Pyridine N-Oxide

[694-59-7]  · C5H5NO  · Pyridine N-Oxide  · (MW 95.11)

(oxidation of alkyl halides to aldehydes; oxidative decarboxylation of certain carboxylic acids, anhydrides, and a-halo acids; dehydrogenation of carboxamides)

Physical Data: mp 66 °C; bp 270 °C.

Solubility: sol water, most polar solvents.

Form Supplied in: deliquescent colorless solid.

Analysis of Reagent Purity: 1H NMR d 7.35 (3H, m), 8.35 (3H, m).

Purification: distillation at aspirator pressure.

Handling, Storage, and Precautions: very hygroscopic; irritant; use in a fume hood.

Oxidative Decarboxylation.

Certain substituted acetic acids and their anhydrides undergo oxidative decarboxylation to aldehydes and ketones on treatment with pyridine N-oxide in toluene or xylene at reflux (eqs 1-3). Acids require an equivalent of Acetic Anhydride to dehydrate them to the anhydride.1,2

In a reaction of perhaps greater synthetic interest, a-halo acids are converted with 4 equiv of pyridine N-oxide to aldehydes and ketones, losing a carbon atom in the process (eqs 4-6).3,4

Oxidation of Alkyl Halides.

Pyridine N-oxide oxidizes even unactivated alkyl halides to carbonyl compounds (eqs 7-9). This is of some importance as most related methods9 (e.g. Kröhnke and Kornblum oxidations) are limited to activated halides. The reaction can be performed in two ways. In the first, the halide is treated with the N-oxide in the presence of a base such as NaHCO3. In the second, the intermediate N-alkoxypyridinium salt is isolated before base treatment.5-7 2-Picoline N-oxide may be used in a similar oxidation reaction.8

The method is excellent for the synthesis of a-keto esters.9 In the examples in eqs 10 and 11, the a-bromo ester or acid is treated with pyridine N-oxide and Silver(I) Nitrate at 0 °C. Decomposition of the isolated salt with mild base gives the dicarbonyl compound in high yield.

In some cases (e.g. eq 11), it is unnecessary to add silver nitrate, and the bromide salt may be used. For some substrates (e.g. secondary halides), the more powerful nucleophile DMAP 1-oxide may offer some advantages (eq 12).10 However, oxidation of cyclohexyl bromide still fails, due to elimination.

Dehydrogenation of Carboxamides.

Treatment of the imidoyl chlorides of tertiary amides with pyridine N-oxide and Triethylamine in CHCl3 results in dehydrogenation, giving the a,b-unsaturated amides (eqs 13-15).11

Diphenyl sulfoxide may be used as the oxidant, but purification is more difficult. The synthesis of dehydroamino acids derivatives by this reaction is noteworthy (e.g. eq 15).12 The amide must be branched in the a-position, otherwise the sole product formed is the a-chloro amide (eq 16).

1. Cohen, T.; Shaw, C. K.; Jenkins, J. A. JOC 1973, 38, 3737.
2. Rüchardt, C.; Eichler, S.; Krätz, O. TL 1965, 233.
3. Cohen, T.; Song, I. H. JOC 1966, 31, 3058.
4. Cohen, T.; Song, I. H.; Fager, J. H.; Deets, G. L. JACS 1967, 89, 4968.
5. Stowell, J. C. JOC 1970, 35, 244.
6. Henrick, C. A. T 1977, 33, 1845.
7. Feely, W.; Lehn, W. L.; Boekelheide, V. JOC 1957, 22, 1135.
8. Traynelis, V. J.; Kimball, J. P. JOC 1975, 40, 2365.
9. Kilényi S. N. COS 1991, 7, 653.
10. Sliwa, H.; Tartar, A. JOC 1976, 41, 160.
11. Mukaiyama, S.; Inanaga, J.; Yamaguchi, M. BCJ 1981, 54, 2221.
12. Da Costa, R.; Gillard, M.; Falmagne, J. B.; Ghosez, L. JACS 1979, 101, 4381.

S. Nicholas Kilényi

Sanofi Research, Brussels, Belgium

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