In situ formation of ligand and catalyst - Application in ruthenium-catalyzed enantioselective reduction of ketones

Article abstract of DOI:10.1039/b505516d

The direct in situ formation of highly efficient ruthenium-catalysts for the asymmetric reduction of ketones was obtained by combining chiral ligand building blocks with a ruthenium precursor. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b505516d

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
In situ formation of ligand and catalyst—application in
ruthenium-catalyzed enantioselective reduction of ketones
Patrik V a¨ stil a¨ , Jenny Wettergren and Hans Adolfsson*
Received (in Cambridge, UK) 20th April 2005, Accepted 30th June 2005
First published as an Advance Article on the web 12th July 2005
DOI: 10.1039/b505516d
The direct in situ formation of highly efficient ruthenium-
catalysts for the asymmetric reduction of ketones was obtained
by combining chiral ligand building blocks with a ruthenium
precursor.
for the catalytic reaction, the whole process can be performed
using a simple one-pot setup (Fig. 1b and c).
To demonstrate the effectiveness of this novel asymmetric
catalysis strategy we decided to apply the concept to a valuable
4
enantioselective reaction: the reduction of prochiral ketones.
The use of transition-metal catalysts in asymmetric catalysis often
involves tedious preparations of either the catalysts or more
Herein we present a highly convergent approach for a straightfor-
ward formation of efficient ruthenium-catalysts directly used in the
asymmetric reduction of ketones under transfer hydrogenation
conditions. The metal-catalyzed reduction of ketones with
2-propanol or formic acid as hydrogen source is a mild, safe and
1
frequently, the chiral ligands surrounding the metal. The process
of finding a particular catalyst normally goes via an iterative
examination of a number of chiral ligands. The evaluation of each
individual ligand following a conventional catalyst optimization
approach has to go through all the steps illustrated in Fig. 1a. In
addition, the rate-limiting step in such an investigation is most
often the formation of the chiral ligands. If these are made in
several reaction steps, of which one might include an asymmetric
transformation to incorporate chirality into the ligand core, the
ability to construct and evaluate the often huge number of ligands
necessary to find the best metal–ligand combination will be very
limited. The use of combinatorial techniques creating libraries of
ligands significantly speeds up this process but the generation of
5
attractive route for the formation of secondary alcohols. The
6
combination of Ru(II)(g -arene) complexes with chiral amino
alcohols or diamine ligands has resulted in some outstanding
6
catalysts for this particular transformation. We have recently
reported on a new class of ligands for this particular transforma-
tion. We found that pseudo-dipeptides (1) when combined with a
suitable ruthenium precursor resulted in excellent catalysts for
7
enantioselective ketone reduction. The use of simple amino acids
and amino alcohols as building blocks for the formation of these
pseudo-dipeptides allowed for the formation of small ligand
libraries. Screening the libraries we found that the most efficient
and selective catalysts were obtained using either of the alanine-
2
the ligands is still needed. A more efficient route for the synthesis
of a selective catalyst goes via the direct formation of the active
1
2
3
metal complex simply by mixing together a metal precursor with
3
suitable ligand building blocks. In this way, there is no need for
based ligands 1a (R 5 CH , R 5 Ph and R 5 H) or 1b
3
1
(R 5 R 5 CH and R 5 H). In reductions of acetophenone
3
2
3
tedious ligand preparation and/or catalyst formation. In addition,
if the ligand(s) and catalyst are formed in the reaction media used
using [RuCl (p-cymene)] and ligands 1a or 1b (1 mol%) as
2
2
catalysts, we obtained the corresponding secondary alcohol in 94
and 96% ee respectively. The preparation of the ligands is a rather
straightforward process, where the protected amino acid is coupled
with the vicinal amino alcohol using an appropriate coupling
reagent. Nevertheless, the synthesis of the ligand is a time-
consuming step and we thought that a direct formation of not only
the catalyst but also the ligand prior to the reduction reaction
would be highly beneficial. The use of typical peptide building
blocks in the preparation of ligands for asymmetric catalysis is
most advantageous since there are a vast number of suitable
activated derivatives available. To examine the possibility of
directly generating both ligand and catalyst prior to the catalytic
reduction reaction we chose to employ the formation of a
ruthenium complex based on ligand 1b as a model system. We
initially considered that the metal precursor would be an
appropriate template in the formation of the peptide bond. Beck
6
Fig. 1 a) Conventional experimental catalysis setup. b) Efficient one-pot
procedure for in situ ligand and catalyst formation followed by catalysis. c)
Schematic illustration of the process presented in b step 1.
