molecules

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

K. Naresh Babu †, Fedaa Massarwe †, Reddy Rajasekhar Reddy †, Nadim Eghbarieh , Manuella Jakob and Ahmad Masarwa *

Institute of Chemistry, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Jerusalem 9190401, Israel; [email protected] (K.N.B.); [email protected] (F.M.); [email protected] (R.R.R.); [email protected] (N.E.); [email protected] (M.J.) * Correspondence: [email protected]; Tel.: +972-2-6584881 These authors contributed equally. †


Academic Editor: Renata Riva
 Received: 11 January 2020; Accepted: 18 February 2020; Published: 20 February 2020

Abstract: 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.

Keywords: 1,1-bis(boryl)alkanes and alkenes; bismetallated organic compounds; Suzuki–Miyaura cross-coupling; chemoselective transformations

1. 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 [1–6]. 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 [7–11]. Drugs such as Tavaborole and Bortezomib also incorporate boron functionality [12–14]. 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 (Scheme1)[ 15–20]. Recently, our group [16,17] and other research groups have mainly reviewed the new class of symmetrical 1,1-diboranes, I (bis-metallated reagents) (Scheme1A,C), their preparation, and their application in organic synthesis for forming organoboranes and bifunctionalized products [15–20]. In contrast, the unsymmetrical 1,1-bis(boranes), II, have rarely been reviewed, despite their importance in the chemo- and stereoselective building of C–C and C–X bonds. These classes of compounds mainly include 1,1-bis(boron) (III) and alkenyldiboronates (IV) (Scheme1B). These compounds o ffer 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 [21–26]. Most importantly, 1,1-bis(boryl)alkenes have been utilized in the synthesis of the anticancer agent tamoxifen [27].

Molecules 2020, 25, 959; doi:10.3390/molecules25040959 www.mdpi.com/journal/molecules Molecules 2020, 25, 959 2 of 30 Molecules 2020, 24, x FOR PEER REVIEW 2 of 30

SchemeScheme 1.1. Overview of 1,1-bis(boron) species: their pr preparationeparation and chemoselec chemoselectivetive transformations. ((AA)) PreviousPrevious worksworks ((BB)) ThisThis workwork ((C)) Bismetalated-carbon examplesexamples ((D)) ClassificationClassification ofof gemdiborylgemdiboryl compoundscompounds ((E)) examplesexamples ofof selectiveselective transformationstransformations ofof gemdiborylgemdiboryl compoundscompounds ((F)) OverviewOverview ofof selectedselected examplesexamples of of organoboron organoboron that that covered covered in this in review this review (G) Reactivities (G) Reactivities scale of selectedscale of examples selected ofexamples organoborones of organoborones bonds. bonds.

However,However, unsymmetricalunsymmetrical 1,1-bis(boryl)alkanes1,1-bis(boryl)alkanes (III) and -alkenes (IV) representrepresent aa uniqueunique classclass ofof boronboron compoundscompounds withwith aa tunabletunable reactivityreactivity forfor boronboron site-selectivesite-selective functionalization.functionalization. This review willwill covercover syntheticsynthetic approachesapproaches forfor formingforming unsymmetricalunsymmetrical 1,1-bis(boron) species as well as forfor derivingderiving chemo-chemo- and and stereoselective stereoselective transformations transformations for the for synthesis the synthesis of complex of molecularcomplex structures.molecular Itstructures. is hoped It that is hoped this review that this will review provide will provide useful knowledge useful knowledge for scientists for scientists seeking seeking to discover to discover new thingsnew things about about unsymmetrical unsymmetrical 1,1-bis(boryl)alkanes 1,1-bis(boryl)alkanes and -alkenes and -alkenes in organic in synthesis.organic synthesis. The synthesis The ofsynthesis these unsymmetrical of these unsymmetrical 1,1-bisboryls 1,1-bisboryls includes mainlyincludes the mainly hydroboration the hydroboration of alkynes of andalkynes alkenes. 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

Molecules 2020, 25, 959 3 of 30

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 sp3-centered type-III; and (ii) Unsymmetrical sp2-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 Scheme1F) [ 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 (Scheme1G) 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 Scheme1G) [ 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.

2. 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 (Scheme2A) [ 29]. The obtained enriched unsymmetrical 1,1-bis(boryl) compound (2) was then treated with KHF2, 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 (Scheme2)[ 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-20,40,60-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 (Scheme2B) [29]. Molecules 2020, 25, 959 4 of 30

Molecules 2020, 24, x FOR PEER REVIEW 4 of 30

SchemeScheme 2. 2. (A(A)) PreparationPreparation ofof chiralchiral 1,1-bis(boryl)1,1-bis(boryl) carboxycarboxy estersesters viavia copper-catalyzedcopper-catalyzed conjugate borylation.borylation. ( B(B)) Cross-coupling Cross-coupling reaction reaction ofof enantiomericallyenantiomerically purepure 1,1-bis(boryl)1,1-bis(boryl) carboxy ester ester and and the the transitiontransition state state for for the the transmetallation transmetallation reaction. reaction.

InIn 2015, 2015, this this group group expanded expanded its investigations its investigations into palladium into palladium (Pd(dba) (Pd(dba)2) and the2) and XPhos-catalyzed the XPhos- cross-couplingcatalyzed cross-coupling reactions of reactions optically of enriched optically unsymmetrical enriched unsymmetrical 1,1-bisboron 1,1-bisboron compound compound (6), using aryl(6), bromidesusing aryl in abromides chemo- andin a stereoselective chemo- and stereosele manner forctive the manner synthesis for of the the synthesis benzylic secondaryof the benzylic alkyl boronatessecondary7a –alkylh, which boronates had a stereochemistry7a–h, which had inversion a stereochemistry [31]. They alsoinversion noted [31]. an important They also observation: noted an byimportant increasing observation: the Lewis basicity by increasing of a carbonyl the groupLewis frombasicity an ester of a to carbonyl a Weinreb gr amide,oup from the cross-couplingan ester to a reactionWeinreb was amide, more feasible.the cross-coupling The coordination reaction of thewas carbonyl more feasible. oxygen The with coordination the boron atom, of togetherthe carbonyl with theoxygen stability with of the secondboron atom, boron together unit in the withα-B-Pd(II) the stability intermediate, of the second helped boron to overcome unit in the a di αffi-B-Pd(II)culty at theintermediate, transmetallation helped step. to overcome This reaction a difficulty showed at tolerance the transmetallation to a wide range step. of arylThis coupling reaction partners,showed withtolerance excellent to a chemoselectivity wide range of aryl over coupling the Bdan partne functionalityrs, with excellent (Scheme 3chemoselectivity). over the Bdan functionality (Scheme 3).

Molecules 2020, 25, 959 5 of 30

Molecules 2020, 24, x FOR PEER REVIEW 5 of 30 Molecules 2020, 24, x FOR PEER REVIEW 5 of 30

SchemeScheme 3. Cross-coupling 3. Cross-coupling reaction reaction ofof chiralchiral 1,1- 1,1-bis(boryl)alkanebis(boryl)alkane with with aryl aryl bromides. bromides.

TheseThese enantioenriched enantioenriched cross-coupled cross-coupled products produc weretstssubjected werewere subjectedsubjected to various toto synthetic variousvarious transformations, syntheticsynthetic as presentedtransformations,transformations, in Scheme asas presentedpresented4. The Bdan inin SchemeScheme motif was 4.4. TheThe treated BdanBdan with motifmotif acid, waswas atreatedtreatedffording withwith the acid,acid, hydrolyzed affordingaffording product,thethe whichhydrolyzed further underwent product, which esterification further underwent with pinacol, este yieldingrificationrification compound withwith pinacol,pinacol,8. Next,yieldingyielding8 was compoundcompound converted 8.. into Next, 8 was converted into its corresponding potassium trifluoroboronate salt, 9; finally, it underwent its correspondingNext, 8 was converted potassium into its trifluoroboronate corresponding potassium salt, 9; finally, trifluoroboronate it underwent salt, 9 a; finally, cross-coupling it underwent reaction a cross-coupling reaction with aryl bromide, affording compound 10 (with(with anan inversioninversion inin itsits with arylstereochemistry). bromide, aff ordingThe sequence compound of two10 cross-couplings,(with an inversion from in 6 its to stereochemistry). 10, was followed The by sequencedouble of two cross-couplings,stereochemistry). fromThe 6sequenceto 10, was of followedtwo cross-couplings, by double inversionsfrom 6 to of10 stereochemistry., was followed by Finally, double amide inversionsinversions ofof stereochemistry.stereochemistry. Finally,Finally, amideamide 10 waswas transformedtransformed intointo ketoneketone 11 uponupon aa reactionreaction withwith 10 was transformed into ketone 11 upon a reaction with ethylmagnesium bromide (Scheme4)[31]. ethylmagnesium bromide (Scheme 4) [31].

Scheme 4. Synthetic transformations of chiral unsymmetrical 1,1-bis(borane) compounds. SchemeScheme 4. Synthetic 4. Synthetic transformations transformations ofof chiral un unsymmetricalsymmetrical 1,1-bis(borane) 1,1-bis(borane) compounds. compounds.

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]. Molecules 2020, 24, x FOR PEER REVIEW 6 of 30

Molecules 2020, 25, 959 6 of 30 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 Various alkene alkene substitutions, substitutions, such such as aryl, as aryl, primary, primary, and secondaryand secondary alkyls, alkyls, were were well well tolerated tolerated in this in thisreaction reaction and and provided provided excellent excell regioselectivityent regioselectivity (Scheme (Scheme5). 5).

Scheme 5. Copper-catalyzedCopper-catalyzed enantioselective hydroboration of alkenes. Initially, the reaction mechanism involved the reaction of copper tert-butoxide with 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 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, addition reaction into borylalkene 12, yielding the chiral organocopper intermediate 17. Next, this this intermediate 17 underwent stereoretentive transmetallation with one more equivalents of intermediate 17 underwent stereoretentive transmetallation with one more equivalents of pinacolatoborane, finally yielding the desired product 14 and regenerating the catalyst (LCu-H) pinacolatoborane, finally yielding the desired product 14 and regenerating the catalyst (LCu-H) 16 16 for another catalytic cycle (Scheme5). for another catalytic cycle (Scheme 5). These chiral unsymmetrical 1,1-bis(boryl)alkanes were then transformed into allenylboronate These chiral unsymmetrical 1,1-bis(boryl)alkanes were then transformed into allenylboronate 18 18 in a homologation reaction with 3-chloro-3-methylbut-1-ynyllithium, with almost no erosion in a homologation reaction with 3-chloro-3-methylbut-1-ynyllithium, with almost no erosion of its of its enantioselectivity. Similarly, the Suzuki–Miyaura cross-coupling (SMCC) of 19 afforded the 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 corresponding arylated product 20 in a low yield and with little loss of its enantioselectivity (but with retention of its configuration) (Scheme6)[32]. retention of its configuration) (Scheme 6) [32].

