4548
K. R. A. Abdellatif et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4544–4549
14. Abdellatif, K. R. A.; Dong, Y.; Chen, Q.-H.; Chowdhury, M. A.; Knaus, E. E. Bioorg.
Med. Chem. 2007, 15, 6796.
15. Abdellatif, K. R. A.; Chowdhury, M. A.; Dong, Y.; Chen, Q.-H.; Knaus, E. E. Bioorg.
Med. Chem. 2008, 16, 3302.
16. Abdellatif, K. R. A.; Chowdhury, M. A.; Dong, Y.; Knaus, E. E. Bioorg. Med. Chem.
2008, 16, 6528.
SO2CH3), 6.63 (s, 1H, pyrazole H-4), 6.92 (d, J = 8.5 Hz, 2H, hydroxylaminophenyl
H-3, H-5), 7.01 (d, J = 8.5 Hz, 2H, hydroxylaminophenyl H-2, H-6); 7.28 (br m,
2H, NH, OH, exchangeable with D2O), 7.47 (d, J = 8.5 Hz, 2H,
methanesulfonylphenyl
H-2,
H-6),
7.84
(d,
J = 8.5 Hz,
2H,
methanesulfonylphenyl H-3, H-5); MS m/z (ES+) 397.9, C17H15F3N3O3S (M+H)
requires 398.37.
17. Preussmann, R.; Stewart, B. W. Chemical Carcinogens; American Chemical
Society: Washington DC, 1984. pp 643–868.
18. Chowdhury, M. A.; Abdellatif, K. R. A.; Dong, Y.; Knaus, E. E. Bioorg. Med. Chem.
2008, 16, 8882.
19. Abdellatif, K. R. A.; Chowdhury, M. A.; Knaus, E. E. J. Heterocycl. Chem. 2008, 45,
1707.
5-[4-(N-Hydroxylamino)phenyl]-1-(4-sulfamoylphenyl)-3-trifluoromethyl-1H-
pyrazole (12b): the title compound 12b was prepared, using a similar procedure
to that described for the preparation of 12a, using the nitro compound 11b in
place of 11a, in 53% yield as a yellow powder; mp 103–105 °C; IR (film) 3530–
3184 (OH, NH2, NH), 3017 (C–H aromatic), 2923 (C–H aliphatic), 1338, 1161
(SO2) cmÀ1 1H NMR (CDCl3 + DMSO-d6) d 4.78 (br s, 2H, NH2, exchanges with
;
20. Balaban, A. T.; Garfield, R. E.; Lesko, M. J.; Seitz, W. A. Org. Prep. Proced. Int.
1998, 30, 439.
D2O), 6.62 (s, 1H, pyrazole H-4), 6.85 (d, J = 8.5 Hz, 2H, hydroxylaminophenyl H-
3, H-5), 7.00 (d, J = 8.5 Hz, 2H, hydroxylaminophenyl H-2, H-6), 7.01 (br m, 2H,
NH, OH, exchangeable with D2O), 7.36 (d, J = 8.5 Hz, 2H, aminosulfonylphenyl
21. Keefer, L. K.; Christodolou, D.; Dunams, T. M.; Hrabie, J. A.; Maragos, C. M.;
Saavedra, J. E.; Wink, D. A.; Nitrosamines, related N-nitroso compounds
Chemistry and Biochemistry. In A.C.S. Symp. Series No. 553; Loeppky, R. N.,
Michedja, C. J., Eds.; Amer. Chem. Soc: Washington, D.C., 1994; p 136.
22. Hou, Y.; Xie, W.; Janczuk, A. J.; Wang, P. G. J. Org. Chem. 2000, 65, 4333.
23. Garfield, R. E.; Balaban, A. T.; Seitz, W. A.; Klien, D. J.; Lesko, M. J. U.S. Patent
5,698,738 December 16, 1997.
H-2,
H-6),
7.83
(d,
J = 8.5 Hz,
2H,
aminosulfonyl-
phenyl H-3, H-5); MS m/z (ESÀ) 397.1, C16H12F3N4O3S (MÀH) requires 397.36.
5-[4-(O2-Ammonium diazen-1-ium-1,2-diolato)phenyl]-1-(4-methylsulfonylphenyl)-
3- trifluoromethyl-1H-pyrazole (13a): a vigorous stream of gaseous ammonia was
bubbled into a cold solution of the N-hydroxylamino compound 12a (1.91 g,
4.8 mmol) in THF (6 mL) and diethyl ether (50 mL) at 0 °C for 15 min. n-Butyl
nitrite (0.744 g, 7.2 mmol) was added and ammonia gas was bubbled into the
mixture for 1 h. The precipitated ammonium salt 13a was separated by vacuum
filtration and washed with diethyl ether (10 mL) to give 13a as a pale yellow
powder (0.68 g, 32%): mp 130–132 °C; IR (film) 3037 (C–H aromatic), 2927 (C–H
24. Taylor, D. K.; Bytheway, I.; Barton, D. H. R.; Bayse, C. A.; Hall, M. B. J. Org. Chem.
1995, 60, 443.