and co-workers have previously shown that Ru(II)(g -arene)
8
complexes can catalyze the formation of oligopeptides. Thus, in
2 2
an initial experiment we combined [RuCl (p-cymene)] , the methyl
ester of L-alanine and (S)-1-amino-2-propanol with the aim of
forming the active reduction catalyst. This resulted, however, in a
catalyst of low activity, and performing the reduction of
Department of Organic Chemistry, Stockholm University, The Arrhenius
Laboratory, SE 10691, Stockholm, Sweden. E-mail: hansa@organ.su.se;
Fax: +46-8-154908; Tel: +46-8-162479
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 4039–4041 | 4039

View Article Online
1
2
acetophenone in 2-propanol gave 1-phenylethanol in moderate
yield and low ee. In a control experiment employing only the
amino alcohol as ligand we obtained similar results, indicating that
the active catalyst in the above reaction simply was the ruthenium
indeed superior to the other Ru(II)-complexes formed. With
these results in hand we selected a series of different ketones (3–10)
for the evaluation of this novel catalytic reduction approach.{ In
accordance with the previously reported results, we obtained good
conversions and excellent ee’s with simple mono-substituted
derivatives of acetophenone (Table 1). Interestingly, a significant
rate-enhancement was observed using the one-pot in situ method.
The reactions were in almost all cases over after 60 minutes.
This should be compared to the substantially longer reaction times
9
complex of (S)-1-amino-2-propanol. Apparently the peptide was
not formed, and we therefore changed the methyl ester used above
for the corresponding more reactive 4-nitrophenyl analogue.
(2–3 h) which we found using the corresponding preformed ligand.
The reduction of 3-fluoroacetophenone was remarkably fast under
these new conditions (entry 2). In fact, already after 15 minutes this
reaction had reached 73% conversion, with a product ee of 97%.
As the reaction was allowed to reach the full equilibrium
conversion, a small drop in enantioselectivity was observed. The
small decrease is most likely due to the reversible reaction
conditions involved in transfer hydrogenation reactions when
The initial transfer hydrogenation experiments performed using
the 4-nitrophenyl ester of Boc-protected L-alanine as one of the
ligand building blocks were sluggish and we obtained rather
irreproducible results. The outcome of the reduction reaction
proved to be sensitive towards the order of reagent addition, and
2-propanol is used as the hydride source. Electron rich substrates
i
the amount of base (NaOPr) used to activate the catalyst. A key
like ketones 7, 8 and 10, were reduced with excellent selectivity
although the latter two in somewhat lower conversion (entries 7, 8
and 10 respectively).
difference with this methodology as compared to reactions
performed with a preformed ligand is the amount of acidic by-
products formed in the in situ generation of the dipeptide ligand.
The typical quantity of base used in transfer-hydrogenations with
this class of ligands is 5 mol%, and performing the reaction with
i
this amount of NaOPr led to lower conversion of the starting
ketone. Increasing the amount of base to 20 mol% assured the
formation of the active catalyst and higher conversion was
obtained. In addition, we found that performing the ligand
formation using a 1 : 1 stoichiometry between the ligand building
blocks led to incomplete formation of dipeptide 1b. The remaining
1
0
amino acid did not affect the catalytic reaction, however, the
vicinal amino alcohol can act as a ligand for ruthenium in the
ketone reduction and this resulted in a diminished enantiomeric
9
excess of the product alcohol. This obstacle was overcome by
In conclusion, we have introduced a novel concept for the
execution of catalytic reactions. The in situ formation of the active
catalyst by mixing together the chiral ligand with a suitable metal
precursor is a common strategy often applied in asymmetric
catalysis. However, herein we have demonstrated that it is possible
to perform an in situ formation of the chiral ligand and the catalyst
in the same reaction media used for the catalytic reaction. The
employing a slight excess of the amino acid. Hence, after some
optimizations we found appropriate conditions which allowed for
the direct formation of 1-phenylethanol in high yield and with
excellent enantiomeric excess. In fact, the ee turned out to be
slightly better than what we previously obtained using the
7
c
preformed and isolated ligand 1b. The optimized one-pot
procedure for the reduction of acetophenone using the in situ
11
formed ligand 1b and catalyst 2 is shown in Scheme 1.
