α-cyclodextrin compounds containing benzoic, acetylsalicylic, and 2-(4-isobutylphenyl)propionic acid residues

Article abstract of DOI:10.1134/S1070428011070037

Selectively substituted derivatives of α-cyclodextrin and hexa-O-tert-butyldimethylsilyl-α-cyclodextrin containing a definite number of acylated primary or secondary hydroxy groups were synthesized using benzoic, acetylsalicylic, and 2-(4-isobutylphenyl)p

Full text of DOI:10.1134/S1070428011070037

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 7, pp. 981–988. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © A.V. Edunov, G.I. Kurochkina, M.K. Grachev, I.I. Levina, T.A. Batalova, E.E. Nifant’ev, 2011, published in Zhurnal Organicheskoi
Khimii, 2011, Vol. 47, No. 7, pp. 968–974.
α-Cyclodextrin Compounds Containing Benzoic, Acetylsalicylic,
and 2-(4-Isobutylphenyl)propionic Acid Residues
A. V. Edunova, G. I. Kurochkinaa, M. K. Gracheva, I. I. Levinaa,
T. A. Batalovab, and E. E. Nifant’eva
a Moscow State Pedagogical University, Nesvizhskii per. 3, Moscow, 119021 Russia
e-mail: chemdept@mail.ru
b Amur State Medical Academy, Blagoveshchensk, Russia
Received January 4, 2011
Abstract—Selectively substituted derivatives of α-cyclodextrin and hexa-O-tert-butyldimethylsilyl-α-cyclo-
dextrin containing a definite number of acylated primary or secondary hydroxy groups were synthesized using
benzoic, acetylsalicylic, and 2-(4-isobutylphenyl)propionic acid chlorides in various solvents in the presence of
different bases. The acyl residues were assigned to the C2, C3, or C6 atoms in the carbohydrate fragments on the
basis of 13C NMR data. Desilylation of the silyl derivatives with ammonium fluoride in methanol gave the
corresponding O-acyl derivatives having free primary hydroxy groups in the α-cyclodextrin skeleton.
DOI: 10.1134/S1070428011070037
Regioselective functionalization of cyclodextrins is
an experimentally difficult problem due to the pres-
ence of a large number of chemically different hydroxy
groups. In most cases, this problem is solved by pro-
tection of hydroxy groups in the cyclodextrin skeleton
by various protecting groups [1]. We previously devel-
oped procedures for selective acylation of free (unpro-
tected) hydroxy groups in α- [2] and β-cyclodextrins
[2, 3]. These procedures allowed us to synthesize
β-cyclodextrin derivatives containing covalently
bonded (conjugated) residues of some pharmacologi-
cally important acids [4]. In some cases such “cou-
pling” makes it possible to create on the basis of
known pharmacologically active compounds new med-
icines with prolonged and more selective action [5].
Attention was mainly given to derivatives of β-cyclo-
dextrin as least expensive and most accessible
substrate.
propionic acids are as low as 2.5 and 0.021 g/l, re-
spectively], which complicates their administration
because of local irritation of mucous membrane in
stomach. The choice of α-cyclodextrin as a drug-
carrier matrix was determined by its considerably
better solubility in water (145 g/l) as compared to
β-cyclodextrin (18.5 g/l), which was expected to im-
prove pharmacological properties of the resulting com-
pounds upon biological testing.
Taking into account our data on selective acylation
of α- and β-cyclodextrins [2–4], as acylating agents we
used the corresponding acid chlorides, namely benzoyl
chloride (V), 2-acetoxybenzoyl chloride (VI), and
2-(4-isobutylphenyl)propionyl chloride (VII). The
reactions were carried out in DMF in the presence of
different amines (triethylamine, pyridine), as well as in
pyridine. Though α-cyclodextrin is sparingly soluble in
pyridine, the reaction mixture rapidly became homo-
geneous as the reaction progressed. For the sake of
comparison all experiments were performed under
similar conditions (see Experimental). The acylation
with 2, 5, and 7 equiv of acid chloride V–VII gave
α-cyclodextrin derivatives with a degree of primary
hydroxy group substitution m of 1, 4, and 6, respec-
tively (Scheme 1). The average degree of acylation (m)
In continuation of these studies in the present work
we made an attempt to synthesize derivatives of α-cy-
clodextrin (I) having benzoic (II), acetylsalicylic (III),
and 2-(4-isobutylphenyl)propionic acid (IV) residues.
Drugs containing fragments of acids III and IV exhibit
anti-inflammatory, antipyretic, analgesic, and anti-
thrombotic (inhibit platelet aggregation) activity, but
they are poorly soluble in water [for example, the
solubilities of acetylsalicylic and 2-(4-isobutylphenyl)-
1
was estimated by H NMR spectroscopy, from the
intensity ratio of signals from protons in the benzoic
981

EDUNOV et al.
69.9 ppm) relative to the corresponding signal from
982
Scheme 1.
non-acylated carbohydrate fragment. These findings
were consistent with published data [3, 4, 6]. In
addition, we previously found that signals from car-
bonyl carbon atoms in partly and completely acetylat-
ed α- and β-cyclodextrins can also be used to deter-
mine the site of acylation. The carbonyl carbon atoms
in the acetoxy groups on C2, C3, and C6 gave three
separate signals in the 13C NMR spectra [2, 7]. The
carbonyl carbon atoms in compounds VIII–XVII gave
only one signal, which may be regarded as an addition-
al proof for substitution at hydroxy groups on C6 only.
