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A. Boudhar et al. / European Journal of Medicinal Chemistry 119 (2016) 231e249
(phenylthio)phenyl)acetic acid (37a) as a yellow solid; the crude
was used in the next step without further purification.
4.2.31. 1-(10,11-Dihydrodibenzo[b,f]thiepin-10-yl)-4-
methylpiperazine (41a)
4 g of oily P2O5 was heated to 150 ꢀC under stirring. The crude 2-
(2-(phenylthio)phenyl)acetic acid (37a) was added in little portions
and the mixture was stirred at 150 ꢀC for 4 h, then cooled to room
temperature. Ice and water were carefully added, and the resulting
aqueous solution was extracted with EtOAc (5ꢃ). The organic
phases were united, washed with brine, dried over Na2SO4, filtered
and the solvent was removed under reduced pressure. The crude
residue was purified by flash chromatography (eluent Hexane/
EtOAc ¼ 97/3 to 9/1), yielding 403 mg (46%) of dibenzo[b,f]thiepin-
10(11H)-one (38a) as a green-yellow solid.
Under nitrogen, 38a (132 mg, 0.58 mmol, 1.0 equiv.) was dis-
solved in 5.8 mL of toluene. 1-Methylpiperazine (39a) (0.31 mL,
2.86 mmol, 4.9 equiv.) was added, then Ti(i-OPr)4 (0.13 mL,
0.44 mmol, 0.75 equiv.) and the mixture was refluxed for 20 h, then
cooled to room temperature. Ice and water were carefully added,
and the resulting aqueous solution was extracted with EtOAc (5ꢃ).
The organic phases were united, washed with brine, dried over
Na2SO4, filtered and the solvent was removed under reduced
pressure. Thus was obtained 200 mg (100% plus impurities) of the
intermediate enamine 40a as a yellow oil; the crude was used in the
next step without further purification.
The crude intermediate 40a was dissolved in 4.1 mL of glacial
acetic acid and NaBH4 (329 mg, 8.70 mmol, 15 equiv.) was added in
portions. The mixture was stirred at room temperature overnight,
then EtOAc was added. The pH of the mixture was adjusted to 6e7
using first NaOH pellets and then NaHCO3, and the resulting
aqueous solution was extracted with EtOAc (3ꢃ). The organic
phases were united, washed with brine, dried over Na2SO4, filtered
and the solvent was removed under reduced pressure. The crude
residue was purified by flash chromatography (eluent DCM/
Rf (Hexane/EtOAc ¼ 8/2) ¼ 0.15; 1H NMR (400 MHz, CDCl3)
d
(ppm) ¼ 8.20 (1 H, dd, H-13, J ¼ 8.0 Hz, J ¼ 1.7 Hz), 7.65 (1 H, dd, H-
7, J ¼ 7.7 Hz, J ¼ 1.2 Hz), 7.61 (1 H, dd, H-11, J ¼ 7.8 Hz, J ¼ 1.1 Hz),
7.28e7.49 (4 H, m, H-10, H-6, H-12 and H-4), 7.20 (1 H, dt, H-5,
J ¼ 7.6 Hz, J ¼ 1.4 Hz), 4.38 (2 H, s, H-2); 13C NMR (101 MHz, CDCl3)
d
(ppm) ¼ 191.5 (C-1), 140.4 (C-3), 137.8 (C-8), 136.3 (C-9), 134.7 (C-
14), 132.6 (C-11), 131.7 (C-6), 131.4 (C-4), 131.0 (C-13), 130.1 (C-5),
129.6 (C-7), 127.3 (C-12), 127.3 (C-10), 51.2 (C-2).
4.2.29. 8-Chlorodibenzo[b,f]thiepin-10(11H)-one (38b)
Compound 38b was obtained using the same conditions as for
38a, employing KOH (1.29 g, 23.0 mmol, 3.3 equiv.), 4-
chlorobenzenethiol (35b) (1.01 g, 6.96 mmol, 1.0 equiv.). Copper
powder (133 mg, 2.09 mmol, 0.3 equiv.) and 2-(2-iodophenyl)acetic
acid (36) (1.95 g, 6.68 mmol, 0.96 equiv.) Thus were obtained 2.14 g
(100% plus impurities) of 2-(2-((4-chlorophenyl)thio)phenyl)acetic
acid (37b) as a light yellow solid; the crude was used in the next
step without further purification.