25. Guengerich, F. P.; MacDonald, T. L. FASEB J. 1990, 4, 2453.
26. Ortiz de Montellano, P. R. Trends Pharmacol. Sci. 1989, 10, 354.
27. Guengerich, F. P. MacDonald, Acc. Chem. Res. 1984, 17, 9.
28. Experimental procedures and spectral data for compounds 11a–b, 12a–b, 13a–b,
14a–b, 16a–b. General: melting points were determined on a Thomas–Hoover
capillary apparatus and are uncorrected. Infrared (IR) spectra were recorded as
aliphatic), 1317, 1153 (SO2), 1239, 1097 (N@N–O) cmÀ1
;
1H NMR
(CDCl3 + DMSO-d6) d 3.24 (s, 3H, SO2CH3), 4.34 (br s, 4H, NH4, exchangeable
with D2O), 6.98 (s, 1H, pyrazole H-4), 7.24 (d, J = 8.6 Hz, 2H, phenyl H-2, H-6),
7.53 (d, J = 8.6 Hz, 2H, methanesulfonylphenyl H-2, H-6), 7.83 (d, J = 8.6 Hz, 2H,
methanesulfonylphenyl H-3, H-5), 7.94 (d, J = 8.6 Hz, 2H, phenyl H-3, H-5); MS
m/z (ES+) 470.8, C17H12F3N4O4SNa2 (M+2Na) requires 471.36.
films on NaCl plates using a Nicolet 550 Series II Magna FT-IR spectrometer. 1
H
NMR and 13C NMR spectra were measured on a Bruker AM-300 spectrometer in
CDCl3, or CDCl3 + DMSO-d6, with TMS as the internal standard. 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 (Micro
Analytical Service Laboratory, Department of Chemistry, University of Alberta).
Compounds 11a–b, 12a–b, 13a–b, 14a–b and 16a–b showed a single spot on
Macherey–Nagel Polygram Sil G/UV254 silica gel plates (0.2 mm) using a low,
medium, and highly polar solvent system, and no residue remained after
combustion, indicating a purity >95%. Silica gel column chromatography was
performed using Merck Silica Gel 60 ASTM (70–230 mesh). All other reagents,
purchased from the Aldrich Chemical Company (Milwaukee, WI), were used
without further purification. 1-(4-Nitrophenyl)-4,4,4-trifluorobutan-1,3-
dione (9),1 4-methylsulfonylphenylhydrazine hydrochloride (10a),32 4-
sulfamoylphenylhydrazine hydrochloride (10b),33 and 1-bromoethyl acetate
(15)34 were prepared according to literature procedures. The in vivo AI assay
was carried out using a protocol approved by the Health Sciences Animal
Welfare Committee at the University of Alberta.
5-[4-(O2-Ammonium diazen-1-ium-1,2-diolato)phenyl]-1-(4-sulfamoylphenyl)-3-
trifluoromethyl-1H-pyrazole (13b): the title compound 13b was prepared, using
a similar procedure to that described for the preparation of 13a, using the
N-hydroxylamino compound 12b in place of 12a, in 68% yield as a pale yellow
powder; mp 115–117 °C; IR (film) 3310, 3176 (NH2), 3057 (C–H aromatic), 2928
(C–H aliphatic), 1338, 1163 (SO2), 1237, 1097 (N@N–O) cmÀ1 1H NMR
;
(CDCl3 + DMSO-d6) d 4.21 (br s, 2H, NH2, exchangeable with D2O), 6.88 (s, 1H,
pyrazole H-4), 7.35 (dd, J = 1.8, 6.7 Hz, 2H, phenyl H-2, H-6), 7.45 (d, J = 8.5 Hz,
2H, aminosulfonylphenyl H-2, H-6), 7.81 (d, J = 8.5 Hz, 2H, aminosulfonyl-
phenyl H-3, H-5), 7.89 (dd, J = 1.8, 6.7 Hz, 2H, phenyl H-3, H-5); MS m/z (ES+)
427.1, C16H12F3N5O4S (M+H) requires 427.35.
