Improved Synthesis of C2 and C6 Monoderivatives of α- And β-Cyclodextrin via the Click Chemistry Approach

Article abstract of DOI:10.1055/s-0034-1380701

An efficient multigram-scale azide-alkyne coupling of cyclodextrin derivatives mono-6-azido-6-deoxy-β-cyclodextrin, mono-2-O-propargyl-β-cyclodextrin, and mono-2-O-propargyl-α-cyclodextrin with terminal alkynyl aryl ethers or azides, mediated by copper(I) is reported. This process uses a stoichiometric ratio of substrates and 5 mol% of the copper catalyst to give the products with full conversion; thus, no chromatographic purification is necessary. The yields of both α- and β-cyclodextrin derivatives are in the range of 80 to 99%.

Full text of DOI:10.1055/s-0034-1380701

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 1838–1843
psp
1838
K. Chmurski et al.
PSP
Synthesis
Improved Synthesis of C2 and C6 Monoderivatives of α- and
β-Cyclodextrin via the Click Chemistry Approach
Kazimierz Chmurskia
Pawel Stepniaka,b
Janusz Jurczak*b
R2
R1
N
O
OH
(OH)13
OH
(OH)13
(OH)13
N
N
O
R2
a Faculty of Chemistry, University of Warsaw,
Pasteura 1, 02-093 Warsaw, Poland
b Institute of Organic Chemistry, Polish Academy of Sciences,
Kasprzaka 44/52, 01-224 Warsaw, Poland
jurczak@icho.edu.pl
N
(OH)6
(HO)6
O
OH
(HO)6
OH
n
N
N
R1
Received: 03.02.2015
Accepted after revision: 13.04.2015
Published online: 08.05.2015
searchers to search for methods of simple derivatization for
β-CD that would make one or two groups distinguishable
from the others, and allow these groups to be used in fur-
ther modifications. Of the derivatization methodologies
available, copper(I)-mediated azide-alkyne coupling
(CuAAC) is a useful method that could provide good yields
and highly selective reactions.
There are two typical ways of achieving monosubstitut-
ed compounds: 1. monotosylation of the 6-OH position fol-
lowed by substitution with sodium azide, and 2. propar-
gylation of the 2-OH position (Scheme 1). Both give prod-
ucts that can be used as partners in CuAAC that have been
investigated extensively, especially in the field of CD
monoderivatives.5
DOI: 10.1055/s-0034-1380701; Art ID: ss-2015-t0083-psp
Abstract An efficient multigram-scale azide-alkyne coupling of cyclo-
dextrin derivatives mono-6-azido-6-deoxy-β-cyclodextrin, mono-2-O-
propargyl-β-cyclodextrin, and mono-2-O-propargyl-α-cyclodextrin
with terminal alkynyl aryl ethers or azides, mediated by copper(I) is re-
ported. This process uses a stoichiometric ratio of substrates and 5
mol% of the copper catalyst to give the products with full conversion;
thus, no chromatographic purification is necessary. The yields of both
α- and β-cyclodextrin derivatives are in the range of 80 to 99%.
Key words cyclodextrins, azides, copper, cycloaddition, ligands
Cyclodextrins (CDs), readily accessible, nontoxic com-
pounds, have excellent features for the formation of com-
plexes with hydrophobic molecules. Therefore, they can be
applied as hosts for active species (for which CD plays a
protective role) or hydrophobic substances that are to be
dissolved in water or/and other aqueous solvent systems.1
Chemical modifications of CDs strongly affect their proper-
ties, such as solubility or catalytic and complexing abilities.
Their derivatives bearing hydrophobic or hydrophilic sub-
stituents may form intramolecular complexes.2 On the oth-
er hand, there are many examples of intermolecular com-
plex formation; for example, Yamanoi et al.3 described β-CD
derivatives containing one or two arbutin moieties in the
side chain. The affinity constants of complexes with doxo-
rubicin were much higher than those measured for native
β-CD (the 6A,6D-disubstituted derivative showed K of 108
M–1 in comparison to 102 M–1 for β-CD). One of us (K.C.) has
experience of similar work with target molecules of type 3.4
Bearing 21 hydroxy groups, β-CD is certainly a com-
pound that is difficult to modify in an accurate and selec-
tive manner. The similarity of the seven hydroxy groups in
each 2-OH, 3-OH, and 6-OH subset has encouraged re-
Modifying the C6 position of β-CD with an alkyl moiety
would be laborious due to the protection and deprotection
procedures required for 2-OH and 3-OH, whereas the azide
derivative is more readily available. Monomodifications at
C6 proceed via the tosyl derivative that can be easily substi-
tuted with many nucleophiles; mono-6-azido-6-deoxy-β-
CD 1 obtained in this manner is widely used in reactions
with derivatives bearing terminal alkynes.
