Chiral ionic liquids derived from isosorbide: Synthesis, properties and applications in asymmetric synthesis

Article abstract of DOI:10.1039/b902956g

A novel class of chiral ammonium and imidazolium-based ionic liquids has been designed and synthesized using isosorbide as a biorenewable substrate. These chiral ionic liquids were found to catalyze the aza Diels-Alder reaction to give good yields and moderate diastereoselectivitives.

Full text of DOI:10.1039/b902956g

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/njc | New Journal of Chemistry
Chiral ionic liquids derived from isosorbide: synthesis, properties
and applications in asymmetric synthesis
Olivier Nguyen Van Buu, Audrey Aupoix, Nhung Doan Thi Hong
and Giang Vo-Thanh*
Received (in Montpellier, France) 12th February 2009, Accepted 22nd June 2009
First published as an Advance Article on the web 23rd July 2009
DOI: 10.1039/b902956g
A novel class of chiral ammonium and imidazolium-based ionic liquids has been designed and
synthesized using isosorbide as a biorenewable substrate. These chiral ionic liquids were found
to catalyze the aza Diels–Alder reaction to give good yields and moderate diastereoselectivitives.
ester forms in the pharmaceutical industry.10 These commercial
Introduction
starting materials provide an easy and cost effective way
to access optically pure functionalized compounds. Isosorbide
has been used as a chiral auxiliary and chiral ligand in several
reactions among which alkylation,11 Diels–Alder reaction,12
and asymmetric hydrogenation13 are the most important.
Surprisingly, in spite of their potential, to date, only a
few ammonium CILs derived from isomannide have been
reported.14
Over the past decade, ionic liquids (ILs), or room temperature
molten salts, have received considerable attention thanks to
their ability to serve as effective reaction media for a
wide range of organic reactions and other applications in
chemistry.1 By modifying the structure of the cations or anions
of ionic liquids, it has been shown that their properties can be
altered in order to influence the outcomes of reactions.
Advances in IL use have made the development of chiral ionic
liquids (CILs) a subject of intense study in recent years.2
Although a limited number of CILs have been designed and
synthesized, they have already found promising applications in
asymmetric synthesis,3 stereoselective polymerization,4 chiral
chromatography,5 liquid crystal technologies,6 chiral resolution,
and as a NMR shift reagents.7 Nowadays, the design and
synthesis of novel CILs are growing rapidly. The study of CIL
applications in asymmetric synthesis presents a challenge and
an opportunity to researchers. It is, therefore, essential to
synthesize different kinds of CILs from various starting
In a continuation of our research into the synthesis and
applications of new CILs from inexpensive and commercially
available natural chiral auxiliaries,3a,i,15 we have managed to
synthesize and formulate a novel class of chiral ammonium
and imidazolium-based ionic liquids derived from isosorbide.
We also report here some important physical properties of
these new CILs and their application as a chiral reaction
medium as well as catalyst for an asymmetric aza Diels–Alder
reaction.
Results and discussion
materials derived from
biorenewable sources.
a chiral pool, especially from
Chiral ionic liquids: synthesis and characterisation
We focused our attention on designing new chiral
ammonium and imidazolium-based ionic liquids based on
the structurally rigid bicyclic systems isosorbide 1, also known
as (3R, 3aR, 6S, 6aR)-hexahydrofuro[3,2-b]furan-3,6-diol, and
isomannide 2, (3R, 3aR, 6R, 6aR)-hexahydrofuro[3,2-b]furan-
3,6-diol, which are renewable, and commercially available
chiral carbohydrates. Isosorbide is basically two fused
tetrahydrofuran rings with a cis-arrangement at the ring
junction, giving a wedge-shaped molecule.8 The compound
bears two hydroxyl groups, one at C6 having the exo-orientation
with respect to the wedge-shaped molecule, and the other at C3
having the endo-orientation, which makes intramolecular
hydrogen bonding possible with the oxygen atom of the
neighbouring tetrahydrofuran ring (Fig. 1). Isosorbide and
isomannide are industrially obtained by dehydration of
D-sorbitol and D-mannitol, and can therefore be considered
as biomass products.9 They are widely used in their nitrate
Our strategy is to protect one of the free hydroxyl groups as an
ether while transforming the other into the ammonium or
imidazolium function by nucleophilic substitution by a
primary amine or N-methylimidazole. An anion exchange will
be carried out to obtain the desired ILs.
Our synthesis was initiated by the selective monobenzylation
of the hydroxyl group at the endo C3 position, although very
few protocols for isosorbide regioselective alkylation are
reported in the literature.16 In fact, the benzylation of
isosorbide can lead to the formation of the three products,
´
Laboratoire de Catalyse Moleculaire, Institut de Chimie Moleculaire
et des Materiaux d’Orsay, UMR 8182, Universite Paris-Sud 11,
´
´
´
91405 Orsay Cedex, France. E-mail: gvothanh@icmo.u-psud.fr
Fig. 1 Structure of isosorbide 1 and isomannide 2.
ꢀc
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2009
2060 | New J. Chem., 2009, 33, 2060–2072

View Article Online
Scheme 1 Benzylation of isosorbide.
3-benzyl (endo) 3, 6-benzyl (exo) 4 and 3,6-dibenzyl ethers 5, in
ratios depending on the experimental conditions (Scheme 1).17
The best yield (56%) of compound 3 was obtained when
performing the reaction using 1 equivalent of benzyl chloride
along with lithium hydride and lithium chloride in stoichio-
metric quantities. The free hydroxyl group at the exo C6
position was then activated as its sulfonate by treatment with
benzenesulfonyl chloride using an excess of triethylamine,
chiral ammonium bis(trifluoromethanesulfonyl)imides 11 in
excellent yields.
We then proceeded to synthesize the chiral ammonium IL
17 in order to study the effect of 3-exo–6-exo combinations on
prospective applications of these chiral ILs as new reaction
media in asymmetric synthesis. Thus, ammonium salt 17 was
synthesized from compound 4, which was obtained in 40%
yield by isosorbide monobenzylation (Scheme 1).11 Using the
same strategy previously described in Scheme 2, IL 17 was
then obtained in 19% overall yield in 7 steps from isosorbide.
Scheme 3 summarizes the synthesis of this new chiral IL.
For the synthesis of imidazolium salts, using the same
strategy shown in Scheme 2, the sulfonate 6 was converted
to the imidazolium ether 18 by heating with a large excess of
N-methylimidazole at 160 1C.19 However, no product was
detected even after 4 days.
affording the sulfonate
6 in 99% yield (Scheme 2).
Subsequently, the sulfonate 6 was treated with an excess of
primary aromatic and aliphatic amines in a sealed tube at
160 1C to give the corresponding amino ethers 7 via an SN2
substitution reaction with complete inversion of configuration.
Conversion of 7 to tertiary amines 8 was made by means
of an Eschweiler–Clark reaction.18 Generally speaking, the
yields obtained were good. Amino ethers 8 were thereafter
quaternized with iodomethane in refluxing dichloromethane to
form the quaternary ammonium salts 9 in 85–98% yield
(Scheme 2).
We turned out our attention to the use of microwave
irradiation. This technique has been developed in our
laboratory and by other research groups, particularly for the
synthesis of ILs.15,20 The combination of solvent-free
conditions and MW irradiation considerably reduces reaction
time, enhances conversions as well as selectivity and
sometimes enables the preparation of molecules which are
impossible to synthesize under classic conditions.21
The next step in the synthesis was the transformation of
ammonium iodide salts 9 into ionic liquids 10 by removing the
benzyl protecting group at the endo C3 position, followed by
an anion exchange. Unfortunately, all attempts to remove the
benzyl protecting group by hydrogenolysis or Lewis acid
catalysis failed. In the course of our studies we found out that
the use of trifluoromethanesulfonic acid in large excess in
dichloromethane not only allows the cleavage of the benzyl
ether protecting group but it also removes the iodide by triflate
anion exchange. Ionic liquids 10 were obtained in good yields
(90–97%) within a very short reaction time (5 min). On the
other hand, the anion exchange of 10 with LiNTf2 produced
Many experiments were carried out by varying the number
of equivalents of N-methylimidazole, the temperature and
the reaction time as well as the addition of lithium salts
(electrophilic assistance). The best result was obtained when
performing the synthesis in a two-step but one-pot sequence
reaction using solvent-free microwave activation conditions.
The crude product (non isolated) resulting from the
Scheme 2 Synthesis of chiral ammonium ILs 9, 10 and 11.
ꢀc
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2009 New J. Chem., 2009, 33, 2060–2072 | 2061

View Article Online
Scheme 3 Synthesis of chiral ammonium IL 17.
substitution reaction with 6 equivalents of N-methylimidazole
at 130 1C for 4 h (first step) was directly submitted to an anion
exchange step with KOTf at 90 1C for 20 min (Scheme 4).
Purification by chromatography on alumina afforded the
desired imidazolium salt 18 in 50% yield.
The reaction was followed by TLC and indicated a total
conversion after two days. Imidazolium 22 was isolated with
46% yield after purification by chromatography on alumina.
It is again a SN2 substitution reaction with complete inversion
1
of configuration. This was established by H NMR analysis
The last step in the synthesis is the removal of the benzyl
ether protecting group using trifluoromethanesulfonic acid in
dichloromethane. Ionic liquids 19 were obtained in good
yields (97%) within a very short reaction time (5 min). It is
noteworthy that these chiral imidazolium salts 18 and 19 are
viscous liquids at room temperature (Scheme 4).
based on the observation of the H6–H6a coupling constant
(Jcis = 5 Hz and Jtrans = 0 Hz) (Fig. 2). The doublet of H6a in
21 became a doublet of doublets in 22. Due to this inversion
of configuration, the isosorbide skeleton was converted to
isomannide.
The modest yield (40%) of this alkylation could be
explained by the formation of a product of elimination. The
compound 23 (Scheme 5) was indeed isolated with 30% yield,
resulting from the elimination of the triflate 21, which is a very
good leaving group tending to be eliminated easily; especially
since the carbocation, resulting from E1 elimination, must be
stabilized in this ionic medium.
In view of the difficulty encountered in introducing the
imidazolium skeleton on the isosorbide, it was decided to
change the leaving group. It was imagined that a triflate group
could be used, on the one hand as a very good leaving group,
and on the other hand as an associated anion, allowing a
synthesis step to be gained. The acetate seems to be the
protecting group of choice. In fact, the monoacetylation of
the isosorbide was already described and offers a better yield
than the monobenzylation. This protecting group should resist
the alkylation conditions and be removed with no difficulty in
acid as well as basic media according to the stability of the
synthesized ionic liquid. The synthesis of the ionic liquid 19 by
this second method is represented in the Scheme 5.
The next step in the synthesis is the transformation of the
acetylated imidazolium 22 into ionic liquid 19 by removing
the acetyl protecting group at the endo C3 position. Thus,
deacetylation was performed in ethanol in the presence of a
drop of concentrated HCl to afford the CIL 19 with 90% yield
(Scheme 5).
We then proceeded to synthesize the imidazolium CIL 25
possessing the methyl group in position 2 of N-methylimidazole.
Using the same strategy previously described in Scheme 5,
CIL 25 was then obtained in 25% overall yield in 4 steps from
isosorbide. Scheme 6 summarizes the synthesis of this new
chiral IL.
The first step of our synthesis was realized according to the
reaction conditions reported by Stoss and co-workers.22 After
purification by chromatography on silica gel, we obtained the
acetate derivative 20 with 70% of yield. The free hydroxyl
group in the endo position of acetyl isosorbide 20 was then
activated to the triflate form by action of triflic anhydride and
pyridine in dichloromethane. The compound 21 was obtained
with a quasi-quantitative yield. The triflate 21 was converted
to imidazolium 22 by reaction with a slight excess of
N-methylimidazole using no solvent at room temperature.
1
All of these CILs were characterized by H and 13C NMR
spectroscopy, infrared (IR), differential scanning calorimetry
(DSC), thermogravimetric analysis (TGA), optical rotation,
high resolution mass spectroscopy (HRMS) and elemental
analysis. Table 1 gives some physical properties of these CILs.
Scheme 4 Synthesis of imidazolium salts 18 and 19.
ꢀc
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2009
2062 | New J. Chem., 2009, 33, 2060–2072

