Lithium hexafluorophosphate-catalyzed efficient tetrahydropyranylation of tertiary alcohols under mild reaction conditions

Article abstract of DOI:10.1055/s-2004-829550

Lithium hexafluorophosphate is found to be an efficient catalyst for the tetrahydropyranylation of tertiary alcohols with dihydropyran under mild reaction conditions.

Full text of DOI:10.1055/s-2004-829550

1802
LETTER
Lithium Hexafluorophosphate-Catalyzed Efficient Tetrahydropyranylation of
Tertiary Alcohols under Mild Reaction Conditions
Efficient
T
etrahyd
a
ropyranylat
o
ion of Tertiary Alc
H
ohols amada, Tsuneo Sato*
Department of Chemistry and Bioscience, Kurashiki University of Science and the Arts, Kurashiki 712-8505, Japan
Fax +81(86)4401062; E-mail: sato@chem.kusa.ac.jp
Received 26 March 2004
R
R
Abstract: Lithium hexafluorophosphate is found to be an efficient
catalyst for the tetrahydropyranylation of tertiary alcohols with di-
hydropyran under mild reaction conditions.
LiPF6 (3 mol%)
10–15 °C
R
R
R
R
+
OH
OTHP
O
Key words: alcohols, Lewis acids, lithium hexafluorophosphate,
Scheme 1
protecting groups, tetrahydropyranylation
Table 1 Tetrahydropyranylation of 2-Methyl-1-phenyl-2-propanol
Catalyzed by Various Lewis Acidsa
The tetrahydropyranylation is one of the most frequently
used methods for the protection of hydroxyl groups, be-
cause of its easy installation, general stability towards
most non-acidic reagents, and easy removal under mild
acidic conditions.1 By comparison with the ease of tet-
rahydropyranylation of primary and secondary alcohols,
tertiary alcohol tetrahydropyranylation still remains a
challenging problem. There are several reagents available
for the tetrahydropyranylation of alcohols using dihydro-
pyran, which include the use of protic acids [p-toluene-
sulfonic acid2 and pyridinium p-toluenesulfonate
(PPTS)3], Lewis acids [Sc(OTf)3,4 In(OTf)3,5 I2,6 and
OTHP
OH
Lewis acid
+
Ph
Ph
O
Entry
1
Lewis acid
Bi(OTf)3
I2
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
EtOAc
CH2Cl2
CH2Cl2
MeCN
CH2Cl2
Et2O
Time (h) Yield (%)b
2
11
4
2
2
3
In(OTf)3
Sc(OTf)3
PPTS
2
10
56
69
53
10
0
4
2
5
2
7
Bi(OTf)3 ], and many others.8 Recently, a variety of lithi-
um salts such as LiBF4,9 LiOTf,10 LiClO4,11 and LiBr12 as
almost neutral catalysts have also been employed to this
purpose. Nevertheless, there are sufficient drawbacks to
most of these procedures to justify the need for an effi-
cient and general method of generating tetrahydropyranyl
(THP) ethers of tertiary alcohols under mild reaction con-
ditions. As part of our research program to develop new
synthetic methodologies using lithium salts,13 we investi-
gated the utility of lithium hexafluorophosphate (LiPF6)
as a catalyst for the conversion of tertiary alcohols to the
corresponding THP ethers.14 In this paper, we wish to re-
port an efficient and versatile procedure for the synthesis
of tertiary alkyl THP ethers from the parent alcohols in the
presence of a catalytic amount of LiPF6 under mild condi-
tions (Scheme 1).
6
TsOH·H2O
LiBF4
2
7
2
8
LiOTf
LiClO4
LiPF6
2
9
2
0
10
11
12
13
14
Hexane
Toluene
CH2Cl2
Et2O
1.5
1
98 (90)
45
12
12
4
LiPF6
LiPF6
1
LiPF6
1
LiPF6
MeCN
1
a Reaction conditions: alcohol (1 mmol), 3,4-dihydro-2H-pyran (2
mmol), Lewis acid (0.03 mmol), solvent (1 mL), 10–15 °C.
b Based on GC. Isolated yields are given in parentheses.
First, the reaction of 2-methyl-1-phenyl-2-propanol with
3,4-dihydro-2H-pyran (DHP, 2 equiv) was carried out in
the presence of various Lewis acids (3 mol%) at 10–15 °C
(Table 1). After screening various reaction conditions, we
found that LiPF6 in hexane is a very mild and effective re-
action system for the conversion of the tertiary alcohol
into the corresponding THP ether without any other side
products (entry 10).15
The effects of other solvents such as toluene, CH2Cl2, di-
ethyl ether, and MeCN were also studied, but in compari-
son with hexane the yields were found to be considerably
lower (entries 11–14).16
Table 2 summarizes some representative examples of
syntheses of various tertiary alcohol THP ethers and illus-
trates the efficiency and scope of the present method. The
THP ethers of acyclic, alicyclic, and benzylic alcohols
could be obtained in good yields, and no dehydration
SYNLETT 2004, No. 10, pp 1802–1804
0
9
.0
8
.2
0
0
4
Advanced online publication: 15.07.2004
DOI: 10.1055/s-2004-829550; Art ID: U08604ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Efficient Tetrahydropyranylation of Tertiary Alcohols
1803
