Guerrero Macayla, Rentería-Gómez Ángel, Das Deborshee, Gutierrez Osvaldo
Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States.
Org Lett. 2024 Aug 23;26(33):7015-7020. doi: 10.1021/acs.orglett.4c02515. Epub 2024 Aug 14.
In contrast to transition-metal-catalyzed difunctionalization of activated alkenes, selective alkylarylation of vinyl azaarenes is underdeveloped. Consequently, the lack of modular and rapid syntheses of 1,1-bis(hetero)arylalkanes limits their exploration in medicinal chemistry. Herein we report a protocol using commercially available iron salts, bisphosphine ligands, fluoroalkyl halides, and Grignard reagents that enables the selective 1,2-fluoroalkyl(hetero)arylation of vinyl azaarenes. We demonstrate the versatility and robustness of the method through the selective synthesis of a range of unsymmetrical 1,1-bis(hetero)arylalkenes, including pyridine -oxides, triazoles, pyrazines, carbazoles, indazoles, and 1,2-azaborines. Mechanistic insights from experimental and computational investigations support a radical pathway and provide insights into the role of non-covalent interactions in iron catalysis.
与过渡金属催化的活性烯烃双官能化反应不同，乙烯基氮杂芳烃的选择性烷基芳基化反应尚未得到充分发展。因此，缺乏模块化且快速合成1,1-双（杂）芳基烷烃的方法限制了它们在药物化学中的应用探索。在此，我们报道了一种使用市售铁盐、双膦配体、氟代烷基卤化物和格氏试剂的方法，该方法能够实现乙烯基氮杂芳烃的选择性1,2-氟代烷基（杂）芳基化反应。我们通过选择性合成一系列不对称的1,1-双（杂）芳基烯烃，包括吡啶-N-氧化物、三唑、吡嗪、咔唑、吲唑和1,2-氮硼烷，展示了该方法的通用性和稳健性。实验和计算研究的机理见解支持了自由基途径，并为非共价相互作用在铁催化中的作用提供了见解。
