4164 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 14
Grice et al.
solid. The solid was washed with diethyl ether and air-dried to give
214 mg of the product as a white solid (2.3 mmol, 23% yield). MS
(electrospray): exact mass calculated for C25H31N3O3S1, 453.2; m/z
found, 454.4 [M + H]+. 1H NMR (400 MHz, CDCl3): 7.73 (dd, J
) 8.2, 0.6 Hz, 1H), 7.65 (dd, J ) 7.9, 0.7 Hz, 1H), 7.39 (dt, J )
7.4, 1.3 Hz, 1H), 7.29-7.23 (m, 5H), 4.47 (br d, J ) 6.6 Hz, 1H),
3.55-3.45 (m, 1H), 2.93 (br d, J ) 11.3 Hz, 2H), 2.82 (dd, J )
11.0, 7.7 Hz, 2H), 2.60 (dd, J ) 8.6, 5.3 Hz, 2H), 2.16 (t, J ) 11.3
Hz, 2H), 1.97 (br. d, J ) 11.1 Hz, 2H), 1.45 (s, 9H).
1-{2-[4-(Benzothiazol-2-yloxy)phenyl]ethyl}piperidine-4-car-
boxylic Acid Amide (27h). The title compound was prepared
according to the procedure for 11h using 25 and isonipecotamide
to provide 56 mg of 27h as an off-white solid (0.2 mmol, 20%
yield). MS (ESI): mass calculated for C21H23N3O2S, 381.15; m/z
found, 382.3 [M + H]+. 1H NMR (400 MHz, CDCl3): 7.78 (dd, J
) 8.1, 0.4, 1H), 7.71 (dd, J ) 7.9, 0.7, 1H), 7.43 (dt, J ) 7.5, 2.3,
1H), 7.35-7.25 (m, 5H), 5.51 (br d, J ) 26.0, 1H), 3.09 (br d, J
) 11.7, 2H), 2.87 (dd, J ) 8.3, 7.6, 2H), 2.65 (dd, J ) 8.5, 5.4,
2H), 2.29-2.18 (m, 1H), 2.13 (t, J ) 11.4, 2H), 1.98 (br d, J )
11.2, 2H), 1.87-1.77 (m, 2H). Anal. (C21H23N3O2S·0.25H2O) C,
H, N.
1-(1-{2-[4-(Benzothiazol-2-yloxy)phenyl]ethyl}piperidin-4-
yl)pyrrolidin-2-one (27j). The title compound was prepared
according to the procedure for 11h using 25 and 1-piperidin-4-
ylpyrrolidin-2-one to provide 98 mg of 27j as a white solid (0.2
mmol, 31% yield). MS (ESI): mass calculated for C24H27N3O2S,
421.18; m/z found, 422.4 [M + H]+. 1H NMR (400 MHz, CDCl3):
7.76 (d, J ) 8.0, 1H), 7.69 (dd, J ) 8.0, 0.9, 1H), 7.41 (dt, J )
7.5, 1.2, 1H), 7.32-7.27 (m, 5H), 4.05 (dt, J ) 11.9, 4.5, 1H),
3.40 (t, J ) 7.0, 2H), 3.10 (br d, J ) 11.7, 2H), 2.86 (dd, J ) 11.0,
7.7, 2H), 2.66 (dd, J ) 8.8, 5.3, 2H), 2.43 (t, J ) 8.1, 2H), 2.19
(dt, J ) 11.6, 2.8, 2H), 2.09-2.00 (m, 2H), 1.85-1.69 (m, 4H).
The title compound was dissolved in CH2Cl2 and treated with 1 M
HCl (1.5 equiv) in Et2O to give the HCl salt. Anal. (C24H27-
N3O2S·HCl) C, H, N.
89% yield). MS (ESI): exact mass calculated for C25H29N3O4S,
395.2; m/z found, 396.3 [M + H]+. 1H NMR (400 MHz, CDCl3):
7.73 (d, J ) 8.0, 1H), 7.66 (dd, J ) 7.9, 0.6, 1H), 7.42-7.36 (m,
1H), 7.29-7.24 (m, 5H), 5.48 (d, J ) 7.8, 1H), 3.87-3.77 (m 1H),
2.95 (dd, J ) 11.6, 2H), 2.83 (dd, J ) 10.8, 7.6, 2H), 2.62 (dd, J
) 8.5, 5.3, 2H), 2.18 (d, J ) 11.4, 2H), 2.00-1.94 (m, 2H), 1.98
(m, 2H), 1.49 (dddd, J ) 12.3, 12.2, 12.2, 3.6, 2H). Anal.
