Application of copper(II)-dipyridylphosphine catalyst in the asymmetric hydrosilylation of simple ketones in air

Article abstract of DOI:10.1002/chem.200900499

Copper (II)-dipyridylphosphine catalyst was used in the asymmetric hydrosilylation of simple ketones under ambient conditions in competitive levels of enantioinduction and activity. The experiment also described the utility of the combination of copper(II) salt/(S)-1/PhSiH₃ in the enantioselective hydrosilylation of heteroaromatic ketones and several other ketonic substrates leading to some valuable pharmaceutical and agricultural chemical intermediates. A number of the resulting chiral alcohols represented valuable intermediates for some physiologically active compounds, with remarkable temperature effects on the asymmetric induction were observed in some cases of heteroaromatic ketones. The results show that the present catalyst system features widespread substrate scope, high air stability, fast rate of reaction, good-to-excellent enantioselectivity, and mild conditions thereby affording a practical protocol to a vast selection of optically enriched alcohols.

Full text of DOI:10.1002/chem.200900499

DOI: 10.1002/chem.200900499
Application of Copper(II)–Dipyridylphosphine Catalyst in the Asymmetric
Hydrosilylation of Simple Ketones in Air
[
a]
[a]
[a]
[a]
[a]
Xi-Chang Zhang, Yan Wu, Feng Yu, Fei-Fei Wu, Jing Wu,* and
[
b]
Albert S. C. Chan
The asymmetric hydrosilylation of prochiral ketones
mediated by chiral copper catalysts as a desirable approach
toward nonracemic secondary alcohols has recently gained
for effecting the reduction of
aryl alkyl ketones under ambi-
ent conditions in competitive
levels of enantioinduction (up
to 97% ee) and activity (S/L up
to 100000). Moreover, to the
best of our knowledge the first
highly stereoselective hydrosilyl-
ation of diarylketones in air
[1]
considerable attention, owing to the advantages of the in-
expensive metal, mild reaction conditions, and operational
simplicity. The pioneering work in this area was introduced
[7]
[2]
by Brunner and Miehling in 1984. A significant break-
through came in 2001 when Lipshutz and co-workers dis-
I
closed an especially effective Cu Cl/diphosphine (e.g., 3,5-
xyl-MeO-biphep or DTBM-segphos)/tBuONa/PMHS system
was also demonstrated (up to
(
MeO-biphep=(6,6’-dimethoxybiphenyl-2,2’-diyl)bis(diphe-
nylphosphine); DTBM-segphos=(4,4’-bi-1,3-benzodioxol)-
,5’-diylbis(di(3,5-di-tert-butyl-4-methoxyphenyl)phosphine);
98% ee for ortho-substituted
benzophenones). The excellent
practical potential of this cata-
5
PMHS=polymethylhydrosiloxane), which allowed for the
lyst system prompts us to fur-
highly catalytic enantioselective reduction of a broad assort-
