A catalyst for efficient and highly enantioselective hydrogenation of aromatic, heteroaromatic, and α,β-unsaturated ketones

Article abstract of DOI:10.1021/ol000309n

(equation presented) 0.005 mol% catalyst, H₂, i-PrOH, 2.5 mol% t-BuOK 99% ee PhanePhos-ruthenium-diamine complexes catalyze the asymmetric hydrogenation of a wide range of aromatic, heteroaromatic, and α,β-unsaturated ketones with high activity and excellent enantioselectivity.

Full text of DOI:10.1021/ol000309n

ORGANIC
LETTERS
2000
Vol. 2, No. 26
4173-4176
A Catalyst for Efficient and Highly
Enantioselective Hydrogenation of
Aromatic, Heteroaromatic, and
r,â-Unsaturated Ketones
Mark J. Burk,* William Hems, Daniela Herzberg, Christophe Malan, and
Antonio Zanotti-Gerosa*
Chirotech Technology Limited, Ascot Fine Chemicals, Cambridge Science Park,
Milton Road, Cambridge CB4 0WG, U.K.
azanotti-gerosa@ascotfine.com
Received October 10, 2000
ABSTRACT
PhanePhos−ruthenium−diamine complexes catalyze the asymmetric hydrogenation of a wide range of aromatic, heteroaromatic, and r,â-
unsaturated ketones with high activity and excellent enantioselectivity.
The quest for economic methods to prepare enantiomerically
pure alcohols continues as a result of the important role these
intermediates serve in drug design. A direct route to single
enantiomer alcohols through catalytic reduction of ketones
appears most attractive, and various strategies have been
introduced.1-3 Recently, a groundbreaking discovery was
disclosed by Noyori and co-workers, who found that diphos-
phine-ruthenium-diamine complexes are very effective
catalysts for selective hydrogenation of aldehydes and
ketones.4 Significantly, use of the chiral diphosphines BINAP
and xylyl-BINAP, along with certain chiral diamines, allowed
development of very efficient catalysts for highly enantio-
selective hydrogenation of a wide range of prochiral ketones.4a,5
To date, no other asymmetric diphosphine ligand has been
reported to approach the utility of xylyl-BINAP in this
(4) (a) Ohkuma, T.; Ooka, H.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1995, 117, 2675. (b) Ohkuma, T.; Ooka, H.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1995, 117, 10417. (c) Ohkuma, T.; Ooka,
H.; Yamakawa, M.; Ikariya, T.; Noyori, R. J. Org. Chem. 1996, 61, 4872.
(5) (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.
(6) (a) Noyori, R.; Ohkuma, T. Pure Appl. Chem. 1999, 71, 1493. (b)
Mikami, K.; Korenaga, T.; Terada, M.; Ohkuma, T.; Pham, T.; Noyori, R.
Angew. Chem., Int. Ed. 1999, 38, 495. (c) Cao, P.; Zhang, X. J. Org. Chem.
1999, 64, 2127. (d) Ikariya, T.; Ohkuma, T.; Ooka, H.; Hashiguchi, S.;
Seido, N.; Noyori, R. European Pat. Appl. EP 95308891, 1995.
(7) For a recent example of a rhodium catalyst for enantioselective ketone
hydrogenations, see: Jiang, Q.; Jiang, Y.; Xiao, D.; Cao, P.; Zhang, X.
Angew. Chem., Int. Ed. 1998, 37, 1100.
(1) Hydroboration: (a) Itsuno, S.; Nakano, M.; Miyazaki, K.; Masuda,
H.; Ito, K.; Hirao, A.; Nakahama, S. J. Chem. Soc., Perkin Trans. 1 1985,
2039. (b) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551. (c) Singh, V. K. Synthesis 1991, 605. (d) Hayashi, T.; Matsumoto,
Y.; Ito, Y. J. Am. Chem. Soc. 1989, 111, 3426. (e) Brown, J. M.; Hulmes,
D. I.; Layzell, T. P. J. Chem. Soc., Chem. Commun. 1993, 1673.
(2) Hydrosilylation: (a) Brunner, H.; Nishiyama, H.; Itoh, K. In Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993; Chapter 6.
(b) Sun, J.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 5640.
(3) Hydrogen transfer: (a) Noyori, R.; Hashiguchi, S. Acc. Chem. Res.
1997, 30, 97 and references therein. (b) Jiang, Y.; Jiang, Q.; Zhang, X. J.
Am. Chem. Soc. 1998, 120, 3817. (c) Murata, K.; Ikariya, T.; Noyori, R. J.
Org. Chem. 1999, 64, 2186. (d) Nishibayashi, Y.; Takei, I.; Uemura, S.;
Hidai, M. Organometallics 1999, 18, 2291.
10.1021/ol000309n CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/01/2000

