A remarkable solvent effect toward the Pd/C-catalyzed cleavage of silyl ethers

Article abstract of DOI:10.1039/b211313a

Selective hydrogenation conditions of olefin, benzyl ether and acetylene functionalities in the presence of TBDMS or TES ether have been developed.

Full text of DOI:10.1039/b211313a

A remarkable solvent effect toward the Pd/C-catalyzed cleavage of silyl
ethers†
Hironao Sajiki,* Takashi Ikawa, Kazuyuki Hattori and Kosaku Hirota*
Laboratory of Medicinal Chemistry, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu
502-8585, Japan. E-mail: sajiki@gifu-pu.ac.jp; Fax: +81-58-237-5979; Tel: +81-58-237-3931
Received (in Cambridge, UK) 19th November 2002, Accepted 28th January 2003
First published as an Advance Article on the web 11th February 2003
Selective hydrogenation conditions of olefin, benzyl ether
and acetylene functionalities in the presence of TBDMS or
TES ether have been developed.
nylsilyl (TBDPS), triisopropylsilyl (TIPS) and triethylsilyl
(TES) ethers, use of MeOH, THF, EtOAc and MeCN as the
typical solvent was investigated (Table 2). As shown in entries
1
and 2, the TBDPS and TIPS protective groups of 1b and 1c
The protection of alcohols as their silyl ethers has been
recognized as a most useful protective method. Since the
introduction of the tert-butyldimethylsilyl (TBDMS) protective
group in 1972,1 alcohols and phenols have been quite
were stable under hydrogenation conditions using 10% Pd/C
6
even in MeOH. On the other hand, the TES protective group of
1d could be cleaved easily in MeOH to form the parent alcohol
3a (entry 3).4 Although the TBDMS ether 1a in EtOAc
absolutely tolerated the cleavage (Table 1 entry 10), the TES
ether 1d was considerably cleaved (33%) even in EtOAc to give
a mixture of 2d and 3a (Table 2, entry 5). Gratifyingly, the
desilylation of the TES ether was absolutely depressed in
2
commonly protected as their TBDMS ethers. TBDMS ethers
have the virtue of being very stable to a variety of organic
2
reactions. In general, TBDMS ethers have been believed to be
1
also stable under hydrogenation conditions. Synthesis involv-
ing hydrogenation and/or hydrogenolysis processes of reducible
functionalities (e.g., olefin and benzyl ether) offer the complete
stability of the coexisting silyl ether as a protective group
because the unexpected loss of the silyl protective group from a
hydroxylic function would greatly impair a synthetic process.
However, we have quite recently reported the frequent and
unexpected cleavage of TBDMS ethers to form the parent
a
Table 1 Solvent effect toward the TBDMS cleavage of 1a
alcohols under mild hydrogenation conditions (ambient H
2
3
Relative yield (%)b
pressure and temperature) using 10% Pd/C in MeOH. In a
related reaction, we found that the cleavage of the silyl ether
under hydrogenation conditions using 10% Pd/C was strongly
affected by the solvent. Encouraged by this interesting observa-
tion, we became interested in exploring the stability of silyl
ethers under the Pd/C-catalyzed hydrogenation conditions using
various solvents to see if perfect stability could be achieved in
a specific solvent and to provide an extremely safe and
applicable hydrogenation method for reducible functionalities
with coexisting silyl ethers. Herein we report the result of our
investigation.
Entry
Solvent
2a
3a
1
2
3
4
5
6
7
8
9
MeOHc
EtOH
BuOH
0
34
92
23
86
89
87
98
100
66
8
77
14
11
13
2
t
2
H O
Hexanes
Cyclohexane
DMF
THF
Many representative protic and non-protic solvents were
chosen for the hydrogenation of 1-tert-butyldimethylsilyloxy-
Toluene
EtOAc
MeCN
100
100
100
0
0
0
1
1
0
1
3
-phenyl-2-propene (1a). Needless to say, the hydrogenation of
a
10% Pd/C was purchased from Aldrich. b Determined by H NMR. No
1
c
the olefin function of 1a was smoothly achieved in all the
investigated solvents under the hydrogenation conditions [0.5
mmol of 1a and 10% Pd/C (10% of the weight of 1a) in 1 mL
reaction was observed under Ar atmosphere.
