New synthesis of optically active α-arylpropanoic acid: The asymmetric hydrogenation of atropic acid over cinchona-modified Pd/Fe2O3 catalysts

Article abstract of DOI:10.1081/SCC-120015697

The first satisfactory application of the heterogeneous cinchona-modified Pd/Fe₂O₃ catalyst system in the synthesis of optically active α-arylpropanoic acid, namely, the highly enantioselective (up to 87% ee) hydrogenation of atropic acid to S-(+)-naproxen is described.

Full text of DOI:10.1081/SCC-120015697

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New Synthesis of Optically Active α-Arylpropanoic
Acid: The Asymmetric Hydrogenation of Atropic Acid
over Cinchona-Modified Pd/Fe2O3 Catalysts
H.-Zh. Ma a , B. Wang a b & Q.-Zh. Shi a
a College of Chemistry and Materials Science , Shaanxi Normal University , Xi'An, P.R., China
b College of Chemistry and Materials Science , Shaanxi Normal University , 710062, Shaanxi
Province, Xi'An, P.R., China
Published online: 21 Aug 2006.
To cite this article: H.-Zh. Ma , B. Wang & Q.-Zh. Shi (2003) New Synthesis of Optically Active α-Arylpropanoic Acid: The
Asymmetric Hydrogenation of Atropic Acid over Cinchona-Modified Pd/Fe2O3 Catalysts, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:2, 175-182, DOI: 10.1081/SCC-120015697
To link to this article: http://dx.doi.org/10.1081/SCC-120015697
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 2, pp. 175–182, 2003
New Synthesis of Optically Active
a-Arylpropanoic Acid: The Asymmetric
Hydrogenation of Atropic Acid over
Cinchona-Modified Pd/Fe2O3 Catalysts
*
H.-Zh. Ma, B. Wang, and Q.-Zh. Shi
College of Chemistry and Materials Science, Shaanxi Normal
University, Xi’An, P.R. China
ABSTRACT
The first satisfactory application of the heterogeneous cinchona-
modified Pd/Fe2O3 catalyst systemin the synthesis of optically
active a-arylpropanoic acid, namely, the highly enantioselective (up
to 87% ee) hydrogenation of atropic acid to S-(þ)-naproxen is
described.
Key Words: a-Arylpropanoic acid; Cinchona; Catalyst; S-(þ)-
Naproxen.
*Correspondence: B. Wang, College of Chemistry and Materials Science,
Shaanxi Normal University, 710062, Xi’An, Shaanxi Province, P.R. China.
Fax: 0086 029 8373492; E-mail: wangbo@nwu.edu.cn.
175
DOI: 10.1081/SCC-120015697
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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176
Ma, Wang, and Shi
The increasing use of chiral compounds has raised the profile of
asymmetric synthesis, in particular the environmentally more friendly
heterogeneous enantioselective hydrogenations.[1,2] One of them, the
industrially useful chiral catalysts based on 2,20-bis(diarylphosphino)-
1,10-binaphthyl (BINAP) rutheniumsystem, was found to be effective
in the hydrogenation of unsaturated carboxylic acids to optically active
saturated carboxylic acids. The chiral hydrogenation in the synthesis of
S-(þ)-naproxen provides excellent enantioselectivity (up to 99% ee) and
chemical yield (92%) by using BINAP-Ru dicarboxylate complexes,[3]
but the relatively high pressures (135–150 atm) may present a practical
limitation. In recent years new methodologies have also been studied such
as asymmetric methylation of 2-arylacetic acids, asymmetric
hydroformylation/hydrocarboxylation of the appropriate styrene deriva-
tives, asymmetric alkylation of appropriate aromatic compounds.
Unfortunately, the optical yields in these latter cases are far from
excellent.
To widen the cinchonidine-Pt-Al2O3 catalyzed hydrogenation,[4–6]
here we report our initial findings on enantioselective hydrogenation of
atropic acid in the presence of cinchona-modified Pd/Fe2O3. The enan-
tioselectivity of this reaction has been optimized by change the prepara-
tion method of an easily cinchona-modified Pd/Fe2O3 catalyst system,
and good optical yield was obtained. Atropic acids are an important class
of substrates for this reaction because the resulting a-arylpropanoic acids
are a variety of commercially important non-steroidal anti-inflammatory
agents. Because of its current commercial importance, we chose atropic
acid as substrates for our initial studies. In sharp contrast to the well-
known hydrogenation catalyzed by (S)-BINAP–Ru(III) complex,[1,4] the
asymmetric hydrogenation of atropic acid over cinchona-modified
Pd/Fe2O3 (CN-Pd/Fe2O3) carried out according to the Sch. 1 show,
gave the corresponding (S)-(þ)-naproxen with unprecedented enantio-
selectivity.
Atropic acid itself has already been reduced to the corresponding
optically active compounds by chiral phosphine rhodium complexes,[7]
Scheme 1.

