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5.1.35. Methyl 1-benzyl-4-[4-cyano-3-(trifluoromethyl)phenyl]-
2,5-dimethyl-1H-pyrrole-3-carboxylate (4i)
5.1.41. 4-(4-Cyanophenyl)-2,5-dimethyl-1-(pyridin-3-ylmethyl)-
1H-pyrrole-3-carbonitrile (4k)
A mixture of 28 (0.15 g, 0.522 mmol), 30 (0.13 g, 0.520 mmol),
tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.026 mmol),
anhydrous Na2CO3 (0.17 g, 1.56 mmol), DMF (4 mL), and H2O
(1 mL) was stirred at 130 °C for 2 h under argon atmosphere. After
cooling to room temperature, the mixture was partitioned between
EtOAc and H2O. The organic layer was washed with brine, dried
over anhydrous MgSO4, and concentrated in vacuo. The residue
was purified by silica gel column chromatography (hexane–EtOAc)
to give 4i (0.14 g, 64%) as a colorless amorphous. 1H NMR
(300 MHz, CDCl3) d: 2.05 (3H, s), 2.51 (3H, s), 3.62 (3H, s), 5.14
(2H, s), 6.92–6.97 (2H, m), 7.28–7.38 (3H, m), 7.53–7.57 (1H, m),
7.68 (1H, s), 7.80 (1H, d, J = 8.1 Hz). Analytical HPLC showed
99.3% purity.
Compound 4k was prepared in a manner similar to that de-
scribed for 4j in 55% yield as colorless crystals, mp 160–164 °C.
1H NMR (300 MHz, DMSO-d6) d: 2.20 (3H, s), 2.36 (3H, s), 5.34
(2H, s), 7.39–7.40 (2H, m), 7.59 (2H, d, J = 8.1 Hz), 7.92 (2H, d,
J = 8.1 Hz), 8.37 (1H, br s), 8.52 (1H, t, J = 3.0 Hz). Anal. Calcd for
C20H16N4: C, 76.90; H, 5.16; N, 17.94. Found: C, 76.68; H, 5.15; N,
17.82.
5.1.42. 1-[(6-Chloropyridin-3-yl)methyl]-4-(4-cyanophenyl)-2,5-
dimethyl-1H-pyrrole-3-carbonitrile (4l)
Compound 4l was prepared in a manner similar to that de-
scribed for 2 in 60% yield as colorless crystals, mp 209–210 °C.
1H NMR (200 MHz, CDCl3) d: 2.01 (3H, s), 2.40 (3H, s), 5.13 (2H,
s), 7.16 (1H, dd, J = 2.2, 8.0 Hz), 7.35 (1H, d, J = 8.0 Hz), 7.51 (2H,
d, J = 8.4 Hz), 7.72 (2H, d, J = 8.4 Hz), 8.13 (1H, d, J = 2.2 Hz). Analyt-
ical HPLC showed 98.3% purity.
5.1.36. 1-Benzyl-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-
carbonitrile (4j)
To a solution of 27 (0.10 g, 0.452 mmol) in DMF (1.2 mL) was
added NaH (60% in mineral oil, 0.03 g, 0.678 mmol) portionwise
at room temperature. After stirring at room temperature for 15
minutes, benzyl bromide (0.093 g, 0.542 mmol) was added. The
mixture was stirred at room temperature for 1.5 h, poured into
H2O, and extracted with EtOAc. The organic layer was washed with
H2O, dried over anhydrous Na2SO4, and concentrated in vacuo. The
residue was purified by silica gel column chromatography (hex-
ane–EtOAc) to give 4j (0.105 g, 75%) as a colorless powder, mp
125–126 °C. 1H NMR (300 MHz, CDCl3) d: 2.20 (3H, s), 2.38 (3H,
s), 5.12 (2H, s), 6.92–6.94 (2H, m), 7.28–7.40 (3H, m), 7.53 (2H, d,
J = 8.4 Hz), 7.70 (2H, d, J = 8.4 Hz). Anal. Calcd for C21H17N3: C,
81.00; H, 5.50; N, 13.49. Found: C, 80.83; H, 5.45; N, 13.47.
5.1.43. 1-{[6-Chloro-5-(hydroxymethyl)pyridin-3-yl]methyl}-4-
(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile (4n)
