Asymmetric synthesis of (S)-bufuralol and a propafenone analogue

Article abstract of DOI:10.1016/S0957-4166(03)00276-3

Asymmetric synthesis of (S)-bufuralol of 87% ee from 3-ethyl-2-hydroxybenzaldehyde, via the reduction of 2-bromo-1-(7-ethylbenzofuran-2-yl)ethanone with (-)-B-chlorodiisopinocampheylborane as the key step, followed by cyclization of the product bromohydrin to the corresponding epoxide and treatment with tert-butylamine, is described. (S)-1-(3-Phenethylbenzofuran-2-yl)-2-propylaminoethanol of 73% ee, a propafenone analogue, was prepared following the same approach.

Full text of DOI:10.1016/S0957-4166(03)00276-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1659–1664
Asymmetric synthesis of (S)-bufuralol and a propafenone
analogue
Marek Zaidlewicz,* Agnieszka Tafelska-Kaczmarek, Andrzej Prewysz-Kwinto and
Aldona Chechłowska
Department of Chemistry, Nicolaus Copernicus University, 87-100 Torun´, Poland
Received 25 February 2003; accepted 26 March 2003
Abstract—Asymmetric synthesis of (S)-bufuralol of 87% ee from 3-ethyl-2-hydroxybenzaldehyde, via the reduction of 2-bromo-1-
(7-ethylbenzofuran-2-yl)ethanone with (−)-B-chlorodiisopinocampheylborane as the key step, followed by cyclization of the
product bromohydrin to the corresponding epoxide and treatment with tert-butylamine, is described. (S)-1-(3-Phenethylbenzo-
furan-2-yl)-2-propylaminoethanol of 73% ee, a propafenone analogue, was prepared following the same approach. © 2003
Elsevier Science Ltd. All rights reserved.
1. Introduction
receptor antagonist,12 an inhibitor of testosterone 6b-
hydroxylase,10 and is widely used in studies of
cytochrome P450.13 1-(3-Phenethylbenzofuran-2-yl)-2-
propylaminoethanol 2, a propafenone 3 analogue,
shows antiarrhythmic activity, but in contrast to 3 lacks
b-adrenoacceptor blocking activity.9b
Benzofuran derivatives have been the subject of
increased interest in recent years due to their diverse
biological activities.1 For example, they act as
inhibitors of 5-lipoxygenase,2 cyclooxygenase-2,3 and
b-amyloid (Ab) aggregations,4 antagonists for the brain
CB1 receptor,5 the central and peripheral GABAB-
receptor,6 the angiotensin II receptor,7 and the oxytocin
(OT) hormone.8
Synthetic approaches to racemic 1 and 2 have been
described, and the racemates have been resolved.9,12a,14
However, asymmetric syntheses of 1 and 2 have not
been reported. Recently, we have developed an enan-
tioselective synthesis of model benzofuryl b-amino alco-
hols,15 using as a key reaction the reduction of the
corresponding a-bromo ketones with (−)-B-chlorodi-
isopinocampheylborane ((−)-DIP-Cl).16 Following this
approach, here we wish to report on the first asymmet-
ric synthesis of 1 and 2 (Fig. 1).
Among these derivatives, b-amino alcohols play an
important role showing antiarrhythmic,9 enzyme
inhibitory,9b,10 antihypertensive,11 and b-andrenoaccep-
tor blocking activity.12 Bufuralol 1, the most studied
compound of this class, proved effective for treatment
of hypertension,11 is a potent non selective b-adrenergic
Figure 1.
* Corresponding author. Tel.: (+4856) 6114522; fax: (+4856) 6542477; e-mail: zaidlevi@chem.uni.torun.pl
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00276-3

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M. Zaidlewicz et al. / Tetrahedron: Asymmetry 14 (2003) 1659–1664
2. Results and discussion
tion of an authentic racemic sample (F. Hoffmann-La
Roche Ltd.) as reported in the literature.12,20
3-Ethyl-2-hydroxybenzaldehyde 5 is a convenient pre-
cursor for the synthesis of 1. However, the reported
methods for its preparation furnish the compound only
in low to moderate yields.17 Consequently, we devel-
oped a convenient procedure starting from 2-ethylphe-
nol 4, involving a modified Casiraghi formylation,18
producing 5 in 72% yield. The aldehyde was trans-
formed into 1-(7-ethylbenzofuran-2-yl)ethanone 6 by
the reaction with chloroacetone and cyclization
(Scheme 1). Bromination of 6 with pyridinium tribro-
mide gave bromo ketone 7, easily isolated by
crystallization.
