5222 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 17
Sikazwe et al.
(4:1) to afford the dimethylated free base as a pale-yellow oil (0.70
g, 86%). Gaseous HCl was bubbled through a solution of the free
base in MeOH/Et2O. Recrystallization from MeOH/Et2O afforded
7 as a white solid (0.42 g): mp 189-191 °C; 1H NMR (CDCl3) δ
2.82 (s, 3H, CH), 2.84 (s, 3H, CH), 3.01-3.08 (m, 2H, CH), 3.13-
3.18 (m, 2H, CH), 6.20 (dd, J ) 3.0, 1.5, 1H, ArH), 7.03-7.05
(m, 1H, ArH), 7.13-7.15 (m, 1H, ArH), 7.51-7.57 (m, 2H, ArH),
7.62-7.67 (m, 1H, ArH), 7.85-7.86 (m, 1H, ArH), 7.87-7.88 (m,
1H, ArH). Anal. (C14H18N2O2S‚HCl) C, H, N.
was purified by column chromatography (silica gel, 20 g) using
CH2Cl2/MeOH (4:1) as eluent to afford the free base of 12 as a
pale yellow solid (0.15 g): mp 176-177 °C. Oxalic acid was added
to a solution of the free base in acetone, and the salt was collected
and recrystallized from acetone to give 12 as a white solid (0.1 g,
1
48%): mp 206-208 °C; H NMR (CD3OD) δ 1.88 (s, 2H, CH),
2.61 (s, 2H, CH), 2.86 (s, 2H, CH), 6.93 (m, 3H, ArH), 7.12 (m,
1H, ArH), 7.47-7.57 (m, 3H, ArH), 7.75(m, 2H, ArH). Anal.
(C15H18N2O2S‚C2H2O4) C, H, N, except that Ncalc ) 7.36%, Nfound
) 7.77%.
4-(3-Benzenesulfonamidophenyl)piperazine Hydrochloride
(9a). A saturated solution of HCl (g) in dry EtOAc (25 mL) was
added in a dropwise manner to a solution of 1-Boc-4-(3-benzene-
sulfonamidophenyl)piperazine (2.85 g, 5.0 mmol) (39a) in dry
EtOAc (25 mL). The reaction mixture was allowed to stir for 3 h,
and solvent was evaporated under reduced pressure to give a brown
semisolid material. The crude product was purified by flash
chromatography (silica gel; CH2Cl2/MeOH, 4:1) to give a gray-
brown solid that was subsequently recrystallized from iPrOH/Et2O
to afford 1.26 g (69%) of 9a as a gray powder: mp 141-143 °C
N-[(3-Aminomethyl)phenyl]benzenesulfonamide Oxalate (13).
The free base of 13 was prepared from N-(3-cyanophenyl)-
benzenesulfonamide (27)30 using the procedure of Satoh and
Suzuki.31 The crude free base was purified by column chromatog-
raphy (silica gel, 30 g) using CH2Cl2/MeOH (4:1) and converted
to its oxalate salt to give 13 (0.15 g, 53%) as white crystals
following recrystallization from acetone: mp 153-154 °C. 1H NMR
(DMSO-d6) δ 3.95 (s, 2H, CH), 7.10 (dd, J ) 4.05, 13.65, 2H,
ArH), 7.27 (t, J ) 7.8, 2H, ArH), 7.52-7.62 (m, 3H, ArH), 7.80
(d, J ) 4.2, 2H, ArH). Anal. (C13H14N2O2S‚1.25C2H2O4) C, H, N.
N-(3-Aminophenyl)benzenesulfonamide Hydrochloride (14).
