Angewandte
Chemie
Table 1: Catalytic transfer hydrogenation of methyl aryl ketones
(MeCOAr) with complexes 1–5.[a]
mer catalysts cis-[RuCl2(Josiphos)RPyme]—also in situ—
from [RuCl2(PPh3)3], Josiphos ligands, and a racemic mixture
of RPyme ligands, avoiding the need for the resolution of the
aminopyridine ligands. These complexes efficiently catalyze
the asymmetric transfer hydrogenation of ketones with both a
very high TOF (up to 70000 hÀ1 at 608C)and enantioselec-
tivity (up to 99% ee)which is due to the correctly matched
diphosphane and aminopyridine ligands. Work is in progress
to extend this practical approach to other metal-catalyzed
asymmetric reactions.
Complex
Ar
Conversion
[%][b]
t [min]
TOF [hÀ1 [c]
]
ee [%][b]
1
1
1
2
3
3
3
3
4
5
5
5
5
Ph
97
95
98
97
96
98
99
94
97
97
99
98
97
5
10
5
63000
44000
66000
67000
70000
26000
27000
30000
40000
34000
24000
25000
26000
96 (R)
98 (R)
99 (R)
95 (R)
95 (S)
97 (S)
98 (S)
97 (S)
96 (S)
97 (S)
97 (S)
98 (S)
>99 (S)
2’-MeC6H4
3’-MeOC6H4
Ph
10
10
40
30
10
10
10
30
30
10
Ph
2’-MeC6H4
2’-ClC6H4
2’-MeOC6H4
Ph
Experimental Section
Ph
1: Toluene (2 mL)was added to [RuCl 2(PPh3)3] (175 mg, 0.182 mmol)
and (R,S)-Josiphos·C2H5OH (120 mg, 0.187 mmol)and the suspen-
sion was heated to reflux for 2 h. After addition of (Æ )-MePyme
(50 mg, 0.409 mmol), the solution was heated to reflux again for a
further 2 h and thereafter the solvent was evaporated. The solid was
treated with 2-propanol (2 mL), and the solution was heated to reflux
for 1 h, affording a yellow precipitate, which was collected by
filtration and dried under reduced pressure. Yield: 89 mg (55%).
2: The synthesis of the yellow compound 2 was carried out as
described for 1, using (Æ )-PhPyme (75 mg, 0.407 mmol) in place of
(Æ )-MePyme. Yield: 140 mg (81%).
2’-ClC6H4
2’-MeOC6H4
3’-MeOC6H4
[a]Conditions: MeCOAr (0.1 m), complexes 1–5 (0.05 mol%), and
NaOiPr (2 mol%) in 2-propanol at 608C. [b]The conversion and
ee values were determined by GC analysis. [c]Turnover frequency
(moles of ketone converted into alcohol per mole of catalyst per hour)
at 50% conversion.
and have much the same enantioselectivity as the isolated
compounds. Regarding the effect of the matched/mismatched
ligands in catalysis, when the single enantiomer (R)-MePyme
is employed in combination with (R,S)-Josiphos, 2’-methoxy-
acetophenone is reduced to the R-alcohol with 71% ee
(TOF = 15000 hÀ1), whereas with (S,R)-Josiphos, which
leads to a single ruthenium diastereomer, the conversion
into the S-alcohol occurs with both higher ee value (98%)and
rate (TOF = 32000 hÀ1).
3: The synthesis of 3 was carried out as described for 1, using
(S,R)-Josiphos·C2H5OH (120 mg, 0.187 mmol)and ( Æ )-tBuPyme
(66 mg, 0.402 mmol)in place of ( Æ )-MePyme. The toluene solution
was concentrated, and addition of pentane afforded
a yellow
precipitate, which was collected by filtration and dried under reduced
pressure. Yield: 120 mg (71%).