important reaction.6,7 We now have found that ruthenium
complexes based upon the novel PhanePhos series8 of ligands
1 (Figure 1) serve as efficient catalyst precursors for highly
Table 1. Hydrogenation of Acetophenone 3 Using
PhanePhos-Ru Precatalysts 2a
entry phosphine
diamine
S/Cb
timec
% eed,e
1
2
3
4
5
6
7
8
9
(S)-1a
(S)-1a
(S)-1b
(R)-1b
(S)-1b
(S)-1b
(S)-1b
(R)-1b
(R)-1b
(R)-1b
(R)-1b
(R)-1b
(S,S)-DPEN
(R,R)-DPEN
(S,S)-DPEN
(S,S)-DPEN
(S,S)-DACH
(R,R)-DACH
(S)-AMP
3 000
3 000
3 000
3 000
3 000
3 000
3 000
3 000
3 000
1.25
0.5
1
0.5
2
0.5
2
2.5
2
43 (S)
98 (S)
41 (R)
99 (R)
8 (R)
98 (S)
53 (S)
92 (R)
80 (R)
99 (R)
99 (R)
98.5 (R)
(S)-AMP
(S)-DAIPEN
(S,S)-DPEN
(S,S)-DPEN
(S,S)-DPEN
10
11
12
10 000f
20 000g
40 000h
1
1.5
4
Figure 1.
a Reactions were performed with 2-2.5 M solutions of acetophenone in
i-PrOH with added t-BuOK (base/Ru ) 50/1) at 18-20 °C and 8 bar initial
hydrogen pressure. b Substrate-to-catalyst molar ratio. c Time in hours
allowed for reaction to proceed. In all cases complete (100%) conversion
to 4 was observed. d Enantiomeric excess was determined by chiral GC or
chiral HPLC. e Configuration of major enantiomer determined by compari-
son of GC retention time and sign of optical rotation with authentic material.
f Base/Ru ) 250/1. g Base/Ru ) 500/1. h Experiment performed in ther-
mostated 600 mL vessel at 25 °C using 96 g of acetophenone substrate and
base/Ru ) 1000.
enantioselective hydrogenation of a wide array of ketones,
including heteroaromatic and R,â-unsaturated derivatives.
The rates, catalytic efficiencies, and enantioselectivities
achieved with these catalysts are comparable to those
reported for the single best system based upon xylyl-BINAP
and the diamine DIAPEN.5,9
Our initial efforts were aimed at assessing the utility of
different asymmetric diphosphine/diamine combinations in
the Noyori reduction system. These experiments were
conducted using the catalyst precursors obtained by reacting
diphosphine ligands with [(C6H6)RuCl2]2 in DMF, or prefer-
ably a toluene/DMF mixture, followed by treatment with an
appropriate diamine.9 The complexes thus obtained either
were isolated and purified, or were used directly in the
catalytic reactions illustrated below. Spectroscopic data
indicated that these adducts possess a trans-dichloro geom-
etry and may be assigned the general structure 2, analogous
to that of the structurally characterized Tol-BINAP-Ru-
diamine derivatives.10 Preliminary catalytic results revealed
that complexes of type 2, derived from the PhanePhos ligands
(1), displayed both high catalytic activity and high enantio-
selectivity in hydrogenation of the model substrate acetophe-
