Efficient chemoselective sequential Pd-catalyzed Suzuki coupling of highly functionalized iodoaryl triflates

The Pd-catalyzed Suzuki-Miyaura (SM) cross-coupling of aryl halides with organoboron compounds is a widely used tool in organic synthesis for the construction of C-C bonds. Alternative methods using pseudohalides, such as triflates or nonaflates, are also suitable for this transformation. These substrates offer the advantages of simple access from readily available phenols and possible use for chemodivergent sequential SM couplings using electronically differentiated leaving groups. However, the hydrolysis of triflates is a common side reaction under Suzuki-coupling conditions especially if the substrates contain polar functional groups. Here we present a systematic study of the hydrolysis of aryl triflates, which allowed the identification of reaction conditions suitable for the sequential Suzuki-Miyaura coupling of substituted iodoaryl triflates with various substituted pyridine boronic acids. Protic solvents proved beneficial for the chemoselective coupling producing biaryl triflates. In a subsequent Suzuki coupling the synthesis of terayl-based alpha helix mimetics as potential protein-protein interaction inhibitors was achieved. - providing a systematic study of the hydrolytic stability of iodoaryl triflates bearing a large variety of substituents - identifying conditions for the efficient chemoselective Suzuki coupling leading to biaryl triflates without hydrolysis of the triflate group - converting the resulting biaryl triflates to teraryls by a second Suzuki coupling reaction delivering structures suitable as teraryl-based alpha-helix mimetics.