OH
RO
OH
6
m
6–m
6
6
Base
–HCl
+ nRCl
3
2
OH
OH
OH
OH
6
6
I
V–VII
VIII–XVII
V, VIII–X, R = PhC(O), VI, XI–XIII, R = 2-AcOC6H4C(O);
VII, XIV–XVII, R = Me2CHCH2C6H4CH(Me)C(O); VIII,
XI, n = 2, m = 1; XIV, n = m = 2; IX, XII, XV, n = 5, m = 4;
XVI, n = m = 5; X, XIII, XVII, n = m = 6.
While developing studies in this line, we synthe-
sized analogous acylated α-cyclodextrin derivatives
containing residues of acids II–IV on C2 and C3 (at
broad part of the cyclodextrin skeleton). As substrate
we used accessible 6-hexa-O-tert-butyl(dimethyl)silyl-
α-cyclodextrin (XVIII) in which primary hydroxy
groups on C6 were protected with silyl groups. Taking
into account specificity of the synthesis of compounds
VIII–XVII, the acylation was carried out in pyridine
with 5 equiv of acid chloride V–VII (Scheme 2; see
Experimental). The average degree of substitution was
(VIII–X), acetylsalicylic (XI–XIII), or 2-(4-isobutyl-
phenyl)propionic acid residues (XIV–XVII) and those
in the cyclodextrin skeleton in the region δ 3.20–
4.45 ppm. The degree of acylation of compounds
VIII–XIII, XV, XVII was relatively high; for com-
pounds IX, X, XII, XIII, XV, and XVII, it was only
slightly smaller than the number of equivalents (n) of
acid chloride V–VII involved in the reaction. The
degree of acylation of XIV and XVI was the maxi-
mum possible (m = 2 and 5, respectively), presumably
due to higher reactivity of propionyl chloride VII com-
pared to benzoyl chlorides V and VI. When the acyla-
tion was incomplete (compounds VIII–XIII, XV,
XVII), prolonged reaction did not result in higher
degree of acylation, but the yield of by-products in-
creased. It was difficult to determine the predominant
acylation direction (i.e., whether it occurred at primary
hydroxy groups on C6 or at secondary hydroxy groups
on C2 and C3) because of problems in signal assign-
ment, whereas 13C NMR spectra turned out to be more
informative. In the 13C NMR spectra of all compounds
VIII–XVII, signals from the C6′ atoms linked to acyl-
oxy substituent were displaced downfield (δC 63.5–
64.0 ppm) relative to those from C6 linked to free
hydroxy groups (δC 60.1–60.6 ppm). Signals from C5′
in the carbohydrate fragment containing an acyloxy
residue on C6′ appeared in a stronger field (δC 69.0–
1
determined by H NMR spectroscopy from the inten-
sity ratio of signals from protons in the corresponding
acid residue and signals from protons in the tert-butyl
groups on the silicon atom (δ 0.60–1.00 ppm). In all
cases we isolated silyl derivatives XIX–XXI which
contained four acyl residues at the broad part of the
cyclodextrin skeleton. The site of acylation (at C2
or C3) was determined by 13C NMR spectroscopy.
13
Compound XIX displayed in the C NMR spectrum
a downfield shift of the C2 signal from δC 72.3 (in the
spectrum of initial compound XVIII) to 73.9 ppm and
an upfield shift of the C1 signal from δC 101.6 to
98.9 ppm, while the C4 signal (δC 81.1 ppm) did not
change its position. These data indicated that acylation
involved only the hydroxy group on C2. The above
assignment of 1H and 13C signals was additionally con-
Scheme 2.
OSiMe2Bu-t
OSiMe2Bu-t
OH
6
6
6
5RCl, pyridine
–HCl
NH4F, MeOH, 70°C
OH
OH
OH
OR
OH
8
OR
6
8
4
4
XVIII
XIX–XXI
XXII–XXIV
XIX, XXII, R = PhC(O), XX, XXIII, R = 2-AcOC6H4C(O); XXI, XXIV, R = Me2CHCH2C6H4CH(Me)C(O).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 7 2011

α-CYCLODEXTRIN COMPOUNDS CONTAINING BENZOIC, ACETYLSALICYLIC
983
firmed by the two-dimensional {1H–13C} HETCOR
spectrum (see figure).
1-H
4-H
3-H 6′-H
5-H
6-H
2-H
δC, ppm
A more complicated pattern was observed in the 13C
NMR spectrum of acyl derivative XX which displayed
signals from C1 at δC 98.8 ppm and C4 at δC 80.9 ppm;
this means that the hydroxy groups on C2 and C3 were
acylated. Compound XXI showed a similar pattern. In
60
C6
C3
C5
C2
70
80
1
the H NMR spectrum of XX signals from methyl
protons in the acetyl groups appeared as two singlets
with equal intensities at δ 2.25 and 2.38 ppm, and the
13C NMR spectrum of XX contained two signals with
equal intensities* corresponding to carbonyl carbon
atoms in the acyloxy groups on C2 and C3. We can
conclude that two acyloxy groups are linked to C2, and
the other two, to C3.
