AI(OTf)3 - A highly efficient catalyst for the tetrahydropyranylation of alcohols under solvent-free conditions

Article abstract of DOI:10.1139/V08-164

A simple and highly efficient method has been developed for the tetrahydropyranylation of alcohols by their reaction with 3,4-dihydro-2H-pyran (DHP) using a catalytic amount (0.01-1 mol%) of aluminium triflate under solvent-free conditions. The effect of various factors like temperature, amount of the catalyst, and molar ratio of substrates on the reaction conditions has also been studied. The comparative study of tetrahydropyranylation of benzyl alcohol using various catalysts including some reported ones shows the efficiency of this catalyst.

Full text of DOI:10.1139/V08-164

1099
Al(OTf)3 — A highly efficient catalyst for the
tetrahydropyranylation of alcohols under
solvent-free conditions
Ahmed Kamal, M. Naseer A. Khan, Y.V.V. Srikanth, and K. Srinivasa Reddy
Abstract: A simple and highly efficient method has been developed for the tetrahydropyranylation of alcohols by their
reaction with 3,4-dihydro-2H-pyran (DHP) using a catalytic amount (0.01–1 mol%) of aluminium triflate under solvent-
free conditions. The effect of various factors like temperature, amount of the catalyst, and molar ratio of substrates on
the reaction conditions has also been studied. The comparative study of tetrahydropyranylation of benzyl alcohol using
various catalysts including some reported ones shows the efficiency of this catalyst.
Key words: tetrahydropyranylation, aluminium triflate, alcohols, catalysis.
Résumé : On a mis au point une méthode simple et efficace de préparer des dérivés tétrahydropyranyles d’alcools en
les faisant réagir avec du 3,4-dihydro-2H-pyrane (DHP), dans des conditions sans solvant et en faisant intervenir une
quantité catalytique (0,01 à 1 mol %) de triflate d’aluminium. On a aussi étudié les effets de divers facteurs, telle la
température, la quantité de catalyseur et le rapport molaire des substrats sur les conditions de la réaction. Une étude
comparative de la réaction de tétrahydropyranylation de l’alcool benzylique en faisant intervenir divers catalyseurs, y
compris celui mentionné dans ce travail, met en évidence l’efficacité de ce catalyseur.
Mots-clés : tétrahydropyranylation, triflate d’aluminium, alcools, catalyse.
[Traduit par la Rédaction] Kamal et al. 1104
Introduction
groups, and involving expensive and toxic catalysts apart
from the occurrence of side-products and poor yield of de-
sired products.
Protection of hydroxy groups by their conversion to the
corresponding tetrahydropyranyl (THP) ethers is one of the
most frequently employed transformations in organic
syntyhesis (1, 2). The wide use is due to their ease of prepa-
ration and stability under a variety of reaction conditions
such as with hydrides, alkylating reagents, Grignard re-
agents, and organometallic reagents (2, 3). THP groups are
also the protective groups of choice in peptide, nucleotide,
carbohydrate, and steroid chemistry (4). A variety of cata-
lysts that have been reported for this conversion includes the
use of protic acids (5–7), acidic clay (4), triflates (8–11), ion
exchange resins (12, 13), alumina impregnated with ZnCl2
(14), sulfuric acid on silica gel (15), heteropoly acids (16),
polystyrene supported aluminum chloride (17), ionic liquids
(18), and many others (19–25). However, despite their
potential utility in the protection of simple hydroxyl com-
pounds, many of these methods have limitations such as
elevated reaction temperatures, longer reaction times, non-
reusability of catalysts, the use of volatile organic solvents,
being incompatible with other acid-sensitive functional
In view of the modern demands of organic synthesis, there
is a need for a solvent-free and catalytically efficient alterna-
tive for the protection of hydroxy functionality as a THP
ether, which works under mild and economically benign
conditions in a cost-effective manner. In recent years, alu-
minium triflate has been found to be an efficient catalyst for
various transformations like epoxide ring openings (26, 27),
thiol protections (28), and silylation of alcohols as well as
phenols (29). Recently, we have reported (30) the acylation
of alcohols, phenols, and thiophenols in an efficient manner
by employing this catalyst. In view of the high catalytic ac-
tivity and in continuation to our earlier studies on this re-
agent, we wish to report a highly efficient method for the
tetrahydropyranylation of alcohols in the presence of a cata-
lytic amount of Al(OTf)3 (0.01–1 mol%) under solvent-free
conditions in excellent yields.
Results and discussion
The treatment of benzyl alcohol with 3,4-dihydro-2H-
pyran in the presence of 0.01 mol% Al(OTf)3 afforded the
tetrahydropyranyl derivative in 92% yield in 2 h at room
temperature (RT) (Table 1, entry 1b). Further, the rate of re-
action enhanced by using 1 mol% of the catalyst at RT,
along with the formation of side-products (10%–25%). To
overcome this limitation, the reaction conditions were opti-
mized by employing 1 mol% of the catalyst at 20 °C. A
wide range of hydroxy compounds were converted to their
Received 28 April 2008. Accepted 6 October 2008. Published
on the NRC Research Press Web site at canjchem.nrc.ca on
15 November 2008.
A. Kamal,1 M.N.A. Khan, Y.V.V. Srikanth, and
K. Srinivasa Reddy. Biotransformation Laboratory, Division
of Organic Chemistry, Indian Institute of Chemical
Technology, Hyderabad 500 007, India.
1Corresponding author (e-mail: ahmedkamal@iict.res.in).
Can. J. Chem. 86: 1099–1104 (2008)
doi:10.1139/V08-164
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Can. J. Chem. Vol. 86, 2008
Table 1. Tetrahydropyranylation of alcohols catalyzed by 1 mol% Al(OTf)3 at 20 °C.
Table 2. The effect of the amount of catalyst on the
tetrahydropyranylation of benzyl alcohol at 20 °C.
Scheme 1. Synthesis of tetrahydropyranyl ethers.
S. No.
Catalyst (mol%)
T (min)
Yield (%)
1
2
3
4
5
0.01
0.1
0.5
1
120
50
20
5
90a
90
95
95
80
corresponding THP ethers in excellent yields by using this
procedure (Scheme 1 and Table 1). The reactions are mild
enough for functionalities like allylic ones (Table 1, entry 6)
or other acid sensitive groups like epoxide (Table 1, entry 7)
and triphenylsilyl groups (Table 1, entry 17), compared with
the conventional conditions. All the assigned structures were
established from their spectral properties (NMR, mass, and
IR) and by comparison with available authentic data.
The reaction of benzyl alcohol and DHP was chosen as a
model reaction to evaluate the effect of the amount of the
catalyst employed for the conversion (%) of DHP ethers at
20 °C. As illustrated in Table 2, an increase in the amount of
catalyst substantially increases the conversion. The reaction
proceeds by using 0.01 mol% of the catalyst to yield 90% of
2
2
aYield obtained by performing the reaction at RT.
the product in 2 h at RT. The reaction is greatly enhanced by
increasing the quantity of catalyst. The enhanced rates are
due to the increase in the number of catalytically active
sites. However, this process reaches its optimum at 1 mol%,
and further increases in the amount of catalyst fastens the
process along with the formation of side-products (10%–
25%). In addition, the effect of temperature on the
© 2008 NRC Canada

