The amine-catalysed Suzuki-Miyaura-type coupling of aryl halides and aryl boronic acids
The coupling of aryl halides and arylboronic acids is generally performed by metal-catalysed Suzuki–Miyaura reactions while metal-free approaches remain elusive. Here an organocatalytic approach based on amine catalysts is introduced for the preparation of commercially relevant asymmetric biaryls.
Our paper is available in Nature Catalysis at https://www.nature.com/articles/s41929-020-00564-z
The Suzuki-Miyaura coupling (SMC) reaction is a practical and attractive method for the construction of carbon−carbon bonds; it is used in more than 60% of the carbon−carbon bond formation processes in medicinal chemistry and its coupling products, especially unsymmetrical biaryl compounds, are a common structural motif in pharmaceuticals. In general, the SMC relies upon a transition metal catalyst, such as palladium (the most versatile), nickel, copper, cobalt, and iron, while an organocatalytic version remain elusive. Herein, we developed a transition-metal-free, amine-catalysed Suzuki-Miyaura-type coupling reaction for the construction of asymmetric biaryl skeleton (Figure 1c). Advantages associated with this reaction include the versatility, scalability, and metal-free nature of the product.
Figure 1. Important drugs with biphenyl substituents and synthetic strategies. (a) Drugs and pesticide containing asymmetric biphenyls. (b) The transition-metal-catalysed Suzuki-Miyaura coupling reaction. (c) The amine-catalysed Suzuki-Miyaura-type coupling reaction. OA, oxidative addition, TM, transmetalation, RE, reductive elimination.
Various aryl halides (including furan, thiophene, pyridine, quinoline, pyrimidine derivatives) and aryl boronic acids bearing a variety of functional groups underwent the reaction successfully. The utility and scope of this reaction were further exemplified in the synthesis of several economically important small molecules (o-tolyl benzonitrile, boscalid, adapalene, ledipasvir) and a selection of derivatives of pharmaceutical drugs (fenofibrate, bezafibrate, clofibrate, loratadine, indomethacin). To establish the industrial viability of our method, we scaled it up. At a catalyst loading of 0.5 mol%, p-triphenyl was prepared from 4-phenylbromobenzene and phenylboronic acid in 67% yield on a 50 gram-scale.
Another peculiarity is that this reaction undergoes a different mechanism from the metal-catalysed SMC, although the details of the mechanism are not clear yet. Based on a combination of the mechanism experiments (radical trapping experiments, EPR studies, deuterium labeling experiments, ICP-MS analysis, kinetic studies) and DFT calculations, we propose a catalytic cycle (Figure 2), which consists of the binding of catalyst (Cat) with two K2CO3 and Ar1-B(OH)2 (Cat + 2K2CO3 + Ar1-B(OH)2 → Int3), B-Ar1 bond dissociation (Int3 → TS3-4 → Int4), dissociation of the catalyst with a synergistic H-transfer (Int4 → Int5 + Cat), and organopotassium-mediated nucleophilic aromatic substitution (Int5 → TS5-pro → Ar1-Ar2) steps. Herein, Int and TS are short for intermediates and transition states, respectively.
Figure 2. Possible mechanistic probes. Gibbs free energy (ΔG0, in kcal/mol) profiles for the proposed mechanism and some competitive pathways, using K2CO3, PhB(OH)2, PhBr and cat. 7 as the energetic reference state. Me, methyl; Ph, pheny.
In our Nature Catalysis work, an amine-catalysed Suzuki-Miyaura-type coupling reaction broad in scope, tolerant of a variety of functional groups, and proven on a 50 gram-scale has been developed. Its utility was exemplified in the synthesis of several economically important small molecules and a mechanism elucidated, based on the results of DFT calculations. More details of this work can be found here: “The amine-catalysed Suzuki-Miyaura-type coupling of aryl halides and aryl boronic acids” in Nature Catalysis (https://doi.org/10.1038/s41929-020-00564-z).