A convenient procedure for the formation of per(6-deoxy-6-halo) cyclodextrins using the combination of tetraethylammonium halide with [Et 2NSF2]BF4

Article abstract of DOI:10.1055/s-0033-1339762

A convenient and efficient procedure for the regioselective halogenation of the primary alcohols of cyclodextrins using the reagent combination of tetraethylammonium halide with [Et₂NSF₂]BF₄ is described. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339762

SHORT PAPER
▌3103
sAhorCt paopnervenient Procedure for the Formation of Per(6-deoxy-6-halo)cyclodextrins
Using the Combination of Tetraethylammonium Halide with [Et NSF ]BF
2
2
4
Convenient Preparation of Per(6-d
a
eoxy-6-halo)cyclodextrins
b
b
b
Xiaofeng Liu, Sen Cheng, Xiaolei Wang, Weihua Xue*
a
School of Life Science and Engineering, Lanzhou University of Technology, Lanzhou 730000, P. R. of China
b
School of Pharmacy, Lanzhou University, Lanzhou 730000, P. R. of China
Fax +86(931)8915686; E-mail: xuewh@lzu.edu.cn
Received: 07.07.2013; Accepted after revision: 16.08.2013
oxy-6-halo)cyclodextrins in high yield from commercial-
ly available starting materials. Since XtalFluor-E and
tetraethylammonium halides are inexpensive, nontoxic
and easily handled organic reagents, this method may
have wide application.
Abstract: A convenient and efficient procedure for the regioselec-
tive halogenation of the primary alcohols of cyclodextrins using the
reagent combination of tetraethylammonium halide with [Et NSF ]BF
4
®
2
2
is described.
Key words: cyclodextrins, regioselectivity, halogenation, [Et NSF ]BF
4
2
2
In our study, we initially optimized the bromination reac-
tion conditions with β-CD (1, n = 7) as a test substrate.
Several acid scavengers, including triethylamine, N,N-di-
Cyclodextrins (CDs) are cyclic oligosaccharides, com-
posed of six, seven and eight α-(1→4)-D-glucopyranosyl
units for α-CD, β-CD and γ-CD, respectively. The chem-
ical modification of cyclodextrins is of great interest in or-
der to enhance their as well as to widen their applications.
isopropylethylamine, DBU, DABCO, pyrrolidine and
5
2
,6-lutidine, were screened; 4-(1-pyrrolidino)pyridine
(
PPY) promoted the reaction in DMF to quantitative
yields in 8 hours, while the other bases were found to be
less efficient. The bromination proceeded well with Xtal-
6
-Deoxyhalocyclodextrins are key building blocks in a
®
1
Fluor-E (as little as 2.0 equiv per glucose unit) in the
multitude of interesting supramolecules and valuable
multivalent drug vehicles, rendering their synthesis an
2
presence of tetraethylammonium bromide (2.0 equiv per
glucose unit) and PPY (1.0 equiv per glucose unit) in an-
hydrous DMF, but an increased reaction rate was ob-
objective of high priority from the perspective of medici-
nal chemistry and biomaterials. Generally, the existing
approaches toward these cyclodextrin derivatives utilize a
nucleophilic substitution reaction of the primary hydroxy
®
served with excess XtalFluor-E . α-CD, β-CD and γ-CD
(1, n = 6, 7 and 8) were investigated and found to be con-
3
verted into the expected bromide compounds 2 (X = Br)
groups with diverse halogenation reagents. Some of these
in >90% yield and substantially free of impurities (as de-
methods are characterized by common requirements;
namely, the procedures must be performed under heating
conditions, frequently utilize moisture-sensitive reagents
and also suffer the inconvenience of producing stoichio-
metric byproducts. To resolve these drawbacks, [chlo-
ro(phenylthio)methylene]dimethylammonium bromide
was reported as a mild reagent for selectively brominating
1
termined by H NMR spectroscopy). The starting material
was consumed in 8–15 hours, as indicated by TLC analy-
sis. Tetraethylammonium bromide and the side products
resulting from the reactions are highly soluble in acetone
and water, which facilitates their removal by washing. We
recognized the potential extension of this method to the
introduction of other halogens (Cl, I) simply by switching
the tetraethylammonium salt (Scheme 1). This protocol
4
primary alcohols in cyclodextrins; however, this com-
mercially unavailable compound has to be prepared
through a two-step procedure that requires chromato-
graphic workup. The lack of mild, convenient and scal-
able methods for regioselective halogenation came to our
attention during recent efforts to prepare large quantities
of CD derivatives. Recent studies on the regioselective
chlorination, bromination and iodination reaction of pri-
mary alcohols using the combination of tetraethylammo-
®
for the use of XtalFluor-E is insensitive to the presence
of air moisture. Moreover, the halogenated CDs 2 are eas-
ily prepared on a multigram scale with no loss of regiose-
lectivity and in high isolated yield.
