InCl3 immobilized in ionic liquids: A novel and recyclable catalytic system for tetrahydropyranylation and furanylation of alcohols

Article abstract of DOI:10.1039/b210044b

A mild and highly efficient method has been developed for the protection of hydroxyl compounds as tetrahydropyranyl and furanyl ethers using a catalytic amount of indium trichloride immobilized in 1-butyl-3-methylimidazolium hexafluorophosphate ionic liquid under mild conditions. A wide range of functional and protecting groups such as THP, TBDMS, TBDPS, PMB, MOM ethers, acetonides, olefins and epoxides are compatible with ionic liquids. Monoprotection of diols has also been achieved using this novel procedure.

Full text of DOI:10.1039/b210044b

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InCl3 immobilized in ionic liquids: a novel and recyclable catalytic
system for tetrahydropyranylation and furanylation of alcohols
Jhillu Singh Yadav,* Basi. V. Subba Reddy and Dughani Gnaneshwar
Division of Organic Chemistry, Indian Institute of Chemical Technology,
Hyderabad 500 007, India. E-mail: yadav@iict.ap.nic.in; Fax: +91 40 716 0512
L e t t e r
Received (in Montpellier, France) 10th October 2002, Accepted 23rd November 2002
First published as an Advance Article on the web 18th December 2002
mainly protic acids,5 Lewis acids,6 solid acids,7 solid supported
reagents,8 catalysts immobilized in ionic liquids,9 and many
others.10 However, in spite of their potential utility in the pro-
tection of simple hydroxyl compounds, many of these methods
have limitations when applied to complex molecules contain-
ing acid-sensitive functional groups and polyhydroxyl com-
pounds bearing acid-labile protecting groups. Thus, there is
a need for the development of a more general and efficient
alternative for the pyranylation of alcohols. In recent years,
InCl3 has evolved as a versatile Lewis acid for a variety of
organic transformations, such as the Diels–Alder reaction,
Mukaiyama-aldol reactions, Mannich reaction, Michael addi-
tions, Prins cyclization, glycosylation reactions and Sakurai
allylation reactions under mild conditions.11 Compared to con-
ventional Lewis acids, indium trichloride has the advantages of
low catalyst loading, moisture stability and catalyst recycling.
However, there are no examples of the tetrahydropyranylation
of alcohols using indium halides. The unique catalytic features
of indium trichloride prompted us to explore further appli-
cations of InCl3 as a catalyst in other carbon-carbon and
carbon-heteroatom bond forming reactions.12
In view of the emerging importance of ionic liquids as novel
reaction media, we wish to report a mild and highly efficient
method for the tetrahydropyranylation of alcohols using a cat-
alytic amount of indium trichloride in ionic liquids (Scheme 1).
The treatment of cinnamyl alcohol with 3,4-dihydro-2H-
pyran in the presence of 5 mol % InCl3 in 1-butyl-3-methyl-
imidazolium hexafluorophosphate ([bmim]PF6) ionic liquid
afforded the tetrahydropyranyl derivative in 92% yield. Simi-
larly, a wide range of hydroxy compounds were converted to
the corresponding THP ethers in excellent yields by using this
procedure. The reactions proceeded efficiently at ambient tem-
perature with high chemoselectivity. The reaction conditions
are mild enough not to induce isomerization of multiple bonds
during pyranylation of allylic and propargylic systems and are
selective for the protection of hydroxyl groups in the presence
of other acid-sensitive protecting groups, which is difficult to
achieve under conventional conditions. Furthermore, the reac-
tions of alcohols with 2,3-dihydrofuran under the influence of
indium trichloride in [bmim]PF6 ionic liquid afforded the cor-
responding tetrahydrofuranyl ethers in high yields (Scheme 2).
The reaction proceeds smoothly at ambient temperature with
high chemoselectivity. The products were isolated in high
yields after 3–6 h.
A mild and highly efficient method has been developed for the
protection of hydroxyl compounds as tetrahydropyranyl and
furanyl ethers using a catalytic amount of indium trichloride
immobilized in 1-butyl-3-methylimidazolium hexafluoropho-
sphate ionic liquid under mild conditions. A wide range of func-
tional and protecting groups such as THP, TBDMS, TBDPS,
PMB, MOM ethers, acetonides, olefins and epoxides are
compatible with ionic liquids. Monoprotection of diols has also
been achieved using this novel procedure.
Environmental protection laws and corporate pressure to
minimize the amount of toxic waste arising from chemical
processes have motivated the development of innovative and
environmentally friendly chemical technologies. As a result,
enviro-economics has become the focused theme for the devel-
opment of new processes for existing products or new products.
The fact is that recently discovered room temperature ionic
liquids are emerging as a set of green solvents, mainly as a
replacement for conventional organic solvents, especially
those that are volatile and difficult to handle.1 Ionic liquids,
especially those based on the 1-n-alkyl-3-methylimidazolium
cation, have shown great promise as an attractive alternative
to conventional solvents. They are non-volatile, recyclable,
non-explosive, easy to handle, thermally robust, and in addi-
tion they are compatible with various organic compounds
and organometallic reagents.2 The unique property of ionic
liquids is that they have essentially no vapor pressure, which
makes them optimal replacements for volatile organic solvents.
A nice feature of ionic liquids is that yields can be optimized by
changing anions or properties of the cation. These ionic liquids
show enhancement in reaction rates and selectivity, compared
to molecular organic solvents. The use of room temperature
ionic liquids has led to significant advances in the development
of clean chemical processes in organic synthesis targeted to
avoid or at least minimize the use of toxic or waste generating
reagents or solvents. Because of the distinct advantages of
ionic liquids, they can make an important contribution to
green chemistry.
Protective groups play an important role in the multi-step
synthesis of complex natural products; hence there is always
a demand for selective reagents. Tetrahydropyranylation is
one of the most widely used processes for the protection of
alcohols and phenols.3 Due to the remarkable stability of tetra-
hydropyranyl ethers toward a variety of reaction conditions
such as strong basic media, oxidative conditions, reduction
with metal hydrides, reactions involving Grignard reagents,
lithium alkyls and alkylating and acylating reagents, etc., tetra-
hydropyranylation is one of the methods of choice to protect
a hydroxyl group in a multi-step organic synthesis.4 Conse-
quently, a variety of reagents have been developed for the
tetrahydropyranyl protection of alcohols, which include
Scheme 1
202
New J. Chem., 2003, 27, 202–204
DOI: 10.1039/b210044b
This journal is # The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2003

