Ionic liquids as recyclable reaction media for the tetrahydropyranylation of alcohols

Article abstract of DOI:10.1016/S0040-4020(01)00373-8

A comparative study of the catalysed tetrahydropyranylation of 1-phenylethanol by p-toluenesulphonic acid (TsOH), pyridinium p-toluenesulphonate (PPTS) and triphenylphosphine hydrobromide (TPP.HBr) using 3,4-dihydro-2H-pyran in dichloromethane or in the i

Full text of DOI:10.1016/S0040-4020(01)00373-8

TETRAHEDRON
Pergamon
Tetrahedron 57 &2001) 4405±4410
Ionic liquids as recyclable reaction media for the
tetrahydropyranylation of alcohols
p
Lu Âõ s C. Branco and Carlos A. M. Afonso
Departamento de Qu Âõ mica, Centro de Qu Âõ mica Fina e Biotecnologia, Faculdade de Ci eà ncias e Tecnologia, Universidade Nova de Lisboa,
825-114 Caparica, Portugal
2
Received 20 November 2000; revised 26 March 2001; accepted 29 March 2001
AbstractÐA comparative study of the catalysed tetrahydropyranylation of 1-phenylethanol by p-toluenesulphonic acid &TsOH), pyridinium
p-toluenesulphonate &PPTS) and triphenylphosphine hydrobromide &TPP.HBr) using 3,4-dihydro-2H-pyran in dichloromethane or in the
ionic liquids 1-n-butyl-3-methylimidazolium tetra¯uoroborate &[bmim][BF
4
]) or 1-n-butyl-3-methylimidazolium hexa¯uorophosphate
&
media were recycled on 22 occasions without loss of activity and their scope of application to other alcohols was also studied. q 2001
[bmim][PF ]) showed that the reaction occurs readily in [bmim][PF ] for PPTS or TPP.HBr by a non-reversible process. These reaction
6
6
Elsevier Science Ltd. All rights reserved.
1. Introduction
ionic liquids based on the 1-n-butyl-3-methylimidazolium
bmim] unit and also the possibility of the product being
[
Room temperature ionic liquids, mainly consisting of 1,3-
dialkylimidazolium cations are attracting increasing interest
as alternative environmentally benign reaction media.
further extracted with diethyl ether, prompted us to study the
tetrahydropyranylation of alcohols under this potentially
reusable reaction medium &Scheme 1).
1
These solvents are non-volatile, thermally stable and,
depending on the anion, can present low miscibility with
water, alkanes and dialkyl ethers while also being com-
patible with transition metal catalysts. These media have
2
. Results and discussion
1
,2
1,3
been applied in non-catalytic and catalytic reactions
Using 1-phenylethanol 2a as an example and following by
GLC the conversion of 2a into the corresponding tetra-
hydropyran 3a, a comparative study was performed between
the catalysts TsOH, PPTS and TPP.HBr in the common
organic solvent dichloromethane &DCM) and in the ionic
solvents 1-n-butyl-3-methylimidazolium tetra¯uoroborate
4
and also in selective extraction procedures. Catalysts that
have polar or ionic character can be immobilised in these
ionic media permitting a practical method of recycling by
the simple extraction of products from the ionic reaction
3
a±c,e,g±l
media.
&
¯
[bmim][BF ]) and 1-n-butyl-3-methylimidazolium hexa-
4
uorophosphate &[bmim][PF ]), &Table 1). In the absence
6
3
,4-Dihydro-2H-pyran 1 is a versatile and low-cost reagent
for the protection of hydroxyl groups giving tetrahydro-
of catalyst no reaction was observed in all solvents during
the ®rst 3 h. For longer time periods some formation of
product 3a was detected, where after 24 h the conversion
was higher in DCM &30%) than in [bmim][PF ] &14.4%) or
6
[
contrast, when the reaction was performed in DCM and in
the presence of catalyst &10 mol%) at room temperature, the
conversion was almost complete after 5 min for the three
catalysts tested &Table 1, entries 4±6). In the case of the ionic
liquids [bmim][PF ] and [bmim][BF ] the milder catalysts
pyranyl ethers 3, which are robust protective groups, easy
to remove and also useful intermediates for further func-
tional transformations. The tetrahydropyranylation gener-
ally requires protic or Lewis acid catalysis. Among a
considerable number of reported methods, including hetero-
geneous catalysis,
pyridinium p-toluenesulphonate &PPTS) and triphenyl-
phosphine hydrobromide &TPP.HBr) are the most reliable
and readily accessible catalysts for the tetrahydropyranyl-
ation of alcohols using 1. According to the observation that
the catalysts TsOH, PPTS and TPP.HBr are soluble in the
5
5
,6
bmim][BF ] &4.9%) &Table 1, entries 1, 2 and 3). In
4
5,7
5,8
p-toluenesulphonic acid &TsOH),
5
,9
5
,10
6
4
Keywords: ionic liquid; recyclable reaction media; tetrahydropyranylation;
alcohols.
