Asymmetric hydrogenation of amino ketones using chiral RuCl2(diphophine)(1,2-diamine) complexes [12]

Full text of DOI:10.1021/ja001098k

6510
J. Am. Chem. Soc. 2000, 122, 6510-6511
(S)-3a was produced in a 92% ee and 99% yield. Pure S amino
alcohol was obtained via its crystalline hydrochloride. The
diphosphine/diamine Ru catalyst 1a is much more reactive than
the earlier devised diamine-free BINAP-Ru catalysts that require
the assistance of heteroatom/Ru interaction and shows an opposite
sense of asymmetric induction.3,11 2-Dimethylaminoacetophenone
(2c) was hydrogenated with the same Ru catalyst to give (R)-3c
in 93% ee. The R-amino group in ketonic substrates exerts a
directive influence but not through the ligation to the Ru center.
The relative enantio-directing effect in this hydrogenation appears
to decrease in the order C6H5 > (CH3)2NCH2 > CH3. Therefore,
in going from acetophenone to the aromatic R-amino ketone 2c
to nonaromatic amino ketone 2a, the ee value varies from 99%7b
to 93% (lower selectivity) and -92% (reversed asymmetric
sense),10 respectively.
Asymmetric Hydrogenation of Amino Ketones Using
Chiral RuCl2(diphophine)(1,2-diamine) Complexes
Takeshi Ohkuma, Dai Ishii, Hiroshi Takeno, and
Ryoji Noyori*
Department of Chemistry and
Research Center for Materials Science
Nagoya UniVersity, Chikusa, Nagoya 464-8602, Japan
ReceiVed March 29, 2000
There are ample examples of asymmetric hydrogenation of
functionalized ketones catalyzed by chiral phosphine-Ru and
-Rh complexes.1 The high efficiency of this process is considered
to arise from a chelate mechanism involving the ligation of a
heteroatom to the metallic center that facilitates hydride delivery
from the metal to carbonyl carbon in the chiral template.
Enantioselective hydrogenation of amino ketones provides a
particularly important tool for synthesis of physiologically active
chiral compounds. Unfortunately, most reported procedures used
relatively high catalyst loading [substrate to catalyst molar ratio
(S/C) ) 200-1000 for Rh2 and 1000 for Ru3] and hydrogen
pressures as high as 20-100 (Rh) or 100 atm (Ru). A notable
exception is Achiwa’s MCCP-Rh catalyst hydrogenating 2-di-
ethylaminoacetophenone with an S/C of 100 000 at 20 atm at 50
°C to give the amino alcohol in 96% ee,4,5 while the reactions of
other amino ketones show less satisfactory rates and selectivities.2d,6
Thus development of practical asymmetric hydrogenation under
a mild hydrogen pressure and with a wide scope is highly
desirable. The recently devised chiral RuCl2(diphophine)(1,2-
diamine) complexes are marvelously effective in differentiating
enantiofaces of unfunctionalized simple ketones,7,8 so that various
R-, â-, and γ-amino ketones can be asymmetrically hydrogenated
at <8 atm and room temperature with an S/C value of 2000-
10000, as described below. The diversity of substrates now relies
on the capability of the Ru catalysts to effect hydrogenation
without nitrogen/Ru coordination.
When a 1.0 M solution of R-dimethylaminoacetone (2a) in
2-propanol containing trans-RuCl2[(R)-xylbinap][(R)-daipen] [(R,R)-
1a]7-9 and t-C4H9OK (ketone:Ru:base molar ratio ) 2000:1:16)
was stirred under 8 atm of H2 at 25 °C for 4 h, the amino alcohol
(1) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New
York, 1994; Chapter 2.
(2) (a) Hayashi, T.; Katsumura, A.; Konishi, M.; Kumada, M. Tetrahedron
Lett. 1979, 425-428. (b) T_oro¨s, S.; Kolla´r, L.; Heil, B.; Marko´, L. J.