(C22H25N3O2S) C, H, N.
AceticAcid(1-{2-[4-(Benzothiazol-2-yloxy)phenyl]ethyl}piperidin-
4-ylcarbamoyl)methyl Ester (27o). The title compound was
prepared from 27m according to the procedure for 33o to provide
253 mg of 27o of a solid (0.6 mmol, 95% yield). MS (ESI): exact
mass calculated for C24H27N3O4S, 453.2; m/z found, 454.3 [M +
1
H]+. H NMR (400 MHz, CDCl3): 7.73 (dd, J ) 8.2, 0.6, 1H),
7.67 (dd, J ) 7.9, 0.7, 1H), 7.42-7.36 (m, 1H), 7.29-7.24 (m,
5H), 6.05 (d, J ) 8.0, 1H), 4.54 (s, 2H), 3.96-3.85 (m 1H), 3.00
(d, J ) 8.2, 0.6, 2H), 2.85 (dd, J ) 10.6, 7.4, 2H), 2.85 (dd, J )
10.6, 7.4, 2H), 2.66 (dd, J ) 8.6, 5.3, 2H), 2.23 (t, J ) 11.4, 2H),
2.18 (s, 3H), 1.98 (d, J ) 9.7, 2H), 1.57 (dddd, J ) 12.4, 12.4,
12.3, 3.6, 2H). Anal. (C24H27N3O4S) C, H, N.
4-(Benzothiazol-2-yloxy)benzaldehyde (30). To a mixture of
4-hydroxybenzaldehyde, 28 (1.0 g, 8.2 mmol), and 2-chloroben-
zothiazole (2.0 mL, 16.4 mmol) in CH3CN (100 mL) was added
Cs2CO3 (5.5 g, 17.2 mmol). The reaction mixture was stirred at 60
°C for 24 h. The resulting mixture was cooled to room temperature,
filtered through diatomaceous earth, and concentrated under reduced
pressure to yield the crude product as an orange oil. The oil was
triturated with hexanes/CH2Cl2 (100 mL) and the solvent layer
decanted and concentrated under reduced pressure to yield an orange
oil which was further purified on SiO2 (120 g, 0-50% ethyl acetate/
hexanes) to give 853 mg of a white solid (3.4 mmol, 41% yield).
1H NMR (400 MHz, CDCl3): 10.1 (s, 1H), 7.97-7.78 (m, 2H),
7.78-7.70 (m, 2H), 7.60-7.50 (m, 2H), 7.48-7.38 (m, 1H),
7.36-7.30 (m, 1H).
[4-(Benzothiazol-2-yloxy)phenyl]methanol (31). To a mixture
of 4-hydroxybenzyl alcohol, 29 (12 g, 97 mmol) in CH3CN (200
mL) containing K2CO3 (22 g, 159 mmol) was added 2-chloroben-
zothiazole (22 g, 130 mmol), and the mixture was heated to reflux
for 72 h. The mixture was cooled to room temperature, filtered,
and concentrated under reduced pressure to give the crude product
as a golden oil. The crude oil was purified on SiO2 (300 g, 5%
acetone/CH2Cl2) to give 15 g of a clear, colorless oil (58 mmol,
60% yield). MS (ESI): exact mass calculated for C14H11NO2S,
257.1; m/z found, 258.3 [M + H]+. 1H NMR (400 MHz, DMSO-
d6): 7.92 (d, J ) 7.4, 1H), 7.69 (d, J ) 8.0, 1H), 7.50-7.31 (m,
5H), 7.32 (t, J ) 7.5, 1H), 5.32 (t, J ) 5.7, 1H), 4.55 (d, J ) 5.7,
2H).
3-(1-{2-[4-(Benzothiazol-2-yloxy)phenyl]ethyl}piperidin-4-
yl)oxazolidin-2-one (27l). The title compound was prepared
according to the procedure for 27i using 19 and 26 to provide 249
mg of 27l as an off-white solid (0.5 mmol, 92% yield). MS (ESI):
exact mass calculated for C23H25N3O3S1, 423.2; m/z found, 424.4
1
[M + H]+. H NMR (400 MHz, CDCl3): 7.77 (dd, J ) 8.1, 0.5,
1H), 7.69 (dd, J ) 7.9, 1.1, 1H), 7.41 (dt, J ) 8.5, 1.2, 1H),
7.35-7.28 (m, 5H), 4.36, (t, J ) 7.8, 2H), 3.72 (t, J ) 4.8, 2H),
3.86-3.76 (m, 1H), 3.57 (t, J ) 8.1, 2H), 3.11 (br d, J ) 11.8,
2H), 2.86 (dd, J ) 11.0, 7.6, 2H), 2.66 (dd, J ) 8.6, 5.2, 2H), 2.18
(dt, J ) 11.7, 2.7, 2H), 1.89-1.72 (m, 4H). Anal. (C23H25N3-
O3S·HCl·0.5H2O) C, H, N
1-{2-[4-(Benzothiazol-2-yloxy)phenyl]ethyl}piperidin-4-
ylamine (27m). To a stirred solution of 27i (4.0, 8.8 mmol) in
88% formic acid (40 mL) was added 5.0 N HCl (1.8 mL, 8.8 mmol).
