Air-stable catalysts for highly efficient and enantioselective hydrogenation of aromatic ketones

Article abstract of DOI:10.1021/jo026168f

A series of chiral trans-[RuCl₂(dipyridylphosphine)(1,2-diamine)] complexes have been synthesized and characterized by NMR and single-crystal X-ray diffraction studies. These Ru complexes combined with (CH₃)₃COK in 2-propanol formed a very effective catalyst system for the hydrogenation of a diverse range of simple aromatic ketones with high activity (substrate-to-catalyst ratio up to 100 000) and excellent enantioselectivity (up to > 99.9%). The catalyst system was also found to be stable in solution even under a normal atmosphere.

Full text of DOI:10.1021/jo026168f

SCHEME 1
Air -Sta ble Ca ta lysts for High ly Efficien t
a n d En a n tioselective Hyd r ogen a tion of
Ar om a tic Keton es
J ing Wu, Hua Chen, Waihim Kwok, Rongwei Guo,
Zhongyuan Zhou, Chihung Yeung,* and
Albert S. C. Chan*
Open Laboratory of Chirotechnology of the Institute of
Molecular Technology for Drug Discovery and Synthesis†
and Department of Applied Biology and Chemical
Technology, The Hong Kong Polytechnic University,
Hung Hom, Kowloon, Hong Kong
Among these catalysts, trans-RuCl2[(S)-XylBINAP][(S)-
DAIPEN]5 or its R,R isomer very often gave the best
results.6 Burk et al. reported that PhanePhos-ruthenium-
diamine7 complexes also showed high activity and enan-
tioselectivity in the asymmetric hydrogenation of a wide
range of ketones.8 To our knowledge, no other diphos-
phine ligand except PhanePhos has been reported so far
to approach the utility of XylBINAP in this reaction.
Recently, we have developed a new class of chiral
dipyridylphosphine ligands (Scheme 1) P-Phos (1a ),9a,9b
Tol-P-Phos (1b),9c and Xyl-P-Phos (1c).9d Their Ru(II)
complexes were found to be highly effective catalysts in
the asymmetric hydrogenation of 2-(6′-methoxy-2′-naph-
thyl)propenoic acid and â-ketoesters. In addition, it is of
high interest to note that the Ru(C6H6)(P-Phos)Cl2 cata-
lyst is air-stable even in solution.9c,9d Because of the high
potential of the practical application of the air-stable
catalysts in reactions of industrial interest, we explored
the Ru-(P-Phos) catalyzed hydrogenation of aromatic
ketones employing Noyori’s protocol. In this study, we
are delighted to find that a wide variety of aromatic
ketones can be hydrogenated quantitatively with excel-
lent enantioselectivities (up to >99.9%) by using a highly
air-stable catalyst trans-[RuCl2{(R)-1c}{(R,R)-DPEN}]
((R,RR)-2c, DPEN ) 1,2-diphenyl ethylenediamine) com-
bined with (CH3)3COK in 2-propanol solution with a
substrate-to-catalyst ratio (S/C) up to 100 000 under
atmospheric to 400 psi hydrogen pressure. In the mean-
while, unlike the Ru-BINAP catalyst system, which often
needs the fancy diamine DAIPEN for the optimum
results, the present catalyst system employing much less
expensive diamine DPEN gave comparable results to
bcachan@polyu.edu.hk
Received J uly 9, 2002
Ab st r a ct : A series of chiral trans-[RuCl2(dipyridylphos-
phine)(1,2-diamine)] complexes have been synthesized and
characterized by NMR and single-crystal X-ray diffraction
studies. These Ru complexes combined with (CH3)3COK in
2-propanol formed a very effective catalyst system for the
hydrogenation of a diverse range of simple aromatic ketones
with high activity (substrate-to-catalyst ratio up to 100 000)
and excellent enantioselectivity (up to >99.9%). The catalyst
system was also found to be stable in solution even under a
normal atmosphere.
