A highly efficient and convenient method for the direct conversion of alkyl THP ethers into the corresponding alkyl benzyl ethers

Article abstract of DOI:10.1055/s-1999-3564

Direct conversion of alcohol tetrahydropyranyl (THP) ethers into the corresponding benzyl ethers can be conveniently performed by reaction with triethylsilane and benzaldehyde in the presence of a catalytic amount of trimethylsilyl trifluoromethanesulfona

Full text of DOI:10.1055/s-1999-3564

SHORT PAPER
1561
A Highly Efficient and Convenient Method for the Direct Conversion of Alkyl
THP Ethers into the Corresponding Alkyl Benzyl Ethers
Takeshi Suzuki, Kousaburo Ohashi, Takeshi Oriyama*
Faculty of Science, Ibaraki University, Bunkyo, Mito 310-8512, Japan
Fax: +81-29-228-8406; E-mail: tor@mito.ipc.ibaraki.ac.jp
Received 15 March 1999; revised 30 April 1999
Et3SiH
PhCHO
Abstract: Direct conversion of alcohol tetrahydropyranyl (THP)
ethers into the corresponding benzyl ethers can be conveniently per-
formed by reaction with triethylsilane and benzaldehyde in the pres-
ROTHP
ROSiEt3
RO CHPh
Lewis acid
ence of
a
catalytic amount of trimethylsilyl trifluoro-
Et3SiH
methanesulfonate (TMSOTf) in a one-pot procedure.
ROCH2Ph
Key words: THP ethers, benzyl ethers, triethylsilane, benzalde-
hyde, one-step conversion of protecting group
Scheme 2
Alkyl ethers such as benzyl and substituted benzyl ethers
are important functional groups in synthetic organic
chemistry and have been widely used as protecting groups
of the hydroxyl function as well as other-type protecting
First, we examined the reaction of the THP ether of 3-phe-
nylpropanol (1a) with triethylsilane (2.2 equiv) and ben-
zaldehyde (1.1 equiv) under the influence of 0.1
equivalent of Sn(OTf) in acetonitrile (Scheme 3).After 1
1
2
groups such as silyl ether, acetal and ester types. Dialkyl
h at 0°C, the usual workup of the reaction mixture gave
the desired benzyl ether of 3-phenylpropanol (2a) in 96%
yield (Table 1, Run 1). In a screening of other Lewis acid
catalysts, we found that using 0.1 equivalent of trimethyl-
silyl triflate (TMSOTf) afforded the best result (Table 1,
Run 4). However, when the amount of TMSOTf was re-
duced to 0.03 equivalent, the yield of benzyl ether was
slightly decreased (Table 1, Run 5). We have, therefore,
ethers are generally formed by the treatment of parent al-
cohols with the corresponding alkyl halides under the in-
2
fluence of a base such as sodium hydride, sodium
3
hydroxide, and so on. Direct transformation between the
four typical types of protecting groups of the hydroxyl
function is of great importance from the standpoint of ef-
ficiency (time, reagent) and convenience.
4
In our series of studies on the direct transformation of a tentatively chosen a combination of the THP ether, trieth-
protecting group of the hydroxyl function into another, we ylsilane, benzaldehyde, and TMSOTf (molar ratio;
have previously demonstrated that direct conversion of 1:2.2:1.1:0.1) as the optimum reaction condition.
aryl trialkylsilyl ethers and aryl acetates into the corre-
sponding aryl benzyl ethers can be conveniently per-
formed by reaction with benzyl bromide under the
Et3SiH
Ph(CH2)3OTHP
+
PhCHO
Ph(CH2)3OBn
Lewis acid
CH3CN
influence of cesium fluoride and sodium methoxide, re-
5
1a
2a
spectively. However, direct conversion of alcohol tet-
0
°C / 1 h
rahydropyranyl (THP) ethers into the corresponding
benzyl ethers has not been reported. On the other hand, we
had found that alcohol THP ethers can be readily convert-
ed into silyl ether-protected alcohols in good yields by re-
action with trialkylsilane in the presence of tin(II)
Scheme 3
4
e
Table 1 The Effect of Lewis Acid in the Conversion of THP Ether
a to Benzyl Ether 2aa
trifluoromethanesulfonate (Sn(OTf) ) (Scheme 1). This
2
1
result suggested that the reaction of alcohol THP ethers
with benzaldehyde and triethylsilane under the influence
of a Lewis acid catalyst would afford directly the corre-
sponding benzyl ethers via reduction of the oxonium ions6
Yield of 2a (%)b
Run
Lewis Acid (equiv)
1
2
3
4
5
Sn(OTf) (0.1)
96
20
88
98
90
2
BF ⋅OEt (0.1)
3
2
(
Scheme 2). In this communication, we wish to report a
TMSI (0.1)
TMSOTf (0.1)
TMSOTf (0.03)
highly efficient and convenient method for the direct con-
version of alkyl THP ethers into the corresponding alkyl
benzyl ethers in a one-pot procedure.
a
Molar ratio of THP ether/Et SiH/PhCHO = 1:2.2:1.1.