View Article Online
Scheme 5 Synthesis of imidazolium salt 19.
stability. We proceeded to study some CILs behaviour in
neutral, basic and acid aqueous media. Compounds 10a, 11a
and 19 were chosen for this study. These compounds (30 mg)
are not miscible with water; they will thus be solubilized in a
small quantity of dichloromethane (30 mL). The solution was
stirred with 1 mL of water distilled (neutral conditions) or with
1 mL of a saturated aqueous solution of potassium carbonate
(basic conditions) or with 1 mL of a 2 N hydrochloric acid
solution (acid conditions) for 2 h. For all compounds studied,
after extraction of the aqueous phase by dichloromethane,
dried over magnesium sulfate and concentrated under vacuum
pressure, the same mass was found. 1H NMR analysis and
optical rotation data showed that they were intact, confirming
their stability in neutral, basic and acid aqueous conditions.
1
Fig. 2 Inversion of configuration confirmed by H NMR.
As can be seen from Table 1, most of these CILs are viscous
liquids at room temperature, except the salt 10c which is a
solid with a melting point of 125 1C. Glass transition
temperatures ranging from À51 to À15 1C were measured.
All of these are found to be thermally stable up to 180 1C.
In addition, good optical rotation was measured for all the
CILs synthesized in the present work, indicating that the
chirality of isosorbide has been retained in the CILs. It was
observed that the chirality of all CILs remained unchanged
even after 3 months or longer. This is different to some
stereogenic centers in CILs, which have been reported to
undergo racemization after a certain time.23 Solubility and
miscibility of these CILs depend on the alkyl chain length and
the nature of the associated anion. Nevertheless, all of them
are immiscible with ether and very miscible with methanol,
dichloromethane or acetonitrile.
Chiral ionic liquids: applications in catalysis
After achieving the synthesis of these ILs that contain a chiral
moiety and a free hydroxyl functional group, we were
interested in testing their potential for asymmetric induction.
To that end, as a model reaction, we studied the asymmetric
aza Diels–Alder reaction of Danishefsky’s diene 26 with a
chiral imine 27 in the presence of CIL (Scheme 7, Table 2).
This reaction has proved to perform better at room temperature
in ionic liquid without either Lewis acid catalyst or organic
solvent24 and with significant diastereoselectivity using an
ephedrinium-based ionic liquid.3i
The results summarized in Table 2 shown that ammonium
or imidazolium CILs could catalyze the aza Diels–Alder
reaction. Good yields and significant diastereoselectivities
Before testing the potential of our CILs for asymmetric
induction, it is advisable to make sure of their chemical
Scheme 6 Synthesis of CIL 25.
ꢀc
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2009 New J. Chem., 2009, 33, 2060–2072 | 2063

View Article Online
Table 1 Properties of CILsa
19 was protected with a benzyl group (compounds 29 or 18) or
an acetyl group (compounds 22), approximately 60% de
but with only around 30% yield was achieved (Table 2,
entries 3, 4 and 6). The CILs 11a and 19 turn out to catalyze
in an effective way the reaction. The best yields and diastereo-
selectivities were thus observed. CILs are highly recyclable and
do not lose any of their properties even when used four
consecutive times (Table 2, entry 1 and 5). However, in the
case of the CIL 24, only 5% yield was obtained, showing a loss
of catalytic reactivity due to the complete absence of mobile
hydrogen on the hydroxyl function or the imidazolium
nucleus. No hydrogen bonding could be formed in this case
(Table 2, entry 8). Finally, only 32% de was obtained when we
used the chiral imine in the presence of ZnCl2 as Lewis acid
catalyst (Table 2, entry 10).
CIL structure
R
X
CIL Td/1Cb Tm/1Cc Tg/1Cd
C8H17 OTf 10a 195
NTf2 11a 180
C12H25 OTf 10b 192
NTf2 11b 180
CH2Ph OTf 10c 210
40
nd
45
nd
125
À33
À49
À51
À47
À15
NTf2 11c 200
nd
42
À29
À15
C8H17 OTf 16
204
198
210
NTf2 17
nd
nd
À35
À40
H
OTf 19
These results confirmed that not only may CILs be used as
catalysts but they also play the role of chiral inductors in the
asymmetric aza Diels–Alder reaction. The key to effective
asymmetric induction is the existence of strong intermolecular
interactions, like electrostatic attraction and hydrogen
bonding, between ionic solvents and intermediates or
transition states on the diastereoselective reaction pathway.
This observation was made by our group3a and further
confirmed by Leitner and co-workers.3e
CH3
25
214
nd
À45
a
b
For optical rotation: see experimental section. Decomposition
temperature (Td) was determined by thermogravimetric analysis,
heating at 10 1C minÀ1
c
.
Melting point (Tm) was determined by
differential scanning calorimetry, heating at 10 1C minÀ1. nd: not
detected. Glass transition temperature (Tg) was determined by
With these results in hand, we proceeded to examine the
CIL effects on the reaction. To this end, a series of tests using
the chiral ammonium salts with different combinations of
alkyl chain length and associated anion were carried out.
The best result (75% yield and 65% de) was obtained with
R = C8H17. A drop in yield and in diastereoselectivity were
observed with R = C12H25 and CH2Ph (Table 3, entries 1, 3
and 5). No interpretation of these obtained results is
suggested.
d
differential scanning calorimetry, heating at 10 1C minÀ1
.
Generally speaking, better yields were observed when using
OTf as opposed to NTf2 as the associated anion. In addition,
for the same alkyl chain length, a slight drop in de was
detected with NTf2. The anion nature has a significant
influence on the catalytic reactivity and the asymmetric
induction of this reaction. The results obtained are shown in
Table 3.
Scheme 7 Asymmetric aza Diels–Alder reaction of Danishefsky’s
diene 26 with imine 27.
are obtained when performing the experiments with
0.5 equivalents of IL and 1.5 equivalents of Danishefsky’s
diene at room temperature for 5 h. The two diastereomers
obtained were separated by column chromatography and the
assignment of the absolute configuration of the major product
28 was determined by comparison of its optical rotation and
NMR spectral data with the reported values.25
Therefore, our preliminary studies on the application of
these CILs for the aza Diels–Alder reaction showed that the
chiral reaction medium has a significant influence on chiral
induction. Further investigations to provide useful insight into
the understanding of the use of these CILs in asymmetric
induction are in progress in our laboratory. The results of
these studies will be communicated in due course.
As mentioned in the literature, the presence of the hydroxyl
group is very important for reactivity and especially for
chirality transfer. This fact has already been reported by
Colonna and co-workers26 in the borohydride asymmetric
reduction of carbonyl compounds using a chiral phase-
transfer catalyst. This observation is also supported by our
studies on the asymmetric Baylis–Hillman reaction.3a On the
other hand, the imidazolium functionality can catalyze the
Diels–Alder reaction thanks to the formation of hydrogen
Conclusion
In summary, we have designed and synthesized a novel family
of chiral ammonium and imidazolium-based ionic liquids that
contain a chiral moiety and a hydroxyl function derived from
isosorbide. The synthesis of these ionic liquids is easy and
practical due to the commercially inexpensive and readily
available starting materials. We have also reported some
physical properties of these new CILs. These CILs can serve
as chiral reaction media as well as catalysts in the asymmetric
aza Diels–Alder reaction. Further improvements to the
bonds between the mobile hydrogen in position
2 of
imidazolium and the substrate as observed by Welton and
co-workers.27 Thus, when isosorbide 1 was used as a chiral
source without Lewis acid catalyst, no product was observed
(Table 2, entry 9), a fact already mentioned in the literature.28
On the other hand, when the hydroxyl group of the CIL 11a or
ꢀc
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2009
2064 | New J. Chem., 2009, 33, 2060–2072

View Article Online
Table 2 Asymmetric aza Diels–Alder reaction of Danishefsky’s diene 26 with imine 27. Conditionsa: imine 27 : diene 26 : CIL = 1 : 1.5 : 0.5;
temperature: 30 1C; time: 5 h
Entry
CIL
R1
R2
Isolated yield 28 (%)
de 28b (%)
1
2
3
4
5
6
7
8
9
10
11a
17
29
18
19
22
73 (75, 73, 75)e
56
63 (65, 62, 64)e
60
33
39
59
60
H
Bn
H
Ac
H
74 (74, 75, 73)e
68 (66, 67, 68)e
25
40
5
0
60
59
65
69
0
25
24
Me
Ac
1c
No CILd
32
a
b
Diene added into reaction medium in three phases: 0.5 equiv. at equal intervals. de determined by chiral HPLC with a margin of error
c
about 1%. Compound 1 (1 equiv.) was used as a chiral source. ZnCl2 (10 mol%) added. results obtained by reaction with recycled IL are
d
e
given in brackets.
Table 3 Symmetric aza Diels–Alder reaction of Danishefsky’s diene 26 with imine 27. Conditionsa: imine 27 : diene 26 : CIL = 1 : 1.5 : 0.5;
temperature: 30 1C; time: 5 h
Entry
CIL
R
X
Isolated yield 28 (%)
de 28b (%)
1
2
3
4
5
6
10a
11a
10b
11b
10c
11c
C8H17
OTf
NTf2
OTf
NTf2
OTf
NTf2
75
41
56
40
48
38
65
54
55
54
54
52
C12H25
CH2Ph
a
b
Diene added into reaction medium in three phases: 0.5 equiv. at equal intervals; de determined by chiral HPLC with a margin of error of about 1%.
application of CILs in asymmetric synthesis are currently
underway in our laboratory.
or phosphomolybdic acid solution. The columns were
hand-packed with silica gel 60 (200–300).
All reagents and solvents were purchased from commercial
sources (Acros, Aldrich) and were used without further
purification.
Experimental
General information
General procedure for the synthesis of compounds 6 and 12
Melting points were measured on a Kofler bank. The NMR
spectra were recorded in CDCl3, DMSO-d6, MeOD-d4 or in
acetone-d6. 1H NMR spectra were recorded at 360 or
250 MHz. The chemical shifts (d) are reported in parts per
million relative to TMS as internal standard. J values are given
in Hz. 13C NMR spectra were recorded at 90 or 62.5 MHz. IR
spectra were recorded on a FT-IR Perkin–Elmer instrument.
TLC experiments were carried out in 0.2 mm thick silica gel
plates (GF254) and visualization was accomplished by UV light
A mixture of the alcohol 3 (or 4) (65 mmol, 15.4 g), triethyl-
amine (390 mmol, 55 mL) and benzenesulfonyl chloride
(78 mmol, 10 mL) was stirred under an argon atmosphere
for 10 h. The reaction mixture was diluted with water
(200 mL), acidified with 5 N HCl (60 mL) and the hydrolysis
was continued for a further 2 h. The resulting mixture was
extracted with dichloromethane (3 Â 120 mL). The organic
phases were washed with brine, dried over anhydrous MgSO4,
ꢀc
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2009 New J. Chem., 2009, 33, 2060–2072 | 2065

