The Ru-catalyzed enantioselective preparation of chiral halohydrins and their application in the synthesis of (R)-clorprenaline and (S)-sotalol

Article abstract of DOI:10.1016/j.tetasy.2011.04.017

The asymmetric transfer hydrogenation of a series of halo-substituted aryl methyl ketones, including those substituted in both α-methyl and aryl rings, was studied for the preparation of chiral halohydrins. Up to 99.7% ee was obtained with 2-chloro-1-(2-chlorophenyl)ethanone as the substrate and Ru-CsDPEN as the catalyst in an HCOONa/H₂O system. (R)-Clorprenaline, a drug used in the treatment of respiratory disorders, such as bronchitis and asthma, and (S)-sotalol, a class-III antiarrhythmic compound, were prepared with these chiral halohydrins.

Full text of DOI:10.1016/j.tetasy.2011.04.017

Tetrahedron: Asymmetry 22 (2011) 722–727
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
The Ru-catalyzed enantioselective preparation of chiral halohydrins
and their application in the synthesis of (R)-clorprenaline and (S)-sotalol
⇑
Chuanjun Lu, Zonghua Luo, Ling Huang, Xingshu Li
Institute of Drug Synthesis and Pharmaceutical Processing, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 February 2011
Accepted 1 April 2011
The asymmetric transfer hydrogenation of a series of halo-substituted aryl methyl ketones, including
those substituted in both a-methyl and aryl rings, was studied for the preparation of chiral halohydrins.
Up to 99.7% ee was obtained with 2-chloro-1-(2-chlorophenyl)ethanone as the substrate and Ru-CsDPEN
as the catalyst in an HCOONa/H2O system. (R)-Clorprenaline, a drug used in the treatment of respiratory
disorders, such as bronchitis and asthma, and (S)-sotalol, a class-III antiarrhythmic compound, were pre-
pared with these chiral halohydrins.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
co-workers, has become one of the most useful methods to obtain
chiral secondary alcohols in recent years. A variety of aromatic ke-
Chiral halohydrins, especially those substituted in the
a
-methyl
tones in an isopropanol system or HCOOH–Et3N azeotropic system
can be reduced by this catalyst or its analogues10 with excellent
chemical yields and enantioselectivities. However, the asymmetric
group, can be smoothly converted to epoxides, which are very
important intermediates in asymmetric and pharmaceutical
synthesis as they provide a range of biologically interesting com-
pounds or important molecules. For example, selective b3 adrener-
gic receptor agonists, Solabegron (CL 316243) 1 and 2, have been
shown to elicit anti-obesity effects and exhibit potent anti-diabetic
properties in relevant in vivo rodent models;1 compounds 3
(SR58611A) and 4 (FK175) have been reported to be effective
anti-obesity and anti-diabetic agents in rodents, and the latter
has been developed in the potential treatment of irritable bowel
syndrome and obesity and also for depression;2 (R)-clorprenaline
hydrochloride 5 is a b2-agonist, which is effective in the treatment
of respiratory disorders, such as bronchitis and asthma;3 BMS-
536924 6 is a novel small-molecular inhibitor of the insulin-like
growth factor receptor kinase with equal potency against the
insulin receptor;4 The biphenyl analogue of the halo-substituted
aryl ketone 7, exhibits an excellent balance of high potency
(EC50 = 0.38 nM) for b3, high selectivity over b1 and b2, and good
pharmacokinetic properties in rats, dogs, and monkeys (Fig. 1).5
Although a number of chemical6 and biological7 methods have
recently been developed to obtain enantiomerically pure styrene
oxide derivatives recently, one of the most useful methods is still
the use of enantiomerically pure 2-halohydrins or their analogues
as intermediates, which can be converted smoothly to an epoxide
without a loss in enantiomeric purity.8 On the other hand, the
asymmetric transfer hydrogenation of prochiral ketones with
Ru-TsDPEN as the catalyst, initially developed by Noyori9 and
transfer hydrogenation of
a-bromoacetophenone cannot be per-
formed in the azeotrope system due to the formate displacement
reaction.11 Therefore, from a practical standpoint, it is desirable
to develop an effective asymmetric transfer hydrogenation method
for preparing enantiomerically pure halohydrins. In our previous
studies, we have reported the enantioselective preparation of
(R)-salmeterol12 and (R,R)-formoterol,13 (selective long-acting
b2-adrenoreceptor agonists) by using asymmetric transfer hydro-
genation as the key strategy. Herein, we report our study of the
ruthenium-catalyzed asymmetric transfer hydrogenation of halo-
substituted aryl methyl ketones in the HCOONa/H2O system and
their application in the synthesis of (R)-clorprenaline and (S)-
sotalol.
