Efficient synthesis of CCR5 antagonist, 2,3-dihydro-1-benzothiepine derivatives by improved intramolecular Claisen type reaction using dialkylcarbonate

Article abstract of DOI:10.1016/j.tet.2004.09.039

The efficient synthesis of 2,3-dihydro-1-benzothiepine derivatives 4 has been developed. The intramolecular Claisen type reaction of the new products, 4-(o-formylphenylthio)butyrate 9, with alcoholate in dialkylcarbonate as a solvent afforded 4 in good yields. According to this new procedure, we have accomplished the practical preparation of CCR5 antagonist 1 as a candidate for oral HIV-1 therapy.

Full text of DOI:10.1016/j.tet.2004.09.039

Tetrahedron 60 (2004) 10851–10857
Efficient synthesis of CCR5 antagonist,
2,3-dihydro-1-benzothiepine derivatives by improved
intramolecular Claisen type reaction using dialkylcarbonate
*
Tomomi Ikemoto, Tatsuya Ito, Atsuko Nishiguchi and Kiminori Tomimatsu
Chemical Development Laboratories, Takeda Pharmaceutical Company Limited, 2-17-85 Jusohonmachi, Yodogawa-ku,
Osaka 532-8686, Japan
Received 3 September 2004; revised 14 September 2004; accepted 15 September 2004
Available online 2 October 2004
Abstract—The efficient synthesis of 2,3-dihydro-1-benzothiepine derivatives 4 has been developed. The intramolecular Claisen type
reaction of the new products, 4-(o-formylphenylthio)butyrate 9, with alcoholate in dialkylcarbonate as a solvent afforded 4 in good yields.
According to this new procedure, we have accomplished the practical preparation of CCR5 antagonist 1 as a candidate for oral HIV-1
therapy.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
similar problems in the preparation of 4f via b-oxo-ester.
There has been no report of synthesis of 4 based on an other
generation to the best of our knowledge. On the other hand,
2,3-dihydro-1-benzoxepine and 2,3-dihydro-1-benzazepine
could be synthesized from the analogues of 9 with
alcoholate according to the Claisen type reaction.4,5a,6 The
Recently, various small-molecular nonpeptide compounds
have been reported as CC chemokine receptor 5 (CCR5)
antagonist, because CCR5 was found to be a coreceptor for
the entry of macrophage-tropic human immunodeficiency
virus type 1 (HIV-1) into host cells.1,2 Shiraishi et al.
previously reported that TAK-779 as a CCR5 antagonist
appeared to be a candidate for the therapy of HIV-1 infected
individuals.3 Furthermore, N-[4-[N-methyl-N-(tetrahydro-
pyran-4-yl)aminomethyl]phenyl]-7-(4-propoxyphenyl)-
1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide 1
showed CCR5 antagonistic activity when orally adminis-
tered.4 Hence, an efficient preparation of 1 on a large scale
was required to support pharmacological and toxicological
evaluations. In the early report,4 the oxidation of 2,3-
dihydro-1-benzothiepine 4f with H2O2 followed by aryla-
tion and hydrolysis gave the acid 2, which was amidated
with the aniline 3 to provide the desired 1 (Scheme 1). For
the preparation of 2,3-dihydro-1-benzothiepine 4, there
have been some syntheses based on the same generation
(Scheme 2).4,5 Compound 4 was led from b-oxo-ester 6
prepared from the ketone 5. These methods via 6, however,
had some drawbacks, for example, the production of over-
reduced compound 8 in the reduction of 7, and the
requirement of several processes to 4 from 5. There were
Keywords: 2,3-Dihydro-1-benzothiepine; Claisen type condensation;
Dialkylcarbonate; CCR5 antagonist.
* Corresponding author. Tel.: C81 6 6300 6378; fax: C81 6 6300 6251;
e-mail: ikemoto_tomomi@takeda.co.jp
Scheme 1.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.09.039

10852
T. Ikemoto et al. / Tetrahedron 60 (2004) 10851–10857
(Table 1), although there has been no report about the
synthesis of 9. Most thioalkylations of 10 gave 9 in good to
excellent yields, while 10d having an electron-donating
group at the p-position of the halogen gave lower yields
(entry 5).
To optimize the reaction conditions, the intramolecular
cyclization of 9a for producing 4a was examined (Table 2).
First, the conditions for synthesizing benzoxepines5 were
applied to the cyclization of 9a. The treatment of 9a was
conducted with NaOEt in EtOH to give many products.
After the workup, the chromatographic purification
provided the desired 4a in 27% yield and the hydrolyzed
12 in 18% yield (entry 1). The combinations of NaOEt and
1,2-dimethoxyethane (DME) or NaH and THF decreased
the hydrolysis to increase the yields of 4a (entries 2 and 3).
However, these reactions could neither depress the
production of impurities of which the structures were
unknown, nor increase the total yields of cyclization
(4aC12). It was thought that the value of pKa at the a
carbon of ester was insufficient for cyclization of 9a,
resulting in the production of impurities.8 To decrease the
value of pKa, the reaction of 9a was performed with the
combination of NaOEt and diethylcarbonate as a solvent,
which was converted to the malonate derivatives.9 Surpris-
ingly, this treatment made a breakthrough in the yield of
cyclization, giving 4a in 71% yield without detection of the
malonate derivative and 12 (entry 4). For this reaction, 1.2
equiv of diethylcarbonate affected the cyclization to
increase the yield of 4a (entry 6 vs 1). Moreover, the
same reaction of 9a with NaOEt using ethyl formate as a
solvent, expected to produce a similar effect, gave a slightly
higher yield of 4a than that using DME as a solvent
(entry 2 vs 5).10
Scheme 2.
preparation of 4 from 9 attracted our interest regarding
large-scale preparations because of its simple and wasteless
protocol, even though the yields based on this generation
were not sufficiently high. In this paper, we announce the
facile and efficient synthesis of 4, and the application for 1.
