Bis-paracyclophane N-heterocyclic carbene-ruthenium catalyzed asymmetric ketone hydrosilylation

Article abstract of DOI:10.1016/j.tetlet.2005.03.026

New chiral bis-paracyclophane N-heterocyclic carbene (NHC) ligands 1-3 have been explored for ruthenium catalyzed asymmetric hydrosilylation of ketones using diphenylsilane to give enantioenriched alcohols. These ligands provide for efficient asymmetric reduction in the presence of silver(I) triflate (1 mol %) at room temperature with high reactivity and selectivity. Acetophenone 4 was reduced with 1 mol % catalyst in 96% isolated yield, 97% ee. Following removal of the silyl ether, various alcohols 5 were obtained from aromatic ketones in high yield and selectivity.

Full text of DOI:10.1016/j.tetlet.2005.03.026

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3241–3244
Bis-paracyclophane N-heterocyclic carbene–ruthenium
catalyzed asymmetric ketone hydrosilylation
Chun Song,b Changqin Ma,a Yudao Ma,a,* Wenhua Feng,a Shutao Ma,a Qiang Chaia
and Merritt B. Andrusb,*
aChemistry College of Shandong University, Shanda South Road #27, Jinan, Shandong 250100, PR China
bBrigham Young University, C100 BNSN, Department of Chemistry and Biochemistry, Provo, UT 84602-5700, USA
Received 15 February 2005; accepted 4 March 2005
Available online 24 March 2005
Abstract—New chiral bis-paracyclophane N-heterocyclic carbene (NHC) ligands 1–3 have been explored for ruthenium catalyzed
asymmetric hydrosilylation of ketones using diphenylsilane to give enantioenriched alcohols. These ligands provide for efficient
asymmetric reduction in the presence of silver(I) triflate (1 mol %) at room temperature with high reactivity and selectivity. Aceto-
phenone 4 was reduced with 1 mol % catalyst in 96% isolated yield, 97% ee. Following removal of the silyl ether, various alcohols 5
were obtained from aromatic ketones in high yield and selectivity.
ꢀ 2005 Elsevier Ltd. All rights reserved.
-
Asymmetric ketone reduction under nonhydrogenation
conditions provides a useful route to secondary alcohols
under mild, chemo-selective conditions. Meerwien–
Ponndorf–Verley and oxazaborolidine based methods
have been developed that demonstrate great success
with this important synthetic transformation.1 Hydrosil-
ylation using transition metal catalysts, primarily based
on rhodium and ruthenium, has also been reported to
access enantioenriched alcohols from ketones.2 Follow-
ing previous success with rhodium catalyzed arylboronic
acid additions,3 the use of novel, chiral paracyclophane
N-heterocyclic carbene ligands (Scheme 1) for highly
selective ruthenium catalyzed hydrosilylation is now
reported.
BF4
N+
N
-
BF4
Ph
Ph
N
N+
1
2
-
BF4
OMe
MeO
N
N+
3
Nishiyama established the standard for asymmetric
hydrosilylation reporting pyridylbisoxazoline–rhodium
catalysts (4 mol %) and diphenylsilane to reduce ace-
tophenone in 91% yield and 94% ee.4 P,N-Phosphine–
oxazoline and ferrocene based catalysts have also been
reported with promising results.5 More recently Fu has
reported the use of a planar chiral P,N-ferrocene based
catalyst that shows very high selectivity (98% ee) at room
temperature using mesitylphenylsilane6 and Lipshutz
and co-workers have reported the use of biphenyl-bis-
Scheme 1.
dixylylphosphine ligands under copper catalysts with
polymethylsilyl hydride at low temperature.7 Imidazo-
lium N-hetrocyclic carbene (NHC) based ligands have
also been reported for hydrosilylation reactions. Mono-
dentate rhodium bis-naphthyl and aminoalcohol derived
catalysts showed moderate selectivity.8 Shi reported the
development of a highly selective binaphthyl-bisbenzo-
imidazole ligand and Gade and co-workers have demon-
strated the success of NHC–oxazoline ligands.9
Keywords: Hydrosilylation; Paracyclophane; Asymmetric catalysis.
*
We recently reported a new class of bis-paracyclophane–
NHC ligands 1–3 and demonstrated their use as
Corresponding authors. Tel.: +1 8014228171; fax: +1 8014220153;
e-mail: mbandrus@chem.byu.edu
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.026