In our work we have obtained mono-6-O-tosyl-β-CD by
treatment of native β-CD with p-toluenesulfonic anhydride
(according to Bittman6). Next, we transformed the monoto-
sylate into mono-6-azido-6-deoxy-β-CD 1 using sodium
azide in N,N-dimethylformamide at 60 °C. As conjugation
partners for this compound, alkyl aryl ethers of type 2,
bearing alkyl chains of various lengths with a terminal
alkyne group were synthesized.7 We then subjected com-
pounds 1 and 2 to the CuAAC reaction. Several examples of
typical conditions for this method are known, however,
many papers report ‘click chemistry’ as laborious and com-
plicated. To avoid these problems, an excess of one of sub-
strates is often used, including stoichiometric amounts of
Cu(I) catalyst.8 This approach is especially inconvenient be-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1838–1843

1839
K. Chmurski et al.
PSP
Synthesis
(OH)13
O
(OH)13 OH
OH
3a: n = 1, R1 = H
3c: n = 1, R1 = Me
3b: n = 2, R1 = H
3d: n = 2, R1 = Me
n
R1
3e: n = 1, R1 = OMe 3f: n = 2, R1 = OMe
3g: n = 1, R1 = NO2 3h: n = 2, R1 = NO2
2
1. Ts2O
2. NaN3
N
N3
(HO)6
O
(HO)6
n
N
1
N
OH
(OH)13
R1
1. LiH
2.
R2
R2
R1
Br
N
O
O
R1
O
(OH)13
(HO)6
(OH)13
OH
N
N
O
N3
R2
R2
β-CD
5
6a: R1 = R2 = H
6b: R1 = OMe, R2 = H
6c: R1 = H, R2 = OMe
(HO)6
(HO)6
OH
OH
4
Scheme 1 Monoderivatization of C6 (upper path) and C2 (lower path) positions of β-CD via CuAAC
cause of the difficult purification that results as it is neces-
sary to remove unreacted hydrophobic substrate or Cu(I)
and Cu(II) compounds that can remain complexed inside
the CD cavity.9 The use of dry, unstable copper catalysts
[e.g., Cu(MeCN)4PF6, CuI–P(OEt)3] typically provides reac-
tion yields below 80%.10 Ultrasonic or microwave irradiation
rarely improves reaction yields, even when applied togeth-
er.11 Moreover, problems with the solubility of substrates
are often identified. Therefore, to apply CuAAC for selective
CD modification, we have to consider the solvent, tempera-
ture, substrate ratio, amount of catalyst.
Our first attempts of to react 1 with 2 via CuAAC meth-
odology in N,N-dimethylformamide or dimethyl sulfoxide
as solvent resulted with low conversion, due to copper(I)
iodide disproportionation; replacing copper(I) iodide with
copper(II) sulfate and ascorbic acid [Cu(I) ions were gener-
ated in situ] and tris[(1-benzyl-1H-1,2,3-triazol-4-yl)meth-
yl]amine (TBTA) provided higher, but not completely satis-
factory yields (20–50%). The reaction can, however, be car-
ried out almost quantitatively when the conditions are
adjusted to fulfill three requirements: (a) a degassed mix-
ture of dimethyl sulfoxide–water (4:1) is used; (b) the Cu(I)
is generated in situ using sodium ascorbate; and (c) the re-
action is performed under an inert atmosphere and tris[(1-
benzyl-1H-1,2,3-triazol-4-yl)methyl]amine is added as a
stabilizing agent. These conditions appeared to be optimal
for various alkyne partners used (Table 1). It is noteworthy
that temperature used for this reaction (50 °C) was much
lower than that reported by Ritter et al.12
Table 1 Results of the CuAAC Reaction of 1 with 2
Product
R
n
Yield (%)
3a
3b
3c
3d
3e
3f
H
1
2
1
2
1
2
1
2
90
98
99
98
94
96
95
93
H
Me
Me
OMe
OMe
NO2
NO2
3g
3h
Monomodification of β-CD at the C2 position began by
treating native β-CD with lithium hydride in dimethyl sulf-
oxide.13 Initially generated C6 alkoxide rearranged into C2
alkoxide within 24 hours of stirring under inert atmo-
sphere, and it was then transformed into intermediate 4 by
alkylation with propargyl bromide, to give the product 4 in
38% yield after purification. Mono-2-O-propargyl-β-CD 4
was then subjected to CuAAC with reagent 514 under the
previously optimized conditions. Again the reactions pro-
ceeded with very good yields (Table 2), so there was no
need for chromatography and the product was sufficiently
pure after trituration with acetone.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1838–1843

1840
K. Chmurski et al.
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Synthesis
Table 2 Results of the CuAAC Reaction of 4 with 5
If not stated otherwise, all compounds are commercially available.
Monoazide 1 and mono-2-O-propargyl-β-CD 4 were prepared in 60%
and 40% yields, respectively, according to known procedures.5,12
Mono-2-O-propargyl-α-CD was synthesized similarly to its β-ana-
logue in 30% yield. Toluene was dried and distilled over Na. TLC was
performed on silica gel plates (Merck Kieselgel 60 F254) and spots were
visualized with Mo-Ce spray. All NMR spectra were recorded on
Bruker DRX 500 MHz and Varian VNMRS 500 MHz spectrometers in
DMSO-d6. Mass spectra were recorded using Shimadzu LCMS-IT-TOF
spectrometer using ESI+.
