Asymmetric Transfer Hydrogenation of Ketones
aqueous media. We reported a novel chiral water-soluble
catalyst based on the Noyori-Ikariya system, which was
successfully used in the asymmetric transfer hydrogena-
tion of R-bromomethyl aromatic ketones in aqueous
media.12 To the best of our knowledge, few reports13
involving asymmetric reduction of R-bromomethyl ke-
tones catalyzed by transition metal complexes are known,
which is possibly due to catalyzed dehalogenation. In this
paper, we report our recent results which reveal that the
unmodified catalyst can increase the rate of the asym-
metric transfer hydrogenation of acetophenone in aque-
ous media.14 Moreover, the unmodified hydrophobic
catalyst could be separated from the organic phase with
the products and were reused in the presence of micelle-
forming surfactants in water. We discuss herein the
influence of surfactants on the asymmetric transfer
hydrogenation of prochiral ketones, especially R-bromo-
methyl aromatic ketones. Our approach should provide
an alternative method for the synthesis of â-adrenergic
receptor agonists.15,16
Results and Discussion
It is well-known that the nature of surfactant plays a
very important role in catalytic reactions involving
micelles. The charge of the constituent surfactant mol-
ecules is particularly important in catalysis involving
micelles.17 Noyori-Ikariya catalyst, (R,R)-TsDPEN-[Ru-
Cl(cymene)] (1a), and most ketone substrates are gener-
ally hydrophobic and neutral and tend to locate within
the micelles. Unfortunately, the hydrogen source used
in this reaction, sodium formate (HCOO-), is an anion
and is readily soluble in water. Thus the cationic sur-
factant, CTAB, was initially applied to accelerate the
asymmetric transfer hydrogenation of acetophenone (2a)
in aqueous media, on the basis of the consideration that
HCOO- ions should be attracted by cationic charge
around the micelle surface. Besides, CTAB was chosen
as the surfactant due to its low critical micelle concentra-
tion (cmc).3d
It was found that even in the absence of any surfactant
molecules, the reduction of 2a proceeded quickly in water,
leading to (R)-1-phenylethanol (3a) with 94% enantio-
meric excess (ee) and 99% isolated yield within 7 h.9b In
this case, higher turn over frequency (TOF, 52 h-1) was
observed than that of the reaction using formic acid-
triethylamine (azeotrope) as the hydrogen source and
solvent18 (Table 1, entry 1), since the hydrophobic catalyst
was soluble in liquid acetophenone. Interestingly, marked
increase of reaction activity (TOF, 69 h-1) was observed
by employing cationic CTAB as a surfactant (entry 2).
As expected, reactions involving neutral and anionic
surfactants resulted in lower reactivities as compared to
the control without surfactant (entries 3 and 4 vs entry
1). The lowest TOF value was obtained when the anionic
surfactant, SDS, was used, which was most likely due to
the repulsion between the negatively charged formates
and the micelles formed from the anionic surfactants.
Zwitterionic surfactant DDAPS led to higher reactivity
(entry 5). Because vesicles were used as microreactors19b
and could be formed by mixing simple single-tailed
cationic and anionic surfactants,19 mixtures of SDS and
CTAB of different ratios were therefore tested in the
transfer hydrogenation of 2a. The highest TOF value (76
h-1) was obtained in 95% ee with a 2:1 molar ratio of
SDS and CTAB (entry 6).
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J. Org. Chem, Vol. 70, No. 23, 2005 9425