3306
K. R. A. Abdellatif et al. / Bioorg. Med. Chem. 16 (2008) 3302–3308
where J (coupling constant) values are estimated in
Hertz (Hz). Mass spectra (MS) were recorded on a
Water’s Micromass ZQ 4000 mass spectrometer using
the ESI ionization mode. Microanalyses were performed
for C, H, N by the Microanalytical Service Laboratory,
Department of Chemistry, University of Alberta. Silica
gel column chromatography was performed using
Merck silica gel 60 ASTM (70–230 mesh). All other re-
agents, purchased from the Aldrich Chemical Company
(Milwaukee, WI), were used without further purification.
The (E)-3-(4-methanesulfonylphenyl)-2-(phenyl)acrylic
acids (8a–d, R = 4-H, 4-OMe, 4-F, 4-Br),12 O2-acetoxy-
methyl-1-[N-(2-methylsulfonyloxyethyl)-N-methylamino]-
diazen-1-ium-1,2-diolate (9),26 2-bromoethylnitrate (10)22,
O2-sodium 1-[N-(2-hydroxyethyl)-N-methylamino]diazen-
1-ium-1,2-diolate (13),26 and glycerol trinitrate (14)27 were
prepared according to literature procedures. Nitric oxide
gas was purchased from BOC Scientific (Burlington,
Ontario).
3H, COCH3), 3.01 (s, 3H, NCH3), 3.03 (s, 3H,
CH3SO2), 3.74 (t, J = 5.2 Hz, 2H, CH2N), 3.85 (s, 3H,
OCH3), 4.42 (t, J = 5.2 Hz, 2H, CO2CH2), 5.76 (s, 2H,
OCH2O), 6.91 (dd, J = 7.1, 2.0 Hz, 2H, 4-methoxyphenyl
H-3, H-5), 7.11 (dd, J = 7.1, 2.0 Hz, 2H, 4-methoxy-
phenyl H-2, H-6), 7.27 (d, J = 8.2 Hz, 2H, 4-metha-
nesulfonylphenyl H-2, H-6), 7.75 (d, J = 8.2 Hz, 2H, 4-
methanesulfonylphenyl H-3, H-5), 7.80 (s, 1H, H-3);
MS 543.93 (M+Na). Anal. Calcd for C23H27N3O9S: C,
51.58; H, 5.38; N, 7.85. Found: C, 51.84; H, 5.82; N,
7.84.
5.1.3. O2-Acetoxymethyl-1-(N-ethyl-N- methylamino)dia-
zen-1-ium-1,2-diolate (E)-2-(4-fluorophenyl)-3-(4-metha-
nesulfonylphenyl)acrylate (11c). Yield, 36%; yellow
gum; IR (film) 2965 (C–H aromatic), 2927 (C–H ali-
phatic), 1735, 1717 (CO2), 1307, 1148 (SO2), 1220,
1025 (N@N–O) cmÀ1 1H NMR (CDCl3) d 2.10 (s,
;
3H, COCH3), 3.02 (s, 3H, NCH3), 3.08 (s, 3H,
CH3SO2), 3.72 (t, J = 5.2 Hz, 2H, CH2N), 4.45 (t,
J = 5.2 Hz, 2H. CO2CH2), 5.78 (s, 2H, OCH2O), 7.01–
7.17 (m, 4H, fluorophenyl hydrogens), 7.22 (d,
J = 8.2 Hz, 2H, 4-methanesulfonylphenyl H-2, H-6),
7.76 (d, J = 8.2 Hz, 2H, 4-methanesulfonylphenyl H-3,
H-5), 7.91 (s, 1H, H-3); MS 531.90 (M+Na). Anal.
Calcd for C22H24FN3O8S: C, 51.86; H, 4.75; N, 8.25.
Found: C, 51.96; H, 5.01; N, 7.95.
5.1. General method for preparation of the O2-acetoxy-
methyl-1-(N-ethyl-N-methylamino)diazen-1-ium-1,2-dio-
late acrylate esters (11a–d)
Sodium carboxylates of the respective acrylic acids 8a–d
(R = H, OMe, F, Br) were prepared in situ by stirring
each acid (2.5 mmol) in a suspension of sodium carbon-
ate (0.27 g, 2.5 mmol) and HMPA (3.5 mL) for 19 h at
25 ꢁC. A solution of O2-acetoxymethyl-1-[N-(2-meth-
ylsulfonyloxyethyl)-N-methylamino]diazen-1-ium-1,2-
diolate (9, 2.5 mmol) in HMPA (1.5 mL) was then
added, and the reaction was allowed to proceed for
72 h at 25 ꢁC. EtOAc (30 mL) was added, the mixture
was washed with water (5 · 15 mL), the organic phase
was dried (Na2SO4), and the solvent was removed in va-
cuo. The residue obtained was purified by silica gel col-
umn chromatography using EtOAc/hexane (2:1, v/v) as
the eluent. Physical and spectral data for 11a–d are listed
below.
