A novel and efficient method for the synthesis of tetrahydropyranyl ethers catalyzed by Sc(OTf)3

Article abstract of DOI:10.1246/bcsj.75.367

Reaction of alcohols with dihydropyran in the presence of a catalytic amount of Sc(OTf)₃ provides efficiently the corresponding tetrahydropyranyl ethers. After the reaction, the catalyst can be recovered quantitatively from the aqueous media and reused without loss of the activity.

Full text of DOI:10.1246/bcsj.75.367

c. Jpn.
Bull. Chem. Soc. Jpn., 75, 367–368 (2002)
367
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Short Articles
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(DHP) in the presence of 5 mol% of Sc(OTf)3 in dichlo-
romethane. After 45 min, the usual work up of the reaction
mixture gave the corresponding THP ether in 62% yield (Table
1, Run 1). In the case of using CH3CN, the corresponding
THP ether was obtained in lower yield (Table 1, Run 2). On
the other hand, when ether solvents such as THF and DME
were used, transformation took place very smoothly to give the
THP ethers in high yields (Table 1, Runs 3–5). Furthermore,
when the reaction was carried out with 1.8 equivalents of dihy-
dropyran in the presence of 0.2 mol% of Sc(OTf)3 in AcOEt
for 1 h, the reaction proceeded very cleanly and the corre-
sponding THP ether was obtained in 98% isolated yield with-
out any other side products (Table 1, Run 7).
A Novel and Efficient Method for the
Synthesis of Tetrahydropyranyl
Ethers Catalyzed by Sc(OTf)3
T. Watahiki et al.
02
7
8
SJA8
09-2673
1036
Tsutomu Watahiki, Hisashi Kikumoto, Masaya
Matsuzaki, Takeshi Suzuki, and Takeshi Oriyama*
Faculty of Science, Ibaraki University,
Bunkyo, Mito 310-8512
(Received August 28, 2001)
Representative and successful examples of syntheses of var-
ious alcohol THP ether are collected in Table 2.5 Like primary
01
Reaction of alcohols with dihydropyran in the presence
of a catalytic amount of Sc(OTf)3 provides efficiently the cor-
responding tetrahydropyranyl ethers. After the reaction, the
catalyst can be recovered quantitatively from the aqueous me-
dia and reused without loss of the activity.
Table 2. Synthesis of Various THP Ethers from Alcohols
01
.2
Run
1
ROH
Time/h
Yielda)/%
Tetrahydropyranyl (THP) ethers have been the most useful
and representative protecting group of alcohols in synthetic or-
ganic chemistry.1 THP ethers are very easy to introduce and to
remove, as well as having general stability for most non-acidic
reagents, so that several methods for the introduction of THP
ether under various reaction conditions have been reported so
far in the literature.2 On the other hand, scandium(Ⅲ) trifluo-
romethanesulfonate (Sc(OTf)3) is a new type of water-soluble
Lewis acid, and many useful reactions using Sc(OTf)3 have
been developed.3 Our previous report has also documented
that Sc(OTf)3 is a very effective catalyst for the silylation of al-
cohols with methallylsilane.4
In this paper, we wish to report a useful and convenient pro-
cedure for the synthesis of THP ethers from the parent alcohols
in the presence of a catalytic amount of Sc(OTf)3.
In the first place, we examined the reaction of 3-phenyl-1-
propanol as a model substrate with 3,4-dihydro-2H-pyran
1
1
1
1
1
95
97
98
98
97
2
3
4b)
5
6
7
3
7
97
97
92
86
89
97
62
94
92
95
98
8
7
9c)
10c)
11
12
13
14
15
16
24
7
Table 1. The Effect of Various Reaction Conditions
1
15
5
Run
1
2
x/equiv
1.2
1.2
1.2
1.2
1.5
1.5
1.8
y/mol%
5
5
5
Solvent
CH2Cl2
CH3CN
THF
DME
DME
Yielda)/%
62
42
91
93
95
96
98
4
3
4
2
5
5b)
6b)
7b)
0.2
0.2
0.2
1
AcOEt
AcOEt
a) Isolated yields of purified product.
b) Reaction was carried out for 1 h.
a) Isolated yields of purified product. b) 3 equiv of Dihy-
dropyran were used. c) 0.05 mol% of Sc(OTf)3 was used.

