900
M. Wang et al. / Steroids 74 (2009) 896–905
afford 12 (10.1 g, 72%) as a pale yellow oil, which was used for
next step without further purification. 1H NMR (CDCl3) ı: 7.45 (d,
J = 7.0 Hz, 2H), 7.40 (t, J = 7.0 Hz, 2H), 7.35 (d, J = 7.0 Hz, 1H), 6.94 (d,
J = 8.5 Hz, 2H), 6.86 (d, J = 8.0 Hz, 1H), 5.06 (s, 2H), 4.46 (s, 2H), 1.00
(s, 9H), 0.15 (s, 6H). HRMS (CI, m/z): calculated for C20H28O2BrSi
([M]+) 407.1036; found 407.1029.
To a stirred solution of 20 (125 mg, 0.25 mmol) in THF (1 mL) was
added 1.0 M solution of TBAF in THF (0.8 mL, 0.80 mmol) slowly at
0 ◦C under nitrogen atmosphere. After stirring at room tempera-
ture for 30 min, the reaction mixture was poured into ice-water
and extracted with EtOAc. The combined organic layer was washed
with brine, and dried over anhydrous Na2SO4. The solvent was
evaporated in vacuo, and the crude product was purified by prepar-
ative TLC plate (1:7 MeOH/CHCl3) to give 16 (75.0 mg, 77%) as a
white solid. 1H NMR (DMSO-d6) ı: 9.85 (s, 1H), 8.71 (s, 2H), 7.83 (s,
2H), 7.76 (d, J = 8.0 Hz, 2H), 7.19 (s, 1H), 6.96 (d, J = 7.5 Hz, 1H), 6.85
(d, J = 8.5 Hz, 1H), 6.77 (d, J = 8.5 Hz, 2H), 4.94 (s, 2H). HRMS (TOF
ES+, m/z): calculated for C16H15N6O4S ([M+H]+) 387.0876; found
387.0858.
2.2.18. 4-((4-(Benzyloxy)-3-(tert-butyldimethylsilyloxy)benzyl)
(4H-1,2,4-triazole-4-yl)amino)benzonitrile (13)
A mixture of 5 (3.88 g, 21.0 mmol), 12 (8.50 g, 21.0 mmol) and
K2CO3 (5.79 g, 41.9 mmol) in CH3CN (150 mL) was stirred at room
temperature overnight. The reaction mixture was quenched with
water and extracted with CH2Cl2. The combined organic layer was
washed with brine, and dried over anhydrous Na2SO4. The solvent
was evaporated in vacuo, and the crude product was purified by
column chromatography on silica gel (1:30 MeOH/CH2Cl2) to give
13 (4.97 g, 46%) as a yellow solid, m.p. 137–139 ◦C. 1H NMR (CDCl3)
ı: 8.09 (s, 2H), 7.58 (d, J = 9.0 Hz, 2H), 7.41–7.31 (m, 5H), 6.83 (d,
J = 8.0 Hz, 1H), 6.71–6.66 (m, 4H), 5.01 (s, 2H), 4.77 (s, 2H), 0.91 (s,
9H), 0.03 (s, 6H). HRMS (TOF ES+, m/z): calculated for C29H34N5O2Si
([M+H]+) 512.2482; found 512.2502.