The asymmetric hydrogenation of prochiral ketones is
one of the most efficient methods of producing enantio-
merically enriched secondary alcohols.1 In contrast to the
fruitful results of the asymmetric hydrogenation of func-
tionalized ketones catalyzed by Ru-phosphines com-
plexes,1,2 only limited examples have been reported for
simple ketones because such substrates lack heteroatoms
that enable the substrate to anchor strongly to the metal
center. Recently, Noyori and co-workers achieved an
important breakthrough in this area by using appropriate
diphosphine/diamine Ru complexes along with an inor-
ganic base in 2-propanol and obtained the most effective
catalyst system for the hydrogenation of ketones.3,4
* Address correspondence to this author. Phone: +00-852-27665646.
Fax: +00-852-23649932. E-mail: bcachan@polyu.edu.hk.
† A University Grants Committee Area of Excellence Scheme (Hong
Kong).
(1) For comprehensive reviews, see: (a) Noyori, R. Asymmetric
Catalysis in Organic Synthesis; Wiley: New York, 1993. (b) Compre-
hensive Asymmetric Catalyses; J acobsen, E. N., Pfaltz, A., Yamamoto,
H., Eds.; Springer: Berlin, Germany, 1999. (c) Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley: New York, 2000. (d) Bhaduri,
S.; Mukesh, D. Homogeneous Catalysis Mechanisms and Industrial
Applications; Wiley: New York, 2000. (e) Lin, G.-Q.; Li, Y.-M.; Chan,
A. S. C. Principles and Applications of Asymmetric Synthesis; Wiley:
New York, 2001.
(2) (a) Noyori, R. Chem. Soc. Rev. 1989, 18, 187. (b) Noyori, R.
Science 1990, 248, 1194. (c) Noyori, R.; Takaya, H. Acc. Chem. Res.
1990, 23, 345. (d) Burk, M. J .; Gross, M. F.; Harper, G. P.; Kalberg, C.
S.; Lee, J . R.; Martinez, J . P. Pure Appl. Chem. 1996, 68, 37. (e) Naota,
T.; Takaya, H.; Murahashi, S. Chem. Rev. 1998, 98, 2599.
(3) For review, see: (a) Noyori, R.; Ohkuma, T. Pure Appl. Chem.
1999, 71, 1493. (b) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed.
2001, 40, 40.
(5) XylBINAP
) 2,2′-bis(di-3,5-xylylphosphino)-1,1′-binaphthyl;
DAIPEN ) 1,1-di(4-anisyl)-2-isopropyl-1,2-ethylenediamine.
(6) (a) Ohkuma, T.; Koizumi, M.; Doucet, H.; Pham, T.; Kozawa, M.;
Murata, K.; Katayama, E.; Yokozawa, T.; Ikariya, T.; Noyori, R. J . Am.
Chem. Soc. 1998, 120, 13529. (b) Ohkuma, T.; Koizumi, M.; Ikehira,
H.; Yokozawa, T.; Noyori, R. Org. Lett. 2000, 2, 659. (c) Ohkuma, T.;
Koizumi, M.; Yoshida, M.; Noyori, R. Org. Lett. 2000, 2, 1749.
(7) PhanePhos ) 4,12-bis(diphenylphosphino)[2.2]paracyclophane.
(8) Burk, M. J .; Hems, W.; Herzberg, D.; Malan, C.; Zanotti-Gerosa,
A. Org. Lett. 2000, 2, 4173.
(9) P-Phos ) 2,2′,6,6′-tetramethoxy-4,4′-bis(diphenylphosphino)-3,3′-
bipyridine; Tol-P-Phos ) 2,2′,6,6′-tetramethoxy-4,4′-bis[di(p-tolyl)phos-
phino]-3,3′-bipyridine; Xyl-P-Phos ) 2,2′,6,6′-tetramethoxy-4,4′-bis[di-
(3,5-dimethylphenyl)phosphino]-3,3′-bipyridine. (a) Chan, A. S. C.; Pai,
C.-C. U.S. Patent 5 886 182, 1999. (b) Pai, C.-C.; Lin, C.-W.; Lin, C.-
C.; Chen, C.-C.; Chan, A. S. C.; Wong, W. T. J . Am. Chem. Soc. 2000,
122, 11513. (c) Wu, J .; Chen, H.; Zhou, Z.-Y.; Yeung, C.-H.; Chan, A.