Isolated yield of purified product.
3
b
R´
3
SiH
ROTHP
ROSiR´
3
Sn(OTf)
2
Scheme 1
Synthesis 1999, No. 9, 1561–1563 ISSN 0039-7881 © Thieme Stuttgart · New York

1
562
T. Suzuki et al.
SHORT PAPER
Representative examples of direct conversion of alcohol Table 3 Synthesis of Various Substituted Benzyl Ethers from THP
THP ethers into the corresponding benzyl ethers are given Ethersa
in Table 2. As can be seen, the reaction was successful
Run
RCHO
Product
Yield of 2b
%)
with the THP ethers of secondary alcohols (1b and 1c) as
well as primary alcohols (Runs 2 and 3). In the presence
of other-type protecting groups, such as benzyl ether (1d)
and benzoate (1e), THP ethers are selectively transformed
into the corresponding benzyl ethers in excellent yields
(
1
2
3
4
4-CIC
H
CHO
2g
2h
2i
95
90
90
98
6
4
4-NO C H CHO
2
6
4
c
4-MeOC H CHO
4-MeC H CHO
6
4
2j
6
4
(
Runs 4 and 5). It is worth pointing out that an aromatic
a
ketone (1f), which is reducible by triethylsilane under
Unless otherwise mentioned, reaction was carried out at 0°C for 1 h
7
in MeCN. Molar ratio of THP ether/Et SiH/RCHO/TMSOTf =
acidic conditions, is tolerated under these reaction condi-
3
1
:2.2:1.1:0.1.
tions (Run 6). However, the reaction of aryl THP ethers
resulted in deprotection of THP group to yield the corre-
sponding phenols.
b
Isolated yield of purified product.
Reaction was carried out at –40°C for 15 min. TMSOTf
c
(
0.05 equiv).
Et3SiH
In summary, the present direct conversion of THP ethers
into the benzyl ethers has the following synthetic advan-
tages:1) high efficiency 2) mild reaction conditions 3)
one-pot procedure 4) chemoselectivity toward THP
ethers. In our series of studies on the one-step conversion
between typical protecting groups of the hydroxyl func-
tion, we have added a new, direct conversion of THP
ethers into benzyl ethers.
ROTHP
+
PhCHO
ROBn
TMSOTf
1
2
Scheme 4
Table 2 Synthesis of Various Benzyl Ethers from THP Ethersa
Prod- Yield of 2b
Run ROTHP
uct
1a 2a
1b 2b
1c 2c
(%)
All reactions were carried out under argon atmosphere. H and 13C
1
1
2
3
Ph(CH ) CH OTHP
2 2 2
98
NMR spectra were recorded at 400 and 100 MHz on a JEOL GSX-
4
00, respectively. The chemical shifts are reported in ppm (d) rela-
Ph(CH ) CH(Me)OTHP
95
-1
2
2
tive to TMS in CDCl . IR spectra were recorded in cm on a JAS-
3
CO FT/IR-300E. MeCN was distilled from CaH . TLC was
performed on Wakogel B-5F silica gel with Et O and hexane as elu-
2
97
2
ents.
4
5
BnO(CH ) CH OTHP
1d 2d
1e 2e
95
98
90
2
3
2
1
-Benzyloxy-3-phenylpropane (2a); Typical Procedure
To a solution of 1a (66.1 mg, 0.30 mmol) and Et SiH (76.7 mg, 0.66
mmol) in MeCN (1 mL) was added a solution TMSOTf (6.7 mg,
0
3
PhCO (CH ) CH OTHP
2
2 3
2
.03 mmol) in MeCN (0.5 mL) and a solution of benzaldehyde
6
4-MeCOC H (CH ) CH OTHP
1f
2f
6
4
2 2
2
(
35.0 mg, 0.33 mmol) in MeCN (1.0 mL) sequentially at 0°C under
a
Reaction was carried out at 0°C for 1 h in MeCN. Molar ratio of THP
an argon atmosphere. The mixture was stirred for 1 h at this temper-
ature and quenched with satd aq NaHCO solution. The organic ma-
terials were extracted with CH Cl and dried (Na SO ). The solvent
ether/ Et SiH/PhCHO/TMSOTf = 1:2.2:1.1:0.1.
3
3
b
Isolated yield of purified product.
2
2
2
4
was evaporated and the product 2a (66.5 mg, 98%) was isolated by
TLC on silica gel (Et O/hexane, 1:10).
