Heterogeneous enantioselective hydrogenation of hydroxy-substituted (E)-2,3-diphenylpropenoic acids over Pd/Al2O3 modified by cinchonidine

Article abstract of DOI:10.1007/s10562-012-0777-5

The enantioselective hydrogenation of (E)-2,3-diphenylpropenoic acids substituted by hydroxyl group has been studied over Pd/Al₂O ₃ catalyst modified by cinchonidine. The effect of the acidic hydroxyl substituents was compared with that of the methoxy group in the same position. The para-hydroxyl substituent on the 3-phenyl ring had similar effect on the enantioselectivity as the methoxy group, whereas the meta positioned decreased the optical purity of the saturated acid. This was explained by different origin of the increase in the enantioselectivity obtained in the presence of electron releasing substituents in these positions. Although, the para-hydroxyl group on the 2-phenyl ring had beneficial influence on the enantioselectivity of the hydrogenation of the mono-substituted acid, in the presence of fluorine or hydroxyl group on the 3-phenyl ring the effect of the two substituents was not additive. This study demonstrated that the cinchonidine-modified Pd catalyst is appropriate for the preparation of several hydroxy-substituted 2,3-diphenylpropionic acids in good optical purities, extending the scope of this catalytic system to new types of versatile chiral building blocks.

Full text of DOI:10.1007/s10562-012-0777-5

Catal Lett (2012) 142:345–351
DOI 10.1007/s10562-012-0777-5
Heterogeneous Enantioselective Hydrogenation of Hydroxy-
substituted (E)-2,3-diphenylpropenoic Acids over Pd/Al2O3
Modified by Cinchonidine
} }
Gyorgy Szollosi
¨
Received: 4 December 2011 / Accepted: 25 January 2012 / Published online: 11 February 2012
Ó Springer Science+Business Media, LLC 2012
Abstract The enantioselective hydrogenation of (E)-2,3-
diphenylpropenoic acids substituted by hydroxyl group has
been studied over Pd/Al2O3 catalyst modified by cincho-
nidine. The effect of the acidic hydroxyl substituents was
compared with that of the methoxy group in the same
position. The para-hydroxyl substituent on the 3-phenyl
ring had similar effect on the enantioselectivity as the
methoxy group, whereas the meta positioned decreased the
optical purity of the saturated acid. This was explained by
different origin of the increase in the enantioselectivity
obtained in the presence of electron releasing substituents
in these positions. Although, the para-hydroxyl group on
the 2-phenyl ring had beneficial influence on the enanti-
oselectivity of the hydrogenation of the mono-substituted
acid, in the presence of fluorine or hydroxyl group on the
3-phenyl ring the effect of the two substituents was not
additive. This study demonstrated that the cinchonidine-
modified Pd catalyst is appropriate for the preparation of
several hydroxy-substituted 2,3-diphenylpropionic acids in
good optical purities, extending the scope of this catalytic
system to new types of versatile chiral building blocks.
1 Introduction
Catalytic hydrogenations are widely applied processes for
preparing fine chemicals, including optically pure inter-
mediates used in the pharmaceutical and agrochemical
industries [1–3]. Numerous industrially important hydro-
genations are carried out in heterogeneous catalytic sys-
tems over metal catalysts [1]. The adsorption of optically
pure compounds, so-called modifiers, on metal surfaces
provided efficient heterogeneous catalysts for the asym-
metric hydrogenation of several types of prochiral com-
pounds [4–8]. Among these are a, b-unsaturated carboxylic
acids, which were hydrogenated enantioselectively over Pd
catalysts modified by cinchona alkaloids [6, 9]. The
structure of the acid was found to have decisive influence
on the enantiomeric excess (ee) [10–20]. Until now the
best, over 90% ees were obtained in the hydrogenation of
(E)-2,3-diphenylpropenoic acid and its methoxy and/or
fluorine derivatives using Pd catalysts modified by
cinchonidine (CD) (see Scheme 1) [21–25].
