Synthesis of α-heteroarylpropanoic acid via asymmetric hydroformylation catalyzed by Rh(I)-(R,S)-BINAPHOS and the subsequent oxidation

Article abstract of DOI:10.1021/jo0712190

(Chemical Equation Presented) The asymmetric hydroformylation of vinyl heteroarenes (vinylfurans and vinylthiophenes) was investigated by using Rh(I)-BINAPHOS derivatives as a catalyst. The hydroformylation of vinylthiophenes 1 gave the corresponding branched aldehydes 2 with high enantiopurities as major products. Oxidation of the aldehydes 2 successfully afforded α-heteroarylpropanoic acids 4 in good yields. In addition, the aldehydes 2 were reduced to alcohols 5 without loss of enantiomeric excess.

Full text of DOI:10.1021/jo0712190

Synthesis of r-Heteroarylpropanoic Acid via Asymmetric
Hydroformylation Catalyzed by Rh(I)-(R,S)-BINAPHOS and the
Subsequent Oxidation‡
Ryo Tanaka, Koji Nakano, and Kyoko Nozaki*
Department of Chemistry and Biotechnology, Graduate School of Engineering, The UniVersity of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
nozaki@chembio.t.u-tokyo.ac.jp
ReceiVed June 8, 2007
The asymmetric hydroformylation of vinyl heteroarenes (vinylfurans and vinylthiophenes) was investigated
by using Rh(I)-BINAPHOS derivatives as a catalyst. The hydroformylation of vinylthiophenes 1 gave
the corresponding branched aldehydes 2 with high enantiopurities as major products. Oxidation of the
aldehydes 2 successfully afforded R-heteroarylpropanoic acids 4 in good yields. In addition, the aldehydes
2 were reduced to alcohols 5 without loss of enantiomeric excess.
Introduction
eroarenes and the subsequent oxidation of the resulting optically
active aldehydes. Previously, we have reported the enantiose-
lective syntheses of hydratopic acid,7 pyrrolidine carboxylic acid,
and tetrahydrofuran carboxylic acid8 via hydroformylation of
the corresponding olefins by using Rh-BINAPHOS catalyst. In
addition, recent reports show that the hydroformylation of
R-Heteroarylpropanoic acids are an important class of
compounds due to their biological activities. For example,
tiaprofenic acid is known as one of the most popular nonsteroidal
anti-inflammatory drugs. Because their one enantiomer shows
higher biological activity than the other, stereoselective synthetic
routes for these compounds are of great interest.1
In recent years, various synthetic methods for racemic2 or
optically active3 R-arylpropanoic acids have been developed.
However, only a limited number of methods are applied to the
synthesis of R-heteroarylpropanoic acids: stereospecific kinetic
resolution by using lipases,4 resolution of diastereomeric
mixtures,1 and stereoselective aromatic substitution with cam-
phorsultam.5
(6) For recent reviews, see: (a) Yamashita, M.; Nozaki, K. In Compre-
hensiVe Organometallic Chemistry III; Mingos, D. M. P., Crabtree, R. H.,
Hiyama, T., Eds.; Elsevier: Oxford, UK, 2007; Vol. 11, Chapter 11.13.
(b) Nozaki, K.; Ojima, I. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.;
Wiley-VCH: New York, 2000; Chapter 7. (c) Dieguez, M.; Pamies, O.;
Claver, C. Tetrahedron: Asymmetry 2004, 15, 2113. (d) Breit, B.; Seiche,
W. Synthesis 2001, 1. (e) Claver, C.; van Leeuwen, P. W. N. M. In Rhodium
Catalyzed Hydroformylation; Kluwer Academic Publishers: Dordrecht, The
Netherlands, 2000; Chapter 5. For recent reports on asymmetric hydro-
formylation, see: (f) Thomas, P. J.; Axtell, A. T.; Klosin, J.; Peng, W.;
Rand, C. L.; Clark, T. P.; Landis, C. R.; Abboud, K. A. Org. Lett. 2007, 9,
2665. (g) Yan, Y.; Zhang, X. J. Am. Chem. Soc. 2006, 128, 7198. (h) Clark,
T. P.; Landis, C. R.; Freed, S. L.; Klosin, J.; Abboud, K. A. J. Am. Chem.
Soc. 2005, 127, 5040. (i) Axtell, A. T.; Cobley, C. J.; Klosin, J.; Whiteker,
G. T.; Zanotti-Gerosa, A.; Abboud, K. A. Angew. Chem., Int. Ed. 2005,
44, 5834. (j) Huang, J.; Bunel, E.; Allgeier, A.; Tedrow, J.; Storz, T.; Preston,
J.; Correll, T.; Manley, D.; Soukup, T.; Jensen, R.; Syed, R.; Moniz, G.;
Larsen, R.; Martinelli, M.; Reider, P. Tetrahedron Lett. 2005, 46, 7831.
(k) Cobley, C. J.; Klosin, J.; Qin, C.; Whiteker, G. Org. Lett. 2004, 6, 3277.
(l) Dieguez, M.; Pamies, O.; Ruiz, A.; Castillon, S.; Claver, C. Chem. Eur.
