2640 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14
Notes
J ) 6 Hz, 1 H), 3.13 (m, 2 H), 1.7-2.1 (m, 4 H); 13C NMR (D2O/
DCl) δ 174.41, 166.91, 150.37, 132.18, 132.06, 128.00, 110.19,
55.44, 45.03, 30.15, 26.48; MS m/z [M + H]+ 270. Anal.
(C12H17N3O4‚HCl) C, H, N.
7: yield 63%; yellow solid; mp 246-249 °C (water/ethanol);
1H NMR (D2O/NaOD) δ 8.02 (s, 1 H), 7.42 (dd, 5.7 H, J ) 1.5
Hz, 1 H), 6.83 (d, J ) 5.7 Hz, 1 H), 3.29 (m, 2 H), 1.7 (m, 4 H);
13C NMR (D2O/NaOD) δ 185.43, 149.43, 131.93, 126.69, 126.13
(q, J ) 271 Hz), 119.23 (q, J ) 34 Hz), 117.59, 58.72, 45.47,
35.49, 27.58; MS m/z calcd for C12H15N3O4F3 322.1015, found
322.1022. Anal. (C12H14N3O4F3) C, H, N.
8: yield 50%; amorphous yellow powder; mp 253-255 °C dec
(ethanol); Rf 0.25 (6:1:1 acetonitrile/water/acetic acid); 1H NMR
(D2O/NaOD) δ 8.52 (d, J ) 0.6 Hz, 1 H), 7.88 (dd, J ) 5.7, 0.6
Hz, 1 H), 6.89 (d, J ) 5.7 Hz, 1 H), 3.30 (m, 3 H), 1.71 (m, 4
H); 13C NMR (D2O/NaOD) δ 186.13, 176.06, 149.80, 139.62,
132.47, 130.91, 125.68, 116.68, 58.68, 45.41, 35.16, 27.56; MS
m/z [M + H]+ 298. Anal. (C12H15N3O6‚0.8 HCl) C, H, N.
9: yield 46%; mp 240 °C dec (H2O); 1H NMR (DCl/D2O) δ
7.81 (bs, 1 H), 6.72 (d, J ) 9 Hz, 1 H), 6.12 (d, J ) 9 Hz, 1 H),
4.20 (t, J ) 6 Hz, 1 H), 3.13 (m, 2 H), 1.7-2.1 (m, 4 H); 13C
NMR (HCl/D2O) δ 174.41, 166.91, 150.37, 132.18, 132.06,
128.00, 110.19, 55.44, 45.03, 30.15, 26.48; MS [M + H]+ 270.
11: yield 40%; yellow crystals; mp 245-246 °C (acetic acid/
water); 1H NMR (D2O/NaOD) δ 7.33 (dd, J ) 8.4, 5.7 Hz, 1
H), 5.69 (m, 1 H), 5.52 (m, 1 H), 3.52 (s, 3 H), 3.10 (m, 1 H),
2.81 (m, 2 H), 1.45 (m, 4 H); 13C NMR (D2O/NaOD) δ 185.47,
168.65, 150.74, 131.00, 127.20, 108.64, 96.78, 58.48, 45.27,
35.37, 27.37; MS (DCI/NH3) m/z [M + H]+ 284. Anal.
(C12H17N3O5‚0.2H2O) C, H, N.
concentrated in vacuo to a foam. The foam was dissolved in
20 mL of 1:1:1 acetic acid/water/12 M HCl and stirred at 25
°C for 12 h. Concentration in vacuo gave a yellow powder,
which was recrystallized from ethyl acetate/ethanol to give 55
1
mg (15%) of a yellow powder: mp 202-204 °C dec; H NMR
(D2O) δ 8.00 (d, J ) 8.4 Hz, 1 H), 6.82 (s, 1 H), 6.55 (dd, J )
8.4, 0.6 Hz, 1 H), 3.35-3.45 (m, 3 H), 2.33 (s, 3 H), 1.80 (m, 4
H); HRMS (FAB+) calcd for C12H20N3O3 254.1505, found
254.1505. Anal. (C12H19N3O3‚2.8HCl) C, H, N.
19: yield 90%; orange powder; mp 55-56 °C, purified by
sublimation (50 °C, 0.07 mm); Rf 0.66 (6:1:1 acetonitrile/water/
acetic acid); 1H NMR (300 MHz, CD3OD) δ 8.04 (d, J ) 8.4
Hz, 1 H), 6.61 (s, 1 H), 6.43 (dd, J ) 1, 8.4 Hz, 1 H), 3.31 (m,
2 H), 2.8 (t, J ) 7.5 Hz, 2 H), 1.5-1.7 (m, 6 H); 13C NMR (75.5
MHz, CD3OD) δ 147.56, 145.55, 130.30, 126.78, 116.82, 113.28,
42.85, 41.75, 31.11, 26.44, 22.04. Anal. (C11H17N3O2) C, H,
N.
