**1. Introduction**

Boron is a peculiar metalloid with fascinating chemical complexity. The unusual properties of boron stem from its three valence electrons, which can be easily torn away, favoring metallicity and making it electron-deficient, yet sufficiently localized and tightly bound to the nucleus, consequently allowing the insulating states to emerge [1]. Boron compounds have been intensively investigated for energy storage applications, particularly due to the relatively low atomic mass of boron (10.811 ± 0.007 amu). The energy-related uses of boron compounds range from high-energy fuels for advanced aircrafts to boron–nitrogen–hydrogen compounds as hydrogen storage materials for fuel cells [2]. The rich

pioneering research on boron resulted in the consecutive awarding of two Nobel Prizes in chemistry in 1976 and 1979 [3,4]. aircrafts to boron–nitrogen–hydrogen compounds as hydrogen storage materials for fuel cells [2]. The rich pioneering research on boron resulted in the consecutive awarding of two Nobel Prizes in chemistry in 1976 and 1979 [3,4].

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0.007 amu). The energy-related uses of boron compounds range from high-energy fuels for advanced

Organoboron compounds (e.g., boronic acids, boronic esters and boronamides) generally comprise at least one carbon–boron (C–B) bond (Scheme 1A) [5–8]. Organoboron compounds were initially used in organic synthesis 60 years ago [9,10]. Ever since, chemistries involving such compounds continued to advance until these reagents have become one of the most diverse, widely studied and applied families in catalysis and organic synthesis [10,11]. Currently, they are engaged in numerous classic and important reactions such as hydroborations and Suzuki–Miyaura cross-couplings (SMCs), among others [8]. The SMC reaction generally involves the conjoining of an organoboron reagent and an organic halide or pseudohalide in the presence of palladium (or other relevant metal/ligand) as a catalyst and a base for the activation of the boron compound (Scheme 1B) [5–7,12]. Organoboron compounds have also found several applications in pharmaceuticals where boron-based drugs exemplify a novel class of molecules for several biomedical applications as molecular imaging agents (optical/nuclear imaging) and neutron capture therapy agents (BNCT), as well as therapeutic agents (anticancer, antiviral, antibacterial, etc.) [13]. Likewise, the utility and ubiquity of boron-based compounds have bolstered the development of agricultural and material sciences [14,15]. Organoborane polymers have been investigated as electrolytes for batteries, electro-active materials, and supported Lewis acid catalysts [16,17]. Organoboron compounds (e.g., boronic acids, boronic esters and boronamides) generally comprise at least one carbon–boron (C–B) bond (Scheme 1A) [5–8]. Organoboron compounds were initially used in organic synthesis 60 years ago [9,10]. Ever since, chemistries involving such compounds continued to advance until these reagents have become one of the most diverse, widely studied and applied families in catalysis and organic synthesis [10,11]. Currently, they are engaged in numerous classic and important reactions such as hydroborations and Suzuki–Miyaura crosscouplings (SMCs), among others [8]. The SMC reaction generally involves the conjoining of an organoboron reagent and an organic halide or pseudohalide in the presence of palladium (or other relevant metal/ligand) as a catalyst and a base for the activation of the boron compound (Scheme 1B) [5–7,12]. Organoboron compounds have also found several applications in pharmaceuticals where boron-based drugs exemplify a novel class of molecules for several biomedical applications as molecular imaging agents (optical/nuclear imaging) and neutron capture therapy agents (BNCT), as well as therapeutic agents (anticancer, antiviral, antibacterial, etc.) [13]. Likewise, the utility and ubiquity of boron-based compounds have bolstered the development of agricultural and material sciences [14,15]. Organoborane polymers have been investigated as electrolytes for batteries, electroactive materials, and supported Lewis acid catalysts [16,17].

**Scheme 1.** (**A**) Examples of organoboron compounds, (**B**) Suzuki–Miyaura cross-coupling reaction. **Scheme 1.** (**A**) Examples of organoboron compounds, (**B**) Suzuki–Miyaura cross-coupling reaction.

Metal catalysis has had a major impact on numerous research fields from energy, biomass, environmental and water purification to synthesis of otherwise challenging and even inaccessible materials and medicinal adducts [18–30]. In line, the intensive research in metal catalysis has led to significant progress in borylation of primary C(sp3)–H bonds of unfunctionalized hydrocarbons, allowing access to a variety of C(sp3)–B reagents and consequent breakthroughs in C(sp3)– C(sp,sp2,sp3) cross-couplings. Comprehensive work has been done on the development of an efficient *sp*2−*sp*2 SMC; however, there have been far fewer reports on *sp*3−*sp*2 or *sp*3−*sp*3 variants [31–38]. Among the different hybridized boron reagents employed in SMCs (e.g., aryl, heteroaryl, and vinylboronic acids and esters), the use of organoboron compounds with alkyl groups (*sp*3 carbon) was severely limited in these coupling reactions due to competitive side reactions [39,40]. Organometallic compounds that are metalated at sp3 carbon atoms and especially containing *β*-hydrogen atoms give Metal catalysis has had a major impact on numerous research fields from energy, biomass, environmental and water purification to synthesis of otherwise challenging and even inaccessible materials and medicinal adducts [18–30]. In line, the intensive research in metal catalysis has led to significant progress in borylation of primary C(sp<sup>3</sup> )–H bonds of unfunctionalized hydrocarbons, allowing access to a variety of C(sp<sup>3</sup> )–B reagents and consequent breakthroughs in C(sp<sup>3</sup> )–C(sp,sp<sup>2</sup> ,sp<sup>3</sup> ) cross-couplings. Comprehensive work has been done on the development of an efficient *sp*2−*sp*<sup>2</sup> SMC; however, there have been far fewer reports on *sp*3−*sp*<sup>2</sup> or *sp*3−*sp*<sup>3</sup> variants [31–38]. Among the different hybridized boron reagents employed in SMCs (e.g., aryl, heteroaryl, and vinylboronic acids and esters), the use of organoboron compounds with alkyl groups (*sp*<sup>3</sup> carbon) was severely limited in these coupling reactions due to competitive side reactions [39,40]. Organometallic compounds that are metalated at sp<sup>3</sup> carbon atoms and especially containing β-hydrogen atoms give rise to alkyl–palladium complexes that

