Enantioselective reduction of benzofuryl halomethyl ketones: Asymmetric synthesis of (R)-bufuralol

Article abstract of DOI:10.1016/j.tetasy.2005.08.012

Enantioselective reduction of representative 2-(bromoacetyl)- and 2-(chloroacetyl)benzofurans with (-)-B-chlorodiisopinocampheylborane and by transfer hydrogenation with formic acid/triethylamine in the presence of RhCl[R,R-TsDPEN](C₅Me₅

Full text of DOI:10.1016/j.tetasy.2005.08.012

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3205–3210
Enantioselective reduction of benzofuryl halomethyl
ketones: asymmetric synthesis of (R)-bufuralol
Marek Zaidlewicz,* Agnieszka Tafelska-Kaczmarek and Andrzej Prewysz-Kwinto
Department of Chemistry, Nicolaus Copernicus University, 87-100 Torun´, Poland
Received 22 July 2005; accepted 12 August 2005
Abstract—Enantioselective reduction of representative 2-(bromoacetyl)- and 2-(chloroacetyl)benzofurans with (ꢀ)-B-chloro-
diisopinocampheylborane and by transfer hydrogenation with formic acid/triethylamine in the presence of RhCl[R,R-TsD-
PEN](C5Me5) is described. Transfer hydrogenation of the chloro ketones produced the corresponding chlorohydrins of P95%
ee. (R)-Bufuralol of 96% ee was prepared from the corresponding chloro ketone by transfer hydrogenation–substitution.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
b-amino alcohol (Scheme 1). However, the enantioselec-
tivity of the reduction was only moderate, while the isola-
tion of bromohydrins, (R)-1a and (R)-2a, required
tedious purification and labile epoxides, (S)-1b and (S)-
2b, had to be used as crude products for the reaction with
amines.
Recently, we reported the enantioselective synthesis of
two important physiologically active benzofuryl b-amino-
alcohols, (S)-bufuralol (S)-1c and a propafenone ana-
logue (S)-2c.1 Bufuralol is a nonselective b-adrenoceptor
blocking agent of comparable potency to propranolol.2–4
It is also a widely used substrate in studies of cyto-
chrome P450 (CYP) enzymes, and undergoes enantio-
and regioselective oxidation in the liver.5 (R)-Bufuralol
is a commonly used marker of hepatic CYP 2D6
activity.6
It was clear that improvements in the methodology to
achieve higher enantiomeric excess and modification of
the approach to avoid the formation of labile epoxides
were needed. Considering the first aim, we decided to
examine the enantioselective reduction of representative
2-(chloroacetyl)benzofurans with (ꢀ)-DIP-Cl and by
catalytic transfer hydrogenation introduced recently for
the enantioselective reduction of ketones and deriva-
tives.7–13 For comparison, selected 2-(bromoacetyl)ben-
zofurans were also reduced by transfer hydrogenation.
The key step in our syntheses of (S)-1c and (S)-2c was the
reduction of bromo ketones 1 and 2 with (ꢀ)-B-chloro-
diisopinocampheylborane [(ꢀ)-DIP-Cl], followed by a
sequence of transformations bromohydrin–epoxide–
R1
R1
O
R1
R1
R2
R2
R2
R2
4
R NH
NaH
2
(—)-DIP-Cl
THF
NHR4
O
O
Br
O
Br
O
O
R3
R3
R3
OH
R3
OH
1 R1, R2= H; R3= Et
2 R1= CH2CH2Ph, R2, R3= H
(R)-1a
(R)-2a
(S)-1b
(S)-2b
(S)-1c R4= t-Bu
(S)-2c R4= n-Pr
Scheme 1.
*
Corresponding author. Tel.: +48 56 6114522; fax: +48 56 6542477; e-mail: zaidlevi@chem.uni.torun.pl
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.08.012

3206
M. Zaidlewicz et al. / Tetrahedron: Asymmetry 16 (2005) 3205–3210
2. Results and discussion
While searching for a more selective reducing agent, we
turned to the transfer hydrogenation. Complexes of rho-
dium and ruthenium with various chiral ligands find
increasing applications as catalysts for the asymmetric
transfer hydrogenation of ketones and derivatives.7–13
2-Propanol/potassium hydroxide or formic acid/trieth-
ylamine are the hydrogen sources most often used.
Avoiding strong alkaline reaction conditions for our
product halohydrins, we selected formic acid/triethyl-
amine, 5:2, and RhCl[(R,R)-TsDPEN](C5Me5) catalyst
for the reduction of halo ketones 1–10. Reductions were
run at room temperature and the reaction progress
conveniently monitored by TLC analysis. The product
halohydrins were readily isolated by column chromato-
graphy. The results are presented in Table 1.
As reported earlier,14 the reduction of 2-bromo-1-(ben-
zofuran-2-yl)ethanone 3 with (ꢀ)-DIP-Cl produced the
corresponding bromohydrin (R)-3a in 77% ee. The
3-methyl derivative 4 was reduced with higher enantio-
selectivity (88% ee, Table 1), whereas 2, which had a
more sterically demanding 2-phenylethyl substituent
at the 3-position, reacted with lower selectivity
(73% ee). The 7-ethyl derivative 1 afforded (R)-1a
in 87% ee. The results indicate a moderate enantio-
selectivity of the reduction of bromo ketones 1–4 with
(ꢀ)-DIP-Cl.
The reduction of unsubstituted chloro ketone 5 with
(ꢀ)-DIP-Cl produced the corresponding chlorohydrin
(R)-5a in 92% ee (Table 1). The selectivity is consider-
ably higher when compared to the 77% ee obtained in
the reduction of the corresponding bromo ketone 3.
