Undesirable deprotection of O-TBDMS groups by Pd/C-catalyzed hydrogenation and chemoselective hydrogenation using a Pd/C(en) catalyst

Article abstract of DOI:10.1016/S0040-4020(01)00060-6

In general, O-TBDMS protective groups have been believed to be stable toward Pd/C-catalyzed hydrogenation conditions. In practice, however, frequent and unexpected loss of the TBDMS protective group of a variety of hydroxyl functions occurred under neutral and mild hydrogenation conditions using 10% Pd/C in MeOH. When a 10% Pd/C-ethylenediamine complex catalyst [10% Pd/C(en)] was used instead of 10% Pd/C, the undesirable problem was perfectly overcome and the chemoselective hydrogenation of reducible functionalities leaving intact the TBDMS protective group was achieved.

Full text of DOI:10.1016/S0040-4020(01)00060-6

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2109±2114
Undesirable deprotection of O-TBDMS groups by Pd/C-catalyzed
hydrogenation and chemoselective hydrogenation using
a Pd/C(en) catalyst
Kazuyuki Hattori, Hironao Sajikip and Kosaku Hirotap
Laboratory of Medicinal Chemistry, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585, Japan
Received 1 December 2000; accepted 10 January 2001
AbstractÐIn general, O-TBDMS protective groups have been believed to be stable toward Pd/C-catalyzed hydrogenation conditions. In
practice, however, frequent and unexpected loss of the TBDMS protective group of a variety of hydroxyl functions occurred under neutral
and mild hydrogenation conditions using 10% Pd/C in MeOH. When a 10% Pd/C±ethylenediamine complex catalyst [10% Pd/C(en)] was
used instead of 10% Pd/C, the undesirable problem was perfectly overcome and the chemoselective hydrogenation of reducible function-
alities leaving intact the TBDMS protective group was achieved. q 2001 Elsevier Science Ltd. All rights reserved.
Since a hydroxyl group can participate in numerous trans-
formations under mild conditions, a central problem in
organic synthesis is to ensure that a speci®c hydroxyl
function in a multifunctional molecule is protected from
unwanted reactions altogether or until such time as its
intrinsic reactivity is required. Protective groups suitable
for contemporary synthesis should ensure ef®ciency of
preparation, selective removal and stability under the
intended reaction conditions. Silyl-protective groups have
been and are widely used among organic chemists
especially in multi-step natural product synthesis. An
especially important requirement of the protective groups
is to have sets of orthogonally usable groups available,
which can be introduced and removed in essentially quanti-
tative yields. Since the introduction of a tert-butyldimethyl-
silyl (TBDMS) group to synthetic chemistry by Corey,1 the
TBDMS ether has become among the most frequently used
silyl protective groups for a hydroxyl 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.2 Although it has been common
knowledge that the TBDMS ether is inert towards palla-
dium-catalyzed hydrogenation conditions,1 we have
frequently observed that it can be completely or partially
hydrogenolyzed to form the parent alcohols (e.g. using 10%
Pd/C, 1 atm H2, MeOH solvent, at 208C).3 The unexpected
loss of the TBDMS protective group from a hydroxyl
function would cause extensive damage to a synthetic
process. Further, Cormier et al. have reported the removal
of the TBDMS protective group from primary and secon-
dary hydroxyl groups by catalytic transfer hydrogenolysis
(CTH) using PdO as a catalyst in re¯uxing cyclohexene±
MeOH.4 Therefore, we questioned whether the TBDMS
group is essentially stable under palladium-catalyzed hydro-
genation conditions. Herein we provide a detailed dis-
cussion regarding the stability of the TBDMS ether under
hydrogenation conditions using Pd catalysts and further,
disclose a very practical catalyst that overcomes the unde-
sirable problem.