View Article Online
and then concentrated under reduced pressure. The residue
was purified by flash column chromatography on silica gel
(heptane : ethyl acetate = 1 : 1) to afford 6 (or 12).
(CH), 80.1 (CH), 80.8 (CH), 127.4, 127.5, 128.0 (5 CHAr),
137.5 (C); HRMS (MH+) m/z (%) calcd for [C21H33NO3]+:
348.2533, found: 348.2539.
(3R, 3aR, 6S, 6aS)-3-(benzyloxy)hexahydrofuro[3,2-b]furan-
6-yl benzenesulfonate (6). Yield: 99%; white crystals, mp:
25
(3R, 3aR, 6R, 6aS)-6-benzyloxy-3-(docecylamino)hexahydro-
20
furo[3,2-b]furan (7b). Yield: 76%; Yellowish oil; [a]D
=
93–95 1C; [a]D = +92.7 (c = 0.25, CHCl3); IR (neat) u =
+99.9 (c = 3.91, CHCl3); IR (neat) u = 3321, 2924, 2853,
1674, 1496, 1466, 1456, 1367, 1309, 1206, 1142, 1071, 1084,
3065, 3032, 2877, 1449, 1367, 1189, 1100, 1043, 971, 947, 902,
1
820, 750 cmÀ1; H NMR (250 MHz, CDCl3) d 3.57 (dd, J =
970, 825, 735, 698 cmÀ1; H NMR (360 MHz, CDCl3) d 0.88
1
7.6; 9.0 Hz, 1H), 3.82 (dd, J = 6.6 and 9.0 Hz, 1H), 3.95–4.08
(m, 3H), 4.52 (d, J = 4.3 Hz, 1H), 4.53 (d, J = 12.0 Hz, 1H),
4.68 (dd, J = 4.3 and 5.0 Hz, 1H), 4.73 (d, J = 12.0 Hz, 1H),
4.91 (m, 1H), 7.26–7.40 (m, 5H, benzyl), 7.54–7.71 (m, 3H,
phenyl), 7.91–7.97 (m, 2H, phenyl). 13C NMR (62.5 MHz,
CDCl3) d 70.5 (CH2), 72.5 (CH2), 73.2 (CH2), 78.9 (CH), 80.6
(CH), 84.2(CH), 85.8 (CH), 127.8, 127.9, 128.0, 128.5, 129.5,
134.1 (10 CHAr), 136.3 (C), 137.5 (C); anal. calcd for
C19H20O6S: C, 60.62; H, 5.36; O, 25.50; S, 8.52; found: C,
60.54; H, 5.25; O, 25.41; S, 8.49.
(t, J = 7.2 Hz, 3H), 1.20–1.36 (m, 18H), 1.43–1.53 (m, 2H),
1.90 (s br, NH), 2.51–2.58 (m, 1H), 2.66–2.73 (m, 1H),
3.30–3.36 (m, 1H), 3.41 (dd, J = 10.1 and 8.0 Hz, 1H), 3.64
(dd, J = 7.9 and 8.3 Hz, 1H), 3.91 (dd, J = 6.1 and 8.3 Hz, 1H),
4.05–4.11 (m, 1H), 4.14 (dd, J = 8.0 and 7.2 Hz, 1H), 4.46
(dd, J = 4.3 and 4.3 Hz, 1H), 4.54 (d, J = 12.8 Hz, 1H), 4.61
(dd, J = 4.3 and 4.7 Hz, 1H), 4.75 (d, J = 12.8 Hz, 1H),
7.23–7.40 (m, 5H phenyl). 13C NMR (90 MHz, CDCl3) d 13.8
(CH3), 22.4 (CH2), 27.0 (CH2), 29.1 (CH2), 29.4 (5 CH2), 30.3
(CH2), 31.6 (CH2), 48.4 (CH2), 62.8 (CH), 71.0 (CH2), 72.1
(CH2), 72.4 (CH2), 79.7 (CH), 80.2 (CH), 80.9 (CH), 127.6,
128.1 (5 CH), 137.6 (C); anal. calcd for C25H41NO3: C, 74.40;
H, 10.24; N, 3.47; O, 11.89, found: C, 74.26; H, 10.21; N, 3.48;
O, 12.09.
(3S, 3aR, 6R, 6aS)-3-(benzyloxy)hexahydrofuro[3,2-b]furan-
25
6-yl benzenesulfonate (12). Yield: 93%; yellowish oil; [a]D
=
+100.6 (c = 0.50, CHCl3); IR (neat) u = 3063, 2874, 1449,
1365, 1188, 1097, 1043, 1008, 972, 911, 850, 824 cmÀ1
;
1H NMR (360 MHz, CDCl3) d 3.68 (dd, J = 6.3 and
9.2 Hz, 1H), 3.75–3.83 (m, 2H), 3.94 (d, J = 10.8 Hz, 1H), 4.00
(d, J = 3.2 Hz, 1H), 4.44–4.46 (m, 3H), 4.56 (dd, J = 4.0 and
5.8 Hz, 1H), 4.86 (q, J = 6.0 Hz, 1H), 7.20–7.30 (m, 5H,
benzyl), 7.46 (t, J = 7.6 Hz, 2H, phenyl), 7.57 (t, J = 7.6 Hz,
1H, phenyl), 7.90 (d, J = 8.6 Hz, 2H, phenyl). 13C NMR
(90 MHz, CDCl3) d 68.8 (CH2), 70.7 (CH2), 72.9 (CH2), 78.8
(CH), 79.7 (CH), 82.7 (CH), 85.3 (CH), 127.1, 127.3, 127.9,
128.8 (8 CHAr), 133.6 (2 CHAr), 135.7 (C), 137.1 (C); anal.
calcd for C19H20O6S: C, 60.62; H, 5.36; O, 25.50; S, 8.52,
found: C, 60.65; H, 5.39; O, 25.38; S, 8.39.
(3R, 3aR, 6R, 6aS)-3-benzylamino-6-(benzyloxy)hexahydro-
20
furo[3,2-b]furan (7c). Yield: 75%; yellowish oil; [a]D
=
+145.3 (c = 1.47, CHCl3); IR (neat) u = 3321, 3087, 3062,
3029, 2942, 2871, 1955, 1880, 1815, 1695, 1604, 1586, 1496,
1463, 1455, 1367, 1312, 1259, 1206, 1136, 1084, 1045, 1027, 970
;
cmÀ1 1H NMR (250 MHz, CDCl3) d 2.27 (s br, NH),
3.27–3.46 (m, 2H), 3.62 (dd, J = 7.7 and 8.5 Hz, 1H), 3.72
(d, J = 12.3 Hz, 1H), 3.85 (d, J = 12.3 Hz, 1H), 3,87 (dd, J =
8.5 and 6.8 Hz, 1H), 3.98–4.11 (m, 2H), 4.40 (dd, J = 4.0 and
4.3 Hz, 1H), 4.49 (d, J = 12.0 Hz, 1H), 4.51–4.54 (m, 1H), 4.71
(d, J = 12.0 Hz, 1H), 7.14–7.40 (m, 10H). 13C NMR
(62.5 MHz, CDCl3) d 52.3 (CH2), 62.1 (CH), 71.1 (CH2),
72.4 (CH2), 72.6 (CH2), 79.8 (CH), 80.2 (CH), 81.1 (CH),
127.0, 127.8, 128.0, 128.3 (10 CHAr), 137.7 (C), 140.0 (C); anal.
calcd for C20H23NO3: C, 73.82; H, 7.12; N, 4.30, O, 14.75,
found: C, 73.52; H, 7.11; N, 4.46; O, 14.77.
General procedure for the synthesis of compounds 7a–c and 13
A solution of the sulfonate 6 (or 12) (64 mmol), freshly
distilled amine (386 mmol) and lithium chloride (32 mmol)
was heated at 160 1C in a sealed tube for 24 h. The contents
were cooled to room temperature and the excess of amine was
removed under reduced pressure. The residue was purified by
flash column chromatography on silica gel (CH2Cl2 : MeOH =
98 : 2) to afford 7a–c (or 13) as a yellowish oil (75–80%)
(3S, 3aR, 6S, 6aS)-6-benzyloxy-3-(octylamino)hexahydro-
25
furo[3,2-b]furan (13). Yield: 77%; yellowish oil; [a]D
=
+21.8 (c = 0.5, CHCl3); IR (neat) u = 3315, 3064, 3031,
2926, 2855, 1497, 1455, 1366, 1341, 1207, 1082, 1029, 857, 914,
1
841, 783, 735, 697 cmÀ1; H NMR (360 MHz, CDCl3) d 0.88
(3R, 3aR, 6R, 6aS)-6-benzyloxy-3-(octylamino)hexahydro-
[25]
(t, J = 6.5 Hz, 3H), 1.20–1.35 (m, 10H), 1.40–1.50 (m, 2H),
2.60–2.65 (m, 2H), 3.25–3.30 (m, 1H), 3.66 (dd, J = 2.7 and
9.6 Hz, 1H), 3.85–3.90 (m, 3H), 4.03–4.06 (m, 1H), 4.51–4.64
(m, 4H), 7.25–7.35 (m, 5H phenyl). 13C NMR (90 MHz,
CDCl3) d 13.9 (CH3), 22.5 (CH2), 27.1 (CH2), 29.1 (CH2),
29.3 (CH2), 30.0 (CH2), 31.7 (CH2), 48.0 (CH2), 64.7 (CH),
71.3 (CH2), 72.0 (CH2), 72.8 (CH2), 82.9 (CH), 85.4 (CH), 87.0
(CH), 127.6, 128.3 (5 CHAr), 137.5 (C); anal. calcd for
C21H33NO3: C, 72.58; H, 9.57; O, 13.81; N, 4.03, found: C,
72.52; H, 9.61; O, 13.91; N, 4.02.
furo[3,2-b]furan (7a). Yield: 80%; [a]D
= +123.5 (c =
1.83, CHCl3); IR (neat) u = 3322, 3064, 3031, 2926, 2855,
1496, 1455, 1367, 1309, 1207, 1143, 1084, 1027, 826, 736,
;
698 cmÀ1 1H NMR (250 MHz, CDCl3) d 0.87 (t, J = 6.7
Hz, 3H), 1.20–1.40 (m, 10H), 1.40–1.60 (m, 2H), 1.96
(s br, NH), 2.47–2.57 (m, 1H), 2.63–2.73 (m, 1H), 3.25–3.43
(m, 2H), 3.62 (dd, J = 8.0 and 8.5 Hz, 1H), 3.88 (dd, J = 8.5
and 6.75 Hz, 1H), 4.00–4.05 (m, 1H), 4.12 (dd, J = 7.5 and
7.25 Hz, 1H), 4.43 (dd, J = 4.25 and 4.5 Hz, 1H), 4.51
(d, J = 11.5 Hz, 1H), 4.57 (dd, J = 4.5 and 4.5 Hz, 1H),
4.72 (d, J = 11.5 Hz, 1H), 7.25–7.45 (m, 5H phenyl). 13C
NMR (62.5 MHz, CDCl3) d 13.7 (CH3), 22.3 (CH2), 26.9
(CH2), 28.9 (CH2), 29.1 (CH2), 30.2 (CH2), 31.4 (CH2), 48.3
(CH2), 62.7 (CH), 70.9 (CH2), 72.0 (CH2), 72.4 (CH2), 79.6
General procedure for the synthesis of compounds 8a–c and 14
To a solution of formaldehyde (79 mmol), and formic acid
(79 mmol) was added at 0 1C the secondary amine 7 (or 13)
ꢀc
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2009
2066 | New J. Chem., 2009, 33, 2060–2072

