Synthesis of 1,2,3,5-tetrahydro-4,1-benzothiazepine-2-thione derivatives via cyclization of 2-[(2-isothiocyanatophenyl)methylsulfanyl]acetates with sodium hydride

Article abstract of DOI:10.3987/COM-11-12283

A convenient method for the preparation of the title derivatives, 2-thioxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-carboxylates and 2-alkylsulfanyl- 3,5-dihydro-4,1-benzothiazepine-3-carboxylates, has been developed. It is depends on cyclization of 2-[(2

Full text of DOI:10.3987/COM-11-12283

HETEROCYCLES, Vol. 83, No. 9, 2011
2127
HETEROCYCLES, Vol. 83, No. 9, 2011, pp. 2127 - 2135. © The Japan Institute of Heterocyclic Chemistry
Received, 15th June, 2011, Accepted, 14th July, 2011, Published online, 21st July, 2011
DOI: 10.3987/COM-11-12283
SYNTHESIS
THIONE
OF 1,2,3,5-TETRAHYDRO-4,1-BENZOTHIAZEPINE-2-
DERIVATIVES VIA CYCLIZATION OF
2-[(2-ISOTHIOCYANATOPHENYL)METHYLSULFANYL]ACETATES
WITH SODIUM HYDRIDE
Kazuhiro Kobayashi,* Yoshinori Enmi, Daisuke Iitsuka, Yuuki Kanbe, and
Hisatoshi Konishi
Division of Applied Chemistry, Department of Chemistry and Biotechnology,
Graduate School of Engineering, Tottori University, 4-101 Koyama-minami,
Tottori 680-8552, Japan; E-mail: kkoba@chem.tottori-u.ac.jp
Abstract – A convenient method for the preparation of the title derivatives,
2-thioxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-carboxylates and 2-alkyl-
sulfanyl-3,5-dihydro-4,1-benzothiazepine-3-carboxylates, has been developed. It
is depends on cyclization of 2-[(2-isothiocyanatophenyl)methylsulfanyl]acetates,
generated in situ from the corresponding isocyanides on treatment with sulfur in
the presence of a catalytic amount of selenium, using sodium hydride as a base.
These isocyanides can be easily prepared from N-[(2-chloromethyl)phenyl]-
formamides via an easy two-step sequence.
INTRODUCTION
The 4,1-benzothiazepine structure is found in some biological active compounds.1 For example,
7-chloro-5-(2-chlorophenyl)-1,2,3,5-tetrahydro-4,1-benzothiazepin-2-one (CGP-37157) is known as a
mitochondrial Na+–Ca2+ exchange inhibitor.1d A number of 1,2,3,5-tetrahydro-4,1-benzothiazepine-2-
thione derivatives have been prepared and most of them also have been reported to exhibit variety of
biological activities.2 Several methods exist for the preparation of 4,1-benzothiazepine derivatives.1a,b,3
However, there have been few reports on the practical preparation of 1,2,3,5-tetrahydro-4,1-
benzothiazepine-2-thione derivatives.4 In this paper we report a simple one-pot procedure for the
preparation of 1,2,3,5-tetrahydro-4,1-benzothiazepine-2-thione derivatives, ethyl 2-thioxo-1,2,3,5-
tetrahydro-4,1-benzothiazepine-3-carboxylates
benzothiazepine-3-carboxylates (7),
(6)
and
ethyl
2-alkylsulfanyl-3,5-dihydro-4,1-
of ethyl 2-[(2-
using
cyclization
isothiocyanatophenyl)methylsulfanyl]acetates (4), generated in situ from ethyl 2-[(2-

2128
HETEROCYCLES, Vol. 83, No. 9, 2011
isocyanophenyl)methylsulfanyl]acetates (3).
RESULTS AND DISCUSSION
The isocyano compounds (3) could be prepared by an easy four-step sequence starting with readily
available N-[2-(chloromethyl)phenyl]formamides (1) as illustrated in Scheme 1. Thus, compounds 1 were
transformed into ethyl 2-[(2-formylaminophenyl)methyl]acetates (2) on treatment with ethyl
sulfanylacetate in DMF in the presence of sodium hydride as a base at 0 ˚C in relatively good yields.
Formamides (2) were then converted into the corresponding isocyanides (3) by dehydration with
phosphoryl chloride in THF in the presence of triethylamine at 0 ˚C5 in good yields.