Product
R1
R2
Yield (%)
6a
6b
6c
H
H
87
90
93
OMe
H
H
OMe
Finally, we applied this methodology to the α-CD sys-
tem to obtain compounds 7 (Figure 1) under similar reac-
tion conditions; tert-butyl alcohol was added in order to
eliminate inclusion complex formation between α-CD and
the alkyl chains of 5.
Conjugation of Mono(6-azido-6-deoxy)-β-CD and Terminal Alkyne
Containing Alkyl Aryl Ethers; General Procedure
A 3-necked flask was charged with mono-6-azido-6-deoxy-β-CD (1
mmol), alkyl aryl ether (1 equiv), and ascorbic acid [0.15 equiv, as a
solution of acid (200 mg) in H2O (10 mL)]. The contents of the flask
were dissolved in DMSO–H2O (4:1 mixture, 50 mL). A stream of argon
was passed through the solution (in order to maintain O2-free condi-
tions). Tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA, 0.2
R2
R1
N
O
(OH)11
N
N
O
equiv) was added.
A pressure-equalizing dropping funnel was
R2
charged with CuSO4 [0.05 equiv as a solution in H2O (10 mL)]. The
solution was heated to 50 °C and the CuSO4 solution was added to the
vigorously stirred mixture (a transient brown coloration occurred).
Stirring at 50 °C was continued overnight and the reaction was moni-
tored by TLC. After 16 h the mono-azide spot disappeared and mix-
ture was evaporated under reduced pressure. The solid residue was
suspended in acetone (100 mL) and filtered on a sintered funnel. Next
the residue was washed with acetone, CH2Cl2, and Et2O (100 mL of
each) and dried (P2O5).
7a: R1 = R2 = H
7b: R1 = OMe, R2 = H
7c: R1 = H, R2 = OMe
(HO)5
OH
Figure 1 α-CD derivatives obtained via CuAAC reaction of mono-2-O-
propargyl-α-CD with 5
Although preparation of mono-2-O-propargyl-α-CD
was less efficient, CuAAC proceeded with the high yields
expected (Table 3).
Mono-6-[4-(2-phenoxyethyl)-1H-1,2,3-triazol-1-yl]-6-deoxy-β-CD
(3a)
White powder after additional trituration with acetone; yield: 1175
mg (0.9 mmol, 90%).
Table 3 Results of the CuAAC Reaction of Mono-2-O-propargyl-α-CD
with 5
IR (KBr): 3316, 2926, 2111, 2042, 1642, 1600, 1496, 1425, 1368, 1334,
1302, 1242, 1156, 1080, 1031, 945, 844, 757, 694, 580, 529 cm–1
.
1H NMR: δ = 7.88 (s, 1 H), 7.28 (dd, J = 8.6, 7.4 Hz, 2 H), 7.01–6.85 (m,
3 H), 6.00–5.52 (m, 14 H), 5.03 (d, J = 3.5 Hz, 1 H), 4.91–4.70 (m, 7 H),
4.64–4.35 (m, 6 H), 4.23 (t, J = 7.0 Hz, 2 H), 3.98 (t, J = 10.1 Hz, 1 H),
3.77–3.47 (m, 17 H), 3.47–3.19 (m, 21 H), 3.18–3.01 (m, 4 H).
13C NMR: δ = 158.3, 155.6, 143.1, 129.5, 123.8, 120.6, 114.5, 102.2,
102.1, 102.0, 101.9, 101.3, 83.5, 81.9, 81.6, 81.5, 81.0, 77.6, 73.2, 73.1,
73.0, 72.9, 72.7, 72.4, 72.2, 72.1, 71.8, 70.1, 66.4, 60.1, 59.9, 59.0, 50.3,
28.2, 25.4, 22.5, 21.5.
Product
R1
R2
Yield
7a
7b
7c
H
H
80
89
86
OMe
H
H
OMe
Summing up, the introduction of a highly specific
CuAAC reaction provides an opportunity to combine these
compounds with non-orthogonal functional groups. We
have presented an example of using this method to create
new functional hybrids that can potentially behave like
drug-complexing agents. We have tuned the CuAAC reac-
tion conditions to obtain products quantitatively, using a
stable catalytic system and slightly elevated temperatures,
without sophisticated equipment (e.g., microwaves or ul-
trasound) and chromatographic purification. Moreover, we
have synthesized β-CD derivatives, containing electron-rich
side chains at the primary as well as the secondary rim of
the β-CD; this methodology also works efficiently for α-CD.
HRMS: m/z [M + H]+ calcd for C52H80N3O35: 1306.4567; found:
1306.4599.
Mono-6-[4-(3-phenoxypropyl)-1H-1,2,3-triazol-1-yl]-6-deoxy-β-
CD (3b)
White powder; yield: 1290 mg (0.98 mmol, 98%).
IR (KBr): 3268, 2927, 2109, 2043, 1642, 1601, 1496, 1415, 1369, 1335,
1302, 1245, 1157, 1080, 1037, 945, 845, 757, 693, 608, 581, 529 cm–1
.
