44 Pyridines
Synthesis of pyridines from 1,5-dicarbonyl compounds
(1,2- and 1,6-bonds made)
An obvious route to a pyridine involves a fi ve-carbon unit and a source of nitrogen – in practice, the interaction
of ammonia with a 1,5-dicarbonyl compound. Successive inter- and then intramolecular nucleophilic additions of
ammonia/amine nitrogen to the two carbonyl groups, followed by loss of two molecules of water complete the forma-
tion of a dihydropyridine, probably a 1,4-dihydropyridine, then requiring a relatively easy oxidation to achieve the
aromatic oxidation level, shown in general terms below.
A preferred variant of this avoids the oxidation step by the use of hydroxylamine in place of ammonia, where aromatisa-
tion of a 1,4-dihydro-1-hydroxypyridine intermediate occurs in situ by loss of water. 1,5-Diketones are accessible via a
number of routes, for example by Michael addition of enolate to enone (or precursor Mannich base, as in the example).
The use of an unsaturated 1,5-dicarbonyl compound will produce an aromatic pyridine directly. In a nice example,
2,2':6',2"-terpyridine can be synthesized in one pot from 2-acetylpyridine, N,N-dimethylformamide dimethyl acetal
(DMFDMA) and ammonia; the fi rst step is presumed to be dimethylaminomethylenation of the ketone methyl group
followed then by addition/elimination by the enolate of the starting ketone.
Precursors with carbons at a higher oxidation level lead to a correspondingly oxidised pyridine. As an example, a di-
enamine, generated easily by reaction of a ketone with DMFDMA, is a synthetic equivalent of a 1,5-dialdehyde but
additionally it has a high oxidation level central carbon so that when the ring closes, by reaction with methylamine, a
4-pyridone results.
When one of the ‘carbonyl’ groups is, instead, a nitrile, this oxidation level is refl ected in the product, which will then
have an amino group at an -position. In the example shown, a pyrrolidine enamine represents the other carbonyl