Easily accessible mono- and polytopic β-cyclodextrin hosts by click chemistry

Article abstract of DOI:10.1002/ejoc.200800728

A great variety of mono- and polytopic β-cyclodextrin hosts have been easily synthesized by using the Cu^I-catalyzed azide-alkyne cycloaddition reaction. Of particular interest for their multibinding properties, dimeric and trimeric CD compounds

Full text of DOI:10.1002/ejoc.200800728

FULL PAPER
DOI: 10.1002/ejoc.200800728
Easily Accessible Mono- and Polytopic β-Cyclodextrin Hosts by Click
Chemistry
Maxime Mourer,[a] Frédéric Hapiot,[a] Sébastien Tilloy,[a] Eric Monflier,[a] and
Stéphane Menuel*[a]
Keywords: Click chemistry / Cycloaddition / Cyclodextrins
A great variety of mono- and polytopic β-cyclodextrin hosts
have been easily synthesized by using the CuI-catalyzed az-
ide–alkyne cycloaddition reaction. Of particular interest for
their multibinding properties, dimeric and trimeric CD com-
pounds were obtained by “clicking” mono-6-azido-β-cyclo-
dextrin derivatives with flexible or rigid dialkynyl spacers.
The reaction is general, high-yielding for some of the synthe-
sized molecules (Ͼ80%) and proceeds under mild conditions.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
rently extending our approach to more complex but better
performing systems. The need to easily access elaborated
CDs prompted us to develop new synthetic pathways. In
recent work we demonstrated that CD dimers are easily ac-
cessible by click chemistry starting from mono-6-azido-β-
CD and ortho-, meta- or para-bis(prop-2-ynyloxy)benzenes
as spacers.[6] Herein, we show that CuI-catalyzed azide–
alkyne cycloaddition can be of general use in the synthesis
of mono- and polytopic CD derivatives starting from a pool
of easily accessible mono-azide CDs and alkynyl derivatives
of different nature. The scope of the reaction was explored
by using mono-, di- or trialkynyl linkers and hydroxylated
or randomly methylated mono-6-azido-β-CDs. Randomly
methylated mono- or polytopic β-CDs are particularly
interesting species as it is well known that partially methyl-
ated CDs are much more water-soluble than hydroxylated
ones.[7]
Introduction
During the past 30 years cyclodextrins (CDs) have
gained wide recognition for their ability to form inclusion
complexes with organic, inorganic, organometallic or bio-
logical molecules.[1] However, the binding properties of
native CDs are generally limited and more elaborated struc-
tures are often needed. Thus, modified CDs have been syn-
thesized to efficiently accommodate structurally matched
guests. The strength of the interaction between CD hosts
and their guests can vary significantly depending on their
structures. In particular, owing to multiple simultaneous in-
teractions and collective binding properties, it has been
shown that CD dimers and trimers are interesting polytopic
supramolecular hosts with stronger binding ability than
simple CD receptors.[2] In addition to the enhanced com-
plexing power generated by the presence of two or three
CDs around the guest, the linker that ties the CDs together
may also contribute to an increased binding ability because
it can provide an additional pseudo-cavity. This cooperative
binding could have beneficial effects and has been turned to
account in many fields, for example, in catalysis, templated
synthesis, photochemistry, enzyme mimicking and molecu-
lar imprinting.[3] For this reason, numerous modified CDs
Results and Discussion
Synthesis of β-CD and Alkynyl Precursors
The hydroxylated mono-6-azido β-CD (1) was prepared
have already been elaborated but the synthesis of many of by using a two-step approach with tosylation of the native
them have proved to be fastidious, time-consuming and β-CD followed by sodium azide substitution, as described
yields were often low especially for trimeric species due to previously.[8] The randomly methylated mono-6-azido-β-
steric hindrance.[4]
CD (2, Scheme 1) was synthesized by reaction of 1 in basic
In recent years we have developed a synthesis of modified conditions with a dimethyl sulfate solution. After work-up,
CDs and applied them to catalytic processes.[5] We are cur- 2 was isolated as a pale yellowish-white powder in 85%
yield. Compound 2 contained a mixture of partially methyl-
ated β-CDs with an average degree of substitution of 1.8
methyl groups per glucopyranose unit. The solubility of 2
in water is 30-fold that of 1 (500 vs. 17 gL–1). Products syn-
thesized from 2 are of particular interest in biphasic cataly-
[a] Université d’Artois, Unité de Catalyse et de Chimie du Solide-
UMR 8181,
rue Jean Souvraz, S.P.18, 62307 Lens Cedex, France
Fax: +33-3-21791755
E-mail: stephane.menuel@univ-artois.fr
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M. Mourer, F. Hapiot, S. Tilloy, E. Monflier, S. Menuel
FULL PAPER
sis as we have demonstrated that partially methylated β- DMF (solvent used in our previous study[6]). The more dis-
CDs efficiently adsorbed at the organic/aqueous interface sociating character of DMSO[10] certainly prevented CuII to
promote mass-transfer.[9] Concerning alkynyl precursors, associate with the CD secondary face[11] and thus improved
some of them were commercial and others were synthesized their activity towards alkynyl derivatives. An excess alkynyl
divergently starting with propargyl bromide and alcoholate reactant (1.5 equiv.) with respect to the CD was also used
derivatives or with propargyl alcohol and bromomethylben- to convert all the hydroxylated β-CD–N3 and to avoid puri-
zene derivatives, both in basic conditions (Scheme 1). For fication problems. After the addition of 3 equiv. sodium as-
example, (Ϯ)-2,2Ј-dihydroxy-1,1Ј-binaphthalene or 1,3,5- corbate the blue solution became orange-yellow. As the
trihydroxybenzene were propargylated by treatment with CuI-catalyzed triazole synthesis was somewhat sensitive to
potassium carbonate and propargyl bromide to afford 8 the steric environment of the azide,[12] a reaction time of
and 9 in 98 and 61% yields, respectively. Conversely, 10 and 18 h was chosen to allow completion of the cycloaddition.
