Chemoselective Suzuki-Miyaura Cross-Coupling of Substrates Containing an Aryl and a Secondary Benzylic Boronic Ester
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The Suzuki-Miyaura cross-coupling reaction has become extremely important in the area of industry and academia. The ability to cleanly cross-couple aryl, alkyl, or alkenyl boronic acids/esters with aryl, alkyl, or alkenyl halides to generate new C-C bonds has proven to be a versatile tool towards the synthesis of complex molecules. Over the past three decades, there has been an array of developments and accomplishments in this area of research including the joint awarding of the 2010 Nobel Prize in Chemistry to Suzuki, Heck, and Negishi. Our group published the first successful example of the cross-coupling of chiral secondary benzylic boronic esters. The key components in this reaction were the incorporation of silver oxide and excess triphenyl phosphine. Silver oxide was required for the transmetallation step to occur. Remarkably, the reaction was not only effective for the coupling of these challenging substrates; it was also selective for the branched benzylic species in the presence of a linear alkyl boronic ester. In order to further probe the selectivity of the aforementioned cross-coupling reaction, we have prepared a substrate that incorporates both an aryl and a secondary benzylic boronic ester. Since the secondary benzylic boronic ester requires specialized conditions for the cross-coupling to proceed, we have been able to employ this reaction to introduce two different substituents in place of the boron groups based solely on reaction conditions. Herein, we discuss the optimization and successful chemoselective/iterative Suzuki-Miyaura cross-coupling of a substrate that incorporates both an aryl and a secondary benzylic boronic ester without the need of protecting groups on the boron atoms.