Unusual asymmetric oxidation of sulfide; the diastereoselective oxidation of prochiral sulfide-chiral acid salt with hydrogen peroxide without metal

Article abstract of DOI:10.1016/j.tet.2005.03.036

The sulfide 4 was treated with chiral acid in a mixture of toluene and methyl iso-butylketone to precipitate the salt, which reacted with 30% H ₂O₂ for 3 weeks at rt. The resulting crystals were collected followed by recrystallizatio

Full text of DOI:10.1016/j.tet.2005.03.036

Tetrahedron 61 (2005) 5043–5048
Unusual asymmetric oxidation of sulfide; the diastereoselective
oxidation of prochiral sulfide-chiral acid salt with hydrogen
peroxide without metal
†
*
Tomomi Ikemoto, Atsuko Nishiguchi, Tatsuya Ito and Hiroyuki Tawada
Chemical Development Laboratories, Takeda Pharmaceutical Company Limited, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan
Received 10 February 2005; revised 9 March 2005; accepted 9 March 2005
Available online 2 April 2005
Abstract—The sulfide 4 was treated with chiral acid in a mixture of toluene and methyl iso-butylketone to precipitate the salt, which reacted
with 30% H2O2 for 3 weeks at rt. The resulting crystals were collected followed by recrystallization to give the salt of enantiometrically pure
sulfoxide and chiral acid 7 in 72% yield and 98.1% de, which was led to chiral sulfoxide S-3 after neutralization. Sulfoxide S-3 was led to
S-1a as the candidate for an orally active HIV-1 therapeutic agent.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Over the past three decades, many asymmetric synthetic
methods have been developed in the pharmaceutical and
agricultural industries because of switching to chiral
compounds from racemic compounds.1 For asymmetric
oxidation, especially for enantioselective oxidation of
sulfide, there have been many reports because of the
increasing use of chiral sulfoxides both as biological
products2 and chiral auxiliaries.3 Although the asymmetric
oxidation of prochiral sulfides with chiral metal complexes
such as Ti/diol, V, Ti and Mn/salen, and V-Schiff bases are
generally used,4 the Kagan method and its improvements
are mainly used in preparations for a large scale.5 However,
these preparations have some drawbacks: (1) difficulty in
removing or recovering the expensive auxiliaries, and (2)
metals remaining in drug substances.
Recently, Seto et al. have reported that benzazepines having
the chiral sulfoxide moiety S-1 could be candidates for an
orally active HIV-1 therapeutic agent, showing CCR5
antagonist activities.6 In an early synthesis, S-1 was
prepared by the separation of rac-1 using a chiral column
by HPLC.7 Therefore, the preparation of S-1 amerable a
large scale was required to support pharmacological and
Scheme 1.
toxicological evaluations. To accomplish this goal, sulfide 4
was enantiometrically oxidated to give S-3, which led to S-1
(Scheme 1).
Keywords: Diastereoselective sulfoxidation; Benzazepine; CCR5
antagonist.
2. Results and discussion
*
Corresponding author. Tel.: C81 6 6300 6378; fax: C81 6 6300 6281;
e-mail: ikemoto_tomomi@takeda.co.jp
† Present address: Central Pharmaceutical Research Institute, Japan
Tobacco Inc., Takatsuki, Osaka 569-1125, Japan.
First, the preparation of S-3 was conducted using the optical
resolution of rac-3, which was produced by the alkylation of
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.036

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T. Ikemoto et al. / Tetrahedron 61 (2005) 5043–5048
S-3$D-PTTA monohydrate (7) in 41% yield and O99% de,
which gave S-3 in 90% yield and O99% ee after
neutralization. The absolute configuration of 7 was
determined by X-ray crystallographic analysis (Fig. 1).8
Next, the diastereoselective oxidation of the derivatives led
from 4 was carried out. Namely, prochiral sulfide 4 yielded
8 by the salt formation with chiral acid, which was reacted
with the oxidation reagent to afford the asymmetric
oxidation (Table 1). Initially, D-PTTA as a chiral acid
and 30% H2O2 as an oxidation reagent were chosen. The
treatment of 4 was carried out with an equivalent of D-PTTA
in methyl iso-butylketone (MIBK) to precipitate the salt of 4
and D-PTTA. Subsequently, 3 equiv of 30% H2O2 was
added to the resulting mixture, and the suspension was
stirred at rt for 24 h (Table 1). Surprisingly, the oxidation
afforded the diastereoselective reaction, giving 7 in 42%
conversion and 52% de, and sulfone 9 was not detected,
while the reaction mixture was kept in suspension (run 1).9
This result showed that the reaction of 8 with 30% H2O2
asymmetrically afforded the oxidation of sulfide, giving 7,
however, not the kinetic resolution of racemic sulfoxide
to sulfone. Increasing the equivalent of H2O2 to 5 did not
affect the conversion or diastereoselectivity (run 2). When
m-chlorobenzoic peracid (mCPBA) was used, the oxidation
afforded the diastereoselectivity, however, giving a large
amount of sulfone 9 (run 3). A variety of solvents were also
examined. The reactions in CH2Cl2 or toluene showed
almost the same diastereoselectivities as that in MIBK,
and gave an increased conversion (runs 4 and 5). The use of
2-propanol decreased both the conversion and diastereo-
selectivity (run 6). Mixed solvent, for instance, CH2Cl2/
toluene and MIBK/toluene, increased the diastereoselec-
tivity (runs 7 and 8). Using the conditions of run 8, 4 were
reacted for 8 days at rt to give 92% conversion and 68% de
(run 9). After the reaction was continued for 3 weeks, the
resulting solid was filtered off followed by recrystallization
from aqueous MeCN, giving 7 in 72% yield and 98.1% de
(Scheme 3). On the other hand, the solution of 4 dissolved in
a large amount of MIBK and toluene was reacted with 30%
H2O2, showing lower selectivity (4% de, run 10). From
these results, it was considered that the steric formation of 8
was held by deposition from the solution, which reacted
heterogenously with H2O2 to afford the asymmetric
oxidation. Moreover, the practical preparation was studied.
