Phosphino-Triazole Ligands for Palladium-Catalysed Cross-Coupling

Abstract

<div>Twelve 1,5-disubtituted and fourteen 5-substituted 1,2,3-triazole derivatives bearing diaryl or dialkyl phosphines at the 5-position were synthesised and used as ligands for palladium-catalysed Suzuki-Miyaura cross-coupling reactions. Bulky substrates were tested, and lead-like product formation was demonstrated. The online tool SambVca 2.0 was used to assess steric parameters of ligands and preliminary buried volume determination using XRD obtained data in a small number of cases proved to be informative. Two modelling approaches were compared for the determination of</div><div>the buried volume of ligands where XRD data was not available. An approach with imposed steric restrictions was found to be superior in leading to buried volume determinations that closely correlate with observed reaction conversions. The online tool LLAMA was used to determine lead-likeness of potential Suzuki-Miyaura cross-coupling products, from which ten of the most lead-like were successfully synthesised. Thus, confirming these readily accessible triazole-containing phosphines as highly suitable ligands for reaction screening and optimisation in drug discovery campaigns.</div>

Phosphino-Triazole Ligands for Palladium-Catalyzed Cross-Coupling

“…However, further study of cross-couplings of very bulky aryl chlorides may be warranted in the future since an intriguing balance between bulk and centroid distance is suggested (see the Supporting Information), but across only four data points surveyed to date, it may be too early to draw conclusion yet . A pre-peer-reviewed preprint of this article was deposited and may be viewed elsewhere …”

“…130 A pre-peer-reviewed preprint of this article was deposited and may be viewed elsewhere. 131 ■ CONCLUSIONS Two series of 1,2,3-triazole-containing 5-phosphino ligands were synthesized and tested as ligands in palladium catalyzed cross-coupling Suzuki−Miyaura reactions of bulky and heteroatom-containing substrates. The structural parameters of the 4-H triazole series (29) were determined by a restricted dihedral angle, phosphine oxide surrogate model, and a strong dependence upon bulkiness and catalytic activity were noted.…”