S. C. Synlett 2001, 1050. (d) Wu, J .; Chen, H.; Kwok, W.-H.; Lam, K.-
H.; Zhou, Z.-Y.; Yeung, C.-H.; Chan, A. S. C. Tetrahedron Lett. 2002,
43, 1539.
(4) (a) Ohkuma, T.; Ooka, H.; Ikariya, T.; Noyori, R. J . Am. Chem.
Soc. 1995, 117, 10417. (b) Doucet, H.; Ohkuma, T.; Murata, K.;
Yokozawa, T.; Kozawa, M.; Katayama, E.; England, A. F.; Ikariya, T.;
Noyori, R. Angew. Chem., Int. Ed. 1998, 37, 1703.
10.1021/jo026168f CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/10/2002
7908
J . Org. Chem. 2002, 67, 7908-7910

TABLE 1. Asym m etr ic Hyd r ogen a tion of Acetop h en on e
3a Ca ta lyzed by 2a
S/B resulted in a somewhat higher enantioselectivity
(entries 4-6). The enantioselectivity remained high even
when the substrate-to-catalyst ratio was increased to as
high as 100 000 (entries 7-9).
Because the selectivity of the Ru-catalyzed hydrogena-
tion relies on the synergistic effects of the chiral diphos-
phine and diamine ligands, the phosphine and diamine
ancillaries must be carefully selected. For example, the
mismatching precatalyst (S,RR)-2c (trans-[RuCl2{(S)-
1c}{(R,R)-DPEN}]) provided 3b in only 78% ee under
otherwise identical conditions (entry 11 vs 7). Particularly
noteworthy was the observation that the use of Xyl-P-
Phos (1c) as the chiral diphosphine provided far superior
ee to those values obtainable with the parent ligand
P-Phos (1a ) or Tol-P-Phos (1b) (entry 9 vs 12 and 13).
We previously reported that Ru(C6H6)(P-Phos)Cl2 cata-
lyst was rather air-stable even in solution.9c,9d In this
study, high air-stability of the catalyst system was also
demonstrated by performing the experimental procedures
in air at S/C ) 50 000 prior to the introduction of
hydrogen. Complete conversion was observed within 24
h with no diminution of enantioselectivity in comparison
with the air-proved system (entry 14 vs 8). The efficiency
and enantioselectivity remained unchanged even when
the solution of (R,RR)-2c in 2-propanol was exposed to
air for 5 h (entry 15).
In addition to the marked activity and enantioselec-
tivity observed for the new catalyst system in the
hydrogenation of acetophenone 3a , similarly excellent
results were obtained in the hydrogenation of a variety
of ring-substituted aromatic ketones (Table 2). Introduc-
tion of a methyl, methoxy, or trifluoromethyl substituent
to the meta (3e, 3f) or para (3h , 3i, 3k ) position of
acetophenone had almost no effect on the enantioselec-
tivity of the reaction (entries 6, 7, 9, 10, and 12). A
substrate possessing an electron-withdrawing group on
ortho position of 3a (3d , entry 5) was more reactive than
those with an electron-donating substituent (3b, 3c,
entries 1 and 2). The ortho-, meta-, and para-brominated
acetophenones (3d , 3g, 3j) all displayed excellent enan-
tioselectivities (>99.5% ee) with the use of (R,RR)-2c as
catalyst. The hydrogenation of 3d gave over 99.9% ee
irrespective of the use of P-Phos, Tol-P-Phos, or Xyl-P-
Phos as the chiral ligand in the catalyst.
