Chemoselective hydrosilylation of hydroxyketones

Article abstract of DOI:10.1016/j.tet.2013.04.055

A chemoselective method for the hydrosilylation of ketones has been developed, using the combination of triphenylsilane and a catalyst prepared from Ni(COD)₂ and the simple N-heterocyclic carbene IMes. The most notable feature of this method is that free hydroxyls are largely unaffected, thus providing a simple one-step procedure for the conversion of hydroxyketones to mono-protected diols, wherein the protecting group is exclusively installed on the ketone-derived hydroxyl. The process is typically high yielding with both simple ketones and more complex hydroxyketone substrates.

Full text of DOI:10.1016/j.tet.2013.04.055

Tetrahedron xxx (2013) 1e5
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Chemoselective hydrosilylation of hydroxyketones
*
Marta L. Lage, Scott J. Bader, Kanicha Sa-ei, John Montgomery
Department of Chemistry, University of Michigan, Ann Arbor, MI 48109-1055, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A chemoselective method for the hydrosilylation of ketones has been developed, using the combination
of triphenylsilane and a catalyst prepared from Ni(COD)2 and the simple N-heterocyclic carbene IMes.
The most notable feature of this method is that free hydroxyls are largely unaffected, thus providing
a simple one-step procedure for the conversion of hydroxyketones to mono-protected diols, wherein the
protecting group is exclusively installed on the ketone-derived hydroxyl. The process is typically high
yielding with both simple ketones and more complex hydroxyketone substrates.
Received 13 March 2013
Received in revised form 12 April 2013
Accepted 15 April 2013
Available online xxx
Keywords:
Hydrosilylation
Site-selective
Ó 2013 Published by Elsevier Ltd.
Chemoselective
Nickel
Dehydrogenative silylation
1. Introduction
of carbonyls.4 The direct silylation of alcohols in the presence of
carbonyl functionality is straightforward using electrophilic silyla-
The addition or condensation of trialkylsilanes to either ketone
or alcohol functional groups has been widely developed using the
catalytic properties of a range of transition metal and Lewis acid
catalysts.1 The hydrosilylation of ketones proceeds by direct addi-
tion of the siliconehydrogen bond across the carbonyl functional-
ity,2 whereas the catalyzed addition of trialkylsilanes to alcohols
proceeds with the extrusion of hydrogen gas by a dehydrogenative
silylation.3 Therefore, irrespective of the oxidation state of the
starting material employed (ketone or alcohol), a simple silyl ether
results (Scheme 1).
tion reagents, such as chlorides or triflates. However, general pro-
tocols for the hydrosilylation of ketones in the presence of
unprotected alcohols have not been developed. In many cases, such
a transformation requires four distinct operations: alcohol pro-
tection, ketone reduction, orthogonal protection of the newly formed
hydroxyl, then removal of the initially installed protecting group
(Scheme 2). Devising a one-step process that accomplishes this
conversion would streamline synthetic routes that require this
conversion. Herein, we describe that ketone hydrosilylations readily
proceed in the presence of free hydroxyls with the specific combi-
nation of a nickeleN-heterocyclic carbene catalyst with triphe-
nylsilane, thus providing an efficient one-step process for this
commonly-used chemical conversion (Scheme 2).
Scheme 1. Silane additions to ketones or alcohols.
Despite the large number of reports describing either the
hydrosilylation of ketones or the dehydrogenative silylation of
alcohols, little attention has been placed on the development of the
chemoselective addition of silanes to hydroxyketones. Of the few
reports that address this issue, the dehydrogenative silylation of
alcohols typically proceedsfaster than thecompeting hydrosilylation
* Corresponding author. Tel.: þ1 734 764 4424; fax: þ1 734 763 1106; e-mail
Scheme 2. Selective reduction/protection of hydroxyketones.
address: jmontg@umich.edu (J. Montgomery).
0040-4020/$ e see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tet.2013.04.055
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2
M.L. Lage et al. / Tetrahedron xxx (2013) 1e5
2. Results and discussion
both a-positions (Table 1, entry 2). A simple acyclic methyl ketone
also underwent high-yielding hydrosilylation to afford the corre-
sponding triphenylsilyl ether (Table 1, entry 3). Both menthone and
fenchone underwent high-yielding hydrosilylation as well, al-
though diastereoselectivities were modest to poor in these cases
(Table 1, entries 4 and 5). A limitation of this process is that strong
back-bonding ligands inhibit the catalyst reactivity. For this reason,
conjugated enones were generally unreactive, and their presence in
polyfunctional molecules prevented efficient reduction of isolated
ketones that would otherwise be reactive.