11 were successfully prepared in good yields (80 and 70%, Satisfyingly, after 18 h reaction time, the reaction was found
respectively) from tris(1,3,5-bromomethyl)benzene and pro- to be clean as TLC analysis of the crude product only re-
pargyl alcohol or butyn-1-ol, respectively.
vealed three spots, two corresponding to the organic com-
pounds (desired product and excess alkyne) and the third
one to copper salts. The latter can be easily removed by
addition of an ammoniac solution (8%) and subsequent
chromatography on a silica gel column using water as elu-
ent. The copper salts remained at the top of the column
(Rf = 0), whereas the cycloaddition product easily migrated
through the silica gel. Excess alkyne was also easily re-
moved during the chromatographic purification. Depending
on the nature of the alkyne, evaporation of water from the
CD-containing fractions led to 12–15 in good yields
(Ͼ61%). The compounds obtained were shown to be pure
1
by MALDI-TOF/TOF mass spectrometry and H and 13C
NMR spectroscopy. The four products were soluble in D2O.
Their 1H NMR spectra revealed a characteristic peak at
around 8 ppm, which was assigned to the triazole proton.
On the other hand, as generally observed for substituted
CDs, other signals were hardly exploitable due to overlap-
ping and broadening. This suggests a modification of the
conical β-CD structure leading to non-equivalent glucopyr-
anose units. As a consequence, complete signal assignment
was therefore difficult. By contrast, the 13C NMR spectra
were much more informative as distinct peaks could be de-
tected. As an example, the carbon atoms adjacent to the
triazole cycle were readily distinguished from the carbon
atoms adjacent to the alkyne or azido groups. The purity
of the compounds was fully established by mass spectra for
which peaks were assigned with high confidence. Some of
the mass spectra of the synthesized products are displayed
in Figure 1.
Scheme 1. β-CD and alkyne precursors. DS: degree of substitution.
A few modifications were required to access the hydrox-
ylated dimeric derivatives 16–19 and hydroxylated trimeric
species 20–22. First, longer reaction times were required for
Synthesis of Mono- and Polytopic Hydroxylated 1,2,3-
Triazole-β-CD Derivatives
Once the reactants had been prepared, the Huisgen [2+3] trimers than for dimers (48 vs. 18 h) to achieve complete
cycloaddition reaction was applied to the synthesis of conversion of the di- or trialkyne linkers, probably because
mono- and polytopic 1,2,3-triazole-β-CD derivatives. The of the steric hindrance between the bulky CDs interfering
procedure was slightly different depending on the CD sub- with the formation of the terminal alkyne–CuI species.[13]
stituents and the mono- or polytopic character. The CuI- Note that although trimers reacted over a longer period,
catalyzed cycloaddition, which leads to hydroxylated mono- yields could be high (87% for 20), in contrast to those pre-
topic compounds 12–15, proceeded at room temperature in viously reported for hindered azides.[4] Secondly, to orient
DMSO with 1.1 equiv. CuSO4·xH2O (with respect to the the reaction towards dimers or trimers, excess CD
CD) required for completion in 18 h (Scheme 2). An excess (1.33 equiv.) with respect to the alkynyl derivative was used.
of CuSO4·xH2O was also used to force the reaction to pro- Consequently, at the end of the reaction, an additional puri-
ceed quantitatively. DMSO was chosen as the solvent as it fication step was necessary to remove excess mono-6-azido-
appeared to be far more efficient in terms of yields than β-CD. Addition of acetone to the reaction solution led to
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Mono- and Polytopic β-Cyclodextrin Hosts
Scheme 2. Synthesis of hydroxylated mono- and polytopic β-CD derivatives.
the precipitation of CDs. The solid was recrystallized in a nally to green-yellow at the end of the reaction (18 h reac-
water/acetone mixture and then purified as described above tion time). After evaporation of the solvent, the randomly
with an ammoniac solution. Compounds 16–22 were iso- methylated mono- or polytopic compounds were subjected
lated as yellowish-white powders. Mass spectrometry con- to an ammoniac solution and purified by chromatography
firmed the dimeric and trimeric nature of the products. on a silica gel column. Evaporation of water gave 23–30
NMR measurements also confirmed their polytopic charac- as yellowish-white powders in moderate-to-good yields (32–
ter, in particular through a comparison of the integrations 83%; Scheme 3).
Note that stoichiometric amounts of alkynes and CD
were used because the randomly methylated products ob-
tained and RAME-β-CD-N3 were not easily separated by
column chromatography. Complete conversion of RAME-
β-CD-N3 was therefore essential to avoid purification prob-
of CD protons with those of the spacers.
Synthesis of Mono- and Polytopic Randomly Methylated
1,2,3-Triazole-β-CD Derivatives
The reaction conditions were also optimised for ran- lems. The randomly methylated mono- and ditopic com-
domly methylated CD precursors. In this case, the copper- pounds could barely be characterized by their 1H NMR
catalyzed 1,3-dipolar cycloaddition proceeded at room tem- spectra as the signals were even broader than those ob-
perature starting from an acetone solution containing stoi- served for hydroxylated β-CD derivatives because of the
chiometric amounts of alkynyl derivative, RAME-β-CD-N3 non-symmetric character of the partially methylated CDs.
and CuSO4·xH2O. Addition of 2 equiv. sodium ascorbate Conversely, the efficiency of the reaction was unambigu-
led to a change of colour from blue to brown-red and fi- ously proven by 13C NMR and MALDI analysis, the latter
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M. Mourer, F. Hapiot, S. Tilloy, E. Monflier, S. Menuel
FULL PAPER
Figure 1. MALDI-TOF/TOF mass spectra of the hydroxylated
1,2,3-triazole β-CD derivatives 14 (top) and 19 (bottom).