ther broaden its application scope. Thus, in this contribution
we describe the utility of the combination of copper(II) salt/
[3]
ment of simple ketones even at a substrate-to-ligand (S/L)
ratio of over 100000. At the same time, Riant et al. discov-
ered an air-accelerated CuF /binap/PhSiH (binap=2,2’-bis-
(S)-1/PhSiH in the enantioselective hydrosilylation of hetero-
3
aromatic ketones and several other ketonic substrates lead-
ing to some valuable pharmaceutical and agricultural chemi-
cal intermediates.
2
3
(
diphenylphosphino)-1,1’-binaphthyl) system for the hydrosi-
[4]
lylation of aryl alkyl ketones. From then on, some other ef-
ficient chiral copper catalysts were developed accordingly
for the relevant hydrosilylation reactions in good-to-excel-
lent yields and enantiomeric excesses (ees).
Recently, we reported the use of CuF –dipyridylphosphine
Optically active alcoholic compounds with heterocyclic
moieties serve as useful building blocks for a vast array of
[5]
[8]
physiologically active target products, such as reserpinin
[9]
and (S)-duloxetine . The asymmetric hydrosilylation of het-
2
[6]
(
P-Phos 1a or Xyl-P-Phos 1b) catalyst along with PhSiH3
eroaromatic ketones to these alcohols represents a formida-
[10]
ble challenge. By using a segphos-ligated CuH hydrosilyl-
ation system, Lipshutz et al. found that the heteroaromatic
ketones were converted to the corresponding alcohols in
[
a] X.-C. Zhang, Y. Wu, F. Yu, F.-F. Wu, Prof. Dr. J. Wu
College of Material Chemistry and Chemical Engineering
Key Laboratory of Organosilicon Chemistry and Material Technology
of Ministry of Education
[3b]
good-to-excellent enantiopurities.
Our study began with three pyridyl ketones 2a–c, as sum-
marized in Table 1. In most cases, the reactions reached full
conversions in air even at À508C by simply prolonging the
reaction time. It is known that varying the reaction tempera-
ture usually serves as a powerful means of attaining optimal
selectivity in asymmetric catalysis and also affords some
mechanism implications. Thus, the ees of alcohols 3a–c
formed at various temperatures mediated by (S)-1a or (S)-
Hangzhou Normal University, Hangzhou 310036 (P.R. China)
Fax : (+86)571-2886-8023
E-mail: jingwubc@hznu.edu.cn
[
b] Prof. Dr. A. S. C. Chan
Open Laboratory of Chirotechnology of the Institute of Molecular
Technology for Drug Discovery and Synthesis
Department of Applied Biology and Chemical Technology
The Hong Kong Polytechnic University
Hung Hom, Kowloon (Hong Kong)
1
b ligand were examined and the plots of ln AHCTUNGTERNNNU(G S/R) versus 1/T
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900499.
(Eyringꢀs curves) were also drawn (Figures 1 and 2). The re-
5888
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 5888 – 5891

