Asymmetric transfer hydrogenation of aromatic ketones by Rh(I)/bimorpholine complexes

Article abstract of DOI:10.1016/j.tetasy.2004.07.017

Bimorpholine 1 and Rh(I)-complex catalyse the hydride transfer reduction of prochiral aromatic ketones to give the corresponding alcohols in excellent yields with ees up to 83%. The asymmetric hydride transfer reduction of aromatic ketones, using a [Rh(cod)Cl]₂ complex as a catalyst and (3S,3′S)-bimorpholine as a chiral ligand, was studied. By varying the amount of ligand, basic co-catalyst and temperature, high yields (>90%) and good enantiomeric excesses of the alcohols (ee up to 83%) were achieved.

Full text of DOI:10.1016/j.tetasy.2004.07.017

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2687–2691
Asymmetric transfer hydrogenation of aromatic ketones by
Rh(I)/bimorpholine complexes
*
Kadri Kriis, T o˜ nis Kanger and Margus Lopp
Department of Chemistry, Tallinn University of Technology, Akadeemia tee 15, Tallinn 12618, Estonia
Received 25 June 2004; accepted 23 July 2004
Available online 14 August 2004
0
Abstract—The asymmetric hydride transfer reduction of aromatic ketones, using a [Rh(cod)Cl] complex as a catalyst and (3S,3 S)-
2
bimorpholine as a chiral ligand, was studied. By varying the amount of ligand, basic co-catalyst and temperature, high yields (>90%)
and good enantiomeric excesses of the alcohols (ee up to 83%) were achieved.
Ó 2004 Elsevier Ltd. All rights reserved.
1
. Introduction
initial achiral metal complex and the chiral N-contain-
ing ligand. Therefore, the structure of the catalytic com-
plex has been thoroughly studied with help of
The significance of transition metal assisted asymmetric
1
catalysis is constantly growing. The chiral catalyst is
12,13
spectroscopic methods and theoretical calculations.
required in small amounts and usually consists of a
metal and a chiral organic ligand (or ligands). High
asymmetric induction is achieved only with a suitable
combination of the molecular structure of the chiral
metal complex and the substrate under appropriate
reaction conditions.
However, it is complicated to draw a general conclusion
from these data because the stereoselectivity of the
reduction usually depends on many factors: the source
of the metal, the structure of the ligand, the structure
of the substrate, the reaction conditions, etc. For these
reasons, each particular case (substrate) has to be inves-
tigated and optimised individually in order to find an
appropriate combination of the catalyst, the ligand
and the reaction conditions.
Nitrogen-containing ligands are widely used in asym-
2
metric catalysis. These ligands have good chelating
abilities with various metals. Nitrogen-containing lig-
ands can be separated from the nonbasic reaction prod-
ucts and thus are easily recyclable. Many successful
examples of catalytic asymmetric transfer hydrogena-
tion have demonstrated that this type of ligands can
afford similar or even higher selectivity than can be
Special attention in a wide variety of chiral ligands used
in hydride transfer reductions has been paid to the com-
pounds with a C -symmetry because there is no possibil-
ity of enantioface discrimination over the course of
ligand exchange during the chiral catalyst forma-
2
3
–5
7,9,14–17
achieved with the chiral phosphines. Excellent enan-
tioface-discrimination abilities have been obtained with
ruthenium catalysts (using different sources of hydrogen,
tion.
chiral C -symmetric bimorpholines. We previously re-
Our contribution to this field is the novel
1
8
2
0
ported the first application of (3S,3 S)-bimorpholine 1
as a ligand in the metal mediated hydride transfer reduc-
6
–9
10,11
e.g., isopropanol, formic acid
).
tion of aromatic ketones by help of [Rh(cod)Cl] as
2
1
9
It is assumed that the mechanism of the hydride transfer
reduction involves a step of formation of nonracemic
metal hydride. The structure of this chiral intermediate
metallic precursor (ee up to 75%, Scheme 1). However,
the data obtained were not sufficient enough to predict
the behaviour of the catalyst with different substrates.
3
complex is responsible for the stereodifferentiation of
the faces of the prochiral ketone. This nonracemic com-
plex can only be formed by ligand exchange between the
Herein we report a detailed study of the main factors
(ratio of the chiral ligand and base to the metallic pre-
cursor, ratio of the catalyst to the substrate, tempera-
ture, concentration) that influence the stereoselectivity
of the reduction. The results obtained reveal a complex
influence of separate factors on the whole process.
