Asymmetric hydrogenation of aryl ketones mediated by a copper catalyst

Article abstract of DOI:10.1021/ol070289q

A novel asymmetric hydrogenation protocol using a copper catalyst is reported. A Cu(I) complex in the presence of nonracemic BDPP hydrogenates aryl ketones with moderate to high enantioselectivity.

Full text of DOI:10.1021/ol070289q

ORGANIC
LETTERS
2007
Vol. 9, No. 9
1655-1657
Asymmetric Hydrogenation of Aryl
Ketones Mediated by a Copper Catalyst
Hideo Shimizu,* Daisuke Igarashi, Wataru Kuriyama, Yukinori Yusa,
Noboru Sayo, and Takao Saito
Takasago International Corporation, Corporate Research & DeVelopment DiVision
1-4-11, Nishi-yawata, Hiratsuka City, Kanagawa 254-0073, Japan
hideo_shimizu@takasago.com
Received February 5, 2007
ABSTRACT
A novel asymmetric hydrogenation protocol using a copper catalyst is reported. A Cu(I) complex in the presence of nonracemic BDPP
hydrogenates aryl ketones with moderate to high enantioselectivity.
There is no doubt that homogeneous asymmetric hydrogena-
tion plays an especially important role in asymmetric
syntheses, providing an effective route to optically active
compounds.1 A majority of these reactions are catalyzed by
transition metal complexes such as Rh and Ru catalysts, some
of which have been successfully applied to industrial
production.2
We envisioned that if the reaction could be catalyzed by
a less-expensive base metal, it would be more industrially
attractive in terms of cost. Copper catalysts have shown
exceptional enantioselectivity in asymmetric reductions such
as hydrosilylation,3 hydroboration,4 and transfer hydrogena-
tion.5 On the other hand, it is known that copper is a useful
catalyst for heterogeneous hydrogenation.6 In addition, a
landmark study by Stryker showed that a copper hydride
([CuH(PPh3)]6) has the ability to catalyze homogeneous hy-
drogenation.7 These studies encouraged us to develop a new
system for homogeneous asymmetric hydrogenation medi-
ated by a copper catalyst. Reported herein is a novel copper-
based system that hydrogenates aryl ketones in moderate to
high enantioselectivity, and with high catalytic activity.8
(3) (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. (c) Lipshutz, B. H.; Noson, K.; Chrisman, W. J. Am. Chem.
Soc. 2001, 123, 12917. (d) Sirol, S.; Courmarcel, J.; Mostefai, N.; Riant,
O. Org. Lett. 2001, 3, 4111. (e) Lipshutz, B. H.; Lower, A.; Noson, K.
Org. Lett. 2002, 4, 4045. (f) Lipshutz, B. H.; Noson, K.; Chrisman, W.;
Lower, A. J. Am. Chem. Soc. 2003, 125, 8779. (g) Czekelius, C.; Carreira,
E. M. Angew. Chem., Int. Ed. 2003, 42, 4793. (h) Lipshutz, B. H.; Servesko,
J. M.; Petersen, T. B.; Papa, P. P.; Lover, A. A. Org. Lett. 2004, 6, 1273.
(i) Lipshutz, B. H.; Servesko, J. M.; Taft, B. R. J. Am. Chem. Soc. 2004,
126, 8352. (j) Czekelius, C.; Carreira, E. M. Org. Lett. 2004, 6, 4575. (k)
Lipshutz, B. H.; Shimizu, H. Angew. Chem., Int. Ed. 2004, 43, 2228.
(4) Lipshutz, B. H.; Papa, P. Angew. Chem., Int. Ed. 2002, 41, 4580.
(5) Yang, J. W.; List, B. Org. Lett. 2006, 8, 5653.
(6) (a) Barto´k, M. In Stereochemistry of Heterogeneous Metal Catalysis;
Wiley & Sons: Chichester, U.K., 1985; pp 335-382. (b) Nishimura, S. In
Handbook of Heterogeneous Catalytic Hydrogenation for Organic Synthesis;
Wiley & Sons: New York, 2001; pp 26-28.
(7) (a) Mahoney, W. S.; Stryker, J. M. J. Am. Chem. Soc. 1989, 111,
8818. (b) Stryker, J. M.; Mahoney, W. S.; Daeuble, J. F.; Brestensky, D.
M. In Catalysis of Organic Reactions; Pascoe, W. E., Ed.; Marcel Dekker:
New York, 1992; pp 29-44. (c) Daeuble, J. F.; Stryker, J. M. In Catalysis
of Organic Reactions; Sacros, M. G., Prunier, M. L., Eds.; Marcel Dekker:
New York, 1995; pp 235-247. (d) Chen, J.-X.; Daeuble, J. F.; Brestensky,
D. M.; Stryker, J. M. Tetrahedron 2000, 56, 2153. (e) Chen, J.-X.; Daeuble,
J. F.; Stryker, J. M. Tetrahedron 2000, 56, 2789.
(1) For recent reviews: (a) Ohkuma, T.; Kitamura, M.; Noyori, R. In
Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New
York, 2000; Chapter 1, pp 1-110. (b) Tang, W.; Zhang, X. Chem. ReV.
2003, 103, 3029.
(2) (a) Kumobayashi, H. Recl. TraV. Chim. Pays-Bas 1996, 115, 201.
(b) Kumobayashi, H.; Miura, T.; Sayo, N.; Saito, T.; Zhang, X. Synlett
2001, 1055. (c) Blaser, H.-U.; Pugin, B.; Spindler, F. In Applied Homo-
geneous Catalysis with Organometallic Compounds, 2nd ed.; Cornils, B.,
Hermann, W. A., Eds.; Wiley-VCH: Weinheim, Germany, 2002; Vol. 3,
pp 1131-1149. (d) Blaser, H.-U.; Malan, C.; Pugin, B.; Spindler, F.; Steiner,
H.; Studer, M. AdV. Synth. Catal. 2003, 345, 103.
10.1021/ol070289q CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/28/2007