The enantioselectivities were influenced by the substit-
uents position. Acids substituted in para position on the
3-phenyl ring and in para or ortho positions on the
2-phenyl ring were hydrogenated in the highest enanti-
oselectivities [21–24]. The influence of the para-methoxy
substituent on the 3-phenyl is due to its electron releasing
mesomeric effect, which leads to increase in the basic
character of the carboxylate ion, hence interacting stronger
with the protonated CD when compared to the unsubsti-
tuted acid [26]. Few other alkoxy derivatives were also
tested resulting in decreased ee by replacing the methyl
group with n-octyl, but keeping the high ees in the presence
of 3-phenyl-n-propyl or Me(OCH2CH2)3 groups [24, 27].
In consequence, the optical purity of the alkoxy-substituted
2,3-diphenylpropionic acids prepared by this method was
Keywords Heterogeneous catalysis Á Asymmetric
hydrogenation Á Enantioselectivity Á Cinchonidine Á
2,3-Diphenylpropenoic acid Á Palladium Á Hydroxyl
substituent
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-012-0777-5) contains supplementary
material, which is available to authorized users.
} }
G. Szollosi (&)
Stereochemistry Research Group of the Hungarian Academy of
´ ´
Sciences, University of Szeged, Dom ter 8, Szeged H-6720,
Hungary
e-mail: szollosi@chem.u-szeged.hu
123

} }
G. Szollosi
346
2.2 Preparation of Hydroxy-substituted (E)-2,3-
diphenylpropenoic Acids
X
X
+ H2, Pd, CD
Y
Y
The substituted 2,3-diphenylpropenoic acids were prepared
by Perkin condensation using the corresponding benzal-
dehydes and phenylacetic acids [22, 23]. A stirred mixture
of the corresponding arylacetic acid (40 mmol), aldehyde
(40 mmol), 12 cm3 triethylamine and 8 cm3 acetic anhy-
dride was refluxed for 4–6 h. To the cooled mixture 12 cm3
conc. HCl solution was added followed by 30–40 cm3 cold
water; the precipitate was filtered and washed with cold
water. After drying the solid was dissolved in 1% NaOH
aqueous solution, the alkaline solution was stirred with
charcoal at room temperature and filtered. The solution was
acidified with 1/1 conc. HCl/water solution, the precipitate
was filtered and purified by several crystallization in eth-
anol–water mixtures. The isomer distribution of the crude
reaction products and the purity of the E isomers after
crystallizations were monitored by analytical TLC (Fluka
Silica gel TLC cards) and GC-MSD (Agilent Techn.
6890 N GC-5973 MSD, HP-1MS, 60 m capillary column)
analysis after methylation of both the carboxylic acid and
the phenolic group in 20% NaOH solution using
(CH3O)2SO2. The acids were identified and their purities
COOH
COOH
S
(2)
(1)
X, Y: H, OCH3 , F
ee > 90%, up to 96%
N
OH
H
H
S
R
(CD)
N
Scheme 1 Enantioselective hydrogenation of (E)-2,3-diphenylprop-
enoic acids over Pd catalyst modified by cinchonidine (CD)
influenced by the substituent position as well as by the
structure of the substituent.
A convenient method for obtaining alkoxy derivatives
could be the preparation of the corresponding hydroxy-
substituted compounds and their transformation follow-
ing the enantioselective hydrogenations. Moreover, the
presence of the free phenolic hydroxyl group provides
additional possibilities for obtaining synthetically useful
chiral intermediates. However, the enantioselective
hydrogenation of hydroxy-substituted (E)-2,3-diphenyl-
propenoic acids was not yet attempted. The aim of the
present study was the preparation of (E)-2,3-diphenyl-
propenoic acids substituted by hydroxyl group in various
positions and examination of their enantioselective
hydrogenation over Pd catalyst modified by CD, this way
broadening the scope of this asymmetric heterogeneous
catalytic system.
1
were checked by melting point measurements and by H-
and 13C-NMR spectroscopy using BRUKER AVANCE
DRX 400 NMR spectrometer (1H at 400 MHz, 13C at
100 MHz) in (CD3)2SO solution. The E isomers were
purified to 97–98% purities (for analytical data see the
Supplementary material).
2.3 Hydrogenation Procedure and Product Analysis
The hydrogenations were carried out under atmospheric H2
pressure at room temperature in a glass hydrogenation
apparatus equipped with a gas-burette and magnetic stirrer.