are susceptible to β-hydride elimination rather than reductive elimination [41]. Furthermore, although boronic acids are relatively stable at ambient temperature and can be isolated by chromatography and crystallization, they favor other side reactions such as protodeboronation under SMC conditions [42]. The undesired decomposition pathways in sp3–boron couplings are mostly circumvented by using tetrahedral boronates (e.g., potassium trifluoroborates (RBF3K) and N-methyliminodiacetyl boronates (RB–[MIDA]; Scheme 1A) or stoichiometric loadings of palladium catalysts. On the other hand, the use of alkylborane (B-alkyl-9-borabicyclo [3.3.1]nonane: B-alkyl-9-BBN) in sp<sup>3</sup> SMCs suffers from isolation difficulties, lack of atom economy, air sensitivity and functional group tolerance (e.g., to ketones). Trialkylboranes (R3B) have also been employed in SMCs [43,44].

The alkyl–alkyl SMCs (sp3–sp<sup>3</sup> ) were recently reviewed in 2017 [45]. Hence, we will focus here on the recent development in cross-coupling reactions using sp3–boron reagents and C(sp<sup>2</sup> )–reagents. One class of the sp3–sp<sup>2</sup> SMC is commonly known as *B*–*alkyl Suzuki–Miyaura cross-coupling*. It is distinguished from the other SMCs in that this cross-coupling occurs between an alkyl borane and an aryl or vinyl halide, triflate or enol phosphate. Generally, the most reactive partners for B–alkyl SMC are unhindered electron-rich organoboranes and electron-deficient coupling partners (halides or triflates). Notably, this type of coupling is highly affected by all the reaction parameters including the type of organoborane, base, solvent and metal catalyst, and the nature of the halide partner. The effects of these parameters were detailed in the review by Danishefsky et al. on B–alkyl SMC in 2001 [33]. This work will thus summarize the C(sp<sup>3</sup> )–C(sp<sup>2</sup> ) cross-couplings covering the more recent progress in this area after 2001. The advances in stereospecific sp3–sp<sup>2</sup> SMCs will be out of the scope of this highlight. However, it is worth noting that different versions that proceed with either retention or inversion of configuration have been well established [46,47]. Acyl SMC (acid halides, anhydrides, amides, esters), decarbonylative SMC and Liebeskind–Srogl cross-couplings are also not covered here and were recently reviewed in the literature extensively [48–52].

### **2. Suzuki–Miyaura Cross-Coupling (SMC)**

As mentioned in the introduction, SMC is the conjoining of an organoboron reagent and an organic halide or pseudohalide in the presence of palladium (or other relevant metal) as a catalyst and a base for the activation of the boron compound (Scheme 1B) [5–7]. The efficiency of palladium has contributed to the ever-accelerating advances in catalysis, where coupling reactions, including SMC ones, are nowadays performed at ppb (parts per billion) molar catalyst loadings [53]. Nickel has also proved to have an efficient catalytic activity for SMC as the expensive palladium catalysts [54,55]. The high reactivity of nickel was revealed with difficult substrates such as aryl chlorides/mesylates, whose coupling reactions do not proceed easily with conventional Pd catalysis. In addition to being inexpensive, nickel catalysts can be more easily removed from the reaction mixtures while their economic practicality eliminates the need to recycle them [56]. Other metal catalytic systems have been investigated in SMC reactions such as Fe, Co, Ru, Cu, Ag, etc. However, their applications are by far less than Pd and Ni catalysts [56–58].

Since its discovery in 1979 [59], the Suzuki–Miyaura reaction has arguably become one of the most widely-applied, simple and versatile transition metal-catalyzed methods used for the construction of C–C bonds [60]. The general catalytic cycle is similar to other metal-catalyzed cross-couplings starting with an oxidative addition followed by a transmetalation and ending with a reductive elimination (Scheme 2). Transmetalation or the activation of the boron reagent makes Suzuki–Miyaura coupling different than other transition-metal cross-couplings processes. Mechanistic investigations were able to illustrate the role of each reagent in the reaction medium in addition to the metal. Some insights are now well established such as the necessity of sigma-rich electron-donor ligands, protic solvents and the base [61,62]; other mechanistic insights are still active areas of research including the activation way of boron in presence of the base. Two main analysis routes can be outlined as can be seen in Scheme 2: A) Boronate pathway: tetracoordinate nucleophilic boronate species **III** is generated *in situ* and substitutes the halide ligand of the Pd intermediate **I** issued from the oxidative addition, followed

