Synthesis of Unsymmetrical Urea Derivatives via PhI(OAc) 2 and Application in Late-Stage Drug Functionalization

• Published in: Molecules (Basel, Switzerland) Switzerland), 2024-11, Vol.29 (23), p.5669
• Main Authors: Kathiravan, Subban, Dhillon, Prakriti, Zhang, Tianshu, Nicholls, Ian A
• Format: Article
• Language: English
• Subjects: amides; Amides - chemical synthesis; Amides - chemistry; amines; Amines - chemistry; Benzamides - chemical synthesis; Benzamides - chemistry; Catalysis; drugs; hypervalent iodine; Iodine; late-stage functionalization; Molecular Structure; Organic Chemistry; Organisk kemi; Pharmaceutical sciences; Reagents; Toxicity; urea; Urea - chemical synthesis; Urea - chemistry
• ISSN: 1420-3049; 1431-5157; 1420-3049
• DOI: 10.3390/molecules29235669

Unsymmetrical urea derivatives are essential structural motifs in a wide array of biologically significant compounds. Despite the well-established methods for synthesizing symmetrical ureas, efficient strategies for the synthesis of unsymmetrical urea derivatives remain limited. In this study, we present a novel approach for the synthesis of unsymmetrical urea derivatives through the coupling of amides and amines. Utilizing hypervalent iodine reagent PhI(OAc) as a coupling mediator, this method circumvents the need for metal catalysts, high temperatures, and inert atmosphere. The reaction proceeds under mild conditions and demonstrates broad substrate scope, including various primary and secondary amines and primary benzamides. This protocol not only offers a practical and versatile route for synthesizing unsymmetrical ureas but also shows significant potential for the late-stage functionalization of complex molecules in drug development.