In the second step, 4 g of oily P2O5 was heated with (((4-
chlorophenyl)thio)phenyl)acetic acid (37b) (750 mg, 2.69 mmol,
1.0 equiv.) The crude residue was purified by flash chromatography
(eluent Hexane/EtOAc ¼ 95/5 to 9/1), yielding 541 mg (50%) of 8-
chlorodibenzo[b,f]thiepin-10(11H)-one (38b) as a light-yellow oil.
Rf (Hexane/EtOAc ¼ 8/2) ¼ 0.15; 1H NMR (400 MHz, CDCl3)
MeOH
¼
95/5 to 9/1), yielding 99 mg (55%) of 1-(10,11-
dihydrodibenzo[b,f]thiepin-10-yl)-4-methylpiperazine (41a) as an
orange solid.
Rf (DCM/MeOH ¼ 9/1) ¼ 0.31; 1H NMR (400 MHz, CDCl3)
d
(ppm) ¼ 7.63 (1 H, d, H-6, J ¼ 7.8 Hz), 7.51 (1 H, d, H-11, J ¼ 7.8 Hz),
7.41 (1 H, dd, H-12, J ¼ 7.8 Hz, J ¼ 1.4 Hz), 7.18e7.30 (2 H, m, H-4 and
H-5), 7.02e7.18 (3 H, m, H-7, H-10 and H-13), 4.01 (1 H, dd, J ¼ 11.2,
3.6 Hz, H-1), 3.89 (1 H, dd, J ¼ 13.2, 11.6 Hz, H-2a), 3.18 (1 H, dd,
J ¼ 12.8, 3.6 Hz, H-2b), 2.62e2.80 (4 H, m, H-15), 2.28e2.62 (4 H, m,
H-16), 2.31 (3 H, s, H-17); 13C NMR (101 MHz, CDCl3)
d
(ppm) ¼ 142.6 (C-9), 140.3 (C-8), 137.0 (C-3), 135.3 (C-14), 132.6
(C-11), 131.6 (C-6), 131.3 (C-4), 129.7 (C-13), 128.7 (C-5), 127.1 (C-7),
126.9 (C-12), 126.4 (C-10), 65.8 (C-1), 55.6 (C-15), 48.3 (C-16), 45.9
(C-17), 33.4 (C-2); MS(ESI) m/z ¼ 311.0 [MþH]þ; HRMS(ESI) m/
z ¼ 311.1581 [MþH]þ, calc.: 311.1576, Diff.: 1.4 ppm.
d
(ppm) ¼ 8.17 (1 H, d, H-13, J ¼ 2.7 Hz), 7.63 (1 H, d, H-7, J ¼ 8.0 Hz),
7.54 (1 H, d, H-11, J ¼ 8.4 Hz), 7.45 (1 H, d, H-10, J ¼ 7.7 Hz),
7.36e7.40 (2 H, m, H-6 and H-4), 7.21 (1 H, dt, H-5, J ¼ 7.6 Hz,
J ¼ 1.5 Hz), 4.36 (2 H, s, H-2); 13C NMR (101 MHz, CDCl3)
4.2.32. tert-Butyl 4-(10,11-dihydrodibenzo[b,f]thiepin-10-yl)
piperazine-1-carboxylate (41c)
d
(ppm) ¼ 191.2 (C-1), 138.3 (C-3), 137.5 (C-8), 136.5 (C-9), 136.4 (C-
12), 134.7 (C-14), 131.5 (C-11), 131.3 (C-6), 130.6 (C-4), 130.0 (C-13),
129.5 (C-5), 128.3 (C-7), 127.3 (C-10), 51.2 (C-2), 15.7 (C-15). The
analytical data matched the published data [30].
Compound 41c was obtained using the same conditions as for
41a, employing 28a (180 mg, 0.80 mmol, 1.0 equiv.), 1-Boc-piper-
azine (39b) (726 mg, 3.90 mmol, 4.9 equiv.) and Ti(i-OPr)4 (0.18 mL,
0.60 mmol, 0.75 equiv.) and the mixture was refluxed for 40 h. Thus
were obtained 800 mg (100% plus impurities) of the intermediate
enamine 40c as a yellow oil; the crude was used in the next step
without further purification.