Similarly, chloro ketones 6 and 7 were reduced with
(ꢀ)-DIP-Cl to chlorohydrins (R)-6a and (R)-7a with
higher enantioselectivity when compared to the reduc-
tion of the corresponding bromo ketones 4 and 1 (Table
1). On the other hand, >95% ee was achieved in the
reduction of 7.
The transfer hydrogenation of unsubstituted chloro
ketone 5 produced chlorohydrin (S)-5a with 97% ee.
The enantiomeric excess of chlorohydrins (S)-5a,
(S)-9a and (S)-10a was >95% ee. Under the same condi-
tions, the reduction of bromo ketones 1, 3 and 4
proceeded with slightly lower enantioselectivity as
compared to the corresponding chloro ketones 7, 5
and 6. The high enantiomeric excess obtained in the
transfer hydrogenation of 2, in contrast to much lower
Table 1. The reduction of halo ketones 1–10 with formic acid/triethylamine/RhCl[R,R-TsDPEN](C5Me5) in ethyl acetate, and with
(–)-B-chlorodiisopinocampheylborane in tetrahydrofuran
R1
R1
R2
R2
A or B
O
X
O
X
R3
O
R3
OH
1a—10a
1—10
Halo ketone
Reducing agenta
Time (h)
Product halohydrin
Compound number
X
R1
R2
R3
Conf.b and number
eec (%)
Yieldd (%)
1
Br
H
H
H
H
H
H
H
H
Et
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
72
168
96
(S)-1a
(R)-1a
(S)-2a
(R)-2a
(S)-3a
(R)-3a
(S)-4a
(R)-4a
(S)-5a
(R)-5a
(S)-6a
(R)-6a
(S)-7a
(R)-7a
(S)-8a
(R)-8a
(S)-9a
(R)-9a
(S)-10a
92
87e
96
73e
91
77f
94
88
97
92
97
90
98
98
98
92
96
86
97
66
64
90
56
83
23
57
35
84
82
76
94
85
61
82
68
77
35
74
2
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
CH2CH2Ph
H
3
H
H
4
Me
H
H
72
5
H
96
6
Me
H
H
72
7
Et
H
96
8
Me
Me
Me
Me
H
72
9
Me
H
72
10
Et
120
a A = HCOOH/NEt3, 5:2, RhCl[R,R-TsDPEN](C5Me5), ethyl acetate, rt. B = (ꢀ)-B-Chlorodiisopinocampheylborane (Aldrich), THF, ꢀ25 ꢁC, 2 h,
rt, 12 h.
b Assignments based on the configuration of (R)-(ꢀ)-1a, Ref. 1; (R)-(ꢀ)-2a, Ref. 1 and (R)-(–)-3a, Ref. 14. Halohydrins with opposite signs of
rotation were obtained from reagents A and B.
c HPLC or GC analysis on chiral columns as described in Section 4. Racemates were analyzed for comparison.
d Isolated yields.
e Ref. 1.
f Ref. 14.

M. Zaidlewicz et al. / Tetrahedron: Asymmetry 16 (2005) 3205–3210
3207
selectivity in the reduction with (ꢀ)-DIP-Cl is notewor-
thy. In general, transfer hydrogenation of halo ketones
1–10 with formic acid/triethylamine/RhCl[R,R-TsD-
PEN](C5Me5) produced the corresponding halohydrins
of higher enantiomeric excess as compared to the reduc-
tion with (ꢀ)-DIP-Cl. Isolation of the product halohyd-
rins produced by transfer hydrogenation is simpler and
the yields are higher.
column chromatography on silica gel Merck grade
7734, 70–230 mesh. Rotations were measured on an
Optical Activity Ltd, PolAAr 3000, automatic polari-
meter. Elemental analyses were performed by the Micro-
analysis Laboratory, Institute of Organic Chemistry,
Polish Academy of Sciences, Warsaw, and by the
Microanalysis Laboratory, Department of Chemistry,
´
Nicolaus Copernicus University, Torun.
The high enantiomeric excess obtained for chlorohydrin
(S)-7a prompted us to transform it into (R)-bufuralol
(R)-1c (Scheme 2), avoiding cyclization to the labile
epoxide. Attempts to substitute the chlorine atom with
a tert-butylamino group via the reaction of (S)-7a with
tert-butylamine in several solvents were unsuccessful.
Fortunately, the reaction worked well in ethanol provid-
ing (R)-1c with 96% ee, in 53% yield.
4.2. Materials
(ꢀ)-B-Chlorodiisopinocampheylborane [(ꢀ)-DIP-Cl],
>99% ee, was a commercial product (Aldrich). Tetra-
hydrofuran was freshly distilled from sodium benzo-
phenone ketyl. Triethylamine was distilled from
lithium tetrahydridoaluminate. 3-Methylbenzofuran,15
3,5-dimethylbenzofuran,16 1-(benzofuran-2-yl)-2-chloro-
ethanone,17 1-(benzofuran-2-yl)-2-bromoethanone,18 2-
bromo-1-(3-methylbenzofuran-2-yl)ethanone,15 2-chloro-
1-(7-ethylbenzofuran-2-yl)ethanone,19 2-bromo-1-(7-ethyl-
benzofuran-2-yl)ethanone,1 2-bromo-1-(3-phenethylbenzo-
furan-2-yl)ethanone,1 RhCl[R,R-TsDPEN]-C5Me5),10
were prepared according to the literature. 3,7-Di-
3. Conclusion
A convenient highly enantioselective reduction of ben-
zofuryl chloromethyl ketones by transfer hydrogena-
tion, producing the corresponding chlorohydrins, has
been developed. (R)-Bufuralol of 96% ee was synthe-
sized via the sequence chloro ketone–b-chlorohydrin–
b-amino alcohol, circumventing the intermediate epox-
ide formation employed in the earlier syntheses.1–3 The
approach can be applied to asymmetric syntheses of
other b-amino alcohols.