J. 2001, 7, 3086. (m) Breeden, S.; Cole-Hamilton, D. J.; Foster, D. F.;
Schwarz, G. J.; Wills, M. Angew. Chem., Int. Ed. 2000, 39, 4106.
(7) Nozaki, K.; Sakai, N.; Nanno, T.; Higashijima, T.; Mano, S.; Horiuchi,
T.; Takaya, H. J. Am. Chem. Soc. 1997, 119, 4413.
Our strategy for enantioselective synthesis of R-heteroaryl-
propanoic acids is asymmetric hydroformylation6 of vinylhet-
‡ This paper is dedicated to the memory of the late Professor Emeritus
Yoshihiko Ito.
(1) Droux, S.; Gigliotti, G.; Joly, P.; Perrier, F.; Vincent, V.; Robson, P.
A.; Williamson, R. A.; Petit, F. Eur. J. Med. Chem. 1997, 32, 159.
(2) Rieu, J. P.; Boucherle, A.; Cousse, H.; Mouzin, G. Tetrahedron 1986,
42, 4095.
(3) Sonawane, H. R.; Bellur, N. S.; Ahuja, J. R.; Kulkarni, D. G.
Tetrahedron: Asymmetry 1992, 3, 163.
(4) Garcia, M.; Delcampo, C.; Llama, E. F.; Sanchezmontero, J. M.;
Sinisterra, J. V. Tetrahedron 1993, 49, 8433.
(8) Horiuchi, T.; Ohta, T.; Shirakawa, E.; Nozaki, K.; Takaya, H. J. Org.
Chem. 1997, 62, 4285.
(5) Baciocchi, E.; Muraglia, E.; Villani, C. Synlett 1994, 821.
10.1021/jo0712190 CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/10/2007
J. Org. Chem. 2007, 72, 8671-8676
8671

Tanaka et al.
TABLE 1. Asymmetric Hydroformylation of Vinylthiophenesa
of R-(5-acetoxyfuran-2-yl)propanal to the corresponding car-
boxylic acid by sodium chlorite has been reported.15 However,
R-thienylpropanoic acids have never been synthesized from
R-thienylpropanals.
In this paper, we report the synthesis of R-heteroarylpropals
using asymmetric hydroformylation of vinylheteroarenes cata-
lyzed by Rh-BINAPHOS complex and the subsequent oxidation
of the resulting optically active aldehydes without racemization
at the asymmetric center.
Results and Discussion
Asymmetric Hydroformylation. First, the hydroformylation
of vinylthiophenes was investigated. The results are summarized
in Table 1. The reaction was carried out in the presence of Rh-
(acac)(CO)2 (0.50 mol %) and (R,S)-MeO-BINAPHOS (2.0 mol
%) in benzene under H2/CO pressure (1.0 MPa/1.0 MPa). The
ratio of branched product 2 and linear product 3 was determined
1
by H NMR spectroscopic analysis of the reaction mixture.
Hydroformylation of 2-vinylthiophene (1a) resulted in a quan-
titative conversion within 3 h, and no hydrogenated or polym-
erized products were detected (Table 1, run 1). The branched
aldehyde, 2-(2-thienyl)propanal (2a), was regioselectively formed
(2a/3a ) 94/6) and isolated in a high yield (93%) by silica gel
column chromatography. Although the precise enantiomeric
excess (ee) of 2a was undetermined because of incomplete
separation by chromatography, the ee should be g93% for
S-isomer (vide infra). The reaction of 3-vinylthiophene (1b) gave
branched aldehyde 2b in high regio- and enantioselectivity [2b/
3b ) 92/8, g91% ee for R-isomer (vide infra)], while the
complete conversion required longer reaction time than that for
1a (Table 1, run 2). Substituted vinylthiophenes were also
employable. Hydroformylation of 5-methyl-2-vinylthiophene
(1c) gave the branched aldehyde 2c (2c/3c ) 95/5) with a high
ee of 95% in 92% yield (Table 1, run 3). In the case of benzo-
annulated derivatives 1d, the resulting reaction mixture con-
tained the aldehydes 2d and 3d as exclusive products after the
complete conversion. However, the isolated yield was moderate,
which should be due to decomposition of the aldehydes during
the purification process. The regioselectivity was slightly lower
than those for the other substrates.
time
(h)
isolated yield
of 2 (%)
ee of 2
(%)
run
substrate
2:3b
1
2
3
4
1a
1b
1c
1d
3
6
3
6
94:6
92:8
95:5
84:16
93
91
92
68
g93 (S)c
g91 (R)c
95 (S)d
88 (R)d
a Reaction conditions: 1 (2.0 mmol), H2 (1.0 MPa), CO (1.0 MPa),
[Rh(acac)(CO)2] (0.010 mmol), (R,S)-MeO-BINAPHOS (0.040 mmol) in
benzene (1.0 mL) at 60 °C. b Determined by 1H NMR spectroscopic
analysis. c Not fully separated by HPLC. Therefore, the ee was estimated
based on ee of its reduction product 5 (vide infra). d Determined by HPLC
with CHIRALPAK IA column.
2-vinylfuran9 and 2-vinylthiophene10 with Rh catalysts gives
the corresponding branched aldehydes as main products.