2. Results and discussion
2.1. Development of new preparation of 2,3-dihydro-1-
benzothiepines
We synthesized 9, having various substituted groups, to
develop a new synthetic procedure for 4. The synthesis of
new products 9a–e was accomplished by thioalkylation of
o-halogenobenzaldehyde 10 with 4-mercaptobutyrate 117
and K2CO3 in DMF overnight at room temperature
For research into the scope and limitation of the intramo-
lecular Claisen type reaction, a variety of 9 reactions
were next performed under the conditions of alcoholate/
dialkylcarbonate (Table 3). The use of dimethylcarbonate
Table 1. Thioalkylation of o-halogenobenzaldehydesa
Entry
Substrates
Yield (%)b
10
11
1
2
3
4
5
10a (R1ZR2ZR3ZH, XZF)
10a
11a (R4ZEt)
11b (R4ZMe)
11a
11a
11a
9a: 67
9b: 95
9c: 78
9d: 70
9e: 27
10b (R1ZR2ZH, R3ZBr, XZF)
10c (R1ZCl, R2ZR3ZH, XZCl)
10d (R1ZR2ZH, R3ZOMe, XZBr)
a General procedure. To a suspension of 10 (1.0 g, 1.0 equiv), K2CO3 (2.0 equiv) and DMF (3 v/w) was added 11 (2 equiv), and the whole suspension was
stirred overnight at room temperature.
b Isolated yield.

T. Ikemoto et al. / Tetrahedron 60 (2004) 10851–10857
10853
Table 2. Optimization of reaction conditionsa
Entry
Solvent
Base
Conditions
Isolated yield (%)
9a
4a
12
1
2
3
4
5
6
EtOH
DME
THF
(EtO)2CO
HCO2Et
EtOH, (EtO)2CO (1.2 eqiv)
20% NaOEt in EtOH
20% NaOEt in EtOH
NaH
20% NaOEt in EtOH
20% NaOEt in EtOH
20% NaOEt in EtOH
rt, 3 h, then refluxed, 1 h
rt, 45 min
rt, 1 h, then refluxed, 0.5 h
rt, 2 h
rt, 4 h
ND
ND
ND
ND
26
27
37
44
71
58
53
18
6
6
ND
ND
4
rt, 3 h, then refluxed, 1 h
ND
a The mixture of 9a (1.0 g, 1.0 equiv), base (1.2 equiv) and solvent (20 v/w) was reacted.
malonate derivative 13, which smoothly afforded the
cyclization to give 4. However, the role of dialkylcarbonate
in the intramolecular cyclization also might be thought to
the acceleration of dehydration of 16 (Scheme 3).
Table 3. The intramolecular Claisen type reactiona
2.2. Large-scale preparation of 1 as a candidate for
orally administered HIV-1 therapy
Entry
Substrate Time (h) Isolated yield (%)
According to the new procedure for 2,3-dihydro-1-ben-
zothiepines, we tried to develop a large-scale preparation of
the desired 1 (Scheme 4). The biarylaldehyde 10f was
selected as an intermediate, because the intramolecular
condensation of 9c as a substrate afforded a lower yield, as
mentioned. Although there were many syntheses of biaryl
compounds, the preparation of 10f was attempted using the
convenient procedure of the Suzuki–Miyaura reaction in
one-pot for large-scale preparation.11,12 The treatment of 17
was conducted with magnesium in THF under the refluxing
condition, followed by cooling to K10 8C and boronation
with trimethoxyborane, which was reacted with 10b,
aqueous K2CO3, and a catalytic amount of Pd(PPh3)4
under the refluxing condition to give 10f in excellent yield.
The coupling reaction also proceeded smoothly when
0.05 mol% of Pd(OAc)2 and 0.2 mol% of PPh3 instead of
Pd(PPh3)4 were employed. As a result, all reactions from the
Grignard reaction of 17 to the cross-coupling reaction were
performed in one-pot to give 10f almost quantitatively.
After workup followed by extraction and concentration, 10f
was used without further purification. The thioalkylation of
crude 10f with 11a using K2CO3 in DMF as a base, followed
1b
2
3
4
9b
9c
9d
9e
15
2
7
4b (R1ZR2ZR3ZH, R4ZMe): 71
4c (R1ZR2ZH, R3ZBr, R4ZEt): 32
4d (R1ZCl, R2ZR3ZH, R4ZEt): 46
4e (R1ZH, R2ZR3ZOMe, R4ZEt): 70
6
a To a solution of 9 (1.0 g) and diethyl carbonate (20 v/w) was added 20%
NaOEt in EtOH (1.2 equiv), and the whole mixture was stirred at room
temperature.
b 28% NaOMe in MeOH (1.2 equiv) and (MeO)2CO (20 mL) were used.
instead of diethylcarbonate as a solvent also affected the
intramolecular condensation of 9b to give 4b in 71% yield
(entry 1). The yields of 4 were decreased by the electron-
withdrawing groups at the o- or p-position of thiobutyrate,
while the treatment of 9e having an electron donor group at
the p-position of the sulfur atom afforded 4e in 70% yield
(entries 2, 3 and 4).
The reaction mechanism to 4 from 9 was not clear, although
the addition of dialkylcarbonate was required for improve-
ment in these reactions. We deduced that the treatment of 9
with alcoholate and dialkylcarbonate converted it to the
Scheme 3.

