Enantioselective synthesis of (R)-(-)-baclofen via Ru(II)-BINAP catalyzed asymmetric hydrogenation

Article abstract of DOI:10.1016/S0957-4166(03)00024-7

A short and efficient enantioselective synthesis of (R)-(-)-baclofen, a selective GABA_B agonist has been described with an overall yield of 26% and 90% ee. Ru(II)-(S)-BINAP catalyzed asymmetric hydrogenations of C=C and C=O groups constitute the key steps in introducing stereogenic centers into the molecule.

Full text of DOI:10.1016/S0957-4166(03)00024-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 581–586
Enantioselective synthesis of (R)-(−)-baclofen via Ru(II)–BINAP
catalyzed asymmetric hydrogenation
Vinay V. Thakur, Milind D. Nikalje and A. Sudalai*
Process Development Division, National Chemical Laboratory, Pashan Road, Pune 411 008, India
Received 18 November 2002; accepted 2 January 2003
Abstract—A short and efficient enantioselective synthesis of (R)-(−)-baclofen, a selective GABAB agonist has been described with
an overall yield of 26% and 90% ee. Ru(II)–(S)-BINAP catalyzed asymmetric hydrogenations of CꢀC and CꢀO groups constitute
the key steps in introducing stereogenic centers into the molecule. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
butenoate 6 as well as ethyl 4-chlorophenylbenzoyl
acetate 5.
Baclofen [g-amino-b-(p-chlorophenyl)butyric acid], 1, a
derivative of g-aminobutyric acid (GABA), plays an
important role as an inhibitory neurotransmitter in
central nervous system (CNS) of mammalians.1,2 It
helps to reduce the excitatory effect of active com-
pounds such as benzodiazepine, barbiturates, etc.3 The
deficiency of GABA is associated with diseases that
exhibit neuromuscular dysfuntions such as epilepsy,
Huntington, Parkinsons’ diseases, etc.4 Baclofen is also
one of the most promising drugs in the treatment of the
paroxysmal pain of trigeminal neuralgia5 as well as
spasticity of spinal without influencing the sedation.6
Although baclofen is commercialized in its racemic
form, it has been reported that its biological activity
resides exclusively in (R)-enantiomer.7
2. Results and discussion
Retrosynthetic analysis (Fig. 1) of (R)-(−)-baclofen 1
reveals that many precursors such as b-hydroxy ester 2,
azidoester 6, b-cyano ester 3 or nitroketone 7 can be
visualized as the key intermediates. In order to prepare
enantiomerically pure b-hydroxy ester 2, Pd-catalyzed
oxidative kinetic resolution11 of the corresponding
racemic b-hydroxyester ( )-4 was attempted. However,
the desired chiral alcohol 2 was obtained in low enan-
tiomeric excess (7% ee). Further, the Michael addition
of nitromethane catalyzed by L-proline on 4-chloroben-
zylideneacetophenone was also attempted to get the
chiral nitroketone 7 (Corey’s intermediate) but with
poor enantioselectivity (15% ee). Ni-catalyzed asymmet-
ric hydrocyanation of 4-chlorobenzylideneacetophe-
none was also attempted using trimethylsilyl cyanide
and acetone cyanohydrin as the HCN source but the
catalyst failed to induce any stereoselectivity although it
gave the racemic product. We then turned our attention
to asymmetric hydrogenation of azidoester 6.
