Asymmetric hydrosilylation of ketones catalyzed by zinc acetate with hindered pybox ligands

Article abstract of DOI:10.1002/adsc.201300682

A highly efficient asymmetric hydrosilylation (AHS) of a wide variety of prochiral aryl ketones catalyzed by zinc acetate with TPS-he-pybox (tert-butyldiphenylsilyl hydroxyethyl pybox) ligand has been successfully developed. Cheap and readily available chiral Lewis acids based on zinc salts have been used as promising catalyst for the reduction of aryl ketones under mild conditions at room temperature leading to chiral alcohols in excellent yields and good to high enantioselectivities (up to 85% ee).

Full text of DOI:10.1002/adsc.201300682

UPDATES
DOI: 10.1002/adsc.201300682
Asymmetric Hydrosilylation of Ketones Catalyzed by Zinc
Acetate with Hindered Pybox Ligands
Daniel Łowicki,a Agata Bezłada,a and Jacek Mlynarskia,b,*
a
Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland
Fax : (+48)-12-634-0515; phone: (+48)-12-663-2035; e-mail: jacek.mlynarski@gmail.com (homepage:
www.jacekmlynarski.pl)
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, Warsaw, Poland
b
Received: July 31, 2013; Revised: November 15, 2013; Published online: February 6, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300682.
Abstract: A highly efficient asymmetric hydrosilyla-
tion (AHS) of a wide variety of prochiral aryl ke-
tones catalyzed by zinc acetate with TPS-he-pybox
(tert-butyldiphenylsilyl hydroxyethyl pybox) ligand
has been successfully developed. Cheap and readily
available chiral Lewis acids based on zinc salts have
been used as promising catalyst for the reduction of
aryl ketones under mild conditions at room temper-
ature leading to chiral alcohols in excellent yields
and good to high enantioselectivities (up to 85%
ee).
should be directed towards the development of cheap,
reliable and safe zinc complexes for asymmetric hy-
drosilylation.
For the first time an inorganic zinc salt was applied
for asymmetric hydrosilylation by Nishiyama et al. in
2009.[5] These authors demonstrated that ketones can
undergo reduction in an asymmetric manner with ees
ranging at about 80% (one example with 92% ee) by
using zinc acetate complexes with a ligand based on
chiral diaminocyclohexane (DACH). Recently Lai[6]
applied a similar zinc-based catalyst with chiral
DACH ligands containing furan rings.
In 2012 Beller and co-workers[7] used chiral i-Pr-(1)
and Ph-pybox (2) ligands (Scheme 1) with either zinc
acetate or diethylzinc. These authors showed that
both of these catalysts can induce stereoselectivity in
the reduction of acetophenone, but the reactions cata-
Keywords: asymmetric synthesis; chiral alcohols;
metal complexes; reduction; zinc
lyzed by ZnACTHUNRGTNEUNG(OAc)2–pybox led to poor ees and conver-
Asymmetric hydrosilylation (AHS) of prochiral ke-
tones represents one of the most efficient methods for
the preparation of chiral secondary alcohols. Al-
though the asymmetric hydrosilylation using catalysts
based on expensive precious metals such as rutheni-
um, rhodium or iridium is well established,[1] an effi-
cient means to access chiral alcohols by using cheaper
and more environmentally friendly metals still re-
mains a significant challenge. Noteworthy recent con-
tributions in this field have emerged by utilizing
chiral iron[2] and copper[3] complexes. Despite some
advances, the demand for less expensive, environmen-
tally more benign zinc-based catalytic systems for the
asymmetric hydrosilylation of ketones is still an
urgent need and of great significance because of the
broad availability and biomimetic nature of zinc. Sur-
prisingly, only few studies have been presented in this
field, mostly utilizing zinc catalysts made of unstable
and hazardous dialkylzinc compounds.[4] Synthesis
and application of these organometallic species is
dangerous and inconvenient, especially for industrial
Scheme 1. Structures of pybox-type ligands used in this
or large-scale use. Therefore, considerable efforts work: i-Pr-pybox, Ph-pybox and he-pyboxes.