In the course of screening conditions for the hydrosilylation of
ketones in connection with a program devoted to the reductive
glycosylation of ketones,5 we observed that carbohydrate-derived
silanes were effective in both the hydrosilylation of ketones and
the dehydrogenative silylation of alcohols when nickel(0) com-
plexes of N-heterocyclic carbenes were employed as the catalyst. In
contrast, triphenylsilane was especially effective in the nickel-
catalyzed hydrosilylation of ketones, but was relatively ineffective
for the dehydrogenative silylation of alcohols. We therefore antic-
ipated that the combination of triphenylsilane with Ni(0)eNHC
catalysts might be effective for chemoselective ketone hydro-
silylations of hydroxyketone substrates.
When examining the potential for chemoselective ketone
hydrosilylations using hydroxyketone substrates, common hydro-
silylation catalysts, such as CueIMes complexes,2 Wilkinson’s cat-
alyst,6 and Karstedt’s catalyst7 typically produced complex reaction
mixtures. In these cases, the alcohol dehydrogenative silylation
pathway was typically preferred, and substantial bis-silylation of
both the alcohol and ketone functionality was observed in reactions
carried out with complete consumption of the hydroxyketone
substrate. In contrast, the use of Ph3SiH with a catalyst derived from
a mixture of Ni(COD)2, 1,3-bis-(2,4,6-trimethylphenyl)imidazolium
hydrochloride (IMes$HCl), and t-BuOK (0.1 equiv of each) provided
a highly active combination for ketone hydrosilylations at rt, with
minimal competing reactivity of the hydroxyl functionality when
hydroxyketones substrates were employed.8,9
Table 2
Hydrosilylation of hydroxyketones
Ni(COD)2 (10 mol %)
O
OSiPh3
R1 R2
+ Ph3SiH
(1.1 equiv)
R1 R2
(1.0 equiv)
IMes•HCl (10 mol %)
t-BuOK (10 mol %)
THF, rt
Entry
Substrate
Product (% yield isomer ratio)
OSiPh3
OH
O
1
OH
(75 %)
OSiPh3
H
+
O
H
OSiPh3
2
OH
OH
OH
(87%, 13:1)
Several examples of simple hydrosilylations of cyclic and acyclic
ketones were conducted to illustrate that a range of substitution
patterns are tolerated in the process. For example, an unhindered
enolizable cyclohexanone derivative underwent facile hydro-
silylation in near quantitative yield (Table 1, entry 1), as did a much
more hindered derivative that possessed quaternary substitution at
OH
OH
3
Ph3SiO
84%, (1.2:1)
O
OSiPh3
Table 1
Hydrosilylation of simple ketones
H
Ni(COD)2 (10 mol %)
O
OSiPh3
R2
O
+ Ph3SiH
H
H
R1
R2
R1
HO
IMes•HCl (10 mol %)
t-BuOK (10 mol %)
THF, rt
H
OSiPh3
4
(1.0 equiv) (1.2 equiv)
+
H
H
H
HO
H
H
Entry
1
Substrate
Product (% yield isomer ratio)
HO
OSiPh3
O
91% (2:1)
Ph3SiO
(95%)
O
O
OSiPh3
H
5
H
2
3
H
H
(98%)
H
H
HO
HO
94% (2.8:1)
O
OSiPh3
(98%)
Ph
Ph
OSiPh3
OH
OH
OSiPh3
H
O
OH
+
H
H
H
H
4
Ph3SiO
Ph3SiO
H
6
(97%, 1.3:1)
+
+
H
H
H
O
H
H
H
OSiPh3
5
H
OSiPh3
H
O
94% (2.4:1)
(98%, 2.7:1)
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M.L. Lage et al. / Tetrahedron xxx (2013) 1e5
3
Following these studies with simple ketones, a range of hydrox-
yketones were examined (Table 2). By employing only 1.1 equiv of
Ph3SiH, complete conversionwas noted in most cases, with very high
selectivity for ketone hydrosilylation. Under these conditions, very
little dehydrogenative silylation of the alcohol functionality was
observed.
Chemical 13C NMR shifts are reported in CDCl3 solution and refer-
enced to the central signal of CDCl3 (77.00 ppm). IR spectra were
conducted on a PerkineElmer FT-IR BX Spectrometer. High resolu-
tion mass spectra were obtained on a VG-70-250-s mass spec-
trometer manufactured by Micromass Corp. (Manchester, UK) at the
University of Michigan Mass Spectrometry Laboratory.
With a simple hydroxyketone substrate, hydrosilylation of the
methyl ketone was observed in good yield (Table 2, entry 1), and only
4% of the bis-silylated derivative was observed. With 2-hydroxy-3-
pinanone, highly diastereoselective ketone hydrosilylation was ob-
served to afford the mono-protected syn-diol derivative in a 13:1
ratio with the anti diastereomer as a minor component of the re-
action mixture (Table 2, entry 2). With a hydroxyadamantanone
derivative, highly chemoselective ketone hydrosilylation was ob-
served to provide monosilylated product in 84% as a 1.2:1 ratio of
diastereomers, with only 2% of the bis-silylated derivative observed
(Table 2, entry 3).