p
Corresponding author. Tel.: 1351-21-294-8358; fax: 1351-21-294-
8550; e-mail: cma@dq.fct.unl.pt
Scheme 1.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020&01)00373-8

4406
L. C. Branco, C. A. M. Afonso / Tetrahedron 57 ꢀ2001) 4405±4410
Table 1. Comparative conversion study &by GLC) of the tetrahydropyra-
nylation of 1-phenylethanol 2a
a
b
Conversion 3a &%)
Entry
1
Solvent
DCM
Catalyst
No
Time
3 h
0.0
6
2
3 h
h
4 h
15.0
30.0
0.0
2
3
[bmim][PF
6
]
No
No
6
2
6 h
h
4 h
2.8
14.4
0.0
[bmim][BF
4
]
1
2
0 h
4 h
2.2
4.9
96.6
95.9
98.7
97.0
96.8
97.4
98.9
40.5
67.2
74.1
75.8
96.9
97.4
c
4
5
DCM
DCM
TPP.HBr
TsOH
5 min
5 min
1
5 min
5 min
1
2
5 min
1
2
5 min
1
2
5 min
5 min
1
2
5 min
1
1
c
5 min
c
6
7
DCM
PPTS
TPP.HBr
[bmim][PF
[bmim][PF
[bmim][PF
6
]
]
]
5 min
h
8
9
6
6
TsOH
PPTS
5 min
h
Figure 1. Conversion &by GLC) of 1-phenylethanol 2a into tetrahydropyr-
anyl ether 3a at 38C in the presence of PPTS &10 mol%). Relative rates for
[
6 4
bmim][PF ]:DCM:[bmim][BF ] are 5.2:3.6:1.0; obtained by comparison
5 min
h
of initial rate constants &t#t1/2).
c
1
1
0
1
[bmim][BF
[bmim][BF
4
]
]
TPP.HBr
TsOH
94.4
4
12.2
36.9
66.5
28.1
80.1
above results imply that at room temperature the tetra-
hydropyranylation is reversible for TsOH &or CSA) and
irreversible for the catalysts PPTS and TPP.HBr. This fact
is consistent with the stronger acidity of the TsOH. On the
other hand, the lower reactivity observed for the catalyst
TsOH in the ionic solvents [bmim][PF ] and [bmim][BF ]
5 min
h
1
2
[bmim][BF
4
]
PPTS
5 min
h
c
90.3
a
6
4
2
a
&0.82 mmol), 3,4-dihydro-2H-pyran 1
10 mol%) in solvent &1 ml) at room temperature &188C).
&2 equiv.), and catalyst
could eventually result from the effect of the solvent on the
reaction equilibrium.
&
Conversion of 3a obtained by GLC analysis.
Minimum time necessary to achieve the maximum conversion observed
for the time-scale studied &2 h).
b
c
Using the ionic solvent [bmim][PF ] and the catalysts PPTS
6
PPTS and TPP.HBr gave higher ®nal conversions and
cleaner reaction mixtures than the catalyst TsOH &Table 1,
entries 7±12). In the case of TPP.HBr the reaction is still
complete after 5 min in both ionic liquids, while for PPTS
the reaction is considerably slower in the ionic solvent
[
bmim][BF ] &Table 1, entries 7 and 10 vs. entries 9 and
4
12). By performing a comparative study at lower tempera-
ture &38C) using the catalyst PPTS, we observed that the
reaction in [bmim][PF ] is slightly faster than in the conven-
6
tional solvent DCM and much faster than in [bmim][BF4]
Fig. 1). The relative rates observed in [bmim][PF ], DCM
6
&
and [bmim][BF ] are, respectivelly, 5.2, 3.6 and 1.0.
