Unsymmetrical 1,1-Bisboryl Species: Valuable Building Blocks in Synthesis

Unsymmetrical 1,1-bis(boryl)alkanes and alkenes are organo-bismetallic equivalents, which are synthetically important because they allow for sequential selective transformations of C–B bonds. We reviewed the synthesis and chemical reactivity of 1,1-bis(boryl)alkanes and alkenes to provide information for the synthetic community. In the first part of this review, we disclose the synthesis and chemical reactivity of unsymmetrical 1,1-bisborylalkanes. In the second part, we describe the synthesis and chemical reactivity of unsymmetrical 1,1-bis(boryl)alkenes.


Introduction
Over the last 70 years, organoboron compounds have dramatically changed the landscape of organic chemistry through a wide range of valuable and indispensable synthetic applications, e.g., cross-coupling chemistry, photochemistry, and alkylboration, which has led to new constructions of C-C and C-heteroatom bonds [1][2][3][4][5][6]. Additionally, boron functionality is dispersed in natural products and synthetic drugs. Natural products include the antibiotics aplasmomycin, boromycin, and tartolon B, in which boron functionality appears as a borate complex [7][8][9][10][11]. Drugs such as Tavaborole and Bortezomib also incorporate boron functionality [12][13][14]. In terms of these aspects, multiborylated compounds, e.g., I, are even more attractive due to their synthetic versatility and chemical stability, which allow for the selective synthesis of multifunctionalized molecules (Scheme 1) [15][16][17][18][19][20]. Recently, our group [16,17] and other research groups have mainly reviewed the new class of symmetrical 1,1-diboranes, I (bis-metallated reagents) (Scheme 1A,C), their preparation, and their application in organic synthesis for forming organoboranes and bifunctionalized products [15][16][17][18][19][20]. In contrast, the unsymmetrical 1,1-bis(boranes), II, have rarely been reviewed, despite their importance in the chemoand stereoselective building of C-C and C-X bonds. These classes of compounds mainly include 1,1-bis(boron) (III) and alkenyldiboronates (IV) (Scheme 1B). These compounds offer two distinct boron substituents for ideal sites as well as stereoselective synthetic strategies to obtain stereo-controlled alkanes [16,17] and multisubstituted olefins, which are of major importance in organic synthesis [21][22][23][24][25][26]. Most importantly, 1,1-bis(boryl)alkenes have been utilized in the synthesis of the anticancer agent tamoxifen [27]. However, unsymmetrical 1,1-bis(boryl)alkanes (III) and -alkenes (IV) represent a unique class of boron compounds with a tunable reactivity for boron site-selective functionalization. This review will cover synthetic approaches for forming unsymmetrical 1,1-bis(boron) species as well as for deriving chemo-and stereoselective transformations for the synthesis of complex molecular structures. It is hoped that this review will provide useful knowledge for scientists seeking to discover new things about unsymmetrical 1,1-bis(boryl)alkanes and -alkenes in organic synthesis. The synthesis of these unsymmetrical 1,1-bisboryls includes mainly the hydroboration of alkynes and alkenes. Unsymmetrical 1,1-bis(boryl)alkanes and -alkenes are mainly utilized in chemo-and stereoselective (sequential) cross-coupling reactions and other chemoselective transformations. In However, unsymmetrical 1,1-bis(boryl)alkanes (III) and -alkenes (IV) represent a unique class of boron compounds with a tunable reactivity for boron site-selective functionalization. This review will cover synthetic approaches for forming unsymmetrical 1,1-bis(boron) species as well as for deriving chemo-and stereoselective transformations for the synthesis of complex molecular structures. It is hoped that this review will provide useful knowledge for scientists seeking to discover new things about unsymmetrical 1,1-bis(boryl)alkanes and -alkenes in organic synthesis. The synthesis of these unsymmetrical 1,1-bisboryls includes mainly the hydroboration of alkynes and alkenes. Unsymmetrical 1,1-bis(boryl)alkanes and -alkenes are mainly utilized in chemo-and stereoselective (sequential) cross-coupling reactions and other chemoselective transformations. In order to simplify things for the readers, we classified this review article into two categories based on the hybridization of the carbon attached to the 1,1-bis(boron) functionalities: (i) Unsymmetrical sp 3 -centered type-III; and (ii) Unsymmetrical sp 2 -centered type-IV.
In both cases, we discuss the synthesis and utility of the unsymmetrical 1,1-bis(boron) species in organic chemistry.