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as in the first run and no decrease in yields was obtained in
runs carried out using recycled ionic liquid. For example, the
treatment of cinnamyl alcohol with 3,4-dihydro-2H-pyran in
the presence of 5 mol % InCl3in [bmim]BF4 afforded 92%,
91%, 92%, 91% and 90% yields over five cycles. Another
advantage of this method is in the selective protection of alco-
hols in the presence of highly acid-sensitive epoxides, silyl
ethers and acetals. As evident from Table 1, the acid-sensitive
protecting groups such as THP, TBDMS, TBDPS, PMB,
MOM ethers, acetonides and epoxides survived under these
reaction conditions. Thus, the present method is mild enough
to tolerate a wide range of functional groups present in
the substrate. Monoprotection of diols was also achieved by
this procedure (entry o). This method is equally effective for
the protection of primary, secondary and tertiary alcohols
(entries p, q). In the absence of indium trichloride, the reac-
tions proceeded smoothly in 1-butyl-3-methylimidazolium tet-
rafluoroborate ([bmim]BF4), but longer reaction periods (8–12
h) are required to achieve comparable yields to those obtained
with indium trichloride in 1-butyl-3-methylimidazolium
Scheme 2
This method is highly chemoselective to protect hydroxyl
groups as THP and THF ethers. Enhanced reaction rates,
improved yields and high functional group compatibility are
the features obtained in these ionic liquids. Another advantage
of the use of ionic liquids as a novel reaction medium as well as
promoters for this transformation is that these ionic solvents
can be easily recovered after completion of the reaction and
can be reused in subsequent reactions. As the products were
weakly soluble in the ionic phase, they were easily separated
by simple extraction with ether. The rest of the viscous ionic
liquid was thoroughly washed with ether and dried at 80 ꢀC
under reduced pressure and recycled in five runs without any
loss of activity. The products obtained were of the same purity
Table 1 Ionic-liquids-promoted protection of alcohols as THP and THF ethersa
5% InCI3–[bmim]PF6
Time/h
[bmim]BF4
Time/h
Entry
a
Alcohol
Enol ether
% Yieldb
90
% Yieldb
84
3.0
4.5
3.5
4.0
3.5
4.0
5.0
4.0
4.5
4.0
4.5
5.0
4.0
8.0
9.0
b
c
d
e
f
87
92
90
91
82
90
88
85
91
90
87
85
81
85
80
83
71
85
81
78
87
83
79
80
10.0
9.5
8.0
12.0
8.0
g
h
i
11.0
10.0
8.0
j
k
l
7.5
12.0
9.0
m
n
o
p
3.0
6.0
3.5
5.5
87
85c
81
89
12.0
9.5
8.0
8.5
75
80c
70
q
a
All products were characterized by 1H NMR, IR and mass spectroscopy. b Isolated and unoptimized yields after purification. c Monoprotection
of diol was obtained.
New J. Chem., 2003, 27, 202–204
203