After the reaction of 5 with 6$HCl was completed, 4 was
extracted with MIBK, and a solution of D-PTTA in toluene
and 30% H2O2 were added to the solution. The mixture was
stirred for 24 h at rt to give 7 in 60% conversion and 70% de.
Subsequently, the addition of methanol to the reaction
mixture followed by stirring for 8 h at 50 8C gave 98.5%
conversion and 42% de, which was led to diastereo-
metrically pure 7 (98.2% de) in 53% yield (2 steps) after
the crystallization from the reaction solution.
Scheme 2.
4-aminothiophenol 5 with 5-(chloromethyl)-1-propyl-1H-
imidazole hydrochloride 6$HCl6a and triethylamine in
aqueous 2-propanol followed by the oxidation with 30%
H2O2 in AcOH in 77% yield (2 steps) as shown in Scheme 2.
Di-p-toluoyl-D-tartaric acid (D-PTTA) was found as a
suitable acid of optical resolution by the screening of
various acids. The optical resolution of rac-3 was carried
out with D-PTTA in aqueous 1,2-dimethoxyethane (DME)
followed by recrystallization from aqueous MeCN to give
Chiral sulfoxide S-3 led to S-1a as one of the biologically
active products (Scheme 4). In the previous report, 2a was
prepared in 3% from starting material using 10 steps.6 We
already reported the efficient synthesis of benzazepines.11
According to our procedure, the synthesis of 2a was carried
out. The hydrolysis of 1-isobutylpyrrolidin-2-one with
aqueous MsOH followed by neutralization and anilination
of 11 gave butyric acid 12 in one-pot. After workup, 12 was
Figure 1. Molecular structure of 7.

T. Ikemoto et al. / Tetrahedron 61 (2005) 5043–5048
5045
Table 1. Oxidation of 4 with D-PTTAa
Entry
Solvent (v/w)
Chiral acid
Reagent (eq)
Conditions
Conversion (%)
7
10
de (%)b
1
2
3
4
5
6
7
8
MIBK (25)
MIBK (25)
MIBK (25)
CH2Cl2 (50)
Toluene (50)
2-Propanol (50)
CH2Cl2 (20)/toluene (40)
MIBK (25)/toluene (25)
MIBK (25)/toluene (25)
MIBK (1000)/toluene (1000)
D-PTTA
D-PTTA
D-PTTA
D-PTTA
D-PTTA
D-PTTA
D-PTTA
D-PTTA
D-PTTA
D-PTTA
30% H2O2 (3)
30% H2O2 (5)
mCPBA (1.1)
30% H2O2 (3)
30% H2O2 (3)
30% H2O2 (3)
30% H2O2 (3)
30% H2O2 (3)
30% H2O2 (3)
30% H2O2 (3)
rt, 24 h
rt, 24 h
rt, 24 h
rt, 24 h
rt, 24 h
rt, 24 h
rt, 24 h
rt, 24 h
rt, 8 days
rt, 3 days
42
48
31
68
75
11
64
40
92
5
—
—
41
—
3
—
1
—
5
52
47
47
49
42
28
66
76
68
4
9
10c
—
a To a mixture of 4 (99 mg, 0.4 mmol), D-PTTA (150 mg, 0.4 mmol) and solvent was added oxidation reagent (0.14 g, 1.2 mmol), and the suspension was
stirred at rt.
b Determined by HPLC on a Daicel Chiralcel OD (85/15 n-hexane/ethanol).
c The reaction mixture was solution.
used in the next step without purification. Compound 12 was
esterified with MeI and K2CO3, which was treated with the
combination of NaOMe and dimethyl carbonate followed
by hydrolysis to give 13 in 52% Yield (2 steps, one-pot).
