C O M M U N I C A T I O N S
In summary, chiral η6-arene/N-tosylethylenediamine-Ru(II)
complexes are excellent catalysts not only for ATH but also for
AH of aromatic ketones. Various base-sensitive ketonic substrates
can be enantioselectively hydrogenated by this method.14
Table 1. Asymmetric Hydrogenation of 4-Chromanones Catalyzed
by Chiral Ru Complexesa
conditions
H2, atm T,
(S)-7d
% yield
ketone
cat
S/Cb
additivec
°
C
% ee
6a
6a
6a
6a
6a
6a
6ae
6a
6a
6b
6c
(S,S)-8a 3000
(S,S)-8a 3000
(S,S)-8a 3000
(S,S)-8b 3000
(S,S)-8b 7000
10
10
50
10
100
10
17
10
15
10
10
30
34
64
99
100
100
60
99
99
98
95
97
95
97
97
96
96
98
97
95
98
98
Acknowledgment. This work was supported by Grants-in-Aid
from the Japan Society for the Promotion of Science (JSPS) (Nos.
14GS0214 and 15350079), the New Energy and Industrial Technol-
ogy Development Organization (NEDO), and the Sumitomo
Foundation.
60
60
60
60
60
36-57
60
50
60
(S,S)-9
(S,S)-9
(S,S)-9
(S,S)-9
7000 1.0 TfOH
1000 1.0 TfOH
3000 1.0 HBF4
3000 0.7 Yb(OTf)3
Supporting Information Available: Preparative methods and
properties of chiral Ru complex 8b, procedures for asymmetric
hydrogenation of chromanones, NMR, GC, and HPLC behavior, and
[R]D values of products. This material is available free of charge via
(S,S)-8b 1500
(S,S)-8b 1000
60
100
a Unless otherwise stated, reactions were conducted using a 0.3-1.0 M
solution of 6 and a 0.1-3.5 mM solution of 8 or 9 in methanol in a silanized
glass vessel. The reaction time was 15 h. b Substrate/catalyst molar ratio.
c Molar equiv to Ru. d Determined by NMR, the sign of rotation, and chiral
HPLC analysis. e A 2.4 kg scale reaction using a 2.0 M solution of 6a in
a 20 L SUS autoclave for 8 h.
References
(1) Noyori, R.; Kitamura, M.; Ohkuma, T. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5356-5362.
(2) (a) Ohkuma, T.; Noyori, R. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
Vol. 1, Chapter 6.1. (b) Ohkuma, T.; Kitamura, M.; Noyori, R. In Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; Wiley-VCH: New York, 2000;
Chapter 1. (c) Ohkuma, T.; Noyori, R. In Transition Metals for Organic
Synthesis: Building Blocks and Fine Chemicals; Beller, M., Bolm, C.,
Eds.; Wiley-VCH: Weinheim, Germany, 1998; pp 25-69. (d) Brown, J.
M. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 1, Chapter 5.1. (e)
Brown, J. M. J. Organomet. Chem. 2004, 689, 4006-4015. (f) Halpern,
J. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New
York, 1994; Vol. 5, Chapter 1. (g) Mechanisms in Homogeneous Catalysis;
Heaton, B., Ed.; Wiley-VCH: Weinheim, Germany, 2005; Chapter 1.
(3) BINAP/Ru complexes effect AH and ATH of unsaturated carboxylic acids.
See: (a) Ohta, T.; Takaya, H.; Kitamura, M.; Nagai, K.; Noyori, R. J.
Org. Chem. 1987, 52, 3174-3175. (b) Brown, J. M.; Brunner, H.; Leitner,
W.; Rose, M. Tetrahedron: Asymmetry 1991, 2, 331-334.
30 °C, 10 atm, 15 h) retarded the reaction to afford (S)-7a with
92% ee in only 6% yield.
This AH procedure, though viable, remains unoptimized because
the Ru-Cl bond in the precatalyst is not fully dissociated in
alcohols. The concentration of the cationic amino Ru complex 4
can be maximized by using a more ionizable precatalyst 1 (X )
weakly nucleophilic anion) or by combining the 16e amido Ru
complex 2 and an appropriate acid. Notably, the operation of a
specific acid/base catalysis requires careful adjustment of the acidity
and basicity of the reaction medium to retain a smooth metal-
ligand bifunctional catalytic cycle (Figure 1). Pure alcoholic solvents
are unable to protonate 2.8 Strong acid additives facilitate this step,
but hamper the deprotonation of 5 and also decoordinate the
ethylenediamine ligand from Ru.
(4) Achiral (cyclopentadienone)Ru carbonyl complexes effect hydrogenation
(34 atm, 145 °C, S/C ) 1000) and transfer hydrogenation (2-propanol
with KOH, S/C ) 6000) of acetophenone. See: (a) Blum, Y.; Czarkle,
D.; Rahamim, Y.; Shvo, Y. Organometallics 1985, 4, 1459-1461. (b)
Casey, C. P.; Singer, S. W.; Powell, D. R.; Hayashi, R. K.; Kavana, M.