Table 1 Enantioselective transfer hydrogenation of different aro-
matic ketones
Having established reaction conditions for efficient one-pot
generation of the pseudo-dipeptides and ruthenium(II)-catalysts
based on these ligands, we employed this novel technology in the
formation of a small library of structurally similar catalysts. The
evaluation of the results obtained in the reduction of acetophenone
showed, not surprisingly, that the catalyst based on ligand 1b was
a
b
c
Entry
Ketone
t (min)
Conv. (%)
ee (%)
1
2
3
4
5
6
7
8
9
3a
3b
3c
4
5
6
7
8
9
10
60
30
60
60
60
60
60
60
60
60
83
95
86
66
90
64
82
45
64
31
97 (S)
96 (S)
97 (S)
96 (S)
92 (S)
97 (S)
97 (S)
99 (S)
97 (S)
. 99 (S)
1
0
a
Reaction conditions: Ketone (1 equiv., 0.2 M in 2-propanol),
RuCl (p-cymene)] (1 mol% in Ru), in situ formed ligand 1b
1.1 mol%) and i-PrONa (20 mol%). All reactions were performed
[
(
2
2
b
at ambient temperature. Conversion was determined by GLC
analysis. The products can be isolated in high yields as reported in
ref. 7b and c. Enantiomeric excess and absolute configuration were
c
Scheme 1 Reduction of acetophenone with in situ formed ligand and
determined by chiral GC (CP Chirasil DEX CB).
catalyst.
4
040 | Chem. Commun., 2005, 4039–4041
This journal is ß The Royal Society of Chemistry 2005

View Article Online
10, 2045–2061; (d) F. Fache, E. Schulz, M. L. Tommasino and
M. Lemaire, Chem. Rev., 2000, 100, 2159–2231.
(a) S. Hashiguchi, A. Fujii, J. Takehara, T. Ikariya and R. Noyori,
J. Am. Chem. Soc., 1995, 117, 7562–7563; (b) A. Fujii, S. Hashiguchi,
N. Uematsu, T. Ikariya and R. Noyori, J. Am. Chem. Soc., 1996, 118,
concept was exemplified in the asymmetric reduction of ketones
under transfer hydrogenation conditions using a ruthenium-based
catalyst. By the careful choice of appropriate ligand building
blocks and reaction conditions we obtained a highly efficient and
enantioselective catalyst for the reduction of variously substituted
aryl alkyl ketones. Under optimized conditions it was possible to
form the product alcohols in up to . 99% ee. The simplicity of this
method in combination with its excellent performance in the
transfer hydrogenation reaction suggests that the concept of
forming ligand(s) and the active metal-catalyst in a one-pot
procedure prior to the catalytic reaction can be applied to other
asymmetric transformations.
6
2521–2522; (c) D. A. Alonso, D. Guijarro, P. Pinho, O. Temme and
P. G. Andersson, J. Org. Chem., 1998, 63, 2749–2751; (d) D. A. Alonso,
S. J. M. Nordin, P. Roth, T. Tarnai, P. G. Andersson, M. Thommen
and U. Pittelkow, J. Org. Chem., 2000, 65, 3116–3122; (e) S. J. M.
Nordin, P. Roth, T. Tarnai, D. A. Alonso, P. Brandt and P. G.
Andersson, Chem.–Eur. J., 2001, 7, 1431–1436; (f) K. Everaere,
A. Mortreux and J.-F. Carpentier, Adv. Synth. Catal., 2003, 345,
67–77; (g) M. Palmer, T. Walsgrove and M. Wills, J. Org. Chem., 1997,
62, 5226–5228; (h) M. Wills, M. Gamble, M. Palmer, A. Smith,
J. Studley and J. Kenny, J. Mol. Catal. A: Chem., 1999, 146, 139–148; (i)
M. J. Palmer, J. A. Kenny, T. Walsgrove, A. M. Kawamoto and
M. Wills, J. Chem. Soc., Perkin Trans. 1, 2002, 416–427.
We gratefully acknowledge the Swedish Research Council for
financial support.
7
(a) I. M. Pastor, P. V a¨ stil a¨ and H. Adolfsson, Chem. Commun., 2002,
2
2
046–2047; (b) I. M. Pastor, P. V a¨ stil a¨ and H. Adolfsson, Chem.–Eur. J.,
003, 9, 4031–4045; (c) A. Bøgevig, I. M. Pastor and H. Adolfsson,
Chem.–Eur. J., 2004, 10, 294–302.