by the elimination of B(OH)2OR from the resulting intermediate **IV** to transfer the organic moiety to palladium species **V**. B) Oxo-palladium pathway: the RO− substitute ligand X on the palladium center leading to oxo-palladium **II** which acts as a nucleophile toward the boronic acid species, generating the tetracoordinate species **IV**. Ambiguity occurs since inorganic bases in aqueous or alcohol solvents, generating the required alkoxy or hydroxy ligands, are commonly employed in the SMC, to accelerate either pathway **A** or **B**. However, all DFT (Density Functional Theory) studies and ES-MS (Electrospray Ionization-Mass Spectrometry) investigations [63,64], where boronate species were observed and not oxo-palladium ones [65–67], support pathway **A**. Studies defending the suggestion of pathway **B** consist of kinetic analysis and experimental observations of the lack of activities in some cases in the presence of organic Lewis bases or lithium salts of boronic species. The group of Maseras claimed that while pathway **A** and pathway **B** are competitive, the first has lower energy barriers than the second [68]. Therefore, the boronate pathway (**A**) is faster. Additionally, they stated that their theoretical report is consistent with the experimental observations they reproduced [63]. intermediate **IV** to transfer the organic moiety to palladium species **V**. B) Oxo-palladium pathway: the RO− substitute ligand X on the palladium center leading to oxo-palladium **II** which acts as a nucleophile toward the boronic acid species, generating the tetracoordinate species **IV**. Ambiguity occurs since inorganic bases in aqueous or alcohol solvents, generating the required alkoxy or hydroxy ligands, are commonly employed in the SMC, to accelerate either pathway **A** or **B**. However, all DFT (Density Functional Theory) studies and ES-MS (Electrospray Ionization-Mass Spectrometry) investigations [63,64], where boronate species were observed and not oxo-palladium ones [65–67], support pathway **A**. Studies defending the suggestion of pathway **B** consist of kinetic analysis and experimental observations of the lack of activities in some cases in the presence of organic Lewis bases or lithium salts of boronic species. The group of Maseras claimed that while pathway **A** and pathway **B** are competitive, the first has lower energy barriers than the second [68]. Therefore, the boronate pathway (**A**) is faster. Additionally, they stated that their theoretical report is consistent with the experimental observations they reproduced [63].

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**Scheme 2.** General mechanism of Suzuki–Miyaura cross-coupling. **Scheme 2.** General mechanism of Suzuki–Miyaura cross-coupling.

Further investigation is needed to conclude which pathway is the actual one, or whether both exist in a competitive manner in each catalytic cycle. One point supporting pathway **A** can still be considered here. The formation of oxo palladium **II** is less favored in the case where the palladium center is electron-rich (bearing a good sigma donor and weak π acceptor ligands), which is more likely to react with a weaker nucleophile like boronate [R–B(OH)3]− rather than with a strong nucleophile, such as hydroxy or alkoxy groups. Further investigation is needed to conclude which pathway is the actual one, or whether both exist in a competitive manner in each catalytic cycle. One point supporting pathway **A** can still be considered here. The formation of oxo palladium **II** is less favored in the case where the palladium center is electron-rich (bearing a good sigma donor and weak π acceptor ligands), which is more likely to react with a weaker nucleophile like boronate [R–B(OH)3] − rather than with a strong nucleophile, such as hydroxy or alkoxy groups.

The success of the SMC method originates from its high regio- and stereo-selectivity, extremely low catalytic loadings, and the exceptionally mild reaction conditions. The employed conditions are compatible with aqueous and heterogeneous media and tolerate steric hindrance and a wide range of functional groups. In addition, the readily available organoboron reagents and the versatile developed methods that permit access to challenging boron-functionalized adducts as well as the easy incorporation of nontransferable boron ligands have contributed to the appeal of SMC reactions. Most boron starting materials are thermally stable and inert to oxygen, water and related solvents. In general, they are relatively non-toxic and environmentally benign, and so are their by-products. Thus, they can be handled and separated easily from the reaction mixtures [69–72]. These unique features The success of the SMC method originates from its high regio- and stereo-selectivity, extremely low catalytic loadings, and the exceptionally mild reaction conditions. The employed conditions are compatible with aqueous and heterogeneous media and tolerate steric hindrance and a wide range of functional groups. In addition, the readily available organoboron reagents and the versatile developed methods that permit access to challenging boron-functionalized adducts as well as the easy incorporation of nontransferable boron ligands have contributed to the appeal of SMC reactions. Most boron starting materials are thermally stable and inert to oxygen, water and related solvents. In general, they are relatively non-toxic and environmentally benign, and so are their by-products. Thus, they can be handled and separated easily from the reaction mixtures [69–72]. These unique

features have allowed researchers to utilize SMC in a great variety of applications from development of polymeric materials to total synthesis of complex natural products. SMCs also constitute an important tool in medicinal chemistry, in production of fine chemicals and innovative materials as organic-light emitting diodes and in large-scale syntheses of pharmaceuticals [73–75]. Several reviews and textbooks have been dedicated to the applications of SMCs. Our review will only highlight a few examples of target molecules in Section 9. The relevant reports of C(sp<sup>3</sup> )–C(sp<sup>2</sup> ) cross-couplings are summarized in Table 1 (*reaction partners and conditions)* in order of the respective sections where they are discussed.


**Table 1.** General summary of the relevant reports of C(sp<sup>3</sup> )–C(sp<sup>2</sup> ) cross-couplings in this review.


**Table 1.** *Cont.*

## **3. First Reports of B-alkyl SMC and Methods Employing 9-BBN Derivatives**

The alkylboron cross-coupling was disclosed in 1986 by Suzuki and Miyaura using B-alkyl-9-BBN **2** or trialkylboranes (R3B) in the presence of PdCl2(dppf) and a base (sodium hydroxide or methoxide) (Scheme 3A). The reaction proceeded readily providing alkylated arenes **3** and alkenes in excellent yields of 75%–98%. On the other hand, no coupling was observed when sec-butylboranes were used [76]. In 1989, the same group revealed the reactivity of different alkyl boranes **5** in B-alkyl SMC (Scheme 3B). Pinacolborane **10** was almost unreactive (1% yield), while 9-BBN derivatives **7** showed the highest efficiencies (e.g., 99%). Thus, functionalized alkenes, arenes and cycloalkenes were synthesized via a hydroboration-coupling sequence of 9-BBN derivatives with haloalkenes or haloarenes **4** (interand intramolecular). Good yields of geometrically pure alkenes and arenes were afforded from the performed reactions with a variety of functionalities on either coupling partner. The reaction could also be carried out using K2CO<sup>3</sup> instead of NaOH with base-sensitive compounds [77–79].