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a-Arylpropanoic Acid
177
ruthenium[3] or enzymatic resolutions.[8] Although each method is
satifactory, in cost or simplicity they cannot be compared to the
cinchona-modified Pd-catalyzed hydrogenations.
Note that Fe2O3 is inactive for the reaction and Pd and Pd/Fe2O3
exhibit relative high active but no chiral product produced, the cinchona-
modified Pd/Fe2O3 catalyst show both active and enantioselective
in the heterogeneous hydrogenation, indicating that cinchona is the
origin of asymmetric induction for the asymmetric hydrogenation of
atropic acid.
Taking into account the fact that the different preparation methods
of the catalysts have been applied, it was necessary to find the most
suitable strategy to prepare the efficiency catalyst.
In our experiment three preparation methods were adopted and the
results with or without CN cinchona-modified are listed in Table 1. The
synthetic methods are as follows: catalyst(I) was prepared by simply
mixing Pd and Fe2O3. Catalyst(II) was prepared by using PdCl2 instead
of Pd, reduced by HCHO in the mixture of Fe2O3 and NaOH. Using
Fe(Ac)3Á6H2O and PdCl2 as starting material, catalyst(III) was prepared
by co-precipitation from the mixture solution of starting material.
For catalyst(I), the Pd active center is just on the surface of Fe2O3
and no or little interaction can be formed between Pd and Fe or O
atom, results in the ee of the hydrogenation product is less than 3%
(Table 1, Entry 3). In the second methodology much Pd is ‘‘dispersed’’
on the surface of Fe2O3 and exist a little interaction of Pd with Fe or O
atom, the ee of the product is up to 10% (Table 1, Entry 4). For
catalyst(III) the ee’s up to 15% (Table 1, Entry 5). When modified
with CN, the reaction rates and the optical yield are greatly increased
(Table 1, Entries 6–8).
For the model reaction, the influence of substrate, solvent, and modi-
fier concentration were also investigated. According to the ee data the
enantioselectivity seems to be strongly solvent dependent. It was found
that the application of CN provides the higher optical yields in methanol.
In our opinion this significant solvent dependence is a result of the
weaker absorption of atropic acids in the case of benzene (6ꢀ electrons
vs. 2ꢀ electrons). While using methanol the substrate can form an ester
with the solvent as pointed out for atropic acid. However, the increase is
more pronounced in benzene than in methanol, for which only a slight
increase was observed.
The reaction rates of the modified and the unmodified system were
compared in methanol. The modified reaction all take place at
higher rates than the unmodified one as Table 1 show, indicating a

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178
Ma, Wang, and Shi

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a-Arylpropanoic Acid
179
ligand accelerated mechanism. As a result, the highest enantioselectivity
was obtained at the highest reaction rate (Table 1, Entry 8). However,
explaining the roles of geometrical and electronic factors is not possible at
this level of the study.
Figure 1 shows the dependence of ee and rates on the modifier con-
centration. Both curves had a similar shape and could be modeled with a
simple kinetic model assuming reversible but strong absorption of the
modifier on the Pd surface. As expected, the ee values are rather low at
low modifier concentration, it is probably because the modifier is hydro-
genated and thereby made ineffective during the course of the reaction.
In this way, both ibuprofen and flurbiprofen can be prepared in
excellent optical purity (Table 1, Entry 10,12), and no further optimiza-
tion is needed.
The present study provides the first experimental proof that atropic
acid can be hydrogenated with excellent optical yields over cinchona-
modified Pd catalysts. Since the synthetic importance of S-(þ)-naproxen
as useful anti-inflammatory agents is well-known, this new, environ-
mentally friendly method for their preparation may even widen their
applications.
In conclusion, the cinchona-modified Pd/Fe2O3 catalytic systemwas
found to be effective in the enantioselective hydrogenation of atropic
acids, providing the opportunity to still widen the practical applications
and potential of this unique and important catalytic system.
Figure 1. Enantiomeric excess and rates vs. modifier concentration: cinchona-
modified 5% Pd/Fe2O3 (30 mg) catalyst(III) system at 20ꢁC ((^) rate, (f) ee
value).

