Recent Advances in Borylation and Suzuki-Type Cross-Coupling—One-Pot Miyaura-Type CX and CH BorylationSuzuki Coupling Sequence

Abstract

In the last decades, numerous approaches have been explored for the cross-coupling of biaryl building blocks depending on the presence of boron sources. In fact, these changes have been catalyzed by transition metal complexes. This review focuses on the progress of the last decade in transition metal-catalyzed C–X borylation and direct C–H borylation, with emphasis on nickel-catalyzed C–H borylation, as effective and affordable protocols for the borylation of aryl substrates. In addition, Suzuki-type cross-coupling by activation of C–H, C–C, or C–N bonds is also reported. This study then offers an overview of recent advances for the synthesis of bi- and multi-aryls found in synthetic molecular complexes and natural products using the transition metal-catalyzed one-pot Miyaura-type C–X and C–H borylation–Suzuki coupling sequence.

1. Introduction

Transition metal-catalyzed cross-coupling reactions such as Suzuki–Miyaura, Mizoroki–Heck, Negishi, Sonogashira, Kumada–Tamao–Corriu, Migita–Kosugi–Stille, Tsuji–Trost, and Buchwald–Hartwig involving C–X coupling and also a direct C–H functionalization has emerged as an important and highly effective strategy for building carbon–carbon bonds, with particular emphasis on the synthesis of unsymmetrical biaryl systems [1,2,3,4,5,6,7,8,9]. These systems are known for their complex, multifaceted molecular architectures, making them an exciting field of study in organic chemistry for the development of pharmaceuticals and materials. The Suzuki–Miyaura coupling is the reaction of a (hetero)aryl halide with an organoboron compound, and it is one of the most popular and widely used cross-coupling processes [2,10].

The formation of carbon–carbon bonds in organic synthesis has resulted from the widespread use of organoboron compounds and arylboronic acids, which are highly stable, affordable, and compatible with almost any functional group. Indeed, there has been great interest in arylboronic acids and esters because of their use in organic synthesis [11,12,13], their interaction with biologically significant ligands [14], and their molecular recognition ability [15]. It has also been pointed out that density functional theory (DFT) is used in borylation reactions to comprehend the interplay of reactants, intermediates, and products. For more efficient borylation, DFT aids in the design of novel catalysts and the optimization of reaction conditions by forecasting activation energies, geometrical structures, and intricate reaction pathways [16]. The Miyaura borylation was the first Pd-catalyzed borylation of aryl halides using bis(pinacolato)diboron B₂(pin)₂ [17], a reagent that was later replaced by the more reactive pinacolyl borane; it is known as Masuda borylation [18]. A recent review by Shaya, Polychronopoulou, and co-authors describes progress during the 21st century concerning the utilization of C(sp³)–organoboranes as partners in metal-catalyzed C(sp³)–C(sp²) cross-couplings, such as B–alkyl Suzuki–Miyaura reactions. Their review gives a particular emphasis on the use of organic halides or pseudohalides as coupling partners, and also a strong interest in C–O–alkyl electrophiles [19]. Aryl and alkyl halides are important coupling partners in this type of reaction, and, for this reason, several procedures have been developed for their synthesis, with particular interest focusing on green and efficient methods such as the direct halogenation of alcohols with halosilanes under catalyst- and organic solvent-free reaction conditions [20].

Recently, Müller’s group published an interesting review gathering all the works describing an efficient procedure for the synthesis of (hetero)biaryl compounds via a one-pot Masuda borylation–Suzuki coupling (MBSC) sequence [21]. In fact, the methodology is based on the conversion of halogenated (hetero)cycles and vinyl compounds into the corresponding pinacolyl boronic acid esters, allowing a subsequent Suzuki coupling with a second halogenated compound. The review surveys the MBSC sequence since its first development by Baudoin in the spring of the new millennium [22] and covers significant improvements by various research groups (Baudoin’s, Queiroz’s, Levacher’s, Colobert’s, Chai’s, Huleatt’s, and Müller’s groups). The sequences described in Müller’s review are mainly catalyzed by palladium catalysts.

The preparation of organoboron species via transition metal-catalyzed borylation of aryl and vinyl halides is a process that allows the generation of boron derivatives, which serve as valuable precursors for subsequent transition metal-catalyzed coupling reactions. The borylation can be carried out using palladium as well as other transition metal catalysts. The aim of the present study is to review the progress of borylation, including transition metal-catalyzed C–X and direct C–H borylation as well as metal-free C–H borylation approaches developed using hydroborane and pinacolborane moieties and related species, Suzuki coupling of borylated structures, and the combination of one-pot transition metal-catalyzed borylation–arylation sequences. This is a comprehensive survey from borylation to the Suzuki coupling, covering mainly the last decade, and therefore provides an added value to existing reviews, the content of which is given concisely and avoids duplication. It also pointed out that the one-pot Miyaura borylation–Suzuki coupling (MIBSC) sequence, recent advances of which are provided in the present study, has not been reviewed until today.

2. Borylation

2.1. Transition Metal-Catalyzed C–X Borylation

Several techniques have been developed for the synthesis of organoboronic substances due to their significant value for the preparation of pharmaceuticals, functional materials, and synthetic intermediates. As mentioned above, among the most efficient methods for the generation of arylboronate esters are the Miyaura [17] and Masuda [18] borylation of aryl (pseudo)halides by the borylation of iodides, bromides, triflates, chlorides, and aryl fluoride electrophiles, catalyzed by palladium, nickel, copper, cobalt, and zinc [23,24,25,26,27]. In a review in 2013, Kwong’s group described the progress of the past decade in the transition metal-catalyzed borylation of aryl halides and sulfonates [28]. This section offers an overview of important achievements in transition metal-catalyzed aryl(alkyl) halide borylation during the last decade.