5-[4-(O2-Methyl diazen-1-ium-1,2-diolato)phenyl]-1-(4-methylsulfonylphenyl)-3-
trifluoromethyl-1H-pyrazole (14a):
a mixture of the ammonium salt 13a
(0.443 g, 1.0 mmol) and anhydrous Na2CO3 (0.16 g, 1.5 mmol) in anhydrous
MeOH (10 mL) was cooled to 0 °C under a N2 atmosphere. Dimethyl sulfate
(0.19 g, 1.5 mmol) was added drop wise with stirring. The reaction mixture was
maintained at 0 °C for 1 h prior to standing at 25 °C for an additional 24 h. The
solvent was removed in vacuo, and the residue was extracted with CH2Cl2
(3 Â 20 mL). The organic extract was dried (Na2SO4) over sodium sulfate, the
solvent was removed in vacuo, and the residue obtained was purified by silica
gel column chromatography using EtOAc/hexane (2:1, v/v) as eluent to give 14a
as a pale yellow powder (0.255 g, 58%): mp 171–173 °C; IR (film) 3012 (C–H
1-(4-Methylsulfonylphenyl)-5-(4-nitrophenyl)-3-trifluoromethyl-1H-pyrazole (11a):
4-methylsulfonylphenylhydrazine hydrochloride (10a, 0.980 g, 4.4 mmol) was
added to a stirred solution of the dione 9 (0.921 g, 4.0 mmol) in EtOH (50 mL),
and the reaction was allowed to proceed at reflux for 20 h. After cooling to 25 °C,
the solvent was removed in vacuo. The residue was dissolved in EtOAc (25 mL),
washed with water and then brine, the EtOAc fraction was dried (Na2SO4),
filtered, and the solvent was removed in vacuo to furnish 11a (0.91 g, 56%) as a
pale yellow powder; mp 203–204 °C; IR (film) 3014 (C–H aromatic), 2932 (C–H
aromatic), 2927 (C–H aliphatic), 1319, 1154 (SO2), 1238, 1097 (N@N–O) cmÀ1
;
1H NMR (CDCl3) d 3.09 (s, 3H, SO2CH3), 4.27 (s, 3H, OCH3), 6.89 (s, 1H, pyrazole
H-4), 7.36 (d, J = 9.2 Hz, 2H, phenyl H-2, H-6), 7.53 (dd, J = 1.8, 6.7 Hz, 2H,
methanesulfonylphenyl H-2, H-6), 7.99 (d, J = 9.2 Hz, 2H, phenyl H-3, H-5), 8.06
(dd, J = 1.8, 6.7 Hz, 2H, methanesulfonylphenyl H-3, H-5); 13C NMR (CDCl3) d
44.4, 62.2, 107.4, 120.7, 122.0, 125.8 128.8, 129.4, 131.4, 140.5, 142.9, 143.3,
143.5, 144.3; MS m/z (ES+) 441.1, C18H16F3N4O4S (M+H) requires 441.40. Anal.
Calcd for C18H15F3N4O4S: C, 49.09; H, 3.43. Found: C, 49.51; H, 3.52.
aliphatic), 1514, 1347 (NO2), 1319, 1159 (SO2) cmÀ1 1H NMR (CDCl3) d 3.09 (s,
;
3H, SO2CH3), 6.93 (s, 1H, pyrazole H-4), 7.45 (dd, J = 1.8, 6.7 Hz, 2H,
methanesulfonylphenyl H-2, H-6), 7.53 (d, J = 8.5 Hz, 2H, nitrophenyl H-2, H-
6); 8.00 (dd, J = 1.8, 6.7 Hz, 2H, methanesulfonylphenyl H-3, H-5), 8.27 (d,
J = 8.5 Hz, 2H, nitrophenyl H-3, H-5); 13C NMR (CDCl3) d 44.4, 107.9, 120.8,
124.4, 125.8, 128.9, 129.7, 134.6, 140.8, 142.7, 144.5, 145.0, 148.2; MS m/z (ESÀ)
410.9, C17H11F3N3O4S (MÀH) requires 410.36.