*
Corresponding author. Tel.: +372-6204371; fax: +372-6547524;
e-mail: kanger@chemnet.ee
0
957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.07.017

2688
K. Kriis et al. / Tetrahedron: Asymmetry 15 (2004) 2687–2691
O
O
O
L*, M (5mol%)
OH
L*:
M = [Rh(cod)Cl]
2
*
R1
R
2
KOH, i-PrOH
R1 R2
N
H
N
H
1
ee up to 75%
Scheme 1. Asymmetric hydride transfer reduction of aromatic ketones using bimorpholine 1.
2
. Results and discussion
formed in excellent yield (>90%) and at least two times
faster (reaction time 21h instead of 46h) than with the
catalyst derived from 4moles of the ligand and metal
precursor. Extending the reaction time further did not
2
.1. Influence of the molar ratio of bimorpholine 1 and
Rh(cod)Cl] on the transfer hydrogenation of aromatic
[
ketones
2
*
increase the yield in the case of M/L molar ratio 1:4.
*
It is possible that the excess of the ligand (M/L molar
2
ratio 1:4) inhibits the catalyst by saturating the metal.
0
Although the excellent stereodifferentiation ability of
many catalytic systems has been observed, only a few
structures of complexes have been defined. Lemaire
and co-workers has investigated the catalytic complex
The stereoselectivity of these two different catalytic sys-
tems clearly depends on the substrate. Generally, the
1
3
*
derived from [Rh(cod)Cl]2 and chiral 1,2-diamine.
complex derived using M/L molar ratio 1:2 gives higher
According to his studies, the active complex species con-
sists of a rhodium atom complexed with one diamine
and one diene ligand. Despite that, an excess of diamine
is used to stabilise the complex and to prevent the for-
mation of black particles of rhodium, leading to the
racemic product.
ee values of alcohols (Table 1, entries 2–4 and 6). The
most remarkable increase of the enantioselectivity was
determined in the reduction of isobutyrophenone 4 (ee
increased from 44% to 57%). Aconsiderable difference
in the value of the enantiomeric excess of the products
formed in the reduction of 1- and 2-acetonaphthones 5
and 6 remained (Table 1, entries 4 and 5). For 1-aceto-
*
Our previous results were obtained using the same
*
naphthone 5, the preferable M/L molar ratio was 1:2,
*
model: M/L = 1:4 (4moles of bimorpholine 1 (L ) per
mole of the metallic precursor (M); as [Rh(cod)Cl] is
a dimeric metal complex, the molar ratio of M/
but for 2-acetonaphthone 6, the ratio 1:4 gave a slightly
higher ee value. The highest enantioselectivity was
observed with 2-methylbenzophenone 7, using the M/
1
2
*
*
L = 1:4 corresponds to two molecules of bimorpholine
9
L molar ratio 1:2. In addition, an excellent yield of
the product was obtained (Table 1, entry 6, ee 83% vs
75%, yield increased from 33% to 95%). Only in the case
1
1
per one Rh atom). In a typical experiment, the cata-
lytic complex (5mol%) was synthesised in situ from
*
bimorpholine 1, [Rh(cod)Cl] and KOH in i-PrOH by
2
of acetophenone 2 and 2-acetonaphthone 6, the M/L
molar ratio 1:4 was preferable (Table 1, entries 1 and 5).
stirring the mixture at room temperature (20°C) for
1
h prior to the addition of the substrate (Table 1).
These results indicate that by using a different metal/lig-
and molar ratio, different catalytic complexes are
formed. These complexes have different catalytic proper-
ties, causing changes in the stereoselectivity of the
reduction.
We carried out our experiments using the molar ratio of
*
M/L = 1:2 with different substrates. Comparing these
results, a higher activity of the latter catalytic system is
clearly seen (Table 1): the corresponding alcohols were
a
Table 1. Asymmetric reduction of ketones 2–7 catalysed by Rh-bimorpholine 1 complex
O
O
O
O
O
O
2
3
4
5
6
7
*
Molar ratio of M:L :KOH
Entry
Ketone
19
:4:6
1
1:2:6
b
c
b
c
Time (h)
Yield (%)
Ee (%)
Time (h)
Yield (%)
Ee (%)
1
9
19
1
2
3
4
5
6
2
3
4
5
6
7
21
46
46
46
46
46
96
77
55
83
82
33
32
40
44
63
21
75
21
21
21
21
21
21
98
95
95
91
94
95
27
46
57
68
16
83
a
*
Molar ratio of M/L = 1:2 corresponds to one molecule of ligand per one atom of Rh. Concentration of catalyst was 0.004M in its synthesis step.