The Suzuki–Miyaura reaction of 13 with boronate complex
led from aryl bromide gave 2a in 86% yield. The treatment
of carboxylic acid 2a with 1.1 equiv of oxalyl chloride and a
catalystic amount of DMF in THF, followed by amidation
with 1.3 equiv of S-3 and 3.5 equiv of i-Pr2NEt, gave crude
S-1a without the Pummerer rearrangement. Crude S-1a was
recrystallized from t-BuOMe to give high quality S-1a
(purity O99%, O99% ee) as a solvate of t-BuOMe in 77%
yield (Scheme 5).10
Scheme 3.
3. Conclusion
A new type of asymmetric sulfoxidation has been
developed. Treatment of prochiral sulfide 4 having imida-
zole moiety with tartaric acid derivative led to imidazole-
sulfide having the chiral moiety, which was reacted with
H2O2 to afford diastereometrically oxidation. Subsequently,
the de of the resulting diastereomer sulfoxide 7 was
increased by recrystallization, which was converted to
high enantiometrically pure sulfoxide S-3 after neutraliz-
ation. For the procedure described here, it was easy to
recover the tartaric acid derivative as an auxiliary, and this
synthesis perfectly prevented contamination by metal.
4. Experimental
4.1. General
Melting points were recorded on a Bu¨chi B-540 micro
melting apparatus and were uncorrected. Optical rotation
values were recorded on a JASCO DIP-370 polarimeter
under standard conditions. IR spectra were recorded on a
Horiba FT-210 spectrophotometer, and absorptions are
reported in cmK1 1H NMR (300 MHz) and 13C NMR
.
Scheme 4.

5046
T. Ikemoto et al. / Tetrahedron 61 (2005) 5043–5048
(75.5 MHz) spectra were recorded on a Bruker DPX-300
spectrometer at ambient temperature. H NMR spectra are
1 h. Water was added to a reaction mixture, and the
remaining solution was extracted with methyl iso-butyl-
ketone (MIBK). The organic layer was washed with brine,
dried with Na2SO4 and concentrated in vacuo. To the
resulting residue were added MIBK (30 mL), D-PTTA
(7.7 g, 20 mmol) in toluene/MIBK (90 mL/60 mL) and
water (3.6 mL), and the mixture was stirred for 2 h at rt.
Subsequently, 30% H2O2 (6.8 g, 60 mmol) were added to
the resulting suspension, and stirred for 24 h. Methanol
(30 mL) was added to the mixture, and the mixture was
stirred for 8 h at 50 8C. Water (30 mL) was added to the
reaction mixture, and the mixture was stirred for 5 h at rt.
The resulting solid was collected by filtration to give 7 as a
white crystalline (7.1 g, yield 53%, 98.2% de).
1
reported as follows: Chemical shifts in ppm downfield
from tetramethylsilane as an internal standard, multiplicity
(sZsinglet, dZdoublet, tZtriplet and mZmutiplet),
coupling constants spectra (Hz) and integration. 13C NMR
spectra recorded in ppm relative to the central line for
CDCl3 at 77 ppm, DMSO-d6 at 39.7 ppm, and CD3OD at
49.0 ppm. The column chromatography was performed on
Chromatorex (Fuji Silysia Chemical Ltd). Elemental
analyses were performed at Takeda Analytical Research
Laboratories, Ltd.
4.1.1. 4-{[(1-Propyl-1H-imidazol-5-yl)methyl]thio}phe-
nylamine (4). The solution of 6$HCl (3.90 g, 20 mmol)
and water (2.5 mL) was added to a suspension of
4-aminothiophenol (5, 2.56 g, 20 mmol), NEt3 (5.5 mL,
40 mmol) and 2-propanol (10 mL) at K10 to 0 8C, and
stirred for 1 h. Water was added to a reaction mixture,
and the remaining solution was extracted with methyl iso-
butylketone (MIBK). The organic layer was washed with
brine, dried with Na2SO4 and concentrated in vacuo. The
resulting residue was purified by chromatography on silica-
gel with AcOEt to give 4 as a white crystalline (4.85 g, yield
4.1.4. 4-{[(1-Propyl-1H-imidazol-5-yl)methyl]sulfinyl}-
phenylamine (rac-3). The solution of 6$HCl (0.78 g,
4.0 mmol) and water (0.5 mL) was added to a suspension
of 5 (0.46 g, 3.64 mmol), NEt3 (1.1 mL, 8.0 mmol) and
MeOH (2 mL) at 0–5 8C, and stirred for 1 h. After warmed
to rt, AcOH (1 mL) and 30% H2O2 (0.62 g, 5.46 mmol)
were added to the resulting mixture, and stirred for 17 h.