A set of steroid derivatives were also examined and uniformly
provided chemoselective ketone hydrosilylation. Hydrosilylation of
a D-ring ketone proceeded to provide a 2:1 ratio of diastereomers
without affecting the A-ring hydroxyl (Table 2, entry 4). Similarly,
a simple methyl ketone was hydrosilylated with 2.8:1 diaster-
eoselectivity also without affecting the A-ring hydroxyl (Table 2,
entry 5). Finally, chemoselective hydrosilylation of the A-ring ketone
in a saturated derivative proceeded in 2.4:1 diastereoselectivity to
provide the anticipated monosilylated product (Table 2, entry 6).
Given the air-sensitive nature of Ni(COD)2, the corresponding
procedure employing stable and inexpensive Ni(acac)2 as pre-
catalyst was also developed. Reduction of Ni(acac)2 with DIBAL-H
in the presence of cyclooctadiene afforded Ni(COD)2 in situ,10
which was washed with ether and then used in the procedure as
described above in the hydrosilylation of 5-hydroxy-2-
adamantanone (500 mg) with triphenylsilane. By this protocol, an
82% yield (1.3:1 dr) of the expected mono-protected diol was ob-
tained along with 14% of the corresponding bis-protected diol.
4.2. General procedure for nickel-catalyzed hydrosilylation of
carbonyl compounds
To a round-bottom flask placed inside a glovebox were added
Ni(COD)2 (0.10 equiv), 1,3-bis-(2,4,6-trimethylphenyl)imidazolium
hydrochloride (IMes$HCl) (0.10 equiv), and potassium tert-butoxide
(0.10 equiv). The flask was then sealed with a rubber septum, re-
moved from the glovebox, and placed under a positive nitrogen
atmosphere. THF (1.5 mL) was added and the resulting dark green/
blue mixture was stirred for 15 min at rt. This solution was then
added via gas-tight syringe to a stirring solution of triphenylsilane
(1.2 equiv for hydrosilylation of simple ketones and 1.1 equiv for
hydroxy-ketones) and the corresponding carbonyl compound
(1 equiv) under nitrogen. The reaction mixture was stirred at rt and
was monitored by TLC until total consumption of the corresponding
carbonyl compound was noted. Upon completion, the reaction was
exposed to air, silica gel was added, solvent was evaporated in
vacuo, and the resulting residue was directly loaded on a silica
column and purified.
4.2.1. Triphenyl(3,3,5,5-tetramethylcyclohexyloxy)silane (Table 1, entry
1). According to general procedure described above, 3,3,5,5-
tetramethylcyclohexanone (77 mg, 0.5 mmol), Ph3SiH (156 mg,
0.6 mmol), Ni(COD)2 (14 mg, 0.05 mmol), IMes$HCl (17 mg,
0.05 mmol), and t-BuOK (6 mg, 0.05 mmol) were reacted to yield,
after purification of the crude product (SiO2, hexanes), 197 mg
(95%) of triphenyl(3,3,5,5-tetramethylcyclohexyloxy)silane as
a white solid. 1H NMR (CDCl3, 400 MHz)
d 7.72 (m, 6H), 7.56e7.31
(m, 9H), 4.10 (tt, J¼3.9, 11.2 Hz, 1H), 1.70e1.65 (m, 2H), 1.28 (t,
3. Summary and conclusions
J¼11.9 Hz, 2H), 1.16 (dt, J¼13.6, 1.9, 1.6 Hz, 1H), 1.07 (d, J¼13.6 Hz,
1H), 0.92 (s, 6H), 0.81 (s, 6H); 13C NMR (CDCl3, 100 MHz)
d 135.4,
In summary, a highly chemoselective ketone hydrosilylation
reaction has been developed employing triphenylsilane and
a nickel NHC catalyst. In contrast to most catalytic ketone hydro-
silylation methods, this procedure occurs chemoselectively in the
presence of free hydroxyls. Therefore the procedure provides
a convenient one-step procedure for the conversion of hydrox-
yketones to mono-protected diols, with selective installation of the
protecting group onto the ketone-derived hydroxyl. We anticipate
that this feature will be beneficial in streamlining synthetic se-
quences that require this common operation.
135.0, 129.9, 127.8, 68.1, 51.4, 48.6, 35.1, 32.5, 27.6; IR (film, cmꢁ1
)
3067, 2950, 1589, 1428, 1115, 1069; HRMS (EI) m/z calculated for
C
28H34OSi [M]þ¼414.2379, found 414.2373.