The synthesis of arylboronate esters by the subtle but efficient transition metal-catalyzed borylation method has gained significant attention. Given that both highly selective metal-catalyzed aryl halide borylation and direct C–H borylation of arenes are frequently dependent on precious metal catalysts, front-line earth-abundant metal catalysts have grown in popularity due to their low cost and low toxicity. Marder, Radius, and colleagues reported the C–Cl bond borylation of a variety of aryl chlorides [29]. This reaction is catalyzed by NHC-stabilized Cu(I) complexes of the type [Cu(NHC)(Cl)] [30], KO^tBu as the base, and B₂pin₂ (pin = pinacolato) (1) as the borylation reagent. Good yields of aryl boronic esters 3 are obtained from aryl chlorides 2 (Scheme 1). This novel process demonstrates broad functional group tolerance, and B₂neop₂ (bis(neopentylglycolato)diboron) (4) can also be employed as a borylation reagent.

In the same context, copper (II) salts are appealing due to their affordability, minimal handling costs, and their ability to withstand oxidation in air. Marder and colleagues developed a new catalytic system based on a copper (II)-NHC precursor that exhibits good functional group compatibility and broad substrate selectivity for the borylation of alkyl halides 10, including unactivated chlorides, using the B₂pin₂ in mild conditions and open air (Scheme 2) [31]. Mechanistic studies suggested that the reaction involves a one-electron process.

Palladium is the transition metal most widely used for the catalytic borylation of aryl halides. However, in recent years, more affordable and ecologically friendly base metal catalysts, such as copper, zinc, and iron complexes, have been developed. Compared to palladium catalysts, these systems typically have lower catalytic efficiency. Furthermore, it is uncommon to find accessible and reasonably priced aryl chloride borylations using base metals other than nickel. Therefore, it is highly desirable to develop economical and ecologically friendly base metal catalysts for the borylation of aryl halide, especially for aryl chloride borylation. Hu, Huang, and colleagues reported the first cobalt-catalyzed borylation of aryl (pseudo)halides. The synthesis of arylboronate esters 13 was accomplished by the borylation of aryl halides with bis(pinacolato)diboron (B₂pin₂) (1) (Scheme 3) [32]. Catalysis was achieved in methyl t-butyl ether (MTBE) by 5 mol% of cobalt complex 15 as a precatalyst, which was activated by LiMe to form a Co methyl complex. The readily accessible ligands 14, the low cost of the corresponding cobalt complexes, and the mild reaction conditions make this process more economical and efficient for demanding borylations compared to the commonly used palladium catalysts.

Ho, Bissember, and colleagues prepared copper complexes with acridine-based PNP pincer ligands as the first examples of first-row late transition metal complexes with this type of ligand [33]. The copper complex formed an efficient catalyst for the borylation of aryl iodide 16 with B₂pin₂ (1) (Scheme 4) as well as the hydroboration of alkynes.

Aryl chlorides have low reactivity when catalyzed by palladium, nickel, and cobalt; nonetheless, borylation of alkyl halides by iron has long been recognized [34]. Ilies, Nakamura, and colleagues reported iron-catalyzed borylation of several aryl and heteroaryl chlorides such as 1-chloronaphthalene (18), in which potassium t-butoxide is an essential component [35]. The catalytic amount of an iron complex, such as Fe(acac)₃, is reported to be essential in this process. As the active species, the alkoxide is thought to generate an electron-rich iron alkoxide complex in situ. All that is needed for the reaction to proceed is an iron complex and potassium t-butoxide, which can be readily scaled up (Scheme 5). Under Suzuki–Miyaura conditions, the aryl boron molecule 19 produced by this reaction can be coupled in situ with an aryl halide.

Martin and colleagues described the first nickel-catalyzed (Ni(COD)₂; COD = 1,5-cyclooctadiene) borylation of monofluorarenes 20 with B₂neop₂ (4) as a boron source (Scheme 6) [36]. In order to identify possible reaction pathways, the reaction of 20 with Ni(COD)₂/PCy₃ in THF was monitored in situ by NMR spectroscopy and, although the results cannot definitively rule out other possible reaction pathways, the authors propose an initial oxidative addition to the C(sp²)–F bond of 20 to form complex II, followed by boryl transfer with the aid of NaOPh base, forming [(Ar)Ni(PCy₃)₂(Bneop)] (III). Finally, the C–B bond is reductively eliminated and releases the targeted boronate arene 21 while generating the active propagating species Ni(PCy₃)₂ (I). The reaction was shown to be highly chemoselective and was not affected by the presence of other functional groups. This work represents a rare example of C–heteroatom bond formation via catalytic C–F cleavage of unactivated fluoroarenes. The protocol stands out for its broad scope of application without compromising its practicability, efficiency, and scalability for the development of new molecules of interest.

Since borylated fluoroaromatics 23 are very useful as precursors in chemical synthesis, the research groups led by Marder and Radius explored the potential of nickel-catalyzed borylation of polyfluorinated aromatic systems 22 (Scheme 7) [37]. They assessed the effects of the Ni(IMes)₂ (IMes = 1,3-dimesitylimidazolin-2-ylidene) catalyst on C–F bond cleavage and subsequent borylation in a number of polyfluoroarenes to afford the products in moderate to good yields. It is interesting to note that while Ni(IPr)₂ (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazolin-2-ylidene) significantly increased the reaction yield, the Ni(IMes)₂ catalytic system proved less effective for pentafluorobenzene, and it can be explained by the sterically more demanding NHC IPr ligand in the nickel complex [37]. In a mechanism like that proposed in Scheme 6, [Ni(IMes)₂] (IV) reacts with fluoroarene 22 and, as a result of oxidative addition of the C−F bond, [(Ar^Fn)Ni(IMes)₂(F)] (V) is initially formed. Despite being an initial step, complex V then undergoes a boryl transfer reaction with M⁺[B₂pin₂F]⁻ to form trans-[(Ar^Fn)Ni(IMes)₂(Bpin)] (VII) and M⁺[F₂Bpin]⁻. The boron-substituted fluoroaromatic 23 is obtained by a final reductive elimination step. This step also regenerates [Ni(IMes)₂] (IV). It was found that borylation of the nickel fluoride complex appears to be the rate-limiting step.

Recently, Bose’s group reported a nickel-benzene tricarboxylic acid (Ni-BTC) (26) metal−organic framework (MOF) that efficiently catalyzes the borylation of aryl halides 24, including the inexpensive and broadly available aryl chlorides, using B₂(pin)₂ (1) as the boron source (Scheme 8) [38]. The method exhibits excellent functional group tolerance, the catalyst can be recycled up to four times, and the reaction can be scaled up to the gram scale, making this process industrially attractive. As shown by mechanistic investigations, the active catalyst is a Ni(I) species.

