Highly efficient and highly enantioselective asymmetric hydrogenation of ketones with tunesPhos/1,2-diamine-ruthenium(II) complexes

Article abstract of DOI:10.1021/jo802372w

The TunePhos/diamine-Ru(II) complex combined with t-BuOK in 2-propanol effectively catalyzes enantioselective hydrogenation of a wide range of simple ketones including aromatic, heteroaromatic, α,β-unsaturated, and cyclopropyl ketones, affording high reactivity (up to 1 000 000 TON) and excellent enantioselectivities (>99% ee for 13 examples).

Full text of DOI:10.1021/jo802372w

Highly Efficient and Highly Enantioselective
Asymmetric Hydrogenation of Ketones with
TunesPhos/1,2-Diamine-Ruthenium(II)
Complexes
SCHEME 1. Structure of Aprepitant
†
†
‡
†
Wei Li, Xianfeng Sun, Le Zhou, Guohua Hou,
†
,†
Shichao Yu, and Xumu Zhang*
Department of Chemistry and Chemical Biology &
Pharmaceutical Chemistry, Rutgers, The State UniVersity of
New Jersey, Piscataway, New Jersey 08854, and College of
Science, Northwest A&F UniVersity, Yangling, Shaanxi
4
5
a few analogue ligands, such as PhanePhos, P-Phos, and SDP
6
ligand, were developed and proved to be effective for the
7
12100, People’s Republic of China
ruthenium-catalyzed asymmetric hydrogenation. However, de-
velopment of more efficient catalyst systems comprised of more
readily accessible ligands of high enantioselectivity for practical
xumu@rci.rutgers.edu
7
8
ReceiVed October 23, 2008
applications is still of significant importance for chemists.
Despite the great success that has been achieved, asymmetric
hydrogenation of ketones has not gained the same amount of
attention in practical applications as in academia. The main
obstacles include the use of a high level of metal catalysts, which
not only dramatically increases the cost but also raises serious
issues of heavy metal contamination. Thus it is necessary to
develop and demonstrate such catalytic systems that remain
effective even at an extremely low level without compromising
the selectivity. Herein, we would like to report our achievements
in the preparation of a wide variety of chiral alcohols in ideal-
approaching enantioselectivities (>99% ee for 13 examples)
The TunePhos/diamine-Ru(II) complex combined with
t-BuOK in 2-propanol effectively catalyzes enantioselective
hydrogenation of a wide range of simple ketones including
aromatic, heteroaromatic, R,ꢀ-unsaturated, and cyclopropyl
ketones, affording high reactivity (up to 1 000 000 TON) and
excellent enantioselectivities (>99% ee for 13 examples).
with only a ppm level of C
catalysts (TON up to 1 000 000).
Recently, we have developed a practical and convenient
synthetic route to prepare a series of air-stable modular C
3
*-TunePhos/diamine-Ru(II)
3
-
9
3
Tunephos-type chiral diphosphine ligands (C *-TunePhos),
which have been demonstrated earlier to be highly effective in
the hydrogenation N-substituted allylphthalimides and R-keto
Catalytic enantioselective hydrogenation of prochiral ketones
has been a powerful method to prepare enantiomerically pure
secondary alcohols, which are key structural elements in a large
9
c
esters. These ligands were designed to achieve superior
enantioselectivities for asymmetric hydrogenations utilizing their
highly modular nature. To illustrate potential utilities of Tune-
1
number of pharmaceutical products. For example, (R)-1-(3,5-
bis(trifluoromethyl)phenyl)ethanol is a key intermediate in the
(
4) Burk, M. J.; Hems, W.; Herzberg, D.; Malan, C.; Zanotti-Gerosa, A. Org.
synthesis of the neurokinin 1 (NK
1
) receptor antagonist Emend
Lett. 2000, 2, 4173.
