Synthesis of a β-cyclodextrin derivative bearing an azobenzene group on the secondary face

Article abstract of DOI:10.1016/j.tetlet.2008.09.032

An oxidative coupling Sonogashira-type reaction has been used to synthesize a β-cyclodextrin derivative bearing an azobenzene group on the secondary face for the first time starting from a β-cyclodextrin propargylated at one of its C-2 positions. The de-O

Full text of DOI:10.1016/j.tetlet.2008.09.032

Tetrahedron Letters 49 (2008) 6778–6780
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Tetrahedron Letters
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Synthesis of a b-cyclodextrin derivative bearing
an azobenzene group on the secondary face
*
Juan M. Casas-Solvas, Antonio Vargas-Berenguel
Área de Química Orgánica, Univesidad de Almería, 04120 Almería, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 June 2008
Revised 5 September 2008
Accepted 8 September 2008
Available online 11 September 2008
An oxidative coupling Sonogashira-type reaction has been used to synthesize a b-cyclodextrin derivative
bearing an azobenzene group on the secondary face for the first time starting from a b-cyclodextrin prop-
argylated at one of its C-2 positions. The de-O-propargylation reaction and the formation of an oxidative
homocoupling dimer were found to compete with the desired product under several Sonogashira-type
reaction conditions. However, the use of a diluted reductive atmosphere of H2 avoided the former and
diminished the latter.
Keywords:
b-Cyclodextrin
Azobenzene
Ó 2008 Elsevier Ltd. All rights reserved.
Oxidative coupling
Sonogashira reaction
b-Cyclodextrin (b-CD) is a naturally occurring cyclic oligosac-
charide comprising seven -glucopyranose units linked by
-(1?4) bonds. It possesses a relatively rigid thorus-shaped struc-
OH
O
HO
D
O
O
OH
HO
a
HO
O
ture, which defines an inner hydrophobic cavity rimmed by two
hydrophilic openings. These openings are different in diameter,
the narrower containing the primary hydroxy groups located
on the C-6 of the glucopyranose units and the wider containing
the secondary ones on C-2 and C-3 positions (Chart 1). As a con-
sequence, b-CD is well-known to form inclusion complexes in
aqueous solution with a large variety of organic molecules of
hydrophobic nature and suitable size and geometry.1 In addition
to other applications, this feature has been explored for the design
and construction of molecular machines in which the inclusion of
the guest molecule can be controlled through external stimuli.2
One of the strategies followed to reach this goal has been the
attachment of a chemical group sensitive to pH variations,3 metal-
lic cations,4 electrochemical signals,5 or irradiation with light6 onto
the b-CD. Among the photosensitive groups, azobenzene has re-
ceived much attention in recent years due to its easy and reversible
cis–trans isomerization.7 Azobenzene derivatives undergo trans to
cis isomerization upon irradiation with UV light and isomerize
back to trans with visible light exposure or simply in the dark. Such
remarkable behavior makes azobenzene a good building block for
the preparation of photoswitchable molecular receptors by conju-
gation with molecules involved in molecular recognition processes.
As a part of a project that involved b-CD-based photocontrol-
lable receptors, we turned our attention to the synthesis of azo-
OH
O
OH
OH
HO
O
O
HO
β
HO
O
OH
OH
O
HO
O
OH
OH
O
HO
OH
O
O
OH
O
HO
OH
Chart 1. Schematic representation of b-CD.
benzene-containing b-CD derivatives.8 Recently, we have pre-
pared some azobenzene derivatives carrying one or two b-CD
residues linked through their primary faces.9 In this Letter, we wish
to report the synthesis of a b-CD derivative bearing an azobenzene
group on the secondary face. Location of the photosensitive residue
in such face could enhance the effect of the light over the supramo-
lecular chemistry of the conjugate given that guest molecules pref-
erably penetrate the cavity through such opening.1 To the best of
our knowledge, this is the first time that an azobenzene structure
is grafted onto the secondary face of the b-CD.
To achieve this aim, we decided to start from mono-2-O-propar-
gyl-b-CD 1 (Scheme 1). This compound is a very convenient build-
ing block for the construction of b-CD functionalized on the
secondary face. The terminal alkyne group linked to C-2 of the
* Corresponding author. Tel.: +34 950 015315; fax: +34 950 015481.
E-mail address: avargas@ual.es (A. Vargas-Berenguel).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.032