Figure 2. MALDI-TOF/TOF mass spectra of the randomly meth-
ylated 1,2,3-triazole-β-CD derivatives 25 (top) and 27 (bottom).
Scheme 3. Synthesis of randomly methylated mono- and polytopic β-CD derivatives.
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Mono- and Polytopic β-Cyclodextrin Hosts
(589 mg, 6.40 mmol) in THF (15 mL) at 0 °C. The solution was
vigorously stirred for 10 min. Propargyl bromide (4.57 g,
38.4 mmol) in toluene was added at 0 °C and the solution was
brought to room temperature. The mixture was stirred for 5 h. Ex-
cess NaH was then neutralized by the slow addition of ice–water.
The solution was concentrated and the product extracted from the
aqueous phase with CH2Cl2 (3ϫ500 mL). Once dried on MgSO4,
the crude product was subjected to chromatography on a silica gel
column with CH2Cl2/hexane (90:10) as eluent. After evaporation
of the solvent, the expected product was isolated as an orange oil
(830 mg, 63%). 1H NMR (300 MHz, CDCl3): δ = 4.34 (d, J =
2.1 Hz, 2 H), 4.19 (d, J = 2.1 Hz, 4 H), 3.92 (m, 1 H), 3.67 (m, 4
H), 2.43 (br. s, 3 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 80.31,
79.87, 76.58, 75.08, 74.84, 70.02, 59.02, 57.94 ppm.
showing a distribution of partially methylated β-CDs that
was consistent with the assigned structures (Figure 2).
Conclusions
Highly efficient CuI-catalyzed cycloaddition was
achieved starting from easily accessible β-CD azides and
alkyl- or arylalkynyl precursors. Thus, significant structural
diversity of β-CD derivatives was obtained through the for-
mation of a stable 1,2,3-triazole linkage. Of particular inter-
est was the synthesis of randomly methylated mono- and
polytopic β-CDs, which were very soluble in water. The
methodology is general, high-yielding for some of the syn-
thesized compounds, proceeds under mild conditions and
affords building blocks useful for organic and supramolec-
ular chemistry. The potential of the synthesized compounds
as mono- and polytopic β-CD hosts is presently under pro-
gress and shall be reported in due course.
(؎)-2,2Ј-Bis(prop-2-ynyloxy)-1,1Ј-binaphthalene (8): Yield 925 mg,
98%. 1H NMR (300 MHz, CDCl3): δ = 8.01 (d, J = 9 Hz, 2 H),
7.92 (d, J = 8.1 Hz, 2 H), 7.62 (d, J = 9 Hz, 2 H), 7.38 (t, J =
6.7 Hz, 2 H), 7.26 (t, J = 6.7 Hz, 2 H), 7.18 (d, J = 8.1 Hz, 2 H),
4.64 (s, 4 H), 2.43 (s, 2 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ
= 153.6, 134.4, 130.2, 129.8, 128.4, 126.9, 126.0, 124.5, 121.0, 116.4,
79.7, 75.7, 57.66 ppm.
1,3,5-Tris(prop-2-ynyloxy)benzene (9): The title compound was syn-
thesized following a procedure described in the literature[13]
(634 mg, 61%). 1H NMR (300 MHz, CDCl3): δ = 6.27 (s, 3 H),
4.65 (d, J = 2.2 Hz, 6 H), 3.53 (t, J = 2.2 Hz, 3 H) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 159.5, 95.5, 78.4, 75.9, 56.1 ppm.
Experimental Section
General: All chemicals were purchased from Acros and Aldrich
Chemicals in their highest purity. All solvents were used as supplied
without further purification. Distilled water was used in all experi-
ments. Analytical thin-layer chromatography (TLC) was performed
on E. Merck aluminium-backed silica gel (Silica Gel F254). Com-
pounds were identified by using UV fluorescence and/or staining
with a solution of phosphomolybdic acid in aqueous sulfuric acid
and ethanol. NMR spectra were recorded with a Bruker DRX300
1,3,5-Tris(prop-2-ynyloxymethyl)benzene (10): A 60% NaH (0.18 g,
4.51 mmol) oil dispersion was added to a solution of propargyl
alcohol (0.25 g, 4.51 mmol) in DMF (15 mL) at 0 °C under nitro-
gen. After stirring for 10 min, tris-1,3,5-bromomethylbenzene
(0.5 g, 1.4 mmol) was added and the resulting solution was stirred
for 5 h at room temperature. After addition of ice to the reaction
solution to neutralize the excess NaH and subsequent addition of
CH2Cl2, the organic phase was recovered. The aqueous phase was
washed with CH2Cl2 (20 mL). After decantation and separation,
the organic phases were gathered, dried with anhydrous MgSO4,
filtered and concentrated. Purification by chromatography on a sil-
ica gel column gave the product as a colourless oil (316 mg, 80%).
1H NMR (300 MHz, CDCl3): δ = 7.30 (s, 3 H), 4.61 (s, 6 H), 4.19
(d, J = 2.3 Hz, 6 H), 2.47 (t, J = 2.3 Hz, 3 H) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 138.0, 127.2, 79.6, 74.9, 57.4 ppm.
