Enantioselective hydrosilylation of prochiral ketones catalyzed by chiral BINAP-copper(I) complexes

Article abstract of DOI:10.1016/j.crci.2009.11.002

The CuCl/NaOt-Bu/BINAP system was found to efficiently catalyze the hydrosilylation of aryl alkyl ketones with excellent enantioselectivities by using phenyl methyl silane as a stoichiometric hydride source. High enantiomeric excesses (up to 97%) and excellent yields (up to 99%) were obtained.

Full text of DOI:10.1016/j.crci.2009.11.002

C. R. Chimie 13 (2010) 353–357
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Full paper / Memoire
Enantioselective hydrosilylation of prochiral ketones catalyzed by
chiral BINAP-copper(I) complexes
**
*
´
Jean-Thomas Issenhuth, Samuel Dagorne , Stephane Bellemin-Laponnaz
CNRS, universite´ de Strasbourg, institut de chimie, 1, rue Blaise-Pascal, 67000 Strasbourg, France
A R T I C L E I N F O
A B S T R A C T
Article history:
The CuCl/NaOt-Bu/BINAP system was found to efficiently catalyze the hydrosilylation of
aryl alkyl ketones with excellent enantioselectivities by using phenyl methyl silane as a
stoichiometric hydride source. High enantiomeric excesses (up to 97%) and excellent
yields (up to 99%) were obtained.
Received 8 July 2009
Accepted after revision 4 November 2009
Available online 21 January 2010
ß 2009 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Keywords:
Asymmetric catalysis
Hydrosilylation
Copper
Hydride
Catalytic asymmetric reduction of prochiral ketones
using transition metal complexes is an easy way for the
access to chiral non-racemic secondary alcohols, which are
very important intermediates in organic synthesis. Al-
though conversion of the ketone in the corresponding
alcohol by hydrosilylation requires a two-step reaction
(addition of Si-H bond followed by hydrolysis), it is still an
attractive method since quantitative yields are usually
obtained. It is also a good alternative to hydrogenation,
which usually requires H2 pressure [1].
Investigations on hydrosilylation of ketones with
rhodium-phosphine systems [2] have led to the develop-
ment of efficient catalysts that achieve high levels of
enantiomeric excess (above 90%) [3,4]. Ruthenium-based
systems may also afford good enantioselectivities [5].
More recently, efficient asymmetric hydrosilylation reac-
tions using cheaper and less toxic metals such as zinc [6],
titanium [7], iron [8] and copper [9] have been reported.
The first report on the use of copper hydride along with
a chiral phosphine for asymmetric hydrosilylation was
published by Brunner and Miehling in 1984 [10]. Almost
two decades later, Lipshutz and coworkers accomplished a
breakthrough [9,11].1 Thus, when coordinated by a highly
sterically demanding BIPHEP or SEGPHOS-type ligand, CuH
appears to be an efficient catalyst for the hydrosilylation of
ketones with a high level of enantioselectivity (above
90% ee). Moreover, they showed that inexpensive silanes
such as polymethylhydrosiloxane (PMHS) could be used.
Among the ligands tested, cheap BINAP was found to lead a
somewhat lower level of enantioselectivity (e.g. 75% ee
with acetophenone) [12].
We recently reported that the Cu(I)/BINAP catalytic
system, when combined with PhMeSiH2 as a reducing
agent may allow the reduction of various aryl alkyl
ketones with a high-level of enantioselectivity [13]. In
this report, we provide a full account of our investiga-
tions on the Cu(I)/BINAP-catalyzed hydrosilylation of
ketones.
The active species of the system was formed in situ by
the now well-established procedure involving CuCl,
NaOtBu and diphosphine [4]. Acetophenone was chosen
* Corresponding author.
1
** Co-corresponding author.
An efficient asymmetric conjugate reduction of
a, b-unsaturated
E-mail addresses: dagorne@chimie.u-strasbg.fr (S. Dagorne),
bellemin@chimie.u-strasbg.fr (S. Bellemin-Laponnaz).
esters or cyclic enones using chiral phosphine/Cu-H systems was also
reported.
1631-0748/$ – see front matter ß 2009 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.crci.2009.11.002