A mixture of N-(3-nitrophenyl)benzenesulfonamide (28)32 (1.50 g,
5.39 mmol) and SnCl2‚2H2O (6.09 g, 26.98 mmol) in absolute EtOH
(50 mL) was heated at reflux until all the starting material
disappeared (30 min). The reaction mixture was allowed to cool to
room temperature and poured onto a small amount of ice, and the
solution was made slightly basic (pH 8-9) by the addition of
saturated NaHCO3 solution. Solid NaCl (ca. 4-5 g) was added to
the solution, and the solution was extracted with EtOAc (3 × 100
mL). The organic portion was thoroughly washed with brine (3 ×
50 mL) and dried (Na2SO4), and the solvent was evaporated under
reduced pressure. The free base of the title compound was obtained
as a brown solid (1.20 g, 90%). The hydrochloride salt was prepared
in anhydrous MeOH and recrystallized from MeOH/Et2O to give
14 as brown-colored crystals: mp 226-227 °C. 1H NMR (DMSO-
d6) δ: 6.95 (d, J ) 8.1 Hz, 1H, CH); 7.03 (dd, J ) 8.1 Hz, J ) 2.1
Hz, 1H, CH) 7.16 (d, J ) 2.1 Hz, 1H, CH); 7.28 (dd, J ) 8.1 Hz,
J ) 8.1 Hz, 1H, 1CH); 7.51-7.70 (m, 3H, 3CH); 7.80-7.83 (m,
2H, 2CH); 10.70 (s, 1H, NH). Anal. (C12H12N2O2S‚HCl) C, H. N.
N-Phenyl-3-(2-aminoethyl)benzenesulfonamide Oxalate (15).
A mixture of nitromethane (100 mL), N-phenyl-(3-formyl)benzene-
sulfonamide 29 (2.0 g, 7.64 mmol33 and NH4OAc (0.65 g, 8.41
mmol) was heated at reflux overnight (20 h) under N2. Water (20
mL) was added, the organic portion was extracted with EtOAc (4
× 10 mL), the combined organic extract was washed with brine
(20 mL) and dried (Na2SO4), and solvent was removed under
reduced pressure. Column chromatography (silica gel, 30 g) of the
residue using hexane/EtOAc (7:3) afforded intermediate nitrostyrene
30 as a yellow oil in a quantitative yield. 1H NMR (CDCl3) δ 7.12-
7.18 (m, 2H, ArCHdCH), 7.24-7.32 (m, 3H, ArH), 7.41-7.46
(m, 1H, ArH), 7.54-7.60 (m, 1H, ArH), 7.68-7.78 (m, 1H, ArH),
7.88-8.00 (m, 3H, ArH).
1
(dec); H NMR (DMSO-d6) δ 3.13 (m, 4H, CH2), 3.22 (m, 4H,
CH2), 6.57-6.70 (m, 3H, ArH), 7.06 (m, 1H, ArH), 7.52-7.61
+
(m, 3H, ArH), 7.77 (m, 2H, ArH), 9.54 (br.s., 2H, piperazinyl NH2
,
D2O exchangeable). Anal. (C16H19N3O2S‚HCl‚0.7H2O) C, H, N.
4-(4-Benzenesulfonamidophenyl)piperazine Hydrochloride
(9b). A solution of benzenesulfonyl chloride (2.20 g, 12.5 mmol)
in dry CH2Cl2 (10 mL) was added in a dropwise manner to a
mixture of 1-Boc-4-(4-aminophenyl)piperazine28 (38b) (2.77 g, 10.0
mmol) and pyridine (1.18 g, 1.5 mmol) in dry CH2Cl2 (25 mL) at
room temperature under an N2 atmosphere. The reaction mixture
was allowed to stir for 5 h and solvent was evaporated under
reduced pressure. A solution of the residue in CH2Cl2 (100 mL)
was washed with 5% NaOH (2 × 25 mL), then brine (3 × 50 mL),
dried (MgSO4), and solvent was evaporated under reduced pressure.
The resultant crude product was recrystallized from EtOAc/hexane
to give 3.58 g (86%) of 39b as a white solid: mp 180-181 °C; 1H
NMR (CDCl3) δ 1.51 (s, 9H, CH3), 3.11 (m, 4H, CH2), 3.59 (m,
4H, CH2), 6.28 (br.s., 1H, NHSO2, D2O exchangeable), 6.82 (m,
2H, ArH), 6.98 (m, 2H, ArH), 7.48 (m, 2H, ArH), 7.54 (m, 1H,
ArH), 7.73 (m, 2H, ArH).
