Paul M. Murray

Aryl Trifluoroborates in Suzuki–Miyaura Coupling: The Roles of Endogenous Aryl Boronic Acid and Fluoride

A wide range of organoboron reagents can be used as alternative reagents to boronic acids in Suzuki–Miyaura (SM) coupling reactions. The readily prepared, convenient to handle potassium trifluoroborates, RBF3K, which have been developed by the groups of Genet and Molander, are often the reagents of choice for these transformations. Although extensive optimization of the base, solvent, and temperature is required for each class of substrate, their utility in SM coupling reactions has led to their widespread commercial availability. Apart from a preliminary study in 2003, their mode of action has not been investigated in detail, and the origin of their efficacy 5a] remains to be elucidated. Herein, we report the SM coupling of aryl trifluoroborate 1 with aryl bromide 2 to generate biaryl 3 (Scheme 1). We show that endogenous aryl boronic acid 4 and fluoride, both arising from 1, play key roles in the coupling reaction, being involved at all stages: from catalyst activation and catalytic turnover, through to the inhibition of side reactions. Collectively, these phenomena result in the exceptional performance of the reagent in the SM coupling. The SM coupling of 1 with 2 was studied in a toluene/ water (3:1) biphasic solution, and in a tetrahydrofuran/ water (10:1) solution, both systems being commonly employed for the SM coupling of trifluoroborates. The reactions in toluene/water, failed to go to completion: turnover ceased after 6 hours, affording 55 % of the basecatalyzed protodeboronation product 6 and 32% of coupling product 3. In aqueous tetrahydrofuran (Scheme 1) the reaction proceeded much more efficiently (5.5 h; > 95% yield of 3), with few side products ( 0.1–2%), even when the reaction was performed in air. In contrast, reaction of the boronic acid (4) under identical conditions, gave 3 in variable yield, and afforded substantially more of side products 9/10 (2–40%), compared to trifluoroborate substrate 1. The performance of aryl boronic acid reagents can be improved by the addition of KF, whereas trifluoroborate reagents require aqueous solvent systems for SM coupling with standard substrates. This observation has led to suggestions that mixed borates, [RBF(3 n)(OH)n] , 13] are the true transmetalating species. 5a, 10,13b] Base titration of 1 in a solely aqueous medium (D2O) was monitored by F and B NMR spectroscopy. Trifluoroborate 1 underwent hydrolysis via boronic acid 4 to give boronate 5 ; the transformation required approximately three equivalents of K2CO3 or Cs2CO3, or six equivalents of KOH to proceed to completion. At ambient temperature, boronate 5 slowly gave rise to fluorobenzene 6 by protodeboronation; the process was substantially faster at 55 8C. Rapid equilibrium between 4 and 5 gave rise to time-averaged F NMR chemical shifts (p-F-Ar nuclei), from which analysis of DdF values versus [base] was used to establish the mol% of boronate 5 (e.g. Figure 1a). When the dibasic nature of M2CO3 was taken into account, there was no significant difference in the curve Scheme 1. SM coupling of trifluoroborate 1 with bromide 2 to generate biaryl 3 together with the three major side products arising from protodeboronation (6), homocoupling (9), and oxidation (10).

Expansion of the Ligand Knowledge Base for Chelating P,P-Donor Ligands (LKB-PP)

We have expanded the ligand knowledge base for bidentate P,P- and P,N-donor ligands (LKB-PP, Organometallics2008, 27, 1372–1383) by 208 ligands and introduced an additional steric descriptor (nHe8). This expanded knowledge base now captures information on 334 bidentate ligands and has been processed with principal component analysis (PCA) of the descriptors to produce a detailed map of bidentate ligand space, which better captures ligand variation and has been used for the analysis of ligand properties.