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7. Dwyer, M. A.; Bredt, D. S.; Snyder, S. H. Biochem. Bio-
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423.
9. Babbedge, R. C.; Bland-Ward, P. A.; Hart, S. L.; Moore,
P. K. Br. J. Pharmacol. 1993, 110, 225.
10. Elderfield, R. C. In Heterocyclic Compounds; Elderfield,
R. C., Ed.; John Wiley & Sons: New York, 1957; Vol. 5, pp
162.
11. Behr, L. C.; Fusco, R.; Jarobe, C. H. In Pyrazoles, Pyr-
azolines, Pyrazolidines, Indazoles and Condensed Rings; Wiley,
R.H.; Ed.; International Wiley Science: New York, 1969; pp 289.
12. Elguero, J. In Comprehensive Heterocyclic Chemistry;
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14. Kovach, E. G.; Barnes, D. E. J. Am. Chem. Soc. 1954, 76,
1176.
purified by flash chromatography on silica gel (EtOAc/cyclo-
hexane, 1:9) to afford 11b (0.22 g, 72%) as a pink solid: mp
108 ꢀC; IR (KBr) 3160, 2912, 1588, 1261, 951, 727 cmÀ1; H
1
NMR (CDCl3) d 5.23 (s, 2H), 6.81 (d, 1H, J=7.6 Hz), 7.08 (t,
1H, J=7.7 Hz), 7.29–7.49 (m, 6H), 7.99 (s, 1H), 10.73 (br s, 1H).
19. 4-Methoxyindazole (5) (Method A): A cooled aqueous
solution of sodium nitrite (1.22 g in 2.45 mL H2O, 1.79 mmol)
was added at 0 ꢀC dropwise to a ice cooled solution of 3-
methoxy-2-methylaniline (2.45 g, 17.9 mmol) dissolved in
fluoroboric acid (50% solution in water; 7.35 mL). After the
end of the addition, the mixture was stirred 1 h without cool-
ing. The resulting precipitate was filtered and washed with
Et2O (3Â100 mL) to obtain 4-methoxy-2-methylphenyldiazo-
nium tetrafluoroborate salt as a pink solid (4.05 g, 96%): mp
150 ꢀC; IR (KBr): 3426, 2231, 1590, 1062–1027 cmÀ1 1H
;
NMR (DMSO-d6) d 2.65 (s, 3H), 3.95 (s, 3H), 7.72 (t, 1H,
J=9.0 Hz), 7.80 (d, 1H, J=9.0 Hz), 8.17 (d, 1H, J=9.0 Hz).
The diazonium tetrafluoroborate salt (1 g, 4.23 mmol) was
added under nitrogen in one portion to a stirred mixture of
dried and powdered potassium acetate (0.85 g, 8.46 mmol) and
18-crown-6 (0.05 g, 0.21 mmol) in chloroform (40 mL). After
2 h, the resulting precipitate was filtered, washed with H2O
(3Â50 mL), dried over CaCl2 and evaporated in vacuo. The
crude gum was recrystallised in boiling H2O and filtered to
obtain a white solid (0.070 g, 11%): mp 118 ꢀC; IR (KBr):
3117, 2941, 1593, 1254, 983, 735 cmÀ1; 1H NMR (DMSO-d6) d
3.89 (s, 3H), 6.52 (d, 1H, J=7.8 Hz), 7.07 (d, 1H, J=7.8 Hz),
7.23 (t, 1H, J=7.8 Hz), 8.00 (s, 1H), 13.00 (br s, 1H).
15. Collot, V.; Dallemagne, P.; Bovy, P. R.; Rault, S. Tetra-
hedron 1999, 55, 6917.