Molecules 2020, 25, 959 7 of 30 MoleculesMolecules 2020 2020, 24, 24, x, x FOR FOR PEER PEER REVIEW REVIEW 7 7of of 30 30

SchemeScheme 6. 6. Synthetic Synthetic transformations transformations of of chiral chiral unsymmetrical unsymmetrical 1,1-bis(boryl)alkanes. 1,1-bis(boryl)alkanes.

InIn 2015, 2015, Fernandez’sFernandez’s Fernandez’s researchresearch research group group group reported reported reported a a transitiona tr transitionansition metal-free metal-free metal-free approach approach approach for for for the the the synthesis synthesis synthesis of unsymmetricalofof unsymmetrical unsymmetrical 1,1-bis(boron) 1,1-bis(boron) 1,1-bis(boron) compounds compounds compounds from from from diazo diazo diazo compounds, compounds, compounds,23 23 23,, which ,which which werewere were obtainedobtained obtained inin in situ situ fromfrom aldehydes aldehydes as as well well as as from from cycliccyclic cyclic andand and noncyclicnoncyclic noncyclic ketones ketones ( 21(21) ) viavia via inin in situ-generatedsitu-generated situ-generated sodium sodium salts salts ofof tosylhydrazones tosylhydrazones followed followed by by treatment treatment with with sodiumso sodiumdium hydride hydride (Scheme (Scheme7 7) )[7) [33]. 33[33].]. This This method method also also providesprovides aa a widewide wide range range range of of unsymmetricalof unsymmetrical unsymmetrical 1,1-bis(borane) 1,1-bis(borane) 1,1-bis(borane) compounds compounds compounds from from from aldehydes aldehydes aldehydes and ketones,and and ketones, ketones, with goodwithwith good isolatedgood isolated isolated yields. yields. yields. However, However, However, it is strictly it it is is strictly strictly limited limited limited to aliphatic to to aliphatic aliphatic carbonyls. carbonyls. carbonyls. InIn their their work, work, they they provided provided a a rationalizedrationalized rationalized mechanismme mechanismchanism for for this this method method viavia transition transition statestate 26 26 (based(based(based on onon DFT-Density DFT-DensityDFT-Density Functional FunctionalFunctional Theory TheoryTheory calculations). calculations).calculations). The reaction TheThe reactionreaction involved involvedinvolved the heterolytic thethe heterolyticheterolytic cleavage ofcleavagecleavage the mixed of of the the diboron mixed mixed diboron reagentdiboron 25reagent reagentand the25 25 and formationand the the formation formation of geminal of of geminal geminal C–Bpin C–Bpin C–Bpin and C–Bdan and and C–Bdan C–Bdan bonds bonds bonds via a concerted–asynchronousviavia a a concerted–asynchronous concerted–asynchronous mechanism, mechanism, mechanism, as shown as as shown shown in Scheme in in Scheme Scheme7. 7. 7.

SchemeScheme 7. 7. Metal-free Metal-free insertion insertion of of diazo diazo compounds compounds into into pinB–Bdan. pinB–Bdan. Scheme 7. Metal-free insertion of diazo compounds into pinB–Bdan. ToTo exploreexplore thethe diastereoselectivediastereoselective 1,1-dibora1,1-diborationtion ofof diazodiazo compounds,compounds, Fernandez’sFernandez’s groupgroup To explore the diastereoselective 1,1-diboration of diazo compounds, Fernandez’s group substitutedsubstituted cyclohexanones cyclohexanones for for in in situ-formed situ-formed diazo-compound diazo-compoundss and and promoted promoted insertion insertion into into the the substituted cyclohexanones for in situ-formed diazo-compounds and promoted insertion into the pinB–BdanpinB–Bdan bond bond (Scheme (Scheme 8) 8) [33]. [33]. When When they they carried carried out out a a reaction reaction with with 4-substituted 4-substituted cyclohexanones cyclohexanones (28a(28a) )under under optimized optimized reaction reaction conditions, conditions, they they observed observed reasonable reasonable diastereo-selectivity. diastereo-selectivity. An An X-ray X-ray analysisanalysis of of 29a 29a showed showed that that the the Bdan Bdan and and CF CF3 3groups groups were were situated situated at at the the 1,4-diequitorial 1,4-diequitorial (trans) (trans)

Molecules 2020, 25, 959 8 of 30 pinB–Bdan bond (Scheme8)[ 33]. When they carried out a reaction with 4-substituted cyclohexanones (28a) under optimized reaction conditions, they observed reasonable diastereo-selectivity. An X-ray Molecules 2020, 24, x FOR PEER REVIEW 8 of 30 analysis of 29a showed that the Bdan and CF3 groups were situated at the 1,4-diequitorial (trans) positions, as shown in Scheme8 8.. UnderUnder optimizedoptimized conditions,conditions, thethe 3-Ph-cyclohexanone3-Ph-cyclohexanone 28b affordedafforded the 1,3-diequitorial 1,3-diequitorial (cis)-substituted (cis)-substituted isomer isomer as asthethe major major diastereomer diastereomer 29f (64%).29f (64%). Interestingly, Interestingly, under undera similar a similar reaction reaction condition, condition, the the2-Me-cyclohexanone 2-Me-cyclohexanone 31 31affordedafforded excellent excellent diastereo-selectivity diastereo-selectivity (32a/32b32b)),, favoringfavoring thethe BdanBdan andand MeMe groupsgroups withwith aa 1,2-diequitorial1,2-diequitorial (trans)(trans) configuration.configuration. This high diastereo-selectivity was expected because the 2-position2-position substituent can directly influenceinfluence the reaction center.

Scheme 8. Diastereoselective unsymmet unsymmetricalrical 1,1-diboration of substitutedsubstituted cyclohexanones.

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

Molecules 2020, 25, 959 9 of 30

The origin of diastereo-selectivity was explained through DFT analysis by taking the example of the 4-(trifluoromethyl)cyclohexanone 28a, as shown in Scheme9. 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: theMolecules equatorial 2020, 24 conformer, x FOR PEER (REVIEW28aNeq ) was 1.7 kcal/mol lower than the axial conformer (28aNax9 ).of Each30 confirmation could attack the pinB–Bdan substrate through its two diastereo-faces. When the conformer 28aNeq(28aNaxattacked). Each confirmation pinB–Bdan through could attack its two the diastereomeric pinB–Bdan substrate faces, the through observed its two computed diastereo-faces. free energy barriersWhen the for conformer the Bdan equatorial28aNeq attacked and Bdan pinB–Bdan axial positions through its were two 33.9diastereomeric and 38.9 kcal faces,/mol, the respectivelyobserved computed free energy barriers for the Bdan equatorial and Bdan axial positions were 33.9 and 38.9 (Scheme9, left side). Thus, the lowest energy path led to a major diastereomer with Bdan and a CF 3 substituentkcal/mol, respectively in the 1,4-diequitorial (Scheme 9, (trans) left side). of eachThus,29a the. Thelowest high energy energy path (~5.0 led kcalto a/ majormol) in diastereomer the Bdan axial approachwith Bdan was and due a CF to3 destabilized substituent in interactions the 1,4-diequitorial between (trans) 1,3-diaxial of each and 29a cyclohexane.. The high energy Similarly, (~5.0the kcal/mol) in the Bdan axial approach was due to destabilized interactions between 1,3-diaxial and conformer 28aNax also exhibited a low energy barrier in the case of the Bdan equatorial approach, cyclohexane. Similarly, the conformer 28aNax also exhibited a low energy barrier in the case of the as opposed to the Bdan axial approach (Scheme9, right side). 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 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 conformers (28aNeq and 28aNax), with the expected non-negligible formation of conformer 30a with anan observed observed diastereomeric diastereomericratio ratio ofof 7070/30/30 for 29a/30a [33].[33].

Scheme 9. Proposed diastereo-isomeric pathways for the 1,1-bisboration of 4-CF3-cyclohexanone with pinB–BdanScheme 9. andProposed the relative diastereo-isomeric Gibbs free energies pathways in for kcal the/mol. 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] precatalyzedInterestingly, the hydroboration 1,1-bis(boryl)alkanes of terminal can be andhave internalas catalysts, alkynes too. forPiers’s the borane synthesis V [HB(C of E-alkenyl6H5)2] pinacolprecatalyzed boronic the ester hydroboration36, and excellent of terminal selectivities and internal were alkynes reported for the synthesis by Stephan of E and-alkenyl coworkers pinacol in 2016boronic [34]. ester In this 36, and hydroboration, excellent selectivities they found were that reported unsymmetrical by Stephan 1,1-bis(borane)and coworkers in34 2016catalyzed [34]. In the this hydroboration, they found that unsymmetrical 1,1-bis(borane) 34 catalyzed the reaction. An reaction. An independent reaction of Piers borane V [HB(C6H5)2] with phenylacetylene afforded independent reaction of Piers borane V [HB(C6H5)2] with phenylacetylene afforded the the corresponding E-alkenyl boronic ester 33a, which, upon additional treatment with pinacol corresponding E-alkenyl boronic ester 33a, which, upon additional treatment with pinacol boranes, boranes, yielded the regioselective stereogenic unsymmetrical 1,1-bis(borane) 34 (Scheme 10). Actually, yielded the regioselective stereogenic unsymmetrical 1,1-bis(borane) 34 (Scheme 10). Actually, 1,1- 1,1-bis(borane) 34 acted as an electrophilic catalyst for the hydroboration of alkyne into alkene in the bis(borane) 34 acted as an electrophilic catalyst for the hydroboration of alkyne into alkene in the 34 presencepresence of of HBpin HBpin (pinacolborane). (pinacolborane). To supportTo support this, this, the electrophilicthe electrophilic boron boron center center of was of 34 confirmed was throughconfirmed an X-ray through diff anraction X-ray analysisdiffraction of theanalysistert-butylisonitrile of the tert-butylisonitrile adduct 35 adduct. 35. TheThe proposed proposed mechanism mechanism forfor the unsymmetrical 1,1-bis(borane) 1,1-bis(borane) 3434 catalyzingcatalyzing the the hydroboration hydroboration ofof alkynes alkynes for for the the synthesis synthesis ofof EE-alkenyl-alkenyl boronic ester ester 3636 isis shown shown in in Scheme Scheme 10. 10 In. Inthis this mechanism, mechanism, unsymmetricalunsymmetrical 1,1-bisboranes 1,1-bisboranes34 34acts acts asas a Lewis acid acid catalyst, catalyst, which which activates activates alkyne alkyne to toform form complex complex VIVI: then,: then, HBpin HBpin reacts reacts with with complex complexVI VIin in a a concerted concertedsyn syn-1,2-hydroboration-1,2-hydroboration manner (complex VIIVII)) to afftoord afford the hydroborylatedthe hydroborylated product product36 and36 and regenerate regenerate the the unsymmetrical unsymmetrical 1,1-bis(borane) 1,1-bis(borane)34 34 [[34].34].