2. Results and discussion
In a preliminary screen study to develop a chiral Ru catalyst for
the asymmetric transfer hydrogenation of halo-substituted aryl
methyl ketones in an HCOONa/H2O system, we first chose ligand
L1, a widely used chiral ligand in asymmetric transfer hydrogena-
tion as the chiral ligand, and 2-bromo-1-(2-chlorophenyl)ethanone
as the model substrate. Good yield and ee were obtained in the
HCOONa/H2O system when the reaction was performed at 35 °C
for 21 h (Table 1, entry 1: 94% yield of total alcohol and epoxide
with 89% ee). In contrast, L2 and L3, with isopropyl and nitro
groups substituted at the phenyl ring of the benzenesulfonyl moi-
ety, gave 75% and 50% ee, respectively (Table 1, entries 3 and 4). It
is noteworthy that ligand (S,S,S)-CsDPEN L4, which is derived from
⇑
Corresponding author. Tel.: +86 20 39943050; fax: +86 20 39943050.
E-mail address: xsli219@yahoo.com (X. Li).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.04.017

C. Lu et al. / Tetrahedron: Asymmetry 22 (2011) 722–727
723
DPEN and camphorsulfonic acid, gave better results under the
same reaction conditions compared to TsDPEN (Table 1, entry 2:
90% yield of B and 7% of C with 93% ee). Inspired by the introduc-
tion of surfactants to the water-soluble Ru(II)-catalyzed asymmet-
ric transfer hydrogenation of ketones, which led to an increase in
the catalytic activity and enantioselectivity,14 we attempted to
COOH
OH
CO2H
H
N
OH
N
H
H
N
N
H
O
Cl
Cl
Solabegron 1
2
OH
H
Cl
OH
Cl
N
O
CO2Et
H
N
HCl
n
(R)-Clorprenaline hydrochloride 5
SR58611A (n=1) 3, FK175 (n=2) 4
H
O
N
N
CO2H
OH
H
N
H
N
OH
HN
Cl
N
Cl
O
7
BMS-536924 6
Figure 1. Some biologically interesting compounds derived from chiral styrene oxide.
Table 1
Asymmetric transfer hydrogenation of
a
-bromo-2-chloroacetophenonea
Cl
OH
Cl
C
Cl
O
O
[Ru(p-cymene)Cl2]2 /L*
HCOONa/H2O
Br
Br
+
A
B
Entry
Ligand
Additive
Time (h)
Yield of Bb (%)
eec (%)
Cb (%)
Config.d
1
2
3
4
5
6
7
8
(S,S)-TsDPEN
—
—
—
—
21
21
21
21
10
10
10
10
10
10
10
10
10
10
10
10
10
89
90
87
80
85
95
71
91
87
95
93
92
93
91
91
89
83
89
93
75
50
87
93
76
48
96
93
86
97
92
94
96
95
94
5
7
5
4
10
3
28
3
8
—
3
4
(R)
(R)
(S)
(R)
(R)
(R)
(S)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(S)
(R)
(S)
(S,S,S)-CsDPEN
(R,R)-2,4,6-iPro-DPEN
(S,S)-2-NO2-DPEN
(S,S)-TsDPEN
PEG2000
PEG2000
PEG2000
PEG2000
(S,S,S)-CsDPEN
(R,R)-2,4,6-iPro-DPEN
(S,S)-2-NO2-DPEN
(S,S,S)-CsDPEN
(S,S,S)-CsDPEN
(S,S,S)-CsDPEN
(S,S,S)-CsDPEN
(S,S,S)-CsDPEN
(S,S,S)-CsDPEN
(R,R,R)-CsDPEN
(R,S,S)-CsDPEN
(S,R,R)-CsDPEN
9
Steartrimonium bromide
Dodecyl trimethyl ammonium bromide
Cetyltrimethylammonium bromide
Sodium dodecyl sulfate
CH3CH2OH
10
11
12
13
14
15
16
17
5
5
4
4
Triton X-100
Sodium dodecyl sulfate
Sodium dodecyl sulfate
Sodium dodecyl sulfate
3
a
b
c
Reactions conditions: [Ligand-Ru]:[surfactant]:[substrate]:[HCOONa] = 1:50:100:500 and under an argon atmosphere at 35 °C.
