TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2299–2302
A practical, efficient, and rapid method for the oxidation of
electron deficient pyridines using trifluoroacetic anhydride and
hydrogen peroxide–urea complex
Stéphane Caron,∗ Nga M. Do and Janice E. Sieser
Pfizer Central Research, Process Research and Development, Eastern Point Road, 0156-84, Groton, CT 06340, USA
Received 21 December 1999; accepted 20 January 2000
Abstract
A general method for the oxidation of electron-poor pyridines to their N-oxides using UHP and TFAA in
either CH2Cl2 or CH3CN was developed. The methodology proved to tolerate a number of functional groups
and substitution patterns and proceeded on notoriously difficult to oxidize substrates. © 2000 Elsevier Science Ltd.
All rights reserved.
Keywords: oxidation; pyridines; N-oxides; peroxides.
The oxidation of a pyridine to its N-oxide is usually perceived as a straightforward chemical transfor-
mation and is most often accomplished using a peracid1 such as peracetic acid, MCPBA or magnesium
monoperphthalate2 and more recently HOF·CH3CN complex.3 In 1998, Sharpless described a method
for the oxidation of electron deficient pyridines using catalytic MTO (MeReO3) and 30% H2O2 as the
co-oxidant.4
In the course of the development of a drug candidate, we encountered difficulties in the oxidation
of an electron poor pyridine to its N-oxide. Using 3,4,5-trichloropyridine, we investigated a series
of reagents for this transformation. We discovered that using trifluoroacetic anhydride (TFAA) in the
presence of the hydrogen peroxide urea complex (UHP5) was the superior procedure (Table 1). The use
of peroxytrifluoroacetic acid as an efficient oxidizing agent has been known for a long time. In 1954,
Emmons reported the oxidation of electron poor anilines to nitrobenzenes using peroxytrifluoroacetic
acid, which was generated from trifluoroacetic acid (TFA) and 90% H2O2.6 This procedure was also
utilized to oxidize pentachloropyridine.7 However, we found that using TFAA was far more efficient
than TFA in conjunction with UHP, which is more practical and safer to use than 90% H2O2. In the last
few years, several reports appeared on the use of UHP in oxidations, namely for the conversion of amines
to nitroalkane,8 Baeyer–Villiger oxidations of ketones to lactones,9 oxidations of sulfides to sulfones,10
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00165-9
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