Before going into the discussion, let us first introduce the characteristics of the C-boron bond in terms of reactivity, on the basis of their substitution pattern. It is well known that the organoboron groups (see Scheme 1F) [28] have different reactivities due to the steric and electronic properties of the Lewis acidic boron moiety, which can be easily tuned just by changing the substitution around the organoboron group, which allows for diverse reactivity as a stoichiometric reagent and as a catalyst. For example, boron reagents behave like nucleophilic component is a Suzuki-Miyaura (SM) cross-coupling reaction; therefore, their reactivity depends on their nucleophilicity. Nucleophilicity scale of organoborons (Scheme 1G) shows that organoboronic acids and organo-trifluoroborates have greater nucleophilicity than do MIDA-boronates (MIDA = N-methyliminodiacetic acid), (1,8-diaminonaphthyl boronamide, and boronic esters (as described in Scheme 1G) [28]; thus, MIDA-boronates have less reactivity toward the SM cross-coupling reaction [3]. Therefore, the two different organoboron groups in 1,1-bis(boron) species tend to show two different reactivities and perform in a chemoselective manner.

Unsymmetrical sp3-Centered 1,1-Bis(boryl) Compounds: Synthesis and Applications
In 2011, Hall and coworkers elegantly reported the first preparation of optically enriched unsymmetrical 1,1-bis(boryl) compounds (2) with excellent enantioselectivity via a copper-catalyzed asymmetric conjugate borylation of β-boronylacrylates (1) with pinacolatodiborane (Scheme 2A) [29]. The obtained enriched unsymmetrical 1,1-bis(boryl) compound (2) was then treated with KHF 2 , forming the corresponding trifluoroborate salt 3. Of note, the Bpin (Bpin = B-pinacolato) group in 2 selectively underwent a trifluorination reaction over Bdan (Bdan = B-1,8-diaminonaphthalene) functionality, most likely due to the higher Lewis acidity available for activation of the p-orbital of the boron in Bpin compared to the lower Lewis acidity of the p-orbital of the boron in Bdan, which is aromatically busy (Scheme 2) [30]. An X-ray crystallographic analysis confirmed the conjugate borylation product of 2a (R = Me); this provided us with a better understanding of the physical properties of these compounds.
In addition, the trifluoroborate salt 3 was stereo-specifically cross-coupled with aryl bromide in the presence of palladium catalyst and XPhos (2-dicyclohexylphosphino-2 ,4 ,6 -triisopropylbiphenyl) as a ligand: these salts formed the corresponding arylated product 4 in high yield and with good-to-excellent enantioselectivity (88-99% ee). The coordination of the carbonyl oxygen with the boron atom (see 5) and the stabilization provided by the second boronyl unit in the α-B-Pd(II) complex are thought to facilitate the transmetallation process and the cross-coupling reaction. Interestingly, in this cross-coupling reaction, an inversion of the stereochemistry was observed. The rationale for this inversion was presented through a transmetallation reaction that took place via transition state 5, which was responsible for inverting the stereochemistry (Scheme 2B) [29]. In 2015, this group expanded its investigations into palladium (Pd(dba)2) and the XPhoscatalyzed cross-coupling reactions of optically enriched unsymmetrical 1,1-bisboron compound (6), using aryl bromides in a chemo-and stereoselective manner for the synthesis of the benzylic secondary alkyl boronates 7a-h, which had a stereochemistry inversion [31]. They also noted an important observation: by increasing the Lewis basicity of a carbonyl group from an ester to a Weinreb amide, the cross-coupling reaction was more feasible. The coordination of the carbonyl oxygen with the boron atom, together with the stability of the second boron unit in the α-B-Pd(II) intermediate, helped to overcome a difficulty at the transmetallation step. This reaction showed tolerance to a wide range of aryl coupling partners, with excellent chemoselectivity over the Bdan functionality (Scheme 3).
Yun and coworkers reported the use of copper-catalyzed hydroboration of borylalkenes to synthesize unsymmetrical 1,1-bis(boryl)alkanes in a high regioselective and enantioselective version [32]. Various alkene substitutions, such as aryl, primary, and secondary alkyls, were well tolerated in this reaction and provided excellent regioselectivity (Scheme 5).
Initially, the reaction mechanism involved the reaction of copper tert-butoxide with pinacolatoborane, affording LCu-H species 16, which then underwent a regio-and enantioselective addition reaction into borylalkene 12, yielding the chiral organocopper intermediate 17. Next, this intermediate 17 underwent stereoretentive transmetallation with one more equivalents of pinacolatoborane, finally yielding the desired product 14 and regenerating the catalyst (LCu-H) 16 for another catalytic cycle (Scheme 5).