In 2004, the group of Buchwald reported the design of a new ligand with tuned steric and electronic properties. The phosphane ligand incorporated two methoxy groups on one of phenyls (**L2**, Scheme 3C). The oxygen lone pairs increase the electron density on the biaryl and participate in stabilizing the Pd complex. Simultaneously, the MeO groups increase the steric bulk and prevent cyclometalaton. This as-designed ligand aimed to serve as a universal catalyst for cross-coupling and C–H activation reactions. It was later commercialized under the name of SPhos, and became a basic ligand in today's catalysis toolbox. The ligand demonstrated a wide scope and stability with aryl boronic acids. It was also efficient for coupling of B-alkyl-9-BBN derivatives **14** (and boronic acids) using K3PO4·H2O as an essential base (vs. lower conversions with anhydrous bases) (Scheme 3C). The scope involved challenging aryl halides as 3-dimethylamino-2-bromoanisole and aryl chlorides [80].

In 2013, Wu et al. developed a SMC between B-benzyl-9-BBN **18** and chloroenynes **16** and **17** to synthesize a vast array of 1,5-diphenylpent-3-en-1-yne derivatives **19** and **20** in good yields and full control on the E/Z selectivity using Pd(PPh3)<sup>4</sup> and Cs2CO<sup>3</sup> in pure water (Scheme 4) [81]. The conditions tolerated substrates bearing several electron-donating and withdrawing groups. It is worth remarking that these derivatives are known for their anti-inflammatory activity and can be isolated from plants, but only in minor quantities.

**A)**

I B

Alkyl

1.1 eq.

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**1 2 3**

NaOH (3 M) THF, reflux, 16 h

PdCl Alkyl 2(dppf) (3 mol%)

**(75-98%)**

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**Scheme 3.** First reports of B–alkyl Suzuki–Miyaura cross-coupling (**A-C**) and the reactivity of alkylboranes (**C**). **Scheme 3.** First reports of B–alkyl Suzuki–Miyaura cross-coupling (**A–C**) and the reactivity of alkylboranes (**C**). conditions tolerated substrates bearing several electron-donating and withdrawing groups. It is worth remarking that these derivatives are known for their anti-inflammatory activity and can be

In 2013, Wu et al. developed a SMC between B-benzyl-9-BBN **18** and chloroenynes **16** and **17** to

B Pd(PPh3)4 (3 mol%) Cs2CO3 (3 eq.) **or** 13 examples **16 or Scheme 4.** B–alkyl SMC of chloroenynes. **Scheme 4.** B–alkyl SMC of chloroenynes.

**Ph**

**(50-83 %)**

Fe

P Ph Ph

P

Ph Ph

Cl

isolated from plants, but only in minor quantities.

**Scheme 4.** B–alkyl SMC of chloroenynes. C–O electrophiles represent attractive alternatives to halides. However, research on crosscouplings of aryl methyl ethers was delayed by the perception that they can be challenging coupling water, 60 oC, 12 h 2 eq. R2 Cl R2 **Ph 17 18 20** C–O electrophiles represent attractive alternatives to halides. However, research on crosscouplings of aryl methyl ethers was delayed by the perception that they can be challenging coupling counterparts in comparison to other protected phenol electrophiles such as aryl pivalates, sulfonates and carbamates. Indeed, the activation energy for effecting C–OMe bond cleavage is significantly C–O electrophiles represent attractive alternatives to halides. However, research on cross-couplings of aryl methyl ethers was delayed by the perception that they can be challenging coupling counterpartsin comparison to other protected phenol electrophiles such as aryl pivalates, sulfonates and carbamates. Indeed, the activation energy for effecting C–OMe bond cleavage is significantly higher, with OMe beingmore difficult to separate from the group and more reluctant to oxidative addition. It is noteworthy that C–O electrophiles cross-couplings are predominantly conducted with nickel catalysis, as can be seen in Scheme 5, which depicts the work of the Rueping group in this regard. This demonstrates the higher activity of Ni with such challenging substrates [82–84].

counterparts in comparison to other protected phenol electrophiles such as aryl pivalates, sulfonates

higher, with OMe being more difficult to separate from the group and more reluctant to oxidative addition. It is noteworthy that C–O electrophiles cross-couplings are predominantly conducted with

regard. This demonstrates the higher activity of Ni with such challenging substrates [82–84].

**Scheme 5.** Ni-catalyzed alkylation of CAr−O electrophiles (including aromatic methyl ethers) (**A,B)**  and methyl enol ethers (**C**). **Scheme 5.** Ni-catalyzed alkylation of CAr−O electrophiles (including aromatic methyl ethers) (**A**,**B**) and methyl enol ethers (**C**).

