Suzuki–Miyaura Cross‐Coupling

Abstract

The Suzuki–Miyaura cross coupling reaction uses a metal catalyst to create carbon–carbon bonds from organoboron reagents and organo(pseudo)halides. By careful adjustment of the ligand system, solvents, and other additives, this reaction can couple a diverse range of sp‐, sp 2 ‐, and sp 3 ‐hybridized organoboron and organo(pseudo)halide reactants. The Suzuki–Miyaura cross coupling reaction has become preeminent in both small‐ and large‐scale synthesis owing to its mild reaction conditions, predictable stereochemical outcomes, chemoselectivity, functional‐group compatibility, and use of relatively non‐toxic and air‐stable starting materials. This chapter describes the theoretical and practical aspects of the palladium‐catalyzed Suzuki–Miyaura cross‐coupling reaction. A broad overview of the reaction mechanism and scope is described, with selected examples of how mechanistic insights have enabled progress in the development of this coupling reaction. Examples include early reaction discovery as well as modern applications in synthesis using a diverse array of organoboron and organo(pseudo)halide reactants, and on scales that range from milligram to multi‐kilogram. Tabular surveys are organized by the structure of the transferable group attached to boron as the primary rubric (alkyl, alkenyl, aryl, alkynyl, then heterocyclic), with the structure of the electrophile as the secondary rubric. Selected literature is covered from the seminal paper in 1979 to mid‐2018.

Automated radiosynthesis of [11C]UCB‐J for imaging synaptic density by positron emission tomography

“…The radiosynthesis of [ 11 C]UCB‐J is based on the application of the palladium(0)‐mediated Suzuki cross‐coupling reaction between the carbon‐11 methyliodide ([ 11 C]CH 3 I) and trifluoroborate precursor 3 (Figure ) . Initially explored method employed a more common Suzuki reacting partner, ie, the corresponding boronic acid (eg, 4 in Scheme ) as a radiolabelling precursor; however, the boronic acid precursor 4 proved to be unstable upon storage resulting in poor reproducibility and unreliable radiochemical yields. Further investigation indicated that while trifluoroborate 3 can be used as a radiolabelling precursor for [ 11 C]UCB‐J, the actual reacting specie is the boronic acid, thus necessitating a need for a mixture of trifluoroborate 3 and 3‐10% of the boronic acid 4 to be present in the reaction vessel …”

Activation of Aryl Chlorides in the Suzuki-Miyaura Reaction by “Ligand-Free” Pd Species through a Homogeneous Catalytic Mechanism: Distinguishing between Homogeneous and Heterogeneous Catalytic Mechanisms

“…In the former case, the nature of the Pd complex that activates the competing aryl chloride substrates can be studied during the oxidative addition to a Pd(0) compound, which results in the formation of an ArPdX-type intermediate. 3 In the latter case, the DS patterns of the competing arylboronic acids will characterize the nature of the Pd complex that reacts with the competing arylboronic acids; this occurs through transmetalation of the arylpalladium complexes with the arylboronic acids. Therefore, using these possibilities, a wide set of experimental data can be obtained, leading to further evidence for the obtained conclusions.…”

“…Under Suzuki-Miyaura reaction conditions, it is possible to conduct the experiments using two essentially different competitions between two aryl halides or two arylboronic acids. In the former case, the nature of the Pd complex that activates the competing aryl chloride substrates can be studied during the oxidative addition to a Pd(0) compound, which results in the formation of an ArPdX-type intermediate . In the latter case, the DS patterns of the competing arylboronic acids will characterize the nature of the Pd complex that reacts with the competing arylboronic acids; this occurs through transmetalation of the arylpalladium complexes with the arylboronic acids.…”

“…The reaction has synthetic advantages, such as high selectivity toward target cross-coupling products, tolerance to impurities in the reagents and air oxygen and moisture, and low toxicity of byproducts formed during the reaction. The advantages of the Suzuki-Miyaura reaction led to its extensive implementation in the industrial production of fine chemicals, particularly pharmaceutical, agrochemical, and natural products. − It can be confidently stated that various catalytic systems based on soluble Pd complexes are involved in the process, along with heterogenized catalysts traditionally used in the industry. − However, despite impressive progress in the development of diverse catalytic systems to convert a wide range of reagent types, the mechanistic details of the catalytic cycle, including formation and deactivation of the active species, are unclear. There are contradictory views on whether the Suzuki-Miyaura reaction proceeds in the solution phase through a homogeneous catalytic mechanism or through a heterogeneous catalytic mechanism on the surface of Pd metal particles, including nanoparticles (Figure ).…”

Undirected, Selective Csp2-H Alkynylation of Five-membered Heteroarenes

“…*Address correspondence to this author at the Dipartimento di Chimica e Chimica Industriale, Università di Pisa, 56124 Pisa, Italy; Tel/Fax: ++39-0502219282, +0-000-000-0000; E-mail: fabio.bellina@unipi.it To date, most functionalizations of (hetero)aromatic systems are achieved through the use of methods that require a preactivation of a sp2 carbon atom by halogenation or metallation. Among these, the reactions of Suzuki, [1][2][3][4][5][6][7] Negishi, [8][9][10] and Migita-Stille [11][12][13][14] foresee the creation of the new C-C bond by cross-coupling of organic halides with organometallic compounds in the presence of catalysts based on transition metals. [15][16][17] These procedures, although often characterized by high efficiency and selectivity, have two significant disadvantages: a) the activation of both reagents, which leads to an increase in the stages of the synthetic sequence, and b) the nature and quantity of reaction waste, which is detrimental to the atom economy of the entire synthetic process.…”