S. Ito et al. / Bioorg. Med. Chem. 16 (2008) 9817–9829
9827
J = 4.1 Hz), 138.97 (d, J = 1.7 Hz), 141.05 (s), 144.08 (s), 148.58 (d,
J = 14.1 Hz), 156.62 (d, J = 242.5 Hz); IR(ATR) 2926, 2955, 1607,
1583, 1479, 1454, 1375, 1248, 1213, 999, 968, 847, 806, 671 cm
À1; HRMS (ESI+) m/z [M+H]+ 469.1801 (calcd for C20H34N4FSn:
469.1789).
the reaction mixture was stirred at room temperature for 30 min.
The resulting mixture was partitioned between AcOEt and H2O
and the organic layer was dried over anhydrous Na2SO4, filtered
and then concentrated in vacuo. The residue was purified by silica-
gel column chromatography (Wako C-300, Hexane/AcOEt 2:1) to
give 14.2 mg of target compound as white solid.
4.1.39. 2-Fluoro-3-(4-iodo-5-methyl-1H-1,2,3-triazol-1-yl)-
pyridine (6j)
To a solution of 2-fluoro-3-[5-methyl-4-(tributylstannyl)-1H-
1,2,3-triazole-1-yl]pydidine (2.66 g, 5.69 mmol) in THF (30 ml)
1H NMR (CDCl3) d: 1.32 (9H, s), 2.55 (2H, td, J = 4.9, 2.6 Hz), 3.57
(2H, t, J = 5.6 Hz), 3.94 (2H, q, J = 2.8 Hz), 4.28 (1H, s), 6.48–6.49
(1H, m), 7.19–7.29 (2H, m), 7.34–7.40 (1H, m), 7.88–7.92 (2H,
m); 13C NMR (CDCl3) d: 26.57 (s), 29.51 (3C, s), 39.47 (s), 43.68
(s), 50.86 (s), 117.00 (d, J = 19.9 Hz), 119.97 (d, J = 8.3 Hz), 120.93
(s), 124.76 (s), 125.24 (s), 125.28 (s), 126.36 (s), 130.11 (d,
J = 7.4 Hz), 148.07 (s), 153.21 (d, J = 250.8 Hz), 156.80 (s). ; IR(ATR)
2361, 2341, 1622, 1526, 1506, 1246, 1217, 820 cmÀ1; HRMS (ESI+)
m/z [M+H]+ 344.1882 (calcd for C18H23N5OF: 344.1887); HPLC (a)
99.6%; (b) 99.9%.
was added
a solution of iodine (1.59 g, 6.26 mmol) in THF
(20 ml) at 0 °C, and the reaction mixture was stirred at room tem-
perature for 2 h. The resulting mixture was partitioned between
AcOEt and saturated aqueous Na2S2O3. The organic layer was dried
over anhydrous Na2SO4, filtered and then concentrated in vacuo.
The residue was roughly purified by silicagel column chromatogra-
phy (Wako C-300, Hexane/AcOEt 3:1), and the resulting solid was
washed with hexane to give 1.63 g of target compound.
4.1.42. 1-(3,3-Dimethylbutanolyl)-4-[1-(2-fluorophenyl)-1H-
1,2,3-triazol-4-yl]-1,2,3,6-tetrahydorohydropyridine (9)
To a solution of 4-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]-
1,2,3,6-tetrahydropyridine (14.0 mg, 0.057 mmol) and triethylamine
1H NMR (CDCl3) d: 2.32 (3H, d, J = 2.0 Hz), 7.47 (1H, ddd, J = 7.6,
4.9, 1.2 Hz), 7.97–8.02 (1H, m), 8.42–8.53 (1H, m); 13C NMR (CDCl3)
d: 9.60 (d, J = 5.0 Hz), 90.26 (s), 119.37 (d, J = 28.1 Hz), 122.54 (d,
J = 5.0 Hz), 138.33 (s), 138.85 (d, J = 1.7 Hz), 149.57 (d,
J = 14.1 Hz), 156.39 (d, J = 243.3 Hz); IR(ATR) 1607, 1578, 1479,
1441, 1213, 1080, 966, 749, 806, 822, 841 cm-1; HRMS (ESI+) m/z
[M+H]+ 304.9714 (calcd for C8H7N4FI: 304.9700).
