1H- and 2H-Indazolyl Derivatives
J . Org. Chem., Vol. 66, No. 12, 2001 4225
Sch em e 11
solution of indazole [6 (1.6 g, 13.6 mmol)] in 15 mL of DMSO.
In another flask, NaH (395 mg, 16.5 mmol) was added
portionwise with stirring at 0 °C to a solution of the HCl salt
of 5 (1.5 g, 11.3 mmol) in 15 mL of DMSO. After 10 min, both
solutions were combined, and the resulting reaction mixture
was stirred for 18 h at 100 °C. After cooling, the DMSO was
extracted with 50% aqueous ethyl acetate. The organic phase
was dried over MgSO4 and evaporated in vacuo to yield a crude
product that was separated by column chromatography eluting
with hexane:ethyl acetate (80:20) to provide 652 mg (3.3 mmol,
30%) of 7 as a yellowish oil: 1H NMR (CDCl3, 360 MHz) δ
8.73 (m, 2H), 8.26 (d, J ) 0.9 Hz, 1H), 7.90 (dddd, J ) 0.9 Hz,
J ) 0.9 Hz, J ) 0.9, J ) 8.5 Hz, 1H), 7.83 (ddd, J ) 1.1 Hz, J
) 1.1 Hz, J ) 8.1 Hz, 1H), 7.78 (m, 2H), 7.52 (ddd, J ) 1.2 Hz,
J ) 7.0 Hz, J ) 8.4 Hz, 1H), 7.30 (ddd, J ) 0.8 Hz, J ) 7.0
Hz, J ) 8.0 Hz, 1H); 13C NMR (CDCl3, 90 MHz) δ 151.2, 147.0,
137.6, 128.2, 126.4, 122,6, 121.9, 120.9, 115.2, 110.9; GC-EIMS
m/z (rel int) 195 (M.+ 100), 168 (40), 153 (2), 140 (13), 114 (6),
105 (6), 78 (9), 51 (47); UV (MeOH) 208, 256, 305 nm. This
product was converted to its HCl salt in anhydrous methanolic
HCl. The salt was precipitated with Et2O and was crystallized
and iodomethane (857 mg, 6.0 mmol) gave 930 mg (2.8 mmol,
91%) of 10 as a yellow solid: mp 241-243 °C; 1H NMR (DMSO-
d6, 360 MHz): δ 9.55 (d, J ) 1.0 Hz, 1H), 9.13 (m, 2H), 8.77
(m, 2H), 7.83 (ddd, J ) 1.1 Hz, J ) 1.1 Hz, J ) 8.7 Hz, 1H),
7.74 (dddd, J ) 1.1 Hz, J ) 1.1, J ) 1.1 Hz, J ) 8.9 Hz, 1H),
7.44 (ddd, J ) 1.1 Hz, J ) 6.5 Hz, J ) 8.9 Hz, 1H), 7.2 (ddd,
J ) 1.1 Hz, J ) 6.5 Hz, J ) 8.7 Hz, 1H), 4.4 (s, 3H); 13C NMR
(DMSO-d6, 90 MHz) δ 151.0, 150.2, 147.3, 129.8, 124.7, 124.3,
123.4, 121.5, 117.8, 116.4, 47.1; UV (MeOH) 205, 219, 257, 327
nm. Anal. Calcd for C13H12IN3: C, 46.31; H, 3.59; N, 12.47.
Found: C, 46.38; H, 3.62; N, 12.50.