There are many methods available in the literature on
the synthesis of (R)-(−)-baclofen 1. They are concerned
mostly with resolution,8 chemoenzymatic9 or enantiose-
lective synthesis.10 However, these methods suffer from
disadvantages such as the low overall yields, the need
for separation of diastereoisomers and the use of expen-
sive chiral reagents in stochiometric amounts. In this
context, a more practical approach for the synthesis of
(R)-(−)-baclofen 1 is highly desirable. This article
describes a new enantioselective synthesis of (R)-(−)-
baclofen 1 by employing Ru-catalyzed asymmetric
hydrogenation of ethyl 4-azido-3-(4-chlorophenyl)-2-
The key precursor, (E)-ethyl 3-(4-chlorophenyl)-2-
butenoate 8, was obtained in 78% overall yield (E:Z=
70:30)
by
the
Reformatsky
reaction
of
4-chloroacetophenone with ethyl bromoacetate fol-
lowed by p-TSA catalyzed dehydration of the interme-
diate alcohol. The allylic bromination of 8 with
N-bromosuccinimide (NBS) in the presence of 2,2%-azo-
bisisobutyronitrile (AIBN) resulted in the formation of
ethyl 4-bromo-3-(4-chlorophenyl)-2-butenoate 9 in 92%
yield. The bromoester 9 was then transformed to ethyl
* Corresponding author. Tel.: +91-020-5893300; fax: +91-20-5893359;
e-mail: sudalai@dalton.ncl.res.in
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00024-7

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V. V. Thakur et al. / Tetrahedron: Asymmetry 14 (2003) 581–586
Figure 1. Retrosynthetic analysis of (R)-(−)-baclofen 1.
(R)-ethyl 4-azido-3-(4-chlorophenyl)-1-butanoate 11
formed via the reduction of the olefinic bond. In order
to improve the yield and selectivity of the CꢀC reduc-
tion process and to ensure the simultaneous reduction
of N3 moiety, reaction was performed at higher H2
pressure (500 psi) and at 70°C to afford a single
product 10 (80% yield, 65% ee14), in which all the three
functional groups of olefin, azido and CꢁCl groups had
undergone reduction. Such hydrogenolysis of aryl CꢁCl
bond is known in the literature.13 The formation of
(R)-(−)-3-phenylpyrrolidone 10 is rationalized as a
result of reductive cyclization occurring during the
asymmetric hydrogenation. Co-catalyzed15 reduction of
N3 moiety in 11 with NaBH4 gave the cyclized product
4-(4-chlorophenyl)-2-pyrrolidone 12 in 80% yield. The
hydrolysis of 4-(4-chlorophenyl)pyrrolidine-2-one (12)
4-azido-3-(4-chlorophenyl)-2-butenoate 6 by nucleo-
philic displacement of Br by N3 using NaN3. The IR
spectrum of 6 showed an intense band at 2104 cm−1
indicative of N3 group (Scheme 1).
Diphosphine complexes of Rh and Ru have been used
as catalysts for the asymmetric hydrogenation of CꢀC
and ketoesters.12 The key intermediate, azidoester 6 was
subjected to Ru(II)–(S)-BINAP catalyzed asymmetric
hydrogenation in MeOH in a Parr reactor (Scheme 2).
When the experiment was performed at 200 psi of H2
and 25°C for 24 h, there was no reaction and all the
starting material was recovered. However, increase of
temperature to 50°C and 200 psi of H2 resulted in the
formation of a mixture of products, the major product
(68% yield and 68% ee determined by HPLC) being
Scheme 1. Reagents and conditions: (i) BrCH2CO2Et, Zn, benzene, reflux, p-TSA, toluene, reflux, 78%; (ii) NBS, AIBN, CCl4,
reflux, 10 h, 92%; (iii) NaN3, EtOH:H2O (80:20), 80°C, 8 h, 78%.
Scheme 2. Reagents and conditions: (i) Ru(II)–BINAP, H2 (200 psi), MeOH, 25°C, 24 h; (ii) Ru(II)–BINAP, MeOH, H2 (500 psi),
70°C, 26 h; (iii) Ru(II)–(S)-BINAP, H2 (200 psi), MeOH, 50°C, 20 h; 68%; (iv) CoCl2, NaBH4, H2O, 25°C, 30 min; 80%; (v) 6N
HCl, 100°C, 10 h, 76%.

