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in Table 1.11,12 It is apparent that 1,4-dioxane generally increased
the yield of the N-oxide, although pyrimidine 1h was not oxidized
at all. The reason for this remains unclear.
2. Boekelheide, V.; Linn, W. J. J. Am. Chem. Soc. 1954, 76, 1286.
3. Albini, P. Heterocyclic N-oxides; CRC Press: Boca Raton, FL; 1991, 31.
4. Brougham, P.; Cooper, M. S.; Cummerson, D. A.; Heaney, H.; Thompson, N.
Synthesis 1987, 1015.
5. Murray, R. W.; Jeyaraman, R. J. Org. Chem. 1985, 50, 2847.
6. Robke, J. G.; Behrman, E. J. J. Chem. Soc., D 1971, 2867.
The generality of the method is demonstrated by the range of
pyridine, quinoline and pyrimidine substrates converted (Table
1). For heterocyclic compounds poorly oxidized by mCPBA and
other reagents because of electronic and steric hindrance, signifi-
cantly improved yields were achieved. For example, the yield of
5-bromopyrimidine-N-oxide 2g with mCPBA is just 29%13 and re-
ported yields of quinoline-N-oxide 2f are, respectively, 35% or
50% when using H2O2/Ti-MCM-4114 or RuCl3/bromamine-T.15 Even
for severely hindered biarylpyrimidines and pyridines, improved
conversion rates were achieved over alternative reagents, and the
straightforward purification rendered these preparatively valuable
procedures.
In summary, an improved, safe and convenient method has been
developed for N-oxidation. In most cases, very high conversion
rates were achieved; even so, a major advantage of this method is
that the products are easy to isolate, so the reaction is useful even
for sterically compromised substrates that are usually difficult to
oxidize.
7. Coperet, C.; Adolfsson, H.; Chiand, J. P.; Yudin, A. K.; Sharpless, K. B. Tetrahedron
Lett. 1998, 391, 761; Saladino, R.; Carlucci, P.; Danti, M. C.; Crestini, C.;
Mincione, E. Tetrahedron 2000, 56, 10031.
8. Fray, G. I.; Hilton, R. J.; Teire, J. M. J. Chem. Soc., C 1966, 592.
9. Ziegler, Z. F.; Metcalf, C. A.; Nangia, A.; Schulte, G. J. Am. Chem. Soc. 1993, 115,
2581.
10. Snyder, L. R. J. Chromatogr. Sci. 1978, 16, 223.
11. General method for 2a. In a typical procedure, K2CO3 (20 mmol) and UHP
(10 mmol) were stirred in dry 1,4-dioxane or CHCl3 (100 ml) for 1 h, then TFAA
(10 mmol) was added dropwise below 12°C. The mixture was allowed to reach
rt, the heterocyclic compound (1 mmol) added and the mixture stirred
overnight at 50 °C (1,4-dioxane, if used, was then removed by evaporation
and replaced with DCM). The mixture was washed with water (50 ml), the
organic layer dried over MgSO4 and the solvent removed by evaporation to
produce a yellow oil, 0.179 g (97%) shown to be a single compound by high-
field NMR. 1H NMR (600.17 MHz, CDCl3), 8.34 (s, 1H), 8.13 (d, J = 5.5 Hz, 1H),
7.39 (d, J = 7.9 Hz, 1H), 7.15 (m, 1H). 13C NMR (150.91 MHz, CDCl3) 140.98,
138.1, 128.8, 126.1, 120.6. MS (ES+): m/z 176/174 (100%) (M+H)+, 124 (55%), 42
(25%).
12. N-Oxide 2h was prepared following the general method using chloroform as
solvent and purified by column chromatography (silica gel, chloroform/
methanol 95:5) to give 0.186 g (81%) as a white solid, mp 165–166 °C. 1H
NMR (600.17 MHz, CDCl3), 8.98 (s, 1H), 8.59 (s, 1H), 8.45 (s, 1H), 8.19 (d,
J = 7.4 Hz, 2H), 7.62 (d, J = 7.4 Hz, 2H), 3.95 (s, 3H). 13C NMR (150.91 MHz,
CDCl3) 166.0, 148.6, 142.1, 141.9, 136.0, 134.9, 132.0, 131.0, 127.3, 52.6. MS
(ES+): m/z 231 (100%) (M+H)+, 214 (50%), 183 (60%), 162 (60%); IR (KBr): 3350
(O–H), 3050m (Ar, C–H), 2950m, 1725s (C@O), 1275s (C–O) cmÀ1. CHN: found:
C, 62.40; H, 4.51; N, 11.79. C12H10N2O3 requires: C, 62.60; H, 4.38; N, 12.17.
13. Kress, T. J. J. Org. Chem. 1985, 50, 3073.
Acknowledgement
This work was supported, in part, by a project grant from the
Association for International Cancer Research, St. Andrews, UK.
14. Ramakrishna Prasad, M.; Kamalakar, G.; Madhavi, G.; Kulkarni, S. J.; Raghavan,
K. V. J. Mol. Cat. A: Chem. 2002, 186, 109.
References and notes
15. Sharma, V. B.; Jain, S. L.; Sain, B. Tetrahedron Lett. 2004, 45, 4281.
1. Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005, 127, 18020.