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Daniel Łowicki et al.
sions in comparison with those promoted by Et2Zn low temperature encouraged us for further research.
complexes with the same chiral ligands. Similar conversion and ee were observed for triethox-
In spite of the previous unpromising application of ysilane at 208C while the reaction with polymethylhy-
zinc salts with pybox ligands, we decided to further drosiloxane (PMHS) failed.
explore this field as successful applications of pybox
Although we observed better conversions and
ligands in various areas of asymmetric synthesis are yields in the presence of commercial pybox ligand
well documented.[8] The reason of this success derives when compared to previously published results
from the simple preparation of modified pybox that [Zn
makes the preparation of new derivatives easily real- tioselectivity still left much to be desired.
izable. To address this issue, a family of hydroxyethyl
In this paper we describe a convenient application pybox ligands (3–5) was evaluated in association with
hindered tert-butyldiphenylsilyl-hydroxyethyl- Zn(OAc)2 to identify the most enantioselective and
(OAc)2–Ph-pybox, 608C],[7] the low level of enan-
ACHTUNGTRENNUNG
of
ACHTUNGTRENNUNG
pybox (TPS-he-pybox) (5, Scheme 1) complex with reliable catalytic system. Essential results observed
zinc acetate as highly efficient and stereoselective cat- for the reduction of acetophenone are collected in
alysts for hydrosilylation of prochiral ketones. Table 2. Initial application of hydroxyethyl-pybox 3[11]
ZnACHTUNGTRENNUNG(OTf)2–TPS-he-pybox has been previously used to resulted in poor enantioselectivity (Table 2, entry 1),
catalyze asymmetric Mukaiyama-aldol reactions car- while the application of pybox ligands with hindered
ried out in a water environment, but has never been siloxy substituents (TBS-he-pybox 4[11] and TPS-he-
applied for the asymmetric reduction of ketones.[9]
pybox 5,[9a] Scheme 1) turned out to be far more suc-
Initial optimization of the reaction conditions was cessful and stereoselective (Table 2, entries 2 and 3).
carried out for commercially available i-Pr-pybox (1). The best performance (conversion: 99%, 68% ee) was
From among the tested zinc salts (acetate, chloride, observed for 5 mol% catalyst loading in THF solution
bromide, triflate and trifluoroacetate) applied for the (Table 2, entry 3). The ability to carry out the reaction
reduction of acetophenone, only zinc acetate com- at low temperature without unnecessary heating of
plexes have shown the expected high activity in THF the reaction mixture was an important and distinctive
solution with diethoxymethylsilane as hydrogenating feature of this newly elaborated catalytic system.
agent (Table 1).[10] For this particular reduction, only
Again, among four tested silanes, the best enantio-
low enantioselectivity was observed for the Zn- selectivity was observed for (EtO)2MeSiH (68% ee,
ACHTUNGTRENNUNG(OAc)2–i-Pr-pybox catalyst (38% ee, Table 1, entry 2) Table 2, entry 3) at room temperature. Our further
but the observed outstanding substrate conversion at
Table 2. Conversion and enantiomeric excess of acetophe-
none hydrosilylation catalyzed by Zn–TPS-pybox.[a]
Table 1. Conversion and enantiomeric excess of acetophe-
none hydrosilylation catalyzed by Zn–i-Pr-pybox.[a]
Entry
Silane/Ligand
Temp.
[8C]
Time
[h]
Conv.
[%][b]
ee[c]
Entry Silane
Temp.
[8C]
Time
[h]
Conv.
[%][b]
ee[c]
1
2
3
4
5
6
7
N
20
20
20
4
20
20
20
20
20
20
70
20
20
20
73
11
64
68
74
16
–
1
2
N
20
20
20
20
46
>99
>99
>99
>99
>99
32
38
<5
34
22
> 99
> 99
94
> 99
0
3
20
20
4
4d)
5d)
> 99
0
[a]
[a]
[b]
[c]
[b]
[c]
[d]
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Asymmetric Hydrosilylation of Ketones Catalyzed by Zinc Acetate
Table 3. Enantioselective hydrosilylation of prochiral ke-
Table 3. (Continued)
tones by (EtO)2MeSiH catalyzed by Zn
ACHTUNGRTENN(UNG OAc)2–TPS-
Entry Ketone
Time Conv. Yield ee[b]
pybox.[a]
[h]
[%]
[%][c]
13
14
15
16
20
>99
90
54 (R)
37 (R)
80 (R)
14 (S)[e]
50 (R)
20
20
20
20
>99
>99
>99
>99
93
97
81
80
Entry Ketone
Time Conv. Yield ee[b]
[h]
[%]
[%][c]
1
2
3
4
5
6
20
>99
69
84 (R)[d]
83 (R)
85 (R)
83 (R)
80 (R)
61 (R)
20
20
20
46
70
>99
>99
>99
>99
>99
71
68
76
83
67
17
[a]
Reaction conditions: the catalyst was synthesized by stir-
ring zinc acetate (5 mol%) with pybox ligand (5,
5 mol%) in THF (2 mL) at room temperature under
argon. Ketone (1 mmol) and silane (2 mmol) were added
and the reaction mixture was stirred at the mentioned
temperature for 20–46 h.
