One-Step Regioselective\nSynthesis of N‑1-Substituted\nDihydrouracils: A Motif of Growing Popularity in the Targeted Protein\nDegradation Field

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