State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis , Shanghai Institute of Organic Chemistry , University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road , Shanghai 200032 , China.
School of Physical Science and Technology , ShanghaiTech University , 100 Haike Road , Shanghai 201210 , China.
J Am Chem Soc. 2019 Oct 16;141(41):16237-16242. doi: 10.1021/jacs.9b09099. Epub 2019 Oct 3.
The intermolecular radical addition to the carbonyl group is difficult due to the facile fragmentation of the resulting alkoxyl radical. To date, the intermolecular radical addition to ketones, a valuable approach to construct quaternary carbon centers, remains a formidable synthetic challenge. Here, we report the first visible-light-induced intermolecular alkyl boronic acid addition to α-ketoacids enabled by the Lewis acid activation. The boron complex formation is confirmed by various spectroscopic measurements and mechanistic probing experiments, which facilitates various alkyl boronic acid addition to the carbonyl group and prevents the cleavage of the newly formed C-C bond. Diversely substituted lactates can be synthesized from readily available alkyl boronic acids and ketoacids at room temperature merely under visible light irradiation, without any additional reagent. This boron activation approach can be extended to alkyl dihydropyridines as radical precursors with external boron reagents for primary, secondary, and tertiary alkyl radical additions. The pharmaceutically useful anticholinergic precursors are easily scaled up in multigrams under metal-free conditions in flow reactors.
由于生成的烷氧基自由基容易断裂，因此羰基的分子间自由基加成反应很困难。迄今为止，酮的分子间自由基加成反应——构建季碳原子的一种有价值的方法，仍然是一项艰巨的合成挑战。在这里，我们报告了首例可见光诱导的由路易斯酸活化的α-酮酸的分子间烷基硼酸加成反应。通过各种光谱测量和机理探测实验证实了硼络合物的形成，这有利于各种烷基硼酸与羰基加成，并防止新形成的 C-C 键断裂。各种取代的乳酸盐可以从易得的烷基硼酸和酮酸在室温下仅在可见光照射下合成，无需任何额外的试剂。这种硼活化方法可以扩展到烷基二氢吡啶作为自由基前体，与外部硼试剂一起用于伯、仲和叔烷基自由基加成。在无金属条件下，在流动反应器中可以很容易地将具有药用价值的抗胆碱能前体在多克规模上放大。