(25
ll, 0.18 mmol) in THF (2.0 ml) was added tert-butylacetyl-
chloride (19
l
l, 0.14 mmol) at 0 °C, and the reaction mixture
was stirred at room temperature for 2 h. The resulting mixture
was partitioned between AcOEt and H2O and the organic layer
was dried over anhydrous Na2SO4, filtered and then concen-
trated in vacuo. The residue was purified by silicagel column
chromatography (Wako C-300, Hexane/AcOEt 4:1 and then
CHCl3/MeOH 50:1) to give 11.0 mg of target compound as color-
less gum.
4.1.40. tert-Butyl-4-[1-(2-fuluoropyridine-3-yl)-5-methyl-1H-
1,2,3-triazol-4-yl]-3,6-dihydropyridine-1(2H)-carboxylate (7j)
To a nitrogen flushed flask containing tert-butyl-4-(4,4,5,5-tet-
ramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-car-
boxylate (587 mg, 1.90 mmol), K2CO3 (436 mg, 3.16 mmol) and
2-fluoro-3-(4-iodo-5-methyl-1H-1,2,3-triazol-1-yl)-pyridine (480 mg,
1.58 mmol) was added DMF (20 ml) and PdCl2(dppf)ÁCH2Cl2
(129 mg, 0.16 mmol). The mixture was heated to 90 °C and stirred
under N2 overnight. The resulting mixture was partitioned be-
tween CHCl3 and H2O. The organic layer was dried over anhydrous
Na2SO4, filtered and then concentrated in vacuo. The residue was
purified by silicagel column chromatography (Wako C-300, Hex-
ane/AcOEt 2:1) and the resulting solid was washed with Hexane
to give 352 mg of target compound as white solid.
1H NMR (CDCl3) d: 1.07 (4.5H, s), 1.09 (4.5H, s), 2.32 (1.5H, s),
2.36 (1.5H, s), 2.54–2.60 (1H, m), 2.65–2.75 (1H, m), 3.76 (1H, t,
J = 5.6 Hz), 3.88 (1H, t, J = 5.6 Hz), 4.23 (1H, d, J = 3.4 Hz), 4.30
(1H, d, J = 2.9 Hz), 6.49 (0.5H, br s), 6.60 (0.5H, brs), 7.28–7.36
(2H, m), 7.42–7.47 (1H, m), 7.95–8.01 (2H, m); IR(ATR) 2359,
2341, 1632, 1506, 1466, 1427, 1234, 818, 764 cmÀ1; HRMS (ESI+)
m/z [M+H]+ 343.1930 (C19H24N4OF: 343.1934); HPLC (a) 98.6%;
(b) 98.5%.
4.1.43. iso-Propyl-4-[1-(2-fuluoropyridine-3-yl)-1H-1,2,3-
triazol-4-yl]-3,6-dihydropyridine-1(2H)-carboxylate (10)
To a solution of tert-butyl-4-[1-(2-fuluoropyridine-3-yl)-1H-
1,2,3-triazol-4-yl]-3,6-dihydropyridine-1(2H)-carboxylate (30.0 mg,
0.08 mmol) in CHCl3 (2.0 ml) was added Trifluoroacetic acid
(2.0 ml), and the reaction mixture was stirred at room temperature
for 20 min. After removing the solvents in vacuo, the residue was
partitioned between CHCl3 and saturated aqueous NaHCO3. The
organic layer was dried over anhydrous Na2SO4, filtered and then
concentrated in vacuo to give crude 19.8 mg of 2-fluoro-3-[4-
(1,2,3,6-tetrahydropyridin-4-yl)-1H-1,2,3-triazole-1-yl]pydidine.