These chiral unsymmetrical 1,1-bis(boryl)alkanes were then transformed into allenylboronate 18 in a homologation reaction with 3-chloro-3-methylbut-1-ynyllithium, with almost no erosion of its enantioselectivity. Similarly, the Suzuki-Miyaura cross-coupling (SMCC) of 19 afforded the corresponding arylated product 20 in a low yield and with little loss of its enantioselectivity (but with retention of its configuration) (Scheme 6) [32]. Initially, the reaction mechanism involved the reaction of copper tert-butoxide with pinacolatoborane, affording LCu-H species 16, which then underwent a regio-and enantioselective addition reaction into borylalkene 12, yielding the chiral organocopper intermediate 17. Next, this intermediate 17 underwent stereoretentive transmetallation with one more equivalents of pinacolatoborane, finally yielding the desired product 14 and regenerating the catalyst (LCu-H) 16 for another catalytic cycle (Scheme 5).
In 2015, Fernandez's research group reported a transition metal-free approach for the synthesis of unsymmetrical 1,1-bis(boron) compounds from diazo compounds, 23, which were obtained in situ from aldehydes as well as from cyclic and noncyclic ketones (21) via in situ-generated sodium salts of tosylhydrazones followed by treatment with sodium hydride (Scheme 7) [33]. This method also provides a wide range of unsymmetrical 1,1-bis(borane) compounds from aldehydes and ketones, with good isolated yields. However, it is strictly limited to aliphatic carbonyls.
In their work, they provided a rationalized mechanism for this method via transition state 26 (based on DFT-Density Functional Theory calculations). The reaction involved the heterolytic cleavage of the mixed diboron reagent 25 and the formation of geminal C-Bpin and C-Bdan bonds via a concerted-asynchronous mechanism, as shown in Scheme 7.
In 2015, Fernandez's research group reported a transition metal-free approach for the synthesis of unsymmetrical 1,1-bis(boron) compounds from diazo compounds, 23, which were obtained in situ from aldehydes as well as from cyclic and noncyclic ketones (21) via in situ-generated sodium salts of tosylhydrazones followed by treatment with sodium hydride (Scheme 7) [33]. This method also provides a wide range of unsymmetrical 1,1-bis(borane) compounds from aldehydes and ketones, with good isolated yields. However, it is strictly limited to aliphatic carbonyls.
In their work, they provided a rationalized mechanism for this method via transition state 26 (based on DFT-Density Functional Theory calculations). The reaction involved the heterolytic cleavage of the mixed diboron reagent 25 and the formation of geminal C-Bpin and C-Bdan bonds via a concerted-asynchronous mechanism, as shown in Scheme 7. In 2015, Fernandez's research group reported a transition metal-free approach for the synthesis of unsymmetrical 1,1-bis(boron) compounds from diazo compounds, 23, which were obtained in situ from aldehydes as well as from cyclic and noncyclic ketones (21) via in situ-generated sodium salts of tosylhydrazones followed by treatment with sodium hydride (Scheme 7) [33]. This method also provides a wide range of unsymmetrical 1,1-bis(borane) compounds from aldehydes and ketones, with good isolated yields. However, it is strictly limited to aliphatic carbonyls.
In their work, they provided a rationalized mechanism for this method via transition state 26 (based on DFT-Density Functional Theory calculations). The reaction involved the heterolytic cleavage of the mixed diboron reagent 25 and the formation of geminal C-Bpin and C-Bdan bonds via a concerted-asynchronous mechanism, as shown in Scheme 7.