1H NMR: 1.94 (m, 2 H), 2.71 (t, 2 H, J = 8.0 Hz), 3.49 (t, 2 H,
J = 6.4 Hz), 4.50 (s, 2 H), 7.17 (m, 3 H), 7.28 (m, 3 H), 7.35 (m, 4
H).
2
Next, we examined the direct conversion of THP ethers
into various substituted benzyl ethers. As shown in Table
3
, various p-substituted benzyl ethers are obtained in good
yields with the use of the corresponding p-substituted ben-
zaldehyde instead of benzaldehyde. p-Methoxybenzyl
13C NMR: 31.34, 32.33, 69.44, 72.86, 125.70, 127.49, 127.61,
1
28.26, 128.32, 128.44, 138.55, 141.94.
(
PMB) ether (2i), which is frequently used as a protecting
-
1
IR (neat): 730, 1100, 1460, 2860 cm .
group as well as unsubstituted benzyl ether, is obtained
from the reaction with p-methoxybenzaldehyde (Run 3).
This method is a new access to the synthesis of various
substituted benzyl ethers from protected alcohols, not
from parent alcohols.
2
-Benzyloxy-4-phenylbutane (2b)
1
H NMR: 1.23 (d, 3 H, J = 6.4 Hz), 1.76 (m, 1 H), 1.92 (m, 1 H),
2
.62–2.80 (m, 2 H), 3.54 (m, 1 H), 4.45 (d, 1 H, J = 12.0 Hz), 4.58
(
d, 1 H, J = 12.0 Hz), 7.17 (m, 3 H), 7.27 (m, 3 H), 7.35 (m, 4 H).
13C NMR: 19.62, 31.83, 38.45, 70.34, 74.14, 125.67, 127.42,
27.68, 128.31, 128.34, 128.42, 139.03, 142.40.
1
-
1
Et3SiH
IR (neat):735, 1065, 1454, 2927 cm .
Ph(CH2)3OTHP
+
RCHO
Ph(CH2)3OCH2R
TMSOTf
trans-1-Benzyloxy-4-phenylcyclohexane (2c)
H NMR: 1.41–1.54 (m, 4 H), 1.95 (m, 2 H), 2.23 (m, 2 H), 2.51 (m,
1
1a
2
1
H), 3.41 (m, 1 H), 4.60 (s, 2 H), 7.19 (m, 3 H), 7.26 (m, 3 H), 7.33
Scheme 5
(
m, 4 H).
Synthesis 1999, No. 9, 1561–1563 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
A Highly Efficient and Convenient Method for the Direct Conversion of Alkyl THP Ethers
1563
13C NMR: 2.49, 32.67, 43.72, 69.92, 77.32, 126.00, 126.74, 127.39,
IR (neat): 700, 1035, 1099, 1247, 1512, 2935 cm-1.
1
27.53, 128.34, 139.09, 146.67.
IR (neat): 737, 1100, 1450, 2926 cm .
,4-Dibenzyloxybutane (2d)
1
-(4-Methylbenzyloxy)-3-phenylpropane (2j)
-
1
1
H NMR: 1.92 (m, 2 H), 2.35 (s, 3 H), 2.71 (t, 2 H, J = 8.0 Hz), 3.47
t, 2 H, J = 6.4 Hz), 4.46 (s, 2 H), 7.16 (m, 5 H), 7.26 (m, 4 H).
(
1
1
13C NMR: 21.15, 31.37, 32.36, 69.30, 72.76, 125.70, 127.79,
128.28, 128.47, 129.02, 135.49, 137.19, 142.02.
H NMR: 1.71 (m, 4 H), 3.49 (m, 4 H), 4.50 (s, 4 H), 7.25 (m, 4 H),
7
.33 (m, 6 H).
13C NMR: 26.50, 70.12, 72.84, 127.47, 127.60, 128.34, 138.60.
IR (neat): 746, 802, 1101, 1454, 2856 cm-1.
-
1
IR (neat): 734, 1099, 1454, 2855 cm .
1
-Benzoyloxy-4-benzyloxybutane (2e)
Acknowledgement
1
H NMR: 1.79 (m, 2 H), 1.88 (m, 2 H), 3.54 (t, 2 H, J = 6.4 Hz), 4.85
t, 2 H, J = 6.4 Hz), 4.52 (s, 2 H), 7.28 (m, 2 H), 7.34 (m, 3 H), 7.43
m, 2 H), 7.55 (m, 1 H), 8.03 (m, 2 H).
This work was partially supported by the Uehara Memorial Found-
ation.
(
(
13C NMR: 25.63, 26.40, 64.79, 69.76, 72.94, 127.56, 127.61,
28.31, 128.37, 129.53, 130.39, 132.83, 138.44, 166.63.
1
References
-
1
IR (neat): 712, 1110, 1274, 1718 cm .
