68 Quinolines and Isoquinolines
In a very similar approach, an ,-unsaturated ketone or aldehyde can be employed, though, as the scheme makes
clear, an oxidant is now required and is incorporated into the reaction mixture – Skraup reactions are the classical
examples. The aniline, an oxidant (sometimes simply the aromatic nitro-compound corresponding to the aniline),
concentrated sulfuric acid and glycerol are heated together. From this ‘witches brew’, and often via a very exothermic
and hazardous process, comes a quinoline, unsubstituted on the heterocyclic ring. The glycerol is doubly dehydrated
to produce acrolein, in situ, to which the aniline adds in a conjugate fashion. Acid-catalysed ring closure – another
intramolecular electrophilic attack on a benzene ring – and dehydration, produce a dihydroquinoline, which is
oxidised to the aromatic product. The use of a preformed aniline–acrolein adduct with a milder oxidant (chloranil
(2,3,5,6-tetrachloro-1,4-benzoquinone)) offers greater control and safety.
Synthesis of quinolines from ortho-aminoaryl ketones or aldehydes
(1,2- and 4,4a-bonds made)
Perhaps the most obvious disconnection for a quinoline is to envisage forming the two double bonds of the
heterocyclic ring – the 1,2-double bond is an imine and the 3,4-carbon–carbon double bond by an aldol-type
condensation. An ortho-amino aryl-aldehyde or -ketone is reacted with a ketone (to form the imine) carrying an
-methylene (CH 2 to the ketone for the aldol-type condensation), though the exact order of steps is not known
in the Friedländer synthesis.
An extension of this route, known as the Pfi tzinger synthesis, employs the ortho-aminoaryl-ketone-acids that are readily
available via hydrolysis of an isatin (see page 97 for isatin synthesis), as illustrated below.