Catalytic silylation of secondary alcohols by pyridine N-oxide derivative

Article abstract of DOI:10.1016/j.tetlet.2014.10.087

The reaction of t-butyldiphenylsilyl (TBDPS) chloride with secondary alcohols was catalyzed by pyrrolidinopyridine N-oxide (PPYO) in the presence of diisopropylethylamine (DIPEA) at room temperature, giving the corresponding TBDPS ethers in high yields.

Full text of DOI:10.1016/j.tetlet.2014.10.087

Tetrahedron Letters 55 (2014) 6861–6863
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Catalytic silylation of secondary alcohols by pyridine N-oxide
derivative
⇑
⇑
Keisuke Yoshida , 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:
The reaction of t-butyldiphenylsilyl (TBDPS) chloride with secondary alcohols was catalyzed by pyrroli-
dinopyridine N-oxide (PPYO) in the presence of diisopropylethylamine (DIPEA) at room temperature,
giving the corresponding TBDPS ethers in high yields.
Received 16 September 2014
Revised 7 October 2014
Accepted 14 October 2014
Available online 18 October 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalyst
Silylation
Secondary alcohols
Pyridine N-oxide
The silyl group is one of the most useful protecting groups in
organic synthesis and various methods have been reported for
the t-butyldimethylsilyl (TBDMS) and t-butyldiphenylsilyl (TBDPS)
etherification of alcohols. In the most popular method, treatment
of parent alcohols with silyl halide (e.g., TBDMSCl, TBDPSCl) and
imidazole is available to introduce the silyl group to various alco-
hols in good yields.1 For secondary or bulky alcohols, the combina-
tion of silyl triflate and 2,6-lutidine is a powerful method that is
often chosen.2 Moreover, a number of catalytic conditions for the
silylation have been explored using various combinations of bases
and solvents.3 In particular, it is well known that conditions using
N,N-dimethylaminopyridine (DMAP) catalyst, silyl chloride, and
triethylamine can selectively introduce the silyl group to primary
alcohols in the presence of secondary alcohols.4 However, TBDPS
etherification of secondary alcohols under catalytic conditions
has proved difficult because of steric hindrance. Verkade and co-
workers reported that amino-phosphine P(MeNCH2CH2)3N effec-
tively and strongly catalyzes the silylation of various alcohols,
but a high temperature is needed to complete the reaction in the
case of TBDPS etherification of secondary alcohols.5 In their paper,
DMAP was noted to be an inefficient catalyst for TBDPS etherifica-
tion of secondary alcohol (36% yield after 24 h using 20 mol %
DMAP catalyst at 50 °C). To our knowledge, catalysts that have
strong activity for TBDPS etherification of secondary alcohols at
low temperatures are very rare. Herein, we report the development
of mild catalytic conditions for TBDPS etherification of secondary
alcohols using pyridine N-oxide derivatives. N,N-Dimethylamino-
pyridine N-oxide (DMAPO) and pyrrolidinopyridine N-oxide
(PPYO) can be prepared easily from commercially available DMAP
and pyrrolidinopyridine.6 Shiina et al., reported that the combina-
tion of DMAPO and 2-methyl-6-nitrobenzoic anhydride promotes
efficient peptide coupling and macrolactonization.7 In another
study, chiral pyridine N-oxide derivatives were used as organocat-
alysts for asymmetric allylation of aldehyde.8 Recently, the
combination of DMAPO and a chiral hydrogen-bonding catalyst
was found to exhibit acylation activity for the kinetic resolution
of allylic amine.9 Against this background, the present study is
the first Letter of catalytic silylation of secondary alcohols using
pyridine N-oxide derivatives.
To begin, we chose (À)-menthol (1) as a standard substrate for
investigating the reaction conditions (Table 1). Treatment of 1 with
TBDPSCl and a bulky base such as 2,4,6-collidine or diisopropyleth-
ylamine (DIPEA) in CH2Cl2 at room temperature resulted in no for-
mation of the silylated product 2 (entries 1 and 2). These results
show that the conditions using amine base alone are ineffective
in this case. When 20 mol % of DMAP was used as catalyst, only a
trace amount of TBDPS ether 2 was obtained (entry 3). In contrast,
the use of DMAPO instead of DMAP accelerated the silylation to
provide 2 in 71% yield (entry 4).
We next investigated the optimal base for this reaction. As
shown in entry 5, the conditions using 2 equiv of PPYO in the
absence of amine base resulted in no reaction. By using 1.5 equiv
of NEt3, 2,6-lutidine, or 2,4,6-collidine in the presence of 20 mol %
of PPYO, the silylated product 2 was obtained in moderate yield
⇑
Corresponding authors. Tel.: +81 45 566 1570; fax: +81 45 566 1551.
E-mail addresses: yoshida@applc.keio.ac.jp (K. Yoshida), takao@applc.keio.ac.jp
(K. Takao).
http://dx.doi.org/10.1016/j.tetlet.2014.10.087
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