Racemic 2 was first synthesized from (3-phenethylben-
zofuran-2-yl)methanone by the reduction of its cyanhy-
drin and alkylation of the product amino alcohol.9a The
second synthesis of 2 involving the sequence 10“11“
12 (Scheme 2), followed by the reduction of 12 with
lithium tetrahydridoaluminate, chromatographic reso-
lution of racemic 13 derivatized with (+)-NOE-lactol®
dimer, and treatment with n-propylamine, afforded
both enantiomers of 2.9b
We also followed the same sequence, modifying the
isolation procedure of 11, and the reagent in the next
step. Thus, acetylation of 10 gave a dark-brown oil, and
isolation of 11 required several triturations with
methanol, and final chromatographic purification.
Bromination of 11 with a stoichiometric amount of
bromine afforded a mixture of 12, unreacted 11, and
2,2-dibromo-1-(3-phenethylbenzofuran-2-yl)ethanone,
which was difficult to separate. This difficulty was
circumvented by bromination of 11 with pyridinium
tribromide producing 12 cleanly in 62% yield.
The reduction of 7 with (−)-DIP-Cl at −25°C furnished
the corresponding bromohydrin (R)-8 of 87% ee. The
enantiomeric excess was determined by GC analysis on
a chiral capillary column and comparison with the
racemate prepared by the reduction of 7 with lithium
tetrahydridoaluminate. The bromohydrin was trans-
formed into an unstable epoxide (S)-9. Attempts to
purify the epoxide by column chromatography failed.
Racemic 9 was also reported to be unstable.19 Conse-
quently, the crude epoxide was treated with tert-butyl-
amine, and (S)-1 of 87% ee was isolated as its
hydrochloride. Enantiomeric excess was determined by
GC analysis of (S)-1 on a chiral capillary column.
Absolute configuration was established by comparing
the sign of rotation with (S)-1·HCl, prepared by resolu-
The reduction of 12 with (−)-DIP-Cl furnished (R)-13
of 73% ee, determined by HPLC analysis on a chiral
column and comparison with the racemate prepared by
the reduction of 12 with lithium tetrahydridoaluminate.
Treatment of (R)-13 with sodium hydride in tetra-
Scheme 1. Reagents and conditions: (i) HCHO, NEt3, MgCl2, MeCN; (ii) ClCH2COCH3, K2CO3, MeCN; (iii) C5H6NBr3, AcOH;
(iv) (−)-DIP-Cl, THF; (v) NaH, THF; (vi) t-BuNH2.
Scheme 2. Reagents and conditions: (i) Ac2O, BF3·OEt2; (ii) C5H6NBr3, AcOH; (iii) (−)-DIP-Cl, THF; (iv) NaH, THF; (v)
n-PrNH2.

M. Zaidlewicz et al. / Tetrahedron: Asymmetry 14 (2003) 1659–1664
1661
hydrofuran furnished the corresponding epoxide (S)-14.
4.4. 1-(7-Ethylbenzofuran-2-yl)ethanone, 6
Attempts to purify it by chromatography on silica gel
and on alumina failed. The crude (S)-14 was treated
with n-propylamine and (S)-2 was isolated as hydro-
chloride of 73% ee, determined by HPLC analysis on a
chiral column. Its configuration was assigned by trans-
formation into the tartrate salt and comparing the sign
of rotation with reported data.9b
Chloroacetone (10.03 g, 110 mmol) was added dropwise
to a mixture of 5 (15.02 g, 100 mmol), anhydrous
potassium carbonate (13.82 g, 100 mmol), and acetoni-
trile (70 mL) at 35°C. The mixture was refluxed for 5 h
and cooled to rt. The precipitated solid was filtered off
and washed with acetonitrile (10 mL). The product was
isolated from the filtrate by distillation, 14.66 g, 78%
yield, bp 103–105°C/0.5 mmHg, mp 54–56°C, lit.17a mp
1
54.5°C. H NMR (CDCl3): l 1.34 (t, J=8.0 Hz, 3H),
3. Conclusion
2.61 (s, 3H), 3.00 (q, J=8.0 Hz, 2H), 7.19–7.33 (m,
2H), 7.49 (s, 1H), 7.27 (dd, J=7.4 Hz, J=1.7 Hz, 1H);
13C NMR (CDCl3): l 13.97 (CH3), 22.69 (CH2), 26.45
(CH3), 113.19 (CH), 120 (CH), 124.05 (CH), 126.75 (C),
127.13 (CH), 128.96 (C), 152.46 (C), 154.38 (C), 188.69
(CO).
