Angewandte
Chemie
[2] a) X. F. Wu, X. G. Li, W. Hems, F. King, J. Xiao, Org. Biomol.
Table 2: Asymmetric transfer hydrogenation of ketones in water at
higher S/C ratios.[a]
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F. E. Hancock, F. King, J. Xiao, Org. Lett. 2004, 6, 3321 – 3324.
[3] For recent examples of asymmetric transfer hydrogenation in
water, see: a) P. N. Liu, J. G. Deng, Y. Q. Tu, S. H. Wang, Chem.
Commun. 2004, 2070 – 2071; b) Y. Himeda, N. Onozawa-Komat-
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2003, 195, 95 – 100; c) Y. P. Ma, H. Liu, L. Chen, X. Cui, J. Zhu,
J. G. Deng, Org. Lett. 2003, 5, 2103 – 2106.
[4] A. Benyei, F. Joꢀ, J. Mol. Catal. 1990, 58, 151 – 163.
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2969.
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Steiner, M. Studer, Adv. Synth. Catal. 2003, 345, 103 – 151; b) K.
Everaere, A. Mortrex, J.-F. Carpentier, Adv. Synth. Catal. 2003,
345, 67 – 77.
Ketones
S/C
1000
t [h] Conversion [%][b] ee [%][b]
Acetophenone
9
>99
96
93
95
96
95
96
94
4’-chloroacetophenone
4’-methoxyacetophenone
2-acetylfuran
2’-acetonaphthone
acetophenone
1000
1000
1000
1000
5000[c]
11 >99
32
8
99
>99
11 >99
57
98
98
acetophenone
10000[d] 110
[a] The reactions were carried out in a mixture of H2O (2.5 mL) and
HCOOH–Et3N (2.5 mL; 1.2:1.0) at 408C with 10 mmol of ketone at
pH 5–8. [b] Determined by GC analysis. The configuration of the alcohol
was R. [c] The volume of the mixture of water and HCOOH–Et3N was
10 mL (1:1 volume ratio); ketone: 50 mmol. [d] Water (10 mL), HCOOH
(initially 5 mL), Et3N (20 mL), and ketone (0.1 mol) were used.
[7] a) A. Fujii, S. Hashiguchi, N. Uematsu, T. Ikariya, R. Noyori, J.
Am. Chem. Soc. 1996, 118, 2521 – 2522; b) S. Hashiguchi, A.
Fujii, J. Takehara, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 1995,
117, 7562 – 7563.
[8] a) T. Hamada, T. Torri, K. Izawa, T. Ikariya, Tetrahedron 2004,
60, 7411 – 7417; b) M. Watanabe, K. Murata, T. Ikariya, J. Org.
Chem. 2002, 67, 1712 – 1715, and references therein.
[9] For some recent examples, see: a) J. Hannedouche, G. J.
Clarkson, M. Wills, J. Am. Chem. Soc. 2004, 126, 986 – 987;
b) T. J. Geldbach, P. J. Dyson, J. Am. Chem. Soc. 2004, 126,
8114 – 8115; c) D. Sterk, M. S. Stephan, B. Mohar, Tetrahedron
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Manos, J. Blacker, J. Martin, A. Gavriilidis, Org. Process Res.
Dev. 2004, 8, 909 – 914.
In summary, the results presented herein demonstrate that
aqueous-phase asymmetric transfer hydrogenation of aro-
matic ketones by formic acid with the Noyori–Ikariya Ru–Ts-
dpen catalyst is modulated by the solution pH. By controlling
the pH value, much faster rates and higher turnover numbers
in conjunction with excellent ee values can be delivered.
Evidence is presented that suggests that there may be two
competing catalytic cycles, and hence the reaction rates and
enantioselectivities are a function of solution pH values.
[10] B. Mohar, A. Valleix, J.-R. Desmurs, M. Felemez, A. Wagner, C.