In 2016, Rueping et al. utilized the B-alkyl-9-BBN **2** to report an efficient nickel-catalyzed alkylation of CAr−O electrophiles **21** (pivalates, carbonates, carbamates, sulphamates and tosylates). The optimal conditions involved Ni(COD)2, a IPr**·**HCl ligand and Cs2CO3 in diisopropyl ether (Scheme 5A). This new protocol was tolerant to numerous synthetically important functional groups of phenol pivalates and alkylboranes circumventing the restriction of β-hydride elimination [85]. Soon after, the same group described the use of the first alkylation of polycyclic aromatic methyl ethers **23** and methyl enol ethers **25** and **26** (Scheme 5B,C), which involves the cleavage of the highly inert C(sp2)–OMe bonds, using alkylboron reagents with broad functional group tolerance. As expected, the choice of the base and the ligand is critical in C–O bond-cleaving reactions. Thus, the conditions described for CAr−O electrophiles were not successful, and the optimal conditions necessitated the replacement of the IPr**·**HCl ligand with PCy3. Cs2CO3 was mostly used in couplings of alkenyl ethers, while both CsF and Cs2CO3 could be used in the case of aromatic methyl ethers. The reaction performed better with a Ni/L ratio of 1:4 instead of 1:2, and a prolonged reaction time of 60 h instead of 12 h. The optimal conditions for these novel transformations are summarized in In 2016, Rueping et al. utilized the B-alkyl-9-BBN **2** to report an efficient nickel-catalyzed alkylation of CAr−O electrophiles **21** (pivalates, carbonates, carbamates, sulphamates and tosylates). The optimal conditions involved Ni(COD)2, a IPr·HCl ligand and Cs2CO<sup>3</sup> in diisopropyl ether (Scheme 5A). This new protocol was tolerant to numerous synthetically important functional groups of phenol pivalates and alkylboranes circumventing the restriction of β-hydride elimination [85]. Soon after, the same group described the use of the first alkylation of polycyclic aromatic methyl ethers **23** and methyl enol ethers **25** and **26** (Scheme 5B,C), which involves the cleavage of the highly inert C(sp<sup>2</sup> )–OMe bonds, using alkylboron reagents with broad functional group tolerance. As expected, the choice of the base and the ligand is critical in C–O bond-cleaving reactions. Thus, the conditions described for CAr−O electrophiles were not successful, and the optimal conditions necessitated the replacement of the IPr·HCl ligand with PCy3. Cs2CO<sup>3</sup> was mostly used in couplings of alkenyl ethers, while both CsF and Cs2CO<sup>3</sup> could be used in the case of aromatic methyl ethers. The reaction performed better with a Ni/L ratio of 1:4 instead of 1:2, and a prolonged reaction time of 60 h instead of 12 h. The optimal conditions for these novel transformations are summarized in Scheme 5 [86].

Scheme 5 [86]. In 2018, Zhang et al. reported a hydroboration/Pd-catalyzed migrative SMC of 1,3-dienes **30** with electron-deficient aryl halides **29** (Scheme 6) with a wide scope (>40 examples). This method allows the use of primary homoallylic alkylboranes in the direct synthesis of branched allylarenes. The selectivity of the branched versus linear coupling was found to be tuned by the choice of the ligand. The branch-selective coupling was found to be favored by the more electron-rich bidentate ligand with a larger ligand–metal–ligand (bite) angle (i.e., **L5**: dppb). Their report involved preliminary In 2018, Zhang et al. reported a hydroboration/Pd-catalyzed migrative SMC of 1,3-dienes **30** with electron-deficient aryl halides **29** (Scheme 6) with a wide scope (>40 examples). This method allows the use of primary homoallylic alkylboranes in the direct synthesis of branched allylarenes.The selectivity of the branched versus linear coupling was found to be tuned by the choice of the ligand. The branch-selective coupling was found to be favored by the more electron-rich bidentate ligand with a larger ligand–metal–ligand (bite) angle (i.e., **L5**: dppb). Their report involved preliminary mechanistic studies, showing a palladium migration in the formation of allyl palladium species. The migration proceeded via a sequence of β-hydride elimination and an alkene reinsertion partially involving an alkene dissociation/association process (Scheme 6) [87].

**A)**

involving an alkene dissociation/association process (Scheme 6) [87].

Ph

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mechanistic studies, showing a palladium migration in the formation of allyl palladium species. The migration proceeded via a sequence of *β*-hydride elimination and an alkene reinsertion partially

**Scheme 6.** Hydroboration/Pd-catalyzed migrative SMC of 1,3-dienes aryl halides. **Scheme 6.** Hydroboration/Pd-catalyzed migrative SMC of 1,3-dienes aryl halides.

Very recently, Newhouse et al. described the use of β-triflyl enones **32** as efficient coupling

Very recently, Newhouse et al. described the use of β-triflyl enones **32** as efficient coupling partners in a mild B–alkyl SMC (Pd(dppf)Cl2 (2.5 mol%), Cs2CO3 (2 eq.)), and tolerant of sensitive functional groups (Scheme 7A). The more stable triflate to light and chromatography, in comparison to halogenated analogs, were used to establish challenging cyclic α,β-disubstituted enones **33** with good to excellent yields (10 examples) [88]. In parallel, Usuki et al. reported an SMC between halogenated pyridines **34** and a borated L-aspartic acid derivative (9-BBN) **35** using Pd(PPh3)4 (5 mol%) and K3PO4(aq.) in THF (Scheme 7B). The experimental yield gave insight on the reactivity order of halogen substituents and position, which was found to be as follows: Br > I >> Cl and C3 > Very recently, Newhouse et al. described the use of β-triflyl enones **32** as efficient coupling partners in a mild B–alkyl SMC (Pd(dppf)Cl<sup>2</sup> (2.5 mol%), Cs2CO<sup>3</sup> (2 eq.)), and tolerant of sensitive functional groups (Scheme 7A). The more stable triflate to light and chromatography, in comparison to halogenated analogs, were used to establish challenging cyclic α,β-disubstituted enones **33** with good to excellent yields (10 examples) [88]. In parallel, Usuki et al. reported an SMC between halogenated pyridines **34** and a borated L-aspartic acid derivative (9-BBN) **35** using Pd(PPh3)<sup>4</sup> (5 mol%) and K3PO4(aq.) in THF (Scheme 7B). The experimental yield gave insight on the reactivity order of halogen substituents and position, which was found to be as follows: Br > I >> Cl and C3 > C2, C4 [89]. partners in a mild B–alkyl SMC (Pd(dppf)Cl2 (2.5 mol%), Cs2CO3 (2 eq.)), and tolerant of sensitive functional groups (Scheme 7A). The more stable triflate to light and chromatography, in comparison to halogenated analogs, were used to establish challenging cyclic α,β-disubstituted enones **33** with good to excellent yields (10 examples) [88]. In parallel, Usuki et al. reported an SMC between halogenated pyridines **34** and a borated L-aspartic acid derivative (9-BBN) **35** using Pd(PPh3)4 (5 mol%) and K3PO4(aq.) in THF (Scheme 7B). The experimental yield gave insight on the reactivity order of halogen substituents and position, which was found to be as follows: Br > I >> Cl and C3 > C2, C4 [89].

