Studies in isoquinoline chemistry relating to morphine analgesics

Approaches to the synthesis of partially hydrogenated 8-ketoisoquinolines have been made via 5,6,7,8-tetrahydroisoquinoline and also via attempted Bischler–Napieralski cyclodehydration of a series of 3-oxygenated cyclohexenyl-phenylacetamide derivatives. This latter ring closure has been found not to take, place and the former route also did not prove satisfactory. The synthesis of ring-A bridged isoquinolines has been studied. Although thermal isomerisation of 2,5-dihydrophenylacetamides to give conjugated dienes followed by Diels–Alder reaction met with limited success, the Diels–Alder reaction of 1,2,3,4,7,8-hexahydro-6-methoxy-2-methylisoquinoline has been achieved with methyl vinyl ketone, phenyl vinyl ketone and 2-chloroacrylonitrile. The exo- and endo-cycloadducts have been separated by column- and thin-layer chromatography and their stereochemistry assigned on the basis of n.m.r. studies. [Continues.]