none 3. Results of our screening studies involving catalysts
2 are listed in Table 1.
played considerable effects of matching/mismatching be-
tween stereochemical elements of the chiral diphosphine and
diamine ligands in the hydrogenation of 3. With the parent
PhanePhos ligand (1a), the highest enantioselectivity (98%
ee) was attained using the precatalyst [((S)-1a)Ru((R,R)-
DPEN)Cl2]. Introduction of 3,5-dimethyl groups on the
P-phenyl rings of xylyl-PhanePhos ligand 1b was found to
increase enantioselectivity slightly; the matched precatalyst
[((R)-1b)Ru((S,S)-DPEN)Cl2] provided 1-phenylethyl alcohol
(4) in 99% ee over 30 min at S/C ) 3000 (entry 4).11
Examination of other basic cocatalysts revealed that KOH
is as effective as t-BuOK, while much lower catalytic rates
were observed with K2CO3. We surveyed other diamine
ligands and found that readily available trans-1,2-diami-
nocyclohexane (DACH) was as useful as DPEN in most
cases, whereas 2-aminomethylpyrrolidine (AMP) was some-
what inferior (Table 1, entries 5-8). Surprisingly, the unique
diamine DAIPEN, which was so effective when used in
combination with BINAP-type ligands,5 proved less availing
in the present system (Table 1, entry 9; the analogous
mismatched DAIPEN-based catalyst afforded 4 with only
25% ee and 50% conversion). High catalytic efficiency was
demonstrated by performing the reaction at S/C ) 20,000,
whereby complete conversion was observed over 1.5 h and
with no diminution of enantioselectivity (entry 11).
Under a standard set of reaction conditions (18-20 °C, 8
bar H2, 2.0-2.5 M solutions, i-PrOH solvent, t-BuOK/Ru
) 50/1) we assessed a range of precatalysts 2 composed of
different PhanePhos and diamine ligands. Catalysts 2 dis-
(8) PhanePhos ) 4,12-bis(diphenylphosphino)-[2.2]paracyclophane. (a)
Pye, P. J.; Rossen, K.; Reamer, R. A.; Tsou, N. N.; Volante, R. P.; Reider,
P. J. J. Am. Chem. Soc. 1997, 119, 6207. (b) Pye, P. J.; Rossen, K.; Reamer,
R. A.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1998, 39, 4441.
(9) DAIPEN ) 1,1-dianisyl-2-isopropyl-1,2-ethylenediamine; see: Wey,
S.-J.; O’Conner, K. J.; Burrows, C. J. Tetrahedron Lett. 1993, 34, 1905.
DPEN ) 1,2-diphenylethylenediamine. DACH ) trans-1,2-diaminocyclo-
hexane. AMP ) 2-aminomethylpyrrolidine.
In a preparative scale experiment, 96 g of acetophenone
was hydrogenated smoothly over 4 h at S/C ) 40,000 to
(10) 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
(11) Xylyl-PhanePhos ) 4,12-bis(di-3,5-xylylphosphino)-[2.2]paracy-
clophane (xylyl refers to the 3,5-dimethylphenyl group). Pye, P. J.; Rossen,
K.; Volante, R. P. Merck & Co., PCT Appl. WO 97/47632, 1997.
4174
Org. Lett., Vol. 2, No. 26, 2000

