A practical synthesis of (R)-3-chlorostyrene oxide starting from 3- chloroethylbenzene

Article abstract of DOI:10.1016/S0957-4166(98)00337-1

A novel and practical synthesis of (R)-3-chlorostyrene oxide (-)-1 was achieved starting from commercially available 3-chloroethylbenzene 3. Enantiopure (-)-3-chlorostyrene bromohydrin (-)-5 was obtained by the treatment of racemic (±)-5 with lipase QL in the presence of acylating reagents. 3-Chloro-α,β-dibromoethylbenzene 4, a precursor of (±)-5, was synthesized via the expeditious bromination of 3 which was developed by these authors.

Full text of DOI:10.1016/S0957-4166(98)00337-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3275–3282
A practical synthesis of (R)-3-chlorostyrene oxide starting from
3-chloroethylbenzene
Ken Tanaka ∗ and Mari Yasuda
Yokohama Research Center, Mitsubishi Chemical Corporation, 1000, Kamoshida-cho Aoba-ku, Yokohama,
Kanagawa 227-8502, Japan
Received 24 July 1998; accepted 12 August 1998
Abstract
A novel and practical synthesis of (R)-3-chlorostyrene oxide (−)-1 was achieved starting from commercially
available 3-chloroethylbenzene 3. Enantiopure (−)-3-chlorostyrene bromohydrin (−)-5 was obtained by the treat-
ment of racemic (ꢀ)-5 with lipase QL in the presence of acylating reagents. 3-Chloro-α,β-dibromoethylbenzene4,
a precursor of (ꢀ)-5, was synthesized via the expeditious bromination of 3 which was developed by these authors.
© 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
Homochiral styrene oxides are important chiral starting materials for the pharmaceutical industry.1 In
particular, (R)-3-chlorostyrene oxide (−)-1 is the common key intermediate for the preparation of several
β-3-adrenergic compounds 2 that show antiobesity and antidiabetic activities (Scheme 1).2
Scheme 1.
To date, many kinds of synthetic methods for the preparation of (−)-1 in enantiomerically pure or en-
riched form have been reported. Microbial reduction of α-bromo-3-chloroacetophenone and subsequent
treatment with base afforded (−)-1 in >99% ee.3 Asymmetric reduction of α,3-dichloroacetophenone
using an oxazaborolidine-based catalyst and subsequent treatment with base afforded (−)-1 in 85% ee
∗
Corresponding author. E-mail: kenbo@atlas.rc.m-kagaku.co.jp
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00337-1

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K. Tanaka, M. Yasuda / Tetrahedron: Asymmetry 9 (1998) 3275–3282
and 36% overall yield from 3-chloroacetophenone.2b Asymmetric dihydroxylation of 3-chlorostyrene
followed by a stereospecific ring closure afforded (−)-1 in 98% ee.4 Enzymatic resolution of racemic
(−)-1 has also yielded enantiopure (−)-1 but in only 5% yield.5 These syntheses suffer from the problem
of using expensive materials and/or low productivity.
Recently we discovered an expeditious synthesis of 3-chloro-α,β-dibromoethylbenzene 4 via bromi-
nation of commercially available 3-chloroethylbenzene 3.6 This process was expected to present a highly
attractive method for the preparation of 3-chlorostyrene bromohydrin (ꢀ)-5, a key intermediate of (−)-1.
We describe here a new route to (−)-1, which employs readily available materials and is applicable to
industrial scale preparation because of its high efficiency.
2. Result and discussion
The whole process is delineated in Scheme 2. The readily available 3-chloroethylbenzene 3 was
brominated with 1.0 equiv. of Br2 in the presence of 0.0001 equiv. of 2,20-azobis(isobutyronitrile) (AIBN)
at 50–60°C for 1 h and was successively brominated with 1.5 equiv. of Br2 in the presence of 0.0025
equiv. of I2 at 70°C for 2 h to afford 4 in 95% yield.6
Scheme 2.
Hydrolysis of dibromide 4 with water was examined under various reaction conditions and the results
are illustrated in Table 1. In our initial attempt (entry 1), the result was disappointing because of the low
conversion of 4. The use of DMF and NMP accelerated the conversion of 4, but the yield of bromohydrin
(ꢀ)-5 was quite low (entry 2–5). The addition of KI in DMF–H2O accelerated the reaction rate, but the
predominant formation of 3-chlorostyrene 7 via dehydrobromination of (ꢀ)-5 occurred (entry 6). When
the reaction was carried out in only H2O, the yield of (ꢀ)-5 was increased to 84% (entry 7). Under these
conditions, the addition of KI accelerated the reaction rate without the formation of 7. The use of water
as the reaction solvent allowed the easy separation of (ꢀ)-5 without extraction with solvent.