3242
C. Song et al. / Tetrahedron Letters 46 (2005) 3241–3244
ruthenium complexes for arylboronic acid additions
to enones.3 Planar chiral [2.2]paracyclophane ligands
include diphosphines,10 oxazoline-phosphines,11 oxazo-
line-imidazolium,12 oxazoline-selenides,13 oxazoline-
alcohols,14 and Schiff base-phenols for hydrogenation,
allylic substitution, and organozinc addition reactions.15
Dimeric chiral [2.2]paracyclophanes are rare and their
use as catalysts has not been reported previously.16
(11% ee) and tetrabutylammonium bromide (TBAB)
gave no reaction. Use of 0.1 mol % ruthenium, with
0.24 mol % 3, the reaction rate was very slow, 98 h,
and the yields and selectivities were reduced, 86%, 93%
ee. Use of greater amounts of the catalyst, for example,
1 mol % ruthenium with 2.4 mol % 3, showed no signifi-
cant improvement, 97%, 98% ee. Use of 1 equiv of
diphenylsilane gave a low yield, 56% (24 h) and the
selectivity was reduced, 90% ee. With 2 equiv, the yield
was reduced, 89% (18 h) and the selectivity was the
same, 97% ee. Use of 3 equiv gave no improvement over
the optimal 2.5 equiv shown.
The synthesis of the bis-paracyclophane ligands 1–3
begins with the known compound Sp-pseudo-ortho-
bromoamino [2.2]paracyclophane17 as previously re-
ported.3 The ligands were used under the conditions of
Uemura using conveniently available ruthenium dichlo-
ride tris(triphenylphosphine) (0.5 mol %) with added sil-
ver triflate (1 mol %) in THF at room temperature
(Table 1). With ligand 1, acetophenone was reduced, fol-
lowing work-up with HCl and purification by chroma-
tography, in 98% yield and 90% ee (chiral HPLC).18
Ligands 2 and 3 both gave S-phenylethanol in excellent
selectivity, 98% ee. Use of [RuCl2(PhH)]2 with 3 also
gave a high yield (97%, 24 h) but with reduced selectiv-
ity, 92% ee. The other test substrate at this time was 3-
methylpropylphenylketone, which was reduced using 3
in 97% ee (not shown). Ligand 2 was less selective,
90% ee in this case. Ligand 3 was selected for further
investigation to optimize the conditions and reduce
other substrates. Various solvents were explored with 3
and THF proved to be superior. Use of chloroform low-
ered the selectivity to 77% ee. Toluene and benzene gave
low yields (36% and 20%) and the selectivity was very
low. Dioxane was also low yielding, 58%, however the
selectivity was not greatly reduced, 92% ee. The ratio
of the metal to the ligand was also explored. At 1:1 ratio,
the reactivity was high, 96% in 16 h, and the selectivity
was compromised, 83% ee. At 1:2 ratio, the yield
(97%, 20 h) and the selectivity improved, 96% ee. The
optimal ratio at 1:2.4 (98%, 97% ee) is superior to 1:3
where both the yield (67%) and the selectivity (91% ee)
begin to be lowered.
Other methyl ketones were used under the optimized
conditions using the RuÆ3 complex as catalyst (Table
2). Cyclohexylmethyl ketone was one the of few sub-
strates that did not show high selectivity, 58% ee. All
other arylmethyl ketones, including ortho-substituted
substrates gave excellent yields and selectivities. More
electron rich, methyl and methoxy aryl ketones reacted
with high rates. p-Trifluoromethyl acetophenone
required 24 h and gave an 81% yield with only 77% ee.
This ligand 3–ruthenium combination also gave excel-
lent yields and selectivities for more hindered aryl
ketone substrates (Table 3). Ethyl, isopropyl, and sec-
butyl phenyl ketones were highly selective, 90–93% ee.
Even cyclohexylphenyl ketone reacted in 90% yield with
88% ee. Cyclic aryl ketones, indanone and benzocyclo-
hexanone also reacted with high selectivity, 93% and
92% ee.
While the origin of the stereoinduction remains difficult
to elucidate at this time, the nature of the Ru–ligand for-
mation and the step responsible for the selectivity may
be compared to mechanistic findings reported by Prock
and Giering for the related rhodium based process
(Scheme 2). Key findings in this and previous studies
determined that the reaction is first order in silane and
rhodium and there is a saturation effect with acetophe-
none only when ketone is present at high concentra-
tion.19 In the case of ruthenium with 3, excess ligand
may be needed to favor formation of mono-NHC com-
plex A. Silane then adds to the 14 e complex to give the
Various additives were also explored along with catalyst
and silane loadings for the process. Use of copper(II) tri-
flate, in place of silver(I) triflate, gave high reactivity,
97% (20 h) with lowered selectivity, 92% ee. Use of 18-
c-6 with potassium carbonate gave very low selectivity
Table 2. Reduction of methyl ketones
1.2 mol%
OH
3
O
Table 1. Hydrosilylation with cyclophane ligands
4
RuCl2(PPh3)3 0.5 mol%
R
R
OH
Ligand
O
AgOTf, THF, rt
/ H2O, HCl
5
+ Ph2SiH2
2.5 equiv.
RuCl2(PPh3)3 0.5 mol%
4
5
AgOTf, THF, rt
/ H2O, HCl
R =
Time (h)
% Yield
% ee
+ Ph2SiH2
2.5 equiv.
Ph
c-Hexyl
2-PhEt
16
36
15
20
15
16
36
20
12
12
48
98
93
95
98
92
96
91
90
98
91
81
97
58
93
96
96
94
93
97
96
93
77
Ligand
Ru/lig. ratio
Time (h)
% Yield
% ee
1
2
3
3
3
3
3
1:2.4
1:2.4
1:2.4
1:2.4
1:1
16
16
16
24
16
20
24
98
98
98
86
96
97
67
90
97
97
77a
83
96
91
2-Naphthyl
o-MeOPh
o-Tolyl
o-BrPh
o-ClPh
1:2
1:3
p-Tolyl
p-MeOPh
p-F3CPh
a CHCl3 used as solvent.