S/C
S/B
pH
time conv
2
entry catalyst
(M/M) (M/M) (psi) (h)
(%)b ee (%)b
1
2
(R,RR)-2c
(R,RR)-2c
2000
2000
2000
2000
2000
2000
2000
50000
300
300
14
500
300
300
300
300
300
500
500
500
300
500
500
500
500
6
6
6
93.4 98.4 (S)
100
98.5 (S)
3c (R,RR)-2c
4
5
6
7
8
9
(R,RR)-2c
(R,RR)-2c
(R,RR)-2c
(R,RR)-2c
(R,RR)-2c
50
125
300
800
800
800
800
800
800
800
800
800
12 100
12 100
12 100
96.9 (S)
97.6 (S)
98.3 (S)
2
24
36
99.2 99.0 (S)
99.8 99.1 (S)
99.7 99.1 (S)
(R,RR)-2c 100000
10d (R,RR)-2c 100000
18 100
100
36 100
96.6 (S)
78.0 (R)
83.3 (S)
11
12
13
(S,RR)-2c
2000
2
(R,RR)-2a 100000
(R,RR)-2b 100000
36
24
99.7 84.9 (S)
99.8 99.0 (S)
14e (R,RR)-2c
50000
50000
15f
(R,RR)-2c
24 100
99.1 (S)
a
Reaction conditions: 100-1000 mg of substrate; substrate
concentration ) 1.0-2.5 M, 25-28 °C. The substrate and catalyst
were added to a stainless steel autoclave under N2 and the solvents
were degassed and dried prior to use unless otherwise stated. b The
conversions were determined by NMR and by the relative peak
sizes in GC. The ee were determined by chiral GC (Chrompack
Chirasil-DEX CB columns). The absolute configuration was de-
termined by comparison of the sign of optical rotation or retention
time with literature data (ref 6). c The reaction was performed
without the addition of (CH3)3OK and no product was detected.
The reaction was performed at 50 °C. e The substrate and
d
catalyst were added to the stainless steel autoclave in air. f The
catalysts solutions in 2-propanol were stirred for 5 h under air
before the addition of substrate, (CH3)3OK, and H2.
those achieved with the best system XylBINAP-
Ru-DAIPEN6a
Using a method reported by Doucet et al.,4b we first
prepared catalysts (2) by reacting ligands 1 with [RuCl2-
(C6H6)]2 in DMF at 100 °C, followed by treatment of the
resulting reddish brown solution with 1 equiv of DPEN
at room temperature, and the complex was isolated and
purified as light brown solid. 1H, 31P NMR and the single-
crystal X-ray diffraction analysis of these complexes
showed that they existed as a single conformer in
solution.
In conclusion, Ru complex (R,RR)-2c or its isomer
combined with (CH3)3COK in 2-propanol gave a very
effective catalyst system for highly enantioselective
hydrogenation of a diverse range of simple aromatic
ketones. The combination of desirable features, such as
fast rate of reaction, broad substrate scope, excellent
enantioselectivity, high substrate-to-catalyst ratio, em-
ployment of less expensive diamine, and high air-stability
of catalysts in solution makes the present catalyst system
of high practical interest. The studies on the hydrogena-
tion of heteroaromatic, alkenyl, cyclopropyl, and amino
ketones by using this catalyst system are in progress.
Preliminary experimental results revealed that rapid,
highly enantioselective catalytic hydrogenation of ac-
etophenone 3a was achieved with complex 2 as catalyst
(Table 1). The hydrogenation of acetophenone 3a with
S/C ) 2000 under 300 psi hydrogen pressure at 25 °C in
2-propanol containing (R,RR)-2c and (CH3)3COK gave
99.2% conversion and 99.0% ee within 2 h (entry 7).