OH
O
X
O
®
5
nium halide and [Et NSF ]BF (XtalFluor-E ) led us to
HO
2
2
4
HO
HO
O
O
envision that halogenation of interesting carbohydrate
compounds could be achieved with this strategy. Herein,
we report the halogenation of cyclodextrins using the
above reagent system in N,N-dimethylformamide (DMF)
under mild conditions. This reaction enables an efficient,
operationally simple and scalable approach to per(6-de-
HO
n
n
1
2
n = 6, 7 or 8
X = Cl, Br or I
+
–
®
Scheme 1 Reagents and conditions: Et N X , XtalFluor-E , PPY,
4
DMF, r.t., 88–97%.
SYNTHESIS 2013, 45, 3103–3105
Advanced online publication: 10.09.2013
In conclusion, we have developed a facile method for prepar-
ing per(6-deoxy-6-halo)cyclodextrins with XtalFluor-E .
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
®
DOI: 10.1055/s-0033-1339762; Art ID: SS-2013-H0456-OP
Georg Thieme Verlag Stuttgart · New York
©

3104
X. Liu et al.
SHORT PAPER
The protocol adopts an easily accessible reagent system 13C NMR (DMSO-d
affording extremely easy workup and high yields of prod-
): δ = 102.1 (C-1), 83.6 (C-4), 72.5 (C-2), 72.2
C-3), 72.0 (C-5), 45.0 (C-6).
6
(
+
uct, free from difficult-to-handle reagents and byproducts. HRMS (ESI): m/z [M + Na] calcd for C48
H72Cl
O32Na: 1463.1413;
8
found: 1463.1410.
Therefore, this preparation should find practical applica-
tions in glycochemistry.
Hexakis(6-bromo-6-deoxy)-α-cyclodextrin (2, n = 6)4
Yield: 2.6 g (95%); white solid; mp 262 °C.
2
0
All the reagents and solvents were commercial products and used as
received, unless otherwise noted. Cyclodextrins were recrystallized
[α]
1
D
+97.7 (c 1.0, DMF); R = 0.65.
f
H NMR (DMSO-d ): δ = 3.36 (br, 12 H, H-6), 3.62–3.67 (m, 12 H,
H-2, H-4), 3.81 (t, J = 8.4 Hz, 6 H, H-3), 3.99 (d, J = 10.0 Hz, 6 H,
H-5), 4.97 (s, 6 H, H-1), 5.90 (s, 6 H, OH-3), 6.04 (d, 6 H, OH-2).
6
from water and dried over CaCl under reduced pressure in a drying
2
pistol at 110 °C prior to use. DMF was distilled over CaH prior to
2
use. Thin-layer chromatography (TLC) was performed on precoat-
ed plates of silica gel HF254 (0.5 mm, Yantai, China), using
EtOAc–i-PrOH–25% aq NH Cl–H O (7:7:5:4) as eluent. Visualiza-
13
C NMR (DMSO-d ): δ = 102.1 (C-1), 84.6 (C-4), 72.3 (C-3), 72.0
C-2), 71.1 (C-5), 34.4 (C-6).
6
(
4
2
+
tion was effected by dipping the plates into 30% H SO in EtOH and
HRMS (ESI): m/z [M + Na] calcd for C H Br O Na: 1366.8003;
found: 1366.8006.
2
4
36 54
6
24
subsequent rapid heating. Optical rotations were measured with a
Jasco DIP-370 digital polarimeter, using a sodium lamp (λ = 589
1
13
Heptakis(6-bromo-6-deoxy)-β-cyclodextrin (2, n = 7)4
Yield: 3.1 g (97%); white solid; mp 248 °C.