The mixture was stirred at room temperature for 7 h and
concentrated under reduced pressure to give a glass, which was
triturated with Et2O and filtered to give a solid (3.6 g, 8.8 mmol,
>99% crude yield). MS (electrospray): exact mass calculated for
C20H23N3O1S1, 353.5; m/z found, 354.4 [M + H]+. 1H NMR (400
MHz, DMSO-d6): 8.22 (s, 1H), 7.90 (d, J ) 7.9, 1H), 7.66 (d, J )
7.6, 1H), 7.47-7.27 (m, 5H), 3.17-3.03 (m, 3H), 2.90-2.81 (m,
2H), 2.78-2.69 (m, 2H), 2.32 (t, J ) 11.8, 2H), 1.96 (d, J ) 10.7,
2H), 1.71-1.59 (m, 2H). The crude solid (1.3 g) was suspended in
EtOAc (100 mL) and washed with saturated aqueous NaHCO3 (30
mL). The organic layer was dried (Na2SO4) and concentrated to
yield the desired product (1.0 g, 23 mmol, 77% yield), which was
used without further purification.
N-(1-{2-[4-(Benzothiazol-2-yloxy)phenyl]ethyl}piperidin-4-yl)-
N-acetamide (27n). To a solution of 27m (213 mg, 0.6 mmol) in
CH2Cl2 (7 mL) at room temperature was added triethylamine (0.12
mL, 0.9 mmol), followed by acetyl chloride (0.06 mL, 0.8 mmol).
The resulting mixture was stirred at room temperature 1 h. The
reaction mixture was dissolved in CH2Cl2 (20 mL), washed with
saturated aqueous NaHCO3 (1 × 10 mL), dried (Na2SO4), and
concentrated under reduced pressure to yield 211 mg (0.5 mmol,
2-(4-Chloromethylphenoxy)benzothiazole (32). To a mixture
of 31 (11 g, 43 mmol) in CH2Cl2 (100 mL) containing triethylamine
(9 mL, 65 mmol) at 5 °C was added dropwise over 15 min thionyl
chloride (4 mL g, 55 mmol). The ice bath was removed and the
mixture warmed to room temperature and stirred for 24 h. The
mixture was washed once with saturated K2CO3 (100 mL), dried
(MgSO4), and concentrated under reduced pressure to give a black
oil. The crude oil was purified on SiO2 (300 g, 100% CH2Cl2) to
give 10 g of a clear orange oil (36 mmol, 84% yield). MS (ESI):
exact mass calculated for C14H10ClNOS, 275.0; m/z found, 276.2
[M + H]+. 1H NMR (400 MHz, DMSO-d6): 7.95 (d, J ) 7.3, 1H),
7.70 (d, J ) 7.6, 1H), 7.59 (d, J ) 8.6, 2H), 7.47 (d, J ) 8.6, 2H),
7.37 (t, J ) 7.4, 1H), 7.33 (t, J ) 7.5, 1H), 4.84 (s, 2H).
2-(4-Piperidin-1-ylmethylphenoxy)benzothiazole (33b). The
title compound was prepared according to the procedure for 33j,
using piperidine to provide 125 mg of 33b as a pale-yellow solid
(0.4 mmol, 47% yield). MS (ESI): mass calculated for C19H20N2OS,
324.4; m/z found, 325.3 [M + H]+. 1H NMR (400 MHz, CDCl3):
7.75 (d, J ) 8.2, 1H), 7.73 (d, J ) 8.2, 1H), 7.36-7.42 (m, 3H),
7.24-7.32 (m, 3H), 3.49 (s, 2H), 2.39 (br s, 3H), 1.56-1.64 (m,
5H), 1.40-1.48 (m, 2H). Anal. (C19H20N2OS) C, H, N.
1-[4-(Benzothiazol-2-yloxy)benzyl]piperidin-4-ol (33e). The
title compound was prepared according to the procedure for 33j
using 4-hydroxypiperidine to provide 383 mg of 33e as a white