Many palladium-catalyzed processes have been developed for the conversion of aryl halides to the corresponding aryl pinacol boron esters. However, because the processes are air-sensitive and require purified solvents and substrates and expensive, bulky ligands, the development of aryl boronic esters from aryl halides (bromides or chlorides) using a gentle and eco-friendly process is not always straightforward. A feasible way to obtain such boronic esters and their derivatives is the transition metal-catalyzed Miyaura borylation [17]. An enhancement over the current reaction conditions is described by de Vries, Tran, and colleagues [39]. The catalyst is generated from [(allyl)PdCl]₂ and XPhos (2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl). They have investigated the influence of the base on the efficacy of the Miyaura borylation. The lipophilic base potassium 2-ethyl hexanoate (2-KEH) has the highest yields, and the borylation reaction could be carried out at 35 °C in less than 2 h with a very low palladium loading (0.5 mol%) (Scheme 9). This was determined by comparing the effects of several bases such as KOAc, NaOAc, and NMe₄OAc on Miyaura borylations. According to an initial mechanistic investigation, 2-ethyl hexanoate reduces the inhibitory effect of the carboxylate anion (AcO⁻), which has an as-yet-unidentified inhibitory effect on the catalytic cycle. A wide variety of substrates can be borylated under mild conditions using this protocol.

Tetrahydroxydiboron B₂(OH)₄ 29 is an alternative diboron source that is more environmentally friendly and atom-efficient than B₂pin₂ (1) and produces aryl boronic acids straight from the matching aryl halide in a single step [40]. To achieve this, Wisniewski, Simmons, Frantz, and colleagues used B₂(OH)₄ (29) to borylate aryl (pseudo)halides using three catalytic systems (Scheme 10) [41]. The aryl bromides, iodides, and chlorides 30 were borylated using two palladium-based systems (Pd-I 32a and Pd-II 32b) at moderate temperatures, low catalytic loadings, and below room temperature. Under these circumstances, halide ions might be extracted from KCl (containing aryl chlorides) or from the TMAX salt precipitate (containing aryl iodides and bromides). This sequestration of halide ions produced during the reaction through simple precipitation is key to the success of these Pd-based systems, as it results in catalyst loadings as low as 100 ppm and reaction temperatures as low as room temperature. Furthermore, the use of Ni catalyst 33 generated from NiCl₂^.6H₂O and CyJohnPhos instead of Pd-based systems is intended to reduce system costs.

The majority of C−X borylations require a base. However, borylation of aryl chlorides 34, which contain two ortho-fluorine atoms, was achieved in a base-free process using the catalytic mixture Pd(dba)₂ (dba = dibenzylidene-acetone) and SPhos (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl) as described by Marder, Radius, and colleagues (Scheme 11) [42]. This approach has been challenging because most earlier techniques call for stoichiometric amounts of base to activate the palladium complex and facilitate the exchange of the metal with pinacol diborane ester, and the ortho-fluorine substituents speed up the protodeboronation that occurs in polyfluorinated aryl boronates 35.

In the context of base-free C–X borylation, there have been two recent reports of palladium-catalyzed borylation with aryl halides 36 using either B₂(neop)₂ (4) or B₂(pin)₂ (1) (Scheme 12) [43,44]. The reaction was promoted by the Lewis acidic zinc mediators 38 [43] and 39 [44]. According to mechanistic studies, an aryl(halo) palladium (II) intermediate is activated via halide abstraction by the Lewis acid mediator, enabling transmetalation with the diboron compound, yielding the corresponding aryl boronic esters 37 without the need for an external base.

In contrast to the considerable attention that mono-borylated arenes have received, studies on the multi-borylated analogues are rare. In a very recent publication, Jiao, Wu, and colleagues reported a titanium-catalyzed selective and cost-effective procedure for the synthesis of bis(boronate)arenes 41 via the reaction of aryl halides 40 with B₂(pin)₂ (1) in MTBE (methyl t-butyl ether) in the presence of ^tBuOLi (Scheme 13) [45]. A simultaneous C─X and C─H borylation occurs. Mechanistic studies based on control experiments and DFT calculations revealed that the first step involves ^tBuOLi-promoted Ti-mediated generation of an aryl radical, which drives the Ti-mediated bis-borylation.

2.2. Transition Metal-Catalyzed C–H Bond Activation and Borylation

Transition metal catalysts are crucial for the economical and sustainable synthesis of significant compounds. Since the selective activation and functionalization of various C–H bonds avoid the need for multistep processes and pre-functionalization of starting materials, it is an atom-efficient and environmentally friendly approach that offers the most direct and effective means of fostering the rapid growth of structural diversity and molecular complexity. Several techniques have been used to efficiently and selectively stimulate the C–H activation of aromatic substrates using different reaction conditions involving different ligand frameworks [46,47]. A potent synthetic technique that provides versatile transformation from organoboron compounds to almost all other functional groups is the transition metal-catalyzed C–H borylation using rhenium, rhodium, palladium, ruthenium, iridium, or cobalt catalysts, which is a topic that has been extensively reviewed [48,49]. Since nickel catalysis has not been included in these reviews, in this section, we provide information on recent developments in nickel-catalyzed direct C–H borylation.

The first nickel-catalyzed aromatic C–H borylation was reported independently by Itami’s [50] and Chatani’s [51] groups in 2015. In both publications, several arenes 43 and indoles 44 were borylated with B₂pin₂ (1) or pinacolborane (HBpin) (47) in the presence of [Ni(cod)₂] and either an N-heterocyclic carbene [50,51] or PCy₃ [50] [Scheme 14]. In Itami’s work, the rate-determining step involves the C–H cleavage as indicated by kinetic isotope effect experiments [50], and in Chatani’s work, the extraordinary reactivity of nickel may be partially explained by the heterogeneous nature of the active species produced under the current conditions [51].

