Chemo- and enantioselective hydrogenation of the activated keto group of fluorinated β-diketones

Article abstract of DOI:10.1016/j.tetasy.2003.10.043

Asymmetric hydrogenation of the activated carbonyl group of 1,1,1-trifluoro-2,4-diketones was studied over Pt/Al₂O₃ modified by various chiral 1,2-aminoalcohols and amines. The best chiral modifiers were cinchonidine and O-methyl-cin

Full text of DOI:10.1016/j.tetasy.2003.10.043

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 251–257
Chemo- and enantioselective hydrogenation of the activated keto
group of fluorinated b-diketones
Reto Hess, Simon Diezi, Tamas Mallat and Alfons Baiker*
Institute for Chemical and Bioengineering, Swiss Federal Institute of Technology, ETH-H€onggerberg, CH-8093 Zurich, Switzerland
Received 25 September 2003; accepted 29 October 2003
Abstract—Asymmetric hydrogenation of the activated carbonyl group of 1,1,1-trifluoro-2,4-diketones was studied over Pt/Al2O3
modified by various chiral 1,2-aminoalcohols and amines. The best chiral modifiers were cinchonidine and O-methyl-cinchonidine,
which enhanced the chemoselectivity above 99%. The ee varied in the range of 22–86% depending on the steric hindrance around the
nonactivated carbonyl group of the substrate. In one case the ee inverted from (S)- to the (R)-enantiomer by simply increasing the
solvent polarity. The different reactivities of the substrates are correlated with their adsorption strength and the keto–enol equili-
bration, as only the keto form of the 2-carbonyl group is assumed to react on the chirally modified Pt surface.
ꢀ 2003 Elsevier Ltd. All rights reserved.
1. Introduction
aromatic trifluoromethyl ketones afforded up to 92% ee
(trifluoroacetophenone17) though the enantioselectivity
varied in a broad range depending on the structure of
the substrate.18–21
Compared to the number of highly selective homoge-
neous asymmetric catalysts, the variety and application
range of heterogeneous asymmetric catalysts are limited.
The most effective solid catalysts, the Ni-tartaric acid,1–4
the Pt–cinchona,5–8 and the Pd–cinchona alkaloid sys-
tems,9–12 afford in some cases over 90% ee in the
hydrogenation of C@O and C@C bonds. The obvious
advantages of heterogeneous catalysts in handling and
separation make the easily available catalyst systems
interesting for practical applications.
A few homogeneous transition metal catalysts have
already been tested in the hydrogenation of trifluoro-
methyl ketones.22;23 A rhodium–amidephosphine–phos-
phinite complex afforded excellent yields and up to 97%
ee in a slow reaction.24
Herein we report the structural effects in the hydroge-
nation of trifluoromethyl diketones in which the steric
hindrance around the nonactivated carbonyl group is
varied (Fig. 1). The catalyst system consists of Pt/Al2O3
and various chiral 1,2-aminoalcohols and aminoether
type modifiers, which possess an aromatic ring to favor
adsorption on Pt.
Supported Pt, chirally modified by the simple addition
of a strongly adsorbing cinchona alkaloid, is the
best heterogeneous catalyst for the enantioselective
hydrogenation of a,a,a-trifluoromethyl ketones. To
our knowledge, the 96% ee and 1850 hꢀ1 average TOF
achieved under mild conditions (10 bar, room tempera-
ture) in the hydrogenation of ethyl 4,4,4-trifluoroace-
toacetate to the corresponding chiral trifluoromethyl
alcohol represent the highest values reported for the
catalytic synthesis of this chiral building block.13–15
In this reaction the most effective modifier of Pt is
O-methyl-cinchonidine in AcOH/THF mixtures. The
reaction can also be carried out in a continuous flow
reactor for industrial application.16 Hydrogenation of
2. Results and discussion
2.1. Chemoselectivity
Without modifiers, hydrogenation of 1a–3a was mod-
erately selective (79–83%) on Pt/Al2O3. The main
products 1b–3b always formed by hydrogenation of the
2-keto-carbonyl group activated by the trifluoromethyl
group (Scheme 1). The chemoselectivity was diminished
by the reduction of the 4-keto group and saturation of
* Corresponding author. Tel.: +41-1-632-31-53; fax: +41-1-632-11-63;
e-mail: baiker@tech.chem.ethz.ch
0957-4166/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.10.043