Asymmetric synthesis of (S)-1 of 87% ee and (S)-2 of
73% ee has been achieved employing as a key step the
reduction of 7 and 12 with (−)-DIP-Cl, respectively.
Similarly, the reduction of the model 2-bromo-1-(ben-
zofuran-2-yl)ethanone with (−)-DIP-Cl, leads to the
corresponding b-amino alcohol of S-configuration.15
A
4.5. 2-Bromo-1-(7-ethylbenzofuran-2-yl)ethanone, 7
convenient synthesis of 5, the precursor of both racemic
and optically active 1, has been developed.
Pyridinium tribromide (11.20 g, 35 mmol) was added in
portions to a stirred solution of 6 (5.30, 28 mmol) in
acetic acid (100 mL) at 50–55°C, and stirring was
continued for 4 h. Water (100 mL) was added and the
mixture was extracted with diethyl ether (2×100 mL),
the combined extract was washed with a saturated
solution of sodium hydrogencarbonate (5×30 mL),
water (20 mL), and dried with anhydrous magnesium
sulphate. The solvent was removed and the product was
crystallized from petroleum ether, 5.09 g, 69% yield, mp
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded on a Varian
Gemini 200 and a Bruker AMX 300 spectrometers. GC
analyses were performed on a Hewlett-Packard chro-
matograph provided with a flame ionization detector
and a chiral column Supelco Beta DEX 325, 30 m×0.25
mm. HPLC analyses were carried out with a liquid
chromatography system model LC-5B, Laboratorni
Pristroje, Praha, equipped with chiral columns: Daicel
Chiracel OJ, 10 mm, 25 cm×4.6 mm, and Daicel
Chiracel OD-H 5 mm, 25 cm×4.6 mm. Rotations were
measured on a Lot-Oriel S-2 automatic polarimeter.
1
58–60°C. H NMR (CDCl3): l 1.38 (t, J=7.5 Hz, 3H),
2.99 (q, J=7.5 Hz, 2H), 4.46 (s, 2H, CH2Br), 7.24–7.35
(m, 2H), 7.56 (dd, J=6 Hz, J=1 Hz, 1H), 7.65 (s, 1H);
13C NMR (CDCl3): l 13.92 (CH3), 22,74 (CH2), 30.22
(CH2), 114.99 (CH), 120.86 (CH), 124.41 (CH), 126.58
(C), 127.83 (CH), 129.03 (C), 149.93 (C), 154.61 (C),
182.24 (CO). Anal. calcd for C12H11BrO2: C, 53.96; H,
4.15. Found: C, 53.81; H, 4.11%.
4.2. Materials
4.6. (R)-(−)-2-Bromo-1-(7-ethylbenzofuran-2-yl)ethanol,
(R)-8
Tetrahydrofuran was freshly distilled from sodium ben-
zophenone ketyl. Acetonitrile was distilled from cal-
cium hydride. Triethylamine was distilled from lithium
tetrahydridoaluminate. (−)-DIP-Cl of >99% ee was a
commercial product (Aldrich).
A solution of 7 (4.00 g, 15 mmol) in tetrahydrofuran
(10 mL) was added dropwise to a stirred mixture of
(−)-DIP-Cl (5.58 g, 17 mmol) in tetrahydrofuran (10
mL) at −25°C under nitrogen, and stirring was contin-
ued for 4 h, and then for 20 h at rt. Tetrahydrofuran
was removed, diethyl ether (80 mL) was added, fol-
lowed with diethanolamine (2.10 g, 20 mmol). The
mixture was stirred for 2 h at rt. White precipitate
which was formed was filtered off and washed with
diethyl ether (10 mL). The solvent was removed from
the filtrate and the product was isolated by column
chromatography on silica gel (petroleum ether/diethyl
ether, 4:1), 2.56 g, 64% yield, [h]2D0=−31.7 (c 8.84,
CHCl3). GC analysis on a Supelco Beta-DEX 325, 30
m×0.25 mm, column showed 87% ee. Racemic 8, pre-
pared by the reduction of 7 with lithium tetra-
hydridoaluminate, was also analyzed. 1H NMR
(CDCl3): l 1.34 (t, J=7.5 Hz, 3H), 2.70 (d, J=6.0 Hz,
1H, OH), 2.92 (q, J=7.5 Hz, 2H), 3.80 (dd, J=10.5
Hz, J=6.5 Hz, 1H, CH2Br), 3.87 (dd, J=10.5 Hz,
J=4.4 Hz, 1H, CH2Br), 5.11 (dd, J=6.5 Hz, J=4.4
4.3. 3-Ethyl-2-hydroxybenzaldehyde, 5
Paraformaldehyde (16.21 g, 540 mmol) was added in
small portions to a solution of 2-ethylphenol 4 (9.77 g,
80 mmol), magnesium chloride (11.42 g, 120 mmol),
and triethylamine (30.36 g, 300 mmol) in acetonitrile
(100 mL) at rt. The mixture was refluxed for 5 h, stirred
for 12 h at rt, and acidified with a 5% hydrochloric acid
(ca 200 mL). The mixture was extracted with diethyl
ether (2×100 mL), the extract was dried with magne-
sium sulphate and the product was isolated by distilla-
tion, 8.63 g, 72% yield, bp 55–57°C/1 mmHg; lit.17b bp
117–118°C/28 mmHg. 13C NMR (CDCl3): l 13.62
(CH3), 22.19 (CH2), 119.48 (CH), 120.12 (C), 131.34
(CH), 132.68 (C), 136.21 (CH), 159.66 (C), 196.76
(CO).

