Use of a Droplet Platform To Optimize Pd-Catalyzed C–N Coupling Reactions Promoted by Organic Bases

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.

近年来，钯催化（Pd-catalyzed）的碳-氮交叉偶联（carbon–nitrogen cross-coupling）反应取得了重要进展，可采用可溶性有机碱（soluble organic bases）替代传统使用的不溶性或强无机碱（insoluble or strong inorganic bases）。此类反应体系具备单相特性，便于应用于连续流系统（continuous flow systems）、高通量优化平台（high-throughput optimization platforms）以及大规模应用场景。本研究借助自动化微流控优化平台（automated microfluidic optimization platform），针对三氟甲磺酸芳基酯（aryl triflate）与四类常用胺亲核试剂（amine nucleophiles）——苯胺类（anilines）、酰胺类（amides）、脂肪族伯胺（primary aliphatic amines）及脂肪族仲胺（secondary aliphatic amines）——的偶联反应，确定了最优反应条件。通过分析不同反应温度、碱强度（base strengths）及碱浓度（base concentrations）下的催化剂反应活性（catalyst reactivity）变化规律，我们提出了一套适用于涉及有机碱的钯催化交叉偶联反应的通用优化建议。优化算法结果表明，搭载二烷基三芳基单膦配体（dialkyltriarylmonophosphine ligand）AlPhos的催化剂在各类胺亲核试剂的偶联反应中活性最高。此外，本次自动化优化还发现，磷腈碱（phosphazene base）BTTP可用于促进脂肪族仲胺与三氟甲磺酸芳基酯的偶联反应。