2.2.22. 4-((3-(tert-Butyldimethylsilyloxy)-4-hydroxybenzyl)
(4H-1,2,4-triazol-4-yl)amino)benzonitrile (17) and
4-((4-(tert-butyldimethylsilyloxy)-3-hydroxybenzyl)
(4H-1,2,4-triazol-4-yl)amino)benzonitrile (18)
To a stirred solution of 13 (1.50 g, 2.94 mmol) in EtOH (10 mL)
and THF (12 mL) was added 10% Pd/C (150 mg). The suspension was
stirred under an atmosphere of hydrogen (balloon) at room tem-
perature overnight. The catalyst was removed by filtration through
Celite. The solvent was evaporated in vacuo, and the crude prod-
uct was purified by column chromatography on silica gel (1:30
MeOH/CH2Cl2) to give a mixture of two regioisomers 17 and 18
(750 mg, 61%) as a pale yellow solid. 1H NMR (DMSO-d6) ı: 9.22,
9.13 (s, 1H), 8.66, 8.62 (s, 2H), 7.76, 7.74 (d, J = 9.0 Hz, 2H), 6.78–6.56
(m, 5H), 4.88, 4.86 (s, 2H), 0.93, 0.92 (s, 9H), 0.12, 0.09 (s, 6H). HRMS
(TOF ES+, m/z): calculated for C22H28N5O2Si ([M+H]+) 422.2012;
found 422.2029.
2.2.19. 4-((4-(Benzyloxy)-3-hydroxybenzyl)(4H-1,2,4-triazol-
4-yl)amino)benzonitrile (14)
To a stirred solution of 13 (1.50 g, 2.94 mmol) in THF (20 mL) was
added 1.0 M solution of tetra-n-butylammonium fluoride (TBAF) in
THF(8.81 mL, 8.81 mmol)slowlyat0 ◦Cundernitrogenatmosphere.
After stirring at room temperature for 5 h, the reaction mixture was
poured into ice-water. The precipitate was filtered and the solid was
washed with cold water and Et2O to afford 14 (1.06 g, 91%) as a pink
solid, m.p. 209–211 ◦C. 1H NMR (DMSO-d6) ı: 9.13 (s, 1H), 8.72 (s,
2H), 7.75 (d, J = 9.0 Hz, 2H), 7.45 (d, J = 7.5 Hz, 2H), 7.38 (t, J = 7.5 Hz,
2H), 7.32–7.30 (m, 1H), 6.89 (d, J = 8.5 Hz, 1H), 6.76–6.74 (m, 3H),
6.63 (dd, J = 8.5, 2.0 Hz, 1H), 5.05 (s, 2H), 4.89 (s, 2H). HRMS (TOF ES+,
m/z): calculated for C23H20N5O2 ([M+H]+) 398.1617; found 398.633.
2.2.23. 2-(tert-Butyldimethylsilyloxy)-4-(((4-cyanophenyl)
(4H-1,2,4-triazol-4-yl)amino)methyl)phenyl sulfamate (19) and
2-(tert-butyldimethylsilyloxy)-5-(((4-cyanophenyl)
(4H-1,2,4-triazol-4-yl)amino)methyl)phenyl sulfamate (20)
To a stirred solution of a mixture of two regioisomers 17 and 18
(600 mg, 1.42 mmol) in DMA (5 mL) was added sulfamoyl chloride
(490 mg, 4.27 mmol) at 0 ◦C under nitrogen atmosphere. After stir-
ring at room temperature overnight, the mixture was poured into
ice-water and extracted with EtOAc. The combined organic layer
was washed with brine, and dried over anhydrous Na2SO4. The sol-
vent was evaporated in vacuo, and the crude product was purified
by column chromatography on silica gel (1:10 MeOH/CHCl3) to give
two separated regioisomers 19 (159 mg, 22%) as a white solid and
20 (177 mg, 25%) as a white solid. Compound 19, m.p. 138–140 ◦C.
1H NMR (DMSO-d6) ı: 8.75 (s, 2H), 7.97 (s, 2H), 7.77 (d, J = 9.0 Hz,
2H), 7.31 (d, J = 8.0 Hz, 1H), 6.98 (dd, J = 8.0, 1.5 Hz, 1H), 6.85 (d,
J = 1.5 Hz, 1H), 6.76 (d, J = 9.0 Hz, 2H), 5.03 (s, 2H), 0.94(s, 9H), 0.12 (s,
6H). HRMS (TOF ES+, m/z): calculated for C22H29N6O4SSi ([M+H]+)
501.1740; found 501.1730. Compound 20, m.p. 160–163 ◦C. 1H NMR
(DMSO-d6) ı: 8.81 (s, 2H), 7.96 (s, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.32
(d, J = 2.0 Hz, 1H), 7.05 (dd, J = 8.0, 2.0 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H),
6.77 (d, J = 9.0 Hz, 2H), 4.99 (s, 2H), 0.95(s, 9H), 0.16 (s, 6H). HRMS
(TOF ES+, m/z): calculated for C22H29N6O4SSi ([M+H]+) 501.1740;
found 501.1736.