1
methylbenzofuran, bp 118–120 ꢁC/20 mmHg; H NMR
(200 MHz, CDCl3): d 2.25 (s, 3H, CH3), 2.43 (s, 3H,
CH3), 6.89–7.11 (m, 2H, 2 · CH), 7.23–7.35 (m, 2H,
2 · CH); 13C NMR (50 MHz, CDCl3): d 7.3 (CH3), 14.9
(CH3), 115.6 (C), 118.6 (CH), 121.0 (C), 123.1 (CH),
125.3 (CH), 129.2 (C), 140.3 (CH), 154.8 (C); 5-ethyl-3-
methylbenzofuran, bp 51–53 ꢁC/1.5 mmHg; 1H NMR
(200 MHz, CDCl3): d 1.25 (t, J = 7.6 Hz, 3H, CH3),
1.99 (s, 3H, CH3), 2.62 (q, J = 7.6 Hz, 2H, CH2), 7.20–
7.40 (m, 4H, 4 · CH); 13C NMR (50 MHz, CDCl3): d
8.2 (CH3), 16.0 (CH2), 29.0 (CH2), 111.7 (CH), 115.7
(C), 121.1 (CH), 124.1 (CH), 129.2 (C), 134.9 (C),
140.3 (CH), 151.3 (C), were prepared from 3,7-di-
methylbenzofuran-2-yl carboxylic acid20 and 5-ethyl-3-
methylbenzofuran-2-yl carboxylic acid,21 respectively,
by decarboxylation with copper powder in quinoline at
reflux for 8 h.
4. Experimental
4.1. General
All reactions with air sensitive materials were carried
under a nitrogen atmosphere in a glassware kept in an
oven at 120 ꢁC for 12 h, assembled hot, and cooled un-
1
der nitrogen. H and 13C NMR spectra were recorded
on a Varian Gemini 200 and a Bruker AMX 300 spec-
trometers. Mass spectra were recorded on a AMD 604
mass spectrometer. IR spectra were recorded on a Per-
kin–Elmer Spectrum RX I instrument using sodium
chloride plates. GC analyses were performed on a Hew-
lett–Packard chromatograph provided with a flame ion-
ization detector and a chiral column Supelco Beta-DEX
325, 30 m · 0.25 mm. HPLC analyses were performed
on a Shimadzu VP liquid chromatograph equipped with
a UV254 nm detector and chiral columns: Daicel Chiralcel
OJ, 250 · 4.6 mm, 10 lm and Daicel Chiralcel OD-H,
250 · 4.6 mm, 5 lm. Reactions were monitored by
4.3. 2-Chloro-1-(3-methylbenzofuran-2-yl)ethanone 6
Aluminium chloride (4.67 g, 35 mmol) was added in
portions to a stirred solution of 3-methylbenzofuran
(3.97 g, 30 mmol) and chloroacetyl chloride (3.45 g,
30 mmol) in chloroform (50 mL) at ꢀ5 ꢁC and stirring
continued for 4 h at room temperature. The mixture
was poured into water-ice and acidified with hydrochlo-
ric acid. The organic layer was separated and the aque-
ous layer extracted with chloroform (2 · 15 mL). The
combined organic solutions were washed with a satu-
rated solution of sodium hydrogencarbonate (20 mL)
and dried with magnesium sulfate. The solvent was
TLC using Macherey–Nagel Polygram Sil G/UV254 nm
,
0.2 mm plates. Reaction products were purified by
HCOOH / NEt ,
3
RhCl[R,R-TsDPEN](C Me )
t-BuNH
EtOH,
reflux, 24 h
5
5
2
AcOEt, rt, 96 h
O
NHBut
O
Cl
O
Cl
Et
OH
Et
OH
(R)-1c, 96% ee
Et
O
7
(S)-7a
Scheme 2.

3208
M. Zaidlewicz et al. / Tetrahedron: Asymmetry 16 (2005) 3205–3210
removed and the product crystallized from cyclohexane,
3.05 g, 48% yield, mp 97–98 ꢁC; H NMR (300 MHz,
4.7. (S)-(+)-1-(Benzofuran-2-yl)-2-chloroethanol (S)-5a.