of the solvent at ambient H
2
pressure (balloon) and temperature
Table 2 Solvent effect toward the silyl ether cleavage of 1da
(
ca. 20 °C) for 24 h]. The significant effect of solvents in the
hydrogenation of 1a is shown in Table 1. Absolute solvents
were employed here. Although the unexpected cleavage of the
TBDMS protective group of 1a went essentially to completion
4
in MeOH (entry 1), changing the solvent from MeOH to EtOH,
t
2
BuOH or H O markedly decreased the rate of cleavage (66, 8
or 77%, entries 2–4). The TBDMS ether was apparently stable
in non-protic solvents (entries 5–11), for example, the cleavage
of the TBDMS ether (1a) was considerably depressed in
hexanes, cyclohexane, DMF and THF as the solvent (entries
Relative yield (%)b
Entry
Substrate
X
Solvent
2b–d
3a
c
5
–8). Subsequent screening of reaction conditions revealed that
1
2
3
4
5
6
a
1b
1c
TBDPS
TIPS
TES
TES
TES
MeOH
MeOH
MeOHd
THF
EtOAc
MeCN
100
100
0
63
67
0
0
100
37
33
0
c
no cleavage of the TBDMS ether was detected even after 24 h
5
5
1d
1d
1d
1d
by using toluene, EtOAc and MeCN as the solvent (entries
9–11).
To explore the generality of the solvent effect toward the Pd/
C-catalyzed cleavage of silyl ethers, such as tert-butyldiphe-
TES
100
1
0% Pd/C was purchased from Aldrich. b Determined by 1H NMR.
c
TBDPS and TIPS ethers of 1b and 1c were also completely tolerated in
†
Electronic supplementary information (ESI) available: characterization
THF, EtOAc and MeCN. d No reaction was observed under Ar atmos-
data and references and supplementary Tables 4 and 5. See http://
www.rsc.org/suppdata/cc/b2/b211313a/
phere.
6
54
CHEM. COMMUN., 2003, 654–655
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5
8
MeCN and chemoselective hydrogenation of the olefin was
conditions was observed in all cases in Table 3. By contrast, the
cleavage entirely tolerates the TBDMS ethers upon employ-
ment of EtOAc or MeCN as a solvent and the product was
obtained in quantitative isolated yield. In the cases of TES
ethers, even including a sterically hindered TES group on the
tertiary alcohol (1k), complete loss of the TES protective group
was observed in MeOH (entries 4–7). It is interesting to note
that the perfect and ready cleavage of TES ethers proceeds in
MeOH, suggesting that the process will be applicable to a novel
and selective deprotection method of the TES protective group
achieved to give 2d as the sole product (entry 6).
To elucidate the solvent effect and establish the viability of a
safe hydrogenation process for TBDMS and TES ethers
possessing other reducible functionalities, competition experi-
ments were performed by using a variety of TBDMS and TES
ethers under the same hydrogenation conditions in absolute
MeOH and EtOAc or MeCN, and the results were particularly
informative (Table 3). While consumption of the benzyl ether of
f in EtOAc required somewhat longer reaction time (36 h),
7
1
9
acetylene, olefin and benzyl ether functionalities were easily
hydrogenated in each solvent. The extent of undesirable
cleavage of the alkyl or aryl TBDMS ether in MeOH was
significantly dependent on the structure of the substrate (entries
under neutral and mild conditions. The complete suppression
procedure for the desilylation of the TES protective group was
achieved by making use of MeCN as a solvent (entries 4–7). In
all cases, the hydrogenation gave a single product without any
TES cleavage. These results in EtOAc and/or MeCN provide a
perfectly chemoselective and safe hydrogenation method of
other reducible functionalities leaving intact the TBDMS and
TES ether as a widely applicable protective group.
1
–3) while appreciable cleavage of the TBDMS ether under the
Table 3 Cleavage of the TBDMS or TES ethers under 10% Pd/C-catalyzed
hydrogenation conditions
a
Evidently, the desilylation of 1a and 1d never occurred in the
absence of hydrogen or 10% Pd/C and no suppression was
observed in the presence of a basic gel-type resin (Amberlite®
IRA-40 or IRA-410) as an acid scavenger to eliminate the
possibility of a contaminated acid-catalyzed methanolysis.