α]D20 +90.9 (c 1.0, DMF); R = 0.55.
nm) at 20 °C. H and C NMR spectra were recorded in DMSO-d6
on a Varian Mercury Plus 400 MHz spectrometer, with references
at δ = 2.49 and 39.50 ppm (DMSO). High-resolution mass spectra
[
1
f
(HRMS) were recorded on a Bruker APEX II mass spectrometer us-
H NMR (DMSO-d ): δ = 3.33 (br, 14 H, H-6), 3.60–3.68 (m, 14 H,
H-2, H-4), 3.80 (t, J = 8.0 Hz, 7 H, H-3), 3.99 (d, J = 9.6 Hz, 7 H,
6
ing electrospray ionization (ESI).
H-5), 4.97 (s, 7 H, H-l), 5.92 (s, 7 H, OH-3), 6.03 (d, 7 H, OH-2).
Per(6-deoxy-6-halo)cyclodextrins 2; General Procedure
To a solution of freshly dried cyclodextrin 1 (2 mmol) in anhydrous
13
C NMR (DMSO-d ): δ = 102.1 (C-1), 84.6 (C-4), 72.3 (C-3), 72.0
6
®
DMF (40 mL) were added XtalFluor-E (2 equiv per glucose unit),
(C-2), 71.0 (C-5), 34.4 (C-6).
4-(1-pyrrolidino)pyridine (1 equiv per glucose unit) and an anhy-
+
HRMS (ESI): m/z [M + Na] calcd for C H Br O Na: 1590.7687;
drous tetraethylammonium halide (2 equiv per glucose unit) with
stirring at r.t. After the reaction was complete, as monitored by
TLC, DMF was removed under reduced pressure and the resulting
residue was poured into sat. Na CO solution (50 mL); the reaction
42 63
7
28
found: 1590.7690.
Octakis(6-bromo-6-deoxy)-γ-cyclodextrin (2, n = 8)4
Yield: 3.4 g (95%); white solid; mp 231 °C.
2
3
mixture was stirred for another 1 h. Addition of cold acetone (200
mL) gave a precipitate which was collected by filtration and ex-
[
α]D20 +113.8 (c 1.0, DMF); R = 0.48.
f
haustively washed with H O and acetone to afford 2 as a white or
1
2
H NMR (DMSO-d ): δ = 3.33 (br, 16 H, H-6), 3.60–3.68 (m, 16 H,
6
pale brown solid.
H-2, H-4), 3.82 (t, J = 8.0 Hz, 8 H, H-3), 3.99 (d, J = 10.4 Hz, 8 H,
H-5), 4.97 (s, 8 H, H-1), 5.89 (s, 8 H, OH-3), 6.02 (d, 8 H, OH-2).
Hexakis(6-chloro-6-deoxy)-α-cyclodextrin (2, n = 6)
13C NMR (DMSO-d
C-2), 71.0 (C-5), 34.9 (C-6).
): δ = 102.1 (C-1), 84.6 (C-4), 72.3 (C-3), 72.0
Yield: 2.0 g (91%); white solid; mp 213 °C.
6
(
[
α]D20 +108.3 (c 1.0, DMF); R = 0.43.
f
+
HRMS (ESI): m/z [M + Na] calcd for C H Br O Na: 1814.7371;
1
48 72
8
32
H NMR (DMSO-d ): δ = 3.20 (br, 12 H, H-6), 3.35–3.59 (m, 6 H,
6
found: 1814.7373.
H-5), 3.77–3.84 (m, 12 H, H-2, H-3), 4.06 (d, J = 9.6 Hz, 6 H, H-4),
.94 (d, J = 2.8 Hz, 6 H, H-1), 5.83 (s, 6 H, OH-2), 5.96 (m, 6 H,
OH-3).
4
Hexakis(6-deoxy-6-iodo)-α-cyclodextrin (2, n = 6)
Yield: 3.0 g (91%); pale brown solid; mp 240 °C.
13
C NMR (DMSO-d ): δ = 102.1 (C-1), 83.6 (C-4), 72.5 (C-2), 72.0
[α]D20 +84.3 (c 1.0, DMF); R = 0.92.
6
f
(C-3), 71.2 (C-5), 45.0 (C-6).
1
H NMR (DMSO-d ): δ = 3.29 (t, J = 8.8 Hz, 6 H, H-5), 3.43 (br, 12
6
+
HRMS (ESI): m/z [M + Na] calcd for C H Cl O Na: 1103.1034;
3
6
54
6
24
H, H-6), 3.57–3.67 (m, 12 H, H-2, H-3), 3.81 (d, J = 9.6 Hz, 6 H, H-
found: 1103.1036.
