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首页> 外文期刊>Nature >Metallaphotoredox-catalysed sp(3)-sp(3) cross-coupling of carboxylic acids with alkyl halides
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Metallaphotoredox-catalysed sp(3)-sp(3) cross-coupling of carboxylic acids with alkyl halides

机译：金属氧还原催化的sp（3）-sp（3）羧酸与烷基卤的交叉偶联

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摘要

In the past 50 years, cross-coupling reactions mediated by transition metals have changed the way in which complex organic molecules are synthesized. The predictable and chemoselective nature of these transformations has led to their widespread adoption across many areas of chemical research(1). However, the construction of a bond between two sp(3)-hybridized carbon atoms, a fundamental unit of organic chemistry, remains an important yet elusive objective for engineering cross-coupling reactions(2). In comparison to related procedures with sp(2)-hybridized species, the development of methods for sp(3)-sp(3) bond formation via transition metal catalysis has been hampered historically by deleterious side-reactions, such as beta-hydride elimination with palladium catalysis or the reluctance of alkyl halides to undergo oxidative addition(3,4.) To address this issue, nickel-catalysed cross-coupling processes can be used to form sp(3)-sp(3) bonds that utilize organometallic nucleophiles and alkyl electrophiles(5-7). In particular, the coupling of alkyl halides with pre-generated organozinc(8,9), Grignard(10) and organoborane(11) species has been used to furnish diverse molecular structures. However, the manipulations required to produce these activated structures is inefficient, leading to poor step-and atom-economies. Moreover, the operational difficulties associated with making and using these reactive coupling partners, and preserving them through a synthetic sequence, has hindered their widespread adoption. A generically useful sp(3)-sp(3) coupling technology that uses bench-stable, native organic functional groups, without the need for pre-functionalization or substrate derivatization, would therefore be valuable. Here we demonstrate that the synergistic merger of photoredox and nickel catalysis enables the direct formation of sp(3)-sp(3) bonds using only simple carboxylic acids and alkyl halides as the nucleophilic and electrophilic coupling partners, respectively. This metallaphotoredox protocol is suitable for many primary and secondary carboxylic acids. The merit of this coupling strategy is illustrated by the synthesis of the pharmaceutical tirofiban in four steps from commercially available starting materials.
机译：在过去的50年中，过渡金属介导的交叉偶联反应改变了合成复杂有机分子的方式。这些转化具有可预测和化学选择性的特性，已导致它们在化学研究的许多领域得到广泛采用（1）。但是，两个sp（3）杂化碳原子之间的键结构是有机化学的基本单元，仍然是工程交叉偶联反应的重要但难以捉摸的目标（2）。与sp（2）杂交物种的相关程序相比，有害的副反应（例如消除β-氢化物）阻碍了通过过渡金属催化形成sp（3）-sp（3）键的方法的发展。钯催化或烷基卤化物不愿意进行氧化加成（3,4）。为解决此问题，可使用镍催化的交叉偶联工艺形成利用有机金属亲核试剂的sp（3）-sp（3）键和烷基亲电试剂（5-7）。特别是，烷基卤与预生成的有机锌（8,9），格利雅（10）和有机硼烷（11）的偶联已用于提供各种分子结构。然而，产生这些活化结构所需的操作效率低下，导致差的步阶和原子经济性。而且，与制备和使用这些反应性偶合剂相关的操作困难，以及通过合成的顺序保存它们，阻碍了它们的广泛采用。因此，使用稳定的天然有机官能团而无需预先功能化或底物衍生化的通用有用的sp（3）-sp（3）偶联技术将很有价值。在这里，我们证明了光还原和镍催化的协同合并能够分别仅使用简单的羧酸和卤代烷作为亲核和亲电子偶联伙伴，直接形成sp（3）-sp（3）键。该金属光氧化还原方案适用于许多伯和仲羧酸。该偶联策略的优点通过从可商购的起始原料的四个步骤中合成药物替罗非班来说明。

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  • 来源
    《Nature》 |2016年第7616期|322-325|共4页
  • 作者

    Johnston Craig P.; Smith Russell T.; Allmendinger Simon; MacMillan David W. C.;

  • 作者单位

    Princeton Univ, Merck Ctr Catalysis, Princeton, NJ 08544 USA;

    Princeton Univ, Merck Ctr Catalysis, Princeton, NJ 08544 USA;

    Princeton Univ, Merck Ctr Catalysis, Princeton, NJ 08544 USA;

    Princeton Univ, Merck Ctr Catalysis, Princeton, NJ 08544 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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