However, the mechanism for the remarkable solvent effect
(suppression of the silyl ether cleavage) is not clear yet (see
Supplementary Information†).4
In conclusion, we have discovered a remarkable solvent
effect toward the Pd/C-catalyzed cleavage of TBDMS and TES
ethers and it was applied to the development of a chem-
oselective hydrogenation method for olefin, benzyl ether and
acetylene functionalities distinguishing from the TBDMS and
TES protective groups of a hydroxy group by the employment
of EtOAc or MeCN as a solvent. The ready availability of the
catalyst (commercially available), the high yields, simplicity of
the procedure, and selective nature of the hydrogenation, render
this new and simple methodology advantageous for work
involving TBDMS and TES ether manipulation.
Yield
Entry Substrate
Solvent 2+3b
Product
(%)c
MeOH
0+100
80
1
2
EtOAc 100+0
98
d
MeOH
82+18
EtOAce 100+0
95
d
MeOH
92+8
3
EtOAc 100+0
100
Notes and references
1 E. J. Corey and A. Venkateswarlu, J. Am. Chem. Soc., 1972, 94, 6190.
f
94 (67)g
MeOH
0+100
2
Selected reviews: (a) T. W. Greene and P. G. M. Wuts, Protective Groups
in Organic Synthesis, 3rd edn., Wiley-Interscience, New York, 1999; (b)
P. J. Kocienski, Protecting Groups, Thieme-Verlag, Stuttgart, 1994, p.
4
5
6
MeCN 100+0
99
2
8.
3
(a) K. Hattori, H. Sajiki and K. Hirota, Tetrahedron Lett., 2000, 41, 5711;
(b) K. Hattori, H. Sajiki and K. Hirota, Tetrahedron, 2001, 57, 2109.
4 To eliminate the possibility of a contaminated acid in 10% Pd/C-
catalyzed cleavage of the silyl protective groups, the reactions of 1a and
f
92 (45)g
MeOH
0+100
MeCN 100+0
88
1
d were performed without hydrogen. As a consequence of the reaction,
no cleavage occurred, even after 24 h (see Supplementary Information,
f
90 (21)g
MeOH
0+100
Table 4†) (ref. 3).
2
5 The addition of a small amount of MeOH or H O into the reaction
mixture (0.1 mL per 1.0 mL of EtOAc or MeCN) caused no cleavage of
the TBDMS (1a) or TES (1d) ether for 24 h (see Supplementary
Information, Table 5†).
MeCN 100+0
93
6
The TBDPS and TIPS protective groups are considerably more stable to
a variety of organic reaction conditions than the TBDMS group because
of the greater bulkiness (ref. 2a).
MeOH
0+100
96
7
9
8
7 Several removal methods of OBn in the presence of silyl ethers were
previously reported. See: (a) H. Toshima, S. Yoshida, T. Suzuki, S.
Nishiyama and S. Yamamura, Tetrahedron Lett., 1989, 48, 6721; (b) F.
Yokokawa, Y. Hamada and T. Shioiri, Chem. Commun., 1996, 871; (c) B.
Sas, P. De Clercq and M. Vandewalle, Synlett, 1997, 1167.
MeCN 100+0
a
Unless otherwise specified, the reaction was carried out using 0.5 mmol of
the substrate (1) with 10% Pd/C (10% of the weight of the substrate 1) in
MeOH (2 mL) or EtOAc (2 mL) under hydrogen atmosphere (1 atm) at rt
for 24 h. Determined by H NMR. Isolated yield. The ratio of the
product was estimated by H NMR. The benzyl ether of 1f was completely
hydrogenolyzed in EtOAc for 36 h. Product contaminated with small
amount of TESOH. The yield of isolated and analytically pure product is
indicated in parentheses. The low isolated yield is due to the volatile nature
of the product and difficulty of purification using silica gel column
chromatography.
b
1
c
d
8 In the cases of highly hindered TBDMS ethers, such as (1R, 2S, 5R)-
1
e
1-tert-butyldimethylsilyloxy-2-isopropyl-5-methylcyclohexane,
no
f
cleavage of the TBDMS protective group was observed even in
MeOH.
g
9
The development of mild and effective deprotection methods of silyl
ethers with excellent chemoselectivity are still highly desirable because
of practical benefits for synthetic chemistry. For example, see: S. V.
Ankala and G. Fenteany, Tetrahedron Lett., 2002, 42, 4729.
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