In the same context, Mandal’s group reported the C(sp²)−H borylation of arenes 43 with HBpin (47) catalyzed by the well-defined abnormal N-heterocyclic carbene-based Ni(II) complex 48 (Figure 1), which breaks into Ni nanoparticles, being the actual catalytically active species [52]. n-Propyl, n-butyl, and n-hexylbenzenes, phenylcyclohexane, naphthalene, biphenyl, 1,3-diisopropylbenzene, and 1,3-dimethoxybenzene were borylated for the first time using a first-row transition metal catalyst.

Guo, Radius, Marder, and colleagues developed an efficient, traceless, directed C3-selective C–H borylation of indoles 49 with B₂pin₂ (1) using Ni(IMes)₂ (IMes = 1,3-dimesitylimidazoline-2-ylidene) as a catalyst (Scheme 15) [53]. The reaction proceeds under mild conditions without a base and exhibits a wide range of applicability and functional group tolerance, resulting in borylated indoles 50 in good to outstanding yields with high selectivity. According to the proposed mechanism, the N−H bond of indoles is activated and borylated by Ni(IMes)₂ (IV) to install a Bpin moiety at the N-position. In more detail, in the first step, the indole undergoes rapid oxidative addition to form Ni hydride complex VIII which reacts with B₂pin₂ (1) to install Bpin as a traceless directing group at the indole N-position to form IX and release Ni(IMes)₂. The C3-borylation of IX is then catalyzed by the regenerated Ni(IMes)₂. In this process, Ni(IMes)₂ is inserted into the C3–H bond of IX to produce the hydride complex X, which is then transformed with B₂pin₂ to the bis-N/C3-borylated indole 51, reinstating the Ni(IMes)₂. Finally, it appears that this complex also catalyzes the removal of the directing group, and, therefore, the N–Bpin group in 51 is converted in situ back to an N−H group, yielding the derivatives 50 without leaving any trace of the directing group.

It is commonly accepted that boryl–nickel complexes are elusive, in contrast to other metals such as copper or cobalt. Radius’ group reported the first cis-nickel bis-boryl complexes 55a–c by the reaction of Ni(ⁱPr₂Im^Me)₂ (52) (ⁱPr₂Im^Me = 1,3-di-iso-propyl-4,5-dimethylimidazolin-2-ylidene) with B₂pin₂ (bis(pinacolato)diboron) (1), B₂eg₂ (bis(ethylene glycolato)diboron) (53) and B₂cat₂ (bis(catecholato)diboron) (54), respectively (Scheme 16) [54].

It was also found that when B₂cat₂ (54) is used as the boron source, the catalytic precursor Ni(ⁱPr₂Im^Me)₂ (52) demonstrated an exceptional catalytic activity for the diboration of alkynes 56, indicating that this 3d-metal catalyst offers the potential for novel selectivity for the borylation of alkynes (Scheme 17) [54]. As primary results of the procedure, C–C linked borylation products, as well as tetra-borylated products, can also be formed. The mechanism of catalysis was also investigated based on stoichiometric reactions and DFT calculations. The catalytic cycle starts with the coordination of the alkyne to nickel complex 52 to form the alkyne complex XII and subsequent borylation at the coordinated and, thus, activated alkyne to yield complexes XIII of the type [Ni(NHC)₂(n²-cis-(Bcat)(R)C=C(R)(Bcat))]. The formation of the borylated alkene π-complexes as catalytic intermediates is crucial to understanding the new catalytic pathway and the formation of new borylation products, while oxidative addition of the diboron reagent to the metal is not dominant.

2.3. Metal-Free C–H Borylation

Owing to the low availability and high toxicity of transition metals, together with the economic issues involved, there is growing interest in alternative metal-free activation processes. However, despite the advantages of metal-free borylation, the process still faces several challenges and limitations. In some borylation reactions, substrates must be converted to highly reactive compounds, which leads to poor atom economy. The borylation of alkyl chlorides by this process remains challenging, as the reduction of alkyl chlorides requires a very high reduction potential. Furthermore, the borylation of C(sp³)-H bonds without a directing group has low yields and poor regioselectivity. In addition, enantioselective metal-free borylation is difficult to achieve. However, the topic remains exciting and has been extensively reviewed until 2023 [55,56,57,58], while reviews in 2025 focus on metal-free mechanochemical and electrochemical borylation [59,60]. This section includes significant achievements in the field during the last couple of years without references on mechanochemical and electrochemical borylation, which have been reviewed recently.

In the concept of metal-free C–H borylation, BBr₃-mediated borylation is a common process. Gupta, Maiti, and colleagues developed a technique for the C–H borylation of α-naphthamides 58 as well as phenylacetamide derivatives by their reaction with BBr₃ (59) and subsequent treatment of the boron compounds 60 with pinacol (61) without the need for metals (Scheme 18) [61]. The proposed approach demonstrated high efficiency and good functional group tolerance. The C8-borylated products 62 were synthesized in exceptional yields and site exclusivity under facile, convenient, and affordable conditions. The borylation of α-naphthamide occurs with an overall activation barrier of 23.6 kcal^.mol⁻¹, according to a computational study. Bulky substituents at the α-positions lower the overall activation barrier, favoring product generation under the current reaction circumstances, according to the distortion/interaction study. In the same context, Zhang’s group reported the metal-free ortho-C–H borylation of benzamides 63a [62] and thiobenzamides 63b [63], while the C–H borylation of the N-phenylbenzamide analogues 63c was reported by Wu’s group [64] (Scheme 19). Their findings provided a convenient strategy for the synthesis of functionalized benzamides, which are useful intermediates in the synthesis of fine chemicals and drugs.

Zhang’s group developed a versatile procedure for the C–H borylation of indoles on the benzenoid moiety rather than the more reactive pyrrolic unit [65]. In accordance with this protocol, a B(C₆F₅)₃-catalyzed C–H borylation of indoles 65 with catecholborane (HBcat) (69) afforded C5-borylated indoles 68 via a cascade reaction that involves indoline formation, borylation, and dehydrogenation (Scheme 20). The Lewis acid catalyst (B(C₆F₅)₃) activates the boron reagent, catalyzes selective C5-borylation of indole, and facilitates hydride transfer. C3, C5-Diborylated indoles were also formed, and could be concerted to the C5-monoborylated analogues via an acidic protodeboronation at the C3-position.

