New chiral imidazolium ionic liquids from isomannide

Article abstract of DOI:10.1016/j.carres.2010.11.011

New chiral bis and mono-imidazolium ionic liquids derived from isomannide were synthesized. The structural features of the chiral organic cations impart a special arrangement of the chiral cavity. The new chiral chloride salts of isomannide derivatives ar

Full text of DOI:10.1016/j.carres.2010.11.011

Carbohydrate Research 346 (2011) 197–202
Contents lists available at ScienceDirect
Carbohydrate Research
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Note
New chiral imidazolium ionic liquids from isomannide
⇑
M. D. R. Gomes da Silva, M. Manuela A. Pereira
REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 August 2010
Received in revised form 10 November 2010
Accepted 15 November 2010
Available online 19 November 2010
New chiral bis and mono-imidazolium ionic liquids derived from isomannide were synthesized. The
structural features of the chiral organic cations impart a special arrangement of the chiral cavity. The
new chiral chloride salts of isomannide derivatives are pivotal compounds for the synthesis of different
organic ionic liquids. After metathesis different anions were associated to the chiral cations providing a
new class of chiral ionic liquids.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Chiral ionic liquids
Imidazolium ionic liquids
Sugars
Isomannide
1. Introduction
hydrate derived from ready dehydration of naturally occurring
D
-mannitol during the processing of corn oil or in starch industry. Iso-
Research on the synthesis and use of chiral ionic liquids (CILs) is
maturing.1 Some properties of ionic liquids (ILs) include non-flam-
mability, high thermal stability and negligible volatility. ILs do not
produce atmospheric volatile organic compounds (VOCs) and can
be used in low-pressure (vacuum) environments. It is also known
that the physicochemical properties of ILs can be changed and con-
trolled by careful selection of the cation or of the anion composi-
tions. In CILs, the cation or the anion,2 or even both, can be
responsible for the chiral characteristics of the molecule. Recently,
the synthesis of several new chiral ILs (CILs) derived from the
‘chiral pool’ has been accomplished and amino-acids,3 hydroxy-
acids, amines,4 aminoalcohols, terpenes and alkaloids have been
used in their production.5 The availability of optically pure starting
materials and the inherited chirality of the CILs have been explored
and the use of CILs is increasing.6
Furthermore, ILs have been recently used as stationary phases
in chromatographic analyses. Due to their ability to interact and
separate polar compounds, ILs have received an increased interest
by the chromatographic community for multiple tasks.7 Their un-
ique properties, such as high thermal stability and efficiency on
column separations, have been used to improve gas and liquid
chromatographic techniques.8 However, there are only few exam-
ples in the literature of the synthesis and use of CILs for chromato-
graphic purposes.9,10
mannide has several chemical and pharmaceutical applications.11 Its
diastereoisomer (3R,3aR,6S,6aR)-hexahydrofuro[3,2-b]furan-3,6-diol
or isosorbide 2 (Fig. 1) derived from D-sorbitol differs only on the C(6)
hydroxyl group orientation. These and similar chiral diol derivatives
have been used as monomers in the synthesis of various polymers.12
Recently, their synthetic utility as valuable chiral compounds has
been investigated. The use of these chiral compounds in ionic liquid
synthesis has been explored and the chiral selection of diammonium
derivatives disclosed.13,14
2. Results and discussion
Our interest in the use of low vapour pressure and thermally sta-
ble chiral compounds as chromatographic stationary phases in
enantio-gas chromatography (e-GC) and enantio-liquid chromatog-
raphy (e-LC) directed our efforts in the preparation of new CILs.
Recently, Malhotra and co-workers reported the synthesis of chiral
ammonium ionic liquids derived from isomannide and established
their applications in chiral discrimination and optical resolution of
racemates.11,12 Furthermore, new CILs derived from isosorbide with
a free hydroxyl function were found to catalyse the aza-Diels–Alder
reaction to give product in moderate diastereoselectivities.15 These
observations focused our attention on these biorenewable
substrates.
The primary objective was to use the enantiopure D-isomannide
The enantiopure (3R,3aR,6R,6aR)-hexahydrofuro[3,2-b]furan-3,6-
diol or isomannide 1 (Fig. 1) is a commercially available chiral carbo-
(1) as chiral synthon in the synthesis of new chiral imidazolium-
based ionic liquids, bis-imidazolium 3 (Fig. 1) and mono-imidazo-
lium 4 salts (Fig. 1). Structurally, isomannide 1 is a symmetrical
molecule with C2-axial symmetry comprising two cis-fused furan
⇑
Corresponding author. Tel.: +351 212948300; fax: +351 212948550.