Molecules 2020, 25, 959 10 of 30 Molecules 2020, 24, x FOR PEER REVIEW 10 of 30

O O B O B(C6F5)2 B H O O 33b B H R B(C6F5)2 R R H R 36 HB(C6F2)2 O V B O H R CH Cl (0.2 M) pentane O 2 2 CH2Cl2 34 5h,RT B(C F ) B(C F ) 25 °C, 1 h 6 5 2 5h,RT 6 5 2 86-92% quantitative R B O R 33a t CDCl3 CN Bu O 90-94% rt 34 t BuNC regenerated R=Ph.p-CF3C6H4 B(C6F5)2

Ph B O O 35

O Proposed mechanism: H B O Ph H Ph 36 H B(C6F5)2 37

Ph B O O 34 product alkyne release coordination H O Ph B O H B(C6F5)2 H Ph Ph B B(C F ) OO Ph 6 5 2 B OO VI concerted hydroboration VII

O B H O

Scheme 10. Unsymmetrical 1,1-bis(borane) catalyzing the hydroboration ofof alkyne.alkyne.

InIn 2019,2019, SharmaSharma researchresearch groupgroup reportedreported aa novelnovel andand conciseconcise methodmethod forfor thethe synthesissynthesis ofof aa widewide rangerange ofof MIDAMIDA (MIDA(MIDA == NN-methyliminodiacetic-methyliminodiacetic acid) acylboronates (41) viavia thethe chemoselectivechemoselective oxidation of 1,1-bisboranes (39)) (Scheme(Scheme 1112))[ [35].35]. MIDA acylboronates are synthetically challenging; however, theythey cancan bebe utilizedutilized asas powerfulpowerful buildingbuilding blocksblocks forfor bioorthogonalbioorthogonal amideamide formationformation andand proteinprotein ligation.ligation. First, SharmaSharma prepared prepared unsymmetrical unsymmetr 1,1-bis(borane)ical 1,1-bis(bora productsne) products (39) from (39 symmetrical) from symmetrical diboranes (diboranes38) by heating (38) MIDAby heating and triethylorthoformateMIDA and triethylorthoformate (Scheme 11). (Scheme The mechanism 11). The underlying mechanism this underlying selective desymmetrizationthis selective desymmetrization is still unclear. is still However, unclear. steric However, considerations steric considerations could be among could the be reasonsamong the for thisreasons selectivity. for this selectivity.

Molecules 2020, 25, 959 11 of 30 MoleculesMolecules 20202020,,, 2424,,, xxx FORFORFOR PEERPEERPEER REVIEWREVIEWREVIEW 1111 ofof 3030

SchemeScheme 11. 11. SynthesisSynthesis ofof unsymmetricalunsymmetrical 1,1-bis(borane)1,1-bis(borane) products. products.

Next,Next, Sharma Sharma chemoselectivelychemoselectively oxidized oxidizedoxidized pinacolate pinacolapinacolatete boran boranboran functionality functionalityfunctionality over overover the thethe MIDA MIDAMIDA boronate boronateboronate of α ofunsymmetricalof unsymmetricalunsymmetrical 1,1-bis(borane) 1,1-bis(borane)1,1-bis(borane) products productsproducts (39a–b ((39a-b39a-b) to)) obtain toto obtainobtain-hydroxymethyl αα-hydroxymethyl-hydroxymethyl MIDA MIDAMIDA boronates boronatesboronates (40) with ((4040)) α withgoodwith good yieldsgood yieldsyields (Scheme (Scheme(Scheme 12). Thereafter, 12).12). Thereafter,Thereafter, these -hydroxymethyl thesethese αα-hydroxymethyl-hydroxymethyl MIDA boronates MIDAMIDA (boronates40boronates) were successfully ((4040)) werewere successfullyoxidizedsuccessfully into oxidizedoxidized MIDA acylboronates intointo MIDAMIDA (acylboronatesacylboronates41) using Dess–Martin ((4141)) usingusing periodinane Dess–MartinDess–Martin (DMP), periodinaneperiodinane with moderate (DMP),(DMP), to goodwithwith moderateyieldsmoderate (Scheme toto goodgood 12 ). yieldsyields (Scheme(Scheme 12).12).

SchemeScheme 12.12. SynthesisSynthesisSynthesis ofof of NN-methyliminodiacetic-methyliminodiacetic acidacid acid (MIDA)(MIDA) acylboranates acylboranates via via chemoselectivechemoselective oxidation.oxidation.

Then,Then, Sharma Sharma successfully successfully appliedapplied aa similar similar strategy strategy forfor the the synthesis synthesis ofof unique unique αα,,, ββ-unsaturated-unsaturated-unsaturated MIDAMIDA acyl acyl boronates boronates ( (4444)) with with an an acceptable acceptable yieldyield (Scheme(Scheme 1313).13).).

SchemeScheme 13. 13. SynthesisSynthesis ofof MIDAMIDA acylboranatesacylboranates via via chemoselective chemoselective oxidation. oxidation.

Molecules 2020, 25, 959 12 of 30 MoleculesMolecules 2020 2020, ,24 24,, x x FOR FOR PEER PEER REVIEW REVIEW 1212 of of 30 30

Additionally,Additionally, SharmaSharma appliedapplied thethe samesame strategystrastrategytegy toto thethe unsymmetricalunsymmetricalunsymmetrical diborylmethanediborylmethane 39c39c toto obtainobtain hydroxymethylhydroxymethyl MIDAMIDA 4545.. Interestingly, Interestingly,Interestingly, thethe DMPDMP oxidation oxidation of ofof hydroxymethyl hydroxymethylhydroxymethyl MIDA MIDAMIDA afforded aaffordedfforded acetoxyacetoxy MIDAMIDA boronateboronate 46 46 instead insteadinstead ofofof formylformylformyl MIDA MIDAMIDA boronate boronateboronate (Scheme (Scheme(Scheme 14 14)14))[ [35].35[35].].

Scheme 14. Synthesis of hydroxymethyl MIDA boronates. SchemeScheme 14.14. SynthesisSynthesis ofof hydroxymethylhydroxymethyl MIDAMIDA boronates.boronates. InIn thethe samesame year,year, thethe MasarwaMasarwa researchresearch groupgroup reportedreported aa late-stagelate-stage desymmetrizationdesymmetrization ofof symmetricalsymmetricalIn the same 1,1-bis(boryl)alkanes1,1-bis(boryl)alkanes year, the Masarwa viavia nucleophilicnucleophilic research group trifluorinationtrifluorination reported awhilewhile late-stage constructingconstructing desymmetrization unsymmetricalunsymmetrical of symmetrical1,1-bis(boryl)alkanes1,1-bis(boryl)alkanes 1,1-bis(boryl)alkanes bearingbearing trifluoroboratetrifluoroborate via nucleophilic saltssalts (Scheme(Scheme trifluorination 15)15) [36].[36]. while ThisThis method constructingmethod waswas tolerabletolerable unsymmetrical withinwithin 1,1-bis(boryl)alkanesaa widewide rangerange ofof substratesubstrate bearing scopes,scopes, trifluoroborate withwith goodgood salts toto exceexce (Schemellentllent yields. yields.15)[36 Most].Most This interestingly,interestingly, method was this tolerablethis methodmethod within diddid anotnot wide needneed range anyany of columncolumn substrate purification,purification, scopes, with asas goodthethe producproduc to excellenttt waswas yields.obtainedobtained Most uponupon interestingly, crystallization.crystallization. this method OurOur groupgroup did notproposedproposed need anyaa mechanismmechanism column purification, toto accountaccount as forfor the thisthis product desymmetrizationdesymmetrization was obtained methodology: uponmethodology: crystallization. First,First, nucleophilicnucleophilic Our group proposedfluoridefluoride attacksattacks a mechanism thethe vacantvacant to account pp-orbital-orbital for ofof this oneone desymmetrization ofof thethe boronboron centerscenters methodology: inin thethe symmetricalsymmetrical First, nucleophilic diboranediborane fluoride 3838 andand p attacksgeneratesgenerates the monofluorinatedmonofluorinated vacant -orbital of compoundcompound one of the boronII (step(step centers 1),1), whwh inichich the isis symmetrical moremore electrophilicelectrophilic diborane thanthan 38 and thethe generates parentalparental monofluorinatedsymmetricalsymmetrical diboranediborane compound 38.38. Hence,Hence, I (step itit 1), forcesforces which thethe is second moresecond electrophilic fluorinationfluorination than (step(step the 2)2) parental andand thenthen symmetrical thethe thirdthird diborane 38. Hence, it forces the second fluorination (step 2) and then the third fluorination (step 3) fluorinationfluorination (step(step 3)3) atat thethe boronboron centercenter shownshown inin SchemeScheme 15.15. Consequently,Consequently, thethe newlynewly generatedgenerated BFBF33 atmoietymoiety the boron developsdevelops center aa partialpartial shown negativenegative in Scheme chargecharge 15. Consequently, onon thethe flfluoride,uoride, the andand newly thethe fluoridefluoride generated maymay BF stabilizestabilize3 moiety thethe develops flankingflanking a partialBpinBpin groupgroup negative throughthrough charge aa onfluoridefluoride the fluoride, bridge,bridge, and asas shownshown the fluoride inin 4747′ may′,, whichwhich stabilize helpshelpsthe toto prevent flankingprevent a Bpina subsequentsubsequent group through attackattack abyby fluoride fluoride.fluoride. bridge, as shown in 470, which helps to prevent a subsequent attack by fluoride.

SchemeScheme 15.15. DesymmetrizationDesymmetrization viavia nucleophilicnucleophilic trifluortrifluorinationtrifluorinationination andand thethe proposedproposed mechanism.mechanism.

Molecules 2020, 25, 959 13 of 30 Molecules 2020, 24, x FOR PEER REVIEW 13 of 30

Interestingly,thisInterestingly, this method method exhibited exhibited excellent excellent diastereo-selectivity diastereo-selectivity when the when reaction the wasreaction performed was onperformed the 1,1-bis(boryl)substituted on the 1,1-bis(boryl)substituted cyclopropanes cyclopropanes38a–c (Scheme 38a–c 16). (Scheme This diastereo-selectivity 16). This diastereo- has beenselectivity confirmed has been using confirmed 2D-NMR using spectroscopic 2D-NMR spectroscopic methods. From methods. these From results, these it canresults, beseen it can that be theseen diastereo-selectivity that the diastereo-selectivity mechanism mechanism underlying underlying the reaction the involves reaction the involves selective the nucleophilic selective trifluorinationnucleophilic trifluorination of boron, which of boron, occupies which the lessoccupies hindered the less side hindered of cyclopropane. side of cyclopropane.

3 1 O MF B R R 3 1 3 B R R MF (4 equiv) O 2 AMS (2.05 equiv) O B R 4 O B R2 O R MF = KF, CsF, TBAF 4 MeOH, CH3CN O R AMS = L-tartaric acid, citric acid H2O, 25 °C, 5 min 47e-g 38a-c

Selected examples: favored

KF B KF3B F 3 KF3B O R R O s s B O B NBoc B MF3B O O B MF O O Ph O O B O B O RL O RL 47g, 94% 47e, 85% 47f, 90% dr = 99:0.1 X dr = 99:0.1 dr = 99:0.1

F less favored

Scheme 16. Diastereoselective desymmetrization of cyclop cyclopropanesropanes via nucleophilic trifluorination.trifluorination.

