Concise Synthesis of 2-Arylpropanoic Acids and Study of Unprecedented Reduction of 3-Hydroxy-2-arylpropenoic Acid Ethyl Ester to 2-Arylpropenoic Acid Ethyl Ester by BH3·THF

Article abstract of DOI:10.1002/hlca.201500062

We have developed a concise method of synthesizing racemic arylpropanoic acids, which have been widely used as nonsteroidal anti-inflammatory drugs (NSAIDs). The synthesis involves only four steps from commercially available benzaldehyde. The synthesis incorporates an unprecedented reduction reaction, conversion of 3-hydroxy-2-arylpropenoic acid ethyl ester to 2-arylpropenoic acid ethyl ester by BH₃·THF. The reduction reaction has been investigated and optimized.

Full text of DOI:10.1002/hlca.201500062

Helvetica Chimica Acta – Vol. 98 (2015)
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Concise Synthesis of 2-Arylpropanoic Acids and Study of Unprecedented
Reduction of 3-Hydroxy-2-arylpropenoic Acid Ethyl Ester to
2-Arylpropenoic Acid Ethyl Ester by BH3 · THF
by M. Shahid Islam, Syarhabil Ahmad, Mary Rose Attu, F. Holger Foerstering, and
M. Mahmun Hossain*
Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee,
WI 532011, USA (phone: þ 1414-229-6698; fax: þ 1414-229-5530; e-mail: mahmun@uwm.edu)
We have developed a concise method of synthesizing racemic arylpropanoic acids, which have been
widely used as nonsteroidal anti-inflammatory drugs (NSAIDs). The synthesis involves only four steps
from commercially available benzaldehyde. The synthesis incorporates an unprecedented reduction
reaction, conversion of 3-hydroxy-2-arylpropenoic acid ethyl ester to 2-arylpropenoic acid ethyl ester by
BH3 · THF. The reduction reaction has been investigated and optimized.
Introduction. – 2-Arylpropanoic acids (profens) are very important compounds and
have been widely used as nonsteroidal anti-inflammatory drugs (NSAIDs) for the
relief of acute and chronic rheumatoid arthritis and osteoarthritis, as well as for other
connective tissue disorders and pains [1]. NSAIDs primarily inhibit the binding of
arachidonic acid to the cyclo-oxygenase subunit of prostaglandin synthetase, and
prevent the formation of various prostaglandins and thus control the inflammatory
response [2]. Examples of some of the profens are fenoprofen, ibuprofen, ketoprofen,
flurbiprofen, and naproxen. All of the profens are chiral and, except (S)-naproxen and
(S)-flunoxaprofen, they are marketed in racemic form [3]. Although profen is a
successful and widely used drug, it can cause some serious side effects, such as gastric
intestinal (GI) disturbances, gastric or duodenal ulceration, dizziness, skin rash, and
tinnitus, etc. [4]. The side effects related to gastroenteropathies are generally believed
to be resulted from the direct contact effect, which can be attributed to the combination
of local irritation produced by the free carboxylic group in the molecular structure and
by local blockage of prostaglandin biosynthesis in the GI tract [5]. Thus, it is very
important to synthesize a variety of profen analogues so that the side effects could be
minimized. For example, recently, it has been reported that the methyl-monofluori-
nated ibuprofen was found to have an almost equal pharmacokinetic profile with an
increased analgesic activity and diminished gastric damage in animal models comparing
to the parent drug ibuprofen [6].
A number of synthesis routes are available for the preparation of both racemic [7]
and optically active profens [8]. Most of these methods are applicable for a particular
type of profen and some of them are not cost effective. In this article, we will present a
general procedure to produce racemic arylpropanoic acids and their prochiral
precursors in a few steps and also a study to understand the mechanism of an
unprecedented reduction reaction, conversion of 3-hydroxy-2-arylpropenoic acid ethyl
ꢀ 2015 Verlag Helvetica Chimica Acta AG, Zürich

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ester 2 to 2-arylpropenoic acid ethyl ester 3 by BH3 · THF. Our method can be used to
synthesize the optically pure profens by enantioselective hydrogenation of the
prochiral precursors [9a – 9e] or by enantiomeric resolution of the racemic profens
[9f – 9j].
The synthesis involves a three-step transformation to prepare 2-arylpropanoic acid
5 from 3-hydroxy-2-arylpropenoic acid ethyl ester 2 (Scheme 1). The starting material,
3-hydroxy-2-arylpropenoic acid ethyl ester 2, was synthesized from the corresponding
benzaldehyde 1 according to the method developed in our lab [10][11]. Reduction of
the hydroxypropenoic acid ethyl ester 2 to propenoic acid ethyl ester 3 was achieved by
using BH3 · THF. The olefin was then hydrogenated to give 2-arylpropanoic acid ester 4,
which was then hydrolyzed to give the desired 2-arylpropanoic acid 5.
Scheme 1. Preparation of 2-Arylpropanoic Acids from Aromatic Aldehyde
Results and Discussion. – To improve the overall yields for the final product 5, we
studied and optimized the synthetic procedure. The reaction described in step 1 is
reported elsewhere [10] and will not be discussed here.
Optimization of the Step 2. Previously, our lab reported the reduction of 3-hydroxy-
2-(6-methoxy-2-naphthyl)propenoic acid ethyl ester to 2-(6-methoxy-2-naphthyl)pro-
penoic acid ethyl ester by using BH3 · THF, as a method to synthesize a naproxen
precursor [11]. This time, we wanted to establish this methodology as a general method
for preparing 2-arylpropenoic acid ethyl esters 3. To our delight, we were able to apply
this methodology to convert a number of hydroxypropenoic acid ethyl esters 2 to their
corresponding olefins 3 using BH3 · THF in the presence of an amine catalyst. Initially,
we carried out the reaction using piperidine as the catalyst. The reaction was carried out
at À 208 for 12 h using 1.2 equiv. of BH3 · THF. After the aqueous workup and column
chromatography, 2-arylpropeonic acid ethyl esters 3 were isolated in 20 – 61% yield
(Table 1). As per our observation, the electron-withdrawing or electron-releasing
groups have no effect on the yield of the product. To improve the yield, we investigated
the nature and amount of catalysts and also temperature on this BH3 · THF reduction
reaction.
Effect of Catalysts. Originally, piperidine was used as the catalyst for the conversion
of hydroxypropenoic acid ethyl ester 2 to propenoic acid ethyl ester 3. The amine is very
important for this reduction reaction [11]. In order to improve the yield of the olefin,