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180
Ma, Wang, and Shi
EXPERIMENTAL
General Methods and Materials
The Pd and Fe contents in the catalysts were obtained by inductively
coupled plasma atomic emission spectroscopy (AES) using ICP/6500
fromPerkin–Elmer Inc. The crystallinity of the sample was determined
by powder X-ray diffraction (XRD) using a scanning diffractometer of
D/MAX-RA with Ni-filtered CuK a radiation (ꢁ ¼ 1.5418 A). A scan
speed of 2ꢁ/min was used comparing with the intensity of the reflection
pattern to that of pure sample. The surface area and pore size distribution
of the samples were determined by N2 adsorption–desorption at À197ꢁC
on previously degassed samples at RT and 10À4 torr pressure for BET
surface area and meso-micropore analysis, macropore analysis was
obtained by Hg intrusion, the pore size distribution of the samples was
calculated in accordance with the BJH method.
Preparation of Pd/Fe2O3 Catalyst
The preparation of Pd/Fe2O3 catalyst (Pd/Fe ¼ 1/4, mol/mol) fol-
lows[7] and described below.
Catalyst(I): The quantities of Pd (2.35 mmol, 0.2488 g) and Fe2O3
(4.70 mmol, 0.7511 g) were mixed carefully and dried at 200ꢁC/2 h.
Catalyst(II): Into 30 cm3 water solution of PdCl2 (2.35 mmol,
0.416 g), Fe2O3(4.70 mmol, 0.525 g) were suspended and 20 cm3 of
HCHO (30%, m/m) was dropped in then 20 cm3 of 20% NaOH solution
were added and stirred for about 30 min, the solid were filtered and
washed with water (3 Â 20 cm3), dried at 100ꢁC in vacuo (80 mmHg),
finally the sample were roasted at 280ꢁC in air for 3 h after cooled
before use.
Catalyst(III): Into 50 cm3 water solution of PdCl2 (2.35 mmol,
0.416 g), and Fe(Ac)3Á6H2O (9.4 mmol, 3.206 g), 20 cm3 of HCHO
(30%, m/m) were dropped in with stirring, then 50 cm3 of 20% NaOH
solution were added and stirred for about 30 min, the solid were filtered
and washed with demineral water (3 Â 30 cm3), dried at 100ꢁC in vacuo
(80 mm Hg), finally the sample were roasted at 280ꢁC in air for 3 h after
cooled before use.
The physical characteristics of the catalysts along with their
compositions are shown in Table 2, which shows that the surface areas
and pore volumes are increased in the catalyst in comparison with the

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a-Arylpropanoic Acid
Table 2. Physical characteristics of the Pd/Fe2O3 catalysts.
181
Fe Content
(g/gcat.
Pd Content
(g/gcat.
SBET
(m2/g)
Vp
(cm3/gcat.
Catalysts
)
)
)
XRD Peak
Pd
Fe2O3
Catalyst(I)
Catalyst(II)
Catalyst(III)
0
0.08
0.0547
0.0547
0.0548
0.05
0
0.0259
0.0259
0.0258
150
260
280
265
360
0.08
0.35
0.50
0.56
0.58
Pd
Fe2O3
Pd/Fe2O3
Pd/Fe2O3
Pd/Fe2O3
corresponding Pd(0) or Fe2O3. The XRD pattern of Pd/Fe2O3 catalyst
shows peaks arising frommetallic Pd(0) and Fe 2O3.
Asymmetric Hydrogenation of Atropic Acid by Pd/Fe2O3 Catalysts
In a typical reaction, a solution of atropic acid (0.228 g, 1.0 mmol) in
10 mL methanol and Pd/Fe2O3 (0.085 g, contains Pd, 0.0003 mmol) were
added to a 50 mL three-neck flask fitted with an inert gas inlet and reflux
condenser, then H2 (10 Kg/cm2, 25ꢁC) was introduced and the reaction
mixture was analyzed by GC and HPLC after 4 h. The ee value of the
product was determined (on a sample filtered through silica gel; ether/
hexane) by HPLC using Daicel Chiralcel column: 10% ether/hexane,
2 mL/min, 25ꢁC. The ee values were reproducible to within 1%. The
eluting enantiomer was determined to be S isomer by comparison with
25
pure sample (Ref. [5]. M.p. 155ꢁC, ½ꢂꢂD ¼ þ 65ꢁ, c ¼ 1, CHCl3).
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Received in the Netherlands December 10, 2001