Organomet. Chem. 1982, 232, C17-C18. (c) Yoshikawa, K.; Yamamoto, N.;
Murata, M.; Awano, K.; Morimoto, T.; Achiwa, K. Tetrahedron: Asymmetry
1992, 3, 13-16. (d) Devocelle, M.; Agbossou, F.; Mortreux, A. Synlett 1997,
1306-1308. (e) Pasquier, C.; Naili, S.; Pelinski, L.; Brocard, J.; Mortreux,
A.; Agbossou, F. Tetrahedron: Asymmetry 1998, 9, 193-196.
(3) (a) Kitamura, M.; Ohkuma, T.; Inoue, S.; Sayo, N.; Kumobayashi, H.;
Akutagawa, S.; Ohta, T.; Takaya, H.; Noyori, R. J. Am. Chem. Soc. 1988,
110, 629-631. (b) Mashima, K.; Kusano, K.; Sato, N.; Matsumura, Y.; Nozaki,
K.; Kumobayashi, H.; Sayo, N.; Hori, Y.; Ishizaki, T.; Akutagawa, S.; Takaya,
H. J. Org. Chem. 1994, 59, 3064-3076.
Table 1 illustrates some examples of asymmetric hydrogenation.
In the presence of (R,R)-1a, acetophenone derivatives 4a-e pos-
sessing an acetamido, benzamido, or alkoxycarbonylamino group
at the R position were hydrogenated with a high enantioselectivity,
up to 99.8% ee for 5c. This reaction can be conducted even at 1
atm of H2. The tert-butoxycarbonyl group can be removed from
the product under both acidic (HCl in ether) and basic (0.4 M
KOH in aqueous C2H5OH, 80 °C) conditions. The N-methoxy-
carbonyl analogue 4d gave the cyclization product (R)-612 in 99%
ee, which is easily hydrolyzed to (R)-2-methylamino-1-phenyl-
ethanol (KOH in aqueous C2H5OH, 80 °C). This direction of
(4) Takeda, H.; Tachinami, T.; Aburatani, M.; Takahashi, H.; Morimoto,
T.; Achiwa, K. Tetrahedron Lett. 1989, 30, 363-366.
(5) For Rh-catalyzed hydrogenation at atmospheric pressure (S/C ) 200),
see: Devocelle, M.; Mortreux, A.; Agbossou, F.; Dormoy, J.-R. Tetrahedron
Lett. 1999, 40, 4551-4554.
(6) (a) Sakuraba, S.; Achiwa, K. Synlett 1991, 689-690. (b) Sakuraba, S.;
Nakajima, N.; Achiwa, K. Synlett 1992, 829-830.
(7) For example: (a) 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, 1703-1707. (b) 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, 13529-13530. (c) Ohkuma, T.;
Koizumi, M.; Ikehira, H.; Yokozawa, T.; Noyori, R. Org. Lett. 2000, 2, 659-
662.
(10) In going from 1-phenylethanol to the amino alcohols 5, the R,S
nomenclature is reversed by the change of atom priority.
(11) High-pressure hydrogenation of 2a with RuCl2[(R)-xylbinap](dmf)n
in methanol (S/C ) 500, 50 atm, 25 °C) gave (R)-3a in 99% ee but with only
44% conversion after 48 h. No reaction took place at 8 atm.
(12) (a) Delaunay, D.; Le Corre, M. J. Chem. Soc., Perkin Trans. 1 1994,
3041-3042. (b) Matsumura, Y.; Ohishi, T.; Sonoda, C.; Maki, T.; Watanabe,
M. Tetrahedron 1997, 53, 4579-4592.
(8) Noyori, R.; Ohkuma, T. Pure Appl. Chem. 1999, 71, 1493-1501 and
references therein.
(9) XylBINAP ) 2,2′-bis(di-3,5-xylylphosphino)-1,1′-binaphthyl.3b DAIPEN
) 1,1-di(4-anisyl)-2-isopropyl-1,2-ethylenediamine.
