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The diazotation method generally requires the isolation of a potentially explosive diazonium salt intermediate. The formation and cyclization of the diazonium salt proceed simultaneously under the reaction conditions only in the presence of additional highly electron-withdrawing groups (e.g., nitro): (a) Bartsch, R. A.; Tang, I.-W. J. Heterocycl. Chem. 1984, 21, 1063.
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Even the most advanced modification of the Jacobsen reaction remains relatively impractical, as it requires the addition of 0.1 equiv of expensive and toxic crown ether catalyst, employs toxic chloroform as a preferred solvent, and adds a deprotection step to recover the indazole: (a) Beadle, J. R.; Korzeniowski, S. H.; Rosenberg, D. E.; Garcia-Slanga, B. J.; Gokel, G. W. J. Org. Chem. 1984, 49, 1594-1603.
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Bromoindazole 3 was obtained as one of the products resulting from the condensation of bromobenzyne with (trimethylsilyl)diazomethane: Shoji, Y.; Hari, Y.; Aoyama, T. Tetrahedron Lett. 2004, 45, 1769-1771.
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33750022802
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note
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It is possible that intramolecular cyclization of hydrazones with the formation of indazoles still could be accomplished at higher temperatures. In the related study of the intramolecular cyclizations of 2-mesyloxyacetophenones hydrazones (ref 18, eq 4), the indazole formation was observed at temperatures above 130 °C. However, a DSC scan of hydrazone 13 indicated that it underwent highly exothermic decomposition at 140-150 °C, prompting us to set 110 °C as the upper limit for all our experiments.
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28
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0021808398
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Strupezewski, J. T.; Allen, R. C.; Gardner, B. A.; Schmid, B. L.; Stache, U.; Glamkowski, E. J.; Jones, M. C.; Ellis, D. B.; Huger, F. P.; Dunn, R. W. J. Med. Chem. 1985, 28, 761-769.
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Dunn, R.W.10
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31
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33750001926
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note
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We did not attempt to identify the structures of minor side products formed in these reactions in less than 5% peak area by HPLC methodology.
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34
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33749994644
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note
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19F coupling.
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35
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37049044543
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For examples of halogen displacement with hydrazine in substituted benzonitrile see: (a) Parnell J. Chem. Soc. 1959, 2363.
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Parnell1
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37
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33750024430
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note
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Alternatively, nitrile formation could occur after fluoride substitution with hydrazine. This, however, seems less likely, as a highly electron-donating hydrazide will deactivate the methyloxime group for elimination.
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