Sodium sulfite and 6 N NaOH (3 mL) were added to a
reaction mixture at 0 8C, and stirred for 1 h. The remaining
solution was extracted with a mixture of AcOEt and
2-propanol. The organic layer was washed with brine,
dried with Na2SO4 and concentrated in vacuo. To the
resulting residue was added AcOEt (4 mL), and stirred for
1 h at rt. The resulting solid was collected by filtration to
give rac-3 monohydrate as a white crystalline (0.73 g, yield
1
98%). Mp 49–51 8C. H NMR (CDCl3): d 0.96 (3H, t, JZ
7.3 Hz), 1.76–1.88 (2H, m), 3.76 (2H, br s), 3.86–3.92 (4H,
m), 6.54–6.59 (2H, m), 6.64 (1H, s), 7.06–7.11 (2H, m),
7.42 (1H, s). 13C NMR (CDCl3): d 11.0, 24.0, 30.6, 46.3,
115.2, 121.0, 126.9, 128.8, 135.3, 137.5, 146.9. IR (KBr):
1633, 1600, 1496. Anal. Calcd for C13H17N3S$0.1H2O: C,
62.67; H, 6.96; N, 16.86. Found: C, 62.74; H, 6.83; N, 16.77.
1
71% from 5). Mp 145–146 8C. H NMR (CDCl3): d 0.90
(3H, t, JZ7.4 Hz), 1.69–1.78 (2H, m), 3.60–3.80 (2H, m),
3.97–4.08 (4H, m), 6.61 (1H, s), 6.67–6.72 (2H, m), 7.15–
7.20 (2H, m), 7.44 (1H, s). 13C NMR (CDCl3): d 11.1, 24.0,
46.5, 52.4, 114.7, 120.0, 126.2, 129.7, 131.3, 138.4, 149.9.
IR (KBr): 3214, 1650, 1596, 1500. Anal. Calcd for
C13H17N3OS: C, 59.29; H, 6.51; N, 15.96. Found: C,
59.19; H, 6.63; N, 15.84.
4.1.2. (S)-4-{[(1-Propyl-1H-imidazol-5-yl)methyl]sul-
finyl}phenylammonium (2S,3S)-2,3-bis-[(4-methyl-
benzoyl)oxy]-butenoate hydrate (7) using asymmetric
oxidation. The solution of 4 (1.24 g, 5.0 mmol) and MIBK
(15 mL) was added to a solution of D-PTTA (1.94 g,
5.0 mmol), MIBK (15 mL) and toluene (30 mL) at rt.
Subsequently, 30% H2O2 (1.73 g, 15.0 mmol) were added to
the resulting suspension, and stirred for 3 weeks. The
resulting solid was collected by filtration and recrystallized
from a mixture of MeCN (9 mL) and water (9 mL) to give 7
as a white crystalline (2.4 g, yield 72%, 98.1% de).
[a]2D5ZK31.5 (c 1.014, MeOH). Mp 140–141 8C. 1H
NMR (CD3OD): d 0.89 (3H, t, JZ7.41 Hz), 1.70–1.77
(2H, m), 2.40 (6H, s), 3.82 (2H, t, JZ7.53 Hz), 4.18–4.38
(2H, m), 5.90 (2H, s), 6.7–6.74 (2H, m), 7.01 (1H, s), 7.18–
7.14 (2H, m), 7.28–7.31 (4H, m), 7.98–8.00 (4H, m), 8.46
(1H, d, JZ1.2 Hz). 13C NMR (CD3OD): d 11.0, 21.7, 24.3,
50.6, 74.4, 115.4, 124.4, 126.7, 127.4, 128.1, 130.2, 131.0,
137.6, 145.6, 154.2, 167.2, 171.0. IR (KBr): 1708, 1592.
Anal. Calcd for C33H35N3O9S: C, 61.00; H, 5.43; N, 6.47.
Found: C, 59.26; H, 5.67; N, 6.18. HPLC conditions:
column, Chiralcel OD, mobile phase: n-hexane/2-propanol
(85/15), flow rate: 1.0 mL/min, detection: UV (277 nm),
column temp.: 35 8C, retention time; 19.9 (substrate), 22.2
(R-product), 24.7 (sulfone product) and 28.5 (S-product)
min.
