Molyneux Samuel, Goss Rebecca J M
School of Chemistry, University of St Andrews, North Haugh, St Andrews, Fife KY16 9ST, U.K.
ACS Catal. 2023 Apr 24;13(9):6365-6374. doi: 10.1021/acscatal.3c00252. eCollection 2023 May 5.
Aqueous transformations confer many advantages, including decreased environmental impact and increased opportunity for biomolecule modulation. Although several studies have been conducted to enable the cross-coupling of aryl halides in aqueous conditions, until now a process for the cross-coupling of primary alkyl halides in aqueous conditions was missing from the catalytic toolbox and considered impossible. Alkyl halide coupling in water suffers from severe problems. The reasons for this include the strong propensity for β-hydride elimination, the need for highly air- and water-sensitive catalysts and reagents, and the intolerance of many hydrophilic groups to cross-coupling conditions. Here, we report a broadly applicable and readily accessible process for the cross-coupling of water-soluble alkyl halides in water and air by using simple and commercially available bench-stable reagents. The trisulfonated aryl phosphine TXPTS in combination with a water-soluble palladium salt NaPdCl allowed for the Suzuki-Miyaura coupling of water-soluble alkyl halides with aryl boronic acids, boronic esters, and borofluorate salts in mild, fully aqueous conditions. Multiple challenging functionalities, including unprotected amino acids, an unnatural halogenated amino acid within a peptide, and herbicides can be diversified in water. Structurally complex natural products were used as testbeds to showcase the late-stage tagging methodology of marine natural products to enable liquid chromatography-mass spectrometry (LC-MS) detection. This enabling methodology therefore provides a general method for the environmentally friendly and biocompatible derivatization of sp alkyl halide bonds.
水相转化具有许多优点，包括减少环境影响和增加生物分子调节的机会。尽管已经进行了几项研究以实现芳基卤化物在水相条件下的交叉偶联，但到目前为止，催化工具箱中缺少在水相条件下伯烷基卤化物交叉偶联的方法，并且被认为是不可能的。水相中卤代烃的偶联存在严重问题。其原因包括β-氢消除的强烈倾向、对空气和水高度敏感的催化剂和试剂的需求，以及许多亲水基团对交叉偶联条件的不耐受性。在这里，我们报告了一种广泛适用且易于实现的方法，通过使用简单且市售的稳定试剂，在水和空气中实现水溶性烷基卤化物的交叉偶联。三磺化芳基膦TXPTS与水溶性钯盐NaPdCl相结合，能够在温和的全水相条件下实现水溶性烷基卤化物与芳基硼酸、硼酸酯和硼氟酸盐的铃木-宫浦偶联。多种具有挑战性的官能团，包括未保护的氨基酸、肽中的非天然卤代氨基酸和除草剂，都可以在水中实现多样化。结构复杂的天然产物被用作测试平台，以展示海洋天然产物的后期标记方法，从而实现液相色谱-质谱（LC-MS）检测。因此，这种使能方法为sp烷基卤化物键的环境友好和生物相容性衍生化提供了一种通用方法。
