Quinolines and Isoquinolines 69Synthesis of isoquinolines from 2-arylethamines
(1,2- and 1,8a-bonds made)
The trivial conversion of a 2-arylethanamine into an amide provides a substrate that will undergo ring closure to a
3,4-dihydroisoquinoline; these can be easily dehydrogenated to the aromatic species; the approach is known as the
Bischler–Napieralski reaction, which was fi rst described in 1893 and is still the most popular route to isoquinolines. The
ring closure – another intramolecular electrophilic attack on a benzene ring – is usually effected with a phosphorus
halide, the electrophilic species being exactly of the type involved in Vilsmeier reactions – a chloro-iminium ion (page 12).
Because of the nature of the ring-closing step, electron-releasing substituents on the benzene ring improve the effi ciency;
the ring closure occurs para to the activating group where that is possible, as in the example shown.
Synthesis of isoquinolines from aryl-aldehydes and an
aminoacetaldehyde acetal (1,2- and 4,4a-bonds made)
A quite different route to isoquinolines – the Pomeranz–Fritsch synthesis – begins with an aryl-aldehyde which is con-
densed with aminoacetaldehyde dimethyl acetal (H 2 NCH 2 CH(OMe) 2 ) a bifunctional component with the aldehyde
masked. Although the product imines can be ring closed directly, it is much more effi cient to reduce the imine and
protect the resulting amine as a tosylamide before the acid-catalysed ring closure, which also causes elimination of
para-toluenesulfi nic acid (Note: the sulfur has changed oxidation level) leading directly to the aromatic isoquinoline,
unsubstituted on the heterocyclic ring.