1-Met h yl-4-(2H-in d a zolyl)-1,2,3,6-t et r a h yd r op yr id in e
(4). Sodium borohydride (160 mg, 4 mmol) was added in small
portions to a suspension of 10 (340 mg, 1 mmol) in 5 mL of
methanol at room temperature while stirring. After 2 h
methanol was evaporated in vacuo, and the residue was
partitioned between dichloromethane and saturated aqueous
NaCl. The organic layer was dried over anhydrous Na2SO4,
and the solvent was evaporated in vacuo to give 185 mg (0.88
mmol, 88%) of the corresponding tetrahydropyridinyl product
4 free base as a white solid: mp 101-103 °C; 1H NMR (DMSO-
d6, 360 MHz) δ 8.62 (d, J ) 0.7 Hz, 1H), 7.69 (ddd, J ) 1.1 Hz,
J ) 1.1 Hz, J ) 8.5 Hz, 1H), 7.62 (dddd, J ) 1.0 Hz, J ) 1.0
Hz, J ) 1.0 Hz, J ) 8.8 Hz, 1H), 7.26 (ddd, J ) 1.1 Hz, J )
6.6 Hz, J ) 8.8 Hz, 1H), 7.05 (ddd, J ) 0.9 Hz, J ) 6.6 Hz, J
) 8.4 Hz, 1H), 6.51 (m, 1Η), 3.10 (m, 2H), 2.81 (m, 2H), 2.67
(t, J ) 5.3 Hz, 2H), 2.32 (s, 3H);13C NMR (DMSO-d6, 100 MHz)
δ 148.0, 134.9, 126.3, 121.5, 121.4, 120.7, 120.4, 117.1, 114.5,
52.8, 51.0, 44.9, 26.2; GC-EIMS m/z (ret int) 258 (M•+, 2), 212
(65), 185 (73), 169 (54), 157 (69), 131 (26), 94 (100), 53 (39);
UV (MeOH) 207, 229, 297 nm. Anal. Calcd for C13H15N3: C,
73.21; H, 7.09; N, 19.70. Found: C, 72.70; H, 7.17; N, 19.55.
2-Nitr oben za ld eh yd e 4-P yr id in ylh yd r a zon e (13). A
mixture of 4-hydrazinylpyridine free base 12 (570 mg, 5.2
mmol) and 2-nitrobenzaldehyde (780 mg, 5.2 mmol) in 20 mL
of ethanol was heated under reflux for 3 h. The residue
obtained after removing the solvent was purified by column
chromatography eluting with hexane:ethyl acetate (60:40)
followed by ethyl acetate:methanol (95:5). Crystallization from
acetone gave 678 mg (2.8 mmol, 53%) of an orange solid: mp
1
from MeOH (90% yield): mp 222-224 °C; H NMR (DMSO-
d6, 360 MHz) δ 8.92 (m, 2H), 8.76 (d, J ) 0.9 Hz, 1H), 8.47 (m,
2H), 8.34 (dddd, J ) 0.8 Hz, J ) 0.8 Hz, J ) 0.8, J ) 8.6 Hz,
1H), 8.03 (ddd, J ) 1.0 Hz, J ) 1.0 Hz, J ) 8.0 Hz, 1H), 7.73
(ddd, J ) 1.1 Hz, J ) 7.1 Hz, J ) 8.4 Hz, 1H), 7.49 (ddd, J )
0.7 Hz, J ) 7.1 Hz, J ) 7.9 Hz, 1H); 13C NMR (DMSO-d6, 90
MHz) δ 152.1, 143.6, 141.6, 138.2, 129.6, 127.1, 124.3, 122.6,
115.1, 112.6; UV (MeOH, nm) 208, 256, 321, 332.
4-(2H-In d a zolyl)p yr id in e (8). Continued elution of the
column with hexane:ethyl acetate (70:30) gave 589 mg (3.0
mmol, 27%) of 8 as white crystals: mp 120-121 °C; 1H NMR
(CDCl3, 360 MHz) δ 8.76 (m, 2H), 8.54 (d, J ) 0.9 Hz, 1H),
7.89 (m, 2H), 7.76 (dddd, J ) 0.9 Hz, J ) 0.9 Hz, J ) 0.9, J )
8.5 Hz, 1H), 7.70 (ddd, J ) 1.1 Hz, J ) 1.1 Hz, J ) 8.5 Hz,
1H), 7.35 (ddd, J ) 1.1 Hz, J ) 6.6 Hz, J ) 8.8 Hz, 1H), 7.13
(ddd, J ) 0.9 Hz, J ) 6.6 Hz, J ) 8.5 Hz, 1H); 13C NMR (CDCl3,
90 MHz) δ 151.5, 150.8, 146.9, 128.0, 123.5, 123.2, 120.6, 120.1,
118.3, 114.3; GC-EIMS m/z (rel int) 195 (M•+ 100), 168 (21),
155 (1), 140 (8), 118 (8), 91 (6), 78 (15), 51 (35); UV (MeOH)
205, 240, 303 nm. Anal. Calcd for C12N3H9: C, 73.83; H, 4.65;
N, 21.52. Found: C, 73.32; H, 4.77; N, 21.22.