Initial concentration of substrate was 0.05M.
Determined as area % by GC analysis.
b
c
Enantiomeric excess of obtained alcohol was determined by chiral HPLC (column: Chiralcel OD–H).

K. Kriis et al. / Tetrahedron: Asymmetry 15 (2004) 2687–2691
2689
2
.2. Influence of the amount of the basic co-catalyst
centrations. Usually, the amount of the chiral catalyst
was connected with its activity in the reaction and thus
it varied in a wide range (from 0.05 to 5mol%).
We studied the effect of the concentration of the catalyst
and substrate on the stereoselectivity and reactivity of
the hydride transfer reduction. 1-Acetonaphthone 5
was selected as a model substrate (Table 3).
1
4,22
It is known that the base activates the catalyst mark-
21
edly. The base has to deprotonate i-PrOH, allowing
the complexation of the metal and isopropoxide ion, fol-
lowed by the formation of the nonracemic metal hydride
and elimination of acetone. Lemaire et al. have shown
that their [Rh(cod)Cl] /chiral 1,2-diamine catalytic
2
1
4
system is inactive without the base. We have studied
the effect of the concentration of the basic co-catalyst
in the reduction of 1-acetonaphthone 5.
Table 3. Influence of the concentration of the catalyst and substrate on
a
the enantioselectivity of the reduction of 1-acetonaphthone 5
b
Temperature Yield Ee
c
Entry Mol% of Initial
catalyst
concentration
of substrate (M)
(°C)
(%)
(%)
These results indicate that an increase as well as a de-
crease in the base concentration had a lowering effect
on the stereoselectivity of the reaction. The best molar
1
2
3
4
5
5
1
5
5
5
0.05
0.05
0.025
0.05
0.1
20
20
20
25
25
96
33
80
86
68
60
68
75
64
ratio of [Rh(cod)Cl] to KOH in our catalytic system
2
was 1:6. Smaller amounts of the base (3equiv instead
of 6) led to a drop in the enantioselectivity from 68%
to 62% (Table 2, entries 2 and 1). The use of 3equiv
of the base obviously could not generate a sufficient
amount of active chiral species resulting in a decrease
of catalyst concentration.
d
96
a
The catalytic complex was synthesised in situ from bimorpholine 1,
[Rh(cod)Cl]2 and KOH (M:L :KOH = 1:2:6) in i PrOH by stirring
*
the mixture at room temperature for 1h prior to the addition of the
substrate. Yield and ee were determined after 46h.
Determined as area % by GC analyses.
Determined by chiral HPLC.
b
c
Table 2. Influence of the amount of the basic co-catalyst on the
a
enantioselectivity of the reduction of 1-acetonaphthone 5
d
The reaction time was 21h.
b
c
Entry
Molar ratio of
*
M:L :KOH
Yield (%)
Ee (%)
The best selectivity and reactivity were obtained with the
mol% catalyst (Table 3, entries 1, 3 and 4). Decreasing
5
1
2
3
1:2:3
1:2:6
1:2:8
48
96
89
62
68
65
the amount of catalyst to 1mol% at a constant substrate
concentration led to a drop in yield and selectivity (from
96% to 33% and from 68% to 60%, respectively; Table 3,
entries 1 and 2). We also noticed a decrease in enantio-
selectivity when the initial concentration of substrate
was increased (Table 3, entries 4 and 5, with 0.05M sub-
strate concentration ee 75% was obtained against 64% at
0.1M).
a
5
mol% of the catalytic complex was synthesised in situ from
bimorpholine 1, [Rh(cod)Cl] and KOH in i-PrOH by stirring the
2
mixture at 20°C for 1h prior to the addition of the substrate. Yield
and ee were determined after 46 h.
Determined as area % by GC analysis.
b
c
Enantiomeric excess was determined by chiral HPLC.
The same effect was observed when a larger amount of
the base was used (Table 2, entries 2 and 3, from ee
In most cases, an increase in temperature leads to an
improvement in the catalytic activity. The influence of
this factor on the stereoselectivity of the reaction is more
complex. Many catalytic systems provide a high conver-
sion and enantioselectivity at room temperature, while
some catalysts show a high activity only at increased
6
8% to 65%). Also, the activity of the catalytic system
0
is affected by this change. The yield of 1-(1 -naphth-
yl)ethanol decreased twice with lowering the amount
of the base (Table 2, entry 1 vs 2, from 96% yield to
9
,16,23
48%). An increase in the amount of KOH did not
noticeably change the activity of the catalyst.
temperatures (80°C).
