Up to 96% enantioselectivities in the hydrogenation of fluorine substituted (E)-2,3-diphenylpropenoic acids over cinchonidine-modified palladium catalyst

Article abstract of DOI:10.1002/adsc.200800458

The enantioselective hydrogenation of methoxy-and fluorine-substituted (E)-2,3-diphenylpropenoic acid derivatives was studied over cinchonidine- modified, supported palladium catalysts in the absence and presence of benzylamine as additive. The fluorine substituent in the appropriate position was even more efficient than the methoxy group in increasing the optical purity of the saturated product. High enantioselectivities, up to 96%, were obtained in the hydrogenation of some disubstituted derivatives, unprecedented in the hydrogenation of prochiral unsaturated carboxylic acids over modified heterogeneous catalyst. The best optical purities were reached in the hydrogenation of derivates bearing a para-substituent on the β phenyl and an ortho-substituent on the a phenyl ring, respectively. The influence of the substituent on the β phenyl ring was attributed to the increase in the efficiency of the modifier-substrate interaction by electronic effects or to a decrease in the adsorption strength of the substituted acid over modified surface sites. The beneficial effect of the ortho-substituent on the a phenyl ring was assumed to be due to the additional interaction of this substituent with the modifier on the surface, its steric hindrance contributing only in a small part to the observed effect. These suggestions were supported by results obtained in the hydrogenations of some methyl-substituted derivatives.

Full text of DOI:10.1002/adsc.200800458

FULL PAPERS
DOI: 10.1002/adsc.200800458
Up to 96% Enantioselectivities in the Hydrogenation of Fluorine
Substituted (E)-2,3-Diphenylpropenoic Acids over Cinchonidine-
Modified Palladium Catalyst
a,
a,b
c
a,b
˝ ˝
Gyçrgy Szollosi, * Beꢀta Hermꢀn, Kꢀroly Felfçldi, Ferenc Fꢁlçp,
and Mihꢀly Bartꢂka,c
Research Group of Stereochemistry of the Hungarian Academy of Sciences, University of Szeged, H-6720 Szeged, Dꢂm
tꢃr 8, Hungary
a
Fax : (+36)-62-544-200; e-mail: szollosi@chem.u-szeged.hu
Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eçtvçs utca 6, Hungary
Department of Organic Chemistry, University of Szeged, H-6720 Szeged, Dꢂm tꢃr 8, Hungary
b
c
Received: July 24, 2008; Revised: October 20, 2008; Published online: November 17, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800458.
Abstract: The enantioselective hydrogenation of me- ence of the substituent on the b phenyl ring was at-
thoxy- and fluorine-substituted (E)-2,3-diphenylpro- tributed to the increase in the efficiency of the modi-
penoic acid derivatives was studied over cinchoni- fier-substrate interaction by electronic effects or to a
dine-modified, supported palladium catalysts in the decrease in the adsorption strength of the substituted
absence and presence of benzylamine as additive. acid over modified surface sites. The beneficial effect
The fluorine substituent in the appropriate position of the ortho-substituent on the a phenyl ring was as-
was even more efficient than the methoxy group in sumed to be due to the additional interaction of this
increasing the optical purity of the saturated product. substituent with the modifier on the surface, its steric
High enantioselectivities, up to 96%, were obtained hindrance contributing only in a small part to the ob-
in the hydrogenation of some disubstituted deriva- served effect. These suggestions were supported by
tives, unprecedented in the hydrogenation of prochi- results obtained in the hydrogenations of some
ral unsaturated carboxylic acids over modified heter- methyl-substituted derivatives.
ogeneous catalyst. The best optical purities were
reached in the hydrogenation of derivates bearing a Keywords: asymmetric hydrogenation; cinchonidine;
para-substituent on the b phenyl and an ortho-sub- diphenylpropenoic acid; fluorine; palladium; sub-
stituent on the a phenyl ring, respectively. The influ- stituent effect
Introduction
Following the exceptional results obtained in the
enantioselective hydrogenation of b-keto esters and
Optically pure carboxylic acids are valuable pharma- activated ketones over tartaric acid-modified Raney-
ceuticals or chiral building blocks used in the prepara- Ni[4,5] and Cinchona alkaloid-modified, supported Pt
tion of biologically active compounds.[1] Among the catalysts,[4,6] Cinchona alkaloid-modified Pd catalysts
simplest methods for the production of optically en- were developed for the enantioselective hydrogena-
riched chiral carboxylic acids and their derivatives are tion of prochiral olefinic compounds, particularly a,b-
the enantioselective catalytic hydrogenations of the unsaturated carboxylic acids[7,8] and 2-pyrone deriva-
corresponding prochiral unsaturated carboxylic tives.[9] The hydrogenation of a,b-unsaturated carbox-
acids.[2] The most widely used catalysts for these pur- ylic acids over cinchonidine (1)-modified Pd catalyst
poses are chiral homogeneous metal complexes.[2,3] was found to be highly substrate sensitive. The best
Due to the advantages of the heterogeneous catalytic enantioselectivities were obtained in the hydrogena-
systems, metal catalysts modified on the surface by tion of a-phenylcinnamic acid and its methoxy-substi-
optically pure compounds are attractive potential al- tuted derivatives.[10,11] As a result of the extended ef-
ternatives of the highly selective soluble complexes.[4] forts of Nitta and co-workers up to 92% enantiomeric
excess (ee) was obtained in the hydrogenation of (E)-
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Up to 96% Enantioselectivities in the Hydrogenation
FULL PAPERS
2,3-di(4-methoxyphenyl)propenoic acid in the pres- the preparation of fluorine-containing, optically pure
ence of benzylamine (2) as additive.[10d] The excellent chiral building blocks.[14] Among these are the enan-
ee values obtained in the hydrogenation of the para- tioselective hydrogenations of fluorinated prochiral
methoxy-substituted derivatives were explained by substrates.[15] Chiral heterogeneous catalysts, such as
the enhanced modifier-acid interaction due to the Pt modified by Cinchona derivatives, were found to
strong electron-releasing effect of the para-methoxy be efficient in the enantioselective hydrogenation of
substituents.