2
(
Aprepitant; Scheme 1). This FDA-approved drug is for
(5) (a) Wu, J.; Chen, H.; Kwok, W.-H.; Guo, R.-W.; Zhou, Z.-Y; Yeung,
C.-H.; Chan, A. S. C. J. Org. Chem. 2002, 67, 7908. (b) Wu, J.; Ji, J.-X.; Guo,
R.-W.; Yeung, C.-H.; Chan, A. S. C. Chem. Eur. J. 2003, 9, 2963.
(6) Xie, J.-H.; Wang, L.-X; Fu, Y.; Zhu, S.-F.; Fan, B.-M.; Duan, H.-F.;
Zhou, Q.-L. J. Am. Chem. Soc. 2003, 125, 4404.
prevention of acute and delayed chemotherapy-induced nausea
and vomiting (CINV).
The milestone discoveries have been done by Noyori and
co-workers, who developed the BINAP-ruthenium-diamine
complexes as a highly effective catalyst system for asymmetric
(
7) (a) Cao, P.; Zhang, X. J. Org. Chem. 1999, 64, 2127. (b) Li, X.; Chen,
W.; Hems, W.; King, F.; Xiao, J. Org. Lett. 2003, 5, 4559. (c) Hu, A.; Ngo,
H. L.; Lin, W. Org. Lett. 2004, 6, 2937. (d) Genov, D. G.; Ager, D. J. Angew.
Chem., Int. Ed. 2004, 43, 2816. (e) Xu, Y.; Alcock, N. W.; Clarkson, G. J.;
Docherty, G.; Woodward, G.; Wills, M. Org. Lett. 2004, 6, 4105. (f) Burk, S.;
Franci o` , G.; Leitner, W. Chem. Commun. 2005, 3460. (g) Jing, Q.; Zhang, X.;
Sun, J.; Ding, K. AdV. Synth. Catal. 2005, 347, 1193.
(8) (a) Ohkuma, T.; Hattori, T.; Ooka, H.; Inoue, T.; Noyori, R. Org. Lett.
2004, 6, 2681. (b) Ohkuma, T.; Sandoval, C. A.; Srinivasan, R.; Lin, Q.; Wei,
Y.; Mu n˜ iz, K.; Noyori, R. J. Am. Chem. Soc. 2005, 127, 8288. (c) Arai, N.;
Suzuki, K.; Sugizaki, S.; Sorimachi, H.; Ohkuma, T. Angew. Chem., Int. Ed.
2008, 47, 1770.
(9) For general Tunephos structure, preparation and synthesis see: (a) Zhang,
X. U.S. Patent 6521769, September 19, 2000. (b) Zhang, Z.; Qian, H.; Longmire,
3
J.; Zhang, X. J. Org. Chem. 2000, 65, 6223. For the modular synthesis of C *-
TunePhos see: (c) Sun, X.; Zhou, L.; Li, W.; Zhang, X. J. Org. Chem. 2008, 73,
1143. (d) The ligand in catalyst 1c was also prepared by Chan et al., see: Qiu,
L.; Kwong, F. Y.; Wu, J.; Lam, W. H.; Chan, S.; Yu, W.-Y.; Li, Y.-M.; Guo,
R.; Zhou, Z.; Chan, A. S. C. J. Am. Chem. Soc. 2006, 128, 5955.
3
hydrogenation of ketones. Prompted by this fundamental study,
†
Rutgers, The State University of New Jersey.
Northwest A&F University.
‡
(
1) For reviews, see: (a) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed.
2
001, 40, 40. (b) Noyori, R. AdV. Synth. Catal. 2003, 345, 15.
(
McNamara, J. M.; Ho, G.-J.; Emerson, K. M.; Song, Z. J.; Tschaen, D. M.;
2) (a) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359. (b) Zhao, M. M.;
Brands, K. M. J.; Dolling, U.; Grabowski, E. J. J.; Reider, P. J. J. Org. Chem.