However, to the best of our knowledge, there have been only a
few reports of asymmetric hydroformylation of vinylheteroare-
nes. Stille reported the asymmetric hydroformylation of 5-ben-
zoyl-2-vinylthiophene with Pt(II)-BPPM/SnCl2 catalyst,11 al-
though the reaction rate was not satisfactory and triethyl
orthoformate was necessary to avoid racemization of the product.
Recently, we have demonstrated the asymmetric hydroformy-
lation of vinylfurans with Rh-BINAPHOS catalyst,12 and
synthesized the corresponding aldehydes in good yields and with
high enantioselectivity. It should be noted that optically active
R-heteroarylpropanals, the products of asymmetric hydroformy-
lation, could be useful as chiral building blocks not only for
R-heteroarylpropanoic acid but also for the synthesis of other
biologically active compounds. For example, 2-(2-furyl)propanal
could be a starting material for monensin, a polyether antibi-
otic.13 In addition, 2-(2-furyl)propanol, the reduction product
of 2-(2-furyl)propanal, could be transformed into a series of
antitumor, 1,10-seco-eudesmanolides.14
Oxidation of Aldehydes. Next, we investigated the oxidation
of the hydroformylation products. Oxidation of the isolated
branched aldehydes 2b by using silver oxide,16 which is effective
for oxidation of R-arylpropanals, gave methyl 3-thienyl ketone,
as a result of loss of one carbon unit (eq 1).17
The use of other oxidation reagents such as Jones reagent,7
pyridinium dichromate,8 and potassium permanganate also
resulted in the formation of the ketone. When using sodium
The subsequent oxidation of R-heteroarylpropanal to R-het-
eroarylpropanoic acids is also a challenging target. Oxidation
(9) Kalck, P.; Sereinspirau, F. New J. Chem. 1989, 13, 515.
(10) Browning, A. F.; Bacon, A. D.; White, C.; Milner, D. J. J. Mol.
Catal. 1993, 83, L11.
(11) Stille, J. K.; Su, H.; Brechot, P.; Parrinello, G.; Hegedus, L. S.
Organometallics 1991, 10, 1183.
(12) Nakano, K.; Tanaka, R.; Nozaki, K. HelV. Chim. Acta 2006, .89,
1681.
(14) Merten, J.; Frohlich, R.; Metz, P. Angew. Chem., Int. Ed. 2004, 43,
5991.
(15) Schmidt, U.; Werner, J. Synthesis 1986, 986.
(16) Pe´rez-Estrada, S.; Lagunas-Rivera, S.; Vargas-D´ıaz, M. E.; Ve-
la´zquez-Ponce, P.; Joseph-Nathan, P.; Zepeda, L. G. Tetrahedron: Asym-
metry 2005, 16, 1837.
(13) Schmid, G.; Fukuyama, T.; Akasaka, K.; Kishi, Y. J. Am. Chem.
Soc. 1979, 101, 259.
(17) Hunter, D.; Neilson, D. G. J. Chem. Soc., Perkin Trans. 1988, 1,
1439.
8672 J. Org. Chem., Vol. 72, No. 23, 2007

Synthesis of R-Heteroarylpropanoic Acid
TABLE 2. Asymmetric Hydroformylation and Subsequent
Oxidation of Vinylheteroarenesa
SCHEME 1. Asymmetric Synthesis of (S)-Tiaprofenic Acid
(4g)
SCHEME 2. Determination of Absolute Configuration of 5c
and 5d
yield of
ee of
run
substrate
4 (%)
4 (%)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
80b
71c
64c
69c
69c
93 (S)e
91 (R)e
83 (S)e
92 (R)f
77 (S)g
d
-
a Reaction conditions: 1 (1.0 mmol), H2 (1.0 MPa), CO (1.0 MPa),
[Rh(acac)(CO)2] (0.0050 mmol), (R,S)-MeO-BINAPHOS (0.020 mmol) in
benzene (0.50 mL) at 60 °C for 3-6 h, then NaOClO (11 mmol), 2-methyl-
2-butene (5.5 mL of 2 M THF solution, 11 mmol), aqueous NaH2PO4‚2H2O
(1.77 mmol in 2 mL of H2O), tBuOH (10 mL) at room temperature for 30
min. b Isolated yield. c NMR yield by using naphthalene as an internal
standard. d The desired oxidation product was not detected. e Determined
by GC with Chirasil DEX CB column. f Determined by HPLC with
CHIRALPAK IA column. g Determined by HPLC with CHIRALPAK IB
column.
TABLE 3. Asymmetric Hydroformylation and Subsequent
Reduction of Vinylthiophenesa
hypochlorite, a complex mixture was obtained, without the
desired carboxylic acid. After optimizing the reaction conditions,
we found that the use of sodium chlorite brought the successful
oxidation to give the corresponding R-thienylpropanoic acid in
moderate to good yields.15 The results of hydroformylation of
vinylthiophenes 1 and the subsequent oxidation without the
isolation of aldehydes are summarized in Table 2. The ee values
of the obtained carboxylic acids were generally high, which
indicates that the oxidation proceeded without any (or with few)
loss in ee from aldehydes (vide supra).
