**6. Alkylboronic Acids in sp3–sp<sup>2</sup> SMCs**

Alkylboronic acids (R(BOH)2), like their aryl analogs, exist in equilibrium with their trimeric cyclic anhydrides—boroxines, which also proved to be efficient coupling partners in SMCs [109]. Thus, the determination of the concentration of boroxine vs. boronic acid in the catalytic reaction can be difficult, requiring the employment of excess boronic acid to ensure the completion of the reaction [110]. Gibbs et al. were among the first to use alkylboronic acids as coupling partners with alkenyl triflates in 1995 [111]. The group of Falck widened the scope by reporting an efficient Ag(I)-promoted SMC of *n*-alkylboronic acids **68** (Scheme 12A) [112]. cyclic anhydrides—boroxines, which also proved to be efficient coupling partners in SMCs [109]. Thus, the determination of the concentration of boroxine vs. boronic acid in the catalytic reaction can be difficult, requiring the employment of excess boronic acid to ensure the completion of the reaction [110]. Gibbs et al. were among the first to use alkylboronic acids as coupling partners with alkenyl triflates in 1995 [111]. The group of Falck widened the scope by reporting an efficient Ag(I)-promoted SMC of *n*-alkylboronic acids **68** (Scheme 12A) [112].

*Catalysts* **2020**, *10*, x FOR PEER REVIEW 14 of 24

Alkylboronic acids (R(BOH)2), like their aryl analogs, exist in equilibrium with their trimeric

**Scheme 12.** Alkylboronic acids as coupling partners in sp3–sp2 SMCs (**A-E**). **Scheme 12.** Alkylboronic acids as coupling partners in sp3–sp<sup>2</sup> SMCs (**A–E**).

The progress of utilizing alkylboronic acids was reviewed in 2008 [110]. Next, the SMC of primary alkylboronic acids **72** with alkenyl halides **73** was reported using air-stable catalyst PdCl(C3H5)(dppb) and Cs2CO3, and toluene or xylene as solvents (Scheme 12B) [113]. In 2012, Ma et al. used Pd(OAc)2 with K2CO3 and an air-stable monophosphine HBF4 salt (**L9**: LB-Phos.HBF4) as an efficient ligand to couple primary and secondary alkylboronic acids **75** with 2-bromoalken-3-ol derivatives **76** (Scheme 12C) [114]. In 2014, Tang et al. revealed a sterically demanding aryl–alkyl SMC between di-ortho-substituted arylhalides **79** and (secondary) cycloalkylboronic acids **78** using a highly reactive Pd-AntPhos catalyst that allowed to reduce the β-hydride elimination (Scheme 12D). The method comprised a scope of sterically hindered substituted aryl compounds, including highly substituted benzene, naphthalene and anthracene derivatives [115]. The same group described the cross-coupling between aryl/alkenyl triflates **82** and acyclic secondary alkylboronic acids **81** in good The progress of utilizing alkylboronic acids was reviewed in 2008 [110]. Next, the SMC of primary alkylboronic acids **72** with alkenyl halides **73** was reported using air-stable catalyst PdCl(C3H5)(dppb) and Cs2CO3, and toluene or xylene as solvents (Scheme 12B) [113]. In 2012, Ma et al. used Pd(OAc)<sup>2</sup> with K2CO<sup>3</sup> and an air-stable monophosphine HBF<sup>4</sup> salt (**L9**: LB-Phos.HBF4) as an efficient ligand to couple primary and secondary alkylboronic acids **75** with 2-bromoalken-3-ol derivatives **76** (Scheme 12C) [114]. In 2014, Tang et al. revealed a sterically demanding aryl–alkyl SMC between di-ortho-substituted arylhalides **79** and (secondary) cycloalkylboronic acids **78** using a highly reactive Pd-AntPhos catalyst that allowed to reduce the β-hydride elimination (Scheme 12D). The method comprised a scope of sterically hindered substituted aryl compounds, including highly substituted benzene, naphthalene and anthracene derivatives [115]. The same group described the cross-coupling between aryl/alkenyl triflates **82** and acyclic secondary alkylboronic acids **81** in good to excellent yields (Scheme 12E). The employment of sterically bulky P,P=O ligands (**L11**/**12**) was found to be critical to achieve the

chemoselectivity by inhibiting the isomerization of the secondary alkyl coupling partner (e.g., *i*Pr vs. *n*Pr) and to obtain high yields [116]. to excellent yields (Scheme 12E). The employment of sterically bulky P,P=O ligands (**L11/12**) was found to be critical to achieve the chemoselectivity by inhibiting the isomerization of the secondary alkyl coupling partner (e.g., *i*Pr vs. *n*Pr) and to obtain high yields [116].