COMMUNICATION
[
a]
Table 1. Asymmetric hydrosilylation of acetyl pyridine.
[
b]
Entry
Ketone
Ligand
T [8C]
Time [h]
ee [%]
1
2
3
4
5
6
7
8
9
2a
2a
2a
2b
2b
2b
2b
2b
2b
2c
2c
(S)-1a
(S)-1a
(S)-1b
(S)-1a
(S)-1a
(S)-1b
(S)-1b
(S)-1b
(S)-1b
(S)-1b
(S)-1b
22
À20
À50
50
3
24
40
1
40
1
3
3
40
3
40
56 (S)
64 (S)
83 (S)
64 (S)
10 (S)
52 (S)
20 (S)
17 (R)
49 (R)
38 (S)
47 (R)
À50
90
22
0
À50
10
1
22
1
À40
[
a] Conditions: CuF
2
/ligand (0.5–1 mol% each) and substrate (50–
1
50 mg, 0.6–1m) in toluene; see the Supporting Information for the pro-
Figure 2. Effect of temperature on the enantioselectivities of 3b and 3c.
cedure. [b] The conversions in all cases were >95%. The ee values were
determined by chiral HPLC analysis. The absolute configuration was de-
termined by comparing the retention times or optical rotations with
known data (see the Supporting Information).
entry 2 vs. entry 1). The much lower temperature didn’t
render a higher ee (Figure 1). Alternatively, for bulky ligand
(
S)-1b the Eyringꢀs curve displayed a somewhat different
sults indicated that the temperature had a dramatic effect
on the outcome of the reactions whereas the relationship be-
tween ee and temperature was highly dependent both on the
positioning of the acetyl group on the pyridyl ring and on
the ligand used. For instance, 2-acetylpyridine 2a proved to
trend and the steric hindrance of the ligand had an appa-
rently beneficial influence on the enantioselectivity, espe-
cially at lower temperature. As the temperature decreased
from 908C a gradual decrease in ee was observed until a
minimum was reached around 508C (29%). Then further
lowering of the temperature resulted in a sharp linear in-
crease in ee and (S)-3a was obtained in 83% ee at À508C
(Table 1, entry 3). Such nonlinear temperature behavior has
been proposed to be a shift in the rate-determining step of
the reaction accompanying the alteration in temperature
[11]
be very inert to the standard hydrogenation conditions.
However, when it was treated with 1 mol% CuF and (S)-
2
1
a and 1.2 equivalent of PhSiH at room temperature in air,
3
the product (S)-3a was obtained in quantitative yield and
6% ee after 3 h (Table 1, entry 1). Elevated temperatures
50–908C) diminished the optical yield (Figure 1), whereas a
5
(
[5d,12]
and has recently attracted much theoretical interest.
slight enhancement in ee was achieved at À208C (Table 1,
In the conversion of 3-acetylpyridine 2b by using ligand
S)-1a, the enantiopurity of product (S)-3b gradually in-
(
creased to a maximum between 90 and 508C (64% ee;
Table 1, entry 4 and Figure 2), then rapidly fell to 10% ee at
À508C (Table 1, entry 5). Hence, the so-called “inversion
temperature”, which lied between the two intercepting
linear regions, occurred at 508C. Particularly worth noting
was that, if ligand (S)-1b was used the temperature had a
much more pronounced influence on the asymmetric induc-
tion than if the (S)-1a system was used under otherwise
identical conditions. For example, from 908C to room tem-
perature the ee of (S)-3b dropped from 52 to 20% (Table 1,
entries 6 and 7). Surprisingly, when the reaction was con-
ducted at 08C, ligand (S)-1b exhibited an asymmetric induc-
tion of the opposite sense to give the R enantiomer of 3b in
1
7% ee (Table 1, entry 8) and the optical purity of (R)-3b
improved to 49% at À508C (Table 1, entry 9). This dramatic
trend was consistently observed in the case of 4-acetylpyri-
dine 2c (Table 1, entries 10 and 11, Figure 2). Although the
origin of this marked temperature effect remains unclear at
this stage, both the bulkiness of ligands around the copper
atom and the relative positions of the carbonyl and nitrogen
atoms could make the approach of the ketone to the copper
hydride more temperature dependant. As we know, 2-acetyl-
Figure 1. Effect of temperature on the enantioselectivity of (S)-3a.
Chem. Eur. J. 2009, 15, 5888 – 5891
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5889