Kamal et al.
1101
Table 1 (concluded).
Note: All the reactions were performed using 1.5 equiv. of DHP unless otherwise stated.
aYields refer to isolated products.
bReaction carried out at RT using 0.01 mol% of the catalyst at large scale.
cFirst time reported.
dTo solubilize solid substrates, 5 equiv. of DHP were added.
Table 3. The effect of the temperature on the tetrahydropy-
ranylation of benzyl alcohol using 1 mol% of catalyst.
crease in temperature, and the conversion is maximum at
20 °C. When the reaction was carried out at 30 °C, the for-
mation of the side-products was observed. Moreover, no
side-products were observed at this temperature when
0.01 mol% catalyst was employed, however the reaction
time was much longer (Table 1, entry 1b). Therefore, the re-
actions carried out at 20 °C gave the desired results using an
optimal amount of catalyst.
S. No.
Temp. (°C)
T (min)
Yield (%)
0
10
20
30
1
2
3
4
120
50
5
90
95
95
75
5
To investigate the efficiency of Al(OTf)3, the results of the
tetrahydropyranylation of benzyl alcohol were compared
with those of the reported methods as well as various new
catalysts (Table 4). This catalyst has been found to be more
efficient with respect to reaction times, mol% of the catalyst
conversion of DHP ethers was also investigated for the
temperatures ranging between 0 °C to 30 °C, with benzyl al-
cohol and DHP as a representative reaction using 1 mol% of
catalyst (Table 3). The rate of conversion increases with in-
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Can. J. Chem. Vol. 86, 2008
Table 4. Comparison of the activity of various catalysts in the tetrahydropyranylation of benzyl alcohol.
Entry
Catalyst
Mol (%)
Conditions
Time (min)
Yield (%)
Ref.
1
2
1
1
5
2
Al(OTf)3
Al(OTf)3
20 °C, solvent-free
RT, solvent-free
95
80a
This work
This work
3
4
LiOTf
In(OTf)3
60
1
reflux, DCE
0 °C, DCM
150
30
96
85
8
9
5
6
7
Fe(OTf)3
Fe(OTf)3
Yb(OTf)3
1
1
1
20 °C, solvent-free
RT, solvent-free
RT, solvent-free
5
1
90
This work
This work
This work
75a
10
80
60a
95
8
9
TMSOTf
Cu(OTf)2
1
1
RT, solvent-free
RT, solvent-free
1
25
This work
This work
10
11
12
13
Cu(BF4)2·xH2O
Nd2(SO4)3·xH2O
CuSO4·5H2O
2
5
RT, solvent-free
RT, solvent-free
RT, acetonitrile
RT, solvent-free
20
15
90
85
91
93
This work
This work
21
20
10
40
La(NO3)3·6H2O
150
22
14
15
Copper methanesulfonate-HOAc
Eu2(SO4)3·xH2O
2:80
1
RT, solvent-free
RT, solvent-free
60
5
94
85
23
This work
16
Bu4N Br3
2.5
RT, DCM
60
85
24
Note: All experiments have been carried out according to the general experimental procedure under the conditions given in the table.
aSide-products were obtained in addition to the desired products.
Scheme 2. Proposed mechanism for tetrahydropyranylation of alcohols.
used, and the yields of the desired products when compared
with other catalysts.
of organic solvents, and large scale practical synthesis.
Moreover, the effect of temperature and amount of the cata-
lyst on the reaction feasibility has been investigated. We be-
lieve that this protocol makes an attractive strategy, offering
advantages over other methods.
The mechanism for tetrahydropyranylation can be ratio-
nalized based on the experimental and theoretical ap-
proaches reported in the literature (31). The mechanism
pathway involves the coordination of Al(OTf)3 to the oxygen
atom of alcohol giving intermediate complex A. This inter-
mediate may be in equilibrium with chelate B (in which the
catalyst is coordinated with both the C–C double bond of
DHP as well as the oxygen atom of the alcohol) and com-
plex C (in which only the C–C double bond is coordinated
with the catalyst) (Scheme 2). Finally, these transition states
result in the formation of DHP ethers.
Experimental
General
1H NMR spectra were recorded on Gemini Varian-VXR-
Unity (200 MHz) or Bruker UXNMR/XWIN-NMR
(300 MHz) instrument. Chemical shifts (δ) are reported in
ppm downfield from internal standard TMS. LC-MS was re-
corded on an LC-MSD-Trap-SL instrument, and ESI mass
spectra were recorded on a VG-7070H Micromass mass
spectrometer at 200 °C, 70 eV, with a trap current of 200 µA
and 4 kV of acceleration voltage. Reactions were monitored
by TLC, performed on silica gel glass plates containing 60
F-254. Visualization on TLC was achieved by UV light or
iodine indicator. Column chromatography was performed
with Merck 60–120 mesh silica gel. Yields reported are
based on isolated compounds. All the reagents used were ei-
Conclusion
In conclusion, we have developed a simple and highly ef-
ficient method for the conversion of alcohols to
tetrahydropyranyl ethers using catalytic amount of Al(OTf)3
under solvent-free conditions, thereby leaving the acid and
base sensitive groups intact. The added features of this
method over earlier reported processes include its simplicity,
clean reactions, high yields, shorter reaction times, absence
© 2008 NRC Canada