368 Bull. Chem. Soc. Jpn., 75, No. 2 (2002)
© 2002 The Chemical Society of Japan
(1994).
2
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Husain, and B. P. Singh, Synthesis, 1983, 892. e) G. A. Olah, A.
Husain, and B. P. Singh, Synthesis, 1985, 703. f) S. Hoyer and P.
Laszlo, Synthesis, 1986, 655. g) R. D. Johnston, C. R. Marston, P.
E. Krieger, and G. L. Goe, Synthesis, 1988, 393. h) V. Bolitt, C.
Mioskowski, D.-S. Shin, and J. R. Falck, Tetrahedron Lett., 29,
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Chem. Commun., 1990, 1766. j) K. Tanemura, T. Horaguchi, and
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Scheme 1. Recovery and Reuse of Sc(OTf)3.
Scheme 2. Synthesis of THF Ether.
alcohols, secondary alcohols, tertiary alcohol, and phenol were
readily transformed into the corresponding THP ether in good
to excellent yields. In the case of tertiary alcohol and phenol,
the yields of THP ethers are slightly lower (Table 2, Runs 9
and 10). Additionally, alcohols having other functional groups
underwent chemoselective reaction to give the THP ethers in
excellent yields with no undesired reactions (Table 2, Runs
11–16). Especially, acid-sensitive functional groups such as an
allylic alcohol, methoxymethyl ether, and t-butyldimethylsilyl
ether were significantly unaffected under these reaction condi-
tions (Table 2, Runs 3, 5, 14, and 15).
Next, we investigated the recovery and reuse of Sc(OTf)3.
After treatment of 3-phenyl-1-propanol with DHP under the
optimal reaction conditions, the reaction mixture was
quenched with water. Extraction with Et2O afforded the de-
sired THP ether in organic solvents. After the water was evap-
orated under reduced pressure, heating in vacuo at 200 °C for 2
h dried the resulting white powder. The catalyst was recovered
quantitatively and reused at least six times without loss of the
activity (Scheme 1).
Finally, we attempted the synthesis of tetrahydrofuranyl
(THF) ether by the reaction of alcohol with 2,3-dihydrofuran
instead of dihydropyran. The THF ether has also been used as
an acetal-type protecting group for alcohols.6 The correspond-
ing THF ether was similarly obtained in 96% yield, as shown
in Scheme 2.
In conclusion, we have developed a new method for the syn-
thesis of tetrahydropyranyl ethers from alcohols catalyzed by
Sc(OTf)3. This method proceeded smoothly at room tempera-
ture under very mild reaction conditions. Additionally, the cat-
alyst could be recovered quantitatively and reused without loss
of the activity. These features show that this new method is
very efficient and will be applicable to the synthesis of com-
plex natural products.
3
a) S. Kobayashi, H. Ishitani, I. Hachiya, and M. Araki, Tet-
rahedron Lett., 34, 3755 (1993). b) S. Kobayashi, I. Hachiya, H.
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4
T. Suzuki, T. Watahiki, and T. Oriyama, Tetrahedron Lett.,
41, 8903 (2000).
5
A typical experimental procedure is as follows (Table 1,
Run 7): To a mixutre of scandium(Ⅲ) trifluoromethanesulfonate
(1.0 mg, 0.0020 mmol) and 3-phenyl-1-propanol (136.2 mg, 1.0
mmol) in AcOEt (4 mL) was added 3,4-dihydro-2H-pyran (164
µL, 1.8 mmol) at room temperature under an argon atomsphere.
The resultant mixture was stirred for 1 h at room temparature and
quenched saturated sodium hydrogencarbonate. The organic ma-
terials were extracted with Et2O and dried over anhydrous magne-
sium sulfate. The solvent was evaporated and 1-tetrahydropyrany-
loxy-3-phenylpropane (215.9 mg, 98%) was isolated by thin-layer
chromatography on silica gel (ether:hexane = 1:3). The product
gave satisfactory 1H NMR and IR spectra.
6
a) C. G. Kruse, N. L. J. M. Broekhof, and A. van der Gen,
Tetrahedron Lett., 1976, 1725. b) A. M. Maione and A. Romeo,
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References
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T. W. Greene and P. G. M. Wuts, “Protective Group in Or-
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