Notes and references
{
General procedure for the in situ formation of ligand 1b and ruthenium
8 (a) K. Haas and W. Beck, Z. Anorg. Allg. Chem., 2002, 628, 788–796;
(b) K. Haas and W. Beck, Eur. J. Inorg. Chem., 2001, 2485–2488; (c)
W. Hoffm u¨ ller, M. Maurus, K. Severin and W. Beck, Eur. J. Inorg.
Chem., 1998, 729–731; (d) K. Severin, R. Bergs and W. Beck, Angew.
Chem., Int. Ed., 1998, 37, 1634–1654; (e) R. Kr a¨ mer, M. Maurus,
K. Polborn, K. S u¨ nkel, C. Robl and W. Beck, Chem.–Eur. J., 1996, 2,
1518–1526.
complex 2 followed by the direct reduction of ketones presented in Table 1.
Boc-L-Ala-ONp (0.01375 mmol) and (S)-1-amino-2-propanol (0.011 mmol)
were mixed in 2-propanol (1 mL) and refluxed for 1 hour in a dry Schlenck
tube, under inert atmosphere (N
temperature before i-PrONa (0.20 mmol in 2 mL 2-propanol) was added
followed by acetophenone (1 mmol), [RuCl (p-cymene)] (0.005 mmol) and
2
). The mixture was cooled to ambient
2
2
additional 2-propanol (2 mL). The reaction mixture was stirred at ambient
temperature. Aliquots were taken at different time intervals and quenched
with diluted brine (1 mL), extracted with EtOAc (1 mL), passed through a
pad of silica and washed with EtOAc. The resulting solution was analyzed
by GLC (CP Chirasil DEX CB).
2 2
9 The reduction of acetophenone, catalyzed by [RuCl (p-cymene)] and
(S)-1-amino-2-propanol, gave the corresponding secondary alcohol in
83% conversion and 67% ee (S-isomer).
10 In control experiments using acetophenone and a catalyst based on
either Boc-L-Ala-ONp or Boc-L-Ala and [RuCl (p-cymene)] we
2
2
observed no product formation. However, Ru-complexes based on
unprotected amino acids are reported to act as catalysts in the transfer
hydrogenation of aryl alkyl ketones, see: (a) T. Ohta, S.-I. Nakahara,
Y. Shigemura, K. Hattori and I. Furukawa, Chem. Lett., 1998, 491–492;
1
2
Comprehensive Asymmetric Catalysis, E. N. Jacobsen, A. Pfaltz,
H. Yamamoto, Eds.; Springer-Verlag: Berlin, 1999.
(a) C. Gennari and U. Piarulli, Chem. Rev., 2003, 103, 3071–3100; (b)
K. D. Shimizu, M. L. Snapper and A. H. Hoveyda, Chem.–Eur. J.,
(b) T. Ohta, S.-I. Nakahara, Y. Shigemura, K. Hattori and I. Furukawa,
Appl. Organomet. Chem., 2001, 15, 699–709; (c) A. Katho, D. Carmona,
F. Viguri, C. D. Remacha, J. Kov a´ cs, F. Jo o´ and L. A. Oro,
J. Organomet. Chem., 2000, 593–594, 299–306.
1998, 4, 1885–1889; (c) J. F. Traverse and M. L. Snapper, Drug
Discovery Today, 2002, 7, 1002–1012.
For a combinatorial approach using mixtures of chiral ligands in
catalysis, see: M. T. Reetz, T. Sell, A. Meiswinkel and G. Mehler,
Angew. Chem., Int. Ed., 2003, 42, 790–793.
H.-U. Blaser, C. Malan, B. Pugin, F. Spindler, H. Steiner and M. Studer,
Adv. Synth. Catal., 2003, 345, 103–151.
(a) G. Zassinovich, G. Mestroni and S. Gladiali, Chem. Rev., 1992, 92,
3
11 The proposed structure of catalyst 2 is displayed in Scheme 1. Attempts
to isolate and analyze this complex have so far been unsuccessful.
12 As an example, the reduction of acetophenone using the in situ formed
catalyst based on Boc-L-Val-ONp, (S)-1-amino-2-propanol and
4
5
2 2
[RuCl (p-cymene)] gave 1-phenylethanol in merely 29% conversion
1
051–1069; (b) R. Noyori and S. Hashiguchi, Acc. Chem. Res., 1997, 30,
with 96% ee (S-isomer, reaction time 1 h). See Scheme 1 for the result
obtained with ligand 1b.
97–102; (c) M. J. Palmer and M. Wills, Tetrahedron: Asymmetry, 1999,
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 4039–4041 | 4041