August 2011
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N-(6-Trifluoromethyl-3-pyridyl)ethanesulfonamide (3): White needles,
mp 101—102 °C. Recrystallization from a mixture of Et2O and hexane. H-
phenoxy)-6- and 5-trifluoromethyl-3-pyridyl]sulfonamides 4
and 5, and revealed their inhibitory activity against sPLA2.
The potency of 4c and 5c increased by 5—7 fold as compar-
ed to the previous series of compounds 2a and 2b.
1
NMR (300 MHz, CDCl3) d: 1.42 (3H, t, Jꢁ7.5 Hz), 3.24 (2H, q, Jꢁ7.5 Hz),
5.99 (1H, bs), 7.67 (1H, d, Jꢁ8.4 Hz), 7.85 (1H, dd, Jꢁ8.4, 2.1 Hz), 8.53
(1H, d, Jꢁ2.1 Hz). IR (KBr) cmꢄ1
: 1321, 1146. Anal. Calcd for
C8H9F3N2O2S: C, 37.79; H, 3.57; N, 11.02. Found: C, 37.73; H, 3.42; N,
10.92.
Experimental
General Melting points were determined on a Yanagimoto micro-melt-
ing point apparatus and were not corrected. H-NMR spectra were recorded
N-[2-(2,4-Difluorophenoxy)-6-trifluoromethyl-3-pyridyl]methanesulfon-
amide (4a): White powder, mp 104—105 °C. Purification by flash chro-
matography on silica gel eluted with 20% EtOAc in hexane. Rfꢁ0.37 (33%
EtOAc in hexane). 1H-NMR(CDCl3) d: 3.16 (3H, s), 6.91—7.01 (2H, m),
7.13 (1H, bs), 7.29 (1H, m), 7.44 (1H, d, Jꢁ8.0 Hz), 8.04 (1H, d, Jꢁ8.0 Hz).
IR (KBr) cmꢄ1: 1331, 1164. Anal. Calcd for C13H9F5N2O3S: C, 42.40; H,
2.46; N, 7.61. Found: C, 42.64; H, 2.45; N, 7.58.
1
on a JEOL JNM-GSX 400 (400 MHz) or JNM-AL 300 (300 MHz) spec-
trometers in CDCl3 with tetramethylsilane as an internal standard. IR spectra
were recorded on JASCO FT/IR-410 instrument. Column chromatography
was carried out using Merck silica gel 60 (70—230 mesh). Mass spectra
were recorded on a JEOL JMS-GCmate spectrometer.
Preparation of 2-(2,4-Difluorophenoxy)pyridine To a solution of 2-
chloropyridine (3.0 mmol) and 2,4-difluorophenol (3.0 mmol) in anhydrous
acetone (20 ml) was added powdered K2CO3 (480 mg, 3.45 mmol). The mix-
ture was stirred for 1—2 h at room temperature and refluxed for 3 h. After
cooling, ice water (50 ml) was added to the reaction mixture and the mixture
was extracted with ether (100 ml). The organic layer was dried over Na2SO4,
and condensed. The crude product was purified by flash chromatography on
silica gel eluted with 10 to 20% EtOAc in hexane to give the aryl ether.
Compound 10 was obtained from 7 in 62% yield. Oil, Rfꢁ0.31 (10%
EtOAc in hexane). 1H-NMR (300 MHz, CDCl3) d: 6.91—7.02 (2H, m),
7.22—7.30 (1H, m), 7.57 (1H, d, Jꢁ8.1 Hz), 8.54 (1H, dd, Jꢁ8.1, 0.73 Hz).
Electron ionization (EI)-MS m/z: 320 (M+), 129, 101, 63. EI-high resolution
(HR)-MS m/z: 320.0212 (Calcd for C12H5F5N2O3: 320.0220).
N-[2-(2,4-Difluorophenoxy)-5-trifluoromethyl-3-pyridyl]methanesulfon-
amide (5a): Pale yellow powder, mp 88—90 °C. Purification by flash chro-
matography on silica gel eluted with 20% EtOAc in hexane. Rfꢁ0.17 (20%
1
EtOAc in hexane). H-NMR (300 MHz, CDCl3) d: 3.16 (3H, s), 6.94—7.03
(3H, m), 7.22 (1H, m), 8.13 (2H, s). IR (KBr) cmꢄ1: 1330, 1139. Anal.
Calcd for C13H9F5N2O3S: C, 42.40; H, 2.46; N, 7.61. Found: C, 42.57; H,
2.48; N, 7.63.