10854
T. Ikemoto et al. / Tetrahedron 60 (2004) 10851–10857
Scheme 4.
by cyclization with the combination of NaOEt in EtOH
solution and diethyl carbonate at room temperature
provided 1-benzothiepine 4g in one-pot. However, it was
difficult to adopt these conditions for a large-scale
preparation, because the reaction time was unstable in the
thioalkylation when the reaction was scaled up to multi-
decade grams. It was thought that the thioalkylation of 10f
with 11a proceeded heterogenously. The use of DBU
instead of K2CO3 afforded a stable reaction time, because
the salt was dissolved in DMF. The reactions to 4g in two
steps afforded 48% yield using only the crystallization
procedure.
Furthermore, the practical preparation of 1 as a candidate
for orally administered HIV-1 therapy was accomplished by
employing the new method, and did not require any
chromatographic purification. This synthetic route was
consisted of five steps in 35% yield, as compared with the
previous nine steps.
4. Experimental
4.1. General
Melting points were recorded on a Bu¨chi B-540 micro
melting apparatus and were uncorrected. IR spectra were
recorded on a Horiba FT-210 spectrophotometer. H and
The preparation of 2 from 4g was conducted using two
methods. The hydrolysis of 4g with 2 N NaOH gave
carboxylic acid, which was oxidated with H2O2 in AcOH.
However, the oxidation was not completed, giving 2
containing the sulfoxide. The oxidation from the sulfide
4g to the sulfone 18 was accomplished in 94% yield by the
reaction of 30% hydrogen peroxide in acetic acid. The
sulfone 18 was hydrolyzed with aqueous K2CO3 solution in
a mixture of THF and MeOH under the refluxing condition
to give 2 in 95% yield. The hydrolysis using NaOH as a base
provided some by-products, and the hydrolysis of 18 also
was not completed under the acidic conditions.
1
13C NMR spectra were recorded on a Bruker DPX-300
spectrometer. 1H NMR spectra are reported as follows:
chemical shifts in ppm (d) downfield from tetramethylsilane
as an internal standard, multiplicity (s, singlet; d, doublet; t,
triplet and m, mutiplet), coupling constants spectra (Hz) and
integration. 13C NMR spectra recorded in ppm (d) relative to
the central line for CDCl3 at 77 ppm and DMSO-d6 at
39.7 ppm. The column chromatography was performed on
BW820 (Fuji Silysia Chemical Ltd) Elemental and HRMS
analyses were performed at Takeda Analytical Research
Laboratories, Ltd.
Finally, the acid-chloride generated from 2 was amidated
with the amine 3$2HCl (3 dihydrochloride)13 to give 1. The
reaction in N,N-dimethylacetamide (DMAc) proceeded
smoothly, although the acid 2 was left in 1 when DMF or
1-methyl-2-pyrrolidone was used. After the reaction was
completed, the addition of water to the reaction mixture
caused crystallization to give the high-quality target product
1 in 82% yield.
4.1.1. General procedure for the preparation of 9.
Compound 11 (2 equiv) was added to a suspension of 10
(1.0 g) and K2CO3 (2 equiv) in DMF (3 v/w), and stirred
overnight at room temperature. The reaction mixture was
diluted in AcOEt, and washed successively with water,
0.5 N HCl, and brine. The organic layer was dried by
Na2SO4 and concentrated in vacuo. The residue was purified
by column chromatography on silica-gel with n-hexane–
AcOEt.
3. Conclusion
4.1.2. Ethyl 4-(2-formylphenylthio)butyrate (9a), from
10a and 11a. A pale yellow oil; yield: 67%; H NMR
1
We have developed a facile and novel synthetic preparation
of 2,3-dihydro-1-benzothiepine derivatives 4. The new
compound, alkyl 4-(o-formylphenylthio)butyrate 9, was
prepared from o-halogenobenzaldehyde 10 and mercapto-
butylate 11. The improved intramolecular Claisen type
reaction of 9 with alcoholate in dialkylcarbonate as a solvent
provided 4 in good yields.
(300 MHz, CDCl3) d 1.26 (t, JZ7.1 Hz, 3H), 1.95–2.07 (m,
2H), 2.49 (t, JZ7.2 Hz, 2H), 3.02 (t, JZ7.1 Hz, 2H), 4.13
(q, JZ7.1 Hz, 2H), 7.27–7.34 (m, 1H), 7.45–7.53 (m, 2H),
7.83–7.86 (m, 1H), 10.38 (s, 1H); 13C NMR (75 MHz,
CDCl3) d 14.2, 23.9, 32.4, 33.0, 60.5, 125.5, 128.3, 132.1,
134.0, 134.2, 141.3, 172.7, 191.4; IR (neat) 1731, 1695,

T. Ikemoto et al. / Tetrahedron 60 (2004) 10851–10857
10855
1196 cmK1; HRMS (EI) calcd for C13H16O3S ([M]C)
252.0820; Found 252.0820.
4.1.7. Ethyl 2,3-dihydro-1-benzothiepin-4-carboxylate
(4a). A yellow oil; yield: 71%; 1H NMR (300 MHz,
CDCl3) d 1.35 (t, JZ7.1 Hz, 3H), 2.96–3.00 (m, 2H),
3.16–3.21 (m, 2H), 4.28 (q, JZ7.1 Hz, 2H), 7.18–7.27
(m, 2H), 7.36–7.48 (m, 2H), 7.81 (s, 1H); 13C NMR
(75 MHz, CDCl3) d 14.2, 32.8, 35.3, 61.1, 127.0, 128.5,
132.2, 133.4, 134.4, 136.8, 138.8, 139.4, 168.1; IR (neat)
1703, 1267, 1240 cmK1; HRMS (EI) calcd for C13H14O2S
([M]C) 234.0715; Found 234.0715.