#### **7. Boronic Esters and MIDA Boronates in sp3–sp<sup>2</sup> SMCs 7. Boronic Esters and MIDA Boronates in sp3–sp2 SMCs**

Prior to the work of Rueping on more general cross-coupling methods of challenging C–O electrophiles with organoboron reagents, a robust Ru-catalyzed SMC of aryl methyl ethers **84** with boronic esters **85** was elegantly revealed by chelation assistance (Scheme 13A) [84,117]. Aromatic ketones **84** where the carbonyl is located in an ortho position were reported to assist in the cleavage of C–OMe bonds. Neopentyl boronates **85** were the most reactive among all the tested boronic esters. The conditions were employed to couple aryl, alkenyl and even alkyl boronates with the same efficiency by using a RuH2(CO)(PPh3)<sup>3</sup> catalytic system. The C–OMe bond-cleavage was facilitated by the coordination of the carbonyl group to the Ru center, in an analogous mechanistic scenario to C–H activation (Scheme 13B). The suggested chelation-assisted mechanism was later supported by the isolation of the oxidative addition complex of an aryl C–O bond using low-valent Ru complexes **91** (Scheme 13C) [84,118,119]. The C–O bond-cleavage occurred at high temperatures (thermodynamic control) as compared to the C–H functionalization that rapidly took place at room temperature (Scheme 13C). The Ru-catalyzed SMC of aryl methyl ethers remained restricted to the presence of an ortho directing group to the reactive site [84,118,119]. The reported more general Ni-catalyzed coupling version of aryl methyl ether without directing group involved aryl boranes, and did not involve a scope of alkyl boranes [84,117–120]. Prior to the work of Rueping on more general cross-coupling methods of challenging C–O electrophiles with organoboron reagents, a robust Ru-catalyzed SMC of aryl methyl ethers **84** with boronic esters **85** was elegantly revealed by chelation assistance (Scheme 13A) [84,117]. Aromatic ketones **84** where the carbonyl is located in an ortho position were reported to assist in the cleavage of C–OMe bonds. Neopentyl boronates **85** were the most reactive among all the tested boronic esters. The conditions were employed to couple aryl, alkenyl and even alkyl boronates with the same efficiency by using a RuH2(CO)(PPh3)3 catalytic system. The C–OMe bond-cleavage was facilitated by the coordination of the carbonyl group to the Ru center, in an analogous mechanistic scenario to C–H activation (Scheme 13B). The suggested chelation-assisted mechanism was later supported by the isolation of the oxidative addition complex of an aryl C–O bond using low-valent Ru complexes **91** (Scheme 13C) [84,118,119]. The C–O bond-cleavage occurred at high temperatures (thermodynamic control) as compared to the C–H functionalization that rapidly took place at room temperature (Scheme 13C). The Ru-catalyzed SMC of aryl methyl ethers remained restricted to the presence of an ortho directing group to the reactive site [84,118,119]. The reported more general Nicatalyzed coupling version of aryl methyl ether without directing group involved aryl boranes, and did not involve a scope of alkyl boranes [84,117–120].

**Scheme 13.** Chelation-assisted Ru-catalyzed sp3–sp2 SMCs of C–OMe electrophiles (**A**) and mechanistic insight (**B,C**). **Scheme 13.** Chelation-assisted Ru-catalyzed sp3–sp<sup>2</sup> SMCs of C–OMe electrophiles (**A**) and mechanistic insight (**B**,**C**).

