Solvolysis of benzyl alcohols and ethers in 1,2-diols and application to a deprotection of benzyl ether-type protecting groups

Article abstract of DOI:10.1246/cl.2006.778

Some kinds of benzyl alcohols and ethers react with 1,2-diols, such as ethylene glycol and propylene glycol, at 130-190°C to give 2-hydroxyethyl or 2-hydroxypropyl ethers. Application of this reaction to a deprotection of benzyl ether-type protecting groups, under neutral conditions, was also described. Copyright

Full text of DOI:10.1246/cl.2006.778

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78
Chemistry Letters Vol.35, No.7 (2006)
Solvolysis of Benzyl Alcohols and Ethers in 1,2-Diols and Application to a Deprotection
of Benzyl Ether-type Protecting Groups
Ã1
1
2
2
Hideyoshi Miyake, Masahiro Fujimura, Takatsugu Tsumura, and Mitsuru Sasaki
1Faculty of Agriculture, Kobe University, Rokkodai, Nada-ku, Kobe 657-8501
Graduate School of Science and Technology, Kobe University, Rokkodai, Nada-ku, Kobe 657-8501
2
(Received April 24, 2006; CL-060491; E-mail: miyakeh@kobe-u.ac.jp)
Some kinds of benzyl alcohols and ethers react with 1,2-di-
p-methoxybenzyl (MPM) ethers 1a and 1b proceeded smoothly
ꢀ
ꢀ
ols, such as ethylene glycol and propylene glycol, at 130–190 C
to give 2-hydroxyethyl or 2-hydroxypropyl ethers. Application
of this reaction to a deprotection of benzyl ether-type protecting
groups, under neutral conditions, was also described.
at 130–150 C to give 2 in good yield. However, in the cases of
less polar substrates such as 1c and 1d, which are not soluble in
hot EG, using PG gave better results. When PG was used instead
of EG, the mixture of 2-(4-methoxyphenylbenzyloxy)-1-propa-
0
nol (4a) and 1-(4-methoxyphenylbenzyloxy)-2-propanol (4a )
was obtained; the ratio of them are not determined.
Not only MPM ethers, diphenylmethyl (DPM) ethers 1h and
1i also react with PG to give 2a and 2b, respectively.
MPM esters 1f and 1g also reacted with EG under similar
conditions to give carboxylic acid.
Recently, we have reported that acetal-type protecting
groups, such as methoxymethyl (MOM) ethers, can be removed
under neutral conditions by heating with 1,2-diols. Those re-
sults suggest that some kinds of C–O bonds may cleave because
of the reaction with ethylene glycol. In this paper, we wish to
report the solvolysis of some benzyl ethers and benzyl alcohols
in 1,2-diols. The former reaction can be used for deprotection
of benzyl ether-type protecting groups under neutral conditions
1
Table 1. Deprotection of benzyl ether- and ester-type protect-
ing groups
Substrates (1)
Ph OMPM
OMPM
Conditions Isolated yield/%
(
Scheme 1).
Benzyl ether-type protecting groups are very popular in or-
ganic syntheses. Not only simple benzyl ethers, substituted ben-
EG
30 °C, 2 h
2a 90
(3a 88)
1
2
1a
zyl ethers are also used to control the easiness for deprotection.
The deprotection of benzyl ether often accomplished with reduc-
tive method using such as H2/Pd–C or Raney Nickel, and ox-
idative method using DDQ is also successful for some benzyl
ethers such as p-methoxybenzyl (MPM) ethers. However,
the deprotection of MPM ether bearing a proximal hydroxyl
group by DDQ is not succesful, and acetal are formed as a main
product.6
O
2b 93
(3a 84)
3
4
EG
50 °C, 4 h
1
MeO
1b
4
,5
OMPM
2c 92
(4a + 4a' 85)
PG
60 °C, 2 h
Ph
1
1c
The new method for the deprotection of benzyl ether-type
protecting groups, described as follows, is quite different from
those methods reported. It is neither a reductive nor an oxidative
method.
When many kinds of benzyl ethers of alcohols and phenols
were heated with ethylene glycol (EG) or propylene glycol (PG),
the solvolysis proceeded smoothly to give alcohols or phenol.
The results are summarized in Table 1. The C–O bond cleavage
proceeded regioselectively, and alcohols (2) and ethers (3 or 4)
were obtained.
COOMe
Ph
Ph
PG
2d 76
160 °C, 2 h
(4a + 4a' 86)
OMPM
1d
PG
2e 97
Ph
OMPM
1
60 °C, 1.5 h (4a + 4a' 82)
1e
COOMPM
2
f 92
EG
40 °C, 4 h
(3a 86)
1
AcO
So far as the substrate is soluble in hot EG, the solvolysis of
1f
COOMPM
EG
2g 96
R2
OH
1
(3a 93)
R −OH +
1
40 °C, 4 h
EG
O
O
2
3
1
g
1
R −O−R2
130−190 °C
PG
150 °C, 7 h
2a 89
(4b + 4b' 88 )
1
Ph
ODPM
ODPM
a
PG
1
2
R −OH +
R
OH
OH
1h
1
R = alkyl, aryl, acyl, H
R = substituted benzyl
2
4
2
O
2b 88
(4b + 4b' 92 )
PG
40 °C, 7 h
R2
a
1
EG = ethylene glycol
PG = propylene glycol
MeO
O
+
1
i
4
'
a4b: 2-(diphenylmethoxy)-1-propanol, 4b :1-(diphenylmethoxy)-
0
Scheme 1.
2-propanol.
Copyright Ó 2006 The Chemical Society of Japan

