Enantioselective hydrogenation of exocyclic α,β-unsaturated ketones part III. Hydrogenation with Pd in the presence of cinchonidine

Article abstract of DOI:10.1016/S1381-1169(02)00413-2

Cinchonidine as a chiral modifier was used in the hydrogenation of exocyclic α,β-unsaturated ketones with palladium black catalyst, producing the corresponding saturated ketones up to 54% optical purity (2-benzyl-1-benzosuberone) in toluene under 50 bar hydrogen pressure. The influence of different parameters (solvent, catalyst) on the optical yield was investigated.

Full text of DOI:10.1016/S1381-1169(02)00413-2

Journal of Molecular Catalysis A: Chemical 192 (2003) 189–194
Enantioselective hydrogenation of exocyclic
␣
,␤-unsaturated ketones
Part III. Hydrogenation with Pd in the presence of cinchonidine
a
a,∗
b
Gabriella Fogassy , Antal Tungler , Albert Lévai
a
Department of Chemical Technology, Budapest University of Technology and Economics, H-1111 Budapest, Hungary
b
Department of Organic Chemistry, Kossuth Lajos University, H-4010 Debrecen, Hungary
Received 17 April 2002; received in revised form 8 July 2002; accepted 9 July 2002
Abstract
Cinchonidine as a chiral modifier was used in the hydrogenation of exocyclic ␣,␤-unsaturated ketones with palladium black
catalyst, producing the corresponding saturated ketones up to 54% optical purity (2-benzyl-1-benzosuberone) in toluene under
50 bar hydrogen pressure. The influence of different parameters (solvent, catalyst) on the optical yield was investigated.
©
2002 Elsevier Science B.V. All rights reserved.
Keywords: Enantioselective hydrogenation; (E)-2-Benzylidene-1-benzosuberone; Cinchonidine; Palladium black; Enantiomeric excess
1
. Introduction
in the mixture of dimethyl formamide and water af-
forded 72% optical yield [14].
Reduction of prochiral unsaturated substrates is an
The Pd/TiO2/cinchonidine system was the best
in the hydrogenation of the double bond of C
== C
important method for the synthesis of chiral com-
pounds. The enantioselective hydrogenation of the
C == O group was widely studied [1], but the reduc-
tion of the C == C bond, especially that in exocyclic
,␤-unsaturated ketones was less published [2,3].
There are two synthetically useful catalytic systems:
tartaric acid modified Ni catalysts for enantioselective
hydrogenation of ␤-ketoesters [4,5] and cinchona alka-
loid modified Pt catalysts for reduction of ␣-ketoesters
of 4-hydroxy-6-methyl-2-pyrone in acetonitrile with
85% enantioselectivity [15,16].
Another alkaloid, (−)-ephedrine was found to be
effective modifier, or more correctly effective aux-
iliary in the hydrogenation of the double bond of
C
== C of (E)-2-benzylidene-1-tetralone over Pd/C in
acetonitrile, with 36% optical purity and 82% yield
[3].
␣
[
6–9].
Besides platinum, cinchonidine modifies palladium
in the hydrogenation of the double bond of C == C of
Previously, we have reported on the enantioselective
hydrogenation of exocyclic ␣,␤-unsaturated ketones
using Pd-on-carbon in the presence of (S)-proline as
a chiral auxiliary with an enantiomeric excess of 20%
under optimal conditions [3]. To improve the effi-
ciency of the asymmetric hydrogenation several chiral
modifiers were tested, the highest optical yield was
achieved with cinchonidine.
(
E)-␣-phenylcinnamic acid [10–13]. Pd/TiO2 catalyst
∗
Corresponding author. Tel.: +36-1-463-1203;
fax: +36-1-463-1913.
E-mail address: tungler.ktt@chem.bme.hu (A. Tungler).
1
381-1169/02/$ – see front matter © 2002 Elsevier Science B.V. All rights reserved.
PII: S1381-1169(02)00413-2