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hexafluorophosphate ([bmim]PF6) ionic liquid. In the absence
of catalyst, low conversions (25–55%) were obtained in
[bmim]PF6 ionic liquid. No significant differences in reaction
rates and yields were observed with either the [bmim]BF4–
InCl3 or [bmim]PF6–InCl3 catalytic systems.
3.78–3.90 (m, 1H), 4.05 (dd, 1H, J ¼ 6.0, 11.7 Hz), 4.18–4.28
(m, 3H), 4.60 (br s, 1H), 5.55–5.70 (m, 2H). 3j: 1H NMR
(CDCl3) d: 1.45–1.80 (m, 12H), 3.40–3.57 (m, 2H), 3.75–3.85
(m, 2H), 4.0–4.15 (m, 2H), 4.18–4.28 (m, 1H), 4.60 (br s,
2H), 5.63–5.70 (m, 2H).
Finally, the catalytic performance of various quaternary
ammonium salts was studied for this conversion. The tetra-
hydropyranylation was not successful when n-tetrabutyl ammo-
nium chloride (n-Bu4NCl) or 1-n-butyl-3-methylimidazolium
chloride ([bmim]Cl) was used as the reaction media. Similar
results were obtained even in the n-Bu4NCl–InCl3 or
[bmim]Cl–InCl3catalytic systems. This indicates that both
cation and anion play an important role as the solvent in this
transformation. Furthermore, the recovery and reuse of
indium trichloride is especially simple in ionic liquids
compared to organic solvents.
In summary, this paper describes a method for the chemo-
selective conversion of alcohols to tetrahydropyranyl and
furanyl ethers using a catalytic amount of indium trichloride
in ionic liquids that operates under mild conditions, thereby
leaving acid- and base-labile protecting groups intact. The sim-
ple experimental and product isolation procedures combined
with ease of recovery and reuse of this novel reaction media
is expected to contribute to the development of a green strat-
egy for the tetrahydropyranylation and furanylation of alco-
hols in protective group chemistry. Furthermore, the use of
1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF4)
ionic liquid as promoter for this transformation avoids the
use of toxic or corrosive and moisture-sensitive reagents.
Acknowledgements
BVS thanks CSIR, New Delhi, for the award of a fellowship.
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204
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