4.1.3. Methyl 4-(2-formylphenylthio)butyrate (9b), from
10a and 11b. A pale yellow oil; yield: 95%; H NMR
1
(300 MHz, CDCl3) d 1.96–2.06 (m, 2H), 2.50 (t, JZ7.2 Hz,
2H), 3.01 (t, JZ7.1 Hz, 2H), 3.68 (s, 3H), 7.27–7.34
(m, 1H), 7.46–7.55 (m, 2H), 7.81–7.84 (m, 1H), 10.36
(s, 1H); 13C NMR (75 MHz, CDCl3) d 23.8, 32.3, 32.7, 51.6,
125.5, 128.2, 132.1, 134.0, 134.1, 141.3, 173.1, 191.3; IR
(neat) 1735, 1693, 1197 cmK1; HRMS (EI) calcd for
C12H14O3S ([M]C) 238.0664; Found 238.0664.
4.1.8. Methyl 2,3-dihydro-1-benzothiepin-4-carboxylate
(4b). A white solid; yield: 71%; 1H NMR (300 MHz,
CDCl3) d 2.96–3.00 (m, 2H), 3.16–3.21 (m, 2H), 3.83
(s, 3H), 7.18–7.27 (m, 2H), 7.36–7.48 (m, 2H), 7.81 (s, 1H);
13C NMR (75 MHz, CDCl3) d 32.9, 35.2, 52.2, 127.0, 128.6,
132.2, 133.0, 134.5, 136.7, 138.8, 139.7, 168.5; IR (KBr)
1706, 1631, 1428 cmK1; mp 52–54.3 8C; HRMS (FAB)
calcd for C12H12O2S ([M]C) 220.0558; Found 220.0558.
Anal. Calcd for C12H12O2S: C, 65.43; H, 5.49; S, 14.56.
Found: C, 65.57; H, 5.43; F, 14.32.
4.1.4. Ethyl 4-(4-bromo-2-formylphenylthio)butyrate
(9c), from 10b and 11a. A pale yellow solid; yield: 78%;
1H NMR (300 MHz, CDCl3): d 1.26 (t, JZ7.1 Hz, 3H),
1.95–2.05 (m, 2H), 2.48 (t, JZ7.1 Hz, 2H), 3.00 (t, JZ
7.2 Hz, 2H), 4.13 (q, JZ7.1 Hz, 2H), 7.35 (d, JZ8.5 Hz,
1H), 7.60–7.64 (m, 1H), 7.94 (d, JZ2.3 Hz, 1H), 10.32
(s, 1H); 13C NMR (75 MHz, CDCl3) d 14.2, 23.9, 32.7, 32.9,
60.6, 119.6, 130.4, 134.1, 135.5, 136.7, 140.3, 172.6, 189.8;
IR (KBr) 1732, 1678, 1458, 1178 cmK1; mp 48–49 8C;
HRMS (FAB) calcd for C13H16O3BrS ([MH]C) 331.0004;
Found 331.0004. Anal. Calcd for C13H15O3SBr: C, 47.14;
H, 4.56; S, 9.68; Br, 24.12. Found: C, 47.19; H, 4.48; S,
9.58; Br, 24.23.
4.1.9. Ethyl 7-bromo-2,3-dihydro-1-benzothiepin-4-car-
boxylate (4c). A yellow solid; yield: 32%; 1H NMR
(300 MHz, CDCl3) d 1.35 (t, JZ7.1 Hz, 3H), 2.95–2.99
(m, 2H), 3.15–3.20 (m, 2H), 4.28 (q, JZ7.1 Hz, 2H), 7.26–
7.34 (m, 2H), 7.51–7.52 (m, 1H), 7.69 (s, 1H); 13C NMR
(75 MHz, CDCl3) d 14.7, 33.1, 35.8, 61.7, 121.1, 131.6,
134.1, 135.3, 136.9, 138.2, 138.3, 139.2, 168.0; IR (KBr)
1704, 1629, 1465 cmK1; mp 82–83 8C; HRMS (FAB) calcd
for C13H13O2SBr ([M]C) 311.9820; Found 311.9820. Anal.
Calcd for C13H13O2SBr: C, 49.85; H, 4.18; S, 10.24; Br,
25.51. Found: C, 50.13; H, 4.12; S, 10.11; Br, 25.55.
4.1.5. Ethyl 4-(2-chloro-6-formylphenylthio)butyrate
(9d), from 10c and 11a. A pale yellow oil; yield: 70%;
1H NMR (300 MHz, CDCl3) d 1.26 (t, JZ7.2 Hz, 3H),
1.84–1.94 (m, 2H), 2.43 (t, JZ7.2 Hz, 2H), 2.95 (t, JZ
7.2 Hz, 2H), 4.11 (q, JZ7.2 Hz, 2H), 7.42 (dd, JZ7.9,
7.2 Hz, 1H), 7.71 (d, JZ7.9 Hz, 1H,), 7.84 (d, JZ7.7 Hz,
1H), 10.77 (s, 1H); 13C NMR (75 MHz, CDCl3) d 14.1, 24.7,
32.8, 36.0, 60.5, 126.9, 129.8, 135.0, 136.8, 140.2, 141.2,
172.5, 192.0; IR (neat) 1739, 1685, 1037 cmK1; HRMS
(FAB) calcd for C13H16O3ClS ([MH]C) 287.0509; Found
287.0509.