Inspired by the pioneering work of Wrackmeyer on protected boronic acids by iminodiacetic acids [121], the groups of Burke, Yudin and others developed the use of *N*-methyliminodiacetic acid (MIDA) boronates **92** in direct and iterative SMC reactions [122–124]. In addition to stability and compatibility with chromatography, the advantage of MIDA boronates is their mild hydrolysis to Inspired by the pioneering work of Wrackmeyer on protected boronic acids by iminodiacetic acids [121], the groups of Burke, Yudin and others developed the use of *N*-methyliminodiacetic acid (MIDA) boronates **92** in direct and iterative SMC reactions [122–124]. In addition to stability and compatibility with chromatography, the advantage of MIDA boronates is their mild hydrolysis to

liberate the corresponding boronic acids compared to the harsh conditions needed in the case of

reaction medium [127].

liberate the corresponding boronic acids compared to the harsh conditions needed in the case of sterically bulky boronic esters. This class found various applications in synthesis, and the efficient iterative assembly of the MIDA building blocks was recently reviewed in 2015 [122]. A direct SMC between MIDA boronates **92** and aryl and heteroaryl bromides **93** is presented in Scheme 14 [43]. *Catalysts* **2020**, *10*, x FOR PEER REVIEW 16 of 24 sterically bulky boronic esters. This class found various applications in synthesis, and the efficient iterative assembly of the MIDA building blocks was recently reviewed in 2015 [122]. A direct SMC between MIDA boronates **92** and aryl and heteroaryl bromides **93** is presented in Scheme 14 [43].

**Scheme 14.** sp3–sp2 SMCs using N-methyliminodiacetic acid (MIDA) boronates. **Scheme 14.** sp3–sp<sup>2</sup> SMCs using N-methyliminodiacetic acid (MIDA) boronates.

#### **8. B–Alkyl SMCs Using BBN Variants (9-MeO-9-BBN and OBBD Derivatives) 8. B–Alkyl SMCs Using BBN Variants (9-MeO-9-BBN and OBBD Derivatives)**

The basic set-up of the SMC has essentially stayed similar for decades. However, the '9-MeO-9- BBN variant' is one of the alternative formats for this transformation that has permitted advanced applications of the sp3–sp2 coupling process (Scheme 15A,B). This method is distinguished by the absence of the essential base that acts as a promoter in the classical SMC version. Rather, the R–M (sp3, sp2, or sp) is first intercepted with 9-MeO-9-BBN, resulting in the corresponding borinate complex **97**, which then passes the R-group onto an organopalladium complex generated *in situ* as the electrophilic partner (Scheme 15A). The 9-MeO-9-BBN variant was reviewed by Seidel and Fürstner in 2011 [125]. In 2013, Dai et al. reported a 9-MeO-9-BBN variant methodology, depicted in Scheme 15B, using Pd(OAc)2 and a hemilabile P,O-ligand, Aphos-Y **L13** under mild reaction conditions (K3PO4**·**3H2O, THF/H2O, rt) coupling the alkyl iodide **99** and the alkenyl bromide **100**. This new process serves as an improvement of the Johnson protocol, which generally employs two ligands (dppf and Ph3As) and two organic solvents (THF and DMF) in the SMC step in the total synthesis of structurally complex natural products, by using one ligand (**L13**, Aphos-Y) and one organic solvent The basic set-up of the SMC has essentially stayed similar for decades. However, the '9-MeO-9-BBN variant' is one of the alternative formats for this transformation that has permitted advanced applications of the sp3–sp<sup>2</sup> coupling process (Scheme 15A,B). This method is distinguished by the absence of the essential base that acts as a promoter in the classical SMC version. Rather, the R–M (sp<sup>3</sup> , sp<sup>2</sup> , or sp) is first intercepted with 9-MeO-9-BBN, resulting in the corresponding borinate complex **97**, which then passes the R-group onto an organopalladium complex generated *in situ* as the electrophilic partner (Scheme 15A). The 9-MeO-9-BBN variant was reviewed by Seidel and Fürstner in 2011 [125]. In 2013, Dai et al. reported a 9-MeO-9-BBN variant methodology, depicted in Scheme 15B, using Pd(OAc)<sup>2</sup> and a hemilabile P,O-ligand, Aphos-Y **L13** under mild reaction conditions (K3PO4·3H2O, THF/H2O, rt) coupling the alkyl iodide **99** and the alkenyl bromide **100**. This new process serves as an improvement of the Johnson protocol, which generally employs two ligands (dppf and Ph3As) and two organic solvents (THF and DMF) in the SMC step in the total synthesis of structurally complex natural products, by using one ligand (**L13**, Aphos-Y) and one organic solvent (THF) [126].