4
We observed that for the milder catalysts PPTS and
TPP.HBr at room temperature or at 38C and in all the
solvents tested &DCM, [bmim][PF ] or [bmim][BF ]) the
6
4
diastereomeric ratio &d ) of the tetrahydropyran 3a was
r
constantly between 0.95 and 1.0. In contrast, for the
TsOH the d was higher at room temperature and also
r
increased with reaction time as presented in Fig. 2. Only
at lower temperature &38C) was the observed d similar to
r
that obtained for PPTS and TPP.HBr catalysts. A similar
dependence was also observed for camphorsulphonic acid
&
CSA). When a 1:1 diastereomer reaction mixture of 3a
previously obtained at 2138C using TsOH) was left at
room temperature for 1 h, the d value changed to 3.32. A
&
r
similar result was observed by adding the catalyst TsOH
&10 mol%) to a solution of the previously isolated 1:1 dia-
stereomer mixture of 3a in DCM at room temperature. The
Figure 2. Dependence of the diastereomeric ratio &d
conditions. The d values were determined by GLC and refer, respectively,
to diastereomer retention times &t ) of 4.0 min and 4.7 min.
r
) of 3a on the reaction
r
R

L. C. Branco, C. A. M. Afonso / Tetrahedron 57 ꢀ2001) 4405±4410
Table 2. Representative examples for the preparation of tetrahydropyranes
4407
the conversion on the type of extraction is due to simul-
taneous extraction of the catalyst by diethyl ether from the
ionic phase. We also observed that the volume of the ionic
reaction medium was reduced to approximately 80% of the
initial volume after the maximum of 22 cycles tested &run C
and run F), which result from some solubillity of the ionic
a
3a±3f in ionic solvent
b
Yield 3 &%)
Entry
Alcohol 2
Solvent
Catalyst
TsOH
c
1
PhCH
PhCH
PhCH
PhCH
PhCH
PhCH
2
OH 2b
2
OH 2b
2
OH 2b
2
OH 2b
2
OH 2b
2
OH 2b
DCM
DCM
[bmim][BF ]
4
99
c
2
TPP.HBr 87
TPP.HBr 96
c
3
c
liquid [bmim][PF ] in diethyl ether. The isolated yields
6
4
[bmim][PF
[bmim][PF
[bmim][PF
[bmim][PF
[bmim][PF
[bmim][PF
[bmim][PF
[bmim][PF
[bmim][PF
[bmim][PF
[bmim][PF
[bmim][PF
[bmim][PF
6
]
TsOH
TPP.HBr 92
PPTS 91
TPP.HBr 78
PPTS 81
TPP.HBr 81
PPTS 83
TPP.HBr 62
PPTS 80
TPP.HBr 74
PPTS 69
TPP.HBr 75
PPTS 86
28
c
obtained for some representative cycles are also in the
same range as those observed for the one-cycle reaction
presented in Table 2 &entries 7 and 8). It is particularly
noteworthy that the same ionic liquid was used for 22 cycles
and also could be used without further addition of catalyst
for 12 and 17 cycles, respectively, for PPTS &run C) and
TPP.HBr &run F) with a reduction in the conversion of less
than 7%.
5
6
]
6
]
6
]
6
]
6
]
6
]
6
]
6
]
6
]
6
]
6
]
6
]
c
6
d
7
PhCHMeOH 2a
PhCHMeOH 2a
&2)-Menthol 2c
&2)-Menthol 2c
Cholesterol 2d
Cholesterol 2d
Geraniol 2e
Geraniol 2e
1-Adamantanol 2f
1-Adamantanol 2f
d
8
c
9
c
1
1
1
1
1
1
1
0
1
2
3
4
5
6
e
e
c
c
f
f
In summary, this study presented here shows that at room
temperature the catalyst TsOH promotes the tetrahydro-
pyranylation of alcohols under reversible conditions, while
for the milder catalysts PPTS and TPP.HBr the transform-
ation occurs under a non-reversible process. The ionic liquid
a
2
&
&0.82±1.64 mmol), 3,4-dihydro-2H-pyran 1 &2 equiv.), and catalyst
10 mol%) in solvent &0.2±1.0 M) at room temperature.
b
c
d
e
f
Isolated product after ¯ash chromatography.