A mixture of sodium borohydride (0.50 g, 13.2 mmol), calcium
chloride (1.00 g, 9.01 mmol), THF (40 mL), and EtOH (20 mL) was
stirred at room temperature for 0.5 h. To the mixture was added
38 (1.80 g, 4.30 mmol), and the mixture was stirred at room tem-
perature for 14 h. The mixture was poured into a saturated aque-
ous solution of citric acid and extracted with EtOAc. The organic
layer was washed with brine, dried over anhydrous MgSO4, and
concentrated in vacuo. The residue was purified by silica gel col-
umn chromatography (hexane–EtOAc). The product was recrystal-
lized from EtOH to give 4n (1.26 g, 78%) as colorless crystals, mp
147–148 °C. 1H NMR (300 MHz, DMSO-d6) d: 2.21 (3H, s), 2.37
(3H, s), 4.52 (2H, d, J = 5.1 Hz), 5.37 (2H, s), 5.61 (1H, t,
J = 5.1 Hz), 7.57–7.60 (3H, m), 7.92 (2H, d, J = 8.4 Hz), 8.06 (1H, d,
J = 2.4 Hz). Anal. Calcd for C21H17ClN4O: C, 66.93; H, 4.55; N,
14.87. Found: C, 66.74; H, 4.46; N, 14.68.
5.1.37. Methyl 5-{[3-cyano-4-(4-cyanophenyl)-2,5-dimethyl-1H-
pyrrol-1-yl]methyl}pyridine-3-carboxylate (37)
Compound 37 was prepared in a manner similar to that de-
scribed for 4j in 20% yield as a colorless powder. 1H NMR
(300 MHz, DMSO-d6) d: 2.20 (3H, s), 2.36 (3H, s), 3.88 (3H, s),
5.45 (2H, s), 7.59 (2H, d, J = 8.1 Hz), 7.91–7.94 (3H, m), 8.52 (1H,
d, J = 2.1 Hz), 9.02 (1H, d, J = 2.1 Hz).
5.1.44. 1-{[5-(Hydroxymethyl)pyridin-3-yl]methyl}-4-(4-cyano-
phenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile (4m)
Compound 4m was prepared in a manner similar to that de-
scribed for 4n in 49% yield as colorless powder, mp 214–215 °C.
1H NMR (300 MHz, DMSO-d6) d: 2.21 (3H, s), 2.37 (3H, s), 4.52
(2H, d, J = 5.4 Hz), 5.32–5.37 (3H, m), 7.36 (1H, br s), 7.59 (2H, d,
J = 8.1 Hz), 7.92 (2H, d, J = 8.1 Hz), 8.23 (1H, d, J = 2.4 Hz), 8.45
(1H, d, J = 1.5 Hz). Analytical HPLC showed 99.2% purity.
5.1.38. Ethyl 2-chloro-5-{[3-cyano-4-(4-cyanophenyl)-2,5-di-
methyl-1H-pyrrol-1-yl]methyl}pyridine-3-carboxylate (38)
Compound 38 was prepared in a manner similar to that de-
scribed for 4j in 64% yield as crystals. 1H NMR (300 MHz, DMSO-
d6) d: 1.31 (3H, t, J = 7.2 Hz), 2.20 (3H, s), 2.37 (3H, s), 4.34 (2H,
q, J = 7.2 Hz), 5.40 (2H, s), 7.59 (2H, d, J = 8.1 Hz), 7.91–7.94 (3H,
m), 8.24 (1H, d, J = 2.7 Hz).
5.1.45. 1-{[6-Chloro-5-(hydroxymethyl)pyridin-3-yl]methyl}-4-
(4-cyanophenyl)-5-methyl-1H-pyrrole-3-carbonitrile (4o)
Compound 4o was prepared in a manner similar to that de-
scribed for 4n in 74% yield as a colorless amorphous powder.
1H NMR (300 MHz, DMSO-d6) d: 2.21 (3H, s), 4.53 (2H, d,
J = 5.7 Hz), 5.35 (2H, s), 5.64 (1H, t, J = 5.7 Hz), 7.57 (2H, d,
J = 8.7 Hz), 7.79 (1H, d, J = 2.4 Hz), 7.92 (2H, d, J = 8.7 Hz), 7.94
(1H, s), 8.24 (1H, d, J = 2.4 Hz). Analytical HPLC showed 100%
purity.
5.1.39. Ethyl 2-chloro-5-{[3-cyano-4-(4-cyanophenyl)-5-methyl-
1H-pyrrol-1-yl]methyl}pyridine-3-carboxylate (39)
Compound 39 was prepared in a manner similar to that de-
scribed for 4j in 50% yield as colorless crystals. 1H NMR
(300 MHz, CDCl3) d: 1.42 (3H, t, J = 7.2 Hz), 2.31 (3H, s), 4.44 (2H,
q, J = 7.2 Hz), 5.30 (2H, s), 7.27 (1H, s), 7.49 (2H, d, J = 8.7 Hz),
7.74 (2H, d, J = 8.7 Hz), 7.84 (1H, d, J = 2.6 Hz), 8.21 (1H, d,
J = 2.6 Hz).
5.1.40. Ethyl 2-chloro-5-{[3-cyano-4-(4-cyanophenyl)-2-methyl-
1H-pyrrol-1-yl]methyl}pyridine-3-carboxylate (40)
5.1.46. 1-{[6-Chloro-5-(hydroxymethyl)pyridin-3-yl]methyl}-4-
(4-cyanophenyl)-2-methyl-1H-pyrrole-3-carbonitrile (4p)
Compound 4p was prepared in a manner similar to that
described for 4n in 55% yield as a colorless powder, mp 181–
182 °C. 1H NMR (300 MHz, CDCl3) d: 2.15 (1H, br s), 2.41 (3H, s),
4.79 (2H, s), 5.10 (2H, s), 6.88 (1H, s), 7.59–7.79 (5H, m), 8.13
(1H, d, J = 2.3 Hz). Analytical HPLC showed 100% purity.
Compound 40 was prepared in a manner similar to that de-
scribed for 4j in 36% yield as
a
yellow powder. 1H NMR
(300 MHz, CDCl3) d: 1.40 (3H, t, J = 7.2 Hz), 2.41 (3H, s), 4.42 (2H,
q, J = 7.2 Hz), 5.13 (2H, s), 6.87 (1H, s), 7.60–7.77 (4H, m), 7.80–
7.87 (1H, m), 8.30 (1H, d, J = 2.6 Hz).