Asymmetric hydrosilylation of ketones catalyzed by magnetically recoverable and reusable copper ferrite nanoparticles

Article abstract of DOI:10.1021/jo9002823

(Chemical Equation Presented) Herein we present magnetically recoverable and reusable copper ferrite nanoparticles for asymmetric hydrosilylation of several ketones. Up to 99% enantiometric excess was obtained at room temperature using polymethylhydrosiloxane as the stoichiometric reducing agent. The copper ferrite nanoparticles were magnetically separated, and the efficiency of the catalyst remains almost unaltered up to three cycles.

Full text of DOI:10.1021/jo9002823

complexes. As a result of exceedingly mild reaction conditions
and operational simplicity, much effort has been directed toward
the development of asymmetric hydrosilylation of carbon-carbon
and carbon-heteroatom bonds using precious metals such as
rhodium,5 ruthenium,6 and iridium.7 Recently, asymmetric
hydrosilylation of prochiral ketones using polymethylhydrosi-
loxane (PMHS), an inexpensive, nontoxic polymer coproduct
of the silicon industry, as hydride source and easily accessible
catalysts based on titanium,8 zinc9 and tin10 have opened a new
pathway in this area. Very recently, iron-catalyzed asymmetric
hydrosilylation reactions are also reported.11 The utility of
copper for hydride delivery was studied with the Stryker reagent
[CuH·PPh3], a stoichiometric reducing agent for the reduction
of enones.12 Buchwald described a highly enantioselective 1,4-
reduction of R,ꢀ-unsaturated esters and ꢀ-substituted enones
using an active catalyst generated in situ from CuCl/NaO-t-Bu/
chiral diphosphine ligands and PMHS.13 The effectiveness of
[CuH·PPh3] for the hydrosilylation of carbonyl compounds was
reported by Lipshutz.14 Subsequent studies by the same group
led to the development of highly enatioselective hydrosilylation
of ketones based on CuCl/NaO-t-Bu/chiral diphosphine
ligands.15 Copper fluoride and copper acetate also catalyzed the
asymmetric hydrosilylation reaction of prochiral ketones in
presence of BINAP ligand.16
Asymmetric Hydrosilylation of Ketones Catalyzed
by Magnetically Recoverable and Reusable
Copper Ferrite Nanoparticles
M. Lakshmi Kantam,*,† Jagjit Yadav,† Soumi Laha,†
Pottabathula Srinivas,† Bojja Sreedhar,† and F. Figueras‡
Indian Institute of Chemical Technology, Hyderabad-500007,
India, and Institut de recherches sur la catalyse et
l’enVironnement de Lyon, Lyon 69626 Cedex, France
mlakshmi@iict.res.in
ReceiVed February 10, 2009
Industry favors the catalytic process induced by a heteroge-
neous catalyst over the homogeneous one in view of its ease of
handling, simple workup, and regenerability. Recently, Lipshutz
Herein we present magnetically recoverable and reusable
copper ferrite nanoparticles for asymmetric hydrosilylation
of several ketones. Up to 99% enantiometric excess was
obtained at room temperature using polymethylhydrosiloxane
as the stoichiometric reducing agent. The copper ferrite
nanoparticles were magnetically separated, and the efficiency
of the catalyst remains almost unaltered up to three cycles.
(4) (a) Liu, P. N.; Deng, J. G.; Tu, Y. Q.; Wang, H. Chem. Commun. 2004,
2070. (b) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1996, 118, 2521. (c) Sterk, D.; Stephen, M.; Mohar, B. Org. Lett.
2006, 8, 5935. (d) Liu, G.; Yao, M.; Zhang, F.; Gao, Y.; Li, H. Chem. Commun.
2008, 347.
(5) (a) Gade, L. H.; Cesar, V.; Bellemin-Laponnaz, S. Angew. Chem., Int.
Ed. 2004, 43, 1014. (b) Duan, W.-L.; Shi, M.; Rong, G. B. Chem. Commun.