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G. Fogassy et al. / Journal of Molecular Catalysis A: Chemical 192 (2003) 189–194
Scheme 1. The heterogeneous catalytic hydrogenation of (E)-2-benzylidene-1-indanone, (E)-2-benzylidene-1-tetralone and (E)-2-benzylidene-
1
-benzosuberone to the corresponding saturated ketones.
In the present work, the palladium catalysed
hydrogenation of (E)-2-benzylidene-1-indanone (1) to
-benzyl-1-indanone (2), (E)-2-benzylidene-1-tetra-
lone (3) to 2-benzyl-1-tetralone (4) and (E)-2-benzy-
lidene-1-benzosuberone (5) to 2-benzyl-1-benzosu-
berone (6) was investigated in order to find
appropriate reaction conditions to obtain the highest
enantioselectivity (Scheme 1).
The Rh/C catalyst was commercial product of
Aldrich. Cinchonidine, cinchonine, quinidine and
quinine were purchased from Fluka. Toluene, hexane,
ethyl acetate, methanol, acetonitrile, dimethylfor-
mamide and acetic acid were supplied by Fluka.
2
2.2. Hydrogenations
The hydrogenations were carried out in a stainless
steel autoclave (Technoclave) with magnetic stirrer at
room temperature and at 50 bar hydrogen pressure.
Before hydrogenation, the reaction mixtures were
stirred under nitrogen (2–3 bar) for 10 min in the
reaction vessel.
The working-up procedure of the reaction mix-
tures was the catalyst filtration and the removal of
the solvent in vacuum. The residue was dissolved
in dichloromethane and extracted with 5% HCl and
distilled water. The organic phase was separated and
dried over Na2SO4. After filtration, the solvent was
removed in vacuum.
2
. Experimental
2
.1. Materials
Compounds 1 and 3 were prepared according to the
procedure described in [17], while 5 was synthesised
as described in [18].
Pd black catalysts were prepared according to the
following procedure: 9 mmol (3.0 g) K2PdCl4 was dis-
solved in 30 ml water and reduced at boiling point with
2
.5 g HCOONa in 20 ml water. The pH value of the
solution was adjusted to 9 by addition of KOH. The
suspension was boiled for 1 h then cooled, the catalyst
filtered and washed several times with distilled water
until the water became neutral.
The product was analysed by HPLC, from these
chromatography data conversion, selectivity and enan-
tioselectivity values were calculated.
Pd/TiO2 catalysts were prepared according to
the following procedure: calculated amount of the
K2PdCl4 was added to the aqueous suspension of the
support. The pH value was adjusted to 11 by addition
of KOH. The suspension was boiled for 1 h, then the
reducing agent HCOONa (three times the stoichio-
metric amount) was added to the boiling mixture.
After 30 min, the suspension was cooled, the catalyst
was filtered and washed with distilled water.
2.3. Analysis
The HPLC analyses were carried out on a Chiralcel
OJ column (0.46 cm × 25 cm). The column contains
silica gel as packing material coated with a cellulose
derivative. The eluent was hexane/2-propanol 90:10
(v/v), the flow rate was 1.0 ml/min and the column
2
pressure was 50 kg/cm . The UV absorbance was

G. Fogassy et al. / Journal of Molecular Catalysis A: Chemical 192 (2003) 189–194
191
measured at 249 nm. Enantiomeric excesses were
calculated according to the following equation:
45% was achieved over Pd black in toluene. It has
to be mentioned that this solvent was not completely
water-free. In hexane and ethyl acetate these val-
ues were among 37–35%, in acetonitrile, methanol
and dimethyl formamide were lower, in acetic acid
racemic product was formed.
[
A] − [B]
A] + [B]
e.e. (%) =
× 100
[
where [A] is the concentration of major enantiomer
and [B] the concentration of minor enantiomer.
3.2. Effect of the concentration of the modifier
3
. Results and discussion
The effect of the concentration of modifiers on the
e.e. is shown in Fig. 2.
3
.1. Effect of solvents
Our experience was that the e.e. values deviated
in repeated experiments. It turned out that the reac-
tion is very sensitive to the water content of toluene.
Further on, the reactions were carried out in abso-
lute toluene. The conversion and the chemoselectiv-
ity were 100% in all the cases. An enhancement of
the enantioselectivity was observed with increasing
amount of cinchonidine, it reached a maximum at 5%
(w/w) modifier with respect to the catalyst. Increas-
ing the modifier concentration above this value the
optical purity decreased. These hints that not only
modification but also poisoning of the catalyst surface
occurs.
It is well known that in the catalytic hydrogenation
the selectivity of the reaction, as well as the activity
of the catalyst, can be influenced by using appropriate
solvents [19]. The results of the hydrogenations of the
substrate 5 in different solvents, over palladium black
modified with cinchonidine are shown in Fig. 1. The
effect of conditions was investigated with compound
5
, because it gave the highest e.e. values among the
three unsaturated ketones.
The conversion and the chemoselectivity were
1
00% in all solvents. The highest enantioselectivity
Fig. 1. The influence of different solvents on the enantioselectivity. Conditions: 0.5 g (E)-2-benzylidene-1-benzosuberon, 0.05 g Pd black,
◦
2
0 ml solvent, 0.005 g cinchonidine, 2 h, 50 bar, 25 C.

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G. Fogassy et al. / Journal of Molecular Catalysis A: Chemical 192 (2003) 189–194
Fig. 2. The influence of the quantity of cinchonidine on the enantioselectivity. Conditions: 0.5 g (E)-2-benzylidene-1-benzosuberon, 0.05 g
◦
Pd black, 20 ml toluene, 2 h, 50 bar, 25 C.
3
.3. Conversion and reaction rate
The hydrogenation was complete within 1.5 h and
the chemoselectivity was 100%. The reaction rate was
constant up to 90% conversion, this means that the
reaction is zero order. The e.e. did not change with
conversion.
The enantiomeric excess and the conversion as
a function of the reaction time were illustrated in
Fig. 3.
Fig. 3. The conversion and enantiomeric excess in the function of time. Conditions: 1 g (E)-2-benzylidene-1-benzosuberon, 0.1 g Pd black,
◦
4
0 ml toluene, 0.005 g modifier, 50 bar, 25 C.