V. V. Thakur et al. / Tetrahedron: Asymmetry 14 (2003) 581–586
583
Scheme 3. Reagents and conditions: (i) PCC, CH2Cl2, 25°C, 3 h or H2Cr2O7, Et2O, 0–25°C, 4 h, 75%; (ii) Ru(II)–(S)-BINAP,
MeOH, H2 (800 psi), 95% yield, 96% ee; (iii) PBr3, pyridine, Et2O, −20 to 0°C, 53 h, 79%; (iv) NaCN, DMF, 70°C, 18 h, 88%;
(v) NiCl2·6H2O, NaBH4, MeOH, 25°C, 1 h, 75%; (vi) 6N HCl, reflux, 16 h, 78%.
with 6N HCl at 100°C gave (R)-(−)-baclofen hydro-
chloride 1 as a white solid in 76% yield, enantiomeric
excess of 1 was identical, as expected, to 11.
4. Experimental
4.1. General information
As the enantiomeric excess of 1 obtained by the above
method was low (67%), we decided to explore an
alternative route involving b-ketoester 5 as a prochiral
substrate (Scheme 3). (R)-b-Hydroxyester 2, the key
intermediate was synthesized by the enantioselective
reduction of b-ketoester 5, which was in turn prepared
from 4-chlorobenzaldehyde in two steps with an overall
yield of 72%. The asymmetric reduction of keto func-
tion was performed using (S)-BINAP–Ru(II) complex
and H2 at a pressure of 800 psi at 30°C to afford the
corresponding (R)-b-hydroxy ester 2 in 95% yield and
96% ee [determined by Eu(hfc)3 shift reagent]. Alcohol
2 was then converted to bromoderivative 13 using PBr3
and pyridine in Et2O at −20°C in 79% yield with
complete inversion of configuration.16 The b-bromo
ester 13 was subjected to SN2 nucleophilic displacement
using NaCN in DMF at 70°C to afford the b-cya-
noester 3 in 88% yield. Cyano ester 3 was chemoselec-
Solvents were purified and dried by standard proce-
dures before use; petroleum ether of boiling range
60–80°C was used. Melting points are uncorrected.
Optical rotations were measured using sodium D line
on a JASCO-181 digital polarimeter. Infrared spectra
were recorded on an Shimadzu FTIR-8400 spectrome-
1
ter. H NMR and 13C NMR were recorded on Bruker
AC-200 and MSL-300 NMR spectrometers, respec-
tively. Mass spectra were obtained with a Finnigan
MAT-1020 B-70 eV mass spectrometer. Elemental anal-
ysis was carried on a Carlo Erba CHNS-O analyzer.
Enantiomeric excess was determined by chiral HPLC or
by using chiral shift reagent Eu(hfc)3.
4.2. Ethyl 3-(4-chlorophenyl)-2-butenoate 8
A 100 ml two-necked round-bottomed flask was
charged with activated zinc (2.32 g, 35.7 mmol), and
kept under N2 atmosphere. Dry benzene (30 ml) was
introduced and the reaction mixture was heated to 80°C
(oil bath temp.). A solution of ethyl bromoacetate (5.88
g, 35.7 mmol) and p-chloroacetophenone (5.0 g, 32.46
mmol) in dry benzene (20 ml) was added dropwise to
the reaction mixture. After completion of the addition,
the resulting reaction mixture was refluxed for 6 h,
cooled to rt and quenched by adding ice cold 4N
H2SO4 (30 ml). The crude hydroxyester was extracted
in diethyl ether and then was subjected to dehydration
with p-toluenesulphonic acid (0.7 g, 3.68 mmol) in
toluene at reflux. The water generated during the dehy-
dration was azeotropically separated and then toluene
was distilled off. The crude olefinic ester 8 was purified
by column chromatography packed with silica gel, elut-
ing with petroleum ether to give 5.67 g (78%, trans/
cis=70/30). Yield: 78%; bp: 154°C at 0.64 mm; IR
(CHCl3, cm−1): 3060, 2982, 1712, 1625, 1577, 1448,
17
tively reduced either with NaBH4 and NiCl2 or with
catalytic amount of PtO2 in presence of H2 (40 psi)18 to
afford the lactam 12 in 75% yield. The enantiomeric
purity of lactam 12 was determined to be 92% by
comparison of its specific rotation [h]2D5=−35.8 (c 1,
EtOH) with that reported {lit. [h]2D5=−39.1 (c 1,
EtOH)}. The loss in ee can probably be attributed to
the successive nucleophilic SN2 displacements at the
stereogenic center causing marginal racemization. Lac-
tam 12 was finally hydrolyzed with 6N HCl to give
(R)-(−)-baclofen 1 as its hydrochloride salt with 26%
overall yield and 90% ee {[h]D=−1.81, (c 0.6, H2O)}.