2003, 2916. (c) Evans, D.; Micheal, A. F. E.; Tedrow, J. S.; Campos, K. R.
J. Am. Chem. Soc. 2003, 125, 3534.
(6) (a) Zhu, G.; Terry, M.; Zhang, X. J. Organomet. Chem. 1997, 547, 97.
(b) Nishibayashi, Y.; Takei, I.; Uemura, S.; Hidai, M. Organometallics 1998,
17, 3420.
(7) Chianese, A. R.; Crabtree, R. H. Organometallics 2005, 24, 4432.
(8) (a) Yun, J.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 5640. (b)
Halterman, R. L.; Ramsey, T. M.; Chen, Z. J. Org. Chem. 1994, 59, 2642. (c)
Riant, O.; Mostefai, N.; Courmarcel, J. Synthesis 2004, 2943.
(9) (a) Mimoun, H.; Laumer, J. Y.; L.; Scopelliti, R.; Floriani, C. J. Am.
Chem. Soc. 1999, 121, 6158. (b) Bette, V.; Mortreux, A.; Savoia, D.; Carpentier,
J.-F. AdV. Synth. Catal. 2005, 347, 289.
(10) Lawrence, N.; Bushell, S. M. Tetrahedron Lett. 2000, 41, 4507.
(11) (a) Nishiyama, H.; Furuta, A. Chem. Commun. 2007, 760. (b) Shaikh,
N. S.; Enthaler, S.; Junge, K.; Beller, M. Angew. Chem., Int. Ed. 2008, 47, 2497.
(12) (a) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem.
Soc. 1988, 110, 291. (b) Koenig, T. M.; Daeuble, J. F.; Brestensky, D. M.;
Stryker, J. M. Tetrahedron Lett. 1990, 31, 3237.
(13) (a) Appella, D. H.; Moritani, Y.; Shintani, R.; Ferreira, E. M.; Buchwald,
S. L. J. Am. Chem. Soc. 1999, 121, 9473. (b) Moritani, Y.; Appella, D. H.;
Jurkauskas, V.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 6797.
(14) Lipshutz, B. H.; Chrisman, W.; Noson, K. J. Organomet. Chem. 2001,
624, 367.
Intensive studies have recently been focused on the develop-
ment of asymmetric catalytic systems owing to their importance
in synthetic organic chemistry.1 Catalytic asymmetric reduction
of prochiral ketones leads to the formation of enantiomerically
pure chiral alcohols, which are key building blocks for the
manufacture of pharmaceuticals, agrochemicals, and advanced
materials.2 Asymmetric hydrogenation3 and transfer hydrogena-
tion4 are the most frequently used catalytic methods for the
reduction of prochiral ketones using transitional metal chiral
† Indian Institute of Chemical Technology.
‡ Institut de recherches sur la catalyse et l’environnement.
(1) (a) Ohkuma, T.; Kitamura, M.; Noyori, R. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiely-VCH: New York, 2000; Chapter 1,
1-110. (b) Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029.
(2) (a) Astleford, B. A.; Weigel, L. O. In Chirality in Industry II; Collins,
A. N., Ed.; Wiley: New York, 1997, p 99. (b) Lennon, I. C.; Ramsden, J. A.
Org. Process Res. DeV. 2005, 9, 110.
(3) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New
York, 1994. (b) Mikami, K.; Wakabayashi, K.; Aikawa, K. Org. Lett. 2006, 8,
1517. (c) Ohkuma, T.; Utsumi, N.; Watanabe, M.; Tsutsumi, K.; Arai, N.; Murata,
K. Org. Lett. 2007, 9, 2565. (d) Shimizu, H.; Igarashi, D.; Kuriyama, W.; Yusa,
Y.; Sayo, N.; Saito, T. Org. Lett. 2007, 9, 1655. (e) Hamilton, R. J.; Berger,
S. H. J. Am. Chem. Soc. 2006, 128, 13700.
(15) (a) Lipshutz, B. H.; Noson, K.; Chrisman, W. J. Am. Chem. Soc. 2001,
123, 12917. (b) Lipshutz, B. H.; Lower, A.; Noson, K. Org. Lett. 2002, 4, 4045.
