Tetrahedron Letters
Amine-free silylation of alcohols under 4-methylpyridine
N-oxide-catalyzed conditions
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Keisuke Yoshida , Yuta Fujino, Yukihiro Itatsu, Hiroki Inoue, Yohei Kanoko, Ken-ichi Takao
Department of Applied Chemistry, Keio University, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Amine-free silylation of various alcohols catalyzed by 4-methylpyridine N-oxide in the presence of MS4A
at room temperature was developed. This simple method gave various silyl ethers in a high yield.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 25 November 2015
Revised 22 December 2015
Accepted 28 December 2015
Available online xxxx
Keywords:
Amine-free
Silylation
4-Methylpyridine N-oxide
MS4A
The silyl group is one of the most useful protecting groups in
organic synthesis and various methods have been reported for
the triethylsilyl (TES), t-butyldimethylsilyl (TBS), t-butyldiphenyl-
silyl (TBDPS), and triisopropylsilyl (TIPS) etherification of alcohols.
Generally, silyl groups can be introduced to various alcohols in
good yield by treating the parent alcohols with a silyl halide and
an amine (imidazole or tertiary amine such as NEt3, DIPEA) to trap
the strong acid that is generated.1 The combination of silyl triflate
and 2,6-lutidine is often chosen for secondary or bulky alcohols.2
Moreover, a number of conditions for various purposes, such as
regio- or chemoselective silylation, have been explored with vari-
ous combinations of reagents, catalysts, bases, and solvents.3 These
are simple, effective methods for silyl etherification. However, silyl
etherification often requires the addition of more than equivalent
of the amine with respect to the silyl reagent and substrate. Low
molecular weight amines, such as triethylamine, are toxic and
irritating to the eyes, nose, and skin, although the amines play a
significant role for silyl etherification. Therefore, safer conditions
for alcohol silylation are required. Recently, we reported that the
combination of TBDPSCl, DIPEA, and pyrrolidinopyridine N-oxide
(PPYO) catalyst silylates various secondary alcohols (Scheme 1),4
and that pyridine N-oxide has excellent catalytic activity. Herein,
we focused on molecular sieves (MS) as an alternative to amines
in combination with the pyridine N-oxide catalyst. Molecular
sieves have a three-dimensional interconnecting network of silica
TBDPSCl (1.5 eq)
PPYO (20 mol %)
DIPEA (2.0 eq)
N
N
OH
OTBDPS
CH2Cl2 (0.2 M), r.t.
O
98% yield
Scheme 1. Catalytic silylation of secondary alcohol by PPYO.
PPYO
and alumina tetrahedra and absorb molecules of a specific size
after water is removed from this network.5 Thus, MS are widely
used as water scavengers to dry organic solvents and reagents in
organic synthesis. Some reactions using MS as an acidic or basic
reagent have been reported. For instance, acetylation,6 deacetyla-
tion,7 and polycyclization8 using MS3A or 4A have been developed,
and MS5A-mediated acetal protection also has been reported.9
However, to our knowledge, catalytic silylation using MS4A as an
alternative to amines has not yet been reported. Herein, we
describe the amine-free silylation of primary and secondary
alcohols using 4-methylpyridine N-oxide and MS4A.
We chose 2-(3,4-dimethoxyphenyl)ethanol (1) as a standard
substrate for catalyst screening (Table 1). Treatment of 1 with
2 equiv TBDPSCl and 500 wt % activated MS4A powder10 in CH2Cl2
at room temperature for 1 h did not produce silylated product 2
(entry 1). These results show that the conditions using MS4A alone
are ineffective. When 30 mol % imidazole was used as the catalyst,
only a small amount of TBDPS ether 2 was obtained (entry 2).
Dimethylaminopyridine (DMAP)-catalyzed conditions gave 2 in
moderate yield (entry 3). In contrast, using pyridine N-oxide
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Corresponding authors. Tel.: +81 45 566 1570; fax: +81 45 566 1551.
(K. Takao).
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.