To a solution of 2-fluoro-3-[4-(1,2,3,6-tetrahydropyridin-4-yl)-
1H-1,2,3-triazole-1-yl]pydidine (18.0 mg, 0.073 mmol) and trieth-
1H NMR (CDCl3) d: 1.50 (9H, s), 2.35 (3H, d, J = 2.0 Hz), 2.72–2.77
(2H, m), 3.68 (2H, t, J = 5.9 Hz), 4.13 (2H, brs), 6.05 (1H, brs), 7.46
(1H, ddd, J = 7.8, 4.9, 1.0 Hz), 7.99–8.04 (1H, m), 8.43 (1H, td,
J = 3.2, 1.6 Hz); 13C NMR (CDCl3) d: 9.67 (d, J = 4.1 Hz), 27.20 (s),
28.46 (3C, s), 39.67 (0.5C, s), 43.07 (0.5C, s), 43.37 (s), 79.77 (s),
119.54 (d, J = 28.1 Hz), 122.49 (d, J = 5.0 Hz), 123.12 (s), 127.57
(s), 130.79 (s), 139.07 (d, J = 1.7 Hz), 144.71 (s), 149.11 (d, J = 14.1
Hz), 154.85 (s), 156.59 (d, J = 242.5 Hz); IR(ATR) 1678, 1659,
1456, 1412, 1366, 1248, 1169, 1115, 970, 851, 816, 750 cmÀ1
;
HRMS (ESI+) m/z [M+H]+ 360.1832 (calcd for C18H23N5O2F:
360.1836); HPLC (a) 97.1%; (b) 97.2%.
4.1.41. N-(tert-Butyl)-4-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-
yl]-3,6-dihydropyridine-1(2H)-carboxamide (8)
ylamine (25
chloroformate (10
l
l, 0.18 mmol) in THF (4.0 ml) was added isopropyl
ll, 0.088 mmol) at 0 °C, and the reaction mix-
To a solution of tert-butyl-4-[1-(2-fluorophenyl)-1H-1,2,3-tria-
zol-4-yl]-3,6-dihydropyridine-1(2H)-carboxylate (60 mg, 0.17 mmol)
in CHCl3 (2.0 ml) was added trifluoroacetic acid (2.0 ml), and the
reaction mixture was stirred at room temperature for 20 min. After
removing the solvents in vacuo, the residue was partitioned be-
tween CHCl3 and saturated aqueous NaHCO3. The organic layer
was dried over anhydrous Na2SO4, filtered and then concentrated
in vacuo to give crude 42 mg of 4-[1-(2-fluorophenyl)-1H-1,2,3-
triazol-4-yl]-1,2,3,6-tetrahydropyridine.
ture was stirred at room temperature for 45 min. The resulting
mixture was partitioned between AcOEt and H2O and the organic
layer was dried over anhydrous Na2SO4, filtered and then concen-
trated in vacuo. The residue was purified by silicagel column chro-
matography (Wako C-300, Hexane/AcOEt 2:1) to give 16.9 mg of
target compound as white solid.
1H NMR (CDCl3) d: 1.28 (6H, d, J = 6.3 Hz), 2.60 (2H, br s),
3.70–3.74 (2H, m), 4.16–4.20 (2H, m), 4.95–5.01 (1H, m), 6.58
(1H, brs), 7.44 (1H, ddd, J = 7.8, 4.9, 1.0 Hz), 8.07 (1H, d,
J = 2.9 Hz), 8.29–8.31 (1H, m), 8.50–8.55 (1H, m); 13C NMR
(CDCl3) d: 22.27 (2C, s), 26.29 (s), 40.01 (s), 43.30 (s), 68.73
(s), 119.26 (d, J = 9.1 Hz), 120.79 (d, J = 25.7 Hz), 122.11 (s),
To a solution of 4-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]-
1,2,3,6-tetrahydropyridine (14.7 mg, 0.06 mmol) in THF (2.0 ml)
was added tert-butyl isocyanate (12 ll, 0.11 mmol) at 0 °C, and