2
002, 67, 6743.
3) (a) Doucet, H.; Ohkuma, T.; Murata, K.; Yokozawa, T.; Kozawa, M.;
Katayama, E.; England, A. F.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed.
998, 37, 1703. (b) Ohkuma, T.; Koizumi, M.; Doucet, H.; Pharm, T.; Kozawa,
(
1
M.; Murata, K.; Katayama, E.; Yokozawa, T.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1998, 120, 13529.
1
0.1021/jo802372w CCC: $40.75  2009 American Chemical Society
J. Org. Chem. 2009, 74, 1397–1399 1397
Published on Web 12/31/2008

TABLE 1. Screening of TunePhos-Ru(II) Precatalyst for the
a
Hydrogenation of Acetophenone
b
c
d
entry
catalyst
S/C
t (h)
conv (%)
ee % (config)
1
2
3
4
5
6
7
8
(S),(S,S)-1a
(S),(R,R)-1a
(S),(S,S)-1b
(S),(S,S)-1c
(S),(R,R)-1d
(S),(S,S)-1d
(S),(S,S)-1e
(S),(S)-1f
10 000
10 000
10 000
10 000
10 000
10 000
10 000
10 000
2
2
2
2
2
2
2
2
<99.9
<99.9
<99.9
<99.9
<99.9
<99.9
<99.9
>99.9
83.3(R)
24.3(S)
83.0(R)
79.5(R)
72.1(R)
98.0(R)
91.2(R)
99.8(R)
a
Reactions were performed with 2-2.5 M solutions of acetophenone
in 2-propanol with added t-BuOK (base/Ru ) 220/1) at 20-22 °C and
0 atm initial hydrogen pressure. Substrate-to-catalyst molar ratio.
Determined by GC analysis. The ee was determined by chiral GC
b
5
c
d
analysis. The absolute configuration was determined by comparison of
the retention times with literature data.
a
TABLE 2. Asymmetric Hydrogenation of Ketones
conv
ee %
d
R1
R2
S/C
b
t (h) (%) (config)
c
entry
1
2
C
C
C
C
C
6
6
6
6
6
H
H
H
H
H
5
5
5
5
5
CH
CH
CH
CH
3
3
3
3
10 000
4
>99.9 99.8(R)
FIGURE 1. TunePhos and C -TunePhos/1,2-diamine-Ru(II) catalysts.
3
100 000 12 >99.9 99.8(R)
500 000 24
1 000 000 48
e
3
4
97.0 99.2(R)
94.5 98.0(R)
f
Phos ligands, we envisioned that application of these ligands
in a diphosphine-ruthenium-diamine system for reduction of
simple ketones is a natural choice (Figure 1).
5
6
7
8
9
2
C H
5
10 000
10 000
10 000
10 000
10 000
10 000
10 000
10 000
10 000
10 000
10 000
10 000
10 000
10 000
10 000
10 000
10 000
8
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
8
>99.9 99.8(R)
>99.9 99.7(R)
>99.9 99.6(R)
>99.9 99.5(R)
>99.9 99.6(R)
>99.9 99.6(R)
>99.9 99.6(R)
>99.9 99.3(R)
>99.9 99.6(R)
>99.9 99.6(R)
>99.9 99.7(R)
>99.9 99.7(R)
>99.9 97.0(R)
>99.9 97.5(R)
>99.9 97.9(R)
>99.9 97.4(R)
>99.9 93.2(R)
m-CH
m-CH
m-ClC H
6 4
3
C
6
H
4
CH
CH
CH
3
3
3
3
OC
6
H
4
3
a
By employing Noyori’s protocol, the diphosphine ligands
were reacted with [Ru(benzene)Cl in DMF and this was
]
2 2
p-CH C H
CH3
3
6
4
followed by addition of diamine. The resulting diphosphine-
ruthenium-diamine complexes were used as the precatalyst
directly in the hydrogenation reactions without any further
purification. We initiated our studies by screening catalysts 1a-f
in the hydrogenation of acetophenone. Under the conditions of
10 p-CH
3
OC
H
6 4
6
H
4
CH
CH
CH
CH
CH
3
3
3
3
3
1
1
1
1
1
2
3
4
p-ClC
p-FC H