J. Am. Chem. Soc. 2001, 123, 1090-1110.
The best solution to this problem was provided by invention of
the chiral Ru triflate (S,S)-8b, which could be obtained simply by
adding CF3SO3H (TfOH) to (S,S)-98 in CH2Cl2 at 0 °C. In methanol,
the Ru triflate precatalyst is cleanly converted to an ion pair acting
as an ideal AH catalyst. An equimolar mixture of (S,S)-9 and TfOH
in methanol was also usable. TfOH could be used in slight excess
but not large excess. Thus, when the simple ketone 6a was
hydrogenated in methanol under 10 atm of H2 with S/C ) 3000 in
a silanized glass vessel ([6a] ) 1.0 M, [8b] ) 0.33 mM, 60 °C, 15
h), (S)-7a was obtained in 100% yield and 97% ee (Table 1). The
reaction with S/C of 7000 took place smoothly at 100 atm. The
hydrogenation was accomplished even on a 2.4 kg scale in 8 L of
methanol, giving (S)-7a with 98% ee in 99% yield. Now less polar
alcohols may be used in place of methanol, though the reaction is
somewhat slower. TfOH was the best acid to activate (S,S)-9, but
other non-nucleophilic acids can be employed as well. For example,
an equimolar mixture of (S,S)-9 and HBF4‚O(CH3)2 or Yb(OTf)3
in methanol catalyzed the hydrogenation of 6a at 10 atm giving
(S)-7a in 97% ee in high yield. The results of AH of some
4-chromanone derivatives 6 are listed in Table 1.
The reaction mixture retains a yellow color throughout the
hydrogenation. This implies that the amide complex (S,S)-9 (purple)
is mostly protonated to the amino compounds under the steady-
state catalytic conditions. Reduction does not proceed without H2,
indicating that this is a net hydrogenation using H2 gas. Alcohols
are involved in the catalytic cycle, but only as proton sources and
bases, not as reducing agents. The sense and degree of enantiose-
lection are the same as those observed in ATH13 because both AH
and ATH involve a common chiral RuH intermediate possessing
an R configuration at Ru.8
(5) (Diphosphine)(R-picolylamine)RuCl2 complexes catalyze both hydrogena-
tion and transfer hydrogenation, depending on the phosphine ligands, under
basic conditions: (a) Ohkuma, T.; Sandoval, C. A.; Srinivasan, R.; Lin,
Q.; Wei, Y.; Mun˜iz, K.; Noyori, R. J. Am. Chem. Soc. 2005, 127, 8288-
8289. (b) Baratta, W.; Herdtweck, E.; Siega, K.; Toniutti, M.; Rigo, P.
Organometallics 2005, 24, 1660-1669. (c) See also: Naud, F.; Malan,
C.; Spindler, F.; Ru¨ggeberg, C.; Schmidt, A. T.; Blaser, H. U. AdV. Synth.
Catal. 2006, 348, 47-50.
(6) (a) Noyori, R.; Yamakawa, M.; Hashiguchi, S. J. Org. Chem. 2001, 66,
7931-7944. (b) Clapham, S. E.; Hadzovic, A.; Morris, R. H. Coord.
Chem. ReV. 2004, 248, 2201-2237.
(7) (a) Yamakawa, M.; Ito, H.; Noyori, R. J. Am. Chem. Soc. 2000, 122,
1466-1478. (b) Alonso, D. A.; Brandt, P.; Nordin, S. J. M.; Andersson,
P. G. J. Am. Chem. Soc. 1999, 121, 9580-9588.
(8) Haak, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew.
Chem., Int. Ed. Engl. 1997, 36, 285-288.
(9) ATH reaction of ketones is attained mostly by 2-propanol containing a
strong base or a formic acid/triethylamine mixture as reducing agent.
See: (a) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97-102.
(b) Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry 1999, 10, 2045-
2061. (c) Ikariya, T.; Murata, K.; Noyori, R. Org. Biomol. Chem. 2006,
4, 393-406.
(10) A BINAP/aminophosphine-Ir complex catalyzes AH of 6a at >50 atm
and 90 °C, giving 7a in 93% ee and 89% yield, but only with S/C of 200:
Zhang, X.; Takemoto, T.; Yoshizumi, T.; Kumobayashi, H.; Akutagawa,
S.; Mashima, K.; Takaya, H. J. Am. Chem. Soc. 1993, 115, 3318-3319.
(11) BINAP/1,4-diamine-Ru complexes are effective for AH of 1-tetralone
but not 6: Ohkuma, T.; Hattori, T.; Ooka, H.; Inoue, T.; Noyori, R. Org.
Lett. 2004, 6, 2681-2683.
(12) For AH with RuH(η1-BH4)(binap)(1,2-diamine) under slightly basic
conditions, see: Ohkuma, T.; Koizumi, M.; Mun˜iz, K.; Hilt, G.; Kabuto,
C.; Noyori, R. J. Am. Chem. Soc. 2002, 124, 6508-6509.
(13) ATH of 6a using a formic acid/triethylamine mixture catalyzed by (S,S)-
8a with S/C ) 500 at 30 °C for 17 h afforded (S)-7a with 97% ee but in
only 37% yield.
(14) For AH of simple ketones under basic conditions, see: (a) Noyori, R.;
Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40-73. (b) Noyori, R.
Angew. Chem., Int. Ed. 2002, 41, 2008-2022. (c) Sandoval, C. A.;
Ohkuma, T.; Mun˜iz, K.; Noyori, R. J. Am. Chem. Soc. 2003, 125,
13490-13503.
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