**Scheme 7.** Latest reports of SMCs using 9BBN (**A and B**). **Scheme 7.** Latest reports of SMCs using 9BBN (**A** and **B**).

**34 35 36**

**Scheme 7.** Latest reports of SMCs using 9BBN (**A and B**). Although decarbonylative and acyl cross-coupling reactions are not covered in this review [48–52,90], it is worth mentioning two very recent novel reports from the groups of Rueping and Nishihara. Rueping et al. (Scheme 8A) described an elegant ligand-controlled and site-selective nickel catalyzed SMC with aromatic esters **37** and alkyl organoboron reagents (majorly 9-BBN **2** and 6 examples with triethylboron). Ester substrates **37** were transformed into alkylated arenes **38** and ketone products **39** simply by switching the ligand from bidentate phosphine (**L6**: dcype) to monodentate phosphine (P(*n*Bu)<sup>3</sup> or PCy3). The regioselectivity was rationalized by DFT studies and the reported method has shown broad tolerance to functional groups and a wide substrate scope. The reaction was tested successfully on a large scale (1 g) using a cheaper NiCl<sup>2</sup> catalyst [91]. The group of Nishihara reported an elegant nickel-catalyzed decarbonylative C−F bond alkylation of aroyl fluorides **40**; the conditions are depicted in Scheme 8B [92]. Nishihara. Rueping et al. (Scheme 8A) described an elegant ligand-controlled and site-selective nickel catalyzed SMC with aromatic esters **37** and alkyl organoboron reagents (majorly 9-BBN **2** and 6 examples with triethylboron). Ester substrates **37** were transformed into alkylated arenes **38** and ketone products **39** simply by switching the ligand from bidentate phosphine (**L6**: dcype) to monodentate phosphine (P(*n*Bu)3 or PCy3). The regioselectivity was rationalized by DFT studies and the reported method has shown broad tolerance to functional groups and a wide substrate scope. The reaction was tested successfully on a large scale (1 g) using a cheaper NiCl2 catalyst [91]. The group of Nishihara reported an elegant nickel-catalyzed decarbonylative C−F bond alkylation of aroyl fluorides **40**; the conditions are depicted in Scheme 8B [92].

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52,90], it is worth mentioning two very recent novel reports from the groups of Rueping and

**Scheme 8.** Novel decarbonylative cross-coupling reactions with alkylboranes (**A and B**). **Scheme 8.** Novel decarbonylative cross-coupling reactions with alkylboranes (**A** and **B**).

#### **4. Organotrifluoroborates in sp3–sp2 SMCs 4. Organotrifluoroborates in sp3–sp<sup>2</sup> SMCs**

The tetracoordinate nature of the boron in organotrifluoroborates fortified by strong boron– fluorine bonds has been found to inhibit the undesirable reactions typical of trivalent organoborons. All of these complexes are crystalline solids and stable in water and under air; thus they can be stored on the shelf indefinitely. Besides, the manipulation of remote functional groups within the organotrifluoroborates is feasible while retaining the valuable C–B bond. Borates (RBF3K) **45** can be easily prepared on a large scale by the addition of inexpensive fluoride source (KHF2) **44** to a variety of organoboron intermediates **43**, such as boronic acids/esters, organodihaloboranes and The tetracoordinate nature of the boron in organotrifluoroborates fortified by strong boron–fluorine bonds has been found to inhibit the undesirable reactions typical of trivalent organoborons. All of these complexes are crystalline solids and stable in water and under air; thus they can be stored on the shelf indefinitely. Besides, the manipulation of remote functional groups within the organotrifluoroborates is feasible while retaining the valuable C–B bond. Borates (RBF3K) **45** can be easily prepared on a large scale by the addition of inexpensive fluoride source (KHF2) **44** to a variety of organoboron intermediates **43**, such as boronic acids/esters, organodihaloboranes and organodiaminoboranes (Scheme 9A) [93].

organodiaminoboranes (Scheme 9A) [93]. Molander and coworkers were the first to use potassium alkyltrifluoroborates **45** as coupling partners with aryl halides/triflates and vinyl triflates **46**/**47** using PdCl2(dppf)·CH2Cl<sup>2</sup> as the catalyst in THF-H2O and Cs2CO<sup>3</sup> as the base (Scheme 9B). Two successive reports in 2001 and 2003 studied the scope of this B–alkyl SMC, reporting more than 50 examples with acceptable to very good yields, hence revealing a potential general method to a wide range of functionalities [44,94]. Later, the same group used microscale parallel experimentation to describe the first comprehensive study of the coupling of secondary alkylborons (organotrifluoroborates) and aryl chlorides (and bromides), elaborating different catalytic systems for this purpose. Their results demonstrated a ligand-dependent β-hydride elimination/reinsertion mechanism in the cross-couplings of hindered partners, which can result in isomeric products of coupled products [34]. The use of trifluoroborates in SMC was validated by numerous publications that appeared thereafter and was reviewed many times by different research groups, as the one by Molander in 2015 [79,95–98].