1. Results and discussion
In our initial investigations, the stability of the TBDMS
group of cinnamyl alcohol TBDMS ether (1a)5 under hydro-
genation conditions using several Pd catalysts was studied
(Table 1). All the reactions were carried out on a 0.25 mmol
scale in MeOH (1 mL) under hydrogen atmosphere (1 atm)
at room temperature for 24 h. When 2 mol% of Pd black as a
catalyst was used, 73% of the TBDMS protective group was
deprotected (entry 1). Moreover, when 5% Pd/C or 10% Pd/
C (10% of the weight of the substrate) purchased from
Aldrich was used, the TBDMS protective group was sur-
prisingly and completely deprotected to give 3-phenyl-1-
propanol (3a) as the sole product (entries 2 and 3). To elimi-
nate the possibility of the methanolysis by a contaminated
acid in Pd/C-catalyzed cleavage of the TBDMS protective
group, the reaction of 1a was performed without the hydro-
gen condition. As a consequence of the reaction, neither
desilylation nor hydrogenation occurred, even after 24 h
(entry 4). Further, by use of freshly prepared absolute
hexane6 as a non-protic solvent, partial but appreciable
cleavage of the TBDMS group of 1a was observed (entry 5).
Keywords: TBDMS ethers; desilylation; Pd/C; Pd/C(en); chemoselective
hydrogenation.
p
Corresponding authors. Tel.: 181-58-237-3931; fax: 181-58-237-5979;
e-mail: sajiki@gifu-pu.ac.jp
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00060-6

2110
K. Hattori et al. / Tetrahedron 57 (2001) 2109±2114
Table 1. Hydrogenation of 1a using various Pd catalysts
Product (%)a
Entry
Catalyst
2a
27
3a
73
100
100
No reaction
14
0
1
2
3
4
5
6
7
Pd blackb
5% Pd/Cc
10% Pd/Cc
0
0
No reaction
86
100
100
(Without H2)
(In hexane instead of MeOH)
(With NH3)d
10% Pd/C(en)
0
Unless otherwise speci®ed, the reaction was carried out using 0.25 mmol of 1a with catalyst (10% of the weight of the substrate) in MeOH (1 mL) under
hydrogen atmosphere (1 atm) at room temperature for 24 h.
a
b
c
d
1
Determined by H NMR.
2 mol% of Pd.
Purchased from Aldrich.
Ammonia±methanol (0.5 equiv. of NH3) was added to the reaction mixture.
Scheme 1.
When using CD3OD as a solvent for the 10% Pd/C-cata-
lyzed hydrogenation of 1a, quantitative formation of
TBDMS-OCD3 and TBDMS-OD was observed by 13C
NMR together with the desilylated alcohol (3a±D) (Scheme
1). No reaction (solvolysis) was observed, as well as when
MeOH was used as a solvent (Table 1, entry 4), even after
24 h without hydrogen conditions. Although tert-butyldi-
methylsilane (TBDMS-H) has not been detected, probably
owing to its instability in the presence of 10% Pd/C in
CD3OD,7 TBDMS-OCD3 and TBDMS-OD were formed
by the 10% Pd/C-catalyzed solvolysis of TBDMS-H with
CD3OD and contaminated water in commercial CD3OD
(Scheme 1). The theory was further tested by the 10% Pd/
C-catalyzed solvolysis using a commercial TBDMS-H in
CD3OD under hydrogen or Ar atmosphere. Although
TBDMS-H was stable without 10% Pd/C in CD3OD at
least during the 13C NMR operation period, the result
showed that the formation of the same solvolysis products,
TBDMS-OCD3 and TBDMS-OD, was observed within only
0.5 h by 13C NMR as expected (Scheme 2). This provides
evidence that TBDMS-H is a key product in this reaction
and suggests that the 10% Pd/C-catalyzed solvolysis of
TBDMS-H with MeOH (CD3OD) and water (D2O or
DHO) must proceed subsequently. Therefore, it was clearly
suggested that the deprotection of the TBDMS group
proceeded through hydrogenolysis catalyzed by palladium.
