Stereospecific 1,2-Migrations of Boronate Complexes Induced by Electrophiles.

The stereospecific 1,2-migration of boronate complexes is one of the most representative reactions in boron chemistry. This process has been used extensively to develop powerful methods for asymmetric synthesis, with applications spanning from pharmaceuticals to natural products. Typically, 1,2-migration of boronate complexes is driven by displacement of an α-leaving group, oxidation of an α-boryl radical, or electrophilic activation of an alkenyl boronate complex. The aim of this article is to summarize the recent advances in the rapidly expanding field of electrophile-induced stereospecific 1,2-migration of groups from boron to sp2 and sp3 carbon centers. It will be shown that three different conceptual approaches can be utilized to enable the 1,2-migration of boronate complexes: stereospecific Zweifel-type reactions, catalytic conjunctive coupling reactions, and transition metal-free sp2 -sp3 couplings. A discussion of the reaction scope, mechanistic insights, and synthetic applications of the work described is also presented.

Introduction

Chiral class="Chemical">boronic acids and related derivatives are valuable building blocks in modern synthesis as they can be easily prepared with high levels of enantioselectivity.1 Crucial to the synthetic utility of <class="Chemical">span class="Chemical">organoboron compounds is their ability to be transformed stereospecifically into a range of functional groups.2 In general terms, these transformations are initiated by the addition of a nucleophile to the boron atom, resulting in boronate complex formation, followed by a stereospecific 1,2‐migration of a metal migrating group to the adjacent carbon centre.3 An example of such a process is the homologation of boronic esters with carbenoids (Scheme 1 a), which has seen wide application in asymmetric synthesis. In this context, Matteson's substrate‐controlled homologation4 and Aggarwal's reagent‐controlled lithiation‐borylation5 methodologies are particularly noteworthy. Recently, the fields of radical chemistry with stereospecific 1,2‐migration has been shown that radicals next to boronates can be generated by the addition of carbon‐centred radicals to alkenyl boronates6 or by α‐C(sp3)−H abstraction.7 These α‐boryl radical anions can then undergo single‐electron oxidation followed by 1,2‐migration to afford the desired products. This active field has been recently reviewed so will not be discussed further here.8

Scheme 1

Strategies for stereospecific 1,2‐migrations of boronate complexes. Cb=N,N‐diisopropylcarbamoyl. RM=Migrating group.

Strategies for stereospecific 1,2‐migrations of <span class="Chemical">boronate complexes. Cb=N,N‐diisopropylcarbamoyl. RM=Migra<class="Chemical">span class="Chemical">ting group.

Stereospecific 1,2‐migrations of class="Chemical">alkenyl or aryl boronates can be induced by reactions with suitable electrophiles (Scheme 1 c). Although significant and substantial work in this field has been reported, systematic review articles are rare.9 Therefore, the aim of this Minireview is to provide an overview of recent developments in electrophile‐induced stereoclass="Chemical">specific 1,2‐migration of <class="Chemical">span class="Chemical">boronate complexes, including Zweifel‐type reactions, conjunctive cross‐couplings, and transition metal‐free sp2–sp3 couplings. The scope of this review also extends to boronate complexes containing strained σ‐bonds, which exhibit similar reactivity to π‐bonds.

Stereospecific 1,2‐Migration of Alkenyl Boronates Induced by Electrophiles

Zweifel‐type Coupling Reactions

In 1967, class="Chemical">Zweifel first reported the stereoselective synthesis of <class="Chemical">span class="Chemical">alkenes using organoboron intermediates (Scheme 2 a).10 The reaction was initiated by hydroboration of alkyne 1 with dicyclohexylborane, resulting in the formation of alkenyl borane 2 a, which was then reacted with iodine in the presence of sodium hydroxide, leading to Z‐alkene 5. The reaction proceeds via cyclic iodonium ion intermediate 3, followed by a stereospecific 1,2‐migration affording β‐iodoborinic acid 4. This species then undergoes anti elimination in the presence of base, which results in an overall inversion of alkene geometry from 2 to 5. Furthermore, it was later proved that the migrating moiety underwent 1,2‐migration with complete retention of configuration by employing diastereomerically pure borane 6 as a substrate in the reaction (Scheme 2 b).11 Considering the stereochemical features of this process, a syn elimination (giving the E‐alkene) should be possible if the interaction between the β‐halogen and boron of the β‐haloboron intermediate could be enhanced. Indeed, Zweifel demonstrated that syn elimination was favoured if a strong electron‐withdrawing group (CN) was introduced on boron, which allowed coordination of the bromide to boron in intermediate 10 and resulted in the formation of E‐olefins 11 (Scheme 2 c).12

Scheme 2

Zweifel olefination: selective synthesis of olefins.

<span class="Chemical">Zweifel olefination: selective synthesis of <class="Chemical">span class="Chemical">olefins.

The vinyl group is an important functional group, commonly found in natural products and functional materials.13 In this context, the <span class="Chemical">Zweifel olefination provides an excellent method to convert a <class="Chemical">span class="Chemical">boronic ester into a vinyl group by employing vinyl lithium or the corresponding Grignard reagent.14 In 2009, Aggarwal applied this concept to the total synthesis of (+)‐faranal (Scheme 3).15 Enantioenriched boronic ester 12 was reacted with vinyl lithium and then treated with iodine and sodium methoxide, which provided alkene intermediate 13. Without isolation of 13, in situ hydroboration and oxidation gave alcohol 14 in 69 % yield and with excellent diasteroselectivity. Finally, (+)‐faranal was obtained by oxidation of 14 with pyridinium chlorochromate (PCC). Additionally, this strategy was also successfully used by Morken to introduce an isoprenyl group in the total synthesis of debromohamigeran E (Scheme 4).16 Alkene 16 was formed in high yield on a gram‐scale by Zweifel olefination of boronic ester 15 with isopropenyllithium.