Determined by 1H NMR analysis with 1,3,5-trimethylbenzene as the internal standard.
Ee values were determined by chiral OB-H column.
d
The configuration was determined by comparison of the specific rotation with the literature value.

724
C. Lu et al. / Tetrahedron: Asymmetry 22 (2011) 722–727
O
O
O
iPr
iPr
H2N
HN
iPr
S
H2N
HN
S
H2N
HN
S
NO2
O
O
O
(R,R)-2,4,6-iPr3-C6H2SO2-DPEN
(S,S)-Ts-DPEN
(S,S)-o-NO2-C6H4SO2-DPEN
L1
L2
L3
O
O
S
O
O
S
S
H2N
HN
H2N
HN
S
H2N
HN
O
H2N
HN
O
O
O
O
O
O
O
(S,S,S)-Cs-DPEN
(R,R,R)-Cs-DPEN
(R,S,S)-Cs-DPEN
(S,R,R)-Cs-DPEN
L4
L5
L6
L7
Figure 2. Chiral ligands used in the asymmetric transfer hydrogenation of halo-substituted aryl methyl ketone.
perform the asymmetric transfer hydrogenation of halo-substi-
tuted aryl methyl ketone in water by using surfactants. The screen-
ing tests included variant surfactants and different loading of the
surfactants. The catalytic activity increased when PEG2000 was
introduced to the catalytic system (Table 1, entries 5–8). Catalytic
system L1-[RuCl2(p-cymene)]2, gave 95% yield (the total of alcohol
and epoxide) with 87% ee for the model substrate; catalytic system
L2-[RuCl2(p-cymene)]2, which has three isopropyl groups on the
sulfonyl part, gave 28% yield of epoxide and 71% yield of alcohol
with 76.0% ee. The electron-withdrawing group on the sulfonyl
part of the ligands seems to be not favorable to the enantioselectiv-
ity, L3-[RuCl2(p-cymene)]2, with a nitro group on the sulfonyl part,
gave the lowest enantioselectivity even in the presence of surfac-
tants (Table 1, entry 8, 94% yields with 48% ee). On the other hand,
catalytic system L4-[RuCl2(p-cymene)]2 provided 98% yield with
93% ee, which is still to be the best one in the four catalytic
systems. Variant other surfactants were screened subsequently
(Table 1, entries 9–14) with L4-[RuCl2(p-cymene)]2 as the catalyst.
The addition of cationic surfactants, steartrimonium bromide and
dodecyl trimethyl ammonium bromide could effectively enhance
the enantioselectivity (Table 1, entries 9 and 10, 96% and 93% ee,
respectively). However, when cetyltrimethylammonium bromide
was introduced to the catalytic system, only 86% ee was obtained
(Table 1, entry 11). The highest ee value was obtained when so-
dium dodecyl sulfate (an anionic surfactant) was introduced into
the catalytic system (Table 1, entry 12, 92% yield with 97% ee).
