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 Na2PdCl4allowed 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 sp3alkyl halide bonds.