Mioskowski, Chem. Commun. 2001, 2572 – 2573.
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Viguri, E. S. Jose, C. Vega, J. Reyes, F. Joꢀ, A. Katho, Chem. Eur.
J. 1999, 5, 1544 – 1564.
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Noyori, M. Yamakawa, S. Hashiguchi, J. Org. Chem. 2001, 66,
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Am. Chem. Soc. 1999, 121, 9580 – 9588; b) D. G. I. Petra, J. N. H.
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Brussee, H. E. Schoemaker, P. W. N. M. van Leeuwen, Chem.
Eur. J. 2000, 6, 2818 – 2829.
Experimental Section
[{RuCl2(p-cymene)}2] (3.1 mg, 0.005 mmol) and (R,R)-Ts-dpen
(4.4 mg, 0.012 mmol) were dissolved in degassed water (0.5 mL).
After stirring at 408C for 1 h, HCOOH (0.13 mL, 3.3 mmol), Et3N
(0.37 mL, 2.7 mmol), and acetophenone (120 mg, 1.0 mmol) were
added to the solution. Following degassing three times, the mixture
was allowed to react at 408C for a certain period of time. The workup
was the same as before[2] and the product was analyzed by GC
(Chrompack Chirasil-Dex CB column).
The reduction at S/C = 10000:1 was carried out as follows: After
preparation of the precatalyst in water (10 mL), HCOOH (5 mL,
0.13 mol), Et3N (20 mL, 0.14 mol), and acetophenone (12 g, 0.10 mol)
were introduced. The reaction was conducted in a way similar to that
above, except that during the reduction HCOOH was periodically
added to keep the pH value between 5 and 8.
The reduction could also be performed in the absence of water.
An example under comparable conditions is given here. The catalyst
was prepared in a similar way in degassed HCOOH–NEt3 (1 mL;
molar ratio = 0.9:1). The reduction started with the introduction of
acetophenone (120 mg, 1 mmol; S/C = 100:1) and resulted in a
complete reaction at 408C in 7 h with 97% ee.
[14] G. Zassinovich, G. Mestroni, S. Gladiali, Chem. Rev. 1992, 92,
1051 – 1069.
[15] F. Wang, H. Chen, Dr. S. Parsons, I. D. H. Oswald, J. E.
Davidson, P. J. Sadler, Chem. Eur. J. 2003, 9, 5810 – 5820.
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Castellano, E. Gianolio, R. Pagliarin, J. Am. Chem. Soc. 2001,
123, 7601 – 7609.
[17] For examples, see: a) J. K. Beattie, H. Elsbernd, J. Am. Chem.
Soc. 1969, 91, 4573 – 4574; b) J. A. Broomhead, L. Kane-
Maguire, D. Wilson, Inorg. Chem. 1975, 14, 2575 – 2577.
[18] K. J. Haack, S. Hashiguchi, A. Fujii, T. Ikariya, R. Noyori,
Angew. Chem. 1997, 109, 297 – 300; Angew. Chem. Int. Ed. Engl.
1997, 36, 285 – 288.
Received: January 4, 2005
Published online: April 25, 2005
[19] In neat HCOOH–NEt3, the reduction was faster when the
HCOOH/NEt3 ratio decreased, but slower than that in the
aqueous solution (see Experimental Section).
Keywords: acidity · asymmetric catalysis · ketones · ruthenium ·
transfer hydrogenation
.
[1] For recent reviews, see: a) T. Dwars, G. Oehme, Adv. Synth.
Catal. 2002, 344, 239 – 260; b) D. Sinou, Adv. Synth. Catal. 2002,
344, 221 – 237; c) F. Joꢀ, Acc. Chem. Res. 2002, 35, 738 – 745;
d) U. M. Lindstrꢁm, Chem. Rev. 2002, 102, 2751 – 2772.
Angew. Chem. Int. Ed. 2005, 44, 3407 –3411
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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