D. Sampson et al. / Bioorg. Med. Chem. 22 (2014) 3105–3114
3113
1.98–1.93 (m, 2H), 1.72–1.62 (m, 2H). Calcd for C21H24ClN3O 0.18
H2O: C 67.60, H 6.48, N 11.26. Found: C 67.69, H 6.61, N 10.98.
26.32, 24.88. Calcd for C21H23ClN2Oꢁ0.3H2O: C 70.01, H 6.43, N
7.78. Found: C 69.9, H 6.41, N 7.42.
4.1.22. 2-(3-(4-(4-Chlorophenyl)piperazin-1-
yl)propyl)benzo[d]oxazole, 21
4.1.28. 2-(3-(Benzofuran-2-yl)propyl)-5-(4-chlorophenyl)-2,5-
diazabicyclo[2.2.1]heptane, 25
Yield 37%, mp 98–99 °C. 1H NMR (CDCl3): d 7.68–7.65 (m, 1H),
7.49–7.46 (m, 1H), 7.30–7.28 (m, 2H), 7.18 (d, J = 9.3 Hz, 2H),
6.80 (d, J = 9.0 Hz, 2H), 3.09 (t, J = 5.1 Hz, 4H), 3.01 (t, J = 7.8 Hz,
2H), 2.59 (t, J = 5.1 Hz, 4H), 2.53 (t, J = 6.9 Hz, 2H), 2.14–2.09 (m,
2H). Calcd for C20H22ClN3O: C 67.50, H 6.23, N 11.81. Found: C
67.28, H 6.35, N 11.56.
Yield 70%, mp 88.1–89.5 °C. 1H NMR (CDCl3): d 7.46 (dd, J = 5.4,
4.5 Hz,1H), 7.19 (m, 1H), 7.17 (m, 1H), 7.13 (d, J = 9.6 Hz, 2H), 6.45
(d, J = 12.0 Hz, 2H), 6.35 (s, 1H), 4.18 (br s, 1H), 3.57 (br s, 1H), 3.35
(dd, J = 4.5, 3.3 Hz, 1H,), 3.22 (d, J = 9 Hz, 1H), 2.99 (dd, J = 4.5,
4.5 Hz, 1H), 2.78 (t, J = 9.0 Hz, 2H), 2.55 (m, 4H), 1.94 (t, J = 9 Hz,
2H), 1.84 (t, J = 9 Hz, 2H). 13C NMR (CDCl3): d 158.9, 154.2, 145.7,
128.9, 123.3, 122.2, 120.9, 120.05, 113.8, 110.6, 102.1, 61.7, 57.7,
56.9, 52.05, 36.3, 27.1, 26.01. Calcd for C22H23ClN2O: C 72.02, H
6.32, N 7.64. Found: C 71.75, H 6.38, N 7.51.
4.1.23. 2-(2-(4-(4-Chlorophenyl)piperazin-1-
yl)ethyl)benzo[d]oxazole, 22
Yield 58%, mp 110–112 °C. 1H NMR (CDCl3): d 7.69–7.66 (m,
1H), 7.52–7.47 (m, 1H), 7.32–7.30 (m, 2H), 7.19 (d, J = 9.3 Hz,
2H), 6.83 (d, J = 9.0 Hz, 2H), 3.18–3.14 (m, 6H), 3.01 (t, J = 6.9 Hz,
2H), 2.70 (t, J = 5.1 Hz, 4H). Cacld for C19H20ClN3O: C 66.76, H
5.90, N 12.29. Found: C 67.06, N 5.97, H 11.90.
4.1.29. 1-(3-(Benzofuran-2-yl)propyl)-4-(4-chlorophenyl)-1,4-
diazepane dihydrochloride, 26
Yield 89%, mp 138.1–139.9 °C. 1H NMR (CDCl3): d 7.46 (dd,
J = 6.0, 4.8 Hz, 1H), 7.39 (dd, J = 6.0Hz, 3.3 Hz, 1H), 7.14–7.22 (m,
2H), 7.12 (d, J = 7.2 Hz, 2H), 6.57 (d, J = 6.0 Hz, 2H), 6.35 (s, 1H),
3.53 (t, J = 6.0 Hz, 2H), 3.44 (t, J = 9.0 Hz, 2H), 2.73–2.81 (m, 4H),
2.66 (t, J = 6.0 Hz, 2H), 2.58 (t, J = 6.0 Hz, 2H), 1.91–2.00 (m, 4H).
Calcd for C22H27Cl3N2Oꢁ0.5H2O: C 63.77, H 6.32, N 6.76. Found: C
63.78, H 6.35, N 6.61.
4.1.24. General method for tosylated alkyl benzofurans
The method reported in Bakunova et al.,16 was followed to con-
struct the benzofuran moiety. A mixture of 2-iodophenol (3 g,
1 equiv), alkyl-1-yn-1-ol (1.1 equiv), and copper(I) oxide (1.36 g,
0.7 equiv) in dry pyridine (15 mL) was stirred at 100–120 °C over-
night. The mixture was allowed to cool to rt, diluted with EtOAc
(50 mL), filtered through celite and concentrated. The residue
was dissolved in EtOAc (100 mL), washed with 2 M HCl (50 mL)
and brine (100 mL), dried over Na2SO4, and concentrated. The res-
idue was, then, dissolved in CH2Cl2 (10 mL) and TsCl (1.1 equiv)
and Et3N (1.4 equiv) were added at rt while stirring overnight.
The solution was diluted with EtOAc (50 mL), washed with H2O
(3 ꢀ 50 mL) and brine (50 mL). The pooled organic solvent was
dried (Na2SO4), concentrated under reduced pressure and purified
using column chromatography with hexane/EtOAc (7:3) as the
eluent.
