Heterocyclic Chemistry at a Glance

Pyridines 43

Amine substituents

All the amino-pyridines exist in the amino tautomeric form (not the alternative imine form) and protonate on the
ring nitrogen, the 2- and 4-isomers giving particularly stabilised salts due to involvement of the substituent amine lone
pair in stabilising the positive charge (3-aminopyridine has a pKaH of 6.6). For this reason, 4-dimethylaminopyridine
(DMAP) is a very widely used nucleophilic catalyst in organic synthesis.

Aminopyridines undergo many standard aniline-type reactions, such as diazotisation, and the diazonium salts can
be utilised for the introduction of halogen. However, care is necessary, because pyridine diazonium salts are more
reactive than those from anilines, and are thus easily hydrolysed forming pyridones, as illustrated by the conversion
of 4-aminopyridine, via hydrolysis of the diazonium salt, into 4-pyridone. The pyridine-2- and 4-diazonium salts are
especially destabilised, having opposing electron-withdrawing systems.

Ring synthesis – disconnections

Pyridine rings have been synthesised by many different methods, however three important disconnections for the
construction of pyridines from precursors without a pyridine ring are exemplifi ed in what follows. These are shown
together with the new bonds formed in each route. Pyridine rings are also generated by various cycloaddition strategies
(see pages 54, 115 and 141).