R1
R2
CH2SCH2CO2Et
NHCHO
R1
R2
CH2Cl
R1
R2
CH2SCH2CO2Et
NC
POCl3, Et3N
HSCH2CO2Et
THF, 0 ˚C
NaH, DMF, 0 ˚C
NHCHO
3a R1 = R2 = H 82%
2a R1 = R2 = H 78%
2b R1 = H, R2 = Cl 73%
2c R1 = OMe, R2 = H 68%
1
3b R1 = H, R2 = Cl 76%
3c R1 = OMe, R2 = H 83%
R1
R2
R1
R2
CH2SCH2CO2Et
S
DMSO, NaH, rt
S, cat. Se, Et3N
THF, rt
CO2Et
N
Na
NCS
S
4
5
H3O+
R3X
S
R1
R2
S
R1
R2
CO2Et
CO2Et
N
H
S
N
SR3
6a R1 = R2 = H 70%
6b R1 = H, R2 = Cl 74%
6c R1 = OMe, R2 = H 70%
7
Scheme 1
The preparations of 1,2,3,5-tetrahydro-4,1-benzothiazepine-2-thione derivatives (6) and (7) from
isocyanides (3) was shown in Scheme 1 as well. First, the synthesis of 6 was achieved as follows.
Reaction of 3 with sulfur in THF in the presence of a catalytic amount of selenium and excess
triethylamine at room temperature according to the procedure reported by Fujiwara et al.6 generated the
corresponding isothiocyanates (4). To these solutions of 4 was added to a half volume of DMSO relative
to THF and the mixture was treated with an equimolar amount of sodium hydride at the same temperature.

HETEROCYCLES, Vol. 83, No. 9, 2011
2129
Deprotonation of !-hydrogen of the ester moiety and subsequent cyclization by the addition of the
resulting carbanion to the isothiocyanate carbon proceeded rapidly and cleanly to generate the sodio
thioamide intermediates (5). In the absence of DMSO cyclization proceeded very sluggishly even at
elevated temperatures. Quenching with saturated aqueous ammonium chloride afforded, after purification
by preparative TLC on silica gel, ethyl 2-thioxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-carboxylates
(6) in fair yields, as shown in Scheme 1.
Table 1. Preparation of 2-alkylsulfanyl-3,5-dihydro-4,1-benzothiazepine-3-carboxylates 7
Entry
1
R3X
MeI
7
Yield/%a
70
1
2
3
4
5
6
7
1a (R1 = R2 = H)
1a
1a
1a
7a
7b
7c
7d
7e
7f
EtI
62
67
72
73
69
66
CH2=CHCH2Br
BnBr
EtI
CH2=CHCH2Br
BnBr
1b (R1 = H, R2 = Cl)
1b
1c (R1 = OMe, R2 = H)
7g
a Yields of isolated products.
The synthesis of ethyl 2-alkylsulfanyl-3,5-dihydro-4,1-benzothiazepine-3-carboxylates (7) were
accomplished by alkylation of the anionic intermediates (5) with reactive alkyl halides at the same
temperature, followed by aqueous workup and subsequent purification by preparative TLC on silica gel.
The yields based on 3 were relatively good as summarized in Table 1. Alkylation with a less reactive alkyl
halide, such as bromoethane, under the same conditions was examined. However, the intermediates (5)
did not ethylated at all (data not shown).
When ethyl 2-[(2-isothiocyanatophenyl)methylsulfanyl]acetates (4) were treated with two equivalents of
sodium hydride under the same conditions as described for the preparation of 7 and were allowed to react
with two equivalents of iodomethane, ethyl 3-methyl-2-methylsulfanyl-3,5-dihydrobenzothiazepine-3-
carboxylates (8) were obtained in moderate yields, as shown in Scheme 2. Subsequently, we tried to
prepare ethyl 3-ethyl-2-ethylsulfanyl-3,5-dihydro-4,1-benzothiazepine-3-carboxylate by using two
equivalents of ethyl iodide under the same conditions as for the preparation of 8. Unfortunately, however,
no trace of the desired product could be produced and only ethyl 2-ethylsulfanyl-3,5-dihydro-4,1-
benzothiazepine-3-carboxylate (7b) was obtained in 60% yield. This result indicates that only methyl
group can be introduced at the 3-position of the 4,1-benzothiazepine-3-carboxylate structure.
R1
S
Me
CO2Et
1. DMSO, 2 NaH, rt
2. 2 MeI
4
8a R1 = R2 = H 70%
8b R1 = H, R2 = Cl 74%
R2
N
SMe
Scheme 2

2130
HETEROCYCLES, Vol. 83, No. 9, 2011
In conclusion, we have synthesized ethyl 2-thioxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-carboxylates
(6) and ethyl 2-alkylsulfanyl-3,5-dihydro-4,1-benzothiazepine-3-carboxylates (7) and (8). The method
developed here for the construction of 1,2,3,5-tetrahydro-4,1-benzothiazine-2-thione derivatives is
convenient and of use in organic synthesis because of the ready availability of the starting materials and
the easiness of operations.