These unsymmetrical 1,1-bis(boryl)alkanes, bearin bearingg a a trifluoroborate trifluoroborate group, were utilized for various selective functionalizations. For example, the simple hydrolysis of the trifluoroborate trifluoroborate group aaffordedfforded thethe 1,1-bis(borane) 1,1-bis(borane) products products48a–c 48a–c, which, which has a boronic has a acidboronic moiety acid (Scheme moiety 17 A).(Scheme Additionally, 17A). compoundAdditionally,47 compoundtreated with 47 diamines treated with and diolsdiamines as coupling and diols partners, as coupling yielded partners, the unsymmetrical yielded the 1,1-bis(borane)unsymmetrical products1,1-bis(borane)49a–c (Schemeproducts 17 49a–cB). (Scheme 17B).

Molecules 2020, 25, 959 14 of 30 Molecules 2020, 24, x FOR PEER REVIEW 14 of 30

Scheme 17. Synthetic transformation of trifluoroborane salt 47 into (A) boronic acid 48;(B) Scheme 17. Synthetic transformation of trifluoroborane salt 47 into (A) boronic acid 48; (B) unsymmetrical 1,1-bis(borane) product 49. unsymmetrical 1,1-bis(borane) product 49. Finally, trifluoroborylated unsymmetrical 1,1-bis(boryl)alkanes were also utilized for Finally, trifluoroborylated unsymmetrical 1,1-bis(boryl)alkanes were also utilized for cross- cross-coupling reactions. Intermolecular palladium(II) catalyzed a cross-coupling reaction with coupling reactions. Intermolecular palladium(II) catalyzed a cross-coupling reaction with aryl aryl bromide, which afforded arylated product 50a, which had excellent yield (Scheme 18A). Similarly, bromide, which afforded arylated product 50a, which had excellent yield (Scheme 18A). Similarly, an intramolecular cross-coupling reaction of 2-bromo-substituted phenyl substrates under the same an intramolecular cross-coupling reaction of 2-bromo-substituted phenyl substrates under the same reaction conditions yielded the cyclic product 50b, with a 90% yield (Scheme 18B) [36]. reaction conditions yielded the cyclic product 50b, with a 90% yield (Scheme 18B) [36].

Molecules 2020, 25, 959 15 of 30

Molecules 2020, 24, x FOR PEER REVIEW 15 of 30

Molecules 2020, 24, x FOR PEER REVIEW 15 of 30

SchemeScheme 18. (18.A) ( IntermolecularA) Intermolecular Suzuki–Miyaura Suzuki–Miyaura cross-coupling cross-coupling (SMCC); (SMCC); (B) (intramolecularB) intramolecular SMCC. SMCC.

In 2017,InScheme 2017, Erker 18.Erker (A and) Intermolecular and coworkers coworkers Suzuki–Miyau reportedreported rathat cross-coupling Lewis Lewis acid acid (SMCC); induced induced (B) intramoleculara cyclopropyl a cyclopropyl SMCC. acetylene acetylene rearrangementrearrangement for for the the synthesis synthesis of of unsymmetrical unsymmetrical 1,1-bis(borane) [37]. [37 ].In this In thissynthesis, synthesis, when when cyclopropylIn 2017, acetylene Erker and 51 was coworkers treated withreported two equivalents that Lewis of acid Piers’s induced borane aV cyclopropyl[HB(C6F5)2], itacetylene resulted cyclopropyl acetylene 51 was treated with two equivalents of Piers’s borane V [HB(C6F5)2], it resulted in inrearrangement the formation for of substitutedthe synthesis α-boryl-tetrahydroborole of unsymmetrical 1,1-bis(borane) 53a-cis and 53b [37].-trans In inthis a 7:1synthesis, ratio (Scheme when the formation of substituted α-boryl-tetrahydroborole 53a-cis and 53b-trans in a 7:1 ratio (Scheme 19A): 19A):cyclopropyl this was acetylene confirmed 51 was by in treated situ NMR with twospectros equivalentscopic studies. of Piers’s Furthermore, borane V [HB(C they confirmed6F5)2], it resulted these this wasstructuresin the confirmed formation using by ofX-ray insubstituted situ diffraction NMR α-boryl-tetrahydroborole spectroscopic and found that studies. the pair Furthermore,53a of-cis substituents and 53b they-trans at C1 confirmed in and a 7:1 C4 ratio (in these terms(Scheme structures of usingstereochemistry)19A): X-ray this di ffwasraction confirmed differed and found structurallyby in thatsitu theNMR from pair spectros the of cis substituents andcopic trans studies. isomers. at C1 Furthermore, and C4 (in termsthey confirmed of stereochemistry) these differedstructures structurallyThe mechanism using X-ray from underlying diffraction the cis and this andtrans reaction foundisomers. thatinvolves the pair the ofsequential substituents hydroboration at C1 and C4of cyclopropyl(in terms of acetyleneThestereochemistry) mechanism 51 with differed 2.0 underlying eq. ofstructurally Piers’s this borane reaction from Vthe, affording involves cis and trans 1,1-bis(boryl) the isomers. sequential compound hydroboration VIII. Then, of cyclopropyl one of acetylenethe frustratingThe51 withmechanism borons 2.0 eq. underlying of of product Piers’s VIIIthis borane reactionacts asV ,a ainvolvesLewisffording acid the1,1-bis(boryl) and sequential induces cyclopropylhydroboration compound ring-opening ofVIII cyclopropyl. Then, and one of acetylene 51 with 2.0 eq. of Piers’s borane V, affording 1,1-bis(boryl) compound VIII. Then, one of the frustratingthe hydride borons sequence. of productThen, arylVIII 1,2 actsshifts as to a form Lewis borole acid 53 and (Scheme induces 19B). cyclopropyl The stereochemical ring-opening the frustrating borons of product VIII acts as a Lewis acid and induces cyclopropyl ring-opening and and theoutcome hydride of the sequence. reaction largely Then, depends aryl 1,2 on shifts the least to formsterically borole hindered53 (Scheme pathway, 19 leadingB). The to stereochemical the major diastereomerthe hydride sequence.cis-borole. Then, aryl 1,2 shifts to form borole 53 (Scheme 19B). The stereochemical outcomeoutcome of the of the reaction reaction largely largely depends depends on on thethe least sterically sterically hindered hindered pathway, pathway, leading leading to the to major the major diastereomerdiastereomercis-borole. cis-borole.

Scheme 19. (A) Formation and (B) rearrangement of tetrahydroboroles.

SchemeScheme 19. 19.(A ()A Formation) Formation andand (B) rearrangement rearrangement of oftetrahydroboroles. 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 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 Molecules 2020, 24, x FOR PEER REVIEW 16 of 30 Moleculescis-borole2020 compound, 25, 959 and tri-tert-butylphosphine (as a Lewis base with 2.0 bar of hydrogen in pentane16 of 30 solution) Theresulted cyclic in1,1-bis(boryl) the precipitation contains oftwo product Lewis acid cisic-54a boron. Similarly, sites: they upon can coordinatetreatment only with as carbon a cisdioxide-borolefrustrated instead compound Lewis of hydrogen, pair and (FLP) tri-tert aor new-butylphosphine can servesix-membered as a dihydr (as ogencyclic a Lewis splitting ring base was reagent. with formed, 2.0 Treatment bar in of addition hydrogen of a 1:1 to ratio inthe pentane ofborole cis-borole compound and tri-tert-butylphosphine (as a Lewis base with 2.0 bar of hydrogen in pentane solution)ring cis-54b resulted (Scheme in the 20). precipitation of product cis-54a. Similarly, upon treatment with carbon dioxide solution) resulted in the precipitation of product cis-54a. Similarly, upon treatment with carbon insteaddioxide of hydrogen, instead of a hydrogen, new six-membered a new six-membered cyclic ring cyclic was formed,ring was informed, addition in addition to the borole to the ringborolecis -54b (C6F5)2 (Scheme 20). t ring cis-54b (Scheme 20). Bu3P H B H tBu PH H2 (2.0 bar) 3 (C6BF5)C2 F t 6 5 overnight,Bu3P RT H B H tBu PH H2 (2.0 bar) 3 H C6F5 B C6F5 H B(C6F5)2 overnight, RT 54a, 71% H C6F5 B C F H B(C66F55)2 54a, 71%

H C FB C6F5 6 5 (C6F5)2 53a B H C F O 6 5 tBu P H (C6F5)2 (rac)53a cis 3 B PtBu O 3 CO2t (2.0 bar) H (rac) cis Bu3P B O PtBu C F 3 overnight,CO2 (2.0 bar) RT B O 6 5 H overnight, RT CC66FF5 H C6F5 54b, 73% 54b, 73% Scheme 20. Frustrated Lewis pair (FLP) reaction of unsymmetrical 1,1-bisboroles. SchemeScheme 20.20. Frustrated Lewis Lewis pair pair (FLP) (FLP) reaction reaction of unsymmetrical of unsymmetrical 1,1-bisboroles. 1,1-bisboroles. Interestingly, Erker and coworkers interconverted cis-borole 53a into trans-isomer 53b by Interestingly, Erker and coworkers interconverted cis-borole 53a into trans-isomer 53b by treatingInterestingly, it with a Erkercatalytic and amount coworkers of TEMPO interconverted (2,2,6,6-tetramethylpiperidinecis-borole 53a into trans-isomer 1-oxyl).53b Thisby reaction treating it withtreating a catalytic it with amount a catalytic of TEMPOamount of (2,2,6,6-tetramethylpiperidine TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl). 1-oxyl). This reactionThis reaction followed followed reversible H-abstraction at the activated C1 position of the heterocycle. After they subjected followed reversible H-abstraction at the activated C1 position of the heterocycle. After they subjected reversible H-abstraction at the activated C1 position of the heterocycle. After they subjected trans-borole trans-boroletrans-borole to a to similar a similar FLP FLP reacti reaction,on, they they obtainedobtained productsproducts 54c 54c and and 54d 54d in goodin good yields yields (Scheme (Scheme to a similar FLP reaction, they obtained products 54c and 54d in good yields (Scheme 21)[37]. 21). [37].21). [37].

Scheme 21. Interconversion of cis-borolone into trans-borole and its FLP reactions. In the same year, Erker and coworkers reported that cyclic 1,1-bis(borane) 53 catalyzed the Scheme 21. Interconversion of cis-borolone into trans-borole and its FLP reactions. hydroborationScheme of 21.N-methylindole.Interconversion Here, of cis -borolone1,1-bis(borane) into trans compounds-borole and were its FLP utilized reactions. as effective Incatalysts the same for C–Hyear, bond Erker activating and coworkers the borylation reported of N that-methylindole cyclic 1,1-bis(borane) with catechol 53borane. catalyzed This the hydroborationreaction afforded of N -methylindole.3-boryl-N-methylindole Here, with1,1-bis(borane) a 59% yield andcompounds N-methylindoline were withutilized a Lewis as paireffective 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

Molecules 2020, 25, 959 17 of 30

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 forMolecules C–H bond2020, 24 activating, x FOR PEER the REVIEW borylation of N-methylindole with catechol borane. This reaction17 a offf orded30 3-boryl-N-methylindole with a 59% yield and N-methylindoline with a Lewis pair adduct (with adduct (with HBcat). Furthermore, this adduct, upon treatment with the same catalyst for several HBcat). Furthermore, this adduct, upon treatment with the same catalyst for several hours, yielded a hours, yielded a 5-boryl-N-methylindoline product through the evolution of molecular hydrogen 5-boryl-(SchemeN -methylindoline22) [38]. product through the evolution of molecular hydrogen (Scheme 22)[38].

