Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
J Am Chem Soc. 2020 Jun 24;142(25):11252-11269. doi: 10.1021/jacs.0c04486. Epub 2020 Jun 11.
Bis(phosphine) copper hydride complexes are uniquely able to catalyze direct dearomatization of unactivated pyridines with carbon nucleophiles, but the mechanistic basis for this result has been unclear. Here we show that, contrary to our initial hypotheses, the catalytic mechanism is monometallic and proceeds via dearomative rearrangement of the phenethylcopper nucleophile to a C-metalated form prior to reaction at heterocycle C4. Our studies support an unexpected heterocycle-promoted pathway for this net 1,5-Cu-migration beginning with a doubly dearomative imidoyl-Cu-ene reaction. Kinetics, substituent effects, computational modeling, and spectroscopic studies support the involvement of this unusual process. In this pathway, the CuL fragment subsequently mediates a stepwise Cope rearrangement of the doubly dearomatized intermediate to the give the C4-functionalized 1,4-dihydropyridine, lowering a second barrier that would otherwise prohibit efficient asymmetric catalysis.
双(膦)铜氢化物配合物具有独特的催化能力，可使未活化的吡啶与碳亲核试剂直接进行脱芳构化反应，但这一结果的机理基础尚不清楚。在这里，我们表明，与我们最初的假设相反，催化机理是单金属的，并且在杂环 C4 反应之前，通过苯乙基铜亲核试剂的 dearomative 重排，生成 C-金属化形式，然后进行反应。我们的研究支持了一种出乎意料的杂环促进途径，该途径通过双 dearomative 亚氨酰基-Cu-ene 反应开始，实现净 1,5-Cu-迁移。动力学、取代基效应、计算建模和光谱研究支持了这一不寻常过程的参与。在这条途径中，CuL 片段随后介导双 dearomated 中间体的逐步 Cope 重排，生成 C4 官能化的 1,4-二氢吡啶，降低了否则会阻止有效不对称催化的第二个能垒。