K. Tanaka, M. Yasuda / Tetrahedron: Asymmetry 9 (1998) 3275–3282
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Table 1
Hydrolysis of 4 with water in various reaction conditions
Next, we examined the kinetic resolution of (ꢀ)-5 by lipase catalyzed transesterification in organic
media. We first explored the resolution of (ꢀ)-5 using different lipases with vinyl acetate7 at rt and the
results are illustrated in Table 2. In this resolution, (+)-5 was mainly acylated to give acetate 6a and (−)-5
remained in low to high enantiomeric purity. Among the lipases examined, lipase QL (Alcaligenes sp.)
was effective for the resolution of (ꢀ)-5 and (−)-5 was obtained in 97% ee (entry 6).
Table 2
Resolution of (ꢀ)-5 using various lipases with vinyl acetatea
It is well known that the variation of acylating reagents may influence the reaction rate as well as
enantiomer selectivity.9 Therefore several vinyl esters7 were examined to find a more suitable acylating
reagent for this resolution with lipase QL. The results are illustrated in Table 3. Among vinyl esters

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K. Tanaka, M. Yasuda / Tetrahedron: Asymmetry 9 (1998) 3275–3282
Table 3
Resolution of (ꢀ)-5 using lipase QL with various vinyl estersa
examined, the use of vinyl acetate exhibited a fast reaction rate in this resolution with lipase QL (entry
1).
The solvent effects were examined for this resolution with lipase QL in the presence of vinyl acetate
at 35°C. The results are illustrated in Table 4. Among the solvents examined, the use of i-Pr2O gave a
good E value (E=43), but the reaction rate was not fast enough to apply to a practical resolution of (ꢀ)-1
(entry 5).
Table 4
Solvent effect of resolution of (ꢀ)-5 with vinyl acetatea
Finally, several acid anhydrides10 were examined and the results are illustrated in Table 5. Among the
acid anhydrides examined, the use of propionic anhydride exhibited a fast reaction rate, especially with
t-BuOMe as the reaction solvent which gave a high E value (E>116, entry 4).
The isolation method of (−)-1 is shown in Scheme 3. The racemic alcohol (ꢀ)-5 was reacted with
propionic anhydride in the presence of 20% (W/W) lipase QL at 35°C for 24 h to give a mixture of
alcohol (−)-5 and propionate 6b, and then the mixture was treated with aqueous NaOH to afford a
mixture of epoxide (−)-1 and ester 6b. Under these reactions conditions, ester 6b was not hydrolyzed

K. Tanaka, M. Yasuda / Tetrahedron: Asymmetry 9 (1998) 3275–3282
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Table 5
Resolution of (ꢀ)-5 using lipase QL with various acid anhydrides
and the racemization of (−)-1 did not occur. The epoxide (−)-1 was separated from the mixture by
distillation in >99% ee and 36% isolated yield from racemate (ꢀ)-5.
Scheme 3.
The propionate 6b was treated with NaOH/MeOH at rt to give (+)-1 in 85% ee and 71% isolated yield
from 6b (Scheme 4).
Scheme 4.
The utilization of the ester 6b is also important for economical reasons. The ester 6b is treated with
MeOH in the presence of H2SO4 to give (+)-5. The racemization of (+)-5 was examined in the presence
of various acids such as H2SO4, CF3CO2H, MeSO3H, and CF3SO3H. Of these, the use of 65% aqueous
H2SO4 at 80°C was shown to be best, giving racemic (ꢀ)-5 in high overall yield (92% from 6b) and with
a fast reaction rate (Scheme 5).