trifluoromethyl ketones[16,17] and even some a-fluoro
Recently, we reported that (E)-2-(2-methoxyphen- ketones.[18] The attempts on the hydrogenation of flu-
yl)-3-(4-methoxyphenyl)propenoic acid is hydrogenat- orine-containing, aliphatic a,b-unsaturated carboxylic
ed in even higher ee then the di-para-methoxy-substi- acids over Pd catalysts in the presence of 1 resulted in
tuted derivative.[11] We supposed that the favourable low optical yields,[7e,19] while the enantioselective hy-
effect of the methoxy substituents in the ortho-posi- drogenation of prochiral cinnamic acid derivatives
tion on the a phenyl ring was due to its steric effect. substituted with fluorine on the aromatic ring has not
Moreover, beside substitution in the para-position the yet been attempted.
meta-methoxy-substituent on the b phenyl ring also
In the present study we investigated the effect of
increased the enantioselectivity. It was suggested that fluorine and mixed fluorine and methoxy substitution
either the steric effect of the methoxy substituent or on both phenyl rings in (E)-2,3-diphenylpropenoic
an additional interaction with the modifier on the cat- acid in comparison with the unsubstituted form and
alyst surface could be the reason of the observed sub- some relevant methoxy-substituted derivatives. Beside
stituent effect. The hydrogen bond acceptor ability of the fluorine- and methoxy-substituted compounds, the
the methoxy group may further increase the strength effect of the methyl substituent in certain positions
of the modifier-acid interaction by additional hydro- was also examined to ascertain the role of the elec-
gen bonding.[11] The effect of the substituent on the tronic and steric effects of the substituents.
adsorption on the metal surface of the phenyl-substi-
tuted olefins[12] and consequently on the hydrogena-
tion rate of the acid or the 1-acid intermediate may Results and Discussion
also have an effect on the ee. Accordingly, we contin-
ued our investigation on the effect of substituents in The hydrogenation of (E)-2,3-diphenylpropenoic acid
different positions on both a and b phenyl rings in [(E)-3a] and its substituted derivatives over supported
order to explore the reason for the ee increase ob- Pd results in the formation of the corresponding 2,3-
served in the hydrogenation of methoxy-substituted diphenylpropionic acid derivatives. The solvent (DMF
derivatives, also attempting the extension of the scope with 2.5 vol% water) was selected according to previ-
of this highly effective heterogeneous asymmetric cat- ous studies.[10,11] Commercial 5% Pd/Al2O3 (Engelhard
alytic system.
40692) was chosen from a range of catalysts and was
Based on the above considerations, we chose to prereduced in flow of H2 at 523 K.[11] Complete con-
study the effect of fluorine substituents. Fluorine versions were reached in 1–4 h under 0.1 MPa H2
exerts smaller steric hindrance and has a stronger in- pressure at room temperature. In the presence of the
ductive electron-withdrawing coupled with a weaker chiral modifier 1 (5 mol%) under the same conditions
resonance electron-releasing effect as compared with the hydrogenations took 6–8 h (over 99% conver-
the methoxy group. As a consequence the effect of sions) and (S)-2,3-diphenylpropionic acid derivatives
the fluorine substituents on the ee may lead to new in- were formed in excess, as shown by the identical
sights into the interaction mode of the modifier with sense of rotation of the excess enantiomers (see
the unsaturated acid on the catalyst surface. More- Scheme 1). The enantioselective hydrogenations were
over, the hydrogen-bond forming ability of fluorine is carried out both in the absence and the presence of 1
weaker than that of oxygen. Although it was found equivalent of 2. This achiral additive increased the ee
that covalently bonded fluorine hardly ever accepts in the hydrogenation of a-phenyl- and a-alkylcinnam-
hydrogen bonds,[13] C F···H C weak contacts are ic acid derivatives[10,11] and aliphatic and cycloaliphatic
more frequent and these may also contribute to the unsaturated carboxylic acids.[8,19] Although the in-
enantiodiscrimination.[13a] Furthermore, the effect of crease in the ee seems to be a common feature of the
the additive 2 on the ee and initial rate may also pro- hydrogenations of prochiral carboxylic acids, the
vide useful information on the substrate-modifier in- effect of 2 on the initial rates showed that the influ-
ꢀ
ꢀ
teraction.
ence of this additive varies as a function of the sub-
Beside the expected mechanistic findings, the opti- strate structure. The initial rate and ee increase ob-
cally enriched fluorinated products are of high practi- tained in the hydrogenation of (E)-3a in the presence
cal importance. The exceptional chemical and phar- of 2 was attributed to acceleration of the desorption
maceutical properties of fluorinated compounds pro- of the saturated product from the modified sites of
moted the development of asymmetric methods for the catalyst, where the adsorbed (S)-3b interacts with
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FULL PAPERS
Similar phenomenon was described in the hydrogena-
tion of substituted anisole derivatives,[20] although, in
the present study the effect is smaller, as the substitut-
ed rings are not hydrogenated, but rather an adjacent
olefinic bond. A larger Ru decrease was observed in
the hydrogenation of the compounds substituted on
the a phenyl ring in the ortho-position, due to the ori-
entation of this ring.[11,21] The tilted arrangement of
this phenyl group with respect to the acrylic acid
moiety results in stronger hindering of the adsorption
on the C=C group by both the ortho-methoxy and the
ortho-fluorine substituent.