View Article Online
(49 mmol). After being refluxed for 2 h, the reaction mixture
was allowed to warm at 0 1C and 5 N HCl (64 mmol) was
added. Water and the excess formic acid were removed under
reduced pressure. The residue was treated with excess 2 N
NaOH (98 mmol) and the aqueous phase was extracted with
ethyl acetate (3 Â 60 mL). The combined organic phases were
washed with brine, dried over anhydrous MgSO4, and then
concentrated under reduced pressure. The resulting residue
was finally purified by flash column chromatography on silica
gel (CH2Cl2 then EtOAc) to afford 8a–c (or 14) as a yellowish
oil or white solid (73–84%).
C21H25NO3: C, 74.31; H, 7.42; N, 4.13, O, 14.14, found: C,
74.16; H, 7.23; N, 4.17; O, 14.07.
(3S, 3aR, 6S, 6aS)-6-benzyloxy-3-(N-methyl-N-octylamino)-
hexahydrofuro[3,2-b]furan (14). Yield: 81%; yellowish oil;
25
[a]D = +30.1 (c = 0.50, CHCl3); IR (neat) u = 3065,
3031, 2965, 2855, 2798, 1497, 1455, 1367, 1340, 1312, 1207,
;
1084, 1045, 941, 959, 919, 772, 735, 697 cmÀ1 1H NMR
(360 MHz, CDCl3) d 0.88 (t, J = 7.0 Hz, 3H), 1.20–1.40
(m, 10H), 1.40–1.58 (m, 2H), 2.23 (s, 3H), 2.26–2.32 (m, 1H),
2.47–2.55 (m, 1H), 2.92–2.98 (m, 1H), 3.64 (dd, J = 7.7 and
8.5 Hz, 1H), 3.83–3.92 (m, 2H), 3.98–4.02 (m, 2H), 4.51–4.61
(m, 3H), 4.64–4.67 (m, 1H), 7.25–7.45 (m, 5H phenyl). 13C
NMR (90 MHz, CDCl3) d 13.8 (CH3), 22.4 (CH2), 26.8 (CH2),
27.1 (CH2), 29.0 (CH2), 29.2 (CH2), 31.5 (CH2), 39.3 (CH3),
55.4 (CH2), 70.8 (CH2), 71.0 (CH2), 71.3 (CH), 71.5 (CH2),
82.8 (CH), 85.6 (CH), 86.3 (CH), 127.4, 128.1 (5 CHAr), 137.4
(C); anal. calcd for C22H35NO3: C, 73.09; H, 9.76; O, 13.28; N,
3.87, found: C, 72.94; H, 9.88; O, 12.99; N, 3.81.
(3R, 3aR, 6R, 6aS)-6-benzyloxy-3-(N-methyl-N-octylamino)-
hexahydrofuro[3,2-b]furan (8a). Yield: 84%; yellowish oil
25
[a]D = +95.8 (c = 2.40, CHCl3); IR (neat) u = 3031,
2928, 2855, 2788, 1496, 1455, 1368, 1304, 1208, 1134, 1087,
1026, 823, 735, 698 cmÀ1; 1H NMR (250 MHz, CDCl3) d 0.87
(t, J = 6.4 Hz, 3H), 1.16–1.36 (m, 10H), 1.40–1.60 (m, 2H),
2,32 (s, 3H), 2.37–2.57 (m, 2H), 2.83–2.91 (m, 1H), 3.75
(dd, J = 10.5 and 8.5 Hz, 1H), 3.79 (dd, J = 9.0 and
8.0 Hz, 1H), 3.95 (dd, J = 6.25 and 9.0 Hz, 1H), 4.04–4.15
(m, 2H), 4.48 (dd, J = 3.75 and 3.75 Hz, 1H), 4.56 (d, J = 12.0
Hz, 1H), 4.60 (dd, J = 3.75 and 3.75 Hz, 1H), 4.72 (d, J =
12.0 Hz, 1H), 7.25–7.40 (m, 5H phenyl). 13C NMR (62.5 MHz,
CDCl3) d 14.0 (CH3), 22.5 (CH2), 25.0 (CH2), 27.5 (CH2), 29.1
(CH2), 29.4 (CH2), 31.7 (CH2), 40.7 (CH3), 56.7 (CH2), 69.1
(CH), 71.1 (CH2), 72.3 (2 CH2), 79.6 (CH), 81.3 (CH), 81.6
(CH), 127.7, 128.3 (5 CH2), 137.7 (C); HRMS (MH+) m/z (%)
calcd for [C22H35NO3]+: 362.2690, found: 362.2692.
General procedure for the synthesis of compounds 9a–c and 15
To a solution of the amine 8 (or 14) (41 mmol) in dichloro-
methane (100 mL) was added iodomethane (2.8 mL, 45 mmol).
After refluxing the mixture for 4 h the solvent was removed
under reduced pressure. The residue was washed with ether to
give 9a–c (or 15) as an orange oil or white solid (85–98%). The
products were used for the next step directly without further
purification.
(3R, 3aR, 6R, 6aS)-N-[6-(benzyloxy)hexahydrofuro[3,2-b]-
furan-3-yl]-N,N-dimethyl-N-octylammonium iodide (9a). Yield:
98%; Orange oil; [a]D25 = +67.2 (c = 5.29, CHCl3); IR (neat)
u = 3460, 2954, 2926, 2857, 1455, 1372, 1135, 1104,
(3R, 3aR, 6R, 6aS)-6-benzyloxy-3-(N-dodecyl-N-methylamino)-
hexahydrofuro[3,2-b]furan (8b). Yield: 77%; yellowish oil;
20
[a]D = +89.9 (c = 0.89, CHCl3); IR (neat) u = 3064,
1027 cmÀ1 1H NMR (360 MHz, CDCl3) d 0.88 (t, J =
;
3031, 2925, 2853, 2788, 1496, 1466, 1455, 1368, 1342, 1304,
1
1237, 1207, 1134, 1087, 1073, 1026, 735, 698 cmÀ1; H NMR
6.7 Hz, 3H), 1.20–1.43 (m, 10H), 1.75–1.90 (m, 2H), 3.38
(s, 3H), 3.47 (s, 3H), 3.54–3.62 (m, 1H), 3.79–3.86 (m, 1H),
3.89 (d, J = 6.1 Hz, 2H), 4.17–4.20 (m, 1H), 4.24 (dd, J = 8.6
and 9.7 Hz, 1H), 4.36 (dd, J = 8.6 and 7.9 Hz, 1H), 4.52
(d, J = 11.5 Hz, 1H), 4.73 (d, J = 11.5 Hz, 1H), 4.84–4.92
(m, 2H), 4.98 (dd, J = 4.7 and 4.3 Hz, 1H), 7.27–7.41 (m, 5H
phenyl). 13C NMR (62.5 MHz, CDCl3) d 13.9 (CH3), 22.4
(CH2), 23.0 (CH2), 26.0 (CH2), 28.9 (CH2), 29.0 (CH2), 31.5
(CH2), 51.0 (CH3), 51.3 (CH3), 65.2 (CH2), 66.7 (CH2), 72.5
(CH2), 72.8 (CH2), 78.4 (CH), 80.3 (CH), 82.2 (CH), 127.8,
127.9, 128.4 (5 CHAr), 137.2 (C); HRMS (M-I) m/z (%) calcd
for [C23H38NO3]: 376.2846, found: 376.2849.
(360 MHz, CDCl3) d 0.88 (t, J = 6.7 Hz, 3H), 1.14–1.36
(m, 18H), 1.44–1.54 (m, 2H), 2.31 (s, 3H), 2.38–2.51 (m, 2H),
2.82–2.88 (m, 1H), 3.73–3.81 (m, 2H), 3.94 (dd, J = 9.0 and
6.8 Hz, 1H), 4.04–4.13 (m, 2H), 4.47 (dd, J = 4.3 and 3.6 Hz, 1H),
4.56 (d, J = 12.2 Hz, 1H), 4.59–4.61 (m, 1H), 4.72 (d, J =
12.2 Hz, 1H), 7.25–7.42 (m, 5H phenyl). 13C NMR (62.5 MHz,
CDCl3) d 13.9 (CH3), 22.5 (CH2), 25.0 (CH2), 27.4 (CH2), 29.1
(CH2), 29.4 (5 CH2), 31.7 (CH2), 40.7 (CH3), 56.7 (CH2), 69.2
(CH), 71.1 (CH2), 72.2 (2 CH2), 79.5 (CH), 81.2 (CH), 81.6
(CH), 127.6, 128.2 (5 CHAr), 137.6 (C); HRMS (M-H) m/z (%)
calcd for [C26H43NO3]: 417.3237, found: 417.3233.
(3R, 3aR, 6R, 6aS)-3-(N-benzyl-N-methylamino)-6-(benzyloxy)-
hexahydrofuro[3,2-b]furan (8c). Yield: 73%; White solid;
mp: 54–55 1C; [a]D20 = +119.7 (c = 1.09, CHCl3); IR (neat)
u = 3086, 3062, 3029, 2944, 2874, 2788, 1495, 1454, 1367,
1304, 1208, 1133, 1110, 1087, 1073, 1040, 937, 913, 891, 849,
(3R, 3aR, 6R, 6aS)-N-[6-(benzyloxy)hexahydrofuro[3,2-b]-
furan-3-yl]-N,N-dimethyl-N-dodecylammonium iodide (9b).
20
Yield: 85%; Orange oil; [a]D = +73.1 (c = 1.04, CHCl3);
IR (neat) u = 3445, 2925, 2854, 1615, 1470, 1456, 1373, 1211,
1135, 1105, 1071, 1027, 891, 845, 740, 700 cmÀ1 1H NMR
;
1
823, 741 cmÀ1; H NMR (250 MHz, CDCl3) d 2.24 (s, 3H),
(250 MHz, CDCl3) d 0.87 (t, J = 6.6 Hz, 3H), 1.20–1.40
(m, 18H), 1.72–1.91 (m, 2H), 3.37 (s, 3H), 3.47 (s, 3H),
3.51–3.63 (m, 1H), 3.76–3.84 (m, 1H), 3.89 (d, J = 8.3 Hz, 1H),
4.16–4.27 (m, 2H), 4.37 (dd, J = 8.8 and 7.2 Hz, 1H), 4.52
(d, J = 11.6 Hz, 1H), 4.74 (d, J = 11.6 Hz, 1H), 4.86 (dd, J =
5.0 and 3.8 Hz, 1H), 4.89–4.99 (m, 2H), 7.30–7.42 (m, 5H
phenyl). 13C NMR (62.5 MHz, CDCl3) d 13.9 (CH3), 22.4
(CH2), 22.9 (CH2), 26.0 (CH2), 29.0 (CH2), 29.1 (CH2), 29.2
2.86–2.94 (m, 1H), 3.52 (d, J = 13.2 Hz, 1H), 3.72–3.87
(m, 3H), 3.98 (dd, J = 6.5 and 8.8 Hz, 1H), 4.05–4.18
(m, 2H), 4.54–4.63 (m, 3H), 4.74 (d, J = 12.3 Hz, 1H),
7.20–7.40 (m, 10H). 13C NMR (62.5 MHz, CDCl3) d 40.6
(CH3), 60.7 (CH2), 68.6 (CH), 71.1 (CH2), 71.9 (CH2), 72.1
(CH2), 79.3 (CH), 80.9 (CH), 81,5 (CH), 126.9, 127.6, 127.9,
128.1, 129.2 (10 CHAr), 137.2 (C), 137.6 (C); anal. calcd for
ꢀc
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2009 New J. Chem., 2009, 33, 2060–2072 | 2067