J. M. Casas-Solvas, A. Vargas-Berenguel / Tetrahedron Letters 49 (2008) 6778–6780
6779
N
N
2
2
2
2
O
S
O
F
F
N
N
O
O
O
O
F
O
3
β
β
β
β
+
[Pd(PPh3)4], CuI, Et3N,H2,
DMF, 100 ºC, 4 h
1
4
5
Scheme 1.
tons. In the 13C NMR spectrum of 4 appeared a series of peaks
between 151.9 and 122.7 ppm indicating the presence of the
azobenzene rings. Likewise, alkyne carbons signals observed at
79.9 and 77.8 ppm on the spectrum of 1 did not appear on the
spectra of 4 and 5. Instead, the spectrum of 4 showed peaks at
88.5 and 85.6 ppm corresponding to aryl alkyne carbons, while
that of 5 showed signals at 76.4 and 69.8 assigned to the 1,3-diyne
carbons.
In conclusion, an oxidative coupling Sonogashira-type reaction
has been used to synthesize a b-cyclodextrin derivative bearing
an azobenzene group on the secondary face for the first time. We
started from a b-cyclodextrin propargylated at C-2 position of only
(F3CSO2)2, Py
95 %
O
S
O
N
N
F
F
N
N
HO
F
O
2
3
Scheme 2.
macrocycle offers the possibility of the attachment of the azobenz-
ene structure by oxidative coupling Sonogashira reaction. The nec-
essary electrophile for the oxidative coupling reaction was
provided by triflation of 4-hydroxyazobenzene 2 to give the triflat-
ed azobenzene 3 (Scheme 2). This reaction was performed in the
presence of triflic anhydride in pyridine and gave desired com-
pound in 95% yield. Triflation was easily confirmed by 13C NMR
as it showed the appearance of a quartet at 118.8 ppm with a cou-
pling constant of 320.9 Hz, which is typical of the CF3 group. In
addition, the signal of C-4 carbon of the phenol ring suffered a sig-
nificant displacement of ca. 10 ppm to lower frequency.
one of its D-glucose units. The de-O-propargylation reaction and
the formation of an oxidative homocoupling dimer were found to
compete with the desired product under several Sonogashira-type
reaction conditions. However, the exhaustive degassing of
the reaction mixture and the use of [Pd(PPh3)4] instead of
[PdCl2(PPh3)2], a pre-heated oil bath, and a diluted reductive atmo-
sphere of H2 avoided the former and diminished the latter.
Targeting b-CD bearing azobenzene on secondary face
4
(Scheme 1), we performed the reaction of 1 and 3 under several
Sonogashira-type reaction conditions.10,11 Presence of CuI and
Et3N as a nitrogenated base showed to be essential for the synthe-
sis of 4. We found that the formation of oxidative homocoupling
product 5 and the de-O-propargylation reaction competed with
the formation of 4 in all cases. In fact, compound bis(b-CD) 5 was
obtained in 98% yield, after column chromatography purification,
when the oxidative coupling reaction was performed in the
absence of compound 3. Our attempts to reduce the homocoupling
reaction included the use of [Pd(PPh3)4] instead of [PdCl2(PPh3)2],
exhaustive degassing of the reaction mixture before adding the
propargyl derivate 1, and pre-heating of the oil bath. These condi-
tions led to a slight decrease in the extension of the homocoupling
though dimer 5 remained the major product. However, a much
better result for the heterocoupling reaction was obtained when
the reaction was performed in DMF at 100 °C with Et3N as a base
using [Pd(PPh3)4] and CuI as catalysts and an atmosphere of hydro-
gen gas diluted with nitrogen (seeSupplementary data). The reduc-
tive atmosphere was key for diminishing homocoupling, since it
seems to reduce the concentration of oxygen in the reaction which
may be the major responsible for the homocoupling reaction.11c
Under these reaction conditions, compounds 1 and 3 gave rise to
the desired 2-O-azobenzene-b-CD 4 in 62% yield along with homo-
coupling product 5 in 37% yield, after silica gel column chromato-
graphy. Furthermore, no traces of the de-O-propargylation product
were found in this case.
Acknowledgments
The authors acknowledge the Spanish Ministry of Education
and Science for the financial support (Grant CTQ2007-61207) and
for a Ph.D. scholarship (J.M.C.-S.).
Supplementary data
Supplementary data (general methods, 1H NMR, 13C NMR and
MALDI-TOF-MS spectra for compounds 1 and 3–5) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2008.09.032.
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