The initial rates in presence of 1 (Rm) decreased in
all these reactions as compared with the racemic hy-
drogenations. Higher ees were obtained in the reac-
tions of the acids substituted in the para-position on
the b phenyl ring [(E)-4a and (E)-5a)] and in the
Scheme 1. The enantioselective hydrogenation of substituted
(E)-2,3-diphenylpropenoic acid derivatives over 1 modified
Pd/Al2O3.
1. This indicated that the rate-determining step over ortho-position on the a phenyl ring [(E)-8a and (E)-
modified catalyst is the product desorption.[10b]
9a)] with respect to (E)-3a. On the other hand, the
Rm values decreased in the hydrogenation of the me-
thoxy-substituted compounds (E)-4a and (E)-8a,
while a surprising increase in Rm was observed as the
effect of fluorine in the same positions as compared
with (E)-3a. Substitution in the ortho-position on the
Hydrogenation of Methoxy- or Fluorine-
Monosubstituted Derivatives
The hydrogenations of (E)-2,3-diphenylpropenoic b phenyl ring [(E)-6a and (E)-7a)] decreased both
acids substituted on the a phenyl ring in the ortho-po- the Rm and ee, with the fluorine substituent affecting
sition or on the b phenyl ring in the ortho- or para-po- both values less than the methoxy group.
sition either with a methoxy group or with fluorine
The higher ee obtained in the hydrogenation of
was compared with that of the unsubstituted acid in (E)-4a as compared with (E)-3a was attributed to the
Table 1. In line with the small effect of the substitu- electron-releasing resonance effect of the methoxy
ents on the hydrogenation of phenyl-substituted ole- substituents in the para-position.[10c,11] However, the
fins described by Kieboom and van Bekkum,[12] the fluorine substituent in this position has an opposite,
initial rate over unmodified catalyst (Ru) decreased electron-withdrawing effect, as indicated by the sign
only slightly and in a similar extent as the effect of of the Hammett parameters (s para-CH3O=ꢀ0.27 or
both substituents in a given position on the b phenyl ꢀ0.17; s para-F=+0.06 or +0.15)[22,23] and also by
ring. The decrease is the consequence of the reduced the acidities of cinnamic acid and its fluorine-substi-
adsorption strength and accordingly the lower surface tuted derivative (cinnamic acid pKa =4.44; para-fluo-
concentration of the reaction intermediates formed rocinnamic acid pKa =4.21),[24] thus, will not increase
from the substituted acids as compared with (E)-3a. the interaction strength with 1. Furthermore, over un-
Table 1. Hydrogenation of monomethoxy- or fluorine-substituted (E)-2,3-diphenylpropenoic acids.[a]
[b]
[b]
[c]
[e]
Substrate
Substituent
R2
Ru
Rm
ee [%]
RA
eeA[d] [%]
RA/X[e]
eeA [%]
R1
(E)-3a[11]
(E)-4a[11]
(E)-5a
H
H
H
H
H
50.8
41.7
41.8
49.2
49.5
22.9
20.1
8.6
6.2
11.0
2.2
8.5
5.7
70
83
73
13
27
76
80
12.4
17.8
18.8
3.1
6.8
11.1
14.4
73
89
84
10
22
85
84
2.7/99
2.9/76
3.2/99
1.0/43
2.1/82
1.9/42
3.7/99
80
89
86
10
16
86
85
4-OCH3
4-F
2-OCH3
2-F
H
(E)-6a[11]
(E)-7a
H
(E)-8a[11]
(E)-9a
2-OCH3
2-F
H
11.0
[a]
Reaction conditions: 25 mg 5% Pd/Al2O3, 5 mL DMF+2.5 vol% H2O, 0.025 mmol 1, 0.5 mmol substrate, 0.1 MPa H2,
294 K, conversions of 98–100% in 2–8 h.
[b]
[c]
[d]
[e]
Inital rates [mmolhꢀ1 gꢀ1] obtained in the absence (Ru) and the presence of 1 (Rm).
Inital rates [mmolhꢀ1 gꢀ1] obtained in the presence of 1 and 0.5 mmol 2.
ee values obtained in the presence of 1 and 0.5 mmol 2.
Hydrogenation at 273 K in the presence of 1 and 0.5 mmol 2; X=conversion [mol%] reached in 8 h.
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Up to 96% Enantioselectivities in the Hydrogenation
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modified catalyst the two substituents had similar ef- 8a] and Rm, according to the train of thoughts pre-
fects on the initial rate, while in the presence of 1 sented before, this substituent increased the strength
these substituents had opposite effects on Rm.