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M. Zaidlewicz et al. / Tetrahedron: Asymmetry 14 (2003) 1659–1664
Hz, 1H), 6.76 (d, J=1 Hz, 1H), 7.10–7.23 (m, 2H), 7.40
(dd, J=7.5 Hz, J=1.8 Hz, 1H); 13C NMR (CDCl3): l
14.06 (CH3), 22.78 (CH2), 36.58 (CH2), 68.18 (CH),
104.34 (CH), 118.72 (CH), 123.17 (CH), 123.75 (CH),
127.42 (C), 127.77 (C), 153.41 (C), 155.03 (C). Anal.
calcd for C12H13BrO2: C, 53.55; H, 4.87. Found: C,
53.60; H, 4.82%.
22.60 (CH2), 25.92 (3×CH3), 46.47 (CH2), 57.82 (C),
63.85 (CH), 104.50 (CH), 118.72 (CH), 123.09 (CH),
123.60 (CH), 127.44 (C),127.70 (C), 153.46 (C), 154.77
(C).
4.9. 1-(3-Phenethylbenzofuran-2-yl)ethanone, 11
A mixture of 3-phenethylbenzofuran 109a (20.00 g, 90
mmol), acetic anhydride (43 mL), and boron trifluoride
etherate (1.2 mL) was stirred at 50°C for 10 h. Water
(100 mL) was added and stirring was continued for 12
h at rt. The mixture was extracted with diethyl ether
(3×50 mL), the combined extract was washed with a
saturated solution of sodium hydrogencarbonate (5×30
mL), water (2×30 mL), and dried with magnesium
sulphate. Ether was removed, and a dark brown viscous
liquid was triturated several times with methanol.
Methanol was removed under reduced pressure and the
crude product was purified by column chromatography
on silica gel (petroleum ether/diethyl ether, 9:1), 10.85
4.7. (S)-7-Ethyl-2-oxiranyl-benzofuran, (S)-9
A solution of (R)-8 (2.20 g, 8 mmol) in tetrahydrofuran
(10 mL) was added dropwise to a stirred suspension of
sodium hydride (0.60 g, 25 mmol) in tetrahydrofuran
(10 mL), at rt, under nitrogen, and stirring was contin-
ued for 24 h. Solids were filtered off and washed with
diethyl ether (10 mL). Solvents were removed and the
1
crude epoxide was obtained as a red oil, 1.71 g. H
NMR (CDCl3): l 1.34 (t, J=7.6 Hz, 3H), 2.92 (q,
J=7.6 Hz, 2H), 3.24 (dd, J=5.5 Hz, J=4.2 Hz, 1H),
3.37 (dd, J=5.5 Hz, J=2.6 Hz, 1H), 4.02 (ddd, J=4.1
Hz, J=2.6 Hz, J=0.4 Hz, 1H), 6.80 (d, J=0.4 Hz,
1H), 7.09–7.20 (m, 2H), 7.38 (ddt, J=6.8 Hz, J=2.0
Hz, J=0.2 Hz, 1H); 13C NMR (CDCl3): l 14.02 (CH3),
22.71 (CH2), 46.67 (CH), 48.27 (CH2), 106.46 (CH),
118.44 (CH), 123.07 (CH), 123.84 (CH), 127.59 (C),
127.78 (C), 152.51 (C), 153.51 (C).
