摘要：IanD. G. Nixon, Joseph M. Bateman, Iacovos N. Michaelides, Gary Fairley, Miles J.Pemberton, Erin L. Braybrooke, Kyran Sutton,andPe

转自：康龙化成

One-Step Regioselective Synthesisof N‑1-Substituted Dihydrouracils A Motif of Growing Popularity in the Targeted Protein DegradationField

IanD. G. Nixon, Joseph M. Bateman, Iacovos N. Michaelides, Gary Fairley, Miles J.Pemberton, Erin L. Braybrooke, Kyran Sutton, andPeter J. Lindsay-Scott*

Medicinal Chemistry, Oncology R&D,AstraZeneca, Cambridge, United Kingdom

—J.Org. Chem. 2024, 89,24, 18301–18312.

Recommended by Bing Han_MC3

KEY WORDS:Pdcatalysis (反应类型), (hetero)arylhalides, dihydrouracil, cereblon (CRBN) (反应物), C(sp2)–N (成键类型);

ABSTRACT: Theincreasing popularity of the dihydrouracil motif in cereblon (CRBN) recruitingproteolysis-targeting chimeras (PROTACs) has necessitated the development of afacile, cost-effective, and high-yielding method for its introduction intomolecules. To that end, we disclose herein an N-1 selective Pd-catalyzedcross-coupling of dihydrouracil with aryl electrophiles to provide access tomedicinally relevant scaffolds in a single step. This approach exhibitsexcellent functional group tolerance and broad applicability to an abundance of(hetero)aryl halides and phenol derivatives and utilizes readily availablecatalyst/ligand systems. Thus, our strategy should find broad utility in thearena of PROTAC research, as it obviates the drawbacks of previous methodologiesthat rely on multistep synthetic routes and protecting group strategies toachieve N-1 selectivity.

Background

Optimizationof Reaction Conditions

Selected SubstrateScope of Aryl Electrophiles and DHU

PeterJ. Lindsay-Scott and co-workers reported a direct, protecting group free N-1selective cross-coupling reaction between DHU and aryl electrophiles using readilyavailable catalyst systems,overcoming the drawbacks associated with existing methodologies. DFTcalculations for the different regiochemical pathways are consistent with theN-1 selectivity observed experimentally. This facile reaction benefits from abroad scope thatis easily leveraged due to the abundance of commercially available arylbromides, chlorides, iodides, and phenolderivatives.Additionally, the reaction can be readily scaled up using a streamlinedprocedure that utilizes low catalyst loadings and avoids chromatographicpurification.

来源：新浪财经