C4
90
C1
100
Compounds XIX–XXI were deprotected by treat-
ment with a solution of ammonium fluoride in meth-
anol [8]. As a result, compounds XXII–XXIV were
formed in high yields (Scheme 2), and the acyl groups
5.5
5.0
4.5
δ, ppm
4.0
3.5
Two-dimensional HETCOR {1H–13C} NMR spectrum of
compound XIX in CDCl3.
1
were conserved, which was confirmed by H NMR
data (see Experimental).
stirring at 0°C to a solution of 1.00 g (1.03 mmol) of
α-cyclodextrin and 0.23 g (2.26 mmol) of triethyl-
amine in 25 ml of DMF. The mixture was stirred for
24 h at 20°C and filtered, the filtrate was evaporated to
a volume of 2 ml, and the residue was ground with
40 ml of diethyl ether, washed with chloroform (3×
10 ml), and dried under reduced pressure (1 mm) for
4 h at 90°C. Yield 0.94 g (85%), mp 277–279°C (de-
comp.), Rf 0.53 (A). 1H NMR spectrum (DMSO-d6), δ,
ppm: 3.25–4.25 m (36H, 2-H, 3-H, 4-H, 5-H, 6-H),
4.75–4.79 m (6H, 1-H), 5.10–5.40 br.s (17H, 6-OH,
2-OH, 3-OH), 7.35–8.10 m (5H, Harom). 13C NMR spec-
trum (DMSO-d6), δC, ppm: 60.6 (C6), 63.9 (C6′), 69.9
(C5′); 73.7, 73.9, 74.5 (C2, C3, C5); 82.6 (C4), 102.5
(C1), 128.0–134.2 (Carom), 166.5 (C=O). Found, %:
C 48.08; H 5.93. C43H64O31. Calculated, %: C 47.96;
H 5.99.
Thus we have proposed procedures for the syn-
thesis of α-cyclodextrin derivatives containing a re-
quired number of pharmacologically important acid
residues at both primary hydroxy groups on C6 (narrow
part of the cyclodextrin skeleton) and secondary hy-
droxy groups on C2 and C3 (broad part). Such com-
pounds attract interest as nanosized structures for phar-
macological studies, which may ensure highly efficient
selective and specific drug delivery.
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on
a Jeol ECX400 spectrometer at 400 and 100.53 MHz,
respectively, using tetramethylsilane as internal refer-
ence. Thin-layer chromatography was performed on
Silufol UV-254 plates using acetonitrile–water (5:1,
A), acetonitrile–water–25% aqueous ammonia (6:3:1,
B), benzene–ethanol (5:1, C), and benzene–ethanol
(7:1, D) as eluents; the chromatograms were devel-
oped by treatment with iodine vapor. α-Cyclodextrin
(Merck, Germany) was subjected to additional thor-
ough dehydration.
b. As described above in a, from 1.00 g (1.03 mmol)
of α-cyclodextrin and 0.18 g (2.26 mmol) of pyridine
in 25 ml of DMF and 0.29 g (2.06 mmol) of benzoyl
chloride (V) in 5 ml of DMF we obtained 1.02 g (92%)
of compound VIII, mp 277–279°C (decomp.), Rf 0.53
1
(A). The H and 13C NMR spectra of the product
6I-O-Benzoyl-α-cyclodextrin (VIII). a. A solution
of 0.29 g (2.06 mmol) of benzoyl chloride (V) in 5 ml
of DMF was added over a period of 20 min under
coincided with those given above.
Tetrakis(6-O-benzoyl)-α-cyclodextrin (IX). a. As
described above for compound VIII, the reaction of
1.00 g (1.03 mmol) of α-cyclodextrin and 0.57 g
(5.65 mmol) of triethylamine in 25 ml DMF with
0.72 g (5.14 mmol) of benzoyl chloride (V) in 5 ml of
* In order to compare signal intensity, the 13C NMR spectrum of
compound XX (Fourier transform) was recorded with a long
pulse delay (8 s).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 7 2011

EDUNOV et al.
984
under stirring at 0°C to a solution of 1.00 g
(1.03 mmol) of α-cyclodextrin and 0.41 g (2.26 mmol)
of triethylamine in 25 ml of DMF. The mixture was
stirred, kept for 24 h at 20°C, and filtered, the filtrate
was concentrated to a volume of 4 ml, the residue was
poured into 40 ml of acetone, and the precipitate was
filtered off, washed with acetone (3×5 ml), ground
with 10 ml of chloroform, washed with chloroform
(3×5 ml), and dried for 4 h at 90°C under reduced
pressure (1 mm). Yield 1.10 g (94%), mp 268–270°C
(decomp.), Rf 0.69 (B). 1H NMR spectrum (DMSO-d6),
δ, ppm: 2.20 s (3H, CH3), 3.20–4.45 m (36H, 2-H,
3-H, 4-H, 5-H, 6-H), 4.50–4.75 br.s (5H, 6-OH), 4.78–
4.92 m (6H, 1-H), 5.10–5.55 br.s (12H, 2-OH, 3-OH),
7.10–8.15 m (4H, Harom). 13C NMR spectrum
(DMSO-d6), δC, ppm: 20.9 (CH3), 60.4 (C6), 63.5 (C6′),
69.0 (C5′), 70.9–75.5 (C2, C3, C5), 82.6 (C4), 102.5
(C1), 122.5–134.8 (Carom), 150.9 (C2″), 164.2
(6-OC=O), 169.5 [C(O)CH3]. Found, %: C 48.22;
H 5.71. C45H66O33. Calculated, %: C 47.62; H 5.86.