20: To a suspension of 571 mg of potassium hydride (5.0
mmol of a 35% suspension in mineral oil) in 5 mL of THF at
0 °C was added dropwise a solution of 842 mg (5.5 mmol) of
2-nitro-5-methylphenol in 5 mL of THF. After 15 min at 0
°C, a solution of 1.644 g (4.1 mmol) of mesylate 25 in 5 mL of
diethyl ether was added, and the reaction was heated at reflux
for 14 h. The reaction was concentrated in vacuo and purified
by flash chromatography, eluting with ethyl acetate/dichlo-
romethane. The product was dissolved in 25 mL of a 30% (w/
v) solution of HBr in acetic acid. After 5 h at room tempera-
ture, the solvent was removed in vacuo and purified by flash
chromatography, eluting with a 3:1:1 mixture of acetonitrile/
water/acetic acid. Product-containing fractions were combined
and concentrated in vacuo to a white foam, 210 mg (18%): 1H
NMR (CD3OD) δ 7.76 (d, J ) 8.7 Hz, 1 H), 7.11 (d, J ) 0.5 Hz,
1 H), 6.92 (dd, J ) 8.7, 0.5 Hz, 1 H), 4.23 (t, J ) 6.0 Hz, 2 H),
4.05 (t, J ) 7.5 Hz, 1 H), 2.0-2.2 (m, 4 H); 13C NMR (D2O) δ
175.31, 155.23, 151.30, 138.95, 129.06, 124.61, 118.49, 112.10,
71.87, 29.96, 26.97, 24.01; MS (DCI/NH3) [M + H]+ 269. Anal.
(C12H16N2O5‚2.0HBr‚0.2H2O) C, H, N.
21: A mixture of 485 mg (1.21 mmol) of mesylate 25, 206
µL of mercaptoacetic acid, and 400 mg of potassium carbonate
in 3 mL of THF was stirred at 25 °C for 18 h. The mixture
was then treated with 5 mL of THF and 3 mL of 12 M
ammonium hydroxide solution. After 15 min at 25 °C, the
mixture was poured into 80 mL of water and brought to pH 7
with 12 M HCl. The aqueous phase was extracted with
dichloromethane. The organic phase was washed with satu-
rated aqueous NaHCO3, dried over Na2SO4, and concentrated
in vacuo to give a white solid. The white solid mercaptan was
combined with 107 mg (0.69 mmol) of 2-nitro-5-methylfluo-
robenzene and heated at reflux in a mixture of 0.69 mL of 1 N
NaOH and 2 mL of ethanol for 15 min. The mixture was
poured into 80 mL of dichloromethane, washed with 120 mL
of water, dried over Na2SO4, and concentrated in vacuo to a
yellow powder. The yellow powder was dissolved in 5 mL of
1.1 M HBr in acetic acid and stirred at 25 °C for 48 h. Removal
of solvent and purification by flash chromatography, eluting
with 10:5:1:1 ethanol/ether/acetic acid/water, gave a yellow
solid that was recrystallized from water to give 118 mg of a
yellow powder (34%): mp 212-214 °C dec; 1H NMR (DCl/D2O)
