Investigations Into Cross-Coupling of Secondary Organoboronic Esters

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Holland, Amy Marie
Organometallics , Cross-Coupling
Until recently, secondary organoboronic esters were not viable substrates in the Suzuki-Miyaura cross-coupling reaction; however under recently reported conditions from the Crudden group1, which includes the addition of silver oxide to a palladium/phosphine catalyst system, this coupling can now be achieved. This thesis centres on optimizing the reaction conditions and expanding the substrate scope of this difficult but important secondary coupling. Optimal coupling conditions, for the example reaction of 4-iodoacetophenone and (R)-pinacol(1-phenylethyl)boronate, were found to be 8 mol% Pd(PPh3)4, 32 mol% PPh3, 1.5 eq. Ag2O and 1.5 eq. K2CO3 in DME at 85 °C for 24 h. This gave the desired coupling product in 64 % yield with 99.5 % retention of stereochemistry. Using this set of conditions, an array of aryl iodides were screened. The reaction conditions could not be extended to triflate or diazonium electrophiles. Amide functionality is important in many natural products and pharmaceuticals. The extension of reaction conditions to amides possessing boronic ester functionality at the β-position was attempted; however, no conditions could be determined to generate the cross-coupling product. An α-substitution pattern would better exemplify the benzylic positioning found to work for the original substrates. Attempts to synthesize the α-substituted amide were made without success. The optimal reaction conditions gave hope for differentiation between an aryl and a secondary aliphatic boronic ester. Using an aryl triflate to couple the aryl position and an aryl iodide to couple the aliphatic position, conditions for selective coupling were determined and applied to a one-pot procedure.
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