(THF) [126]. OBBD (B-alkyl-9-oxa-10-borabicyclo[3.3.2]decane) derivatives **104/105** represent another variant of 9-BBN (Scheme 15C-D). OBBD reagents **104/105** were used successfully to perform B-Alkyl SMC under mild aqueous micellar catalysis conditions. The straightforward preparation of OBBD **104/105** OBBD (B-alkyl-9-oxa-10-borabicyclo[3.3.2]decane) derivatives **104**/**105** represent another variant of 9-BBN (Scheme 15C,D). OBBD reagents **104**/**105** were used successfully to perform B-Alkyl SMC under mild aqueous micellar catalysis conditions. The straightforward preparation of OBBD **104**/**105** is shown in Scheme 15C.

is shown in Scheme 15C. OBBD derivatives showed similar reactivity to 9-BBN reagents in SMCs, with the advantage of increased stability and isolable nature. The optimized SMC conditions (Scheme 15D) comprised dtbpf **L14** as the supporting ligand, which allows the reaction to be run at a catalyst loading as low as 0.25 mol% (i.e., 2500 ppm). The optimization was carried out in aqueous surfactant media, with TPGS-750-M as the preferred amphiphile and Et3N or K3PO4 as the base. The substrate scope **108** was shown by more than 34 examples with good to excellent yields (56%–100%). Lower yields were observed with steric hindrance next to the boronate group, and the conditions were limited on secondary OBBD reagents (even upon using 9-BBN derivatives instead). The synthetic utility of this methodology was demonstrated by a four-step one-pot synthesis and a successful recycling of the OBBD derivatives showed similar reactivity to 9-BBN reagents in SMCs, with the advantage of increased stability and isolable nature. The optimized SMC conditions (Scheme 15D) comprised dtbpf **L14** as the supporting ligand, which allows the reaction to be run at a catalyst loading as low as 0.25 mol% (i.e., 2500 ppm). The optimization was carried out in aqueous surfactant media, with TPGS-750-M as the preferred amphiphile and Et3N or K3PO<sup>4</sup> as the base. The substrate scope **108** was shown by more than 34 examples with good to excellent yields (56%–100%). Lower yields were observed with steric hindrance next to the boronate group, and the conditions were limited on secondary OBBD reagents (even upon using 9-BBN derivatives instead). The synthetic utility of this methodology was demonstrated by a four-step one-pot synthesis and a successful recycling of the reaction medium [127].

*Catalysts* **2020**, *10*, x FOR PEER REVIEW 17 of 24

**Scheme 15.** B–alkyl SMCs using BBN variants (9-MeO-9-BBN (**A,B**) and OBBD derivatives (**C,D**)). **Scheme 15.** B–alkyl SMCs using BBN variants (9-MeO-9-BBN (**A**,**B**) and OBBD derivatives (**C**,**D**)).

#### **9. Selected Examples of Applications of SMCs and B–alkyl SMC in the Synthesis of Target Molecules 9. Selected Examples of Applications of SMCs and B–alkyl SMC in the Synthesis of Target Molecules**

It is rare nowadays to find a total synthesis that does not involve at least a cross-coupling reaction, and in particular, a Suzuki–Miyaura reagent [6]. The use of SMC in total synthesis has been extensively reviewed by Heravi et al. [128,129]. It is rare nowadays to find a total synthesis that does not involve at least a cross-coupling reaction, and in particular, a Suzuki–Miyaura reagent [6]. The use of SMC in total synthesis has been extensively reviewed by Heravi et al. [128,129].