4.2.2. Triphenyl(2,2,6,6-tetramethylcyclohexyloxy)silane (Table 1, entry
2). 2,2,6,6-Tetramethylcyclohexanone (77 mg, 0.5 mmol), Ph3SiH
(156 mg, 0.6 mmol), Ni(COD)2 (14 mg, 0.05 mmol), IMes$HCl (17 mg,
0.05 mmol), and t-BuOK (6 mg, 0.05 mmol) were reacted following the
general procedure. After purification of the crude product thus ob-
tained (SiO2, hexanes), triphenyl(2,2,6,6-tetramethylcyclohexyloxy)si-
lane was afforded as a white solid (207 mg, 98%). 1H NMR (CDCl3,
4. Experimental
4.1. General
400 MHz) d 7.64 (m, 6H), 7.48e7.39 (m, 9H), 3.11 (s, 1H), 1.58 (qt,
J¼13.6, 3.2 Hz, 1H), 1.44e1.39 (m, 2H), 1.28 (dquint, J¼13.6, 3.6 Hz, 1H),
1.20 (s, 6H), 1.02 (td, J¼13.6, 3.6 Hz, 2H), 0.78 (s, 6H); 13C NMR (CDCl3,
100 MHz) d 135.8, 135.4, 129.5, 127.6, 87.0, 40.4, 36.8, 32.9, 20.5, 18.3; IR
All reagents were used as received unless otherwise noted. Tet-
rahydrofuran (THF), dichloromethane (DCM), diethyl ether (Et2O),
and N,N-dimethylformamide (DMF) were treated under nitrogen
using a solvent purification system (Innovative Technology, Inc.,
Model # SPS-400-3 and PS-400-3). Ni(COD)2 (Strem Chemicals Inc.,
used as received), potassium tert-butoxide (t-BuOK), and 1,3-bis-
(2,4,6-trimethyl-phenyl)imidazolium chloride (IMes$HCl) were
stored and weighed in an inert atmosphere glovebox. All reactions
were conducted in flame-dried glassware under an oxygen-free
atmosphere of nitrogen. 1H and 13C spectra were recorded in
CDCl3 at rt (25 ꢀC), on a Varian Inova 400 or Varian MR400. Chemical
1H NMR shifts were recorded in parts per million (ppm) on the
(film, cmꢁ1) 3067, 2925, 1589, 1428, 1113, 1072; HRMS (EI) m/z calcu-
lated for C28H34OSi [M]þ¼414.2379, found 414.2392.
4.2.3. Triphenyl(4-phenylbutan-2-yloxy)silane(Table 1,entry3). Benzylace-
tone (45 mL, 0.3 mmol), Ph3SiH (94 mg, 0.36 mmol), Ni(COD)2
(8 mg, 0.03 mmol), IMes$HCl (10 mg, 0.03 mmol), and t-BuOK
(3 mg, 0.03 mmol) were reacted under nitrogen following general
procedure. After purification of the crude product (SiO2, hexanes/
ethyl acetate: 10:1), the desired product was achieved as a colorless
oil (122 mg, 98%). 1H NMR (CDCl3, 400 MHz)
d 7.55 (m, 6H),
7.34e7.24 (m, 9H), 7.12e7.03 (m, 3H), 6.94 (m, 2H), 3.96 (sex,
J¼6.4 Hz, 1H), 2.62e2.45 (m, 2H), 1.84e1.75 (m, 1H), 1.71e1.62 (m,
d
scale and referenced to residual chloroform peak (7.27 ppm).
1H), 1.12 (d, J¼5.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
d 142.3, 135.5,
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4
M.L. Lage et al. / Tetrahedron xxx (2013) 1e5
135.0, 129.8, 128.3, 128.2, 127.8, 125.6, 69.5, 41.1, 31.8, 23.5; IR (film,
cmꢁ1) 3067, 2025, 2968, 2927, 1589, 1428, 1115, 1060, 1025; HRMS
(ESI, Naþ added) m/z calculated for C28H28OSi [MþNa]þ¼431.1807,
found 431.1815.
hydroxy-3-pinanone (84 mg, 0.5 mmol), Ph3SiH (143 mg,
0.55 mmol), Ni(COD)2 (14 mg, 0.05 mmol), IMes$HCl (17 mg,
0.05 mmol), and t-BuOK (6 mg, 0.05 mmol) were reacted under ni-
trogen to give, after purification of the crude product (SiO2, hexanes/
ethyl acetate 10:1), 2,6,6-trimethyl-3-(triphenylsilyloxy)bicyclo[3.1.1]
heptan-2-ol (186 mg, 87%) as a 13:1 mixture of two diastereomers.
Both isomers were isolated and fully characterized (Assignment of
stereochemistry was made on the basis of NOE experiments for both
isomers).