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**Scheme 9.** Alkyltrifluoroborates salts: General synthesis and first report in sp3–sp2 SMC (**A** and **B**); Pd-catalyzed SMC report of Harris et al. (**C**). **Scheme 9.** Alkyltrifluoroborates salts: General synthesis and first report in sp3–sp<sup>2</sup> SMC (**A** and **B**); Pd-catalyzed SMC report of Harris et al. (**C**).

Molander and coworkers were the first to use potassium alkyltrifluoroborates **45** as coupling partners with aryl halides/triflates and vinyl triflates **46**/**47** using PdCl2(dppf)**·**CH2Cl2 as the catalyst in THF-H2O and Cs2CO3 as the base (Scheme 9B). Two successive reports in 2001 and 2003 studied the scope of this B–alkyl SMC, reporting more than 50 examples with acceptable to very good yields, hence revealing a potential general method to a wide range of functionalities [44,94]. Later, the same Harris et al. recently reported a Pd-catalyzed SMC reaction with tertiary trifluoroborate salts **49** to synthesize 1-heteroaryl-3-azabicyclo[3.1.0]hexanes **51**, an interesting scaffold in medicinal studies with limited synthetic approaches. The SMC protocol was compatible with a range of aryl and heteroaryl chlorides and bromides **50** (Scheme 9C) [99]. The optimized conditions involved CatacXium-A-Pd-G3, Cs2CO<sup>3</sup> in toluene/water and were applied in synthesis of 18 examples with good to excellent yields.

group used microscale parallel experimentation to describe the first comprehensive study of the coupling of secondary alkylborons (organotrifluoroborates) and aryl chlorides (and bromides), elaborating different catalytic systems for this purpose. Their results demonstrated a liganddependent *β*-hydride elimination/reinsertion mechanism in the cross-couplings of hindered partners, which can result in isomeric products of coupled products [34]. The use of trifluoroborates in SMC was validated by numerous publications that appeared thereafter and was reviewed many times by different research groups, as the one by Molander in 2015 [79,95–98]. Harris et al. recently reported a Pd-catalyzed SMC reaction with tertiary trifluoroborate salts **49**  to synthesize 1-heteroaryl-3-azabicyclo[3.1.0]hexanes **51**, an interesting scaffold in medicinal studies with limited synthetic approaches. The SMC protocol was compatible with a range of aryl and heteroaryl chlorides and bromides **50** (Scheme 9C) [99]. The optimized conditions involved CatacXium-A-Pd-G3, Cs2CO3 in toluene/water and were applied in synthesis of 18 examples with good to excellent yields. The group of Molander, after their review [98], has extended the scope of sp2–sp3 cross-couplings to fluoroborates that show recalcitrance to Pd-catalyzed classical couplings via dual catalysis (Scheme 10). The first comprised the coupling of aryl bromides **53** to secondary alkyl β-trifluoroboratoketones The group of Molander, after their review [98], has extended the scope of sp2–sp<sup>3</sup> cross-couplings to fluoroborates that show recalcitrance to Pd-catalyzed classical couplings via dual catalysis (Scheme 10). The first comprised the coupling of aryl bromides **53** to secondary alkyl β-trifluoroboratoketones and -esters **52** using Ir-based photoredox/nickel dual catalysis (Scheme 10A). This dual catalysis relies on a single-electron transmetalation and provides a complementary toolbox to the classical couplings that are based on two-electron processes. The oxidative fragmentation in the dual catalysis activates the organometallic reagent into its corresponding alkyl radical, which is then readily intercepted by the nickel catalyst mediating the formation of the C−C bond formation with the aryl halide partner. Their optimized conditions consisted of a catalytic system of Ir[dFCF3ppy]2(bpy)PF<sup>6</sup> photocatalyst (2.5 mol%), NiCl2·dme (2.5 mol%), dtbbpy (2.5 mol%), Cs2CO<sup>3</sup> (0.5 eq.) and 2,6-lutidine (0.5 eq.) in 1,4-dioxane, tolerating various functionalities in addition to sterically and electronically diverse coupling partners (Scheme 10A) [100]. The second report described a photoredox/nickel dual catalysis alternative approach to the protecting-group-independent cross-coupling of α-alkoxyalkyland α-acyloxyalkyltrifluoroborates **55** with aryl (and heteroaryl) bromides **53**, which can also be achieved by palladium catalysis. This method was compatible with various functional groups and N,N-diisopropylcarbamoyl, pivaloyl and benzyl protecting groups (Scheme 10B) [101]. Their

and -esters **52** using Ir-based photoredox/nickel dual catalysis (Scheme 10A). This dual catalysis relies

third dual catalysis report (Scheme 10C) contributed to the construction of sterically demanding quaternary centers **58**, an area that is not yet comprehensive and suffers from the absence of general methodologies and the copious limitations of the currently used metal-catalyzed methods. Various tertiary organotrifluoroborates reagents **57** were coupled using different conditions and light intensities, which were found to be crucial depending on the nature of the substituents (e.g., bridged versus acyclic). The scope of the coupled aryl bromides **53** in this method was limited to electron-poor and electron-neutral systems [102]. N,N-diisopropylcarbamoyl, pivaloyl and benzyl protecting groups (Scheme 10B) [101]. Their third dual catalysis report (Scheme 10C) contributed to the construction of sterically demanding quaternary centers **58**, an area that is not yet comprehensive and suffers from the absence of general methodologies and the copious limitations of the currently used metal-catalyzed methods. Various tertiary organotrifluoroborates reagents **57** were coupled using different conditions and light intensities, which were found to be crucial depending on the nature of the substituents (e.g., bridged versus acyclic). The scope of the coupled aryl bromides **53** in this method was limited to electronpoor and electron-neutral systems [102].

