Metalation vs nucleophilic addition in the reactions of N-phenethylimides with organolithium reagents. Ready access to isoquinoline derivatives via N-acyliminium ions and Parham-type cyclizations

Sequential carbophilic addition of organolithium reagents and N-acyliminium ion cyclization of N-phenethylimides 1 affords the substituted isoquinolones 3 in high yields, with the possibility of varying the substituent at the C-1 position of the isoquinoline ring by changing the organolithium reagent. Ready access to the isoquinoline nucleus via Parham-type cyclizatian of imides 2 is also described. We have shown that iodinated imides 2 tolerate the metal-halogen exchange in the presence of the imide group, and the intramolecular cyclization of the so-obtained aromatic organometallic derivatives leads to the corresponding enamides 4. Both approaches have allowed the efficient preparation of various types of the isoquinoline class of alkaloids, just by changing the substitution pattern on the readily available starting imides. Thus, we have developed convenient alternative routes for the synthesis of benzo[a]quinolizidones and their 2-oxa analogs,isoindoloisoquinolones, dibenzo[a,h]quinolizidones, and thiazolo- and oxazolo[4,3-a]isoquinolanes.