4.2.4. ((2S,5R)-2-Isopropyl-5-methylcyclohexyloxy)triphenylsilane
(Table 1, entry 4). (ꢁ)-Menthone (77 mg, 0.5 mmol) was reacted with
Ph3SiH (156 mg, 0.6 mmol) in the presence of Ni(COD)2 (14 mg,
0.05 mmol), IMes$HCl (17 mg, 0.05 mmol), and t-BuOK (6 mg,
0.05 mmol) following general procedure (12 h). The crude product
thus obtained was purified (SiO2, 3% ethyl acetate in hexanes) to give
Major diastereomer: 1H NMR (CDCl3, 400 MHz)
d 7.70 (m, 6H),
7.50e7.40 (m, 9H), 4.23 (dd, J¼9.2, 5.2 Hz, 1H), 4.13 (s, 1H, OH),
2.21e2.16 (m, 1H), 2.07e2.03 (m, 1H), 2.00 (t, J¼5.6 Hz, 1H),
1.83e1.74 (m, 2H), 1.59 (d, J¼10.4 Hz, 1H), 1.33 (s, 3H), 1.22 (s, 3H),
((2S,5R)-2-isopropyl-5-methylcyclohexyloxy)triphenylsilane
as
a mixture of isomers (201 mg, 97%, dr 1.3:1). The establishment of
the relative stereochemistry of both isomers was made by reacting
the crude with n-Bu4NF (3 equiv of a 0.2 M solution in THF, rt,
overnight) and comparing the crude thus obtained with the known
corresponding alcohols (menthol vs neomenthol).11 1H NMR (CDCl3,
0.73 (s, 3H); 13C NMR (CDCl3, 100 MHz)
d 135.5, 133.7, 130.3, 128.0,
73.1, 71.8, 53.8, 40.5, 38.4, 38.2, 29.8, 28.5, 28.0, 24.2; IR (film, cmꢁ1
)
3498, 3068, 2906, 1587, 1426, 1117, 1058; HRMS (EI) m/z calculated
for C28H32O2Si [M]þ¼428.2172, found 428.2175.
400 MHz)
d
7.68e7.65 (m, 12H), 7.47e7.37 (m, 18H), 4.28 (m, 1H)
Minor diastereomer: 1H NMR (CDCl3, 400 MHz)
d 7.71 (m, 6H),
major isomer, 3.56 (m, 1H) minor isomer, 2.41 (qd, J¼7.2, 2.7 Hz,1H),
7.48e7.40 (m, 9H), 4.41 (dd, J¼9.9, 5.9 Hz, 1H), 2.27 (ddd, J¼13.9,
10.4, 4.4 Hz, 1H), 2.06 (dddd, J¼16.4, 10.4, 5.9, 1.6 Hz, 1H), 1.85e1.82
(m, 3H), 1.37 (s, 3H), 1.32 (d, J¼10.4 Hz, 1H), 1.23 (s, 3H), 1.06 (s, 3H);
1.99e1.90 (m, 1H), 1.79e1.54 (m, 7H), 1.37 (m, 2H), 1.20 (m, 2H),
0.92e0.74 (m, 17H), 0.55 (d, J¼6.8 Hz, 3H), 0.42 (d, J¼6.8 Hz, 3H); 13
C
NMR (CDCl3, 400 MHz)
d
135.6, 135.3, 135.2, 129.8, 127.8, 127.7, 73.9,
13C NMR (CDCl3, 100 MHz)
d 135.6, 134.6, 130.1, 127.9, 78.5, 76.0,
70.0, 50.3, 49.6, 45.4, 42.5, 35.3, 34.5, 31.6, 28.6, 26.0, 25.3, 24.5, 22.6,
22.3, 22.1, 21.4, 21.2, 20.9, 15.4, IR (film, cmꢁ1) 3068, 3049, 2952,
2919, 1589, 1428, 1115, 1082, 1064, 1050; HRMS (EI) m/z calculated
for C28H34OSi [Mþ]¼414.2379, found 4141.2380.
54.1, 40.1, 39.0, 36.6, 27.3, 26.1, 25.3, 23.0; IR (film, cmꢁ1) 3569,
3068, 2905, 1588, 1427, 1116, 1106, 1082; HRMS (EI) m/z calculated
for C28H32O2Si [M]þ¼428.2172, found 428.2176.
4.2.8. 4-(Triphenylsilyloxy)adamantan-1-ol (Table 2, entry 3). According
to the general procedure, 5-hydroxy-2-adamantanone (100 mg,
0.6 mmol), Ph3SiH (172 mg, 0.66 mmol), Ni(COD)2 (16 mg, 0.06 mmol),
IMes$HCl (20 mg, 0.06 mmol), and t-BuOK (7 mg, 0.06 mmol) were
reacted under nitrogen. After purification of the crude product thus
obtained (SiO2, hexanes/ethyl acetate 2:1), 4-(triphenylsilyloxy)ada-
mantan-1-ol was obtained as white solid (213.9 mg, 84%, 1.2:1 dr). Both
diastereomers were isolated and fully characterized. (2% of the bis-
silylated product was also observed.)