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Table 1. Piperidine-Catalyzed Reduction of Hydroxyarylpropenoic Acid Ester
Entry
R
Product
Yield of isolated product [%]
1
2
3
4
2-NO2 (2b)
3b
3c
3d
3e
61
40
20
30
3,4-OCH2O-6-NO2 (2c)
2-Cl-5-NO2 (2d)
4-MeO (2e)
we performed the reduction reaction with several amines such as piperidine, CBS
catalyst, 2-aminophenol, and Et3N. The reaction was carried out at À 208 for 12 h with
1.2 equiv. of BH3 · THF in presence of 10% amine. Among these bases, the racemic
CBS catalyst afforded the best yield of 70% (Table 2). The CBS catalyst was prepared
in the lab following procedures by Corey [12] and was used without further purification.
2-Aminophenol and Et3N (Entries 3 and 4, Table 2) gave low yields, and a considerable
amount of starting material was left in the reaction mixture after 12 h. Increasing amine
loading to 20% lowered the yield even more. We believe that this happened due to the
fact that the amine binds to BH3, thus reducing the activity of the reagent and as a
result, lowered the yield of the reaction.
Table 2. Catalyst Screening
Entry
Catalyst
Yield of isolated product [%]
1
2
3
4
Piperidine
CBS catalyst
2-Aminophenol
Et3N
50
70
10
20
Amount of BH3 · THF. In order to determine the optimum BH3 · THF concen-
tration, we studied the reduction with various amounts of BH3 · THF. The reduction
was carried out using the standard reaction condition as described previously, and
the results are depicted in Table 3. From this study, we concluded that 1.2 equiv. of
BH3 · THF per equiv. of hydroxypropenoic acid ester are required to obtain the best
yield of the product. However, excess BH3 · THF lowers the yield of the olefin product,
as it further reacts with BH3 · THF to give an unidentified complex.

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Table 3. Optimization of the Amount of BH3 · THF
Entry
BH3 · THF [equiv.]
Yield of isolated product [%]
1
2
3
4
5
0.5
1
1.2
2
0
50
70
40
0
3
Effect of Temperature. In our next effort, we studied the temperature effect on the
yield of the product of the reduction. The results are summarized in Table 4. From
this study, BH3 · THF was found to be inactive at À 788 and did not produce any olefin
3a. At À 208, the reaction gave the best result and the aryl propenoic acid ethyl
ester was obtained in 65% yield. At 08, the reaction was almost comparable to the yield
at À 208, whereas no olefin was obtained, when the reduction was performed at 408, but
some unidentified products were formed.
Table 4. Temperature Screening
Entry
Temperature [8]
Yield of isolated product [%]
1
2
3
4
À 78
À 20
0
0
65
60
0
40
Step 2 with Optimized Reaction Condition. The outcome of our experiments for the
optimization of the yield for the reduction step suggest that 1) the optimal amount of
BH3 · THF should be 1.2 equiv; 2) the choice of catalyst should be 10% CBS; and 3) the
preferred temperature should be 08. Although reactions both at À 208 and 08 gave the
similar results, we choose to run the reaction at 08 rather than at À 208, mainly due to
the ease of operation. With these optimal reaction conditions, we tried the reduction for
a number of hydroxypropenoic acid ethyl esters using the CBS catalyst. The results are
presented in Table 5. The yields of the corresponding olefins were good, around ca.
70%. The electron-donating or -withdrawing substituents on the hydroxyacrylate have
no effect on the yield of the olefin product.

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Table 5. Optimized Reduction of Hydroxyarylpropenoic Acid Ethyl Ester
Entry
R
Product
Yield of isolated product [%]
1
2
3
4
5
6
H (2a)
3a
3f
3g
3h
3i
60
70
66
69
65
70
2-MeO (2f)
4-Me (2g)
2-Br (2h)
2-Me (2i)
2,4-Cl2 (2j)
3j
Hydrogenation of Arylpropenoic Acid Ethyl Ester to Arylpropanoic Acid Ethyl
Ester (Step 3). The third step was the hydrogenation on the propenoic acid ester 3 to
the propanoic acid ester 4. This procedure employs the typical hydrogenation reaction
using palladium on carbon as the catalyst at 45 psi for four hours in MeOH. The yields
were very high (ca. 90%), and purification was also simple. The catalyst was removed
using Celite, and pentane was added to elute the product. Rotary evaporation of the
solvent gave pure 2-arylpropanoic acid ethyl esters in high yields (Table 6).
Hydrolysis of Arylpropanoic Acid Ethyl Esters 4 to Arylpropanoic Acids 5 (Step 4).
The final step in the synthesis was to hydrolyze the ester group to an acid group.
Aqueous KOH was added in acetone and the mixture was allowed to stir overnight at
room temperature. After reaction was completed, the mixture was washed with Et2O.
The aqueous layer was acidified with aqueous HCl and extracted with Et2O (three
Table 6. Hydrogenation Reaction of Propenoic Acid Ethyl Ester
Entry
R
Product
Yield of isolated product [%]
1
2
3
4
5
6
H (3a)
4a
4f
4g
4h
4i
95
95
90
95
93
84
2-MeO (3f)
4-Me (3g)
2-Br (3h)
2-Me (3i)
2,4-Cl2 (3j)
4j

