2866 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 15
Collins et al.
N-(3-Br om oph en yl)acetam idin e‚HCl (55): prepared from
3-bromoaniline using thioimidate 21a ‚HCl. Recrystallization
from MeOH/Et2O gave 800 mg of a solid. The solid was
dissolved in Et2O/saturated NaHCO3, and the aqueous layer
was extracted with Et2O. The combined organics were dried
(Na2SO4), filtered, and concentrated in vacuo. The residue was
treated with Et2O and a small amount of HCl/ethanol. The
resulting white solid was collected to give 778 mg (54%) of title
with MeOH/Et2O provided 1.9 g (90%) of title compound as a
white solid; mp 115-118 °C; 1H NMR (D2O, 300 MHz) δ 7.25
(dt, 1 H, J ) 8.0, 2.1), 6.81 (d, 1 H, J ) 8.0), 6.73 (d, 1 H, J )
8.0), 6.66 (br s, 1 H), 2.24 (s, 3 H); low-resolution MS (CI) 151
(MH+). Anal. (C8H10N2O‚HBr‚0.35H2O) C, H, N, Br.
N-(3-Acetylp h en yl)a ceta m id in e‚HCl (62): prepared from
3-aminoacetophenone using thioimidate 21a ‚HCl. Recrystal-
lization from MeOH/Et2O gave 1.16 g of a white solid. The
solid was dissolved in Et2O/saturated NaHCO3, and the
aqueous layer was extracted with Et2O. The combined organ-
ics were dried (Na2SO4), filtered, and concentrated in vacuo.
The residue was dissolved in Et2O and treated with a small
amount of HCl/ethanol. The resulting white solid was col-
lected to give 325 mg (21%) of title compound: mp 204-206
°C; 1H NMR (D2O, 300 MHz) δ 7.94 (d, 1 H, J ) 7.8), 7.77 (br
s, 1 H), 7.55 (t, 1 H, J ) 7.8), 7.46 (br d, 1 H, J ) 7.8), 2.52 (s,
3 H), 2.29 (s, 3 H); low-resolution MS (CI) 177 (MH+). Anal.
(C10H12N2O‚HCl) C, H, N, Cl.
3-(Acetim idoylam in o)ben zam ide‚HCl (64): prepared from
3-aminobenzamide and thioimidate 21a ‚HCl; recrystallization
from MeOH/Et2O provided 1.1 g (70%) of title compound as a
white solid; mp 290-292 °C; 1H NMR (D2O, 300 MHz) δ 7.74
(d, 2 H, J ) 7.8), 7.62 (s, 1 H), 7.53 (t, 1 H, J ) 7.8), 7.43 (d,
1 H, J ) 7.8), 2.29 (s, 3 H); low-resolution MS (CI) 178 (MH+).
Anal. (C9H12N3O‚HCl) C, H, N.
3-(Acetim id oyla m in o)ben za m id in e‚HCl (69): prepared
from 3-aminobenzamidine‚2HCl, 21a ‚HCl, and Et3N (1 equiv);
recrystallization from MeOH/Et2O gave 1.48 g (82%) of title
compound as an off-white solid; mp 263-265 °C; 1H NMR
(D2O, 300 MHz) δ 7.80-7.60 (m, 4 H), 2.29 (s, 3 H); low-
resolution MS (CI) 177 (MH+). Anal. (C9H12N4‚2HCl‚0.45NH4-
Cl) C, H, N, Cl.
1
compound: mp 208-210 °C; H NMR (D2O, 300 MHz) δ 7.51
(d, 1 H, J ) 7.5), 7.43 (br s), 7.31 (t, 1 H, J ) 8.0), 7.18 (d, 1
H, J ) 7.5), 2.26 (s, 3 H); low-resolution MS (CI) 213 (M+),
215 (M+). Anal. (C8H9BrN2‚HCl) C, H, N.
