Studies on the Syntheses of 7, 8-Disubstituted 1-Benzylisoquinoline and Related Compounds. (4). Synthesis of dl-Cularidine

Abstract

Bischler-Napieralski reaction of phenolic bromo amide (VIII), which was obtained from the Schotten-Baumann reaction of 4-benzyloxy-2-bromo-5-hydroxyphenethylamine (VI) with 2-bromo-4, 5-dimethoxyphenylacetyl chloride (VII) and then reduction with NaBH₄ of the resultant dihydroisoquinoline (IX) gave 7-benzyloxy-5-bromo-1-(2-bromo-4, 5-dimethoxybenzyl)-8-hydroxy-1, 2, 3, 4-tetrahydroisoquinoline(X). N-Methylation of X afforded XI. The Ullmann reaction of XI in the presence of potassium carbonate and cupric oxide in pyridine gave 6-benzyloxy-4-brome-1-methyl-9, 10-dimethoxy-1, 2, 3, 12, 12a-pentahydrobenzoxepino[2, 3, 4-i, j]isoquinoline (XII). Subsequent debenzylation and debromination of XII with hydrogen over 10% palladium-charcol gave dl-cularidine (Id) which was identified with natural cularidine by infrared and nuclear magnetic resonance spectral comparisons.