Elaine C. Reichert, Kaibo Feng, Aaron C. Sather and Stephen L. Buchwald*,
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引用次数: 4
Abstract
We report a versatile and functional-group-tolerant method for the Pd-catalyzed C–N cross-coupling of five-membered heteroaryl halides with primary and secondary amines, an important but underexplored transformation. Coupling reactions of challenging, pharmaceutically relevant heteroarenes, such as 2-H-1,3-azoles, are reported in good-to-excellent yields. High-yielding coupling reactions of a wide set of five-membered heteroaryl halides with sterically demanding α-branched cyclic amines and acyclic secondary amines are reported for the first time. The key to the broad applicability of this method is the synergistic combination of (1) the moderate-strength base NaOTMS, which limits base-mediated decomposition of sensitive five-membered heteroarenes that ultimately leads to catalyst deactivation, and (2) the use of a GPhos-supported Pd catalyst, which effectively resists heteroarene-induced catalyst deactivation while promoting efficient coupling, even for challenging and sterically demanding amines. Cross-coupling reactions between a wide variety of five-membered heteroaryl halides and amines are demonstrated, including eight examples involving densely functionalized medicinal chemistry building blocks.
我们报道了一种多功能和官能团耐受的方法,用于pd催化的五元杂芳卤化物与伯胺和仲胺的C-N交叉偶联,这是一个重要但尚未开发的转化。偶联反应的挑战性,药学上相关的杂芳烃,如2- h -1,3-唑,报道了良好到优异的产率。本文首次报道了广泛的五元杂芳卤化物与空间要求高的α-支环胺和无环仲胺的高收率偶联反应。该方法广泛适用性的关键在于(1)中等强度碱NaOTMS的协同组合,它限制了碱介导的敏感五元杂芳烃的分解,最终导致催化剂失活;(2)使用gphos负载的Pd催化剂,它有效地抵抗杂芳烃诱导的催化剂失活,同时促进有效的偶联,即使是具有挑战性和空间要求的胺。演示了各种各样的五元杂芳基卤化物和胺之间的交叉偶联反应,包括八个涉及密集功能化药物化学构建块的例子。
期刊介绍:
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