1
spectrometer operating at 300 MHz for H nuclei and at 75 MHz
for 13C nuclei. CDCl3 (99.50% isotopic purity), [D6]DMSO
(99.80% isotopic purity) and D2O (99.92% isotopic purity) were
purchased from Euriso-Top. Mass spectra were recorded with a
MALDI-TOF/TOF Bruker Daltonics Ultraflex II spectrometer in
positive reflectron mode with 2,5-DHB as the matrix.
Randomly Methylated Mono-6-azido-6A-deoxy-β-
D-cyclodextrin (2):
A concd. NaOH solution was added dropwise to a suspension of
mono-6-azido-6A-deoxy-β--cyclodextrin (20 g, 17 mmol) in water
(50 mL) at 0 °C over a period of 20 min. A solution of dimethyl
sulfate (90 mL, 950 mmol) in THF (15 mL) at 0 °C was then added
dropwise to the resulting clear solution. Ethanol (10 mL) was
added to the solution which was brought to room temperature and
stirred for 18 h. After addition of an ammoniac solution (20%,
10 mL), THF was evaporated and the product was extracted from
the aqueous phase with chloroform (3ϫ500 mL). The organic
phase was dried with anhydrous MgSO4. Chloroform was removed
under reduced pressure to give the product as a white powder
1,3,5-Tris[(but-3-ynyl)oxymethyl]benzene (11): A 60% NaH (0.18 g,
4.51 mmol) oil dispersion was added to a solution of butyn-1-ol
(0.31 g, 4.50 mmol) in DMF (15 mL) at 0 °C under nitrogen. After
stirring for 10 min, 1,3,5-tris(bromomethyl)benzene (0.50 g,
1.4 mmol) was added and the resulting solution stirred at room
temperature. After stirring for 5 h, ice and CH2Cl2 were added to
the solution. After decantation and separation, the organic phase
was recovered. The aqueous phase was washed with CH2Cl2
(20 mL). The organic phases were collected, dried with anhydrous
MgSO4, filtered and concentrated. Purification by chromatography
on a silica gel column (CH2Cl2) gave the product as a colourless
oil (317 mg, 70%). 1H NMR (300 MHz, CDCl3): δ = 7.26 (s, 3 H),
1
(19.33 g, 85%). H NMR (300 MHz, D2O): δ = 5.14 (br. s, 3.7 H),
4.93 (br. s, 3.3 H), 3.83–3.62 (m, 12.2 H), 3.59–3.47 (m, 32.6 H),
3.44 (br. s, 15.4 H), 3.29–3.22 (m, 22.1 H) ppm. 13C NMR
(75.5 MHz, D2O): δ = 101.8–101.6, 99.5–99.3, 82.9–81.6, 79.1–78.6,
73.6–70.0, 61.6, 60.2–58.7, 51.6, 32.0, 29.3, 28.6, 25.6 ppm. MS:
m/z (%) = 1322.40 (2.1) (calcd. 1322.48 for [C52H89N3O34 + Na]+),
1336.41 (14.8) (calcd. 1336.49 for [C53H91N3O34 + Na]+), 1350.41
(10.6) (calcd. 1350.50 for [C54H93N3O34 + Na]+), 1364.45 (53.4)
(calcd. 1364.51 for [C55H95N3O34 + Na]+), 1378.47 (13.6) (calcd.
1378.52 for [C56H97N3O34 + Na]+), 1392.54 (5.5) (calcd. 1392.53
for [C57H99N3O34 + Na]+). Average DS: 1.8.
4.55 (s, 6 H), 3.60 (t, J = 6.9 Hz, 6 H), 2.51 (td, J1 = 6.9, J2
=
2.2 Hz, 6 H), 1.99 (br. s, 3 H) ppm. 13C NMR (75.5 MHz, CDCl3):
δ = 139.2, 126.5, 82.8, 72.8, 72.4, 68.9 ppm.
General Procedure for the Synthesis of Hydroxylated Monotopic β-
CD Derivatives: Mono-6-azido-β-CD (3.3 mmol) and hydrated cop-
per sulfate (2.8 mmol) was added to a solution of the alkynyl deriv-
ative (2.8 mmol) in DMSO (25 mL). After subsequent dropwise ad-
1,2,3-Tris(prop-2-ynyloxy)propane (7):
A
60% NaH (461 mg,
dition of
a freshly prepared solution of sodium ascorbate
19.2 mmol) oil dispersion was added to a solution of glycerol
(5.6 mmol) dissolved in water, the solution was stirred for 18 h at
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M. Mourer, F. Hapiot, S. Tilloy, E. Monflier, S. Menuel
FULL PAPER
room temperature. After evaporation of the solvents, the crude
product was dissolved in an ammoniac solution (8%) and stirred
overnight before being purified by column chromatography on sil-
ica gel with water as eluent.
2 H), 5.15–4.95 (m, 28 H), 4.00–3.48 (m, 66 H), 3.13 (d, J =
12.3 Hz, 2 H), 2.78 (m, 6 H), 2.03 (m, 2 H) ppm. 13C NMR
(75.5 MHz, [D6]DMSO): δ = 146.3, 123.3, 102.2, 81.6, 73.1, 72.4,
72.3, 72.1, 71.8, 71.6, 60.0, 30.7 ppm. MS: m/z = 2433.66 (calcd.
2433.80 for [C91H146N6O68 + Na]+).
1-(6A-Deoxy-β-
D-cyclodextrin)-4-(aminomethyl)-1,2,3-triazole (12):
1
2,2Ј-Bis[1-(6A-deoxy-β-
D-cyclodextrin)-1,2,3-triazol-4-ylmethoxy]-
Yield 2.44 g, 61%. H NMR (300 MHz, D2O): δ = 8.06 (s, 1 H),
4.96–4.82 (m, 8 H), 4.08 (m, 2 H), 3.91–3.71 (m, 28 H), 3.60–3.34
(m, 11 H), 3.01 (m, 1 H), 2.68 (m, 1 H) ppm. 13C NMR (75.5 MHz,
D2O): δ = 156.0, 127.3, 101.9, 81.4, 73.4, 73.2, 72.7, 63.3, 60.6 ppm.
