Scheme 2. Conversion of Benzylic Halides 5a-e, Benzaldehydes 5f-l, or Acetophenones 5m into 1N-Hydroxyindazoles 4a-m
2.5 Unfortunately, unfavorable atom economy and lengthy
synthetic sequences required for construction of isoxazolone
intermediates detract from the synthetic utility of these
approaches.
amine side chains were recently described during the course
of this study.11
Treatment (Scheme 2) of 2-nitrobenzyl halides 5a-d with
ammonia furnished the corresponding amines 3a-d in
satisfactory yields (56-83%; see Table 1). We were de-
lighted to find that these were smoothly cyclized on exposure
to hot methanolic sodium hydroxide. The products 4a-d,
whose NMR spectra and HRMS data were consistent with
a 1N-hydroxyindazole structure, were obtained in good to
excellent yields (75-95%; see Table 1). To avoid the
potentially problematic isolation of amino acid derivative 3e,
a one-pot amination-cyclization procedure was developed.
After amination, the crude reaction mixture was evaporated
and then treated with methanolic sodium hydroxide to give
the indazole 4e directly and in good overall yield (74% from
5e). That several useful functionalities capable of undergoing
further manipulation were readily incorporated into the final
products (4a,c,e) was particularly pleasing.
To increase the scope and utility of this novel cyclization
process (Scheme 2), we then incorporated a range of
commercial 2-nitrobenzaldehydes as starting materials 5f-l.
Reductive amination of these substrates with methyl car-
bamate was anticipated to afford 2-nitrobenzyl carbamates
3f-l. We hoped that treatment of carbamates 3f-l with base
would result in concomitant deprotection and cyclization,
providing hyroxyindazoles in one pot. In practice, treatment
of the carbamates 3f-l with methanolic sodium hydroxide
led only to formation of complex mixtures. Fortunately, we
found that trimethylsilyl iodide (TMSI) was effective in
unmasking the amine cleanly, and after acid-base workup,
they could be cyclized directly.
Despite the paucity of useful synthetic methods, 1N-
hydroxyindazole derivatives have nonetheless been claimed
in patent applications as kinase inhibitors,6 peptide-coupling
reagents,7 optoelectronic materials, and dye additives.8
Recently related N-hydroxypyrazole-containing compounds
were found to display potent antitumor activity in rodent
models.9
Our interest in N-N bond-forming processes that involve
interaction of aromatic nitro groups with ortho-substituents10
led us to speculate that intramolecular base-catalyzed con-
densation of 2-nitrobenzylamine derivatives 3 could provide
a valuable and concise route to 1N-hydroxyindazoles 4.
Importantly, 2-nitrobenzylamines 3 were expected to be
conveniently prepared from readily available starting materi-
als (Scheme 2). Formal dehydrations between aromatic nitro
groups and aliphatic primary amine-containing side chains
are to our knowledge unknown. However, related base-
promoted condensations in systems containing secondary
(5) Steglich, W.; Kubel, B. Gruber. Chem. Ber. 1973, 106, 2870. (b)
D’Anello, M.; Erba, E.; Gelmi, M. L.; Pocar, D. Chem. Ber. 1987, 121,
67.
(6) Bhagwat, S. S.; Satoh, Y.; Sakata, S. T.; Buhr, C. A.; Albers, R.;
Sapienza, J.; Plantevin, V.; Chao, Q.; Sahasrabudhe, K.; Ferri, R. U.S. Patent
2004/127536. (b) Hagihara, M.; Komori, K.; Sunamoto, H.; Nishida, H.;
Matsugi, T.; Nakajima, T.; Hatano, M.; Kido, K.; Hara, H. WO 2005035506.
(c) Wei, C. C.; Huang, P.; Xia, Y. WO 2004014368.
(7) Horiki, K.; Murakami, A.; Chomei, N. React. Polym. 1987, 6, 127.
(8) (a) Ishikawa, T.; Elman, J. F.; Massa, D. J.; Montbach, E. N.;
Teegarden, D. M. U.S. Patent 2005/089676. (b) Lim, M. U.S. Patent 2006/
0156486. (c) Glenn, R. W.; Lim, M.; Murphy, B. P. U.S. Patent 2006/
042026.
Thus, carbamates 3f-l were prepared (Table 1) by
reductive amination of 2-nitrobenzaldehydes 5f-l with
methyl carbamate and tert-butyldimethylsilane (TBDMSH).12
(9) Wenckens, M.; Jakobsen, P.; Vedso, P.; Huusfeldt, P. O.; Gissel,
B.; Barfoed, M.; Brockdorff, B. L.; Lykekesfeldt, A. E.; Begtrup, M. Bioorg.
Med. Chem. Lett. 2003, 11, 1883.
(11) (a) Mills, A. D.; Nazer, M. Z.; Haddadin, M. J.; Kurth, M. J. J.
Org. Chem. 2006, 71, 2687. (b) Butler, J. D.; Solano, D. M.; Robins, L. I.;
Haddadin, M. J.; Kurth, M. J. J. Org. Chem. 2008, 73, 234. (c) Bouillion,
I.; Zajicek, J.; Pudelova, N.; Krchnak, V. J. Org. Chem. 2008, 73, 9027.
(10) (a) Slevin, A.; Koolmeister, T.; Scobie, M. Chem. Commun. 2007,
24, 2306. (b) Scobie, M.; Tennant, G. Chem. Commun. 1994, 21, 2451. (c)
Scobie, M.; Tennant, G. Chem. Commun. 1993, 23, 1756.
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