1
g, 46% yield, mp 85–87°C, lit.9b mp 85–87°C. H NMR
(CDCl3): l 2.61 (s, 3H), 2.93–3.01 (m, 2H), 3.35–3.41
(m, 2H), 7.15–7.35 (m, 6H), 7.45–7.60 (m, 3H); 13C
NMR (CDCl3): l 26.40 (CH3), 27.75 (CH2), 35.81
(CH2), 112.17 (CH), 121.56 (CH), 123.22 (CH), 126.05
(CH), 127.98 (C), 128.03 (CH), 128.33 (2×CH), 128.54
(2×CH), 128.65 (C), 141.42 (C), 148.09 (C), 154.00 (C),
191.13 (CO).
4.8. (S)-2-tert-Butylamino-1-(7-ethylbenzofuran-2-yl)-
ethanol, (S)-1
4.10. 2-Bromo-1-(3-phenethylbenzofuran-2-yl)ethanone,
12
A mixture of (S)-9 (1.89 g, 10 mmol) and tert-butyl-
amine (7.31 g, 100 mmol) was placed in an autoclave
for 6 h at 55°C. After cooling to rt, excess of tert-butyl-
amine was removed under vacuum, diethyl ether (50
mL) and water (10 mL) was added, and the mixture
was stirred for 15 min. The organic layer was separated,
washed with water (5 mL), and dried with magnesium
sulphate. Ether was evaporated and 2.03 g of a red oil
was obtained. GC analysis on a Supelco Beta-DEX
325, 30 m×0.25 mm, column showed 87% ee. An
authentic sample of racemic 1 was also analyzed.
Pyridinium tribromide (16.26 g, 50 mmol) was added in
portions to a stirred solution of 11 (12.00 g, 40 mmol)
in acetic acid (150 mL) at 50–55°C, and stirring was
continued for 4 h. Water (150 mL) was added and the
mixture was extracted with diethyl ether (2×100 mL).
The combined extract was washed with saturated solu-
tion of sodium hydrogencarbonate (5×30 mL), water
(2×30 mL), and dried with magnesium sulphate. Ether
was removed and the product was isolated by column
chromatography on silica gel (petroleum ether/diethyl
ether, 1:1), 9.46 g, 62% yield, mp 64–66°C, lit.9b mp
65–67°C. 1H NMR (CDCl3): l 2.93–3.01 (m, 2H),
3.36–3.44 (m, 2H), 4.54 (s, 2H, CH2Br), 7.15–7.40 (m,
3H), 7.47–7.62 (m, 6H); 13C NMR (CDCl3): l 26.51
(CH2), 32.14 (CH2Br), 35.65 (CH2), 112.34 (CH),
121.74 (CH), 123.60 (CH), 126.16 (CH), 128.37 (2×
CH), 128.40 (C), 128.54 (2×CH), 128.86 (CH), 131.09
(C), 141.12 (C), 145.81 (C), 154.32 (C), 183.62 (CO).
MTPA derivative. Derivatization with (S)-(+)-MTPA–
Cl.21 1H NMR (CDCl3): l 1.10 (s, 9H, CH3), 1.29 (t,
J=7.6 Hz, 3H, CH3), 2.86 (q, J=7.6 Hz, 2H, CH2),
3.23 (d, J=5.6 Hz, 1H, NCH2), 3.34 (d, J=7.6 Hz, 1H,
NCH2), 3.58 (q, J=1.0 Hz, 3H, OCH3), 6.20 (dd,
J=7.6 Hz, J=5.6 Hz, 1H, OCH), 6.72 (s, 1H), 7.1–7.58
(m, 8H). The spectrum indicated 88% ee.
