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reproducible, and efficient. First of all, the concentrations of HOAc
and 2 were kept constant while the final concentration of HNO3
changed. Concentrations of HNO3 above 6 M lead to the formation
of mainly oxidative by-products whereas concentrations below
that gave fairly consistent yields. However, the concentration of
4 M HNO3 (Table 1, entry 2) gave the highest yield. Second, acetic
acid was first kept in the system (entries 1–4) to prevent oxidative
by-products from forming due to excess acetyl nitrate in
solution,12,13 though it was found that the lack of acetic acid did
not affect either the reaction time or yield (entries 2 and 5). Third,
when the reaction was scaled up from 1.17 mmol (entry 5) of the
substrate 2 to 9.35 mmol (entry 6) a significant increase of yield
was observed.14 Most significantly, for all the conditions we tried,
the authors and does not necessarily represent the official views
of the National Institute of AIDS and Infectious Diseases or the Na-
tional Institutes of Health.
References and notes
1. Olah, G. A.; Malhotra, R.; Narang, S. C. Nitration: Methods and Mechanisms; VCH:
New York, 1989. pp 1–7.
2. Ridd, J. H. Acta Chem. Scand. 1998, 52, 11.
3. Olah, G. A.; Narang, S. C.; Olah, J. A.; Lammertsma, K. Proc. Natl. Acad. Sci. USA
1982, 79, 4487.
4. Lemaire, M.; Guy, A.; Roussel, J.; Guette, J. P. Tetrahedron 1987, 43, 835.
5. Lemaire, M.; Guy, A.; Boutin, P.; Guette, J. P. Synthesis 1989, 761.
6. Coombes, R. G.; Ridd, J. H. J. Chem. Soc., Chem. Commun. 1992, 174.
7. Coombes, R. G.; Hadjigeorgiou, P.; Jensen, D. G. J.; Morris, D. L. ACS Symposium
Series 623; 1996; p 19.
the reaction substrate
2 was consumed completely within
8. Parker, D. L.; Meng, D.; Ratcliffe, R. W.; Wilkening, R. R.; Sperbeck, D. M.;
Greenlee, M. L.; Colwell, L. F.; Lambert, S.; Birzin, E. T.; Frisch, K.; Rohrer, S. P.;
Nilsson, S.; Torsell, A. G.; Hammond, M. L. Bioorg. Med. Chem. Lett. 2006, 16,
4652.
9. Yu, Y.; Singh, S. K.; Liu, A.; Li, T. K.; Liu, L. F.; LaVoie, E. J. Bioorg. Med. Chem.
2003, 11, 1475.
5–10 min after the addition of nitric acid.
In summary, nitrocyclohexadienones represent mild and selec-
tive nitration reagents that have seen a variety of applications in
the synthesis of complex pharmacological compounds. We devel-
oped a new procedure for the facile synthesis of 2,3,5,6-tetrab-
romo-4-methyl-4-nitrocyclohexa-2,5-dien-1-one (1) using acetic
anhydride and 70% HNO3 system at 0 °C. Compared to the original
10. Ban, H.; Muraoka, M.; Ohashi, N. Tetrahedron 2005, 61, 10081.
11. For example synthesis, see Ref. 4.
12. Hoggett, J. G.; Moodie, R. B.; Penton, J. R.; Schofield, K. Nitration and Aromatic
Reactivity; University Press: Cambridge, 1971. pp 79–106.
13. Fischer, A.; Read, A. J.; Vaughan, J. J. Chem. Soc. 1964, 3691.
14. Optimized procedure: To a solution of 4.0 g (9.35 mmol) of 2 in 28 mL of acetic
anhydride was added, drop-wise, 6 mL (135 mmol) HNO3 (d 1.42) at 0 °C. The
suspension was stirred at that temperature for 10 min and the product was
precipitated out with the addition of 40 mL H2O. The product, 1, was filtered
out and the resultant pale yellow crystals were washed with H2O and hexane
and dried under vacuum giving a yield of 4.15 g (95%). 1H NMR (400 MHz,
synthesis, our method provides
a practical approach with
efficiency and reliable yields.
Acknowledgements
We are grateful to the funding support from NIH/NIAID
AI69975 and AI074461. The content is solely the responsibility of
CDCl3) d 2.26 (s, 3H), mp: decomposed 80 °C, IR Vmax (ATR): 1682 cmÀ1
.