2 Experimental
The initial hydrogenation rates (rum, rm, rm,BA-1, rm,BA-2
;
2.1 Materials
where the subscript annotations stand for unmodified,
modified, modified with the addition of 1 or 2 equivalent
(eq) BA) were determined from the H2 up-take curves
between 0.05 and 0.15 mmol H2 consumption. In a typical
run 0.025 g catalyst and 3 cm3 DMF ? 2.5 vol% H2O
were placed in the reactor, the apparatus was flushed with
H2, the catalyst was pretreated by stirring for 0.5 h under
H2 followed by addition of 0.025 mmol CD (except in
hydrogenations over unmodified catalyst), 0.5 mmol
unsaturated acid, the given amount of BA (when used) and
another 2 cm3 solvent. The system was flushed with H2 and
the slurry was stirred under 0.1 MPa H2 pressure with
1,000 rpm. After the given time 5 cm3 methanol was
added, the catalyst was filtered and washed with 5 cm3
methanol.
The catalyst used was 5% Pd/Al2O3 (Engelhard, 40692,
BET 200 m2 g-1, Pd dispersion 0.21 [28]) reduced in H2
flow prior reactions as earlier described [22, 29]. Cincho-
nidine (CD, Alfa Aesar, 99%), benzylamine used as addi-
tive (BA, Fluka, C99.5%) and H2 gas (Linde AG,
99.999%) were used as received. Benzaldehyde and
phenylacetic acid derivatives for the preparation of (E)-2,3-
diphenylpropenoic acids were purchased from Aldrich and
used as received. The hydrogenations were carried out in
N,N-dimethylformamide (DMF, Scharlau, Multisolvent
grade) with 2.5 vol% distilled water. Solvents and reagents
of analytical grade were used in the preparation of unsat-
urated acids and product derivatizations.
123

Enantioselective Hydrogenation over Cinchonidine-modified Pd
347
OH
+ (MeO)2SO2
+ NaOH aq.
Me
HO
O
COOH
COOMe
(2)
Scheme 2 Product derivatization for GC analysis
COOH
COOH
COOH
(PCA)
(1a)
(1c)
Portions of products were methylated using (CH3O)2SO2
as follows (see Scheme 2). The methanol was evaporated
from 0.5 cm3 samples, 0.3 cm3 40% NaOH was added to
the product followed by addition of 0.1 cm3 of (CH3O)2SO2.
The mixture was shaken for few minutes accompanied by
increase in the temperature. The precipitated methoxy-
substituted methyl esters were extracted in tert-butyl methyl
ether. Identification and enantiomeric separation of the
methylated products was described previously [23]. Con-
versions (X) and ees were calculated based on GC-FID
analysis using chiral capillary column (Cyclosil-B, 30 m 9
0.25 mm, J & W Sci. Inc.) according to the formulae: X
(%) = 100 9 ([S-2] ? [R-2])/[10]; ee (%) = 100 9 |[S-2]-
[R-2]|/([S-2] ? [R-2]); where [S-2], [R-2] are the concen-
trations of the methylated product enantiomers and [10] is
the initial concentrations of the unsaturated acids. No other
products than the saturated acids were detected in the
resulting solutions and the reactions were reproducible
within 1%. The absolute configuration of the excess
enantiomer was assigned to be S by GC based on the pre-
viously published results obtained using methoxy-substi-
tuted 2,3-diphenylpropionic acids (see the Supplementary
material). Optical rotation measurements (Polamat A polar-
imeter) using the crude products showed the excess formation
of the dextrorotatory enantiomers in each reaction except the
racemic hydrogenations.
MeO
HO
HO
HO
COOH
(1b)
HO
COOH
MeO
COOH
(1d)
(1e)
Fig. 1 Selected hydroxy-(E)-2,3-diphenylpropenoic acids 1a–e
summarized in Table 1 and were compared with data
obtained with the unsubstituted (PCA) and the corre-
sponding methoxy-substituted acids (where available)
[22].