C. Song et al. / Tetrahedron Letters 46 (2005) 3241–3244
3243
Table 3. Ketone hydrosilylation
In summary, asymmetric hydrosilylation of ketones was
performed with new paracyclophane NHC ligands com-
plexed to ruthenium to give secondary alcohols in high
yield and selectivity under mild conditions. These results
expand the scope of these ligands and point the way
toward their use in other transition metal catalyzed
applications.
1.2 mol%
OH
R'
3
RuCl2(PPh3)3 0.5 mol%
Ketone
4
R
AgOTf, THF, rt
/ H2O, HCl
5
+ Ph2SiH2
2.5 equiv.
Ketone
Time (h)
16
% Yield
96
% ee
92
O
Acknowledgments
We are grateful to Brigham Young U. (M.B.A.), and
The Chemistry College of Shandong U. (Y.M.) for
funding this work.
O
O
O
18
36
95
89
93
90
Supplementary data
1H NMR and optical rotation data for all compounds.
Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/
j.tetlet.2005.03.026.
30
18
90
80
88
93
O
References and notes
O
30
90
92
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RuCl2(PPh3)3
OH
imid,THF
Ag+
Ar
R
H
5
Ph2SiH2
N
N
Ar
Ar
Ru
S
PPh3
A
N
N
N
N
Ar
Ar
Ar
Ar
Ar
Ru
Ru
H
S
D
H
B
SiPh2H
R
OSiPh2H
N
N
O
Ar
Ar
Ar
H
O
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Ru
Ar
R
C
4
R
SiPh2H
Scheme 2.
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metal hydride B. This step may be considered as the
turnover-limiting step. Dissociation of a solvent ligand
then allows for ketone coordination to give intermediate
C. Rapid transfer of silane to the carbonyl oxygen then
gives the inserted silyl ether D and reductive elimination
generates product and the complex A. The influence of
the chiral paracyclophanes would be expressed with
the reversible formation of the distorted square planar
g2-carbonyl complex C.

3244
C. Song et al. / Tetrahedron Letters 46 (2005) 3241–3244
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18. Representative procedure: A dry flask was charged with
[RuCl2(PPh3)3] (4.8 mg, 0.005 mmol), ligand 3 (9.4 mg,
0.012 mmol) and AgOTf (2.4 mg, 0.01 mmol, 1.0 mol %)
in THF (5.0 mL) under argon. The mixture was stirred in
rt for 30 min and ketone (1.0 mmol) was added, followed
by diphenylsilane (0.46 mL, 2.5 mmol) in THF (3.0 mL)
added slowly by syringe. The reaction was kept in 0 ꢁC
and the progress of the reaction was monitored by TLC.
After the reaction was judged to be complete, methanol
(2.0 mL) was added slowly and the mixture was poured
into a solution of hydrochloride acid (1 N, 6 mL). The
mixture was stirred for 30 min and extracted by CH2Cl2
(3 · 10 mL). The combined organic layers were washed
with brine and dried over anhydrous magnesium sulfate.
The solvent was concentrated by rotary evaporation and
the crude material was purified by silica gel chromato-
graphy using ethyl acetate/hexanes (10–25%). The known
product compounds, with the isolated yields indicated in
the tables were characterized by the individual data as
shown in the Supplementary data. % Ee was measured by
chiral HPLC (Chiracel, OD column) or GC (b-Dex
column).
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