Navigating Competing Retro-Aldol and Retro-Mannich Reaction Pathways in Realizing Syntheses of 2,5-Dihydrofuran, 2,5-Dihydropyrrole, and 2,3-Pyrrole Architectures

Abstract

We report a new scalable strategy for assembling 2,5-dihydrofuran, 2,5-dihydropyrrole, and 2,3-pyrrole products in two steps from readily available aldehyde and imine precursors, respectively. This approach relies on an initial titanium dienolate aldol or Mannich step from commercially available ethyl bromocrotonate, which ensures high yields while suppressing competing retro-aldol and Mannich pathways. Most significantly, we describe how alkali and simple amine bases fail to furnish the desired heterocyclic products and instead trigger undesired retro-aldol and -Mannich reactions or do not proceed, while superbases such as DBU can precisely navigate these challenging obstacles and facilitate the desired olefin isomerization and heterocycle-forming cyclization steps in high yields for both aldol and Mannich adducts. Importantly, we demonstrate how unexpectedly and differently suited syn-vs anti- and alkyl vs aryl aldol adducts are for the key cyclization cascade, while their Mannich counterparts are not. Evans aldol reactions can be employed to access chiral dihydrofuran by using ytterbium(III) triflate to directly esterify aldol adducts. We also report how the use of another superbase (TBD) can transform Mannich adducts directly into 2,3-disubstituted pyrrole products.