We also investigated the hydroformylation of vinylfurans and
their subsequent oxidation (Table 2, runs 5 and 6). When
2-vinylfuran was employed, the corresponding carboxylic acid
was obtained in moderate yield (69%) with 77% ee for the
R-isomer (run 5). In contrast, oxidation of the hydroformylation
product from 3-vinylfuran gave the complex mixture without
the desired carboxylic acid (run 6).
On the basis of the successful synthesis of enantio-enriched
R-thienylpropanoic acids, we demonstrated the asymmetric
synthesis of tiaprofenic acid. By using (R,S)-MeO-BINAPHOS
ligand in the hydroformylation step, (S)-tiaprofenic acid with
84% ee was obtained in 55% yield (Scheme 1).
Reduction of Aldehydes. The subsequent reduction after the
asymmetric hydroformylation of vinylthiophenes was also
demonstrated (Table 3). According to our previous report of
asymmetric hydroformylation of vinylfurans and the subsequent
reduction,12 the crude mixture of hydroformylation was treated
with NaBH4 in ethanol at -78 °C. The reduction caused a slight
reduction in enantioselectivity as compared to that of aldehydes
2 (vide supra), producing the enantio-enriched alcohols 5 in high
isolated yield
of 5 (%)
ee of
run
substrate
5 (%)b
1
2
3
4
1a
1b
1c
1d
91
85
89
55
93 (S)
91 (R)
93 (S)
85 (R)
a Reaction conditions: 1 (2.0 mmol), H2 (1.0 MPa), CO (1.0 MPa),
[Rh(acac)(CO)2] (0.010 mmol), (R,S)-MeO-BINAPHOS (0.040 mmol) in
benzene (1.0 mL) at 60 °C for 3-6 h, then NaBH4 (2.0 mmol), EtOH (4.0
mL) at -78 °C. b Determined by HPLC with CHIRALPAK IA column.
yields (Table 3, runs 1-3). When using 1d as a starting material,
the yield and the ee of alcohol 5d (55% yield, 85% ee (R), see
Table 3, run 4) slightly decreased from those of the aldehyde
intermediate (68% yield, 88% ee (R), see Table 1, run 4).
Determination of Absolute Configurations. The absolute
configuration of major enantiomers of 5a and 5b was found to
be S and R, respectively, based on the sign of specific rotation.18
The configuration of the major enantiomer of 5c was determined
to be S through X-ray crystallographic analysis of its (S)-1-
phenylethylcarbamate derivative 6 (Scheme 2). The configura-
tion of the major enantiomer of 5d was also determined to be
J. Org. Chem, Vol. 72, No. 23, 2007 8673

Tanaka et al.
) 99:1, 1.0 mL/min, tR ) 23.6 min for (S)-2d and 26.0 min for
R by X-ray crystallographic analysis of its p-iodobenzoate
derivative 7.
1
(R)-2d]; [R]17 -31.4 (c 0.29, CHCl3); IR (neat) 1722 cm-1; H
D
NMR (CDCl3) δ 9.67 (d, J ) 2.1 Hz, 1H), 7.91-7.88 (m, 1H),
7.78-7.75 (m, 1H), 7.43-7.37 (m, 2H), 7.27 (m, 1H), 4.05 (qdd,
J ) 7.0, 1.9, 0.8 Hz, 1H), 1.58 (d, J ) 6.9 Hz, 3H); 13C NMR
(CDCl3) δ 199.9, 140.6, 138.0, 132.3, 124.7, 124.4, 123.6, 123.0,
121.5, 46.7, 13.6. Anal. Calcd for C11H10OS: C 69.44, H 5.30.
Found: C 69.20, H 5.49.
Thus, the absolute configurations of aldehydes 2 and car-
boxylic acids 4 were determined based on those of the reduction
products 5. Finally, the sense of enantioface selection in
hydroformylation of vinylthiophenes is the same as that observed
for styrenes.
Oxidation of 2-(3-Thienyl)propanal (2b) by Silver Oxide.
Silver oxide (61 mg, 266 µmol) was suspended in a solution of
NaOH (10 mg) in H2O (1.0 mL). To this suspension was added a
solution of 2b (36 mg, 253 µmol) in EtOH (1.0 mL), and the
resulting mixture was stirred at 40 °C overnight. The reaction
mixture was acidified with 1 M aqueous HCl (15 mL) and extracted
with CH2Cl2 (3 × 5 mL). The combined organic layers were dried
over MgSO4, filtered, and evaporated to give methyl 3-thienyl
ketone (25 mg, 79% yield).