EXPERIMENTAL
The melting points were obtained on a Laboratory Devices MEL-TEMP II melting apparatus and are
uncorrected. IR spectra were recorded with a Perkin-Elmer Spectrum65 FTIR spectrophotometer. The 1H
NMR spectra were recorded in CDCl3 using TMS as an internal reference with a Bruker Biospin
AVANCE II 600 spectrometer operating at 600 MHz, a JEOL ECP500 FT NMR spectrometer operating at
13
500 MHz, or JEOL LA400FT NMR spectrometer operating at 400 MHz. The C NMR spectra were
recorded in CDCl3 using TMS as an internal reference with a Bruker Biospin AVANCE II 600
spectrometer operating at 150 MHz, a JEOL ECP500 FT NMR spectrometer operating at 125 MHz, or
JEOL LA400FT NMR spectrometer operating at 100 MHz. Low- and high-resolution MS spectra (EI, 70
eV) were measured by a JEOL JMS AX505 HA spectrometer. TLC was carried out on a Merck Kieselgel
60 PF254. Column chromatography was performed using WAKO GEL C-200E. All of the organic solvents
used in this study were dried over appropriate drying agents and distilled prior to use.
Starting Materials. (2-Amino-5-methoxyphenyl)methanol,7 N-[2-(chloromethyl)phenyl]formamide (1a)8
and N-[5-chloro-2-(chloromethyl)phenyl]formamide (1b)9 were prepared by the appropriate reported
methods. All other chemicals used in this study were commercially available.
N-[2-(Hydroxymethyl)-4-methoxyphenyl]formamide. This compound was prepared by the
N-formylation of (2-amino-5-methoxyphenyl)methanol7 with HCO2Et under the previously reported
conditions;9 53% yield; a pale-yellow solid; mp 93–95 ˚C (hexane–CH2Cl2); IR (KBr) 3248, 1657, 1613
1
cm–1; H NMR (500 MHz) " 2.1–2.4 (br, 1H), 3.80 and 3.81 (2s, combined 3H), 4.68 and 4.69 (2s,
combined 2H), 6.79–8.45 (m, 5H). Anal. Calcd for C9H11NO3: C, 59.66; H, 6.12; N, 7.73. Found: C,
59.63; H, 6.13; N, 7.49.
N-[2-(Chloromethyl)-4-methoxyphenyl]formamide (1c). This compound was prepared by the treatment
of N-[2-(hydroxymethyl)-4-methoxyphenyl]formamide with SOCl2/pyridine under the previously
reported conditions;8 71% yield; a pale-yellow solid; mp 110–111 ˚C (hexane–Et2O); IR (KBr) 3221,
1
1653, 1620 cm–1; H NMR (500 MHz) " 3.81 and 3.82 (2s, combined 3H), 4.56 and 4.57 (2s, combined
2H), 6.89–8.45 (m, 5H). Anal. Calcd for C9H10ClNO2: C, 54.15; H, 5.05; N, 7.02. Found: C, 54.02; H,
5.25; N, 6.74.
General Procedure for the Preparation of Ethyl 2-[(2-Formylaminophenyl)methylsulfanyl]acetates

HETEROCYCLES, Vol. 83, No. 9, 2011
2131
(2). These compounds were prepared by the treatment N-[2-(chloromethyl)phenyl]formamides (1) (5.0
mmol) with NaSCH2CO2Et (5.5 mmol), generated in situ from HSCH2CO2Et (5.5 mmol) and NaH (60%
in mineral oil; 5.5 mmol) in DMF (15 mL) at 0 ˚C for 1 h, followed by usual aqueous workup (aq.
NH4Cl/AcOEt) and subsequent purification using column chromatography on silica gel.
Ethyl 2-[(2-Formylaminophenyl)methylsulfanyl]acetate (2a): a pale-yellow oil; Rf 0.45 (THF–hexane,
1
2:5); IR (neat) 3254, 1726, 1647 cm–1; H NMR (500 MHz) " 1.31 and 1.33 (2t, J = 7.3 Hz each,
combined 3H), 3.08 and 3.20 (2s, combined 2H), 3.86 and 3.88 (2s, combined 2H), 4.22 and 4.24 (2q, J =
7.3 Hz, combined 2H), 7.09–7.34 (m, 4H), 8.08–8.86 (m, 2H). Anal. Calcd for C12H15NO3S: C, 56.90; H,
5.97; N, 5.53. Found: C, 56.74; H, 5.90; N, 5.46.
Ethyl 2-[(4-Chloro-2-formylaminophenyl)methylsulfanyl]acetate (2b): a white solid; mp 49–51 ˚C
1
(hexane–Et2O); IR (KBr) 3302, 1736, 1690 cm–1; H NMR (500 MHz) " 1.30 and 1.32 (2t, J = 7.3 Hz,
each, combined 3H), 3.08 and 3.23 (2s, combined 2H), 3.82 and 3.84 (2s, combined 2H), 4.22 and 4.24
(2q, J = 7.3 Hz each, combined 2H), 7.06–9.08 (m, 5H). Anal. Calcd for C12H14ClNO3S: C, 50.09; H,
4.90; N, 4.87. Found: C, 50.04; H, 5.17; N, 4.72.