1H NMR: δ = 7.81 (s, 1 H), 7.38–7.21 (m, 3 H), 6.98–6.87 (m, 2 H), 5.73
(br s, 14 H), 5.03 (d, J = 3.6 Hz, 1 H), 4.91–4.69 (m, 7 H), 4.66–4.29 (m,
6 H), 4.08–3.92 (m, 3 H), 3.82–3.49 (m, 21 H), 3.49–3.14 (m, 17 H),
3.09 (d, J = 11.3 Hz, 1 H), 2.90 (d, J = 10.4 Hz, 1 H), 2.76 (d, J = 7.8 Hz, 2
H), 2.04 (tt, J = 10.8, 5.4 Hz, 2 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1838–1843

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K. Chmurski et al.
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Synthesis
13C NMR: δ = 172.4, 171.5, 158.6, 146.1, 129.5, 122.8, 120.4, 114.5,
102.2, 102.1, 101.2, 83.6, 82.1, 81.6, 81.4, 80.8, 73.1, 72.5, 72.4, 72.2,
72.1, 71.8, 70.0, 66.7, 59.9, 50.3, 40.4, 28.5, 22.5, 21.6, 21.5.
HRMS: m/z [M + H]+ calcd for C53H82N3O36: 1336.4673; found:
1336.4697.
HRMS: m/z [M + H]+ calcd for C53H82N3O35: 1320.4723; found:
1320.4720.
Mono-6-{4-[3-(4-methoxyphenoxy)propyl]-1H-1,2,3-triazol-1-yl}-
6-deoxy-β-CD (3f)
White polymorphic solid; yield: 1300 mg (0.96 mmol, 96%).
Mono-6-[4-(2-(p-tolyloxy)ethyl]-1H-1,2,3-triazol-1-yl)-6-deoxy-β-
CD (3c)
IR (KBr): 3303, 2927, 2119, 2043, 1644, 1509, 1442, 1416, 1369, 1334,
1300, 1231, 1156, 1080, 1030, 945, 829, 754, 706, 653, 608, 528 cm–1
.
White powder; yield: 1305 mg (0.99 mmol, 99%).
1H NMR: δ = 7.80 (s, 1 H), 6.97–6.74 (m, 4 H), 5.98–5.43 (m, 13 H),
5.03 (d, J = 3.6 Hz, 1 H), 4.95–4.68 (m, 7 H), 4.48 (br s, 6 H), 4.04–3.90
(m, 3 H), 3.79–3.49 (m, 21 H), 3.50–3.15 (m, 20 H), 3.10 (d, J = 11.5 Hz,
1 H), 2.91 (d, J = 10.4 Hz, 1 H), 2.74 (t, J = 7.7 Hz, 2 H), 2.06–1.94 (m, 2
H).
13C NMR: δ = 153.3, 152.7, 146.1, 122.8, 115.4, 114.6, 102.2, 102.0,
101.9, 101.9, 101.2, 83.6, 82.1, 81.6, 81.5, 81.4, 80.8, 73.2, 73.1, 73.1,
73.0, 72.9, 72.9, 72.6, 72.5, 72.4, 72.3, 72.2, 72.1, 72.1, 71.9, 70.1, 67.3,
60.2, 59.9, 58.9, 55.4, 50.3, 40.4, 30.7, 29.6, 28.6, 22.5, 21.6.
IR (KBr): 3283, 2927, 2115, 2043, 1643, 1556, 1512, 1415, 1369, 1334,
1300, 1240, 1157, 1080, 1031, 945, 844, 818, 755, 706, 663, 607, 581,
531 cm–1
.
1H NMR: δ = 7.87 (s, 1 H), 7.07 (d, J = 8.3 Hz, 2 H), 6.83 (d, J = 8.5 Hz, 2
H), 5.91–5.55 (m, 14 H), 5.03 (d, J = 3.5 Hz, 1 H), 4.93–4.72 (m, 7 H),
4.62–4.39 (m, 6 H), 4.30 (s, 1 H), 4.18 (t, J = 7.0 Hz, 2 H), 3.97 (t, J =
10.0 Hz, 1 H), 3.83–3.50 (m, 20 H), 3.50–3.18 (m, 20 H), 3.11 (d, J = 9.2
Hz, 1 H), 3.04 (t, J = 6.8 Hz, 2 H), 2.92 (br s, 1 H).
13C NMR: δ = 171.5, 156.2, 143.2, 129.8, 129.2, 123.8, 114.4, 102.2,
102.1, 102.0, 101.9, 101.2, 83.5, 81.9, 81.6, 81.5, 81.0, 73.2, 73.1, 73.0,
73.0, 72.9, 72.7, 72.5, 72.4, 72.3, 72.1, 72.1, 71.8, 70.1, 66.5, 60.1, 59.9,
59.9, 59.0, 50.3, 40.4, 25.5, 22.5, 20.1.
HRMS: m/z [M + H]+ calcd for C54H84N3O36: 1350.4829; found:
1350.4796.
Mono-6-{4-[2-(4-nitrophenoxy)ethyl]-1H-1,2,3-triazol-1-yl}-6-de-
oxy-β-CD (3g)
HRMS: m/z [M + H]+ calcd for C53H82N3O35: 1320.4723; found:
1320.4747.
White polymorphic solid; yield: 1280 mg (0.95 mmol, 95%).