252
R. Hess et al. / Tetrahedron: Asymmetry 15 (2004) 251–257
Reactants:
O
O
O
O
O
O
F3C
F3C
F3C
1
2
3
Modifiers:
non-cinchona alkaloids
HO
N
HO
N
H
NH2
HO
Eph
PhG
PNE
cinchona-alkaloids
H
H
H
H
OMe
N
N
H
N
N
H
N
H
H
H
OH
O
OH
Cl
OH
N
N
N
CD
MeOCD
CD•HCl
HQN
Figure 1. Structure of the substrates and chiral modifiers.
O
O
Pt / Al2O3
OH
O
O
OH
OH OH
H2, toluene
F3C
F3C
F3C
F3C
2h, 24 °C
1a
1b
19
1c
1.5
1d
2.5
O
O
OH
O
OH
O
OH OH
F3C
F3C
F3C
F3C
2a
2b
71
2c
4.5
2d
14.5
O
O
OH
O
O
OH
OH OH
F3C
F3C
F3C
F3C
3b
19
3c
0
3d
4
3a
Scheme 1. Products and yields (%) identified in the hydrogenation of 1a–3a on Pt/Al2O3 in the absence of chiral modifier.
the aromatic ring 2c. Addition of the chiral 1,2-amino-
alcohol and aminoether type modifiers (Fig. 1) sup-
pressed these side reactions and in the best cases (CD,
MeOCD, HQN) gave a chemoselectivity higher than
99%. This effect was attributed to the basic amine
function of the modifiers, and also partly to site block-
ing, that is, the coverage of a considerable fraction of
surface Pt sites by the strongly adsorbing modifiers. A
general feature of heterogeneous catalytic hydrogena-
tions is the improved chemoselectivity when decreasing
the active site/substrate ratio.25
2.2. Influence of catalyst pretreatment
It was early recognized5;26 that a reductive catalyst pre-
conditioning at elevated temperatures enhanced the
enantioselectivity of cinchona-modified Pt. Treatment in