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Table 7. Hydrolysis of Arylpropanoic Acid Ethyl Ester
Entry
R
Product
Yield of isolated product [%]
1
2
3
4
5
6
H (4a)
5a
5f
5g
5h
5i
92
90
93
90
95
90
2-MeO (4f)
4-Me (4g)
2-Br (4h)
2-Me (4i)
2,4-Cl2 (4j)
5j
times). The Et2O layer was dried using anhydrous MgSO4, and the solvent was
removed by rotary evaporation to produce the product 5 as white solid. The yield for
this hydrolysis was almost quantitative (Table 7).
Study of the Mechanism of BH3 · THF Reduction of Hydroxyarylpropenoic Acid
Ethyl Ester. In our initial study towards the mechanism of Step 2, i.e., reduction of
hydroxypropenoic acid ethyl ester 2 to propenoic acid ethyl ester 3, we identified and
characterized a novel dihydroborane intermediate 6 (Scheme 2) [13]. Here, we would
like to report the further development of our study to understand this unprecedented
transformation.
Hydride Migration. After the formation of the dihydroborane intermediate 6, a
hydride shift from BH3 is needed to obtain the final product, propenoic acid ethyl ester
3. This hydride migration could happen in an (a) intra- or (b) inter-molecular process,
as shown in Scheme 3.
Scheme 2. Formation of Dihydroborane Intermediate 6
Scheme 3. Plausible Hydride Migration in the Reduction Reaction

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In our previous article [13], we proposed that hydride migration occurs through
intermolecular fashion (path b). The evidences for this argument were: 1) when 0.5
equiv. of BH3 was used, no olefin was formed, once all BH3 was used up. This assump-
tion was verified by repeating the reaction using only 0.5 equiv. of BH3, which showed
very clearly that olefin formation ceased once all BH3 had been consumed; and 2) when
BD3 was used as reactant, NMR spectra of the olefin 3a formed under those conditions
showed that the deuterium was incorporated in the cis and trans positions in equal
amounts, which is more likely to occur in an intermolecular rather than intramolecular
hydrogen transfer step. Here, we performed more experiments to further prove that the
hydride migration more likely occurs via the intermolecular process.
Since the intermediate 6 is very unstable, air- and temperature-sensitive, we aimed to
synthesize more stable boron intermediates similar to the intermediate 6, and we used
catechoboron or 9-boronbicyclo[3,3,1]nonane (BBN). In addition, catechoboron or BBN
have only one b-H hydrogen, and no intramolecular hydride shift is possible in such case.
Reaction of the Acrylate with Catechol Borane. A reaction was carried out using 2
equiv. of catechol borane and 1 equiv. of 2a at 08. As usual, H2 gas evolved vigorously.
In the NMR spectrum, the OH peak of 2 had disappeared instantly. We observed a new
peak around 8.1 ppm (Fig. 1), which was characterized to belong to intermediate 7. This
intermediate was stable, and no formation of compound 3 was observed. After few
hours, we added 1 equiv. of BH3 · THF, and we observed new peaks corresponding to
the olefin 3. Initially, the olefin peak was rising, as the intermediate peak was
decreasing, and after several hours, we found the olefin peak decreasing along with the
intermediate peak. This is due the further reaction of the olefin.
Reaction of the Acrylate with 9-BBN. A similar NMR study was carried out using 2
equiv. of 9-BBN and 1 equiv. of 2a at 08. As usual, H2 evolved, and the signal of the OH
group of ester 2 disappeared. We observed a new peak around 7.9 ppm (Fig. 2) which
was attributed to the complex 8. This intermediate 8 seemed to be stable, however no
olefin 3 were observed. After few hours, we added 1 equiv. of BH3 · THF, and new peaks
corresponding to the olefin was observed. Initially, the olefin peak was rising as the
intermediate peak was decreasing, and after several hours, we found that the olefin
peak was decreasing along with the intermediate peak. This is due to the further
reaction of the olefin. These two experiments present further evidence that the hydride
shift occurs in intermolecular fashion.
Role of H2O in the Reduction. In our previously proposed mechanism [11], we
assumed that H2O is required for the formation of product, and to verify this
speculation, we added D2O to find out whether the H in the olefin comes from H2O or
not. After analysis of the product, we did not find any incorporation of deuterium in the
product. We also observed that, when we were monitoring the reaction in the NMR
tube, we found the formation of product without the addition of H2O. We assumed that
H2O is not required for the reaction, and it is only useful to quench the reaction that
removes the excess of boron compounds.
Effect of Hydride Source. In order to check if the reaction occurs with an other
hydride source, we tried the reaction under standard conditions with various hydrides
such as LiAlH4 and DIBAL-H at different temperatures. But none of these reducing
agents gave the desired olefin. These experiments suggest that the reduction is specific
to BH3 · THF.

