Facile one-step synthesis of mono-2-(p-tolylsulfonyl)-β-cyclodextrin under aqueous conditions

Article abstract of DOI:10.1055/s-2007-965885

A new and convenient method is presented for the synthesis of mono-2-(p-tolylsulfonyl)-β-cyclodextrin under aqueous conditions that does not require large amounts of polar organic solvents such as DMF, metal-containing reagents such as dibutyltin oxide, o

Full text of DOI:10.1055/s-2007-965885

348
SHORT PAPER
Facile One-Step Synthesis of Mono-2-(p-Tolylsulfonyl)-b-cyclodextrin under
Aqueous Conditions
S
ynthesis of Mono-2-(
i
p
-tolyl
c
sulfonyl)-
b
-
h
cyclodextrinael Strerath, Martin Meng, Stefan Kubik*
Technische Universität Kaiserslautern, Fachbereich Chemie - Organische Chemie, Erwin-Schrödinger-Strasse, 67663 Kaiserslautern,
Germany
Fax +49(631)2053921; E-mail: kubik@chemie.uni-kl.de
Received 21 September 2006; revised 30 October 2006
OH
Abstract: A new and convenient method is presented for the syn-
thesis of mono-2-(p-tolylsulfonyl)-b-cyclodextrin under aqueous
conditions that does not require large amounts of polar organic sol-
vents such as DMF, metal-containing reagents such as dibutyltin
oxide, or flammable bases such as NaH. Yields are typically around
20%.
O
HO
O
O
O
H
O
H
RO
O
H
O
O
OH
OH
O
HO
O
1
2
R = H
HO
HO
OH
O
R = Ts
Key words: cyclodextrins, sulfonates, regioselectivity, host-guest
systems
O
HO
OH
H
O
H
O
OH
O
H
O
O
H
O
O
O
HO
Cyclodextrins, cyclic oligosaccharides composed of six
(a), seven (b), or eight (g) a-1,4-linked D-anhydroglucose
units, and their derivatives have evolved into a versatile
class of macrocyclic compounds with applications in ba-
sic research,1 for example in the synthesis and investiga-
tion of artificial receptors, sensors, and enzyme mimics,2
and in industry.3 Derivatization of cyclodextrins can in-
volve the complete or incomplete statistical conversion of
the hydroxyl groups along the ring into, for example,
ethers or esters, or the selective modification of a few or
only one of these OH groups.1a,4 The latter is often
achieved by tosylation followed by substitution of the re-
sulting sulfonate with an appropriate nucleophile such as
a halide, an azide, or a thiol. The reaction of b-cyclodex-
trin (1) with p-toluenesulfonyl chloride in aqueous alka-
line medium, for example, selectively yields mono-6-(p-
tolylsulfonyl)-b-cyclodextrin5 while the corresponding
mono-2-(p-tolylsulfonyl)-b-cyclodextrin (2) is more diffi-
cult to obtain (Figure 1). Successful strategies involve the
reaction of anhydrous 1 with p-toluenesulfonyl chloride in
anhydrous DMF using NaH as base6 or a mixture of dibu-
tyltin oxide and triethylamine.7 A three-step reaction se-
quence has also been developed that proceeds via a b-
cyclodextrin derivative with all primary hydroxyl groups
protected by TBDMS ethers.8 Yields along these routes
are usually 20–30%.
O
HO
Figure 1
Regioselective monotosylation of 1 at a 6-hydroxyl group
in aqueous solution has been attributed to the formation of
an inclusion complex between 1 and p-toluenesulfonyl
chloride which brings the sulfonyl chloride group in close
proximity to the primary hydroxyl group of an anhydro-
glucose unit.1a,5a Indeed, in solvents such as DMF in
which no complexes are formed, reaction occurs preferen-
tially in the 2-position because of the higher acidity of the
corresponding hydroxyl group with respect to a primary
6-OH.9 We reasoned that addition of a co-solvent, that re-
duces solvent polarity, to an aqueous solution of 1, should
also direct tosylation into the 2-position, as it should
weaken the stability of the p-toluenesulfonyl chloride
complex. This effect should be even more pronounced if
the molecules of the co-solvent are able to compete with
the tosylation agent in binding to 1. An ideal co-solvent
would therefore be one that is chemically inert, complete-
ly miscible with water, relatively non-polar and a weak
binder to 1.
To test this assumption, we investigated the effect of sol-
vent composition on the tosylation of 1 (4.4 mmol) in the
presence of one equivalent of p-toluenesulfonyl chloride
and three equivalents of NaOH. As expected, in water re-
gioselective formation of mono-6-(p-tolylsulfonyl)-b-cy-
clodextrin was observed. In a 1:1 mixture of 1,4-dioxane–
water, however, only formation of 2 could be detected,
clearly demonstrating the strong influence of the solvent
on the regioselectivity of the reaction. Presumably, the
presence of 1,4-dioxane in the reaction medium does in-
deed prevent the formation of the inclusion complex be-
tween p-toluenesulfonyl chloride and 1. This effect might
solely be due to the reduction of solvent polarity but for-
Since 2 is a valuable starting material, particularly in su-
pramolecular chemistry, for the synthesis of b-cyclodex-
trin derivatives with substituents along the wider rim of
the cavity,1a we sought after a simpler way to synthesize
this compound. The results of our investigations are re-
ported here.
SYNTHESIS 2007, No. 3, pp 0348–0350
x
x
.
x
x
.2
0
0
7
Advanced online publication: 12.01.2007
DOI: 10.1055/s-2007-965885; Art ID: T14706SS
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
Synthesis of Mono-2-(p-Tolylsulfonyl)-b-cyclodextrin
349
mation of a dioxane inclusion complex, that is known for solution, product isolation now could simply be achieved
a-cyclodextrin,10 can be a contributing factor.
by evaporation of the organic solvent, removal of insolu-
ble higher substituted products by filtration, and recrystal-
lization. In this way, compound 2 was obtained in similar
yields as in the presence of Na2CO3 but without the need
of a chromatographic purification step. Chromatographic
purification did furnish purer product, however, because
higher tosylated products could not be removed complete-
ly by recrystallization. The properties of pure 2 are in full
agreement with previously published data.6,7,8a,12
HPLC was used to quantify the ratio between 2 and unre-
acted starting material 1 in the reaction mixtures. It has to