However, some catalysts
8
operate successfully even at ꢀ30°C. We studied the
influence of the reaction temperature on the reduction
of ketones 2, 5 and 7 (Table 4).
It is difficult to find a reasonable explanation for the
results with a higher concentration of KOH. It is as-
sumed that isopropoxide competes with chiral diamine
In all cases, the temperature had a considerable influ-
ence on the stereoselectivity of the reduction. Adrop
in the temperature of the reduction of acetophenone 2
from room temperature to 5°C resulted in a notable in-
crease in enantioselectivity (ee 38% instead of 27%,
Table 4, entry 1 vs 2). At the same time, the reaction rate
decreased. However, in the case of 1-acetonaphthone 5
and 2-methylbenzophenone 7, the lower temperature
14
in the complexation with the metallic precursor. The
activation of the catalyst without a chiral ligand leads
to the formation of a racemic product. In our case that
model can be excluded because the catalyst derived from
[Rh(cod)Cl] in the presence of KOH (without bimorpho-
line 1) was very inactive. After 48h of reduction under
2
typical conditions, only 1.5% of alcohol was obtained.
(5°C) decreased the enantiomeric purity of the corre-
2
.3. Influence of other parameters (concentration of the
sponding alcohols (Table 4, entries 3 vs 4 and 8 vs 9,
ee 53% instead of 68% at 20°C for 1-acetonaphthone
5, ee 70% vs 83% for 2-methylbenzophenone 7). During
long reaction times, catalyst deactivation may take
place. The optimal stereoselectivity value was very sub-
strate dependent. Thus, the highest enantioselectivity
catalytic complex, initial concentration of the substrate
and temperature)
To find an appropriate concentration range, the reaction
was performed at different catalyst and substrate con-

2690
K. Kriis et al. / Tetrahedron: Asymmetry 15 (2004) 2687–2691
Table 4. Influence of the temperature on the enantioselectivity of the
a
reductions of ketones 2, 5 and 7
of KOH obviously contains a different catalytic species.
Nevertheless, reduction under the optimised conditions
gives enantiomeric alcohols with excellent yields and
high enantiomeric excesses.
b
c
Entry
Ketone
Temperature
Time
(h)
Yield
(%)
Ee
(%)
(°C)
1
2
3
4
5
6
7
8
9
2
2
5
5
5
5
5
7
7
7
5
7days
21
46
77
98
96
91
83
89
100
28
95
84
38
27
53
68
75
72
39
70
83
77
20
5
4. Experimental
20
25
30
65
5
21
21
The conversions were measured by capillary gas chro-
matography on a Dani GC-1000 (column 122-5022
DB-5, length 25m, I.D. 0.25mm, film 0.25lm). Enantio-
meric excesses of the alcohols obtained were determined
by HPLC on a LKB 2150 system, using a Chiralcel OD–
21
1
5days
21
21
20
25
10
1
9
H column.
a
The catalytic complex was synthesised in situ from bimorpholine 1,
*
[
2
Rh(cod)Cl] and KOH (M:L :KOH = 1:2:6) in i-PrOH by stirring
4
.1. General procedure for the reduction of ketones
the mixture at room temperature for 1h prior to the addition of the
substrate.
b
c
Asolution of bimorpholine (9mg, 10mol%, 0.053mmol
or 18mg, 20mol%, 0.105mmol), [Rh(cod)Cl] (13mg,
Determined as area % by GC analyses.
Determined by chiral HPLC.
2
5
0
mol%, 0.026mmol) and KOH (1.56mL, 30mol%,
.156mmol, 0.1M in i-PrOH) in dry degassed i-PrOH
obtained for 1-acetonaphthone 5 was at 25°C (Table 4,
entry 5, ee 75%), while for 2-methylbenzophenone 7 it
was 20°C (Table 4, entry 9, ee 83%) and for acetophe-
none 2 5°C (Table 4, entry 1, ee 38%).
(5mL) was stirred for 1h under an Ar atmosphere at
room temperature. Asolution of ketone (0.52mmol) in
i-PrOH (5mL) was added and the reaction mixture stir-
red for an appropriate time. Aliquots were taken at dif-
ferent times, Et O added, the precipitate centrifuged and
2
Generally, working at lower temperature leads to an in-
crease in the enantioselectivity of the catalytic system.
However, the experimental results are quite contradic-
tory in this respect. It is possible that the co-existence
of different active species in the reaction medium causes
different effects and thus, the nonlinear dependence of the
stereoselectivity on the temperature of reaction. On the
other hand, a reverse reaction, the re-oxidation of the ob-
the clear solution analysed by GC and HPLC. Detailed
analytical data were provided in our previous
publication.