General procedure
1
CDCl3): d 2.65 (s, 3H, CH3), 4.78 (s, 2H, CH2Cl),
7.29–7.38 (m, 1H, CH), 7.49–7.55 (m, 2H, 2 · CH),
7.68 (dt, J = 7.8, 0.9 Hz, 1H, CH); 13C NMR
(75 MHz, CDCl3): d 9.5 (CH3), 46.8 (CH2), 112.2
(CH), 121.7 (CH), 123.6 (CH), 127.1 (C), 128.9 (C),
129.0 (CH), 146.0 (C), 154.2 (C), 187.7 (CO); MS
(70 eV): m/z 210 (M+2, 6.6), 208 (M+, 19.1), 160
(11.0), 159 (100.0), 103 (23.0), 102 (11.9), 77 (22.4), 51
(11.0); IR (KBr): 2935, 1693, 1576, 1397, 1251, 1129,
752. Anal. Calcd for C11H9ClO2: C, 63.32; H, 4.35; Cl,
16.99. Found: C, 63.34; H, 4.34; Cl, 17.43.
To RhCl[R,R-TsDPEN](C5Me5) (1.4 mg, 0.0022 mmol)
was added under nitrogen a solution of 5 (0.19 g,
1 mmol) in ethyl acetate (7 mL) and a mixture of formic
acid/triethylamine (5:2, 0.3 mL), and the mixture stirred
for 96 h at room temperature. The solvent was removed
and the product isolated by column chromatography on
silica gel (petroleum ether/diethyl ether, 3:2), 0.16 g, as
25
an oil, 84% yield, ½aꢁD ¼ þ27.7 (c 3.60, CHCl3), 97%
ee, determined by GC analysis on a Supelco Beta-
DEX 325, 30 m · 0.25 mm, chiral column; 1H NMR
(300 MHz, CDCl3): d 2.79 (br s, 1H, OH), 3.92 (dd,
J = 11.4, 6.6 Hz, 1H, CH2Cl), 3.98 (dd, J = 11.4,
4.5 Hz, 1H, CH2Cl), 5.09 (ddd, J = 6.6, 4.5, 0.9 Hz,
1H, CH), 6.77 (t, J = 0.9 Hz, 1H, CH), 7.21–7.35 (m,
2H, 2 · CH), 7.45–7.48 (m, 1H, CH), 7.55–7.58 (m,
1H, CH); 13C NMR (50 MHz, CDCl3): d 47.5 (CH2),
68.4 (CH), 104.3 (CH), 111.2 (CH), 121.2 (CH), 122.9
(CH), 124.5 (CH), 127.7 (C), 154.8 (C), 155.1 (C); IR
(neat): 3391, 1454, 1253, 1172, 1085, 752. Anal. Calcd
for C10H9ClO2: C, 61.08; H, 4.61; Cl, 18.03. Found: C,
60.80; H, 4.68; Cl, 18.23.
4.4. 2-Chloro-1-(3,5-dimethylbenzofuran-2-yl)ethanone 8
Prepared from 3,5-dimethylbenzofuran following the
procedure described for 6, 36% yield, mp 99–100 ꢁC
1
(from methanol); H NMR (300 MHz, CDCl3): d 2.47
(s, 3H, CH3), 2.61 (s, 3H, CH3), 4.76 (s, 2H, CH2Cl),
7.30–7.40 (m, 2H, 2 · CH), 7.44–7.45 (m, 1H, CH);
13C NMR (50 MHz, CDCl3): d 9.3 (CH3), 21.2 (CH3),
46.6 (CH2), 111.6 (CH), 121.0 (CH), 126.7 (C), 129.0
(C), 130.5 (CH), 133.2 (C), 146.1 (C), 152.7 (C), 183.6
(CO); MS (70 eV): m/z 224 (M+2, 6.2), 222 (M+,
19.1), 174 (11.9), 173 (100.0), 117 (10.2), 115 (24.5), 91
(11.1); IR (KBr): 2936, 1682, 1575, 1300, 1257, 1129,
722. Anal. Calcd for C12H11ClO2: C, 64.73; H, 4.97;
Cl, 15.92. Found: C, 64.94; H, 5.12; Cl, 15.82.
4.8. (R)-(ꢀ)-1-(Benzofuran-2-yl)-2-chloroethanol (R)-5a.
General procedure
A solution of 5 (1.95 g, 10 mmol) in tetrahydrofuran
(10 mL) was added dropwise to a solution of (ꢀ)-DIP-
Cl (3.85 g, 12 mmol) in tetrahydrofuran (10 mL) at
ꢀ25 ꢁC under nitrogen and the mixture stirred for 2 h,
and then for 12 h at room temperature. Tetrahydro-
furan was removed, diethyl ether (50 mL) was then
added, followed by diethanolamine (4.20 g, 40 mmol)
and the mixture was stirred for 2 h at room temperature.
A white precipitate was filtered off and washed with
diethyl ether (2 · 10 mL). The solvent was removed
4.5. 2-Chloro-1-(3,7-dimethylbenzofuran-2-yl)ethanone 9
Prepared from 3,7-dimethylbenzofuran following the
procedure described for 6, 48% yield, mp 122–123 ꢁC
1
(from methanol); H NMR (300 MHz, CDCl3): d 2.54
(s, 3H, CH3), 2.63 (s, 3H, CH3), 4.80 (s, 2H, CH2Cl),
7.21–7.32 (m, 2H, 2 · CH), 7.48–7.51 (m, 1H, CH);
13C NMR (50 MHz, CDCl3): d 9.5 (CH3), 14.7 (CH3),
46.7 (CH2), 119.0 (CH), 122.4 (C), 123.6 (CH), 127.4
(C), 128.5 (C), 129.5 (CH), 145.8 (C), 153.4 (C), 183.7
(CO); MS (70 eV): m/z 224 (M+2, 6.6), 222 (M+,
20.3), 174 (11.9), 173 (100.0), 117 (11.8), 115 (32.6), 91
(12.0); IR (KBr): 2936, 1689, 1579, 1252, 1124, 783,
751. Anal. Calcd for C12H11ClO2: C, 64.73; H, 4.97;
Cl, 15.92. Found: C, 64.34; H, 4.97; Cl, 15.80.
and the product was isolated by distillation, 1.60 g,
20
82% yield, bp 112–113 ꢁC/1 mmHg, ½aꢁD ¼ ꢀ26.0 (c
5.10, CHCl3), 92% ee, determined by GC analysis on a
Supelco Beta-DEX 325, 30 m · 0.25 mm, chiral column;
1H, 13C NMR and IR spectra were the same as
described above for its enantiomer.