of the modifier-acid interaction and decreased the ad-
The ee value obtained over a heterogeneous cata- sorption strength on the surface. While the methoxy
lyst is influenced by the fraction of the chiral surface group in this position had an anchoring effect of the
sites, the intrinsic enantiodifferentiating ability of a phenyl ring, fluorine impeded the strong contact with
surface chiral site and the ratio of the turnover fre- the surface. However, this effect cannot explain the
quencies on modified and unmodified sites (if the lower ee obtained with (E)-8a as compared with (E)-
fraction modified sites/total active sites <1). In the 9a. The combination of the aforementioned effect
reaction studied the fraction of the chiral sites is not with the formation of an additional interaction of the
influenced significantly by the substitution of the substituents in the ortho position on the a phenyl ring
acids. The enantiodifferentiating ability of a chiral site with adsorbed 1 via formation of a hydrogen bond
was improved by the methoxy substituents due to in- could be the cause of the observed results. Although
crease in the strength of the substrate-modifier inter- covalently bonded F is a weak hydrogen bond accept-
action,[10c] but not by the para-fluorine substituent. On or,[13] it was shown that it is able to form hydrogen
the other hand, the rate-determining step over modi- bond during hydrogenation leading to stabilization of
fied catalyst was shown to be the product desorp- a compound which had a crucial role on the outcome
tion.[10b] In this step the olefinic bond is already hy- of the reaction.[17] Moreover, recently it was suggested
drogenated.[12] Lacking the extended conjugated that in the enantioselective hydrogenation of 2,2,2-tri-
system the product interacts with the surface only via fluoroacetophenone over Pt the modifier interacts
+
ꢀ
ꢀ
the b-phenyl moiety and with 1 via the carboxylic with the substrate through a C F···H N (1) hydrogen
group. Accordingly, the fluorine substituent in the bond.[25] Although, in the hydrogenation of the unsa-
para-position on the b phenyl ring instead of enhanc- turated acids 1 is protonated by the substrate,[7,8] an
ing the interaction with the modifier, decreased the additional interaction of the substituent in the ortho
+
ꢀ
adsorption strength on the Pd surface leading to an position on the a phenyl ring either with the H N (1)
ꢀ
increase in the turnover frequency on the modified or with a H C(1) may explain the effect of these sub-
sites and consequently to a small increase in the ee. stituents. Another possible explanation could be the
Using 2 as additive resulted in an increase in ee and influence of these substituents on the dipole moment
initial rate (RA) in the hydrogenations of both (E)-4a (the orientation of the vector of the dipole moment)
and (E)-5a. Thus, the amine additive accelerated the of the acid molecule leading to a favourable effect on
desorption as suggested by Nitta of both saturated the modifier-acid interaction, as was suggested in the
acids.[10b]
hydrogenation of trifluoromethyl ketones over Pt.[13c]
The drastic ee and Rm decrease observed in the hy- Thus, further studies are needed to reveal the mode
drogenation of the ortho-methoxy-substituted (E)-6a of the interaction of 1 with the ortho-substituted com-
was explained by the substituent steric effect.[11] This pounds on the a phenyl ring.
was confirmed by the results obtained with (E)-7a.
A decrease in the hydrogenation temperature has a
The steric hindrance of the ortho-fluorine substituent beneficial effect on the ee in the hydrogenation of
on the b phenyl ring is much smaller than that of the various unsaturated carboxylic acids.[7,8,11] Increases in
methoxy group, thus it is reasonable to obtain a the ee were observed in the hydrogenations of both
higher ee in the hydrogenation of (E)-7a than in that methoxy- and fluorine-substituted compounds, except
of (E)-6a. The ortho substituents had a similar effect (E)-6a and (E)-7a (see Table 1). At low temperature
in the enantioselective hydrogenation of ring-substi- the initial rates decreased, however, the tendencies
tuted acetophenones over 1 modified Pt catalyst.[23]
observed at room temperature were kept. Under
The higher ee obtained in the hydrogenation of the these reaction conditions the ee obtained in the hy-
fluorine-substituted (E)-9a as compared with (E)-8a drogenations of the two ortho-substituted compounds
was surprising, as we supposed that the ee increase (E)-8a and (E)-9a were almost identical, while signifi-
observed in the hydrogenation of (E)-8a was mostly cant ee difference was observed in the hydrogenation
due to steric effects of the substituent.[11] Moreover, of (E)-4a and (E)-5a in favour of the methoxy-substi-
the Rm value obtained in the hydrogenation of (E)-9a tuted acid. These observations seem to confirm the
was higher as compared with (E)-3a. The electronic above suggestions on the role of these substituents.
effect of the substituents may be disregarded as a
plausible cause, as fluorine has an opposite electronic
effect than the methoxy group and the electronic Hydrogenation of Methoxy and Fluorine
effect of the substituents can be hardly felt due to the Disubstituted Derivatives
tilt of the a phenyl ring.[21]
As fluorine increased significantly both the ee The hydrogenations of (E)-2,3-diphenylpropenoic
[higher than in the hydrogenations of (E)-5a and (E)- acids substituted on both phenyl rings with two me-
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Table 2. Hydrogenation of disubstituted (E)-2,3-diphenylpropenoic acids bearing two methoxy or methoxy and fluorine sub-
stituents.[a]
[b]
[b]
[c]
Substrate
Substituent
Ru
Rm
ee [%]
RA
eeA[d] [%]
R1
R2
(E)-10a[11]
(E)-11a
(E)-12a
(E)-13a
(E)-14a[11]
(E)-15a
(E)-16a
(E)-17a
(E)-18a
4-OCH3
4-OCH3
4-F
4-F
2-OCH3
2-F
2-OCH3
2-OCH3
2-OCH3
4-OCH3
4-F
28.9
15.9
28.4
70.8
8.2
10.5
7.1
14.9
17.6
4.0
4.1
8.2
3.4
3.7
4.5
2.9
4.1
2.1
86
74
83
24
83
85
86
87
20
7.5
89
82
88
20
90
92
93
91
29
10.4
11.7
3.3
3.8
8.5
5.4
6.8
5.5
4-OCH3
2-OCH3
4-OCH3
4-OCH3
4-F
3-F
2-F
[a]
Reaction conditions: 25 mg 5% Pd/Al2O3, 5 mL DMF+2.5 vol% H2O, 0.025 mmol 1, 0.5 mmol substrate, 0.1 MPa H2,
294 K, conversions of 98–100% in 2–8 h.
[b]
[c]
[d]
Inital rates [mmolhꢀ1 gꢀ1] obtained in the absence (Ru) and the presence of 1 (Rm).