View Article Online
(2 CH2), 29.3 (2 CH2), 31.6 (CH2), 50.9 (CH3), 51.3 (CH3),
65.1 (CH2), 66.7 (CH2), 72.4 (CH2), 72.7 (CH2), 78.3 (CH),
80.1 (CH), 82.1 (CH), 127.7, 127.8, 128.3 (5 CHAr), 137.1 (C);
HRMS (M-I) m/z (%) calcd for [C27H46NO3]: 432.3472,
found: 432.3475
(m, 3H), 4.67 (dd, J = 4.3 and 4.7 Hz, 1H), 4.78 (dd, J = 4.3
and 3.6 Hz, 1H). 13C NMR (90 MHz, CDCl3) d 13.8 (CH3),
22.3 (2 CH2), 25.9 (CH2), 28.8 (2 CH2), 31.4 (CH2), 50.1
(CH3), 51.0 (CH3), 64.7 (CH2), 66.6 (CH2), 71.6 (CH), 72.4
(CH), 73.8 (CH2), 79.6 (CH), 83.0 (CH), 112.7, 117.8, 122.8,
127.9 (C); HRMS (M-OTf) m/z (%) calcd for [C16H32NO3]:
286.2377, found: 286.2389.
(3R, 3aR, 6R, 6aS)-N-benzyl-N-[6-(benzyloxy)hexahydrofuro-
[3,2-b]furan-3-yl]-N,N-dimethylammonium iodide (9c). Yield:
20
90%; White solid; mp: 137–138 1C; [a]D = +97.9 (c =
(3R, 3aR, 6R, 6aS)-N-[6-(benzyloxy)hexahydrofuro[3,2-b]-
furan-3-yl]-N,N-dimethyl-N-dodecylammonium trifluoromethane-
20
sulfonate (10b). Yield: 97%; yellowish oil; [a]D = +41.4
0.75, CHCl3); IR (neat) u = 3455, 3029, 2952, 2882, 1605,
1584, 1495, 1477, 1454, 1410, 1372, 1323, 1312, 1272, 1243,
1216, 1134, 1104, 1071, 1027, 922, 881, 851, 741, 703 cmÀ1; 1H
NMR (360 MHz, CDCl3) d 3.26 (s, 3H), 3.43 (s, 3H), 3.91
(d, J = 6.1 Hz, 2H), 4.15–4.25 (m, 3H), 4.51 (d, J = 11.5 Hz, 1H),
4.73 (d, J = 11.5 Hz, 1H), 4.81 (dd, J = 4.3 and 4.3 Hz, 1H),
4.94–5.00 (m, 2H), 5.15–5.21 (m, 1H), 5.28 (d, J = 12.6 Hz,
1H), 7.32–7.57 (m, 4H), 7.44–7.53 (m, 4H), 7.67–7.70 (d, J =
7.9 Hz, 2H). 13C NMR (90 MHz, CDCl3) d 49.6 (CH3), 50.2
(CH3), 65.2 (CH2), 69.0 (CH2), 72.2 (CH), 72.3 (CH2), 72.4
(CH2), 78.2 (CH), 80.2 (CH), 81.4 (CH), 126.4 (C), 127.6,
128.2, 129.0, 130.7, 133.1 (10 CHAr), 137.1 (C); HRMS (M-I)
m/z (%) calcd for [C22H28NO3]: 354.2064, found: 354.2072.
(c = 0.97, CHCl3); IR (neat) u = 3445, 2956, 2923, 1488, 1469,
1
1258, 1255, 1162, 1030, 831, 639 cmÀ1; H NMR (360 MHz,
CDCl3) d 0.88 (t, J = 6.1 Hz, 3H), 1.15–1.50 (m, 18H), 1.78
(m, 2H), 3.24 (s, 3H), 3.29 (s, 3H), 3.36–3.50 (m, 1H),
3.52–3.64 (m, 1H), 3.79–3.83 (m, 1H), 3.91–3.95 (m, 1H), 4.13
(s br, OH), 4.22–4.43 (m, 4H), 4.64–4.72 (m, 1H), 4.76–4.84
(m, 1H). 13C NMR (62.5 MHz, MeOD-d4) d 14.4 (CH3), 23.6
(CH2), 23.7 (CH2), 27.4 (CH2), 30.2 (CH2), 30.4 (CH2), 30.5
(CH2), 30.6 (CH2), 30.7 (2 CH2), 33.1 (CH2), 51.2 (CH3), 51.7
(CH3), 66.0 (CH2), 68.5 (CH2), 73.3 (CH), 73.8 (CH), 75.0
(CH2), 81.1 (CH), 84.8 (CH); HRMS (M-OTf) m/z (%) calcd
for [C20H40NO3]: 342.3003, found: 342.3010.
(3S, 3aR, 6S, 6aS)-N-[6-(benzyloxy)hexahydrofuro[3,2-b]furan-
3-yl]-N,N-dimethyl-N-octylammonium iodide (15). Yield: 99%;
25
yellowish oil; [a]D = +29.7 (c = 0.50, CHCl3); IR (neat)
(3R, 3aR, 6R, 6aS)-N-benzyl-N-[6-(benzyloxy)hexahydro-
furo[3,2-b]furan-3-yl]-N,N-dimethylammonium trifluoromethane-
sulfonate (10c). Yield: 90%; White solid; mp: 125–126 1C;
[a]D20 = +58.8 (c = 1.56, acetone); IR (neat) u = 3459, 3040,
2965, 1637, 1480, 1475, 1415, 1259, 1225, 1161, 1130, 1099,
1067, 1030, 744, 706, 638 cmÀ1; 1H NMR (360 MHz, DMSO-d6)
d 3.10 (s, 3H), 3.13 (s, 3H), 3.65 (dd, J = 6.8 and 9.0 Hz, 1H),
3.85 (dd, J = 6.1 and 9.0 Hz, 1H), 4.02–4.08 (m, 1H), 4.14
(dd, J = 8.6 and 10.8 Hz, 1H), 4.23–4.27 (m, 2H), 4.46
(dd, J = 5.4 and 4.3 Hz, 1H), 4.61 (d, J = 12.6 Hz, 1H),
4.71 (d, J = 12.6 Hz, 1H), 4.82 (dd, J = 4.3 and 4.3 Hz, 1H),
5.21 (s br, OH), 7.53–7.60 (m, 5H phenyl). 13C NMR
(62.5 MHz, MeOD-d4) d 50.8 (CH3), 50.9 (CH3), 66.1 (CH2),
71.2 (CH2), 73.3 (CH), 74.4 (CH), 75.0 (CH2), 81.3 (CH), 84.6
(CH), 119.3, 124.4 (C), 128.4 (C), 130.5 (2 CHAr), 132.2
(CHAr), 134.4 (2 CHAr); HRMS (M-OTf) m/z (%) calcd for
[C15H22NO3]: 264.1594, found: 264.1589.
u = 3436, 2967, 2857, 1606, 1471, 1455, 1372, 1213, 1084,
1005, 915, 745, 700 cmÀ1; 1H NMR (360 MHz, CDCl3) d 0.88
(t, J = 7.0 Hz, 3H), 1.26–1.46 (m, 10H), 1.70–1.80 (m, 2H),
3.37 (s, 3H), 3.40 (s, 3H), 3.56–3.73 (m, 2H), 3.95–4.02
(m, 2H), 4.07–4.09 (m, 1H), 4.22–4.28 (m, 2H), 4.30–4.35
(m, 1H), 4.53 (d, J = 11.3 Hz, 1H), 4.63 (d, J = 11.3 Hz,
1H), 4.81 (d, J = 5.4 Hz, 1H), 5.20 (d, J = 5.0 Hz, 1H),
7.27–7.36 (m, 5H phenyl). 13C NMR (90 MHz, CDCl3) d 13.9
(CH3), 22.4 (CH2), 22.5 (CH2), 25.9 (CH2), 28.8 (CH2), 28.9
(CH2), 31.4 (CH2), 49.9 (CH3), 50.7 (CH3), 65.3 (CH2),
66.6 (CH2), 71.4 (CH2), 71.9 (CH2), 77.1 (CH), 81.0 (CH),
82.2 (CH), 86.8 (CH),127.8, 128.3 (5 CHAr), 137.0 (C); anal.
calcd for C23H38NO3I: C, 54.87; H, 7.61; O, 9.53; N, 2.78; I:
25.21, found: C, 54.91; H, 7.71; O, 9.53; N, 2.81; I: 25.05.
General procedure for the synthesis of compounds 10a–c and 16
(3S, 3aR, 6S, 6aS)-N-[6-(benzyloxy)hexahydrofuro[3,2-b]-
furan-3-yl]-N,N-dimethyl-N-octylammonium trifluoromethane-
20
Trifluoromethanesulfonic acid (10 mL, 113 mmol) was added
under an argon atmosphere to a solution of ammonium iodide
9 (or 15) (36 mmol) in dichloromethane (150 mL). After
stirring the mixture for 5 min at room temperature, the solvent
was removed under reduced pressure. The residue was washed
with ether and dried under vacuum to give 10a–c (or 16) as a
yellowish oil or white solid (90–97%).
sulfonate (16). Yield: 85%; yellowish oil; [a]D = +42.0
(c = 0.50, CHCl3); IR (neat) u = 3436, 2930, 1485, 1256,
1226, 1165, 1093, 1031, 640 cmÀ1; 1H NMR (360 MHz, acetone)
d 0.86 (t, J = 6.5 Hz, 3H), 1.20–1.50 (m, 10H), 1.92–1.99
(m, 2H), 3.31 (s, 3H), 3.34 (s, 3H), 3.62 (dd, J = 10.1 and
7.2 Hz, 2H), 3.80 (d, J = 9.3 Hz, 1H), 3.91 (dd, J = 9.5 and
3.4 Hz, 1H), 4.18–4.34 (m, 4H), 4.58 (d, J = 5.0 Hz, 1H),
5.20–5.31 (m, 1H). 13C NMR (90 MHz, MeOD-d4) d 14.4 (CH3),
23.3 (CH2), 23.6 (CH2), 27.2 (CH2), 30.0 (2 CH2), 32.7 (CH2),
49.6 (CH3), 49.9 (CH3), 66.6 (CH2), 67.1 (CH2), 74.9 (CH2), 76.4
(CH), 78.8 (CH), 82.2 (CH), 90.5 (CH); HRMS (M-OTf) m/z
(%) calcd for [C16H32NO3]: 286.2377, found: 286.2389.
(3R, 3aR, 6R, 6aS)-N-[6-(benzyloxy)hexahydrofuro[3,2-b]-
furan-3-yl]-N,N-dimethyl-N-octylammonium trifluoromethane-
20
sulfonate (10a). Yield: 91%; yellowish oil; [a]D = +46.5
(c = 3.25, CHCl3); IR (neat) u = 3445, 2958, 2930, 2860, 1634,
1488, 1471, 1418, 1258, 1226, 1163, 1100, 1031, 975, 834, 758,
640 cmÀ1; 1H NMR (360 MHz, CDCl3) d 0.87 (t, J = 6.5 Hz,
3H), 1.20–1.40 (m, 10H), 1.70–1.86 (m, 2H), 3.24 (s, 3H), 3.29
(s, 3H), 3.37–3.45 (m, 1H), 3.54–3.62 (m, 1H), 3.73 (s br, OH),
3.82 (dd, J = 5.8 and 9.0 Hz, 1H), 3.89 (dd, J = 5.8 and
9.0 Hz, 1H), 4.21 (dd, J = 7.2 and 9.0 Hz, 1H), 4.29–4.39
General procedure for the synthesis of compounds 11a–c and 17
Lithium bis(trifluoromethanesulfonyl)imide (5.6 mmol) was
added to a solution of ammonium trifluoromethanesulfonate
ꢀc
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2009
2068 | New J. Chem., 2009, 33, 2060–2072