B–alkyl SMC, in particular, was likewise applied in the synthesis of beneficial products [130– 132]. Two examples are shown in Scheme 16: **Cytochalasin Z8** and **Ieodomycin D**, which belong to

B–alkyl SMC, in particular, was likewise applied in the synthesis of beneficial products [130–132]. Two examples are shown in Scheme 16: **Cytochalasin Z<sup>8</sup>** and **Ieodomycin D**, which belong to the family of secondary fungal metabolite with a wide range of biological activities that target cytoskeletal processes [133–135]. Scheme 16 also includes examples of complex molecules that were achieved by synthetic routes involving SMCs with C(sp<sup>2</sup> )–B reagents; namely **Michellamine** (an anti-HIV viral replication receptor) and **(-)-steganone** (an antileukemic lignan precursor) [136,137]. *Catalysts* **2020**, *10*, x FOR PEER REVIEW 18 of 24 cytoskeletal processes [133–135]. Scheme 16 also includes examples of complex molecules that were achieved by synthetic routes involving SMCs with C(sp2)–B reagents; namely **Michellamine** (an anti-HIV viral replication receptor) and **(-)-steganone** (an antileukemic lignan precursor) [136,137]**.**

**Scheme 16.** Examples of drugs and active molecules whose total synthesis involved SMC. **Scheme 16.** Examples of drugs and active molecules whose total synthesis involved SMC.

#### **10. Conclusion 10. Conclusion**

The present review focused on the use of C(sp3)–organoboranes as cross-coupling partners in metal-catalyzed C(sp3)–C(sp2) cross-couplings, such as B–alkyl Suzuki–Miyaura reactions. Indeed, metal-catalyzed cross-coupling reactions have become mature tools in organic synthesis. Nevertheless, C(sp3)–C cross-couplings are far less reported than other C-C coupling reactions. Furthermore, this field is largely dominated by using organic halides or pseudohalides as coupling partners. C–O–Alkyl electrophiles remain an area of research that is attracting strong attention. Undoubtedly, the progress made in the syntheses of stable and isolable sp3-boron reagents is impacting the development of C(sp3)–C(sp2) cross-couplings of the Suzuki–Miyaura type. The attention given to dual and photocatalysis is also strongly contributing to the furnishing of a toolbox that can achieve active adducts, which impact all fields of research and industry and cannot be The present review focused on the use of C(sp<sup>3</sup> )–organoboranes as cross-coupling partners in metal-catalyzed C(sp<sup>3</sup> )–C(sp<sup>2</sup> ) cross-couplings, such as B–alkyl Suzuki–Miyaura reactions. Indeed, metal-catalyzed cross-coupling reactions have become mature tools in organic synthesis. Nevertheless, C(sp<sup>3</sup> )–C cross-couplings are far less reported than other C-C coupling reactions. Furthermore, this field is largely dominated by using organic halides or pseudohalides as coupling partners. C–O–Alkyl electrophiles remain an area of research that is attracting strong attention. Undoubtedly, the progress made in the syntheses of stable and isolable sp<sup>3</sup> -boron reagents is impacting the development of C(sp<sup>3</sup> )–C(sp<sup>2</sup> ) cross-couplings of the Suzuki–Miyaura type. The attention given to dual and photocatalysis is also strongly contributing to the furnishing of a toolbox that can achieve active adducts, which impact all fields of research and industry and cannot be otherwise obtained.

otherwise obtained. **Author Contributions:** J.S., J.E.M. and T.M.E.D wrote the manuscript; I.K. wrote the mechanistic insight (section 2) and proofread the whole manuscript; C.S.L., A.K. and K.P. and proofread the manuscript and provided critical **Author Contributions:** J.S., J.E.-M. and T.M.E.D. wrote the manuscript; I.K. wrote the mechanistic insight (Section 2) and proofread the whole manuscript; C.-S.L., A.K. and K.P. and proofread the manuscript and provided critical revision throughout the process. All authors have read and agreed to the published version of the manuscript.

revision throughout the process. **Funding:** This publication is based upon work supported by the Khalifa University of Science and Technology **Funding:** This publication is based upon work supported by the Khalifa University of Science and Technology under Award No. RC2-2018-024".

under Award No. RC2-2018-024". **Conflicts of Interest:** "The authors declare no conflict of interest."

for energy storage. *Chem. Soc. Rev.* **2019**, *48*, 5350–5380.

#### **Conflicts of Interest:** "The authors declare no conflict of interest." **References**


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