16. Bocchi, V.; Palla, G. Synthesis 1982, 1096.
17. 7-Hydroxyindazole (10): Boron tribromide (1.0 M solu-
tion in CH2Cl2) (32.4 mL, 32.4 mmol) was added dropwise to a
cold solution of 7-methoxyindazole 8 (1.80 g, 12.1 mmol) in
CH2Cl2 (30 mL). The reaction mixture was stirred and heated
to reflux. After 4 h, the solution was cooled to 0 ꢀC. Water
(7.4 mL) was added dropwise then 10% aqueous NaHCO3
until pH 7–8. The reaction mixture was extracted with EtOAc
(3Â50 mL). The combined organic layers were dried (MgSO4),
filtered and evaporated in vacuo. The residue was purified by
flash chromatography on silica gel (acetone/cyclohexane, 3:7)
to afford 10 (1.30 g, 80%) as a beige solid: mp 179 ꢀC (tolu-
20. 3-Iodo-7-methoxyindazole (9):
A solution of iodine
(4.45 g, 17.54 mmol) and potassium hydroxide pellets (1.85 g,
32.89 mmol) were successively added into a DMF solution
(25 mL) of 7-methoxyindazole 8 (1.30 g, 8.77 mmol) at room
temperature under stirring. After 1 h, the reaction mixture was
poured into 10% aqueous NaHSO3 (100 mL) and extracted
with Et2O (3Â100 mL). The combined organic layers were
washed with water and brine, dried (MgSO4), and the solvent
was evaporated. The residue was purified by flash chromato-
graphy on silica gel (EtOAc/cyclohexane, 1:5) to afford 9
(1.80 g, 75%) as a beige solid: mp 140 ꢀC (toluene); IR (KBr)
1
ene); H NMR (DMSO-d6) d 6.64 (d, 1H, J=8.1 Hz), 6.87 (t,
1H, J=8.1 Hz), 7.14 (d, 1H, J=8.1 Hz), 7.94 (s, 1H), 10.02 (br
s, 1H), 12.99 (br s, 1H).
18. 7-Ethoxyindazole (11a): To a solution of 10 (0.30 g,
2.24 mmol) in acetone (8 mL) was added iodoethane (0.22 mL,
2.24 mmol) and potassium carbonate (1.55 g, 11.20 mmol). The
mixture was heated 3 h to reflux, and then the solvent was
removed in vacuo. The residue was dissolved in EtOAc
(30 mL), washed with H2O (2Â15 mL), dried (MgSO4), filtered
and evaporated. The solid residue was purified by flash chro-
matography on silica gel (EtOAc/cyclohexane, 1:8) to afford
11a (0.25 g, 68%) as a white solid: mp 112 ꢀC; IR (KBr) 3155,
1
3334, 1516, 1313, 1258, 1004, 775 cmÀ1; H NMR (CDCl3) d
3.98 (s, 3H), 6.79 (d, 1H, J=8.0 Hz), 7.08 (d, 1H, J=8.0 Hz),
7.14 (t, 1H, J=8.0 Hz), 10.82 (br s, 1H).
21. Bland-Ward, P. A.; Moore, P. K. Life Sci. 1995, 57, 131.
22. MacKenzie, G. M.; Rose, S.; Bland-Ward, P. A.; Moore,
P. K.; Jenner, P.; Marsden, C. D. Neuroreport 1994, 5, 1993.
23. Koster, R.; Anderson, M.; de Beer, E. J. Fed. Proc. 1959,
18, 412.
1
2918, 1590, 1261, 953, 724 cmÀ1; H NMR (CDCl3) d 1.34 (t,
3H, J=7.2 Hz), 4.12 (q, 2H, J=7.2 Hz), 6.64 (d, 2H,
J=7.5 Hz), 6.98 (t, 1H, J=7.5 Hz), 7.24 (d, 1H, J=7.9 Hz),
8.00 (s, 1H), 10.92 (br s, 1H). 7-Benzyloxyindazole (11b): As
above, starting from 10 (0.18 g, 1.34 mmol) in solution in ace-
tone (8 mL) was added benzyl bromide (0.15 mL, 1.34 mmol)
and potassium carbonate (0.93 g, 6.70 mmol). The residue was
24. Zagvazdin, Y.; Sancesario, G.; Wang, Y. X.; Share, L.;
Fitzgerald, M. E.; Reiner, A. Eur. J. Pharmacol. 1996, 303, 61.
25. Sopkova-De Oliveira Santos, J.; Collot, V.; Rault, S. Acta
Cryst. C 2000, 56, 1503.
26. Raman, C. S.; Li, H.; Martasek, P.; Kral, V.; Masters,
B. S.; Poulos, T. L. Cell 1998, 95, 939.