Additionally, poly(ethylene glycol) mono-4-(1,1,3,3-tetrame-
thylbutylphenyl) ether (Triton X-100, a non-ionic surfactant) gave
94% ee under the same reaction conditions (Table 1, entry 14). On
the other hand, the addition of alcohol to the catalytic system had
no effect on the enantioselectivity (Table 1, entry 13, 92% ee). Li-
gands (R,R,R)-CsDPEN L5, (R,S,S)-CsDPEN L6 and (S,R,R)-CsDPEN
product in nearly the same ee as that of ligand (S,S,S)-CsDPEN,
but with an (S)-configuration (Table 1, entry 15). On the other
hand, ligand (R,S,S)-CsDPEN provided 95% ee with an (R)-configura-
tion, and (S,R,R)-CsDPEN gave 94% ee with an (S)-configuration. The
results imply that the DPEN moiety of the ligand plays a key role in
the asymmetric induction although CsDPEN presegavented better
results than TsDPEN (Fig. 2).
To obtain the optimal reaction conditions for avoiding the
formation of more epoxides in the reaction, the time–conversion
relationships of typical substrates such as 2-bromo-1-(2-chloro-
phenyl)ethanone and 2-bromo-1-(4-chlorophenyl)ethanone were
carried out. The results in Figure 3 show 2-bromo-1-(2-chloro-
phenyl)ethanone could be converted in 5 h, while some other
substrates required more time for the translation. Various
100
100
90
80
Conversion of A
Conversion of B
ee of A ATH
ee of B ATH
80
70
60
40
20
0
2
4
6
8
10
Time (h)
L7, which derived from (R,R)-DPEN, (S,S)-DPEN, D-camphorsulfonic
acid and (R)-camphorsulfonic acid, respectively, were also pre-
pared and tested in the reaction. Ligand (R,R,R)-CsDPEN gave the
Figure 3. The time–conversion relationships of 2-bromo-1-(2-chlorophenyl)etha-
none (A) and 2-bromo-1-(4-chlorophenyl)ethanone (B). ATH = asymmetric transfer
hydrogenation.

C. Lu et al. / Tetrahedron: Asymmetry 22 (2011) 722–727
725
halo-substituted aryl methyl ketones were catalyzed by Ru-(S,S,S)-
CsDPEN under the optimal reaction conditions and the results are
listed in Table 2. All substrates in the reaction gave the products
(mainly 2-halo-1-phenylethanol and some of the styrene oxide
derivatives) with good to excellent ee values (Table 2, entries
1–7: nearly full conversion with 95–99.7% ee). The highest ee value
obtained was with the 2-chloro-1-(2-chlorophenyl)ethanone as
the substrate (Table 2, entry 4: 93% yield of the corresponding sec-
ondary alcohol with 99.7% ee).
With chiral halohydrins in hand, (R)-clorprenaline 5, whose
hydrochloride is effective in the treatment of respiratory disorders
such as bronchitis and asthma, was prepared in a very simple
Table 2
Asymmetric transfer hydrogenation of
a
-halo ketones under optimal conditionsa
O
OH
O
X
[Ru(p-cymene)Cl2]2/ L*
X
R
R
+
R
HCOONa/H2O
A
C
B
Entry
Substrate
L*
Time (h)
S/C
Yield of Bb (%)
eec (%)
Cb (%)
Config.d
1
2
3
4
5
6
7
8
R = o-Cl, X = Br
R = m-Cl, X = Br
R = p-Cl, X = Br
R = o-Cl, X = Cl
R = o-Br, X = Br
R = m-Br, X = Br
R = p-Br, X = Br
R = p-NO2, X = H
R = p-NO2, X = Br
R = m-NO2, X = Br
R = o-Cl, X = Br
R = o-Cl, X = Br
R = o-Cl, X = Br
R = o-Cl, X = Br
L4
L4
L4
L4
L4
L4
L4
L5
L5
L5
L4
L4
L4
L4
5
5
6
5
8
8
5
5
8
100
100
100
100
100
100
100
100
100
100
200
500
1000
100
90
91
87
93
86
94
97
93
88
85
90
80
24
85
97
96
96
1
8
3
—
3
6
3
—
9
5
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(S)
(S)
(R)
(R)
(R)
(R)
99.7e
97f
95
97e
90e
93e
90
97
97
9
10
11
12g
13
14h
8
10
24
48
5
3
1
0.5
2
96
97
a
b
c
Reactions condition: [Ligand-Ru]:[surfactant]:[substrate]:[HCOONa] = 1:50:100:500 and under an argon atmosphere at 35 °C.
