The undesirable lability of tert-butyldimethylsilyl ethers under Pd/C- catalyzed hydrogenation conditions and solution of the problem by using a Pd/C(en) catalyst

Article abstract of DOI:10.1016/S0040-4039(00)00935-7

While the frequent and unexpected loss of the TBDMS protective group of a variety of hydroxylic functions was demonstrated under neutral and mild hydrogenation conditions using 10% Pd/C, the undesirable problem was perfectly overcome by using a 10% Pd/C-ethylenediamine complex catalyst. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00935-7

Tetrahedron Letters 41 (2000) 5711±5714
The undesirable lability of tert-butyldimethylsilyl ethers
under Pd/C-catalyzed hydrogenation conditions and
solution of the problem by using a Pd/C(en) catalyst
Kazuyuki Hattori, Hironao Sajiki* and Kosaku Hirota*
Laboratory of Medicinal Chemistry, Gifu Pharmaceutical University, 5-6-1, Mitahora-higashi,
Gifu 502-8585, Japan
Received 11 May 2000; accepted 23 May 2000
Abstract
While the frequent and unexpected loss of the TBDMS protective group of a variety of hydroxylic
functions was demonstrated under neutral and mild hydrogenation conditions using 10% Pd/C, the
undesirable problem was perfectly overcome by using a 10% Pd/C-ethylenediamine complex catalyst.
#
2000 Elsevier Science Ltd. All rights reserved.
Keywords: TBDMS ethers; desilylation; Pd/C; Pd/C(en); chemoselective hydrogenation.
The continuing evolution of organic synthesis is dependent in many ways on complementary
advances in the introduction and manipulation of protective groups. Protective groups suitable
for contemporary synthesis should comprise eciency of preparation, selective removal and
stability under the intended reaction conditions. Since the introduction of a tert-butyldimethylsilyl
1
(TBDMS) group to synthetic chemistry by Corey and Venkateswarlu in 1972, the TBDMS ether
has become among the most frequently used silyl protective groups for a hydroxylic function. It is
well known that the TBDMS ether is remarkably more stable to a variety of organic reaction
conditions than the trimethylsilyl (TMS) ethers, yet it undergoes selective removal under mild
2
conditions that do not attack other functional groups. Although it has been common knowledge
1
that the TBDMS ether is inert towards hydrogenation conditions, we have made the critical
observation that the TBDMS ether can be hydrogenolyzed frequently to form the parent alcohols
ꢀ
e.g. using 10% Pd/C, 1 atm H , MeOH solvent, at 20 C). This is a serious problem, not only
2
3
(
because of the fundamental importance of the TBDMS protective group, but also with regard to
its role in multi-step synthesis of complex natural products. The unexpected loss of the TBDMS
protective group from a hydroxylic function would cause extensive damage to a synthetic process.
We describe herein the frequent loss of the TBDMS protective group when a variety of TBDMS
*
Corresponding author. Fax: +81 58 237 5979; e-mail: sajiki@gifu-pu.ac.jp
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00935-7

5
712
ethers were subjected to 10% Pd/C-catalyzed hydrogenation at ambient pressure and temperature.
Further, we now also disclose a very practical catalyst that overcomes this undesirable problem.
In our initial investigations, the stability of the O-TBDMS group of 3-phenyl-1-propyl
4
5
TBDMS ether (1a), 3,7-dimethyl-1-octyl TBDMS ether (1b) and O-TBDMS-cholesterol (1c)
under hydrogenation conditions [0.25 mmol of the substrate (1a±c) in MeOH (1 mL) under
hydrogen atmosphere (1 atm) at room temperature for 24 h] using 10% Pd/C (10% of the weight
of the substrate) purchased from Aldrich was studied. Under the reaction conditions, the
TBDMS ether (1a) was surprisingly and completely hydrogenolyzed to give 3-phenylpropane-1-ol
(2a) as the sole product in 97% isolated yield (100% conversion yield) and further, the TBDMS
ether of 1b or 1c underwent slow but appreciable hydrogenolysis (41 or 44%, respectively) under
these conditions to give a mixture of 1b and 2b or 1c and 2c (Fig. 1). On the other hand, the
tri-substituted ole®n function of 1c was stable under the conditions. To eliminate the possibility
of a contaminated acid or base in 10% Pd/C-catalyzed cleavage of the TBDMS protective group,
the reaction of 1a was performed without hydrogen. As a consequence of the reaction, no
desilylation occurred, even after 24 h.
Figure 1.
Recently, we reported a couple of chemo- and regio-selective hydrogenation methods using a
6
carbon-supported Pd-ethylenediamine complex [Pd/C(en)] which possesses less catalytic activity
6c
6
a
6a
6b
toward benzyl ethers, N±Z protective groups, aromatic carbonyls, and epoxides, compared
to commercial Pd/C because the coordinated ethylenediamine acts as a gentle catalyst-poison. We
7
expected that employment of 10% Pd/C(en) instead of 10% Pd/C for the hydrogenation of the
TBDMS ethers could not be induced to deprotect the TBDMS group. In fact, the hydrogenolysis
of the TBDMS ethers (1a±c), using 10% Pd/C(en), led to complete recovery of the starting
materials.
In the light of these results, we decided to explore the generality of the undesirable
hydrogenolysis of the TBDMS ether with commercial 10% Pd/C and the adaptability to the
chemoselective hydrogenation of 10% Pd/C(en) using various substrates possessing some other
reducible functionality such as an ole®n, benzyl ether or nitro group within the molecule. The
results shown in Table 1 demonstrate that the hydrogenation of readily reducible (less steric
hindrance) ole®n (entries 1±6, 9 and 10) and nitro (entries 11 and 12) functionalities can be
successfully carried out using either 10% Pd/C or 10% Pd/C(en). Although the hydrogenolytic
8
debenzylation of 3d using commercial 10% Pd/C proceeded smoothly (entry 7), the hydrogenation
using 10% Pd/C(en) thoroughly tolerates the benzyl ether of 3d (entry 8) as already reported by
6
a
us. We have made the unexpected and extremely serious observation that the TBDMS protective
group of alkyl alcohols (3a±d) can be hydrogenolyzed easily using commercial 10% Pd/C
9
(
Aldrich) as a catalyst to form the parent alcohols as the sole product, although an aryl TBDMS