The acid substituted on the 2-phenyl ring in para posi-
tion (1a) was hydrogenated slower and provided higher ee
than PCA and the corresponding methoxy derivative both
in the absence and presence of 1 eq BA. Considering that
the 2-phenyl ring is tilted when the (E)-2,3-diphenylprop-
enoic acids are adsorbed on flat metal surface [23, 32], the
interaction of the hydroxyl group in 1a with the metal is
unlikely. In contrast with the unsubstituted and methoxy-
substituted acids decrease in the temperature resulted in
significant ee drop, as well as the use of 2 eq of BA. The
temperature affects several crucial reaction parameters,
such as the solubility of the reactants, the diffusion and
surface reaction rates, the adsorption, desorption processes
from unmodified and modified surface sites and the
hydrogenation of the modifier [33], just to mention the
most important [6, 9]. Thus, it is difficult to identify
the main reason of the observed ee decrease without further
kinetic studies. On the other hand the BA used in excess is
able to interact with the acidic Ph–OH group, forming
strongly basic phenoxide species. These may corrupt the
stereocontrol of the reaction by interacting with the pro-
tonated CD or due to the steric effect of the phenoxide–
benzylammonium ion pair. Further investigations are
planned to elucidate the interactions occurring under these
conditions, however, from practical point of view the
results obtained using 1 eq BA at 295 K are more
attractive.
3 Results and Discussions
The influence of the hydroxyl group was studied under
identical reaction conditions as applied for the hydroge-
nation of methoxy-substituted acids both in the absence
and presence of BA. The base additive as well as
decreasing the reaction temperature increases the ee in the
hydrogenations of the latter acids [22, 30, 31]. The ben-
eficial effect of the methoxy substituent was explained by
decrease in the acidity of the substrate due to its strong
electron releasing mesomeric effect. Accordingly, the
hydroxyl group with even stronger mesomeric effect
should give similar results. However, possible additional
interactions of the acidic Ph–OH group with the modifier
and/or the additive or alteration in the adsorption strength
of the acid by adsorption of the –OH group make the
results unpredictable. Compounds selected for the initial
study are shown in Fig. 1. Results of hydrogenations were
123

} }
G. Szollosi
348
Table 1 Hydrogenation of selected hydroxy-substituted (E)-2,3-diphenylpropenoic acid derivatives
rum; Xat ,b,c
rm; Xat ,c,d
rm,BA-1; Xat ,c,d
rm,BA-2; Xat ,c,d
ee (%)a
eeBA-1 (%)a,e
eeBA-2 (%)e
ee
(%)a,f
273
BAÀ1
Substrate
PCA [16]
51; 1001.5
9; 996
12; 996
–
70
73
80
–
1a
1b
1c
1d
1e
36 (45); 1002
8 (39); 1005
14; 1004
7 (11); 996
4 (8); 926
4; 958
9 (21); 996
5 (32); 946
3; 808
8; 986
3; 776
2; 728
5; 998
7; 986
75 (70)
67 (77)
70
78 (77)
68 (87)
73
61 (80)
66 (90)
70
48
61
71
87
85
22 (42); 1004
26; 1003
4 (6); 988
7; 996
8 (18); 995
13; 1006
75 (83)
85
90 (89)
89
82 (89)
88
Reaction conditions: 25 mg 5% Pd/Al2O3, 5 cm3 DMF ? 2.5 vol% H2O, 0.025 mmol CD, 0.5 mmol substrate, 0.1 MPa H2, 295 K
a
Values in brackets are previously published data obtained using the corresponding methoxy-substituted acids under identical conditions
included for comparison [22]
b
rum: initial H2 up-take rate (mmol h-1 g-1) over unmodified catalyst
c
Xt: conversions (%) reached in t (h) time
rm, rm,BA-1, rm,BA-2: initial H2 up-take rates (mmol h-1 g-1) over catalyst modified by CD in the absence, presence of 1 and 2 eq BA
d
e
eeBA-1, eeBA-2: enantiomeric excesses obtained in the presence of 1 and 2 eq of BA additive
273
BAÀ1
f
ee
: enantiomeric excess obtained in the presence of 1 eq of BA at 275 K
Replacement of the methoxy group on the 3-phenyl ring
aromatic ring and the O lone electron pairs [35]. Thus, the
anchoring effect of the phenolic group may cause a
decrease in hydrogenation rate over modified surface sites
leading to drop in the ee values when the methoxy sub-
stituent on the 3-phenyl ring is replaced by hydroxyl group.