3,5-(CF
2-furyl
6
4
3 2 6 3
) C H
15 2-thienyl
16 2-naphthyl
1
1
1
2
CH3
room temperature (20-22 °C), 50 atm of H
solvent, and t-BuOK as the base (substrate/base ) 220), (S)-
-TunePhos and DPEN (DPEN ) 1,2-diphenyl ethylenedi-
2
, 2-propanol as the
CH
CH
CH
CH
3
3
3
3
3
7
8
9
0
1-naphthyl
o-CH
cyclopropyl
3
6 4
C H
C
3
amine) were utilized to distinguish the matching/mismatching
stereochemical elements between the two chiral components in
this catalyst system. From the results in entries 1 and 2 in Table
trans-PhCH)CH CH
21
C
6
H
5
cyclopropyl
a
Unless otherwise noted, reactions were performed with 2-2.5 M
1
, it can be derived that the (S,S) isomer of DPEN should be
the matching partner with (S)-C -TunePhos. Thereafter when
switching to the modular (S)-C *-TunePhos, the highest enan-
tioselectivity 98.0% ee was achieved by applying precatalyst
S),(S,S)-1d (Table 1, entry 6) when assessing the effect from
solutions of acetophenone in 2-propanol with added t-BuOK (base/Ru )
220/1) at 20-22 °C and 10c atm initial hydrogen pressure.
3
b
d
Substrate-to-catalyst molar ratio. Determined by GC. The ee were
3
determined by Chiral GC analysis. The absolute configuration was
determined by comparison of the retention times with literature data.
Initial hydrogen pressure was 50 atm. Precatalyst (S),(S,S)-1d was
(
e
f
aryl substituents in the phosphine moiety. On the other hand,
used and initial hydrogen pressure was 50 atm.
when the chiral diamine was further replaced by DACH (trans-
erosion (99.8% ee) (Table 2, entry 2). Furthermore, when TON
was increased to 500 000, this highly active catalyst can still
retain over 99% ee enantioselectivity within 24 h under 50 atm
1
,2-diaminocyclohexane), the ee value decreased to 91.2%
(
Table 1, entry 7). The best combination was not discovered
until DAIPEN (1,1-bis(4-methoxyphenyl)-3-methyl-1,2-butane-
diamine) was introduced to serve as the diamine partner, where
of H
reactivity, in an illustrative extreme example of high TON (TON
1 000 000), the catalyst reached 94.5% conversion with 98.0%
2
pressure (Table 2, entry 3). To test the maximum catalytic
9
9.8% ee was achieved (Table 1, entry 9) with a turnover
)
number (TON) of 10 000. It is noteworthy that this best
combination is consistent with Noyori’s finding with the Xyl-
ee (Table 2, entry 4). These results indicate that this ruthenium
catalyst is practically useful to prepare a variety of chiral
II
3b
BINAP-Ru -DAIPEN system.
1
0,3a
alcohols under mild operational pressure.
The high catalytic capability of the catalyst (S),(S)-1f was
further explored at even lower catalyst loading (0.001%) and
(
10) Noyori et al. reported hydrogenation of acetophenone of 2 400 000 TON
milder conditions (10 atm of H
2
). The acetophenone substrate
within 48 h giving 80% ee, under reaction conditions of 45 atm of H
See ref 3a.