Chemistry Letters Vol.35, No.7 (2006)
779
Table 2. Solvolysis of benzyl alcohols in EG
OH
3l−3o
Isolated yield/%
OCH Ar
OH
2
2
2
Ph
Ph
+ 4 + 4'
R −OH
l−1o
R O
PG
j: Ar = 4-methylphenyl
90 °C, 9 h
k: Ar = phenyl
90 °C, 15 h
EG
1
1
1
2c 76%, 4c + 4c' 69%,
1j 21%
1
Substrates (1)
Conditions
Ph
2c 24%, 4d + 4d' 21%,
1k 70%
1
Ph
Ph
OH
OH
1l
190 °C, 2 h
190 °C, 6 h
3l
92
91
4
4
4
c: 2-(4-methylphenylmethoxy)-1-propanol
Ph
Ph
c': 1-(4-methylphenylmethoxy)-2-propanol
d: 2-benzyloxy-1-propanol, 4d': 1-benzyloxy-2-propanol
1m
3m
Scheme 2.
H
Me
Ph
OMOM
Ph
Ph
OH
1
1
n
o
190 °C, 8 h
3n
3o
95
62
OMPM
H
5
OH
OH
9
0 °C, 4 h
Ph
OH
EG 82%
40 °C, 4 h
EG 93%
190 °C, 10 h
OMPM
Ph
6
1
OH
OH
7
racemization
OH
O
EG
Scheme 3.
+
1p
1
90 °C, 3 h
Ph
>
Ph
On the other hand, the corresponding solvolysis of p-meth-
ylbenzyl ether 1j and benzyl ether 1k proceeded slowly even at
higher temperature. For example, when EG solution of 1j was
heated to 190 C for 9 h, 3-phenyl-2-butanol (2c) was obtained
in 76% yield, and 21% of 1j was recovered. The reaction of
benzyl ether 1k is slower than that of 1j, and 70% of 1k was re-
covered after heating to 190 C for 15 h. Results are summarized
in Scheme 2. The order of the reactivity of benzyl ethers
MPMOR > p-MeC6H4CH2OR > PhCH2OR) consistents with
that of the stability of the benzyl cation intermediates.
The deprotection of MPM ether needs somewhat severe
conditions than that of methoxymethyl (MOM) ethers, and
chemoselective deprotection of MOM group in the presence of
MPM ether is possible (Scheme 3). When the substrate 5 was
heated in EG to 90 C for 4 h, the MOM group was removed che-
moselectively to give alcohol 6 in 82% yield. The deprotection
34%
~
0%ee
98%ee
3n 32%
1p
ꢀ
Scheme 4.
ꢀ
(8 mL) solution of 1a (0.86 g, 3.0 mmol) was heated to 130 C
for 2 h. The solution was cooled to room temperature, and
20 mL of water was added. The mixture was extracted with ethyl
acetate. After usual work up, further purification was achieved
on column chromatography on silica gel (hexane–ethyl acetate),
to give alcohol 2a (0.37 g, 2.7 mmol) in 90% yield and ether 3a
(0.44 g, 2.6 mmol) in 88% yield.
ꢀ
(