N-[2-(2,4-Difluorophenoxy)-6-trifluoromethyl-3-pyridyl]ethanesulfon-
amide (4b): White powder, mp 89—90 °C. Purification by flash chromatog-
raphy on silica gel eluted with 20% EtOAc in hexane. Rfꢁ0.48 (33% EtOAc
in hexane). 1H-NMR (CDCl3) d: 1.45 (3H, t, Jꢁ7.3 Hz), 3.24 (2H, q,
Jꢁ7.3 Hz), 6.92—7.00 (2H, m), 7.01 (1H, bs), 7.27 (1H, m), 7.41 (1H, d,
Jꢁ8.3 Hz), 8.06 (1H, d, Jꢁ8.3 Hz). IR (KBr) cmꢄ1: 1328, 1162. Anal. Calcd
for C14H11F5N2O3S: C, 43.98; H, 2.90; N, 7.33. Found: C, 44.00; H, 2.96; N,
7.31.
N-[2-(2,4-Difluorophenoxy)-5-trifluoromethyl-3-pyridyl]ethanesulfon-
amide (5b): White powder, mp 75—77 °C. Purification by flash chromatog-
raphy on silica gel eluted with 20% EtOAc in hexane.Rfꢁ0.34 (20% EtOAc
in hexane). 1H-NMR (300 MHz, CDCl3) d: 1.46 (3H, t, Jꢁ7.3 Hz), 3.24
(2H, q, Jꢁ7.3 Hz), 6.95—7.19 (3H, m), 7.24 (1H, m), 8.10 (1H, s), 8.15
(1H, s). IR (KBr) cmꢄ1: 1345, 1138. Anal. Calcd for C14H11F5N2O3S: C,
43.98; H, 2.90; N, 7.33. Found: C, 44.07; H, 3.00; N, 7.27.
Compound 11 was obtained from 8 in 96% yield. Yellow prisms, mp 66—
68 °C. Rfꢁ0.39 (10% EtOAc in hexane). 1H-NMR (300 MHz, CDCl3) d:
6.92—7.03 (2H, m), 7.22 (1H, m), 7.44 (1H, s), 8.57 (1H, s). Anal. Calcd
for C12H5F5N2O3: C, 45.02; H, 1.57; N, 8.75. Found: C, 45.22; H, 1.60; N,
8.62.
Compound 12 was obtained from 9 in 83% yield.18) Pale yellow solid, mp
1
53—54 °C, Rfꢁ0.32 (20% EtOAc in hexane). H-NMR (300 MHz, CDCl3)
d: 6.92—7.01 (2H, m), 7.18—7.29 (2H, m), 8.30—8.43 (2H, m).
Reduction of Nitro Group to Amine To a solution of Na2S2O4 (6.3 g,
36 mmol) in water (60 ml) was added a solution of 2-(2,4-difluorophenoxy)-
3-nitropyridine (2.5 mmol) in THF (15 ml) with dropwise at room tempera-
ture. The reaction mixture was stirred for 2.5 h at the same temperature.
Then, THF (50 ml) was added to the mixture. THF layer was separated and it
was washed with brine and dried over MgSO4. The solvent was removed to
give solid product, which was purified by recrystalization from a mixture of
EtOAc and hexane to give pure amine.
N-[2-(2,4-Difluorophenoxy)-6-trifluoromethyl-3-pyridyl]-2-naphthalene-
sulfonamide (4c): White powder, mp 90—92 °C. Purification by flash chro-
matography on silica gel eluted with 10% EtOAc in hexane. Rfꢁ0.40 (20%
1
EtOAc in hexane). H-NMR (CDCl3) d: 6.83—6.95 (2H, m), 7.01 (1H, m),
7.38 (1H, d, Jꢁ8.0 Hz), 7.62 (1H, bs), 7.66—7.75 (2H, m), 7.90 (1H, dd,
Jꢁ8.6, 1.8 Hz), 7.95 (1H, d, Jꢁ8.0 Hz), 8.00 (1H, s), 8.02 (1H, m), 8.11
(1H, d, Jꢁ8.0 Hz), 8.54 (1H, s). Anal. Calcd for C22H13F5N2O3S: C, 55.00;
H, 2.73; N, 5.83. Found: C, 55.26; H, 2.66; N, 5.76.
Compound 13 was obtained from 10 in 89% yield. White needles, mp
1
78—81 °C. Rfꢁ0.42 (20% EtOAc in hexane). H-NMR (300 MHz, CDCl3)
N-[2-(2,4-Difluorophenoxy)-5-trifluoromethyl-3-pyridyl]-2-naphthalene-
sulfonamide (5c): White powder, mp 44—49 °C. Purification by flash chro-
matography on silica gel eluted with 20% EtOAc in hexane. Rfꢁ0.27 (20%
EtOAc in hexane). 1H-NMR (400 MHz, CDCl3) d: 6.77—6.98 (3H, m), 7.37
(1H, bs), 7.61—7.70 (2H, m), 7.82 (1H, dd, Jꢁ8.4, 1.8 Hz), 7.90—8.00 (4H,
m), 8.22 (1H, d, Jꢁ1.8 Hz), 8.45 (1H, s). Anal. Calcd for C22H13F5N2O3S: C,
55.00; H, 2.73; N, 5.83. Found: C, 54.75; H, 2.45; N, 5.76.