Reaction time of 4 h.
Reaction time of 1 h.
Reaction time of 5 h.
Reaction time of 7 h.
[bmim][PF ] is a convenient medium for this transformation
6
using the catalysts PPTS or TPP.HBr giving moderate to
high yields for representative substrates. This reaction
medium can also be successfully recycled on at least 22
occasions without an appreciable loss of activity. The
decrease in the activity of the process is due to loss of
catalyst and volume reduction of the ionic reaction mixture,
which occurs during the extraction of the product with
diethyl ether.
and TPP.HBr as the best conditions previously identi®ed by
GLC, we then prepared in moderate to high yields the tetra-
hydropyranes 3a±3f from several representative alcohols
2
a±2f &Table 2). In all examples the product was removed
from the ionic reaction mixture by successive extractions
with diethyl ether. The use of catalyst TsOH in the ionic
solvent is inappropriate &Table 2, entries 1 and 4; 99% in
DCM vs. 28% in [bmim][PF ]), and the catalysts PPTS and
6
3. Experimental
TPP.HBr appeared very similar. These preparative results
are in accordance with the comparative conversion GLC
studies described above.
3.1. General remarks
All glassware was oven-dried and cooled in a desiccator
&P O desiccant) prior to use. Commercially supplied
Our attention was then directed towards the possibility of
recycling the reaction media. Using 1-phenylethanol 2a as a
representative example, all reactions were performed for 1 h
using 3,4-dihydro-2H-pyran 1 &2 equiv.) at room tempera-
ture. After each cycle the reaction mixture was extracted
with diethyl ether, the conversion determined by GLC and
in some representative examples, the tetrahydropyran 3a
was isolated by ¯ash chromatography. Then, more alcohol
2
5
reagents were used as supplied, except for benzyl alcohol
which was distilled and stored under argon atmosphere and
protected from light. Dichloromethane was distilled over
calcium hydride powder under an argon atmosphere. 1-n-
Butyl-3-methylimidazolium hexa¯uorophosphate [bmim]
[PF ] and 1-n-butyl-3-methylimidazolium tetra¯uoroborate
6
[bmim][BF ]
4
procedures.
were
prepared
following
reported
4
b,11
2
a and pyran 1 were added into the next cycle. New catalyst
was added only when the last cycle gave low conversion.
Table 3 presents the results obtained for the catalysts PPTS
and TPP.HBr.
1
H NMR spectra were recorded on a Bruker AMX 400
Spectrometer. Chemical shifts are reported down®eld in
parts per million &ppm) from a tetramethylsilane reference.
Infrared &IR) spectra were recorded on a Perkin±Elmer
FTIR 683 as thinly dispersed ®lms. Gas liquid chroma-
tography &GLC) was carried out on a Varian Star 3400 Cx
gas chromatograph, using He as carrier gas and capillary
column Supelco C315602 SW-10. Optical rotations were
carried out using an Optical Activity Mod. AA-1000 digital
polarimeter with a cell path length of 5 cm. Melting points
were carried out on a Gallenkamp melting point apparatus
and are uncorrected.