In another approach, Martin’s group reported the potential of bis(1-methyl-ortho-carboranyl) borane (HB^MeoCb₂) (71) as an electrophilic borylation reagent for the dearomative C2-borylation of indoles 65, yielding the indolenium species 70 (Scheme 21) [66]. For this scope of application, HB^MeoCb₂ was found to be a better borylation reagent compared to fluoroaryl boranes. It was also found that when the parent indole was subjected to borylation under these mild conditions, N-borylation rather than C2-borylation occurred.

Geetharani’s group reported a protocol for a metal-free trifluoromethylative borylation of unactivated alkenes 72, including natural products and drug derivatives (Scheme 22) [67]. This occurs by mutual activation of the bis(catecholato)diboron (54) and Togni II (73) reagents in one step. According to mechanistic studies, this mutual activation plays a vital role in the generation of CF₃ and boryl radicals towards the formation of products 74.

The synthesis of 1,3-disubstituted bicycle[1.1.1]pentanes (BCPs) is very challenging due to their ability to impact valuable pharmacokinetic properties and, therefore, are important molecules in drug discovery. Dong, Hue, and colleagues developed a versatile method for borylation of [1.1.1]propellane (75) towards the synthesis of BCP boronates 77 through difunctionalization of 75 with B₂pin₂ (1) and Katritzky salts 76 (Scheme 23) [68]. The process is metal- and photocatalyst-free. Mechanistic studies provided evidence that the reaction is facilitated by the formation and red-light excitation of a ternary electron donor–acceptor complex between the Katritzky salt, Cs₂CO₃, and B₂pin₂ to form an alkyl or α-ester alkyl radical, which reacts preferentially with propellane, rather than with the a-Bpin acceptor, leading to the formation of an sp²-like BCP radical. The latter radical undergoes polarity-matched addition to B₂pin₂, leading to BCP difunctionalization.

Mane, Bose, and colleagues developed a metal- and solvent-free process for the regioselective di- and triborylation of terminal alkenes 78 and alkynes 79, respectively, using B₂pin₂ (1) as the boron reagent in alkali metal Lewis base (NaOMe)-mediated reactions (Scheme 24) [69]. The reactions could scale up to gram scale, indicating the practical utility of the method. According to DFT calculations, the formation of an acid-base adduct, generated through the reaction of the diboron reagent with the methoxide anion, is the first step that plays a critical role in this borylation.

3. Suzuki-Type Cross-Coupling

The reaction of a (hetero)aryl (pseudo)halide with an organoboron compound, known as the Suzuki–Miyaura coupling, is one of the most important tools of organic chemistry for C–C bond formation and can be performed in organic or environmentally benign solvents such as water. Recent extensions of this methodology have also enabled the formation of C–N, C–O, or C–S bonds in so-called “Suzuki-type” reactions, while maintaining similar key steps in the mechanism (transmetalation, transition metal catalysis, boron activation). Due to the enormous academic and industrial interest, the topic of Suzuki–Miyaura coupling has been extensively reviewed [2,10,70,71]. This coupling is mainly carried out with palladium catalysts (nickel, iron, copper, cobalt, gold, and zirconium are also used), and although the majority of the ligands are P-based [2], phosphane-free ligands are also common, such as porphyrins and thiosemicarbazones with the first papers reported by Kostas/Coutsolelos [72] and Kostas/Demertzi [73], respectively, and also Schiff bases [74]. Suzuki arylation can be carried out not only by C–X activation, as the traditional Suzuki–Miyaura coupling, but also by directly activating C–H, C–C, or C–N in a Suzuki-type reaction, significant recent achievements of which are described in this section. These advancements facilitate the functionalization of structures that are challenging to reach using traditional techniques and provide more efficient and adaptable approaches for the modification of complex molecules.

An early example of the direct C–H arylation of azoles involved the Suzuki–Miyaura arylation of caffeine 82 with a series of arylboronic acids 83, as reported by You’s group [75]. They showed appropriate relevant Suzuki–Miyaura arylation of caffeine 82 with multiple arylboronic acids 83. The reaction was promoted by a catalytic system comprising palladium (II) acetate, copper (II) acetate, and copper(I) chloride. The procedure was carried out using potassium fluoride as a base and benzoquinone (BQ) as an organic oxidant in N-methyl-2-pyrrolidone (NMP). As described in Scheme 25, this approach led to direct C–H arylation, resulting in the synthesis of heterocoupled caffeine 84 in excellent yields.

Tertiary stereogenic centers have been generated via palladium-catalyzed stereospecific and regioselective cross-coupling between enantiopure 2-arylaziridines 85 and arylboronic acids 83 as described by Takeda, Minakata, and colleagues (Scheme 26) [76]. N-heterocyclic carbene (NHC) ligands effectively suppress the removal of β-hydride by promoting the coupling. This enantiospecific cross-coupling was used to prepare several clinically significant 2-arylphenethylamine derivatives 86 in an enantiopure form.

With monosubstituted arenes 43 as the limiting reagent and remarkable tolerance for functional groups and heterocycles, the combination of para-selective thianthrenation and the palladium-catalyzed thio-Suzuki–Miyaura coupling reaction can produce paradiaryls 88 in high yields with thianthrene S-oxide (TTSO) 89 as reported by Wang’s group (Scheme 27) [77]. TTSO acts as a transient mediator, forming a para-selective intermediate species activated by the alkenylation of arenes, followed by para-arylation. The most recent functionalization of intricate bioactive scaffolds and the rapid synthesis of pharmaceutical compounds like tetriprofen, ibuprofen, bifonazole, and LJ570 have demonstrated the value of this approach [77].

Iron-based catalysts have also been investigated for C−C cross-coupling reactions due to affordability, widespread availability, and the environmentally friendly nature of iron. Thus, Hu, Yu, and colleagues described a convenient iron-catalyzed, direct C−H arylation of N-heterocycles 90a–b with arylboronic acids 83 using ferrous oxalate dihydrate or ferric chloride hexahydrate as catalysts in the presence of macrocyclic polyamine ligands 91a–b (Scheme 28) [78]. The Suzuki–Miyaura arylation leads to heterocyclic biaryls 92a–b in moderate to high yields.