View Article Online
10 (or 16) (3.7 mmol) in acetone (5 mL). After stirring for 16 h
at room temperature, the solvent was removed under reduced
pressure. The residue was washed with ether (3 x 10 mL) and
thereafter purified by flash column chromatography on silica
gel (CH2Cl2 : MeOH = 9 : 1) to afford 11a–c (or 17) as a
colorless oil (94–97%)
37.50; H, 4.07; N, 5.14; S, 11.78; F, 20.84, found: C, 37.28; H,
3.96; N, 5.14; S, 11.88; F, 20.67.
(3S, 3aR, 6S, 6aS)-N-[6-(benzyloxy)hexahydrofuro[3,2-b]-
furan-3-yl]-N,N-dimethyl-N-octylammonium bis(trifluoromethane-
20
sulfonyl)imide (17). Yield: 96%; colorless oil; [a]D = +49.4
(c = 0.51, CHCl3); IR (neat) u = 3532, 3050, 2958, 2931, 2861,
1484, 1470, 1350, 1329, 1195, 1135, 1057, 618; 1H NMR
(250 MHz, acetone) d 0.88 (t, J = 6.7 Hz, 3H), 1.20–1.48
(m, 10H), 1.90–2.10 (m, 2H), 3.34 (s, 3H), 3.38 (s, 3H), 3.64
(dd, J = 11.0 and 6.0 Hz, 2H), 3.82 (d, J = 9.2 Hz, 1H), 3.94
(dd, J = 10.1 and 3.9 Hz, 1H), 4.18–4.32 (m, 4H), 4.59 (d, J =
5.0 Hz, 1H), 5.31–5.33 (m, 1H). 13C NMR (250 MHz, MeOD-d4)
d 14.4 (CH3), 23.3 (CH2), 23.5 (CH2), 27.1 (CH2), 30.0 (CH2),
32.7 (CH2), 49.6 (CH2), 49.6 (CH3), 49.7 (CH3), 66.7 (CH2), 67.0
(CH2), 74.8 (CH2), 76.3 (CH), 78.7 (CH), 82.1 (CH), 90.4 (CH),
113.4, 118.5, 123.6, 128.7 (2 C); HRMS (M-NTf2) m/z (%) calcd
for [C16H32NO3]: 286.2377, found: 286.2385.
(3R, 3aR, 6R, 6aS)-N-[6-(benzyloxy)hexahydrofuro[3,2-b]-
furan-3-yl]-N,N-dimethyl-N-octylammonium bis(trifluoromethane-
20
sulfonyl)imide (11a). Yield: 94%; [a]D = +39.8 (c = 0.83,
CHCl3); IR (neat) u = 3516, 2960, 2932, 2861, 1488, 1471,
1418, 1352, 1194, 1135, 1057, 975, 834, 790, 741cmÀ1 1H
;
NMR (360 MHz, CDCl3) d 0.88 (t, J = 7.0 Hz, 3H), 1.20–1.50
(m, 10H), 1.70–1.85 (m, 2H), 3.18 (s, 3H), 3.25 (s, 3H),
3.31–3.40 (m, 1H), 3.44–3.52 (m, 1H), 3.81 (dd, J = 9.7 and
4.0 Hz, 1H), 3.91 (dd, J = 9.7 and 5.4 Hz, 1H), 4.04–4.14
(m, 1H), 4.18 (dd, J = 8.3 and 9.7 Hz, 1H), 4.29 (dd, J = 8.3
and 7.9 Hz, 1H), 4.34–4.41 (m, 1H), 4.65 (dd, J = 5.0 and
4.3 Hz, 1H), 4.75 (dd, J = 4.3 and 4.3 Hz, 1H). 13C NMR
(90 MHz, MeOD-d4) d 14.3 (CH3), 23.4 (2 CH2), 27.0 (CH2),
29.9 (2 CH2), 32.6 (CH2), 51.1 (CH3), 51.6 (CH3), 65.8 (CH2),
68.4 (CH2), 73.1 (CH), 73.6 (CH), 74.7 (CH2), 80.9 (CH),
84.5 (CH), 113.4, 118.5, 123.6, 128.7 (2 C); HRMS (M-NTf2)
m/z (%) calcd for [C16H32NO3]: 286.2377, found: 286.2378.
Synthesis of (3R, 3aR, 6R, 6aS)-N-[6-(benzyloxy)hexahydrofuro-
[3,2-b]furan-3-yl]-N,N-dimethyl-N-octylammonium bis(trifluoro-
methanesulfonyl)imide (29)
Lithium bis(trifluoromethanesulfonyl)imide (5.6 mmol) was
added to a solution of ammonium iodide 9a (3.7 mmol)
in acetone (5 mL). After stirring for 16 h at room temperature,
the solvent was removed under reduced pressure. The
residue was washed with ether (3 Â 10 mL) and thereafter
purified by flash column chromatography on silica gel
(CH2Cl2 : MeOH = 9 : 1) to afford 29 as a yellowish oil.
(3R, 3aR, 6R, 6aS)-N-[6-(benzyloxy)hexahydrofuro[3,2-b]-
furan-3-yl]-N,N-dimethyl-N-dodecylammonium bis(trifluoromethane-
sulfonyl)imide (11b). Yield: 97%; colorless oil; [a]D20 = +34.4
(c = 1.07, CHCl3); IR (neat) u = 3513, 2927, 2856, 1488, 1469,
1420, 1351, 1194, 1135, 1057, 832, 789, 740, 654, 618, 601, 571
cmÀ1; 1H NMR (360 MHz, CDCl3) d 0.88 (t, J = 6.8 Hz, 3H),
1.20–1.50 (m, 18H), 1.72–1.85 (m, 2H), 3.19 (s, 3H), 3.26
(s, 3H), 3.31–3.40 (m, 1H), 3.47–3.54 (m, 1H), 3.82–3.92
(m, 2H), 4.09–4.12 (m, 1H), 4.18 (dd, J = 10.8 and 7.6 Hz, 1H),
4.31 (dd, J = 7.6 and 8.3 Hz, 1H), 4.37–4.40 (m, 1H), 4.67
(dd, J = 4.3 and 5.4 Hz, 1H), 4.75 (dd, J = 4.3 and 4.3 Hz,
1H). 13C NMR (90 MHz, MeOD-d4) d 14.5 (CH3), 23.6 (CH2),
23.7 (CH2), 27.3 (CH2), 30.1, 30.5, 30.6, 30.7 (6 CH2), 33.0
(CH2), 51.2 (CH3), 51.7 (CH3), 65.9 (CH2), 68.5 (CH2), 73.2
(CH), 73.7 (CH), 75.0 (CH2), 81.0 (CH), 84.7 (CH), 113.6,
118.6, 123.8, 128.8 (2 C); HRMS (M-NTf2) m/z (%) calcd for
[C20H40NO3]: 342.3003, found: 342.3010.
25
Yield: 95%; [a]D = +81.3 (c = 0.50, CHCl3); IR (neat)
u = 3445, 2957, 2929, 2859, 1487, 1455, 1470, 1417, 1263,
1
1224, 1153, 1030 cmÀ1; H NMR (360 MHz, CDCl3) d 0.89
(t, J = 6.8 Hz, 3H), 1.25–1.37 (m, 10H), 1.76–1.82 (m, 2H),
3.30 (s, 3H), 3.38 (s, 3H), 3.44–3.54 (m, 1H), 3.67–3.75
(m, 1H), 3.86–3.94 (m, 1H), 4.17–4.24 (m, 2H), 4.33
(dd, J = 7.9 and 8.3 Hz, 1H), 4.53 (d, J = 11.3 Hz, 1H),
4.67–4.72 (m, 1H), 4.75 (d, J = 11.3 Hz, 1H), 4.83 (dd, J = 4.7
and 4.7 Hz, 1H), 4.92 (dd, J = 4.7 and 5.4 Hz, 1H), 7.31–7.40
(m, 5H phenyl). 13C NMR (62.5 MHz, CDCl3) d 13.9 (CH3),
22.4 (CH2), 22.7 (CH2), 26.0 (CH2), 28.8 (2 CH2), 31.4 (CH2),
50.5 (CH3), 51.0 (CH3), 65.0 (CH2), 66.7 (CH2), 72.4 (CH2),
72.7 (CH2), 78.4 (CH), 80.1 (CH), 82.1 (CH), 127.8, 127.9,
128.4 (5 CHAr), 137.2 (C); HRMS (M-NTf2) m/z (%) calcd for
[C23H38NO3]: 376.2846, found: 376.2851.
(3R, 3aR, 6R, 6aS)-N-benzyl-N-[6-(benzyloxy)hexahydrofuro-
[3,2-b]furan-3-yl]-N,N-dimethylammonium bis(trifluoromethane-
20
Synthesis of 3-methyl-1-(3R, 3aR, 6S, 6aR)-[6-(benzyloxy)-
hexahydrofuro[3,2-b]furan-3-yl] imidazolium trifluoromethane-
sulfonate (18)
sulfonyl)imide (11c). Yield: 96%; colorless oil; [a]D
=
+45.9 (c = 0.91, CHCl3); IR (neat) u = 3515, 3065, 2959,
2932, 2862, 1486, 1417, 1352, 1194, 1135, 1057, 1021, 975, 920,
834, 790, 741, 706, 654, 617 cmÀ1
;
1H NMR (360 MHz,
A mixture of the sulfonate 6 (300 mg, 0,8 mmol) and
N-methylimidazole (392 mg, 4.7 mmol) was placed under
microwave irradiated at 130 1C for 4 h. Potassium trifluoro-
methanesulfonate (180 mg, 9.6 mmol) was added and the
resulting mixture was then placed under microwave irradiation
at 90 1C for 20 min. The reaction mixture was brought to room
temperature and filtered on silica gel (CH2Cl2 : MeOH =
80 : 20). Solvents were evaporated under reduced pressure
and the obtained oil was successively washed with toluene
(3 Â 5 mL), with cyclohexane (3 Â 5 mL), then with ethyl ether
(3 Â 5 mL). Purification by flash chromatography on alumina
DMSO-d6) d 3.11 (s, 3H), 3.13 (s, 3H), 3.66 (dd, J = 6.8
and 9.0 Hz, 1H), 3.87 (dd, J = 6.1 and 9.0 Hz, 1H), 4.01–4.07
(m, 1H), 4.16 (dd, J = 9.7 and 9.4 Hz, 1H), 4.24–4.28 (m, 2H),
4.47 (dd, J = 4.7 and 5.7 Hz, 1H), 4.60 (d, J = 12.2 Hz, 1H),
4.70 (d, J = 12.2 Hz, 1H), 4.82 (dd, J = 4.7 and 4.3 Hz, 1H),
5.17 (d, J = 4.7 Hz, OH), 7.50–7.63 (m, 5H phenyl). 13C NMR
(90 MHz, DMSO-d6) d 49.4 (CH3), 49.6 (CH3), 64.4 (CH2),
68.9 (CH2), 71.4 (CH), 72.0 (CH), 73.1 (CH2), 79.4 (CH), 82.6
(CH), 117.7, 121.2 (2 C), 127.4 (C), 129.0 (2 CHAr), 130.6
(CHAr), 133.2 (2 CHAr); anal. calcd for C17H22N2O7S2F6: C,
ꢀc
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2009 New J. Chem., 2009, 33, 2060–2072 | 2069