We have recently demonstrated the addition of a catalytic
amount of nitrogen containing a base, such as ammonia,
pyridine, ammonium acetate and so on, to the reaction
system selectively suppressed the Pd/C-catalyzed hydro-
genolysis of the O-benzyl protective group of alcohols in
the coexistence of other reducible functionalities (e.g.
ole®n, N-Cbz, nitro, benzyl ester or azide).8 We expected
that the undesirable deprotection of the TBDMS group was
also suppressed by the addition of a catalytic amount of a
nitrogen-containing base if the TBDMS group was actually
hydrogenolyzed by palladium. In fact, the desilylation of the
TBDMS group was thoroughly suppressed, and chemo-
selective hydrogenation of ole®n was achieved in the
presence of 0.5 equiv. vs 1a of ammonia to give 2a as the
sole product (entry 6). Furthermore, we have recently
reported a couple of chemo- and regio-selective hydrogena-
tion methods using a carbon-supported Pd±ethylenediamine
complex [Pd/C(en)]9 that possesses less catalytic activity
toward benzyl ethers,9a N±Z protective groups,9b benzyl
alcohols,9c and epoxides9d compared to commercial Pd/C
because the coordinated ethylenediamine acts as a gentle
catalyst-poison. We expected that employment of 10% Pd/
C(en)10 instead of 10% Pd/C for the hydrogenation of the
TBDMS ethers would inhibit deprotection of the TBDMS
group. As the result, the hydrogenation of 1a using 10% Pd/
C(en) led to the chemoselective hydrogenation of only the
ole®n function (entry 7).
Scheme 2.

K. Hattori et al. / Tetrahedron 57 (2001) 2109±2114
2111
Table 2. Hydrogenation in the presence of O-TBDMS group using 10% Pd/C or 10% Pd/C(en) as a catalyst; 10% Pd/C was purchased from Aldrich and 10%
Pd/C(en) was prepared from 10% Pd/C (Aldrich)9
a
Determined by 1H NMR.
b Isolated yield.
Commercially available (Aldrich or TCI).
c
Unless otherwise speci®ed, the reaction was carried out using 0.25 mmol of the substrate (1a±i and 2a) with catalyst (10% of the weight of the substrate) in
MeOH (1 mL) under hydrogen atmosphere (1 atm) at room temperature for 24 h.
To explore the generality of the undesirable hydrogenolysis
of the TBDMS ether with commercial 10% Pd/C and the
scope of the chemoselective hydrogenation with 10% Pd/
C(en) catalyst, the hydrogenation of various substrates was
investigated (Table 2). The results shown in entries 1, 2, 5±
8, 17±20 demonstrate that the hydrogenation of readily
reducible (less steric hindrance) ole®n (1a, 1b,11 1c and
1i12) and nitro (1h) functionalities can be successfully
carried out using either 10% Pd/C or 10% Pd/C(en) as a
catalyst. Although the hydrogenolytic debenzylation of
1d13 using commercial 10% Pd/C, of course, proceeded
smoothly (entry 9), the hydrogenation using 10% Pd/C(en)
completely tolerates the benzyl ether of 1d (entry 10) as
already reported by us.9a The tri-substituted ole®n function
of 1f14 was stable under these conditions using either 10%
Pd/C or 10% Pd/C(en) (entries 13 and 14). On the other
hand, we made the unexpected and extremely serious
observation that the TBDMS protective group of primary
alcohols (1a±d and 2a15) can be hydrogenolyzed easily
using commercial 10% Pd/C as a catalyst to form the parent
alcohols as the sole product, respectively (entries 1, 3, 5, 7
and 9). The TBDMS ether of 1e, 1f or 1g16 was partially

2112
K. Hattori et al. / Tetrahedron 57 (2001) 2109±2114
Scheme 3.
hydrogenolyzed (41, 44 or 31%, respectively) under these
conditions to give a mixture of 1e and 3e, or 1f and 3f or 1g
and 3g (entries 11, 13 and 15). It should be noted that the
hydrogenolysis tolerates the TBDMS ethers possessing an
amino moiety within a molecule of the product due to the
catalyst-poisonous effect (2h, entry 17 and see also Table 1,
entry 6). An aryl TBDMS ether (1i) seems to be more stable
than an alkyl TBDMS (only 8% of the O-TBDMS cleaved,
entry 19, see also Scheme 1).17 On the other hand, when the
10% Pd/C(en) was used as a catalyst, no competitive and
reluctant hydrogenolysis of the TBDMS ether was
observed, without exception, under the same conditions
(entries 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20) and chemo-
selective hydrogenation proceeded perfectly (entries 2, 6, 8,
18 and 20).