Determined by 1H NMR analysis with 1,3,5-trimethylbenzene as the internal standard.
Ee values were determined by chiral OB-H column.
d
e
f
The configuration was determined by comparison of the specific rotation of the halohydrin or corresponding epoxide with the literature value.7,15
Ee values were determined by chiral OJ-H column.
Ee values were determined by chiral OD-H column.
Dichloromethane (0.5 mL) was added to the reaction system.
The reaction was performed in air.
g
h
Cl
Cl
OH
Cl
OH
O
H
N
K2CO3
i-PrNH2
Cl
MeOH,rt
99.7% ee
(R)-clorprenalline
Scheme 1. The preparation of (R)-clorprenaline.
O
OH
Br
Br
[Ru(p-cymene)Cl2]2 / L5
Pt/C, H2
HCOONa/H2O
O2N
O2N
OH
OH
Br
OH
H
N
Br
i-PrNH2
MsHN
MsCl, pyridine
CH2Cl2
H2N
MsHN
(S)-sotalol
Scheme 2. Enantioselective synthesis of (S)-sotalol.

726
C. Lu et al. / Tetrahedron: Asymmetry 22 (2011) 722–727
procedure with enantiomerically pure 2-chloro-1-(2-chloro-
phenyl)ethanol as the starting material: the secondary alcohol
was converted into the epoxide in the presence of a base, which
upon regioselective opening with an isopropyl amine, afforded
the target product (Scheme 1).16
The total synthesis of (S)-sotalol was also performed (Scheme 2).
Commercially available p-nitroacetophenone was used as the
starting material. The reaction of this ketone with bromine in ace-
tic acid gave the corresponding bromoketone, which was reduced
to chiral bromoalcohol with 93% ee via asymmetric transfer hydro-
genation catalyzed by L5-[RuCl2(p-cymene)]2. The nitro group of
the intermediate was transformed into an amino group by Pt/C cat-
alyzed hydrogenation and then reacted with methylsulfonyl chlo-
ride in the presence of pyridine to give sulfonamide. Finally,
sulfonamide reacted with isopropylamine to afford the desired
product (S)-sotalol in 35% total yield.
chloride was removed under reduced pressure to afford (1S)-(+)-
10-camphorsulfonyl chloride, which was used in the next step
without purification.
To a stirred solution of triethylamine (1.39 mL, 10 mmol) and
(1S,2S)-1,2-diphenylethane-1,2-diamine (1.06 g, 5 mmol) in CH2Cl2
(15 mL) at 0 °C, (1S)-(+)-10-camphorsulfonyl chloride 1 (1.25 g,
5 mmol) in CH2Cl2 (5 mL) was added dropwise. Then after stirring
at the same temperature for 1 h, and then at room temperature for
another 4 h, the reaction mixture was quenched with water and
extracted with CH2Cl2. The organic phase was separated and dried
over anhydrous sodium sulfate, filtered, and concentrated under
reduced pressure. The residue was purified by crystallization with
ethyl acetate and methanol to afford (S,S,S)-CsDPEN as a white so-
lid (1.04 g, 48% yield). 1H NMR (400 MHz, CDCl3): d 7.37–7.20 (m,
10H), 4.71 (d, J = 4.9 Hz, 1H), 4.35 (d, J = 4.9 Hz, 1H), 2.84 (d,
J = 14.9 Hz, 1H), 2.36–2.25 (m, 2H), 2.24–2.14 (m, 1H), 2.01–1.88
(m, 2H), 1.85 (d, J = 18.4 Hz, 1H), 1.66 (m, 1H), 1.32 (m, 1H), 0.89
(s, 3H), 0.69 (s, 3H); 13C NMR (100 MHz, CDCl3) d 215.39, 141.97,
140.28, 128.57, 128.56, 127.74, 127.60, 126.90, 120.86, 63.75,
60.29, 58.60, 50.53, 48.06, 45.06, 42.71, 26.87, 25.63, 19.87,
19.57; LC/MS (ESI) m/z: [M+H]+ 427.2.