10.1021/ja001098k CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/24/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 27, 2000 6511
Table 1. Asymmetric Hydrogenation of Amino Ketones Catalyzed
by Chiral RuCl2(diphosphine)(1,2-diamine) Complexesa
product
structurec % yieldd % eee
Ru
time,
h
ketone complex
S:C:baseb
2a (R,R)-1a 2000:1:16
2b (R,R)-1a 2000:1:20
4
16
12
4
(S)-3a
(S)-3b
(R)-3c
(R)-5ah
(R)-5b
(R)-5c
(R)-5c
(R)-6h
(R)-5eh
(R)-10
(R)-13
(R)-16
99f
93
90
87
92
96
90
98
94
92g
81
93
99
95
99.8
94
99
99
97
2c
(R,R)-1a 2000:1:20
4a (R,R)-1a 2000:1:20
4b (R,R)-1a 1000:1:20
20
8
4c
4c
(R,R)-1a 2000:1:16
(R,R)-1a 250:1:10
11i
14j
7
4d (R,R)-1a 2000:1:20
4e
9
12
15
(R,R)-1a 2000:1:16
(R,R)-1a 2000:1:40
(S,S)-1ak 10000:1:10
24
5
100
96f
97
97.5
99
(S,S)-1a 10000:1:200 32
a Unless otherwise stated, reactions were conducted at 8 atm of H2
and at 25 °C using a 0.5-1.0 M solution in 2-propanol containing 1a
and t-C4H9OK. b Substrate:catalyst:t-C4H9OK molar ratio. c Absolute
configurations were determined by the sign of rotation of the amino
alcohols or their derivatives. d Isolated yield. e Chiral HPLC analysis.
f 1H-NMR analysis. g 1H-NMR analysis using a chiral shift reagent.
h Absolute configuration was determined by chiral HPLC analysis after
conversion to (R)-5c. i At 1 atm of H2. j A 4:1 2-propanol-methanol
mixture was used as solvent. k (S,S)-1a was treated with t-C4H9OK at
60 °C for 30 min before addition of 12.
asymmetric induction is identical with that observed with the di-
methylamino compound 2c. The ketones with a normally strongly
coordinative amido group behave as simple aromatic ketones.
The basic, protic reaction conditions rapidly racemize enanti-
omers of 2-substituted cyclohexanone 7, allowing dynamic kinetic
resolution of the racemate by hydrogenation.8,13 Thus, the reaction
of racemic 7 in a 2-propanol solution containing (R,S)-1b and
KOH ([7] ) 0.2 M, ketone:Ru:base ) 300:1:200, 8 atm, 25 °C,
5 h) led to 1,2-cis-configurated (S,R)-8 in a 98% yield and 82%
ee accompanied by 1% of the trans isomer.14
Asymmetric hydrogenation of the R-benzamido ketone 9
presents a convenient way to prepare (R)-denopamine [(R)-11],
a â1-receptor agonist to treat congestive heart failure.15 The
reaction using a 1.0 M solution of 9 in 2-propanol containing
(R,R)-1a and t-C4H9OK (S/C ) 2000) at 8 atm produced (R)-10
in 97% ee and in 100% yield. Removal of the amide protector
from (R)-10 (KOH in aqueous C2H5OH, reflux, 10 h)16 followed
by treatment with HCl, recrystallization (100% ee), and selective
removal of the O-benzyl group by hydrogenolysis on Pd/C
(aqueous 2-propanol, 25 °C, 3 h) afforded (R)-11 in a 94% yield.
This method is extended to the asymmetric hydrogenation of
â-amino ketones with an S/C of up to 10 000, allowing for a
practical synthesis of the antidepressant (R)-fluoxetine [(R)-14]
without the need of any chromatographic techniques.17,18 A Ru
catalyst was first prepared by mixing (S,S)-1a (7.3 mg) and t-C4H9-
OK (60 µL of 1.0 M t-C4H9OH solution) in 2-propanol (30 mL)
at 60 °C for 30 min.19 Hydrogenation of 3-dimethylaminopro-
piophenone (12) (10.6 g) using this solution (S/C ) 10 000, 8
atm, 25 °C, 5 h) gave (R)-13 in 97.5% ee in a 96% yield. The
NaH-aided condensation of the alcohol with 4-ClC6H4CF3 fol-
lowed by monodemethylation of the dimethylamino group with
R-chloroethyl chloroformate20 afforded (R)-14.