E-mail address: mmm@dq.fct.unl.pt (M. Manuela A. Pereira).
rings, giving
a wedge-shape molecule and two cis-oriented
0008-6215/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2010.11.011

198
M. D. R. Gomes da Silva, M. Manuela A. Pereira / Carbohydrate Research 346 (2011) 197–202
derivatives 4 showing an exo imidazolium cation and an endo hy-
OH
HO
OH
droxyl group derivative will impart better performance to chiral
stationary phases in enantio-GC. Mono-imidazolium salts 4 will
provide a less polar molecule with inverted configuration at C-3
and a different special arrangement of the chiral cavity. These com-
pounds contain two cis-fused rings and have two trans-oriented
substituents, the hydroxyl group with the endo-orientation at C-3
and the imidazolium moiety with the exo-orientation at C-6. In
new chiral bis-imidazolium ionic liquid 3, the absolute configura-
tion at C-3 and C-6 will be opposite to that observed in isomannide
1; however, the absolute configuration at C-3 and C-6 in monoionic
liquids 4 will be analogous to that observed in isosorbide 2 (Fig. 1).
The synthetic strategy of these new CILs is based on the synthesis
of the pivotal bis-imidazolium 3 (X = Cl) and mono-imidazolium 4
(X = Cl) chloride salts derived from isomannide 1 and its easy con-
version into different CIL’s by anion methatesis.
O
O
O
O
OH
Alk
1
2
Ha
Ha
Ha
Ha
OR
Hb2
3
3
2
O
O
X = TsO
Cl
O 3a
O 3a
Hb
Hb
Hb
6N
6
N
N
CF3CO2
Tf2N
6a
N
6a
Alk
N
X
N
Alk
X
X
3
4
Figure 1. Isomannide (1), isosorbide (2) and isomannide bis-imidazolium (3) and
mono-imidazolium (4) ionic liquids.
Reaction of D-isommanide 1 with 2.5 equiv of p-toluenosulfonyl
chloride in dichloromethane and in the presence of pyridine yielded
the enantiopure ditosyl isomannide 5 (Scheme 1). The use of an ex-
cess of tosyl chloride afforded the desired compound 5 (yield = 67%)
as the major compound and the monotosyl derivative (6, R = H,
yield = 24%) as the minor product. Heating compound 5 at 130 °C
in an excess of N-methylimidazole 7a or N-n-butylimidazole 7b un-
der argon for 48 h gave the corresponding bis-imidazolium tosylate
salts, 8a (88% yield) and 8b (78% yield). It is essential to use high tem-
perature reaction conditions and imidazole 7 as solvent in order to
ensure the complete substitution reaction, as well as, to trap the tos-
ylate anion and avoid the elimination reaction.11,13,14,16 Inversion of
configuration at both carbon centres, C-3 and C-6, was confirmed by
comparing the coupling constants Jcis (H-3, H-3a) and Jcis (H-6, H-
6a) = 4.5 Hz in 512 and Jtrans (H-3, H-3a) and Jtrans (H-6, H-6a) = 0 Hz
in 8a. The new nucleus in compound 8 has both imidazolium cation
groups pointing downwards.
hydroxyl groups having the endo-orientation. Substitution of the
hydroxyl groups by N-alkylimidazole moiety will provide a bis-
imidazolium derivative 3 with two cis-oriented imidazolium rings
having the exo-orientation (Fig. 1). To ensure complete inversion of
configuration and to avoid elimination side-reactions, both hydro-
xyl groups should be tosylated, prior to substitution, to yield
ditosylate derivative 5. The positive charged imidazolium moieties
have the desired characteristics to anchor these molecules to the
wall of silica tube during capillary column coating and its
wedge-shape will possibly provide a chiral cavity allowing enan-
tiomeric discrimination during chromatographic analysis. Also
the ILs properties, in particular, its thermal stability and low va-
pour pressure, will presumably allow GC analysis of low volatility
compounds without previous derivatization.
Our interest was not only in symmetrical bis-imidazolium CIL’s
(3) but also unsymmetrical mono-imidazolium CIL’s (4) based on
the isomannide carbon nucleus but with two different substituents
at C-3 and C-6 carbon atoms. We believe that mono-imidazolium
The excess of N-substituted imidazole 7 was removed by distil-
lation under reduced pressure affording a residual oil. The oil was
OTs
N
N R'
R'
N
N
7a: R' = CH3
RO
H
H
HO
H
H
H
O
TsCl / pyr.