The decrease in the ee observed in the presence of 2 eq BA
can be attributed to the interaction of the hydroxyl group
with BA. This interaction results in further alteration of the
acid adsorption and decrease in the number of the surface
chiral sites, affecting unfavourably the ee and the initial
rate.
by hydroxyl substituent either in meta or para position (1b
and 1d) resulted in significant decrease in the initial rates
and ees, the former acid providing even lower ee than
PCA. Addition of 1 eq BA had different effect on the
hydrogenation of the above two compounds, that is had
little influence on the hydrogenation of 1b, whereas
increased significantly both the initial rate and the ee value
in the reaction of 1d. Thus, the ee obtained in the hydro-
genation of the latter compound exceeded that obtained
with the corresponding methoxy derivative. The ee
decreased in the reaction of both acids by decreasing the
temperature or by using 2 eq of BA. It must be noted that in
the hydrogenation of the methoxy analog of 1d the ee was
constant in the presence of 0.5–2 eq BA [24]. The two
acids prepared from isovanillin and vanillin additionally
substituted by methoxy group on the 3-phenyl ring (1c and
1e) gave similar rate and ee trends as obtained with the
acids bearing the hydroxyl substituent in the same posi-
tions, i.e. 1b and 1d, respectively. However, the presence
of the additional methoxy group led to usually higher or at
least similar ees when compared with the mono-substituted
acids.
Comparison of the results obtained using 1b and 1d
clarify the still opened question of the surprisingly bene-
ficial effect of the meta substituents on the ee. It is known
that the meta-methoxy group affects in opposite way the
acidity of the substrate as the para, still their effect on
the ee is similar [22, 23]. According to the above results the
meta substituents influence the enantioselection in a dif-
ferent way, possibly by affecting the interaction strength of
the 3-phenyl ring with the surface. The electron donating
substituents in meta position increase the electron density
on the phenyl ring and consequently the adsorption
strength of the acid. Differences in the effect of BA on the
hydrogenation of meta and para substituted derivatives
also support the different origin of the ee increase in the
reactions of these compounds. Thus, the para substituents
influence the ee mainly by their effect on the acidity,
whereas the meta by affecting the adsorption strength of
the 3-phenyl moiety.
In contrast with the 2-phenyl ring the 3-phenyl moiety is
adsorbed close to parallel on the flat metal surface [32],
which implies the possible interaction of the substituents
with the Pd surface. The adsorption of anisole was found to
be stronger than that of benzene due to the effect of the
substituent on the charge density of the aromatic ring.
However, it was shown that the methoxy substituent does
not interact directly with the metal surface [34]. On the
contrary, phenol is adsorbed dissociatively on Pd surface
and the resulted phenoxide species coordinate close to
parallel to the surface interacting with the metal by the
The ee obtained in the hydrogenation of 1d in the
presence of 1 eq BA equalled that resulted in the hydro-
genation of the corresponding methoxy derivative. This
encouraged me to examine hydroxyl derivatives substituted
on both phenyl rings, since the best ees were obtained in
123

Enantioselective Hydrogenation over Cinchonidine-modified Pd
349
Fig. 2 The examined (E)-2,3-
diphenylpropenoic acids
1f–i substituted on both phenyl
OH
OMe
OMe
rings
F
HO
HO
MeO
MeO
COOH
COOH
COOH
(1f)
(1g)
(1i)
(
p,p-dMeO)
OH
OMe
COOH
HO
OMe
COOH
COOH
(1h)
(
o,p-dMeO)
Table 2 Results of hydrogenations of (E)-2,3-diphenylpropenoic acids substituted on both phenyl rings by methoxy or hydroxyl groups
Substratea
rum; Xbt ,c
rm; Xct ,d
rm,BA-1; Xct ,d