Kamal et al.
1103
ther commercially available or purchased from Lancaster
and Sigma-Aldrich.
69.2, 66.9, 61.3, 54.7, 30.0, 25.9, 25.8, 24.8, 18.9. HRMS
(ESI) m/z: calcd. 317.1728 (M + Na)+: found 317.1720.
Triphenyl silytetrahydropyranyl ether (Table 1, entry 17)
General procedure for the synthesis of
tetrahydropyranyl ethers
IR (KBr, cm–1) ν: 2935, 2840, 1605, 1512, 1336, 1255,
1
1115, 1080, 1008, 805. H NMR (200 MHz, CDCl3) δ:
To
a mixture of alcohol (2 mmol) and 3,4-2H-
7.66–7.58 (m, 6H), 7.40–7.32 (m, 9H), 4.51 (t, J = 3.1 Hz,
1H), 3.90–3.60 (m, 4H), 3.48–3.28 (m, 4H), 1.70–1.38 (m,
6H), 1.12–0.95 (m, 4H). 13C NMR (100 MHz, CDCl3) δ:
135.5, 134.0, 129.4, 127.5, 98.5, 67.6, 64.1, 62.2, 32.4, 30.7,
29.4, 26.8, 22.8, 19.1. HRMS (ESI) m/z (M + Na)+: calcd.
455.2056; found 455.2038.
dihydropyran (3 mmol), Al(OTf)3 (1 mol%) was added. The
reaction mixture was stirred at the given temperature for the
appropriate amount of time (Table 1). After completion of
the reaction as monitored by TLC, water was added to the
reaction mixture and the product was extracted in ethyl ace-
tate (3 × 25 mL). The organic layer was washed with a satu-
rated solution of NaHCO3, dried over anhyd Na2SO4, and
concentrated in vacuo. Purification by column chromatogra-
phy using hexane/ethyl acetate (9:1) furnished the corre-
sponding DHP ethers.
Acknowledgments
The authors MNAK and YVVS are thankful to Council of
Scientific and Industrial Research and University Grants
Commission, New Delhi, respectively, for the awarding of
research fellowships.
Large-scale tetrahydropyranylation
A mixture of benzyl alcohol (10.80 g, 0.1 mol) and 3,4-
2H-dihydropyran (13.70 mL, 0.15 mol) (Table 1, entry 1b)
was stirred at RT (30
1 °C), while Al(OTf)3 (4.75 mg,
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