2.2.20. 2-(Benzyloxy)-5-(((4-cyanophenyl)(4H-1,2,4-triazol-
4-yl)amino)methyl)phenyl sulfamate (15)
To a stirred solution of 14 (600 mg, 1.51 mmol) in DMA (5 mL)
was added sulfamoyl chloride (520 mg, 4.53 mmol) at 0 ◦C under
nitrogen atmosphere. After stirring at room temperature overnight,
the mixture was poured into ice-water and extracted with EtOAc.
The combined organic layer was washed with brine, and dried over
anhydrous Na2SO4. The solvent was evaporated in vacuo, and the
crude product was purified by column chromatography on silica gel
(1:30 MeOH/CHCl3) to give 15 (596 mg, 84%) as a white solid, m.p.
182–184 ◦C. 1H NMR (DMSO-d6) ı: 8.70 (s, 2H), 8.01 (s, 2H), 7.76 (d,
J = 9.0 Hz, 2H), 7.47 (d, J = 7.0 Hz, 2H), 7.38 (t, J = 7.5 Hz, 2H), 7.33–7.30
(m, 2H), 7.12–7.08 (m, 2H), 6.75 (d, J = 8.5 Hz, 2H), 5.15 (s, 2H), 4.99
(s, 2H). HRMS (TOF ES+, m/z): calculated for C23H21N6O4S ([M+H]+)
477.2345; found 477.1366.
2.2.21. 5-(((4-Cyanophenyl)(4H-1,2,4-triazol-
4-yl)amino)methyl)-2-hydroxyphenyl sulfamate (16)
To a stirred solution of 15 (350 mg, 0.74 mmol) in EtOH (5 mL)
and THF (5 mL) was added 10% Pd/C (56 mg). The suspension was
stirred under an atmosphere of hydrogen (balloon) at room tem-
perature overnight. The catalyst was removed by filtration through
Celite. The solvent was evaporated in vacuo, and the crude prod-
uct was purified by column chromatography on silica gel (1:7
MeOH/CH2Cl2) to give 16 (47 mg, 17%) as a white solid, m.p. 149 ◦C
(dec). 1H NMR (DMSO-d6) ı: 9.85 (s, 1H), 8.72 (s, 2H), 7.84 (s,
2H), 7.76 (d, J = 9.0 Hz, 2H), 7.19 (d, J = 2.0 Hz, 1H), 6.97 (dd, J = 8.5,
2.0 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.77 (d, J = 9.0 Hz, 2H), 4.94 (s,
2H). HRMS (TOF ES+, m/z): calculated for C16H15N6O4S ([M+H]+)
387.0876; found 387.0879.
2.2.24. 4-(((4-Cyanophenyl)(4H-1,2,4-triazol-
4-yl)amino)methyl)-2-hydroxyphenyl sulfamate (21)
To a stirred solution of 19 (100 mg, 0.20 mmol) in THF (1 mL)
was added 1.0 M solution of tetra-n-butylammonium fluoride in
THF (0.8 mL, 0.80 mmol) slowly at 0 ◦C under nitrogen atmosphere.
After stirring at room temperature for 1 h, the reaction mixture was
poured into ice-water and extracted with EtOAc. The combined
organic layer was washed with brine, and dried over anhydrous
Na2SO4. The solvent was evaporated in vacuo, and the crude prod-
uct was purified by preparative TLC plate (1:7 MeOH/CHCl3) to give