CH2Cl2
O
7b: R' = n-C4H9
O
OTs
Δ
O
O
O
H
N
OTs
OH
N R'
1
8a: R' = CH3 (88%)
8b: R' = n-C4H9 (78%)
5: R = Tos (67%)
6: R = H (24%)
Cl
H3C N
X
N
H
O
H3C N
N
H
anion metathesis
O
AgX or LiX, H2O
r.t.
O
O
H
N
H
Cl
N CH3
N
N CH3
X
10: X = CF3COO (87%)
11: X = (CF3SO2)2N (69%)
9 (94%)
Scheme 1. Synthesis of bis-imidazolium chiral ionic liquids from isomannide.

M. D. R. Gomes da Silva, M. Manuela A. Pereira / Carbohydrate Research 346 (2011) 197–202
199
dissolved in milli-Q water and traces of N-substituted imidazole 7
were further removed by continuous liquid–liquid extraction by
upward displacement with diethyl ether for four days. Pure 8a
and 8b were attained after water evaporation at reduced pressure.
The opportunity to synthesise mono-imidazolium ionic liquids
4 from isomannide 1 was also explored (scheme 2). The free hydro-
xyl group of monotosyl isomannide 6 previously prepared was
converted into its tert-butyldimethylsilyl ether derivative 12, in
82% yield, by reaction with tert-butyldimethylsilyl chloride
(TBDMSCl) in pyridine and in the presence of imidazole. Subse-
quently, heating the silyl ether 12 in the presence of an excess of
N-methylimidazole 7a, the corresponding imidazolium salt 13
(73% yield) was formed by SN2 substitution with concomitant
inversion of the absolute configuration at C-6 carbon centres. The
new CIL’s 13 with the imidazolium group in the exo position is
the only derivative detected. As done previously, the excess of N-
methylimidazole 7a was removed by distillation at reduced pres-
sure and traces were further removed by continuous liquid–liquid
extraction of aqueous solution by upward displacement with
diethyl ether. Unfortunately, the tert-butyldimethylsilyl ether
group underwent partial hydrolysis during work up, as confirmed
by 1H NMR analysis. The complete hydrolysis of 13 was accom-
plished by treatment of the crude reaction mixture with methanol
in the presence of two drops of HCl concentrated during 12 h at
room temperature.17 The desired pure new CIL alcohol 15 was ob-
tained after treatment of the methanolic solution with solid potas-
sium carbonate, filtration and evaporation of methanol at reduced
pressure in 95% yield. Furthermore, the pivotal chloride imidazoli-
um salt 16 was obtained from the crude 13 in 79% yield. A milli-Q
water solution of 13 was passed through a column containing
AmberliteÒ 900(Cl) resin to achieve the anionic metathesis yielding
the partially-hydrolysed compound 14.
Treatment of the crude 14 with HCl–methanol at room temper-
ature yielded the pure imidazolium chloride 16, with the absolute
configurations at C-3 and C-6 centres similar to that exhibited by
isosorbide 2, with the free hydroxyl group in the endo position
and the imidazolium moiety in the exo position. The stereochemis-
try was confirmed by comparing the coupling constants Jcis (H-3,
H-3a) = 5.92 Hz and Jtrans (H-6, H-6a) = 0 Hz.14
The high resolution mass spectrometric data show, for com-
pounds 8a, 8b, 10, 11, 15 and 16, a fragment representing the loss
of the respective anion [MꢀX]+, where X presents the respective
counter-ion (see Section 3). The fragment presenting m/
z = [M+Na]+ was found for the same compounds (8a, 641.1704;
8b, 725.2635; 10, 525.1189; 11, 858.9787; 15, 405.1100; 16,
269.1159). Whenever two anions were present in the structures,
compounds 8a, 8b, 10 and 11, the fragments presenting the loss
of both counter-ions [MꢀH-2ꢁX]+ were also measured (8a,
275.1495; 8b, 359.2424; 10, 275.1496; 11, 275.1490). Because
the HRESIMS in positive mode was performed above m/z = 140
for compound 10, only in compounds 8a, 8b and 11 was the frag-
ment [Mꢀ2ꢁX]2+ found (8a, 138.0802; 8b, 180.1396; 11,
136.0823). In negative mode, the high resolution HRESIMS pre-
sented the m/z fragment [MꢀH]ꢀ for the compounds 8a, 8b, 10
and 11 (8a, 617.1580; 8b, 701.2525; 10, 501.1263; 11, 834.9766)
Only,
the
(3S,3aR,6S,6aR)-3,6-bis(30-methylimidazolium)-1,4-
dioxabicyclo[3.3.0]octane tosylate (8a) is liquid at room tempera-
ture. The longer N-alkyl chain on imidazolium moiety imparts a
higher melting point (mp 150–152 °C) to compound 8b.