4.2.5. Triphenyl(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yloxy)silane
(Table 1, entry 5). Following the general procedure, (R)-(ꢁ)-fenchone
(76 mg, 0.5 mmol), Ph3SiH (156 mg, 0.6 mmol), Ni(COD)2 (14 mg,
0.05 mmol), IMes$HCl (17 mg, 0.05 mmol), and t-BuOK (6 mg,
0.05 mmol) were reacted under nitrogen (5 h) to afford, after puri-
fication of the crude product (SiO2, 2% ethyl acetate in hexanes),
triphenyl(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yloxy)silane as an
inseparable mixture of diastereomers (206 mg, 98%, dr 2.7:1) As-
signment of stereochemistry was made by reacting the crude mix-
ture with n-Bu4NF (3 equiv of a 0.2 M solution in THF, rt, 2 h) and
Major diastereomer: 1H NMR (CDCl3, 500 MHz)
d 7.64e7.62 (m,
6H), 7.46e7.37 (m, 9H), 3.91 (t, J¼2.9 Hz,1H), 2.33 (d, J¼11.5 Hz, 2H),
2.04 (m, 2H), 1.99 (m, 1H), 1.67 (m, 2H), 1.58 (m, 2H), 1.47 (d,
J¼11.5 Hz, 2H), 1.42e1.37 (m, 3H); 13C NMR (CDCl3, 100 MHz)
comparing the crude with the known corresponding alcohols.12 1
NMR (CDCl3, 400 MHz) 7.72 (m, 6 H), 7.48e7.39 (m, 9H), 3.56 (d,
H
d
J¼1.6 Hz, 1H) major isomer, 3.44 (d, J¼1.6 Hz, 1H) minor isomer, 2.13
(m, 1H), 2.03 (dq, J¼9.6, 1.9 Hz, 1H), 1.80 (m, 1H), 1.62 (m 1H),
1.53e1.30 (m, 4H),1.09e1.00 (m, 3H), 0.98 (s, 3H) minor isomer, 0.91
(s, 3H) minor isomer, 0.88 (d, J¼1.9 Hz, 3H) major isomer, 0.63 (s, 3H)
minor isomer; 0.62 (s, 3H) major isomer; 13C NMR (CDCl3, 100 MHz)
d 135.3, 134.8, 129.9, 127.8, 74.0, 67.8, 45.05, 39.3, 37.6, 34.8, 29.4; IR
(film, cmꢁ1) 3325, 3066, 2909, 1588, 1427, 1115, 1096, 1067; HRMS
(ESI, formic acid added) m/z calculated for
C
28H31O2Si
[MþH]þ¼427.2093, found 427.2083.
Minor diastereomer: 1H NMR (CDCl3, 400 MHz)
d 7.66e7.64 (m,
d
135.9, 135.8, 135.1, 135.1, 129.7, 129.7, 127.6, 87.4, 86.5, 49.9, 49.9,
6H), 7.48e7.38 (m, 9H), 4.08 (t, J¼2.8 Hz, 1H), 2.31 (d, J¼12.4 Hz, 2H),
48.6, 48.3, 44.5, 41.5, 41.1, 39.9, 33.5, 29.8, 26.3, 25.7, 25.5, 24.9, 21.9,
20.2, 18.8; IR (film, cmꢁ1) 3067, 2952, 1588, 1427, 1114, 1089; HRMS
(EI) m/z calculated for C28H32OSi [M]þ¼412.2222, found 412.2219.
2.16 (m,1H),1.95 (m, 2H),1.73 (m, 2H),1.61 (m, 4H),1.37 (d, J¼12.0 Hz,
2H), 1.28 (m, 1H); 13C NMR (CDCl3, 100 MHz)
d 135.3, 134.9, 129.9,
127.8, 74.8, 67.6, 45.4, 43.5, 36.5, 30.0, 29.9; IR (film, cmꢁ1) 3355,
3066, 2916, 1589, 1427, 1115, 1102, 1073; HRMS (ESI, formic acid
added) m/z calculated for C28H31O2Si [MþH]þ¼427.2093, found
427.2080.