6862
K. Yoshida, K. Takao / Tetrahedron Letters 55 (2014) 6861–6863
Table 1
Catalyst and base screening for TBDPS etherification of (À)-menthol (1)
N
N
TBDPSCl (1.3 eq)
Catalyst (20 mol %)
N
O
Base (1.5 eq)
N+
N+
O-
N
N+
O-
OH
OTBDPS
O-
CH2Cl2 (0.2 M), r.t.
DMAP
DMAPO
PPYO
NMO
1
2
Entry
Catalyst
Base
Yield of 2a (%)
Recovery of 1 (%)
1b
2b
3b
4b
5c
6c
7c
8c
9c
10c
None
None
DMAP
DMAPO
PPYOd
PPYO
PPYO
PPYO
PPYO
NMO
2,4,6-Collidine
DIPEA
DIPEA
DIPEA
None
2,4,6-Collidine
NEt3
2,6-Lutidine
DIPEA
0
0
8
71
0
63
75
51
93
0
ꢀ100
ꢀ100
88
25
ꢀ100
34
21
47
0
ꢀ100
DIPEA
a
b
c
Isolated yield.
Reaction time: 14 h.
Reaction time: 24 h.
2.0 equiv of PPYO was used.
d
(3–6, DMAPO, and PPYO), only the N-oxide derivatives bearing an
electron donating group at the 4-position of the pyridine ring were
found to be effective for the silylation. In particular, PPYO showed
the strongest activity of the N-oxide derivatives. The increase in
the activity of the catalyst corresponded to an increase in the basi-
city of the pyridine nitrogen. A similar trend has been observed for
the acylation activity of DMAP and pyrrolidinopyridine.11
A possible reaction mechanism for the catalytic TBDPS etherifi-
cation of secondary alcohol by PPYO is shown in Figure 2. First, an
intermediate (A) is formed from TBDPSCl and PPYO. The formation
of A was supported by an NMR analysis of a mixture of TBDPSCl
and PPYO (see the Supplementary data).12 Then, the secondary
alcohol can receive the TBDPS group from A to give the silylated
product (B) and PPYO is regenerated to return the catalytic cycle.
DIPEA may be necessary to capture HCl.
To expand the scope of this reaction, we explored the use of
various secondary alcohols (Table 2). Substrates 1, trans-2-phe-
nyl-1-cyclohexanol, 2-methyl-2,4-pentanediol, and meso-cyclo-
hexanediol were treated under the optimized conditions to afford
TBDPS ethers in 98%, 97%, 93%, and 94% yields, respectively,
(entries 1–4).13 Moreover, the hindered ortho-disubstituted phenol
derivative was silylated in 96% yield (entry 5). This reaction
reached completion in just 15 min. The silylation of (À)-borneol
(entry 6), which contains a quaternary carbon atom adjacent to
(entries 6–8, respectively). Finally, DIPEA was found to be the opti-
mal base (entry 9). The combination of PPYO catalyst and DIPEA
base gave 2 in excellent yield. In contrast, the use of N-methylmor-
pholine N-oxide (NMO) as catalyst gave no reaction (entry 10).
These results demonstrate that both the pyridine N-oxide catalyst
and the amine base are crucial for this reaction.
To investigate substituent effects at the 4-position of pyridine,
we next examined silylation using various pyridine N-oxide deriv-
atives with different substituents at the 4-position
TBDPSCl (1.3 eq)
Catalyst (30 mol %)
R
DIPEA (2.0 eq)
R = Cl (3)
H (4)
N+
O-
OH
OTBDPS
CH2Cl2 (0.2 M), r.t.
24 h
Me (5)
OMe (6)
1
2
(Fig. 1).10 In this examination, we used 1.3 equiv of TBDPSCl and
2.0 equiv of DIPEA as base, and 30 mol % of a pyridine N-oxide deriv-
ative as catalyst. For comparison, DMAP-catalyzed TBDPS etherifica-
tion was also run under the same reaction conditions, providing 2 in
18% yield with 80% recovery of 1. Among the other catalysts tested
N
OTBDPS
R
R'
B
TBDPSCl
N
O
DIPEA•HCl
OH
N
R
R'
Cl-
N
O
DIPEA
Ph
Si
tBu Ph
A
Figure 1. Substituent effects at the 4-position of the pyridine ring.
Figure 2. A possible mechanism of TBDPS etherification by PPYO.