4.1.5. Synthesis of 7 using optical resolution. To a solution
of D-PTTA (14.7 g, 38.0 mmol), rac-3 (10.0 g, 38.0 mmol)
and DME (90 mL) was added water (90 mL) at rt, and
stirred for 14 h. The resulting solid was collected by
filtration and recrystallized from a mixture of MeCN
(70 mL) and water (70 mL) to give 7 as a white crystalline
(10.5 g, yield 41%, O99% de).
4.1.6. (S)-4-{[(1-Propyl-1H-imidazol-5-yl)methyl]sul-
finyl}phenylamine (S-3). The suspension of 7 (2.7 g,
4.0 mmol, 99% de) and AcOEt (10 mL) was adjusted to
below pHZ3 with 1 N HCl, and separated. The aqueous
layer was adjusted to pHZ10 with 25% Na2CO3 solution,
extracted with a mixture of AcOEt and 2-propanol (4:1,
15 mL!3). The organic layer was washed with brine, dried
with Na2SO4 and concentrated in vacuo. The resulting
residue was triturated with AcOEt and collected by filtration
to give S-3 as a white crystalline (0.79 g, 99% ee, yield
79%). [a]2D5ZK167.2 (c 1.018, MeOH). Mp 141–142 8C.
1H NMR (CDCl3): d 0.90 (3H, t, JZ7.4 Hz), 1.69–1.79 (2H,
m), 3.72–3.77 (2H, m), 3.97–4.08 (4H, m), 6.61 (1H, s),
6.60–6.71 (2H, m), 7.15–7.27 (2H, m), 7.44 (1H, s). 13C
NMR (CDCl3): d 11.1, 24.0, 46.5, 52.4, 114.7, 120.0, 126.2,
129.7, 131.3, 138.4, 149.9. IR (KBr): 3156, 1633, 1592,
4.1.3. Practical preparation of 7. The solution of 6$HCl
(3.90 g, 20 mmol) and water (2.5 mL) was added to a
suspension of 5 (2.56 g, 20 mmol), NEt3 (5.5 mL, 40 mmol)
and 2-propanol (10 mL) at K15 to K10 8C, and stirred for

T. Ikemoto et al. / Tetrahedron 61 (2005) 5043–5048
5047
1500. Anal. Calcd for C13H17N3OS: C, 59.29; H, 6.51; N,
15.96. Found: C, 59.30; H, 6.60; N, 15.96.
was cooled to K10 8C, a solution of trimethylborate
(10.0 mL, 90 mmol) in THF (40 mL) was added dropwise
and the resulting mixture was stirred for 1 h at the same
temperature. After the mixture was warmed to rt, Pd(OAc)2
(27 mg, 0.12 mmol) and PPh3 (126 mg, 0.048 mmol) were
added and the whole mixture was stirred for 0.5 h at the
same temperature. Next, 13 (19.4 g, 60 mmol) and a
solution of K3PO4 (79.6 g, 375 mmol) in water (100 mL)
were added, and the mixture was refluxed for 2 h. After it
was cooled to rt, 3 N HCl was added and the mixture was
separated. The aqueous layer was extracted with toluene.
The organic layer was washed successively with 2 N NaOH
and brine. Activated charcoal (2 g) and tri-n-butylphosphine
(2 mL) were added to the organic layer and the mixture was
stirred for 0.5 h. The charcoal was filtered off and washed
with toluene. The filtrate and washing were combined and
concentrated in vacuo. The residue was dissolved in i-Pr2O
under refluxing conditions. After it was cooled to 0 8C, the
mixture was stirred for 1 h at the same temperature. The
resulting solid was collected by filtration and washed with
cold i-Pr2O to give crude 2a (23.7 g) as a yellow crystalline
powder. Crude 2a (2.0 g) was dissolved in 2-propanol
(10 mL) under refluxing conditions, and tri-n-butylphos-
phine (0.2 mL) was added to the solution. After it was
cooled to 0 8C, the mixture was stirred for 1 h at the same
temperature. The resulting solid was collected by filtration
and washed with cold 2-propanol to give crude 2a as a
yellow crystalline powder (1.9 g, yield 86%): Mp 126–
127 8C. 1H NMR (CDCl3): d 0.91–1.10 (9H, m), 1.35–1.50
(2H, m), 1.55–1.70 (2H, m), 2.00–2.15 (1H, m), 2.85–2.90
(2H, m), 3.20 (2H, d, JZ7.30 Hz), 3.30–3.35 (2H, m), 3.58
(2H, d, JZ6.66 Hz), 3.803.85 (2H, m), 4.15–4.20 (2H, m),
6.92 (1H, d, JZ8.75 Hz), 7.01 (2H, d, JZ8.75 Hz), 7.40–
7.55 (4H, m), 7.91 (1H, s). 13C NMR (CDCl3): d 13.8, 19.2,
20.4, 26.6, 31.7, 32.6, 52.0, 61.8, 67.5, 69.2, 71.4, 115.0,
116.2, 122.5, 127.2, 127.8, 128.4, 130.6, 133.0, 134.9,
142.5, 151.1, 157.8, 173.7. IR (KBr): 1668, 1608, 1500.