Table 1. Asymmetric Hydrogenation of Acetophenonea
Table 2. Asymmetric Hydrogenation of Aryl Ketonesa
conversion
ee
(%)c,d
entry
Cu catalyst
S/Cb
(%)c
1e
2e
3
CuCl
CuClf
[CuH(PPh3)]6
[Cu(NO3)(PPh3)2]
[Cu(NO3)(PPh3)2]f
[Cu(NO3)(P(3,5-xylyl)3)2]
300
300
21
40
48
47
47
48
56
>99
>99
>99
500i
1000
3000
500
g,h
4
5j
6
97 (94k)
>99
a All reactions were carried out with (S,S)-BDPP (1 equiv to Cu) and
NaO-t-Bu (10 equiv to Cu) under an initial hydrogen pressure of 5.0 MPa
unless otherwise noted. bSubstrate to catalyst molar ratio. cConversions and
ee’s were determined by GC analysis using a Chirasil DEX-CB column.
e
dAll absolute configurations were determined as S. NaO-t-Bu (6 equiv to
Cu) was used. fPPh3 (3 equiv to Cu) was added. gPPh3 (1 equiv to Cu) was
added. hWithout NaO-t-Bu. iS/C was calculated on the basis of the Cu atom.
k
jReaction time was 96 h. Isolated yield after distillation.
Our initial screening using acetophenone as substrate is
described in Table 1. Use of a catalyst system consisting of
CuCl, BDPP,9 and NaO-t-Bu (at a substrate to catalyst molar
ratio (S/C) ) 500) afforded the reduced product in moderate
enantioselectivity (40% ee), although with limited catalytic
activity (entry 1). As was reported by Stryker,7b addition of
PPh3 in the system increased catalytic activity, completing
the reaction with slight improvement in enantioselectivity
(entry 2). In these reactions, NaO-t-Bu presumably played a
role to generate a CuO-t-Bu species that should mediate
heterolytic hydrogen activation.10 Use of [CuH(PPh3)]6 led
to completion of the reaction even without NaO-t-Bu (entry
3). We settled on a catalyst precursor [Cu(NO3)(PPh3)2]11
that gave higher catalytic activity, up to a turnover number
of 1000 (entry 4). Further reduced catalyst loading (S/C )
3000) led to near completion of the reaction with additional
PPh3 and an extended reaction time (entry 5). Later, we found
that use of [Cu(NO3)(P(3,5-xylyl)3)2]12 enhanced the enan-
tioselectivity to 56% ee (entry 6).
a All reactions were carried out with [Cu(NO3)(P(3,5-xylyl)3)2] (S/C )
500), (S,S)-BDPP (1 equiv to Cu), P(3,5-xylyl)3 (6 equiv to Cu), and NaO-
t-Bu (10 equiv to Cu) under an initial hydrogen pressure of 5.0 MPa unless
b
otherwise noted. Conversions and ee’s were determined by GC analysis
using a Chirasil DEX-CB column. cIsolated yield. dAll absolute configura-
tions were determined as S. eNaO-t-Bu (30 equiv to Cu) was used. fS/C )
400.
Screening of ligands using [Cu(NO3)(PPh3)2] revealed that
conversions and enantioselectivities were greatly influenced
by choice of a chiral ligand. Surprisingly, CHIRAPHOS,13
a ligand structurally similar to BDPP, resulted in almost no
reaction. Biaryl ligands such as BINAP14 led to a lower
conversion and ee (17% and 24% ee, respectively). Of the
ligands tested, diphosphine ligands with comparatively
flexible C3-C4 linkers, such as DIOP,15 BPPM,16 and
(8) Heterogeneous Cu-catalyzed asymmetric hydrogenation was reported
but with limited enantioselectivity: Klabunovskii, E. I.; Vedenyapin, A.
A.; Airapetov, Y. S.; Fridman, Y. D. React. Kinet. Catal. Lett. 1978, 9, 73.
(9) Bakos, J.; To´th, I.; Marko´, L. J. Org. Chem. 1981, 46, 5427.
(10) Goeden, G. V.; Caulton, K. G. J. Am. Chem. Soc. 1981, 103, 7354.
(11) Gysling, H. J. Inorg. Synth. 1979, 19, 92.
(12) Prepared from Cu(NO3)2‚3H2O and P(3,5-xylyl)3. See Supporting
Information.
(13) Fryzuk, M. D.; Bosnich, B. J. Am. Chem. Soc. 1977, 99, 6262.
(14) Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.; Souchi,
T.; Noyori, R. J. Am. Chem. Soc. 1980, 102, 7932.
Figure 1. Ligands tested.
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Org. Lett., Vol. 9, No. 9, 2007