5-[4-(O2-Methyl diazen-1-ium-1,2-diolato)phenyl]-1-(4-sulfamoylphenyl)-3-
trifluoromethyl-1H-pyrazole (14b): the title compound 14b was prepared,
using a similar procedure to that described for the preparation of 14a, using the
ammonium salt 13b in place of 13a, in 65% yield as a pale yellow powder; mp
88–90 °C; IR (film) 3346, 3250 (NH2), 3014 (C–H aromatic), 2949 (C–H
5-(4-Nitrophenyl)-1-(4-sulfamoylphenyl)-3-trifluoromethyl-1H-pyrazole (11b):
The title compound 11b was synthesized, using a similar procedure to that
described for the preparation of 11a, using 4-sulfamoylphenylhydrazine
hydrochloride (10b) in place of 10a, in 72% yield as a pale brown powder; mp
169–172 °C; IR (film) 3235, 3183 (NH2), 3017 (C–H aromatic), 2917 (C–H
aliphatic), 1340, 1164 (SO2), 1238, 1098 (N@N–O) cmÀ1 1H NMR (CDCl3) d
;
aliphatic), 1521, 1346 (NO2), 1324, 1163 (SO2) cmÀ1
;
1H NMR (CDCl3) d 4.87 (br
4.27 (s, 3H, OCH3), 4.91 (br s, 2H, NH2, exchangeable with D2O), 6.88 (s, 1H,
pyrazole H-4), 7.37 (d, J = 9.2 Hz, 2H, phenyl H-2, H-6), 7.49 (d, J = 9.2 Hz, 2H,
aminosulfonylphenyl H-2, H-6), 7.96 (d, J = 9.2 Hz, 2H, aminosulfonylphenyl H-
3, H-5), 8.05 (d, J = 9.2 Hz, 2H, phenyl H-3, H-5); 13C NMR (CDCl3) d 62.2, 107.2,
120.6, 120.8, 125.6, 127.7, 129.5, 131.5, 141.9, 142.1, 143.2, 143.3, 144.1; MS m/
z (ES+) 442.1, C17H15F3N5O4S (M+H) requires 442.39.
s, 2H, NH2, exchangeable with D2O), 6.92 (s, 1H, pyrazole H-4), 7.45 (d, J = 8.5 Hz,
2H, aminosulfonylphenyl H-2, H-6), 7.48 (d, J = 8.5 Hz, 2H, nitrophenyl H-2, H-
6); 7.99 (d, J = 8.5 Hz, 2H, aminosulfonylphenyl H-3, H-5), 8.28 (d, J = 8.5 Hz, 2H,
nitrophenyl H-3, H-5); 13C NMR (CDCl3) d 107.7, 120.9, 125.6, 126.5, 127.9,
129.7, 134.6, 141.7, 142.2, 142.6, 144.3, 148.1; MS m/z (ESÀ) 411.9,
C16H10F3N4O4S (MÀH) requires 411.34.
5-[4-(O2-(1-Acetoxyethy) diazen-1-ium-1,2-diolato)phenyl]-1-(4-methylsulfonyl-
phenyl)-3-trifluoromethyl-1H-pyrazole (16a): freshly distilled 1-bromoethyl
5-[4-(N-Hydroxylamino)phenyl]-1-(4-methylsulfonylphenyl)-3-trifluoromethyl-
1H-pyrazole (12a): zinc powder (0.183 g, 2.8 mmol) and ammonium chloride
(0.15 g, 2.8 mmol) were added to a solution of the nitro compound 11a (0.582 g,
1.4 mmol) in methanol/water (4:1 v/v, 10 mL), and the reaction was allowed to
proceed at reflux for 90 min with stirring. After cooling to 25 °C, the mixture
was filtered using suction, the solvent from the filtrate was removed in vacuo,
and the residue was extracted with EtOAc (3 Â 20 mL). The combined extracts
were 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 to give 12a as a yellow powder (0.30 g, 53%): mp 172–174 °C;
IR (film) 3533–3350 (OH), 3335–3183 (NH), 3011 (C–H aromatic), 2925 (C–H
acetate (15, 0.184 g, 1.1 mmol) was added to
a mixture of 13a (0.443 g,
1 mmol) and potassium carbonate (0.138 g, 1 mmol) in acetonitrile (10 mL) at
25 °C with stirring. The reaction was allowed to proceed at 25 °C for 18 h with
stirring, insoluble inorganic salts were removed by filtration, and the solvent
was removed in vacuo. Dichloromethane (20 mL) was added to the residue and
once again, the insoluble inorganic salts were removed by filtration. Removal of
the solvent in vacuo gave a residue that was purified by silica gel column
chromatography using EtOAc/hexane (1:1, v/v) as eluent to give 16a as a yellow
powder (0.19 g, 37%): mp 92–94 °C; IR (film) 3012 (C–H aromatic), 2929 (C–H
aliphatic), 1760 (COO), 1320, 1155 (SO2), 1243, 1098 (N@N–O) cmÀ1
;
1H NMR
aliphatic), 1319, 1150 (SO2) cmÀ1 1H NMR (CDCl3 + DMSO-d6) d 3.00 (s, 3H,
;
(CDCl3) d 1.72 (d, J = 5.5 Hz, 3H, CHCH3), 2.13 (s, 3H, COCH3), 3.10 (s, 3H,