Jia Huanhuan, Tan Zhenda, Zhang Min
Key Lab of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510641, China.
Acc Chem Res. 2024 Mar 5;57(5):795-813. doi: 10.1021/acs.accounts.4c00009. Epub 2024 Feb 23.
ConspectusThe selective functionalization/transformation of ubiquitous pyridine-fused N-heteroarenes is a practical method to synthesize structurally novel N-heterocycles, which is important for the development of medicines, bioactive agents, agrochemicals, materials, ligands, sensors, pigments, dyes, etc. However, owing to thermodynamic stability, kinetic inertness, and lone electron pair-induced catalyst deactivation of the pyridine-fused N-heteroarenes, limited strategies (e.g., C-H activation/functionalization, electrophilic substitution, and the Minisci reaction) are available to realize the synthetic purpose and maintain the aromaticity of the final products. Moreover, the relevant transformations have limitations such as needing harsh reaction conditions, requiring the preinstallation of specific coupling agents containing transformable functionalities or directing groups, using less environmentally benign oxidants and/or acidic activators, and poor selectivity. Herein, considering that imines, enamines, radicals, and cyclic amines are generated during the reduction of pyridine-fused N-heteroarenes, the precise transformation of these reductive intermediates offers a fundamental basis for developing novel tandem reactions. Our group revealed that a slow reduction rate, synergistic catalysis, and controlled electroreduction are effective strategies for fulfilling the selective reductive functionalization of pyridine-fused N-heteroarenes. Thus, we established a series of new synthetic methods that provide diverse construction modalities for functionalized N-heterocycles. The striking features of these synthetic methods include high efficiency, atom economy, and the use of readily accessible N-heteroarenes as transformable feedstocks in the absence of flammable and pressurized H gas, alongside a promising potential of the obtained N-heterocyclic products. The present study would be appealing to the fields of synthetic organic chemistry, catalysis, biomedical chemistry, and functional materials. This Account describes the application of reductive dearomatization as substrate-activating and tandem reaction-initiating modes and summarizes the reductive functionalization of pyridine-fused N-heteroarenes via selective alkylation, arylation, and annulation at nitrogen, α, β, and other remote carbon sites achieved over the past 8 years. Details regarding the development of new reactions and their plausible mechanisms and perspectives are discussed. We hope our contributions to this field will aid in the further development of novel strategies for the functionalization/transformation of pyridine-fused N-heteroarenes and tackle the intractable challenges in this area.
综述
对普遍存在的吡啶稠合氮杂芳烃进行选择性官能团化/转化是合成结构新颖的氮杂环化合物的一种实用方法，这对于药物、生物活性剂、农用化学品、材料、配体、传感器、颜料、染料等的开发至关重要。然而，由于吡啶稠合氮杂芳烃具有热力学稳定性、动力学惰性以及孤电子对导致的催化剂失活，实现合成目的并保持最终产物芳香性的策略有限（例如，C-H活化/官能团化、亲电取代和米氏反应）。此外，相关转化存在局限性，如需要苛刻的反应条件、需要预先安装含有可转化官能团或导向基团的特定偶联剂、使用对环境不太友好的氧化剂和/或酸性活化剂以及选择性差。在此，考虑到在吡啶稠合氮杂芳烃的还原过程中会生成亚胺、烯胺、自由基和环胺，这些还原中间体的精确转化为开发新型串联反应提供了基础。我们小组发现缓慢的还原速率、协同催化和可控的电还原是实现吡啶稠合氮杂芳烃选择性还原官能团化的有效策略。因此，我们建立了一系列新的合成方法，为功能化氮杂环化合物提供了多种构建方式。这些合成方法的显著特点包括高效、原子经济性以及在不存在易燃和加压氢气的情况下使用易于获得的氮杂芳烃作为可转化原料，同时所得到的氮杂环产物具有广阔的应用前景。本研究将对合成有机化学、催化、生物医学化学和功能材料领域具有吸引力。本综述介绍了还原脱芳构化作为底物活化和串联反应引发模式的应用，并总结了过去8年中通过在氮、α、β和其他远程碳位点进行选择性烷基化、芳基化和环化实现的吡啶稠合氮杂芳烃的还原官能团化。讨论了新反应的发展细节、其合理机制和前景。我们希望我们在该领域的贡献将有助于进一步开发吡啶稠合氮杂芳烃官能团化/转化的新策略，并应对该领域棘手的挑战。
