Y. Shoji et al. / Tetrahedron Letters 45 (2004) 1769–1771
1771
15 min. A solution of fluorobenzene (47 lL, 0.5 mmol) in
Et2O (0.5 mL) was added dropwise to a refluxing reaction
mixture, and then the whole was heated under reflux for
3 h. After the reaction was quenched by addition of H2O
at 0 ꢁC, a common work-up was carried out. The pure
3-trimethylsilylindazole 1 (81 mg, 86%) as a solid was
obtained by flash silica gel column chromatography
(n-hexane/ethyl acetate ¼ 6:1).
Acknowledgements
This work was financially supported by a Grant-in-Aid
for Scientific Research (KAKENHI), a Grant-in-Aid
from The Fujisawa Foundation, and a Grant-in-Aid for
Research in Nagoya City University.
17. Each regioisomer could be separated by flash silica gel
column chromatography.
18. Selected data for 2–11. 2a, 1H (CDCl3) d: 0.45 (9H, s), 3.97
(3H, s), 6.72 (1H, d, J ¼ 8 Hz), 7.07 (1H, dd, J ¼ 8, 8 Hz),
7.39 (1H, d, J ¼ 8 Hz); 2b, 1H (CDCl3) d: 0.42 (9H, s), 3.98
(3H, s), 6.47 (1H, d, J ¼ 8 Hz), 7.12 (1H, d, J ¼ 8 Hz),
7.26–7.31 (1H, m); 3a, 1H (CDCl3) d: 0.46 (9H, s), 5.24
(2H, s), 6.81 (1H, dd, J ¼ 8, 8 Hz), 7.06 (1H, dd, J ¼ 8,
References and notes
€
1. For a review, see Brase, S.; Gil, C.; Knepper, K. Bioorg.
Med. Chem. 2002, 10, 2415–2437.
2. (a) Poter, H. D.; Perterson, W. D. In Organic Syntheses;
Wiley: New York, 1955; Collect. Vol. 3, pp 660–661; (b)
Bartsch, R. A.; Yang, I.-W. J. Heterocycl. Chem. 1984, 21,
1063–1064.
1
8 Hz), 7.36–7.48 (6H, m); 3b, H (CDCl3) d: 0.43 (9H, s),
5.22 (2H, s), 6.52 (1H, d, J ¼ 8 Hz), 7.12 (1H, d,
J ¼ 8 Hz), 7.37–7.49 (6H, m); 4a, 1H (CDCl3) d: 0.46
(9H, s), 2.95 (6H, s), 6.77 (1H, d, J ¼ 8 Hz), 7.07 (1H, dd,
J ¼ 8, 8 Hz), 7.42 (1H, d, J ¼ 8 Hz); 4b, 1H (CDCl3) d:
0.45 (9H, s), 2.78 (6H, s), 6.85 (1H, dd, J ¼ 2, 7 Hz), 7.23–
7.32 (2H, m); 5a, 1H (CDCl3) d: 0.48 (9H, s), 7.05 (1H, dd,
J ¼ 8, 8 Hz), 7.52 (1H, d, J ¼ 8 Hz), 7.77 (1H, d,
J ¼ 8 Hz); 5b, 1H (CDCl3) d: 0.57 (9H, s), 7.20 (1H,
dd, J ¼ 8, 8 Hz), 7.36 (1H, d, J ¼ 8 Hz), 7.52 (1H, d,
J ¼ 8 Hz); 6a, 1H (CDCl3) d: 0.45 (9H, s), 1.47 (9H, s),
6.95 (1H, d, J ¼ 8 Hz), 7.05 (1H, dd, J ¼ 8, 8 Hz), 7.49
(1H, d, J ¼ 8 Hz); 6b, 1H (CDCl3) d: 0.46 (9H, s), 1.68
(9H, s), 6.68 (1H, d, J ¼ 8 Hz), 7.05 (1H, d, J ¼ 8 Hz),
7.21 (1H, dd, J ¼ 8, 8 Hz); 7a, 1H (CDCl3) d: 0.46 (9H, s),
2.57 (3H, s), 7.08–7.16 (2H, m), 7.67 (1H, d, J ¼ 8 Hz); 7b,
1H (CDCl3) d: 0.49 (9H, s), 2.73 (3H, s), 6.94 (1H, d,
J ¼ 8 Hz), 7.23–7.29 (1H, m), 7.39 (1H, d, J ¼ 8 Hz); 8a,
1H (CDCl3) d: 0.47 (9H, s), 3.88 (3H, s), 7.07 (1H, dd,
J ¼ 2, 9 Hz), 7.15 (1H, d, J ¼ 2 Hz), 7.47 (1H, d,
J ¼ 9 Hz); 8b, 1H (CDCl3) d: 0.46 (9H, s), 3.86 (3H, s),
6.82 (1H, dd, J ¼ 2, 9 Hz), 6.91 (1H, d, J ¼ 2 Hz), 7.67
3. (a) Cadogan, J. I. G.; Cameron-Wood, M.; Mackie, R. K.;
Searle, R. J. G. J. Chem. Soc. 1965, 4831; (b) Akazome,
M.; Kondo, T.; Watanabe, Y. J. Org. Chem. 1994, 59,
3375–3380.
4. (a) Kovach, E. G.; Barnes, D. E. J. Am. Chem. Soc. 1954,
76, 1176–1178; (b) Huisgen, R.; Bast, K. Org. Synth. 1962,
42, 69–72.
5. Fernandez, P. A.; Bellamy, T.; Kling, M.; Madge, D. J.;
Selwood, D. L. Heterocycles 2001, 55, 1813–1816.
