Su Siyuan, Guo Yahui, Parnitzke Bryan, Poerio Tegan, Derosa Joseph
Department of Chemistry, Boston University, Boston, Massachusetts 02215, United States.
J Am Chem Soc. 2024 Oct 23;146(42):28663-28668. doi: 10.1021/jacs.4c12520. Epub 2024 Oct 14.
Shono-type oxidation to generate functionalized heterocycles is a powerful method for late-stage diversification of relevant pharmacophores; however, development beyond oxygen-based nucleophiles remains underdeveloped. The limited scope can often be ascribed to constant current electrolysis resulting in potential drifts that oxidize a desired nucleophilic partner. Herein, we report a voltage-controlled strategy to selectively oxidize a broad scope of substrates, enabling modular C-N bond formation from protected amine nucleophiles. We implement an electroanalytically guided workflow using cyclic voltammetry (CV) and differential pulse voltammetry (DPV) to identify oxidation potentials across a range of heterocyclic substrates. Controlled potential electrolysis (CPE) selectively generates α-functionalized C-N products in moderate to good yields using carbamate-, sulfonamide-, and benzamide-derived nucleophiles. The importance of voltage control is further exemplified through a systematic study comparing our developed CPE method to constant current electrolysis (CCE) protocols. Voltage-guided CCE and traditionally optimized CCE reveal the importance of maintaining voltage control for high yields and selectivity over a broad scope; a case study with a morpholine-derived substrate illustrates the negative impact of potential drifting under CCE. Sulfonamide drugs, which have significant oxidation potential overlap with model substrates, are rendered competent nucleophiles under CPE. Lastly, sequential voltage-controlled C-N and C-O functionalization of a model substrate generates difunctionalized pyrrolidines further broadening the utility of this reaction.
用于生成功能化杂环的Shono型氧化反应是相关药效基团后期多样化的有力方法；然而，基于氧以外亲核试剂的发展仍不充分。范围有限通常可归因于恒流电解导致的电位漂移，从而氧化所需的亲核伙伴。在此，我们报告了一种电压控制策略，用于选择性氧化广泛的底物，能够从受保护的胺亲核试剂形成模块化的C-N键。我们采用循环伏安法（CV）和差分脉冲伏安法（DPV）实施电分析指导的工作流程，以确定一系列杂环底物的氧化电位。使用氨基甲酸酯、磺酰胺和苯甲酰胺衍生的亲核试剂，恒电位电解（CPE）以中等至良好的产率选择性地生成α-功能化的C-N产物。通过将我们开发的CPE方法与恒流电解（CCE）方案进行系统比较的研究，进一步例证了电压控制的重要性。电压引导的CCE和传统优化的CCE揭示了在广泛范围内保持电压控制对于高产率和选择性的重要性；以吗啉衍生的底物为例说明了CCE下电位漂移的负面影响。与模型底物具有显著氧化电位重叠的磺酰胺药物在CPE下成为有效的亲核试剂。最后，对模型底物进行连续的电压控制C-N和C-O功能化反应生成双功能化的吡咯烷，进一步拓宽了该反应的应用范围。