MS: m/z = 1237.27 (calcd. 1237.42 for [C45H74N4O34 + Na]+).
(؎)-1,1Ј-binaphthalene (19): Yield 1.17 g, 87 %. 1H NMR
(300 MHz, [D6]DMSO): δ = 8.04 (d, J = 9.1 Hz, 2 H), 7.92 (d, J
= 7.8 Hz, 2 H), 7.77 (d, J = 9.1 Hz, 2 H), 7.62 (s, 1 H), 7.48 (s, 1
H), 7.33 (t, J = 7.2 Hz, 2 H), 7.19 (t, J = 7.8 Hz, 2 H), 6.84 (t, J =
7.2 Hz, 2 H), 5.85–5.67 (m, 28 H), 5.18–5.11 (m, 4 H), 4.99 (br. s,
2 H), 4.83 (br. s, 10 H), 4.72 (br. s, 4 H), 4.49 (br. s, 12 H), 4.30
(br. s, 2 H), 3.65–3.59 (m, 40 H), 3.50–3.00 (m, overlapped with
residual H2O) ppm. 13C NMR (75.5 MHz, [D6]DMSO): δ = 154.0,
153.4, 144.0, 133.7, 130.3, 130.2, 129.9, 127.0, 125.5, 125.0, 124.6,
121.8, 118.7, 102.4, 83.6, 73.6, 72.7, 71.9, 60.5, 30.6 ppm. MS: m/z
= 2703.83 (calcd. 2703.87 for [C110H156N6O70 + Na]+).
1-(6A-Deoxy-β-
D-cyclodextrin)-4-[(dimethylamino)methyl]-1,2,3-tri-
azole (13): Yield 2.91 g, 71%. 1H NMR (300 MHz, D2O): δ = 8.21
(s, 1 H), 5.08 (m, 1 H), 4.96 (m, 8 H), 4.14 (m, 2 H), 3.88–3.68 (m,
26 H), 3.58–3.35 (m, 12 H), 3.09 (d, J = 11.7 Hz, 1 H), 2.78 (d
overlapped with s, 7 H) ppm. 13C NMR (75.5 MHz, D2O): δ =
136.9, 129.6, 102.2, 83.3, 73.4, 72.7, 71.8, 60.8, 42.5, 30.6 ppm. MS:
m/z = 1265.30 (calcd. 1265.41 for [C47H78N4O34 + Na]+).
1,2,3-Tris[1-(6A-deoxy-β-
D-cyclodextrin)-1,2,3-triazol-4-ylmethoxy]-
1-(6A-Deoxy-β-
D-cyclodextrin)-4-(hydroxymethyl)-1,2,3-triazole
propane (20): Yield 1.60 g, 87%. 1H NMR (300 MHz, D2O): δ =
8.05 (s, 3 H), 5.18–4.97 (m, 21 H), 4.64 (s, 6 H), 4.19 (m, 3 H),
3.98–3.83 (m, 24 H), 3.70–3.50 (m, 38 H), 3.13 (d, J = 10.8 Hz, 3
H), 2.81 (d, J = 10.8 Hz, 3 H) ppm. 13C NMR (75.5 MHz, D2O):
δ = 144.2, 127.0, 101.9, 83.4, 81.6, 73.4, 72.3, 71.8, 70.8, 59.5, 51.5,
30.6 ppm. MS: m/z = 3707.30 (calcd. 3707.21 for [C138H221N9O105
+ Na]+).
1
(14): Yield 3.21 g, 80%. H NMR (300 MHz, D2O): δ = 7.99 (s, 1
H), 5.36 (s, 1 H), 5.03 (m, 8 H), 4.60 (m, 1 H), 4.16 (m, 1 H), 3.94–
3.71 (m, 26 H), 3.68–3.48 (m, 12 H), 3.11 (d, J = 13.5 Hz, 1 H),
2.77 (d, J = 13.5 Hz, 1 H), 2.78 (d, 1 H) ppm. 13 C NMR
(75.5 MHz, D2O): δ = 147.2, 125.8, 102.2, 81.6, 73.4, 72.4, 72.2,
60.7, 60.6, 59.5 ppm. MS: m/z = 1238.24 (calcd. 1238.39 for
[C45H73N3O35 + Na]+).
1-(6A-Deoxy-β-
D
-cyclodextrin)-4-(2-hydroxyethyl)-1,2,3-triazole
1,3,5-Tris[1-(6A-deoxy-β-
D-cyclodextrin)-1,2,3-triazol-4-ylmeth-
oxy]benzene (21): Yield 893 mg, 48%. H NMR (300 MHz, D2O):
δ = 8.15 (br. s, 3 H), 6.42 (br. s, 3 H), 5.22–4.96 (m, 48 H), 4.19–
1
1
(15): Yield 3.16 g, 78%. H NMR (300 MHz, D2O): δ = 7.87 (s, 1
H), 5.17 (s, 1 H), 4.98 (m, 8 H), 4.58 (m, 1 H), 4.19 (m, 1 H), 4.03–
3.78 (m, 26 H), 3.76–3.48 (m, 12 H), 3.15 (d, J = 12.2 Hz, 1 H), 3.22 (m, 99 H), 3.18 (d, J = 9.3 Hz, 3 H), 2.85 (d, J = 9.3 Hz, 3
2.94 (s, 2 H), 2.78 (d, J = 12.2 Hz, 1 H) ppm. 13C NMR (75.5 MHz, H) ppm. 13C NMR (75.5 MHz, [D6]DMSO): δ = 160.83, 143.08,
D2O): δ = 163.5, 126.4, 102.4, 81.6, 73.4, 72.4, 71.2, 60.7, 35.2,
28.2 ppm. MS: m/z = 1252.42 (calcd. 1229.42 for C46H75N3O35
[M]+).