R. Hess et al. / Tetrahedron: Asymmetry 15 (2004) 251–257
253
Table 1. Influence of catalyst pre-treatment (H2, 400 ꢁC) on the reac-
tion rate (TOF) and enantioselectivity in the hydrogenation of 1a and
3a; standard conditions, toluene
for understanding the substrate–modifier interaction on
the Pt surface. Protonation of CD (in CDÆHCl) dimin-
ished the ee but did not hinder the enantiodifferentia-
tion.
Pre-reduc-
tion
1a
3a
TOF (hꢀ1
)
Ee (%)
TOF (hꢀ1
)
Ee (%)
It has been shown for the hydrogenation of another
activated ketone, ethyl pyruvate, that PNE is a struc-
turally simple analogue of CD.30;31 Similar ee values
achieved with the two modifiers in the hydrogenation of
3a (33–35%) are in line with this conclusion.
No
Yes
25
70
11
19.2
66
88
17
35
flowing hydrogen at 400 ꢁC (almost) doubled the ee of
the hydrogenation of 1a and 3a (Table 1). Probable
explanations for this effect are a change of morphology
of Pt particles, as indicated by TEM measurements,27
and the removal of surface impurities.
PhG and Eph were barely effective modifiers, though it
must be noted that Eph afforded the highest ee (8%) to
(R)-2b. Their low efficiency is probably connected with
the size of the aromatic ring: The single aromatic ring in
PhG and Eph adsorbs less strongly on Pt than the
naphthalene or quinoline rings of the other modifiers
and the steric hindrance against the formation of the
minor enantiomer is expected to be smaller.
Besides catalyst pre-reduction in the gas phase, the effect
of some liquid phase treatments has also been tested. In
these procedures the catalyst was stirred together with
some of the reaction components for 10 min before
hydrogenation. Though the ee varied significantly, no
clear correlation could be established as the direction
and size of the effect also depended on the solvent and
substrate.
Yields achieved in 2 h (8–80%) under standard condi-
tions in toluene show that the reaction rates varied in a
broad range depending on the substrate and modifier. A
comparison of the data in Scheme 1 (unmodified Pt) and
Table 2 (modified Pt) reveals that the addition of a
modifier either increased or decreased the reaction rate.
Fortunately, with the good modifiers always rate accel-
eration was observed when compared to the unmodified
reaction. In our best case, the hydrogenation of 3a over
MeOCD-modified Pt, the yield to 3b was more than
tripled due to the substrate–modifier interaction. Not
considering this reaction, the hydrogenation of 2a
proved to be the fastest on all chirally modified and
unmodified Pt/Al2O3. A feasible explanation may be the
stronger adsorption of 2a on Pt due to the aromatic
substituent, resulting in a higher surface concentration
and thus faster reaction. Support for this assumption
could be the saturation of the phenyl ring and the for-
mation of a significant amount of 2c (Scheme 1)––a
reaction in which Pt is usually poorly active.25 Another
possible reason for the different reactivities of 1a–3a is
connected with the keto–enol equilibration, as discussed
below.
2.3. Test of different modifiers
Hydrogenation of 1a–3a on Pt/Al2O3, previously modi-
fied by seven different chiral amines and 1,2-amino-
alcohols, revealed strong structural effects (Table 2). In
general, hydrogenation of the sterically less demanding
substrate 3a proved to be the most selective while that of
the bulkiest, 2a, proved to be the least selective (ee ¼ 8%).
In the hydrogenation of 1a and 3a, CD and MeOCD
were the best modifiers. The strikingly different effects of
methylation of CD to MeOCD in the two reactions are
most likely due to steric effects, as the OH group of CD
is assumed not to be involved in the CD–substrate
interaction in the hydrogenation of activated ketones.28
Another interesting observation is that in the hydroge-
nation of 1a and 3a, the ee dropped close to zero on
replacement of CD with the 60-methoxy derivative HQN
(hydrogenation of the C@C bond of cinchona alkaloids
present in CD but absent in HQN is a fast side reaction
and has practically no influence on the enantioselec-
tion29). For comparison, all cinchona alkaloids gave
very similar eeꢀs in the hydrogenation of a-ketoesters on
Pt/Al2O3.26 These two steric effects may be useful hints
2.4. Solvent effect
Figure 2 shows the influence of solvents on the enantio-
selectivity in the hydrogenation of 1a under standard
conditions, testing only the three good modifiers: CD,
Table 2. Enantioselective hydrogenation of 1a–3a on Pt/Al2O3 with different modifiers under standard conditions, in toluene
Modifier
1a
2a
3a
Yield (%)
Ee (%)
Yield (%)
Ee (%)
Yield (%)
Ee (%)
CD
22
11
30
8
19
10
3
80
68
60
40
––
56
51
5
4
28
15
66
21
23
16
15
35
32
64
3
CDÆHCl
MeOCD
HQN
PNE
2
<1
––
4*
2
<1
––
6
––
23
13
33
1
PhG
Eph
8*
5
The (S)-enantiomer of 1b–3b is formed in excess, except when indicated by a (*).

254
R. Hess et al. / Tetrahedron: Asymmetry 15 (2004) 251–257
(S)40
30
20
10
0
10
(R) 20
CD
CD•HCl
MeOCD
2.38
6.02
6.17
7.58
19.92
35.94
36.71
i
Figure 2. Solvent effect in the hydrogenation of 1a using different modifiers under standard conditions.
Table 4. Keto–enol equilibrium and the fraction of the keto form of
1a–3a in different solvents
MeOCD, and CDÆHCl. The solvents are characterized
by their relative permittivity (dielectric constant, eT).
Generally, weakly polar solvents favor enantioselection.
An inversion of the absolute configuration of the major
enantiomer was observed in the polar, aprotic solvents
acetonitrile and DMF. The most extreme values are 36%
ee to (S)-1b in THF with CD and 13% ee to (R)-1b with
MeOCD in DMF. Similar effects of solvent polarity
have also been observed in the hydrogenation of other
activated ketones on chirally modified Pt.32;33
slow
fast
keto
enol-1
enol-2
Solvent
Keto form (%)
1a
2a
3a
Toluene
THF
Acetonitrile
3
3
9
1
3
6
2
5
The solvent effect in the hydrogenation of 3a under
standard conditions is shown in Table 3. Here, no clear
correlation between the solvent polarity and the ee could
be established. THF and MeOCD were the best solvent
and modifier: 76.5% ee and 78.5% yield were achieved in
only 2 h.
10
the reactants, the fraction of the keto form was the
highest in acetonitrile. It has been proposed for the
enantioselective hydrogenation of ethyl 4,4,4-trifluoro-
acetoacetate39 that the C@O bond in the keto form is
hydrogenated on Pt and not the C@C bond in the enol
form. Thus, the enol form is only a spectator species that
equilibrates to the keto form before hydrogenation. This
model is in accordance with all mechanistic models
suggested for the enantioselective hydrogenation of
activated ketones on cinchona-modified Pt.7;8;28;40;41 The
In acetonitrile the yields were higher than 90% for all
three modifiers (Table 3). A feasible explanation for the
high reaction rate in acetonitrile can be found in Table
4. The keto–enol equilibration of 1a–3a was measured
1
by H NMR in different solvents. In these solvents the
trifluoromethyl derivatives 1a–3a mainly exist in their
enol form.34–36 The low keto content for 2a can be
attributed to the presence of the phenyl ring.37;38 For all
Table 3. Solvent effect in the hydrogenation of 3a to (S)-3b using different modifiers under standard conditions
Solvent
eT
CD
CDÆHCl
Ee (%)
MeOCD
Ee (%)
Yield (%)
Ee (%)
Yield (%)
Yield (%)
Toluene
Ethyl acetate
AcOH
2.4
28
52
31
52
<1
93
––
35
15
32
10
3
66
94
64
6.0
6.2
21.5
15.5
30.5
––
14.5
18
65.5
58.5
76.5
––
55.5
78.5
<1
THF
iPrOH
7.6
16
10
13.5
3
19.9
35.9
36.7
53.5
95.5
9
Acetonitrile
DMF
8
––
95.5
23
27.5
53.5
4.5

