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ProPhos: A Ligand for Promoting Nickel-Catalyzed Suzuki-Miyaura Coupling Inspired by Mechanistic Insights into Transmetalation
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2024-02-23 , DOI: 10.1021/jacs.4c00370 Jin Yang 1 , Michelle C Neary 2 , Tianning Diao 1
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2024-02-23 , DOI: 10.1021/jacs.4c00370 Jin Yang 1 , Michelle C Neary 2 , Tianning Diao 1
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Nickel-catalyzed Suzuki–Miyaura coupling (Ni-SMC) offers the potential to reduce the cost of pharmaceutical process synthesis. However, its application has been restricted by challenges such as slow reaction rates, high catalyst loading, and a limited scope of heterocycles. Despite recent investigations, the mechanism of transmetalation in Ni-SMC, often viewed as the turnover-limiting step, remains insufficiently understood. We elucidate the “Ni-oxo” transmetalation pathway, applying PPh2Me as the ligand, and identify the formation of a nickel-oxo intermediate as the turnover-limiting step. Building on this insight, we develop a scaffolding ligand, ProPhos, featuring a pendant hydroxyl group connected to the phosphine via a linker. The design preorganizes both the nucleophile and the nickel catalyst, thereby facilitating transmetalation. This catalyst exhibits fast kinetics and robust activity across a wide range of heteroarenes, with a catalyst loading of 0.5–3 mol %. For arene substrates, the catalyst loading can be further reduced to 0.1 mol %.
中文翻译：
ProPhos：受转金属化机理启发的促进镍催化铃木-宫浦偶联的配体
镍催化的铃木-宫浦偶联（Ni-SMC）具有降低制药工艺合成成本的潜力。然而，其应用受到反应速率慢、催化剂负载量高和杂环范围有限等挑战的限制。尽管最近进行了研究，但 Ni-SMC 中的金属转移机制（通常被视为限制营业额的步骤）仍然没有得到充分的了解。我们阐明了“Ni-oxo”金属转移途径，应用 PPh 2 Me 作为配体，并将镍-氧中间体的形成确定为周转限制步骤。基于这一见解，我们开发了一种支架配体 ProPhos，其特点是通过连接体与膦连接的羟基侧基。该设计预组织了亲核试剂和镍催化剂，从而促进金属转移。该催化剂在多种杂芳烃中表现出快速的动力学和强大的活性，催化剂负载量为 0.5–3 mol%。对于芳烃基材，催化剂负载量可以进一步降低至0.1 mol%。
更新日期：2024-02-23
中文翻译：
ProPhos：受转金属化机理启发的促进镍催化铃木-宫浦偶联的配体
镍催化的铃木-宫浦偶联（Ni-SMC）具有降低制药工艺合成成本的潜力。然而，其应用受到反应速率慢、催化剂负载量高和杂环范围有限等挑战的限制。尽管最近进行了研究，但 Ni-SMC 中的金属转移机制（通常被视为限制营业额的步骤）仍然没有得到充分的了解。我们阐明了“Ni-oxo”金属转移途径，应用 PPh 2 Me 作为配体，并将镍-氧中间体的形成确定为周转限制步骤。基于这一见解，我们开发了一种支架配体 ProPhos，其特点是通过连接体与膦连接的羟基侧基。该设计预组织了亲核试剂和镍催化剂，从而促进金属转移。该催化剂在多种杂芳烃中表现出快速的动力学和强大的活性，催化剂负载量为 0.5–3 mol%。对于芳烃基材，催化剂负载量可以进一步降低至0.1 mol%。
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