4.1.10. Ethyl 9-chloro-2,3-dihydro-1-benzothiepin-4-car-
boxylate (4d). A yellow oil; yield: 46%; 1H NMR
(300 MHz, CDCl3) d 1.35 (t, JZ7.1 Hz, 3H), 2.99–3.03
(m, 2H), 3.15–3.20 (m, 2H), 4.28 (q, JZ7.1 Hz, 2H), 7.12–
7.27 (m, 1H), 7.26–7.36 (m, 2H), 7.77 (s, 1H); 13C NMR
(75 MHz, CDCl3) d 14.3, 33.2, 34.3, 61.2, 126.9, 129.3,
133.5, 134.1, 135.6, 137.9, 138.6, 138.9, 167.8; IR (neat)
1712, 1631 cmK1. HRMS (FAB) calcd for C13H13O2ClS
([M]C) 268.0325; Found 268.0325.
4.1.6. Ethyl 4-(3,4-dimethoxy-6-formylphenylthio)buty-
rate (9e), from 10d and 11a. A pale yellow solid; yield:
27%; 1H NMR (300 MHz, CDCl3) d 1.24 (t, JZ7.1 Hz, 3H),
1.80–2.07 (m, 2H), 2.43 (t, JZ7.1 Hz, 2H), 2.92 (t, JZ
7.4 Hz, 2H), 3.93 (s, 3H), 3.99 (s, 3H), 4.12 (q, JZ7.1 Hz,
2H), 7.02 (s, 1H),7.41 (s, 1H), 10.48 (s, 1H); 13C NMR
(75 MHz, CDCl3) d 13.6, 23.9, 32.2, 35.1, 55.5, 55.8, 60.0,
110.0, 114.4, 129.2, 133.3, 148.3, 153.3, 172.1, 189.7; IR
(nujol) 1718, 1671, 1272 cmK1; mp 87–88 8C; HRMS
(FAB) calcd for C15H20O5S ([M]C) 312.1031; Found
312.1031. Anal. Calcd for C15H20O5S: C, 57.67; H, 6.45;
S, 10.26; O, 25.61. Found: C, 57.50; H, 6.47; S, 10.37.
4.1.11. Ethyl 7,8-dimethoxy-2,3-dihydro-1-benzothiepin-
4-carboxylate (4e). A yellow oil; yield: 70%; H NMR
1
(300 MHz, CDCl3) d 1.35 (t, JZ7.1 Hz, 3H), 2.95–2.98
(m, 2H), 3.16–3.21 (m, 2H), 3.88 (s, 3H), 3.89 (s, 3H), 4.28
(q, JZ7.1 Hz, 2H), 6.86 (s, 1H), 6.96 (s, 1H), 7.74 (s, 1H);
13C NMR (75 MHz, CDCl3) d 14.3, 32.8, 35.7, 55.9, 60.9,
114.7, 116.6, 129.4, 130.9, 131.8, 139.2, 147.8, 148.8,
168.1; IR (neat) 1700, 1594, 1502 cmK1; HRMS (FAB)
calcd for C15H18O4S ([M]C) 294.0926; Found 294.0926.
General procedure for the preparation of 4. 20% NaOEt
(1.2 equiv) in EtOH (or 28% NaOMe in MeOH) was added
to a solution of 9 (1.0 g) and diethyl carbonate (20 v/w) (or
dimethyl carbonate), and stirred at room temperature. After
cooling to 0 8C, the reaction mixture was neutralized with
1 N HCl. The resulting solution was extracted with AcOEt,
and the organic layer was washed with water, dried by
Na2SO4 and concentrated in vacuo. The residue was purified
by column chromatography on silica-gel with n-hexane–
AcOEt.
4.1.12. Ethyl 7-(4-propoxyphenyl)-2,3-dihydro-1-ben-
zothiepin-4-carboxylate (4g). Under an argon atmosphere,
a solution of 17 (37.1 g, 172.4 mmol) and THF (90 mL) was
added dropwise to a suspension of magnesium (4.3 g,
177.3 mmol) and THF (270 mL) under a refluxing con-
dition, and the whole was stirred for 1.5 h under the same
conditions. After cooling to K11 8C, a solution of
trimethoxyborane (17.9 g, 172.4 mmol) and THF (90 mL)
was added dropwise to the reaction mixture and stirred for
1 h at K10 8C. After warming to room temperature,

10856
T. Ikemoto et al. / Tetrahedron 60 (2004) 10851–10857
palladium (II) acetate (11 mg, 0.049 mmol) and triphenyl-
phosphine (52 mg, 0.197 mmol) were added to the resulting
mixture, and stirred for 30 min at room temperature.
Compound 10b (20.0 g, 98.5 mmol), K2CO3 (71.5 g,
517.2 mmol) and distilled water (85 mL) were added to
the resulting mixture, and the whole was refluxed for 4 h.
After cooling to room temperature, 2 N HCl (450 mL) was
added dropwise to the reaction mixture at 20–30 8C and
separated. The aqueous solution was extracted with toluene
(450 mL), and the combined organic solution was washed
successively with 2 N HCl (300 mL), 2 N NaOH
(300 mL!2), 2 N HCl (300 mL) and 20% NaCl solution
(300 mL!2). Activated charcoal (1.0 g) was added to the
organic solution, and the mixture was stirred for 20 min at
room temperature. The charcoal was filtered off and washed
with toluene (50 mL). The filtrate and washing were
concentrated in vacuo to give crude 2-fluoro-5-(4-propoxy-
phenyl)benzaldehyde (10f, 30.5 g) as a brown oil. An
analytically pure sample of 10f was obtained by chroma-
tography on silica-gel as a white solid; 1H NMR (300 MHz,
CDCl3) d 1.06 (t, JZ7.4 Hz, 3H), 1.77–1.90 (m, 2H), 3.96
(t, JZ6.6 Hz, 2H), 6.95–6.98 (m, 2H), 7.18–7.25 (m, 1H),
7.46–7.50 (m, 2H), 7.74–7.78 (m, 1H), 8.00–8.04 (m, 1H),
10.41 (s, 1H); 13C NMR (75 MHz, CDCl3) d 10.5, 22.6,
70.0, 115.0, 116.7, 117.0, 124.1, 126.3, 128, 131.1, 134.3,
137.8, 159.2, 162.1, 165.6, 187.2; IR (KBr) 2875, 1691,
1608, 1484, 1216 cmK1; mp 42–43 8C; HRMS (FAB) calcd
for C16H15O2F ([M]C) 258.1056; Found 258.1056. Anal.