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K. Tanaka, M. Yasuda / Tetrahedron: Asymmetry 9 (1998) 3275–3282
Scheme 5.
3. Conclusion
In conclusion, a novel and practical synthesis of (−)-1 was accomplished starting from commercially
available 3-chloroethylbenzene 3. This method employs readily available materials and proceeds with
high efficiency. Also, the overall process does not require restricted reaction conditions. These features
make this process applicable to industrial scale preparation of (−)-1.
4. Experimental
4.1. General
1H NMR (300 MHz) spectra were recorded on a Varian UNITY 300 spectrometer in CDCl3 solutions,
using tetramethylsilane as an internal standard. IR spectra were recorded on JASCO IR-810 spectro-
photometer. Reactions and purities were checked by Shimadzu GC-14B gas chromatography using
biphenyl as an internal standard (column: SE-30 10%, 4.0 mm×2.0 m; detector: FID; carrier gas: N2).
High performance liquid chromatography (HPLC) was used for the enantiomeric excess analyses of 1,
5, 6a and 6b. Chiralcel OJ (eluent: n-hexane:i-PrOH (90:10), 1.0 mL/min; detect: 220 nm) was used for
determination of enantiomeric excess for 5. Chiralcel OJ (eluent: n-hexane:i-PrOH (95:5), 1.0 mL/min;
detect: 220 nm) was used for determination of enantiomeric excess for 6b. Chiralcel OJ (eluent: n-
hexane, 1.0 mL/min; detect: 220 nm) was used for determination of enantiomeric excess for 6a. Chiralpak
AD (eluent: n-hexane:i-PrOH (1000:0.4), 1.0 mL/min; detect: 220 nm) was used for determination
of enantiomeric excess for 1. Specific rotations were recorded on JASCO DIP-370 polarimeter in the
indicated solvent.
4.2. Materials
Solvents and materials were industrial grade and used without further purification. Lipase QL was a
gift from Meito Sangyo Co. Novozym 435 was a gift from Novo-Nordisk Co. Lipase PS, D, G, and AY
were gifts from Amano Pharmaceutical Co.
4.3. 2-Bromo-1-(3-chlorophenyl)ethanol (ꢀ)-5
A mixture of 4 (1065 g, purity 88%, 3.14 mol),6 KI (10.8 g, 65.1 mmol), and H2O (10.5 L) was refluxed
with stirring for 32 h. The reaction mixture was cooled to rt and washed with 5% aqueous NaHCO3 and
10% aqueous NaCl. The lower organic layer was separated to give crude (ꢀ)-5 (yellow oil, 714 g, purity
87%, 2.64 mol, 84% from 4). The low boiling materials were distilled off from crude (ꢀ)-5 (710 g) at rt to
115°C/0.5 mmHg to afford purified (ꢀ)-5 (yellow oil, 593 g, purity 92%, 2.31 mol, 74% from 4), which
was used in the next step without further purification. The small portion of purified (ꢀ)-5 was subjected
to silica gel column chromatography to give pure (ꢀ)-5. Yellow oil; IR (neat) 3400, 1425, 1195, 1062,