There is a general understanding that the physical properties of
ionic liquids and their chemical structure are related and that the
anionic structure has a major effect on the physical properties of
ionic liquids, including the melting points.7j Ionic liquids with
bulky and weakly coordinating anions are known to have lower
melting points. The Tf2Nꢀ anion, if present in organic salts, usually
confers on them low melting points and ionic liquid characteristics.
The charge of the Tf2Nꢀ anion is diffuse, spread through the S–N–S
core and Coulombic interactions between the cation and anion are
minimised. These features do not encourage crystallographic order,
thus lowering the melting point. Similar features are also present
in Tosꢀ, TFAꢀ and TfOꢀ anions, which can delocalise the charge
via resonance or an an inductive effect to highly electronegative
fluorine atoms. The corresponding chloride salts have the expected
high melting points and are not liquids at room temperature.
Herein, we use the water soluble chloride salts as pivotal com-
pounds to obtain the desired ionic liquids. They can be easily man-
aged to give salts with different anions due to the water solubility
of the ILs and insolubility of silver chloride formed. Otherwise, lith-
ium salts were used for water insoluble ionic liquids as bis-(tri-
flic)imide 8.
Considering these facts, the (3S,3aR,6S,6aR)-3,6-bis(30-methyl-
imidazolium)-1,4-dioxabicyclo[3.3.0]octane chloride 9 was syn-
thesised by replacing the tosylate anion in CIL 8a. The (3S,3aR,6S,
6aR)-3,6-bis(30-methylimidazolium)-1,4-dioxabicyclo[3.3.0]octane
tosylate 8a was dissolved in milli-Q water and the solution passed
througha columncontainingamberlite900(Cl)resin toreach thean-
ionic exchange. The filtrate was collected and the (3S,3aR,6S,6aR)-
3,6-bis(30-methylimidazolium)-1,4-dioxabicyclo[3.3.0]octanechlo-
ride 9 (94% yield) was recovered as a solid after water evaporation
under reduced pressure. The acidity of the proton on the 20-position
of the imidazolium rings was confirmed by the signal absence in 1H
NMR spectrum after its exchange with deuterium in a D2O solution.
The synthesis of the new chiral ionic liquids (3S,3aR,6S,6aR)-3,6-
bis(30-methylimidazolium)-1,4-dioxabicyclo[3.3.0]octane trifluo-
roacetate 10 (87% yield) and (3S,3aR,6S,6aR)-3,6-bis(30-methylimi-
dazolium)-1,4-dioxabicyclo[3.3.0]octane bis-(triflic)imide 11 (69%
yield)was accomplished ingoodyields, bytreatmentofawatersolu-
tion of 9 with silver trifluoracetate (1 equiv) and lithium bis-(tri-
flic)imide (1 equiv), respectively. The structure and stereochem
istry of compounds 8–11 were established by 1H and 13C NMR
spectroscopy. NOESY and the correlation techniques, HMQC and
HMBC, were used to provide the correct assignments.
RO
H
TBDMSO
H
O
N
N
O
TBDMCl/ pyr.
CH2Cl2
6
O
X
H
O
N
Δ
H
OTos
N
13: R= TBDMS, X = TosO
14: R= TBDMS, X = Cl
12 (82%)
MeOH
HCl (aq.)
15: R= H, X = TosO (95%)
16: R= H, X = Cl (79%)
Scheme 2. Synthesis of mono-imidazolium chiral ionic liquids from isommanide.

200
M. D. R. Gomes da Silva, M. Manuela A. Pereira / Carbohydrate Research 346 (2011) 197–202
and m/z fragment [M+Cl]ꢀ for compounds 15 and 16 (15, 417.0852;
16 281.0425). These results together with 1H, 13C NMR spectros-
copy and NOESY and the correlation techniques, HMQC and HMBC,
allow the confirmation of the structures identity and stereochem-
istry when applied.
