Biswas Soumen, Hughes William B, De Angelis Luca, Haug Graham C, Trevino Ramon, Fremin Seth O, Arman Hadi D, Larionov Oleg V, Doyle Michael P
Department of Chemistry, The University of Texas at San Antonio One UTSA Circle San Antonio TX 78249 USA
Chem Sci. 2024 Mar 6;15(14):5277-5283. doi: 10.1039/d4sc00316k. eCollection 2024 Apr 3.
Chemodivergent construction of structurally distinct heterocycles from the same precursors by adjusting specific reaction parameters is an emergent area of organic synthesis; yet, understanding of the processes that underpin the reaction divergence is lacking, preventing the development of new synthetic methods by systematically harnessing key mechanistic effects. We describe herein cesium carbonate-promoted oxadiaza excision cross-coupling reactions of β-ketoesters with 1,2,3-triazine 1-oxides that form pyridones in good to high yields, instead of the sole formation of pyridines when the same reaction is performed in the presence of other alkali metal carbonates or organic bases. The reaction can be further extended to the construction of synthetically challenging pyridylpyridones. A computational study comparing the effect of cesium and sodium ions in the oxadiaza excision cross-coupling reactions reveals that the cesium-coordinated species changes the reaction preference from attack at the ketone carbonyl to attack at the ester carbon due to metal ion-specific transition state conformational accommodation, revealing a previously unexplored role of cesium ions that may facilitate the development of chemodivergent approaches to other heterocyclic systems.
通过调整特定反应参数，从相同前体构建结构不同的杂环的化学发散性构建是有机合成的一个新兴领域；然而，目前缺乏对支撑反应发散性的过程的理解，这阻碍了通过系统利用关键机理效应来开发新的合成方法。我们在此描述了碳酸铯促进的β-酮酯与1,2,3-三嗪1-氧化物的氧二氮杂环切除交叉偶联反应，该反应能以良好至高收率生成吡啶酮，而在其他碱金属碳酸盐或有机碱存在下进行相同反应时，只会生成吡啶。该反应可进一步扩展到合成具有挑战性的吡啶基吡啶酮的构建。一项比较铯离子和钠离子在氧二氮杂环切除交叉偶联反应中的作用的计算研究表明，铯配位的物种由于金属离子特定的过渡态构象适应性，将反应偏好从进攻酮羰基转变为进攻酯羰基，揭示了铯离子以前未被探索的作用，这可能有助于开发针对其他杂环系统的化学发散性方法。