A saturated solution of HCl (g) in dry EtOAc (25 mL) was added
in a dropwise manner to a stirred solution of 39b (2.85 g, 5 mmol)
in dry EtOAc (25 mL). The reaction mixture was allowed to stir
for 3 h and concentrated under reduced pressure, and solids were
removed by filtration. The grayish-white solid was recrystallized
from MeOH/Et2O to afford 1.62 g (92%) of 9b as a gray powder:
1
mp >205 °C (dec). H NMR (DMSO-d6) δ 3.17 (m, 4H, CH2),
3.25 (m, 4H, CH2), 6.85 (d, J ) 9.3 Hz, 2H, ArH), 6.95 (d, J )
8.7 Hz, 2H, ArH), 7.58 (m, 3H, ArH), 7.71 (m, 2H, ArH), 9.04
(br.s., 2H, piperazinyl NH2+, D2O exchangeable), 9.92 (br.s., 1H,
NHSO2, D2O exchangeable). Anal. (C16H19N3O2S‚HCl‚1.5H2O) C,
H, N.
N-[3-(3-Aminopropyl)phenyl]benzenesulfonamide Oxalate (12).
Benzenesulfonyl chloride (2.1 g, 11.7 mmol) was added to a
solution of 2-(3-aminophenyl)acrylonitrile (25)29 (1.4 g, 9.7 mmol)
in pyridine (20 mL), and the solution was allowed to stir at 60 °C
overnight (18 h). Pyridine was removed under reduced pressure,
HCl (1 N, 50 mL) was added to the residue, and the mixture was
extracted with EtOAc (4 × 20 mL). The combined organic portion
was washed with brine (20 mL) and dried (Na2SO4), and solvent
was removed under reduced pressure. The residue was diluted with
EtOAc (20 mL), and upon addition of hexane, benzenesulfonamide
26 precipitated out as a beige solid (2.2 g, 80%): mp 188-190
Nitrostyrene 30 (0.80 g, 2.61 mmol) in dry THF (10 mL) was
slowly added to a suspension of LiAlH4 (0.40 g, 10.44 mmol) in
THF (30 mL) at 0 °C under N2. The reaction mixture was heated
at reflux for 3 h, allowed to cool to room temperature, and placed
in an ice bath. Water (1 mL) was carefully added to the reaction
mixture followed by the dropwise addition of NaOH (15%, 2 mL).
The mixture was allowed to stir for 20 min, and the supernatant
was removed. The solid material was washed with hot THF (5 ×
30 mL). Solvent was removed from the combined supernatant
fractions and washings under reduced pressure. The residue was
purified by column chromatography (silica gel, 20 g) using CH2-
Cl2/MeOH (4:1) to afford the free base of 15 as a white solid (0.44
g, 61%): mp 140-142 °C. Oxalic acid was added to a solution of
the free base in acetone to obtain 15 as a white solid following
recrystallization from acetone: mp 179-181 °C; 1H NMR (DMSO-
d6) δ 2.83-2.95 (m, 4H, CH), 6.96-7.06 (m, 3H, ArH), 7.16-
7.21 (m, 2H, ArH), 7.43-7.50 (m, 2H, ArH), 7.58-7.62 (m, 2H,
ArH). Anal. (C14H16N2O2S‚C2H2O4) C, H, N.
1
°C; H NMR (CDCl3) δ 5.84 (d, J ) 8.4, 1H, CHdCH), 7.12-
7.34 (m, 6H, ArH), 7.46-7.62 (m, 3H, ArH), 7.81 (d, J ) 4.2,
1H, CHdCH).
Raney Ni (0.05 g of 2800 Ni slurry in H2O, 0.9 mmol) was added
to a solution of 26 (0.5 g, 1.8 mmol) in NH3/MeOH (2 M, 20 mL).
The mixture was hydrogenated at ca. 50 psi overnight (12 h), and
the solid material was removed by filtration. Solids were washed
with CH2Cl2 (5 × 10 mL). The combined filtrate and washings
were evaporated to dryness under reduced pressure. The residue
2-(3-Benzenesulfonyl)phenyl-1-aminoethane Hydrochloride