One-Step Regioselective Synthesis of N‑1-Substituted Dihydrouracils: A Motif of Growing Popularity in the Targeted Protein Degradation Field

The increasing popularity of the dihydrouracil motif in cereblon (CRBN) recruiting proteolysis-targeting chimeras (PROTACs) has necessitated the development of a facile, cost-effective, and high-yielding method for its introduction into molecules. To that end, we disclose herein an N-1 selective Pd-catalyzed cross-coupling of dihydrouracil with aryl electrophiles to provide access to medicinally relevant scaffolds in a single step. This approach exhibits excellent functional group tolerance and broad applicability to an abundance of (hetero)aryl halides and phenol derivatives and utilizes readily available catalyst/ligand systems. Thus, our strategy should find broad utility in the arena of PROTAC research, as it obviates the drawbacks of previous methodologies that rely on multistep synthetic routes and protecting group strategies to achieve N-1 selectivity.