Phenol oxidation. Part III. Synthesis of the benzylisoquinoline alkaloid cularine

Abstract

(±)-Cularine has been synthesised via phenolic coupling of 1,2,3,4-tetrahydro-1-(3-hydroxy-4-methoxybenzyl)-7-methoxy-2-methylisoquinolin-8-ol; the latter was prepared by a new variant of the Pomeranz–Fritsch synthesis which leads directly to isoquinolines in good yield, with introduction of the 1-benzyl substituent by the Reissert method. Syntheses of open-chain phenolic bis-(2-phenylethyl)amine derivatives related to cularine are also described; however, none of these could be oxidatively coupled to give cularine derivatives. Other routes to 7,8-dioxygenated isoquinolines were also inveestigated, but, although moderately successful, additions of 3,4-dialkoxybenzylmagnesium halides to 3,4-dihydroisoquinolines could not be effected owing to formation of dihydrostibenes from the benzyl halides. The synthesis of a 7,8-dialkoxy-3,4-dihydroquinolone from a bromoindanone is also described.