K. Tanaka, M. Yasuda / Tetrahedron: Asymmetry 9 (1998) 3275–3282
3281
1
782 cm−1; H NMR δ 2.66 (1H, d, J=3.3 Hz), 3.51 (1H, dd, J=8.7 and 10.5 Hz), 3.64 (1H, dd, J=3.3
and 10.5 Hz), 4.91 (1H, dt, J=3.3 and 8.7 Hz), 7.26–7.32 (3H, m), 7.41 (1H, s).
4.4. Lipase catalyzed resolution of bromohydrin (ꢀ)-5: typical procedure
Bromohydrin (ꢀ)-5 (1.60 g, 6.79 mmol) was dissolved in vinyl acetate (8.0 mL). After the addition
of lipase QL (320 mg), the mixture was stirred at rt for 7 days. The lipase was removed by filtration
and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column
chromatography with n-hexane:ethyl acetate (20:1) to give pure (R)-2-bromo-1-(3-chlorophenyl)ethanol
(−)-5 (529 mg, 2.25 mmol, 97% ee, 33% from (ꢀ)-5) and (S)-2-bromo-1-(3-chlorophenyl)ethyl acetate
20
6a (910 mg, 3.28 mmol, 75% ee, 48% from (ꢀ)-5). (−)-5: Yellow oil; [α]D −24.3 (c 1.05; CHCl3). 6a:
Yellow oil; [α]D20 +34.1 (c 1.14; CHCl3); IR (neat) 1755, 1375, 1240, 1210 cm−1; 1H NMR δ 2.16 (3H,
s), 3.57 (1H, dd, J=5.1 and 10.8 Hz), 3.63 (1H, dd, J=7.5 and 10.8 Hz), 5.93 (1H, dd, J=5.1 and 7.5 Hz),
7.22–7.26 (1H, m), 7.31–7.35 (3H, m).
4.5. (R)-3-Chlorostyrene oxide (−)-1 and (S)-2-bromo-1-(3-chlorophenyl)ethyl propionate 6b
Purified (ꢀ)-5 (53.8 g, purity 92%, 0.210 mol) and propionic anhydride (19.5 g, 0.150 mol) were
dissolved in t-butyl methyl ether (330 mL). After the addition of lipase QL (10 g), the mixture was stirred
at 35°C for 24 h. The lipase was removed by filtration and the filtrate was treated with 1N aqueous NaOH
(260 g, 0.260 mol) at rt for 2 h. The organic layer was separated and washed with water and brine. The
solvent was removed under reduced pressure and the residual oil was purified by bulb to bulb distillation
at 60–90°C/0.5 mmHg to give the distillate (15.7 g), which was purified by fractional distillation to afford
(−)-1 boiling at 77–80°C/3.0 mmHg (11.8 g, 76.2 mmol, >99% ee, 36% from racemate (ꢀ)-5). Colorless
liquid; [α]D −11.1 (c 1.23; CHCl3); IR (neat) 3057, 2994, 1600, 1576, 1478, 1198 cm−1; H NMR
δ 2.76 (1H, dd, J=2.4 and 5.4 Hz), 3.14 (1H, dd, J=4.2 and 5.4 Hz), 3.83 (1H, dd, J=2.4 and 4.2 Hz),
7.15–7.19 (1H, m), 7.26–7.28 (3H, m).
20
1
The residue of the distillation was crude 6b (32.4 g, purity 83%, 92.3 mmol, 85% ee, 44% from
racemate 5). The small portion was purified by silica gel column chromatography to give pure 6b. Yellow
oil; [α]D20 +50.8 (c 1.00; CHCl3); IR (neat) 1740, 1170, 1078, 1089 cm−1; 1H NMR δ 1.18 (3H, t, J=7.5
Hz), 2.34–2.54 (2H, m), 3.57 (1H, dd, J=5.1 and 10.8 Hz), 3.62 (1H, dd, J=7.5 and 10.8 Hz), 5.94 (1H,
dd, J=5.1 and 7.5 Hz), 7.22–7.28 (1H, m), 7.30–7.35 (3H, m).
Found: C, 45.08; H, 4.16. Calcd for C11H12BrClO2; C, 45.31; H, 4.15.
4.6. (S)-3-Chlorostyrene oxide (+)-1
To a solution of MeOH (100 mL) and NaOH (5.4 g, 135 mmol) was added crude 6b (20.0 g, purity
81%, 55.8 mmol, 85% ee) and the resulting solution was stirred at rt for 0.5 h. The reaction mixture was
diluted with water and extracted with ethyl ether. The organic layer was separated and washed with water
and brine. The solvent was removed under reduced pressure, and the residue was purified by fractional
distillation to afford (+)-1 boiling at 77–80°C/3.0 mmHg (6.14 g, 39.7 mmol, 85% ee, 71% from 6b).
Colorless liquid; [α]D20 +9.4 (c 1.07; CHCl3).

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4.7. Preparation of 2-bromo-1-(3-chlorophenyl)ethanol (ꢀ)-5: by acid catalyzed racemization
MeOH (31 mL) and conc. H2SO4 (2.0 mL) were added to 6b (31.0 g, purity 83%, 88.4 mmol, 85%
ee) and the resulting mixture was refluxed for 2 h. After cooling, the reaction mixture was quenched by
saturated aqueous NaHCO3 and extracted with toluene. The organic layer was separated, washed with
brine, and concentrated under reduced pressure to afford the residue (27.0 g). To the residue (14.9 g)
was added 65% aqueous H2SO4 (15 g) and the mixture was heated with stirring at 80°C for 7 h. After
cooling, the reaction mixture was diluted with toluene, the organic layer was separated and washed with
water, saturated aqueous NaHCO3, and brine. The solvent was removed under reduced pressure to afford
yellow oil (ꢀ)-5 (13.1 g, purity 81%, 45.1 mmol, 0% ee, 92% from 6b).
Acknowledgements
We are grateful to Professor T. Kitahara, The University of Tokyo, for his reviewing of this article. We
are also grateful to the members of the Kurosaki Research Center and the Analytical Laboratory in the
Yokohama Research Center of the Mitsubishi Chemical Corporation for their expert technical assistance.
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