Scheme 22. 1,1-bis(borane)-catalyzed borylation of N-methylindole. Scheme 22. 1,1-bis(borane)-catalyzed borylation of N-methylindole.

2 3.3. Unsymmetrical Unsymmetrical sp2-Centered-Centered 1,1-bis(boron) 1,1-bis(boron) Compounds: Compounds: Synthesis Synthesis and and Applications Applications In 2007, Chirik and coworkers developed a cobalt that catalyzed the 1,1-diboration of readily In 2007, Chirik and coworkers developed a cobalt that catalyzed the 1,1-diboration of readily available terminal alkyne 58 with an unsymmetrical (pinB–Bdan) diboron reagent for the synthesis available terminal alkyne 58 with an unsymmetrical (pinB–Bdan) diboron reagent for the synthesis of of stereoselective trisubstituted 1,1-bis(boryl)alkenes (59a–d), with good yields (Scheme 23) [39]. stereoselective trisubstituted 1,1-bis(boryl)alkenes (59a–d), with good yields (Scheme 23)[39]. The mechanism proposed by Chirik’s group involved the initial formation of cobalt acetylide 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 (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 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 complexstereoselective (XII) underwent alkene 59. syn-borylcobaltation, selectively affording XIII, which finally produced the stereoselective alkene 59.

Molecules 2020, 25, 959 18 of 30 Molecules 2020, 24, x FOR PEER REVIEW 18 of 30

Scheme 23. Cobalt-catalyzed stereoselective 1,1-diboration of terminal alkynes with pinB–Bdan.

Taking advantage of the different chemical reactivities of two boron moieties (Bpin, Bdan) Scheme 23. Cobalt-catalyzed stereoselective 1,1-diboration of terminal alkynes with pinB–Bdan. in 1,1-unsymmetrical bis(boryl)alkenes (59), an SMCC reaction was carried out with aryl iodides to affTakingord corresponding advantage of the (Z)-alkenes different chemical (60), which reactivities had an of extended two boron conjugation moieties (Bpin, and Bdan) good in yields. 1,1- unsymmetricalInterestingly, they bis(boryl)alkenes observed that the (59 cross-coupling), an SMCC reaction took place was selectivelycarried out at with the Bpin aryl moietyiodides over to afford Bdan corresponding (Z)-alkenes (60), which had an extended conjugation and good yields. Interestingly, they observed that the cross-coupling took place selectively at the Bpin moiety over Bdan (Scheme

Molecules 2020,, 2524,, 959x FOR PEER REVIEW 19 of 30 Molecules 2020, 24, x FOR PEER REVIEW 19 of 30 24) [39]. The whole methodology, which includes the 1,1-diboration of alkynes (Scheme 23) and the (Scheme 24)[39]. The whole methodology, which includes the 1,1-diboration of alkynes (Scheme 23) cross-coupling24) [39]. The whole reaction methodology, of 1,1-unsymmetrical which includes bis(boryl)alkenes the 1,1-diboration (Scheme of alkynes 24), represents (Scheme a 23)formal and 1,1-the and the cross-coupling reaction of 1,1-unsymmetrical bis(boryl)alkenes (Scheme 24), represents a carboborationcross-coupling of reaction hept-1-y ofne 1,1-unsymmetrical with Ar–Bdan [40–42]. bis(boryl)alkenes (Scheme 24), represents a formal 1,1- formalcarboboration 1,1-carboboration of hept-1-y ofne hept-1-ynewith Ar–Bdan with [40–42]. Ar–Bdan [40–42]. OMe I OMe I (1 equiv) MeO (1 equiv) O O H B MeO t O O H Pd[P( Bu3)]2 (10 mol%) C5H11 NH Me B N Pd[P(tBu )] (10 mol%) C H B N B H aq. KOH3 2 (3 equiv) 5 11 B Me N aq. KOH (3 equiv) HN HNB THF HN 59a 60 78% HN 23 THFC, 8 h , 59a 60, 78% 23 C, 8 h

Scheme 24. Selective Suzuki–Miyaura cross-coupling at Bpin. Scheme 24. Selective Suzuki–Miyaura cross-coupling at Bpin. In 2018, the Molander group reported the borylation of 3-bromo-2,1-borazaronaphthalenes (61) with Inboronic 2018, the acid Molander pinacol group esters, reported affording the borylationbory lation3-boryl-2,1-borazaronaphthalene of 3-bromo-2,1-borazaronaphthalenes 62a–f (1,1-( 61) withunsymmetrical boronicboronic acid bis(boryl)alkenes)acid pinacol pinacol esters, aesters,ff [4ording3]. These affording 3-boryl-2,1-borazaronaphthalene borazaronaphthalenes 3-boryl-2,1-borazaronaphthalene (62) also62a–f exhibited(1,1-unsymmetrical an62a–f umpolung (1,1- bis(boryl)alkenes)characterunsymmetrical in cross-coupling bis(boryl)alkenes) [43]. These reactions. borazaronaphthalenes [43]. TheseThis methodborazaronaphthalenes allows (62) also for exhibited the ( 62synthesis) also an umpolungexhibited of a wide an character umpolung range inof cross-couplingheterocyclescharacter in withcross-coupling reactions. different This substituents reactions. method allowsThisat the method boro for then center, synthesisallows with for of electron-richthe a wide synthesis range and ofof electron-poor heterocyclesa wide range with aryl of diandheterocyclesfferent heteroaryl substituents with groups different at and the boron upsubstituents to center,an 83% withat yield the electron-rich boro(Schemen center, 25A). and with Next, electron-poor electron-rich compound aryl and62 and was electron-poor heteroaryl converted groups intoaryl and up to an 83% yield (Scheme 25A). Next, compound 62 was converted into organotrifluroborate organotrifluroborateand heteroaryl groups salt and (63 up) by to treating an 83% yieldit with (Scheme commercially 25A). Next, available compound KHF2 as 62 a wasfluoride converted ion source into salt(Schemeorganotrifluroborate (63) by 25B). treating it salt with (63 commercially) by treating it available with commercially KHF2 as a fluoride available ion KHF source2 as a (Scheme fluoride 25 ionB). source (Scheme 25B).

Scheme 25. ((AA)) Pd-catalyzed Pd-catalyzed borylation borylation of of brom brominatedinated 2,1-borazaronaphthalenes; 2,1-borazaronaphthalenes; (B ()B synthesis) synthesis of of3- Scheme 25. (A) Pd-catalyzed borylation of brominated 2,1-borazaronaphthalenes; (B) synthesis of 3- 3-BFBF3K-2,1-borazaronaphthalenes.3K-2,1-borazaronaphthalenes. BF3K-2,1-borazaronaphthalenes. Later, they they also also utilized utilized the the bis-boryl bis-boryl compounds compounds 62a 62aand and63d for63d a forpalladium-catalyzed a palladium-catalyzed cross- cross-couplingcouplingLater, strategy they strategy also with utilized witha variety athe variety bis-boryl of aryl of aryl halides compounds halides containing containing 62a and an an63d electron-withdrawing electron-withdrawing for a palladium-catalyzed group group cross-or or an electron-donatingcoupling strategy group,group,with a whichwhichvariety yielded yielded of aryl the thehalides corresponding corresponding containing coupling couplingan electron-withdrawing products products64a–h 64a–h(Scheme (Schemegroup 26 or)[ 26). 43an]. [43].electron-donating group, which yielded the corresponding coupling products 64a–h (Scheme 26). [43].

Molecules 2020, 25, 959 20 of 30 Molecules 2020, 24, x FOR PEER REVIEW 20 of 30

SchemeScheme 26. 26.Scope Scope of of the the directdirect cross-coupling with with ( (AA) )3-Bpin- 3-Bpin-BB-phenyl-2,1-borazaronaphthalene-phenyl-2,1-borazaronaphthalene and and

(B)(B 3-BF) 3-BF3K-3K-B-phenyl-2,1-borazaronaphthalene.B-phenyl-2,1-borazaronaphthalene.

InIn 2014, 2014, thethe NishiharaNishihara research research group group reported reported the the platinum-catalyzed platinum-catalyzed diborylation diborylation of 1- of 1-phenylethynylphenylethynyl MIDA MIDA boronate boronate 65a65a withwith bis(pinacolato)diboron, bis(pinacolato)diboron, affording aff ordingstereoselective stereoselective 1,1,2- 1,1,2-triboryl-2-phenylethenetriboryl-2-phenylethene 66a with66a withan 86% an yield 86% [44]. yield Under [44]. similar Under reaction similar conditions, reaction they conditions, also theyextended also extended diboration diboration with the aliphatic with the 1-alkynyl aliphatic MIDA 1-alkynyl boronate MIDA 65b, yielding boronate the65b 1,1,2-triboryl-2-, yielding the 1,1,2-triboryl-2-hexylethenehexylethene 66b, as shown66b in, asScheme shown 27A. in Scheme Furthermor 27A. Furthermore,e, 1,1,2-triboryl-2-phenylethene, 1,1,2-triboryl-2-phenylethene, 66, was 66,successfully was successfully applied applied to chemoselec to chemoselectivetive palladium-catalyzed palladium-catalyzed Suzuki Suzuki−MiyauraMiyaura coupling coupling with aryl with − arylhalides halides bearing bearing electron-donating electron-donating and and electron-withdrawing electron-withdrawing groups. groups. Under Under optimized optimized reaction reaction conditions,conditions, they they synthesized synthesized aalibrary library ofof syntheticallysynthetically useful useful 1,1-bis(boryl)olefins, 1,1-bis(boryl)olefins, 67a–f67a–f, with, with up up to to 91% yields (Scheme 27B). 91% yields (Scheme 27B).

Molecules 2020, 25, 959 21 of 30 Molecules 2020, 24, x FOR PEER REVIEW 21 of 30

SchemeScheme 27. ((AA)) Stereoselective Stereoselective platinum-catalyzed platinum-catalyzed 1,2-diborylation 1,2-diborylation of of alkyne; alkyne; ( (BB)) chemoselective Suzuki–MiyauraSuzuki–Miyaura coupling coupling of 66..