3. Conclusion
In conclusion, we have developed a very effective method for
the asymmetric transfer hydrogenation of a-halo-substituted aryl
methyl ketones. Up to 99% ee was obtained with Ru-Cs-DPEN as
the catalyst in the HCOONa/H2O system. This efficient and practical
approach to prepare enantiomerically pure halohydrins or the cor-
responding styrene oxide derivatives is a promising prospect for its
industrial application in the synthesis of biologically interesting
compounds.
4.3.2. Preparation of (R,R,R)-CsDPEN L5
White solid, 45% yield. 1H NMR (400 MHz, CDCl3): d 7.39–7.19
(m, 10H), 4.72 (d, J = 5.5 Hz, 1H), 4.40 (d, J = 5.5 Hz, 1H), 2.83 (d,
J = 14.8 Hz, 1H), 2.36–2.26 (m, 2H), 2.23–2.13 (m, 1H), 2.01–1.92
(m, 2H), 1.85 (d, J = 18.5 Hz, 1H), 1.64 (m, 1H), 1.34–1.29 (m, 1H),
0.87 (s, 3H), 0.67 (s, 3H); 13C NMR (100 MHz, CDCl3) d 215.27,
141.20, 140.02, 128.54, 128.50, 127.75, 127.60, 127.10, 127.08,
63.83, 60.12, 58.48, 50.50, 48.02, 45.90, 42.64, 26.86, 25.40,
19.76, 19.48; LC/MS (ESI) m/z: [M+H]+ 427.2.
4. Experimental
4.1. General
4.3.3. Preparation of (R,S,S)-CsDPEN L6
The 1H NMR spectra were recorded with TMS as an internal
standard on a Bruker AV400 spectrometer. Ee values were deter-
mined on a SHIMADZU LC-20AT chromatography using Daicel
Chiralcel columns (OD-H, OB-H and OJ-H). The optical rotation
was measured with a Perkin–Elmer Model 341 polarimeter at
589 nm and 25 °C, using a 1 dm path length. Pure water was used
in the asymmetric transfer hydrogenation of all the ketones. Chiral
ligands, substrates were prepared as the procedure described in
our previous work.17
Yellow solid, 44% yield. 1H NMR (400 MHz, CDCl3): d 7.26–7.04
(m, 10H), 6.61 (s, 1H), 4.60 (d, J = 6.7 Hz, 1H), 4.24 (d, J = 7.0 Hz,
1H), 2.64 (d, J = 15.0 Hz, 1H), 2.47 (d, J = 15.0 Hz, 1H), 2.30–2.21
(m, 1H), 2.00–1.89 (m, 4H), 1.85 (d, J = 18.6 Hz, 1H), 1.40–1.30
(m, 1H), 0.78 (s, 3H), 0.39 (s, 3H); 13C NMR (100 MHz, CDCl3) d
216.27, 141.57, 139.14, 128.52, 128.31, 127.73, 127.65, 127.54,
127.24, 65.02, 60.69, 59.22, 51.58, 48.36, 42.84, 42.57, 27.08,
26.93, 19.52, 19.26; LC/MS (ESI) m/z: [M+H]+ 427.2.
4.3.4. Preparation of (S,R,R)-CsDPEN L7
4.2. Typical procedure for asymmetric transfer hydrogenation
in water with the use of surfactants
Yellow solid, 46% yield. 1H NMR (400 MHz, CDCl3): d 7.25–7.14
(m, 10H), 6.61 (s, 1H), 4.60 (d, J = 7.0 Hz, 1H), 4.24 (d, J = 7.0 Hz,
1H), 2.64 (d, J = 15.0 Hz, 1H), 2.47 (d, J = 15.0 Hz, 1H), 2.26 (m,
1H), 2.02–1.90 (m, 4H), 1.85 (d, J = 18.6 Hz, 1H), 1.40–1.31 (m,
1H), 0.78 (s, 3H), 0.39 (s, 3H). 13C NMR (100 MHz, CDCl3) d
216.28, 141.55, 139.14, 128.52, 128.31, 127.73, 127.65, 127.54,
127.25, 65.04, 60.68, 59.22, 51.57, 48.36, 42.84, 42.57, 27.07,
26.93, 19.52, 19.26; LC/MS (ESI) m/z: [M+H]+ 427.2.