Bao’s group developed an eco-friendly palladium (II)-catalyzed protocol for Suzuki coupling of the ortho-C−H bond of aromatic aldehydes 93 with the versatile arylboron reagents 83, 94, and 95 towards the formation of aldehydes 96 (Scheme 29) [79]. For the first time, C−H arylation of aldehydes was achieved by a transient directing strategy, in which the best results were observed using 3-amino benzoic acid (97) as a transient directing group (TDG). The method used 1,4-benzoquinone (BQ)/trifluoroacetic acid (TFA) as a weak oxidation system for the Pd (II) / Pd (0) redox cycle. The results showed that the TDG helps the −CHO group in harnessing palladium with adjacent C(sp²)−H or C−Br bonds, and the cross-coupling of C−Br bond with boronic acids cannot be achieved without TDG. Mechanistic studies provided evidence that the first step of the C−H arylation reaction is the transient formation of an imine from the benzaldehyde and TDG. Following Pd coordination, a five-member palladacycle is generated by C(sp²)−H activation by TFA-assisted concerted metalation−deprotonation, after which, transmetalation takes place with various arylboron reagents. This approach has a broad applicability and is suitable for a gram-scale reaction.

Naik and Khan reported a versatile method in which 2-bromo-3-(arylamino)-1H-inden-1-one derivatives (98) led to indenoindoles 99 via palladium-catalyzed C−H activation and subsequent Heck coupling, while an intermolecular Suzuki coupling with the boron reagent 101, followed by an intramolecular annulation, generated indenoisoquinolines 100 (Scheme 30) [80].

By catalytic activation of unstrained C−C bonds, simple ketones can be effectively used as electrophiles in Suzuki−Miyaura coupling reactions. With strong site-selectivity, a variety of common ketones, including cyclopentanones, acetophenones, acetone, and 1-indanones, can be directly coupled with different arylboronates, providing a clear route to highly functionalized aromatic ketones, as reported by Dong’s group [81]. The α-C−C bond of the ketone was cleaved by oxidative addition, according to a preliminary mechanistic analysis, which explains how unstrained C−C bonds are activated by rhodium catalysts to produce a Suzuki−Miyaura coupling between simple ketones 102 and arylboronates 83 (Scheme 31). Although there is still a need to improve the efficiency of the reaction, the overall applicability is positive. There should be wide-ranging effects when unstrained C−C bonds are used as electrophiles in cross-couplings.

A novel method for the synthesis of diaryl ketones 106a–b via C−C coupling reactions between aromatic aldehydes 104a–b and arylboronic acids 83a–b was developed using the palladium (II) thiosemicarbazonato complex 105, as reported by Prabhu and Ramesh (Scheme 32) [82]. Isolated yields of the desired compounds ranged from good to outstanding. The first instances of a palladium (II) thiosemicarbazonato complex acting as a precatalyst for this type of coupling reaction are shown by this protocol, investigating its scope, mechanism, and synthetic applications.

Liu’s group reported a palladium-catalyzed Suzuki reaction and an orthogonal copper-catalyzed O-arylation of aromatic carboxylic acids [83]. They demonstrated the functionalization of substituted benzoic acids 107 with a wide range of aryl boronic acids and esters 108 possessing different electronic properties (Scheme 33). Rapid decarboxylative Suzuki coupling, catalyzed by trifluoroacetic acid palladium (II) salt and silver carbonate in refluxing DMSO, resulted in the formation of biaryls 109 in good to excellent yields. Notably, chloro and bromo groups were well tolerated, thus expanding the chemical toolkit for multistep cross-coupling strategies. On the other hand, copper catalysis didn’t promote the decarboxylation but instead favored O-arylation, yielding aromatic esters 110 with high chemoselectivity.

Lei, Szostak, and colleagues reported the first Suzuki−Miyaura cross-coupling of 2-pyridyl ammonium salts 112 with arylboronic acids 83 via a highly selective C–N activation (Scheme 34) [84]. The overall process begins with the Chichibabin C–H amination of pyridines 111, while the subsequent C–N activation is catalyzed by air- and moisture-stable palladium(II) complexes with N-heterocyclic carbenes (NHC), with the most reactive precatalysts being [Pd(IPr)(3-CF₃-An)Cl₂] (An = aniline) or [Pd(IPr)(cin)Cl] (cin = cinnamyl). This new C–H/C–N activation strategy has the potential for a broad applicability towards the development of new (hetero)biarylpyridines 113, which are important compounds in medicinal chemistry as well as agrochemicals. Of course, the high Pd loading required for the reaction is a certain disadvantage in view of the atom economy. Regarding the synthesis of biaryls 113 via the reaction of an organometallic reagent at the 2-position of the pyridine ring and an aryl halide, the 2-pyridyl-metal bond is prone to protodemetalation, and thus, this route is extremely difficult. On the other hand, the method based on polarity reversal in the cross-coupling using halopyridines is less attractive in medicinal chemistry and agrochemical research because this approach relies on the availability of pre-functionalized and highly reactive substrates.

Garg’s group reported the pioneering nickel-catalyzed Suzuki–Miyaura coupling of amides [85]. The reaction between amides 114 and aryl boronic acids or esters 116a–b uses a catalytic system consisting of bis(cyclooctadiene)nickel and 1,3-bis(2,6-di-isopropylphenyl)-4,5-dihydroimidazol-2-ylidine (SIPr) (115), in combination with potassium phosphate as a base (Scheme 35). The acylation products 117 were obtained in yields ranging from poor to excellent, with the outcome being influenced by factors such as the boron source, the amount of catalysts, and the presence of water. This process operates through an unusual cleavage of the amide C–N bond post N-tert-butoxycarbonyl activation. Noteworthy for its mild conditions and compatibility with various functional groups, this methodology can be strategically integrated into successive transition metal-catalyzed cross-coupling sequences, facilitating the fusion of heterocyclic fragments.