Inital rates [mmolhꢀ1 gꢀ1] obtained in the presence of 1 and 0.5 mmol 2.
ee values obtained in the presence of 1 and 0.5 mmol 2.
thoxy groups resulted in lower Ru and Rm, but higher derivatives (E)-8a and (E)-9a. Thus, 92% ee was ob-
ee than the monosubstituted derivatives, except when tained even at room temperature in the presence of 2.
the b phenyl ring was substituted in the ortho posi- These results confirmed the beneficial effect of the
tion.[10c,11] Next we examined the effect of replacement fluorine substituent in the ortho position on the a
of one of the methoxy substituents with fluorine. The phenyl. As discussed above the results may be ex-
results obtained at room temperature are summarized plained by a combination of decreasing the adsorp-
in Table 2 and compared with two dimethoxy-substi- tion strength by fluorine and the interaction of this
tuted compounds, (E)-10a and (E)-14a.
substituent with the adsorbed 1.
In the hydrogenations of the compounds substitut-
Even higher ee values were obtained when the
ed in both para positions the replacement of the elec- para-methoxy group on the b phenyl ring in (E)-14a
tron-releasing methoxy substituent on the b phenyl was replaced with fluorine [(E)-16a]. Thus, the effect
ring with fluorine [(E)-11a] decreased the ee as com- of fluorine in the para position was enough to reach
pared with the dimethoxy-substituted acid (E)-10a, high ee when an ortho substituent on the a phenyl
while in the hydrogenation of (E)-12a having the ring also enhanced the interaction of the acid with the
para-fluorine on the a phenyl ring similar ees were modifier. Moreover, similar results were obtained in
obtained as with (E)-10a. Accordingly, strong elec- the hydrogenation of (E)-17a with fluorine in the
tron-releasing groups are necessary in the para posi- meta position on the b phenyl ring. The surprisingly
tion on the b phenyl ring in order to obtain high ee, beneficial effect of both methoxy[11] and fluorine in
while the effect of the para substituent on the a this position is in contrast with the electronic effect of
phenyl ring is smaller. This confirmed the proposed these substituents. Both meta substituents have posi-
electronic effect of the substituent on the b phenyl tive Hammett parameters (s meta-CH3O=+0.15; s
ring due to the influence on the electron distribution meta-F=+0.35)[22,23] and lead to increased acidities as
along the conjugated system, while the substituents indicated by the pKa values of cinnamic acid and its
on the a phenyl ring barely have any effect. The shift meta-substituted derivatives (cinnamic acid pKa =
of the methoxy substituent on the b phenyl ring to 5.68; meta-metoxycinnamic acid pKa =5.62; meta-fluo-
the ortho position [(E)-13a] decreased the ee and Rm, rocinnamic acid pKa =5.44).[26] Thus, the electronic
similarly with the hydrogenation of all the compounds effect of the substituents in the meta position would
substituted either with methoxy group or with fluo- not increase the interaction strength with the modifi-
rine in this position, such as (E)-6a, (E)-7a and (E)- er. Although further studies are necessary to find the
18a, irrespective of absence or presence of other sub- explanation for the increased ee obtained in the reac-
stituents on the a phenyl ring.
tion of (E)-17a, we note that the higher initial rate
The best ee in our recent study was obtained in the obtained in this hydrogenation as compared with (E)-
hydrogenation of (E)-14a bearing a methoxy substitu- 16a may indicate that the substituents in the meta po-
ent in the ortho position on the a phenyl ring.[11] Re- sition hinder to some extent the adsorption of these
placement of the methoxy group in this position with acids. This could lead to a higher rate over modified
fluorine [(E)-15a] further increased the ee in accord- sites increasing the ee. This suggestion correlates with
ance with the hydrogenation of the monosubstituted the smaller increase obtained in the presence of 2 in
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Up to 96% Enantioselectivities in the Hydrogenation
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Scheme 2. Products obtained in the hydrogenation of selected methoxy- and fluorine-disubstituted (E)-2,3-diphenylpropeno-
ic acids in comparison with (E)-3a at 273 K in presence of 0.025 mmol 1 and 0.5 mmol 2. Reaction conditions: see Table 2; in-
itial rates [mmolhꢀ1 gꢀ1] are shown in parenthesis; conversions (X) and the reaction times necessary to reach these are given
below the structures.
the hydrogenation of (E)-17a as compared with (E)- than the methoxy group. This observation led us to in-
16a. We stress that both the meta and para substitu- vestigate the hydrogenations of some difluorine-sub-
ents on the b phenyl ring led to excellent ee only stituted derivatives (see Table 3).
when their effect was complemented with the effect
The enantioselective hydrogenation of the di-para-
of the ortho substituent on the a phenyl ring. As men- fluorine substituted compound (E)-19a resulted in ee
tioned before it is also possible that these substituents values close to that obtained in the reaction of (E)-
affected the dipole moments of the unsaturated acids, 11a, lower than in the reaction of (E)-10a or (E)-12a.
thus, both the meta and para substituents leading to This confirmed our previous observation that the
increase in the efficiency of the 1-acid interaction.
para-fluorine substituent on the b phenyl ring is less
According to these results high enantioselectivities efficient in enhancing the modifier-acid interaction
can be obtained in the hydrogenations of disubstitut- than the methoxy group, also supporting our interpre-
ed compounds bearing methoxy and fluorine substitu- tation of the effect of the substituents in this position.
ents in appropriate positions. The ee values increased Similar, but slightly higher ee values were obtained in
a few percent by decreasing the reaction temperature the hydrogenation of (E)-20a, with the substituent in
(see Scheme 2). Although, under these reaction con- the meta position, accompanied with much higher Rm
ditions, the initial rates were low, full conversions and RA, as compared with (E)-19a, similarly as in the
could be obtained by extending the hydrogenation hydrogenation of (E)-17a in comparison with that of
time without altering the stereochemical outcome of (E)-16a. This demonstrated that the effect of the meta
the reactions. Under these conditions the saturated substituent on the b phenyl ring is general and inde-
products could be prepared in excellent, up to 93– pendent from the position of the substituent on the a
96%, optical purities [see Scheme 2, (S)-13b, (S)-14b phenyl ring. In light of the findings described in the
and (S)-15b], unprecedented in the enantioselective previous subsections the low ee obtained in the reac-
hydrogenation of prochiral carboxylic acids over tion of (E)-21a as an effect of the ortho position of
modified heterogeneous catalyst.
the fluorine on the b phenyl ring could be anticipated.