A mixture of [Ru(p-cymene)Cl2]2 (3.06 mg, 0.005 mmol), (S,S,S)-
CsDPEN (4.26 mg, 0.010 mmol) and sodium dodecyl sulfate
(0.5 mmol) in degassed water (1 mL) was stirred and heated at
40 °C for 1 h under an argon atmosphere. After cooling to room
temperature, 2-bromo-1-(2-chlorophenyl)ethanone (0.2335 g,
1.0 mmol) and HCOONaꢀ2H2O (520 mg, 5.0 mmol) were subse-
quently introduced. Following quickly being degassed three times,
the solution was allowed to react at 35 °C for a certain period of
time. After the reaction was completed (monitored by TLC), the
reaction mixture was extracted with CH2Cl2 twice. The combined
extracts were dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuum to afford the crude product, which was
purified by silica gel chromatography to determine the enantiose-
lective excess.
4.4. Preparation of (R)-clorprenaline
A solution of epoxide (0.2 g, 1.29 mmol), excess isopropylamine
(4 mL) and 4 drops of water was stirred at room temperature for
30 min. Next, the mixture was heated at 60 °C for 6 h. After re-
moval of the excess isopropylamine, the residue was dissolved in
50 mL ether, dried, filtered, and concentrated. The solid was recrys-
tallized from hexane to afford (R)-clorprenaline (270 mg, 90%) as a
white solid, >99% ee, mp 79–80 °C; ½a D25
ꢁ
¼ ꢂ71:6 (c 1.5, EtOH).16 1
H
4.3. Preparation of ligands
NMR (400 MHz, CDCl3) d 7.62 (dd, J = 7.7, 1.5 Hz, 1H), 7.34–7.27
(m, 2H), 7.20 (td, J = 7.6, 1.7 Hz, 1H), 5.05 (dd, J = 8.7, 3.4 Hz, 1H),
3.08 (dd, J = 12.3, 3.4 Hz, 1H), 2.91–2.77 (m, 1H), 2.53 (dd,
J = 12.3, 8.6 Hz, 1H), 2.06 (br s, 2H), 1.09 (t, J = 6.5 Hz, 6H). 13C
4.3.1. Preparation of (S,S,S)-CsDPEN L4
(1S)-(+)-Camphor-10-sulfonic acid (1.16 g, 5 mmol) was re-
fluxed in thionyl chloride (8 mL) for 12 h. Then, the excess thionyl

C. Lu et al. / Tetrahedron: Asymmetry 22 (2011) 722–727
727
NMR (100 MHz, CDCl3) d 140.27, 131.70, 129.22, 128.33, 127.23,
Acknowledgments
127.00, 68.58, 52.33, 48.56, 23.24, 22.99.
We thank the Ministry of Science and Technology of China (No.
2009ZX09501-017) and the Natural Science Foundation of China
(20972198) for financial support of this study.
4.5. Preparation of (S)-sotalol
4.5.1. 2-Bromo-1-(4-nitrophenyl)ethanol
The tittle compounds were obtained according to the aforemen-
tioned typical procedure for the asymmetric transfer hydrogena-
tion of halo-substituted aryl methyl ketone (93% ee). Up to 99%
ee could be obtained after recrystallization from ethyl acetate.
Mp 96.5 °C; 1H NMR (400 MHz, CDCl3) d 8.23–8.21 (d, J = 8.0,
2H), 7.59 (d, J = 8.0, 2H), 4.99 (dd, J = 8.3, 3.3 Hz, 1H), 3.61 (dd,
J = 10.6, 3.4 Hz, 1H), 3.46 (dd, J = 10.5, 8.4 Hz, 1H). 13C NMR
(100 MHz, CDCl3) d 149.0, 148.6, 128.1, 127.0, 123.8, 73.9, 39.2;
Anal. Calcd for C8H8BrNO3: C, 39.05; H, 3.28; N, 5.69. Found: C,
39.03; H, 3.28; N, 5.69.
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A
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ꢁ
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