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Fig. 1. Long-range optimized 1H{11B} HSQC experiment (mixing time 12.5 ms) of a 2 :1 mixture of
catechol-borane and hydroxypropenoic acid ethyl ester 2 after one hour at 268 K. The correlation arising
from intermediate 7 is highlighted.
Conclusions. – In conclusion, a general method for the synthesis of prochiral
arylpropenoic acid ethyl ester has been developed. These prochiral precursors of
profens were synthesized in two steps with good yields, and these compounds can be
converted to the respective optically active profens by asymmetric hydrogenation. A
method to achieve the racemic profens is also provided. These racemic profens can be
converted to optically active profens by chiral resolution.

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1
Fig. 2. Long-range H{11B} HMBC spectrum (mixing time 50 ms) of a 2 :1 mixture of 9-BBN and the
hydroxypropenoic acid ethyl ester 2 after 24 h at room temperature (298 K). Correlations from the
intermediate 8 are highlighted.
Experimental Part
General Considerations. All operations were performed under a dry N2 atmosphere with standard
Schlenk techniques. Column chromatography (CC): silica gel (SiO2; 40 – 140 mesh). HPLC grade CH2Cl2
was distilled under N2 from P2O5. HPLC grade pentane was distilled from Na under an inert atmosphere
immediately prior to use. Reagent grade Et2O and THF were freshly distilled under a N2 atmosphere
from sodium benzophenone ketyl. Compounds 2a, 2b, 2c, 2d, 2e, 2g, and 2j were synthesized by the