3.2.2. (3S,3aR,6S,6aR)-3,6-Bis(30-n-butylimidazolium)-1,4-
dioxabicyclo[3.3.0]octane tosylate (8b)
Solid (366 mg, 0.59 mmol, 78%), mp150–152 °C, ½a D27
ꢂ
+12.2(c 0.6,
CH3OH); IR (film): m3460, 3099, 2958, 1568, 1494, 1466, 1184, 1121,
1033, 1010, 816, and 681 cmꢀ1; dH (CD3CN, 400 MHz) 9.24 (s, 2H, 20-
H), 7.59 (d, 4H, J 8.0 Hz, H-200, H-600), 7.57 (s, 2H, H-40), 7.41 (s, 2H, H-
50), 7.15 (d, 4H, J 8.0 Hz, H-300, H-500), 5.38 (s, 2H, H-3a, H-6a), 5.12 (dd,
2H, J = 1.4, 4.5 Hz, H-3, H-6), 4.29 (dd, 2H, J = 5.2, 10.9 Hz, H-2a, H-
5a), 4.14 (dd, 2H, J = 2.9, 11.0 Hz, H-2b, H-5b), 4.11 (t, 4H,
J = 7.6 Hz, N(30)–CH2), 2.33 (s, 6H, C-500-CH3), 1.76 (quint., 4H,
J = 7.6 Hz, N(30)CH2–CH2), 1.20 (sext., 4H, J = 6.0 Hz, N(30)C2H4–
CH2), 0.88 (t, 6H, J = 7.3 Hz, N(30)C3H6–CH3) ppm. dC (CD3CN,
100.61 MHz): d 146.37 (C-400), 139.82 (C-100), 136.82 (C-20), 129.38
(C-300, C-500), 126.61 (C-200, C600), 123.55 (C-50), 122.76 (C-40), 87.90
(C-3a, C-6a), 73.16 (C-2, C-5), 65.97 (C-3, C-6), 50.46 (N–CH2),
32.45 (N–CH3), 21.26 (Ar-CH3), 20.02 (NCH2–C2H4), 13.67 (CH3)
ppm. HRESIMS: m/z 531.2701 (calcd for ion pair [C20H32N4O2 + -
C7H7O3S]+, 531.2641).
In conclusion, a new class of bis and mono-imidazolium-based
CILs derived from D-isomannide, a natural renewable source and an
industrial waste, were synthesized and different structural features
of the cation chiral cavity of these ionic liquids were achieved. Our
strategy used the new mono and dichloride imidazolium salts of
isomannide as pivotal compounds for the synthesis of a new class
of chiral ionic liquids. Chloride salts were synthesised by treatment
of the corresponding tosylate imidazolium derivatives with amber-
lite 900(Cl) resin. Anion metathesis provided different chiral ionic
liquids with cation moiety derived from isomannide. Further re-
search into applications of these new CILs as chiral stationary
phases to enantio-GC is in progress in our laboratory.
3. Experimental
3.3. Synthesis of (3S,3aR,6S,6aR)-3,6-bis(30-methylimidazolium)-
1,4-dioxabicyclo[3.3.0]octane chloride (9)
3.1. General methods
Melting points were determined on a Reichert Thermovar Melt-
ing Point apparatus. The specific rotations were measure on a Per-
kin–Elmer, Model 241 MC polarimeter. The 1H and 13C NMR
spectra were recorded on a Bruker, modelo ARX 400 spectrometer
at 400 and at 100.25 MHz, respectively, using TMS as internal stan-
dard. The chemical shift values are on d scale and the coupling con-
stants (J) are in Hertz. The high resolution mass spectra (HRESIMS)
were obtained on an Agilent ESI-TOF and were recorded with ESI in
positive and negative mode. All the chemicals used were pur-
chased from Aldrich Chemical Co., Germany and used with no fur-
ther purification. Analytical TLCs were performed on pre-coated
Merck Silica Gel 60F254 plates; the spots were detected under
UV light. Silica Gel 60 (70–230 mesh) from Merck was used for col-
umn chromatography.
(3S,3aR,6S,6aR)-3,6-bis(30-methylimidazolium)-1,4-dioxabicy-
clo[3.3.0]octane tosylate 8a (105 mg, 0.17 mmol) was dissolved
in 3.5 mL of milli-Q water. Further elution of the aqueous solution
through a column containing AmberliteÒ 900(Cl) resin (3 g) gave
the corresponding chloride salt 9. After water evaporation under
reduced pressure and drying over phosphorus pentoxide pure
compound 9 (55.5 mg, 0.16 mmol, 94%) was obtained as a solid.
½
a 2D5 + 42.7 (c 0.5, CH3OH); dH (400 MHz, D2O) 8.82 (s, 2H, H-20),
ꢂ
7.49 (t, 2H, J = 1.5 Hz, H-40), 7.45 (t, 2H, J = 1.5 Hz, H-50), 5.19 (d,
2H, J = 2.0 Hz, H-3, H-6), 5.09 (d, 2H, J = 4.6 Hz, H-3a, H-6a), 4.34
(m, 4H, H-2, H-5), 3.84 (s, 6H, N–CH3) ppm. dC (D2O,
100.61 MHz) 135.78 (C-20), 124.81 (C-40), 121.35 (C-50), 87.41
(C-3a, C-6a), 72.27 (C-2 C-5), 65.14 (C-3 C-6), 36.39 (N–CH3) ppm.