N-(3-Nitr op h en yl)a ceta m id in e‚HCl (56): prepared from
3-nitroaniline using thioimidate 21a ‚HCl. Recrystallization
from MeOH/Et2O gave 513 mg of a solid. The solid was
dissolved in CH2Cl2/saturated NaHCO3, and the aqueous layer
was extracted with CH2Cl2. The combined organics were dried
(Na2SO4), filtered, and concentrated in vacuo. The residue was
dissolved in 2-propanol and treated with a small amount of
HCl/ethanol. Et2O was added, and the resulting white solid
was collected to give 310 mg (20%) of title compound: mp 226-
1
228 °C; H NMR (D2O, 300 MHz) δ 8.24-8.16 (m, 1 H), 8.12
(br s, 1 H), 7.70-7.58 (m, 2 H), 2.31 (s, 3 H); low-resolution
MS (CI) 180 (MH+). Anal. (C8H9N3O2‚HCl) C, H, N, Cl.
N-(3-Cya n op h en yl)a ceta m id in e‚HCl (57): prepared from
3-aminobenzonitrile using thioimidate 21a ‚HCl. Recrystalli-
zation from MeOH/Et2O gave 814 mg of a solid. The solid was
dissolved in Et2O/saturated NaHCO3, and the aqueous layer
was extracted with Et2O. The combined organics were dried
(Na2SO4), filtered, and concentrated in vacuo. The residue was
dissolved in Et2O and treated with a small amount of HCl/
ethanol. The resulting white solid was collected to give 576
1
mg (35%) of title compound: mp 228-230 °C; H NMR (D2O,
N,N′-(1,3-P h en ylen e)d ia cet a m id in e‚2H Br (70): pre-
pared from 1,3-phenylenediamine using 2 equiv of thioimidate
21b‚HBr; recrystallization from MeOH/EtOAc gave 1.55 g
(53%) of title compound as an off-white solid; mp 256-258 °C;
1H NMR (D2O, 300 MHz) δ 7.56 (t, 1 H, J ) 8.4), 7.36-7.27
(m, 2 H), 7.23 (br s, 1 H), 2.28 (s, 3 H); low-resolution MS (CI)
191 (MH+). Anal. (C10H14N4‚2HBr‚0.5H2O) C, H, N, Br.
N-(4-(Am in om eth yl)p h en yl)a ceta m id in e‚2HBr (33). A
solution of 4-nitrobenzylamine‚HCl (1.15 g, 6.1 mmol) in 76
mL of THF at 25 °C was treated with 38 mL of saturated
NaHCO3 solution followed by BOC2O (1.33 g, 6.1 mmol). After
stirring overnight, the reaction was diluted with H2O, and the
product was extracted with Et2O. The combined organic layers
were dried (MgSO4), filtered, and concentrated in vacuo. The
residue was dissolved in 50 mL of EtOAc and treated with
10% palladium on carbon (150 mg). The reaction was placed
on a Parr shaker under hydrogen atmosphere overnight and
then filtered through a pad of Celite washing with EtOAc. The
filtrate was concentrated in vacuo. The residue was dissolved
in 23 mL of EtOH and treated with thioimidate 21b‚HBr (1.81
g, 6.1 mmol). After stirring overnight the reaction was
concentrated in vacuo, diluted with 10 mL of 1,4-dioxane, and
treated with 1.2 mL of 48% HBr in AcOH. After the mixture
stirred for 5 min Et2O was added, and a solid was collected.
Recrystallization from MeOH/EtOAc provided 1.2 g (61%) of
title compound as a white solid; mp 256-258 °C; 1H NMR
(D2O, 300 MHz) δ 7.46 (d, 2 H, J ) 8.4), 7.29 (d, 2 H, J ) 8.4),
4.10 (s, 2 H), 2.28 (s, 3 H); low-resolution MS (CI) 164 (MH+).
Anal. (C9H13N3‚2HBr‚H2O) C, H, N, Br.
300 MHz) δ 7.72 (dt, 1 H, J ) 6.0, 1.8), 7.64 (br s, 1 H), 7.62-
7.48 (m, 2 H), 2.28 (s, 3 H); low-resolution MS (CI) 160 (MH+).
Anal. (C9H9N3‚HCl) C, H, N, Cl.