be noted that accurate detection of 1 and 2 required the use
of a refractive index (RI) detector which in turn prevented
us from running the chromatographic separations with a
solvent gradient.11 Unfortunately, under isocratic condi-
tions higher substituted products were not visible in the
chromatograms due to large retention times and signifi-
cant line broadening. HPLC therefore only gave informa- In conclusion, we have developed a new and convenient
tion about the ratio between 2 and 1 in solution and did not method for the synthesis of 2 under aqueous conditions
allow us to estimate the overall yield of the reaction.
without the need to use large amounts of polar organic sol-
vents such as DMF, metal-containing reagents such as
dibutyltin oxide, or flammable bases such as NaH. This
should make our procedure an attractive alternative to
those previously described.
Under the initial conditions, tosylation of 1 resulted in a
ratio between product and starting material of 19:81.
From there we improved the synthesis of 2 by varying
several reaction parameters. First, an increase of the
amount of p-toluenesulfonyl chloride added during the re-
action from one to three equivalents shifted the ratio of 2:1
to 29:71 in favor of the desired product. Second, the use
of weaker bases, the additional advantage of which is that
they reduce the risk of tosyl elimination in 2 to give man-
no-2,3-epoxycyclodextrin,12 also proved to be beneficial.
In the presence of three equivalents of Na2CO3, for exam-
ple, a 2:1 ratio of 53:47 was observed. Triethylamine had
1H and 13C NMR spectra were recorded on Bruker DPX 400 and
Bruker Avance 600 spectrometers. CHN analysis was performed in
the Pharmaceutical Institute of the Heinrich-Heine-University,
Düsseldorf. The analytical HPLC equipment consisted of an iso-
cratic pump (Waters 510), an RI detector (Latek, 8110), and a RP-
18 column (Bischoff, ProntoSIL 120-5-C18-ace-EPS 5.0 mm). The
eluent was 18.5% MeOH–H2O. Preparative chromatographic sepa-
rations were carried out using a LiChroprep RP-18 column (Merck,
a similar effect. Finally, the ratio between 2 and 1 ap- prepacked column size C, 40-63 mm). b-Cyclodextrin was pur-
chased from Wacker (Cavamax W7), anion exchange resin from
proached 65:35 when the reaction was performed at
Aldrich (Amberlite IRA-400, 1.4 meq/mL). Technical grade 1,4-di-
50 °C. TLC also indicated a high conversion of the start-
oxane was used without further purification. Reactions were moni-
tored with silica gel 60 F254 TLC plates (Merck) by using n-butanol–
EtOH–H2O (4:3:3) as eluent. The plates were developed by spray-
ing with a 5% H2SO4–EtOH solution followed by heating with a
heat gun.
ing material under these conditions while simultaneously
demonstrating the formation of significant amounts of
higher tosylated products. Since additional modifications
of the reaction conditions did not cause any further im-
provements we then concentrated on establishing an ap-
propriate procedure for the isolation of 2.
Tosylation of b-Cyclodextrin; Reaction in Homogeneous Solu-
tion
b-Cyclodextrin (5.0 g, 4.4 mmol) and Na2CO3 (1.4 g, 13.2 mmol)
were dissolved in a mixture of H2O–1,4-dioxane 1:1 (80 mL). The
Separation of 2 from the starting material, the side prod-
ucts, and the salts could easily be achieved chromato-
graphically on a RP-18 column affording pure 2 in overall solution was heated to 50 °C and a solution of p-toluenesulfonyl
chloride (2.5 g, 13.2 mmol) in 1,4-dioxane (20 mL) was added drop-
wise over the course of 1 h under stirring. Stirring was continued at
50 °C for 30 min. Afterward, the mixture was neutralized with aq 1
yields of ca. 20%. Alternatively, the excess of 1 could be
precipitated from the reaction mixture as the p-xylene
complex after evaporation of the organic solvent. At-
M HCl and evaporated in vacuo to a volume of ca. 10 mL. The res-
tempts to crystallize the product from the filtrate failed
idue was subjected to a RP-18 column conditioned with H2O. Elu-
most probably because the dissolved tosylate salts pre-
vented the crystallization of 2 by forming an inclusion
complex with the cyclodextrin. Indeed, if tosylate was re-
moved by additional treatment of the filtrate with the
chloride form of an anion exchange resin, recrystallization
of the product from a concentrated aqueous solution be-
came possible.
ent composition was gradually changed [EtOH–H2O, 5% → 10%
→ 15%] until the pure product eluted with the last solvent mixture.
The residue obtained after removal of the solvent was triturated
with acetone, filtered, washed with acetone, and dried; yield: 1.3 g
(23%).
Tosylation of b-Cyclodextrin; Reaction in the Presence of an Ion
Exchange Resin
b-Cyclodextrin (5.0 g, 4.4 mmol) and the anion-exchange resin Am-
berlite IRA-400 loaded with carbonate (65 mL) were suspended in
a mixture of H2O–1,4-dioxane 1:1 (80 mL). The solution was heated
to 50 °C, and a solution of p-toluenesulfonyl chloride (2.5 g, 13.2
mmol) in 1,4-dioxane (20 mL) was added dropwise over the course
of 1 h under stirring. Stirring was continued at 50 °C for 30 min. Af-
terward, the resin was filtered off, washed with 1,4-dioxane–H2O
(1:1), and the filtrate was evaporated in vacuo to a volume of ca. 10
mL. The residue was diluted with H2O (140 mL) and the solution
was stirred vigorously for 1 h. Insoluble material was filtered off by
using a glass frit (P4), and the solvent was evaporated to dryness in
The latter result indicated that the use of an anion-
exchange resin as base during the reaction could be an at-
tractive way to avoid free salts in the reaction mixture that
interfere during the recrystallization step. Indeed, treat-
ment of 1 in 1,4-dioxane–water with three equivalents of
p-toluenesulfonyl chloride at 50 °C in the presence of the
carbonate form of an anion exchange resin yielded 2 with
a 2:1 ratio of 37:63. Although this conversion rate is lower
than the one determined for the reaction in homogeneous
Synthesis 2007, No. 3, 348–350 © Thieme Stuttgart · New York