2
at 30 °C.
was smoothly hydrogenated within 12 h, without any ee value
1
398 J. Org. Chem. Vol. 74, No. 3, 2009

To explore the synthetic utility of this catalyst, we have
surveyed the substrate scope. A systematic study of the general
efficiency included different acetophenone-derived substrates
bearing different substituent groups on the phenyl ring, het-
eroaromatic ketones, and some aliphatic ketones. Good conver-
sions were observed for all substrates, with ee values ranging
from 93.2% to 99.8%. The catalyst showed high tolerance of
the various substituent groups on the meta and para positions
bearing different electronic properties (Table 2, entries 6 to 16).
Substrates containing electron-donating groups, such as a methyl
group or a methoxy group, and substrates containing electron-
withdrawing groups, such as a Cl group or a F group, were
hydrogenated successfully at 0.01% catalyst loading within 4 h
Experimental Section
General Procedure for Preparation of C *-TunesPhos-
3
Ru(II)-Diamine Precatalysts. C
3
*-TunePhos (0.105 mmol) and
[
Ru(benzene)Cl (0.05 mmol) were dissolved in anhydrous
2 2
]
degassed DMF (6 mL) under nitrogen protection. The reaction was
heated to 100 °C for 0.5-1 h, followed by addition of (S)-1,1-
bis(4-methoxyphenyl)-3-methylbutane-1,2-diamine ((S)-DAIPEN)
(
0.105 mmol) at room temperature and stirring for 0.5-1 h. The
solvent was removed under high vacuum.
General Hydrogenation Procedure. The precatalyst (0.0025
mmol) was dissolved in degassed 2-propanol (8 mL) in a 20-mL
vial, and distributed equally among ten vials. A solution of t-BuOK
(1 mol/L, 0.114 mL, 0.114 mmol) and substrate (2.5 mmol) were
added via syringe. The resulting mixture was transferred into an
under 10 atm of H pressure, all giving >99% ee. Meanwhile,
2
heteroaromatic ketones, 2-acetofuran and 2-acetothiophene, were
also equally converted to corresponding alcohol products with
autoclave, and the autoclave was purged with H
charged with H (10 atm). After stirring at room temperature for
h, the H was carefully released. The reaction solution was purified
2
(3 × 10 atm) and
2
4
2
>
99% ee. The hydrogenation of some alkyl ketones, for
example, cyclopropyl methyl ketone, also proceeded efficiently
97.9% ee, entry 19). In another example, under the mild
by a silica gel column to give the corresponding hydrogenation
product, which was then directly analyzed by chiral GC to determine
the enantiomeric excess. The hydrogenation products were also
(
conditions, hydrogenation of trans-4-phenyl-3-butenone afforded
the product quantitatively in 97.4% ee, highly selectively
reducing the ketone without reduction of the CdC bond (entry
1
characterized by H NMR (Table 2, entry 1, (R)-1-phenylethanol;
1
H NMR (CDCl , 400 MHz) δ 1.49 (d, J ) 6.4 Hz, 3H), 2.02 (br,
3
1
4
H), 4.88 (q, J ) 6.4 Hz, 1H), 7.25-7.29 (m, 1H), 7.29-7.39 (m,
2
1
0). It noteworthy that the result (99.6% ee) in Table 2, entry
3 justified the potential utility of this Ru-C *-TunePhos
H)).
3
complex in the practical synthesis of Emend (Aprepitant).
In conclusion, we have developed a highly efficient catalyst
system for practical asymmetric hydrogenations of a wide range
of unfunctionalized ketones. Its nature of extremely high
reactivity and enantioselectivity, broad substrate scope, and mild
reaction conditions enables practical application for production
of enantiomerically enriched alcohols. Further modification of
the linker length in the ligands to improve the enantioselectivity
for more substrates is underway and will be reported in due
course.
Acknowlegement. We thank the National Institutes of Health
GM58832) and Merck & Co., Inc., for the financial support.
(
Supporting Information Available: Complete description
of catalyst preparation, asymmetric hydrogenation, and product
characterization together with photocopies of spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO802372W
J. Org. Chem. Vol. 74, No. 3, 2009 1399