3. Conclusion
We have achieved an efficient, enantioselective synthesis
of (R)-(−)-baclofen 1 using two different routes. In one
route, Ru-catalyzed asymmetric hydrogenation of ethyl
4-azido-3-(4-chlorophenyl)-2-butenoate 6 was used as a
key step to give (R)-(−)-baclofen 1 in 24% overall yield
and 67% ee. Alternately, Ru-catalyzed asymmetric
reduction of ethyl 4-chlorophenylbenzoyl acetate 5 was
used as a key step to afford (R)-(−)-baclofen 1 in 26%
overall yield and 90% ee.
1
1367, 1344, 1286, 1176, 1047, 879, 769, 696; H NMR
(CDCl3): l 1.25 (t, J=7.4 Hz, 3H), 2.48 (s, 3H), 4.12
(q, J=7.4 Hz, 2H), 6.02 (s, 1H), 7.23–7.35 (dd, J=8.0
Hz, 4H); 13C NMR (CDCl3): l 14.14, 17.58, 59.78,
117.56, 127.55, 128.62, 134.93, 140.51, 153.68, 166.31;
MS m/z (% rel. int.): 224 (M+, 96), 209 (8), 195 (55),

584
V. V. Thakur et al. / Tetrahedron: Asymmetry 14 (2003) 581–586
179 (100), 152 (32), 115 (92). Anal. calcd for
C12H13ClO2 requires: C, 64.15; H, 5.83; Cl, 15.78.
Found: C, 63.94; H, 5.81; Cl, 15.72%.
directly used as catalyst for the asymmetric
hydrogenation.
4.6. Asymmetric reduction of azidoester 6 using Ru(II)–
BINAP
4.3. Ethyl 4-bromo-3-(4-chorophenyl)-2-butenoate 9
A solution of a,b-unsaturated ester 8 (3.5 g, 15.62
mmol), NBS (2.81 g, 17.2 mmol) and AIBN (0.102 g,
0.62 mmol) in dry CCl4 (35 ml) was refluxed under
nitrogen atmosphere for 10 h. The resulting reaction
mixture was cooled to room temperature and then
filtered through a sintered funnel to separate succin-
imide formed during the reaction. The filtrate was
concentrated under reduced pressure to obtain bro-
moester 9. It was then purified by column chromatogra-
phy packed with silica gel to give pure 4.37 g of pale
yellow colored gum, bromoester 9. Yield: 92%; IR
(CHCl3, cm−1): 3060, 2982, 1710, 1625, 1490, 1369,
A 100 ml autoclave charged with azidoester 6 (0.200 g,
1.88 mmol), Ru(II)–(S)-BINAP (10 mg), dry MeOH
(40 ml) and the resulting yellowish-orange solution was
degassed with N2. It was then pressurized with H2 to
200 psi and the reaction mixture was vigorously stirred
at 50°C for 20 h. Resulting solution cooled to room
temperature and the excess of H2 was carefully blend
off. The deep reddish-orange colored reaction mixture
was transformed to 100 ml round bottomed flask and
the solvent was removed under reduced pressure. The
residue was purified by column chromatography
packed with silica gel to give pure (0.137 g) light yellow
colored viscous liquid of (R)-ethyl 4-azido-3-(4-
chlorophenyl)-1-butanoate 11. Yield: 68%; [h]2D5=−18.7
(c 0.3, MeOH), 68% ee, HPLC: LichroCART® 250-4
ChiraDex® GAMMA, 5 mm, 5% EtOH/hexane, 0.5
ml/min, retention time: 14.22 min; IR (CHCl3, cm−1):
3020, 2928, 2103, 1730, 1692, 1493, 1374, 1305, 1261,
1
1340, 1288, 1182, 1095, 1012, 908, 734, 649; H NMR
(CDCl3): l 1.34 (t, J=8.0 Hz, 3H), 4.26 (q, J=8.0 Hz,
2H), 4.94 (s, 2H), 6.19 (s, 1H), 7.36–7.51 (dd, J=8.0
Hz, 4H); 13C NMR (CDCl3): l 14.10, 26.09, 60.52,
119.94, 127.85, 128.88, 135.66, 136.70, 151.74, 165.17;
MS m/z (% rel. int.): 304 (M+, 5), 289 (5), 224 (8), 179
(10), 152 (100), 137 (55), 115 (92), 101 (48), 91 (22), 75
(15). Anal. calcd for C12H12BrClO2 requires: C, 47.48;
H, 3.95; Br, 26.32; Cl, 11.71. Found: C, 47.75; H, 4.18;
Br, 26.44; Cl, 11.34%.
