42 Pyridines
N-Oxides
Pyridine N-oxides are very useful synthetic reagents, having an ambiphilic nature, that is they can react with elec-
trophiles or nucleophiles because either the positive charge on nitrogen or the negative charge on oxygen can be delo-
calised to the - or -positions, depending on demand from the reagent: 4-bromination and 4-nitration under standard
conditions are examples of electrophilic substitution. In the sequence shown, 4-nitropyridine N-oxide undergoes easy
nucleophilic substitution (nitrite is the leaving group). A pyridine N-oxide oxygen can be easily removed using a variety
of reducing agents, revealing the aromatic pyridine – reaction with a trivalent phosphorus compound has often been
used (see also page 33).
Nucleophilic additions at -positions of pyridine N-oxides are often carried out under conditions where the oxygen is
fi rst acylated, enhancing the positive character of the nitrogen and the polarisation of the iminium unit. The initially
formed dihydropyridine adduct undergoes re-aromatisation via a 1,2-elimination in which the oxygen substituent
is lost from the nitrogen. Using 4-methoxypyridine N-oxide as a substrate, reaction with acetic anhydride leads to
2-acetoxy-4-methoxypyridine; such esters (of 2- and 4-hydroxypyridines) are very easily hydrolysed to reveal the cor-
responding pyridone – overall, an -unsubstituted pyridine has been converted into a 2-pyridone.
Another useful process is the conversion of a pyridine, via its N-oxide, into a 2-halopyridine, again achieving function-
alisation of an -unsubstituted pyridine in two easy steps; the sequence shown is for pyridine N-oxide itself, proceed-
ing via an adduct which fi nally loses phosphorodichloridic acid.
2-Methylpyridine N-oxides react with hot acetic anhydride and produce 2-acetoxymethylpyridines; once again elec-
trophilic attack at the N-oxide oxygen initiates the sequence.