IR (KBr): 3302, 2927, 2113, 2041, 1643, 1594, 1513, 1415, 1341, 1302,
1264, 1156, 1112, 1080, 1030, 848, 754, 706, 654, 608, 580, 530 cm–1
.
Mono-6-(4-[3-(p-tolyloxy)propyl]-1H-1,2,3-triazol-1-yl)-6-deoxy-
β-CD (3d)
1H NMR: δ = 8.19 (d, J = 9.3 Hz, 2 H), 7.90 (s, 1 H), 7.15 (d, J = 9.3 Hz, 2
H), 5.84 (d, J = 6.2 Hz, 1 H), 5.80–5.55 (m, 11 H), 5.00 (d, J = 3.4 Hz, 1
H), 4.90–4.71 (m, 6 H), 4.58–4.41 (m, 5 H), 4.41–4.34 (m, 2 H), 4.30 (br
s, 1 H), 3.96 (t, J = 9.9 Hz, 1 H), 3.77–3.48 (m, 20 H), 3.44–3.19 (m, 18
H), 3.16–3.03 (m, 3 H), 2.88 (d, J = 10.4 Hz, 1 H).
White powder; yield: 1310 mg (0.98 mmol, 98%).
IR (KBr): 3290, 2926, 2113, 2042, 1643, 1615, 1556, 1512, 1416, 1369,
1334, 1301, 1242, 1157, 1080, 1030, 946, 844, 817, 756, 706, 608, 580,
530 cm–1
.
1H NMR: δ = 7.78 (s, 1 H), 7.07 (d, J = 8.3 Hz, 2 H), 6.82 (d, J = 8.5 Hz, 2
H), 5.85 (d, J = 6.3 Hz, 1 H), 5.81–5.54 (m, 13 H), 5.03 (d, J = 3.1 Hz, 1
H), 4.92–4.68 (m, 7 H), 4.59–4.39 (m, 6 H), 4.28 (br s, 1 H), 3.97 (dd, J =
9.8, 6.3 Hz, 3 H), 3.79–3.48 (m, 20 H), 3.46–3.15 (m, 19 H), 3.10 (d, J =
8.1 Hz, 1 H), 2.91 (br s, 1 H), 2.75 (t, J = 7.5 Hz, 2 H), 2.07–1.93 (m, 2
H).
13C NMR: δ = 171.4, 163.7, 142.7, 140.9, 125.9, 123.9, 115.1, 109.6,
102.2, 102.1, 102.0, 101.9, 101.2, 83.5, 81.9, 81.6, 81.5, 81.4, 81.0,
73.2, 73.1, 73.0, 72.8, 72.7, 72.4, 72.4, 72.2, 72.1, 71.8, 70.1, 67.5, 60.1,
59.9, 59.0, 50.3, 40.4, 25.2, 22.5, 21.1.
HRMS: m/z [M + H]+ calcd for C52H79N4O37: 1351.4418; found:
1351.4419.
13C NMR: δ = 156.5, 146.1, 129.8, 129.0, 122.8, 114.3, 102.2, 102.0,
101.9, 101.2, 83.5, 82.0, 81.6, 81.4, 80.8, 73.2, 73.1, 73.0, 72.9, 72.9,
72.6, 72.5, 72.4, 72.3, 72.1, 71.8, 70.1, 66.8, 59.9, 58.9, 50.3, 40.4, 29.6,
28.5, 25.5, 21.6, 20.1.
HRMS: m/z [M + H]+ calcd for C54H84N3O35: 1334.4880; found:
1334.4906.
Mono-6-{4-[3-(4-nitrophenoxy)propyl]-1H-1,2,3-triazol-1-yl}-6-
deoxy-β-CD (3h)
White polymorphic solid; yield: 1270 mg (0.93 mmol, 93%).
IR (KBr): 3314, 2927, 2111, 2041, 1650, 1607, 1593, 1513, 1415, 1340,
1301, 1264, 1156, 1111, 1080, 1030, 945, 848, 754, 706, 655, 608, 580,
530 cm–1
.
Mono-6-{4-[2-(4-methoxyphenoxy)ethyl]-1H-1,2,3-triazol-1-yl]-
6-deoxy-β-CD (3e)
1H NMR: δ = 8.21 (d, J = 9.3 Hz, 2 H), 7.84 (s, 1 H), 7.16 (d, J = 9.3 Hz, 2
H), 6.03–5.50 (m, 12 H), 5.03 (d, J = 3.5 Hz, 1 H), 4.91–4.72 (m, 6 H),
4.63–4.39 (m, 5 H), 4.19 (t, J = 6.4 Hz, 2 H), 3.99 (t, J = 10.2 Hz, 1 H),
3.83–3.49 (m, 21 H), 3.48–3.19 (m, 19 H), 3.08 (d, J = 11.5 Hz, 1 H),
2.88 (d, J = 10.7 Hz, 1 H), 2.83–2.70 (m, 2 H), 2.10 (dt, J = 13.4, 6.5 Hz,
2 H).
White powder; yield: 1255 mg (0.94 mmol, 94%).
IR (KBr): 3322, 2926, 2129, 2042, 1743, 1643, 1510, 1415, 1369, 1334,
1302, 1231, 1156, 1080, 1030, 946, 830, 756, 707, 639, 607, 580, 529
cm–1
.