Anal. Calcd for C27H35NO4: C, 74.11; H, 8.06; N, 3.20.
Found: C, 74.18; H, 8.33; N, 2.95.
4.1.7. 7-Bromo-1-isobuthyl-1-2,3-dihydro-1H-1-benza-
zepine-4-carboxylic acid (13). A solution of 1-isobutyl-
pyrrolidin-2-one (28.0 g, 0.2 mol) in a mixture of MsOH
(26 mL, 0.8 mol) and water (66 mL) was refluxed for 24 h.
After the solution was cooled to rt, Na2CO3 (84.8 g,
0.8 mol) and water (30 mL) were added, and the mixture
was stirred for 1 h. After addition of DMSO (30 mL) to the
resulting mixture, a solution of 11 (12.2 g, 0.06 mol) in
DMSO (66 mL) was added dropwise to the whole mixture
under refluxing conditions. The mixture was refluxed for
9 h. After it was cooled to 30 8C, the mixture was treated
with 6 N HCl until the pH was adjusted to 3 and extracted
with AcOEt. The organic layer was washed with brine. The
organic layer was extracted with 1 N NaOH. The aqueous
layer was treated with 6 N HCl until the pH was adjusted to
3 and extracted with AcOEt. The organic layer was
concentrated in vacuo to give crude 12 as a brown oil,
which was used directly in further reactions without
purification.
To a solution of crude 12 and K2CO3 (9.1 g, 0.066 mol) in
DMF (50 mL) was added dropwise a solution of MeI
(10.2 g, 0.072 mol) in DMF (10 mL) at rt, and the mixture
was stirred for 1 h. After addition of dimethyl carbonate
(120 mL) to the mixture, 28% NaOMe in MeOH (27.8 g,
0.144 mol) was added and the whole mixture was stirred for
1 h at 60 8C. After the mixture was cooled to 5 8C, 2 N HCl
(100 mL) was added, and the whole mixture was concen-
trated in vacuo and extracted with toluene. The organic
layer was washed successively with 1 N NaOH, brine and
water, and concentrated in vacuo. To the resulting residue
were THF (85 mL), MeOH (85 mL) and 1 N NaOH
(120 mL, 0.12 mol), and the mixture was stirred for 1.5 h
at 50 8C. After the mixture was concentrated in vacuo, the
resulting solution was washed with toluene. The aqueous
layer was treated with 6 N HCl until the pH was adjusted to
3 and extracted with AcOEt. The organic layer was washed
with brine, and concentrated in vacuo. The residue was
dissolved in MeOH (45 mL) at 60 8C, and water (9 mL) was
added dropwise to the solution. The mixture was stirred for
8 h at rt, and stirred for 1 h at 0–5 8C. The resulting solid
was collected by filtration and washed with a mixture of
MeOH (15 mL) and water (15 mL) to give 13 as a yellow
crystalline powder (10.1 g, yield 52% from 11): Mp 144–
4.1.9. 7-[4-(2-Butoxyethoxy)phenyl]-1-isobuthyl-1-N-
(4-{[(1-propyl-1H-imidazol-5-yl)methyl]-(S)-sulfinyl}-
phenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide
(S-1a). The suspension of 7 (5.0 g, 7.5 mmol, O99% de)
and AcOEt (15 mL) was adjusted to below pHZ3 with 1 N
HCl, and separated. The aqueous layer was adjusted to pHZ
9 with 25% K2CO3 solution, extracted with a mixture of
AcOEt and 2-propanol. The organic layer was washed with
brine, dried with Mg2SO4 and concentrated in vacuo to give
S-3. Oxalyl chloride (0.56 mL, 6.4 mmol) was dropped to a
solution of 2a (2.56 g, 5.9 mmol), DMF (1 drop) and THF
(8 mL) at 0–5 8C, and stirred for 1 h. The resulting acid
chloride was dropped to a mixture of S-3, NEt3 (2.9 mL,
20.8 mmol) and THF (18 mL) below 10 8C and stirred for
1 h. Water was added to the reaction mixture, which was
separated and extracted with AcOEt. The organic solution
was washed with 10% acetic acid, 7% NaHCO3 aqueous
solution, and 10% NaCl aqueous solution. Activated carbon
(0.4 g), silica-gel (4 g) and Na2SO4 (2 g) were added to an
organic solution, and stirred for 10 min. Solid was filtered
off, and the mother solution was concentrated in vacuo.
