A practical, efficient, and rapid method for the oxidation of electron deficient pyridines using trifluoroacetic anhydride and hydrogen peroxide- urea complex

Article abstract of DOI:10.1016/S0040-4039(00)00165-9

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

Full text of DOI:10.1016/S0040-4039(00)00165-9

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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2300
and more recently conversion of pyridines to pyridine N-oxides,11 although this last protocol proceeded
at 85°C in the solid state.
Table 1
Oxidation of 3,4,5-trichloropyridine in CH2Cl2
A rapid evaluation of different solvents using 2.1 equivalents of UHP and 2.0 equivalents of TFAA
demonstrated that either THF, CH2Cl2 or CH3CN provided an acceptable rate for the reaction to go to
completion (Table 2). While methanol was ineffective, DMAC and toluene proved to slow down the
reaction. We found that the yield of the reaction could depend on the solvent selected in the case of some
of the substrates, but we could not identify a general trend which would guide us in solvent selection
based on the starting material. CH2Cl2 and CH3CN were usually preferred because of the increased
solubility of some of the starting materials.
Table 2
Solvent effect of the oxidation of 3,4,5-trichloropyridine with TFAA and UHP
We found that the oxidation of pyridines to their N-oxides using our protocol proceeded efficiently on
a number of electron deficient substrates (Table 3). For instance, carbonyls (esters, amides, ketones) are
tolerated and no Baeyer–Villiger oxidation was observed. The reaction also proceeds in the presence of
halides, trifluoromethyl groups, nitriles, and even nitropyridines. The oxidation also permits a number
of different substitution patterns and only proved to be much slower in the case of a 2,6-disubstituted
pyridine.
As a general procedure, the pyridine was dissolved in the preferred solvent (10 volumes) and UHP
(2.1 equivalents) was added to the solution, which was cooled to 0°C. TFAA (2.0 equivalents) was then
slowly added to the reaction mixture (the reaction is exothermic). The reaction was followed by TLC
and HPLC analysis until completion. In the cases where the reaction required more than 30 minutes,

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Table 3
Oxidation of pyridines using UHP (2.1 equiv.) and TFAA (2.0 equiv.)
it was allowed to warm to room temperature. The reaction was quenched with an aqueous solution of
Na2S2O3 and stirred for 15 minutes to destroy any residual peroxides before being poured into a 0.5
M HCl solution and extracted with CH2Cl2. The organic extracts were washed with saturated NaHCO3,
dried over MgSO4 and concentrated. The crude product was purified by either trituration with methyl
t-butyl ether or by a filtration on a plug of silica gel to afford the pure pyridine N-oxides.

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In conclusion, we have developed an efficient, rapid, and practical method for the oxidation of electron-
poor pyridines to their N-oxide. The methodology requires relatively safe and commercially available
reagents and proved to tolerate a number of functional groups and substitution patterns.
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