1H NMR: δ = 7.87 (s, 1 H), 6.94–6.78 (m, 4 H), 5.74 (br s, 14 H), 5.03 (d,
J = 3.3 Hz, 1 H), 4.92–4.72 (m, 7 H), 4.64–4.24 (m, 6 H), 4.16 (t, J = 6.9
Hz, 3 H), 3.98 (t, J = 9.9 Hz, 1 H), 3.82–3.50 (m, 20 H), 3.50–3.20 (m, 20
H), 3.12 (d, J = 11.7 Hz, 1 H), 3.03 (t, J = 6.8 Hz, 2 H), 2.92 (d, J = 11.0
Hz, 1 H).
13C NMR: δ = 172.3, 171.5, 164.0, 145.9, 140.8, 125.9, 122.8, 115.1,
102.2, 102.1, 101.9, 101.8, 101.1, 83.6, 82.1, 81.6, 81.5, 81.4, 81.4,
80.7, 73.2, 73.1, 73.1, 73.0, 72.9, 72.6, 72.5, 72.4, 72.3, 72.2, 72.1, 72.0,
71.8, 70.1, 68.1, 60.2, 59.9, 58.8, 50.4, 40.4, 28.2, 22.5, 21.5, 21.4.
HRMS: m/z [M + H]+ calcd for C53H81N4O37: 1365.4574; found:
13C NMR: δ = 172.7, 171.5, 153.4, 152.3, 143.2, 129.8, 123.8, 115.5,
114.6, 114.4, 102.2, 102.1, 102.0, 101.9, 101.2, 83.5, 81.9, 81.5, 81.5,
81.0, 73.1, 73.0, 73.0, 72.9, 72.8, 72.7, 72.5, 72.4, 72.4, 72.2, 72.1, 72.0,
71.8, 70.0, 67.0, 60.0, 59.9, 59.0, 55.3, 54.9, 50.3, 40.4, 25.5, 22.5, 21.8.
1365.4572.
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Synthesis
Conjugation of Mono-2-O-propargyl-β-CD and Terminal Azide
Containing Alkyl Aryl Ethers
Mono-2-O-{[1-(3-phenoxypropyl)-1H-1,2,3-triazol-4-yl]methyl}-
α-CD (7a)
Mono-2-O-propargyl-β-CD 4 and aryloxy-substituted alkyl azides re-
acted by the general procedure for mono(6-azido-6-deoxy)-β-CD.
White powder; yield: 950 mg (0.80 mmol, 80%).
IR (KBr): 3316, 2928, 2149, 1649, 1601, 1497, 1456, 1407, 1363, 1333,
1296, 1243, 1154, 1080, 1036, 949, 846, 757, 696, 608, 574, 532 cm–1
.
Mono-2-O-{[1-(3-phenoxypropyl)-1H-1,2,3-triazol-4-yl]methyl}-
β-CD (6a)
1H NMR: δ = 8.14 (s, 1 H), 7.28 (t, J = 8.0 Hz, 2 H), 6.93 (dd, J = 7.8, 4.0
Hz, 3 H), 5.72 (d, J = 6.4 Hz, 1 H), 5.65–5.39 (m, 7 H), 4.92–4.71 (m, 6
H), 4.60–4.42 (m, 6 H), 4.35–4.27 (m, 1 H), 3.96 (t, J = 5.6 Hz, 2 H),
3.85–3.71 (m, 4 H), 3.71–3.49 (m, 14 H), 3.49–3.19 (m, 18 H), 2.35–
2.21 (m, 2 H).
White powder; yield: 1170 mg (0.87 mmol, 87%).
IR (KBr): 3320, 2926, 2102, 1647, 1601, 1588, 1497, 1413, 1367, 1334,
1300, 1245, 1156, 1082, 1030, 946, 858, 757, 695, 609, 580, 529 cm–1
.
13C NMR: δ = 158.4, 143.9, 129.6, 128.8, 128.1, 127.8, 124.2, 120.7,
114.5, 102.1, 102.0, 101.9, 100.1, 82.7, 82.3, 82.1, 82.1, 79.3, 73.3,
73.2, 72.7, 72.1, 71.9, 71.8, 64.3, 64.2, 60.0, 46.6, 40.4, 30.8, 29.6, 15.2.
1H NMR: δ = 8.15 (s, 1 H), 7.29 (t, J = 7.7 Hz, 2 H), 6.93 (dd, J = 7.5, 5.0
Hz, 3 H), 5.98–5.81 (m, 1 H), 5.79–5.54 (m, 8 H), 4.99–4.72 (m, 7 H),
4.63–4.27 (m, 8 H), 3.97 (t, J = 6.0 Hz, 2 H), 3.82 (t, J = 9.7 Hz, 1 H),
3.74–3.47 (m, 21 H), 3.47–3.20 (m, 23 H), 2.35–2.21 (m, 2 H).
HRMS: m/z [M + H]+ calcd for C48H74N3O31: 1188.4301; found:
13C NMR: δ = 158.4, 129.5, 128.7, 128.0, 124.2, 120.7, 114.5, 102.0,
101.7, 100.2, 82.1, 81.6, 79.5, 73.2, 73.1, 73.0, 72.7, 72.4, 72.2, 72.1,
71.8, 71.7, 64.2, 59.9, 47.8, 46.6, 40.4, 29.6, 28.2.
