Pyridines 45group and the fi rst step is the displacement of pyrrolidine by the ammonia, via addition/elimination, ring closure then
producing the 2-aminopyridine.
Synthesis of pyridines from an aldehyde, two equivalents of a
1,3-dicarbonyl compound and ammonia (1,2-, 3,4-, 4,5-, and
1,6-bonds made)
This is the classical Hantzsch pyridine synthesis. Two equivalents of a 1,3-dicarbonyl compound (diketone or keto-ester),
and one equivalent each of an aldehyde and ammonia, are reacted together in a one-pot process. The products, which are
necessarily symmetrically substituted 1,4-dihydropyridines, can be aromatised by any of a number of oxidising agents,
although the dihydro-compounds themselves can be the desired products, and are stable – the conjugation of the nitro-
gen with the 3- and 5-carbonyl groups is responsible for the stabilisation of these dihydropyridines – they can be viewed
as vinylogous amides. The exact sequence of steps involved in this synthesis is not certain, but one plausible route is that
a 1,5-dicarbonyl intermediate (see above) is formed in situ, by successive aldol condensation and then Michael addition.
Particularly important examples of 1,4-dihydropyridines that can be prepared by this route are used as anti-
hypertensive agents (calcium channel blockers, see page 173). The medicinal examples are not symmetrical so a
modifi cation of the sequence must be used in which an aldol condensation product from the aldehyde and one of the
1,3-dicarbonyl components is reacted with the primary enamine obtained from the other 1,3-dicarbonyl compound
by its reaction with ammonia.
Synthesis of pyridines from 1,3-dicarbonyl compounds and a C 2 N unit
(3,4- and 1,6-bonds made)
This route utilises a 1,3-diketone in reaction with a second component that provides the other two carbons and the
nitrogen. One example of such a second component is cyanoacetamide, which leads then to a 3-cyano-2-pyridone,
and this variant is referred to as the Guareschi synthesis. Clearly two bonds are formed, a double bond at C-3-C-4 in a