4.9. (S)-(+)-2-Bromo-1-(7-ethylbenzofuran-2-yl)ethanol
(S)-1a
4.6. 2-Chloro-1-(5-ethyl-3-methylbenzofuran-2-yl)etha-
none 10
Prepared from 1 following the procedure described for
(S)-5a, isolated by column chromatography on silica
Prepared from 5-ethyl-3-methylbenzofuran following
the procedure described for 6, 53% yield, bp 140–
141 ꢁC/1 mmHg, mp 63–64 ꢁC; 1H NMR (300 MHz,
CDCl3): d 1.29 (t, J = 7.6 Hz, 3H, CH3), 2.58 (s, 3H,
CH3), 2.77 (q, J = 7.6 Hz, 2H, CH2), 4.75 (s, 2H,
CH2Cl), 7.23–7.48 (m, 3H, 3 · CH); 13C NMR
(50 MHz, CDCl3): d 9.4 (CH3), 15.9 (CH3), 28.7
(CH2), 46.6 (CH2), 111.8 (CH), 119.8 (CH), 126.9 (C),
129.0 (C), 129.5 (CH), 139.8 (C), 146.2 (C), 152.9 (C),
183.6 (CO); MS (70 eV): m/z 238 (M+2, 5.7), 236
(M+, 17.5), 188 (13.6), 187 (100.0), 115 (16.3); IR
(KBr): 2974, 1691, 1578, 1382, 1124, 828, 719. Anal.
Calcd for C13H13ClO2: C, 65.97; H, 5.53; Cl, 14.98.
Found: C, 65.86; H, 5.58; Cl, 14.52.
gel (petroleum ether/diethyl ether, 3:2), as an oil, 66%
20
yield, ½aꢁD ¼ þ33.0 (c 9.35, CHCl3), 92% ee, determined
by HPLC analysis on Daicel Chiralcel OD-H, chiral col-
1
umn, n-hexane/isopropanol, 95:5; H NMR (200 MHz,
CDCl3): d 1.34 (t, J = 7.5 Hz, 3H, CH3), 2.70 (d,
J = 6.0 Hz, 1H, OH), 2.92 (q, J = 7.5 Hz, 2H, CH2),
3.80 (dd, J = 10.5, 6.5 Hz, 1H, CH2Br), 3.87 (dd,
J = 10.5, 4.4 Hz, 1H, CH2Br), 5.11 (dd, J = 6.5,
4.4 Hz, 1H, CH), 6.76 (d, J = 1.0 Hz, 1H, CH), 7.10–
7.23 (m, 2H, 2 · CH), 7.40 (dd, J = 7.5, 1.8 Hz, 1H,
CH); 13C NMR (50 MHz, CDCl3): d 14.0 (CH3), 22.7
(CH2), 36.5 (CH2), 68.1 (CH), 104.3 (CH), 118.7 (CH),
123.1 (CH), 123.7 (CH), 127.4 (C), 127.7 (C), 153.4

M. Zaidlewicz et al. / Tetrahedron: Asymmetry 16 (2005) 3205–3210
3209
(C), 155.0 (C); IR (neat): 3409, 2968, 1426, 1181, 748.
Anal. Calcd for C12H13BrO2: C, 53.55; H, 4.87. Found:
C, 53.60; H, 4.82.
1039, 746. Anal. Calcd for C11H11BrO2: C, 51.79; H,
4.35. Found: C, 51.66; H, 4.30.
4.13. (S)-(+)-2-Chloro-1-(3-methylbenzofuran-2-yl)etha-
nol (S)-6a
4.10. (S)-(+)-2-Bromo-1-[3-(2-phenylethyl)benzofuran-2-
yl]ethanol (S)-2a
Prepared from 6 following the procedure described for
(S)-5a, isolated by column chromatography on silica
Prepared from 2 following the procedure described for
(S)-5a, isolated by column chromatography on silica
gel (petroleum ether/diethyl ether, 3:2), as an oil, 90%
yield, 96% ee, determined by HPLC analysis on Daicel
Chiralcel OD-H, chiral column, n-hexane/isopropanol,
95:5, and identified by comparison with (R)-2a prepared
earlier1; 1H NMR (300 MHz, CDCl3): d 1.80 (d,
J = 4.2 Hz, 1H, OH), 2.99–3.08 (m, 4H, 2 · CH2), 3.19
(dd, J = 10.5, 5.4 Hz, 1H, CH2Br), 3.55 (dd, J = 10.5,
8.1 Hz, 1H, CH2Br), 4.64 (dd, J = 8.1, 5.4 Hz, 1H,
CH), 7.01–7.04 (m, 2H, 2 · CH), 7.20–7.36 (m, 5H,
5 · CH), 7.44–7.47 (m, 1H, CH), 7.56–7.60 (m, 1H,
CH); 13C NMR (50 MHz, CDCl3): d 25.6 (CH2), 34.8
(CH2), 35.5 (CH2), 66.6 (CH), 111.5 (CH), 116.9 (CH),
119.6 (CH), 122.6 (CH), 124.8 (CH), 126.3 (CH), 128.3
(C), 128.4 (CH), 128.7 (CH), 141.1 (C), 150.0 (C),
154.2 (C); IR (neat): 3546, 3027, 2926, 1453, 1261,
1199, 1077, 748, 699. Anal. Calcd for C18H17BrO2: C,
62.62; H, 4.97. Found: C, 62.57; H, 4.81.
