Investigation of the grewe codeine method. Attempts to achieve a practical synthesis

The svnthesis of 1-(2′-bromo-4′-methoxy-5-hydroxybenzyl)-6-keto-Δ4a-5-decahydroisoquinoline (IX) is described. Efforts to cyclize this intermediate or its N-acyl derivatives in acidic media to morphinan products were unsuccessful. The presence of the para-bromine blocking group apparently exerts a deactivating influence on the phenolic ring. 1-(3′,5′-Dihydroxy-4′-methoxybenzyl)-6-methoxy-1,2,3,4,5,8-hexahydroisoquinoline (XVIII) was readily cyclized to 2-hydroxydihydronorthebainone. However, attempts to remove the 2-hydroxy group and subsequent conversion to dihydronorcodeine were unrewarding.