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known published procedure [10][11]. NMR Data: Bruker 300 MHz instrument: the chemical shifts (d)
are expressed in ppm relative to tetramethylsilane, and CDCl3 was used as the solvent. Elemental
analyses: Perkin-Elmer 240C elemental analyzer was employed.
General Procedure for the Preparation of 3-Hydroxy-2-aryl Propenoic Acid Ethyl Esters (2). In a
typical experiment, 1 equiv. of aromatic aldehyde (3 – 6 mmol) was dissolved in 20 – 30 ml of freshly dist.
CH2Cl2 under N2. Then, 0.3 – 0.6 mmol (0.l equiv) of catalyst HBF4 · OEt2 was added and stirred for
several minutes and cooled down to the temp. required from À 788 to 08. Then, 1.2 equiv. of ethyl
diazoacetate (EDA) was diluted with 5 – 15 ml of CH2Cl2 and dripped slowly from a gas-tight syringe
using a syringe pump over a period of 7 – 18 h. After the addition was complete, NMR and TLC were
taken to check if the reaction was complete. If not, the mixture was stirred for more hours, until no more
starting material was observed. The reaction was stopped by passing through a SiO2 plug and the solvent
removed using rotary evaporation. The products were isolated by CC (2 – 20% Et2O in pentane).
1H-NMR was recorded and compared to literature values.
3-Hydroxy-2-(2-methoxyphenyl)propenoic Acid Ethyl Ester (¼ Ethyl 3-Hydroxy-2-(2-methoxyphe-
nyl)prop-2-enoate; 2f) [14]. From 2.00 g (14 mmol) of o-anisaldehyde, 2.01 g (17.63 mmol) of EDA, and
1
0.2 ml (1.4 mmol) of HBF4 · OEt2 at À 788. Yield: 95%. H-NMR (CDCl3, 300 MHz): 12.10 (d, J ¼ 13,
1 H, OH); 7.50 (d, J ¼ 13, 1 H, ¼CH); 7.00 – 7.70 (m, 4 H, Ph); 4.26 (q, J ¼ 7, 2 H, OCH2); 3.80 (s, 3 H,
MeO); 1.29 (t, J ¼ 7, 3 H, Me).
3-Hydroxy-2-(2-bromophenyl)propenoic Acid Ethyl Ester (¼ Ethyl 2-(2-Bromophenyl)-3-hydroxy-
prop-2-enoate; 2h) [15]. From 1.5 g (8.1 mmol) of 2-bromobenzaldehyde, 1.11 g (9.7 mmol) of EDA, and
1
0.11 ml (0.81 mmol) HBF4 · OEt2 at À 788. Yield: 89%. H-NMR (CDCl3, 300 MHz): 11.99 (d, J ¼ 13,
1 H, OH); 7.70 (d, J ¼ 13, 1 H, ¼CH); 7.20 – 7.40 (m, 4 H, Ph); 4.25 (q, J ¼ 7, 2 H, OCH2); 1.32 (t, J ¼ 7, 3 H,
Me).
3-Hydroxy-2-(2,5-dichlorophenyl)propenoic Acid Ethyl Ester (¼ Ethyl 2-(2,5-Dichlorophenyl)-3-
hydroxyprop-2-enoate; 2i) [14]. From 2.0 g (11.4 mmol) of 2,5-dichlorobenzaldehyde, 1.56 g (13.7 mmol)
1
of EDA, and 0.15 ml (1.14 mmol) of HBF4 · OEt2 at À 788. Yield: 60%. H-NMR (CDCl3) 300 MHz):
12.06 (d, J ¼ 13, 1 H, OH); 7.20 – 7.60 (m, 4 H, ¼CH and Ph); 4.22 (q, J ¼ 7, 2 H, OCH2); 1.25 (t, J ¼ 7, 3 H,
Me).
General Procedure for Reduction of 3-Hydroxy-2-arylpropenoic Acid Ethyl Esters 2 to 2-
Arylpropenoic Acid Ethyl Esters 3. In a typical experiment, 1 equiv. of 3-hydroxy-2-arylpropenoic ethyl
ester 2 was dissolved in 20 – 30 ml of freshly dist. THF under N2. Then, 0.1 equiv. of CBS catalyst or
piperidine was added. Then, the soln. was cooled to 08 and 1.2 equiv. of BH3 · THF were added and the
progress of the reaction was monitored using TLC and NMR. The mixture was kept at 08 for 5 – 6 h, until
the enol peak had disappeared. Then, the reaction was quenched with 10 ml of H2O, and the mixture was
stirred for several min. THF was removed by rotary evaporation, and the residue was extracted with
Et2O. Removal of the Et2O yielded a liquid product. CC was performed using 1 – 2% Et2O in pentane to
obtain the product in 50 – 70% yield.
Piperidine-Catalyzed Reduction of 3-Hydroxy-2-arylpropenoic Acid Ethyl Esters 2 with BH3 · THF.
2-(2-Nitrophenyl)propenoic Acid Ethyl Ester (¼ Ethyl 2-(2-Nitrophenyl)prop-2-enoate; 3b). From 0.5 g
(2.1 mmol) of ethyl 3-hydroxy-2-(2-nitrophenyl)prop-2-enoate (2b), 3.8 ml (3.8 mmol) of BH3 · THF, and
42 ml (0.42 mmol) of piperidine at 08. Yield: 61%. 1H-NMR (CDCl3, 300 MHz): 8.04 (d, J ¼ 8, 1 H, Ph);
7.57 (t, J ¼ 8, 1 H, Ph); 7.44 (t, J ¼ 8, 1 H, Ph); 7.28 (m, 1 H, Ph); 6.47 (s, 1 H, ¼CH); 5.80 (s, 1 H, ¼CH);
4.13 (q, J ¼ 7, 2 H, OCH2); 1.14 (t, J ¼ 7, 3 H, Me).
2-(4,5-Methylenedioxy-2-nitrophenyl)propenoic Acid Ethyl Ester (¼ Ethyl 2-(6-Nitro-1,3-benzodiox-
ol-5-yl)prop-2-enoate; 3c). From 0.48 g (1.7 mmol) of ethyl 3-hydroxy-2-(6-nitro-1,3-benzodioxol-5-
yl)prop-2-enoate (2c), 3 ml (3.07 mmol) of BH3 · THF, and 34 ml (0.34 mmol) of piperidine at 08. Yield:
1
40%. H-NMR (CDCl3, 300 MHz): 7.65 (s, 1 H, Ph); 7.28 (s, 1 H, Ph); 6.77 (s, 1 H, ¼CH); 6.17 (s, 2 H,
OCH2O); 5.79 (s, 1 H, ¼CH); 4.22 (q, J ¼ 7, 2 H, OCH2); 1.24 (t, J ¼ 7, 3 H, Me). Anal. calc. for
C12H11NO6 (265.22): C 54.34, H 4.18, N 5.28; found: C 53.79, H 4.15, N 5.03.
2-(5-Chloro-2-nitrophenyl)propenoic Acid Ethyl Ester (¼ Ethyl 2-(5-Chloro-2-nitrophenyl)prop-2-
enoate; 3d). From 0.463 g (1.7 mmol) of ethyl 2-(2-chloro-5-nitrophenyl)-3-hydroxyprop-2-enoate (2d),
3 ml (3.07 mmol) of BH3 · THF 0.463 g (1.7 mmol), and 30 ml of piperidine (0.34 mmol) at 08. Yield:
20%. 1H-NMR (CDCl3, 300 MHz): 8.19 (m, 2 H, Ph); 7.28 (d, J ¼ 2, 1 H, Ph); 6.67 (s, 1 H, ¼CH); 5.91 (s,