Higher ee values were obtained when the position
of the fluorine was changed to ortho on the a phenyl
ring [(E)-22a and (E)-23a]. Similar results were ob-
tained as in the hydrogenations of (E)-16a and (E)-
Hydrogenation of Difluorine Derivatives
Comparison of the results obtained in the hydrogena- 17a, although, in the hydrogenation of the difluorine
tion of the derivatives disubstituted with both fluorine substituted compounds the para-fluorine substituent
and methoxy groups with those obtained in the reac- was also more efficient in the absence of 2. The fa-
tion of the corresponding dimethoxy derivatives indi- vourable effect of the fluorine substituent was evi-
cated that the fluorine substituent in certain com- denced even more by the results obtained at lower
pounds is even more efficient in increasing the ee temperature (see Scheme 3). Thus, in the hydrogena-
Adv. Synth. Catal. 2008, 350, 2804 – 2814
ꢄ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2809

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Gyçrgy Szollosi et al.
FULL PAPERS
Table 3. Hydrogenation of disubstituted (E)-2,3-diphenylpropenoic acids bearing fluorine substituents on both phenyl
rings.[a]
[b]
[b]
[c]
Substrate
Substituent
Ru
Rm
ee [%]
RA
eeA[d] [%]
R1
R2
(E)-19a
(E)-20a
(E)-21a
(E)-22a
(E)-23a
4-F
4-F
4-F
2-F
2-F
4-F
3-F
2-F
4-F
3-F
14.4
24.1
33.5
8.9
4.8
14.0
6.9
4.8
10.2
73
78
27
86
84
8.5
26.7
5.9
10.5
11.9
84
85
25
91
87
16.5
[a]
Reaction conditions: 25 mg 5% Pd/Al2O3, 5 mL DMF + 2.5 vol% H2O, 0.025 mmol 1, 0.5 mmol substrate, 0.1 MPa H2,
294 K, conversions of 98–100% in 2–8 h.
[b]
[c]
[d]
Inital rates [mmolhꢀ1 gꢀ1] obtained in the absence (Ru) and the presence of 1 (Rm).
Inital rates [mmolhꢀ1 gꢀ1] obtained in the presence of 1 and 0.5 mmol 2.
ee values obtained in the presence of 1 and 0.5 mmol 2.
tion of fluorine-substituted (E)-2,3-diphenylpropenoic
acids as in the reaction of the methoxy-substituted de-
rivatives. This is surprising considering the small steric
hindrances and the electron-withdrawing effect of flu-
orine, however, the additional interactions of this sub-
stituent in some position either with the modifier or
the surface increased the ee. Confirmation of the sug-
gestions explaining the substituent effects was sought
for by continuing our study with examining the effect
of a substituent having a different character as those
examined.
Hydrogenation of Methyl-Substituted Derivatives
The methyl group has an electron-releasing inductive
effect, practically no hydrogen bonding ability and an
intermediate steric effect between the methoxy group
Scheme 3. Products obtained in the hydrogenation of select-
ed difluorine-substituted (E)-2,3-diphenylpropenoic acids at
273 K in the presence of 0.025 mmol 1 and 0.5 mmol 2. Re-
action conditions: see Table 3; initial rates [mmolhꢀ1 gꢀ1] are
shown in parenthesis; conversions (X) and the reaction
times necessary to reach these are given below the struc-
tures.
and fluorine. The methyl group in the para position
on the b phenyl ring [(E)-24a] having a negative
Hammett parameter (s para-CH3 =ꢀ0.13)[22] and
slightly increasing the acidity [(E)-3a pKa =7.00; (E)-
24a pKa =6.99],[27] increased the ee both in the ab-
sence and in the presence of 2 as compared with (E)-
3a, although this increase was much smaller than that
in the reaction of (E)-4a (see Table 4). Extremely in-
tion of (E)-22a a similarly high ee (96%) was obtained formative are the initial rates obtained in the reac-
under these reaction conditions as in that of (E)-16a, tions of (E)-24a. The identical Ru with (E)-4a and
the highest value reached up to now in this reaction. (E)-5a and the higher Rm as compared even with the
The initial rates usually exceeded those obtained in fluorine-substituted acid supported our previous sug-
the hydrogenations of the methoxy-substituted deriva- gestions. Thus, it became unambiguous that the elec-
tives, even at decreased temperature, in accordance tronic effect of the para substituent on the b phenyl
with the weaker adsorption of the fluorine-substituted ring is of paramount importance for increasing the ef-
compounds. We note that the hydrogenation of the di- ficiency of the interaction with 1 and obtaining good
fluorine derivatives evidenced even more the higher ee. Furthermore, the steric effect of the substituent
efficiency of the ortho substituents on the a phenyl caused the weaker adsorption of (E)-24a on modified
ring in increasing the ee in comparison with the sub- sites leading to increased Rm and contributing to the
stituents in the para position on the same ring.
increase in the ee.