gel (petroleum ether/diethyl ether, 3:2), as an oil, 76%
25
yield, ½aꢁD ¼ þ12.4 (c 3.22, CHCl3), 97% ee, determined
by GC analysis on
a Supelco Beta-DEX 325,
30 m · 0.25 mm, chiral column; 1H NMR (300 MHz,
CDCl3): d 2.30 (s, 3H, CH3), 2.63 (br s, 1H, OH), 3.86
(dd, J = 11.1, 5.4 Hz, 1H, CH2Cl), 3.98 (dd, J = 11.1,
7.8 Hz, 1H, CH2Cl), 5.10 (t, J = 6.0 Hz, 1H, CH),
7.24–7.34 (m, 2H, 2 · CH), 7.42–7.45 (m, 1H, CH),
7.49–7.52 (m, 1H, CH); 13C NMR (75 MHz, CDCl3): d
7.8 (CH3), 47.1 (CH2), 67.0 (CH), 111.2 (CH), 113.9
(C), 119.6 (CH), 122.5 (CH), 124.8 (CH), 129.5 (C),
148.8 (C), 153.9 (C); IR (neat): 3351, 2906, 1455, 1367,
1040, 1004, 745. Anal. Calcd for C11H11ClO2: C, 62.71;
H, 5.26; Cl, 16.83. Found: C, 62.55; H, 5.39; Cl, 16.78.
4.14. (S)-(+)-2-Chloro-1-(7-ethylbenzofuran-2-yl)ethanol
(S)-7a
Prepared from 7 following the procedure described for
(S)-5a, isolated by column chromatography on silica
4.11. (S)-(+)-1-(Benzofuran-2-yl)-2-bromoethanol (S)-3a
gel (petroleum ether/diethyl ether, 3:2), as an oil, 85%
25
Prepared from 3 following the procedure described for
(S)-5a, isolated by column chromatography on silica
yield, ½aꢁD ¼ þ29.6 (c 5.40, CHCl3), 98% ee, determined
by HPLC analysis on Daicel Chiralcel OD-H, chiral col-
umn, n-hexane/isopropanol, 80:20; 1H NMR (300 MHz,
CDCl3): d 1.34 (t, J = 7.5 Hz, 3H, CH3), 2.74 (d,
J = 5.1 Hz, 1H, OH), 2.93 (q, J = 7.5 Hz, 2H, CH2),
3.93 (dd, J = 11.4, 6.6 Hz, 1H, CH2Cl), 3.99 (dd,
J = 11.4, 4.2 Hz, 1H, CH2Cl), 5.10 (dd, J = 6.6,
4.2 Hz, 1H, CH), 6.76 (d, J = 0.9 Hz, 1H, CH), 7.10–
7.20 (m, 2H, 2 · CH), 7.40 (dd, J = 7.5, 1.5 Hz, 1H,
CH); 13C NMR (50 MHz, CDCl3): d 14.0 (CH3), 22.7
(CH2), 47.6 (CH2), 68.5 (CH), 104.4 (CH), 118.7 (CH),
123.1 (CH), 123.7 (CH), 127.4 (C), 127.7 (C), 153.4
(C), 154.7 (C); IR (neat): 3393, 2968, 1427, 1180, 1087,
821, 747. Anal. Calcd for C12H13ClO2: C, 64.15; H,
5.83; Cl, 15.78. Found: C, 64.06; H, 5.91; Cl, 15.57.
gel (petroleum ether/diethyl ether, 3:2), as an oil, 83%
20
yield, ½aꢁD ¼ þ15.9 (c 5.03, CHCl3), 91% ee, determined
by HPLC analysis on Daicel Chiralcel OD-H, chiral col-
1
umn, n-hexane/isopropanol, 98:2; H NMR (200 MHz,
CDCl3): d 2.83 (br s, 1H, OH), 3.79 (dd, J = 10.5,
6.5 Hz, 1H, CH2Br), 3.86 (dd, J = 10.5, 4.7 Hz, 1H,
CH2Br), 5.09 (t, J = 4.9 Hz, 1H, CH), 6.76 (t,
J = 0.9 Hz, 1H, CH), 7.23–7.35 (m, 2H, 2 · CH), 7.44–
7.51 (m, 1H, CH), 7.54–7.59 (m, 1H, CH); 13C NMR
(50 MHz, CDCl3): d 36.4 (CH2), 68.0 (CH), 104.1
(CH), 111.2 (CH), 121.3 (CH), 122.9 (CH), 124.5
(CH), 127.7 (C), 154.7 (C), 155.3 (C); IR (neat): 3351,
1454, 1367, 1040, 1004, 750. Anal. Calcd for
C10H9BrO2: C, 49.82; H, 3.76. Found: C, 49.51; H, 3.67.
