Chemodivergent Synthesis of γ- and δ-Lactone-Fused Uracils via NHC-Catalyzed Base-Controlled Processes

Abstract

We report an NHC-catalyzed chemodivergent transformation of 6-methyluracil-5-carbaldehydes with trifluoromethyl ketones, providing selective access to CF3-substituted gamma- and delta-lactone-fused uracils from the same substrates. The key to this transformation is the unprecedented generation of uracil-derived NHC-bound o-quinodimethane (oQDM) intermediates combined with precise control of the base conditions. Notably, in sharp contrast to previous studies that exclusively afforded six-membered products, our protocol delivers the first entry to synthetically valuable five-membered gamma-lactone-fused uracils via a base-controlled relay sequence of NHC-catalyzed [4+2] annulation followed by skeletal rearrangement. These findings expand the scope of NHC-catalyzed vinylogous transformations and open new avenues for the synthesis of novel heterocyclic scaffolds with potential applications in drug discovery.