Title : Design of Alkyl-Heteroaryl-Based Phosphine Ligands and Their Application in Chemoselective Coupling Reactions of Polyhalogenated Aryl Triflates
Aryl bromides, chlorides, and triflates are the most widely used electrophiles in pharmaceutical, industrial, and routine synthesis. However, having the approximate reactivity order of C−I> C−Br?C−OTf>> C−Cl, we are still always struggling with multiple factors and drawbacks during the use of multiple(pseudo)halides. For each substrate, we need to carefully consider and perform tedious trial and error of the use of ligand, base, solvent, temperature, and steric and electronic biases of the substrate itself. As ligands are indispensable factors in crosscoupling reactions, developing the appropriate ligands that can easily alternate the reactivity sequence is an extremely attractive strategy to align with the ideal synthetic pathways. In this study, we have newly designed and developed a series of phosphine ligands with a C2-alkyl group on the indole ring and realized the chemoselective cross-coupling processes of polyhalogenated aryl triflates (e.g., Suzuki-Miyaura coupling reaction). The Pd/SelectPhos system showed excellent chemoselectivity toward the Ar−Cl bond in the presence of the Ar−OTf bond with broad substrate scopes and excellent product yields. The chemoselective reactions are easily be scaled up to the gram scale. Especially in the Suzuki-Miyaura reactions, the use of parts per million levels of Pd catalyst (as low as 10 ppm Pd) is achieved. A further mechanistic investigation with the X-ray crystallographic data and the computational studies suggested that the methine hydrogen and the steric hindrance offered by the C2-alkyl group play a key role in reactivity and chemoselectivity.
Audience take away:
We anticipate that this finding would be of interest to the general organic chemistry audience, especially to those in the fields of ligand design and catalysis. The benefits of this protocol are shown as follows
- The reaction sequence can be directly manipulated.
- It can be time- and effort-saving for the correct prediction of the actual chemoselectivity of Pd-catalyzed cross-coupling reactions using multiple(pseudo)halides.
- The choice of synthetic routes in actual applications would be significantly broadened.
- The chemodivergent approach is useful in the synthesis of pharmaceutically active molecules and functional materials.