DMF gave 0.63 g (44%) of compound IX, mp 269–
271°C (decomp.), Rf 0.76 (A). H NMR spectrum
1
(DMSO-d6), δ, ppm: 3.25–4.25 m (36H, 2-H, 3-H,
4-H, 5-H, 6-H), 4.74–4.80 m (6H, 1-H), 5.09–5.39 br.s
(14H, 6-OH, 2-OH, 3-OH), 7.25–8.15 m (20H, Harom).
13C NMR spectrum (DMSO-d6), δC, ppm: 60.6 (C6),
63.9 (C6′), 69.9 (C5′); 73.7, 73.9, 74.5 (C2, C3, C5), 82.6
(C4), 102.6 (C1), 127.9–134.3 (Carom), 166.5 (C=O).
Found, %: C 55.80; H 5.43. C64H76O34. Calculated, %:
C 55.33; H 5.51.
b. As described above for compound VIII, by reac-
tion of 1.00 g (1.03 mmol) of α-cyclodextrin and
0.48 g (5.65 mmol) of pyridine in 25 ml of DMF with
0.72 g (5.14 mmol) of benzoyl chloride (V) in 5 ml of
DMF we obtained 0.86 g (60%) of compound IX,
1
mp 269–271°C (decomp.), Rf 0.76 (A). The H and
13C NMR spectra of the product coincided with those
given above.
Hexakis(6-O-benzoyl)-α-cyclodextrin (X). a. As
described above for compound VIII, the reaction
of 1.00 g (1.03 mmol) of α-cyclodextrin and 0.80 g
(7.91 mmol) of triethylamine in 25 ml of DMF with
1.01 g (7.20 mmol) of benzoyl chloride (V) in 5 ml of
DMF gave 1.38 g (84%) of compound X, mp 234–
b. As described above in a, the reaction of 1.00 g
(1.03 mmol) of α-cyclodextrin and 0.18 g (2.26 mmol)
of pyridine in 25 ml of DMF with 0.41 g (2.06 mmol)
of acid chloride VI in 5 ml of benzene gave 1.13 g
(97%) of compound XI, mp 268–270°C (decomp.),
1
236°C, Rf 0.79 (A). H NMR spectrum (DMSO-d6), δ,
1
13
Rf 0.69 (B). The H and C NMR spectra of the prod-
ppm: 3.25–4.25 m (36H, 2-H, 3-H, 4-H, 5-H, 6-H),
3
uct coincided with those given above.
4.77 d (6H, 1-H, JHH = 3.5 Hz), 5.06–5.37 br.s (12H,
2-OH, 3-OH), 7.20–8.20 m (30H, Harom). 13C NMR
spectrum (DMSO-d6), δ, ppm: 64.0 (C6′), 69.9 (C5′),
73.9, 74.5 (C2, C3), 82.6 (C4), 102.6 (C1), 127.7–134.5
(Carom), 166.5 (C=O). Found, %: C 58.75; H 5.27.
C78H84O36. Calculated, %: C 58.64; H 5.30.
Tetrakis[6-O-(2-acetoxybenzoyl)]-α-cyclodextrin
(XII). a. As described above for compound XI, the
reaction of 1.00 g (1.03 mmol) of α-cyclodextrin and
0.57 g (5.65 mmol) of triethylamine in 25 ml of DMF
with 1.02 g (5.14 mmol) of acid chloride VI in 5 ml of
benzene. Yield 0.68 g (41%), mp 210–212°C, Rf 0.77
(B). 1H NMR spectrum (DMSO-d6), δ, ppm: 2.05–2.25
m (12H, CH3), 3.20–4.45 m (36H, 2-H, 3-H, 4-H, 5-H,
6-H), 4.48–4.73 br.s (2H, 6-OH) 4.79–4.91 m (6H,
1-H), 5.10–5.55 br.s (12H, 2-OH, 3-OH), 7.09–8.16 m
b. As described above for compound VIII, the reac-
tion of 1.00 g (1.03 mmol) of α-cyclodextrin and
0.63 g (7.91 mmol) of pyridine in 25 ml of DMF with
1.01 g (7.20 mmol) of benzoyl chloride (V) in 5 ml of
DMF gave 1.41 g (86%) of compound X, mp 234–
13
(16H, Harom). C NMR spectrum (DMSO-d6), δ, ppm:
1
13
236°C, Rf 0.79 (A). The H and C NMR spectra of
20.9 (CH3), 60.4 (C6), 63.5 (C6′), 69.0 (C5′), 70.9–75.4
(C2, C3, C5), 82.6 (C4), 102.5 (C1), 122.5–134.8 (Carom),
150.9 (C2″), 164.2 (6-OC=O), 169.5 [C(O)CH3].
Found, %: C 53.45; H 5.18. C72H84O42. Calculated, %:
C 53.33; H 5.22.
the product coincided with those given above.
c. As described above for compound VIII, a sus-
pension of 1.00 g (1.03 mmol) of α-cyclodextrin in
25 ml of pyridine was treated with 1.01 g (7.20 mmol)
of benzoyl chloride (V) in 5 ml of pyridine. Yield
1.43 g (87%), mp 234–236°C, Rf 0.79 (A). The 1H and
13C NMR spectra of the product coincided with those
given above.