N-[2-(2,4-Difluorophenoxy)-3-pyridyl]ethanesulfonamide (6): White powder,
mp 109—110 °C. Purification by flash chromatography on silica gel eluted
with 5% Et2O in hexane. Rfꢁ0.18 (20% EtOAc in hexane). 1H-NMR
(300 MHz, CDCl3) d: 1.43 (3H, t, Jꢁ7.5 Hz), 3.18 (2H, q, Jꢁ7.5 Hz), 6.86
(1H, bs), 6.94—6.98 (2H, m), 7.04 (1H, m), 7.24 (1H, m), 7.86 (1H, m),
7.96 (1H, m). Anal. Calcd for C13H12F2N2O3S: C, 49.68; H, 3.85; N, 8.91.
Found: C, 49.83; H, 4.14; N, 8.90.
d: 4.20 (2H, bs), 6.90—7.01 (2H, m), 7.18 (1H, dd, Jꢁ2.1, 0.3 Hz), 7.24
(1H, m), 7.74 (1H, dd, Jꢁ2.1, 1.2 Hz). Anal. Calcd for C12H7F5N2O: C,
49.67; H, 2.43; N, 9.65. Found: C, 49.89; H, 2.44; N, 9.67. EI-MS m/z: 290
(Mꢂ), 271, 193, 141. EI-HR-MS m/z: 290.0484 (Calcd for C12H7F5N2O:
290.0478).
Compound 14 was obtained from 11 in 97% yield. White prisms, mp
1
68—70 °C. Rfꢁ0.28 (20% EtOAc in hexane). H-NMR (300 MHz, CDCl3)
d: 4.32 (2H, bs), 6.90—7.04 (2H, m), 7.02 (1H, d, Jꢁ7.8 Hz), 7.22 (1H, d,
Jꢁ7.8 Hz), 7.28 (1H, m). Anal. Calcd for C12H7F5N2O: C, 49.67; H, 2.43; N,
9.65. Found: C, 49.91; H, 2.21; N, 9.59. EI-MS m/z: 290 (Mꢂ). EI-HR-MS
m/z: 290.0473 (Calcd for C12H7F5N2O: 290.0478).
Compound 15 was obtained from 12 in 80% yield.19) Pale yellow powder,
mp 87—89 °C. Rfꢁ0.21 (20% EtOAc in hexane). 1H-NMR (300 MHz,
CDCl3) d: 1.97 (2H, bs), 6.84 (1H, dd, Jꢁ7.5, 4.8 Hz), 6.87—6.97 (2H, m),
7.30 (1H, dd, Jꢁ7.5, 1.5 Hz), 7.23 (1H, m), 7.49 (1H, dd, Jꢁ4.8, 1.5 Hz).
General Synthesis of Sulfonamide To a stirred solution of 3-aminopy-
ridine 13, 14, or 15 (3.0 mmol) in pyridine (3 ml) were added dropwise
methane-, ethane-, or 2-naphthalenesulfonyl chloride (9 mmol) at room tem-
perature, and the mixture was stirred for 2—6 h at the same temperature.
Then, the mixture was quenched with cold 2 N hydrochloric acid (50 ml), and
extracted with EtOAc (50 ml). The organic extract was washed with brine
and the solvent was removed. The residual oil was dissolved in a mixture of
3 M aqueous KOH (5 ml) and 1,4-dioxane (13 ml) and heated at 90 °C for
30 min. After cooling, ice water (60 ml) was added to the reaction mixture,
and the pH was adjusted to 5 with 1 N hydrochloric acid. The mixture was
extracted with EtOAc (50 mlꢃ2) and the combined extract was washed with
brine, and dried over MgSO4. Evaporation of solvent and purification of the
crude product by recrystalization or column chromatography on silica gel
provided sulfonamides.
Acknowledgement The authors acknowledge to Drs. T. Haga, T. Ko-
yanagi, S. Mizukoshi, F. Kato, H. Kimura and Mr. S. Yotsuya for their kind
suggestions and support on this work.
References and Notes
1) Hagmann W. K., J. Med. Chem., 51, 4359—4369 (2008).
2) Purser S., Moore P. R., Swallow S., Gouverneur V., Chem. Soc. Rev.,
37, 320—330 (2008).
3) Jeschke P., Pest Manag. Sci., 66, 10—27 (2010).
4) Tomashenko O. A., Grushin V. V., Chem. Rev. ASAP. DOI:
10.1021/cr1004293
5) Nie J., Guo H.-C., Cahard D., Ma J. A., Chem. Rev., 111, 455—529
(2011).
6) Sato K., Tarui A., Omote M., Ando A., Kumadaki I., Synthesis, 2010,
1865—1882 (2010).