Helvetica Chimica Acta – Vol. 98 (2015)
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1 H, ¼CH); 4.30 (q, J ¼ 7, 2 H, OCH2); 1.31 (t, J ¼ 7, 3 H, Me). Anal. calc. for C11H10ClNO4 (255.65): C
51.68, H 3.94, N 5.48; found: C 51.32, H 3.91, N 5.20.
2-(4-Methoxyphenyl)propenoic Acid Ethyl Ester (¼ Ethyl 2-(4-Methoxyphenyl)prop-2-enoate; 3e)
[16]. From 0.1 g (0.45 mmol) of ethyl 3-hydroxy-2-(4-methoxyphenyl)prop-2-enoate (2e), 1.4 ml
(1.4 mmol) of BH3 · THF, and 5 ml of piperidine (0.045 mmol) at 08. Yield: 30%. 1H-NMR (CDCl3,
300 MHz): 7.37 (d, J ¼ 9, 2 H, Ph); 6.88 (d, J ¼ 9, 2 H, Ph); 6.25 (d, J ¼ 1, 1 H, ¼CH); 5.82 (d, J ¼ 1, 1 H,
¼CH); 4.28 (q, J ¼ 7, 2 H, OCH2); 3.81 (s, 3 H, MeO); 1.33 (t, J ¼ 7, 3 H, Me).
CBS-Catalyzed Reduction of 3-Hydroxy-2-arylpropenoic Acid Ethyl Esters 2 with BH3 · THF. 2-
Phenylpropenoic Acid Ethyl Ester (¼ Ethyl 2-Phenylprop-2-enoate; 3a) [17]. From 0.2 g (1.0 mmol) of
ethyl 3-hydroxy-2-phenylprop-2-enoate (2a), 1.0 ml (1.0 mmol) of BH3 · THF, and 0.1 ml (0.10 mmol) of
CBS catalyst at 08. Yield: 70%. 1H-NMR (CDCl3, 300 MHz): 7.30 – 7.60 (m, 5 H, Ph); 6.35(d, J ¼ 1, 1 H,
¼CH); 5.90 (d, J ¼ 1, 1 H, ¼CH); 4.27 (q, J ¼ 7, 2 H, OCH2); 1.22 (t, J ¼ 7, 3 H, Me).
2-(2-Methoxyphenyl)propenoic Acid Ethyl Ester (¼ Ethyl 2-(2-Methoxyphenyl)prop-2-enoate; 3f)
[18]. From 0.45 g (2.1 mmol) of 2f, 2.52 ml (2.52 mmol) of BH3 · THF, and 0.2 ml (0.2 mmol) at 08. Yield:
70%. 1H-NMR (CDCl3, 300 MHz): 7.30 – 7.70 (m, 4 H, Ph); 6.27 (d, J ¼ 1, 1 H, ¼CH); 5.84 (d, J ¼ 1, 1 H,
¼CH); 4.29 (q, J ¼ 7, 2 H, OCH2); 3.83 (s, 3 H, MeO); 1.20 (t, J ¼ 7, 3 H, Me).
2-(4-Methylphenyl)propenoic Acid Ethyl Ester (¼ Ethyl 2-(4-Methylphenyl)prop-2-enoate; 3g) [19].
From 0.55 g (2.69 mmol) of 2g, 3.23 ml (3.23 mmol) of BH3 · THF, and 0.2 ml (0.2 mmol) at 08. Yield:
65%. 1H-NMR (CDCI3, 300 MHz): 7.30 – 7.60 (m, 4 H, Ph); 6.31 (d, J ¼ 1, 1 H, ¼CH); 5.87 (d, J ¼ 1, 1 H,
¼CH); 4.29 (q, J ¼ 7, 2 H, OCH2); 2.34 (s, 3 H, Me); 1.29 (t, J ¼ 7, 3 H, Me).
2-(2-Bromophenyl)propenoic Acid Ethyl Ester (¼ Ethyl 2-(2-Bromophenyl)prop-2-enoate; 3h) [20].
From 0.66 g (2.43 mmol) of ethyl 2-(2-bromophenyl)-3-hydroxyprop-2-enoate (2h), 2.91 ml (2.91 mmol)
of BH3 · THF, and 0.2 ml (0.2 mmol) at 08. Yield: 69%. 1H-NMR (CDCl3, 300 MHz): 7.00 – 7.50 (m, 4 H,
Ph); 6.53 (d, J ¼ 1, 1 H, ¼CH); 5.77(d, J ¼ 1, 1 H, ¼CH); 4.28 (q, J ¼ 7, 2 H, OCH2); 1.23 (t, J ¼ 7, 3 H,
Me).
2-(2-Methylphenyl)propenoic Acid Ethyl Ester (¼ Ethyl 2-(2-Methylphenyl)prop-2-enoate; 3i) [19].
From 0.70 g (3.40 mmol) of 2i, 4.1 ml (4.10 mmol) of BH3 · THF, and 0.34 ml (0.34 mmol) at 08. Yield:
1
66%. H-NMR (CDCI3, 300 MHz): 7.3 – 7.6 (m, 4 H, Ph); 6.51 (d, J ¼ 2, 1 H, ¼CH); 5.72 (d, J ¼ 2, 1 H,
¼CH); 4.27 (q, J ¼ 7, 2 H, OCH2); 2.24 (s, 3 H, Me); 1.32 (t, J ¼ 7, 3 H, Me).
2-(2,4-Dichlorophenyl)propenoic Acid Ethyl Ester (¼ Ethyl 2-(2,4-Dichlorophenyl)prop-2-enoate;
3j) [21]. From 0.95 g (3.6 mmol) of ethyl 2-(2,4-dichlorophenyl)-3-hydroxyprop-2-enoate (2j), 4.32 ml
(4.32 mmol) of BH3 · THF, and 0.36 ml (0.36 mmol) at 08. Yield: 70%. 1H-NMR (CDCl3 300 MHz): 7.20 –
7.40 (m, 4 H, Ph); 6.59 (d, J ¼ 1, 1 H, ¼CH); 5.93 (d, J ¼ 1, 1 H, ¼CH); 4.31 (q, J ¼ 7, 2 H, OCH2); 1.32 (t,
J ¼ 7, 3 H, Me).
General Procedure of the Hydrogenation of 2-Arylpropenoic Acid Ethyl Esters 3 to 2-Arylpropanoic
Acid Ethyl Esters 4. In a typical experiment, 1 equiv. of olefin was dissolved in 5 – 10 ml of freshly dist.
MeOH in a high-pressured hydrogenation flask. Then, 0.1 equiv. of Pd/C was added in the reaction flask.
Atmospheric air was removed and replaced by H2 gas three times and the pressure of H2 gas was
increased to 45 psi. The reactions were performed for 4 h and then passed through a Celite pad, and all
products formed were arylpropanoic acid ethyl ester.
2-Phenylpropanoic Acid Ethyl Ester (¼ Ethyl 2-Phenylpropanoate; 4a) [22]. From 0.2 g (1.13 mmol)
of 3a and 0.1 equiv. of Pd/C at 45 psi H2 pressure. Yield: 95%. 1H-NMR (CDCl3 300 MHz): 7.30 – 7.60 (m,
5 H, Ph); 4.20 (q, J ¼ 7, 2 H, OCH2); 3.95 (q, J ¼ 7, 1 H, CH); 1.52 (d, J ¼ 7, 3 H, Me); 1.27 (t, J ¼ 7, 3 H,
Me).
2-(2-Methoxyphenyl)propanoic Acid Ethyl Ester (¼ Ethyl 2-(2-Methoxyphenyl)propanoate; 4f) [23].
From 0.40 g (1.94 mmol) of 3f and 0.1 equiv. of Pd/C at 45 psi H2 pressure. Yield: 95%. 1H-NMR (CDCl3,
300 MHz): 7.30 – 7.60 (m, 5 H, Ph); 4.18 (q, J ¼ 7, 2 H, OCH2); 3.92 (q, J ¼ 7, 1 H, CH); 3.87 (s, 3 H,
MeO); 1.52 (d, J ¼ 7, 3 H, Me); 1.27 (t, J ¼ 7, 3 H, Me).
2-(4-Methylphenyl)propanoic Acid Ethyl Ester (¼ Ethyl 2-(4-Methylphenyl)propanoate; 4g) [24].
From 0.20 g (1.0 mmol) of 3g and 0.1 equiv. of Pd/C at 45 psi H2 pressure. Yield: 90%. 1H-NMR (CDCl3,
300 MHz): 7.30 – 7.60 (m, 5 H, Ph); 4.11 (q, J ¼ 7, 2 H, OCH2); 3.95 (q, J ¼ 7, 1 H, CH); 2.40 (s, 3 H, Me);
1.52 (d, J ¼ 7, 3 H, Me); 1.27 (t, J ¼ 7, 3 H, Me).