δ 8.2 (d, J ) 8.7 Hz, 1 H), 7.37 (s, 1 H), 7.19 (d, J ) 8.7 Hz, 1
H), 4.05 (t, J ) 6.0 Hz, 1 H), 3.30 (t, J ) 7.5 Hz, 2 H), 2.42 (s,
3 H), 2.15 (m, 2 H), 1.7-1.9 (m, 2 H); MS (FAB+) [M + H]+
285. Anal. (C12H16N2O4S‚3.0HBr‚2.0AcOH) C, H, N.
12: yield 38%; yellow amorphous powder; mp 215-220 °C
dec (ethanol/ethyl acetate/hexane); Rf 0.53 (12:1:1 acetonitrile/
1
water/acetic acid); H NMR (300 MHz, D2O) δ 8.0 (d, J ) 7.8
Hz, 2 H), 6.92 (t, J ) 7.8 Hz, 1 H), 4.09 (t, J ) 6.0 Hz, 1 H),
3.08 (m, 2 H), 1.6-2.1 (m, 4 H); MS (DCI/NH3) m/z [M + H]+
299. Anal. (C11H14N4O6‚0.9HCl) C, H, N.
13: yield 30%; red-orange powder; mp 205-207 °C dec
(water); Rf 0.62 (6:1:1 acetonitrile/water/acetic acid); 1H NMR
(300 MHz, D2O/DCl) δ 8.02 (dd, J ) 7.8, 1 Hz, 1 H), 7.76 (dd,
J ) 7.8, 1 Hz, 1 H), 7.11 (t, J ) 7.8 Hz, 1 H), 3.42 (td, J ) 6.6,
0.8 Hz, 2 H), 1.8-2.0 (m, 4 H); 13C NMR (75.5 MHz, D2O/DCl)
δ 178.20, 142.08, 139.04, 138.88, 128.79, 127.57, 125.13, 54.46,
49.66, 28.95, 26.49; MS (FAB+) m/z calcd for C11H15N3O4Cl
288.0751, found 288.0751. Anal. (C11H14N3O4Cl‚0.3HCl) C,
H, N.
14: yield 22%; yellow needles; mp >260 °C dec (2-propanol/
1
acetic acid); H NMR (CD3OD) δ 8.05 (dd, J ) 5.1, 9.0 Hz, 1
H), 6.9 (br s, 1 H), 6.73 (d, J ) 1.2 Hz, 1 H), 6.53 (dd, J ) 1.2,
9.0 Hz, 1 H), 4.21 (t, 6.3 Hz, 1 H), 3.70 (t, J ) 6.3 Hz, 2 H),
3.59 (m, 2 H); 1H NMR (1 M NaOD/D2O) δ 7.58 (d, J ) 8.1 Hz,
1 H), 6.43 (s, 1 H), 6.22 (d, J ) 8.1 Hz, 1 H), 3.30 (t, J ) 4.5
Hz, 1 H), 3.12 (m, 2 H), 1.64 (m, 4 H); MS (DCI/NH3) [M +
H]+ 254. Anal. (C11H15N3O4‚1.0i-PrOH‚0.25AcOH) C, H, N.
15: yield 42%; bright-orange prisms; mp 234-235 °C dec
(water/methanol); Rf 0.24 (12:1:1 acetonitrile/water/acetic acid);
1H NMR (300 MHz, D2O) δ 7.32 (d, J ) 7.8 Hz, 1 H), 6.07 (s,
1 H), 5.88 (d, J ) 7.8 Hz, 1 H), 2.99 (t, J ) 6.0 Hz, 1 H), 2.78
(t, J ) 6.6 Hz, 2 H), 1.1-1.45 (m, 6 H); 13C NMR (75.5 MHz,
D2O) δ 185.73, 151.31, 148.37, 131.02, 119.60, 116.09, 58.83,
45.20, 37.87, 31.19, 25.86; MS (DCI/NH3) m/z [M + H]+ 282.
Anal. (C13H19N3O4) C, H, N.
17: yield 95%; yellow needles; mp 240-243 °C dec (hydro-
chloride salt); 1H NMR (300 MHz, D2O/DCl) δ 8.11 (d, J ) 9.3
Hz, 1 H), 7.12 (s, 1 H), 6.95 (d, J ) 9.3 Hz, 1 H), 4.20 (t, J )
6.6 Hz, 1 H), 3.55 (t, J ) 7.5 Hz, 2 H), 1.7-2.2 (m, 4 H); MS
(DCI/NH3) [M + H]+ 268. Anal. (C12H17N3O4‚0.5HCl) C, H,
N.
18: A solution of 384 mg (1.05 mmol) of N-Boc-protected
10 in 4 mL of THF was cooled to 0 °C, and 1.3 mL of 1 M
solution of borane in THF was added dropwise over 2 min.
After 1 h, 1.3 mL more of borane-THF was added. After 1 h,
4 mL of methanol was added, and the mixture was poured
into 125 mL of dichloromethane. The organic phase was
washed with 125 mL of water, dried over MgSO4, and
22: To a solution of 621 mg (1.55 mmol) of mesylate 25 in
5 mL of THF were added 432 µL of triethylamine and 369 µL
of m-thiocresol. After 12 h, the reaction was concentrated in
vacuo and purified by flash chromatography, eluting with 2:1
hexane/ethyl acetate to give 351 mg of a thick oil; 200 mg of
the oil was treated with 1.6 M HBr in acetic acid for 30 min.
The reaction was diluted with ether, and the precipitated solid
was collected by filtration and triturated with hot ethanol to
give 46 mg (41%) of the target compound. A portion was
purified by ion exchange on Dowex 50W (H+ form), eluting
with 1 N ammonium hydroxide to give a solid: mp 263-264
°C dec; 1H NMR (1 M NaOD/D2O) δ 6.5-7 (m, 3 H) 6.74 (m, 1