Asymmetric hydrogenation of α-chloro aromatic ketones catalyzed by η6-arene/TsDPEN-ruthenium(II) complexes

Article abstract of DOI:10.1021/ol062661s

(Chemical Equation Presented) Asymmetric hydrogenation of various α-chloro aromatic ketones with Ru(OTf)(TsDPEN)(η⁶-arene) (TsDPEN = N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine) produces the chiral chlorohydrins in up to 98% ee. This reac

Full text of DOI:10.1021/ol062661s

ORGANIC
LETTERS
2007
Vol. 9, No. 2
255-257
Asymmetric Hydrogenation of
Aromatic Ketones Catalyzed by
6-Arene/TsDPEN
Ruthenium(II)
Complexes
r-Chloro
η
−
Takeshi Ohkuma,*,† Kunihiko Tsutsumi,‡ Noriyuki Utsumi,‡ Noriyoshi Arai,†
Ryoji Noyori,§ and Kunihiko Murata‡
DiVision of Chemical Process Engineering, Graduate School of Engineering,
Hokkaido UniVersity, Sapporo 060-8628, Japan, Central Research Laboratory,
Technology and DeVelopment DiVision, Kanto Chemical Co., Inc., Soka,
Saitama 340-0003, Japan, and Department of Chemistry and Research Center for
Materials Science, Nagoya UniVersity, Chikusa, Nagoya 464-8602, Japan
ohkuma@eng.hokudai.ac.jp
Received October 31, 2006
ABSTRACT
Asymmetric hydrogenation of various
r
-chloro aromatic ketones with Ru(OTf)(TsDPEN)(
η
6-arene) (TsDPEN
)
N-(p-toluenesulfonyl)-1,2-
diphenylethylenediamine) produces the chiral chlorohydrins in up to 98% ee. This reaction can be conducted even on a 206-g scale. The
hydrogenation of an
r
-chloro ketone with a phenol moiety has been utilized for the synthesis of (R)-norphenylephrine without protection
−
deprotection operations.
Optically active chlorohydrins are versatile intermediates for
the syntheses of biologically active compounds, including
â-amino alcohols,1,2 substituted pyrrolidines,3 and a func-
tionalized cyclopropane compound.4 Asymmetric reduction
of the R-chloro ketones is a straightforward method to
produce this important class of compounds. Hydroboration
catalyzed by chiral oxazaborolidines1-3,5 and transfer hy-
drogenation with chiral Rh6 and Ru7 catalysts show excellent
(5) Recent reviews: (a) Itsuno, S. Org. React. 1998, 52, 395-576. (b)
Itsuno, S. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 1, pp 289-315. (c)
Cho, B. T. Aldrichimica Acta 2002, 35, 3-16. (d) Ohkuma, T.; Noyori, R.
In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 2004; Supplement 2, pp 7-19.
(6) (a) Hamada, T.; Torii, T.; Izawa, K.; Noyori, R.; Ikariya, T. Org.
Lett. 2002, 4, 4373-4376. (b) Hamada, T.; Torii, T.; Onishi, T.; Izawa,
K.; Ikariya, T. J. Org. Chem. 2004, 69, 7391-7394. (c) Matharu, D. S.;
Morris, D. J.; Kawamoto, A. M.; Clarkson, G. J.; Wills, M. Org. Lett. 2005,
7, 5489-5491.
(7) (a) Bayston, D. J.; Travers, C. B.; Polywka, M. E. C. Tetrahedron:
Asymmetry 1998, 9, 2015-2018. (b) Cross, D. J.; Kenny, J. A.; Houson,
I.; Campbell, L.; Walsgrove, T.; Wills, M. Tetrahedron: Asymmetry 2001,
12, 1801-1806. (c) Morris, D. J.; Hayes, A. M.; Wills, M. J. Org. Chem.
2006, 71, 7035-7044.
† Hokkaido University.
‡ Kanto Chemical Co., Inc.
