Hydroxyguanidines as NOS Substrates
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 4 951
methanol and precipitated after the addition of a solution of
anhydrous HCl, HBr, or acetic acid in diethyl ether.
N-(4-Meth oxyp h en yl) N′-Hyd r oxygu a n id in e Hyd r o-
ch lor id e (11). Compound 11 was prepared as a white solid
in 51% yield from (4-methoxyphenyl)cyanamide; mp 128-131
°C. 1H NMR (DMSO-d6): δ 10.64 (br s, 1H), 9.96 (br s, 1H),
9.67 (br s, 1H), 7.67 (br s, 2H), 7.15 (d, 2H, J ) 8.5), 6.98 (d,
2H, J ) 8.5), 3.75 (s, 3H). IR (KBr): 3420, 3320, 830. MS
(FAB): 182.22 (MH+). Anal. (C8H11N3O2, HCl) C, H, N.
N-(3-Am in op h en yl) N′-H yd r oxygu a n id in e Dih yd r o-
br om id e (12). Compound 12 was prepared as a beige solid in
64% yield from 3-(N-tert-butyloxycarbonylamino)phenylcy-
anamide; mp 192-194 °C (dec). 1H NMR (DMSO-d6): δ 10.84
(br s, 1H), 10.03 (br s, 1H), 9.77 (s, 1H), 8.07 (br s, 2H), 7.33
(m, 1H), 6.88 (m, 3H). IR (KBr): 3380, 3200. MS (FAB): 167.2
(MH+). Anal. (C7H10N4O, 2HBr) C, H, N.
Gen er a l P r otocol for Boc or Ter t-bu tyl Ester Dep r o-
tection . A solution of the Boc-protected amine (corresponding
to 12, 13, 18, or 23) or of the tert-butyl ester (corresponding to
20), in dioxane, was treated with anhydrous HCl (4 M) in
dioxane at room temperature for 12 h.
N-P h en yl N′-Hyd r oxygu a n id in e Hyd r och lor id e (1).
Compound 1 was obtained as a beige solid in 63% yield from
phenylcyanamide; mp 128-129 °C. 1H NMR (dimethyl sul-
foxide (DMSO)-d6): δ 10.87 (br s, 1H), 10.01 (br s, 1H), 9.93
(br s, 1H), 7.78 (br s, 2H), 7.42 (m, 2H), 7.23 (m, 3H). IR
(KBr): 3380, 3340, 3200, 765, 700. MS (CI): 152 (MH+). Anal.
(C7H9N3O, HCl) C, H, N.
N-(4-F lu or op h en yl) N′-Hyd r oxygu a n id in e Hyd r och lo-
r id e (2). Compound 2 was prepared as a white solid in 67%
yield from (4-fluorophenyl)cyanamide; mp 131-132 °C. 1H
NMR (DMSO-d6): δ 10.83 (br s, 1H), 10.18 (br s, 1H), 9.87 (br
s, 1H), 7.84 (br s, 2H), 7.25 (m, 4H). IR (KBr): 3380, 3330,
830. MS (EI): 169 (M+). Anal. (C7H8N3OF, HCl) C, H, N.
N-(2-Ch lor op h en yl) N′-Hyd r oxygu a n id in e Hyd r och lo-
r id e (3). Compound 3 was prepared as a colorless oil in 68%
yield from (2-chlorophenyl)cyanamide.49 1H NMR (DMSO-d6):
δ 10.78 (br s, 1H), 10.05 (br s, 1H), 9.72 (br s, 1H), 7.84 (br s,
2H), 7.59 (d, 2H, J ) 8.5), 7.40 (m, 3H). IR (film): 3450, 3120,
760, 730;.MS (CI): 186 and 188 (MH+). HRMS calcd for
C7H8N3O,37 Cl 187.0320 and for C7H8N3O,35 Cl 185.0359; found,
187.0328 and 185.0356.
N-(3-Ch lor op h en yl) N′-Hyd r oxygu a n id in e Hyd r och lo-
r id e (4). Compound 4 was prepared as a white solid in 51%
yield from (3-chlorophenyl)cyanamide; mp 164 °C. 1H NMR
(DMSO-d6): δ 11.06 (br s, 1H), 10.18 (br s, 1H), 10.04 (br s,
1H), 8.06 (br s, 2H), 7.42 (m, 1H), 7.29 (m, 2H), 7.17 (m, 1H).
IR (KBr): 3380, 3240, 3120, 780. MS (CI): 186 and 188 (MH+).
Anal. (C7H8N3OCl, HCl) C, H, N.
