Water is cheap, generally available, non-toxic and non-flammable. Hence, research on application of water as a benign and sustainable alternative to organic solvents has become a highly active research field addressing upcoming requirements in synthesis and catalysis. Chemically, water is a unique solvent as it combines high nucleophilicity with and donor-strength with a large dielectric constant and excellent hydrogen-bonding ability as well as the intrinsic availability of protons. While most of these properties commonly limit applications of aqueous reactions due to the low stability and solubility of reactants as well as catalysts, we recently established cross-coupling protocols utilizing the high polarity of water for straightforward product isolation by basic filtration since lipophilic coupling products separate from the aqueous phase under optimized conditions. [1, 2, 3]<br/>In this presentation we detail our studies on the influence of water as a solvent on palladium catalysed cross-coupling reactions, which represent one of the most powerful tools in organic synthesis. We report new palladacyclic and amino acid derived catalysts achieving high activities at room temperature at typical catalyst loadings of 0.02 mol-% in aqueous Suzuki-Miyaura, Sonogashira and Tsuji-Trost cross-coupling reactions, the addition of arylboronic acids to aldehydes and the borylation of aryl halides. Under certain conditions the combination of aqueous protocol and microwave heating only requires 10<sup>-5</sup> mol-% of palladium to achieve quantitative conversions in 15 min.<br/>The high activity achieved by our catalyst motifs in water facilitates the application of cross-coupling reactions in combination with biocatalysis and biologic ligands. Based on our aqueous organometallic cross-coupling protocols we are able to introduce site-directed transformation on proteins, which contain a suitable unnatural amino acid. Overall, our results show that water is a particularly versatile solvent for palladium catalysed cross-coupling reactions.

Cross-coupling catalysis in water – a versatile approach

249th National Meeting (2015)

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