Ethyl 2-[(2-Formylamino-5-methoxyphenyl)methylsulfanyl]acetate (2c): a pale-yellow solid; mp
77–79 ˚C (hexane–Et2O); IR (KBr) 3270, 1726, 1655, 1614 cm–1; 1H NMR (500 MHz) " 1.29 and 1.31 (2t,
J = 7.3 Hz each, combined 3H), 3.06 and 3.16 (2s, combined 2H), 3.58, 3.79, 3.81, and 3.82 (4s,
combined 5H), 4.23 and 4.24 (2q, J = 7.3 Hz each, combined 2H), 6.81–8.56 (m, 5H). Anal. Calcd for
C13H17NO4S: C, 55.11; H, 6.05; N, 4.94. Found: C, 55.03; H, 6.15; N, 4.87.
Ethyl 2-[(2-Isocyanophenyl)methylsulfanyl]acetates (3). These compounds were prepared by
dehydration of ethyl 2-[(2-formylaminophenyl)methylsulfanyl]acetates with POCl3/Et3N under the
previously reported conditions.5
Ethyl 2-[(2-Isocyanophenyl)methylsulfanyl]acetate (3a): a pale-green oil; Rf 0.47 (C6H6); IR (neat)
2122, 1732 cm–1; 1H NMR (500 MHz) " 1.30 (t, J = 7.3 Hz, 3H), 3.13 (s, 2H), 3.98 (s, 2H), 4.20 (q, J =
7.3 Hz, 2H), 7.31 (dd, J = 7.8, 7.3 Hz, 1H), 7.38 (dd, J = 7.8, 7.3 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.46
(d, J = 7.8 Hz, 1H). HR-MS. Calcd for C12H13NO2S: M, 235.0667. Found: m/z 235.0684.
Ethyl 2-[(4-Chloro-2-isocyanophenyl)methylsulfanyl]acetate (3b): a yellow oil; Rf 0.47 (C6H6); IR
(neat) 2126, 1716 cm–1; 1H NMR (400 MHz) " 1.30 (t, J = 7.3 Hz, 3H), 3.11 (s, 2H), 3.94 (s, 2H), 4.20 (q,
J = 7.3 Hz, 2H), 7.36 (d, J = 8.3 Hz, 1H), 7.41–7.43 (m, 2H). HR-MS. Calcd for C12H12ClNO2S: M,
269.0277. Found: m/z 269.0301.
Ethyl 2-[(2-Isocyano-5-methoxyphenyl)methylsulfanyl]acetate (3c):
a
yellow oil; Rf 0.47
1
(AcOEt–hexane, 1:2); IR (neat) 2119, 1731, 1607 cm–1; H NMR (400 MHz) " 1.30 (t, J = 6.9 Hz, 3H),
3.15 (s, 2H), 3.83 (s, 3H), 3.93 (s, 2H), 4.20 (q, J = 6.9 Hz, 2H), 6.79 (dd, J = 8.8, 2.9 Hz, 1H), 6.97 (d, J
= 2.9 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H). HR-MS. Calcd for C13H15NO3S: M, 265.0773. Found: m/z
265.0793.

2132
HETEROCYCLES, Vol. 83, No. 9, 2011
Typical Procedure for the Preparation of 2-Thioxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-
carboxylates (6). Ethyl 2-Thioxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-carboxylate (6a). A
solution of 3a (0.15 g, 0.64 mmol) and Et3N (0.16 g, 1.6 mmol) in THF (5 mL) containing sulfur (25 mg,
0.77 mmol) and selenium (1.5 mg, 0.019 mmol) was stirred at rt for 3 h. The mixture was cooled to 0 ˚C,
and DMSO (2.5 mL) and then NaH (60% in oil; 51 mg, 1.3 mmol) was added. After 15 min saturated
aqueous NH4Cl (10 mL) was added. The organic materials were extracted with Et2O twice (10 mL each),
and the combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated by
evaporation. The residue was purified by preparative TLC on silica gel (THF–hexane, 1:6) to afford 6a
1
(0.10 g, 60%); a beige solid; mp 96–97 ˚C (hexane–CH2Cl2); IR (KBr) 3179, 1730, 1487 cm–1; H NMR
(600 MHz) " 1.20 (t, J = 6.9 Hz, 3H), 3.80 (d, J = 13.0 Hz, 1H), 3.93 (d, J = 13.0 Hz, 1H), 4.01–4.11 (m.