K. Yoshida, K. Takao / Tetrahedron Letters 55 (2014) 6861–6863
6863
Table 2
Supplementary data
Formation of TBDPS ethers from various secondary alcohols
TBDPSCl (1.5 eq)
PPYO (20 mol %)
DIPEA (2.0 eq)
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.10.
087.
OTBDPS
R'
OH
R'
R
R
CH2Cl2 (0.2 M), r.t.
24 h
References and notes
OTBDPS
Ph
1. (a) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190–6191; (b)
Hanessian, S.; Lavallee, P. Can. J. Chem. 1975, 53, 2975–2977.
2. Corey, E. J.; Cho, H.; Rücker, C.; Hua, D. H. Tetrahedron Lett. 1981, 22, 3455–
3458.
OH OTBDPS
OTBDPS
Me
Me
Me
3. (a) Kim, S.; Chang, H. Synth. Commun. 1984, 14, 899–904; (b) Lombardo, L.
Tetrahedron Lett. 1984, 25, 227–228; (c) Kim, S.; Chang, H. Bull. Chem. Soc. Jpn.
1985, 58, 3669–3670; (d) Aizpurua, J. M.; Palomo, C. Tetrahedron Lett. 1985, 26,
475–476; (e) Ireland, R. E.; Obrecht, D. M. Helv. Chim. Acta 1986, 69, 1273–
1286; (f) Tanabe, Y.; Murakami, M.; Kitaichi, K.; Yoshida, Y. Tetrahedron Lett.
1994, 35, 8409–8412; (g) Tanabe, Y.; Okumura, H.; Maeda, A.; Murakami, M.
Tetrahedron Lett. 1994, 35, 8413–8414; (h) Suzuki, T.; Watahiki, T.; Oriyama, T.
Tetrahedron Lett. 2000, 41, 8903–8906; (i) Takeichi, T.; Kuriyama, M.; Onomura,
O. Tetrahedron Lett. 2011, 52, 6646–6648.
4. (a) Chaudhary, S. K.; Hernandez, O. Tetrahedron Lett. 1979, 20, 99–102; (b)
Patschinski, P.; Zhang, C.; Zipse, H. J. Org. Chem. 2014, 79, 8348–8357.
5. D’Sa, B. A.; McLeod, D.; Verkade, J. G. J. Org. Chem. 1997, 62, 5057–5061.
6. DMAPO and PPYO were prepared by the described procedure: Katritzky, A. R.;
Rasala, D.; Brito-Palma, F. J. Chem. Res. (S) 1988, 42–43.
1. 98%
2. 97%
CHO
3. 93%
OTBDPS
OTBDPS
Br
OMe
OTBDPS
OTBDPS
6. 95%
4. 94%
a Reaction time: 15 min.
5.a 96%
7. (a) Shiina, I.; Ushiyama, H.; Yamada, Y.; Kawakita, Y. Nakata. K Chem. Asian J.
2008, 3, 454–461; (b) Shiina, I.; Sasaki, A.; Kikuchi, T.; Fukui, H. Chem. Asian J.
2008, 3, 462–472.
8. Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S. J. Am. Chem. Soc. 1998, 120,
6419–6420.
9. Klauber, E. G.; Mittal, N.; Shah, T. K.; Seidel, D. Org. Lett. 2011, 13, 2464–2467.
10. For the data in Figure 1, see the Table in the Supplementary data.
11. Sammakia, T.; Hurley, T. B. J. Org. Chem. 1999, 64, 4652–4664.
12. PPYO disappeared and the new signals were observed in the 1H NMR spectrum
of a mixture of TBDPSCl and PPYO (ca. 1:0.3).
the hydroxyl group, also proceeded smoothly. These results show
that PPYO can be used to catalyze the formation of TBDPS ethers
from a wide range of secondary alcohols.
In conclusion, we have developed a novel method for catalytic
TBDPS etherification of various secondary alcohols using DMAPO
and PPYO. The reaction proceeds under mild conditions to provide
the TBDPS ethers in high yields. Our group is currently working on
an asymmetric version of this reaction using chiral pyridine
N-oxide catalysts.
13. Typical procedure for the silylation of 1 in Table 2: To a stirred solution of (À)-
menthol (1) (20.0 mg, 0.128 mmol, 1.0 equiv), PPYO (4.2 mg, 20 mol %), and
DIPEA (44.6
lL, 0.256 mmol, 2.0 equiv) in CH2Cl2 (0.6 mL) was added TBDPSCl
(49.9 L, 0.192 mmol, 1.5 equiv). The mixture was stirred at room temperature
l
for 24 h, quenched with 1 M aqueous HCl (10 mL), and extracted with EtOAc
(10 mL Â 3). The combined extracts were washed with water (10 mL) and
saturated brine (10 mL), dried, and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel (EtOAc/hexane,
20:1) to give 49.4 mg (98% yield) of 2.
Acknowledgments
This work was supported by Keio Gijuku Academic
Development Funds.