(
1) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 2nd Ed., John Wiley & Sons: New York,
1991.
1
-(4-Acetylphenyl)-4-benzyloxypropane (2f)
1
H NMR: 1.94 (m, 2 H), 2.58 (s, 3 H), 2.78 (t, 2 H, J = 8.0 Hz), 3.48
t, 2 H, J = 6.0 Hz), 4.51 (s, 2 H), 7.26 (d, 2 H, J = 8.0 Hz), 7.31 (m,
(
(b) Kocienski, P. J. Protective Groups, Georg Thieme Verlag:
New York, 1994.
2
H), 7.34 (m, 3 H), 7.87 (d, 2 H, J = 8.0 Hz).
(
(
2) Czernecki, S.; Georgoulis, C.; Provelenghiou, C. Tetrahedron
Lett. 1976, 3535.
3) Freedman, H. H.; Dubois, R. A. Tetrahedron Lett. 1975, 3251.
13C NMR: 26.54, 31.00, 32.41, 69.16, 72.97, 127.60, 127.68,
1
28.39, 128.51, 128.69, 135.04, 138.41, 147.88, 197.88.
-
1
IR (neat): 737, 1102, 1267, 1358, 1606, 1681, 2857 cm .
(4) (a) Oriyama, T.; Kimura, M.; Oda, M.; Koga, G. Synlett 1993,
37.
(b) Oriyama, T.; Kimura, M.; Koga, G. Bull. Chem. Soc. Jpn.
994, 67, 885.
c) Oriyama, T.; Oda, M.; Gono, J.; Koga, G. Tetrahedron
Lett. 1994, 35, 2027.
d) Oriyama, T.; Yatabe, K.; Kawada, Y.; Koga, G. Synlett
1995, 45.
e) Oriyama, T.; Yatabe, K.; Sugawara, S.; Machiguchi, Y.;
Koga, G. Synlett 1996, 523.
f) Oriyama, T.; Noda, K.; Sugawara, S. Synth. Commun.
999, 29, 2217.
4
1
-(4-Chlorobenzyloxy)-3-phenylpropane (2g)
1
H NMR: 1.93 (m, 2 H), 2.71 (t, 2 H, J = 7.6 Hz), 3.47 (t, 2 H,
J = 6.4 Hz), 4.61 (s, 2 H), 7.18 (m, 3 H), 7.28 (m, 6 H).
1
(
13C NMR: 31.27, 32.33, 69.58, 72.10, 125.80, 128.32, 128.45,
1
28.50, 128.94, 133.24, 137.05, 141.84.
(
-
1
IR (neat): 700, 1088, 1491, 2858 cm .
(
1
-(4-Nitrobenzyloxy)-3-phenylpropane (2h)
1
H NMR: 1.98 (m, 2 H), 2.74 (t, 2 H, J = 7.6 Hz), 3.54 (t, 2 H,
J = 6.0 Hz), 4.59 (s, 2 H), 7.18 (m, 3 H), 7.28 (m, 2 H), 7.50 (d, 2
H, J = 8.8 Hz), 8.21 (d, 2 H, J = 8.8 Hz).
(
1
(5) Oriyama, T.; Noda, K.; Yatabe, K. Synlett 1997, 701.
(6) Kato, J.; Iwasawa, N.; Mukaiyama, T. Chem. Lett. 1985, 743.
(7) (a) West, C. T.; Donnelly. S. J.; Kooistra, D. A.; Doyle, M. P.
J. Org. Chem. 1973, 38, 2675.
13C NMR: 21.01, 29.71, 38.51, 48.08, 55.24, 77.32, 101.35, 113.79,
1
29.08, 134.08, 134.09, 157.75.
IR (neat): 738, 1105, 1346, 1419 cm .
-(4-Methoxybenzyloxy)-3-phenylpropane (2i)
-
1
(
b) Fry, J. L.; Orfanopoulos, M.; Adlington, M. G.; Dittman,
1
W. R. Jr.; Silverman, S. B. J. Org. Chem. 1978, 43, 374.
1
H NMR: 1.92 (m, 2 H), 2.70 (t, 2 H, J = 8.4 Hz), 3.46 (t, 2 H,
J = 6.0 Hz), 3.81 (s, 3 H), 4.43 (s, 2 H), 6.88 (d, 2 H, J = 8.8 Hz),
7
.18 (m, 3 H), 7.26 (m, 4 H).
13C NMR: 31.35, 32.38, 55.26, 69.19, 72.56, 113.75, 125.71,
28.28, 128.47, 129.26, 130.65, 142.00, 159.12.
Article Identifier:
1437-210X,E;1999,0,09,1561,1563,ftx,en;F11999SS.pdf
1
Synthesis 1999, No. 9, 1561–1563 ISSN 0039-7881 © Thieme Stuttgart · New York