1
203-205 °C; H NMR (DMSO-d6, 360 MHz) δ 11.31 (s, 1H),
8.35 (s, 1H), 8.26 (m, 2H), 8.15 (dd, J ) 1.4 Hz, J ) 7.9 Hz,
1H), 7.80 (dd, J ) 1.2 Hz, J ) 8.2 Hz, 1H), 7.73 (ddd, J ) 1.2
Hz, J ) 7.7 Hz, J ) 7.7 Hz, 1H), 7.56 (ddd, J ) 1.4 Hz, J )
7.4 Hz, J ) 8.3 Hz, 1H), 7.01 (m, 2H); 13C NMR (DMSO- d6,
90 MHz) δ 150.1, 149.8, 147.2, 135.2, 133.2, 129.2, 128.9, 127.5,
124.5, 107.2; UV (MeOH) 218, 245, 283, 324 nm. Anal. Calcd
for C12H10N4O2: C, 59.50; H, 4.16; N, 23.13. Found: C, 59.25;
H, 4.19; N, 23.06.
4-(1H-In d a zolyl)-1-m eth ylp yr id in iu m Iod id e (9). 4-(1H-
Indazolyl)pyridine [7 (246 mg, 1.2 mmol)] was dissolved in 20
mL of acetone. Iodomethane (341 mg, 2.4 mmol) was added
dropwise while stirring. The resulting reaction mixture was
stirred for 18 h at 25 °C. The mixture was filtered to give 404
1
mg (1.2 mmol, 99%) of 9 as a tan solid: mp 261-263 °C; H
NMR (DMSO-d6, 360 MHz): δ 8.94 (m, 2H), 8.77 (d, J ) 0.9
Hz, 1H), 8.53 (m, 2H), 8.36 (dddd, J ) 0.9 Hz, J ) 0.9 Hz, J
) 0.9 Hz, J ) 8.6 Hz, 1H), 8.02 (ddd, J ) 0.9 Hz, J ) 0.9 Hz,
J ) 8.0 Hz, 1H), 7.73 (ddd, J ) 0.9 Hz, J ) 7.1 Hz, J ) 8.5
Hz, 1H), 7.49 (ddd, J ) 0.9 Hz, J ) 7.2 Hz, J ) 8.0 Hz, 1H),
4.3 (s, 3H); 13C NMR (DMSO-d6, 90 MHz) 150.9, 146.6, 142.1,
138.2, 129.8, 127.2, 124.6, 122.7, 115.2, 112.8, 46.6; UV
(MeOH) 209, 224, 266, 335 nm. Anal. Calcd for C13H12IN3: C,
46.31; H, 3.59; N, 12.47. Found: C, 46.41; H, 3.62; N, 12.40.
4-(2H-In d a zolyl)-1-m eth ylp yr id in iu m Iod id e (10). In a
similar way 4-(2H-indazolyl)pyridine [8 (589 mg, 3.0 mmol)]
2-F lu or oben za ld eh yd e 4-P yr id in ylh yd r a zon e (15). A
mixture of 4-hydrazinylpyridine free base 12 (545 mg, 5.0
mmol) and o-fluorobenzaldehyde [14 (620 mg, 5.0 mmol)] in
15 mL of ethanol was heated under reflux for 18 h in the
presence of 4 Å molecular sieves. After filtering and removing
the solvent, the residue was purified by column chromatog-
raphy, eluting with hexane:ethyl acetate (9:1) followed by ethyl
acetate:methanol (9.5:0.5). The compound was crystallized
from ethyl acetate to yield 258 mg (1.2 mmol, 24%) of a yellow
solid: mp 204-205 °C; 1H NMR (DMSO-d6, 360 MHz) δ 11.03