To explore the diastereoselective 1,1-diboration of diazo compounds, Fernandez's group substituted cyclohexanones for in situ-formed diazo-compounds and promoted insertion into the pinB-Bdan bond (Scheme 8) [33]. When they carried out a reaction with 4-substituted cyclohexanones (28a) under optimized reaction conditions, they observed reasonable diastereo-selectivity. An X-ray analysis of 29a showed that the Bdan and CF 3 groups were situated at the 1,4-diequitorial (trans) positions, as shown in Scheme 8. Under optimized conditions, the 3-Ph-cyclohexanone 28b afforded the 1,3-diequitorial (cis)-substituted isomer as the major diastereomer 29f (64%). Interestingly, under a similar reaction condition, the 2-Me-cyclohexanone 31 afforded excellent diastereo-selectivity (32a/32b), favoring the Bdan and Me groups with a 1,2-diequitorial (trans) configuration. This high diastereo-selectivity was expected because the 2-position substituent can directly influence the reaction center. The origin of diastereo-selectivity was explained through DFT analysis by taking the example of the 4-(trifluoromethyl)cyclohexanone 28a, as shown in Scheme 9. After the reaction of hydrazide and NaH with compound 28a, Fernandez's group considered in situ-generating two possible chair conformations (28aNeq and 28aNax) that were different in terms of their CF3 substituent arrangement: the equatorial conformer (28aNeq) was 1.7 kcal/mol lower than the axial conformer  The origin of diastereo-selectivity was explained through DFT analysis by taking the example of the 4-(trifluoromethyl)cyclohexanone 28a, as shown in Scheme 9. After the reaction of hydrazide and NaH with compound 28a, Fernandez's group considered in situ-generating two possible chair conformations (28aNeq and 28aNax) that were different in terms of their CF 3 substituent arrangement: the equatorial conformer (28aNeq) was 1.7 kcal/mol lower than the axial conformer (28aNax). Each confirmation could attack the pinB-Bdan substrate through its two diastereo-faces. When the conformer 28aNeq attacked pinB-Bdan through its two diastereomeric faces, the observed computed free energy barriers for the Bdan equatorial and Bdan axial positions were 33.9 and 38.9 kcal/mol, respectively (Scheme 9, left side). Thus, the lowest energy path led to a major diastereomer with Bdan and a CF 3 substituent in the 1,4-diequitorial (trans) of each 29a. The high energy (~5.0 kcal/mol) in the Bdan axial approach was due to destabilized interactions between 1,3-diaxial and cyclohexane. Similarly, the conformer 28aNax also exhibited a low energy barrier in the case of the Bdan equatorial approach, as opposed to the Bdan axial approach (Scheme 9, right side).
The energy difference between the two Bdan equatorial approaches was not too large in the two conformers (28aNeq and 28aNax), with the expected non-negligible formation of conformer 30a with an observed diastereomeric ratio of 70/30 for 29a/30a [33].
Molecules 2020, 24, x FOR PEER REVIEW 9 of 30 (28aNax). Each confirmation could attack the pinB-Bdan substrate through its two diastereo-faces. When the conformer 28aNeq attacked pinB-Bdan through its two diastereomeric faces, the observed computed free energy barriers for the Bdan equatorial and Bdan axial positions were 33.9 and 38.9 kcal/mol, respectively (Scheme 9, left side). Thus, the lowest energy path led to a major diastereomer with Bdan and a CF3 substituent in the 1,4-diequitorial (trans) of each 29a. The high energy (~5.0 kcal/mol) in the Bdan axial approach was due to destabilized interactions between 1,3-diaxial and cyclohexane. Similarly, the conformer 28aNax also exhibited a low energy barrier in the case of the Bdan equatorial approach, as opposed to the Bdan axial approach (Scheme 9, right side). The energy difference between the two Bdan equatorial approaches was not too large in the two conformers (28aNeq and 28aNax), with the expected non-negligible formation of conformer 30a with an observed diastereomeric ratio of 70/30 for 29a/30a [33]. Scheme 9. Proposed diastereo-isomeric pathways for the 1,1-bisboration of 4-CF3-cyclohexanone with pinB-Bdan and the relative Gibbs free energies in kcal/mol. Interestingly, 1,1-bis(boryl)alkanes can behave as catalysts, too. Piers's borane V [HB(C6H5)2] precatalyzed the hydroboration of terminal and internal alkynes for the synthesis of E-alkenyl pinacol boronic ester 36, and excellent selectivities were reported by Stephan and coworkers in 2016 [34]. In this hydroboration, they found that unsymmetrical 1,1-bis(borane) 34 catalyzed the reaction. An independent reaction of Piers borane V [HB(C6H5)2] with phenylacetylene afforded the corresponding E-alkenyl boronic ester 33a, which, upon additional treatment with pinacol boranes, yielded the regioselective stereogenic unsymmetrical 1,1-bis(borane) 34 (Scheme 10). Actually, 1,1bis(borane) 34 acted as an electrophilic catalyst for the hydroboration of alkyne into alkene in the presence of HBpin (pinacolborane). To support this, the electrophilic boron center of 34 was confirmed through an X-ray diffraction analysis of the tert-butylisonitrile adduct 35.
