Simple benzyl selective deprotonation alkylation and Negishi cross-coupling reaction with tetrahydroquinolines | Poster Board #226

The functionalization of amines like tetrahydroquinoline is a powerful tool in the pharmaceutical industry and in natural product synthesis. The functionalization of these bonds is a pressing challenge in organic synthesis. Despite the work done to functionalize quinoline and quinoline derivatives, there are difficult positions that synthetic procedures have yet to access.

Using hexamethylphosphoramide (HMPA) and Tris(N,N-tetramethylene)phosphoric acid triamide (TPPA), our group recently published a lithiation protocol that allows us to access an alternate pathway toward activating the saturated positions of these amines while overriding substrate-directing effects.

Phospohramide ligands like HMPA and TPPA can alter the aggregation state of alkylithium species in solution to create triple ion pair species. The triple ion species produces separated ion pairs that act as active metalation species that override embedded directing groups and allow for alternate selectivity creating new sp3-sp3 carbon-carbon bonds.