3.4. Synthesis of (3S,3aR,6S,6aR)-3,6-bis(30-methylimidazolium)-
1,4-dioxabicyclo[3.3.0]octane trifluoroacetate (10)
3.2. Synthesis of bis-imidazolium tosylates (8a–b)
To compound 513 (0.5 mmol) the appropriate N-substituted
imidazole (7a–b) (0.2 mL) was added and the reaction mixture
was stirred at 130 °C under nitrogen atmosphere for 24 h. After
consumption of 5, the reaction mixture was cooled to room tem-
perature and excess N-substituted imidazole 7 was removed by
distillation under reduced pressure at 110–130 °C. The residue
was dissolved in about 50 mL of desionised water (milli-Q) and
continuously extracted in a liquid–liquid apparatus by upward dis-
placement with diethyl ether. After four days, the water phase was
taken, the solvent was evaporated under reduced pressure and the
residue was dried over phosphorus pentoxide to afford the corre-
sponding pure bis-imidazolium tosylate salts 8.
To a solution of the bis-chloride salt 9 (135 mg, 0.389 mmol) in
water (2.5 mL) at room temperature aqueous solution of silver tri-
fluoracetate (171.9 mg, 0.778 mmol) was added. A precipitate of
silver chloride was immediately formed. The reaction mixture
was stirred for 12 h and the precipitate was filtered and washed
two times with water. The water solution of 8 was evaporated un-
der reduced pressure to yield the compound 10 as a solid
(171.8 mg, 0.34 mmol, 87%) mp 118–122 °C, ½a D27
ꢂ
+28.6 (c 0.3,
H2O); IR:
m 3418, 3153, 3106, 1688, 1202, 1174, 1128, 1096, 831,
801 and 720 cmꢀ1; dH (D2O, 400 MHz) 7.44 (s, 2H, H-40), 7.41 (s,
2H, H-50), 5.16 (d, 2H, J = 1.5 Hz, H-3, H-6), 5.02 (s, 2H, H-3a, H-
6a), 4.31 (m, 4H, H-2, H-5), 3.80 (s, 6H, N-CH3) ppm. dC (D2O,
100.61 MHz) 163.30 (q, J = 34 Hz, 2 ꢁ CO2ꢀ), 135.74 (t, J = 33 Hz
(D coupling), C-20), 124.77 (C-40), 121.25 (C-50), 117.74 (q,
J = 292 Hz, 2 ꢁ CF3), 87.37 (C-3a, C-6a), 72.18 (C-2, C-5), 65.10 (C-
3 and C-6), 36.26 (N–CH3) ppm. HRESIMS: m/z 389.1432 (calcd
for ion pair [C14H20N4O2 + C2F3O2]+, 389.1437).
3.2.1. (3S,3aR,6S,6aR)-3,6-Bis(30-methylimidazolium)-1,4-
dioxabicyclo[3.3.0]octane tosylate (8a)
Yellow oil, 88%, ½a D25
ꢂ
+22.8 (c 0.3, H2O); dH (CD3CN, 400 MHz)
9.09 (s, 2H, H-20), 7.58 (d, 4H, J = 8.0 Hz, H-200, H-600), 7.53 (s, 2H,
H-40), 7.24 (s, 2H, H-50), 7.15 (d, 4H, J = 8.0 Hz, H-300, H-500), 5.29
(s, 2H, H-3a, H-6a), 5.10 (dd, 2H, J = 2.8, 4.7 Hz, H-3, H-6), 4.26
(dd, 2H, J = 5.12, 11.0 Hz, H-2a, H-5a), 4.12 (dd, 2H, J = 2.8,
11.0 Hz, H-2b, H-5b), 3.78 (s, 6H, N(30)–CH3), 2.32 (s, 6H, C-500-
CH3) ppm. dC (CD3CN, 100.61 MHz): 146.06 (C-400), 139.98 (C-100),
137.41 (C-20), 129.43 (C-300, C-500), 126.58 (C-200, C-600), 124.76 (C-
50), 122.54 (C-40), 87.89 (C-3a, C-6a), 73.17 (C-2, C-5), 65.89 (C-3,
*
The Hs in the 20-position of imidazolium ring are acidic and
permuted with D in the presence of the solvent D2O.