1188.4317.
Mono-2-O-({1-[3-(4-methoxyphenoxy)propyl]-1H-1,2,3-triazol-4-
yl}methyl)-α-CD (7b)
HRMS: m/z [M + H]+ calcd for C54H84N3O36: 1350.4829; found:
1350.4797.
White powder; yield: 1080 mg (0.89 mmol, 89%).
IR (KBr): 3357, 2928, 2055, 1647, 1509, 1462, 1407, 1363, 1333, 1295,
1231, 1154, 1080, 1032, 949, 831, 750, 705, 608, 574, 526 cm–1
.
Mono-2-O-{[1-(3-(4-methoxyphenoxy)propyl]-1H-1,2,3-triazol-4-
yl}methyl)-β-CD (6b)
1H NMR: δ = 8.12 (s, 1 H), 6.92–6.76 (m, 4 H), 5.81–5.33 (m, 8 H),
4.91–4.66 (m, 6 H), 4.58–4.41 (m, 6 H), 4.29 (s, 1 H), 3.95 (s, 1 H),
3.93–3.84 (m, 2 H), 3.84–3.71 (m, 4 H), 3.71–3.49 (m, 16 H), 3.48–3.34
(m, 18 H), 3.28 (dd, J = 8.7, 6.2 Hz, 4 H), 2.29–2.19 (m, 2 H).
White powder; yield: 1240 mg (0.90 mmol, 90%).
IR (KBr): 3302, 2926, 2060, 1649, 1510, 1414, 1368, 1334, 1299, 1232,
1157, 1082, 1030, 946, 830, 756, 706, 609, 579, 528 cm–1
.
13C NMR: δ = 153.5, 152.4, 128.8, 128.3, 128.0, 124.3, 115.5, 114.6,
102.1, 102.0, 101.9, 100.1, 82.7, 82.3, 82.1, 79.3, 73.3, 72.7, 72.1, 71.9,
71.8, 64.8, 64.3, 60.0, 55.3, 46.5, 40.4, 29.6.
1H NMR: δ = 8.14 (s, 1 H), 6.93–6.77 (m, 4 H), 6.04–5.84 (m, 1 H),
5.84–5.55 (m, 8 H), 4.94–4.73 (m, 7 H), 4.61–4.31 (m, 8 H), 3.90 (t, J =
5.9 Hz, 2 H), 3.82 (t, J = 9.1 Hz, 1 H), 3.76–3.50 (m, 24 H), 3.48–3.24
(m, 22 H), 2.31–2.16 (m, 2 H).
HRMS: m/z [M + H]+ calcd for C49H76N3O32: 1218.4406; found:
13C NMR: δ = 153.5, 152.4, 143.6, 124.2, 115.5, 114.7, 102.0, 100.2,
82.1, 81.6, 81.5, 81.4, 79.5, 73.2, 73.2, 73.1, 73.1, 73.0, 73.0, 72.7, 72.7,
72.5 (3 overlapping signals), 72.4, 72.1, 72.1, 72.1, 72.1, 71.8, 71.7,
64.9, 64.5, 60.0, 55.4, 46.6, 40.4, 29.6.
1218.4380.
Mono-2-O-({1-[3-(2,6-dimethoxyphenoxy)propyl]-1H-1,2,3-tri-
azol-4-yl}methyl)-α-CD (7c)
HRMS: m/z [M + H]+ calcd for C55H86N3O37: 1380.4935; found:
White powder; yield: 1070 mg (0.86 mmol, 86%).
1380.4929.
IR (KBr): 3333, 2930, 2844, 2095, 1651, 1509, 1480, 1463, 1409, 1364,
1334, 1297, 1257, 1155, 1111, 1080, 1032, 949, 845, 751, 705, 608,
573, 529 cm–1
.
Mono-2-O-({1-[3-(2,6-dimethoxyphenoxy)propyl]-1H-1,2,3-tri-
azol-4-yl}methyl)-β-CD (6c)
1H NMR: δ = 8.11 (s, 1 H), 7.00 (t, J = 8.4 Hz, 1 H), 6.67 (dd, J = 8.4, 2.4
Hz, 2 H), 5.71 (d, J = 6.6 Hz, 1 H), 5.65–5.37 (m, 7 H), 4.91–4.73 (m, 6
H), 4.59 (t, J = 7.1 Hz, 2 H), 4.54–4.42 (m, 5 H), 4.33 (s, 1 H), 4.04–3.94
(m, 1 H), 3.87 (t, J = 5.9 Hz, 2 H), 3.84–3.71 (m, 9 H), 3.72–3.49 (m, 14
H), 3.47–3.18 (m, 17 H), 2.14 (dd, J = 13.3, 6.3 Hz, 2 H).
13C NMR: δ = 153.3, 143.7, 136.2, 128.8, 128.1, 127.8, 124.2, 123.9,
105.5, 102.1, 102.0, 101.9, 100.0, 82.7, 82.3, 82.1, 79.3, 73.2, 73.2,
72.7, 72.1, 71.9, 71.7, 69.1, 64.3, 60.0, 55.9, 46.7, 40.4, 30.5.