1
2151, 1175, 1095, 827, 761, 668.; H NMR (CDCl3): l
1.18 (t, J=8.0 Hz, 3H), 2.58–2.66 (dd, JAB=16.0 Hz,
JBX=8.0 Hz, 1H); 2.72–2.83 (dd, JBA=16.0 Hz, JBX=
6.0 Hz, 1H), 3.33–3.54 (m, 3H), 4.07 (q, J=8.0 Hz,
2H), 7.15–733 (dd, J=8.0 Hz, 4H); 13C NMR (CDCl3):
l 14.25, 37.74, 41.34, 56.05, 60.57, 129.01, 133.24,
139.16, 159.89, 171.21; MS m/z (% rel. int.): 239 (M+−
N2, 5), 212 (15), 195 (5), 169 (65), 152 (30), 139 (100),
125 (50), 115 (30), 103 (70), 89 (20), 77 (40). Anal. calcd
for C12H14ClN3O2 requires: C, 53.84; H, 5.27; Cl, 13.24;
N, 15.70. Found: C, 53.74; H, 5.21; Cl, 13.19; N,
15.68%.
4.4. Ethyl 4-azido-3-(4-chlorophenyl)-2-butenoate 6
A 50 ml round-bottomed flask containing a solution of
bromoester 9 (1.85 g, 6.1 mmol) and sodium azide
(0.594 g, 9.14 mmol) in ethanol: water (80:20, 15 ml)
mixture was refluxed for 8 h. Resulting yellow color
solution was concentrated under reduced pressure to
yield crude azidoester 6, which was purified by column
chromatography packed with silica gel to give pure
azidoester 6 (1.26 g) as a colorless viscous liquid. Yield:
78%; IR (CHCl3, cm−1): 2982, 2104, 1712, 1629, 1591,
1492, 1454, 1369, 1249, 1180, 1095, 1012, 910, 831, 732;
1H NMR (CDCl3): l 1.34 (t, J=6.0 Hz, 3H), 4.23 (q,
J=6.0 Hz, 2H), 4.71 (s, 2H), 6.29 (s, 1H), 7.32–7.47
(dd, J=8.0 Hz, 4H); 13C NMR (CDCl3): l 13.96, 47.92,
60.53, 120.96, 127.84, 128.83, 135.63, 136.88, 149.12,
165.33. Anal. calcd for C12H12ClN3O2 requires: C,
54.26; H, 4.52; Cl, 13.34; N, 15.82. Found: C, 54.29; H,
4.24; Cl, 13.31, N, 15.99%.