Calcd for C16H15O2F: C, 74.40; H, 5.85; F, 7.36. Found: C,
74.66; H, 5.67; F, 7.28.
C22H24O3S ([M]C) 368.1446; Found 368.1446. Anal. Calcd
for C22H24O3S: C, 71.71; H, 6.56; S, 8.70. Found: C, 71.72;
H, 6.77; S, 8.64.
4.1.13. Ethyl 7-(4-propoxyphenyl)-1,1-dioxo-2,3-dihy-
dro-1-benzothiepin-4-carboxylate (18). After 4g (15.0 g,
40.7 mmol) was dissolved in acetic acid (135 mL) at 56 8C,
30% H2O2 (9.5 g, 83.5 mmol) in acetic acid (15 mL) was
added dropwise to a solution at the same temperature and
stirred for 3 h at 65–70 8C. Water (15 mL) and 5% Na2SO3
solution (60 mL) were added dropwise to the reaction
mixture, and then the whole was cooled to room temperature
and stirred for 2 h at the same temperature. The resulting
crystals were collected by filtration, washed successively
with acetic acid/water (3/2, 15 mL) and water (150 mL), and
dried in vacuo to give 18 (15.4 g, yield, 94%) as a white
1
solid. H NMR (300 MHz, CDCl3) d 1.06 (t, JZ7.4 Hz,
3H), 1.38 (t, JZ7.2 Hz, 3H), 1.78–1.90 (m, 2H), 3.14 (t, JZ
6.3 Hz, 2H), 3.64 (t, JZ7.1 Hz, 2H), 3.98 (t, JZ6.6 Hz,
2H), 4.32 (q, JZ7.2 Hz, 2H), 6.99–7.02 (m, 2H), 7.53–7.57
(m, 2H), 7.65–7.69 (m, 2H), 7.89 (s, 1H), 8.18 (d, JZ
8.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 10.5, 14.3, 22.6,
25.0, 55.8, 61.7, 69.7, 115.2, 126.7, 127.9, 128.4, 130.5,
131.8, 132.6, 132.9, 137.9, 138.3, 146.1, 160.0, 166.6; IR
(KBr) 2933, 1706, 1606, 1517, 1243 cmK1; mp 139–
140 8C; HRMS (FAB) calcd for C22H24O5S ([M]C)
400.1344; Found 400.1344. Anal. Calcd for C22H24O5S:
C, 65.89; H, 6.04; S, 8.01. Found: C, 65.72; H, 5.87; S, 7.96.
4.1.14. 7-(4-Propoxyphenyl)-1,1-dioxo-2,3-dihydro-1-
benzothiepin-4-carboxylic acid (2). A solution of K2CO3
(342 g, 2.47 mol) and water (4.2 L) was added dropwise to a
solution of 18 (495 g, 1.24 mol), THF (4.95 L) and MeOH
(2.48 L), and the whole was refluxed for 6.5 h. Under the
same condition, 3 N HCl (1.85 L) was added dropwise to the
reaction mixture and the whole was cooled to room
temperature. Under the same temperature, 6 N HCl
(84 mL) was added dropwise to the resulting mixture and
stirred for 1 h with ice-bathing. The resulting crystals
were collected by filtration, washed with THF/MeOH/water
(1/1/3, 2.97 L), and dried in vacuo to give 2 (443 g, yield,
DBU (34.4 mL, 229.9 mmol) was added dropwise to a
solution of the above crude 10f and 11a (32.6 mL,
229.9 mmol) in DMF (59 mL) at 0–10 8C under an argon
atmosphere, and the whole was stirred for 1 h at 20–30 8C.
After diethyl carbonate (590 mL) was added the reaction
mixture, 20% NaOEt in EtOH (156.0 g, 459.8 mmol) was
added dropwise to the resulting mixture, and the whole was
stirred for 3 h at 20–30 8C. After cooling to 5 8C, 2 N HCl
(338 mL) was added dropwise to the reaction mixture, and
separated. The aqueous solution was extracted with AcOEt
(290 mL), and the combined organic layer was washed
successively with water (300 mL), 5% NaHCO3 solution
(300 mL) and 5% NaCl solution (300 mL). Activated
charcoal (3.5 g) and tri-n-butylphosphine (4 mL) were
added to the organic solution, and the mixture was stirred
for 20 min. The charcoal was filtered off, and washed with
AcOEt (60 mL). After the filtrate and washing was
concentrated in vacuo, the resulting residue was dissolved
in diisopropyl ether (60 mL) under a refluxing condition.