ToTo determine the (Z)-configuration-configuration of of the chemos chemoselectiveelective arylated arylated product product 6767,, they they carried carried out out Suzuki Miyaura coupling of 1,1,2-triboryl-2-phenylethene 66a and iodobenzene to afford the arylated Suzuki−Miyaura coupling of 1,1,2-triboryl-2-phenylethene 66a and iodobenzene to afford the arylatedunsymmetrical unsymmetrical 1,1-bis(boryl)-2,2-diphenylethene 1,1-bis(boryl)-2,2-diphenylethene67g, with 67g 82%, with yield. 82% Then,yield. transformationThen, transformation of the ofBMIDA the BMIDA group intogroup Bpin into aff Bpinorded afforded the symmetrical the symmetrical 1,1-bis(boryl)-2,2-diphenylethene 1,1-bis(boryl)-2,2-diphenylethene68a at a 98% 68a yield, at a 98% yield, which matched with earlier reported spectroscopic data. This experimental result clearly suggests that selective cross-coupling takes place at the Bpin group, which is geminal to the aryl moiety (Scheme 28).

Molecules 2020, 25, 959 22 of 30 which matched with earlier reported spectroscopic data. This experimental result clearly suggests that Moleculesselective 20202020 cross-coupling,, 2424,, xx FORFOR PEERPEER takes REVIEWREVIEW place at the Bpin group, which is geminal to the aryl moiety (Scheme2222 ofof 28 3030).

Scheme 28. DeterminationDetermination of of the the stereochemistry stereochemistry of arylated product 67..

Furthermore, they changed the electrophile ArI into BnCl BnCl (1.5 (1.5 equiv) equiv) for for an an SMCC SMCC reaction reaction with with compound 66a andand observed observed only only one one isomer isomer of of unsymmetricalunsymmetrical 1,1-bis(boryl) alkene 67h,, with a moderate yield (Scheme 29)29)[ [44].44].

Scheme 29. Suzuki–MiyauraSuzuki–Miyaura coupling coupling of 66a withwith benzyl benzyl chloride. chloride.

InIn 2019, 2019, the the Tsuchimoto Tsuchimoto groupgroup reportedreported thatthat thethe Pt-catalyzed diboration of alkyne had terminal Bdan with pinB–Bpin, resulting in the 1,1,2-triboryalkene1,1,2-triboryalkene 66c,, which which had had perfectperfect stereoselectivitystereoselectivity without suffering suffering directdirect activationactivation by thethe platinumplatinum complexcomplex [[45].45]. Compared to other reports on the diboration of alkynes [46, [46,47]47] with pinB–Bpin, thisthis methodmethod aaffoffordedrdedrded ananan excellentexcellentexcellent yieldyieldyield (Scheme(Scheme(Scheme 3030A).30A).A).

Molecules 2020, 25, 959 23 of 30

Molecules 2020, 24, x FOR PEER REVIEW 23 of 30

O O B B O O O O B O HN Pt(PPh3)4 (0.5 mol%) B (A) Me B O HN toluene B 65c 80 C, 48 h Me HN NH

66c, 99%

(B) F3C CF3 O O I CF3 O O B B O (1 equiv) O B O PdCl2 (5 mol%) O B B NH B NH HN B NH 1.5 M K3PO4 aq. (3 equiv) HN THF, 70 °C, 3 h HN Me 66c Me 92% yield 69a Me 69b 69a/69b =8:92

I OMe (1.2 equiv.) Pd(OAc)2 (5 mol%) SPhos (10 mol%) 1.5 M KOH aq. (3 equiv) THF, 70 °C, 24 h I CN MeO CF MeO CF3 3 (1.2 equiv) pinacol (20 equiv) Pd(OAC)2 (5 mol%) SPhos (10 mol%) 2MH2SO4 aq. (8 equiv) 1.5 M K3PO4 aq. (3 equiv) THF B O THF B NH 70 °C, 3 h O 70 °C, 24 h HN

Me Me MeO CF3 71, 92% 70, 93%

Me CN 72, 99%

SchemeScheme 30. 30. ((AA)) Platinum-catalyzed Platinum-catalyzed 1,2-diboration 1,2-diboration of alkyne of alkyne with withB2(pin) B2;(pin) (B) Suzuki–Miyaura2;(B) Suzuki–Miyaura cross- cross-couplingcoupling reactions reactions to afford to aff theord tetra-arylalkene the tetra-arylalkene 72. 72.

InIn 2019, 2019, utilizing utilizing the thetetra tetrasubstitutedsubstituted triborylalkenetriborylalkene 66c66c, ,for for the the first first time time the the Tsuchimoto Tsuchimoto group group successfullysuccessfully synthesized synthesizedtetra tetrasubstitutedsubstituted arylaryl alkenesalkenes ( 72)) through through sequential sequential SMCC SMCC reactions. reactions. In Inthe the triborylalkenetriborylalkene66c 66c,, the theC Cspsp22-B bond bond is is inactive; inactive; thus, thus, it is it very is very unreactive unreactive under under SMCC SMCC conditions. conditions. Of Ofthe the remaining remaining two two C Cspsp2-B2-B bonds, bonds, one one is isat at the the transposition transposition of ofthe the aryl aryl group, group, which which can can possibly possibly increaseincrease the the nucleophilicity nucleophilicity of of the the boron boron atomatom throughthrough electron electron flow: flow: it it reacts reacts more more facilely facilely than than does does thethe other other under under Pd(II) Pd(II) SMCC SMCC conditions. conditions. In the first first SMCC SMCC reaction, reaction, 4-io 4-iodobenzotrifluoridedobenzotrifluoride was was treated under ligand-free conditions, affording 69 in very good yield (with regioselectivity). In the treated under ligand-free conditions, affording 69 in very good yield (with regioselectivity). In the second SMCC arylation, 4-iodoanisole reacted preferentially with Csp2-Bpin over Csp2-Bdan, second SMCC arylation, 4-iodoanisole reacted preferentially with Csp2-Bpin over Csp2-Bdan, affording

Molecules 2020,, 2524,, 959x FOR PEER REVIEW 24 of 30

affording 70. Since Bdan is unreactive toward SMCC, it was converted into Bpin under acidic 70conditions. Since Bdan with is pinacol. unreactive In the toward final sequence SMCC, it of was SMCC converted arylation, into 4-iodobenzonitrile Bpin under acidic was conditions treated with 2 pinacol.Csp2-Bpin In to the produce final sequence the tetra-arylalkene of SMCC arylation, 72. Importantly, 4-iodobenzonitrile during all of was the SMCC treated reactions with Csp observed,-Bpin to producethere was the only tetra-arylalkene one stereoisomer72. Importantly,with a high yield during (Scheme all of the30B) SMCC [47]. reactions observed, there was onlyIn one 2008, stereoisomer the Walsh with group a high described yield (Scheme the reacti 30B)on [ 47of]. stable pinB-substituted alkynes (65) with dicyclohexylIn 2008, borane the Walsh to afford group unsymm describedetrical the reaction1,1-bis(boryl)alkene of stable pinB-substituted species (73) [48]. alkynes Compound (65) with 73 dicyclohexylwas not isolated borane and toexhibited afford unsymmetrical two peaks at 30 1,1-bis(boryl)alkene ppm and 80 ppm in species a crude (73 11)[B-NMR48]. Compound spectrum. 73In 11 wasaddition, not isolated crude 1H-NMR and exhibited of 73 exhibited two peaks only at one 30 isomer ppm and in the 80 hy ppmdroboration in a crude reaction.B-NMR Later spectrum. on, they 1 Insuccessfully addition, crudeutilizedH-NMR a 1,1-bis(boryl)alkane of 73 exhibited onlyspecie ones for isomer chemoselective in the hydroboration transmetallation reaction. with Later an on, they successfully utilized a 1,1-bis(boryl)alkane species for chemoselective transmetallation with organozinc reagent (in place of Cy2B) to afford the boron/zinc heterobimetallic reagent 74; they then anadded organozinc it to an reagentaldehyde (in to place obtain of CypinB-substituted2B) to afford the (E) boron-allylic/zinc alcohols heterobimetallic (75) with reagentgood yields.74; they By thenutilizing added this it method, to an aldehyde they synthesized to obtain pinB-substituted a library of secondary(E)-allylic alcohols alcohols via (75 hydroboration) with good yields. and Bytransmetallation, utilizing this method,followed they by aldehyde synthesized treatment a library with of secondarypinB-substituted alcohols alkynes via hydroboration (65) (Schemeand 31) transmetallation,[48]. followed by aldehyde treatment with pinB-substituted alkynes (65) (Scheme 31)[48].

Scheme 31. Synthesis of allylic alcohols from alkyne via unsymmetrical diborylalkenes.

In 2013, 2013, the the Braunschweig Braunschweig group group demonstrated demonstrated a photolytic a photolytic approa approachch to creating to creating a new class a new of classthree-membered of three-membered borirenes borirenes using an aminoboryl using an aminoboryl complex [(OC) complex5Cr=B=N(SiMe [(OC)5Cr=3)B2]= inN(SiMe the presence3)2] in of the a presenceseries of ofmono- a series or of mono-bis(boryl) or bis(boryl)alkynes: alkynes:1-phenyl-2-bis-(dimethylamino 1-phenyl-2-bis-(dimethylamino)borylethyne,)borylethyne, bis{bis- bis{bis-(dimethylamino)boryl}ethyne,(dimethylamino)boryl}ethyne, and and1-trimethylsil 1-trimethylsilyl-2-bis-(dimethylamino)borylethyneyl-2-bis-(dimethylamino)borylethyne [49]. [49]. As depicted in Scheme 3232A,A, aminoboryl complex 76 was irradiated with alkyne 77 at room temperature to produceproduce the the desired desired unsymmetrical unsymmetrical 1,1-bis(boryl) 1,1-bis(boryl) alkenes alkenes (i.e., (i.e., iminoboranes) iminoboranes) (78a–c (78a–c) (Scheme) (Scheme 32A). 32A).

Molecules 2020, 25, 959 25 of 30 Molecules 2020, 24, x FOR PEER REVIEW 25 of 30

Scheme 32.32. ((AA)) Photolytic Photolytic synthesis synthesis of of borirenes; borirenes; ( (BB)) reactivity reactivity of of borirenes toward bases; ( C) dequarternization of borirenes.borirenes.

Generally, aminoboranes (i.e., (i.e., compound compound 8080) )do do not not follow follow quat quaternization,ernization, since since the the p-orbitalp-orbital of ofboron boron is filled is filled by the by theπ-basicπ-basic amino amino group. group. The utility The utility of iminoboranes of iminoboranes (78) was (78 established) was established by the bysynthesis the synthesis of quaternary of quaternary aminoboranes aminoboranes (79): these kinds (79): of theseaminoboranes kinds of are aminoboranes very rare, according are very to rare,the accordingliterature to(Scheme the literature 32B). (SchemeThe iminoborane 32B). The iminoborane78 did not78 didreact not with react withDMAP DMAP (4- (4-(dimethylamino)pyridine),(dimethylamino)pyridine), pyridine, pyridine, PCy PCy3, or3 ,PMe or PMe3 even3 even at 80 at °C, 80 whereas◦C, whereas it reacted it reacted with withIMe (IMe IMe (IMe= 1,3-dimethyl-2,3-dihydro-1= 1,3-dimethyl-2,3-dihydro-1H-imidazole)H-imidazole) at ambient at ambient temperature temperature to produce to produce quaternization quaternization in the inendocyclic the endocyclic boryl borylgroup. group. Interestingly, Interestingly, the theBraunschweig Braunschweig group group observed observed that that there there was was no quaternization ofof thethe exocyclic exocyclic boryl boryl groups groups even even upon upon the the addition addition of an ofexcess an excess of IMe of (SchemeIMe (Scheme 32B). 32B). The dequarternization of borirenes also afforded the parental unsymmetrical 1,1- bis(boryl)alkanes and alkenes (80) in the presence of B(C6F5)3 (Scheme 32C) [49].

