Chemical Research and Development Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, USA.
University of Rochester, Rochester, New York 14627-0216, USA.
Nat Chem. 2016 Dec;8(12):1126-1130. doi: 10.1038/nchem.2587. Epub 2016 Aug 8.
Ligands are essential for controlling the reactivity and selectivity of reactions catalysed by transition metals. Access to large phosphine ligand libraries has become an essential tool for the application of metal-catalysed reactions industrially, but these existing libraries are not well suited to new catalytic methods based on non-precious metals (for example, Ni, Cu and Fe). The development of the requisite nitrogen- and oxygen-based ligand libraries lags far behind that of the phosphines and the development of new libraries is anticipated to be time consuming. Here we show that this process can be dramatically accelerated by mining for new ligands in a typical pharmaceutical compound library that is rich in heterocycles. Using this approach, we were able to screen a structurally diverse set of compounds with minimal synthetic effort and identify several new ligand classes for nickel-catalysed cross-electrophile coupling. These new ligands gave improved yields for challenging cross-couplings of pharmaceutically relevant substrates compared with those of those of previously published ligands.
配体对于控制过渡金属催化反应的反应性和选择性至关重要。获得大型膦配体库已成为金属催化反应在工业中应用的重要工具，但这些现有的配体库并不适合基于非贵金属（例如 Ni、Cu 和 Fe）的新催化方法。基于氮和氧的必需配体库的发展远远落后于膦配体，预计开发新的配体库将是耗时的。在这里，我们展示了通过在富含杂环的典型药物化合物库中挖掘新配体，可以显著加快这一过程。使用这种方法，我们能够以最小的合成工作量筛选出一组结构多样的化合物，并确定了几种用于镍催化交叉亲电子偶联的新配体类别。与以前发表的配体相比，这些新配体在具有挑战性的药物相关底物的交叉偶联中提高了产率。