6I-[O-(2-Acetoxybenzoyl)]-α-cyclodextrin (XI).
a. A solution of 0.41 g (2.06 mmol) of acid chloride VI
in 5 ml of benzene was added over a period of 20 min
b. As described above in a, from 1.00 g (1.03 mmol)
of α-cyclodextrin and 0.45 g (5.65 mmol) of pyridine
in 25 ml of DMF and 1.02 g (5.14 mmol) of acid
chloride VI in 5 ml of benzene we obtained 0.82 g
(49%) of compound XII, mp 210–212°C, Rf 0.77 (B).
1
13
The H and C NMR spectra of the product coincided
with those given above.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 7 2011

α-CYCLODEXTRIN COMPOUNDS CONTAINING BENZOIC, ACETYLSALICYLIC
985
for 4 h at 90°C under reduced pressure (1 mm).
Yield 0.62 g (45%), mp 222–224°C, Rf 0.66 (C).
1H NMR spectrum (DMSO-d6), δ, ppm: 0.84 d (12H,
Hexakis[6-O-(2-acetoxybenzoyl)]-α-cyclodextrin
(XIII). a. A solution of 1.43 g (7.20 mmol) of acid
chloride VI in 5 ml of benzene was added over
a period of 20 min under stirring at 0°C to a solution of
1.00 g (1.03 mmol) of α-cyclodextrin and 0.80 g
(7.91 mmol) of triethylamine in 25 ml of DMF. The
mixture was stirred, kept for 24 h at 20°C, and filtered,
the filtrate was concentrated to a volume of 4 ml and
poured into 40 ml of diethyl ether, and the precipitate
was filtered off, washed with diethyl ether (3×10 ml),
dried, and ground with 10 ml of water. The precipitate
was filtered off, dried, and dissolved in 2 ml of
acetone, the solution was poured into 20 ml of diethyl
ether, the mixture was stirred, and the precipitate was
filtered off and dried for 4 h at 90°C under reduced
pressure (1 mm). Yield 1.16 g (58%), mp 190–192°C,
3
CH3, JHH = 8.0 Hz), 1.26–1.42 m (6H, CH3), 1.73–
3
1.89 m [2H, CH(CH3)2], 2.40 d (4H, CH2, JHH
=
4.6 Hz), 3.15–3.90 m (38H, CH, 2-H, 3-H, 4-H, 5-H,
6-H), 4.20–4.40 m (4H, 6-OH), 4.79 d (6H, 1-H,
3JHH = 3.4 Hz), 4.95–5.55 br.s (12H, 2-OH, 3-OH),
6.98–7.22 m (8H, Harom). 13C NMR spectrum
(DMSO-d6), δC, ppm: 18.3–18.7 (CH3), 22.5 (CH3),
30.0 [CH(CH3)2], 40.4 (CHCH3), 44.5 (CH2), 60.2
(C6), 63.7 (C6′), 69.2 (C5′), 72.2–73.4 (C2, C3, C5), 82.5
(C4), 102.3 (C1), 126.5–140.0 (Carom), 174.4 (C=O).
Found, %: C 55.34; H 7.01. C62H92O32. Calculated, %:
C 55.19; H 6.87.
b. Compound XIV was synthesized as described
above in a by reaction of 1.00 g (1.03 mmol) of
α-cyclodextrin and 0.18 g (2.26 mmol) of pyridine in
25 ml of DMF with 0.46 g (2.06 mmol) of acid chlo-
ride VI in 5 ml of DMF. Yield 0.68 g (49%), mp 222–
1
Rf 0.80 (B). H NMR spectrum (DMSO-d6), δ, ppm:
2.02–2.40 m (18H, CH3), 3.20–4.45 m (36H, 2-H, 3-H,
4-H, 5-H, 6-H), 4.86 d (6H, 1-H, 3JHH = 3.4 Hz), 5.10–
5.55 br.s (12H, 2-OH, 3-OH), 7.05–8.19 m (24H,
1
224°C, Rf 0.66 (C). The H and 13C NMR spectra of
13
Harom). C NMR spectrum (DMSO-d6), δC, ppm: 20.9
(CH3), 63.5 (C6′), 69.0 (C5′), 71.5–73.9 (C2, C3), 82.4
(C4), 102.5 (C1), 122.1–135.1 (Carom), 150.8 (C2″),
164.2 (C=O), 169.5 [C(O)CH3]. Found, %: C 55.63;
H 5.13. C90H96O48. Calculated, %: C 55.56; H 4.97.
the product coincided with those given above.
Tetrakis{6-O-[2-(4-isobutylphenyl)propionyl}-α-
cyclodextrin (XV). A solution of 1.15 g (5.14 mmol)
of acid chloride VII in 5 ml of DMF was added over
a period of 20 min under stirring at 0°C to a solution
of 1.00 g (1.03 mmol) of α-cyclodextrin and 0.57 g
(5.65 mmol) of triethylamine in 25 ml of DMF. The
mixture was stirred, kept for 24 h at 20°C, concen-
trated to a volume of 4 ml, and poured into 40 ml of
water. The precipitate was filtered off, washed with
water (3×5 ml), dried, and dissolved in 2 ml of chloro-
form, the solution was poured into 35 ml of hexane,
the mixture was stirred, and the precipitate was filtered
off, washed with hexane (3×5 ml), and dried for 4 h at
90°C under reduced pressure (1 mm). Yield 0.92 g
(52%), mp 220–222°C, Rf 0.82 (C). 1H NMR spectrum
(DMSO-d6), δ, ppm: 0.84 d (24H, CH3, 3JHH = 7.9 Hz),
1.20–1.43 m (12H, CH3), 1.71–1.89 m [4H, CH(CH3)2],
b. As described above in a, the reaction of 1.00 g
(1.03 mmol) of α-cyclodextrin and 0.63 g (7.91 mmol)
of pyridine in 25 ml of DMF with 1.43 g (7.20 mmol)
of acid chloride VI in 5 ml of benzene gave 1.24 g
(62%) of compound XIII, mp 190–193°C, Rf 0.80 (B).