4.15. (S)-(+)-2-Chloro-1-(3,5-dimethylbenzofuran-2-yl)-
ethanol (S)-8a
4.12. (S)-(+)-2-Bromo-1-(3-methylbenzofuran-2-yl)etha-
nol (S)-4a
Prepared from 8 following the procedure described for
(S)-5a, isolated by column chromatography on silica gel
Prepared from 4 following the procedure described for
(S)-5a, isolated by column chromatography on silica
(petroleum ether/diethyl ether, 3:2), an oil, 82% yield,
25
gel (petroleum ether/diethyl ether, 3:2), as an oil, 57%
½aꢁD ¼ þ17.1 (c 5.26, CHCl3), 98% ee, determined by
20
yield, ½aꢁD ¼ þ44.6 (c 3.92, CHCl3), 94% ee, determined
GC analysis on a Supelco Beta-DEX 325, 30 m · 0.25
mm, chiral column; 1H NMR (300 MHz, CDCl3): d
2.26 (s, 3H, CH3), 2.45 (s, 3H, CH3), 2.67 (br s, 1H,
OH), 3.84 (dd, J = 11.1, 5.4 Hz, 1H, CH2Cl), 3.97 (dd,
J = 11.1, 7.8 Hz, 1H, CH2Cl), 5.06 (dd, J = 7.8, 5.4 Hz,
1H, CH), 7.11 (dd, J = 8.4, 1.8 Hz, 1H, CH), 7.26–7.32
(m, 2H, 2 · CH); 13C NMR (50 MHz, CDCl3): d 7.7
(CH3), 21.2 (CH3), 47.1 (CH2), 67.1 (CH), 110.6 (CH),
113.6 (CH), 119.3 (CH), 125.9 (2 · CH), 129.5 (C),
131.9 (C), 148.9 (C), 152.3 (C); IR (neat): 3546, 2921,
1475, 1455, 1266, 1203, 1089, 1057, 834, 801. Anal. Calcd
by HPLC analysis on Daicel Chiralcel OD-H, chiral col-
1
umn, n-hexane/isopropanol, 96:4; H NMR (200 MHz,
CDCl3): d 2.29 (s, 3H, CH3), 2.71 (d, J = 4.8 Hz, 1H,
OH), 3.73 (dd, J = 10.4, 5.6 Hz, 1H, CH2Br), 3.84 (dd,
J = 10.4, 7.6 Hz, 1H, CH2Br), 5.11 (dd, J = 7.6,
5.6 Hz, 1H, CH), 7.21–7.35 (m, 2H, 2 · CH), 7.41–7.53
(m, 1H, CH); 13C NMR (50 MHz, CDCl3): d 7.8
(CH3), 35.6 (CH2), 66.9 (CH), 111.2 (CH), 113.8 (C),
119.6 (CH), 122.5 (CH), 124.8 (CH), 129.5 (C), 149.0
(C), 153.9 (C); IR (neat): 3367, 2921, 1455, 1258, 1088,

3210
M. Zaidlewicz et al. / Tetrahedron: Asymmetry 16 (2005) 3205–3210
for C12H13ClO2: C, 64.15; H, 5.83; Cl, 15.78. Found: C,
64.10; H, 5.84; Cl, 15.73.
(300 MHz, CDCl3): d 1.12 (s, 9H, 3 · CH3), 1.34 (t,
J = 7.5 Hz, 3H, CH3), 2.92 (q, J = 7.5 Hz, 2H, CH2),
3.00 (dd, J = 12.0, 6.0 Hz, 1H, NCH2), 3.06 (dd,
J = 12.0, 4.5 Hz, 1H, NCH2), 4.80 (ddd, J = 6.0,
4.5 Hz, J = 0.9 Hz, 1H, CH), 6.66 (d, J = 0.9 Hz, 1H,
CH), 7.06–7.17 (m, 2H, 2 · CH), 7.37 (dd, J= 7.5,
1.5 Hz, 1H, CH); 13C NMR (75 MHz, CDCl3): d 14.1
(CH3), 22.8 (CH2), 29.1 (3 · CH3), 46.2 (C), 50.3
(CH2), 66.5 (CH), 103.1 (CH), 118.4 (CH), 122.8 (CH),
123.0 (CH), 127.6 (C), 127.8 (C), 153.4 (C), 158.3 (C).
4.16. (S)-(+)-2-Chloro-1-(3,7-dimethylbenzofuran-2-yl)-
ethanol (S)-9a
Prepared from 9 following the procedure described for
(S)-5a, isolated by column chromatography on silica
gel (petroleum ether/diethyl ether, 3:2), as an oil, 77%
25
yield, ½aꢁD ¼ þ8.1 (c 4.91, CHCl3), 96% ee, determined
by GC analysis on
a Supelco Beta-DEX 325,
30 m · 0.25 mm, chiral column; 1H NMR (300 MHz,
CDCl3): d 2.28 (s, 3H, CH3), 2.50 (s, 3H, CH3), 2.62
(d, J = 4.5 Hz, 1H, OH), 3.87 (dd, J = 11.1, 5.4 Hz,
1H, CH2Cl), 4.00 (dd, J = 11.1, 7.8 Hz, 1H, CH2Cl),
5.09 (dd, J = 7.8, 5.4 Hz, 1H, CH), 7.09–7.18 (m, 2H,
2 · CH), 7.32–7.35 (m, 1H, CH); 13C NMR (50 MHz,
CDCl3): d 7.8 (CH3), 14.8 (CH3), 47.1 (CH2), 67.2
(CH), 114.1 (CH), 116.9 (CH), 121.4 (C), 122.5 (CH),
125.7 (CH), 129.0 (C), 148.6 (C), 153.0 (C); IR (neat):
3350, 2922, 1453, 1367, 1040, 1003, 746. Anal. Calcd
for C12H13ClO2: C, 64.15; H, 5.83; Cl, 15.78. Found:
C, 63.85; H, 5.89; Cl, 15.19.
Acknowledgements
The authors thank Dr. Eva-Maria Gutknecht and Pierre
Weber, F. Hoffmann-La Roche Ltd, Basel, for a gift of
racemic bufuralol.
References
1. Zaidlewicz, M.; Tafelska-Kaczmarek, A.; Prewysz-
Kwinto, A.; Chechłowska, A. Tetrahedron: Asymmetry
2003, 14, 1659–1664.
2. Fothergill, G. A.; Osbond, J. M.; Wickens, J. C. Arzneim.-
Forsch. Drug Res. 1977, 27, 978–981.
3. Weerawarna, S. A.; Guha-Biswas, M.; Nelson, W. L. J.
Heterocycl. Chem. 1991, 28, 1395–1403.
