Synthesis of a proposed 1,3,4-trisubstituted isoquinoline

The isoquinoline ring system is a reoccurring structural motif in alkaloids1 and pharmaceuticals.2 Consequently, the synthesis and functionalization of isoquinolines have attracted considerable attention from the synthetic community.3 We previously reported a facile synthesis of 1,3,4-trisubstituted isoquinolines from commercially available 1,3-dichloroisoquinoline 1 (Scheme 1).4 A key step in the process is the direct lithiation of 1 at C4. The resulting lithium species 2 was trapped with a variety of electrophiles to produce 4-substituted-1,3-dichloroisoquinoline 3, which was further elaborated to give1,3,4-trisubstituted isoquinoline 4 by exploiting the different reactivity of C1–Cl and C3–Cl bonds under Pd-catalysis.