1
13
The H and C NMR spectra of the product coincided
with those given above.
c. As described above in a, the reaction of a suspen-
sion of 1.00 g (1.03 mmol) of α-cyclodextrin in 25 ml
of pyridine with 1.43 g (7.20 mmol) of acid chloride
VI in 5 ml of benzene gave 1.28 g (64%) of compound
1
XIII, mp 190–193°C, Rf 0.80 (B). The H and 13C
NMR spectra of the product coincided with those
given above.
3
2.39 d (8H, CH2, JHH = 4.7 Hz), 3.15–3.90 m (40H,
2-H, 3-H, 4-H, 5-H, 6-H), 4.20–4.40 m (2H, 6-OH),
4.81 d (6H, 1-H, JHH = 3.3 Hz), 5.05–5.73 br.s (12H,
Bis{6-O-[2-(4-isobutylphenyl)propionyl}-α-cyclo-
dextrin (XIV). a. A solution of 0.46 g (2.06 mmol) of
acid chloride VII in 5 ml of DMF was added over
a period of 20 min under stirring at 0°C to a solution
of 1.00 g (1.03 mmol) of α-cyclodextrin and 0.23 g
(2.26 mmol) of triethylamine in 25 ml of DMF. The
mixture was stirred, kept for 24 h at 20°C, concen-
trated to a volume of 4 ml, and poured into 40 ml of
acetone, and the precipitate was filtered off, washed
with acetone (3×5 ml), ground with 10 ml of chloro-
form, washed with chloroform (3×5 ml), and dried
3
2-OH, 3-OH), 6.95–7.24 m (16H, Harom). 13C NMR
spectrum (DMSO-d6), δC, ppm: 18.2 (CH3), 22.2
(CH3), 29.7 [CH(CH3)2], 40.3 (CHCH3), 44.4 (CH2),
60.1 (C6), 63.6 (C6′), 69.3 (C5′), 71.8–73.6 (C2, C3, C5),
81.9 (C4), 102.1 (C1), 126.4–140.1 (Carom), 174.0
(C=O). Found, %: C 61.42; H 7.18. C88H124O34. Cal-
culated, %: C 61.24; H 7.24.
Pentakis{6-O-[2-(4-isobutylphenyl)propionyl]}-
α-cyclodextrin (XVI) was synthesized as described
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 7 2011

EDUNOV et al.
986
above for compound XIV by reaction of 1.00 g
(1.03 mmol) of α-cyclodextrin and 0.45 g (5.65 mmol)
of pyridine in 25 ml of DMF with 1.15 g (5.14 mmol)
of acid chloride VII in 5 ml of DMF. Yield 1.71 g
(87%), mp 218–220°C, Rf 0.84 (C). 1H NMR spectrum
(DMSO-d6), δ, ppm: 0.84 d (30H, CH3, 3JHH = 8.0 Hz),
1.20–1.43 m (15H, CH3), 1.71–1.89 m [5H, CH(CH3)2],
α-cyclodextrin and 0.63 g (7.91 mmol) of pyridine in
25 ml of DMF with 1.62 g (7.20 mmol) of acid chlo-
ride VII in 5 ml of DMF. Yield 1.84 g (85%), mp 164–
1
166°C, Rf 0.86 (C). The H and 13C NMR spectra of
the product coincided with those given above.
c. Compound XVII was synthesized as described
above in a by reaction of a suspension of 1.00 g
(1.03 mmol) of α-cyclodextrin in 25 ml of pyridine
with 1.62 g (7.20 mmol) of acid chloride VII in 5 ml
of pyridine. Yield 1.92 g (89%), mp 164–166°C,
3
2.39 d (10H, CH2, JHH = 4.6 Hz), 3.15–3.90 m (41H,
CH, 2-H, 3-H, 4-H, 5-H, 6-H), 4.17–4.38 m (1H,
6-OH), 4.81 d (6H, 1-H, 3JHH = 3.4 Hz), 5.05–5.73 br.s
(12H, 2-OH, 3-OH), 6.95–7.24 m (20H, Harom).
13C NMR spectrum (DMSO-d6), δ, ppm: 18.2 (CH3),
22.2 (CH3), 29.7 [CH(CH3)2], 40.3 (CHCH3), 44.3
(CH2), 60.2 (C6), 63.6 (C6′), 69.3 (C5′), 71.8–73.6 (C2,
C3, C5), 81.9 (C4), 102.1 (C1), 126.3–140.2 (Carom),
174.1 (C=O). Found, %: C 63.89; H 7.31. C101H140O35.
Calculated, %: C 63.37; H 7.37.
1
13
Rf 0.86 (C). The H and C NMR spectra of the prod-
uct coincided with those given above.