350
M. Strerath et al.
SHORT PAPER
vacuo. The residue was triturated with acetone, filtered, dried and
recrystallized from hot H2O (20 mL). Upon cooling, the product
precipitated very slowly. After 7 d at 4 °C, the product was collect-
ed by filtration, washed with a small amount of cold water and ace-
tone, and dried (0.7 g). Another batch of 0.4 g was obtained by
reducing the volume of the filtrate to 10 mL and storing the solution
at 4 °C for additional 7 d. According to TLC, the material thus ob-
tained was contaminated with higher tosylated b-cyclodextrins;
yield: 1.1 g (19%). Impurities could be removed almost quantita-
tively by another recrystallization from 10 mL of water, which,
however, reduced the yield to 0.4 g (7%).
1H NMR (400 MHz, D2O–DMSO-d6, 1:1): d = 2.39 (s, 3 H), 3.24 (t,
3J = 9.2 Hz, 1 H), 3.36–3.80 (m, 39 H), 3.95 (t, 3J = 9.2 Hz, 1 H),
4.19 (dd, 3J = 10.0, 2.9 Hz, 1 H), 4.74 (d, 3J = 3.5 Hz, 1 H), 4.90 (br
s, 6 H), 7.46 (d, 3J = 8.3 Hz, 2 H), 7.86 (d, 3J = 8.3 Hz, 2 H).
13C NMR (125 MHz, D2O–DMSO-d6, 1:1): d = 22.6, 61.2, 61.3,
61.5, 70.9, 73.0, 73.2, 73.3, 73.4, 73.5, 73.6, 74.5, 74.6, 80.9, 82.3,
82.6, 82.7, 82.8, 99.8, 103.3, 103.4, 129.7, 131.7, 133.3, 147.9.
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Acknowledgment
Financial support from Cognis GmbH & Co. KG, Düsseldorf,
Germany is gratefully acknowledged. We also thank D. Mampe,
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Synthesis 2007, No. 3, 348–350 © Thieme Stuttgart · New York