4.7. (R)-3-(4-Chloropheny)-2-pyrrolidone 12
To a 25 ml round-bottomed flask containing a mixture
of azidoester 11 (0.100 g, 0.375 mmol) and CoCl2·6H2O
(0.010 g, 0.042 mmol) in 0.5 ml water, at 25°C was
added dropwise under stirring a solution of NaBH4
(0.028, 0.75 mmol) in 0.5 ml H2O. The resulting reac-
tion mixture was stirred for 30 min in which the
appearance of black precipitate indicated the formation
of cobalt–boride species. After the reaction was com-
plete, the mixture was extracted with chloroform (3×10
ml). The chloroform layer was washed with brine, dried
over anhydrous Na2SO4 and evaporated under reduced
pressure. The residue obtained was then purified by
column chromatography to give pure light yellow col-
ored solid of (R)-3-(4-chloropheny)-2-pyrrolidone 12,
0.058 g. Yield: 80%; mp: 115–117°C; [h]2D5=−26.35 (c
1.0, EtOH), 68% ee {lit.13 [h]2D5=−39.0 (c 1, EtOH)}; IR
(CHCl3, cm−1): 3420, 3200, 2103, 1698, 1492, 1374,
4.5. Preparation of (S)-2,2%-bis(diphenylphosphino)-1,1%-
binaphthyl Ru(II) complex19
A dry, 25 ml two-necked, round bottomed flask was
charged with [RuCl2(benzene)2] (38.3 mg, 0.0765 mmol)
and (S)-BINAP (100 mg, 0.16 mmol). The flask was
then evacuated, filled with argon and then N,N%-
dimethylformamide (2.6 ml) was introduced through
syringe. The suspension was stirred under argon atmo-
sphere at 100°C for 10 min the resulting clear reddish
brown reaction mixture was cooled and concentrated at
60°C (3 mmHg) with vigorous stirring. Finally, it was
dried at 3 mmHg for 3 h to yield reddish brown solid of
Ru(II)–(S)-BINAP complex (135 mg). This solid was
1
1216, 1090, 758, 700, 668; H NMR (CDCl3): l 2.39–
2.51 (dd, J=16.90 Hz and 8.41 Hz, 1H), 2.68–2.81 (dd,
J=16.90 Hz and 8.72 Hz, 1H); 3.35–3.43 (m, 1H),
3.62–3.84 (m, 2H), 7.18 (d, J=9.12 Hz, 2H), 7.31 (d,
J=9.12 Hz, 2H); 13C NMR (CDCl3): l 38.22, 39.51,
49.43, 128.02, 128.83, 132.72, 140.59, 178.01; MS m/z
(% rel. int.): 195 (M+, 15), 140 (24), 138 (100), 75 (5).

V. V. Thakur et al. / Tetrahedron: Asymmetry 14 (2003) 581–586
585
Anal. calcd for C10H10ClNO requires: C, 61.39; H, 5.15;
Cl, 18.12; N, 7.16. Found: C, 61.29; H, 4.98; Cl, 18.18;
N, 7.09%.
169.41, 172.50, 190.77; MS m/z (% rel. int.): 226 (M+,
16), 180 (8), 139 (100), 111 (19), 75 (10). Anal. calcd for
C11H11ClO3 requires: C, 58.29; H, 4.89; Cl, 15.64.
Found: C, 58.31; H, 4.80; Cl, 15.55%.
4.8. (R)-(−)-Baclofen hydrochloride 1
4.10. Asymmetric reduction of ethyl 4-chlorophenylben-
zoyl acetate 5
A mixture of compound 12 (0.050 g, 0.256 mmol) in
aqueous 6N HCl (0.5 ml) was heated at 100°C for 10 h.
The excess of water in the reaction mixture was
removed under reduced pressure to obtain solid residue,
which was triturated in isopropanol affording (R)-(−)-
baclofen hydrochloride as a colorless solid (0.045 mg).
Yield: 76%; mp: 195–197°C; [h]2D5=−1.34 (c 0.6, H2O),
67% ee {lit.10c [h]D25=−2.00 (c 0.6, H2O)}; IR (CHCl3,
cm−1): 3200, 2092, 2955, 1620, 1550, 1490, 1090, 758,
A dry two-necked round-bottomed flask was charged
with b-ketoester 5 (2.27 g, 10 mmol) and dry ethanol
(60 ml). To this mixture was added (S)-BINAP–Ru(II)
complex (40 mg, 0.05 mmol) under a stream of argon.
The resulting yellowish orange solution was degassed
with argon and then transferred by cannula to dry and
clean autoclave. Hydrogen was introduced into the
autoclave until the pressure gauge indicates 5 atm. The
pressure was then carefully released to 1 atm. This
procedure was repeated twice, and finally hydrogen was
pressurized to 800 psi. The reaction mixture was vigor-
ously stirred at 30°C for 100 h. The stirring was
stopped and excess hydrogen was carefully bled off.