4.2.6. 2-Methyl-3-(triphenylsilyloxy)butan-2-ol (Table 2, entry 1). 3-
Hydroxy-3-methylbutan-2-one (31 mg, 0.3 mmol), Ph3SiH (86 mg,
0.33 mmol), Ni(COD)2 (8 mg, 0.03 mmol), IMes$HCl (10 mg,
0.03 mmol), and t-BuOK (3 mg, 0.03 mmol) were reacted following
the general procedure. After purification of the crude (SiO2, hex-
anes/ethyl acetate: 10:1), 2-methyl-3-(triphenylsilyloxy)butan-2-ol
was achieved as a colorless oil (79 mg, 75%). 1H NMR (CDCl3,
4.2.9. 5-Ene-17-(triphenylsilyloxy)-3b-andostranol(Table 2,entry4). Follo-
wing the general procedure, 5-andostren-3b-hydroxy-17-one (100 mg,
0.35 mmol), Ph3SiH (108 mg, 0.42 mmol), Ni(COD)2 (10 mg, 0.03 mmol),
IMes$HCl (12 mg, 0.03 mmol), t-BuOK (4 mg, 0.03 mmol) were reacted
under nitrogen for 3 h. The reaction crude was purified (SiO2, 1:3 ethyl
acetate/hexanes) to afford the desired compound as a 2:1 mixture of
diastereomers (175 mg, 91%) The stereochemistry of both isomers was
established by reacting the mixture with n-Bu4NF (3 equiv of a 0.2 M
solution in THF, rt, overnight) and comparing the resulting crude to
400 MHz)
d
7.69e7.66 (m, 6H), 7.50e7.40 (m, 9H), 3.85 (q, J¼6.4 Hz,
1H), 2.35 (s, 1H), 1.22 (s, 3H), 1.18 (s, 3H), 1.15 (d, J¼6.4 Hz, 3H); 13
C
NMR (CDCl3, 100 MHz)
d 135.5, 134.4, 130.0, 127.9, 76.9, 73.1, 26.0,
23.8, 18.5; IR (film, cmꢁ1) 3446, 3068, 2978, 1589, 1428, 1115; HRMS
(ESI, Naþ added) m/z calculated for C23H26O2Si [MþNa]þ¼385.1600,
found 385.1586. Note: in this reaction a 4% yield of the bis-silylated
compound was also observed.
known compounds.13 1H NMR (CDCl3, 400 MHz)
d 7.64e7.60 (m, 6H),
7.45e7.36 (m, 9H), 5.38 (m, 1H) minor isomer, 5.32 (m, 1H) major isomer,
4.01 (d, J¼5 Hz, 1H) minor isomer, 3.79 (t, J¼8 Hz, 1H) major isomer, 3.69
(m, 1H), 2.31e2.21 (m, 2H), 1.85e1.42 (m, 14H), 1.28e1.03 (m, 3H), 1.01 (s,
4.2.7. 2,6,6-Trimethyl-3-(triphenylsilyloxy)bicyclo[3.1.1]heptan-2-ol
(Table 2, entry 2). Following general procedure (1S,2S,5S)-(ꢁ)-2-
3H), 0.92 (s, 3H), 0.78 (m, 2H); 13C NMR (CDCl3, 100 MHz)
d 140.8, 140.7,
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M.L. Lage et al. / Tetrahedron xxx (2013) 1e5
5
135.6, 135.5, 135.0, 129.8 (ꢂ2), 127.7, 121.7, 121.4, 82.6, 81.3, 77.2, 71.8, 71.7,
50.6, 50.2, 49.9, 49.6, 45.7, 43.4, 42.3, 42.2, 37.3, 37.2, 36.6, 36.5, 33.1, 32.2
(ꢂ2), 32.1, 31.9, 31.6, 31.5, 31.4, 30.8, 24.9, 23.6, 20.7, 19.4 (ꢂ2),16.8, 11.7; IR
(film, cmꢁ1) 3338, 3066, 2933, 188, 1428, 1115, 1083, 1060; HRMS (EI) m/z
calculated for C37H44O2Si [M]þ¼548.3111, found 548.3121.
added dropwise to give a brown solution, which was stirred at
ꢁ78 ꢀC for 30 min, and then at 0 ꢀC for another 30 min. THF was
then removed under vacuum and the resulting brownish oil was
washed with ether (1 mL portions) until all brown residues were
removed to give a bright yellow solid remaining (Ni(COD)2).
The ‘in situ’ generated Ni(COD)2 was dissolved in THF (5 mL) and
was transferred by cannula under nitrogen to a stirring solution of
IMes$HCl (102 mg, 0.3 mmol) and t-BuOK (34 mg, 0.3 mmol) in THF
(5 mL). The resulting dark green/blue solution was stirred under
nitrogen for 15 min and was then added by gas-tight syringe to
4.2.10. 5-Ene-20-(triphenylsilyloxy)-3b-pregnol (Table 2, entry 5). Pregn-
5-ene-3b-ol, 20-one (100 mg, 0.32 mmol) was reacted with Ph3SiH
(92 mg, 0.35 mmol) in the presence of Ni(COD)2 (9 mg, 0.03 mmol),
IMes$HCl (11 mg, 0.032 mmol), and t-BuOK (4 mg, 0.032 mol) following
general procedure. After total consumption of the starting material
(16 h), the crude mixture was purified to yield the desired compound as
a
stirring solution of 5-hydroxy-2-adamantanone (500 mg,
3 mmol) and Ph3SiH (859 mg, 3.3 mmol) in THF (20 mL). After total
consumption of the starting ketone (30 min), the reaction mixture
was opened to air, silica gel was added, the solvent was evaporated
in vacuo, and the crude mixture was directly loaded onto a silica
column and purified (ethyl acetate/hexanes: 2:1). This afforded the
desired product as a mixture of two isomers (dr: 1.3:1) (1.04 g, 82%),
as well as the bis-silylated product (319 mg, 14%). (See Section 4.2.8
for characterization).