Although the enantioselectivity was found to be inde-
pendent of hydrogen pressure, the rate of reaction was
slower at lower pressure (entry 1 vs 2). High reaction
temperature gave a higher rate of reaction at the expense
of ee (entry 9 vs 10). Consistent with Noyori’s findings,
the presence of a base was absolutely crucial for high
activity in this catalyst system. When 3a was hydroge-
nated without the addition of (CH3)3COK, no desirable
product was detected after 6 h (entry 3). The substrate-
to-base ratio (S/B) was important as well. An increase of
Exp er im en ta l Section
Gen er a l a n d Ma ter ia ls. All manipulations with air-sensitive
reagents were carried out under a dry nitrogen atmosphere using
standard Schlenk techniques or in
a nitrogen atmosphere
glovebox unless otherwise stated. The ketones were stirred over
CaH2 to remove acidic impurities and distilled prior to use. DMF
J . Org. Chem, Vol. 67, No. 22, 2002 7909

TABLE 2. Asym m etr ic Hyd r ogen a tion of Su bstitu ted Acetop h en on e Ca ta lyzed by 2a
S/C
(M/M)
pH
(psi)
time
(h)
conv
(%)
2
entry
ketone
R
catalyst
ee (%)b
1
2
3
4
5
6
7
8
9
3b
3c
3d
3d
3d
3e
3f
3g
3h
3i
o-CH3
o-OCH3
o-Br
o-Br
o-Br
m-CH3
m-OCH3
m-Br
p-CH3
p-OCH3
p-Br
(R,RR)-2c
(R,RR)-2c
(R,RR)-2a
(R,RR)-2b
(R,RR)-2c
(R,RR)-2c
(R,RR)-2c
(R,RR)-2c
(R,RR)-2c
(R,RR)-2c
(R,RR)-2c
(R,RR)-2c
4000
4000
4000
300
300
300
300
400
300
300
300
300
300
300
300
24
30
7
100
99.6
90.7
100
100
100
100
100
99.1
99.6
100
100
97.7 (S)
93.3 (S)
>99.9 (S)
>99.9 (S)
>99.9 (S)
97.7 (S)
98.8 (S)
99.5 (S)
98.8 (S)
98.7 (S)
>99.9 (S)
97.7 (S)
4000
7
10000
12000
4000
18
50
6
4000
6
20000
20000
50000
12000
14
10
20
24
10
11
12
3j
3k
p-CF3
a
Reaction conditions: 100-1000 mg of substrate; substrate concentration ) 1.0-2.5 M; 25-28 °C; S/B (M/M) ) 50-800. b The conversions
were determined by NMR and by the relative peak sizes in GC. The ee values were determined by chiral GC (Chrompack Chirasil-DEX
CB columns). The absolute configuration was determined by comparison of the sign of optical rotation or retention time with literature
data (ref 6).
and 2-propanol were freshly distilled over CaH2 before use.
Optically pure P-Phos (1a ), Tol-P-Phos (1b), and Xyl-P-Phos (1c)
were synthesized according to our previously reported pro-
cedures.9a-d
A Typ ica l P r oced u r e for th e Ru (II)-Ca ta lyzed Asym -
m etr ic Hyd r ogen a tion of Ar om a tic Keton e. A solution of
2.19 × 10-3 mol‚L-1 (R,RR)-2c in 2-propanol (97 µL, 2.13 × 10-4
mmol), acetophenone (50 µL, 0.425 mmol), 2-propanol (251 µL),
and a 0.02 mol‚L-1 (CH3)3COK solution in t-BuOH (26.5 µL, 5.3
× 10-4 mmol) were added to a 50-mL autoclave under a nitrogen
atmosphere. Hydrogen was initially introduced into the auto-
clave at a pressure of 300 psi before being reduced to 1 atm by
carefully releasing the stop valve. After this procedure was
repeated three times, the vessel was pressurized to 300 psi. The
reaction mixture was stirred at room temperature for 2 h before
releasing the H2. The conversion and enantiomeric excess of (S)-
1-phenylethanol (4a ) were determined by NMR and chiral GC
analysis to be 99.2% and 99.0%, respectively (column, Chirasil-
DEX CB; 50 m × 0.25 mm or 25 m × 0.25 mm, CHROMPACK,
carrier gas, N2).
tr a n s-[R u Cl2{(R)-P -P h os}{(R,R)-DP E N}] [(R,RR)-2a ].