rm,BA-2; Xct ,d
ee (%)
eeBA-1 (%)e
eeBA-2 (%)e
(%)f
273
BAÀ1
ee
1f
10; 1005
29; 1004
8; 1005
6; 975
6; 946
4; 996
2; 848
3; 696
4; 858
1; 8520
8; 976
8; 996
5; 998
5; 926
4; 908
2; 9320
5; 856
61
86
80
78
83
87
69
89
82
83
90
91
67
90
82
81
92
90
66
p,p-dMeO
1 g
–
–
4; 978
5; 736, 3g; 66g6
78
69, 63g
1 h
o,p-dMeO
1i
8; 755
–
–
6; 936
1; 9220
92
Reaction conditions: 25 mg 5% Pd/Al2O3, 5 cm3 DMF ? 2.5 vol% H2O, 0.025 mmol CD, 0.5 mmol substrate, 0.1 MPa H2, 295 K
a
Results obtained with dimethoxy-derivatives (p,p-dMeO and o,p-dMeO) under identical reaction conditions [22]
rum: initial H2 up-take rate (mmol h-1 g-1) over unmodified catalyst
b
c
Xt: conversions (%) reached in t (h) time
rm, rm,BA-1, rm,BA-2: initial H2 up-take rates (mmol h-1 g-1) over catalyst modified by CD in the absence, presence of 1 and 2 eq BA
d
e
eeBA-1, eeBA-2: enantiomeric excesses obtained in the presence of 1 and 2 eq of BA additive
273
BAÀ1
Results obtained in the presence of 3 eq BA
f
ee
: enantiomeric excess obtained in the presence of 1 eq of BA at 275 K
g
the hydrogenation of such compounds [21–24]. Structures
of selected compounds and some of the corresponding
methoxy derivatives are shown in Fig. 2. The results
obtained in the hydrogenation of these acids are summa-
rized in Table 2.
evidence the interactions in which the hydroxyl substituent
on the 2-phenyl is involved.
Replacing either one or both methoxy substituent by
hydroxyl group in the para, para-dimethoxy substituted
acid (p,p-dMeO) had detrimental effect on both the ees and
the initial rates. Both hydroxy-substituted acids (1g and 1h)
were hydrogenated in lower ee when compared with p,p-
dMeO. Slightly lower ee values were obtained in the
hydrogenation of 1h with hydroxyl substituent on the
2-phenyl ring as compared with 1g. Both acids were
hydrogenated in similar optical purities at 294 and 275 K,
whereas, the ee decreased significantly when more than 1
eq of BA was used. The best enantioselectivities were
obtained in the hydrogenation of (E)-2-(2-methoxyphenyl)-
3-(4-hydroxyphenyl)propenoic acid (1i), which exceeded
those resulted in that of the corresponding dimethoxy-
derivative (o,p-dMeO) both in the absence and presence of
Disappointing ees were obtained in the hydrogenation of
1f, either when compared with 1a or with the corre-
sponding methoxy substituted acid (not shown, see [23]).
Thus, the beneficial effect of the fluorine substituent was
suppressed by the presence of the hydroxyl group on the
2-phenyl ring. The discrepancies observed in the effect of
the hydroxyl group on the 2-phenyl ring during the
hydrogenation of the mono- and di-substituted derivatives
(1a and 1f), showed that the effects of the substituents on
the two phenyl rings in this case are not additive as was
suggested to be in the hydrogenation of dimethoxy-
substituted compounds [15]. Further studies are needed to
123

} }
G. Szollosi
350
BA. Although, the ee decreased by decreasing the reaction
temperature, in the presence of 2 eq of BA up to 92% ee
was obtained, value reached only at 275 K with o,p-dMeO
under otherwise identical reaction conditions.
strongly basic phenolate anions, the ee decreased signifi-
cantly (except 1i). However, in the presence of 1 eq of BA
the ee always increased (with up to 15% in case of 1d).
These observations indicate that the 5 mol % excess of
additive (1 eq BA ? 5 mol % CD) was not interacting
with the phenolic group, otherwise a small decrease in the
ee should be observed. Accordingly, one may assume that
the excess BA will continue to be bonded to the cincho-
nidinium-carboxylate species and will participate in the
formation of the surface intermediate complex during the
enantioselective hydrogenation.
Finally, results obtained with the hydroxy-substituted
acids showed that this group in para position on the
3-phenyl ring has a similar effect as the methoxy group.
