Synthesis of a Unique Isoindoline/Tetrahydroisoquinoline-based Tricyclic Sultam Library Utilizing a Heck-aza-Michael Strategy

The synthesis of a unique isoindoline- and tetrahydroisoquinoline (THIQ)-containing trycyclic sultam library, utilizing a Heck-aza-Michael (HaM) strategy is reported. Both isoindoline and THIQ rings are installed through a Heck reaction on a vinylsulfonamide, followed by one-pot deprotection and intramolecular aza-Michael reaction. Subsequent cycfization with either paraformaldehyde condensation or 1,1'-carbonyldiimidazole coupling generates a variety of tricyclic sultams. Overall, a 160-member library of these sultams, together with their isoindolines/THIQ and secondary sulfonamides precursors, were constructed using this strategy.