Molecules 2020, 25, 959 26 of 30

The dequarternization of borirenes also afforded the parental unsymmetrical 1,1-bis(boryl)alkanes Molecules 2020, 24, x FOR PEER REVIEW 26 of 30 and alkenes (80) in the presence of B(C6F5)3 (Scheme 32C) [49]. In 2013, Weber et al. reported the hydroboration of 2-alkyl- and 2-aryl-ethynyl-1,3,2- In 2013, Weber et al. reported the hydroboration of 2-alkyl- and 2-aryl-ethynyl-1,3,2- benzodiazaboroles with dicyclohexylborane (DCB) under metal-free conditions at room temperature, benzodiazaboroles with dicyclohexylborane (DCB) under metal-free conditions at room temperature, affording the cis-1,1-bis(boryl)alkene 82 as a major regioisomer, with quantitative yields [50]. affording the cis-1,1-bis(boryl)alkene 82 as a major regioisomer, with quantitative yields [50]. Interestingly, they also observed the hydroboration of 2-silylethynyl-1,3,2-benzodiazaborole with DCB, Interestingly, they also observed the hydroboration of 2-silylethynyl-1,3,2-benzodiazaborole with which afforded 1,1-bis(boryl)alkene (82) as a minor regioisomer and trans-1,2-bis(boryl)alkene as a DCB, which afforded 1,1-bis(boryl)alkene (82) as a minor regioisomer and trans-1,2-bis(boryl)alkene major regioisomer (83), with quantitative yields (Scheme 33)[50]. as a major regioisomer (83), with quantitative yields (Scheme 33) [50].

Scheme 33. Hydroboration of alkynes with HBCy 2 (dicyclohexylborane).(dicyclohexylborane).

InIn 2015, 2015, the the Erker Erker group group reported reported the the preparation preparation of 1,2,5-trisubstituted of 1,2,5-trisubstituted boroles boroles containing containing 1,1- bis(boryl)1,1-bis(boryl) groups groups from from the the bis(ethynyl)borane bis(ethynyl)borane 8484 andand B(C B(C6F6F5)53 )3viavia a a 1,1-carboboration 1,1-carboboration sequence followedfollowed byby di- di-π-boraneπ-borane rearrangement rearrangement [51 ].[51]. Initially, Initially, the reaction the reaction of bis(ethynyl)borane of bis(ethynyl)borane with B(C 6withF5)3 B(Cresulted6F5)3 resulted in 44:56 mixturesin 44:56 mixtures of the 1,1-carboboration of the 1,1-carboboration product Zproduct-85 and Z the-85 trisubstituted and the trisubstituted borole 87 borolevia 86, 87which via 86 was, which isolated was after isolated treatment after treatment with pyridine with (Scheme pyridine 34 (SchemeA). 34A). Under thermal conditions, a a mixture mixture of Z-85-85 and 87 aaffordedfforded the [4 ++ 2] cycloaddition product 88,, which which was was formed formed after after the the dimerization dimerization of of reactive reactive borole borole 87.87 The. The Erker Erker group group observed observed that that the unreactedthe unreacted Z-85Z -85remainedremained under under thermal thermal conditions conditions (Scheme (Scheme 34B). 34B). Since Since compound compound ZZ-85-85 waswas not isomerizedisomerized thermally, thermally, they triedtried photolysis. Un Underder photolysis, photolysis, ZZ-85-85 isomerizedisomerized to to EE-85-85,, which which can can easily be converted into 87,, as as shown in Scheme 34A,34A, and compound 87 also cleanly isomerized to thethe new trisubstituted borole borole 9090 via di- π-borane rearrangements (two (two formal 1,3-boron 1,3-boron migrations) migrations) followedfollowed by ring opening. Consequently Consequently,, thethe photolysisphotolysis ofof aa solutionsolution ofof thethe Z-85 + 8787 mixturemixture resulted resulted inin 1,1-bis(boryl)alkanes1,1-bis(boryl)alkanes and and alkenes alkenes (90 ()90 (1,2,5-trisubstituted) (1,2,5-trisubstituted boroles) boroles) in quantitative in quantitative conversion, conversion, which whichwas isolated was isolated after treatment after treatment with pyridine with pyridine (Scheme (Scheme 34B) [51 34B)]. [51].

Molecules 2020, 24, x FOR PEER REVIEW 27 of 30

Molecules 2020, 25, 959 27 of 30

Molecules 2020, 24, x FOR PEER REVIEW 27 of 30

Scheme 34. (A) 1,1-carboboration of 84; (B) the synthesis of 1,1-bis(borane) from a mixture of 1,3,4- Scheme 34. (A(A) 1,1-carboboration) 1,1-carboboration of of84;84 (B;() theB) thesynthesis synthesis of 1,1-bis(borane) of 1,1-bis(borane) from froma mixture a mixture of 1,3,4- of trisubtituted boroles and Z-7. 1,3,4-trisubtitutedtrisubtituted boroles boroles and Z-7 and. Z-7. In 2018, the same group prepared a 1,1-bis(boryl)alkene by reacting tetraaryldiborane(4) 92 with In 2018, the same group prepared a 1,1-bis(boryl)alkene by reacting tetraaryldiborane(4) 92 with In1-pentyne 2018, the (Scheme same group 35) [52]. prepared a 1,1-bis(boryl)alkene by reacting tetraaryldiborane(4) 92 with 1-pentyne (Scheme 35)[52]. 1-pentyneUnder (Scheme thermal 35) [52]. conditions, diborane(4) underwent 1,2-migration in its acetylenic hydrogen Underalong the thermalthermal alkyne conditions, πconditions,-bond to afford diborane(4) diborane(4) 1,1-bis(boryl)alkene underwent underwen 93 1,2-migrationt, along1,2-migration with 94 in, itsin in a acetylenic 42:37its acetylenic ratio. hydrogen During hydrogen the along thealong alkynereaction, the alkyneπ-bond one πB—B to-bond a ffbondord to 1,1-bis(boryl)alkenewasafford cleaved, 1,1-bis(boryl)alkene and new93 C—B, along bonds 93 with, along were94 , formedwith in a 42:3794 (Scheme, in ratio. a 42:37 35) During [52]. ratio. the During reaction, the onereaction, B–B bondone B—B was cleaved,bond was and cleaved, new C–B and bonds new C—B were bonds formed were (Scheme formed 35 )[(Scheme52]. 35) [52].

Scheme 35. The diboration of alkyne.

SchemeScheme 35. 35. TheThe diboration diboration of of alkyne. alkyne.

Molecules 2020, 25, 959 28 of 30

4. 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.

Acknowledgments: A.M. is grateful to the Azrieli Foundation for the receipt of an Azrieli Fellowship. K.N.B., N.M., F.M., and R.R.R. are thankful to HUJI for a research fellowship. Conflicts of Interest: The authors declare no conflict of interest.

References

1. Hall, D.G. Boronic Acids: Preparation and Applications in Organic Synthesis and Medicine; Wiley-VCH: Weinheim, Germany, 2005. 2. Hall, D.G. Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials, 2nd ed.; Wiley-VCH, Verlag GmbH & Co. KGaA: New York, NY, USA, 2011. 3. Xu, L.; Zhang, S.; Li, P. Boron-selective reactions as powerful tools for modular synthesis of diverse complex molecules. Chem. Soc. Rev. 2015, 44, 8848–8858. [CrossRef] 4. Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Complete Field Guide to Asymmetric BINOL-Phosphate Derived Brønsted Acid and Metal Catalysis: History and Classification by Mode of Activation; Brønsted Acidity, Hydrogen Bonding, Ion Pairing, and Metal Phosphates. Chem. Rev. 2014, 114, 9047–9153. [CrossRef] 5. Yi, J.; Badir, S.O.; Alam, R.; Molander, G.A. Photoredox-Catalyzed Multicomponent Petasis Reaction with Alkyltrifluoroborates. Org. Lett. 2019, 21, 4853–4858. [CrossRef] 6. Kaiser, D.; Noble, A.; Fasano, V.; Aggarwal, V.K. 1,2-Boron Shifts of β-Boryl Radicals Generated from Bis-boronic Esters Using Photoredox Catalysis. J. Am. Chem. Soc. 2019, 141, 14104–14109. [CrossRef] 7. Touchet, S.; Carreaux, F.; Carboni, B.; Bouillon, A.; Boucher, J.-L. Aminoboronic acids and esters: From synthetic challenges to the discovery of unique classes of enzyme inhibitors. Chem. Soc. Rev. 2011, 40, 3895–3914. [CrossRef] 8. Dembitsky, V.M.; Al Quntar, A.A.A.; Srebnik, M. Natural and Synthetic Small Boron-Containing Molecules as Potential Inhibitors of Bacterial and Fungal Quorum Sensing. Chem. Rev. 2011, 111, 209–237. [CrossRef] 9. Baker, S.J.; Tomsho, J.W.; Benkovic, S.J. Boron-containing inhibitors of synthetases. Chem. Soc. Rev. 2011, 40, 4279–4285. [CrossRef] Molecules 2020, 25, 959 29 of 30