afford 4 in 98.5% ee and 97% isolated yield (Table 1, entry
12). At high S/C ratios (>10,000), it was necessary for
consistent results to purify the substrate by stirring over solid
K2CO3, followed by distillation. In agreement with Noyori’s
results, the stereochemistry of the phosphine ligand in [(1b)-
Ru(DPEN)Cl2] dictates the configuration of product alcohol
4.
We next sought to investigate the scope of ketone
substrates that may be effectively reduced with the xylyl-
PhanePhos-Ru precatalyst [((S)-1b)Ru((R,R)-DPEN)Cl2].
(Table 2). As can be discerned from the data in Table 2, a
enantioselectivity to 71% ee in the hydrogenation of 6d (entry
12). With many substrates essentially identical results were
achieved with the analogous PhanePhos-Ru catalyst systems
derived from the diamine DACH.12
Importantly, the catalysts 2 were found to be very effective
for hydrogenation of a range of other aromatic and het-
eroaromatic ketones 7 (Table 2, entries 13-22). Despite the
versatility of these catalysts, some limitations were noted.
For example, 2-acetylpyridine (7g) was reduced slowly with
catalyst [((S)-1b)Ru((R,R)-DPEN)Cl2] (18 h, S/C ) 1500),
and the corresponding alcohol was obtained with only 78%
ee. It is likely that the pyridyl group proximal to the ketone
functionality in 7g perturbs the catalytic process through
coordination to ruthenium, leading to diminished selectivity.
To further explore substrate scope, we examined the
efficacy of catalysts 2 for chemoselective hydrogenation of
the carbonyl group of two representative R,â-unsaturated
ketones. Both substrates were reduced smoothly with pre-
catalyst [((R)-1b)Ru((S,S)-DPEN)Cl2], to afford the corre-
sponding allylic alcohols 8 and 9 with 97% and 94% ee,
respectively. Precatalyst [((S)-1b)Ru((R,R)-DACH)Cl2] pro-
duced the alcohol 8 with very similar enantioselectivity (96%
ee, S enantiomer). No over-reduction of the alkene func-
tionality was observed in these reactions. Dialkyl ketones
still represent a challenge for the present catalysts; hydro-
genation of acetylcyclohexane with [((R)-1b)Ru((S,S)-DPEN)-
Cl2] furnished 10 with a modest 49% ee (Figure 2).
Table 2. Hydrogenation of Ketones 5-7 Using Precatalyst
[((S)-1b)Ru((R,R)-DPEN)Cl2]a
entry
ketone
% eeb
entry
ketone
% eeb
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
6a
6b
6c
97
99
97
99
98
97
99
94c
98
96
98
12
13
14
15
16
17
18
19
20
21
22
6d
7a
7b
7c
7d
7e
7f
7g
7h
7i
71d
98
99
92
96
96
98
78e
99e
96f
97
Figure 2.
The unique structural features (e.g., very large P-P
distance and P-M-P bite angle)13 and chemical behavior
of the PhanePhos series of ligands8 have allowed develop-
ment of a useful class of catalysts for highly efficient and
highly enantioselective hydrogenation of a diverse range of
simple aromatic, heteroaromatic, and R,â-unsaturated ke-
tones. The results reported above are equivalent to those
achieved with the best system yet described, the xylyl-
BINAP-Ru-DAIPEN catalyst for asymmetric ketone hy-
drogenation. In contrast to the latter catalyst, which requires
the unique diamine DIAPEN9 for optimum results, the
current systems employ significantly less expensive diamine
ligands such as DPEN and DACH.14 This feature, combined
with the broad substrate scope, high catalytic activity, and
10
11
7j
a Reactions were performed with 1.0-2.0 M solutions of ketone in
i-PrOH at S/C 3000/1 unless otherwise noted, with added t-BuOK (base/
Ru ) 50/1) at 18-20 °C and 5.5-8.0 atm initial hydrogen pressure.
Reactions were allowed to proceed for 0.5-2.5 h, giving complete
conversion, unless otherwise noted. The absolute configuration was
determined by comparison of the sign of optical rotation with literature
data. b Enantiomeric excess was determined by chiral GC or chiral HPLC.
c Reaction time was 2.5 h at S/C ) 500. d Reaction conducted with parent
PhanePhos-Ru-DPEN catalyst [((S)-1a)Ru((R,R)-DPEN)Cl2]. e Reaction
conducted at S/C ) 1500 over 18 h. f Reaction conducted at S/C ) 1000
over 16 h. See Supporting Information for analytical details.
range of substituted acetophenone derivatives were hydro-
genated with very high enantioselectivities. Increasing the
size of the nonaromatic group in 6 shows that branching at
the R-position of the R-substituent imposes intolerable steric
restrictions for the xylyl-PhanePhos catalyst (e.g., 31% ee
for 6d). Use of the parent PhanePhos precatalyst [((S)-1a)-
Ru((R,R)-DPEN)Cl2] in this case led to an increase in
(12) Additional catalytic results are included in the Supplementary
Information section.
(13) Dyer, P. W.; Dyson, P. J.; James, S. L.; Martin, C. M.; Suman, P.
Organometallics 1998, 17, 4344.
(14) Strem Chemical Company provides research quantities of all three
diamines. For comparison: DIAPEN ($1200/g), DPEN ($80/g), DACH
($27/g).
Org. Lett., Vol. 2, No. 26, 2000
4175

high level of absolute stereocontrol that these catalysts
exhibit, suggests that they will find wide application in the
cost-effective production of many valuable enantiomerically
pure alcohols.
Supporting Information Available: Experimental pro-
cedures for the synthesis of PhanePhos-diamine-ruthenium
1
complexes, H and 31P NMR spectra, procedures for the
hydrogenation of acetophenone and other ketones, GC and
HPLC data, and summary table of all hydrogenation experi-
ments. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. We gratefully acknowledge Dr. K.
Rossen and Dr. P. Pye of Merck & Co. for helpful
discussions concerning the preparation and properties of the
PhanePhos ligand series.
OL000309N
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Org. Lett., Vol. 2, No. 26, 2000