(c) Lipshutz, B. H.; Noson, K.; Chrisman, W.; Lower, A. J. Am. Chem. Soc.
2003, 125, 8779.
(16) (a) Sirol, S.; Courmarcel, J.; Mostefai, N.; Riant, O. Org. Lett. 2001, 3,
4111. (b) Lee, D. -W.; Yun, J. Tetrahedron Lett. 2004, 45, 5415.
4608 J. Org. Chem. 2009, 74, 4608–4611
10.1021/jo9002823 CCC: $40.75 2009 American Chemical Society
Published on Web 05/19/2009

TABLE 1. Asymmetric Hydrosilylation of Acetophenone by
Different Catalysts and Ligands at Room Temperaturea
SCHEME 1. Asymmetric Hydrosilylation of Ketones Using
Copper Ferrite Nanoparticles
entry
catalyst
ligand
time (h)
yield (%)
ee (%)b
1
2
3
4
5
6
7
8
Fe3O4
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BIPHEP
BINAM
e
24
48
48
14
6
60
24
24
24
24
24
24
CoFe2O4
NiFe2O4
CuFe2O4
CuFe2O4
CuFe2O4
CuFe2O4
CuFe2O4
CuFe2O4
CuFe2O4
CuFe2O4
CuFe2O4
19
24
85
78
55
67
18
26
8
10
31
81
69c
87d
78
0
4
4
5
reported copper-in-charcoal as an efficient heterogeneous cata-
lyst for effective hydrosilylation of carbon-carbon and
carbon-heteroatom bonds with excellent enantioselectivity.17
Magnetic nanoparticles that can be magnetized in the presence
of an external magnet have been studied extensively for various
biological applications such as magnetic resonance imaging,
drug delivery and as biomolecular sensors.18 Recent reports
show that magnetic nanoparticles are efficient supports for
catalysts and can facilitate their separation from the reaction
medium after magnetization with a permanent magnetic field.19
Recently we reported copper-aluminum hydrotalcite catalyst
for asymmetric hydrosilylation of ketones.20 As part of our
ongoing research aimed at the development of reusable catalysts
for various asymmetric organic transformations,21 we herein
present the results on the use of magnetically separable copper
ferrite (CuFe2O4) nanoparticles for the asymmetric hydrosily-
lation of ketones to chiral secondary alcohols in moderate to
good yields and excellent enantiomeric excess (ee) at room
temperature using (S)-BINAP as a chiral auxiliary and PMHS
as the stoichiometric reducing agent (Scheme 1).
Initially, to develop the best magnetically separable catalyst
for the asymmetric hydrosilylation of ketones, Fe3O4 and
different substituted ferrites, MFe2O4 (M ) Cu2+, Co2+ and
Ni2+), were synthesized by coprecipitation methods as described
in the literature22 (see Supporting Information) and screened in
the presence of PMHS. Fe3O4 was found to be completely
inactive, while CoFe2O4 and NiFe2O4 produced very little
product with poor ee (Table 1, entries 2 and 3). However,
CuFe2O4 produced (S)-phenylethanol in 85% yield with 81%
ee (see Table 1). Among the different chiral ligands screened,
commercially available BINAP gave excellent yields and ee’s
greater than that of (R)-(+)-2,2′-bis(diphenylphosphino)-6,6′-
dimethoxy-1,1′-biphenyl (BIPHEP). The use of bidentate nitrogen-
based ligands gave poor yields, and the ee decreased signifi-
cantly (see Table 1). To know the effect of temperature, the
reaction was conducted at 80 and -40 °C. At 80 °C, although
the reaction was completed within 6 h, the ee decreased to 69%.
However, the reaction was not complete even after 60 h, but
the ee increased to 87% when the reaction was carried out at
-40 °C (Table 1, entries 5 and 6).