air pressure (max 1 atm). All reactions were monitored by
thin-layer chromatography (TLC) performed on glass-
backed silica gel 60 F254, 0.2 mm plates (Merck), and
compounds were visualized under UV light (254 nm) or
1
p-anisaldehyde solution with subsequent heating. H and
13C NMR spectra were obtained with a JEOL GX-270
(1H, 270 MHz) or a JEOL EX-400 (1H, 400 MHz, and
13C, 100 MHz) spectrometer. Chemical shifts are given in
parts per million from Me4Si in CDCl3 and coupling
constants (J) were reported in hertz (Hz). Low- and high-
resolution mass spectra were taken on a JEOL JMS-SX
102A machine. Microanalyses were accomplished at the
Microanalytical Laboratory of Gifu Pharmaceutical
University, Japan. All TBDMS ethers were prepared
according to the standard procedure.18
Furthermore, the competitive reaction of bis-TBDMS ether
(1j) possessing an alkyl TBDMS ether and an aryl TBDMS
ether was also examined. Although complete desilylation of
the alkyl TBDMS ether and partial desilylation of the aryl
TBDMS ether proceeded with commercial 10 % Pd/C
(4:5ˆ57:43), no hydrogenolysis of either the alkyl or aryl
TBDMS ether occurred when 10% Pd/C(en) was used as a
catalyst (Scheme 3).
3.1. Hydrogenation of 1a using Pd catalysts (Table 1)
After two vacuum/H2 cycles to remove air from the reaction
tube, a stirred mixture of the substrate (1a)5 (0.25 mmol),
catalyst Pd black (2 mol%), 5% Pd/C, 10% Pd/C or 10% Pd/
C(en) (10% of the weight of the substrate for Pd/Cs) in
MeOH or absolute hexane (1 mL) was hydrogenated at
ambient pressure (balloon) and temperature (ca. 208C) for
24 h. In the case of entry 4, the reaction was performed
without hydrogen. In the case of entry 6, 0.5 equiv. of
2 M ammonia±methanol was added to the reaction mixture.
The reaction mixture was ®ltered using a celite cake or a
membrane ®lter (Advantec Dismic-13HP, 0.45 mm) and the
®ltrate was concentrated in vacuo. The quantitative con-
version of the substrate and the products ratio of 2a15 and
2. Conclusions
We have clearly demonstrated the unreliability of the
TBDMS protective group for hydroxyl functions, especially
primary alcohols, under the hydrogenation conditions using
10% Pd/C catalyst. We believe that deprotection of the
TBDMS group proceeded through hydrogenolysis catalyzed
by palladium on carbon. Moreover, we have found the use
of the 10% Pd/C(en) catalyst totally suppressed the hydro-
genolysis of the TBDMS ether and have developed a
reliable and chemoselective hydrogenation method of
reducible functionalities (e.g. ole®n or nitro group) in the
presence of the TBDMS ether. The simplicity of this method
makes it an attractive new and safe tool for the organic
chemist.
1
3a were con®rmed by H NMR of the crude mixture in
CDCl3.
3.2. Hydrogenation of 1a in CD3OD (Scheme 1)
A stirred mixture of 1a (15 mg, 0.06 mmol), 10% Pd/C
(1.5 mg) in CD3OD (0.5 mL) was hydrogenated at ambient
pressure (balloon) and temperature (ca. 208C) for 24 h. To
determine volatile compounds, the reactions were per-
formed in an NMR tube. The formation of cinnamyl alco-
hol-d1 (3a±D), tert-butyldimetylsilyl methyl-d3 ether
(TBDMS-OCD3)19 and tert-butyldimethylsilanol-d1 (TBDMS-
OD) were con®rmed by 13C NMR of the reaction mixture.
3. Experimental
All reagents were purchased from commercial suppliers and
used without further puri®cation. 10% Pd/C was purchased
from Aldrich. 10% Pd/C(en) was prepared from 10% Pd/C
purchased from Aldrich according to the previously
published procedure.9a Flash column chromatography was
performed with Merck silica gel 60 (230±400 mesh) under
3.3. Pd-catalyzed solvolysis of tert-butyldimethylsilane7
(Scheme 2)
A stirred mixture of tert-butyldimethylsilane (TBDMS-H)
(15 mg, 0.13 mmol), 10% Pd/C (1.5 mg) in CD3OD
(0.5 mL) was stirred at ambient pressure (H2 or Ar balloon)

K. Hattori et al. / Tetrahedron 57 (2001) 2109±2114
2113
and temperature (ca. 208C) for 0.5 h. To determine volatile
compounds, the reactions were performed in an NMR tube.