1
9
Acknowledgements
The authors thank the Estonian Science Foundation for
financial support (grant nos 4976 and 5628).
6
,14
tained alcohol, is also possible.
In this reaction, the
chiral product competes with isopropanol for being a hy-
dride source. The formation of the catalytically active
hydride proceeds via diastereoisomeric complexes while
the kinetics of this process influences the enantioselectiv-
ity of the reduction. As a result, the simultaneous
co-existence of several factors does not lead to an unam-
biguous prediction of the stereoselectivity of the reduction.
References
1
. Comprehensive Asymmetric Catalysis I–III; Jacobsen, E.
N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin,
1999.
2
3
. Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M.
Chem. Rev. 2000, 100, 2159–2231.
. Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry 1999,
3. Conclusion
1
0, 2045–2061.
4
5
. Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008–2022.
. Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40,
Herein, we have shown that the change of the
Rh(cod)Cl] /bimorpholine 1 molar ratio from 1:4 to
[
2
4
. Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.;
0–73.
1
:2 leads to different catalytic systems. The catalyst de-
rived from 2moles of bimorpholine 1 and 1mole
Rh(cod)Cl] gave a clearly higher activity and generally
6
Noyori, R. J. Am. Chem. Soc. 1995, 117, 7562–7563.
7. Gao, J.-X.; Ikariya, T.; Noyory, R. Organometallics 1996,
15, 1087–1089.
8. P u¨ ntener, K.; Schwink, L.; Knochel, P. Tetrahedron Lett.
1996, 37, 8165–8168.
[
2
higher enantioselectivity in the reduction of different ke-
tones (ee up to 83%). However, the stereoselectivity of
both catalytic systems depends on the structure of the
substrate. The reduction of the sterically more hindered
ketones afforded a higher enantioselectivity. The re-
quired catalyst loading is 5mol% and yields of corre-
sponding alcohols are excellent. The optimal
9
. Jiang, Y.; Jiang, Q.; Zhang, X. J. Am. Chem. Soc. 1998,
20, 3817–3818.
0. Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
1
1
1
1
Chem. Soc. 1996, 118, 2521–2522.
1. Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916–4917.
2. Noyori, R.; Yamakawa, M.; Hashiguchi, S. J. Org. Chem.
[Rh(cod)Cl] /KOH molar ratio for our catalytic system
2
is 1:6.
2001, 66, 7931–7944.
13. Bernard, M.; Guiral, V.; Delbecq, F.; Fache, F.; Sautet,
P.; Lemaire, M. J. Am. Chem. Soc. 1998, 120, 1441–1446.
The results obtained indicate that the catalyst derived
from [Rh(cod)Cl] and bimorpholine 1 in the presence
2

K. Kriis et al. / Tetrahedron: Asymmetry 15 (2004) 2687–2691
2691
1
1
1
1
1
4. Gamez, P.; Fache, F.; Lemaire, M. Tetrahedron: Asym-
metry 1995, 6, 705–718.
5. Touchard, F.; Gamez, P.; Fache, F.; Lemaire, M. Tetra-
hedron Lett. 1997, 38, 2275–2278.
6. M u¨ ller, D.; Umbricht, G.; Weber, B.; Pfaltz, A. Helv.
Chim. Acta 1991, 74, 232–240.
7. Jiang, Y.; Jiang, Q.; Zhu, G.; Zhang, X. Tetrahedron Lett.
19. Kriis, K.; Kanger, T.; M u¨ u¨ risepp, A.-M.; Lopp, M.
Tetrahedron: Asymmetry 2003, 14, 2271–2275.
20. Kenny, J. A.; Palmer, M. J.; Smith, A. R. C.; Walsgrove,
T.; Wills, M. Synlett 1999, 1615–1617.
21. Chowdhury, R. L.; B a¨ ckvall Soc, J. E. J. Chem. Soc.,
Chem. Commun. 1991, 1063–1064.
22. Gladiali, S.; Pinna, L.; Delogu, G.; De Martin, S.;
Zassinovich, G.; Mestroni, G. Tetrahedron: Asymmetry
1990, 1, 635–648.
1997, 38, 215–218.
8. Kanger, T.; Kriis, K.; Pehk, T.; M u¨ u¨ risepp, A.-M.;
Lopp, M. Tetrahedron: Asymmetry 2002, 13, 857–
8
23. Kim, G.-J.; Kim, S.-H.; Chong, P.-H.; Kwon, M.-A.
Tetrahedron Lett. 2002, 43, 8059–8062.
65.