group in the â-position to a relatively acidic OH or NH
group. N-Protected amino acid hydroxy-amide ligands (1a)
developed in our group4 represent a different class of ligands
without an explicit basic nitrogen center, for which alkali
ions play a crucial role in the hydrogen transfer step.5
Structural variation in these pseudodipeptides revealed that
the presence of a secondary amide is necessary for high
catalytic activity. In the active complex, the amide is
deprotonated and acts as a coordinating counterion for the
transition metal. To increase the stability of the catalytically
active metal complex, we sought to substitute the amide
functionality for a group of higher acidity. In the present
communication, we report how a seemingly subtle change
in the ligand structure, namely, replacement of the amide
oxygen in Boc-protected amino acid amides by sulfur, and
modification of the catalytic system with a lithium salt lead
to a novel and most efficient class of Ru and Rh catalysts
for the ATH of aromatic ketones in isopropanol. In addition,
as illustrated in the catalytic experiments presented in Scheme
1, the replacement of the amide functionality for the
O-TBS-protected pseudodipeptide using Lawesson’s reagent.
When the O-TBS-protected hydroxy-thioamide was em-
ployed as the ligand for Ru(II) in the reduction of acetophe-
none, we obtained (R)-1-phenylethanol in 51% conversion
and in 50% ee. This result is in striking contrast to previous
results achieved using pseudodipeptide ligands because any
manipulation of the alcohol moiety resulted in no or low
activity of the catalyst.
The increased catalytic activity observed using the poten-
tially bidentate O-silylated hydroxy-thioamide ligand encour-
aged us to further investigate such ligands. A series of simple
Boc-protected amino acid amides were prepared and sub-
sequently converted into the corresponding thioamides.
Ligands 2b-6b were accessed in good yields in two steps
from commercially available Boc-protected amino acids
(Scheme 2).
Scheme 2. Synthesis of the Thioamide Ligands
Scheme 1. Switch of Enantioselectivity in the Reduction of
Acetophenone
Recently, Pelagatti and co-workers reported on the cata-
lytic activity of amino acid amides in the ATH of aromatic
ketones in isopropanol.6 At 90 °C, they achieved good
conversions with ee’s up to 47%, whereas the appropriate
Boc-protected amides displayed no catalytic activity in the
process. As a result of screening the thioamide ligands with
different substitution patterns in the ATH of acetophenone
(Table 1 and Supporting Information), we observed that the
secondary amide NH function as well as the BocNH or NH2
groups in the amino acid moiety are crucial for high catalytic
activity. Ligand 2b gave the highest enantioselectivity among
the simple thioamides examined. The selectivity could be
further increased to 92% ee by addition of LiCl (Ru/Li )
1:10) to the catalytic system. The optimal amount of base
(i-PrONa) was 10 mol %, and the highest conversions were
achieved when the base was added subsequent to all other
components, including the substrate.
In analogy with the results obtained using the pseudo-
dipeptides 1a and 1b, we observed in most cases a switch
of the sign of enantioselectivity on going from amides to
the appropriate thioamides (Table 1).
Screening catalysts derived from other metal precursors
in the ATH of acetophenone using ligand 2b revealed even
higher activity and enantioselectivity of a catalyst based on
[{RhCl2Cp*}2].7 In this case, the addition of LiCl (Rh/Li )
1:10) led to a significant improvement of activity and
enantioselectivity, and excellent results could be obtained
corresponding thioamide resulted in a dramatic switch of the
product enantioselectivity in the ATH.
In the Ru(II) pseudodipeptide-catalyzed reduction of
ketones, we have found a strong correlation between the
product configuration and the stereocenters of the ligand.
Even though the ligand possesses two stereogenic centers,
the configuration of the amino acid part correlates well with
the product configuration, and catalysts with ligands based
on natural amino acids predominately favor the formation
of S-alcohols. Therefore, the outcome of the reaction using
the corresponding thioamide (1b) was most unexpected. In
the reduction of acetophenone, the replacement of the central
amide for a thioamide resulted in the formation of the
secondary alcohol in 20% ee in favor of the R-product.
Apparently, the slight change of the structure had a dramatic
influence on the activity and selectivity of the formed
catalyst. The thioamide was prepared from the corresponding
(3) For mechanistic aspects of transfer hydrogenations, see the following
reviews: (a) Clapham, S. E.; Hadzovic, A.; Morris, R. H. Coord. Chem.
ReV. 2004, 248, 2201-2237. (b) Samec, J. S. M.; Ba¨ckvall, J.-E.; Andersson,
P. G.; Brandt, P. Chem. Soc. ReV. 2006, 35, 237-248.
(4) (a) Pastor, I. M.; Va¨stila¨, P.; Adolfsson, H. Chem. Commun. 2002,
2046-2047. (b) Pastor, I. M.; Va¨stila¨, P.; Adolfsson, H. Chem.-Eur. J.
2003, 9, 4031-4045. (c) Bøgevig, A.; Pastor, I. M.; Adolfsson, H. Chem.-
Eur. J. 2004, 10, 294-302. (d) Va¨stila¨, P.; Wettergren, J.; Adolfsson, H.
Chem. Commun. 2005, 4039-4041. (e) Wettergren, J.; Bøgevig, A.; Portier,
M.; Adolfsson, H. AdV. Synth. Catal. 2006, 348, 1277-1282.
(5) Va¨stila¨, P.; Zaitsev, A. B.; Wettergren, J.; Privalov, T.; Adolfsson,
H. Chem.-Eur. J. 2006, 12, 3218-3225.
(6) (a) Pelagatti, P.; Carcelli, M.; Calbiani, F.; Cassi, C.; Elviri, L.; Pelizzi,
C.; Rizzotti, U.; Rogolino, D. Organometallics 2005, 24, 5836-5844. (b)
For another example of the use of amino acid amides in ATH, see: Faller,
J. W.; Lavoie, A. R. Organometallics 2001, 20, 5245-5247.
5130
Org. Lett., Vol. 8, No. 22, 2006