4. Hamilton, T. C.; Parkes, M. W. Arzneim.-Forsch. Drug
Res. 1977, 27, 1410–1417.
5. Narimatsu, S.; Takemi, C.; Kuramoto, S.; Tsuzuki, D.;
Hiychya, H.; Tamagake, K.; Yamamoto, S. Chirality
2003, 15, 333–339.
6. Pruksaritanont, T.; Dwyer, L. M.; Cribb, A. E. Biochem.
Pharmacol. 1995, 50, 1521–1525.
7. Ohkuma, T.; Noyori, R. In Comprehensive Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer: Berlin, Heidelberg, 2004; Suppl 1, pp 27–
41.
8. Kitamura, M.; Noyori, R. In Ruthenium in Organic
Synthesis; Murahashi, S.-I., Ed.; Wiley-VCH: Weinheim,
2004, pp 31–52.
9. Cross, D. J.; Kenny, J. A.; Houson, I.; Campbell, L.;
Walsgrove, T.; Wills, M. Tetrahedron: Asymmetry 2001,
12, 1801–1806.
4.17. (S)-(+)-2-Chloro-1-(5-ethyl-3-methylbenzofuran-2-
yl)ethanol (S)-10a
Prepared from 10 following the procedure described for
(S)-5a, isolated by column chromatography on silica gel
(petroleum ether/diethyl ether, 3:2), as an oil, 74% yield,
25
½aꢁD ¼ þ9.4 (c 5.30, CHCl3), 97% ee, determined by GC
analysis on a Supelco Beta-DEX 325, 30 m · 0.25 mm,
1
chiral column; H NMR (300 MHz, CDCl3): d 1.28 (t,
J = 7.6 Hz, 3H, CH3), 2.27 (s, 3H, CH3), 2.60 (d,
J = 5.1 Hz, 1H, OH), 2.75 (q, J = 7.6 Hz, 2H, CH2),
3.84 (dd, J = 11.0, 5.3 Hz, 1H, CH2Cl), 3.97 (dd,
J = 11.0, 7.8 Hz, 1H, CH2Cl), 5.07 (dd, J = 7.8,
5.3 Hz, 1H, CH), 7.14 (dd, J = 8.4, 1.8 Hz, 1H, CH),
7.30–7.35 (m, 2H, 2 · CH); 13C NMR (50 MHz,
CDCl3): d 7.7 (CH3), 15.1 (CH3), 28.8 (CH2), 47.1
(CH2), 67.1 (CH), 110.8 (CH), 113.8 (C), 118.1 (CH),
125.0 (CH), 129.5 (C), 138.7 (C), 148.9 (C), 152.5 (C);
IR (neat): 3528, 2964, 1474, 1455, 1267, 1090, 812. Anal.
Calcd for C13H15ClO2: C, 65.41; H, 6.33; Cl, 14.85.
Found: C, 65.25; H, 6.31; Cl, 14.86.
10. Murata, K.; Ikariya, T.; Noyori, R. J. Org. Chem. 1999,
64, 2186–2187.
11. Hamada, T.; Torii, T.; Onishi, T.; Izawa, K.; Ikariya, T. J.
Org. Chem. 2004, 69, 7391–7394.
12. Hamada, T.; Torii, T.; Izawa, K.; Noyori, R.; Ikariya, T.
Org. Lett. 2002, 4, 4373–4376.
4.18. (R)-(+)-2-tert-Butylamino-1-(7-ethylbenzofuran-2-
yl)ethanol (R)-1c
13. Hamada, T.; Torii, T.; Izawa, K.; Ikariya, T. Tetrahedron
2004, 60, 7411–7417.
To a solution of (S)-7a (0.18 g, 0.8 mmol) in absolute
ethanol (10 mL) was added tert-butylamine (0.20 g,
2.8 mmol) and the mixture refluxed for 24 h. The solvent
and excess tert-butylamine were removed under vacuum
and diethyl ether (20 mL) was added. The solution was
washed with 10% sodium hydroxide (5 mL), water
(5 mL), and dried with anhydrous magnesium sulfate.
The solvent was removed and the product isolated by
column chromatography on silica gel (petroleum ether/
ethyl acetate/diethyl ether/methanol/triethylamine,
6:4:1:0.5:0.2), 0.11 g, 53%, mp 57–58 ꢁC, 96% ee, deter-
mined by HPLC analysis on Daicel Chiralcel OD-H, chi-
ral column, n-hexane/isopropanol, 95:5, and identified
14. Zaidlewicz, M.; Chechłowska, A.; Prewysz-Kwinto, A.;
Wojtczak, A. Heterocycles 2001, 55, 569–577.
15. Nielek, B.; Lesiak, T. Chem. Ber. 1982, 115, 1247–1251.
16. Suzuki, T.; Horaguchi, T.; Shimizu, T.; Abe, T. Bull.
Chem. Soc. Jpn 1983, 56, 2762–2767.
17. Royer, R.; Bisagni, E.; Hudry, C. Bull. Soc. Chim. Fr.
1961, 933–938.
18. Shriner, R. L.; Anderson, J. J. Am. Chem. Soc 1939, 61,
2705–2708.
19. Jordan, S.; Markwell, R. E.; Woolcott, B. S. J. Chem.
Soc., Perkin Trans. 1 1978, 928–933.
20. Siła, B. Roczniki Chem. 1967, 41, 157–162.
21. Siła, B.; Wojtanis, J.; Lesiak, T. Roczniki Chem. 1975, 49,
1661–1669.
1
by comparison with (S)-1c prepared earlier1; H NMR