The deep reddish orange reaction mixture was trans-
ferred to 100 ml round bottom flask and the autoclave
was rinsed with dichloromethane (3×15 ml). The sol-
vent was removed in vacuo and the residue was sub-
jected to column chromatography (10% ethyl acetate in
petroleum ether as eluent) to get pure (R)-alcohol 2
(2.24 g). Yield: 95%; gum; [h]2D5=+41.3 (c 1.5, CHCl3),
96% ee (determined by Eu(hfc)3 shift reagent); IR
(Neat, cm−1): 3461, 2981, 1718, 1595, 1490, 1400, 1375,
1
704, 698; H NMR (DMSO-d6): l 2.65–2.91 (AB part
of ABX pattern, JAB=16.6 Hz, JAX=6.9 Hz, JBX=7.7
Hz, 2H), 3.10–3.39 (AB part of ABX pattern, JBA
=
12.8 Hz, JAX=6.0, JBX=8.9 Hz, 2H); 3.64–3.72 (m,
1H), 7.41–7.43 (m, 4H); 13C NMR (DMSO-d6): l 37.70,
40.22, 48.50, 128.11, 128.93, 131.24, 141.81, 176.00; MS
m/z (% rel. int.): 195 (10), 140 (61), 138 (100), 125 (6),
115 (10), 103 (45), 89 (9), 77 (29). Anal. calcd for
C10H13Cl2NO2 requires: C, 48.02; H, 5.24; Cl, 28.35; N,
5.60. Found: C, 48.24; H, 5.15; Cl, 28.41; N, 5.49%.
4.9. Ethyl 4-chlorophenylbenzoyl acetate 5
A 100 ml two-necked round-bottomed flask was
charged with activated zinc (2.32 g, 35.7 mmol), and
kept under N2 atmosphere. Dry benzene (30 ml) was
introduced and the reaction mixture was heated to 80°C
(oil bath temp.). A solution of ethyl bromoacetate (5.88
g, 35.7 mmol) and p-chlorobenzaldehyde (4.56 g, 32.46
mmol) in dry benzene (20 ml) was added dropwise to
the reaction mixture. After completion of the addition,
the resulting reaction mixture was refluxed for 6 h,
cooled to rt and quenched by adding ice cold 4N
H2SO4 (30 ml). The crude hydroxyester 4 was extracted
with diethyl ether evaporated under reduced pressure.
1
1284, 1193, 1091, 1014, 831; H NMR (CDCl3): l 1.25
(t, J=7.10 Hz, 3H), 2.65–2.70 (m, 2H), 4.17 (q, J=7.10
Hz, 2H), 5.07–5.14 (m, 1H), 7.31 (s, 4H); 13C NMR
(CDCl3): l 14.00, 43.22, 60.83, 69.54, 127.03, 128.53,
133.31, 141.11, 171.98; MS m/z (% rel. int.): 228 (M+,
3), 182 (6), 156 (53), 139 (100), 111 (54), 75 (73). Anal.
calcd for C11H13ClO3 requires: C, 57.78; H, 5.73; Cl,
15.50. Found: C, 57.77; H, 5.69; Cl, 15.68%.
4.11. (S)-Ethyl 3-bromo-3-(4-chlorophenyl)propionate
13
To a mixture of b-hydroxy ester 4 (4.56 g, 20 mmol) in
diethyl ether (40 ml) was added dropwise through
addition funnel freshly prepared chromic acid solution
(15 ml) under ice-cold conditions with vigorous stirring.