Hexakis{6-O-[tert-butyl(dimethyl)silyl]}tetrakis-
(2-O-benzoyl)-α-cyclodextrin (XIX). A solution of
0.85 g (6.03 mmol) of benzoyl chloride (V) in 5 ml of
pyridine was added over a period of 20 min under
stirring at 0°C to a solution of 2.00 g (1.21 mmol) of
compound XVIII in 20 ml of pyridine. The mixture
was stirred, kept for 24 h at 20°C, and filtered, the
filtrate was concentrated to a volume of 4 ml and
poured into 75 ml of water, and the precipitate was
filtered off, ground with 10 ml of a 0.5 M aqueous
solution of NaHCO3, washed with water (3×10 ml),
and dried for 4 h at 90°C under reduced pressure
(1 mm). Yield 2.38 g (95%), mp 179–181°C, Rf 0.82
Hexakis{6-O-[2-(4-isobutylphenyl)propionyl]}-α-
cyclodextrin (XVII). a. A solution of 1.62 g
(7.20 mmol) of acid chloride VII in 5 ml of DMF was
added over a period of 20 min under stirring at 0°C to
a solution of 1.00 g (1.03 mmol) of α-cyclodextrin and
0.80 g (7.91 mmol) of triethylamine in 25 ml of DMF.
The mixture was stirred, kept for 24 h at 20°C, and
filtered, the filtrate was concentrated to a volume of
4 ml, 30 ml of diethyl ether was added, the mixture
was filtered and concentrated, the precipitate was
filtered off, washed with hexane (2×20 ml), dried, and
ground with 10 ml of water, and the precipitate was
filtered off, washed with water (3×5 ml), dried, and
dissolved in 2 ml of acetone. The solution was poured
into 35 ml of water, the mixture was stirred, the precip-
itate was filtered off and dissolved in 2 ml of acetone,
the solution was poured into 35 ml of hexane, the
mixture was stirred, and the precipitate was filtered off
and dried for 4 h at 90°C under reduced pressure
(1 mm). Yield 1.79 g (83%), mp 164–166°C, Rf 0.86
1
(D). H NMR spectrum (CDCl3), δ, ppm: 0.06 s [36H,
Si(CH3)2], 0.89 s (54H, t-Bu), 2.25–2.80 br.s (8H,
2-OH, 3-OH), 3.78 m (6H, 6-H), 3.80 m (6H, 5-H),
3
3.86 d.d (6H, 4-H, J3,4 - 4.0 Hz), 4.12 d.d (6H, 6′-H,
2J = 11.7 Hz), 4.36–4.44 br.s (6H, 3-H), 4.89 d.d (6H,
3
3
2-H, J2,3 = 10.3 Hz), 5.29 d (6H, 1-H, J1,2 = 3.3 Hz),
7.25–8.15 m (20H, Harom). 13C NMR spectrum (CDCl3),
δC, ppm: –5.1 and –5.0 [Si(CH3)2], 18.4 [C(CH3)3],
26.0 [C(CH3)3], 62.2 (C6), 70.9 (C3), 72.2 (C5), 73.9
(C2′), 81.1 (C4), 98.9 (C1′), 101.6 (C1), 128.0–134.1
(Carom), 166.0 (C=O). Found, %: C 58.11; H 7.90.
C100H160O34Si6. Calculated, %: C 57.89; H 7.77.
1
(C). H NMR spectrum (DMSO-d6), δ, ppm: 0.84 d
3
Hexakis{6-O-[tert-butyl(dimethyl)silyl]}bis-
[2,3-di-O-(2-acetoxybenzoyl)]-α-cyclodextrin (XX)
was synthesized in a similar way from 2.00 g
(1.21 mmol) of compound XVIII in 20 ml of pyridine
and 1.20 g (6.03 mmol) of acid chloride VI in 5 ml of
benzene. Yield 2.48 g (89%), mp 157–159°C, Rf 0.58
(36H, CH3, JHH = 8.0 Hz), 1.20–1.43 m (18H, CH3),
1.71–1.89 m [6H, CH(CH3)2], 2.39 d (12H, CH2,
3JHH = 4.6 Hz), 3.15–3.90 m (42H, CH, 2-H, 3-H, 4-H,
3
5-H, 6-H), 4.81 d (6H, 1-H, JHH = 3.4 Hz), 5.05–
5.73 br.s (12H, 2-OH, 3-OH), 6.95–7.24 m (24H,
13
H
arom). C NMR spectrum (DMSO-d6), δC, ppm: 18.2
1
(CH3), 22.2 (CH3), 29.7 [CH(CH3)2], 40.3 (CHCH3),
44.3 (CH2), 63.6 (C6′), 69.3 (C5′), 72.1–73.5 (C2, C3),
81.9 (C4), 102.1 (C1), 126.3–140.2 (Carom), 174.2
(C=O). Found, %: C 65.10; H 7.53. C114H156O36. Cal-
culated, %: C 65.13; H 7.48.