achieved by palladium catalysis. This method was compatible with various functional groups and

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that are based on two-electron processes. The oxidative fragmentation in the dual catalysis activates the organometallic reagent into its corresponding alkyl radical, which is then readily intercepted by the nickel catalyst mediating the formation of the C−C bond formation with the aryl halide partner. Their optimized conditions consisted of a catalytic system of Ir[dFCF3ppy]2(bpy)PF6 photocatalyst (2.5 mol%), NiCl2**·**dme (2.5 mol%), dtbbpy (2.5 mol%), Cs2CO3 (0.5 eq.) and 2,6-lutidine (0.5 eq.) in 1,4-dioxane, tolerating various functionalities in addition to sterically and electronically diverse coupling partners (Scheme 10A) [100]. The second report described a photoredox/nickel dual catalysis alternative approach to the protecting-group-independent cross-coupling of α-alkoxyalkyl-

**Scheme 10.** Photoredox/metal dual catalysis of organotrifluoroborates by the Molander group (**A-C**). **Scheme 10.** Photoredox/metal dual catalysis of organotrifluoroborates by the Molander group (**A–C**).

#### **5. Other Alkylboranes in sp3–sp2 SMCs 5. Other Alkylboranes in sp3–sp<sup>2</sup> SMCs**

Tri-*n*-alkylboranes (R3B) can be easily prepared by the reaction of Grignard reagents with boron trifluoride etherate (Scheme 11A) [103]. The use of this class of boranes in B–alkyl SMC was sporadically reported in the literature, probably due to their flammable nature and sensitivity to oxygen, as well as the inefficiency of the transfer of all three alkyl groups from the boron center [104]. In 2009, Wang et al. published optimization studies that presented efficient and chemoselective Pdcatalyzed direct SMCs of trialkylboranes **60** with bromoarenes **59** in the presence of unmasked acidic Tri-*n*-alkylboranes (R3B) can be easily prepared by the reaction of Grignard reagents with boron trifluoride etherate (Scheme 11A) [103]. The use of this class of boranes in B–alkyl SMC was sporadically reported in the literature, probably due to their flammable nature and sensitivity to oxygen, as well as the inefficiency of the transfer of all three alkyl groups from the boron center [104]. In 2009, Wang et al. published optimization studies that presented efficient and chemoselective Pd-catalyzed direct SMCs of trialkylboranes **60** with bromoarenes **59** in the presence of unmasked acidic or basic functions using the weak base Cs2CO<sup>3</sup> under mild non-aqueous conditions (Scheme 11B). The conditions tolerated carbonyl reagents, chlorinated derivatives, nitriles and unprotected and base-labile Piv- and TBS-protected phenols with more than 30 examples incorporating primary alkyls, and especially lower *n*-alkyls such as ethyl groups [105,106].

or basic functions using the weak base Cs2CO3 under mild non-aqueous conditions (Scheme 11B). The conditions tolerated carbonyl reagents, chlorinated derivatives, nitriles and unprotected and

alkyls, and especially lower *n*-alkyls such as ethyl groups [105,106].

**Scheme 11.** Synthesis of alkylboranes (**A and D)** and their uses as coupling partners in sp3–sp2 SMCs (**A-D**). **Scheme 11.** Synthesis of alkylboranes (**A** and **D)** and their uses as coupling partners in sp3–sp<sup>2</sup> SMCs (**A–D**).

Lacôte et al. developed the efficient transfer of all three groups of trialkyl- and triaryl-boranes (0.3–1 eq. instead of 1–3 eq.) in SMC in good yields under base-free conditions, achieving the activation by using N-heterocyclic carbenes (i.e., **63** in Scheme 11C). The C(sp2)-C(sp3) scope involved the NHC–borane complexes **63** with aryl chlorides, bromides, iodides and triflates **62** in 11 examples (65%–99%) using PdCl2(dppf) or Pd(OAc)2 with a ligand (XPhos or RuPhos) under microwave irradiation or classical heating [107]. In 2015, Li et al. described a general, atom-economic methodology that uses peralkyl and peraryl groups of unactivated symmetrical triaryl- and trialkylboranes **66** in SMC (Scheme 11D). The hydroboration of terminal alkenes was carried out *in situ*, and the corresponding trialkylboranes **66** were coupled with alkenyl and aryl halides **65** in a one-pot fashion. The method was compatible with a variety of functional groups and heterocycles [108]. Lacôte et al. developed the efficient transfer of all three groups of trialkyl- and triaryl-boranes (0.3–1 eq. instead of 1–3 eq.) in SMC in good yields under base-free conditions, achieving the activation by using N-heterocyclic carbenes (i.e., **63** in Scheme 11C). The C(sp<sup>2</sup> )-C(sp<sup>3</sup> ) scope involved the NHC–borane complexes **63** with aryl chlorides, bromides, iodides and triflates **62** in 11 examples (65%–99%) using PdCl2(dppf) or Pd(OAc)<sup>2</sup> with a ligand (XPhos or RuPhos) under microwave irradiation or classical heating [107]. In 2015, Li et al. described a general, atom-economic methodology that uses peralkyl and peraryl groups of unactivated symmetrical triaryl- and trialkyl-boranes **66** in SMC (Scheme 11D). The hydroboration of terminal alkenes was carried out *in situ*, and the corresponding trialkylboranes **66** were coupled with alkenyl and aryl halides **65** in a one-pot fashion. The method was compatible with a variety of functional groups and heterocycles [108].