The proposed mechanism for the unsymmetrical 1,1-bis(borane) 34 catalyzing the hydroboration of alkynes for the synthesis of E-alkenyl boronic ester 36 is shown in Scheme 10. In this mechanism, unsymmetrical 1,1-bisboranes 34 acts as a Lewis acid catalyst, which activates alkyne to form complex VI: then, HBpin reacts with complex VI in a concerted syn-1,2-hydroboration manner (complex VII) to afford the hydroborylated product 36 and regenerate the unsymmetrical 1,1-bis(borane) 34 [34]. In 2019, Sharma research group reported a novel and concise method for the synthesis of a wide range of MIDA (MIDA = N-methyliminodiacetic acid) acylboronates (41) via the chemoselective oxidation of 1,1-bisboranes (39) (Scheme 12) [35]. MIDA acylboronates are synthetically challenging; however, they can be utilized as powerful building blocks for bioorthogonal amide formation and protein ligation.
First, Sharma prepared unsymmetrical 1,1-bis(borane) products (39) from symmetrical diboranes (38) by heating MIDA and triethylorthoformate (Scheme 11). The mechanism underlying this selective desymmetrization is still unclear. However, steric considerations could be among the reasons for this selectivity. In 2019, Sharma research group reported a novel and concise method for the synthesis of a wide range of MIDA (MIDA = N-methyliminodiacetic acid) acylboronates (41) via the chemoselective oxidation of 1,1-bisboranes (39) (Scheme 11) [35]. MIDA acylboronates are synthetically challenging; however, they can be utilized as powerful building blocks for bioorthogonal amide formation and protein ligation.
Next, Sharma chemoselectively oxidized pinacolate boran functionality over the MIDA boronate of unsymmetrical 1,1-bis(borane) products (39a-b) to obtain α-hydroxymethyl MIDA boronates (40) with good yields (Scheme 12). Thereafter, these α-hydroxymethyl MIDA boronates (40) were successfully oxidized into MIDA acylboronates (41) using Dess-Martin periodinane (DMP), with moderate to good yields (Scheme 12). Then, Sharma successfully applied a similar strategy for the synthesis of unique α, β-unsaturated MIDA acyl boronates (44)  In the same year, the Masarwa research group reported a late-stage desymmetrization of symmetrical 1,1-bis(boryl)alkanes via nucleophilic trifluorination while constructing unsymmetrical 1,1-bis(boryl)alkanes bearing trifluoroborate salts (Scheme 15) [36]. This method was tolerable within a wide range of substrate scopes, with good to excellent yields. Most interestingly, this method did not need any column purification, as the product was obtained upon crystallization. Our group proposed a mechanism to account for this desymmetrization methodology: First, nucleophilic fluoride attacks the vacant p-orbital of one of the boron centers in the symmetrical diborane 38 and generates monofluorinated compound I (step 1), which is more electrophilic than the parental symmetrical diborane 38. Hence, it forces the second fluorination (step 2) and then the third fluorination (step 3) at the boron center shown in Scheme 15. Consequently, the newly generated BF3 moiety develops a partial negative charge on the fluoride, and the fluoride may stabilize the flanking Bpin group through a fluoride bridge, as shown in 47′, which helps to prevent a subsequent attack by fluoride.  In the same year, the Masarwa research group reported a late-stage desymmetrization of symmetrical 1,1-bis(boryl)alkanes via nucleophilic trifluorination while constructing unsymmetrical 1,1-bis(boryl)alkanes bearing trifluoroborate salts (Scheme 15) [36]. This method was tolerable within a wide range of substrate scopes, with good to excellent yields. Most interestingly, this method did not need any column purification, as the product was obtained upon crystallization. Our group proposed a mechanism to account for this desymmetrization methodology: First, nucleophilic fluoride attacks the vacant p-orbital of one of the boron centers in the symmetrical diborane 38 and generates monofluorinated compound I (step 1), which is more electrophilic than the parental symmetrical diborane 38. Hence, it forces the second fluorination (step 2) and then the third fluorination (step 3) at the boron center shown in Scheme 15. Consequently, the newly generated BF 3 moiety develops a partial negative charge on the fluoride, and the fluoride may stabilize the flanking Bpin group through a fluoride bridge, as shown in 47 , which helps to prevent a subsequent attack by fluoride. In the same year, the Masarwa research group reported a late-stage desymmetrization of symmetrical 1,1-bis(boryl)alkanes via nucleophilic trifluorination while constructing unsymmetrical 1,1-bis(boryl)alkanes bearing