Hydrochloride. Hydrogen chloride was passed through
a solution of (S)-1 (1.31 g, 5.0 mmol) in diethyl ether at
0°C. A white precipitate which was formed was filtered
off and crystallized from acetone, 0.55 g, 37% yield, mp
121–123°C, [h]2D0=−39.5 (c 1.00, EtOH), 87% ee; lit.12a
mp 122–123°C; lit.20a [h]2D0=−43.5, (c 0.6, EtOH), 96%
4.11. (R)-(−)-2-Bromo-1-(3-phenethylbenzofuran-2-
yl)ethanol, (R)-13
A solution of 12 (4.08 g, 12 mmol) in tetrahydrofuran
(10 mL) was added to a stirred suspension of (−)-DIP-
Cl) (4.25 g, 13 mmol) in tetrahydrofuran (10 mL) at
−25°C under nitrogen, stirring was continued for 8 h,
and then for 18 h at rt. Tetrahydrofuran was removed
under vacuum, diethyl ether (40 mL) was added, fol-
lowed with diethanolamine (1.51 g, 14.4 mmol). The
same workup as described in Section 4.6, gave the
product, 2.31 g, 56% yield, [h]2D0=−12.4 (c 8.03,
1
ee. H NMR (CDCl3): l 1.30 (t, J=7.6 Hz, 3H), 1.53
(s, 9H), 2.89 (q, J=7.6 Hz, 2H), 3.32 (dd, J=12.0 Hz,
J=10.2 Hz, 1H, NCH2), 3.46 (dd, J=12.0 Hz, J=2.6
Hz, 1H, NCH2), 5.59 (dd, J=10.2 Hz, J=2.6 Hz, 1H),
5.90 (bs, 1H, OH), 6.77 (d, J=0.8 Hz, 1H), 7.09–7.17
(m, 2H), 7.32 (dd, J=7.0 Hz, J=2.0 Hz, 1H), 8.30 (bs,
1H), 10.07 (bs, 1H); 13C NMR (CDCl3): l 14.00 (CH3),

M. Zaidlewicz et al. / Tetrahedron: Asymmetry 14 (2003) 1659–1664
1663
CHCl3), 73% ee, determined by HPLC analysis: Daicel
Acknowledgements
Chiracel OJ 10 mm, 25 cm×4.6 mm column, n-hexane/
isopropanol, 9:1. Racemic 13, prepared by the reduc-
tion of 12 with lithium tetrahydridoaluminate, was also
The authors thank Dr Eva-Maria Gutknecht and Pierre
Weber, F. Hoffmann-La Roche Ltd., Basel, for a gift of
racemic bufuralol. Financial support from the Commit-
tee for Scientific Research, Warsaw, grant K005/T09/
1999, is acknowledged.
1
analyzed. H NMR (CDCl3): l 1.80 (d, J=4.0 Hz, 1H,
OH), 2.94–3.10 (m, 4H), 3.18 (dd, J=10.4 Hz, J=5.2
Hz, 1H, CH2Br), 3.56 (dd, J=10.4 Hz, J=8.2 Hz, 1H,
CH2Br), 4.64 (dd, J=8.2 Hz, J=5.4 Hz, 1H), 7.00–7.09
(m, 2H), 7.20–7.40 (m, 5H), 7.41–7.52 (m, 1H), 7.53–
7.69 (m, 1H); 13C NMR (CDCl3): l 25.62 (CH2), 34.87
(CH2Br), 35.58 (CH2), 66.62 (CH), 111.52 (CH), 116.92
(C), 119.68 (CH), 122.60 (CH), 124.83 (CH), 126.36
(CH), 128.39 (C), 128.49 (2×CH), 128.75 (2×CH),
141.18 (C), 150.03 (C), 154.21 (C). Anal. calcd for
C18H17BrO2: C, 62.62; H, 4.97. Found: C, 62.57; H,
4.81%.
References
1. (a) Hou, X.-L.; Yang, Z.; Wong, H. N. C. In Progress in
Heterocyclic Chemistry; Gribble, G. W.; Gilchrist, T. L.,
Eds.; Furans and Benzofurans; Pergamon: Oxford, 2002;
Vol. 14, pp. 139–179; (b) Oganesyan, E. T.; Kadieva, M.
G.; Smirnova, L. P. Farm. Zh. (Kiev) 2001, 47–55; (c)
Bodor, N. Pharmazie 2001, 56 (suppl.), S67–S74; (d)
Nicolaou, K. C.; Snyder, S. A.; Pfafferkorn, J. A. Angew.
Chem., Int. Ed. 2000, 39, 1093–1096.
2. Lantos, I.; Flisak, J.; Liu, L; Matsuoka, R.; Mendelson,
W.; Stevenson, D.; Tubman, K.; Tucker, L.; Zhang,
W.-Y.; Adams, J.; Sorenson, M.; Garigipati, R.; Erhardt,
K.; Ross, S. J. Org. Chem. 1997, 62, 5385–5391.
3. Huang, H.-C.; Chamberlain, T. S.; Seibert, K.; Koboldt,
C. M.; Isakson, P. C.; Reitz, D. B. Bioorg. Med. Chem.
Lett. 1995, 5, 2377–2380.
4. (a) Allsop, D.; Gibson, G.; Martin, I. K.; Moore, S.;
Turnbull, S.; Twyman, L. J. Bioorg. Med. Chem. Lett.
2001, 11, 255–257; (b) Twyman, L. J.; Allsop, D. Tetra-
hedron Lett. 1999, 40, 9383–9384.
5. Felder, C. C.; Joyce, K. E.; Briley, E. M.; Glass, M.;
Mackie, K. P.; Fahey, K. J.; Cullinan, G. J.; Hunden, D.
C.; Johnson, D. W.; Chaney, M. O.; Koppel, G. A.;
Brownstein, M. J. Pharmacol. Exp. Ther. 1998, 284,
291–297.
