Bischler-Napieralski Cyclization-N/C-Alkylation Sequences for the Construction of Isoquinoline Alkaloids. Synthesis of Protoberberines and Benzo[c]phenanthridines via C-2'-Functionalized 3-Arylisoquinolines(1).

Efficient synthetic routes to isoquinoline alkaloids of the protoberberine and benzo[c]phenanthridine classes are reported. The key transformations are derived from the intramolecular cyclization of C-2'-functionalized N-(1,2-diarylethyl)amides or enamides via 3-arylisoquinoline derivatives. Thus, under Bischler-Napieralski reaction conditions (PCl(5), nitrile as solvent, room temperature) N-(1,2-diarylethyl)amides 12 regioselectively yielded 2,3-disubstituted 13,14-dihydroprotoberberinium salts 20, a scarcely studied oxidation state in this class of alkaloids. Subsequent reduction of the iminium bond gave the known coralydine (21a) and O-methylcorytenchirine (21b) and their 8-phenyl analogue 21c. The one-pot preparation of these dihydroprotoberberinium salts 20 is shown to proceed with cleavage of the silyl ether and immediate halogenation of the resulting hydroxyl group, followed by cyclization of the obtained N-(1,2-diarylethyl)amide 18 to a 3,4-dihydroisoquinoline derivative 19 and subsequent intramolecular in situ N-alkylation of the latter imine. Ready access to planar 8,9-dialkoxylated benzo[c]phenanthridinium salts is also described. Condensation of ketoester 23 with benzylamine in the presence of titanium(IV) chloride, followed by acetylation, afforded a mixture of naphthylamide 24 and (E)-enamide 25. Both enamides were efficiently cyclized by POCl(3). While the planar benzo[c]phenanthridinium salt 26 was directly produced from 24, the (E)-enamide 25 gave the 3-arylisoquinolinium salt 27, which was reduced and intramolecularly C-alkylated to yield the tetracyclic nucleus of these alkaloids.