6. (a) Caron, S.; Vazquez, E. Synthesis 1999, 588–592; (b)
Lee, F.-Y.; Lien, J.-C.; Huang, L.-J.; Huang, T.-M.; Tsai,
S.-C.; Teng, C.-M.; Wu, C.-C.; Cheng, F.-C.; Kuo, S.-C.
J. Med. Chem. 2001, 44, 3746–3749.
7. (a) Song, J. J.; Yee, N. K. Org. Lett. 2000, 2, 519–521; (b)
Song, J. J.; Yee, N. K. Tetrahedron Lett. 2001, 42, 2937–
2940.
8. Huisgen, R.; Knorr, R. Naturwissenschaften 1961, 48, 716.
€
9. (a) Ried, W.; Schon, M. Ann. Chem. 1965, 689, 141–144;
(b) Garcıa-Abbad, E.; Garcıa-Lopez, M. T.; Garcıa-
ꢀ
ꢀ
ꢀ
ꢀ
~
Munoz, G.; Stud, M. J. Heterocycl. Chem. 1976, 13,
1241–1244.
1
(1H, d, J ¼ 9 Hz); 9a, H (CDCl3) d: 0.47 (9H, s), 7.59–
10. For reviews, see (a) Shioiri, T.; Aoyama, T. In Science of
Synthesis; Fleming, I., Ed.; Georg Thieme: Stuttgart, 2002;
Vol. 4, pp 569–577; (b) Shioiri, T.; Aoyama, T. In
Advances in the Use of Synthons in Organic Chemistry;
Dondoni, A., Ed.; JAI: London, 1993; Vol. 1, pp 51–101.
11. Aoyama, T.; Inoue, S.; Shioiri, T. Tetrahedron Lett. 1984,
25, 433–436.
12. Asaki, T.; Aoyama, T.; Shioiri, T. Heterocycles 1988, 27,
343–346.
13. Ito, T.; Hatano, K.; Aoyama, T.; Shioiri, T. Heterocycles
1993, 35, 41–46.
7.63 (2H, m), 8.10 (1H, s); 9b, 1H (CDCl3) d: 0.48 (9H, s),
7.37 (1H, d, J ¼ 8 Hz), 7.82 (1H, s), 7.92 (1H, d,
J ¼ 8 Hz); 10, 1H (CDCl3) d: 0.40 (9H, s), 3.92 (3H, s),
3.93 (3H, s), 6.31 (1H, d, J ¼ 8 Hz), 6.59 (1H, d,
J ¼ 8 Hz); 11, 1H (CDCl3) d: 0.45 (9H, s), 2.37 (3H, s),
2.37 (3H, s), 7.29 (1H, s), 7.55 (1H, s).
19. (a) 7-Methoxyindazole: See Ref. 4a; (b) 4-Methoxyind-
azole and 7-benzyloxyindazole: Schumann, P.; Collot, V.;
Hommet, Y.; Gsell, W.; Dauphin, F.; Sopkova, J.;
MacKenzie, E. T.; Duval, D.; Boulouard, M.; Rault, S.
Bioorg. Med. Chem. Lett. 2001, 11, 1153–1156; (c)
7-Bromoindazole: Boulton, B. E.; Coller, B. A. W. Aust.
J. Chem. 1974, 27, 2343–2347; (d) 4-Methylindazole and
5-methoxyindazole: DellÕErba, C.; Novi, M.; Petrillo, G.;
Tavani, C. Tetrahedron 1994, 50, 3529–3536; (e)
6-(Trifluoromethyl)indazole was synthesized from
2-methyl-5-(trifluoromethyl)aniline commercially avail-
able according to Ref. 2b.
20. The reaction of nucleophiles with benzynes generated
from halobenzenes bearing substituents such as alkoxy,
amino, and halogen groups at the o-position, which have
+I effect, is well known to give preferentially m-substituted
benzene derivatives. See: (a) Kametani, T.; Kigasawa, K.;
Hiiragi, M.; Aoyama, T.; Kusana, O. J. Org. Chem. 1971,
36, 327–330; (b) Biehl, E. R.; Nieh, E.; Hsu, K. C. J. Org.
Chem. 1969, 34, 3595–3599.
14. Aoyama, T.; Nakano, T.; Nishigaki, S.; Shioiri, T.
Heterocycles 1990, 30, 375–379.
15. Data for 3-trimethylsilylindazole (1): Colorless crystals
(recrystallization from n-hexane). Mp 154–155 ꢁC. IR
1
(neat) mmax: 2986, 1374, 1242, 1048, 847 cmꢀ1. H (CDCl3)
d: 0.46 (9H, s), 7.16 (1H, dd, J ¼ 8, 8 Hz), 7.37 (1H, dd,
J ¼ 8, 8 Hz), 7.54 (1H, d, J ¼ 8 Hz), 7.83 (1H, d,
J ¼ 8 Hz). 13C (CDCl3) d: )0.7 (·3), 110.1, 120.6, 121.6,
126.2, 128.6, 140.7, 147.5. Mass (EI): m=z 190 (Mþ, 41.6),
175 (Mþ)Me, 100). Anal. Calcd for C10H14N2Si: C, 63.11;
H, 7.41; N, 14.72. Found: C, 62.97; H, 7.43; N, 14.79.
16. Representative procedure: To
a solution of lithium
tetramethylpiperidide, which was prepared from TMP
(0.34 mL, 2.0 mmol) and n-BuLi (1.58 M in n-hexane,
1.27 mL, 2.0 mmol) in Et2O (1.5 mL), TMSCHN2 (2.40 M
in n-hexane, 0.42 mL, 1.0 mmol) was added dropwise
under a nitrogen atmosphere at )78 ꢁC and stirred for
21. Aoyama, T.; Kabeya, M.; Fukushima, A.; Shioiri, T.
Heterocycles 1985, 23, 2363–2366.