View Article Online
(CH2Cl2 : MeOH gradually from 7% to 15%) afforded the salt
18 as a yellow viscous oil in 50% yield. [a]D25 = +103.4 (c =
0.53; acetone); IR (neat) u = 3425, 3426, 3152, 3099, 1638,
1560, 1456, 1429, 1368, 1254, 1224, 1166, 1074, 1030cmÀ1; 1H
NMR (300 MHz, CDCl3) d 3.79 (s, 3H), 3.77–3.92 (m, 2H),
4,09 (t, J = 8.7 Hz, 1H), 4.14–4.20 (m, 1H), 4.33 (dd, J = 9.3
and 7.2 Hz, 1H), 4.52 (d, J = 11.4 Hz, 1H), 4.67 (m, 3H),
5.07–5.14 (m, 1H), 7.27 (s, 1H), 7.49 (s, 1H), 9.10 (s, 1H); 13C
NMR (75 MHz, CDCl3) d 36.2 (CH3), 61.7 (CH), 71.0 (CH2),
72.4 (CH2), 72.8 (CH), 79.0 (CH), 81.1 (CH), 82.4 (CH), 122.8,
122.9, 126.8 (5 CHAr), 137.4 (C); HRMS (M-OTf) m/z (%)
calcd for [C17H21N2O3]+: 301.1547, found: 301.1556.
(CH), 123.7 (Cq), 170,0 (Cq); HRMS (MNa+) m/z (%) calcd
for [C9H11O7SF3]: 343.0070, found: 343.0078.
(3R, 3aS, 6aR)-2,3,3a,6a-tetrahydrofuro[3,2-b]furan-3yl acetate (23)
20
Yield: 30% [a]D = +42.5 (c = 0.3, CHCl3); IR (neat) u =
2985, 2920, 2815, 1745, 1415, 1372, 1253, 1225, 1198,
;
952 cmÀ1 1H NMR (360 MHz, CDCl3) d 2.2 (s, 3H), 3.30
(dd, J = 5.0 and 10.4 Hz, 1H), 3.85 (dd, J = 5.5 and 10.4 Hz,
1H), 4.15 (dd, J = 3.5 and 11.6 Hz, 1H), 4.80 (m, 1H), 5,1
(dd, J = 4.7 and 10.2 Hz, 1H), 5.35 (m 1H), 6.7 (d, J = 3.5 Hz,
1H). 13C NMR (90 MHz, CDCl3) d 20.8 (CH3), 64.8 (CH2),
79.3 (CH), 80.6 (CH), 84.7 (CH), 100.2 (CH), 151.5 (CH),
170,0 (Cq); HRMS (MNa+) m/z (%) calcd for [C8H10O4]:
193.0477, found: 193.0480.
Synthesis of 3-methyl-1-(3R, 3aR, 6S, 6aR)-[6-(hydroxy)-hexa-
´
hydrofuro[3,2-b]furan-3-yl] imidazolium trifluoromethane-
sulfonate (19)
General procedure for the synthesis of compounds 22 and 24
Trifluoromethanesulfonic acid (3 mL, 36 mmol) was added
under an argon atmosphere to a solution of benzylated
imidazolium salt 18 (36 mmol) in dichloromethane (80 mL).
After stirring the mixture for 5 min at room temperature, the
solvent was removed under reduced pressure. The residue was
washed with ether and dried under vacuum to give 19 as a
A mixture of the triflate 21 (6 g, 19 mmol) and N-methylimid-
azole (or 1,2-dimethylimidazole) (21 mmol) was stirred under
an argon atmosphere at 40 1C for 2 days. Water (10 mL) was
added before saturating the aqueous phase with potassium
carbonate until obtaining a white dough. The resulting
mixture was then extracted with dichloromethane (3 Â 40 mL).
After evaporation of the solvent, the residue was washed with
toluene (3 Â 30 mL), cyclohexane (3 Â 30 mL) and ethyl ether
(3 Â 30 mL). The crude product was purified by flash
chromatography on alumina (CH2Cl2 then CH2Cl2 : MeOH
gradually from 1% to 15%) to give 22 (or 24) as a yellow oil.
20
yellow viscous oil in 97% yield. [a]D = +62.5 (c = 0.70,
acetone); IR (neat) u = 3500, 3518, 3119, 2965, 2891, 1634,
1
1580, 1558, 1259, 1171, 1031, 851, 760, 639 cmÀ1; H NMR
(360 MHz, acetone-d6) d 3.73 (dd, J = 9.0 and 6.5 Hz, 1H),
3.94 (dd, J = 9.0 and 6.1 Hz, 1H), 4.08 (s, 3H), 4.21 (t, J = 9.0
Hz, 1H), 4.41–4.46 (m, 2H), 4.70 (t, J = 4.9 Hz, 1H), 4.84
(t, J = 4.7 Hz, 1H), 5.28–5.34 (m, 1H), 7.72 (t, J = 2.0 Hz, 1H),
7.83 (t, J = 2.0 Hz, 1H), 9.17 (s, 1H); 13C NMR (75 MHz,
acetone-d6) d 36.8 (CH3), 63.0 (CH), 71.2 (CH2), 73.4 (CH2),
74.7 (CH), 81.8 (CH), 84.4 (CH), 124.0 (CH), 124.1 (CH),
138.0 (CH); HRMS (M-OTf) m/z (%) calcd for [C10H15N2O3]:
211.1077, found: 211.1080.
3-methyl-1-(3R, 3aR, 6S, 6aR)-[6-(acetoxy)-hexahydrofuro-
[3,2-b]furan-3-yl] imidazolium trifluoromethanesulfonate (22).
25
Yield: 46%; [a]D = +82.0 (c = 0.65, acetone); IR (neat)
u = 3521, 3156, 3120, 2984, 2888, 1739, 1580, 1558, 1375,
1
1258, 1164, 1030, 639 cmÀ1; H NMR (360 MHz, MeOD-d4)
d 2.11 (s, 3H), 3.95 (s, 3H), 3.99–4.01 (m, 2H), 4.05 (t, J =
9,2 Hz, 1H), 4.34 (dd, J = 9.0 and 6.8 Hz, 1H), 4.71 (t, J =
4.9 Hz, 1H), 4.67 (t, J = 5.0 Hz, 1H), 5.02–5.08 (m, 1H), 5.26
(q, J = 4.9 Hz, 1H), 7,58 (t, J = 1.8 Hz, 1H), 7.70 (t, J =
1.8 Hz, 1H), 9.04 (s, 1H). 13C NMR (75 MHz, acetone-d6)
d 20.5 (CH3), 36.7 (CH3), 62.1 (CH), 70.2 (CH2), 72.6 (CH2),
75.0 (CH), 81.5 (CH), 83.0 (CH), 124.0 (2CH), 137.9 (CH),
170.8 (Cq); HRMS (M-OTf) m/z (%) calcd for [C12H17N2O4]:
253.1183, found: 253.1185.
Synthesis of (3R, 3aR, 6S, 6aS)-3-(acetoxy)hexahydrofuro[3,2-b]-
furan-6-yl trifluoromethane sulfonate (21)
Pyridine (3.8 mL, 47 mmol) was added to a solution of acetate
20 (8 g, 42.5 mmol) in dichloromethane (100 mL). The
reaction mixture was stirred in an ice-bath at 0–5 1C followed
by slow addition of trifluoromethanesulfonic anhydride
(7.8 mL, 47 mml). The resulting mixture was stirred at room
temperature for 2 h. The organic phase was successively
washed with water (20 mL), a solution of 5 N HCl (20 mL)
and a solution of saturated NaCl (20 mL). The organic layer
was then dried over anhydrous MgSO4 and evaporated under
reduced pressure. The crude product was purified by flash
chromatography on silica gel (pentane : AcOEt = 1 : 1) to give
21 as a colorless oil (13.5g, 99%). [a]D[20] = +86.2 (c = 0.52,
CHCl3); IR (neat) u = 2987, 2937, 2881, 1745, 1415, 1372,
2,3-dimethyl-1-(3R, 3aR, 6S, 6aR)-[6-(acetoxy)-hexahydro-
furo[3,2-b]furan-3-yl] imidazolium trifluoromethanesulfonate (24).
25
Yield: 50%; [a]D = +131.7 (c = 0.50, acetone); IR (neat)
u = 3508, 3147, 2961, 2890, 1591, 1532, 1374, 1739, 1259,
1163, 1031, 639 cmÀ1; 1H NMR (360 MHz, MeOD-d4) d 2.10
(s, 3H), 2.69 (s, 3H), 3.84 (s, 3H), 3.84–3.89 (m, 1H), 3.92–3.98
(m, 1H), 4.19–4.29 (m, 2H), 4.80 (t, J = 5.0 Hz, 1H), 4.88
(t, J = 5.2 Hz, 1H), 5.03–5.09 (m, 1H), 5.19 (q, J = 5,3 Hz,
1H), 7.46 (d, J = 2.2 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H). 13C
NMR (62.5 MHz, MeOD-d4) d 21.0 (CH3), 35.9 (CH3), 60.9
(CH), 70.8 (CH2), 73.0 (CH2), 75.4 (CH), 82.5 (CH), 83.6
(CH), 121.8 (CH), 123.4 (CH), 147.1 (Cq), 171.9 (Cq); HRMS
(M-OTf) m/z (%) calcd for [C13H19N2O4]: 267.1339, found:
267.1345.
1
1243, 1212, 1146, 1098, 948, 908 cmÀ1; H NMR (360 MHz,
CDCl3) d 2.11 (s, 3H), 3.80 (dd, J = 5.0 and 10.1 Hz, 1H), 3.97
(dd, J = 5.8 and 10.1 Hz, 1H), 4.04 (dd, J = 3.4 and 11.9 Hz,
1H), 4.21 (d, J = 11.9 Hz, 1H), 4.67 (d, J = 4.7 Hz, 1H), 4.93
(t, J = 5.0 Hz, 1H), 5.18 (q, J = 5.5 Hz, 1H), 5.30–5.33
(m, 1H). 13C NMR (90 MHz, CDCl3) d 20.5 (CH3), 70.7
(CH2), 72.8 (CH2), 73.4 (CH), 80.8 (CH), 85.4 (CH), 89.3
ꢀc
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2009
2070 | New J. Chem., 2009, 33, 2060–2072