Conclusion
The syntheses of optically active R-heteroarylpropanoic acid
were achieved. The hydroformylation of vinylthiophenes 1 with
Rh-BINAPHOS derivatives and the subsequent oxidation of the
aldehydes 2 with NaOClO successfully afforded R-heteroaryl-
propanoic acids 4 in good yields and enantiopurities. In addition,
the branched aldehydes 2 were reduced with NaBH4 to alcohols
5 without loss of ee. The methodology we developed provides
an effective synthetic route to R-heteroarylpropanoic acids 4,
which would be advantageous to the conventional process of
optical resolution of the racemic mixture,4 or to the usage of
an equimolar amount of chiral axiliaries.1,5
Typical Procedure for Asymmetric Hydroformylation and
Subsequent Oxidation. A solution of [Rh(acac)(CO)2] (1.4 mg,
0.0050 mmol), (R,S)-MeO-BINAPHOS (17 mg, 0.020 mmol), and
olefin 1 (1.0 mmol) in benzene (0.50 mL) was degassed by freeze-
thaw-pump cycles, then was transferred into a 50 mL autoclave
under Ar. Hydrogen (1.0 MPa) and carbon monoxide (1.0 MPa)
were charged and the resulting mixture was stirred at 60 °C for the
appropriate time. After the H2/CO pressure was released, the
reaction mixture was transferred into a 20 mL Schlenk tube, then
tBuOH (10 mL), 2-methyl-2-butene (2.0 M in THF, 5.5 mL, 11
mmol), and NaH2PO4‚2H2O (276 mg, 1.77 mmol) in H2O (2.0 mL)
were added. The mixture was cooled to 0 °C, then NaOClO (994
mg, 11.0 mmol) in 2 mL of H2O was added. After being stirred
for 30 min at room temperature, the reaction was quenched with
saturated aqueous Na2SO3 (10 mL). The aqueous phase was
acidified with 1 M aqueous HCl (10 mL) and extracted with three
portions of EtOAc (10 mL). The combined organic phases were
dried over MgSO4, filtered, and evaporated. An aliquot of the
resulting mixture was analyzed by 1H NMR to determine the yield
of carboxylic acid 4 (naphthalene as an internal standard) and by
HPLC or by GC to determine the ee of carboxylic acid 4.
2-(2-Thienyl)propanoic Acid (4a). Following the typical pro-
cedure with 2-vinylthiophene (1a), the crude product was purified
by silica gel column chromatography (hexane:EtOAc ) 3:1, Rf
0.18): yield 124 mg (80% yield); spectroscopic data were identical
with those in the literature;20 93% ee for (S)-4a [GC with Chirasil
DEX CB column, 150 °C, tR) 18.7 min for (R)-4a and 19.8 min
for (S)-4a].
Experimental Section
Typical Procedure for Asymmetric Hydroformylation of
Vinylthiophenes. A solution of [Rh(acac)(CO)2] (2.8 mg, 0.010
mmol), (R,S)-MeO-BINAPHOS (33 mg, 0.040 mmol), and vinylth-
iophene 1 (2.0 mmol) in benzene (1.0 mL) was degassed by freeze-
thaw-pump cycles and was transferred into a 50 mL autoclave
under Ar. Hydrogen (1.0 MPa) and carbon monoxide (1.0 MPa)
were charged, and the resulting mixture was stirred at 60 °C for
the appropriate time. After the H2/CO pressure was released, an
aliquot of the resulting mixture was analyzed by 1H NMR to
determine the ratios of the aldehydes 3 and 4. The crude product
was purified by silica gel column chromatography.
2-(2-Thienyl)propanal (2a). Following the typical procedure
with 2-vinylthiophene (1a), the crude product was purified by silica
gel column chromatography (hexane:EtOAc ) 10:1, Rf 0.42) to
give 2a as a colorless oil: yield 262 mg (93% yield). Spectroscopic
data were identical with those in the literature.19
2-(3-Thienyl)propanal (2b). Following the typical procedure
with 3-vinylthiophene (1b), the crude product was purified by silica
gel column chromatography (hexane:EtOAc ) 10:1, Rf 0.38): yield
255 mg (91% yield). Spectroscopic data were identical with those
in the literature.18,19
2-(3-Thienyl)propanoic acid (4b). According to the typical
procedure, 3-vinylthiophene (1b) was hydroformylated and further
oxidized: 71% NMR yield; spectroscopic data were identical with
those in the literature;21 92% ee for (R)-4b [GC with Chirasil DEX
CB column, 150 °C, tR ) 19.0 min for (S)-4b and 20.4 min for
(R)-4b].
2-(5-Methylthiophen-2-yl)propanoic Acid (4c). According to
the typical procedure, 5-methyl-2-vinylthiophene (1c) was hydro-
formylated and further oxidized: 64% NMR yield; 83% ee for (S)-
4c [GC with Chirasil DEX CB column, 150 °C, tR ) 22.2 min for
(R)-4c and 24.8 min for (S)-4c].
2-(5-Methylthiophen-2-yl)propanal (2c). Following the typical
procedure with 5-methyl-2-vinylthiophene (1c), the crude product
was purified by silica gel column chromatography (hexane:EtOAc
) 10:1, Rf 0.42): yield 281 mg (92% yield) as a colorless oil; 95%
ee for (S)-2c [HPLC with CHIRALPAK IA column, hexane, 1.0
mL/min, tR ) 17.9 min for (R)-2c and 19.5 min for (S)-2c]; [R]20
D
-78.8 (c 1.39, CHCl3); IR (neat) 1730 cm-1; 1H NMR (CDCl3) δ
9.61 (d, J ) 1.8 Hz, 1H), 6.70 (d, J ) 3.4 Hz, 1H), 6.67 (m, 1H),
3.77 (q, J ) 6.7 Hz, 1H), 2.46 (s, 3H), 1.47 (d, J ) 7.1 Hz, 3H);
13C NMR (CDCl3) δ 199.2, 139.7, 137.5, 125.4, 125.3, 47.9, 15.2,
15.1. Anal. Calcd for C8H10OS: C 62.30, H 6.54. Found: C 62.01,
H 6.65.
