Table 1. Asymmetric Hydrogenation of Alkynyl Ketones 1 with
Chiral Ru or Ir Catalysta
H2,
%
yieldc
%
eed
entry
1
cat.
S/Cb
atm
1
1a
1a
1a
1b
1c
1d
1e
1f
3
3
4
3
3
3
3
3
3
3
3
3
3
3
3
3
1000
5000
1000
1000
1000
1000
100
10
50
10
20
20
10
10
10
10
10
10
10
10
10
20
10
94
96
73
91
94
94
16
94
98
98
63
78
92
88
61g
78
97
95
93
95
96
96
9
2e
3
4
5
6
7
8f
9
200
96
95
96
93
92
88
94
89
95
1g
1h
1i
1000
1000
200
10
11
12
13
14
15
16
1j
200
1k
1l
200
200
1m
1n
200
200
a Unless otherwise stated, the reactions were conducted using 0.3ꢀ
1.5 mmol of 1 in CH3OH containing (S,S)-3 or -4 under H2 at 50 °C for
15ꢀ24 h. b Substrate-to-catalyst molar ratio. c Isolated yield. d Deter-
mined by chiral GC or HPLC analysis of 2 or their derivatives. See the
Supporting Information for details. e This reaction using 8.46 mmol of 1a
was conducted for 40 h. f Reaction at 30 °C. g A small amount (ca. 4ꢀ5%)
of impurity was included.
Figure 2. Diastereomeric transition state models (TSs) in the
hydrogenation of 1 with (S,S)-3.
(see the Supporting Information). Figure 2 illustrates the
diastereomeric transition state models, TSA and TSB, for
hydrogenation of the alkynyl ketone 1 with the RuH[(S,S)-
TsDPEN] species. The HδꢀꢀRuδþꢀNδꢀꢀHδþ quadrupole
of the Ru species and the CδþdOδꢀ dipole form six-mem-
bered pericyclic structures.7,12,13 Ketone is hydrogenated in
the outer coordination sphere of the active species, where
neither carbonyl/Ru nor alkynyl/Ru interaction is involved.
This characteristic TS structure results in the high chemos-
electivity of carbonyl groups over the alkynyl moieties.14
The TSA is expected to be stabilized by the attractive
CH/π interaction between the p-cymene (arene) CH and
the alkynyl π-system as previously proposed for the reaction
of the aromatic ketone.12,13 Thus, the major enantiomer
of propargylic alcohol 2 is produced through the TSA. The
consistentlyhighenantioselectivitythroughthereactionsof
alkynyl ketones 1aꢀ1d with alkyl groups of various sizes as
R2 (Table 1, entries 1 and 4ꢀ6) supports these TS models.
The low enantioselectivity in the reaction of the alkynyl
phenyl ketone 1e, which has π-systems on both sides of the
carbonyl moiety, can be explained by using these models
(Table 1, entry 7). The observation that the electron-rich 40-
CH3O-substituted phenyl ethynyl ketone 1l was hydroge-
nated with higher enantioselectivity than that of the reac-
tion of the electron-deficient 40-Cl-substituted substrate 1k
is also reasonable according to the CH/π interaction-
directed enantioselection (Table 1, entries 13 and 14).
In summary, we have described the first example of the
highly enantioselective hydrogenation of alkynyl ketones
catalyzed by the η6-arene/TsDPENꢀRu(II) triflate 3.
The reaction is conducted with an S/C as high as 5000 to
1% yields, respectively (entries 13 and 14). The stronger
electron-donating ability of the 40-substituent appeared
to increase the enantioselectivity (2k: 4-Cl, 88% ee; 2j:
4-H, 92% ee; 2l: 4-CH3O, 94% ee). The tert-butyl ethynyl
ketone 1m was hardly reducible, so that 2m in 89% ee was
obtained in 61% yield with 4% of the 1,4-reduced com-
pound and undefined products (ca. 4ꢀ5%) under 20 atm
of H2 at an S/C of 200 (entry 15). The reaction of 10-
cyclohexenyl ethynyl ketone 1n selectively afforded the
alcohol with an ene-yne moiety in 95% ee (entry 16). No
diene compounds were observed.
Previous mechanistic studies on the asymmetric hydro-
genation of acetophenone, a simple aromatic ketone, with
the Ru catalyst 3 revealed that the active RuH(TsDPEN)-
(η6-p-cymene) reduces the ketone in the catalytic cycle.5a,12,13
The reaction of alkynyl ketones using the Ru catalyst 3
appears to proceed through the same reaction mechanism
(12) (a) Sandoval, C. A.; Ohkuma, T.; Utsumi, N.; Tsutsumi, K.;
Murata, K.; Noyori, R. Chem.;Asian J. 2006, 1ꢀ2, 102–110.
(b) Sandoval, C. A.; Bie, F.; Matsuoka, A.; Yamaguchi, Y.; Naka, H.;
Li, Y.; Kato, K.; Utsumi, N.; Tsutsumi, K.; Ohkuma, T.; Murata, K.;
Noyori, R. Chem.;Asian J. 2010, 5, 806–816.
(13) For mechanistic studies of asymmetric transfer hydrogenation
of ketones with chiral Ru catalysts, see: (a) Haack, K. J.; Hashiguchi, S.;
Fujii, A.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. Engl. 1997, 36,
285–288. (b) Alonso, D. A.; Brandt, P.; Nordin, S. J. M.; Andersson,
P. G. J. Am. Chem. Soc. 1999, 121, 9580–9588. (c) Yamakawa, M.; Ito,
H.; Noyori, R. J. Am. Chem. Soc. 2000, 122, 1466–1478. (d) Petra,
D. G. I.; Reek, J. N. H.; Handgraaf, J.-W.; Meijer, E. J.; Dierkes, P.;
Kamer, P. C. J.; Brussee, J.; Schoemaker, H. E.; van Leeuwen, P. W. N.
M. Chem.;Eur. J. 2000, 6, 2818–2829. (e) Noyori, R.; Yamakawa, M.;
Hashiguchi, S. J. Org. Chem. 2001, 66, 7931–7944. (f) Yamakawa, M.;
Yamada, I.; Noyori, R. Angew. Chem., Int. Ed. 2001, 40, 2818–2821.
(14) (a) Ohkuma, T.; Ooka, H.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1995, 117, 10417–10418. (b) Noyori, R.; Ohkuma, T. Angew.
Chem., Int. Ed. 2001, 40, 40–73.
€
(g) Samec, J. S. M.; Backvall, J.-E.; Andersson, P. G.; Brandt, P. Chem.
Soc. Rev. 2006, 35, 237–248.
Org. Lett., Vol. XX, No. XX, XXXX
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