In contrast to the acylation of amides shown above, in another approach, Szostak’s group achieved amide arylation by a tandem C(O)−N/C−C bond activation and demonstrated the beneficial effect of the N-pyramidalized mesyl group in a decarbonylative cross-coupling process [86]. Indeed, the palladium-catalyzed Suzuki−Miyaura cross-coupling of N-mesyl amides 118 with a variety of boronic acids 83 led to decarbonylative coupling products 119a with high chemoselectivity compared to the acylation products 119b (Scheme 36). The use of N-mesyl amides resulted in a considerably lower barrier for the rate-limiting transmetalation as demonstrated by DFT studies.

Also noteworthy is a Suzuki-type coupling of allylic alcohols 120 with heteroaryl boronic acids such as 121 in a catalyst-free process, which was reported by Cheng’s group (Scheme 37) [87]. The discovered process is simple, operates in the absence of exogenous oxidants and metals, and exhibits an excellent level of ortho-selectivity (ortho/ipso ratio of up to 9:1) while demonstrating great generality. This method is one of the rare cases of ortho-functionalization of boronic acid.

4. One-Pot C–X and C–H Miyaura-Type Borylation–Suzuki Coupling Sequence

As already mentioned, Müller’s group reported a comprehensive study of the one-pot Masuda Borylation–Suzuki coupling (MBSC) sequence based on their own findings as well as those of several other groups and showed that it is a reliable and adaptable synthetic tool [21]. The Miyaura borylation–Suzuki coupling (MIBSC) sequence also represents a strategy that involves the use of a single or diverse catalytic system to facilitate the coupling of a diverse range of heterocycles in a one-pot reaction. This synthetic approach consists of two key steps: first, the Miyaura borylation, followed by the subsequent Suzuki coupling of the borylated derivatives with aryl halides. The one-pot approach has been extended for many types of compounds using a general procedure similar to the palladium-catalyzed sequential methodology and the equimolar use of coupling partners, which allows the direct coupling of two halides in a single step under relatively mild conditions. This highly efficient synthetic approach has garnered significant attention in the literature in recent years. Its importance lies in its ability to produce heterocyclic biaryls, which have shown promising results in various biological and pharmaceutical applications. This section discusses how the one-pot two-step C–X and C–H Miyaura-type borylation–Suzuki coupling sequence has evolved in recent years.

Aryl halides are very common substrates for one-pot Miyaura borylation–Suzuki coupling, and in most cases, palladium-based catalysts are used. A flexible and efficient method for the room-temperature synthesis of arylboronic esters from aryl (pseudo)halides was developed by Ji, Yi, and colleagues [88]. A variety of aryl or heteroaryl halides 124 with exceptional functional group tolerance may be coupled using this technique, which was extended to the one-pot two-step borylation–Suzuki–Miyaura process (Scheme 38). The precatalyst used in the reaction can be prepared from readily available starting materials and used directly in reactions without isolation. The method also offers the benefits of high efficiency, superior catalyst stability, and mild reaction conditions. Furthermore, the efficient application of the method to the parallel synthesis of biaryl compounds 127 enables the efficient preparation of various biaryl analogues from easily accessible aryl chlorides. In a similar approach, Kiatisevi’s group reported the one-pot two-step synthesis of biphenyl using B₂pin₂ (1) as a borylating reagent and PdCl₂(PPh₃)₂ as a precatalyst [89].

To reduce the cost implications and safety issues associated with the production of boronic acids and esters, a sustainable and environmentally friendly borylation protocol has been developed by Lipshutz’s group, which allows the ethyl pinacol boronic ester (B(Epin)) group 129 to be easily installed in a series of aromatic/heteroaromatic substrates 128 (Scheme 39) [90]. This provides access to boronic acids and their corresponding esters for use in Suzuki–Miyaura cross-couplings. The stable B(Epin) derivatives 130, prepared under near-neat conditions using Pd(AmPhos)₂Cl₂ (AmPhos = di-tert-butyl(4-dimethylaminophenyl)phosphine) as a catalyst, used directly in a one-pot Suzuki–Miyaura coupling with aryl bromides 131, using water as a green solvent and tetrabutylammonium bromide (TBAB) as a phase transfer catalyst under moderate reaction temperatures to yield biaryls 132. This new, environmentally benign process is time- and cost-effective, and is scalable with low residual levels of palladium in the products.

As reported by Yang, Tang, and colleagues, the electron-rich, sterically hindered monophosphine BIDIME forms an efficient palladium catalyst for the homocoupling of heteroaryl bromides 133, to afford symmetrical biheteroaryl compounds, such as bipyridines and bipyrazoles, which are used as ligands in transition metal catalysis and also as synthetic precursors for photocatalysts/sensitizers, bioactive agents, and energetic materials [91]. The coupling protocol features a tandem Miyaura borylation–Suzuki coupling sequence and exhibits unprecedented tolerance for a wide range of heteroaryl bromides 133, affording a series of symmetrical biheteroaryls 134 in moderate to good yields (Scheme 40). It is worth noting that the recycling of the palladium catalyst was made possible by using the corresponding polymer ligand PolyBIDIME, as shown for the homocoupling of bromopyrazole 135 and bromoindole 137.

Zani, Dessì, and colleagues reported a protocol for the one-pot borylation–Suzuki–Miyaura cross-coupling of a variety of (hetero) aromatic halides and triflates 139 in deep eutectic solvents (DESs) using B₂pin₂ (1) as a borylating reagent and a catalyst prepared in situ from Pd₂(dba)₃ and XPhos (Scheme 41) [92]. It was the first time that DESs were applied in borylation reactions, and the best results were obtained in choline chloride (ChCl)/glycerol (Gly) (1:2) mixture. The reaction was successful with (pseudo)halides containing various functional groups such as aldehydes, ketones, thioethers, esters, nitriles, and arylamines. This process proved to be environmentally friendly as indicated by the calculated values of E-factor and eco-scale, which can be classified as excellent or at least acceptable.

Srinivasan’s group investigated the potential of a one-pot strategy to prepare symmetrical biaryls 145 by a tandem iridium-catalyzed C–H borylation and copper-catalyzed homocoupling sequence of arenes 143 (Scheme 42) [93]. The researchers optimized the reaction conditions affording the best yields using 1,3-dichlorobenzene as a precursor of iridium-catalyzed C–H borylation in the presence of B₂pin₂ and dtbpy, followed by a copper diacetate-catalyzed homocoupling in DMF as a solvent in the presence of phenanthroline (phen).