5
713
Table 1
Hydrogenation in the presence of O-TBDMS group using 10% Pd/C or 10% Pd/C(en) as a catalyst
a
ether (3e)10 seems to be more stable than alkyl TBDMS (only 8% of the O-TBDMS cleaved,
entry 9, see also Scheme 1).11 It should be noted that the hydrogenolysis tolerates the TBDMS
ethers in which an amino moiety forms to coexist (e.g. arylamine) within a molecule of the
product due to the catalyst-poisonous e€ect (4f, entry 11).12 On the other hand, when the 10%
Pd/C(en) was used as a catalyst, competitive and reluctant hydrogenolysis of the TBDMS ether
was perfectly suppressed without exception under the same conditions (entries 2, 4, 6, 8, 10 and
1
2). Furthermore, extension of these reactions to bis-TBDMS ethers was also investigated using a
Scheme 1.

5
714
model substrate (3g). Although complete desilylation of the alkyl TBDMS ether and partial
desilylation of the aryl TBDMS ether were observed with commercial 10% Pd/C (6:7=57:43), no
hydrogenolysis of either the alkyl or aryl TBDMS ether occurred when 10% Pd/C(en) was used
as a catalyst (Scheme 1).
In summary, we have clearly demonstrated the unreliability of the TBDMS protective group
for hydroxylic functions under the hydrogenation conditions using 10% Pd/C catalyst. Moreover,
we have found that the use of the 10% Pd/C(en) catalyst totally suppressed the hydrogenolysis of
the TBDMS ether and also applied the catalyst to develop a reliable and chemoselective
hydrogenation method of ole®n and nitro functionalities in the presence of the TBDMS ether.
These ®ndings further reinforce the versatile potential of TBDMS ethers as one of the most
popular protective groups in organic synthesis.
References
1
2
. Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190.
. Selected reviews: (a) Greene, T. W.; Wuts, P. G. M. In Protective Groups in Organic Synthesis, 3rd ed.; John Wiley
&
Sons: New York, 1999; pp. 113±148. (b) Kocienski, P. J. In Protecting Group; Thieme: Stuttgart, 1994; pp. 28±42.
3
. While a removal of the TBDMS group from primary and secondary hydroxy groups by catalytic transfer
hydrogenolysis (CTH) using PdO as a catalyst in re¯uxing cyclohexene±methanol have been reported (see below),
deprotection of the TBDMS group under the hydrogenation conditions using Pd/C has not been reported to our
best knowledge; see, Cormier, J. F.; Isaac, M. B.; Chen, L.-F. Tetrahedron Lett. 1993, 34, 243.
. Honda, T.; Ishikawa, F. Synth. Commun. 1999, 29, 3323.
4
5
6
. Tanemura, K.; Suzuki, T.; Horaguchi, T. J. Chem. Soc., Perkin Trans. 1 1992, 2997.
. (a) Sajiki, H.; Hattori, K.; Hirota, K. J. Org. Chem. 1998, 63, 7990; (b) Sajiki, H.; Hattori, K.; Hirota, K. J. Chem.
Soc., Perkin Trans. 1 1998, 4043; (c) Sajiki, H.; Hattori, K.; Hirota, K. Chem. Commun. 1999, 1041.
. 10% Pd/C(en) was prepared from 10% Pd/C purchased from Aldrich.6
7
8
9
. Ito, A.; Kodama, T.; Maeda, S.; Masaki, Y. Tetrahedron Lett. 1998, 39, 9461.
. By use of 10% Pd/C purchased from N. E. Chemcat or Nacalai, the partial but appreciable hydrogenolysis
cleavage of the O-TBDMS group of 3a was observed. It should be noted that commercial 10% Pd/Cs purchased
from di€erent commercial sources (vendors) possess somewhat di€erent catalytic activities in the TBDMS ether
hydrogenolysis.
10. Ripa, L.; Hallberg, A. J. Org. Chem. 1997, 62, 595.
11. Recently, the higher stability of aryl TBDMS ethers under several deprotection conditions using ultrasound, I2,
TMSCl-H
6
2
O and Oxone was reported, see (a) Lee, A. S.-Y.; Yeh, H.-C.; Tsai, M.-H. Tetrahedron Lett. 1995, 36,
891; (b) Lipshutz, B. H.; Keith, J. Tetrahedron Lett. 1998, 39, 2495; (c) Grieco, P. A.; Markworth, C. J.
Tetrahedron Lett. 1999, 40, 665; (d) Sabitha, G.; Syamala, M.; Yadav, J. S. Org. Lett. 1999, 1, 1701.
2. 10% Pd/C-catalyzed hydrogenolysis of the TBDMS ether of 3a was also blocked by the addition of ammonia±
MeOH (2 equiv.).
1
1
1
3. Farras, J.; Serra, C.; Vilarrasa, J. Tetrahedron Lett. 1998, 39, 327.
4. Marshall, J. A.; Hinkle, K. W. J. Org. Chem. 1997, 62, 5989.