M. Wang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 332–336
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phase, 5.0 mL/min flow rate, UV (270 nm) and c-ray
(NaI) flow detectors. Sterile vented Millex-GS 0.22 lm
filter unit was obtained from Millipore Corporation,
Bedford, MA.
temperature overnight. Water was added and the
reaction mixture was neutralized with 5 N HCl until
pH 1–2. The intermediate precipitate was filtered and
washed with water, which was used in the next reaction.
Then the intermediate was suspended in a 50% KOH
solution and heated at reflux for 2 h. After cooling, it
was neutralized with 5 N HCl until pH 6–7. The
precipitated solid was collected and washed with water.
The product was purified by flash column chromatog-
raphy (1:7 EtOAc/hexanes) to afford desired compounds.
N-(2-Propyloxy-4-nitrophenyl)methanesulfonamide (2a).
Yellow solid, 68% yield. Mp: 116–117 ꢁC (lit.3 117–
119 ꢁC). 1H NMR (300 MHz, CDCl3): d 7.92 (dd,
J = 2.2, 8.9 Hz, 1H, H-5), 7.78 (d, J = 2.9 Hz, 1H, H-
3), 7.66 (d, J = 8.9 Hz, 1H, H-6), 7.23 (br, 1H, NH),
4.12 (t, J = 8.6 Hz, 2H, OCH2CH2CH3), 3.11 (s, 3H,
SO2CH3), 1.95–1.88 (m, 2H, OCH2CH2CH3), 1.09 (t,
J = 7.3 Hz, 3H, OCH2CH2CH3).
N-(2-Isopropyloxy-4-nitrophenyl)methanesulfonamide
(2b). Yellow solid, 80% yield. Mp: 131–132 ꢁC (lit.3 128–
131 ꢁC). 1H NMR (300 MHz, CDCl3): d 7.90 (dd,
J = 2.3, 8.9 Hz, 1H, H-5), 7.77 (d, J = 2.2 Hz, 1H, H-
3), 7.65 (d, J = 8.8 Hz, 1H, H-6), 7.25 (br, 1H, NH),
4.81-4.73 (m, 1H, OCH(CH3)2), 3.10 (s, 3H, SO2CH3),
1.45 (s, 3H, OCH(CH3)CH3), 1.43 (s, 3H,
OCH(CH3)CH3).
N-[2-(1-Ethyl-propyloxy-4-nitrophenyl)]methanesulfona-
mide (2c). Yellow solid, 85% yield. Mp: 104–105 ꢁC(lit.3
100–102 ꢁC). 1H NMR (300 MHz, CDCl3): d 7.89 (dd,
J = 2.3, 8.9 Hz, 1H, H-5), 7.76 (d, J = 2.2 Hz, 1H, H-3),
7.66 (d, J = 8.8 Hz, 1H, H-6), 7.27 (br, 1H, NH), 4.41–
4.33 (m, 1H, OCH(CH2CH3)2), 3.10 (s, 3H, SO2CH3),
1.82–1.72 (m, 4H, OCH(CH2CH3)2 ), 0.98 (t, J = 7.4 Hz,
6H, OCH(CH2CH3)2).
N-(2-Cyclopentyloxy-4-nitrophenyl)methanesulfonamide
(2d). Yellow solid, 84% yield. Mp: 149–151 ꢁC (lit.3 139–
140 ꢁC). 1H NMR (300 MHz, CDCl3): d 7.89 (dd,
J = 2.2, 8.8 Hz, 1H, H-5), 7.77 (d, J = 2.9 Hz, 1H, H-
3), 7.64 (d, J = 8.9 Hz, 1H, H-6), 7.16 (br, 1H, NH),
4.97–4.92 (m, 1H, cyclopentyl CH), 3.10 (s, 3H,
SO2CH3), 2.08–2.03 (m, 2H, cyclopentyl), 1.93–1.71
(m, 6H, cyclopentyl).
(b) General procedure for synthesis of compounds 1a–f.
