Fully Aqueous and Air-Compatible Cross-Coupling of Primary Alkyl Halides with Aryl Boronic Species: A Possible and Facile Method

Abstract

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 Na 2 PdCl 4 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 3 alkyl halide bonds.

Buildup and Consumption of Species in Emulsion Droplets during Aqueous Suzuki Coupling Correlate with Yield

“…Understanding of these phase-separated systems therefore remains substantially limited to computational studies 13,14 and/or information derived from the isolation or study of reaction components under nonsynthetic conditions (e.g., under high vacuum, without organic substrate, and/or at much lower surfactant and/or substrate concentrations where phase separation does not occur). 10,[15][16][17] Yet, the behavior and changing compositions of the organic emulsion droplets over the course of a reaction-in-progress are of keen interest due to their high local concentrations of organics and subsequent anticipated impact on reaction rate, selectivity, and yield. We recently developed the spatial resolution and microenvironmental sensitivity of fluorescence lifetime imaging microscopy (FLIM) [18][19][20] to provide missing information on the size of emulsion droplets and the partitioning of select reagents under conditions relevant to synthesis, making it an emerging analytical technique in this area.…”

Buildup and Consumption of Species in Emulsion Droplets during Aqueous Suzuki Coupling Correlate with Yield

“…Emulsion droplet size, physical environment, and composition under these conditions are highly challenging-to-impossible to study with traditional analytical techniques due to existing requirements for homogeneous phase, high vacuum, or optical transparency (e.g., by NMR spectroscopy, transmission electron microscopy, or dynamic light scattering, respectively) (Figure ). Understanding of these phase-separated systems therefore remains substantially limited to computational studies , and/or information derived from the isolation or study of reaction components under nonsynthetic conditions (e.g., under high vacuum, without organic substrate, and/or at much lower surfactant and/or substrate concentrations where phase separation does not occur). ,,− …”