126.87, 103.03, 82.39, 73.85, 73.60, 73.19, 72.90, 72.57, 72.52,
61.26, 56.88 ppm. MS: m/z = 3740.66 (calcd. 3741.20 for
[C141H219N9O105 + Na]+).
1,3,5-Tris[1-(6A-deoxy-β-
D-cyclodextrin)-1,2,3-triazol-4-ylmethoxy-
General Procedure for the Synthesis of Hydroxylated Polytopic β-
CD Derivatives: Mono-6-azido-β-CD (1.3 mmol) and hydrated cop-
per sulfate (1.1 mmol) were added to a solution of the alkynyl de-
rivative (0.5 mmol alkynyl function) in DMSO (25 mL). After the
subsequent dropwise addition of a freshly prepared solution of so-
dium ascorbate (2.2 mmol) dissolved in water, the solution was
stirred for 18 h at room temperature. Addition of acetone (100 mL)
induced the precipitation of a yellowish-white powder that was
recrystallized from a water/acetone mixture. The solid was re-
covered, dissolved in an ammoniac solution (8%) and stirred over-
night before being purified by column chromatography using silica
gel with water as eluent.
methyl]benzene (22): Yield 771 mg, 41%. 1H NMR (300 MHz,
D2O): δ = 8.04 (s, 3 H), 7.35 (s, 3 H), 5.14–4.95 (m, 42 H), 4.70 (s,
6 H), 4.66 (s, 6 H), 4.18–3.15 (m, 99 H), 3.14 (d, J = 11.0 Hz, 3
H), 2.81 (d, J = 11.0 Hz, 3 H) ppm. 13C NMR (75.5 MHz, [D6]
DMSO): δ = 160.83, 143.08, 126.87, 103.03, 82.39, 73.85, 73.60,
73.19, 72.90, 72.57, 72.52, 61.26, 56.88 ppm. MS: m/z = 3783.01
(calcd. 3783.24 for [C144H225N9O105 + Na]+).
General Procedure for the Synthesis of Randomly Methylated Mono-
and Ditopic β-CD Derivatives: Randomly methylated mono-6-
azido-6A-deoxy-β--cyclodextrin (0.6 mmol) and hydrated copper
sulfate (0.7 mmol) were added to a solution of the alkynyl precur-
sor (0.7 mmol alkynyl function) in acetone (30 mL). After the sub-
sequent dropwise addition of a freshly prepared solution of sodium
ascorbate (1.4 mmol) dissolved in water (3 mL) the solution was
stirred for 18 h at room temperature. After evaporation of the sol-
vent the crude product was dissolved in an ammoniac solution
(8%) and stirred overnight before being purified by column
chromatography on silica gel with water as eluent to give the prod-
uct as a white powder.
Bis[1-(6A-deoxy-β-
D-cyclodextrin)-1,2,3-triazol-4-ylmethyl] Ether
1
(16): Yield 759 mg, 63%. H NMR (300 MHz, D2O): δ = 7.96 (s,
2 H), 5.1–4.8 (m, 18 H), 4.02 (m, 2 H), 3.83–3.63 (m, 56 H), 3.55–
3.42 (m, 22 H), 3.03 (m, 2 H), 2.81 (m, 2 H) ppm. 13C NMR
(75.5 MHz, D2O): δ = 144.0, 127.1, 102.2, 101.8, 83.4, 81.6, 73.4,
42.4, 71.8, 60.6, 51.6 ppm. MS: m/z = 2435.62 (calcd. 2435.79 for
[C90H144N6O69 + Na]+).
1,4-Bis[1-(6A-deoxy-β-
D-cyclodextrin)-1,2,3-triazol-4-yl]benzene
1
(17): Yield 782 mg, 64%. H NMR (300 MHz, D2O): δ = 6.41 (s,
2 H), 7.93 (s, 4 H), 5.20–4.86 (m, 28 H), 4.01–3.36 (m, 66 H), 3.06
(d, J = 11.2 Hz, 2 H), 2.82 (d, J = 11.2 Hz, 2 H) ppm. 13C NMR
(75.5 MHz, D2O): δ = 158.33, 147.31, 130.00, 126.61, 102.34, 83.56,
81.21, 73.61, 72.37, 71.34, 60.57 ppm. MS: m/z = 2467.71 (calcd.
2467.79 for [C94H144N6O68 + Na]+).
Randomly Methylated 1-(6A-Deoxy-β-
D-cyclodextrin)-4-(amino-
methyl)-1,2,3-triazole (23): Yield 300 mg, 36%. 1H NMR
(300 MHz, D2O): δ = 8.10 (s, 1 H), 5.20–5.00 (m, 3.8 H), 5.00–4.80
(m, overlapped with D2O), 4.32–4.18 (m, 8.2 H), 3.91–3.74 (m, 18.9
H), 3.58–3.27 (m, 34.2 H), 3.09 (br. s, 17.3 H), 3.00–2.88 (m, 12.2
H) ppm. 13C NMR (75.5 MHz, D2O): δ = 146.2, 119.9, 118.4,
1,3-Bis[1-(6A-deoxy-β-
(18): Yield 687 mg, 57%. H NMR (300 MHz, D2O): δ = 7.80 (s,
D-cyclodextrin)-1,2,3-triazol-4-yl]propane 101.1–99.8, 83.0–81.6, 73.1–70.6, 86.4, 63.2, 59.2–58.5, 30.8 ppm.