1
a white solid (172 mg, 94%, 2.8:1 mixture of two diastereomers). H
NMR (CDCl3, 400 MHz) d 7.66 (m, 6H), 7.46e7.37 (m, 9H), 5.33 (m, 1H),
3.93 (m, 1H), minor isomer, 3.91 (m, 1H) major isomer, 3.53 (m, 1H),
2.33e2.24 (m, 3H), 2.16e1.96 (m, 2H), 1.85 (m, 3H), 1.63e1.40 (m, 10H),
1.23 (d, J¼6 Hz, 2H), 1.16e1.00 (m, 6H), 0.99 (m, 3H), 0.51 (m, 3H); 13
C
NMR (CDCl3, 100 MHz)
d 140.8, 140.7, 135.6, 135.5, 135.3, 135.2, 129.7,
129.6, 127.6, 127.6, 121.6, 121.5, 72.9, 72.4, 71.1, 71.6, 58.7, 58.3, 56.6, 56.3,
50.1, 50.0, 42.2, 42.2, 42.0, 41.3, 39.4, 38.8, 37.2, 31.2, 36.5, 31.9, 31.8, 31.7,
31.6, 31.5, 31.4, 27.2, 25.5, 24.3, 24.2, 24.1, 23.7, 20.8, 20.7, 19.4, 19.3, 12.3,
12.0; IR (film, cmꢁ1) 3354, 3066, 2931, 1588, 1427, 1114, 1078, 1040;
HRMS (EI) m/z calculated for C39H48O2Si [M]þ¼576.3424, found
576.3437.
Acknowledgements
The authors thank the NIH (GM57014) and Thermo Fisher for
generous financial support of this work. M.L.L. acknowledges
receipt of a summer stay fellowship within FPU-Program of the
Spanish Ministry of Science and Education (MEC).
4.2.11. 17-Hydroxy-3-(triphenylsilyloxy)-androstane(Table 2,entry6). Follo-
wing general procedure, 17-hydroxy-3-androstanone (145 mg, 0.5 mmol),
Ph3SiH (143 mg, 0.55 mmol), Ni(COD)2 (14 mg, 0.05 mmol), IMes$HCl
(17 mg, 0.05 mmol), and t-BuOK (6 mg, 0.05 mol) were reacted under
nitrogen for 1 h, yielding the corresponding carbonyl-hydrosilylated
product (purification achieved using 1:5 ethyl acetate/hexanes as eluent)
as a mixture of two diastereomers in a 2.4:1 ratio (258 mg, 94%). The
stereochemistry of both isomers was determined by n-Bu4NF deprotection
of the crude and comparison of the product thus obtained with known
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diols.14 1H NMR (CDCl3, 400 MHz)
d 7.61e7.58 (m, 12H), 7.42e7.32 (m,
18H), 4.18 (m, 1H), 3.73 (m, 2H), 3.62 (t, J¼8 Hz, 1H) minor isomer, 3.56
(t, J¼8 Hz, 1H) major isomer, 2.08e1.95 (m, 1H), 1.79e1.71 (m, 2H),
1.70e1.43 (m, 15H), 1.41e1.27 (m, 8H), 1.26e1.10 (m, 8H), 1.01e0.81 (m,
5H), 0.79 (s, 3H) major isomer, 0.76 (m, 2H), 0.72 (s, 3H) minor isomer, 0.71
(s, 3H) minor isomer, 0.68 (m, 3H) major isomer, 0.50 (m, 2H); 13C NMR
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77.2, 73.0, 68.4, 54.4, 51.0, 50.9, 44.8, 43.0, 42.9, 39.3, 38.3, 37.0, 36.7, 36.2,
36.1, 35.6, 35.4, 35.4, 32.6, 31.7, 31.6, 30.5, 29.3, 28.5, 28.4, 23.3, 20.7, 20.4,
12.3, 11.4, 11.1, 11.0; IR (film, cmꢁ1) 3373, 3066, 2928, 1428, 1374, 1115, 1073,
1026; HRMS (EI) m/z calculated for C37H46O2Si [M]þ¼550.3267, found
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establishing a positive nitrogen atmosphere, 1 mL THF and 1,5-
cyclooctadiene (146 mL, 1.2 mmol) were added, and the resulting
green slurry was cooled to ꢁ78 ꢀC in a dry ice/acetone bath. At this
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Please cite this article in press as: Lage, M. L.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.055