The authentic sample was synthesized by the following proce-
dure. In a 20 mL Schlenk tube, 2-(5-methylthiophen-2-yl)propanal
t
(255 mg, 1.7 mmol) and BuOH (10 mL), 2-methyl-2-butene (2.0
2-(Benzo[b]thiophen-3-yl)propanal (2d). Following the typical
procedure with 3-vinylbenzo[b]thiophene (1d), the crude product
was purified by silica gel column chromatography (hexane:EtOAc
) 5:1, Rf 0.31): yield 258 mg (68% yield); colorless oil; 88% ee
for (R)-2d [HPLC with CHIRALPAK IA column, hexane:CHCl3
M in THF, 5.5 mL, 11 mmol), and NaH2PO4‚2H2O (276 mg, 1.8
mmol) in H2O (2 mL) were added. The mixture was cooled to
0 °C, then NaOClO (994 mg, 11 mmol) in H2O (2 mL) was added.
After being stirred for 30 min, the reaction was quenched with
saturated aqueous Na2SO3 (10 mL). The aqueous phase was
acidified with 1 M aqueous HCl (10 mL) and extracted with three
portions of EtOAc (10 mL). The combined organic phases were
(18) Nordin, O.; Nguyen, B. V.; Vorde, C.; Hedenstrom, E.; Hogberg,
H. E. J. Chem. Soc., Perkin Trans. 2000, 1, 367.
(19) Tamaru, Y.; Yamada, Y.; Yoshida, Z. Tetrahedron 1979, 35, 329.
(20) Kumamoto, T.; Hosoya, K.; Kanzaki, S.; Masuko, K.; Watanabe,
M.; Shirai, K. Bull. Chem. Soc. Jpn. 1986, 59, 3097.
(21) Jackson, P. M.; Moody, C. J.; Shah, P. J. Chem. Soc., Perkin Trans.
1990, 1, 2909.
8674 J. Org. Chem., Vol. 72, No. 23, 2007

Synthesis of R-Heteroarylpropanoic Acid
dried over MgSO4, filtered, and evaporated. The crude mixture was
purified by the recycling preparative HPLC: yield 172 mg (61%
for (R)-5a and 19.7 min for (S)-5a]; [R]18D +18.1 (c 12.5, CHCl3)
(lit.18 [R]25 -6.2 (c 19, CHCl3) for (R)-5a (31% ee)).
D
yield); IR (neat) 2923, 1712 cm-1; [R]23 -5.1 (c 2.86, CHCl3);
D
2-(3-Thienyl)propanol (5b). Following the typical procedure
with 3-vinylthiophene as olefin (1b), the product was purified by
silica gel column chromatography (hexane:CH2Cl2:EtOAc ) 5:5:
1, Rf 0.39): yield 246 mg (85% yield); spectroscopic data were
identical with those in the literature;18 89% ee for (R)-5b [HPLC
with CHIRALPAK IA column, hexane:CHCl3 ) 80:20, 1.0 mL/
1H NMR (CDCl3) δ 6.75 (d, J ) 3.4 Hz, 1H), 6.61-6.59 (m, 1H),
3.94 (q, J ) 7.3 Hz, 1H), 2.44 (d, J ) 0.9 Hz, 3H), 1.57 (d, J )
7.1 Hz, 3H); 13C NMR (CDCl3) δ 179.9, 139.5, 139.1, 125.0, 124.7,
40.8, 18.8, 15.2. Anal. Calcd for C8H10O2S: C 56.44, H 5.92.
Found: C 56.18, H 6.01.
2-(Benzo[b]thiophen-3-yl)propanoic Acid (4d). According to
the typical procedure, 3-vinylbenzo[b]thiophene (1d) was hydro-
formylated and further oxidized: 69% NMR yield; 92% ee for (R)-
4d [HPLC with CHIRALPAK IA column, hexane:2-propanol:TFA
) 98:2:0.1, 1.0 mL/min, tR ) 15.2 min for (S)-4d and 16.3 min
for (R)-4d].
min, tR ) 17.8 min for (S)-5b and 19.6 min for (R)-5b]; [R]20
D
+15.7 (c 12.3, CHCl3) (lit.18 [R]25D -2.0 (c 11, CHCl3) for (S)-5b
(12.6% ee)).