2H), 4.59 (s, 1H), 7.09 (dd, J = 7.3, 1.5 Hz, 1H), 7.04–7.36 (m, 3H), 9.43 (br s, 1H); 13C NMR (150 MHz)
" 13.89, 30.33, 54.91, 62.56, 123.44, 128.96, 129.04, 129.95, 132.10, 137.19, 166.30, 198.60; MS m/z
267 (M+, 100). Anal. Calcd for C12H13NO2S2: C, 53.91; H, 4.90; N, 5.24. Found: C, 53.93; H, 4.93; N,
5.04.
Ethyl 8-Chloro-2-thioxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-carboxylate (6b): an orange solid;
mp 92–94 ˚C (hexane–CH2Cl2); IR (KBr) 3229, 1730, 1490 cm–1; 1H NMR (400 MHz) " 1.22 (t, J = 6.9
Hz, 3H), 3.80 (d, J = 13.7 Hz, 1H), 3.90 (d, J = 13.6 Hz, 1H), 4.11 (q, J = 6.9 Hz, 2H), 4.59 (s, 1H), 7.10
13
(s, 1H), 7.27–7.30 (m, 2H), 9.53 (br s, 1H); C NMR (150 MHz) " 13.94, 29.85, 55.09, 62.84, 123.74,
129.14, 130.62, 130.97, 134.50, 138.09, 166.23, 198.71; MS m/z 301 (M+, 100). Anal. Calcd for
C12H12ClNO2S2: C, 47.75; H, 4.01; N, 4.64. Found: C, 47.73; H, 4.02; N, 4.55.
Ethyl 8-Methoxy-2-thioxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-carboxylate (6c): a beige solid;
mp 90–92 ˚C (hexane–CH2Cl2); IR (KBr) 3121, 1726, 1604, 1497 cm–1; 1H NMR (400 MHz) " 1.22 (t, J
= 6.9 Hz, 3H), 3.75 (d, J = 12.7 Hz, 1H), 3.83 (s, 3H), 3.89 (d, J = 12.7 Hz, 1H), 4.05–4.14 (m, 2H), 4.59
13
(s, 1H), 6.84–6.86 (m, 2H), 7.01 (dd, J = 6.8 and 2.0 Hz, 1H), 9.18 (br s, 1H); C NMR (100 MHz) "
13.92, 30.57, 54.88, 55.62, 62.59, 114.37, 114.44, 124.83, 129.88, 133.50, 159.70, 166.34, 198.28; MS
m/z 297 (M+, 100). Anal. Calcd for C13H15NO3S2: C, 52.50; H, 5.08; N, 4.71. Found: C, 52.39; H, 5.12; N,
4.70.
Typical Procedure for the Preparation of 2-Alkylsulfanyl-3,5-dihydro-4,1-benzothiazepine-3-
carboxylates (7). Ethyl 2-Methylsulfanyl-3,5-dihydro-4,1-benzothiazepine-3-carboxylate (7a).
Compound (3a) (0.15 g, 0.64 mmol) was converted into the corresponding isothiocyanate (4a) and treated
with an equimolar amount of NaH as described for the preparation of 6a. After 15 min MeI (91 mg, 0.64
mmol) was added and the resulting mixture was stirred for 1 h at the same temperature. A workup similar
to that for the preparation of 6a gave a residue, which was purified by preparative TLC on silica gel
(THF–hexane, 1:10) to afford 7a (0.11 g, 60%); a yellow solid; mp 100–101 ˚C (hexane–Et2O); IR (KBr)
1738, 1604 cm–1; 1H NMR (500 MHz) " 1.15 (t, J = 7.3 Hz, 3H), 2.58 (s, 3H), 3.42 (d, J = 12.4 Hz, 1H),

HETEROCYCLES, Vol. 83, No. 9, 2011
2133
3.71 (d, J = 12.4 Hz, 1H), 3.90–4.01 (m, 2H), 4.07 (s, 1H), 6.88 (dd, J = 7.8, 1.0 Hz, 1H), 7.05 (td, J = 7.3,
1.0 Hz, 1H), 7.19 (dd, J = 7.3, 1.4 Hz, 1H), 7.26 (ddd, J = 7.8, 7.3, 1.4 Hz, 1H); 13C NMR (100 MHz) "
13.72, 13.92, 30.69, 49.82, 62.50, 122.80, 125.16, 126.45, 128.64, 128.92, 148.92, 165.03, 167.08; MS
m/z 281 (M+, 100). Anal. Calcd for C13H15NO2S2: C, 55.49; H, 5.37; N, 4.98. Found: C, 55.30; H, 5.38; N,
4.97.