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Helvetica Chimica Acta – Vol. 98 (2015)
2-(2-Bromophenyl)propanoic Acid Ethyl Ester (¼ Ethyl 2-(2-Bromophenyl)propanoate; 4h) [25].
From 0.40 g (1.56 mmol) of 3h and 0.1 equiv. of Pd/C at 45 psi H2 pressure. Yield: 95%. 1H-NMR
(CDCl3, 300 MHz): 7.30 – 7.60 (m, 4 H, Ph); 4.15 (q, J ¼ 7, 1 H, CH); 3.90 (q, J ¼ 7, 2 H, OCH2); 1.52 (d,
J ¼ 7, 3 H, Me); 1.27 (t, J ¼ 7, 3 H, Me).
2-(2-Methylphenyl)propanoic Acid Ethyl Ester (¼ Ethyl 2-(2-Methylphenyl)propanoate; 4i) [26].
From 0.30 g (1.57 mmol) of 3i and 0.1 equiv. of Pd/C at 45 psi H2 pressure. Yield: 93%. 1H-NMR (CDCl3,
300 MHz): 7.03 – 7.60 (m, 4 H, Ph); 4.15 (q, J ¼ 7, 1 H, OCH2); 3.94 (q, J ¼ 7, 1 H, CH); 2.36 (s, 3 H, Me);
1.49 (d, J ¼ 7, 3 H, Me); 1.27 (t, J ¼ 7, 3 H, Me).
2-(2,4-Dichlorophenyl)propanoic Acid Ethyl Ester (¼ Ethyl 2-(2,4-Dichlorophenyl)propanoate; 4j).
From 0.66 g (2.69 mmol) of 3j and 0.1 equiv. of Pd/C at 45 psi H2 pressure. Yield: 84%. 1H-NMR (CDCl3,
300 MHz): 7.30 – 7.60 (m, 3 H, Ph); 4.11 (q, J ¼ 7, 2 H, OCH2); 3.90 (q, J ¼ 7, 1 H, CH); 1.52 (d, J ¼ 7,
3 H, Me); 1.27 (t, J ¼ 7, 3 H, Me).
General Procedure to Hydrolyze Arylpropanoic Acid Ethyl Esters 4 to Aryl Propanoic Acids 5. In a
typical experiment, arylpropanoic acid ethyl ester (2.20 – 0.56 mmol) was dissolved in 20 ml of acetone.
An aq. soln. of KOH (4.40 – 1.12 mmol) was added to the reaction flask and stirred overnight. Then, the
mixture was washed with Et2O. The aq. layer was then acidified, and the product was extracted with Et2O.
The solvent was removed by rotary evaporation to yield almost pure solid product in almost quantitative
yield.
2-Phenylpropanoic Acid (5a) [27]. From 0.10 g (0.56 mmol) of 4a and 1.12 mmol of aq. KOH. Yield:
90%. 1H-NMR (CDCl3, 300 MHz): 11.93 (s, 1 H, OH); 7.30 – 7.60 (m, 5 H, Ph); 3.9 (q, J ¼ 7, 1 H, CH);
1.49 (d, J ¼ 7, 3 H, Me).
2-(2-Methoxyphenyl)propanoic Acid (5f) [28]. From 0.23 g (1.40 mmol) of 4f and 2.80 mmol of aq.
KOH. Yield: 90%. 1H-NMR (CDCl3, 300 MHz): 11.93 (s, 1 H, OH); 7.30 – 7.60 (m, 4 H, Ph); 4.16 (q, J ¼
7, 1 H, CH); 3.86 (s, 3 H, MeO); 1.52 (d, J ¼ 7, 3 H, Me).
2-(4-Methylphenyl)propanoic Acid (5g) [29]. From 0.30 g (1.56 mmol) of 4g and aq. KOH
(3.12 mmol). Yield: 93%. 1H- NMR (CDCl3, 300 MHz): 12.63 (s, 1 H, OH); 7.30 – 7.60 (m, 4 H, Ph); 3.80
(q, J ¼ 7, 1 H, CH); 2.40 (s, 3 H, Me); 1.50 (d, J ¼ 7, 3 H, Me).
2-(2-Bromophenyl)propanoic Acid (5h) [30]. From 0.23 g (0.9 mmol) of 4h and aq. KOH
1
(1.8 mmol). Yield: 90%. H-NMR (CDCl3, 300 MHz): 12.20 (s, 1 H, OH); 7.3 – 7.6 (m, 4 H, Ph); 3.77
(q, J ¼ 7, 1 H, CH); 1.56 (d, J ¼ 7, 3 H, Me).
2-(2-Methylphenyl)propanoic Acid (5i) [29]. From 0.10 g (0.50 mmol) of 4i and aq. KOH
(1.0 mmol). Yield: 95%. 1H-NMR (CDCl3, 300 MHz): 12.13 (s, 1 H, OH); 7.20 – 7.50 (m, 4 H, Ph);
4.02 (q, J ¼ 7, 1 H, CH); 2.36 (s, 3 H, Me); 1.52 (d, J ¼ 7, 3 H, Me).
2-(2,4-Dichlorophenyl)propanoic Acid (5j) [31]. From 0.56 g (2.20 mmol) of 4j and aq. KOH
(4.40 mmol). Yield: 90%. 1H-NMR (CDCl3, 300 MHz): 12.55 (s, 1 H, OH); 7.30 – 7.60 (m, 3 H, Ph); 3.80
(q, J ¼ 7, 1 H, CH); 1.64 (d, J ¼ 7, 3 H, Me).
Reaction Mechanism Study. Reduction of Acrylate 2a with Various Reducing Agents. Attempted
Reduction of Acrylate with DIBAL-H. 0.098 g (0.51 mmol) of 2a was added to a dried side arm-round
bottom flask. The flask was kept under N2 gas. THF (10 ml) was added, and the mixture was cooled to 08.
DIBAL-H (1m, 1.02 ml, 1.02 mmol) was added to the mixture and stirred for 20 h at 08. After the aqueous
workup, no propenoic acid ethyl ester 3a was obtained. Some unidentified product was obtained. The
reaction was repeated at À 788, and no product formation was observed.
Attempted Reduction of Acrylate 2a with LiAlH4. 0.11 g (0.55 mmol) of 2a was added to a dried side
arm-round bottom flask. The flask was kept under N2 gas. THF (10 ml) was added, and the mixture was
kept at 08. LiAlH4 (1m, 1.1 ml, 1.1 mmol) was added to the mixture which was kept at 08 for 20 h. After
the aqueous workup, no propenoic acid 3a was obtained. Some unidentified product was obtained. The
reaction was repeated at different temps. (r.t., 608, and at À 788), and no product formation was
observed.
Attempted Reduction of Acrylate 2a with Catechol Borane. 0.15 g (0.78 mmol) of 2a was added to a
dried side arm-round bottom flask. The flask was kept under N2 gas. THF (15 ml) was added and the
mixture was cooled to 08. Catechol borane (0.096 g, 0.78 mmol) was added, and the mixture was stirred
for 20 h at 08. After the aqueous workup, no propenoic acid ethyl ester 3a was obtained.