By changing the catalyst &6 mol% for run A, D and 10 mol%
for run B, C, E, F) under identical extraction procedures, we
veri®ed that the number of cycles that allow a conversion of
greater than 40% is dependent on the initial amount and type
of catalyst: TPP.HBr &4 cycles for 6 mol% in run D vs. 5
cycles for 10 mol% in run E); PPTS &2 cycles for 6 mol% in
run A vs. 6 cycles for 10 mol% in run B). We also observed
that long-time extraction procedures &2 h) considerably
reduce the conversion of the next cycle, with this effect
being more relevant for the catalyst TPP.HBr &cycle 15 of
run E and cycle 4 of run F). To circumvent this problem we
used instead fast-time extractions &5 min, cycles 11±22 in
run C and cycles 6±22 in run F). The strong dependence of
Flash chromatography was carried out using an MN Kiesel-
gel 60M gel &40±63 mm, Art. 815381) column. All eluents
were distilled prior to use. Preparative and analytical thin

a
6
Table 3. Reuse of ionic liquid [bmim][PF ] reaction medium for the tetrahydropyranylation of 3a
Run A 3a &1.6 mmol) PPTS
6 mol%)
Run B 3a &1.6 mmol) PPTS
&10 mol%)
Run C 3a
&2.5 mmol) PPTS
10 mol%)
Run D 3a &1.6 mmol)
TPP.HBr &6 mol%)
Run E 3a &1.6 mmol)
TPP.HBr &10 mol%)
Run F 3a &2.5 mmol)
TPP.HBr &10 mol%)
&
&
b
b
b
% 3a GLC &Yield)
c
b
b
b
% 3a GLC &Yield)
c
Cycle
Conversion 3a &% by GLC)
Conversion 3a &% by GLC)
Conversion 3a &% by GLC)
Conversion 3a &% by GLC)
1
2
3
4
5
6
7
8
9
37.0
48.9
31.3
21.8
5.4
98.8
97.6
99.0
97.9
93.7
97.5
31.4
27.2
97.2 &77.9)
95.3
95.7
97.3
88.9
98.6
42.9
5.1
97.8
99.1
99.5
99.6
85.6
31.7
95.9 &77.8)
94.8
94.8
e
97.2
96.3 &81.0)
95.2 &80.1)
44.0 &56.2)
e
e
e
74.8 &66.0)
d,f
96.4 &71.7)
5.4
86.2
0.8
95.1
d
e
d
d
f
72.5
68.2 &60.2)
93.7
94.5
96.4
e
f
64.2
40.4
71.4
67.9
19.1
93.9
99.3
97.9
95.3
21.7
28.5
d
e
f
87.8
64.0
58.7 &62.0)
97.4
97.2
d
e
d
f
10
11
12
13
14
15
16
17
18
19
20
21
22
92.6
94.9
97.3
86.9
98.4
d,f
93.7 &68.8)
f
95.7
29.4
84.2
96.9
91.4 &72.1)
92.4
f
f
96.0
96.2
f
d
f
95.6
98.6
99.1
98.0 &68.1)
f
f
93.9 &71.6)
97.8
e
f
e
f
97.7
71.2
72.0
96.6
99.7
2.8
93.0
97.3
e
f
e
f
93.1
92.8
e
f
e
f
0.3
0.1
97.4
97.0
d
f
e
f
93.1
98.9 &69.6)
f
d
f
92.9
98.3
97.1 &72.0)
97.9
f
f
96.5
89.8
f
f
95.0
92.3
f
f
86.0
a
2
a &1.6 or 2.5 mmol), 3,4-dihydro-2H-pyran 1 &2 equiv.), and catalyst &6 or 10 mol%) in [bmim][PF
6
] &2 or 4 ml) at room temperature &188C) was reacted for 1 h, extracted with diethyl ether &4£3 ml or 5£5 ml, 15 min
for each extraction) and then 2a and 1 were added again for the next cycle.
Conversion of 3a obtained by GLC analysis.
Isolated product 3a after ¯ash chromatography.
New addition of the catalyst was performed.
Slow extraction of the reaction mixture was performed &2 h for each extraction).
Fast extraction of the reaction mixture was performed &5 min for each extraction).
b
c
d
e
f

L. C. Branco, C. A. M. Afonso / Tetrahedron 57 ꢀ2001) 4405±4410
4409
layer chromatography &TLC) was carried out using, respect-
ively, MN Kieselgel G/UV254 &Art. 816320) glass-backed
plates and MN Alugramw SIL G/ UV254 &Art. 818133).
The plates were visualised using ultraviolet light &254 nm).
[&10 mol%), TPP.HBr or PPTS] in ionic liquid
&[bmim][PF ], 1 ml for benzyl alcohol 2b, 4 ml for choles-
6
terol 2e and 2 ml for other alcohols). The resulting mixture
was further stirred &1 h for benzyl alcohol 2b, 5 h for choles-
terol 2d, 7 h for 1-adamantanol 2f and 4 h for other alco-
hols) at room temperature under an argon atmosphere. The
reaction mixture was extracted with diethyl ether &5£5 ml)
and the resulting solution was evaporated in vacuo and
puri®ed by TLC or ¯ash chromatography.