According to these results similarly high or even
The methyl group in the ortho position on the a
higher ee values may be obtained in the hydrogena- phenyl ring [(E)-25a] did not lead to significant ee
2810
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Adv. Synth. Catal. 2008, 350, 2804 – 2814

Up to 96% Enantioselectivities in the Hydrogenation
FULL PAPERS
Table 4. Effect of the methyl substituent on the hydrogenation of (E)-2,3-diphenylpropenoic acids.[a]
[b]
[b]
[c]
[e]
Substrate
Substituent
R2
Ru
Rm
ee [%]
RA
eeA[d] [%]
RA/X[e]
eeA [%]
R1
(E)-24a
(E)-25a
(E)-26a
(E)-27a
(E)-28a
(E)-29a
H
4-CH3
H
4-CH3
4-F
4-CH3
4-CH3
41.9
16.8
6.6
5.8
13.3
11.1
15.9
7.4
3.0
2.8
8.1
4.8
74
71
76
75
81
77
20.4
13.6
2.5
5.2
6.9
76
75
77
84
84
89
3.3/84
2.5/83
0.8/40
1.7/85
1.8/87
1.1/62
80
81
83
84
85
89
2-CH3
2-CH3
2-CH3
2-F
2-OCH3
2.8
[a]
Reaction conditions: 25 mg 5% Pd/Al2O3, 5 mL DMF+2.5 vol% H2O, 0.025 mmol 1, 0.5 mmol substrate, 0.1 MPa H2,
294 K, conversions >95% in 2–8 h.
[b]
[c]
[d]
[e]
Inital rates [mmolhꢀ1 gꢀ1] obtained in the absence (Ru) and the presence of 1 (Rm).
Inital rates [mmolhꢀ1 gꢀ1] obtained in the presence of 1 and 0.5 mmol 2.
ee values obtained in the presence of 1 and 0.5 mmol 2.
Hydrogenation at 273 K in the presence of 1 and 0.5 mmol 2; X=conversion [mol%] reached in 8 h.
and initial rate increase as compared with (E)-3a. bearing a para substituent on the b phenyl and an
This confirmed that neither the electronic nor the ortho substituent on the a phenyl ring, respectively.
steric effects of the substituents in this position were
It was suggested that the substituent on the b
decisive, but the formation of an additional interac- phenyl ring influenced the ee by its electronic effect
tion between the ortho substituents having lone elec- and by its effect on the adsorption strength on the Pd
tron pairs and the modifier is responsible for obtain- surface. Thus, an electron-releasing substituent de-
ing an ee increase in the hydrogenation of the com- creased the acidity of the substrate and consequently
pounds substituted in this position. Similar conclusion increased the interaction efficiency with the modifier.
may be drawn from the ee obtained in the hydrogena- A substituent in this position which decreases the ad-
tion of (E)-26a and (E)-27a, the former giving only sorption strength of the acid may also lead to an in-
slightly higher ee than (E)-24a and the latter having a crease in ee by increasing the rate on the modified
similar behaviour as (E)-5a. On the contrary, when sites. The two effects may act in opposite directions as
fluorine or methoxy group was situated in the ortho in the case of both methoxy and fluorine substituents.
position on the a phenyl ring in the presence of a The beneficial effect of the ortho substituent on the a
para-methyl group on the b phenyl ring [(E)-28a and phenyl ring was not related to its electronic and only
(E)-29a] the ee increased significantly, reaching slight- in small part to its steric effect. We assumed that the
ly higher values than in the hydrogenation of (E)-8a increased enantioselectivity was due to the ability of
and (E)-9a and significantly increased ees as com- the methoxy or fluorine substituents to form addition-
pared with (E)-24a. These observation supported al interactions with the modifier on the surface. These
again the rationalization of the effects of the methoxy suggestions were supported by results obtained in the
and fluorine substituents.
hydrogenations of several methyl-substituted deriva-
tives.
Most important, the present study is the first re-
porting enantioselectivities up to 96% in the hydroge-
nation of unsaturated carboxylic acid derivatives over
Conclusions
We have studied the enantioselective hydrogenation a heterogeneous catalyst in presence of chiral modifi-
of methoxy- and fluorine-substituted (E)-2,3-diphe- ers. The pharmaceutical importance of the optically
nylpropenoic acid derivatives over cinchonidine-modi- pure carboxylic acids and the increased interest in the
fied, supported Pd catalyst in the absence and pres- preparation of fluorinated chiral compounds may lead
ence of benzylamine as additive. The results showed to practical applications of this convenient, highly
that a fluorine substituent in some positions may be enantioselective procedure.
as efficient or even more efficient than the methoxy
group in increasing the optical purity of the resultant
saturated products. Enantioselectivities up to 96%
Experimental Section
were obtained in the hydrogenation of some methoxy-
and fluorine-disubstituted or difluorine-substituted
derivatives, unprecedented in the hydrogenation of
prochiral unsaturated carboxylic acids over modified
heterogeneous catalysts. The highest enantioselectivi-
Materials
The 5% Pd/Al2O3 was purchased from Engelhard (40692)
and used after reducing in a 30 cm3 minꢀ1 H2 flow at 523 K
ties were reached in the hydrogenation of derivatives for 100 min as in our previous study.[11] Cinchonidine (ꢁ
Adv. Synth. Catal. 2008, 350, 2804 – 2814
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asc.wiley-vch.de
2811

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Gyçrgy Szollosi et al.
FULL PAPERS
Scheme 4. Preparation of substituted (E)-2,3-diphenylpropenoic acid derivatives.
98%) and benzylamine (ꢁ99.5%) were commercial prod-
ucts (Fluka) and were used as received. (E)-2,3-Diphenyl-
propenoic acid (Aldrich, ꢁ97%) was purified by crystalliza-
tion in acetone-water, N,N-dimethylformamide (Scharlau,
Multisolvent, HPLC grade) was used without purification.