trifluoroborate salts (Scheme 15) [36]. This method was tolerable within a wide range of substrate scopes, with good to excellent yields. Most interestingly, this method did not need any column purification, as the product was obtained upon crystallization. Our group proposed a mechanism to account for this desymmetrization methodology: First, nucleophilic fluoride attacks the vacant p-orbital of one of the boron centers in the symmetrical diborane 38 and generates monofluorinated compound I (step 1), which is more electrophilic than the parental symmetrical diborane 38. Hence, it forces the second fluorination (step 2) and then the third fluorination (step 3) at the boron center shown in Scheme 15. Consequently, the newly generated BF3 moiety develops a partial negative charge on the fluoride, and the fluoride may stabilize the flanking Bpin group through a fluoride bridge, as shown in 47′, which helps to prevent a subsequent attack by fluoride. Interestingly, this method exhibited excellent diastereo-selectivity when the reaction was performed on the 1,1-bis(boryl)substituted cyclopropanes 38a-c (Scheme 16). This diastereo-selectivity has been confirmed using 2D-NMR spectroscopic methods. From these results, it can be seen that the diastereo-selectivity mechanism underlying the reaction involves the selective nucleophilic trifluorination of boron, which occupies the less hindered side of cyclopropane.
Molecules 2020, 24, x FOR PEER REVIEW 13 of 30 Interestingly, this method exhibited excellent diastereo-selectivity when the reaction was performed on the 1,1-bis(boryl)substituted cyclopropanes 38a-c (Scheme 16). This diastereoselectivity has been confirmed using 2D-NMR spectroscopic methods. From these results, it can be seen that the diastereo-selectivity mechanism underlying the reaction involves the selective nucleophilic trifluorination of boron, which occupies the less hindered side of cyclopropane. These unsymmetrical 1,1-bis(boryl)alkanes, bearing a trifluoroborate group, were utilized for various selective functionalizations. For example, the simple hydrolysis of the trifluoroborate group afforded the 1,1-bis(borane) products 48a-c, which has a boronic acid moiety (Scheme 17A). Additionally, compound 47 treated with diamines and diols as coupling partners, yielded the unsymmetrical 1,1-bis(borane) products 49a-c (Scheme 17B).
The mechanism underlying this reaction involves the sequential hydroboration of cyclopropyl acetylene 51 with 2.0 eq. of Piers's borane V, affording 1,1-bis(boryl) compound VIII. Then, one of the frustrating borons of product VIII acts as a Lewis acid and induces cyclopropyl ring-opening and the hydride sequence. Then, aryl 1,2 shifts to form borole 53 (Scheme 19B). The stereochemical outcome of the reaction largely depends on the least sterically hindered pathway, leading to the major diastereomer cis-borole. In 2017, Erker and coworkers reported that Lewis acid induced a cyclopropyl acetylene rearrangement for the synthesis of unsymmetrical 1,1-bis(borane) [37]. In this synthesis, when cyclopropyl acetylene 51 was treated with two equivalents of Piers's borane V [HB(C 6 F 5 ) 2 ], it resulted in the formation of substituted α-boryl-tetrahydroborole 53a-cis and 53b-trans in a 7:1 ratio (Scheme 19A): this was confirmed by in situ NMR spectroscopic studies. Furthermore, they confirmed these structures using X-ray diffraction and found that the pair of substituents at C1 and C4 (in terms of stereochemistry) differed structurally from the cis and trans isomers.
The mechanism underlying this reaction involves the sequential hydroboration of cyclopropyl acetylene 51 with 2.0 eq. of Piers's borane V, affording 1,1-bis(boryl) compound VIII. Then, one of the frustrating borons of product VIII acts as a Lewis acid and induces cyclopropyl ring-opening and the hydride sequence. Then, aryl 1,2 shifts to form borole 53 (Scheme 19B). The stereochemical outcome of the reaction largely depends on the least sterically hindered pathway, leading to the major diastereomer cis-borole. In 2017, Erker and coworkers reported that Lewis acid induced a cyclopropyl acetylene rearrangement for the synthesis of unsymmetrical 1,1-bis(borane) [37]. In this synthesis, when cyclopropyl acetylene 51 was treated with two equivalents of Piers's borane V [HB(C6F5)2], it resulted in the formation of substituted α-boryl-tetrahydroborole 53a-cis and 53b-trans in a 7:1 ratio (Scheme 19A): this was confirmed by in situ NMR spectroscopic studies. Furthermore, they confirmed these structures using X-ray diffraction and found that the pair of substituents at C1 and C4 (in terms of stereochemistry) differed structurally from the cis and trans isomers.