R. Hess et al. / Tetrahedron: Asymmetry 15 (2004) 251–257
255
high rates (yields) achieved in acetonitrile are in good
agreement with this model.
100
80
60
40
20
0
In 1,3-diketones the situation is more complex because
the enol-2 form also possesses the activated keto-car-
bonyl group in the keto form. It is very likely that the
enol-2 species are reactive species on Pt. On the basis of
the electronic effects of the substituents it is expected
that not only the keto/enol but also the enol-2/enol-1
ratio is highest in substrate 2a.37;38 This ratio, however,
cannot be determined by NMR.
ee
yield
2.5. The influence of reaction conditions
-10
0
10
20
30
40
The effect of some reaction parameters has been inves-
tigated for the most selective reaction, the hydrogena-
tion of 3a. Working at higher pressures (higher surface
hydrogen concentration) increased the reaction rate as
expected but slightly diminished the enantioselectivity
(Fig. 3). A similar influence of surface hydrogen
concentration was found in the Pt-catalyzed enantio-
selective hydrogenation of acetophenone,42 2,2,2-
trifluoroacetophenone,13;41 and ring-substituted ace-
tophenones.43 This correlation is opposite to the typical
behavior of the Pt–cinchona system in the hydrogena-
tion of a-ketoesters and other activated ketones.44 The
surface hydrogen concentration may influence the
adsorption of reactant or modifier and thus the enan-
tioselection. It has recently been shown45 that the
adsorption geometry of methyl pyruvate on Pt changes
temperature / °C
Figure 4. Effect of temperature in the hydrogenation of 3a to 3b (THF,
MeOCD, standard conditions).
feature of hydrogenations over cinchona-modified
Pt.44 A feasible explanation could be the change in
adsorption mode of the substrate and modifier, though
recent NEXAFS studies with quinoline and dihydro-
cinchonidine do not support this assumption.47;48
Another likely explanation is the faster hydrogenation
of the quinoline ring of MeOCD at higher tempera-
ture.
Around the optimum value, the substrate/modifier
(MeOCD) molar ratio could be varied in a broad range
without a significant effect on the ee. For example, at a
substrate/modifier molar ratio of 270 and 2950 the eeꢀs
were 75% and 74%, respectively, under otherwise stan-
dard conditions in THF.
from perpendicular to
a tilted position due to
co-adsorption of hydrogen. This competition of hydro-
gen with the substrate and modifier for surface Pt sites
could be an explanation for the negative pressure effect
as shown in Figure 3. In addition, high surface hydrogen
concentration may accelerate the hydrogenation of the
quinoline ring of MeOCD, leading to weaker adsorption
of the partially saturated modifier.10;46
The best ee of 86%, measured for the hydrogenation of
3a in this limited parameter study, was achieved at 0 ꢁC
and 3 bar (Table 5). Hydrogenation of 1a and 2a was far
less selective, due to steric effects on the substrate–
modifier interaction.
Reaction temperatures above room temperature dimin-
ished the enantioselectivity (Fig. 4), which is a general
100
80
3. Conclusions
Herein we have shown that the Pt–cinchona system
affords an excellent chemoselectivity in the hydrogena-
tion of the 2-keto group of 1,1,1-trifluoro-2,4-diketones.
The enantioselectivity is good but only in the absence of
a bulky substituent at the 5-position. The ee dropped
from 86% to 36% and 22% when replacing the methyl
group in 3a to tert-butyl and phenyl groups in 1a and 2a,
respectively. Another interesting steric effect is the
almost complete loss of enantioselectivity when replac-
ing CD with its 60-methoxy derivative HQN. These
steric effects, together with the inversion of ee by
replacing weak polar solvents with strong polar solvents
may be a useful starting point for future mechanistic
studies.
60
40
ee
20
0
yield
0
5
10
15
20
25
30
35
pressure / bar
Figure 3. Influence of pressure on the yield and ee in the hydrogena-
tion of 3a to 3b (THF, MeOCD, standard conditions).

