Use of a Droplet Platform To Optimize Pd-Catalyzed C-N Coupling Reactions Promoted by Organic Bases
Use of a Droplet Platform To Optimize Pd-Catalyzed C-N Coupling Reactions Promoted by Organic Bases
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DOI：
10.1021/acs.oprd.9b00236
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发表时间：
2019-08-01
影响因子：
3.4
通讯作者：
Jensen, Klays F.
中科院分区：
文献类型：
--
作者：
Baumgartner, Lorenz M.;Dennis, Joseph M.;Jensen, Klays F.
钯催化碳氮交叉偶联的最新进展使得使用可溶性有机碱代替传统上使用的不溶性或强无机碱成为可能。这些反应条件的单相特性有利于它们在连续流系统、高通量优化平台和大规模应用中实现。在这项工作中，我们利用一个自动微流控优化平台来确定三氟化芳基与四种常用的胺亲核试剂（苯胺、酰胺、伯脂肪胺和仲脂肪胺）偶联的最佳反应条件。通过分析不同反应温度、碱强度和碱浓度下催化剂反应性的趋势，我们开发了一套涉及有机碱的pd催化交叉偶联反应的一般建议。优化算法确定了二烷基三芳基单膦配体AlPhos负载的催化剂对各胺亲核试剂的偶联活性最高。此外，我们的自动化优化表明，磷腈基BTTP可以用来促进仲烷基胺和芳基三氟酸酯的偶联。
Recent advances in Pd-catalyzed carbon-nitrogen cross-coupling have enabled the use of soluble organic bases instead of insoluble or strong inorganic bases that are traditionally employed. The single-phase nature of these reaction conditions facilitates their implementation in continuous flow systems, high-throughput optimization platforms, and large-scale applications. In this work, we utilized an automated microfluidic optimization platform to determine optimal reaction conditions for the couplings of an aryl triflate with four types of commonly employed amine nucleophiles: anilines, amides, primary aliphatic amines, and secondary aliphatic amines. By analyzing trends in catalyst reactivity across different reaction temperatures, base strengths, and base concentrations, we have developed a set of general recommendations for Pd-catalyzed cross-coupling reactions involving organic bases. The optimization algorithm determined that the catalyst supported by the dialkyltriarylmonophosphine ligand AlPhos was the most active in the coupling of each amine nucleophile. Furthermore, our automated optimization revealed that the phosphazene base BTTP can be used to facilitate the coupling of secondary alkylamines and aryl triflates.