2-(5-Methylthiophen-2-yl)propanol (5c). Following the typical
procedure with 5-methyl-2-vinylthiophene (1c), the product was
purified by silica gel column chromatography (hexane:EtOAc )
4:1, Rf 0.18): yield 274 mg (89% yield); colorless oil; 93% ee for
(S)-5c [HPLC with CHIRALPAK IA column, hexane:CHCl3 ) 80:
20, 1.0 mL/min, tR ) 17.8 min for (R)-5c and 19.6 min for (S)-
5c]; [R]20D +21.4 (c 1.76, CHCl3); IR (neat) 3361 cm-1; 1H NMR
(CDCl3) δ 6.67 (d, J ) 3.4 Hz, 1H), 6.61-6.59 (m, 1H), 3.69 (dd,
J ) 10.8, 5.7 Hz, 1H), 3.62 (dd, J ) 10.7 Hz, 7.2 Hz, 1H), 3.18-
3.12 (m, 1H), 2.45 (s, 3H), 1.31 (d, J ) 6.9 Hz, 3H); 13C NMR
(CDCl3) δ 144.9, 137.9, 124.7, 123.7, 68.8, 38.2, 18.4, 15.2. Anal.
Calcd for C8H12OS: C 61.50, H 7.74. Found: C 61.32, H 7.86.
The authentic sample was synthesized by the following proce-
dure. In a 20 mL Schlenk tube, 2-(benzo[b]thiophen-3-yl)propanal
t
(226 mg, 70 mmol) and BuOH (10 mL), 2-methyl-2-butene (2.0
M in THF, 5.5 mL, 11 mmol), and NaH2PO4‚2H2O (276 mg, 1.8
mmol) in H2O (2 mL) were added. The mixture was cooled to 0 °C,
then NaOClO (994 mg, 11.0 mmol) in H2O (2 mL) was added.
After stirring for 30 min, the reaction was quenched with saturated
aqueous Na2SO3 (10 mL). The aqueous phase was acidified with 1
M aqueous HCl (10 mL) and extracted with three portions of EtOAc
(10 mL). The combined organic phases were dried over MgSO4,
filtered, and evaporated. The crude mixture was purified by the
recycling preparative HPLC: yield 216 mg (88% yield); IR (neat)
2-(Benzo[b]thiophen-3-yl)propanol (5d). Following the typical
procedure with 3-vinylbenzo[b]thiophene (1d), the crude product
was purified by silica gel column chromatography (hexane:EtOAc
) 5:1, Rf 0.16): yield 203 mg (55% yield); colorless oil; 85% ee
for (R)-5d [HPLC with CHIRALPAK IA column, hexane:CHCl3
) 80:20, 1.0 mL/min, tR ) 19.3 min for (S)-5c and 24.5 min for
(R)-5c]. [R]17D -13.3 (c 1.9, CHCl3); IR (neat) 3354 cm-1; 1H NMR
(CDCl3) δ 7.89-7.87 (m, 1H), 7.83-7.81 (m, 1H), 7.42-7.34(m,
2H), 7.21 (s, 1H), 3.90 (dd, J ) 10.8, 6.0 Hz, 1H), 3.81 (dd, J )
10.7, 6.1 Hz, 1H), 3.49-3.42 (m, 1H), 1.44 (d, J ) 6.9 Hz, 3H);
13C NMR (CDCl3) δ 140.6, 138.6, 138.5, 124.4, 123.9, 122.9, 121.7,
121.1, 67.3, 35.8, 17.1. HRMS calcd for C11H12OS 192.0609, found
192.0601.
1
2937, 1709 cm-1; [R]D -24.6 (c 1.35, CHCl3); H NMR (CDCl3)
δ 7.86 (d, J ) 7.6 Hz, 1H), 7.83 (d, J ) 7.9 Hz, 1H), 7.41-7.34
(m, 3H), 4.17 (q, J ) 7.1 Hz, 1H), 1.67 (d, J ) 7.3 Hz, 3H); 13C
NMR (CDCl3) δ 179.6, 140.5, 138.0, 134.2, 124.6, 124.3, 123.2,
123.0, 121.9, 39.3, 17.3. HRMS calcd for C11H10O2S 206.0402,
found 206.0408.
2-(2-Furyl)propanoic Acid (4e). According to the typical
procedure, 2-vinylfuran (1e) was hydroformylated and further
oxidized. Spectroscopic data were identical with those in the
literature:22 69% NMR yield; 77% ee for (S)-4e [HPLC with
CHIRALPAK IB column, hexane:2-propanol:TFA ) 98:2:0.1, 1.0
mL/min, tR ) 11.6 min for (S)-4e and 12.7 min for (R)-4e].
2-(5-Benzoylthiophen-2-yl)propanoic Acid (Tiaprofenic Acid,
4g). According to the typical procedure, 5-benzoyl-2-vinylthiophene
(1g) was hydroformylated and oxidized:1 55% NMR yield; spec-
troscopic data were identical with those in the literature; 84% ee
for (S)-4g [HPLC with CHIRALPAK IB column, hexane:2-
propanol: TFA ) 95:5:0.1, 1.0 mL/min, tR ) 14.3 min for (S)-4g
and 15.6 min for (R)-4g].
Typical Procedure for Hydroformylation and Subsequent
Reduction. A solution of [Rh(acac)(CO)2] (2.8 mg, 0.010 mmol),
(R,S)-MeO-BINAPHOS (33 mg, 0.040 mmol), and vinylthiophene
1 (2.0 mmol) in benzene (1.0 mL) was degassed by freeze-thaw-
pump cycles, then was transferred into a 50 mL autoclave under
Ar. Hydrogen (1.0 MPa) and carbon monoxide (1.0 MPa) were
charged and the mixture was stirred at 60 °C for the appropriate
time. After the H2/CO pressure was released, the reaction mixture
was transferred into a 20 mL Schlenk tube, and EtOH (4.0 mL)
was added. Powdered NaBH4 (76 mg, 2.0 mmol) was added at
-78 °C, and the resulting mixture was stirred overnight. The
reaction was quenched with H2O (3 mL) and extracted with three
portions of EtOAc (10 mL). The organic layers were dried over
MgSO4, filtered, and evaporated. The residue was purified by silica
gel column chromatography to give the corresponding alcohol.