354
J.-T. Issenhuth et al. / C. R. Chimie 13 (2010) 353–357
Table 1
Table 3
Asymmetric hydrosilylation of acetophenone with the (R)-BINAP/CuCl/
Asymmetric hydrosilylation of acetophenone with various copper-based
systems.
tBuONa system by various silanes.
a
b
Entry Catalyst
ee (%)
Yield (%)
99
1
2
3
4
5
6
7
a
CuCl/t-BuONa/BINAP
CuCl/BINAP
81
Entry
Silane
ee (%) at r. t.
ee (%) at À78 8C
No reaction
No reaction
1
2
3
4
5
6
Ph2SiH2
76
78
77
79
81
79
80
79
90
91
93
93
CuCl/t-BuONa
(Mes)2SiH2
(1-napht)PhSiH2
(o-tol)PhSiH2
PhMeSiH2
(CH3CN)4CuBF4/t-BuONa/BINAP 76
97
98
97
98
CuF2/BINAP
78
78
79
CuCl2.2H2O/t-BuONa/BINAP
Cu(OAc)2.H2O/BINAP
PhtBuSiH2
(R)-BINAP was used.
b
Cat.: CuCl, t-BuONa, (R)-BINAP (5 mol%); reaction time: 18 hours; ee
Isolated yield.
values were determined by chiral GC analysis.
can be used, however, the level of enantioselectivity was
found to be somewhat lower compared to CuCl (entry 1 vs.
entries 4–7). Interestingly, no reaction occurred when
CuCl/BINAP or CuCl/NaOt-Bu systems were used (entries
2–3). Thus, the system that combines CuCl with NaOt-Bu
and BINAP appears to be best suited.
Table 2
Asymmetric hydrosilylation of acetophenone: solvent effect.
We also examined the influence of O2 onto the catalysis,
since Riant et al. showed that the complex fluorotris
(triphenylphosphine)copper-bis(methanol) CuF(PPh3)3.2-
MeOH combined with a chiral diphosphine was a good
catalyst for the hydrosilylation of ketones especially in the
presence of oxygen or air [12b,f]. Fig. 1 displays a parallel
experiment under an atmosphere of dioxygen and
dinitrogen using CuCl/NaOtBu/BINAP as precatalyst. To
some extent, the reaction was found to be slower in the
presence of oxygen. However, the enantiomeric excess of
the final product remained unchanged (93% in both cases).
Thus conducting the reaction under nitrogen seems to be
necessary to get the better results.
Entry
Silane
Toluene
ee (%)
THF
Diethyl ether
ee (%)
ee (%)
1
2
3
(o-tol)PhSiH2
PhMeSiH2
91
93
93
88
91
91
87
88
89
PhtBuSiH2
Cat.: CuCl, t-BuONa, (R)-BINAP (5 mol%); reaction time: 18 hours; ee
values were determined by chiral GC analysis.
as a reference substrate. As an initial study, we screened
various silanes as reducing agents and found that the level
of enantioselectivity was slightly dependent on the nature
of the silane (Table 1). Thus by using various dihydrosilane,
the enantiomeric excess of the alcohol product ranged
between 76% ee with Ph2SiH2 and 81% ee with PhMeSiH2 at
room temperature.2 By lowering the temperature at
À78 8C, four dihydrosilanes out of six allowed ee’s above
90%. In particular, we found that the hydrosilylation of
acetophenone is highly enantioselective in the presence of
PhMeSiH2 or Ph(tBu)SiH2 (93% ee, entries 5–6). The
commercial availability of phenylmethylsilane prompted
us to use this silane for further studies. A study of solvent
effect showed that toluene was the solvent of choice as
displayed Table 2. THF and diethyl ether were also found to
be good solvents for the reaction albeit with somewhat
lower enantioselectivity.
High enantioselectivities were also obtained in the
reduction of a variety of aryl alkyl ketones under the
It has been reported that various copper salts (including
copper(II)) could be used for hydrosilylation reactions [12].
Thus, we investigated the reaction with different copper
sources (Table 3). (CH3CN)4CuBF4, CuCl2, Cu(OAc)2 or CuF2
2
In our preliminarily communication, we originally got a racemic
Fig. 1. Asymmetric hydrosilylation of acetophenone catalysed by CuCl/
NaOt-Bu/(R)-BINAP (5 mol% in toluene). Effect of oxygen.
product when (1-napht)PhSiH2 was used as reducing agent. Reinvestiga-
tion of the reaction revealed that our original silane was not pure.