Goldfogel’s group reported the first nickel-catalyzed one-pot borylation–Suzuki coupling of a variety of complex heterocyclic coupling partners 146 and 148, including bioactive aryl halides with a pharmaceutical interest (Scheme 43) [94]. Catalysis was carried out under homogeneous biphasic conditions, in which the use of water as a co-solvent improved the robustness and tolerance for the excess of the borylating reagent and other borylation byproducts. The process was shown to be efficient on a decagram scale, demonstrating its applicability. This nickel-catalyzed one-pot process was also compared with the analogous palladium-catalyzed process and provided similar results for a variety of substrates.

Iron-based catalysts have also been used in the one-pot MIBSC sequence of aryl halides. As already mentioned above, Ilies, Nakamura, and colleagues reported the iron-catalyzed borylation of (hetero)aryl halides 18 using B₂pin₂ (1) as the borylating reagent and an iron complex (Fe(acac)₃) as the catalyst to form aryl boron species 19 (Scheme 5), which can be coupled in situ with an aryl halide under Suzuki–Miyaura conditions, yielding the corresponding biaryls [35].

The palladium-catalyzed chemoselective borylation of (poly)halogenated aryl triflates 150, with a reactivity order of C–Cl > C–OTf, has been reported in a work by So’s group [95]. A catalytic system consisting of Pd(OAc)₂ and SelectPhos in cyclopentyl methyl ether (CPME) as solvent allows a highly reactive and chemoselective reaction. To generate asymmetric biaryl compounds 153 with the triflate moiety, the one-pot two-step method can be used to perform the successive chemoselective borylation and the intermolecular chemoselective Suzuki–Miyaura reaction (Scheme 44). It is also noted that the yield and chemoselectivity of the reaction did not decrease when it was gram-scaled up.

Das’ group reported the palladium-catalyzed Miyaura borylation–Suzuki arylation of 4-chloroquinolines [96]. This one-pot two-step method in the first step enables the borylation of different substituted 4-chloroquinolines 154 using B₂pin₂ (1) or bis(neopentylglycolato)diboron (B₂neop₂, 4) with Pd(PPh₃)₂Cl₂ as a precatalyst (Scheme 45). Arylation of the borylated quinolines 155 with aryl halides 156 in the presence of PPh₃, K₃PO₄, and H₂O afforded C4-arylated quinolines 157. This simple and efficient method for C–C bond formation provides access to a variety of structurally intriguing and pharmaceutically important 4-arylated quinolines.

The first example of a mechanochemical iridium-catalyzed C–H borylation of heteroaromatic compounds to afford the corresponding arylboronates in good to outstanding yields, using either no liquid or a catalytic quantity of a liquid, has recently been reported by Kubota, Ito, and colleagues [97]. Additionally, a one-pot mechanochemical C–H borylation–Suzuki–Miyaura coupling sequence for the direct production of 2-aryl indole derivatives 159 has also recently been described (Scheme 46). The borylation of indole 49′ with B₂pin₂ (1) was carried out using [Ir(OMe)cod]₂ and 4,4′-di-tert-butyl-2,2′-bipyridine (dtbpy) as a catalytic system. The in situ obtained 2-borylated indole 50′ was directly coupled with aryl iodides using the Pd (II) / ^tBuXPhos (2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl) catalyst. This work was an important step towards the creation of solvent-free C–H bond functionalization in air, which is attractive for industry.

The one-shot functionalization of azapentabenzocorannulenes 160 has been achieved with high regioselectivity by employing an iridium-catalyzed five-fold C–H borylation as reported by Nozaki, Ito, and colleagues (Scheme 47) [98]. Suzuki–Miyaura cross-coupling reactions allow subsequent derivatization of the pentaborylated product 161, using it as a flexible synthetic intermediate. This five-fold borylation–arylation sequence has been applied to prepare liquid-crystalline azapentabenzocorannulenes 163 with five 3,4,5-trialkoxyphenyl groups that assemble into 1D hexagonal columnar structures over a wide temperature range.

Boger’s group studied a total synthesis of vancomycin aglycon 168 via a multi-step methodology involving an atroposelective one-pot Miyaura borylation–Suzuki arylation sequence [99]. As shown in Scheme 48, Pd-catalyzed borylation of bromide 164 using bis(ethylenglycolatodiborane) (53) afforded compound 165 in a high yield, which was used directly in the Suzuki coupling with 166 to form compound 167 as a precursor for the next steps, leading at the end to vancomycin aglycon 168.

5. Conclusions and Future Prospects

Organoboron compounds have received considerable attention due to their widespread use in organic synthesis. Several efficient methods have been developed for their synthesis, such as the transition metal-catalyzed Miyaura and Masuda borylation of aryl (pseudo)halides for a C–X borylation. Furthermore, since the selective activation and functionalization of C–H bonds is an atom-efficient and environmentally friendly approach, the direct transition metal-catalyzed C–H bond activation and borylation has become an important synthetic technique. Scientific interest has also focused on alternative metal-free activation processes. The organoboron species prepared by these methods serve as valuable precursors for subsequent transition metal-catalyzed couplings, including the Suzuki–Miyaura cross-coupling that remains a powerful tool for the synthesis of several molecular scaffolds for industrial, environmental, and medicinal applications. In recent years, one-pot transition metal-catalyzed reactions for the synthesis of aromatic compounds, including heterocycles, have become more frequently employed. The one-pot C–X and C–H borylation–Suzuki coupling sequence, including both Miyaura- and Masuda-type processes, involves simple steps (formation of boronic acid esters and subsequent Suzuki coupling) and is a highly powerful protocol for the synthesis of complicated multi-aryl compounds and obtaining a variety of functional, bioactive, and natural scaffolds. The effects on reactivity depending on the substrate, metal, and ligand used as catalyst, as well as the reaction conditions, have been determined thanks to the intense efforts of several research groups. This approach remains a hot research topic and will undoubtedly be further developed in the future by combining theoretical and experimental research. Its applicability in solvent-free or aqueous systems, as well as in asymmetric syntheses, needs further development. The exploration of new sources under more selective, mild, and environmentally friendly coupling conditions is encouraged.