2-(2-Thienyl)propanol (5a). Following the typical procedure
with 2-vinylthiophene (1a), the crude product was purified by silica
gel column chromatography (hexane:EtOAc ) 5:1, Rf 0.23): yield
259 mg (91% yield); spectroscopic data were identical with those
in the literature;18 93% ee for (S)-5a [HPLC with CHIRALPAK
IA column, hexane:CHCl3 ) 80:20, 1.0 mL/min, tR ) 16.8 min
Determination of Absolute Configuration of (S)-5c. To a
solution of 5c (26 mg, 169 µmol, 93% ee) and DMAP (12.3 mg,
101 µmol) in CH2Cl2 (0.50 mL) was added (S)-(-)-(1-isocyana-
toethyl)benzene (30 µL, 214 µmol). The mixture was stirred for
16 h at room temperature, then 1 M aqueous NaHCO3 (3 mL) was
added. The aqueous layer was extracted with CH2Cl2 (3 × 3 mL),
and the combined organic layers were dried over MgSO4, filtered,
and evaporated. The crude product was purified by silica gel column
chromatography (hexane:EtOAc ) 10:1, Rf 0.17) to give 6 as a
colorless solid: yield 42 mg (82% yield). The solid was recrystal-
lized from ether/hexane. The absolute configuration was confirmed
1
by X-ray crystal analysis. Mp 121-124 °C; H NMR (CDCl3) δ
7.35-7.24 (m, 5H), 6.63-6.59 (br, 1H), 6.58-6.55 (br, 1H), 5.03-
4.93 (br, 1H), 4.88-4.80 (br, 1H), 4.16-4.08 (m, 2H), 3.30-3.21
(m, 1H), 2.44 (s, 3H), 1.48 (d, J ) 6.4 Hz, 3H), 1.30 (d, J ) 5.5
Hz, 3H); 13C NMR (CDCl3) δ 155.5, 144.6, 143.5, 137.6, 128.6,
127.3, 125.9, 124.5, 123.3, 69.8, 50.6, 35.0, 22.4, 18.9, 15.3. HRMS
calcd for C17H21O2NS 303.1293, found 303.1305.
Determination of Absolute Configuration of (R)-5d. To a
solution of 5d (21 mg, 110 µmol, 85% ee) and Et3N (20 µL, 144
µmol) in CH2Cl2 (0.20 mL) was added p-iodobenzoic acid chloride
(40 mg, 149 µmol) in CH2Cl2 (0.50 mL). The mixture was stirred
for 2 h at room temperature, then 1 M aqueous NaHCO3 (1 mL)
was added. The aqueous layer was extracted with CH2Cl2 three
times, and the combined organic layers were dried over MgSO4,
filtered, and evaporated to give 7 as a colorless solid in a yield of
47 mg (quantitative yield). The obtained solid was recrystallized
from ether/hexane. A part of the large single crystal was used for
X-ray analysis, and the absolute configuration was confirmed by
(22) Kuo, Y. C.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull. 1983, 31,
883.
J. Org. Chem, Vol. 72, No. 23, 2007 8675

Tanaka et al.
anomalous dispersion effects. HPLC analysis of the rest of the large
single crystal revealed that the single crystal was the major isomer.
HPLC with CHIRALPAK IC column, hexane:2-propanol ) 98:2,
1.0 mL/min, tR ) 7.2 min for ester from (S)-5d and 7.8 min for
ester from (R)-5c; mp 89-94 °C; 1H NMR (CDCl3) δ 7.91 (d, J )
8.0 Hz, 1H), 7.88 (d, J ) 8.0 Hz, 1H), 7.78 (d, J ) 8.5 Hz, 2H),
7.69 (d, J ) 8.0 Hz, 2H), 7.43-7.35 (m, 2H), 7.25 (s, 1H), 4.65
(dd, J ) 10.8, 5.7 Hz, 1H), 4.37 (dd, J ) 10.8, 7.6 Hz, 1H), 3.74-
3.68 (m, 1H), 1.53 (d, J ) 7.1 Hz, 3H); 13C NMR (CDCl3) δ 166.0,
140.5, 138.4, 137.72, 133.70, 131.0, 129.6, 124.4, 124.0, 122.9,
121.7, 121.2, 100.8, 69.2, 32.6, 17.4. HRMS calcd for C18H15O2SI
421.9838, found 421.9855.
Supporting Information Available: General experimental
procedures, syntheses of 3-vinylfuran (1f), 1H and 13C NMR spectra
for synthesized compounds, and crystallographic information files
(CIF) for 6 and 7. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO0712190
8676 J. Org. Chem., Vol. 72, No. 23, 2007