Anhydrous K2CO3 (6.1 g, 44.0 mmol) and alkyl halide
(53.0 mmol, 1.2 equiv) were added to a solution of 2-
amino-5-nitrophenol (6.8 g, 44.0 mmol) in DMF
(40 mL). The mixture was heated at reflux for 4 h to 5
days. After cooling, the reaction mixture was pour into
water and extracted with CH2Cl2 (3· 200 mL). The
organic layer was washed with saturated aqueous
Na2CO3 solution and water, dried over anhydrous
MgSO4, filtered, and concentrated. The crude product
was purified by flash column chromatography (1:5
EtOAc/hexanes) to give desired compounds.
2-Propyloxy-4-nitroaniline (1a).1-Iodopropane was used
and it was refluxed for 5 h. Yellow solid, 87% yield. Mp:
58–59 ꢁC (lit.3 59–61 ꢁC). 1H NMR (300 MHz, CDCl3):
d
7.80 (dd, J = 2.2, 8.9 Hz, 1H, H-5), 7.65 (d,
J = 1.5 Hz, 1H, H-3), 6.64 (d, J = 8.8 Hz, 1H, H-6),
4.55 (br, 2H, NH2), 4.04 (t, J = 6.8 Hz, 2H,
OCH2CH2CH3), 1.91–1.84 (m, 2H, OCH2CH2CH3),
1.07 (t, J = 7.3 Hz, 3H, OCH2CH2CH3).
2-Isopropyloxy-4-nitroaniline (1b). 2-Iodopropane was
used and it was refluxed for 30 h. Yellow oil, 64% yield.
1H NMR (300 MHz, CDCl3):
d
7.77 (dd, J = 2.2,
8.8 Hz, 1H, H-5), 7.65 (d, J = 2.2 Hz, 1H, H-3), 6.67
(d, J = 8.9 Hz, 1H, H-6), 4.68–4.60 (m, 3H, NH2,
OCH(CH3)2), 1.39 (s, 3H, OCH(CH3)CH3), 1.38 (s,
3H, OCH(CH3)CH3).
2-(1-Ethyl-propyloxy)-4-nitroaniline (1c). 3-Bromopen-
tane was used and it was refluxed for 4 days. Yellow
solid, 41% yield. Mp: 59–61 ꢁC (lit.3 62–63 ꢁC). 1H
NMR (300 MHz, CDCl3): d 7.78 (dd, J = 2.3, 8.9 Hz,
1H, H-5), 7.65 (d, J = 1.6 Hz, 1H, H-3), 6.64 (d,
J = 8.1 Hz, 1H, H-6), 4.56 (br, 2H, NH2), 4.30–4.26
(m, 1H, OCH(CH2CH3)2), 1.78–1.69 (m, 4H,
OCH(CH2CH3)2),
OCH(CH2CH3)2).
0.97
(t,
J = 7.1 Hz,
6H,
2-Cyclopentyloxy-4-nitroaniline (1d). Cyclopentyl iodide
was used and it was refluxed for 23 h. Red oil, 40%
yield. 1H NMR (300 MHz, CDCl3): d 7.76 (dd, J = 2.2,
8.1 Hz, 1H, H-5), 7.63 (d, J = 2.2 Hz, 1H, H-3), 6.62 (d,
J = 8.9 Hz, 1H, H-6), 4.87-4.83 (m, 1H, cyclopentyl
CH), 4.59 (br, 2H, NH2), 2.00–1.62 (m, 8H, cyclopen-
tyl).
2-Cyclohexyloxy-4-nitroaniline (1e). Cyclohexyl iodide
was used and it was refluxed for 5 days. Yellow oil,
5% yield. 1H NMR (300 MHz, CDCl3): d 7.76 (dd,
J = 2.2, 8.8 Hz, 1H, H-5), 7.65 (d, J = 2.9 Hz, 1H, H-3),
6.63 (d, J = 8.8 Hz, 1H, H-6), 4.61 (br, 2H, NH2), 4.39–
4.32 (m, 1H, cyclohexyl CH), 2.04–1.98 (m, 2H,
cyclohexyl), 1.81–1.76 (m, 2H, cyclohexyl), 1.62-1.33
(m, 6H, cyclohexyl).