Conversion and ee were determined by HPLC methods.
Isolated yield.
The absolute (R)-configuration of the product was deter-
mined by comparing the optical rotation and HPLC anal-
ysis with literature data.
[b]
[c]
[d]
[e]
Opposite (S)-configuration results from the CIP conven-
tion only.
7
8
9
46
20
20
>99
>99
>99
92
96
78
77 (R)
73 (R)
62 (R)
effort was to find the best conditions for Zn–TPS-
pybox-promoted reactions, especially in terms of tem-
perature and catalyst loading. Application of
diethoxyACTHNUGRTNEUNGmethylsilane in combination with TPS-he-
pybox at lower temperature (48C) increased the ee up
to 74% (Table 2, entry 4). Reduction of the catalyst
amount from 5 to 2.5 mmol% does not affect the
yields, but the ee drops to 24%. Interestingly, increas-
ing the catalyst amount to 7.5 mmol% did not result
in any change, thus 5 mol% catalyst loading was
taken to be the best.
10
20
54
71
60 (R)
Although Ozasa[12] demonstrated that zinc acetate
itself is a good catalyst for non-asymmetric reduction
of miscellaneous ketones by using PhSiH3, we found
the reducing agent to be active yet unselective in the
presence of chiral Lewis acids. The popular PMHS
does not react with the Zn-based catalyst and con-
firmed the only previous observations of Lai[6] and
Nishiyama.[5]
11
12
20
70
>99
>99
70
84
52 (R)
rac.
Having the best catalyst and conditions in hand, we
tested the scope of the reduction to other prochiral
ketones. As shown in Table 3, a broad range of aryl
Adv. Synth. Catal. 2014, 356, 591 – 595
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Daniel Łowicki et al.
ketones was investigated to demonstrate the scope of duction of alkyl methyl ketones delivered alcohols in
our procedure and also clarify the influence of various ca. 15–20% ee although the observed conversion was
substituents differently placed at the phenyl ring.
To our delight, for most of the substrates, complete
excellent (>99%).
Formation of an equimolar complex between TPS-
hydrosilylation was achieved in the presence of he-pybox and ZnACTHNUGTRENUNG(OAc)2 was confirmed by ESI HR-
5 mol% of the ZnACHTNUTRGNE(NUG OAc)2/pybox within 20 h at room MS. In the mass spectrum the peak of a 1:1 complex
temperature. The isolated yields were substantial and in which one acetate anion is tightly bound with Zn2+
besides such excellent efficiency, many of the studied cation within a complex molecule is found exclusive-
reactions provided alcohols with high stereoselectivity ly.[10]
(up to 85% ee) favoring formation of the (R) isomer.
In summary, we have presented an efficient proto-
Absolute configurations of the resulting alcohols have col for the asymmetric hydrosilylation of aryl ketones
been revealed by comparison of the HPLC analysis in the presence of an inexpensive and easy to handle
on a chiral stationary phase of the products with that zinc catalyst. The newly elaborated Zn
ACHTUNGRTENN(UNG OAc)2–TPS-
reported in the literature. he-pybox complex can be directly used for enantiose-
The best results in terms of high enantioselectivity lective reduction of a wide variety of alkyl aryl ke-
have been observed for ketones that possess electron- tones at room temperature. Such observed high ee
withdrawing groups placed in a meta position (en- values along with the high level of substrate conver-
tries 1–5). For all of these substrates the ees exceed sion at ambient temperature have never been previ-
80%. Interestingly, AHS of 3’-methoxyacetophenone ously presented for a catalyst composed of a zinc salt
gave a lower enantiomeric excess of 61% (entry 6). with a pybox ligand. It is also at least comparable to
This phenomenon suggests that the catalyst is the previously published catalysts based on zinc acetate[5]
most selective for the meta-substituted substrates with and chloride.[6] A family of meta-substituted aryl ke-
lower electron density in the aromatic rings. Interest- tones, mostly neglected in previous studies, has been
ingly, applications of the meta-substituted aryl ketones detected as the most suitable substrates for zinc-based
have not been widely studied in the literature.
para-Substituted acetophenones demonstrated
asymmetric AHS reactions.