J. Wu et al.
pyridine (2a) is a good potential bidentate ligand for cop-
per(II) ions that may alter the properties of the catalyst
during the reactions and thus make this substrate exhibit
distinctly different behavior compared with both 3- and 4-
acetylpyridine (2b and 2c). Furthermore, because the pres-
ent reactions were performed under normal atmospheric
conditions, air could have played an intriguing role in the
formation of the active catalyst precursor during the catalyt-
ic cycle. Studies aimed at examining mechanistic features
relevant to the aforementioned factors are underway in our
laboratory.
entry 4 vs. entry 3). To the best of our knowledge, this is the
first highly effective copper-catalyzed stereoselective hydro-
silylation of acetylated thiophene-type substrates.
In addition, as part of our continuing efforts to further ex-
plore the generality of the present hydrosilylation system,
several ketonic substrates have been selected to produce
some crucial chiral intermediates of physiologically active
targets (Scheme 2). For example, in the presence of 1 mol%
Lipshutz et al. discovered that acetylated thiophene 4a
was sluggish in their hydrosilylation system, which was as-
sumed to be due to ligation of the sulfur atom rendering the
central metal coordinatively saturated and thus leading to a
[3b]
diminution of activity. To our delight, by utilizing ligand
S)-1a, the reaction rate of hydrosilylation of 4a largely
relied on the choice of copper salts; Cu(OAc) ·H O, an air-
(
AHCTUNGTRENNUNG
2
2
[5a,13]
and moisture-stable precursor,
quantitatively provided
desirable product (S)-3a in mediocre ee (59%, Scheme 1)
Scheme 1. Effect of the copper salt on the asymmetric hydrosilylation of
4
a. CuF
2
: 68% conv., 44% ee; Cu
A
H
U
G
R
N
U
2
·H
2
O: >99% conv., 59% ee;
: <40% conv.
CuCl, CUCl
2
, CuCl ·2H O, CuBr , and Cu
2
2
2
A
H
U
G
R
N
U
G
2
after 4 h at room temperature under aerobic conditions. The
ee was enhanced to 83% at À408C, although in low conver-
sion rates (Table 2, entry 1). By switching from (S)-1a to
(
S)-1b, the limitation was overcome and both full conver-
Scheme 2. Representative examples of asymmetric hydrosilylation; all
numbers in parentheses refer to conversions.
sion and high ee (91%) were realized at a sustainable reac-
tion rate (Table 2, entry 2). Similarly, the level of enantiose-
lectivity was essentially maintained in the reduction of 3-
thienyl ketone 4b (Table 2, entries 3–5). In addition, lower
catalyst loading (0.1 mol% 1a) also drove the reaction to
completion without significant reduction in ee (Table 2,
each of CuF and (S)-1a, the hydrosilylation of 3,5-bis(tri-
2
fluoromethyl)acetophenone proceeded in air at À408C to
afford 7a, which is the key building block for aprepitant, an
[14]
NK-1 receptor antagonist, in 92% ee. Likewise, attractive
[15]
[16]
intermediates 7b
and 7c
were also obtained in 90%
[
a]
and 94% ee, respectively. Interestingly, the hydrosilylation
of cyclohexyl phenyl ketone exhibited an enantiomeric in-
duction of the opposite sense to give (R)-7e in 88% ee. The
present system also worked effectively for some other sub-
strates of interest, including 2,2,2-trifluoroacetophenone, di-
alkyl ketone, a-keto ester, under mild conditions, albeit with
lower ees (7 f–i).
Table 2. Asymmetric hydrosilylation of acetyl thiophene.
[
b]
[c]
Entry Ketone Ligand T [8C] Time [h] Conv. [%] ee [%]
1
2
3
4
5
5a
5a
5b
5b
5b
(S)-1a
(S)-1b
(S)-1a
(S)-1a
(S)-1b
À40
À40
À20
À20
À40
72
72
24
24
72
16
97
99
99
95
83
91
86
84
90
In summary, our recently established asymmetric hydrosi-
lylation system, (S)-1/copper(II) salt/PhSiH , has been ap-
3
[
d]
plied in the effective reduction of heteroaromatic and sever-
al other types of ketones. Most of the resulting chiral alco-
hols represent valuable intermediates for some physiologi-
cally active compounds. Remarkable temperature effects on
the asymmetric induction were observed in some cases of
[
a] Conditions: Substrate (50–200 mg, 0.6–1m) in toluene. [b] Determined
by NMR and GC analysis. [c] Determined by chiral GC analysis.
d] 0.1 mol% ligand.
[
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Chem. Eur. J. 2009, 15, 5888 – 5891

Asymmetric Hydrosilylation of Ketones in Air
COMMUNICATION
heteroaromatic ketones. The first highly asymmetric hydro-
silylation of acetyl thiophene-type substrates catalyzed by
copper was also realized. The present catalyst system fea-
tures widespread substrate scope, high air stability, fast rate
of reaction, good-to-excellent enantioselectivity, and mild
conditions and thus affords a practical protocol to a vast se-
lection of optically enriched alcohols.
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Acknowledgements
We thank the National Natural Science Foundation of China (20672026),
the New Century Excellent Talents in Chinese University Program
awarded to Jing Wu (NCET-07-0250), the Natural Science Foundation of
Zhejiang Province (R406378), the University Grants Committee Areas
of Excellence Scheme of Hong Kong (AoE P/10-01), and the Hong Kong
Polytechnic University Strategic Development Fund for financial support
of this study.
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dipyridylphosphine
catalysis
ligands
·
copper
enantioselective
·
[
·
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Received: February 23, 2009
Published online: May 5, 2009
Chem. Eur. J. 2009, 15, 5888 – 5891
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5891