References and Notes
1
ꢀ
H. Miyake, T. Tsumura, M. Sasaki, Tetrahedron Lett. 2004,
45, 7213.
ꢀ
of the MPM group of 6 was accomplished at 140 C to give diol
7
2
T. W. Greene, P. G. M. Wuts, Protective Groups in Organic
Synthesis, 3rd ed., Wiley, New York, 1999.
W. H. Hartung, C. Simonoff, Org. React. 1953, 7, 263.
K. Horita, T. Yoshioka, T. Tanaka, Y. Oikawa, O.
Yonemitsu, Tetrahedron 1986, 42, 3021.
in 93% yield.
The solvolysis of some benzyl alcohols proceeded under
3
4
7
similar conditions. Although there are some exceptions, a direct
replacement of a hydroxy group usually proceeds under acidic
conditions. The replacement of a hydroxy group of benzylic
alcohol with EG proceeded under neutral conditions. When ben-
zylic alcohols (1l–1o) were heated in EG, 2-hydroxyethyl ethers
5
6
T. Tanaka, Y. Oikawa, T. Hamada, O. Yonemitsu, Tetra-
hedron Lett. 1986, 27, 3651.
R. Strurmer, K. Ritter, R. W. Hoffmann, Angew. Chem., Int.
Ed. Engl. 1993, 32, 101; S. Hanessian, N. G. Cooke, B.
DeHoff, Y. Sakito, J. Am. Chem. Soc. 1990, 112, 5276.
K. E. Atkins, W. E. Walker, R. M. Manyik, Tetrahedron
Lett. 1970, 11, 3821; J. Tsuji, R. Takeuchi, H. Ogawa, Chem.
Lett. 1986, 293; R. Davis, K. G. Untch, J. Org. Chem. 1981,
46, 2985; A. Mizuno, Y. Hamada, T. Shioiri, Synthesis 1980,
1007; P. Camps, V. Gasol, A. Guerrero, Synth. Commun.
1988, 18, 445.
(
3l–3o) were obtained. The results are summarized in Table 2.
Although the solvolysis of secondary and tertiary benzylic alco-
hols proceeded in good yield, that of C6H5CH2OH proceeded
very slowly, and less than 10% of 2-benzyloxyethanol was ob-
tained after 20 h at 190 C.
The solvolysis of (R)-1-phenylethanol (1p) proceeded with
7
ꢀ
ꢀ
racemization. When 1p was heated in EG at 190 C for 3 h, about
8
1
:1 enantiomeric mixture of 3n was obtained (Scheme 4). It
suggests that a mechanism of this reaction is not SN2-like, but
SN1-like.
Typical procedure is shown as follows. An ethylenglycol
8
Enantiomeric ratio was determined by HPLC using Daicel
Ò
Chiralcel OD-H. However, configuration of 3n is not deter-
mined.
Published on the web (Advance View) June 10, 2006; doi:10.1246/cl.2006.778