§ Nagoya University
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10.1021/ol062661s CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/22/2006

enantioselectivity for a variety of R-chloroacetophenone
derivatives. Despite the fruitful results of these asymmetric
reactions, to our knowledge no reliable catalyst for asym-
metric hydrogenation of R-chloro ketones exists.8 We previ-
ously exploited RuCl2(binap)(1,2-diamine)9-11 and RuH(η1-
BH4)(binap)(1,2-diamine)11,12 complexes, which show excellent
activity and enantioselectivity for hydrogenation of simple
aromatic, heteroaromatic, R-amino, and R,â-unsaturated
ketones under basic or slightly basic conditions. However,
these catalyst systems cannot be applied to the reaction of
highly base-labile R-chloro ketones.13 We recently reported
that Ru(OTf)(TsDPEN)(η6-p-cymene) (3a) (TfO- ) trifluo-
romethanesulfonate, TsDPEN ) N-(p-toluenesulfonyl)-1,2-
diphenylethylenediamine) in methanol efficiently catalyzes
asymmetric hydrogenation of 4-chromanones, which are
another type of base-sensitive ketonic substrates.14 The
neutral to slightly acidic conditions fit the requirement of
this reaction. We describe here enantioselective hydrogena-
tion of R-chloro aromatic ketones catalyzed by the η6-arene/
TsDPEN-Ru(II) complexes.15 A series of chiral chlorohy-
drins are obtained quantitatively in excellent enantiomeric
excess (ee). This reaction can be conducted even on a
practical (206-g) scale.
Scheme 1
Our previous mechanistic studies on hydrogenation of
ketones with RuX(TsDPEN)(η6-p-cymene) complexes (3a,
X ) OTf; 3b, X ) Cl) revealed that the generation of
cationic Ru(II) species, [Ru(TsDPEN)(η6-p-cymene)]+, is
crucially important to achieve high catalytic activity.14,16 This
is because molecular H2 is activated on the cationic Ru
center, producing a catalytic species, RuH(TsDPEN)(η6-p-
cymene), with release of H+. A highly polarized Ru triflate
3a is smoothly ionized in a methanol solution, supplying
the active Ru cationic species. Thus, we selected 3a as a
precatalyst for asymmetric hydrogenation of R-chloro aro-
matic ketones. When R-chloroacetophenone (1a) (206 g) and
(S,S)-3a (1.02 g) (substrate/catalyst molar ratio (S/C) ) 1000)
in methanol (5.3 L) was stirred under 10 atm of H2 at 30 °C
for 10 h in a stainless steel autoclave, (R)-2-chloro-1-
phenylethanol [(R)-2a] in 96% ee was quantitatively pro-
duced (Scheme 1 and Table 1). Methanol was the solvent
of choice. Use of ethanol or 2-propanol as a solvent instead
of methanol reduced both the reactivity and enantioselec-
tivity.14 The coordinative R-chloro functionality of the
substrate did not prevent the catalyst performance. Complete
conversion within 15 h in the reactions with an S/C of 2000
and 4000 was achieved under 20 and 100 atm of H2,
respectively. When the reaction with (S,S)-3a (S/C ) 2000)
was conducted under 10 atm of H2 at 30 °C for 15 h, (R)-2a
in 96% ee was obtained in 73% yield (Table 1). Under the
same conditions, only 21% yield of the alcohol was attained
by use of the less-polarized Ru chloride 3b as a precatalyst,
while the enantioselectivity was also high. Addition of an
electrolyte, NaClO4, did not help increase the catalytic
activity of 3b (Table 1). The reaction with the mesitylene-
Ru complex 3c in place of the p-cymene-Ru complex 3a
achieved a higher enantioselectivity of 98%.
(8) Hydrogenation of 2,4′-dichloroacetophenone with chiral amidophos-
phine-phosphinite/Rh catalysts afforded the chiral alcohol in up to 68%
ee. See: Devocelle, M.; Mortreux, A.; Agbossou, F. D. J.-R. Tetrahedron
Lett. 1999, 40, 4551-4554.
(9) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40-73.
(10) For asymmetric hydrogenation of 1-tetralones catalyzed by BINAP/
chiral 1,4-diamine-Ru catalysts, see: Ohkuma, T.; Hattori, T.; Ooka, H.;
Inoue, T.; Noyori, R. Org. Lett. 2004, 6, 2681-2683.