256
R. Hess et al. / Tetrahedron: Asymmetry 15 (2004) 251–257
Table 5. Pt-catalyzed enantioselective hydrogenation of fluorinated diketones
Reactant
Modifier
CD
Conditions (solvent, p, T)
THF, 10 bar, 24 ꢁC
TOF (hꢀ1
35
)
Yield (%)
11.1
Ee (%)
36.3
O
O
O
F3C
MeOCD
MeOCD
AcOH, 10 bar, 24 ꢁC
THF, 3 bar, 0 ꢁC
150
128
47.4
39.4
22.2*
86.2
O
F3C
O
O
F3C
The (S)-enantiomer always formed in excess, except when indicated by a (*).
4. Experimental
4.1. Materials
the eeꢀs was within 0.5%. The products in the hydro-
genation of 2a were analyzed by a Merck Hitachi
D-7000 HPLC with Chiralcel OB column (diameter
4.6 mm, particle size 10 lm). The enantiomers were
identified by comparing the sign of their specific rotation
(Perkin Elmer 241 Polarimeter) with literature data.49;50
1,1,1-Trifluoro-5,5-dimethyl-2,4-hexanedione 1a (Ac-
ros), benzoyl-1,1,1-trifluoroacetone 2a (Acros), 1,1,1-
trifluoro-2,4-pentanedione 3a (Acros), cinchonidine
(CD, Fluka), cinchonidine hydrochloride (CDÆHCl,
Sigma), hydroquinine (HQN, Fluka), (1R,2S)-())-
ephedrine (Eph, Fluka), and (R)-())-2-phenylglycinol
(PhG, Fluka) were used as received. Methoxycinchon-
idine (MeOCD)11 and (R)-2-(1-pyrrolidinyl)-1-(1-naph-
thyl)ethanol (PNE)30 were prepared according to known
methods. Elemental analysis and NMR data were in
The average reaction rate is expressed as a turnover fre-
quency (TOF, hꢀ1), that is, the molar amount of sub-
strate converted by one mole of surface Pt atoms in 1 h.
NMR spectra were recorded on a Bruker DPX 500
spectrometer. Keto and enol forms were identified by
1H, 13C, and 19F NMR spectroscopy. The relative
amounts of the different compounds were calculated by
1
good agreement with the structure of the modifiers. H
and 13C NMR spectra were measured using a DPX 300
spectrometer.
1
the integration of the peak areas in the H spectra.
4.2. Catalytic hydrogenation
Acknowledgements
According to standard procedure, the 5 wt % Pt/Al2O3
catalyst (Engelhard 4759) was pre-reduced before use in
a fixed-bed reactor by flushing with N2 at 400 ꢁC for
30 min, followed by reductive treatment in H2 for 90 min
at the same temperature. After cooling to room tem-
perature in hydrogen, the catalyst was immediately
transferred to the reactor.
Financial support by the Swiss National Science Foun-
dation is kindly acknowledged. The authors also thank
Argonaut Technologies for technical support with the
parallel pressure reactor system.
References and notes
Hydrogenations were carried out in the parallel pressure
reactor system Endeavor (Argonaut Technologies), with
eight mechanically stirred 15 ml stainless steel reactors
equipped with glass liners. Controlled experiments using
different amounts of catalyst and varying the stirring
frequency (500–1000 rpm) did not indicate any mass
transport limitation. Under standard conditions
42 2 mg catalyst, 1.84 mmol substrate, 6.8 lmol modi-
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room temperature (23–25 ꢁC) for 2 h. Deviations from
these conditions are indicated in the Tables.
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