Helvetica Chimica Acta – Vol. 98 (2015)
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Attempted Reduction of Acrylate 2a with 9-BBN. 0.054 g (0.28 mmol) of 2a was added to a dried side
arm-round bottom flask. The flask was kept under N2 gas. THF (10 ml) was added, and the mixture was
cooled to 08. 9-BBN (1.13 ml, 0.56 mmol) was added, and the mixture was stirred for 20 h at 08. After the
aqueous workup, no propenoic acid ethyl ester 3a was obtained.
NMR Study of the Reduction of 2a with Catechol Borane. 0.058 g (0.30 mmol) of compound 2a was
added to an NMR tube under N2. 0.3 ml of (D8)THF was added, and the mixture was kept at À 788.
Catechol borane (0.07 g, 0.76 mmol) was added, and the reaction was monitored by 1H-NMR at 08.
Within 2 h, a monohydroborane intermediate was formed. But no 2-phenylpropenoic acid ester 3a was
observed. After 18 h, 1 equiv. of BH3 · THF was added at À 58, and formation of 3a was observed.
NMR Study of the Reduction of 2a with 9-BBN. 0.04 g (0.21 mmol) of 2a was added to an NMR tube
under N2. 0.3 ml of (D8)THF was added, and the mixture was kept at À 788. 9-BBN (0.86 ml, 0.43 mmol)
was added, and the reaction was monitored by NMR at 08. Within 3 h, a monohydroborane intermediate
was formed. But no propenoic acid ester 3a was observed. After 20 h, 1 equiv. of BH3 · THF (0.21 ml,
0.21 mmol) was added at À 58, and formation of propenoic acid ester 3a was observed.
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Received March 10, 2015