4
), 4.98 (d, J = 2.8 Hz, 6 H, H-1), 5.96 (s, 6 H, OH-3), 6.06 (d, 6 H,
OH-2).
13C NMR (DMSO-d
Heptakis(6-chloro-6-deoxy)-β-cyclodextrin (2, n = 7)
Yield: 2.4 g (94%); white solid; mp 239 °C.
6
): δ = 102.1 (C-1), 85.9 (C-4), 72.2 (C-2), 72.0
(C-3), 71.0 (C-5), 9.5 (C-6).
[
α]D20 +85.7 (c 1.0, DMF); R = 0.35.
f
+
HRMS (ESI): m/z [M + Na] calcd for C H I O Na: 1654.7171;
found: 1654.7170.
1
36 54 6 24
H NMR (DMSO-d ): δ = 3.35 (br, 14 H, H-6), 3.60–3.64 (m, 7 H,
6
H-5), 3.78–3.83 (m, 14 H, H-2, H-3), 4.07 (d, J = 9.6 Hz, 7 H, H-4),
.90 (d, J = 3.0 Hz, 7 H, H-1), 5.85 (s, 7 H, OH-2), 5.97–6.00 (m, 7
H, OH-3).
4
Heptakis(6-deoxy-6-iodo)-β-cyclodextrin (2, n = 7)
Yield: 3.5 g (90%); pale brown solid; mp 209 °C.
[α]D20 +65.2 (c 1.0, DMF); R = 0.85.
13
C NMR (DMSO-d ): δ = 102.1 (C-1), 83.6 (C-4), 72.5 (C-2), 72.0
6
f
(C-3), 71.2 (C-5), 45.0 (C-6).
1
H NMR (DMSO-d ): δ = 3.27 (t, J = 8.8 Hz, 7 H, H-5), 3.36 (br, 14
6
+
HRMS (ESI): m/z [M + Na] calcd for C H Cl O Na: 1283.1223;
4
2
63
7
28
H, H-6), 3.55–3.65 (m, 14 H, H-2, H-3), 3.79 (d, J = 9.6 Hz, 7 H, H-
found: 1283.1221.
4
), 4.96 (s, 7 H, H-1), 5.93 (s, 7 H, OH-3), 6.03 (d, 7 H, OH-2).
1
3
C NMR (DMSO-d ): δ = 102.1 (C-1), 85.9 (C-4), 72.2 (C-2), 71.9
Octakis(6-chloro-6-deoxy)-γ-cyclodextrin (2, n = 8)
Yield: 2.66 g (88%); white solid; mp 229 °C.
6
(C-3), 70.9 (C-5), 9.5 (C-6).
+
[
α]D20 +106.7 (c 1.0, DMF); R = 0.28.
HRMS (ESI): m/z [M + Na] calcd for C42H I O28Na: 1926.6716;
63 7
found: 1926.6720.
f
1
H NMR (DMSO-d ): δ = 3.35 (br, 16 H, H-6), 3.42–3.63 (m, 8 H,
6
H-5), 3.77–3.93 (m, 16 H, H-2, H-3), 4.06 (d, J = 10 Hz, 8 H, H-4),
.94 (s, 8 H, H-1), 5.70 (d, 8 H, OH-2), 5.84–5.99 (m, 8 H, OH-3).
4
Synthesis 2013, 45, 3103–3105
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
Convenient Preparation of Per(6-deoxy-6-halo)cyclodextrins
3105
Octakis(6-deoxy-6-iodo)-γ-cyclodextrin (2, n = 8)
References
Yield: 4.0 g (92%); pale brown solid; mp 222 °C.
(
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[
α]D20 +74.1 (c 1.0, DMF); R = 0.76.
f
1
H NMR (DMSO-d ): δ = 3.27 (t, J = 9 Hz, 8 H, H-5), 3.38 (m, 16
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6
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13
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3
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(
+
HRMS (ESI): m/z [M + Na] calcd for C H I O Na: 2198.6262;
48
72 8 32
2
found: 2198.6257.
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http://www.thieme-connect.com/ejournals/toc/synthesis. SnuIoipgfmr tooatrin guSIopi
n
nfo itrmart
©
Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3103–3105