(D). H NMR spectrum (CDCl3), δ, ppm: 0.06 s [36H,
Si(CH3)2], 0.89 s (54H, t-Bu), 2.25 s and 2.38 s [12H,
CH3C(O)], 3.25–4.40 m (36H, 2-H, 3-H, 4-H, 5-H,
6-H), 4.55–5.05 br.s (8H, 2-OH, 3-OH), 5.10–5.20 m
13
(6H, 1-H), 6.95–8.12 m (16H, Harom). C NMR spec-
trum (CDCl3), δC, ppm: –5.1 and –5.0 [Si(CH3)2], 18.4
[C(CH3)3], 21.0 and 21.1 [C(O)CH3], 26.0 [C(CH3)3],
b. Compound XVII was synthesized as described
above in a by reaction of 1.00 g (1.03 mmol) of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 7 2011

α-CYCLODEXTRIN COMPOUNDS CONTAINING BENZOIC, ACETYLSALICYLIC
987
62.1 (C6), 71.5–75.2 (C2, C3, C5), 80.9 (C4′), 81.9 (C4),
98.8 (C1′), 101.6 (C1), 122.5–135.6 (Carom), 150.2 (C2″),
164.1 and 164.3 (C=O), 170.0 and 170.4 [C(O)CH3].
Found, %: C 56.17; H 7.55. C108H168O42Si6. Calculat-
ed, %: C 56.23; H 7.34.
Bis[2,3-di-O-(2-acetoxybenzoyl)]-α-cyclodextrin
(XXIII) was synthesized from 1.50 g (0.650 mmol) of
compound XX using 0.36 g (9.75 mmol) of ammo-
nium fluoride in 40 ml of methanol. Yield 0.92 g
(87%), mp 165–167°C, Rf 0.78 (B). 1H NMR spectrum
(DMSO-d6), δ, ppm: 2.17 s and 2.24 s (12H, CH3),
3.46–4.32 m (36H, 2-H, 3-H, 4-H, 5-H, 6-H), 4.40–
4.85 br.s (14H, 6-OH, 2-OH, 3-OH), 5.09 m (6H, 1-H),
7.35–8.12 m (16H, Harom). Found, %: C 53.68; H 5.16.
C72H84O42. Calculated, %: C 53.33; H 5.22.
Hexakis{6-O-[tert-butyl(dimethyl)silyl]}bis-
{2,3-di-O-[2-(4-isobutylphenyl)propionyl]}-α-cyclo-
dextrin (XXI). A solution of 1.35 g (6.03 mmol) of
acid chloride VII in 5 ml of pyridine was added over
a period of 20 min under stirring at 0°C to a solution of
2.00 g (1.21 mmol) of compound XVIII in 20 ml of
pyridine. The mixture was stirred, kept for 24 h at
20°C, and filtered, the filtrate was concentrated to
a volume of 4 ml and poured into 75 ml of water, and
the precipitate was filtered off, ground with 10 ml of
a 0.5 M solution of NaHCO3 in aqueous acetone (1:1),
washed with water (3×10 ml), and dried for 4 h at
90°C under reduced pressure (1 mm). Yield 2.47 g
(85%), mp 110–112°C, Rf 0.85 (D). 1H NMR spectrum
(CDCl3), δ, ppm: 0.06 s [36H, Si(CH3)2], 0.70–1.00 m
Bis{2,3-di-O-[2-(4-isobutylphenyl)propionyl]}-α-
cyclodextrin (XXIV) was synthesized from 1.50 g
(0.622 mmol) of compound XXI using 0.35 g
(9.33 mmol) of ammonium fluoride in 40 ml of meth-
anol. Yield 0.96 g (89%), mp 158–160°C, Rf 0.80 (C).
1H NMR spectrum (DMSO-d6), δ, ppm: 0.85 d (24H,
3
CH3, JHH = 7.9 Hz), 1.23–1.45 m (12H, CH3), 1.65–
3
1.88 m [4H, CH(CH3)2], 2.35 d (8H, CH2, JHH
=
4.7 Hz), 3.10–4.12 m (40H, CH, 2-H, 3-H, 4-H, 5-H,
6-H), 4.20–4.60 m (6H, 6-OH), 4.70–5.15 m (6H,
1-H), 5.15–5.85 br.s (8H, 2-OH, 3-OH), 6.95–7.30 m
(16H, Harom). Found, %: C 61.42; H 7.19. C88H124O34.
Calculated, %: C 61.24; H 7.24.
(78H, CH3, t-Bu), 1.30–1.42 m (12H, CH3), 1.75–
3
1.92 m [4H, CH(CH3)2], 2.42 d (8H, CH2, JHH
=
4.7 Hz), 3.03–4.25 m (40H, CH, 2-H, 3-H, 4-H, 5-H,
3
6-H), 4.87 d (6H, 1-H, JHH = 3.3 Hz), 4.90–5.10 br.s
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 08-03-00374) and by the President of the Russian
Federation (Progran for Support of Leading Scientific
Schools, project no. NSh-8034.2010.5).
(8H, 2-OH, 3-OH), 6.95–7.34 m (16H, Harom).
13C NMR spectrum (CDCl3), δC, ppm: –5.1 and –5.0
[Si(CH3)2], 18.3 (CH3), 18.4 [C(CH3)3], 22.4
[CH(CH3)2], 26.0 [C(CH3)3], 30.3 [CH(CH3)2], 40.6
(CHCH3), 45.1 (CH2), 61.9 (C6), 70.0–74.1 (C2, C3,
C5), 80.9 (C4′), 82.0 (C4), 99.0 (C1′), 101.6 (C1), 126.2–
141.9 (Carom), 173.4 and 174.9 (C=O). Found, %:
C 62.00; H 8.50. C124H208O34Si6. Calculated, %:
C 61.76; H 8.69.
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0.90 g (90%), mp 171–173°C, Rf 0.77 (A). H NMR
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a similar way.
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