5.1.4. O2-Acetoxymethyl-1-(N-ethyl-N-methylamino)dia-
zen-1-ium-1,2-diolate (E)-2-(4-bromophenyl)-3-(4-metha-
nesulfonylphenyl)acrylate (11d). Yield, 39%; yellow gum;
IR (film) 2965 (C–H aromatic), 2927 (C–H aliphatic),
1754, 1715 (CO2), 1304, 1152 (SO2), 1239, 1073
(N@N–O) cmÀ1 1H NMR (CDCl3) d 2.10 (s, 3H,
;
COCH3), 3.01 (s, 3H, NCH3), 3.04 (s, 3H, CH3SO2),
3.73 (t, J = 5.2 Hz, 2H, CH2N), 4.42 (t, J = 5.2 Hz,
2H, CO2CH2), 5.76 (s, 2H, OCH2O), 7.08 (d,
J = 8.2 Hz, 2H, 4-bromophenyl H-3, H-5), 7.26 (d,
J = 8.5 Hz, 2H, 4-methanesulfonylphenyl H-2, H-6),
7.52 (d, J = 8.2 Hz, 2H, 4-bromophenyl H-2, H-6),
7.77 (d, J = 8.5 Hz, 2H, 4-methanesulfonylphenyl H-3,
H-5), 7.80 (s, 1H, H-3); MS 591.83 (M+Na). Anal.
Calcd for C22H24BrN3O8S: C, 46.32; H, 4.24; N, 7.37.
Found: C, 46.79; H, 4.53; N, 7.23.
5.1.1. O2-Acetoxymethyl-1-(N-ethyl-N- methylamino)dia-
zen-1-ium-1,2-diolate (E)-3-(4-methanesulfonylphenyl)-2-
phenylacrylate (11a). Yield, 48%; white powder; mp
94–96 ꢁC; IR (film) 2972 (C–H aromatic), 2930 (C–H
aliphatic), 1753, 1709 (CO2), 1369, 1151 (SO2), 1237,
1065 (N@N–O) cmÀ1
;
1H NMR (CDCl3) d 2.10 (s,
5.2. General method for preparation of the 2-nitrooxy-
ethyl acrylate esters (12a–d)
3H, COCH3), 2.94 (s, 3H, NCH3), 3.01 (s, 3H,
CH3SO2), 3.72 (t, J = 5.2 Hz, 2H, CH2N), 4.40 (t,
J = 5.2 Hz, 2H, CO2CH2), 5.76 (s, 2H, OCH2O), 7.17–
7.27 (m, 3H, phenyl, H-3, H-4, H-5), 7.30 (d,
J = 8.3 Hz, 2H, 4-methanesulfonylphenyl H-2, H-6),
7.39–7.41 (m, 2H, phenyl H-2, H-6), 7.75 (d,
J = 8.3 Hz, 2H, 4-methanesulfonylphenyl H-3, H-5),
7.85 (s, 1H, H-3); MS 513.90 (M+Na). Anal. Calcd for
C22H25N3O8S: C, 53.76; H, 5.13; N, 8.55. Found: C,
53.67; H, 5.23; N, 8.43.
A solution of 2-nitrooxyethyl bromide (10, 0.22 mmol),
the respective acrylic acid (8a–d, 0.2 mmol), and K2CO3
(0.24 mmol) in dry DMF (10 mL) was stirred at 25 ꢁC
for 36 h. Water (40 mL) was added, the mixture was ex-
tracted with EtOAc (3 · 300 mL), the extract was
washed with water (2 · 40 mL) and then brine
(40 mL), the organic phase was dried (Na2SO4), and
the solvent was removed in vacuo. The residue obtained
was purified by silica gel column chromatography using
EtOAc–hexane (1:1, v/v) as eluent. Physical and spectral
data for 12a–d are listed below.
5.1.2. O2-Acetoxymethyl-1-(N-ethyl-N- methylamino)dia-
zen-1-ium-1,2-diolate (E)-3-(4-methanesulfonylphenyl)-2-
(4-methoxyphenyl)acrylate (11b). Yield, 32%; yellow
gum; IR (film) 2970 (C–H aromatic), 2927 (C–H ali-
phatic), 1733, 1712 (CO2), 1372, 1154 (SO2), 1254,
5.2.1. 2-Nitrooxyethyl (E)-3-(4-methanesulfonylphenyl)-
2-phenylacrylate (12a). Yield, 94%; white powder; mp
102–104 ꢁC; IR (film) 2963 (C–H aromatic), 2926 (C–
1069 (N@N–O) cmÀ1 1H NMR (CDCl3) d 2.10 (s,
;