Lee Geun Seok, Hong Soon Hyeok
Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
Acc Chem Res. 2023 Aug 15;56(16):2170-2184. doi: 10.1021/acs.accounts.3c00252. Epub 2023 Jul 28.
ConspectusSynthetic chemists have consistently aimed to develop efficient methods for synthesizing ketones, which are essential building blocks in organic chemistry and play significant roles in bioactive molecules. Recent efforts have focused on using photoredox catalysis, which enables previously inaccessible activation modes, to synthesize ketones through the cross-coupling of an acyl electrophile and simple C(sp)-H bonds. Over the past few years, we have worked on developing effective and versatile approaches for directly acylating activated hydrocarbons to forge ketones.Initially, thioesters were explored as the acyl source to achieve the direct acylation of ethers, but an unexpected thioesterification reaction was observed instead. To gain insights into this reactivity, we conducted the optimization of reaction conditions, substrate scope evaluation, and mechanistic studies. Drawing from our understanding of Ni/Ir photocatalysis obtained in this study, we subsequently developed a method for the direct acylation of simple hydrocarbons. The use of less-reactive amides as the acyl electrophiles was found to be critical for suppressing undesired pathways. This seemingly counterintuitive reactivity was carefully studied, revealing a substrate-assisted reaction mechanism in which the suppressed oxidative addition leads to early-stage nickel oxidation and C-H activation.To address the drawbacks of this method, which primarily arose from decarbonylative and transmetallative side pathways, we employed -acyllutidiniums as the acyl electrophile. This prevented undesired decomposition pathways, enabling the use of α-chiral acyl substrates with the retention of their stereochemistry, particularly those derived from α-amino acids. The developed versatile methodology allowed us to access a diverse range of α-amino ketones and their homologues.Despite the elegant utility of Ni/photoredox catalysis in developing new synthetic methodologies, the precise behavior of nickel catalysts under redox conditions is incompletely understood. To gain insight into this behavior and develop new chemical reactions, we used a combination of experimental and computational methods. Our investigations revealed that devised adjustments to the reaction conditions in nickel/photoredox catalysis can result in significant differences in the reaction outcomes, providing chemists with opportunities to tailor reactions through carefully designed mechanistic strategies. We believe that continued efforts to study and apply nickel redox modulation will lead to the discovery of additional organic transformations.
综述
合成化学家一直致力于开发高效的酮合成方法，酮是有机化学中必不可少的结构单元，在生物活性分子中发挥着重要作用。最近的研究工作集中在利用光氧化还原催化，这种催化能够实现以前无法实现的活化模式，通过酰基亲电试剂与简单的C(sp)-H键的交叉偶联来合成酮。在过去的几年里，我们致力于开发有效且通用的方法，用于直接酰化活性烃以构建酮。
最初，硫酯被用作酰基源来实现醚的直接酰化，但却观察到了意外的硫酯化反应。为了深入了解这种反应性，我们进行了反应条件的优化、底物范围评估和机理研究。基于我们在本研究中对镍/铱光催化的理解，我们随后开发了一种简单烃直接酰化的方法。发现使用反应活性较低的酰胺作为酰基亲电试剂对于抑制不期望的反应途径至关重要。对这种看似违反直觉的反应性进行了仔细研究，揭示了一种底物辅助的反应机理，其中被抑制的氧化加成导致早期镍氧化和C-H活化。
为了解决该方法主要源于脱羰和转金属化副反应途径的缺点，我们采用了β-酰基吡啶鎓作为酰基亲电试剂。这避免了不期望的分解途径，使得能够使用α-手性酰基底物并保留其立体化学，特别是那些衍生自α-氨基酸的底物。所开发的通用方法使我们能够获得多种α-氨基酮及其同系物。
尽管镍/光氧化还原催化在开发新的合成方法方面具有出色的实用性，但镍催化剂在氧化还原条件下的确切行为尚未完全了解。为了深入了解这种行为并开发新的化学反应，我们结合了实验和计算方法。我们的研究表明，在镍/光氧化还原催化中对反应条件进行精心调整会导致反应结果出现显著差异，为化学家提供了通过精心设计的机理策略来定制反应的机会。我们相信，持续努力研究和应用镍氧化还原调控将导致发现更多的有机转化反应。