3
.2. General procedure for the conversion analysis of 1-
phenylethanol 2a to 1-phenylethanol tetrahydropyranyl
ether 3a followed by GLC
3
,4-Dihydro-2H-pyran &150 ml, 1.64 mmol) was added to a
stirred solution of 1-phenylethanol &100 mg, 0.82 mmol)
and catalyst [10 mol%, triphenylphosphine hydrobromide
3
.4.1. 1-Phenylethanol tetrahydropyranyl ether 3a. 3,4-
Dihydro-2H-pyran &310 ml), 1-phenylethanol 2a &200 ml,
.64 mmol) and TPP.HBr &65 mg) in 2 ml of [bmim][PF6],
&
&
TPP.HBr, 36 mg); p-toluenesulphonic acid monohydrate
TsOH, 19 mg) or pyridinium p-toluenesulphonate &PPTS,
1
were stirred for 1 h. Puri®cation by ¯ash chromatography
using hexane/diethyl ether 9:1 gave 3a as a yellow oil
&263 mg, 78%; 273 mg, 81% in the case of PPTS). Spectral
data are identical to those previously reported.
2
ionic liquid &[bmim][PF ] or [bmim][BF ], 1 ml), under
5 mg)] in a classic solvent &dry dichloromethane, 1ml) or
6
4
argon atmosphere at room temperature &188C, water bath)
or at 08C. The course of the reaction was followed by GLC
by taking 20 ml samples of the reaction medium at deter-
mined time intervals &5, 10, 15, 20, 30, 45, 60 and 120 min)
and diluting in diethyl ether &0.3 ml) in the presence of
Na CO , followed by injection into the gas chromatographer
12
3.4.2. Benzyl alcohol tetrahydropyranyl ether 3b. 3,4-
Dihydro-2H-pyran &175 ml), benzyl alcohol 2b &100 ml,
0.96 mmol) and TPP.HBr &33 mg) in 1 ml of ionic liquid
2
3
2
1
[
carrier gas ¯ow: 21 ml min , T &oven)ˆ1308C, T &injec-
&[bmim][PF ]) were stirred for 4 h. Puri®cation by TLC
6
tor)ˆ1508C and T &detector)ˆ2308C]. The conversion of the
reaction for each sample was determined by comparing the
peak areas of the product 3a &t ˆ4.0 min, t ˆ4.7 min) with
using hexane/ethyl acetate 9.5:0.5 gave 3b as a colourless
oil &170 mg, 92%; 168 mg, 91% in the case of PPTS). Spec-
tral data are identical to those previously reported.
1
2±14
R
R
1
-phenylethanol &t ˆ2.4 min).
R
3
.4.3. ꢀ2)-Menthol tetrahydropyranyl ether 3c. 3,4-
Dihydro-2H-pyran &310 ml), &2)-menthol 2c &391 mg,
.64 mmol) and TPP.HBr &65 mg) in 2 ml of [bmim][PF6]
3.3. Recycling of tetrahydropyranylation of 1-phenyl-
ethanol 2a
1
were stirred for 4 h. Puri®cation by ¯ash chromatography
using hexane/diethyl ether 9:1 gave 3c as a colourless
oil &431 mg, 81%; 439 mg, 83% in the case of PPTS). Spec-
A solution of 3,4-dihydro-2H-pyran &310 ml, 3.28 mmol or
65 ml, 4.92 mmol) was added to a stirred mixture of 1-
phenylethanol &200 ml, 1.64 mmol or 300 ml, 2.46 mmol)
and the catalyst [6 or 10 mol%: triphenylphosphine
hydrobromide &TPP.HBr), 30 or 65 mg; or pyridinium p-
toluenesulphonate &PPTS), 25 or 50 mg] in ionic liquid
4
1
3
tral data are identical to those previously reported;
[
2
5
a
]
ˆ
2
8
6
.
8
&
c
ˆ
1
.
0
,
C
H
C
l
)
.
D
3
&
[bmim][PF ], 2 or 4 ml), under an argon atmosphere. The
6
3.4.4. Cholesterol tetrahydropyranyl ether 3d. 3,4-Dihy-
dro-2H-pyran &160 ml), cholesterol 2d &317 mg, 0.82 mmol)
and TPP.HBr &65 mg) in 4 ml of [bmim][PF ] were stirred
6
resulting mixture was further stirred for 1 h at room
temperature. The reaction medium was extracted with
diethyl ether &4£3 ml or 5£5 ml) through normal extraction
for 5 h. Puri®cation by ¯ash chromatography using hexane/
diethyl ether 9:1 gave 3d as a white solid &240 mg, 62%;
&
corresponding to 15 min for every extraction). In some
cycles different extractions were perfomed: slow extraction
corresponding to 2 h for every extraction) and fast extrac-
13
3
08 mg, 80% in the case of PPTS); mp149.0±149.5 8C, lit.