Ethyl 2-Ethylsulfanyl-3,5-dihydro-4,1-benzothiazepine-3-carboxylate (7b): a yellow oil; Rf 0.48
(AcOEt–hexane, 1: 6); IR (neat) 1738, 1605 cm–1; 1H NMR (400 MHz) " 1.16 (t, J = 7.3 Hz, 3H), 1.44 (t,
J = 7.3 Hz, 3H), 3.19 (q, J = 7.3 Hz, 1H), 3.44 (d, J = 12.7 Hz, 1H), 3.70 (d, J = 12.7 Hz, 1H), 3.90–4.01
(m, 2H), 4.05 (s, 1H), 6.87 (dd, J = 7.8, 1.0 Hz, 1H), 7.05 (ddd, J = 7.8, 7.3, 1.0 Hz, 1H), 7.19 (dd, J = 7.3,
13
1.0 Hz, 1H), 7.26 (td, J = 7.3, 1.0 Hz, 1H); C NMR (100 MHz) " 13.85, 13.88, 24.99, 30.64, 49.88,
62.45, 122.71, 125.08, 126.40, 128.58, 128.87, 148.94, 164.34, 167.08; MS m/z 329 (M+, 100). Anal.
Calcd for C14H16ClNO2S2: C, 50.98; H, 4.89; N, 4.25. Found: C, 50.93; H, 5.03; N, 4.28.
Ethyl 2-(Prop-2-enylsulfanyl)-3,5-dihydro-4,1-benzothiazepine-3-carboxylate (7c): a yellow oil; Rf
0.26 (AcOEt–hexane, 1: 20); IR (neat) 1740, 1605 cm–1; 1H NMR (400 MHz) " 1.16 (t, J = 7.3 Hz, 3H),
3.42 (d, J = 12.7 Hz, 1H), 3.70 (d, J = 12.7 Hz, 1H), 3.85 (d, J = 6.8 Hz, 2H), 3.90–4.01 (m, 2H), 4.06 (s,
1H), 5.19 (d, J = 10.7 Hz, 1H), 5.37 (dd, J = 18.6 Hz, 1H), 5.99–6.05 (m, 1H), 6.87 (d, J = 7.8 Hz, 1H),
13
7.05 (dd, J = 7.8, 6.9 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 7.26 (dd, J = 7.8, 6.8 Hz, 1H); C NMR (125
MHz) " 13.88, 30.63, 33.29, 49.77, 62.49, 118.35, 122.70, 125.15, 126.37, 128.59, 128.89, 132.53,
148.78, 163.57, 166.97. MS m/z 307 (M+, 100). Anal. Calcd for C15H17NO2S2: C, 58.60; H, 5.57; N, 4.56.
Found: C, 58.54; H, 5.65; N, 4.46.
Ethyl 2-Phenylmethylsulfanyl-3,5-dihydro-4,1-benzothiazepine-3-carboxylate (7d): a yellow oil; Rf
1
0.32 (AcOEt–hexane, 1:20); IR (neat) 1738, 1604 cm–1; H NMR (500 MHz) " 1.14 (t, J = 7.3 Hz, 3H),
3.31 (d, J = 12.8 Hz, 1H), 3.59 (d, J = 12.8 Hz, 1H), 3.90–3.99 (m, 2H), 4.05 (s, 1H), 4.41 (d, J = 13.7 Hz,
1H), 4.44 (d, J = 13.7 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 7.06 (ddd, J = 7.8, 7.3, 1.4 Hz, 1H), 7.18 (dd, J =
13
7.8, 1.4 Hz, 1H), 7.25–7.28 (m, 2H), 7.32 (dd, J = 7.8, 7.3 Hz, 2H), 7.46 (d, J = 7.8 Hz, 2H); C NMR
(150 MHz) " 13.91, 30.55, 34.90, 49.73, 62.51, 122.73, 125.21, 126.52, 127.32, 128.47, 128.63, 128.95,
129.24, 137.02, 148.82, 163.79, 167.00; MS m/z 357 (M+, 100). Anal. Calcd for C19H19NO2S2: C, 63.83; H,
5.36; N, 3.92. Found: C, 63.90; H, 5.48; N, 3.84.
Ethyl 8-Chloro-2-ethylsulfanyl-3,5-dihydro-4,1-benzothiazepine-3-carboxylate (7e): a yellow oil; Rf
1
0.30 (AcOEt–hexane, 1:3); IR (neat) 1741, 1605 cm–1; H NMR (400 MHz) " 1.18 (t, J = 6.8 Hz, 3H),
1.43 (t, J = 7.8 Hz, 3H), 3.17 (q, J = 6.8 Hz, 2H), 3.38 (d, J = 12.7 Hz, 1H), 3.69 (d, J = 12.7 Hz, 1H),
3.93–4.40 (m, 2H), 4.06 (s, 1H), 6.88 (d, J = 2.0 Hz, 1H), 7.02 (dd, J = 8.8, 2.0 Hz, 1H), 7.12 (d, J = 8.8
Hz, 1H); 13C NMR (150 MHz) " 13.83, 13.91, 25.18, 30.11, 50.07, 62.75, 122.86, 125.06 (two overlapped
Cs), 129.88, 134.17, 150.03, 165.86, 166.96; MS m/z 329 (M+, 100). Anal. Calcd for C14H16ClNO2S2: C,
50.98; H, 4.89; N, 4.25. Found: C, 50.72; H, 5.03; N, 4.21.