10. Smoum, R.; Rubinstein, A.; Dembitsky, V.M.; Srebnik, M. Boron Containing Compounds as Protease Inhibitors. Chem. Rev. 2012, 112, 4156–4220. [CrossRef] 11. Diaz, D.B.; Yudin, A.K. The versatility of boron in biological target engagement. Nat. Chem. 2017, 9, 731–742. [CrossRef] 12. Adams, J.; Palombella, V.J.; Sausville, E.A.; Johnson, J.; Destree, A.; Lazarus, D.D.; Maas, J.; Pien, C.S.; Prakash, S.; Elliott, P.J. Proteasome Inhibitors: A Novel Class of Potent and Effective Antitumor Agents. Cancer Res. 1999, 59, 2615–2622. 13. Baker, S.J.; Zhang, Y.-K.; Akama, T.; Lau, A.; Zhou, H.; Hernandez, V.; Mao, W.; Alley, M.R.K.; Sanders, V.; Plattner, J.J. Discovery of a New Boron-Containing Antifungal Agent, 5-Fluoro-1,3-dihydro-1-hydroxy-2,1- benzoxaborole (AN2690), for the Potential Treatment of Onychomycosis. J. Med. Chem. 2006, 49, 4447–4450. [CrossRef] 14. Maynard, A.; Crosby, R.M.; Ellis, B.; Hamatake, R.; Hong, Z.; Johns, B.A.; Kahler, K.M.; Koble, C.; Leivers, A.; Leivers, M.R.; et al. Discovery of a Potent Boronic Acid Derived Inhibitor of the HCV RNA-Dependent RNA Polymerase. J. Med. Chem. 2014, 57, 1902–1913. [CrossRef] 15. Neeve, E.C.; Geier, S.J.; Mkhalid, I.A.I.; Westcott, S.A.; Marder, T.B. Diboron(4) Compounds: From Structural Curiosity to Synthetic Workhorse. Chem. Rev. 2016, 116, 9091–9161. [CrossRef] 16. Nallagonda, R.; Padala, K.; Masarwa, A. gem-Diborylalkanes: Recent advances in their preparation, transformation and application. Org. Biomol. Chem. 2018, 16, 1050–1064. [CrossRef] 17. Leonard, N.G.; Palmer, W.N.; Friedfeld, M.R.; Bezdek, M.J.; Chirik, P.J. Remote, Diastereoselective Cobalt-Catalyzed Alkene Isomerization–Hydroboration: Access to Stereodefined 1,3-Difunctionalized Indanes. ACS Catal. 2019, 9, 9034–9044. [CrossRef] 18. Miralles, N.; Maza, R.J.; Fernandez, E. Synthesis and Reactivity of 1,1-Diborylalkanes towards C-C Bond Formation and Related Mechanisms. Adv. Synth. Catal. 2018, 360, 1306–1327. [CrossRef] 19. Royes, J.; Cuenca, A.B.; Fernandez, E. Access to 1,1-Diborylalkenes and Concomitant Stereoselcitive Reactivity. Eur. J. Org. Chem. 2018, 2728–2739. [CrossRef] 20. Wu, C.; Wang, J. Geminal bis(boron) compounds: Their preparation and synthetic applications. Tetrahedron Lett. 2018, 59, 2128–2140. [CrossRef] 21. Ishiyama, T.; Yamamoto, M.; Miyaura, N. A Synthesis of (E)-(1-Organo-1-alkenyl)boronates by the Palladium-Catalyzed Cross-Coupling Reaction of (E)-1,2-Bis(boryl)-1-alkenes with Organic Halides: A Formal Carboboration of Alkynes via the Diboration-Coupling Sequence. Chem. Lett. 1996, 25, 1117–1118. [CrossRef] 22. Brown, S.D.; Armstrong, R.W. Parallel Synthesis of Tamoxifen and Derivatives on Solid Support via Resin Capture. J. Org. Chem. 1997, 62, 7076–7077. [CrossRef] 23. Iwadate, N.; Suginome, M. Differentially Protected Diboron for Regioselective Diboration of Alkynes: Internal-Selective Cross-Coupling of 1-Alkene-1,2-diboronic Acid Derivatives. J. Am. Chem. Soc. 2010, 132, 2548–2549. [CrossRef][PubMed] 24. Iwasaki, M.; Nishihara, Y. Synthesis of Multisubstituted Olefins through Regio- and Stereoselective Addition of Interelement Compounds Having B–Si, B–B, and Cl–S Bonds to Alkynes, and Subsequent Cross-Couplings. Chem. Rec. 2016, 16, 2031–2045. [CrossRef][PubMed] 25. Wang, C.; Wu, C.; Ge, S. Iron-Catalyszed E-selective Dehydrogenative borylation of Vinylarenes with Pinacolborane. ACS Catal. 2016, 6, 7585–7589. [CrossRef] 26. Hu, J.; Zhao, Y.; Shi, Z. Highly tunable multi-borylation of gemdifluoroalkenes via copper catalysis. Nature Catalysis 2018, 1, 860–869. [CrossRef] 27. Shimizu, M.; Nakamaki, C.; Shimono, K.; Schelper, M.; Kurahashi, T.; Hiyama, T. Stereoselective Cross-Coupling Reaction of 1,1-Diboryl-1-alkenes with Electrophiles: A Highly Stereocontrolled Approach to 1,1,2-Triaryl-1-alkenes. J. Am. Chem. Soc. 2005, 127, 12506–12507. [CrossRef] 28. Lennox, A.J.J.; Lloyd-Jones, G.C. Selection of boron reagents for Suzuki-Mayaura coupling. Chem. Soc. Rev. 2014, 43, 412–443. [CrossRef] 29. Lee, J.C.H.; McDonald, R.; Hall, D.G. Enantioselective preparation and chemoselective cross-coupling of 1,1-diboron compounds. Nature Chem. 2011, 3, 894–899. [CrossRef] 30. Sivaev, I.B.; Bregadze, V.I. Lewis acidity of boron compounds. Coord. Chem. Rev. 2014, 270–271, 75–88. [CrossRef] 31. Lee, J.C.H.; Sun, H.-Y.; Hall, D.G. Optimization of Reaction and Substrate Activation in the Stereoselective Cross-Coupling of Chiral 3,3-Diboronyl Amides. J. Org. Chem. 2015, 80, 7134–7143. [CrossRef] Molecules 2020, 25, 959 30 of 30

32. Feng, X.; Jeon, H.; Yun, J. Regio- and Enantioselective Copper(I)-Catalyzed Hydroboration of Borylalkenes: Asymmetric Synthesis of 1,1-Diborylalkanes. Angew. Chem. Int. Ed. 2013, 52, 3989–3992. [CrossRef] 33. Cuenca, A.B.; Cid, J.; García-López, D.; Carbó, J.J.; Fernández, E. Unsymmetrical 1,1-diborated multisubstituted sp3-carbons formed via a metal-free concerted-asynchronous mechanism. Org. Biomol. Chem. 2015, 13, 9659–9664. [CrossRef][PubMed] 34. Fleige, M.; Mo¨bus, J.; Stein, T.V.; Glorius, F.; Stephan, D.W. Lewis acid catalysis: Catalytic hydroboration of alkynes initiated by Piers’ borane. Chem. Commun. 2016, 52, 10830–10833. [CrossRef][PubMed] 35. Lin, S.; Wang, L.; Aminoleslami, N.; Lao, Y.; Yagel, C.; Sharma, A. A modular and concise approach to MIDA acylboronates via chemoselective oxidation of unsymmetrical geminal diborylalkanes: Unlocking access to a novel class of acylborons. Chem. Sci. 2019, 10, 4684–4691. [CrossRef][PubMed] 36. Kumar, N.; Reddy, R.R.; Masarwa, A. Stereoselective Desymmetrization of gem-Diborylalkanes by “Trifluorination”. Chem. Eur. J. 2019, 25, 8008–8012. [CrossRef] 37. Liu, Y.-L.; Kehr, G.; Daniliuc, C.G.; Erker, G. Geminal bis-borane formation by borane Lewis acid induced cyclopropyl rearrangement and its frustrated Lewis pair reaction with carbon dioxide. Chem. Sci. 2017, 8, 1097–1104. [CrossRef] 38. Liu, Y.-L.; Kehr, G.; Daniliuc, C.G.; Erker, G. Metal-Free Arene and Heteroarene Borylation Catalyzed by Strongly Electrophilic Bis-boranes. Chem. Eur. J. 2017, 23, 12141–12144. [CrossRef] 39. Krautwald, S.; Bezdek, M.J.; Chirik, P.J. Cobalt-Catalyzed 1,1-Diboration of Terminal Alkynes: Scope, Mechanism, and Synthetic Applications. J. Am. Chem. Soc. 2017, 139, 3868–3875. [CrossRef] 40. Kehr, G.; Erker, G. 1,1-Carboboration. Chem. Commun. 2012, 48, 1839–1850. [CrossRef] 41. Suginome, M. Catalytic Carboborations. Chem. Rec. 2010, 10, 348–358. [CrossRef] 42. Chen, C.; Voss, T.; Frohlich, R.; Kehr, G.; Erker, G. 1,1-Carboboration of 1-Alkynes: A Conceptual Alternative to the Hydroboration Reaction. Org. Lett. 2011, 13, 62–65. [CrossRef] 43. Compton, J.S.; Saeednia, B.; Kelly, C.B.; Molander, G.A. 3-Boryl-2,1-borazaronaphthalene: Umpolung Reagents for Diversifying Naphthalene Isosteres. J. Org. Chem. 2018, 83, 9484–9491. [CrossRef][PubMed] 44. Hyodo, K.; Suetsugu, M.; Nishihara, Y. Diborylation of Alkynyl MIDA Boronates and Sequential Chemoselective Suzuki Miyaura Couplings: A Formal Carboborylation of Alkynes. Org. Lett. 2014, − 16, 440–443. [CrossRef][PubMed] 45. Tani, T.; Sawatsugawa, Y.; Sano, Y.; Hirataka, Y.; Takahashi, N.; Hashimoto, S.; Sugiura, T.; Tsuchimotoa, T. Alkynyl–B(dan)s in Various Palladium-Catalyzed Carbon–Carbon Bond-Forming Reactions Leading to Internal Alkynes,1,4-Enynes, Ynones, and Multiply Substituted Alkenes. Adv. Synth. Catal. 2019, 361, 1815–1834. [CrossRef] 46. Zhao, F.; Jia, X.; Li, P.; Zhao, J.; Zhou, Y.; Wang, J.; Liu, H. Catalytic and catalyst-free diboration of alkynes. Org. Chem. Front. 2017, 4, 2235–2255. [CrossRef] 47. Ishiyama, T.; Matsuda, N.; Miyaura, N.; Suzuki, A. Platinum(0)-Catalyzed Diboration of Alkynes. J. Am. Chem. Soc. 1993, 115, 11018–11019. [CrossRef] 48. Li, H.; Carroll, P.J.; Walsh, P.J. Generation and Tandem Reactions of 1-Alkenyl-1,1-Heterobimetallics: Practical and Versatile Reagents for Organic Synthesis. J. Am. Chem. Soc. 2008, 130, 3521–3531. [CrossRef] 49. Braunschweig, H.; Damme, A.; Dewhurst, R.D.; Ghosh, S.; Kramer, T.; Pfaffinger, B.; Radacki, K.; Vargas, A. Electronic and Structural Effects of Stepwise Borylation and Quaternization on Borirene Aromaticity. J. Am. Chem. Soc. 2013, 135, 1903–1911. [CrossRef] 50. Weber, L.; Eickhoff, D.; Halama, J.; Werner, S.; Kahlert, J.; Stammler, H.G.; Neumann, B. Hydroboration of Alkyne-Functionalized 1,3,2- Benzodiazaboroles. Eur. J. Inorg. Chem. 2013, 2608–2614. [CrossRef] 51. Ge, F.; Kehr, G.; Daniliuc, C.G.; Lichtenfeld, C.M.; Erker, G. Trisubstituted Boroles by 1,1-Carboboration. Organometallics 2015, 34, 4205–4208. [CrossRef] 52. Ge, F.; Tao, X.; Daniliuc, C.G.; Kehr, G.; Erker, G. The Borole Route to Reactive Pentafluorophenyl-Substituted Diboranes(4). Angew. Chem. Int. Ed. 2018, 57, 14570–14574. [CrossRef]

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).