1
MS: m/z (%) = 1405.53 (7.0) (calcd. 1405.54 for [C57H98N4O34
+
5728
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5723–5730

Mono- and Polytopic β-Cyclodextrin Hosts
Na]+), 1419.54 (52.9) (calcd. 1419.55 for [C58H100N4O34 + Na]+), (calcd. 2906.09 for [C123H202N6O70 + Na]+), 2919.93 (4.6) (calcd.
1433.55 (17.1) (calcd. 1433.56 for [C59H102N4O34 + Na]+), 1447.55
(13.1) (calcd. 1447.57 for [C60H104N4O34 + Na]+), 1461.56 (9.9)
(calcd. 1461.58 for [C61H106N4O34 + Na]+).
2920.10 for [C124H204N6O70 + Na]+).
Randomly Methylated 1,3-Bis[1-(6A-deoxy-β-
D-cyclodextrin)-1,2,3-
triazol-4-ylmethoxy]benzene (29): Yield 640 mg, 32%. 1H NMR
(300 MHz, D2O): δ = 7.78 (br. s, 2 H), 7.21 (m, 2 H), 6.64 (m, 2
H), 5.15–4.46 (m, 12.2 H), 4.10–4.08 (m, 5.9 H), 3.96–3.84 (m, 36.9
H), 3.68–3.44 (m, 74.8 H), 3.44–3.28 (m, 35.8 H), 2.88 (m, 14.8
H) ppm. 13C NMR (75.5 MHz, D2O): δ = 160.1, 142.0–141.8,
122.1–121.9, 101.5–99.6, 81.7–80.9, 73.2–71.0, 70.9, 70.8, 70.6,
70.4, 64.4, 63.2, 63.3–58.5, 39.1 ppm. MS: m/z (%) = 2878.14 (13.0)
(calcd. 2878.07 for [C121H198N6O70 + Na]+), 2892.18 (52.8) (calcd.
2892.08 for [C122H200N6O70 + Na]+), 2906.18 (27.1) (calcd. 2906.09
for [C123H202N6O70 + Na]+), 2920.20 (4.9) (calcd. 2920.10 for
Randomly Methylated 1-(6A-Deoxy-β-
D-cyclodextrin)-4-[(dimeth-
ylamino)methyl]-1,2,3-triazole (24): Yield 707 mg, 83%. 1H NMR
(300 MHz, D2O): δ = 8.27 (s, 1 H), 5.19 (m, 4.9 H), 4.98 (m, 50
H), 4.44 (m, 2.1 H), 4.13 (m, 3.1 H), 3.98–3.88 (m, 13.1 H), 3.68–
3.53 (m, 43.9 H), 3.47–3.29 (m, 17.9 H), 2.82 (s, 6 H) ppm. 13C
NMR (75.5 MHz, D2O): δ = 137.4, 135.2, 112.8, 101.4–99.8, 99.0–
97.4, 82.7–81.6, 78.5, 73.4, 73.3, 73.1, 72.6, 72.3, 72.2, 70.9, 70.3,
64.4–59.4, 42.4, 30.2, 20.2, 19.7 ppm. MS: m/z (%) = 1433.51 (11.6)
(calcd. 1433.57 for [C59H102N4O34 + Na]+), 1447.53 (69.9) (calcd.
1447.58 for [C60H104N4O34 + Na]+), 1461.55 (16.1) (calcd. 1461.59
for [C61H106N4O34 + Na]+), 1477.05 (2.3) (calcd. 1475.6 for
[C62H108N4O34 + Na]+).
[C124H204N6O70
+
Na]+), 2934.17 (2.1) (calcd. 2934.11 for
[C125H206N6O70 + Na]+).
Randomly Methylated 1,4-Bis[1-(6A-deoxy-β-
D-cyclodextrin)-1,2,3-
1-(6A-Deoxy-β-
D-cyclodextrin)-4-(hy-
triazol-4-ylmethoxy]benzene (30): Yield 761 mg, 38%. 1H NMR
(300 MHz, D2O): δ = 7.81 (s, 2 H), 7.00–6.80 (m, 4 H), 5.21–5.04
(m, 10.9 H), 5.00–7.89 (m, overlapped with H2O), 4.44–4.36 (m,
9.4 H), 4.25–4.14 (m, 9.3 H), 3.75–3.40 (m, 110.8 H), 3.28–3.25 (m,
24.1 H), 2.88 (m, 11.6 H) ppm. 13C NMR (75.5 MHz, D2O): δ =
156.2, 155.3, 122.2–121.8, 118.3, 82.0–81.4, 73.3–71.0, 70.9–70.7,
70.4, 64.8, 64.2, 63.4–59.1, 40.2 ppm. MS: m/z (%) = 2849.71 (0.9)
(calcd. 2850.05 for [C119H194N6O70 + Na]+), 2863.73 (5.3) (calcd.