N-(4-Ch lor op h en yl) N′-Hyd r oxygu a n id in e (5).47 Com-
pound 5 was obtained as a white solid in 45% yield from (4-
chlorophenyl)cyanamide; mp 129 °C (literature: 129-131
°C).47
N-(4-Am in op h en yl) N′-H yd r oxygu a n id in e Dih yd r o-
ch lor id e (13). Compound 13 was prepared as an off-white
solid in 74% yield from 4-(N-tert-butyloxycarbonylamino)-
1
phenylcyanamide; mp >200 °C (dec). H NMR (DMSO-d6): δ
10.90 (br s, 1H), 10.10 (br s, 1H), 9.94 (br s, 3H), 7.93 (br s,
2H), 7.25 (m, 4H), 4.10 (br s, 3H). IR (KBr): 3320, 3040, 1660,
830. MS (CI): 167 (MH+). Anal. (C7H10N4O, 2HCl, 0.1MeOH)
C, H, N.
N-(4-Nit r op h en yl) N′-Hyd r oxygu a n id in e (14). Com-
pound 14 was prepared as a yellow solid in 42% yield from
1
(4-nitrophenyl)cyanamide;50 mp 174 °C. H NMR (DMSO-d6):
δ 8.80 (br s, 1H), 8.66 (br s, 1H), 8.07 (d, 2H, J ) 9.2), 7.39 (d,
2H, J ) 9.2), 5.34 (br s, 2H). IR (KBr): 3400, 3350, 3050, 830.
MS (CI): 197 (MH+). Anal. (C7H8N4O3) C, H, N.
N-(3-Tr iflu or om eth yl)ph en yl N′-Hydr oxygu an idin e (15).
Compound 15 was prepared as an off-white solid in 43% yield
from (3-trifluoromethyl)phenylcyanamide; mp 92 °C. 1H NMR
(DMSO-d6): δ 8.55 (s, 1H), 8.03 (s, 1H), 7.88 (s, 1H), 7.35 (m,
2H), 7.05 (s, 1H), 5.15 (s, 2H). IR (KBr): 3460, 3350, 850, 760.
MS (CI): 220 (MH+). Anal. (C8H8N3OF3) C, H, N.
N-(4-Tr iflu or om eth yl)ph en yl N′-Hydr oxygu an idin e (16).
Compound 16 was prepared as an off-white solid in 44% yield
from (4-trifluoromethyl)phenylcyanamide; mp 142 °C. 1H NMR
(DMSO-d6): δ 8.56 (br s, 1H), 8.12 (br s, 1H), 7.44 (m, 4H),
5.19 (br s, 2H). IR (KBr): 3510, 3400, 3150, 830. MS (CI): 220
(MH+). Anal. (C8H8N3OF3) C, H, N.
N-(3-Hydr oxym eth ylph en yl) N′-Hydr oxygu an idin e (17).
Compound 17 was prepared as an oil in 68% yield from (3-
hydroxymethyl)phenylcyanamide. 1H NMR (DMSO-d6): δ 8.32
(br s, 1H), 7.51 (br s, 2H), 7.34 (s, 1H), 7.15-7.04 (m, 2H),
6.69 (d, 1H, J ) 7.1), 5.03 (br s, 3H), 4.37 (s, 2H). IR (film):
3400, 2940, 1040, 860, 750. MS (FAB): 181.13 (M+). HRMS
calcd for C8H11N3O2, 181.1292; found, 181.1308.
N-(3-Am in om eth ylp h en yl) N′-Hyd r oxygu a n id in e Di-
h yd r och lor id e (18). Compound 18 was prepared as an oil in
53% yield from 3-(N-tert-butyloxycarbonyl aminomethyl)-
phenylcyanamide. 1H NMR (DMSO-d6): δ 10.94 (br s, 1H),
10.15 (br s, 2H), 8.53 (br s, 3H), 7.98 (br s, 2H), 7.47-7.33 (m,
3H), 7.20 (m, 1H), 4.01 (s, 2H). IR (film): 3470, 3170, 850, 760.
MS (CI): 181 (MH+). HRMS calcd for C8H13N4O, 181.1089;
found, 181.1092.
4-(N-H yd r oxygu a n id in o)p h en yl-a cet ic Acid H yd r o-
ch lor id e (19).51 This compound was obtained as a white solid
in 30% overall yield from 4-aminophenyl-acetic acid as previ-
ously described; mp 160 °C (literature: 160 °C).51
N-(4-Br om op h en yl) N′-Hyd r oxygu a n id in e (6). Com-
pound 6 was obtained as a white solid in 65% yield from (4-
1
bromophenyl)cyanamide; mp 162 °C. H NMR (DMSO-d6): δ
8.54 (s, 1H), 7.83 (s, 1H), 7.33 (m, 4H), 5.14 (br s, 2H). IR
(KBr): 3470, 3340, 820. MS (EI): 231 and 229 (M+). Anal.