After cooling to room temperature, stirring for 1.5 h at room
temperature and stirring for 2 h at 0 8C, the resulting crystals
were collected by filtration, washed with cold diisopropyl
ether (60 mL) and dried in vacuo to give 4g (20.3 g, yield,
48% based on 10b) as a pale yellow solid. 1H NMR (CDCl3)
d 1.06 (t, JZ7.4 Hz, 3H), 1.36 (t, JZ7.1 Hz, 3H), 1.77–1.90
(m, 2H), 3.00 (t, JZ5.3 Hz, 2H), 3.22 (t, JZ5.6 Hz, 2H),
3.96 (t, JZ6.6 Hz, 2H), 4.29 (q, JZ7.1 Hz, 2H), 6.94–7.00
(m, 2H), 7.36–7.57 (m, 5H), 7.87 (s, 1H); 13C NMR
(75 MHz, CDCl3) d 10.5, 14.4, 22.6, 32.7, 35.6, 61.1, 69.6,
114.9, 126.7, 127.9, 132.0, 132.5, 132.7, 133.6, 136.7,
137.2, 139.6, 139.7, 159.1, 168.1; IR (KBr) 2927, 1704,
1240, 819 cmK1; mp 87–88 8C; HRMS (FAB) calcd for
1
96%) as a light white-yellow solid. H NMR (300 MHz,
DMSO-d6) d 0.98 (t, JZ7.4 Hz, 3H), 1.70–1.78 (m, 2H),
2.95 (t, JZ6.2 Hz, 2H), 3.73 (t, JZ6.4 Hz, 2H), 3.98 (t, JZ
6.5 Hz, 2H), 7.05 (d, JZ8.7 Hz, 2H), 7.75 (d, JZ8.7 Hz,
2H), 7.86–7.88 (m, 2H), 8.02–8.05 (m, 2H); 13C NMR
(75 MHz, DMSO-d6) d 10.6, 22.2, 25.4, 53.9, 69.3, 115.3,
126.4, 127.1, 128.6, 129.9, 132.1, 132.4, 134.0, 136.8,
138.8, 144.9, 160.0, 168.5; IR (KBr) 3500, 1673, 1608,
1519, 1294, 1251 cmK1; mp 271–272 8C; HRMS (FAB)
calcd for C20H20O5S ([M]C) 372.1031; Found 372.1031.
Anal. Calcd for C20H20O5S: C, 64.50; H, 5.41; S, 8.61.
Found: C, 64.40; H, 5.47; S, 8.55.
4.1.15. N-[4-[N-Methyl-N-(tetrahydropyran-4-yl)amino-
methyl]phenyl]-7-(4-propoxyphenyl)-1,1-dioxo-2,3-
dihydro-1-benzothiepin-4-carboxamide (1). Thionyl
chloride (0.70 g, 5.91 mmol) was added dropwise to a
suspension of 2 (2.0 g, 5.37 mmol) in N,N-dimethylacetoa-
mide (10 mL) at room temperature, and the whole was
stirred for 2 h at room temperature. The reaction
mixture was added dropwise to a suspension of 3$2HCl
(1.9 g, 6.44 mmol) and NEt3 (5.8 mL, 41.87 mmol) in

T. Ikemoto et al. / Tetrahedron 60 (2004) 10851–10857
10857
M.; Schlief, W. A.; Emini, E. A. Bioorg. Med. Chem. Lett.
2001, 11, 2475–2479. (d) Palani, A.; Shapiro, S.; Clader, J. W.;
Greenlee, W. J.; Cox, K.; Strizki, J.; Endres, M.; Baroudy,
B. M. J. Med. Chem. 2001, 44, 3339–3342. (e) Tagat, J. R.;
Steensma, R. W.; McCombie, S. W.; Nazareno, D. V.; Lin,
S.-I.; Neustandt, B. R.; Cox, K.; Xu, S.; Wojcik, L.; Murray,
M. G.; Vantuno, N.; Baroudy, B. M.; Strizki, J. M. J. Med.
Chem. 2001, 44, 3343–3346. (f) Maeda, K.; Yoshimura, K.;
Shibayama, S.; Habashita, H.; Tada, H.; Sagawa, K.;
Miyakawa, T.; Aoki, M.; Fukushima, D.; Mitsuya, M.
J. Biol. Chem. 2001, 276, 35194–35200.
N,N-dimethylacetamide (10 mL) at 0–10 8C, and stirred
for 1 h at room temperature. Water (20 mL) was added to
the resulting mixture at room temperature and stirred for
about 1 h at the same temperature. The resulting crystals
were collected by filtration, washed with water (5 mL) and
MeOH (5 mL), and dried in vacuo to give 1 (2.5 g, yield,
1
82%) as a white solid. H NMR (300 MHz, CDCl3) d 1.06
(t, JZ7.4 Hz, 3H), 1.64–1.88 (m, 6H), 2.20 (s, 3H), 2.60–
2.67 (m, 1H), 3.13 (t, JZ6.6 Hz, 2H), 3.33–3.41 (m, 2H),
3.56 (s, 2H), 3.69 (t, JZ6.3 Hz, 2H), 3.95–4.07 (m, 4H),
6.98 (d, JZ8.7 Hz, 2H), 7.29–7.34 (m, 3H, 7.48–7.61
(m, 6H), 8.08–8.16 (m, 2H); 13C NMR (75 MHz, CDCl3) d
10.5, 22.6, 25.0, 29.2, 37.5, 57.3, 57.5, 59.6, 67.7, 69.7,
115.2, 120.3, 126.3, 128.1, 128.4, 129.4, 130.4, 130.6,
132.0, 133.2, 136.4, 136.5, 137.3, 139.3, 146.1, 160.1,
166.6; IR (KBr) 3485, 2948, 1654, 1635, 1606, 1519, 1315,
1292, 1130 cmK1; mp 239.6–240.8 8C; HRMS (FAB) calcd
for C33H39N2O5S ([MH]C) 575.2580; Found 575.2580.