[RuCl2(C6H6)]2 (18.2 mg, 0.036 mmol) and (R)-P-Phos (50 mg,
0.078 mmol) were placed in a 25-mL round-bottom Schlenk flask.
After the air in the flask was replaced by N2, dried and degassed
DMF (2 mL) was added. The mixture was stirred under N2 at
100 °C for 1 h to form a reddish brown solution. After the
solution was cooled to room temperature, (R,R)-DPEN (18.4 mg,
0.078 mmol) was added and the mixture was stirred for 4 h.
The solvent was evaporated under high vacuum. The residue
was dissolved in CH2Cl2 (1 mL) and the turbidity was removed
by filtration. The filtrate was concentrated to about 0.5 mL, then
hexane (2 mL) was added and a brown precipitate was obtained.
The supernatant was removed and the resulting solid was dried
under reduced pressure to give (R,RR)-2a (41.5 mg, 56% yield).
1H NMR (CDCl3, 500 MHz) δ 3.19-3.21 (m, 2H), 3.30-3.33 (m,
2H), 3.39 (s, 6H), 3.79 (s, 6H), 4.27-4.29 (m, 2H), 6.64-6.66 (m,
2H), 6.82-7.82 (m, 30H); 31P NMR (CDCl3, 202 MHz) δ 46.0 (s).
tr a n s-[R u Cl2{(R)-Tol-P -P h os}{(R,R)-DP E N}] [(R,RR)-
2b]. (R,RR)-2b was synthesized in 58% yield according to the
same procedure as in the preparation of (R,RR)-2a . 1H NMR
(CDCl3, 500 MHz) δ 2.18 (s, 6H), 2.29 (s, 6H), 3.24-3.25 (m,
2H), 3.31-3.32 (m, 2H), 3.41(s, 6H), 3.79 (s, 6H), 4.28-4.30 (m,
2H), 6.57-6.58 (m, 2H), 6.85-7.68 (m, 26H); 31P NMR (CDCl3,
202 MHz) δ 45.1 (s).
Ack n ow led gm en t. We thank the Hong Kong Re-
search Grants Council (Project No. PolyU 5177/99P),
The University Grants Committee Area of Excellence
Scheme in Hong Kong (AoE P/10-01), and The Hong
Kong Polytechnic University ASD Fund for financial
support of this study.
Su p p or tin g In for m a tion Ava ila ble: Crystallographic
procedures, ORTEP drawing, and selective bond distances and
angles of (R,RR)-2b (PDF) and X-ray data for (R,RR)-2b,
including tables of coordinates for non-hydrogen atoms, se-
lected bond lengths and angles, anisotropic thermal param-
eters, and coordination of hydrogen atoms (CIF). This material
is available free of charge via the Internet at http://pubs.acs.org.
tr a n s-[Ru Cl2{(R)-Xyl-P -P h os}{(R,R)-DP EN}] [(R,RR)-2c].
(R,RR)-2c was synthesized in 63% yield according to the same
1
procedure as in the preparation of (R,RR)-2a . H NMR (CDCl3,
500 MHz) δ 2.14 (s, 12H), 2.21 (s, 12H), 3.16-3.24 (m, 2H), 3.29-
3.32 (m, 2H), 3.33 (s, 6H), 3.85 (s, 6H), 4.23-4.25 (m, 2H), 6.77-
6.79 (m, 2H), 6.80-7.48 (m, 22H); 31P NMR (CDCl3, 202 MHz)
δ 44.4 (s).
J O026168F
7910 J . Org. Chem., Vol. 67, No. 22, 2002