9
10
11
12
f
g
h
14
a Reaction conditions: substrate (1 mmol), PMHS (4 mmol), CuFe2O4
nanoparticles (10 mg, 4.3 mol % of copper), toluene (3 mL), BINAP (7
mg). b Absolute configurations were determined to be (S). c Reaction at
80 °C. d Reaction at -40 °C. e 1,2-Diaminocyclohexane was used.
f 1,2-Diphenylethelene diamine was used. g 2,6-Bis[(4R)-(+)-isopropyl-2-
oxazoline-2-yl] pyridine was used. h 2,6-Bis[(4R,5R)-4-methyl-phenyl-
2-oxazolinyl] pyridine was used.
porting Information, Table 1). A significant decrease in the rate
of reaction and a small amount of product was obtained using
polar solvents such as THF. Nonpolar solvents such as toluene
produced (S)-phenylethanol in excellent yields and ee at room
temperature. Next, we studied the activities of various silanes
in the asymmetric hydrosilylation of acetophenone in presence
of BINAP and CuFe2O4 nanoparticles (see Supporting Informa-
tion, Table 1).
Monoaryl silanes such as phenylsilane (PhSiH3) afforded
excellent yields with good enantioselectivity in a short period
of time (Supporting Information, Table 1, entry 4), while diaryl
and dialkyl silanes furnish lower yields but the stereoselectivity
remains almost unchanged (Supporting Information, Table 1,
entries 5 and 7). However, with triaryl- or trialkyl silanes, only
a trace amount of product was obtained (Supporting Information,
Table 1, entries 6 and 8).
Eventually, the catalytic system consisting of CuFe2O4
nanoparticles (10 mg, 4.3 mol % of copper), BINAP (7 mg,
1.12 mol %) as chiral auxiliary, the cheaper and readily available
siloxane, PMHS as the stoichiometric reducing agent, and
toluene as solvent were chosen for the asymmetric hydrosily-
lation of an array of aryl alkyl ketones at room temperature.
The results are listed in Table 2. Acetophenone is hydrosilylated
cleanly with good ee (Table 2, entry 1). Introduction of an
electron-withdrawing group at the para-position of acetophenone
requires a shorter reaction time for the completion of the
reactioin (Table 2, entries 2, 5, and 8-10). A higher ee was
obtained when the para-position of acetophenone was substi-
tuted by bromo, chloro, and nitro groups, while fluoro and cyano
groups furnished lower level of ee. Conversely, the presence
of an electron-donating group such as methyl at the para-
position (Table 2, entry 11) has little effect on enantioselectivity
but requires longer reaction time for full conversion.
Another important observation is the dependence of ee on
the position of the substituent group (irrespective of being
electron-withdrawing or electron-donating) of the acetophenone.
These values were highest when the substituent group was
present at the para-position of the acetophenone rather than at
the meta-position, which in turn was higher than at the ortho-
position (Table 2, entries 2-4, 5-7, and 11-13). This
demonstrates the ability of steric hindrance of meta- and ortho-
substituents to modify the ee of the reaction, which is in contrast
The effect of different organic solvents on the asymmetric
hydrosilylation of acetophenone was also examined (see Sup-
(17) Lipshutz, B. H.; Frieman, B. A.; Tomaso, A. E., Jr. Angew. Chem., Int.
Ed. 2006, 45, 1259.
(18) (a) Pankhurst, Q. A.; Connolly, J.; Jones, S. K.; Dobson, J. J. Phys. D:
Appl. Phys. 2003, 36, 167. (b) Perez, J. M.; Simeone, F. J.; Saeki, Y.; Josephson,
L.; Weissleder, R. J. Am. Chem. Soc. 2003, 125, 10192.
(19) (a) Yoon, T. J.; Lee, W.; Oh, Y. S.; Lee, J. K. New J. Chem. 2003, 27,
227. (b) Stevens, P. D.; Fan, J.; Gardimalla, H. M. R.; Yen, M.; Gao, Y. Org.
Lett. 2005, 7, 2085. (c) Stevens, P. D.; Li, G.; Fan, J.; Yen, M.; Gao, Y. Chem.