The mechanism underlying this reaction involves the sequential hydroboration of cyclopropyl acetylene 51 with 2.0 eq. of Piers's borane V, affording 1,1-bis(boryl) compound VIII. Then, one of the frustrating borons of product VIII acts as a Lewis acid and induces cyclopropyl ring-opening and the hydride sequence. Then, aryl 1,2 shifts to form borole 53 (Scheme 19B). The stereochemical outcome of the reaction largely depends on the least sterically hindered pathway, leading to the major diastereomer cis-borole.

Scheme 19. (A) Formation and (B) rearrangement of tetrahydroboroles.
The cyclic 1,1-bis(boryl) contains two Lewis acidic boron sites: they can coordinate only as a frustrated Lewis pair (FLP) or can serve as a dihydrogen splitting reagent. Treatment of a 1:1 ratio of cis-borole compound and tri-tert-butylphosphine (as a Lewis base with 2.0 bar of hydrogen in pentane solution) resulted in the precipitation of product cis-54a. Similarly, upon treatment with carbon dioxide instead of hydrogen, a new six-membered cyclic ring was formed, in addition to the borole ring cis-54b (Scheme 20).
Molecules 2020, 24, x FOR PEER REVIEW 16 of 30 The cyclic 1,1-bis(boryl) contains two Lewis acidic boron sites: they can coordinate only as a frustrated Lewis pair (FLP) or can serve as a dihydrogen splitting reagent. Treatment of a 1:1 ratio of cis-borole compound and tri-tert-butylphosphine (as a Lewis base with 2.0 bar of hydrogen in pentane solution) resulted in the precipitation of product cis-54a. Similarly, upon treatment with carbon dioxide instead of hydrogen, a new six-membered cyclic ring was formed, in addition to the borole ring cis-54b (Scheme 20  Interestingly, Erker and coworkers interconverted cis-borole 53a into trans-isomer 53b by treating it with a catalytic amount of TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl). This reaction followed reversible H-abstraction at the activated C1 position of the heterocycle. After they subjected trans-borole to a similar FLP reaction, they obtained products 54c and 54d in good yields (Scheme 21). [37].
Molecules 2020, 24, x FOR PEER REVIEW 16 of 30 The cyclic 1,1-bis(boryl) contains two Lewis acidic boron sites: they can coordinate only as a frustrated Lewis pair (FLP) or can serve as a dihydrogen splitting reagent. Treatment of a 1:1 ratio of cis-borole compound and tri-tert-butylphosphine (as a Lewis base with 2.0 bar of hydrogen in pentane solution) resulted in the precipitation of product cis-54a. Similarly, upon treatment with carbon dioxide instead of hydrogen, a new six-membered cyclic ring was formed, in addition to the borole ring cis-54b (Scheme 20 Interestingly, Erker and coworkers interconverted cis-borole 53a into trans-isomer 53b by treating it with a catalytic amount of TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl). This reaction followed reversible H-abstraction at the activated C1 position of the heterocycle. After they subjected trans-borole to a similar FLP reaction, they obtained products 54c and 54d in good yields (Scheme 21). [37].
In the same year, Erker and coworkers reported that cyclic 1,1-bis(borane) 53 catalyzed the hydroboration of N-methylindole. Here, 1,1-bis(borane) compounds were utilized as effective catalysts for C-H bond activating the borylation of N-methylindole with catechol borane. This reaction afforded 3-boryl-N-methylindole with a 59% yield and N-methylindoline with a Lewis pair adduct (with HBcat). Furthermore, this adduct, upon treatment with the same catalyst for several hours, yielded a 5-boryl-N-methylindoline product through the evolution of molecular hydrogen (Scheme 22) [38].
The mechanism proposed by Chirik's group involved the initial formation of cobalt acetylide (X), which, upon reacting with pinacolborane, yielded compound XI, which had more Lewis acidic boron substituent (Bpin). This could transfer to the alkyne, and the resulting alkynyl−BPin cobalt complex (XII) underwent syn-borylcobaltation, selectively affording XIII, which finally produced the stereoselective alkene 59.