We have also shown that the asymmetric induction
a similar tendency in terms of reactivity, although strongly depends on the size of substituents at the ox-
they underwent reduction less selectively. Electron- azoline ring of pybox. Further research on the synthe-
withdrawing substituents at the para position did not sis of other pyboxes with bulky substituents and their
affect the enantioselectivity too much (entries 7–9). applications in AHS are ongoing in our laboratory
Ketones containing deactivating groups such as nitro and will be reported in due course.
and halogens were reduced with higher yields and ee
values among all studied para-substituted derivatives.
Again, the donating effect of methoxy group has an
adverse impact on stereoselectivity and reduction of
Experimental Section
para-methoxyacetophenone resulted in the formation
of racemic alcohol (entry 12). A similar tendency was
previously reported by other authors. Observed enan-
tioselectivity in asymmetric hydrosilylation was signif-
icantly diminished when a p-MeO group was present
in the substrate.[2h] This tendency was also visible for
zinc-based catalytic systems.[4]
ortho-Substituted substrates have been also reduced
with high yield but with lower selectivity (entries 13
and 14) probably because of steric hindrance between
catalysts and ketone.
Enantioselective Hydrosilylation of Prochiral Ketones
(Table 3)
The catalyst was prepared by stirring the solution of TPS-
he-pybox[9,10] (5, 0.043 mmol, 33.2 mg) with Zn
ACHTUNGTRENNUNG(OAc)2
(0.043 mmol, 7.6 mg) in 2 mL of THF under argon at room
temperature. To the homogenous solution of the catalyst
both ketone (1 mmol) and silane (2 mmol) were added with
15 min intervals, respectively. The reaction progress was
controlled by TLC analysis using plates with a silica matrix
and a (1:4) mixture of ethyl acetate and hexane. When the
reaction was completed the solution was cooled to ca. 08C
The last tested representative of methyl aryl ke- and quenched with 2 mL of 1M HCl and stirred for 1 h.
After this time organic compounds were extracted 3 times
with ethyl acetate. The combined organic phases were then
washed with concentrated NaHCO3 and brine and then
dried over anhydrous Na2SO4. After filtration of the desic-
cant, the organic solvent was removed by vacuum evapora-
tion. The crude mixture was separated from catalyst by
short column chromatography on silica gel (1:4 ethyl ace-
tate-hexane) and the blend of desired alcohol and eventually
rest of ketone was subjected to HPLC analysis to determine
the conversion and enantiomeric excess and to elucidate the
tones, i.e., b-acetonaphthone was also easily convert-
ed to the appropriate alcohol with 80% ee (entry 15).
Some other ketones were also reduced in the pres-
ence of the new zinc catalyst ZnACTHNUTRGNENUG(OAc)2–TPS-pybox.
The a-methoxyacetophenoene was fully converted
but the ee value is rather poor. The propiophenone
was reduced with 50% of ee only (entry 17).
Initial application of the elaborated catalytic system
to alkyl ketones was unsuccessful, unfortunately. Re-
duction of tetralone led to a racemic product while re- configuration of the enantiomer existing in excess.
594
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Asymmetric Hydrosilylation of Ketones Catalyzed by Zinc Acetate
Wendt, D. Addis, S. Zhou, S. Das, M. Beller, Chem.
Acknowledgements
Eur. J. 2010, 16, 68; f) X.-C. Zhang, Y. Wu, F. Yu, F.-F.
Wu, J. Wu, A. S. C. Chan, Chem. Eur. J. 2009, 15, 5888;
g) D.-W. Lee, J. Yun, Tetrahedron Lett. 2004, 45, 5415;
h) B. H. Lipshutz, A. Lower, K. Noson, Org. Lett. 2002,
4, 4045; i) B. H. Lipshutz, K. Noson, W. Chrisman, A.
Lower, J. Am. Chem. Soc. 2003, 125, 8779; j) S. Sirol, J.
Courmarcel, N. Mostefai, O. Riant, Org. Lett. 2001, 3,
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Project operated within the Foundation for Polish Science
TEAM Programme co-financed by the EU European Re-
gional Development Fund. Financial support from the Polish
National Science Centre (grant number 2012/05/B/ST5/0027)
is gratefully acknowledged. The research was carried out with
the equipment purchased thanks to the financial support of
the European Regional Development Fund in the framework
of the Polish Innovation Economy Operational Programme
(contract no. POIG.02.01.00-12-023/08).
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