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H. Nishida et al. / Bioorg. Med. Chem. 20 (2012) 3925–3938
1.58 mmol) in THF (4 mL) and Et2O (4 mL) at 10 °C. The mixture
was stirred at 10 °C for 1 h, and then poured into ice water. The
resulting mixture was poured into a saturated solution of NH4Cl,
and extracted with Et2O. The extract was washed with brine, dried
over MgSO4, and concentrated under reduced pressure to give pale
brown oil (0.63 g). To a solution of the obtained oil in CH2Cl2
(30 mL) was added MnO2 (2.77 g, 31.9 mmol) at room tempera-
ture. The mixture was stirred at room temperature for 4 h, and fil-
trated. The filtrate was concentrated under reduced pressure, and
the residue was purified by silica gel column chromatography
(hexane/EtOAc = 19:1–4:1) to give 23 (461 mg, 74%) as a colorless
solid: 1H NMR (CDCl3) d 2.49 (3H, s), 6.57 (1H, d, J = 1.9 Hz), 7.12–
7.16 (2H, m), 7.28–7.33 (2H, m), 7.39–7.41 (1H, m), 7.43 (2H, d,
J = 8.4 Hz), 7.57 (2H, d, J = 8.4 Hz), 8.06 (1H, d, J = 1.9 Hz).
5.41. Ethyl 5-butyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbox-
ylate (28)
To a solution of 27 (978 mg, 5.0 mmol) in THF (50 mL) was
added sodium hydride (60% in oil, 240 mg, 6.0 mmol) under Ar
atmosphere. After stirring at room temperature for 30 min, ben-
zenesulfonyl chloride (0.77 mL, 6.0 mmol) was added, and the mix-
ture was stirred at room temperature for 1 h. The mixture was
poured into H2O, and extracted with EtOAc. The extract was
washed with brine, dried over MgSO4, and concentrated under re-
duced pressure. The residue was purified by silica gel column chro-
matography (hexane/EtOAc = 19/1–4/1), and the obtained solid
was washed with hexane to give 28 (780 mg, 47%) as a colorless so-
lid: 1H NMR (CDCl3) d 0.84–0.89 (3H, m), 1.26–1.37 (5H, m), 1.47–
1.55 (2H, m), 2.59–2.64 (2H, m), 4.25–4.32 (2H, m), 6.37 (1H, m),
7.52–7.66 (3H, m), 7.79–7.82 (2H, m), 7.92 (1H, s).
5.38. N-Methyl-1-(5-phenyl-1-{[4-(trifluoromethyl)phenyl]-
sulfonyl}-1H-pyrrol-3-yl)ethanamine hydrochloride (24)
5.42. Methyl 5-cyclopropyl-1-(phenylsulfonyl)-1H-pyrrole-3-
carboxylate (29)
A mixture of 23 (200 mg, 0.51 mmol), 40% MeNH2 in MeOH
(400 mg, 5.2 mmol) and MS4A in EtOH (10 mL) was stirred at
70 °C for 1.5 h, and then cooled to room temperature. NaBH4
(58 mg, 1.53 mmol) was added at room temperature, and the mix-
ture was stirred for 1.5 h, quenched with 1 N HCl (50 mL). The
resulting mixture was stirred for 30 min, basified with a saturated
solution of NaHCO3, and then extracted with EtOAc. The extract
was washed with brine, dried over MgSO4, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (EtOAc/MeOH = EtOAc to 4:1) and the obtained
oil was dissolved in ethyl acetate (5 mL). 4 N HCl/EtOAc (1 mL)
was added and the mixture was concentrated under reduced pres-
sure. The residue was crystallized from iPr2O/EtOAc to give 24
(52 mg, 23%) as colorless crystals: mp 205–208 °C; 1H NMR
(DMSO-d6) d 1.52 (3H, d, J = 6.7 Hz), 2.37 (3H, s), 4.28 (1H, q,
J = 6.7 Hz), 6.55 (1H, s), 7.14–7.45 (5H, m), 7.63 (2H, d, J = 8.4 Hz),
7.78 (1H, s), 7.92 (2H, d, J = 8.4 Hz); Anal. Calcd for C20H20ClF3N2O2S
0.5H2O: C, 52.92; H, 4.66; N, 6.17. Found: C, 53.19; H, 4.53; N, 6.05.
