Phosphino-Triazole Ligands for Palladium-Catalyzed Cross-Coupling

Abstract

Twelve 1,5-disubtituted and fourteen 5-substituted 1,2,3-triazole derivatives bearing diaryl or dialkyl phosphines at the 5-position were synthesized and used as ligands for palladium-catalyzed Suzuki–Miyaura cross-coupling reactions. Bulky substrates were tested, and lead-like product formation was demonstrated. The online tool SambVca2.0 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 modeling approaches were compared for the determination of 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 10 of the most lead-like were successfully synthesized. Thus, confirming these readily accessible triazole-containing phosphines as highly suitable ligands for reaction screening and optimization in drug discovery campaigns.

Balancing Bulkiness in Gold(I) Phosphino‐triazole Catalysis

“…Some authors of this report previously detailed the synthesis, and application to palladium‐catalysed Suzuki–Miyaura cross‐coupling reactions, of 1,2,3‐triazole‐containing phosphines including analogues of the aforementioned Buchwald‐type ligands, such as 1a (Figure ) . Analysis of the steric parameters (buried volume), using the SambVca (2.0) web tool, confirmed that the bulkier ligands of those tested were the most effective in said catalysis …”

“…The 1‐aryl‐5‐phosphino‐triazole ligands, such as 1a , present their 1‐aryl fragment in the same orientation as the phosphorus lone pair (of the free ligand) or in the direction of the metal (of a phosphorus‐metal complex thereof), thus significantly impacting the determined buried volume . Noting that ortho ‐aryl tris‐phenylene phosphines (first reported, and somewhat overlooked, in 1940) can impart favourable properties as ligands in catalysis, it struck us that a bulky, and thus possibly superior, version of the triazole phosphine ligand is possible if the phosphorus atom were to be flanked by up to three, rather than one, triazole.…”

Synthesis of the First Resorcin[4]arene-Functionalized Triazolium Salts and Their Use in Suzuki–Miyaura Cross-Coupling Reactions

“…Infrared spectra were recorded with a Bruker FTIR Alpha-P spectrometer. Elemental analyses were carried out by the Service de [38], tosyl azide [49], and 2-azido-1,3-dimethoxybenzene [50] were prepared as per the standard procedures found in the literature.…”

“…The catalytic solutions were analyzed with a Varian 3900 gas chromatograph, fitted with a WCOT-fused silica column (25 m × 0.25 mm, 0.25 µm film thickness). 5-bromo-4(24),6(10),12(16),18(22)tetramethylenedioxy-2,8,14,20-tetrapentylresorcin[4]arene (3) [48], 5-azido-4(24),6(10),12(16),18(22)tetramethylenedioxy-2,8,14,20-tetrapentylresorcin[4]arene (6)[38], tosyl azide[49], and 2-azido-1,3-dimethoxybenzene[50] were prepared as per the standard procedures found in the literature.…”

Triazole Appended Phosphines: Synthesis, Palladium Complexes, and Catalytic Studies

“…In 2018, Fossey and co‐workers reported the synthesis of several monophosphine ligands having 5‐substituted 1,2,3‐triazole derivatives bearing diaryl or dialkyl phosphines and palladium‐catalyzed Suzuki–Miyaura cross‐coupling reactions . To rectify the inherent problem concerning phosphine protection and deprotection, Fossey and co‐workers also employed triazole‐mediated direct ortho ‐lithiation or halogen‐lithium exchange and subsequent reaction with diphenyl phosphorus chloride to synthesize phosphino‐triazoles 12a‐l (Scheme ).…”