Josiphos,17 gave complete conversion albeit without enhanced
enantioselectivity relative to BDPP (12% ee, 27% ee, and
45% ee, respectively). Investigation of the scope of the
reaction was expanded to various aryl ketones. Table 2 shows
cases tested, beginning with 2′-, 3′-, and 4′-methyl acetophe-
nones in the presense of additional P(3,5-xylyl)3. Of the three,
2′-methylacetophenone was reduced in high enantioselec-
tivity (86% ee), whereas 3′- and 4′-counterparts resulted in
moderate ee’s (entries 1-3). In general, the reaction hydro-
genates various 2′-substituted acetophenone-type substrates
in high enantioselectivity (81-91% ee; entries 4-6). In the
case of 1-acetonaphthone, the enantioselectivity dropped to
63% ee (entry 7).
activity and enantioselectivity is still modest relative to
Noyori’s Ru system,18 Cu catalysis may in time offer a more
economical and effective protocol. Expansion of the scope
to heteroaryl ketones and alkyl ketones, as well as mecha-
nistic details, will be disclosed in due course.
Supporting Information Available: Experimental pro-
cedures and characterization data of products. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL070289Q
(15) Dang, T. P.; Kagan, H. B. Chem. Commun. 1971, 481.
(16) Achiwa, K. J. Am. Chem. Soc. 1976, 98, 8265.
(17) Togni, A.; Breutel, C.; Schnyder, A.; Spindler, F.; Landert, H.;
Tijani, A. J. Am. Chem. Soc. 1994, 116, 4062.
(18) (a) Ohkuma, T.; Ooka, H.; Hashiguchi, S.; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1995, 117, 2675. (b) Noyori, R.; Ohkuma, T. Angew.
Chem., Int. Ed. 2001, 40, 40.
In summary, a homogeneous copper-catalyzed asymmetric
hydrogenation has been discovered. The system afforded
moderate to high enantioselectivity in asymmetric hydroge-
nation of acetophenone-type substrates. Although catalytic
Org. Lett., Vol. 9, No. 9, 2007
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