Khazipova Olga V, Khazipov Oleg V, Shepelenko Konstantin E, Kashin Alexey S, Zhang Yu, Chernyshev Victor M, Ananikov Valentine P
Platov South-Russian State Polytechnic University (NPI), Novocherkassk, Russia.
Skolkovo Institute of Science and Technology, Moscow, Russia.
Commun Chem. 2025 Aug 22;8(1):253. doi: 10.1038/s42004-025-01653-5.
Transition-metal-catalyzed C-H alkylation of heteroaromatics with alkenes represents an atom-economical and cost-effective strategy for accessing industrially and pharmaceutically relevant compounds. However, the selective C5-H alkylation of biomass-derived furfural and its isosteric analog, thiophene-2-carboxaldehyde, highly challenging yet industrially vital substrates, has remained elusive. Herein, we disclose a Ni/NHC-catalyzed strategy for the C5-H alkylation of furan- and thiophene-2-carboxaldehydes with styrenes and norbornene, enabled by a readily installable and recyclable N-PMP (p-methoxyphenyl) imine protecting group. This method also achieves selective C5-H alkenylation with internal alkynes. Mechanistic studies suggest that C-H alkylation proceeds via a ligand-to-ligand hydrogen transfer (LLHT) pathway. The N-PMP imine group effectively suppresses undesirable benzoin condensation of these reactive aldehydes and prevents NHC trapping in Breslow intermediates, a major catalyst deactivation pathway. The protecting group is efficiently cleaved under acid hydrolysis, yielding C5-functionalized aldehydes, while the liberated anisidine can be recycled for imine substrate preparation. This work also highlights the largely unexplored potential of the N-aryl imine group as the protecting group for distal C(sp²)-H functionalization of heteroaromatic aldehydes under Ni catalysis.
过渡金属催化的杂芳烃与烯烃的C-H烷基化反应是一种原子经济且成本效益高的策略，可用于合成具有工业和药学相关性的化合物。然而，生物质衍生的糠醛及其等电子类似物噻吩-2-甲醛的选择性C5-H烷基化反应，这两种极具挑战性但在工业上至关重要的底物，一直难以实现。在此，我们披露了一种镍/氮杂环卡宾（Ni/NHC）催化的策略，用于呋喃-2-甲醛和噻吩-2-甲醛与苯乙烯和降冰片烯的C5-H烷基化反应，该反应由易于安装和可回收的N-对甲氧基苯基（N-PMP）亚胺保护基实现。该方法还实现了与内炔烃的选择性C5-H烯基化反应。机理研究表明，C-H烷基化反应通过配体到配体的氢转移（LLHT）途径进行。N-PMP亚胺基团有效地抑制了这些活性醛的不希望发生的安息香缩合反应，并防止氮杂环卡宾在布雷斯洛中间体中捕获，这是催化剂失活的主要途径。该保护基在酸水解条件下能有效裂解，生成C5-官能化醛，同时释放出的茴香胺可回收用于亚胺底物的制备。这项工作还突出了N-芳基亚胺基团作为镍催化下杂芳醛远端C(sp²)-H官能化保护基的很大程度上未被探索的潜力。