Commun. 2005, 4435.
(20) Kantam, M. L.; Laha, S.; Yadav, J.; Likhar, P. R.; Sreedhar, B.; Jha,
S.; Bhargava, S.; Udayakiran, M.; Jagadeesh, B. Org. Lett. 2008, 10, 2979.
(21) (a) Kantam, M. L.; Laha, S.; Yadav, J.; Likhar, P. R.; Sreedhar, B.;
Choudary, B. M. Ads. Synth. Catal. 2007, 349, 1797. (c) Choudary, B. M.;
Ranganath, K. V. S.; Pal, U.; Kantam, M. L.; Sreedhar, B. J. Am. Chem. Soc.
2005, 127, 13167.
(22) (a) Nedkov, I.; Vandenberghe, R. E.; Marinova, Ts.; Thailhades, Ph.;
Merodiiska, T.; Avramova, I. Appl. Surf. Sci. 2006, 253, 2589. (b) Nordhei, C.;
Ramstad, A. L.; Nicholson, D. G. Phys. Chem. Chem. Phys. 2008, 10, 1053.
J. Org. Chem. Vol. 74, No. 12, 2009 4609

TABLE 2. Asymmetric Hydrosilylation of Prochiral Ketones
Catalyzed by Copper Ferrite Nanoparticles at Room Temperaturea
TABLE 3. Reduction of Keto Esters with CuFe2O4 Nanoparticles
a Reaction conditions: substrate (1 mmol), PMHS (4 mmol), CuFe2O4
nanoparticles (10 mg), toluene (3 mL), BINAP (7 mg).
TABLE 4. Recycling of the Catalytic System for the Asymmetric
Hydrosilylation of Acetophenone at Room Temperaturea
entry
catalyst recovery (%)
product yield (%)
ee (%)b
1
2
3
85
81
76
81
80
81
89
91
a Reaction conditions: substrate (1 mmol), PMHS (4 mmol), CuFe2O4
nanoparticles (10 mg), toluene (3 mL), BINAP (7 mg); reaction time is
14 h. b Absolute configurations were determined to be (S).
hydrosilylation reaction. A heteroaromatic ketone such as
2-acetylpyridine also produced the reduced product in moderate
yields and ee’s (Table 2, entry 20). Next, we performed the
asymmetric hydrosilylation of dialkyl ketones. Cyclohexylm-
ethyl ketone is reduced to the corresponding alcohol in 33% ee
(Table 2, entry 21).
Finally, keto esters were also reduced using CuFe2O4 nano-
particles, PMHS as reducing reagent, and BINAP as chiral
auxiliary at room temperature (see Table 3).
The reduction of methyl benzoyl formate produces methyl
mandelate with 56% yield and 80% ee. The reduction of other
R-keto esters and ꢀ-keto esters proceeded smoothly and afforded
the corresponding reduced products in excellent ee. However,
an aliphatic R-keto ester, methyl pyruvate, produced trace
amount of the desired product under the same reaction conditions.
The feasibility of repeated use of CuFe2O4 was also examined.
In Table 4, we present the results from the investigation of
recycling of CuFe2O4 for three consecutive cycles of the same
reaction. After each cycle, nanoparticles were magnetically
concentrated, washed, air-dried, and used directly for the next
cycle without further purification. No significant loss of catalytic
activity was observed for CuFe2O4 in the asymmetric hydrosi-
lylation of acetophenone.
a Reaction conditions: substrate (1 mmol), PMHS (4 mmol), CuFe2O4
nanoparticles (10 mg, 4.3 mol % of copper), toluene (3 mL), BINAP (7
mg). b Absolute configurations were determined to be (S). c Absolute
configuration was determined to be (R).