products were observed under the reaction conditions (en- and testosterone17 and acid-sensitive primary substrates
tries 1, 2, and 4).
like geraniol and furfuryl alcohol were transformed
smoothly to the corresponding THP ethers using the same
catalyst (entries 11–14).
It is worth mentioning that tertiary alcohols both in allylic
and propargylic positions underwent smooth tetrahydro-
pyranylation without any trace of by-products arising A typical procedure is as follows (Table 2, entry 6): 3,4-
from rearrangement (entries 3, 5, and 6). Exposure of ho- dihydro-2H-pyran (168 mg, 2 mmol) was added dropwise
moallylic and homobenzylic alcohols to LiPF6–DHP fur- to a stirred mixture of 1-ethynyl-1-cyclohexanol (124 mg,
18
nished the corresponding THP ethers in 75% and 90% 1 mmol) and LiPF6 (4.6 mg, 0.03 mmol) in anhydrous
yields, respectively (entries 7 and 8). However, the at- hexane (1 mL) at 11 °C. The reaction was complete in 15
tempt to form the THP ethers from tertiary aldols such as minutes at the same temperature. The reaction mixture
diacetone alcohol and mevalonic lactone was moderately was poured into saturated NaHCO3 and extracted with di-
successful even at 0 °C (entries 9 and 10). In addition, ethyl ether. The organic layer was dried (Na2SO4) and
sterically hindered secondary alcohols such as menthol evaporated. Column chromatography of the residue on sil-
ica gel (2% EtOAc–hexane containing 0.1% Et3N) afford-
ed 1-ethynyl-1-cyclohexanol THP ether (200 mg, 96%) as
a colorless liquid.
Table 2 LiPF6-Catalyzed Tetrahydropyranylation of Tertiary Alco-
holsa
Entry
1
In conclusion, we have developed an efficient and versa-
tile process for the tetrahydropyranylation of tertiary alco-
hols catalyzed by lithium hexafluorophosphate under
mild reaction conditions.19 Works on other reactions cata-
lyzed by LiPF6 and related compounds are currently un-
derway in our laboratory.
Alcohol
Time (min) Yield (%)b
OH
150
71
n-C9H19
2
3
20
15
81
OH
75 (60:40)
References
OH
(1) (a) Reese, C. B. In Protective Groups in Organic Chemistry;
McOmie, J. F. W., Ed.; Plenum: London, 1973, Chap. 3.
(b) Kocienski, P. J. In Protecting Groups; Thieme: New
York, 1994, Chap. 2. (c) Greene, T. W.; Wuts, P. G. M. In
Protective Groups in Organic Synthesis, 3rd ed.; Wiley:
New York, 1999, Chap. 2.
(2) Robertson, D. N. J. Org. Chem. 1960, 25, 931.
(3) Miyashita, M.; Yoshikoshi, A.; Grieco, P. A. J. Org. Chem.
1977, 42, 3772.
n-C9H19
4
5
6
150
15
77
OH
Ph
100 (65:35)
96
OH
15
OH
(4) Watahiki, T.; Kikumoto, H.; Matsuzaki, M.; Suzuki, T.;
Oriyama, T. Bull. Chem. Soc. Jpn. 2002, 75, 367.
(5) Mineno, T. Tetrahedron Lett. 2002, 43, 7975.
(6) Kumar, H. M. S.; Reddy, B. V. S.; Reddy, E. J.; Yadav, J. S.
Chem. Lett. 1999, 857.
(7) Stephens, J. R.; Butler, P. L.; Clow, C. H.; Oswald, M. C.;
Smith, R. C.; Mohan, R. S. Eur. J. Org. Chem. 2003, 3827.
(8) For recent leading references, see: (a) Yadav, J. S.; Reddy,
B. V. S.; Gnaneshwar, D. New J. Chem. 2003, 27, 202.
(b) Khan, A. T.; Mondal, E.; Borah, B. M.; Ghosh, S. Eur. J.
Org. Chem. 2003, 4113. (c) Wang, R.; Yang, L.-M.; Suo,
J.-S. Synth. Commun. 2003, 33, 3929; and references cited
therein.
7
60
75 (55:45)
OH
Ph(CH2)2
OH
8
9c
90
180
270
90
Ph
50d
O
OH
10c
49d (54:46)
OH
O
O
(9) (a) Babu, B. S.; Balasubramanian, K. K. Synlett 1999, 1261.
(b) Kazemi, F.; Kiasat, A. R.; Ebrahimi, S. Synth. Commun.
2002, 32, 2483.
(10) Karimi, B.; Maleki, J. Tetrahedron Lett. 2002, 43, 5353.
(11) Babu, B. S.; Balasubramanian, K. K. Tetrahedron Lett.
1998, 39, 9287.
11
12e
13
14
Menthol
15
300
20
98 (58:42)
96 (50:50)
85
Testosterone
Geraniol
Furfuryl alcohol
60
87
(12) Reddy, M. A.; Reddy, L. R.; Bhanumathi, N.; Rao, K. R.
Synth. Commun. 2000, 30, 4323.
a Reaction conditions: alcohol (1 mmol), 3,4-dihydro-2H-pyran (2
mmol), LiPF6 (0.03 mmol), hexane (1 mL), 10–15 °C, unless other-
wise mentioned.
(13) (a) Sumida, N.; Nishioka, K.; Sato, T. Synlett 2001, 1921.
(b) Nakae, Y.; Kusaki, I.; Sato, T. Synlett 2001, 1584.
(c) Ono, F.; Negoro, R.; Sato, T. Synlett 2001, 1581.
(14) A literature search shows that applications of LiPF6 in
organic synthesis are rather rare. To the best of our
knowledge it has been used only (a) for the oxidation of
alcohols by a combination of cobalt-nitro complexes, see:
b Isolated yield. Diastereomeric ratios are given in parentheses.
c At 0 °C.
d Small amounts of olefin (ca. 3–7%, checked by GC) was detected.
e LiPF6 (0.06 mmol) and hexane (6 mL) were used.
Synlett 2004, No. 10, 1802–1804 © Thieme Stuttgart · New York