G. Fogassy et al. / Journal of Molecular Catalysis A: Chemical 192 (2003) 189–194
193
Table 1
Table 3
Effect of different catalyst on the enantioselectivity
Hydrogenation of 1 and 3 in different solvents and over different
catalysts
Catalyst
Solvent
e.e. (S; %)
Catalyst
Solvent
e.e. (%)
Pd black
Pd/TiO2
Pd/TiO2
Pd/Al2O3
Pd/Al2O3
Ru/C
Toluene
MeCN
DMF/water
MeOH
Toluene
Toluene
MeOH
53.7
37.1
24.9
12.3
4.7
–
2 (S)
4 (R)
Pd black
Pd black
Pd black
Pd black
Pd/TiO2
EtOAc
Toluene
MeOH
DMF/water
MeCN
0
0
4.4
9.6
0
2.5
5.6
4.0
9.1
Ru/C
Chemoselectivity=0
2.3
Conditions: 0.5 g (E)-2-bezylidene-1-benzosuberon, 0.05 g catalyst,
◦
Conditions: 0.5 g substrate, 0.05 g catalyst, 20 ml solvent, 0.0025 g
cinchonidine, 2 h, 50 bar, 25 C.
2
0 ml solvent, 0.0025 g cinchonidine, 2 h, 50 bar, 25 C.
◦
3
.4. Effect of different catalyst
quasi-enantiomers, they afford different enantioselec-
tivity values.
The effect of the catalyst on the enantioselectivity in
the hydrogenation of compound 5 in different solvents
are summarized in Table 1.
The conversion and the chemoselectivity were
3
.6. Hydrogenation of 2 and 4 in different solvent
and over different catalysts
1
00% in all reactions. The highest enantioselectivity
Among the same conditions, described in Table 1,
the substrates 1 and 3 were hydrogenated too, these
results are summarised in Table 3.
value 53.7%, was achieved over Pd black catalyst
in toluene. The second best catalyst was Pd/TiO2
in acetonitrile or dimethyl formamide/water, it gave
somewhat smaller e.e. than the Pd black in toluene.
The conversion and the chemoselectivity were
100% in all solvents. Comparing the corresponding
data of Tables 1 and 3 the enantiomeric excess is
much lower in the hydrogenation of 1 and 3 than in
that of 5.
The tendency is similar to that, which was
achieved in the hydrogenation of these substrates with
3
.5. Effect of cinchona alkaloids
The most frequently used cinchona alkaloid is cin-
chonidine. The results of the reactions with other cin-
chona alkaloids are summarized in Table 2.
The cinchona alkaloid pairs (cinchonidine–
cinchonine and quinidine–quinine) differ in absolute
configuration on C8 and C9 atoms, cinchonidine,
(S)-proline as chiral auxiliary over palladium [2].
4. Conclusion
(dihydrocinchonidine) and quinidine results in the S,
while cinchonine and quinine in the R configuration
of the saturated ketones. As these modifier pairs are
Exocyclic ␣,␤-unsaturated ketones were reduced
to the corresponding saturated ketones over different
catalysts in different solvents up to 53.7% enantios-
electivity. The enantioselectivity is strongly depen-
dent on the water content of the best solvent, toluene.
The most efficient system was palladium black, cin-
chonidine modifier in toluene in the hydrogenation of
the (E)-2-benzylidene-1-benzosuberone (e.e.: 53.7%).
The optimal amount of modifier was 5% (w/w) with
respect to the catalyst in this reaction.
Table 2
Effects of cinchona alkaloid on the enantioselectivity
Modifier
e.e. (%)
Configuration
Cinchonidine
Dihydrochinchonidine
Cinchonine
Quinidine
Quinine
53.7
52.3
36.5
51.4
36.7
S
S
R
S
R
The enantioselectivity was different for the five,
six and seven-membered ring containing com-
pounds among the same conditions. These significant
Conditions: 0.5 g (E)-2-bezylidene-1-benzosuberon, 0.05 g Pd
black, 20 ml toluene, 0.0025 g modifier, 2 h, 50 bar, 25 C.
◦

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G. Fogassy et al. / Journal of Molecular Catalysis A: Chemical 192 (2003) 189–194
differences between the enantioselectivity values can
be attributed to the different rigidity of the substrate
molecules as mentioned in [4].
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79 (2002) 101.
1
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Catalysts, Reidel, Dordrecht, 1986, p. 265.
[7] Y. Orito, S. Imai, S. Niwa, J. Chem. Soc. Jpn. 6 (1979) 1118.
Acknowledgements
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The authors acknowledge the financial support of
the Hungarian OTKA Foundation under the Contract
no. T 029557, of the Ministry of Education, FKFP
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