The formation of tert-butyldimetylsilyl methyl-d3 ether
(TBDMS-OCD3) and tert-butyldimethylsilanol-d1 (TBDMS-
OD) was con®rmed by 13C NMR of the reaction mixture.
the ®ltrate was concentrated in vacuo. The quantitative
conversion of the substrate and the products ratio of 2 and
1
3 were con®rmed by H NMR of the crude mixture in
CDCl3. The crude mixture was puri®ed by ¯ash silica gel
column chromatography, if necessary. The products,
3-phenylpropanol (3a), decanol (3b), cyclohexylmethanol
(3c), ethyleneglycol (3d), 3,7-dimethyl-1-octanol (3e),
cholesterol (3f), 4-tert-butylcyclohexanol (3g), 2-propyl-
phenol (3i) and 2-(2-hydroxyethoxy)phenol (5) agreed
with the analytical data of commercially available samples.
3.3.1. 1-tert-Butyldimethylsilyloxymethyl-3-cyclohexene
(1c). To a solution of 3-cyclohexene-1-MeOH (1.12 g,
10.00 mmol), tert-butylchlorodimethylsilane (1.66 g, 11.00
mmol) and 4-dimethylaminopyridine (48 mg, 0.40 mmol)
in CH2Cl2 (20 mL) was added triethylamine (1.70 mL,
12.00 mmol). The reaction mixture was stirred at room
temperature for 24 h. The solvent was evaporated and the
residue was partitioned between ether (30 mL) and water
(30 mL). The organic layer was washed with water
(30 mL) and brine (30 mL) and dried over anhydrous
sodium sulfate. The solvent was removed in vacuo, and
¯ash column chromatography (hexane) yielded 1c (1.49 g,
66%) as a colorless oil. 1H NMR (400 MHz, CDCl3) d 0.07
(s, 6H), 0.92 (s, 9H), 1.26±1.28 (m, 1H), 1.61±1.82 (m, 3H),
2.10±2.14 (m, 3H), 3.49±3.54 (m, 2H), 5.67±5.72 (m, 2H);
13C NMR (100 MHz, CDCl3) d 25.3, 18.4, 24.8, 25.3, 26.0,
28.2, 36.4, 68.0, 126.3, 127.1; MS (FAB, NBA) m/z (%) 227
(26) [M11H]; Anal. Calcd for C13H26OSi 1/6H2O: C,
68.05; H, 11.57. Found: C, 68.05; H, 11.54.
3.4.1. 1-tert-Butyldimethylsilyloxymethylcyclohexane (2c).
A colorless oil; 1H NMR (270 MHz) d 0.03 (s, 6H), 0.89 (s,
9H), 1.10±1.78 (m, 11H), 3.38 (d, Jˆ6.3 Hz, 2H); 13C NMR
d 25.3, 18.4, 26.0, 26.8, 29.8, 40.5, 68.9; HRMS (EI) Calcd
for C13H28NOSi (M1) 228.1909. Found 228.1901.
3.4.2. 1-tert-Butyldimethylsilyloxy-2-(4-aminophenyl)-
ethane (2h). A brown oil; H NMR (400 MHz) d 0.00 (s,
1
6H), 0.88 (s, 9H), 2.71 (t, Jˆ6.4 Hz, 2H), 3.49 (brs, 2H),
3.74 (t, Jˆ7.3 Hz, 2H), 6.62 (d, Jˆ8.3 Hz, 2H), 6.99 (d,
Jˆ8.3 Hz, 2H); 13C NMR d 25.4, 18.3, 25.9, 38.8, 64.9,
115.1, 129.1, 129.9, 144.5; HRMS (EI) Calcd for
C14H25NOSi (M1) 251.1705. Found 251.1698.