Anal. Calcd for C33H38N2O5S; C, 68.96; H, 6.66; N, 4.87; S,
5.58. Found: C, 68.79; H, 6.56; N, 4.95; S, 5.66.
3. (a) Baba, M.; Nishimura, O.; Kanzaki, N.; Okamoto, M.;
Sawada, H.; Iizawa, Y.; Shiraishi, M.; Aramaki, Y.; Okonogi,
K.; Ogawa, Y.; Meguro, K.; Fijino, M. Proc. Natl. Acad. Sci.
U.S.A. 1999, 96, 5698–5703. (b) Shiraishi, M.; Aramaki, Y.;
Seto, M.; Imoto, H.; Nishikawa, Y.; Kanzaki, N.; Okamoto,
M.; Sawada, H.; Nishimura, O.; Baba, M.; Fijino, M. J. Med.
Chem. 2000, 43, 2049–2063.
4. Seto, M.; Aramaki, Y.; Okawa, T.; Miyamoto, N.; Aikawa, K.;
Kanzaki, N.; Niwa, S.; Iizawa, Y.; Baba, M.; Shiraishi, M.
Chem. Pharm. Bull. 2004, 52, 577.
5. (a) Aramaki, Y.; Seto, M.; Okawa, T.; Oda, T.; Kanzaki, N.;
Shiraishi, M. Chem. Pharm. Bull. 2004, 52, 254. (b) Fukushi,
H.; Mabuchim, H.; Itoh, K.; Terashita, Z.-I.; Nishikawa, K.;
Sugihara, H. Chem. Pharm. Bull. 1994, 42, 541.
References and notes
1. (a) Feng, Y.; Broder, C. C.; Kennedy, P. E.; Berger, E. A.
Science 1996, 272, 872–877. (b) Alkhatib, G.; Combadiere, C.;
Broder, C. C.; Feng, Y.; Keneddy, P. E.; Murphy, P. M.;
Berger, E. A. Science 1996, 272, 1955–1958. (c) Deng, H.;
Liu, R.; Ellmeier, W.; Choe, S.; Unutmaz, D.; Burkhart, M.;
Marzio, P. D.; Marmon, S.; Sutton, R. E.; Hill, C. M.; Davis,
C. B.; Peiper, S. C.; Schall, T. J.; Littman, D. R.; Landau, N. R.
Nature, (London) 1996, 381, 661–666. (d) Dragic, T.; Litwin,
V.; Allaway, G. P.; Martin, S. R.; Huang, Y.; Nagashima,
K. A.; Cayanan, C.; Maddon, P. J.; Koup, R. A.; Moore, J. P.;
Paxton, W. A. Nature, (London) 1996, 381, 667–673.
6. (a) Hatinguais, P.; Patoiseau, J.F.; Marcelon, G. EP67086.
(b) Fuchs, P. L. J. Am. Chem. Soc. 1974, 96, 1607.
7. Compound 12 was purchased from Yodo Kagaku Co. Ltd.
8. March, J. Advanced Organic Chemistry: Reaction, Mechan-
ism, and Structure, 4th ed.; Wiely: New York, 1992; pp 175–
181.
9. (a) Wallingford, V. H.; Homeyer, A. H.; Jones, D. M. J. Am.
Chem. Soc. 1941, 63, 2056. (b) Mori, K.; Kameda, A.; Kido,
M. Liebigs Ann. Chem. 1991, 8, 775. (c) Provencher, L.;
Wynn, H.; Jones, J. B.; Krawczyk, R. Tetrahedron: Asymmetry
1993, 4, 2025. (d) Battersby, A. R.; Cardwell, K. S.; Leeper,
F. J. J. Chem. Soc. Perkin Trans. 1 1986, 1565.
2. (a) Imamura, S.; Ishihara, Y.; Hattori, T.; Kurasawa, O.;
Matsushita, Y.; Sugihara, Y.; Kanzaki, N.; Iizawa, Y.; Baba,
M.; Hashiguchi, S. Chem. Pharm. Bull. 2004, 52(1), 63–73. (b)
Lynch, C. L.; Hale, J. J.; Budhu, R. J.; Gentry, A. L.; Mills,
S. G.; Chapman, K. T.; MacCoss, M.; Malkowitz, L.; Springer,
M. S.; Gould, S. L.; DeMartino, J. A.; Siciliano, S. J.; Cascieri,
M. A.; Carella, A.; Carver, G.; Holmes, K.; Schleif, W. A.;
Danzeisen, R.; Hauzuda, D.; Kessler, J.; Lineberger, J.; Miller,
M.; Schlief, W. A.; Emini, E. A. Bioorg. Med. Chem. Lett.
2002, 12, 3001–3004. (c) Finke, P. E.; Oastes, B.; Mills, S. G.;
MacCoss, M.; Malkowitz, L.; Springer, M. S.; Gould, S. L.;
DeMartino, J. A.; Carella, A.; Carver, G.; Holmes, K.;
Danzeisen, R.; Hauzuda, D.; Kessler, J.; Lineberger, J.; Miller,
10. Seebach, D.; Jacobi, A.; Rueping, M.; Gademann, K.; Eenst,
M.; Jaun, B. Helv. Chim. Acta 2000, 83, 2115.
11. (a) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981,
11, 513. (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
2457. (c) Suzuki, A. J. Organomet. Chem. 1999, 675, 147.
12. (a) Maddaford, S. P.; Keay, B. A. J. Org. Chem. 1994, 59,
6501. (b) Wong, K.; Chien, Y.; Leao, Y.; Lin, C.; Chou, M.;
Leung, M. J. Org. Chem. 2002, 67, 1041.
13. Hashimoto, H.; Ikemoto, T.; Ito, T.; Maruyama, H.; Urai, T.;
Wakimasu, M.; Mitsudera, H.; Tomimatsu, K. Org. Process
Res. Dev. 2002, 6, 70.