J.-T. Issenhuth et al. / C. R. Chimie 13 (2010) 353–357
355
Table 4
Asymmetric hydrosilylation of aryl alkyl ketones by PhMeSiH2 with the (R)-BINAP/CuCl/t-BuONa system (5 mol%).
Entry
1
Substrate
ee [yield] (%)
93 [99]
Entry
9
Substrate
ee [yield] (%)
92 [75]
2
3
4
5
90 [99]
79 [80]
87 [92]
92 [99]
10
11
12
13
X = F
96 [99]
97 [99]
97 [90]
94 [99]
X = Cl
X = Br
6
R = Et
97 [91]
14
92 [99]
7
8
R = iPr
92 [99]
85 [80]
15
16
94 [80]
65 [75]

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J.-T. Issenhuth et al. / C. R. Chimie 13 (2010) 353–357
Table 5
Asymmetric hydrosilylation of dialkyl ketones by PhMeSiH2 with the (R)-
BINAP/CuCl/t-BuONa system (5 mol%).
Entry
1
Substrate
ee [yield] (5)
25 [80]
Fig. 2. Structure of fluoxetine (left) and aprepitant (right).
optimized reaction conditions described above.3 For all
substrates listed in Table 4, the reactions were completed
within 18 hours using 5 mol% catalyst and two equivalents
of phenylmethylsilane. Ketone derivatives exhibiting
different steric or/and electronic properties are reduced
with exceptional enantioselectivities (up to 97% ee) and
yields (up to 99%). Propiophenone and isobutyrophenone
are reduced with good enantioselectivities and yields (97
and 92% ee, respectively; entries 6–7). 85% ee and 80%
isolated yield were obtained for the keto ester (entry 8), a
precursor in the synthesis of the antidepressant fluoxetine
(prozac, Fig. 2) [14]. Reaction with 3,5-bis(trifluoromethyl)
acetophenone leads the corresponding secondary alcohol
in 92% ee and 99% isolated yield (entry 14). This alcohol is
also of special interest for the development of some recent
NK-1 antagonists including aprepitant (Fig. 2) [15].
As anticipated, the excellent enantioselectivity dis-
played by CuCl/NaOt-Bu/BINAP system seems to be limited
to aryl alkyl ketones. Table 5 displays some examples with
dialkyl ketones as substrates. For example, the reduction of
phenyl-3-butanone proceeds with a good yield (92%) albeit
with low enantioselectivity (5% ee). The use of other silane
did not improve the results.
2
3
10 [90]
5 [92]
16 hours. Upon completion, a solution of K2CO3 (or NaOH)
in methanol was added and the resulting solution was
stirred for 1 h at room temperature. Column chromatog-
raphy provided the desired alcohol (60.4 mg, 99% yield). GC
analysis on a chiral column gave a 93% ee (R). Absolute
configuration was determined by comparison of optical
rotation with literature values.
Acknowledgments
`
We thank the CNRS and the Ministere de l’Education
In summary, we have shown that the CuCl/NaOt-Bu/
BINAP system is an efficient catalytic system for the
reduction of prochiral aryl alkyl ketones when phenyl-
methyl silane was used as reducing agent. High enantio-
meric excesses and yields could be achieved with only
5 mol% of the catalytic system generated in situ.
Nationale, de la Recherche et de la Technologie for a Ph.D.
grant (J.T.I) and an « ACI Jeunes chercheuses et jeunes
chercheurs ».
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