4.12. (S)-2-Oxiranyl-3-phenethylbenzofuran, (S)-14
A solution of (R)-13 (2.00 g, 5.8 mmol) in tetra-
hydrofuran (10 mL) was added to a stirred suspension
of sodium hydride (0.60 g, 25 mmol) in tetrahydrofuran
(10 mL) at rt under nitrogen, and the mixture was
stirred for 20 h at rt. Solids were filtered off and washed
with diethyl ether (15 mL). Solvents were removed from
the filtrate and the crude product was obtained as a
1
brown–red oil, 1.79 g. H NMR (CDCl3): l 2.98–3.17
(m, 5H), 3.31 (dd, J=5.4 Hz, J=2.8 Hz, 1H), 3.68 (dd,
J=4.2 Hz, J=2.8 Hz, 1H), 7.08–7.20 (m, 2H), 7.21–
7.38 (m, 5H), 7.39–7.47 (m, 1H), 7.50–7.57 (m, 1H); 13
C
NMR (CDCl3): l 25.47 (CH2), 36.13 (CH2), 45.04
(CH), 47.68 (CH2), 111.36 (CH), 119.26 (CH), 119.97
(C), 122.49 (CH), 124.78 (CH), 126.19 (CH), 128.40
(2×CH), 128.59 (2×CH), 128.83 (C), 141.13 (C), 147.52
(C), 154.07 (C).
4.13. (S)-(−)-1-(3-Phenethylbenzofuran-2-yl)-2-propyl-
aminoethanol hydrochloride, (S)-2·HCl
6. Kerr, D. B.; Ong, J.; Johnston, G. A. R.; Berthelot, P.;
Debaert, M.; Vaccher, C. Eur. J. Pharm. 1989, 164,
361–364.
A mixture of (S)-14 (1.48 g, 5.6 mmol) and n-propyl-
amine (20 mL) was placed in a autoclave for 20 h at
70°C. After cooling to rt, excess of n-propylamine was
removed under vacuum, diethyl ether (20 mL) was
added, and hydrogen chloride was passed through the
solution. White precipitate which was formed was
filtered off and crystallized from ethyl acetate, 0.62 g,
31% yield, mp 144–146°C, [h]2D0=−58.05 (c 4.33,
CHCl3), 73% ee, determined by HPLC analysis: Daicel
Chiracel OD-H 5 mm, 250 cm×4.6 mm column, n-hex-
ane/isopropanol, 95:5. 1H NMR (CDCl3): l 0.94 (t,
J=7.2 Hz, 3H), 1.85 (sext., J=7.2 Hz, 2H), 2.30 (dd,
J=12.4 Hz, J=2.8 Hz, 1H, NCH2), 2.80–3.10 (m, 6H,
NCH2, 2×CH2), 3.23 (dd, J=12.4 Hz, J=10.8 Hz, 1H,
NCH2), 5.20 (bs, 1H, OH), 5.29 (dd, J=10.8 Hz,
J=2.8 Hz, 1H), 7.00–7.38 (m, 8H), 7.45–7.57 (m, 1H),
8.60 (bs, 1H), 9.60 (bs, 1H); 13C NMR (CDCl3): l 11.13
(CH3), 19.26 (CH2), 25.25 (CH2), 35.48 (CH2), 50.00
(CH2), 50.98 (CH2), 61.35 (CH), 111.33 (CH), 116.77
(C), 119.89 (CH), 122.57 (CH), 124.72 (CH), 125.87
(CH), 128.40 (2×CH), 128.43 (C), 129.04 (2×CH),
141.34 (C), 149.69 (C), 154.19 (C). Anal. calcd for
C21H26NO2Cl: C, 70.08; H, 7.28; N, 3.89, Cl, 9.85.
Found: C, 69.65; H, 7.19; N, 3.94, Cl, 9.64%.
7. Yoo, S.; Lee, S. H.; Kim, S. K.; Lee, S.-H. Bioorg. Med.
Chem. 1997, 5, 445–459.
8. (a) Wyatt, P. G.; Allen, M. J.; Chilcott, J.; Foster, A.;
Livermore, D. G.; Mordaunt, J. E.; Scicinski, J.; Wool-
lard, P. M. Bioorg. Med. Chem. Lett. 2002, 12, 1399–
1404; (b) Wyatt, P. G.; Allen, M. J.; Chilcott, J.;
Gardner, C. J.; Livermore, D. G.; Mordaunt, J. E.;
Nerozzi, F.; Patel, M.; Perren, M. J.; Weingarten, G. G.;
Shabbir, S.; Wollrad, P. M.; Zhou, P. Bioorg. Med.