Thus, the ee increase observed with such acids has a
common origin, i.e. due to their electron releasing effect
the electron density on the conjugated acrylic acid moiety
increases, leading to more efficient acid–modifier interac-
tion on the surface. In contrast, the beneficial influence of
the meta positioned electron releasing substituents is sug-
gested to be due to their effect on the adsorption strength of
the 3-phenyl ring, as these substituents increase the elec-
tron density only on this phenyl ring. Additionally the
hydroxyl groups in either para or meta position also
influence the acids adsorption by their anchoring effect
thus affecting the stereochemical out-come of the hydro-
genations. It was shown that the latter effect is more
accentuated when the hydroxyl group is meta positioned,
whereas is less significant when is in para position due to
the extended conjugated system of the acid. The suggested
effects of the substituents in these positions are illustrated
schematically in Fig. 3.
4 Conclusions
The effect of replacement of the methoxy by hydroxyl
group in substituted (E)-2,3-diphenylpropenoic acids on
their enantioselective hydrogenation over Pd catalyst
modified by cinchonidine was examined. The hydrogena-
tion of mono-substituted acids bearing para-hydroxyl
group on the 2-phenyl or 3-phenyl ring provided similar or
better ee than the corresponding methoxy substituted acids.
It was shown that in the hydrogenation of acids substituted
on both phenyl rings the beneficial effect of the substituents
is not always additive, thus, only in the hydrogenation of
the (E)-2-(2-methoxyphenyl)-3-(4-hydroxyphenyl)prope-
noic acid the ee reached the value obtained with the cor-
responding dimethoxy derivative. However, this
asymmetric heterogeneous catalytic method was found to
be appropriate for the preparation of several hydroxy-
substituted (S)-2,3-diphenylpropenoic acids in good yields
and optical purities (see Fig. 4).
Furthermore, results obtained in the presence of BA
allowed drawing conclusions on the way this additive
influences the enantioselection. It was demonstrated that
BA increases the rate and ee by accelerating the desorption
of the saturated acid from chiral surface sites [30, 31]. The
hydroxy-substituted acids contain two acidic groups,
though of different acidities (pKa -COOH & 7; pKa -Ph-
OH & 10). In the hydrogenation of hydroxy-substituted
acids in the presence of 2 eq BA, when the additive surely
interacts with the phenolic hydroxyl group forming
The results obtained with the hydroxy-substituted acids
also shed light on the different origin of the influence of the
electron releasing substituents situated in meta or para
Fig. 3 Schematic illustration of
the substituent electronic effect
in the suggested surface
intermediate complexes:
(E)-2-phenyl-3-(4-
methoxyphenyl)propenoic acid-
CD (a), 1d-CD (b),
(E)-2-phenyl-3-(3-
methoxyphenyl)propenoic acid-
+
+
N
N
H
H
H
H
O
-
H3C
O
-
H
O
H
O
O
O
H
Q
Q
O
O
H
H
*
*
*
*
*
*
*
(B)
(A)
*
CD (c) and 1b-CD (d);
(Q = 4-quinolyl)
+
+
H3C
O
N
N
H
H
H
H
O
-
O
-
H
O
H
O
O
H
Q
Q
O
O
H
H
*
*
*
*
*
*
(D)
(C)
*
*
123

Enantioselective Hydrogenation over Cinchonidine-modified Pd
351
Fig. 4 Hydroxy-substituted
(S)-2,3-diphenylpropionic acids
HO
HO
HO
obtained in over 90% yield and
high optical purity
OMe
COOH
S
COOH
COOH
MeO
S
S
ee up to 89%
ee up to 92%
ee up to 90%
14. Maris M, Huck W-R, Mallat T, Baiker A (2003) J Catal 219:52
15. Sugimura T, Watanabe J, Okuyama T, Nitta Y (2005) Tetrahe-
dron Asymmetry 16:1573
position on the 3-phenyl ring, the former increasing the
adsorption strength of the acids, whereas the latter affecting
favourably the acidity of the substrate and consequently the
interaction strength with the modifier.
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Acknowledgments Financial support by the Hungarian National
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