HETEROCYCLES

Paper | Regular issue | Vol. 83, No. 9, 2011, pp. 2127-2135
Received, 15th June, 2011, Accepted, 14th July, 2011, Published online, 21st July, 2011.
DOI: 10.3987/COM-11-12283

■ Synthesis of 1,2,3,5-Tetrahydro-4,1-benzothiazepine-2-thione 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

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-alkylsulfanyl-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 (6) and ethyl 2-alkylsulfanyl-3,5-dihydro-4,1-benzothiazepine-3-carboxylates (7), using cyclization of ethyl 2-[(2-isothiocyanatophenyl)methylsulfanyl]acetates (4), generated in situ from ethyl 2-[(2- 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.

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. Deprotonation of α-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.

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.

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 500 MHz, or JEOL LA400FT NMR spectrometer operating at 400 MHz. The 13C 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 cm­–1; 1H NMR (500 MHz) δ 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, 1653, 1620 cm­–1; 1H NMR (500 MHz) δ 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 (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, 2:5); IR (neat) 3254, 1726, 1647 cm­–1; 1H NMR (500 MHz) δ 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 (hexane–Et2O); IR (KBr) 3302, 1736, 1690 cm­–1; 1H NMR (500 MHz) δ 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) δ 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) δ 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) δ 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 (AcOEt–hexane, 1:2); IR (neat) 2119, 1731, 1607 cm­–1; 1H NMR (400 MHz) δ 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.
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 (0.10 g, 60%); a beige solid; mp 96–97 ˚C (hexane–CH2Cl2); IR (KBr) 3179, 1730, 1487 cm­–1; 1H NMR (600 MHz) δ 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) δ 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) δ 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 (s, 1H), 7.27–7.30 (m, 2H), 9.53 (br s, 1H); 13C NMR (150 MHz) δ 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) δ 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 (s, 1H), 6.84–6.86 (m, 2H), 7.01 (dd, J = 6.8 and 2.0 Hz, 1H), 9.18 (br s, 1H); 13C NMR (100 MHz) δ 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) δ 1.15 (t, J = 7.3 Hz, 3H), 2.58 (s, 3H), 3.42 (d, J = 12.4 Hz, 1H), 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) δ 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) δ 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, 1.0 Hz, 1H), 7.26 (td, J = 7.3, 1.0 Hz, 1H); 13C NMR (100 MHz) δ 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) δ 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), 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); 13C NMR (125 MHz) δ 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 0.32 (AcOEt–hexane, 1:20); IR (neat) 1738, 1604 cm­–1; 1H NMR (500 MHz) δ 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 = 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); 13C NMR (150 MHz) δ 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 0.30 (AcOEt–hexane, 1:3); IR (neat) 1741, 1605 cm­–1; 1H NMR (400 MHz) δ 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) δ 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.
Ethyl 8-Chloro-2-(prop-2-enylsulfanyl)-3,5-dihydro-4,1-benzothiazepine-3-carboxylate (7f): a yellow oil; Rf 0.68 (AcOEt–hexane, 1:3); IR (neat) 1740, 1636 cm­–1; 1H NMR (400 MHz) δ 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, J = 7.8 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H); 13C NMR (150 MHz) δ 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 yellow oil; Rf 0.52 (AcOEt–hexane, 1:3); IR (neat) 1739, 1609 cm­–1; 1H NMR (400 MHz) δ 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 Hz, 1H), 7.32 (dd, J = 7.8, 6.9 Hz, 2H), 7.46 (d, J = 7.8 Hz, 2H); 13C NMR (125 MHz) δ 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) δ 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, 1H); 13C NMR (125 MHz) δ 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 yellow oil; Rf 0.34 (AcOEt–hexane, 1:3); IR (neat) 1739, 1580 cm­–1; 1H NMR (400 MHz) δ 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, 1H); 13C NMR (150 MHz) δ 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.

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.

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