A mixture of 13 (2.11 g, 6.13 mmol), cyclopropylboronic acid
(683 mg, 7.95 mmol), palladium(II) acetate (69 mg, 0.31 mmol),
tricyclohexylphosphine (174 mg, 0.62 mmol) and tripotassium
phosphate (4.55 g, 21.5 mmol) in toluene (27 mL) and water
(1.3 mL) was stirred at 100 °C for 4 h under Ar atmosphere. After
cooled to room temperature, the reaction mixture was diluted with
H2O (50 mL), and the mixture was extracted with EtOAc. The ex-
tract was washed with brine, dried over MgSO4, and concentrated
under reduced pressure. The residue was purified by silica gel col-
umn chromatography (hexane/EtOAc = 19:1–4/1) to give 29
(406 mg, 22%) as a yellow oil: 1H NMR (CDCl3) d 0.30–0.36 (2H,
m), 0.71–0.77 (2H, m), 2.00–2.08 (1H, m), 3.79 (3H, s), 6.19 (1H,
s), 7.51–7.56 (2H, m), 7.63–7.66 (1H, m), 7.85–7.88 (2H, m), 7.94
(1H, s).
Compounds 30a and 30b were prepared form 28 and 29,
respectively using a similar procedure as for the preparation of
compound 17b from 9b.
5.39. 1-[(1-Isocyanopentyl)sulfonyl]-4-methylbenzene (26)
5.43. 1-[5-Butyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-meth-
A mixture of p-toluenesulfonylmethyl isocyanide 25 (9.75 g,
50 mmol), tetrabutylammonium iodide (3.69 g, 10 mmol), 1-butyl
iodide (11.3 mL, 100 mmol), CH2Cl2 (100 mL) and 30% NaOH solu-
tion (100 mL) was stirred at room temperature for 12 h. The mix-
ture was diluted with water (200 mL), and then extracted with
CH2Cl2. The extract was washed with brine, dried over MgSO4,
and concentrated under reduced pressure. The obtained gum-like
residue was extracted three times with diethyl ether (100 mL).
The extract was concentrated under reduced pressure to give 26
(10.8 g, 86%) as a colorless oil: 1H NMR (CDCl3) d 0.91–0.97 (3H,
m), 1.32–1.66 (4H, m), 1.80–1.90 (1H, m), 2.10–2.25 (1H, m), 2.49
(3H, s), 4.42–4.47 (1H, m), 7.41–7.51 (2H, m), 7.86–7.88 (2H, m).
ylmethanamine hydrochloride (30a)
Colorless crystals (53%): mp 139–140 °C; 1H NMR (DMSO-d6) d
0.79–0.85 (3H, m), 1.24–1.48 (4H, m), 2.48 (3H, s), 2.58–2.63 (2H,
m), 3.91 (2H, s), 6.25 (1H, s), 7.54 (1H, s), 7.66–7.88 (5H, m), 8.91
(2H, br); Anal. Calcd for C16H23ClN2O2S: C, 56.04; H, 6.75; N,
8.17. Found: C, 55.97; H, 6.97; N, 8.15.
5.44. 1-[5-Cyclopropyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-
methylmethanamine hydrochloride (30b)
Colorless crystals (40%): mp 198–199 °C; 1H-NMR (DMSO-d6) d
0.22–0.27 (2H, m),0.75–0.81 (2H, m), 1.97–2.05 (1H, m), 2.47 (3H,
s), 3.87 (2H, s), 6.09 (1H, s), 7.55 (1H, s), 7.66–7.91 (5H, m), 8.92
(2H, br); Anal. Calcd for C15H19ClN2O2S 0.5H2O: C, 53.64; H, 6.00;
N, 8.34. Found: C, 53.88; H, 5.71; N, 8.10.
5.40. Ethyl 5-butyl-1H-pyrrole-3-carboxylate (27)
A solution of 26 (10.8 g, 43.0 mmol) and ethyl acrylate (4.78 mL,
43.0 mmol) in THF (120 mL) was added dropwise to a suspension
of potassium tert-butoxide (5.79 g, 51.6 mmol) in THF (80 mL)
while stirring at room temperature over 1 h. The mixture was fur-
ther stirred at room temperature for 30 min, and then diluted with
water, and extracted with EtOAc. The extract was washed with
brine, dried over MgSO4, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(hexane/EtOAc = 19/1–4/1) to give 27 (6.56 g, 78%) as a yellow
oil: 1H NMR (CDCl3) d 0.89–0.95 (3H, m), 1.24–1.45 (5H, m),
1.55–1.65 (2H, m), 2.55–2.60 (2H, m), 4.23–4.30 (2H, m), 6.33
(1H, s), 7.30 (1H, s), 8.11 (1H, br).
5.45. Ethyl 2-methyl-5-phenyl-1H-pyrrole-3-carboxylate (31)
A solution of ethyl acetoacetate (13.02 g, 100 mmol) in DMF
(40 mL) was added dropwise to a stirred suspension of NaH (60%
in oil, 2.88 g) at 0 °C. The mixture was stirred at 0 °C for 20 min,
and then a solution of phenacyl bromide 2 (20.0 g, 100 mmol) in
DMF (20 mL) was added dropwise slowly. The reaction mixture
was stirred at room temperature for 1.5 h, poured into ice water,
and extracted with EtOAc. The extract was washed with brine,
dried over Na2SO4, and concentrated under reduced pressure to