4: [RuCl2(PPh3)3] (50 mg, 0.052 mmol)and
( S,R)-Josiphos*
(44 mg, 0.062 mmol)were dissolved in dichloromethane (2 mL,)
and the solution was stirred for 2 h. After addition of (Æ )-MePyme
(16 mg, 0.131 mmol), the solution was stirred for 1 h and the solvent
was evaporated. The resulting dark oil was treated with a 2-propanol/
heptane (1:1)mixture (2 mL)and the solution was heated to reflux
overnight. After evaporation, the product was treated with heptane
(2 mL, 1 h at reflux)to give a yellow precipitate, which was collected
by filtration, washed with pentane, and dried under reduced pressure.
Yield: 40 mg (77%).
To extend this method to other diphosphanes, we have
prepared derivatives for the asymmetric reduction of ketones
containing a Josiphos ligand with bulkier aryl groups (Josi-
phos*). Thus, the complexes cis-[RuCl2((S,R)-Josiphos*)(R)-
RPyme] (R = Me (4), tBu (5)),[11] bearing 4-MeO-3,5-
Me2C6H2 in place of phenyl groups have been successfully
isolated by treating [RuCl2(PPh3)3] with (S,R)-Josiphos* and
the corresponding (Æ )-RPyme (1:1.2:2.5) in dichloromethane
at 208C, followed by heating the mixture of products to reflux
in 2-propanol/heptane (1:1 in volume)overnight (Scheme 1).
Preliminary results with atropos ligands show that a single
ruthenium diastereomer is formed using (R)-MeObiphep
(biphep = 6,6’-dimethoxybiphenyl-2,2’-diyl)bis(diphenyl-
phosphane)) in combination with the (Æ )-PhPyme ligand.[13]
Complexes 4 and 5 are found to catalyze the complete
reduction of acetophenone in a few minutes under the same
catalytic conditions used for 1–3, with a high TOF (up to
40000 hÀ1)and a slightly higher ee value (96 and 97%)of the
S-alcohol (Table 1). Furthermore, 2’-chloroacetophenone,
and 2’- and 3’-methoxyacetophenone have been reduced to
the S enantiomers using 5 with ee values in the range 97–99%.
It is likely that the mechanism of the transfer hydro-
genation involves the [RuHX(Josiphos)RPyme] (X = H,
5: The synthesis of the yellow compound 5 was carried out as
described for 4, using (Æ )-tBuPyme (21 mg, 0.128 mmol)in place of
(Æ )-MePyme. Yield: 35 mg (64%).
Typical procedure for the catalytic transfer hydrogenation: The
ruthenium complex (3.0 mmol)was dissolved in 2-propanol (3 mL).
The ketone (2 mmol)was dissolved in 2-propanol (18.6 mL), and the
solution was heated to 608C under argon. Addition of NaOiPr (0.1m,
400 mL)and the solution containing the ruthenium complex (1.0 mL)
led to the reduction of the ketone. The yield was determined by GC
with
a MEGADEX-ETTBDMS-b chiral column (ketone/[Ru]/
NaOiPr= 2000:1:40; 0.1m ketone).
Received: May 23, 2007
Published online: August 27, 2007
Keywords: asymmetric catalysis · chiral resolution ·
.
hydrogen transfer · phosphane ligands · ruthenium
[1] a) The Handbook of Homogeneous Hydrogenation, Vol. 1–3
(Eds.: J. G. de Vries, C. J. Elsevier), Wiley-VCH, Weinheim,
2007; b) Asymmetric Catalysis on Industrial Scale (Eds.: H. U,
Blaser, E. Schmidt), Wiley-VCH, Weinheim, 2004; c) Compre-
hensive Asymmetric Catalysis, Supplements 1–2 (Eds.: E. N.
Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Berlin, 2004;
OR’)species, with
b-hydrogen elimination and ketone
insertion reactions,[14] in accordance with our study on cis-
[RuCl2(PP)Pyme].[5a]
In conclusion, we have described herein a practical
procedure for the simple preparation of the single-diastereo-
Angew. Chem. Int. Ed. 2007, 46, 7651 –7654
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7653