4.1.30. 2-(3-Chloropropyl)benzo[d]thiazole, 48
A mixture of 2-aminobenzenethiol (10 g, 80 mmol) and 4-chlo-
robutyl chloride (14 g, 99 mmol) in toluene (100 mL) was stirred
for 48 h at rt. The mixture was diluted with EtOAc (300 mL) and
washed with saturated aq NaHCO3 (2 ꢀ 100 mL). The organic layer
was dried with Na2SO4, and filtered. The filtrate was concentrated
in vacuo, followed by chromatography on silica gel to afford 2-(3-
chloropropyl)benzo[d]thiazole (13.5 g, 80%) as an oil. 1H NMR
(CDCl3): d 7.98 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.47 (t,
J = 8.4 Hz, 1H), 7.37 (t, J = 8.4 Hz, 1H), 3.69 (t, J = 6.6 Hz, 2H), 3.30
(t, J = 7.5 Hz, 2H), 2.34–2.42 (m, 2H).
4.1.25. General procedure for benzofuran coupling
4.1.31. 2-(3-(4-(Pyrimidin-2-yl)piperazin-1-
yl)propyl)benzo[d]thiazole trihydrobromide, 28
To a stirred solution of CH3CN (10 mL) and Et3N (2 equiv), the
appropriate haloalkylbenzofuran (1 equiv) and an arylcycloalkyl-
amine (1.1 equiv) were added and refluxed overnight. The solution
was allowed to cool to rt, diluted with EtOAc (50 mL) and washed
with H2O and brine, dried over Na2SO4 and concentrated under
reduced pressure. The residue was purified using column chroma-
tography with hexane/EtOAc (6:4) as the eluent to afford an
orange-yellow solid.
A mixture of 2-(3-chloropropyl)benzothiazole (1.5 g, 7.08 mmol),
2-(piperazin-1-yl)pyrimidine dihydrochloride (1.6 g, 6.7 mmol), KI
(200 mg), K2CO3 (1.2 g, 8.7 mmol) in DME (10 mL) was heated to
reflux under N2 for 12 h. The mixture was diluted with EtOAc
(400 mL) and washed with brine (50 mL). The organic layer was
dried over Na2SO4, and filtered. The filtrate was concentrated in
vacuo to dryness and the residue was column chromatographed
on silica gel to afford 2-[3-(4-pyrimidin-2-yl-piperazin-1-yl)
propyl]benzothiazole, 28. The product was converted into the HBr
salt, and recrystallized from MeOH–Et2O (865 mg, 21%), mp
>260 °C. 1H NMR (DMSO-d6): d 12.08 (br s, 2H), 10.13 (br s, 1H),
8.45 (d, J = 4.5 Hz, 2H), 8.07 (d, J = 8.1 Hz, 1H), 7.93 (d, J = 8.1 Hz,
1H), 7.48 (dt, J = 1.5, 8.1 Hz, 1H), 7.40 (dt, J = 1.5, 8.1 Hz, 1H), 6.78
(t, J = 4.5 Hz, 1H), 4.68 (d, J = 14.1 Hz, 2H), 3.63 (d, J = 14.1 Hz, 2H),
3.35–3.44 (m, 2H), 3.20–3.31 (m, 4H), 3.04–3.14 (m, 2H),
2.25–2.35 (m, 2H). Calcd for C18H24Br3N5S: C 37.13, H 4.16,
N 12.03. Found: C 37.22, H 4.11, N 12.01.
4.1.26. 1-(2-(Benzofuran-2-yl)ethyl)-4-(4-
chlorophenyl)piperazine, 23
Yield 93%, mp 166.6–168.2 °C. 1H NMR (CDCl3): d 7.49 (dd,
J = 4.5, 4.5 Hz, 1H), 7.42 (d, J = 12.0 Hz, 1H), 7.24 (m, 4H), 6.87 (d,
J = 9.0 Hz, 2H), 6.46 (s, 1H), 3.19 (t, J = 15 Hz, 4H), 3.03 (t,
J = 9.0 Hz, 2H), 3.85 (t, J = 9.0 Hz, 2H), 2.70 (t, J = 15 Hz, 4H). 13C
NMR (CDCl3): d 157.4, 154.3, 149.98, 128.98, 124.3, 123.2, 122.2,
120.2, 117.3, 110.07, 102.3, 56.1, 52.8, 49.3, 26.2. Calcd for C20H21-
ClN2O: C 70.48, H 6.21, N 8.22. Found: C 70.63, H 6.30, N 8.25.
4.1.27. 1-(3-(Benzofuran-2-yl)propyl)-4-(4-
chlorophenyl)piperazine, 24
4.2. Receptor binding studies
Yield 90%, mp 84.8–85.9 °C. 1H NMR (CDCl3): d 7.49 (dd, J = 6.0,
6.0 Hz, 1H), 7.41 (d, J = 12.0 Hz, 1H), 7.19 (m, 4H), 6.84 (d,
J = 9.0 Hz, 2H), 6.41 (s, 1H), 3.15 (t, J = 15 Hz, 4H), 2.83 (t,
J = 9.0 Hz, 2H), 2.62 (t, J = 12.0 Hz, 2H), 2.49 (t, J = 9 Hz, 4H), 1.97
(m, 2H). 13C NMR (CDCl3): d 158.5, 154.5, 149.98, 128.94, 124.25,
123.21, 122.47, 120.24, 117.22, 110.75, 102.1, 57.66, 53.05, 49.11,
Binding affinities (Ki, nM) reported in Tables 1–4 were con-
ducted by the National Institute of Mental Health Psychoactive
Drug Screening Program (NIMH-PDSP) unless otherwise stated.
Details of the methods and the radioligands used for the binding
assays at each receptor were previously reported.22