The resulting residue was crystallized from a mixture of
t-BuOMe (20 mL) and water (9 mL), and recrystallized
1
145 8C. H NMR (CDCl3): d 0.91 (6H, d, JZ6.60 Hz),
1.90–2.25 (1H, m), 2.75–2.85 (2H, m), 3.12 (2H, d, JZ
7.35 Hz), 3.20–3.30 (2H, m), 6.72 (1H, d, JZ8.97 Hz),
7.20–7.30 (1H, m), 7.44 (1H, s), 7.70 (1H, s). 13C NMR
(CDCl3): d 20.3, 26.5, 32.5, 51.9, 61.8, 109.6, 117.6, 124.1,
128.9, 132.5, 138.6, 140.9, 151.2, 173.6. IR (KBr): 1677,
1614, 1490. Anal. Calcd for C15H18NO2Br: C, 55.57; H,
5.60; N, 4.32. Found: C, 55.52; H, 5.59; N, 4.13.
4.1.8. 7-[4-(2-Butoxyethoxy)phenyl]-1-isobuthyl-2,3-
dihydro-1HK1-benzazepine-4-carboxylic acid (2a).
Under an argon atmosphere, to a suspension of magnesium
(2.25 g, 92 mmol) in THF (140 mL) was added dropwise a
solution of 1-bromo-4-(2-butoxyethoxy)benzene (24.6 g,
90 mmol) in THF (40 mL) under refluxing conditions and
the whole mixture was refluxed for 1 h. After the mixture

5048
T. Ikemoto et al. / Tetrahedron 61 (2005) 5043–5048
(d) Thakur, V. V.; Sudalai, A. Tetrahedron: Asymmetry
2003, 14, 407. (e) Noda, K.; Hosoya, N.; Yanai, K.; Irie, R.;
Katsuki, T. Tetrahedron Lett. 1994, 35, 1887. (f) Nakajima,
K.; Kijima, M.; Fujita, J. Chem. Lett. 1986, 1483. (g) Bolm, C.;
Bienewald, F. Angew. Chem., Int. Ed. Engl. 1995, 34, 2883.
(h) Adam, W.; Korb, M. N.; Roschmann, K. J.; Moller, C. R. S.
J. Org. Chem. 1998, 63, 3423. (i) Vetter, A. H.; Berkessel, A.
Tetrahedron Lett. 1998, 39, 1741.
from a mixture of t-BuOMe (31 mL) and EtOH (3 mL) to
give S-1a as a yellow solid (3.5 g as the solvate of t-BuOMe,
O99%ee, yield 78%). All analytical data of S-1a were
determined as the solvate of t-BuOMe. [a]2D5ZK117.1
(c 1.013, MeOH). Mp 94–96 8C. 1H NMR (CDCl3): d 0.84–
0.97 (12H, m), 1.19 (9H, s), 1.28–1.42 (2H, m), 1.53–1.75
(4H, m), 2.02–2.11 (1H, m), 2.88–2.94 (2H, m), 3.17–3.21
(2H, m), 3.21 (3H, s), 3.33–3.37 (2H, m), 3.53 (2H, t, JZ
6.6 Hz), 3.71–3.81 (4H, m), 3.95–4.10 (2H, m), 4.13–4.16
(2H, m), 6.55 (1H, s), 6.90–6.98 (3H, m), 7.32 (2H, d, JZ
8.7 Hz), 7.43–7.47 (5H, m), 7.75 (2H, d, JZ8.7 Hz), 8.32
(1H, s). 13C NMR (CDCl3): d 11.1, 13.9, 19.2, 20.5, 24.0,
26.7, 27.0, 31.7, 33.3, 46.6, 49.4, 52.0, 52.1, 61.7, 67.6,
69.1, 71.4, 72.8, 115.0, 116.3, 119.7, 120.1, 122.8, 125.3,
127.2, 127.8, 130.8, 131.3, 133.0, 133.6, 134.0, 136.0,
136.3, 138.6, 141.9, 150.7, 157.9, 168.3. IR (KBr): 2956,
1654, 1498, 1241. Anal. Calcd for C40H50N4O4S$C5H12O:
C, 70.10; H, 8.10; N, 7.27. Found: C, 69.82; H, 8.01; N,
7.31. HPLC conditions: column, Chiralcel OJ-R, mobile
phase: 0.05 M KH2PO4/MeCN/MeOH (40/50/10), flow
rate: 1.0 mL/min, detection: UV (295 nm), column temp.:
35 8C, retention time; 11.5 (S-product) and 14.1 (R-product)
min.