(11) BINAP/picolylamine-Ru catalysts are effective for asymmetric
hydrogenation of sterically hindered tert-alkyl ketones: Ohkuma, T.;
Sandoval, C. A.; Srinivasan, R.; Lin, Q.; Wei, Y.; Mun˜iz, K.; Noyori, R. J.
Am. Chem. Soc. 2005, 127, 8288-8289.
(12) Ohkuma, T.; Koizumi, M.; Mun˜iz, K.; Hilt, G.; Kabuto, C.; Noyori,
R. J. Am. Chem. Soc. 2002, 124, 6508-6509.
A series of R-chloroacetophenones 1 substituted on the
phenyl rings were hydrogenated with the η6-arene/TsDPEN-
Ru(II) triflates, 3a and 3c, in methanol to afford quantitatively
the chlorohydrins 2 with consistently high enantioselectivity
(Table 1). Thus, hydrogenation of 3′-CH3-substituted ketone
1b in the presence of (S,S)-3a with an S/C of 1000 under 10
atm of H2 at 30 °C for 15 h gave (R)-2b in 96% ee and 98%
yield. The 4′-CH3-substituted ketone 1c was hydrogenated
in the same manner. Substitution of an electron-donating
CH3O group at the 4′ position (1d) slightly lowered the
reactivity, while the enantioselectivity was not influenced
by the substitution. Thanks to the nonbasic reaction condi-
(13) R-Chloroacetophenone suffers Darzens-like condensation in a basic
alcoholic solvent: (a) Wasserman, H. H.; Aubrey, N. E.; Zimmerman, H.
E. J. Am. Chem. Soc. 1953, 75, 96-98. (b) Stevens, C. L.; Church, R. J.;
Traynelis, V. J. J. Org. Chem. 1954, 19, 522-532.
(14) Ohkuma, T.; Utsumi, N.; Tsutsumi, K.; Murata, K.; Sandoval, C.;
Noyori, R. J. Am. Chem. Soc. 2006, 128, 8724-8725.
(15) For asymmetric transfer hydrogenation of ketones with η6-arene/
TsDPEN-Ru(II) complexes, see: (a) Noyori, R.; Hashiguchi, S. Acc. Chem.
Res. 1997, 30, 97-102. (b) Noyori, R.; Yamakawa, M.; Hashiguchi, S. J.
Org. Chem. 2001, 66, 7931-7944. (c) Ikariya, T.; Murata, M.; Noyori, R.
Org. Biomol. Chem. 2006, 4, 393-406.
(16) For mechanistic studies on asymmetric hydrogenation of ketones
with BINAP/1,2-diamine-Ru catalysts, see: (a) Sandoval, C. A.; Ohkuma,
T.; Mun˜iz, K.; Noyori, R. J. Am. Chem. Soc. 2003, 125, 13490-13503. (b)
Noyori, R.; Sandoval, C. A.; Mun˜iz, K.; Ohkuma, T. Philos. Trans. R Soc.
A 2005, 363, 901-912.
256
Org. Lett., Vol. 9, No. 2, 2007

chlorohydrin 2h in a higher ee of 96% was obtained by hy-
drogenation with the mesitylene-Ru complex 3c. The chiral
chlorohydrins, (R)-2f and (R)-2g, are convertible to â-adreno-
ceptor agonists, including (R)-tulobuterol,19 CL316243,2c
FK175,20 and SR58611A.8,21 The substrate 1i with a strongly
electron-withdrawing CF3 group at the 3′ position was
reduced with 3a to produce quantitatively the chiral alcohol
2i in 93% ee. The hydrogenation tolerated the CO2CH3
moiety, so that 1j was completely converted to 2j in 94%
ee without loss of functionality.