White powder; yield: 1310 mg (0.93 mmol, 93%).
IR (KBr): 3333, 2930, 2139, 1649, 1600, 1480, 1368, 1299, 1257, 1157,
1110, 1081, 1029, 944, 856, 756, 705, 609, 579, 529 cm–1
.
1H NMR: δ = 8.11 (s, 1 H), 7.00 (t, J = 8.3 Hz, 1 H), 6.67 (d, J = 8.3 Hz, 2
H), 6.03–5.85 (m, 2 H), 5.82–5.48 (m, 10 H), 4.98–4.73 (m, 7 H), 4.66–
4.52 (m, 3 H), 4.52–4.32 (m, 7 H), 3.92–3.81 (m, 2 H), 3.77 (s, 6 H),
3.72–3.48 (m, 21 H), 3.47–3.22 (m, 21 H), 2.19–2.11 (m, 2 H).
HRMS: m/z [M + H]+ calcd for C50H78N3O33: 1248.4512; found:
13C NMR: δ = 153.3, 143.6, 136.2, 124.2, 123.8, 105.5, 102.0, 81.6, 73.1,
1248.4487.
72.4, 72.0, 69.1, 64.5, 59.9, 55.9, 46.7, 30.7, 30.5.
HRMS: m/z [M + H]+ calcd for C56H88N3O38: 1410.5040; found:
1410.5001.
Acknowledgment
Conjugation of Mono-2-O-propargyl-α-CD and Terminal Azide
Containing Alkyl Aryl Ethers
This research was financed by the European Union within the Euro-
pean Regional Development Fund, Project POIG.01.01.02.-14-102/09.
Mono-2-O-propargyl-α-CD reacted with aryloxy-substituted alkyl
azides by the general procedure for mono(6-azido-6-deoxy)-β-CD.
t-BuOH (2 equiv) was added to the mixture before the addition of
CuSO4 and sodium ascorbate.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1838–1843

1843
K. Chmurski et al.
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Synthesis
Supporting Information
(7) Prepared by converting the corresponding phenols into the
alkyl phenyl ethers, by reaction with but-1-yn-3-ol or pent-1-
yn-4-ol, under typical Mitsunobu conditions in the presence of
DIAD in toluene, see: Mitsunobu, O.; Masaaki, Y. Bull. Chem. Soc.
Jpn. 1967, 40, 2380.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380701.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(8) Li, N.; Chen, Y.; Zhang, Y.-M.; Wang, L.-H.; Mao, W.-Z. Thermo-
chim. Acta 2014, 576, 18.
References
(9) Mourer, M.; Hapiot, F.; Tilloy, S.; Monflier, E.; Menuel, S. Eur. J.
Org. Chem. 2008, 5723.
(10) (a) Casas-Solvas, J.; Martos-Maldonado, M. C.; Vargas-Beren-
guel, A. Tetrahedron 2008, 64, 10919. (b) Cacciarini, M.; Nielsen,
M. B.; Martinez de Castro, E.; Marinescu, L.; Bols, M. Tetrahedron
Lett. 2012, 53, 973.
(11) Cravotto, G.; Fokin, V. V.; Garella, D.; Binello, A.; Boffa, L.; Barge,
A. J. Comb. Chem. 2010, 12, 13.
(12) Munteanu, M.; Choi, S. W.; Ritter, H. Macromolecules 2008, 41,
9619.
(13) Casas-Solvas, J.; Ortiz-Salmeron, E.; Fernandez, I.; Garcia-Fuen-
tes, L.; Santoyo-Gonzales, F.; Vargas-Berenguel, A. Chem. Eur. J.
2009, 15, 8146.
(14) Bromopropoxybenzenes were synthesized by addition of 1,3-
dibromopropane to a boiling solution of the corresponding
phenol in NaOH solution. Terminal azide moieties were intro-
duced into aryl components via substitution of terminal bromo-
propoxyarenes with sodium azide under typical conditions.
(1) Zhou, Y.; Yoon, J. Chem. Soc. Rev. 2012, 41, 52.
(2) (a) Menuel, S.; Azaroual, N.; Landy, D.; Six, N.; Hapiot, F.;
Monflier, E. Chem. Eur. J. 2011, 17, 3949. (b) Legros, V.;
Vanhaverbeke, C.; Souard, F.; Len, C.; Désiré, J. Eur. J. Org. Chem.
2013, 2583.
(3) Yamanoi, T.; Kobayashia, N.; Takahashib, K.; Hattorib, K. Lett.
Drug Des. Discovery 2006, 3, 188.
(4) Swiech, O.; Mieczkowska, A.; Chmurski, K.; Bilewicz, R. J. Phys.
Chem. B 2012, 116, 1765.
(5) Faugeras, P.-A.; Boëns, B.; Elchinger, P.-H.; Brouillette, F.;
Montplaisir, D.; Zerrouki, R.; Lucas, R. Eur. J. Org. Chem. 2012,
4087.
(6) Bittman, R.; Zhong, N.; Byun, H.-S. Tetrahedron Lett. 1998, 39,
2919.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1838–1843