Chem. Lett. 2002, 12, 1405–1411.
9. (a) Ecker, G.; Fleischhacker, W.; Noe, C. R. Heterocycles
1994, 38, 1247–1256; (b) Ecker, G.; Fleischhacker, W.;
Helml, T.; Noe, Ch. R.; Scasny, S.; Lemmens-Gruber, R.;
Studenik, Ch.; Marei, H.; Heistracher, P. Chirality 1994,
6, 329–336.
10. Li, D. N.; Pritchard, P. M.; Hanlon, S. P.; Burchell, B.;
Wolf, C. R.; Friedberg, T. J. Pharmacol. Exp. Ther. 1999,
289, 661–667.
11. (a) Magometschnigg, D.; Bonelli, J.; Hitzenberger, G.;
Kaik, G.; Korn, A. Int. J. Clin. Pharmacol. Biopharm.
1978, 16, 54–58; (b) Magometschnigg, D.; Bonelli, J.;
Kaik, G.; Rameis, H. Int. J. Clin. Pharmacol. Biopharm.
1979, 17, 334–340.

1664
M. Zaidlewicz et al. / Tetrahedron: Asymmetry 14 (2003) 1659–1664
12. (a) Fothergill, G. A.; Osbond, J. M.; Wickens, J. C.
Arzneim.-Forsch. Drug. Res. 1977, 27, 978–981; (b)
Blaber, L. C.; Burden, D. T.; Eigeumann, R.; Gerold, M.
Cardiovasc. Pharmacol. 1984, 6, 165–175.
13. (a) Guengerich, F. P.; Miller, G. P.; Hanna, I. H.;
Martin, M. V.; Leger, S.; Black, C.; Chauret, N.; Silva, J.
M.; Trimble, L. A.; Yergey, J. A.; Nicoll-Griffith, D. A.
Biochemistry 2002, 41, 11025–11034; (b) Marucci, K. A.;
Pearce, R. E.; Crespi, C.; Steimel, D. T.; Leeder, J. S.;
Gaedigk, A. Drug Metabolism and Disposition 2002, 30,
595–601.
147–210.
17. (a) Renz, J. Helv. Chim. Acta 1947, 30, 124–139; (b)
Bisagni, F.; Royer, R. Bull. Soc. Chim. Fr. 1960, 1968–
1976; (c) Tamura, E.; Kawasaki, K.; Mikame, D.; Kat-
suki, T. Synlett 1994, 609–610.
18. (a) Hofsløkken, N. W.; Skattebøl, L. Acta Chem. Scand.
1999, 53, 258–262; (b) Casiraghi, G.; Casnati, G.; Cornia,
M.; Pochini, A.; Puglia, G.; Sartori, G.; Ungaro, R. J.
Chem. Soc., Perkin Trans. 1 1978, 318–321; (c) Casiraghi,
G.; Casnati, G.; Puglia, G.; Sartori, G.; Terenghi, G. J.
Chem. Soc., Perkin Trans. 1 1980, 1862–1865; (d) Wang,
R. X.; You, X. Z.; Meng, Q. J.; Minz, E. A.; Bu, X. R.
Synth. Commun. 1994, 24, 1757–1760.
14. Weerawarna, S. A.; Guha-Biswas, M.; Nelson, W. L. J.
Heterocyclic Chem. 1991, 28, 1395–1403.
19. Jordan, S.; Markwell, R. E.; Woolcott, B. S. J. Chem.
15. Zaidlewicz, M.; Chechłowska, A.; Prewysz-Kwinto, A.;
Soc., Perkin Trans. 1 1978, 928–933.
Wojtczak, A. Heterocycles 2001, 55, 569–577.
20. (a) Weerawarna, S. A.; Geisshu¨sler, S. M.; Murthy, S. S.;
Nelson, W. L. J. Med. Chem. 1991, 34, 3091–3097; (b)
Machin, P. J.; Hurst, D. N.; Osbond, J. M. J. Med.
Chem. 1985, 28, 1648–1651.
21. Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95,
512–519.
16. (a) Brown, H. C.; Chandrasekharan, J.; Ramachandran,
P. V. J. Am. Chem. Soc. 1988, 110, 1539–1546; (b)
Brown, H. C.; Ramachandran, P. V. In Advances in
Asymmetric Synthesis; Hassner, A. Ed.; Asymmetric Syn-
thesis Via Chiral Organoboranes Based on a-Pinene; JAI
Press: London and Greenwich, CT 1995; Vol. 1, pp.