View Article Online
General procedure for the synthesis of CILs 19 and 25
HRMS (EI) calcd. for C19H19NO (M+) 277.1461, found
277.1460.
Concentrated HCl (2 drops) were added to a solution of
acetate 22 (or 24) (3.6 mmol) in ethanol (60 mL). The mixture
was heated under reflux for 4 h. After cooling, the reaction
mixture was neutralized with a solution of saturated Na2CO3.
Solvents were evaporated and the residue was dissolved in
acetone. The organic phase was dried over anhydrous MgSO4,
filtered and evaporated. The crude product was purified by
flash chromatography alumina (CH2Cl2 then CH2Cl2 : MeOH
gradually from 5% to 20%) to give 19 (or 25) as a yellow oil.
(2R)-2,3-dihydro-2-phenyl-1-[(R)-1-phenylethyl]pyridine-4-
(1H)-one (28 diastereomer). IR (neat) u = 3029, 2975, 1639,
1
1590, 1494, 1451, 1393, 1294, 1152, 762, 700 cmÀ1. H NMR
(CDCl3) d 1.60 (d, 3H, J = 7.0 Hz), 2.55–2.88 (m, 2H), 4.28
(q, 1H, J = 6.8 Hz), 4.70 (dd, 1H, J = 6.8, 8.8 Hz), 5.14
(d, 1H, J = 7.5 Hz), 7.61 (d, 1H, J = 7.7 Hz), 7.09–7.42
(m, 10H). 13C NMR (CDCl3) d 21.4 (CH3), 43.9 (CH2), 59.9
(CH), 60.6 (CH), 99.5 (CH), 125.9, 126.6, 127.8, 128.2, 128.7,
128.9 (10 CHAr), 139.3 (C), 141.8 (C), 152.0 (CH), 190.4 (C);
HRMS (EI) calcd. for C19H19NO (M+) 277.1461, found
277.1460.
3-methyl-1-(3R, 3aR, 6S, 6aR)-[6-(hydroxy)-hexahydrofuro-
´
[3,2-b]furan-3-yl] imidazolium trifluoromethanesulfonate (19).
Yield: 90%.
2,3-dimethyl-1-(3R, 3aR, 6S, 6aR)-[6-(hydroxy)-hexahydrofuro-
Acknowledgements
[3,2-b]furan-3-yl] imidazolium trifluoromethanesulfonate (25).
20
We are grateful to the ‘Ministere de l’Enseignement Supe
et de la Recherche’ for a doctoral fellowship to ONVB, the
CNRS (UMR 8182) and the Universite Paris-Sud 11 for
´
rieur
Yield: 90%; [a]D = +112.3 (c = 0.50; acetone); IR (neat)
u = 3479, 3148, 2960, 2888, 1634, 1591, 1538, 1423, 1253,
1170, 1032, 758, 639 cmÀ1; 1H NMR (360 MHz, MeOD-d4) d
2.66 (s, 3, Hm) ; 3.49 (dd, J = 9.0 ; 7.6 Hz, 1H, Hf) ; 3.82–3.86
(m, 1H, Hf) ; 3,84 (s, 3H, Hk) ; 4.23–4.38 (m, 3H, Hc + e) ; 4,58
(t, J = 4.9 Hz, 1H, Hd) ; 4.83 (t, J = 5.2 Hz, 1H, Ha) ; 5.10
(q, J = 6.1 Hz, Hb); 7.46 (d, J = 2.2 Hz, 1H, Hi) ; 7.65 (d, J =
2.0 Hz, 1H, Hj).. 13C NMR (90 MHz, MeOD-d4) d 10.1 (CH3),
35.6 (CH3), 61.9 (CH), 71.4 (CH2), 73.3 (CH), 74.2 (CH2), 82.8
(CH), 84.9 (CH), 121.4 (CH), 123.3 (CH), 147.1 (CH); HRMS
(M-OTf) m/z (%) calcd for [C11H17N2O3]: 225.1234, found:
225.1241.
´
financial supports.
References
1 (a) T. Welton, Chem. Rev., 1999, 99, 2071; (b) P. Wasserscheid and
W. Keim, Angew. Chem., Int. Ed., 2000, 39, 3772; (c) R. Hagiwara
and Y. Ito, J. Fluorine Chem., 2000, 105, 221; (d) R. D. Rogers and
K. R. Seddon, Ionic Liquids Industrial Applications to
Green Chemistry, 2001, ACS, Symposium Series 818;
(e) P. Wasserscheid and T. Welton, Ionic Liquids in Synthesis,
2nd ed., Wiley-VCH, Weinheim, 2008; (f) J. Dupont, R. F. de
Souza and P. A. Z. Suarez, Chem. Rev., 2002, 102, 3667;
(g) R. A. Sheldon, Green Chem., 2005, 7, 267.
General procedure for the asymmetric aza Diels–Alder reaction
of Danishefsky’s diene with imine 27
2 (a) J. Ding and D. W. Armstrong, Chirality, 2005, 17, 281;
(b) C. Baudequin, D. Bregeon, J. Levillain, F. Guillen,
´
A mixture of imine 27 (1 mmol), chiral ionic liquid (0.5 equiv.)
and Danishefsky’s diene 26 (1.5 equiv. added in three portions)
was stirred at 30 1C for 5 h. The reaction mixture was extracted
from the ionic liquid phase with Et2O (3 Â 10 mL). The
combined ether fractions were dried over anhydrous MgSO4
and evaporated under reduced pressure. The residue was
purified by flash column chromatography (AcOEt : pentane
= 10 : 90 to 70 : 30) to provide 28.
J.-C. Plaquevent and A.-C. Gaumont, Tetrahedron: Asymmetry,
2005, 16, 3921; (c) X. Chen, X. Li, A. Hu and F. Wang,
Tetrahedron: Asymmetry, 2008, 19, 1; (d) K. Bica and
P. Gaertner, Eur. J. Org. Chem., 2008, 3235; (e) J.-C.
Plaquevent, J. Levillain, F. Guillen, C. Malhiac and A.-C.
Gaumont, Chem. Rev., 2008, 108, 5035.
3 (a) B. Pegot, G. Vo-Thanh, D. Gori and A. Loupy, Tetrahedron
´
Lett., 2004, 45, 6425; (b) J. Ding, V. Desikan, X. Han, T. L. Xiao,
R. Ding, W. S. Jenks and D. W. Armtrong, Org. Lett., 2005, 7,
335; (c) Z. Wang, Q. Wang, Y. Zhang and W. Bao, Tetrahedron
Lett., 2005, 46, 4657; (d) S. Luo, X. Mi, L. Zhang; S. Liu, H. Xu
and J.-P. Cheng, Angew. Chem., Int. Ed., 2006, 45, 3093;
(e) R. Gausepohl, P. Buskens, J. Kleinen, A. Bruckmann,
C. W. Lehmann, J. Klankermayer and W. Leitner, Angew. Chem.,
Int. Ed., 2006, 45, 3689; (f) L. C. Branco, P. M. P. Gois, N. M. T.
The chiral ionic liquid was dissolved in dichloromethane
(20 mL) and then recycled by washing with water (10 mL Â 2).
The organic phase was dried over anhydrous MgSO4, filtered
and evaporated in vacuo to afford the recycled ionic liquid.
Spectra data (IR, 1H and 13C) were identical to the initial ionic
liquid sample. This IL was reused without loss of efficiency
(Table 1, entry 2).
Lourenc
2006, 2371; (g) S. V. Malhotra and Y. Wang, Tetrahedron:
Asymmetry, 2006, 17, 1032; (h) P. Padar, A. Bokros, G. Paragi,
P. Forgo, Z. Kele, N. M. Howarth and L. Kovacs, J. Org. Chem.,
2006, 71, 8669; (i) B. Pegot, O. Nguyen Van Buu, D. Gori and
¸ o, V. B. Kurteva and C. A. M. Afonso, Chem. Commun.,
´
´
´
´
´
G. Vo-Thanh, Beilstein J. Org. Chem., 2006, 2, 18; (j) L. Zhou and
L. Wang, Chem. Lett., 2007, 36, 628; (k) B. Ni, Q. Zhang and
A. D. Headley, Green Chem., 2007, 9, 737; (l) L. D. S. Yadav,
A. Rai, V. Rai and C. Awasthi, Tetrahedron, 2008, 64, 1420;
(m) W. Zhou, L. W. Xu, H. Y. Qiu, G. Q. Lai, C. G. Xia and
J. X. Jiang, Helv. Chim. Acta, 2008, 91, 53.
4 (a) T. Biedtron and P. Kubisa, Polym. Int., 2003, 52, 1584;
(b) H.-Y. Ma, X.-H. Wan, X.-F. Chen and Q.-F. Zhou, Chin. J.
Polym. Sci., 2003, 21, 265; (c) T. Biedtron and P. Kubisa, J. Polym.
Sci., Part A: Polym. Chem., 2005, 43, 3454.
(2S)-2,3-dihydro-2-phenyl-1-[(R)-1-phenylethyl]pyridine-4-(1H)-
one (28). Mp: 74 1C; [a]D26:+183.7 (c 1.96, CHCl3) (ed = 97%
determined by chral HPLC). IR (neat) u = 3029, 2975, 1639,
1
1590, 1494, 1451, 1393, 1294, 1152, 762, 700 cmÀ1. H NMR
(CDCl3) d 1.45 (d, 3H, J = 6.8 Hz), 2.55–2.88 (m, 2H), 4.43
(q, 1H, J = 6.8 Hz), 4.70 (dd, 1H, J = 6.8, 8.8 Hz), 5.04
(d, 1H, J = 7.0 Hz), 7.06 (d, 1H, J = 7.0 Hz), 7.09–7.42
(m, 10H). 13C NMR (CDCl3) d 17.4 (CH3), 43.2 (CH2), 59.0
(CH), 60.2 (CH), 98.0 (CH), 125.8, 126.4, 127.3, 128.0, 128.3,
128.8 (10 CHAr), 138.7 (C), 139.6 (C), 149.0 (CH), 189.8 (C);
5 (a) J. Ding, T. Welton and D. W. Armstrong, Anal. Chem., 2004,
76, 6819; (b) S. A. A. Rizvi and S. A. Shamsi, Anal. Chem., 2006,
78, 7061.
ꢀc
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2009 New J. Chem., 2009, 33, 2060–2072 | 2071

View Article Online
6 (a) M. Tosoni, S. Laschat and A. Baro, Helv. Chim. Acta, 2004,
87, 2742; (b) J. Baudoux, P. Judeinstein, D. Cahard and
J.-C. Plaquevent, Tetrahedron Lett., 2005, 46, 1137.
20 (a) R. S. Varma and V. V. Namboodiri, Chem. Commun., 2001,
643; (b) R. S. Varma and V. V. Namboodiri, Pure Appl. Chem.,
2001, 73, 1309; (c) B. M. Khadilkar and G. L. Rebeiro, Org.
Process Res. Dev., 2002, 60, 826; (d) M. C. Law, K. Y. Wong and
T. H. Chan, Green Chem., 2002, 4, 328; (e) R. S. Varma and
V. V. Namboodiri, Chem. Commun., 2002, 342; (f) J. F. Dubreuil,
M. H. Famelart and J. P. Bazureau, Org. Process Res. Dev., 2002,
6, 374; (g) R. S. Varma and V. V. Namboodiri, Tetrahedron Lett.,
2002, 43, 5381; (h) M. Deetlefs and K. S. Seddon, Green Chem.,
7 (a) P. Wasserscheid, A. Bosmann and C. Bolm, Chem. Commun.,
2002, 200; (b) Y. Ishida, H. Miyauchi and K. Saigo, Chem.
Commun., 2002, 2240; (c) J. Levillain, G. Dubant, I. Abrunhosa,
M. Gulea and A.-C. Gaumont, Chem. Commun., 2003, 2914;
(d) H. Clavier, L. Boulanger, N. Audic, L. Toupet, M. Mauduit
and J.-C. Guillemin, Chem. Commun., 2004, 1224; (e) Y. Ishida,
D. Sasaki, H. Miyauchi and K. Saigo, Tetrahedron Lett., 2004, 45,
9455; (f) V. Jurcik and R. Wilhelm, Tetrahedron: Asymmetry, 2006,
17, 801.
8 H. B. Kagan and O. Riant, Chem. Rev., 1992, 92, 1007.
9 R. A. Sheldon, Chirotechnology: Industrial Synthesis of Optically
Active Compounds, Marcel Dekker, New York, 1993, p. 145.
10 J. C. Krantz, C. J. Carr, S. E. Forman and F. W. Ellis,
J. Pharmcol., 1939, 67, 191.
2003, 5, 181; (i) J. M. Le
G. Cravotto and W. Bonrath, Monatsh. Chem., 2007, 138, 1103;
(j) G. Cravotto, E. Calcio-Gaudino, L. Boffa, J. M. Leveque,
J. Estager and W. Bonrath, Molecules, 2008, 13, 149.
´
veque, J. Estager, M. Draye, L. Boffa,
´
21 For recent reviews on microwave chemistry, see: (a) A. De la Hoz,
A. Diaz-Ortis, A. Moreno and F. Langa, Eur. J. Org. Chem., 2000,
3659; (b) M. Alterman and A. Hallberg, J. Org. Chem., 2000, 65,
7984; (c) L. Perreux and A. Loupy, Tetrahedron, 2001, 57, 9199;
11 (a) J. Wang, M. H. Xu, M. Zhong and G. Lin, Chin. Chem. Lett.,
1998, 9, 325; (b) M. H. Xu, H. M. Lin, Q. G. Xia and L. Jun, Chin.
J. Chem., 1998, 16, 561.
12 A. Loupy and D. Monteux, Tetrahedron Lett., 1996, 37, 7023.
13 C. Carcedo, A. Dervisi, A. I. Fallis, L. Ooi and A. K. M. Malik,
Chem. Commun., 2004, 1236.
14 (a) V. Kumar, C. E. Olsen, S. J. C. Schaffer, V. S. Parmar and
S. V. Malhotra, Org. Lett., 2007, 9, 3905; (b) V. Kumar, C. Pei,
C. E. Olsen, S. J. C. Schaffer, V. S. Parmar and S. V. Malhotra,
Tetrahedron: Asymmetry, 2008, 19, 664.
15 G. Vo-Thanh, B. Pegot and A. Loupy, Eur. J. Org. Chem., 2004,
´
1112.
16 Z. Cekovik and Z. Tokic, Synthesis, 1989, 610.
(d) P. Lidstrom, J. Tierney, P. Wathey and J. Westman,
¨
Tetrahedron, 2001, 57, 9225; (e) B. L. Hayes, Microwave Synthesis:
Chemistry at the Speed of Light, CEM Publishing, Matthews, NC,
2002; (f) A. Loupy, Microwaves in Organic Synthesis, Wiley-VCH,
Weinheim, 2006; (g) C. O. Kappe and A. Stadler, Microwaves in
Organic and Medicinal Chemistry, Wiley-VCH, Weinheim, 2005;
(h) V. Polshettiwar and R. S. Varma, Acc. Chem. Res., 2008, 41,
629.
22 P. Stoss, P. Merrath and G. Schluter, Synthesis, 1987, 174.
23 J. J. Jodry and K. Mikami, Tetrahedron Lett., 2004, 45, 4429.
24 B. Pegot and G. Vo-Thanh, Synlett, 2005, 9, 1409.
´
25 K. Hattori and H. Yamamoto, Tetrahedron, 1993, 49, 1749.
26 (a) J. Ballcells, S. Colonna and R. Fornasier, Synthesis, 1976, 266;
(b) S. Colonna and R. Fornasier, J. Chem. Soc., Perkin Trans. 1,
1978, 371.
17 D. Abenhaim, A. Loupy, L. Munnier, R. Tamion, F. Marsais and
G. Queguiner, Carbohydr. Res., 1994, 261, 255.
´
18 S. H. Pine and B. L. A. Sandrez, J. Org. Chem., 1971, 36, 829.
19 (a) R. Tamion, F. Marsais, P. Ribereau, G. Queguiner,
D. Abenhaim, A. Loupy and L. Munnier, Tetrahedron: Asymmetry,
1993, 4, 1879; (b) S. Kuma and U. Ramachandra, Tetrahedron, 2005,
61, 4141.
27 T. Fischer, A. Sethi, T. Welton and J. Woolf, Tetrahedron Lett.,
1999, 40, 793.
28 (a) F. Zulfiqar and T. Kitazume, Green Chem., 2000, 2, 137;
(b) C. Loncaric, K. Manabe and S. Kobayashi, Chem. Commun.,
2003, 574.
ꢀc
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2009
2072 | New J. Chem., 2009, 33, 2060–2072