1804
N. Hamada, T. Sato
LETTER
Tovrog, B. S.; Diamond, S. E.; Mares, F.; Szalkiewicz, A. J.
Am. Chem. Soc. 1981, 103, 3522. (b) For the Diels–Alder
reaction between 9,10-dimethylanthracene and acrylonitrile,
see: Forman, M. A.; Dailey, W. P. J. Am. Chem. Soc. 1991,
113, 2761.
(18) Purchased from Kishida Chemical Co., Ltd.
(19) For recent reports on other catalysts used to prepare tertiary
alkyl THP ethers, see: (a) Ref. 7 (b) Ref. 8a (c) Ref. 8c
(d) Bandgar, B. P.; Sadavarte, V. S.; Uppalla, L. S.; Patil, S.
V. Monatsh. Chem. 2003, 134, 425. (e) Ref. 4 (f) Ref. 9b
and references cited therein. (g) Ref. 10 (h) Palaniappan, S.;
Ram, M. S.; Amarnath, C. A. Green Chem. 2002, 4, 369.
(i) Gajare, A. S.; Sabde, D. P.; Shingare, M. S.; Wakharkar,
R. D. Synth. Commun. 2002, 32, 1549. (j) Namboodiri, V.
V.; Varma, R. S. Tetrahedron Lett. 2002, 43, 1143.
(15) The use of KPF6 instead of LiPF6 did not affect the
protection at all.
(16) The Lewis acidity of lithium ion decreases when lithium ion
is stabilized by coordinative solvation.
(17) Although testosterone is slightly soluble in hexane,
quantitative tetrahydropyranylation was possible by using
longer reaction times.
Synlett 2004, No. 10, 1802–1804 © Thieme Stuttgart · New York