The reaction mixture was allowed to come to room
temperature and stirring continued for 3 h (monitored
by TLC). The organic layer was separated and the
aqueous layer was extracted with ether (2×15 ml). The
combined ethereal extracts were washed with water (15
ml) followed by brine (15 ml) and concentrated under
reduced pressure to give crude product, which was
further purified by column chromatography on silica
gel using petroleum ether:EtOAc (9:1) as eluent to
afford b-ketoester 5 (3.39 g). Yield: 75%; IR (CHCl3,
cm−1): 2981, 2927, 1739, 1689, 1623, 1589, 1490, 1423,
1325, 1265, 1201, 1091, 1012, 840, 819; 1H NMR
(CDCl3): l 1.21–1.36 (m, 3H), 3.96 (s, 2H), 4.19–4.30
(m, 2H), 5.62 (s, 1H), 7.34–7.45 (m, 2H), 7.69 (d,
J=8.21 Hz, 1H), 7.88 (d, J=8.24 Hz, 1H), 12.60 (s,
1H); 13C NMR (CDCl3): l 13.48, 13.67, 45.17, 59.91,
60.83, 87.07, 126.81, 127.95, 128.20, 128.42, 128.68,
129.20, 129.38, 131.29, 133.90, 136.66, 139.45, 166.65,
To a mixture containing b-hydroxy ester 2 (0.500 g, 2.2
mmol) in dry ether (15 ml), pyridine (0.40 ml, 4.84
mmol) was added under argon atmosphere. The reac-
tion mixture was cooled to −20°C. Then PBr3 (0.650 g,
0.230 ml, 2.4 mmol) in ether (5 ml) was added dropwise
at −20°C. The reaction mixture was then stirred for 3 h
at −20°C and then for 50 h at 0°C (monitored by TLC).
The reaction was quenched by the addition of crushed
ice the ether layer was washed with ice water, 85%
phosphoric acid, cold saturated sodium bicarbonate,
twice with cold water and brine, and dried over anhy-
drous Na2SO4. The crude product was finally purified
by column chromatography on silica using petroleum
ether:EtOAc (9:1) as eluent to afford b-bromoester 13
(0.504 g). Yield: 79%; [h]2D5=−104.2 (c 2.0, CHCl3); IR
(CHCl3, cm−1): 2981, 2935, 1735, 1595, 1492, 1411,
1313, 1263, 1199, 1093, 1014, 829, 617; 1H NMR
(CDCl3): l 1.23 (t, J=7 Hz, 3H), 3.08–3.35 (m, 2H),
4.12 (q, J=7 Hz, 2H), 5.33 (t, J=6 Hz, 1H), 7.29–7.38
(m, 4H); 13C NMR (CDCl3): l 14.00, 44.73, 46.42,
60.79, 128.50, 128.79, 134.34, 139.38, 168.82; MS m/z

586
V. V. Thakur et al. / Tetrahedron: Asymmetry 14 (2003) 581–586
(% rel. int.): 292 (M+, 6), 247 (10), 211 (69), 169 (98),
138 (88), 103 (100), 77 (88), 63 (36). Anal. calcd for
C11H12BrClO2 requires: C, 45.31; H, 4.15; Br, 27.41; Cl,
12.61. Found: C, 45.53; H, 4.13; Br, 27.44; Cl, 12.55%.
Acknowledgements
V.V.T. and M.D.N. thank the CSIR, New Delhi, for
research fellowships. The authors wolud also like to
thank Dr. S. Devotta, Head, Process Development
Division, for his constant encouragement and support.
4.12. (R)-Ethyl 3-cyano-3-(4-chlorophenyl)propionate 3
In a 25 ml flask were added b-bromoester 13 (0.474 g,
1.6 mmol), NaCN (0.106 g, 4 mmol) and dry DMF (10
ml) under argon atmosphere. The reaction mixture was
heated at 70°C for 14 h (monitored by TLC). After
completion of the reaction it was diluted with water (5
ml) and extracted with EtOAc (4×15 ml) combined
organic extracts were washed with brine (10 ml), dried
over anhydrous Na2SO4 and concentrated under
reduced pressure to give crude product. The crude
product was further purified by column chromatogra-
phy on silica gel using petroleum ether:EtOAc (8:2) as
eluent to afford cyanoester 3 (0.340 g). Yield: 88%; mp:
62–63°C; [h]2D5=+14.1 (c 1.5, CHCl3); IR (CHCl3,
cm−1): 2983, 2917, 2294, 1737, 1492, 1375, 1251, 1190,
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