2134
HETEROCYCLES, Vol. 83, No. 9, 2011
Ethyl 8-Chloro-2-(prop-2-enylsulfanyl)-3,5-dihydro-4,1-benzothiazepine-3-carboxylate (7f): a yellow
1
oil; Rf 0.68 (AcOEt–hexane, 1:3); IR (neat) 1740, 1636 cm–1; H NMR (400 MHz) " 1.18 (t, J = 7.3 Hz,
3H), 3.37 (d, J = 12.7 Hz, 1H), 3.68 (d, J = 12.7 Hz, 1H), 3.81–3.83 (m, 2H), 4.00 (q, J = 7.3 Hz, 2H),
4.03 (a, 1H), 5.20 (d, J = 9.8 Hz, 1H), 5.38 (d, J = 17.1 Hz, 1H), 5.95–6.05 (m, 1H), 6.88 (s, 1H), 7.03 (d,
13
J = 7.8 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H); C NMR (150 MHz) " 13.91, 30.10, 33.43, 49.96, 62.80,
118.62, 122.85, 125.03, 125.14, 129.90, 132.30, 134.19, 149.88, 165.08, 166.86; MS m/z 341 (M+, 100).
Anal. Calcd for C15H16ClNO2S2: C, 52.70; H, 4.72; N, 4.10. Found: C, 52.52; H, 4.54; N, 4.24.
Ethyl 7-Methoxy-2-phenylmethylsulfanyl-3,5-dihydro-4,1-benzothiazepine-3-carboxylate (7g): a
1
yellow oil; Rf 0.52 (AcOEt–hexane, 1:3); IR (neat) 1739, 1609 cm–1; H NMR (400 MHz) " 1.15 (t, J =
6.9 Hz, 3H), 3.27 (d, J = 12.7 Hz, 1H), 3.57 (d, J = 12.7 Hz, 1H), 3.79 (s, 3H), 3.90–4.02 (m, 2H), 4.04 (s,
1H), 4.39 (d, J = 13.7 Hz, 1H), 4.43 (d, J = 13.7 Hz, 1H), 6.72 (s, 1H), 6.80–6.83 (m, 2H), 7.26 (t, J = 6.9
13
Hz, 1H), 7.32 (dd, J = 7.8, 6.9 Hz, 2H), 7.46 (d, J = 7.8 Hz, 2H); C NMR (125 MHz) " 13.88, 30.67,
34.79, 49.54, 55.44, 62.46, 113.49, 114.53, 123.86, 127.24, 127.57, 128.40, 129.18, 137.00, 141.86,
156.89, 163.31, 167.07; MS m/z 387 (M+, 100). Anal. Calcd for C20H21NO3S2: C, 61.99; H, 5.46; N, 3.61.
Found: C, 61.92; H, 5.68; N, 3.70.
3-Methyl-2-methylsulfanyl-3,5-dihydro-4,1-benzothiazepine-3-carboxylates (8). Ethyl 3-Methyl-2-
methylsulfanyl-3,5-dihydro-4,1-benzothiazepine-3-carboxylate (8a). Compound (3a) (0.15 g, 0.64
mmol) was converted into the corresponding isothiocyanate (4a) and treated with 2 equiv. of NaH as
described above. After 15 min, MeI (0.18 g, 1.3 mmol) was added and the resulting mixture was stirred
for 1 h at the same temperature. A workup similar to that for the preparation of 6a gave a residue, which
was purified by preparative TLC on silica gel (THF–hexane, 1:10) to afford 8a (70 mg, 46%); a yellow
oil; Rf 0.23; IR (neat) 1746, 1586 cm–1; 1H NMR (400 MHz) " 1.07 (t, J = 6.8 Hz, 3H), 1.64 (s, 3H), 2.54
(s, 3H), 3.15 (d, J = 12.7 Hz, 1H), 3.57–3.61 (m, 1H), 3.73–3.76 (m, 1H), 3.96 (d, J = 12.7 Hz, 1H), 6.79
(d, J = 7.8 Hz, 1H), 7.01 (dd, J = 7.8, 7.3 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 7.22 (dd, J = 7.8, 7.3 Hz,
13
1H); C NMR (125 MHz) " 13.71, 13.77, 22.66, 31.50, 56.43, 62.31, 122.97, 124.67, 126.61, 128.20,
128.36, 148.72, 168.98, 171.48; MS m/z 295 (M+, 100). Anal. Calcd for C14H17NO2S2: C, 56.92; H, 5.80;
N, 4.74. Found: C, 56.92; H, 5.90; N, 4.71.
