the presence of K2CO3. The
1,3-dipolar cycloaddition 6-azido-6-deoxy-β-CD was examined under a variety of conditions. The
consumption of starting material was monitored by ESI-MS, and the adduct yield was determined after
separation by column chromatography. As shown in Table 1, the amount of CuSO4 catalyst is crucial for
the click reaction, and there appears to be a critical amount to start the reaction smoothly. Thus, the use of
0.1-0.4 equivalent of CuSO4 resulted in no conversion even after 2 days at 60 °C. However, by using 0.5
equivalent of CuSO4, the cycloaddition proceeded to give adduct 4 in 20% yield.15 Interestingly, a slight
increase in the amount of CuSO4 to 0.55 equivalent led to a dramatic leap of the yield to 72%, and the
yield was further improved up to 84% by using 0.8 equivalent of CuSO4. In comparison to the
conventional click reaction that normally completes within 12-24 h at room temperature with a catalytic

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amount of Cu(I), the present cases need much longer period of time and higher temperature to obtain the
adduct in satisfied yields, indicating that the activation energy is higher in the click reaction of azido-CD.
It is noteworthy to mention that the 1,3-dipolar addition has been demonstrated to proceed smoothly with
compounds bearing a single glucose unit in the presence of catalytic amount of Cu(I) catalyst.16 Thus, we
speculate the reason of lower reactivity in the present system is mainly due to the hydroxyl groups of CD,
particularly those on the secondary rim that weakly coordinate to Cu,17 as well as the steric bulkiness of
the cyclodextrins18 that jointly operates in hindering the access of Cu(I) to the azido group.
Table 1. Syntheses of β-CD derivatives via click chemistry
alkyne
CuSO4/eqb temperature/oC reaction time/h
yield c/%
0.2
1.0
0.2
1.0
0.1
0.3
0.4
0.5
0.55
0.55
0.8
1.0
1.5
0.55
60
60
60
60
60
60
60
60
60
r.t.
60
60
60
60
48
48
48
48
48
48
48
48
48
48
48
24
24
48
d
d
d
d,e
d
d
phenylacetylene
propargyl bromide
A1
d
20
72
41
84
65
73
73
A2
a
The 1,3-dipolar cycloaddition were carried out by reacting
6-azido-6-deoxy-β-CD with corresponding organic alkynes in a 1:1 mixture
b
c
of H2O and THF. Molar ratio of CuSO4 to 6-azido-6-deoxy-β-CD.
d
Isolated yield; average of two independent runs. No aimed adduct was
obtained. e Secondary product, presumably 3, was detected by ESI-MS.
In conclusion, we developed a new efficient method for introducing a functional/chromophoric group to
the primary rim of β-CD through Cu-catalyzed 1,3-dipolar cycloaddition of aromatic alkynes to
6-azido-6-deoxy-β-CD. Although a much larger amount of Cu catalyst, longer reaction period, and higher
temperature are needed as compared with the conventional click reaction, the β-CD adducts were
obtained in satisfactory yields via the crick chemistry of CDs.
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1
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HETEROCYCLES, Vol. 76, No. 1, 2008
(380 mg, 2.1 mmol) with stirring. To the resulting mixture was added an aqueous solution (15 mL)
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was dissolved in DMF (20 mL) and filtered. The filtrate was added dropwise to 300 mL of acetone to
obtain a precipitate, which was collected and recrystallized twice from a 4:1 mixture of water and
acetone (v/v) to give the final product as a light yellow solid.
1
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3.47-2.89 (m, 28H); ESI-MS: 1364.63 [M+Na]+.
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1H), 5.92-5.74 (m, 14H), 5.22-4.36 (m, 15 H), 4.02-3.63 (m, 14H), 3.38-2.73 (m, 28H); ESI-MS:
1365.09 [M+Na]+.
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