In 2019, the Tsuchimoto group reported that the Pt-catalyzed diboration of alkyne had terminal Bdan with pinB-Bpin, resulting in the 1,1,2-triboryalkene 66c, which had perfect stereoselectivity without suffering direct activation by the platinum complex [45]. Compared to other reports on the diboration of alkynes [46,47] with pinB-Bpin, this method afforded an excellent yield (Scheme 30A). In 2019, utilizing the tetrasubstituted triborylalkene 66c, for the first time the Tsuchimoto group successfully synthesized tetrasubstituted aryl alkenes (72) through sequential SMCC reactions. In the triborylalkene 66c, the Csp 2 -B bond is inactive; thus, it is very unreactive under SMCC conditions. Of the remaining two Csp 2 -B bonds, one is at the transposition of the aryl group, which can possibly increase the nucleophilicity of the boron atom through electron flow: it reacts more facilely than does the other under Pd(II) SMCC conditions. In the first SMCC reaction, 4-iodobenzotrifluoride was treated under ligand-free conditions, affording 69 in very good yield (with regioselectivity). In the second SMCC arylation, 4-iodoanisole reacted preferentially with Csp 2 -Bpin over Csp 2 -Bdan, In 2019, utilizing the tetrasubstituted triborylalkene 66c, for the first time the Tsuchimoto group successfully synthesized tetrasubstituted aryl alkenes (72) through sequential SMCC reactions. In the triborylalkene 66c, the Csp 2 -B bond is inactive; thus, it is very unreactive under SMCC conditions. Of the remaining two Csp 2 -B bonds, one is at the transposition of the aryl group, which can possibly increase the nucleophilicity of the boron atom through electron flow: it reacts more facilely than does the other under Pd(II) SMCC conditions. In the first SMCC reaction, 4-iodobenzotrifluoride was treated under ligand-free conditions, affording 69 in very good yield (with regioselectivity). In the second SMCC arylation, 4-iodoanisole reacted preferentially with Csp 2 -Bpin over Csp 2 -Bdan, affording 70. Since Bdan is unreactive toward SMCC, it was converted into Bpin under acidic conditions with pinacol. In the final sequence of SMCC arylation, 4-iodobenzonitrile was treated with Csp 2 -Bpin to produce the tetra-arylalkene 72. Importantly, during all of the SMCC reactions observed, there was only one stereoisomer with a high yield (Scheme 30B) [47].

Conclusions
In this review, we wished to emphasize the importance of unsymmetrical 1,1-bis(boryl) species as unique building blocks that lead to synthetically new connections. For their preparation, we mainly focused on a few main strategies: 1) the metal-catalyzed conjugate borylation of β-boronylacrylates, the hydroboration of boryl-alkenes, the 1,1-diboration of alkynes, the 1,2-diboration of borylated alkyne, and the borylation of brominated 2,1-borazaronaphthalenes; 2) the metal-free insertion of diazo-compounds into pinB-Bdan, the hydroboration of borylated alkenes, the hydroboration of borylated alkyne, and Piers's borane (which induces cyclopropyl rearrangement and the diboration of alkynes); 3) the late-stage desymmetrization of symmetrical 1,1-bis(boryl)alkanes; and 4) the photolytic synthesis of diboranes. Additionally, transformations of unsymmetrical 1,1-bis(boryl) species were extensively studied in this review. Unsymmetrical 1,1-bis(boryl) species are unique because two boryl groups exhibit different chemical reactivities toward chemoselective SMCC reactions, including sequential cross-coupling reactions with alkyl/aryl halides, chemoselective oxidation, hydrolysis, and transmetallation. We also revealed the rare catalytic activity of 1,1-bis(borane). Due to its potential in the synthesis of unsymmetrical 1,1-bis(boryl)alkenes, this field will continue to grow rapidly, and more appealing transformations are expected to appear in the years to come.
Moreover, these classes of unsymmetrical 1,1-bis(boryl) compounds have the potential to be linked to important materials in the late stages of their synthesis, which then (by applying a variety of selective reaction conditions to unsymmetrical 1,1-bis(boryl) units) leads to multiple different functional groups in order to create new chemical libraries of bioactive compounds, drugs, and natural products that are demonstrative of a large serving of these compounds. Therefore, unsymmetrical 1,1-bis(boryl) and its transformations hold great promise in contributing to diversity-oriented synthesis.
Future approaches to expand the synthetic utility of these unsymmetrical 1,1-bis(boryl) compounds (III and IV) can be carried out by selectively transforming their C-B bonds into C-heteroatom bonds.