(C7H8N3OBr) C, H, N.
N-(4-Tolyl) N′-Hyd r oxygu a n id in e (7). Compound 7 was
prepared as a white solid in 32% yield from 4-tolylcyanamide;
1
mp 140-142 °C. H NMR (CD3OD): δ 7.09 (d, 2H, J ) 8.4),
7.01 (d, 2H, J ) 8.4), 2.24 (s, 3H). IR (KBr): 3470, 3360, 3020,
810. MS (EI): 165 (M+). Anal. (C8H11N3O) C, H, N.
N-(4-Ter t-bu tyl)p h en yl N′-Hyd r oxygu a n id in e (8). Com-
pound 8 was prepared as a white solid in 43% yield from (4-
tert-butylphenyl)cyanamide; mp 128-130 °C. 1H NMR (DMSO-
d6): δ 8.31 (br s, 1H), 7.47 (br s, 1H), 7.26 (m, 4H), 5.05 (br s,
2H), 1.28 (s, 9H). IR (KBr): 3480, 3250, 820. MS (CI): 208
(MH+). Anal. (C11H17N3O) C, H, N.
N-(4-Hyd r oxyp h en yl) N′-Hyd r oxygu a n id in e Hyd r o-
ch lor id e (9). Compound 9 was prepared as a beige solid in
27% yield from (4-hydroxyphenyl)cyanamide; mp 85-88 °C
4-(N-Hyd r oxygu a n id in o)p h en oxy-a cetic Acid Hyd r o-
ch lor id e (20). Treatment of (4-cyanamidinophenoxy)-acetic
acid tert-butyl ester with hydroxylamine hydrochloride under
the general conditions afforded 4-(N-hydroxyguanidinophe-
noxy)-acetic acid tert-butyl ester as an oil in 51% yield. 1H
NMR (DMSO-d6): δ 8.21 (br s, 1H), 7.33 (br s, 1H), 7.20 (d,
2H, J ) 9.0), 6.71 (d, 2H, J ) 9.0), 4.96 (br s, 2H), 4.50 (s,
2H), 1.41 (s, 9H). Treatment of this ester with anhydrous HCl
in dioxane gave 20 as an off-white solid in a quantitative yield;
1
(dec). H NMR (DMSO-d6): δ 10.56 (br s, 1H), 9.92 (br s, 1H),
9.70 (br s, 1H), 9.57 (br s, 1H), 7.61 (br s, 2H), 7.00 (d, 2H, J
) 8.5), 6.82 (d, 2H, J ) 8.5). 13C NMR (D2O): δ 159.62 (CdN),
131.71, 129.22 (CH), 128.47, 119.12 (CH). IR (KBr): 3420,
3340, 3260, 3120, 830. MS (CI): 168 (MH+). HRMS calcd for
C7H9N3O2, 167.0695; found, 167.0700.
N-(2-Meth oxyp h en yl) N′-Hyd r oxygu a n id in e Hyd r o-
ch lor id e (10). Compound 10 was prepared as an off-white
solid in 50% yield from (2-methoxyphenyl)cyanamide; mp 122-
123 °C. 1H NMR (DMSO-d6): δ 10.64 (br s, 1H), 9.97 (br s,
1H), 9.37 (br s, 1H), 7.66 (br s, 2H), 7.33 (t, 1H, J ) 8.5), 7.15
(m, 2H), 6.98 (t, 1H, J ) 8.5), 3.80 (s, 3H). IR (KBr): 3460,
3060, 760. MS (CI): 182 (MH+). Anal. (C8H11N3O2, HCl,
0.2H2O) C, H, N.
1
mp 157 °C. H NMR (DMSO-d6): δ 13.03 (br s, 1H), 10.67 (br
s, 1H), 9.98 (br s, 1H), 9.68 (br s, 1H), 7.14 (d, 2H, J ) 8.9),
6.96 (d, 2H, J ) 8.9), 4.67 (s, 2H). IR (KBr): 3450, 3330, 830.
MS (CI): 226 (MH+). Anal. (C9H11N3O4, HCl) C, H, N.
2-[4-(N-Hydr oxygu an idin o)ph en yl] P r opion ic Acid Hy-
d r och lor id e (21).51 This compound was obtained as white