Ethyl 8-Chloro-3-methyl-2-methylsulfanyl-3,5-dihydro-4,1-benzothiazepine-3-carboxylate (8b): a
1
yellow oil; Rf 0.34 (AcOEt–hexane, 1:3); IR (neat) 1739, 1580 cm–1; H NMR (400 MHz) " 1.12 (t, J =
6.9 Hz, 3H), 1.64 (s, 3H), 2.52 (s, 3H), 3.14 (d, J = 12.7 Hz, 1H), 3.64–3.72 (m, 1H), 3.81–3.88 (m, 1H),
3.90 (d, J = 12.7 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H), 6.98 (dd, J = 8.7, 2.0 Hz, 1H), 7.09 (d, J = 8.7 Hz,
13
1H); C NMR (150 MHz) " 13.79, 13.90, 22.70, 30.98, 56.69, 62.70, 123.02, 124.70, 125.30, 129.39,
133.78, 149.87, 170.50, 171.37; MS m/z 329 (M+, 100). Anal. Calcd for C14H16ClNO2S2: C, 50.98; H,
4.89; N, 4.25. Found: C, 50.94; H, 4.99; N, 4.07.

HETEROCYCLES, Vol. 83, No. 9, 2011
2135
ACKNOWLEDGEMENT
This work was partially supported by a Grand-in-Aid for Scientific Research (C) 22550035 from Japan
Society for the Promotion of Science. We thank Mrs. Miyuki Tanmatsu of this university for recording
mass spectra and performing combustion analyses.
REFERENCES
1. (a) T. Miki, M. Kori, A. Fujishima, H. Mabuchi, R. Tozawa, M. Nakamura, Y. Sugiyama, and H.
Yukimasa, Bioorg. Med. Chem., 2002, 10, 385; (b) Y. Pei, M. J. Lilly, D. J. Owen, L. J. D’Souza,
X.-Q. Tang, J. Yu, R. Nazarbaghi, A. Hunter, C. M. Anderson, S. Glasco, N. J. Ede, I. W. James, U.
Maitra, S. Chandrasekaran, W. H. Moos, and S. S. Gosh, J. Org. Chem., 2003, 68, 92; (c) A.
Omelchenko, R. Bouchard, H. D. Le, P. Choptiany, N. Visen, M. Hnatowich, and L. V. Hryshko, J.
Pharm. Exp. Ther., 2003, 306, 1050; (d) L. T. Thu, J. R. Ahn, and S.-H. Woo, Eur. J. Pharmacol.
2006, 552, 15.
2. (a) J. S. Bryans, P. S. Johnson, T. Ryckmans, and A. Stoble, PCT Int. Appl. WO 2004, 074291 (Chem.
Abstr., 2004, 141, 225517); (b) K. Sugita, M. Otsuka, H. Oki, N. Haginoya, M. Ichikawa, and M. Ito,
PCT Int. Appl. WO 2007, 055093 (Chem. Abstr., 2007, 147, 9956); (c) K. Sugita, M. Otsuka, H. Oki,
N. Haginoya, M. Ichikawa, and M. Ito, Jpn. Pat. 2008, 291018 (Chem. Abstr., 2008, 149, 576645);
(d) K. Sugita, M. Otsuka, H. Oki, N. Haginoya, M. Ichikawa, M. Ota, and N. Shibata, Jpn. Pat. 2010,
150142 (Chem. Abstr., 2010, 153, 175010).
3. (a) S.-J. Tu, X.-D. Cao, W.-J. Hao, X.-H. Zhang, S. Yan, S.-S. Wu, Z.-G. Han, and F. Shi, Org.
Biomol. Chem., 2009, 7, 557; (b) P. Csomós, L. Fodor, A.Csámpai, and P. Sohár, Tetrahedron, 2010,
66, 3207.
4. A simple method for the synthesis of 3H-1,5-benzothiazepine derivatives has recently been reported:
S. Itabashi, R. Lu, and T. Miyakoshi, Heterocycles, 2011, 83, 171.
5. Y. Ito, K. Kobayashi, N. Seko, and T. Saegusa, Bull. Chem. Soc. Jpn., 1984, 57, 73.
6. S. Fujiwara, T. Shin-Ike, N. Sonoda, M. Aoki, K. Okada, N. Miyoshi, and N. Kambe, Tetrahedron
Lett., 1991, 32, 3503.
7. G. H. Jones, M. C. Venuti, R. Alvalez, J. J. Bruno, A. H. Berks, and A. Prince, J. Med. Chem., 1987,
30, 295.
8. R. A. Michelin, G. Facchin, D. Braga, and P. Sabatino, Organometallics, 1986, 5, 2265.
9. K. Kobayashi, D. Iitsuka, S. Fukamachi, and H. Konishi, Tetrahedron, 2009, 65, 7523.