5. (a) Bowden, S. A.; Burke, J. N.; Gray, F.; McKown, S.;
Moseley, J. D.; William, O.; Moss, W. O.; Murray, P. M.;
Welham, M. J.; Young, M. J. Org. Process Res. Dev. 2004, 8,
33. (b) Nishi, T.; Nakajima, K.; Iio, Y.; Ishibashi, K.;
Fukuzawa, T. Tetrahedron: Asymmetry 1998, 9, 2567.
(c) Matsugi, M.; Fukuda, N.; Muguruma, Y.; Yamaguchi, T.;
Minamikawa, J.-I.; Otsuka, S. Tetrahedron 2001, 57, 2739.
(d) Pitchen, P. Chem. Ind. (London) 1994, 636. (e) Cotton, H.;
¨
Elebring, T.; Larsson, M.; Li, L.; Sorensen, H.; von Unge, S.
Tetrahedron: Asymmetry 2000, 11, 3819.
6. (a) Seto, M.; Miyamoto, N.; Aikawa, K.; Aramaki, Y.;
Kanzaki, N.; Iizawa, Y.; Baba, M.; Shiraishi, M. Bioorg.
Med. Chem. 2005, 13, 363. (b) Seto, M.; Aramaki, Y.; Okawa,
T.; Miyamoto, N.; Aikawa, K.; Kanzaki, N.; Niwa, S.; Iizawa,
Y.; Baba, M.; Shiraishi, M. Chem. Pharm. Bull.52004,
577–590.
7. The asymmetric synthesis of S-1a as shown in Scheme 5 was
also reported.6a
Acknowledgements
We thank Dr. Kiminori Tomimatsu for helpful discussions;
Mr. Akira Fujishima and Ms. Keiko Higashikawa for X-ray
crystallographic analysis.
References and notes
1. Chirality in Industry; Collins, A. N., Sheldrake, G. N., Crosby,
J., Eds.; Wiley: Chichester, UK, 1997.
2. (a) Tanaka, M.; Yamazaki, H.; Hakasui, H.; Nakamichi, N.;
Sekino, H. Chirality 1997, 9, 17. (b) Von Unge, S.; Langer, V.;
¨
Sjolin, L. Tetrahedron: Asymmetry 1997, 8, 1967. (c) Holland,
Scheme 5.
H. L.; Brown, F. M.; Larsen, B. G. Tetrahedron: Asymmetry
1994, 5, 1129. (d) Hutton, C. A.; White, J. M. Tetrahedron
Lett. 1997, 38, 1643. (e) Morita, S.; Matsubara, J.; Otsubo, K.;
Kitano, K.; Ohatani, T.; Kawano, Y.; Uchida, M. Tetrahedron:
Asymmetry 1997, 8, 3707.
8. Crystallographic data have been deposited with the Cambridge
Crystallographic Data Center (CCDC 249650). Copies of data
can be obtained free of charge via www.ccdc.cam.ac.uk/.
9. The reaction of 4 with an equivalent of (R)-1, 10-binaphathyl-
2,20-diyl hydrogenphosphate and 3 equivalents of 30% H2O2
in CH2Cl2 for 24 h at rt gave the salt of R-3 and (R)-1,
10-binaphathyl-2,20-diyl hydrogenphosphate in 51% conver-
sion and 31% de.
10. In a previous report6, S-1a was isolated as a solvate of AcOEt.
11. (a) Ikemoto, T.; Ito, T.; Nishiguchi, A.; Miura, S.; Tomimatsu,
K. Tetrahedron Lett. 2004, 45, 9335.(b) Ikemoto, T.; Ito, T.;
Nishiguchi, A.; Miura, S.; Tomimatsu, K. Organic Process
Research Development. 2005, published online February 3,
2005, doi; 10.1021/op0497916.
3. (a) Carreno˜, M. C. Chem. Rev. 1995, 95, 1717. (b) Solladie’, G.
Synthesis 1981, 185. (c) Andersen, K. K. In The Chemistry of
Sulfones and Sulfoxides; Patai, S., Rappoport, Z., Stirling,
C. J. M., Eds.; Wiley: Chichester, UK, 1988; Chapter 16,
pp 53–94. (d) Posner, G. H. In The Chemistry of Sulfones and
Sulfoxides; Patai, S., Rappoport, Z., Stirling, C. J. M., Eds.;
Wiley: Chichester, UK, 1988; Chapter 16, pp 823–849.
4. (a) Pitchen, P.; Duna˜ch, E.; Deshmukh, M. N.; Kagan, H. B.
J. Am. Chem. Soc. 1984, 106, 8188. (b) Di Furia, F.; Modena,
G.; Seraglia, R. Synthesis 1984, 325. (c) Palucki, M.; Hanson,
P.; Jacobson, E. N. Tetrahedron Lett. 1992, 33, 7111.