&
25
mp150 8C; [a]D ˆ116.2 &cˆ1.0, CHCl ). Spectral data are
3
12,13
tion &corresponding to 5 min for every extraction). The
combined ethereal extracts were injected on a GLC for
analysis of the reaction conversion as described above. In
certain cycles, the resulting etheral solution was evaporated
under in vacuo and puri®ed on a ¯ash chromatography
column &silica gel, eluent:n-hexane/diethyl ether 9:1). A
new portion of reactants was added to the recycled
identical to those previously reported.
3.4.5. Geraniol tetrahydropyranyl ether 3e. 3,4-Dihydro-
2
TPP.HBr &65 mg) in 2 ml of [bmim][PF ] were stirred for
H-pyran &310 ml), geraniol 2e &288 ml, 1.64 mmol) and
6
4 h. Puri®cation by ¯ash chromatography using hexane/
diethyl ether 9:1 gave 3e as a colourless oil &289 mg,
[
bmim][PF ] and the cycle repeated. When lower yields of
6
product were observed a new portion of catalyst &TPP.HBr
or PPTS) was added into the ionic reaction mixture.
74%; 270 mg, 69% in the case of PPTS). Spectral data are
identical to those previously reported.
1
2,13
3.4. General procedure for preparative tetrahydro-
pyranylation of alcohols 2a±2f
3.4.6. 1-Adamantanol tetrahydropyranyl ether 3f. 3,4-
Dihydro-2H-pyran &310 ml), 1-adamantanol 2f &250 mg,
1.64 mmol) and TPP.HBr &65 mg) in 2 ml of [bmim][PF6]
were stirred for 7 h. Puri®cation by ¯ash chromatography
using hexane/diethyl ether 9:1 gave 3f as a colourless oil
&292 mg, 75%; 333 mg, 86% in the case of PPTS). Spectral
A solution of 3,4-dihydro-2H-pyran &1.92 mmol for benzyl
alcohol 2b, 1.64 mmol for cholesterol 2d and 3.28 mmol for
other alcohols) was added to a stirred solution of alcohol
&0.96 mmol for benzyl alcohol 2b, 0.82 mmol for choles-
terol 2d and 1.64 mmol for other alcohols) and the catalyst
1
3
data are identical to those previously reported.

4410
L. C. Branco, C. A. M. Afonso / Tetrahedron 57 ꢀ2001) 4405±4410
Chem. Comm. 2000, 1743±1744. &l) Song, C. E.; Oh, C. R.;
Acknowledgements
Roh, E. J.; Choo, D. J. Chem. Comm. 2000, 1743±1744.
4. &a) Blanchard, L. A.; Hancu, D.; Beckman, E. J.; Brennecke,
J. F. Nature 1999, 399, 28. &b) Huddleston, J. G.; Willauer,
H. D.; Swatloski, R. P.; Visser, A. E.; Rogers, R. D. Chem.
Commun. 1998, 1765±1766. &c) Cull, S. G.; Holbrey, J. D.;
Vargas-Mora, V.; Seddon, K. R.; Lye, G. J. Biotechnology and
Bioengineering 2000, 69, 227±233.
This work was supported by the Funda cË aÄ o para a Ci eà ncia e
Tecnologia, project PRAXIS/C/QUI/10069/98 and the
Instituto de Biologia Experimental e Tecnol o gica. We also
acknowledge Ana S. C. Rodrigues for technical support.
5
. &a) Greene, T. H.; Wuts, P. G. M. In Protective Groups in
Organic Synthesis, John Wiley ꢀ Sons: New York, 1999; pp
References
4
9±54. &b) Kierkus, P. C. In Handbook of Reagents for
1
2
. &a) Welton, T. Chem Rev. 1999, 99, 2071±2083. &b) Seddon,
K. R. Kinetics and Catalysis 1996, 37, 693±697
http://www.ch.qub.ac.uk/resources/ionic/review/review.html.