2-Cyclohexylethyloxy-4-nitroaniline (1f). 1-Bromo-2-
cyclohexylethane was used and it was refluxed for 6 h.
Yellow solid, 90% yield. Mp: 60–62 ꢁC. 1H NMR
(300 MHz, CDCl3): d 7.79 (dd, J = 2.2, 8.9 Hz, 1H, H-
5), 7.63 (d, J = 2.2 Hz, 1H, H-3), 6.64 (d, J = 8.8 Hz,
1H, H-6), 4.67 (br, 2H, NH2), 4.09 (t, J = 6.6 Hz, 2H,
OCH2CH2), 1.78–1.65 (m, 8H, cyclohexyl), 1.28–1.46
(m, 3H, cyclohexyl), 1.05–0.97 (m, 2H, OCH2CH2).
(c) General procedure for synthesis of compounds 2a–f.
2-Alkyloxy-4-nitroanilin 1a–f (5.0 mmol) was dissolved
in anhydrous DMF (15 mL) and NaH (420.0 mg,
17.5 mmol, 3.5 equiv) was added. The suspension was
stirred for 20 min, and MsCl (1.7 g, 15.0 mmol, 3 equiv)
was added. The reaction mixture was stirred at room
N-(2-Cyclohexyloxy-4-nitrophenyl)methanesulfonamide
(2e). Yellow solid, 54% yield. Mp: 134–135ꢁC (lit.3 124–
126 ꢁC). 1H NMR (300 MHz, CDCl3): d 7.89 (dd,
J = 2.2, 8.8 Hz, 1H, H-5), 7.77 (d, J = 2.2 Hz, 1H, H-
3), 7.65 (d, J = 8.8 Hz, 1H, H-6), 7.23 (br, 1H, NH),
4.50–4.41 (m, 1H, cyclohexyl CH), 3.10 (s, 3H,
SO2CH3), 2.10–2.05 (m, 2H, cyclohexyl), 1.87–1.80 (m,
2H, cyclohexyl), 1.68–1.31 (m, 6H, cyclohexyl).
N-(2-Cyclohexylethyloxy-4-nitrophenyl)methanesulfona-
mide (2f). Pale yellow solid, 76% yield. Mp: 109–111 ꢁC.
1H NMR (300 MHz, CDCl3):
d 7.91 (dd, J = 2.9,
8.8 Hz, 1H, H-5), 7.77 (d, J = 2.2 Hz, 1H, H-3), 7.65
(d, J = 8.8 Hz, 1H, H-6), 7.22 (br, 1H, NH), 4.12 (t,
J = 7.4 Hz, 2H, OCH2CH2), 3.10 (s, 3H, SO2CH3), 1.81–
1.60 (m, 8H, cyclohexyl), 1.30–1.19 (m, 3H, cyclohexyl),
1.07–1.00 (m, 2H, OCH2CH2). LRMS (CI, m/z): 343
([M+H]+, 100%). HRMS (CI, m/z): calcd for
C15H23O5N2S 343.1322 [M+H]+; found 343.1316.
(d) General procedure for synthesis of compounds 3a–f.
N-(2-Alkyloxy-4-nitrophenyl)methanesulfonamide
2a–f
(1.5 mmol) was dissolved in anhydrous DMF (9 mL)
and NaH (43.0 mg, 1.8 mmol, 1.2 equiv) was added. The
suspension was stirred at room temperature for 10 min
and iodomethane (255.5 mg, 1.8 mmol, 1.2 equiv) was
added. The stirring was continued for 2 h. Then the
mixture was taken up with water (14 mL) and saturated
aqueous Na2CO3 solution (4 mL). The solid was