2864.06 for [C120H196N6O70 + Na]+), 2877.75 (22.9) (calcd. 2878.07
for [C121H198N6O70 + Na]+), 2892.17 (45.9) (calcd. 2892.08 for
Randomly
Methylated
droxymethyl)-1,2,3-triazole (25): Yield 652 mg, 78%. 1H NMR
(300 MHz, D2O): δ = 7.99 (s, 1 H), 5.19 (m, 4.7 H), 5.10 (m, 4.1
H), 4.67 (m, 2 H overlapped with H2O), 4.32 (m, 2.1 H), 4.00–3.93
(m, 12.3 H), 3.92–3.47 (m, 32.4 H), 3.17 (br. s, 16 H), 3.20–3.09
(m, 14.6 H) ppm. 13C NMR (75.5 MHz, D2O): δ = 138.6, 126.5,
121.2, 121.0, 101.2–99.7, 82.2–81.3, 73.5–70.9, 64.3, 63.5, 60.2–
58.8, 54.9, 30.6 ppm. MS: m/z (%) = 1406.48 (14.4) (calcd. 1406.52
for [C57H97N3O35 + Na]+), 1420.52 (59.7) (calcd. 1420.53 for
[C58H99N3O35
[C59H101N3O35
+
+
Na]+), 1434.54 (24.7) (calcd. 1434.54 for
Na]+), 1448.55 (1.2) (calcd. 1448.55 for
[C122H200N6O70
[C123H202N6O70
[C124H204N6O70
+
+
+
Na]+), 2905.78 (19.9) (calcd. 2906.09 for
Na]+), 2919.79 (4.0) (calcd. 2920.10 for
Na]+), 2931.72 (1.1) (calcd. 2934.11 for
[C60H103N3O35 + Na]+).
Randomly Methylated 1-(6A-Dexoy-β-
D-cyclodextrin)-4-(2-hydroxy-
[C125H206N6O70 + Na]+).
1
ethyl)-1,2,3-triazole (26): Yield 600 mg, 71%. H NMR (300 MHz,
D2O): δ = 7.81 (s, 1 H), 5.16–5.14 (m, 3.6 H), 5.04–4.92 (m, 4.3
H), 4.43 (m, 4.1 H), 4.09 (m, 4.5 H), 3.95–3.84 (m, 17.2 H), 3.78–
3.59 (m, 32.6 H), 3.27 (m, 19.1 H), 3.20–3.12 (m, 8.5 H), 2.85 (m,
2 H) ppm. 13C NMR (75.5 MHz, D2O): δ = 168.1, 166.6, 125.6,
125.4, 101.0, 99.3, 82.3–81.4, 80.8–73.2, 72.8–70.9, 64.4, 63.6, 63.2,
62.6, 60.9, 59.5, 58.8, 58.7, 58.6, 28.3 ppm. MS: m/z (%) = 1420.75
(15.4) (calcd. 1420.54 for [C58H99N3O35 + Na]+), 1434.79 (55.2)
(calcd. 1434.55 for [C59H101N3O35 + Na]+), 1448.81 (23.3) (calcd.
1448.86 for [C60H103N3O35 + Na]+), 1462.81 (6.2) (calcd. 1462.57
for [C61H105N3O35 + Na]+).
Acknowledgments
This work was supported by the Centre National de la Recherche
Scientifique (CNRS). Dr. M. Mourer is grateful to the Agence Na-
tionale de la Recherche for financial support (ANR-07-CP2D-05-
02). Roquette Frères (Lestrem, France) is gratefully acknowledged
for generous gifts of cyclodextrins. We thank Dr. C. Flahaut and
J. Hachani for mass spectrometry analyses.
Randomly Methylated (؎)-2,2Ј-Bis[1-(6A-deoxy-β-
D-cyclodextrin)-
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1,2,3-triazol-4-ylmethoxy]-1,1Ј-binaphthalene (27): Yield 1.02 g,
48%. 1H NMR (300 MHz, D2O): δ = 8.11 (m, 2 H), 8.09 (m, 2 H),
8.01–7.92 (m, 4 H), 7.43 (m, 2 H), 7.39–7.00 (m, 4 H), 5.18–4.92
(m, 24 H overlapped with H2O), 4.32–4.13 (m, 10.2 H), 3.90–3.80
(m, 28 H), 3.71–3.52 (m, 70 H), 3.29–2.83 (m, 43 H) ppm. 13C
NMR (75.5 MHz, D2O): δ = 166.6–165.9, 142.3, 130.8, 128.4,
125.2, 101.4–99.8, 99.5–98.6, 81.6–80.9, 73.4–70.8, 64.4, 63.6, 63.2,
60.1–58.6, 30.8 ppm. MS: m/z (%) = 3054.22 (11.7) (calcd. 3031.13
for [C135H206N6O70 + Na]+), 3068.26 (51.6) (calcd. 3045.14 for
[C136H208N6O70
[C137H210N6O70
[C138H212N6O70
+
+
+
Na]+), 3082.27 (27.6) (calcd. 3059.15 for
Na]+), 3096.28 (6.7) (calcd. 3073.16 for
Na]+), 3110.21 (2.4) (calcd. 3087.17 for
[C139H214N6O70 + Na]+).
Randomly Methylated 1,2-Bis[1-(6A-deoxy-β-
D-cyclodextrin)-1,2,3-
triazol-4-ylmethoxy]benzene (28): Yield 740 mg, 37%. 1H NMR
(300 MHz, D2O): δ = 7.81 (s, 2 H), 6.91 (m, 4 H), 5.23–4.93 (m,
16.3 H), 3.84–3.49 (m, 75.6 H), 3.39–3.04 (m, 80.8 H) ppm. 13C
NMR (75.5 MHz, D2O): δ = 159.8, 146.4, 146.0, 143.5, 102.1,
100.3, 81.6–80.8, 73.9, 73.2, 72.9, 61.8–59.3, 38.6 ppm. MS: m/z =
2877.89 (18.3) (calcd. 2878.07 for [C121H198N6O70 + Na]+), 2891.63
(55.2) (calcd. 2892.08 for [C122H200N6O70 + Na]+), 2906.01 (21.9)
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5729

M. Mourer, F. Hapiot, S. Tilloy, E. Monflier, S. Menuel
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Received: July 22, 2008
Published Online: October 17, 2008
5730
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5723–5730