3.5. Synthesis of (3S,3aR,6S,6aR)-3,6-bis(30-methylimidazolium)-
1,4-dioxabicyclo[3.3.0]octane bis-(triflic)imide (11)
C-6), 36.90 (N–CH3), 21.26 (Ar-CH3) ppm. IR (film):
m 3436, 1650,
To a solution of the bis-chloride salt 9 (135 mg, 0.389 mmol) in
water (2.5 mL) at room temperature aqueous solution of lithium
bis(triflic) amide (223.3 mg, 0.778 mmol) was added and the reac-
1579, 1554, 1187, 1122, 1034, 1010, 820, 682 cmꢀ1. HRESIMS: m/
z 447.1708 (calcd for ion pair [C14H20N4O2 + C7H7O3S]+, 447.1702).

M. D. R. Gomes da Silva, M. Manuela A. Pereira / Carbohydrate Research 346 (2011) 197–202
201
tion mixture was stirred for 24 h, the product started appearing as
a highly viscous oil. Water was decanted off and the residue was
further washed with water, compound 11 was obtained as viscous
122.23 (C-40), 87.71 (C-6a), 83.14 (C-3a), 74.12 (C-2), 73.49 (C-5),
72.82 (C-3), 66.69 (C-6), 36.88 (N–CH3), 21.26 (Ar-CH3) ppm.
HRESIMS:m/z211.1249([M]+, C10H15N2O3 (theorganiccationicmoi-
ety) calcd, 211.1083).
oil (223 mg, 0.27 mmol, 69%). ½a D25
ꢂ
+24.4 (c 0.29, CH3OH); IR (film):
m
3158, 1580, 1192, 1139, 1056, 790 and 740 cmꢀ1; dH (CD3CN,
400 MHz) 8.47 (s, 2H, H-20), 7.40 (d, 4H, J 1.5 Hz, H-40, H-50), 5.06
(dd, 2H, J 1.5, 4.8 Hz, H-3, H-6), 4.94 (s, 2H, H-3a, H-6a), 4.30 (dd,
2H, J 5.0, 12.4 Hz, 2-Ha, 5-Ha), 4.24 (dd, 2H, J 2.4, 11.6 Hz, H-2b,
H-5b), 3.83 (s, 6H, N–CH3) ppm. dC (CD3CN, 100.61 MHz): d
136.47 (C-20), 125.33 (C-40), 122.16 (C-50), 117.35 (q, J 328.0 Hz,
2 ꢁ (CF3–SO2)2N), 88.04 (C-3a, C-6a), 72.84 (C-2, C-5), 65.98 (C-3,
C-6), 37.06 (N–CH3) ppm. HRESIMS: m/z 556.0801 (calcd for ion
pair [C14H20N4O2 + C2F6NO4S2]+, 556.0759).
3.8. (3R,3aR,6S,6aR)-3-hydroxi-6-(30-methylimidazolium)-1,4-
dioxabicyclo[3.3.0]octane chloride (16)
Elution of an aqueous solution of the crude imidazolium tosylate
13 (290 mg) through a column containing AmberliteÒ 900(Cl) resin
(3 g) following by water evaporation under reduced pressure
yielded the crude (3R,3aR,6S,6aR)-3-tert-butyldimethylsilyloxi-
6-(30-methylimidazolium)-1,4-dioxabicyclo[3.3.0]octane chloride
14. 1H NMR analysis of the crude 14 showed a mixture of compound
14 and its desilylated derivative 16. After treatment of the crude
mixture with 3 mL of methanol with two drops of concentrated
hydrochloric acid for 12 h, followed by addition of solid anhydrous
potassium carbonate (100 mg), filtration and solvent evaporation
under reduced pressure a solid of the pure (3R,3aR,6S,6aR)-3-hydro-
xi-6-(30-methylimidazolium)-1,4-dioxabicyclo[3.3.0]octane chloride
3.6. Synthesis of (3R,3aR,6R,6aR)-3-tert-butyldimethylsilyloxi-
6-p-toluenosulfonyloxy-1,4-dioxabicyclo[3.3.0]octane (12)
White solid (1.13 g, 82%) mp 78–80 °C, ½a D27
ꢂ
+90.9 (c 0.77,
CH3OH); IR:
m
3065, 2928, 1251 and 1189 cmꢀ1; dH (CDCl3,
400 MHz) 7.83 (d, 2H, J = 8.16 Hz, H-20, H-60), 7.34 (d, 2H,
J = 8 Hz, H-30, H-50), 4.83 (q, 1H, J = 6.72 Hz, H-6), 4.44 (t, 1H,
J = 4.82 Hz, H-6a), 4.28 (m, 2H, H-3, H-3a), 3.92 (dd, 1H, J = 9.12,
6.96 Hz, H-2), 3.83 (dd, 1H, J = 9.28, 8.64 Hz, H-5), 3.75 (t, 1H,
J = 8.26 Hz, H-2), 3.56 (t, 1H, J = 8.04 Hz, H-5), 2.44 (s, 3H, C-500-
CH3), 0.9 (s, 9H, C–(CH3)3), 0.08 (s, 3H, Si–(CH3)), 0.07 (s, 3H, Si–
(CH3)) ppm. dC (CDCl3, 100.61 MHz) 145.03 (C-10), 133.30 (C-40),
129.81 (C-200, C-600), 127.99 (C-300, C-500), 81.64 (C-3a), 79.70 (C-
6a), 78.40 (C-6), 73.62 (C-3), 72.97 (C-5), 69.82 (C-2), 25.78 (C-
2000), 21.65 (C-Ar-CH3)), 18.30 (Si–CH3) ppm. EI m/z: 414.2 ([M]+,
0.5%), 357.0 ([MꢀC4H9]+, 27%), 228.8 ([MꢀH]+ꢀHOTs–CH3, 100%).