In conclusion, we report here the first example of highly
enantioselective hydrogenation of R-chloro aromatic ketones
with the η6-arene/TsDPEN-Ru(II) triflates, 3a and 3c. Even
206 g of substrate is completely converted to the desired
chiral alcohol. Synthetically useful chiral chlorohydrins are
quantitatively produced in up to 98% ee by this method. The
hydrogenation tolerates phenolic OH and CO2CH3 function-
alities. A phenol-substituted â-amino alcohol, (R)-norphe-
nylephrine, is synthesized by means of this reaction without
use of protective groups. Thus, this method provides a
practical tool for stereoselective organic synthesis.
Table 1. Asymmetric Hydrogenation of R-Chloro Ketonesa
ketone
conditions
R alcoholb
[1]0
H2
time yield
[h]
ee
no.
Ru cat. no. [M]c S/Cd [atm]
[%]e [%]e
1af
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1e
1f
(S,S)-3a
(S,S)-3a
(S,S)-3ag
(S,S)-3a
(S,S)-3b
(S,S)-3bh
(S,S)-3c
(S,S)-3a
(S,S)-3a
(S,S)-3a
(S,S)-3a
(S,S)-3c
(S,S)-3a
(S,S)-3a
(S,S)-3a
(S,S)-3c
(S,S)-3a
(S,S)-3a
0.25 1000
0.47 2000
0.50 2000
1.00 4000
0.47 2000
0.47 2000
0.25 1000
0.25 1000
0.25 1000
0.25 1000
0.25 1000
0.25 1000
10
10
20
100
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
15
15
15
15
15
16
15
15
20
15
15
15
15
15
15
15
15
>99
73
>99
>99
21
25
>99
98
96
96
95
95
96
95
98
96
95
95
96
98
95
94
93
96
93
94
>99
99
>99
>99
>99
>99
>99
>99
>99
>99
0.13
500
1g
1h
1h
1i
0.25 1000
0.25 1000
0.25 1000
0.13
500
1j
0.25 1000
Acknowledgment. This work was supported by a Grant-
in-Aid from the New Energy and Industrial Technology
Development Organization (NEDO) (Support Program for
Technology Development on the Basis of Academic Find-
ings) and the Japan Society for the Promotion of Science
(JSPS) (No. 18350046).
a
Unless otherwise stated, reactions were conducted in methanol
containing 1.5 µmol of 3 (0.25 mM) at 30 °C in a silanized glass (10 atm)
b
or stainless steel (>20 atm) autoclave. R alcohols were obtained in all
c
d
cases. See Supporting Information. Initial concentration of ketones 1.
e
Substrate/catalyst molar ratio. Determined by chiral GC and/or HPLC
analysis. A 206 g-scale reaction in 5.3 L of methanol in a 20-L stainless
steel autoclave. Reaction using 4.5 µmol of 3a. Fifty equiv of NaClO4
was added to the Ru catalyst.
f
g
h
Supporting Information Available: Preparative methods
and properties of the chiral Ru complex 3c, procedures for
asymmetric hydrogenation of R-chloro aromatic ketones,
NMR, GC, and HPLC behavior of products, together with
[R]D values and absolute configuration determinations (PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
tions, a ketonic substrate 1e with a phenolic hydroxyl group
was completely converted to the chiral alcohol 2e in 96%
ee without protection. The reaction with 3c resulted in an
even better optical yield of 98%. The phenolic chlorohydrin,
(R)-2e, was easily converted to (R)-norphenylephrine [(R)-
5]17 through the â-azido alcohol, (R)-4, without protection-
deprotection processes (conditions: (a) 5 equiv of NaN3,
DMF, 100 °C, 8 h; (b) 1 atm of H2, Pd/C catalyst, methanol,
25 °C, 15 h).18 The Cl-substituted ketones at the 2′, 3′, and
4′ positions, 1f-1h, were hydrogenated with (S,S)-3a to
afford (R)-2f-2h in the range 93-95% ee. The reactivity
of the 2′-substituted ketone 1f was relatively lower than that
of the 3′- and 4′-substituted ketones, 1g and 1h. The chiral
OL062661S
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1083.
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Nakamura, K.; Koibuchi, Y.; Kobayashi, M.; Yamaguchi, O. J. Urol. 1999,
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(18) Characterization of the amino alcohol 5 was done after conversion
to the triacetylated compound due to instability of 5 at ambient temperature
(see Supporting Information).
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