The functionalized γ-amino ketone 15 can be converted directly
to BMS 181100 [(R)-16], a potent antipsychotic agent,21,22 without
affecting the aromatic fluoride or 2-amino-5-fluoropyrimidine
moiety. Hydrogenation using a 0.5 M solution of 15 in 2-propanol
containing (S,S)-1a and t-C4H9OK was accomplished at 8 atm
(S/C ) 10 000) to give (R)-16 in 99% ee and 97% yield.
The sense of enantioselection observed with various R-, â-,
and γ-amino and protected amino ketones supports the operation
of a nonchelate hydrogenation mechanism. This asymmetric
method is highly flexible with respect to the substrate’s structure
and functionality. This hydrogenation can be performed under
low pressure (<8 atm) at room temperature with a high S/C ratio
and in a reasonably high concentration. This method is applicable
to the synthesis of a wide range of pharmaceutically important
chiral amino alcohols and their derivatives.23
Acknowledgment. This work was financially supported by grants-
in-aid from the Ministry of Education, Science, Sports and Culture of
Japan (Nos. 07CE2004 and 11440188).
Supporting Information Available: The procedure for the hydro-
genation of amino ketones, GC and HPLC behavior, and [R]D values of
products, as well as the procedures for synthesizing (R)-denopamine and
(R)-fluoxetine (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) Ohkuma, T.; Ooka, H.; Yamakawa, M.; Ikariya, T.; Noyori, R. J. Org.
Chem. 1996, 61, 4872-4873.
(14) Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995,
68, 36-56 and references therein.
JA001098K
(19) This pretreatment diminishes the induction period and also reduces
the amount of strong base in the reaction system, thereby maximizing the
efficiency of hydrogenation of the base-sensitive substrate 12.
(20) Deeter, J.; Frazier, J.; Staten, G.; Staszak, M.; Weigel, L. Tetrahedron
Lett. 1990, 31, 7101-7104.
(15) (a) Naito, K.; Nagao, T.; Otsuka, M.; Harigaya, S.; Nakajima, H. Jpn.
J. Pharmacol. 1985, 38, 235-241. (b) Yokoyama, H.; Yanagisawa, T.; Taira,
N. J. CardioVasc. Pharmacol. 1988, 12, 323-331. (c) Bristow, M. R.;
Hershberger, R. E.; Port, J. D.; Minobe, W.; Rasmussen, R. Mol. Pharmacol.
1989, 35, 295-303 and references therein.
(21) Yevich, J. P.; New, J. S.; Lobeck, W. G.; Dextraze, P.; Bernstein, E.;
Taylor, D. P.; Yocca, F. D.; Eison, M. S.; Temple, D. L., Jr. J. Med. Chem.
1992, 35, 4516-4525.
(16) Kawaguchi, T.; Saito, K.; Matsuki, K.; Iwakuma, T.; Takeda, M. Chem.
Pharm. Bull. 1993, 41, 639-642.
(17) Racemic fluoxetin is an antidepressant agent (selective serotonic
reuptake inhibitor) developed by Eli Lilly. Its annual sale in 1997 was $2.6
billion. This compound is now in a process of recemic switch. See: Rogers,
R. S. Chem. Eng. News 1998, NoV 30, 11-13.
(18) Robertson, D. W.; Krushinski, J. H.; Fuller, R. W.; Leander, J. D. J.
Med. Chem. 1988, 31, 1412-1417 and references therein.
(22) For asymmetric reduction of an analogue of 15 with DIP-chloride,
see: Ramachandran, P. V.; Gong, B.; Brown, H. C. Chirality 1995, 7, 103-
110.
(23) Other examples include eprozinol (bronchodilator), isoproterenol (â-
adrenoreceptor agonist), proventil (racemate, asthma drug), seldane (racemate,
antihistamic agent), and tomoxetine (antidepressant).