Organic Synthesis: Activating Agents and Protecting Groups,
Pearson, A. J., Roush, W. R., Eds.; John Wiley ꢀ Sons: New
York, 1999; pp 147±150.
&
c) Hussey, C. L. Pure Appl. Chem. 1988, 60, 1763±1772.
. &a) Gordon, C. M.; McCluskey, A. Chem. Commun. 1999,
431±1432. &b) Green, L.; Hemeon, I.; Singer, R. D.
6
7
. &a) Schlama, T.; Gouverneur, V.; Mioskowski, C. Tetrahedron
Lett. 1997, 38, 3517±3520. &b) Bhar, S.; Ranu, B. C. J. Org.
Chem. 1995, 60, 745±747.
1
Tetrahedron Lett. 2000, 41, 1343±1346. &c) Stark, A.;
MacLean, B. L.; Singer, R. D. J. Chem. Soc., Dalton Trans.
. &a) Kumar, H. M. S.; Reddy, B. V. S.; Reddy, E. J.; Yadav, J. S.
Chem. Lett. 1999, 857±858. &b) Chandrasekhar, S.; Takhi, M.;
Reddy, Y. R.; Mohapatra, S.; Rao, C. R.; Reddy, K. V.
Tetrahedron 1997, 53, 14997±15004.
1999, 63±66. &d) Adams, C. J.; Earle, M. J.; Seddon, K. R.
Chem. Commun. 1999, 1043±1044. &e) Earle, M. J.;
McCormac, P. B.; Seddon, K. R. Chem. Commun. 1998,
8
. &a) Ballini, R.; Bigi, F.; Carloni, S.; Maggi, R.; Sartori, G.
Tetrahedron Lett. 1997, 38, 4169±4172. &b) Thompson,
L. A.; Ellman, J. A. Tetrahedron Lett. 1994, 35, 9333±9336.
. Miyashita, M.; Yoshikoshi, A.; Grieco, P. A. J. Org. Chem.
2245±2246.
3
. &a) Chen, W.; Xu, L.; Chatterton, C.; Xiao, J. Chem. Commun.
1
999, 1247±1248. &b) Song, C. E.; Roh, E. J. Chem. Commun.
000, 837±838. &c) Carmichael, A. J.; Earle, M. J.; Holbrey,
9
2
1
977, 42, 3772±3774.
0. Bolitt, V.; Mioskowski, C. Tetrahedron Lett. 1988, 29, 4583±
586.
J. D.; McCormac, P. B.; Seddon, K. R. Organic Lett. 1999, 1,
97±1000. &d) Bellefon, C.; Pollet, E.; Grenouillet, P. J. Mol.
1
1
9
4
Catal. A: Chemical 1999, 145, 121±126. &e) Dyson, P. J.;
Ellis, D. J.; Parker, D. G.; Welton, T. Chem. Commun. 1999,
1. &a) Suarez, P. A. Z.; Dullius, J. E. L.; Einloft, S.; de Souza,
R. F.; Dupont, J. Polyhedron 1996, 15, 1217±1219.
2
5±26. &f) Owens, G. S.; Abu-Omar, M. M. Chem. Commun.
&b) Holbrey, J. D.; Seddon, K. R. J. Chem. Soc., Dalton
Trans. 1999, 2133±2139.
2000, 1165±1166. &g) Earle, M. J.; McCormac, P. B.; Seddon,
K. R. Green Chem. 1999, 23±25. &h) Carmichael, A. J.;
Haddleton, D. M.; Bon, S. A. F.; Seddon, K. R. Chem.
Commun. 2000, 1237±1238. &i) Mathews, C. J.; Smith, P. J.;
Welton, T. Chem. Commun. 2000, 1249±1250. &j) Howarth,
J.; Dallas, A. Molecules 2000, 5, 851±855. &k) Howarth, J.
1
2. Hoyer, S.; Laszlo, P. Synthesis 1986, 655±657.
3. Bongini, A.; Cardillo, G.; Orena, M.; Sandri, S. Synthesis
1
1
979, 618±620.
4. Brown, D. S.; Ley, S. V.; Vile, S.; Thompson, M. Tetrahedron
991, 47, 1329±1342.
1
1