General Ir-Catalyzed N-H Insertions of Diazomalonates into Aliphatic and Aromatic Amines
Zhuang Zhong, Céline Besnard, Jérôme Lacour*
*Department of Organic Chemistry, University of Geneva, Quai Ernest Ansermet 30, CH-1211 Genève 4, Switzerland,
Email: jerome.lacourunige.ch
Z. Zhong, C. Besnard, J. Lacour, Org. Lett., 2024, 26, 983-987.
DOI: 10.1021/acs.orglett.3c03929
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Abstract
[Ir(cod)Cl]2 catalyzes a general N-H insertion of diazo malonate reagents with a large range of amines, including primary and secondary, aliphatic and aromatic amines. Mild temperatures, perfect substrate/reactant stoichiometry, and good functional group compatibility render the process particularly attractive.
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proposed mechanism
post-transformations
Details
The article discusses a general N−H insertion reactivity of acceptor−acceptor diazomalonate reagents using [Ir(cod)Cl]2 as a catalyst. This method is effective for a wide range of primary and secondary, aliphatic and aromatic amines, and operates under mild conditions with good functional group compatibility. The process is particularly useful for the late-stage functionalization of amines, which is significant in pharmaceutical and medicinal chemistry due to the prevalence of nitrogen-containing molecules in small molecule drugs. The study compares the effectiveness of different catalysts, finding [Ir(cod)Cl]2 to be the most efficient at room temperature. The optimized conditions were tested with various diazo reagents and amines, achieving high yields. The method was also applied to the functionalization of complex molecules like Amoxapine, Vortioxetine, and Pomalidomide, demonstrating its utility in medical chemistry. The article concludes that the Ir-catalyzed N−H insertion is a versatile and efficient method for amine functionalization, with broad applicability and excellent yields.
Synthesis of N-H insertion adducts
In a 2 mL screw-cap vial equipped with a magnetic stirring bar, the diazo compound (0.5 mmol, 1.0 equiv), amine (0.5 mmol, 1.0 equiv) and [Ir(cod)Cl]2 (1 mol%) were dissolved in DCM (1.0 mL). The vial was capped and the solution was stirred at 25 or 60 °C for 15-72 h. The solution was concentrated in vacuum and the residue was purified by column chromatography (pentane / EtOAc, 1:1 or 2:1) to afford the desired product.
Key Words
ID: J54-Y2024