The benzaldehyde and phenylacetic acid derivatives, acetic
anhydride and triethylamine used in the preparation of the
(E)-2,3-diphenylpropenoic acid derivatives were purchased
from Aldrich or Fluka and used as received.
into the reactor, the apparatus was flushed with H2 and the
catalyst was pretreated in situ by stirring (1000 rpm) for
0.5 h. After pretreatment 0.025 mmol 1, 0.5 mmol unsaturat-
ed acid, 0.5 mmol 2 (when used) and another 2 cm3 solvent
were added, the system was flushed again with H2 and the
reaction was started by turning on the stirring. Unless other-
wise noted over 98% conversions were obtained in 1–4 h
during hydrogenations in the absence of modifier and in 6–
8 h over modified catalyst.
After the H2 uptake ceased the precipitated products
(when formed) were dissolved by addition of 5 cm3 metha-
nol, the catalyst was filtered, washed with another 2 portions
of methanol and the combined filtrates were concentrated
under reduced pressure. Small portions of these products
were transformed into methyl esters using concentated
H2SO4 in methanol and/or CH2N2 ethereal solution. The re-
sulting compounds were identified by GC-MS analysis. Con-
versions and enantiomeric excesses (ee) were determined by
GC analysis using a HP 5890 II GC-FID and a 30 m chiral
capillary column (Cyclosil-B). The enantiomeric excess
(ee%) was calculated with the formulae ee%=100ꢅj
[S]ꢀ[R]j/([S]+[R]), where [S] and [R] are the concentra-
tions of the product enantiomers. In cases where the separa-
tion of the methyl ester enantiomers was incomplete (few
compounds), samples of the products were transformed into
(R)-2-butyl and (S)-2-butyl esters using (R)-2-butanol and
(S)-2-butanol (Fluka, ꢁ98%), respectively and the ee was
calculated after separation of the diastereomers using the
same chiral capillary column. Repeated experiments gave ee
values reproducible within ꢂ1%.
Preparation of the Substituted (E)-2,3-
Diphenylpropenoic Acids
The substituted (E)-2,3-diphenylpropenoic acid derivatives
were prepared by Perkin condensation as previously de-
scribed using the corresponding benzaldehydes and arylace-
tic acids (see Scheme 4).[11,28] A stirred mixture of arylacetic
acid (40 mmol) and aromatic aldehyde (40 mmol) in 4 cm3
triethylamine and 8 cm3 acetic anhydride was refluxed for 2–
6 h. To the cooled mixture 9 cm3 concentated HCl solution
and 30–40 cm3 water were added, the precipitate was filtered
and washed with cold water. After drying the solid was dis-
solved in 1% NaOH aqueous solution and the alkaline solu-
tion was stirred with charcoal in an ice bath and filtered.
For the separation of isomer acids the alkaline solution was
gradually acidified with 1/1 concentrated HCl/water solu-
tion. If the reaction product after acidification was semi-
solid or oil, it was dissolved in diethyl ether (200–250 cm3).
The ethereal solution was extracted with 1% NaOH solution
and the alkaline solution was treated as above. The isomer
acids were further purified by crystallization in ethanol or
ethanol-water. The isomer distribution of the crude reaction
products and the purity of the prepared acids were moni-
tored by analytical TLC (Fluka silica gel/TLC cards, eluent
hexane-acetone) and GC-MS analysis (as methyl esters pre-
pared using CH2N2 ethereal solution, GC-MS: Agilent
Techn. 6890N GC-5973 MSD, HP-1MS, 60 m capillary
column). The purities of the acids (>98%) were checked by
1H- and 13C NMR spectroscopy using a Bruker Avance
DRX 500 NMR instrument (1H at 500 MHz, 13C at
125 MHz) in (CD3)2SO solution.
The remaining products were taken up in 1 cm3 10% HCl
solution in 9 cm3 water, the crude acids were extracted with
3 portions of 5 cm3 diethyl ether or CHCl3, the combined or-
ganic layers were dried over Na2SO4 and the solvent was
evaporated to give the crude saturated acids in over 90%
yields as pale yellow oils or solids in ꢁ98% purity as deter-
mined by GC-MS and GC analysis of their methyl esters.
The optical purity of these crude products was the same as
determined for the corresponding samples analyzed before
work-up. The absolute configurations of the excess enantio-
mers of unsubstituted and methoxy-substituted 2,3-diphenyl-
propionic acids were assigned in previous studies to be S.[10]
The configuration of the excess enantiomers resulting in the
hydrogenation of the other compounds has not yet been de-
termined, however, based on the same rotation sign and
similar chromatographic behaviour, we assume that also the
S enantiomers were formed in excess. Optical rotation meas-
urements using a Polamat A polarimeter showed that all
products contained the dextrogir enantiomers in excess.
Catalytic Hydrogenations and Product Analysis
The hydrogenations were carried out in batch reactors
under atmospheric H2 pressure in a glass hydrogenation ap-
paratus using magnetic stirring. The H2 consumption up to
25% of the total H2 uptake was used for calculations of the
initial rates taking into account the fast hydrogenation of
the vinyl group of 1. In a typical run 0.025 g reduced catalyst
and 3 cm3 DMF containing 2.5 vol% water were introduced
2812
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Adv. Synth. Catal. 2008, 350, 2804 – 2814

Up to 96% Enantioselectivities in the Hydrogenation
FULL PAPERS
Pfaltz, M. Studer, H.-U. Blaser, Adv. Synth. Catal. 2003,
345, 1253–1260; e) M. Bartꢂk, Curr. Org. Chem. 2006,
10, 1533–1567.
Supporting Information
Spectroscopic and analytical data of the unsaturated acids
and their methyl esters, the analytical data of the saturated
products are available in the Supporting Information.
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Acknowledgements
Financial support by the Hungarian National Science Foun-
dation (OTKA Grants T 048764 and K 72065) is highly ap-
preciated. Gy. Sz. is grateful for the financial support of HAS
through Bolyai Jꢀnos Research grant.
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