3.4.3. 1-tert-Butyldimethylsilyloxy-2-propylbenzene (2i).
A colorless oil, 1H NMR (400 MHz) d 0.23 (s, 6H), 0.94 (t,
Jˆ7.5 Hz, 3H), 1.02 (s, 9H), 1.58 (hex, Jˆ7.5 Hz, 2H), 2.55
(t, Jˆ7.5 Hz, 2H), 6.77 (d, Jˆ7.6 Hz, 1H), 6.87 (t, Jˆ
7.6 Hz, 1H), 7.05 (t, Jˆ7.6 Hz, 1H), 7.12 (d, Jˆ7.6 Hz,
1H); 13C NMR d 24.2, 14.1, 18.2, 23.3, 25.8, 32.7, 118.3,
120.9, 126.5, 130.2, 133.3, 153.5; MS (EI) m/z (%) 250 (36)
[M11H], 193 (100), 163 (65); Anal. Calcd for C15H26OSi:
C, 71.93; H, 10.46. Found: C, 71.68; H, 10.60.
3.3.2. 1-tert-Butyldimethylsilyloxy-3,7-dimethyloctane (1e).
A colorless oil; 1H NMR (400 MHz) d 0.05 (s, 6H), 0.86 (s,
9H), 0.87 (s, 3H), 0.89 (s, 9H), 1.08±1.57 (m, 10H), 3.60±
3.67 (m, 2H); 13C NMR d 25.3, 18.4, 19.8, 22.6, 22.7, 24.7,
26.0, 28.0, 29.5, 37.4, 39.3, 40.0, 61.6; MS (FAB, NBA) m/z
(%) 237 (13) [M11H]; Anal. Calcd for C16H36Osi 1/8H2O:
C, 69.93; H, 13.30. Found: C, 69.90; H, 13.54.
3.3.3.
1-tert-Butyldimethylsilyloxy-2-(4-nitrophenyl)-
1
3.4.4.
2-tert-Butyldimethylsilyloxy(2-hydroxyethoxy)-
ethane (1h). A pale yellow oil; H NMR (400 MHz) d
20.04 (s, 6H), 0.85 (s, 9H), 2.91 (t, Jˆ6.4 Hz, 2H), 3.85
(t, Jˆ6.4 Hz, 2H), 7.37 (d, Jˆ8.8 Hz, 2H), 8.15 (d, Jˆ
8.8 Hz, 2H); 13C NMR d 25.5, 18.2, 25.8, 39.2, 63.3,
123.3, 130.0, 146.6, 147.6; HRMS (FAB, NBA) Calcd for
C14H24NO3Si (M11H) 282.1525. Found 282.1513.
1
benzene (4). A colorless oil; H NMR (400 MHz) d 0.18
(s, 6H), 1.02 (s, 9H), 2.25 (t, Jˆ5.2 Hz, 1H), 3.92 (q, Jˆ
5.2 Hz, 2H), 4.09 (t, Jˆ5.2 Hz, 2H), 6.86±6.92 (m, 4H); 13C
NMR d 24.7, 18.3, 25.6, 61.3, 70.4, 114.6, 121.1, 121.7,
121.9, 145.3, 150.0; HRMS (FAB, NBA) Calcd for
C14H24O3Si (M11H) 269.1573. Found 269.1566.
3.3.4. 2-tert-Butyldimethylsilyloxy(2-tert-butyldimethyl-
silyloxyethoxy)benzene (1j). A pale yellow oil; H NMR
1
(400 MHz) d 0.08 (s, 6H), 0.16 (s, 6H), 0.91 (s, 9H), 1.00 (s,
9H), 3.97 (t, Jˆ5.5 Hz, 2H), 4.03 (t, Jˆ5.5 Hz, 2H), 6.81±
6.88 (m, 4H); 13C NMR d 25.4, 24.6, 18.3, 18.4, 25.8,
25.9, 61.8, 69.9, 113.8, 121.1, 121.2, 121.7, 145.3, 150.4;
MS (FAB, NBA) m/z (%) 383 (20) [M11H]; Anal. Calcd
for C20H38O3Si2: C, 62.77; H, 10.01. Found: C, 62.42; H,
10.20.
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