16(161 g, 0.65 mmol, 79%) was obtained. mp130–133 °C, ½a D25
ꢂ
+19.9
(c 0.24, H2O); IR (KBr):m ;
3394, 1167, 1085, 1038, 1011 and 834 cmꢀ1
dH (400 MHz, D2O) 7.45 (s, 1H, H-40), 7.41 (s, 1H, H-50), 5.05 (s, 1H, H-
6), 4.69 (dd, 1H, J = 5.92, 11.64 Hz, H-3a), 4.28 (d, 1H, J = 11.2 Hz, H-
6a), 4.20 (dd, 1H, J = 4.48, 11.28 Hz, H-3), 3.92 (dd, 2H, J = 6.28,
9.44 Hz, H-5), 3.90 (s, 3H, N–CH3), 3.63 (q, 2H, J = 9.28 Hz, H-2). dC
(100.61 MHz, D2O) 124.55 (C-50), 121.46 (C-40), 87.17 (C-6a), 82.41
(C-3a), 72.90 (C-2, C-5), 71.78 (C-3), 65.68 (C-6), 36.29 (N–CH3)
ppm; HRESIMS: m/z 211.1194 ([M]+, C10H15N2O3 (the organic cat-
ionic moiety) calcd, 211.1083).
3.7. Synthesis of (3R,3aR,6S,6aR)-3-hydroxi-6-(30-
methylimidazolium)-1,4-dioxabicyclo[3.3.0]octane tosylate
(13)
Acknowledgements
This work was supported by the Fundação para a Ciência e
Tecnologia (FCT, Portugal) through PTDC/QUI-QUI/100672/2008.
To (3R,3aR,6R,6aR)-3-tert-butyldimethylsilyloxi-6-p-toluenosul-
fonyloxy-1,4-dioxabicyclo[3.3.0]octane 12 (680 mg, 1.64 mmol) the
N-methylimidazole 7a (2.2 mL) was added and the reaction mixture
was stirred at 130 °C under nitrogen atmosphere for 24 h. After total
consumptionof12, thereactionmixturewascooledtoroomtemper-
ature and excess N-methylimidazole 7a was evaporated under re-
duced pressure. The residue was dissolved in about 20 mL of
deionized water (milli-Q) and continuously extracted with diethyl
ether in an apparatus. After 24 h, the water phase was taken and
the water removed under reduced pressure to afford yellow oil as
crude (3R,3aR,6S,6aR)-3-tert-butyldimethylsilyloxi-6-(30-methyl-
imidazolium)-1,4-dioxabicyclo[3.3.0]octane tosylate 13 (590 mg,
73%). The 1H NMR analysis of the crude showed a mixture of com-
pound 13 and its desilylated derivative 15. Treatment of 290 mg
the crude mixture with 3 mL of methanol with two drops of concen-
trated hydrochloric acid for 12 h at room temperature, followed by
addition of solid potassium carbonate (100 mg), filtration and sol-
vent evaporation under reduced pressure gave yellow oil. The oil
was macerated with diethylether to give the pure (3R,3aR,6S,6aR)-
3-hydroxi-6-(30-methylimidazolium)-1,4-dioxabicyclo[3.3.0]octane
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m 3428, 1650, 1190, 1122, 1034, 1010, 817,
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