In the second step, the intermediate enamine 40c and NaBH4
(451 mg, 11.9 mmol, 15 equiv.) were stirred in 5.7 mL of glacial
acetic acid. The crude residue was purified by flash chromatography
(Hexane/EtOAc ¼ 9/1 to 8/2), yielding 236 mg (74%) of tert-butyl 4-
(10,11-dihydrodibenzo[b,f]thiepin-10-yl)piperazine-1-carboxylate
(41c) as a light-yellow oil.
4.2.30. 8-(Methylthio)dibenzo[b,f]thiepin-10(11H)-one (38c)
Compound 38c was obtained using the same conditions as for
38a, employing KOH (539 mg, 9.60 mmol, 3.3 equiv.), 4-(methyl-
thio)benzenethiol (35c) (454 mg, 2.91 mmol, 1.0 equiv.). Copper
powder (56 mg, 0.87 mmol, 0.3 equiv.) and 2-(2-iodophenyl)acetic
acid (36) (732 mg, 2.79 mmol, 0.96 equiv.) Thus were obtained
1.40 g (100% plus impurities) of 2-(2-(phenylthio)phenyl)acetic acid
(37c) as a light yellow solid; the crude was used in the next step
without further purification.
In the second step, 6 g of oily P2O5 were heated with 37c. The
crude residue was purified by flash chromatography (eluent Hex-
ane/EtOAc ¼ 95/5 to 8/2), yielding 94 mg (12%) of 8-(methylthio)
dibenzo[b,f]thiepin-10(11H)-one (38c) as a light-yellow oil.
Rf (Hexane/EtOAc ¼ 9/1) ¼ 0.42; 1H NMR (400 MHz, CDCl3)
Rf (Hexane/EtOAc ¼ 8/2) ¼ 0.43; 1H NMR (400 MHz, CDCl3)
d
(ppm) ¼ 7.62 (1 H, d, H-6, J ¼ 8.0 Hz), 7.51 (1 H, d, H-11, J ¼ 8.0 Hz),
7.41 (1 H, d, H-12, J ¼ 8.0 Hz), 6.45e7.38 (5 H, m, H-4, H-5, H-7, H-10,
H-13), 3.97e4.07 (1 H, m, H-1), 3.70e3.95 (1 H, m, H-2a), 3.34e3.50
(4 H, m, H-16), 3.05e3.20 (1 H, m, H-2b), 2.38e2.75 (4 H, m, H-15),
d
(ppm) ¼ 8.04 (1 H, d, H-13, J ¼ 2.3 Hz), 7.62 (1 H, d, H-7, J ¼ 7.8 Hz),
1.45 (9 H, s, H-19); 13C NMR (101 MHz, CDCl3)
d
(ppm) ¼ 155.0 (C-
7.49 (1 H, d, H-11, J ¼ 8.4 Hz), 7.43 (1 H, d, H-10, J ¼ 7.2 Hz), 7.35 (1 H,
td, H-6, J ¼ 7.6 Hz, J ¼ 1.3 Hz), 7.28 (1 H, dd, H-4, J ¼ 8.2 Hz,
J ¼ 2.4 Hz), 7.19 (1 H, dt, H-5, J ¼ 7.6 Hz, J ¼ 1.4 Hz), 4.36 (2 H, s, H-2),
2.47 (3 H, s, H-15); MS(ESI) m/z ¼ 273.1 [MþH]þ; HRMS(ESI) m/
z ¼ 271.0270 [MþH]þ, calc.: 271.0257, Diff.: 4.9 ppm.
17), 142.4 (C-9), 140.0 (C-8), 137.1 (C-3), 135.4 (C-14), 132.8 (C-11),
131.7 (C-6), 131.4 (C-4), 129.6 (C-13), 128.7 (C-5), 127.2 (C-7), 126.9
(C-12), 126.5 (C-10), 79.6 (C-18), 66.2 (C-1), 48.8 (C-16), 44.5 (C-15),
33.5 (C-2), 28.6 (C-19); MS(ESI) m/z ¼ 397.0 [MþH]þ; HRMS(ESI) m/
z ¼ 397.1955 [MþH]þ, calc.: 397.1944, Diff.: 2.6 ppm.