Atomic absorption spectroscopy (AAS) was employed to
determine the copper content of CuFe2O4 nanoparticles, and it
was found to be 27.32%. The leaching of the metal after the
first cycle was determined by AAS and was found to be
negligible (0.045%). Figure 1a,b in Supporting Information
shows the TEM images of the CuFe2O4 catalyst before and after
use. It is observed that the synthesized nanoparticles are
spherical, about 10-12 nm in size. The morphology and size
of the particles do not change considerably even after three
cycles. This result supports the nearly unaltered efficiency of
the catalyst.
to the recently reported asymmetric hydrogenation of aryl
ketones catalyzed by copper catalyst reported by Shimizu et
al., where the obtained ee was highest in the case of ortho-
substituted substrates.3d
When the methyl group of the aryl alkyl ketone is substituted
with an ethyl group, the asymmetric hydrosilylation reaction
still gave excellent enantioselectivity (Table 2, entries 15 and
16). Sterically demanding 2-acetonaphthone and 1-acetonaph-
thone (Table 2, entries 18 and 19) also afforded good yields
with moderate enantioselectivity. It is significant to note that
different substituents such as fluoro, bromo, chloro, cyano, and
nitro (Table 2, entries 2-10) were not affected during the
The plausible mechanism of hydrosilylation may be through
the formation of copper hydride species from the reduction of
4610 J. Org. Chem. Vol. 74, No. 12, 2009

SCHEME 2. Possible Mechanism of Asymmetric
Hydrosilylation Catalyzed by Copper Ferrite Nanoparticles
Experimental Section
Representative Procedure for Asymmetric Hydrosilylation.
CuFe2O4 nanoparticles (0.010 g, 4.3 mol % of copper) and (S)-
BINAP (0.007 g, 1.12 mol %) were placed in a 25 mL round-
bottom flask containing toluene (3 mL) at room temperature and
stirred for 1 h. PMHS (4 mmol, 0.24 mL) was then added dropwise,
and after 30 min ketone was added to the reaction mixture. After
completion of the reaction (monitored by TLC), the reaction mixture
was magnetically concentrated with the aid of a magnet to separate
the catalyst and washed several times with ether. The reaction was
quenched with water, and 10 mL of ether was added. Then TBAF
(1.0 M in THF, 1.2 mL) was added, and the reaction mixture was
stirred vigorously for 0.5 h. The layers were separated, and the
aqueous layer was extracted with ether. The combined organic
layers were dried over MgSO4, and the solvent was removed under
reduced pressure. The residue was purified by silica gel flash column
chromatography (eluent, hexane/ethyl acetate) to afford the desired
ligated copper ferrite nanoparticles by PMHS. At this stage we
are not sure whether the active catalytic species is copper(I) or
copper(II) hydride.16b,17 The copper hydride species react with
the ketone, resulting in the formation of a copper alkoxide that
subsequently undergoes σ-bond metathesis with the organosilane
to afford the silyl ether (Scheme 2).13a,16b
1
product. (S)-1-Phenylethanol: H NMR (300 MHz, CDCl3, TMS)
δ 1.35 (d, J ) 6.79 Hz, 3H), 3.09 (br s, 1H), 4.70 (q, J ) 6.04 Hz,
6.79 Hz, 1H), 7.14-7.24(m, 5H); 13C NMR (75 MHz, CDCl3) δ
24.1, 70.0, 125.3, 127.2, 128.2, 145.7; HPLC (Daicel Chiralcel OJ-
H, 5% isopropanol in hexane, flow rate 0.5 mL/min) tR ) 22.53
min (major), 25.37 min (minor); [R]25D ) -39.2° (c 2.54, CHCl3).
In conclusion, copper ferrite nanoparticles are used for the
asymmetric hydrosilylation of ketones. High level of ee can be
obtained by using an inexpensive and nontoxic reducing agent
such as PMHS at room temperature and using commercially
available BINAP as chiral auxiliary. The catalyst can be
activated by the hydrosilylating reagent itself and thus obviates
the need to use alkoxide bases.
Acknowledgment. J.Y. and S.L. thank CSIR, India for their
senior research fellowships.
Supporting Information Available: General experimental
procedures and characterization data of products. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO9002823
J. Org. Chem. Vol. 74, No. 12, 2009 4611