A safe, convenient and efficient method for the preparation of heterocyclic N-oxides using urea·hydrogen peroxide

Article abstract of DOI:10.1016/j.tetlet.2008.09.124

A novel, convenient, and high-yielding method has been developed for the preparation of heterocyclic N-oxides. The reaction uses the urea·hydrogen peroxide addition complex as a peroxide source for the in situ generation of trifluoroperacetic acid. The advantages of this method are easy handling of a stable, solid oxidant; high yields and simple removal of excess reagents and by-products.

Full text of DOI:10.1016/j.tetlet.2008.09.124

Tetrahedron Letters 49 (2008) 6933–6935
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A safe, convenient and efficient method for the preparation of heterocyclic
N-oxides using ureaÁhydrogen peroxide
Dawen Rong a, Victoria A. Phillips a, Ramón Sánchez Rubio b, Ma Ángeles Castro b, Richard T. Wheelhouse a,
*
a School of Pharmacy, University of Bradford, Bradford, West Yorkshire BD7 1DP, UK
b Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, 37007, Salamanca, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 June 2008
Revised 16 September 2008
Accepted 22 September 2008
Available online 25 September 2008
A novel, convenient, and high-yielding method has been developed for the preparation of heterocyclic N-
oxides. The reaction uses the ureaÁhydrogen peroxide addition complex as a peroxide source for the
in situ generation of trifluoroperacetic acid. The advantages of this method are easy handling of a stable,
solid oxidant; high yields and simple removal of excess reagents and by-products.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
N-Oxide
UreaÁhydrogen peroxide
Trifluoroperacetic acid
Pyrimidine
Pyridine
Quinoline
N-Oxides have important roles in organic synthesis, a recent
example being their use as a surrogate for heterocyclic boronic
acids in a Pd-catalyzed cross-coupling reaction.1 A wide variety
of N-oxidation reagents and conditions has been reported, for
example, acetic acid and hydrogen peroxide (AcOH/H2O2),2
m-chloroperbenzoic acid (mCPBA),3 monoperoxyphthalic acid,4
dioxirane5 and Caro’s acid (H2SO5).6 Some methods also employ
transition metal catalysts.7 All of these routes are beset by limita-
tions of incomplete reaction, contaminating by-products and high
cost, in addition to awkward purifications or handling of hazardous
liquid oxidizing agents.
Trifluoroperacetic acid (TFPA) is a powerful and effective oxi-
dant due to the influence of the three electronegative fluorine
atoms. It is typically generated from high-concentration (60–90%)
—
O
O
O
H
2—
1.
2.
HCO3
+
+
CO3
H
O
O
H
H
O
O
O
O
+
OH
O
O
+
+
CF3
+
O
CF3
CF3
O
CF3
O
O
N
N O
OH
3.
4.
CF3
CF3
O
CF3
OH
R
R
2
1
O
O
—
2—
+
+
HCO3
CO3
OH
CF3
O
Scheme 1. Mechanism for the N-oxidation of heterocyclic compounds with UHP and TFAA.
* Corresponding author. Tel.: +44 0 1274 234710; fax: +44 0 1274 235600.
E-mail address: r.t.wheelhouse@brad.ac.uk (R. T. Wheelhouse).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.124

6934
D. Rong et al. / Tetrahedron Letters 49 (2008) 6933–6935
aqueous hydrogen peroxide,8 which is unstable, hazardous to
transport and requires specialist handling. Herein, we report an
adaptation of a Baeyer–Villiger oxidation procedure9 to the prepa-
ration of heterocyclic N-oxides. UreaÁhydrogen peroxide (UHP), an
odourless, white solid which contains 35% of H2O2, acts as hydro-
gen peroxide source for the in situ generation of trifluoroperacetic
acid in the presence of trifluoroacetic anhydride (TFAA). The
process is outlined in Scheme 1. A significant advantage of this
method over the alternative reagents cited above is that all the
reagents and by-products are freely soluble in water. This
means they can be separated from the desired reaction products
by partition between water and an organic solvent such as
dichloromethane.
The influence of solvent on the success of the conversion was
paramount. The reaction involves polar and ionic species that are
insoluble in low-polarity organic solvents, and also intermediates
that are sensitive to water or alcohols. Chloroform and 1,4-dioxane
(polarity index 4.1 and 4.8, respectively)10 were found to possess
suitable physical and chemical properties—stability, solubility of
reagents and boiling point. The yields of N-oxidation are shown
Table 1
N-Oxidation of heterocyclic compounds
Substrate
Product
Yielda (%)
CHCl3 solvent
93 (90)
Dioxane solvent
100 (97)
O-
N+
N
Br
Br
1a
2a
O-
N+
N
Br
97 (93)
100 (97)
100 (96)
Br
1b
2b
O-
N
N+
100 (96)
1c
2c
O-
N+
N
100 (94)
100 (95)
1d
2d
O-
N
N+
100 (96)
100 (95)
1e
2e
-
N+
O
Cl
N
Cl
95 (86)
98 (88)
Cl
Cl
1f
2f
O-
N+
N
N
100 (95)
100 (96)
Br
N
N
Br
1g
2g
O-
N
N+
N
90 (81)
No reaction
CO2Me
CO2Me
1h
2h
a
Conversion determined by 1H NMR; isolated yields are shown in parentheses.

D. Rong et al. / Tetrahedron Letters 49 (2008) 6933–6935
6935
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.