Maity Soham, Lopez Marco A, Bates Desiree M, Lin Shishi, Krska Shane W, Stahl Shannon S
Department of Chemistry, University of Wisconsin─Madison, 1101 University Avenue, Madison, Wisconsin 53706, United States.
Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
J Am Chem Soc. 2023 Sep 13;145(36):19832-19839. doi: 10.1021/jacs.3c05822. Epub 2023 Aug 29.
Site-selective radical reactions of benzylic C-H bonds are now highly effective methods for C(sp-H) functionalization and cross-coupling. The existing methods, however, are often ineffective with heterobenzylic C-H bonds in alkyl-substituted pyridines and related aromatic heterocycles that are prominently featured in pharmaceuticals and agrochemicals. Here, we report new synthetic methods that leverage polar, rather than radical, reaction pathways to enable the selective heterobenzylic C-H chlorination of 2- and 4-alkyl-substituted pyridines and other heterocycles. Catalytic activation of the substrate with trifluoromethanesulfonyl chloride promotes the formation of enamine tautomers that react readily with electrophilic chlorination reagents. The resulting heterobenzyl chlorides can be used without isolation or purification in nucleophilic coupling reactions. This chlorination-diversification sequence provides an efficient strategy to achieve heterobenzylic C-H cross-coupling with aliphatic amines and a diverse collection of azoles, among other coupling partners.
苄基C-H键的位点选择性自由基反应如今是C(sp³-H)官能团化和交叉偶联的高效方法。然而，现有方法对于烷基取代吡啶及相关芳香杂环中的异苄基C-H键往往无效，这些结构在药物和农用化学品中十分常见。在此，我们报告了新的合成方法，该方法利用极性而非自由基反应途径，实现2-和4-烷基取代吡啶及其他杂环的选择性异苄基C-H氯化反应。用三氟甲磺酰氯对底物进行催化活化，可促进烯胺互变异构体的形成，这些异构体可与亲电氯化试剂轻松反应。所得的异苄基氯化物无需分离或纯化即可用于亲核偶联反应。这种氯化-多样化序列提供了一种高效策略，可实现异苄基C-H与脂肪胺以及多种唑类等其他偶联伙伴的交叉偶联。