N-(3-(Dim eth yla m in o)p h en yl)a ceta m id in e‚2HBr (58):
prepared from N,N-dimethyl-1,3-phenylenediamine using thio-
imidate 21a ‚HBr. After removal of EtOH, the reaction was
diluted with 10 mL of 1,4-dioxane and treated with 2 mL of
30% HBr/AcOH. After the mixture stirred for 5 min Et2O was
added, and stirring was continued for 30 min. The mixture
was filtered, and the collected solid was recrystallized from
MeOH/EtOAc to give 1.47 g (72%) of title compound as a white
solid: mp 227-230 °C; 1H NMR (D2O, 300 MHz) δ 7.65-7.32
(m, 4 H), 3.15 (s, 6 H), 2.30 (s, 3 H); low-resolution MS (CI)
178 (MH+). Anal. (C10H15N3‚2HBr) C, H, N, Br.
N-(3-(Meth ylth io)p h en yl)a ceta m id in e‚HCl (59): pre-
pared from 3-(methylmercapto)aniline using thioimidate 21a ‚
HCl. Recrystallization from MeOH/Et2O gave 1.11 g of a
purple solid. The resulting solid was dissolved in Et2O/
saturated NaHCO3, and the aqueous layer was extracted with
Et2O. The combined organics were dried (Na2SO4), filtered,
and concentrated in vacuo. The residue was dissolved in Et2O
and treated with a small amount of HCl/ethanol. The result-
ing solid was collected to give 531 mg (34%) of title com-
pound: mp 134-135 °C; 1H NMR (D2O, 300 MHz) δ 7.33 (t, 1
H, J ) 7.8), 7.24 (dd, 1 H, J ) 7.8, 1.5), 7.09 (d, 1 H, J ) 1.5),
6.97 (d, 1 H, J ) 7.8), 2.36 (s, 3 H), 2.25 (s, 3 H); low-resolution
MS (CI) 181 (MH+). Anal. (C9H12N2S‚HCl) C, H, N, Cl, S.
N-(3-Meth oxyp h en yl)a ceta m id in e‚HCl (60): prepared
from 3-methoxyaniline using thioimidate 21b‚HBr. The re-
sulting solid was dissolved in Et2O/saturated NaHCO3, and
the aqueous layer was extracted with CH2Cl2. The combined
organics were dried (Na2SO4), filtered, and concentrated in
vacuo. The residue was dissolved in Et2O and treated with a
small amount of HCl/ethanol. The resulting solid was recrys-
tallized from MeOH/Et2O to give 267 mg (16%) of title
compound: mp 185-188 °C; 1H NMR (D2O, 300 MHz) δ 7.40-
7.20 (m, 1 H), 7.00-6.65 (m, 3 H), 3.70 (s, 3 H), 2.25 (s, 3 H);
low-resolution MS (CI) 165 (MH+). Anal. (C9H12N2O‚HCl) C,
H, N, Cl.
The following compound was prepared in an analogous
manner.
N-(3-(Am in om eth yl)ph en yl)acetam idin e‚2HBr (14): pre-
pared from 3-nitrobenzylamine hydrochloride using thioimi-
date 21b‚HBr; recrystallization from MeOH/EtOAc provided
the title compound as a white solid: 1H NMR (DMSO-d6, 300
MHz) δ 7.60-7.50 (m, 3 H), 7.30 (m, 1 H), 4.03 (s, 2 H), 2.36
(s, 3 H); low-resolution MS (CI) 164 (MH+). Anal. (C9H13N3‚
2HBr) C, H, N, Br.
N-(3-Am in op h en yl)a ceta m id in e‚2HBr (34). A solution
of 3-nitroaniline (10.0 g, 72.4 mmol) in 200 mL of CH2Cl2 at
25 °C was treated sequentially with 10 mL (71.4 mmol) of
Et3N, 17.4 g (72.4 mmol) of BOC2O, and a catalytic amount of
N-(3-Hyd r oxyp h en yl)a ceta m id in e‚HBr (61): prepared
from 3-aminophenol using thioimidate 21a ‚HBr; trituration