Scheme 3

Zweifel olefination in the total synthesis of (+)‐faranal.

Scheme 4

Zweifel olefination in the total synthesis of debromohamigeran E.

<span class="Chemical">Zweifel olefination in the total synthesis of (+)‐faranal.

<span class="Chemical">Zweifel olefination in the total synthesis of <class="Chemical">span class="Chemical">debromohamigeran E.

Enantioenriched class="Chemical">tertiary boronic esters 17 have also been subjected to the same <class="Chemical">span class="Chemical">Zweifel olefination conditions to form vinyl‐substituted quaternary stereogenic centers 18 with complete enantiospecificity (Scheme 5 a).17 It is noteworthy that allylsilanes 20 could also be obtained in high enantiomeric excess using this protocol (Scheme 5 b).18 However, the preparation of vinyllithium typically relies on in situ lithium–tin exchange of tetravinyltin, or lithium‐bromide exchange of vinyl bromide, which reduces its practicality. Therefore, vinyl Grignard reagents, which are easier to handle and commercially available, have also been explored in the Zweifel olefination (Scheme 5 c).19 A consequence of changing from vinyllithium to vinyl Grignard reagents, is that magnesium pinacolate is readily formed from MgII salts and the pinacol ligand on boron. Therefore, upon reaction of a boronic ester with a vinyl Grignard reagent, trivinyl boronate species 21 is formed instead of the mono‐vinyl pinacolato boronate. Normally, this necessitates the use of an excess of vinyl Grignard (4.0 equivalents) but by screening various reaction conditions, it was found that using a mixed solvent system (1:1 THF/DMSO) allowed boronic esters to undergo vinylation using 1.2 equivalents of vinyl Grignard.20 Whilst this method shows synthetic utility, it is not suitable for sterically hindered tertiary boronic esters, which makes the higher reactivity of vinyllithium more attractive. This is illustrated in a five‐step synthesis of (±)‐grandisol, where a Zweifel olefination was used to convert tertiary boronic ester 24 into terminal alkene 25 (Scheme 5 d). Subsequent hydroboration/oxidation and Cope elimination provided the natural product in good yield and high diastereoselectivity.21

Scheme 5

Enantiospecific Zweifel olefinations of secondary and tertiary boronic esters with vinyl lithium or vinyl Grignard reagents. PMP=4‐methoxyphenyl.

Enantiospecific class="Chemical">Zweifel olefinations of secondary and <class="Chemical">span class="Chemical">tertiary boronic esters with vinyl lithium or vinyl Grignard reagents. PMP=4‐methoxyphenyl.

In the past decade, the scope of the class="Chemical">Zweifel olefination reaction has been greatly expanded. For example, α‐heteroatom‐substituted alkenyl <class="Chemical">span class="Chemical">metals 27 have been successfully coupled with secondary boronic esters (Scheme 6 a),20 which provides great opportunities for application in synthesis as the vinyl ether products 29 can be easily converted into ketones by hydrolysis under mild conditions.19 This methodology was used to convert boronic ester 30 into enol ethers 31 and 32 in the synthesis of the reported and revised structures of baulamycins A and B, respectively (Scheme 6 b).22

Scheme 6

Synthesis of α‐heteroatom‐substituted alkenes by Zweifel olefination and application to the synthesis of baulamycins A and B. PMB=4‐methoxybenzyl.

Synthesis of α‐heteroatom‐substituted class="Chemical">alkenes by <class="Chemical">span class="Chemical">Zweifel olefination and application to the synthesis of baulamycins A and B. PMB=4‐methoxybenzyl.

The enantiospecific alkynylation of secondary and <span class="Chemical">tertiary boronic esters is an extension to the established <class="Chemical">span class="Chemical">Zweifel olefination. In situ α‐lithiation of vinyl bromides or carbamates in the presence of the boronic ester provided boronate complexes 33 that underwent iodine‐induced olefination to give alkenyl bromides or carbamates 34 (Scheme 7 a).23 Subsequent base‐induced 1,2‐elimination afforded the alkynylated products 35. In this reaction, various terminal and silyl‐protected alkynes can be obtained with high enantiospecificity, and a broad range of functional groups (alkenes, azide, alkyne, and ester groups) are tolerated. Furthermore, it was used in the total synthesis of tatanan A, where complex boronic ester 36—constructed using iterative reagent‐controlled homologation—was employed in an enantiospecific Zweifel‐type alkynylation to afford alkyne 37 (Scheme 7 b).24 It should be noted that alkynyl anions cannot be used directly in Zweifel‐type alkynylation since they react reversibly with boronic esters. However, they can used in reactions with boranes or borinic esters.25

Scheme 7

Enantiospecific alkynylation via Zweifel olefination.

Enantiospecific alkynylation via <span class="Chemical">Zweifel olefination.

Intramolecular class="Chemical">Zweifel olefination has also been achieved, which provides access to <class="Chemical">span class="Chemical">methylene cycloalkanes (Scheme 8).26 Alkenyl bromide‐containing boronic ester 39—obtained with high stereoselectivity from 38 by lithiation‐borylation—was treated with BuLi to form an alkenyl lithium intermediate through lithium‐halogen exchange. This species cyclised to give an intermediate cyclic boronate complex. Subsequent treatment with iodine and methanol under Zweifel olefination conditions afforded ring contracted methylene cyclopentane 40 in 97 % yield with 100 % enantiospecificity, which was then transformed into the natural product (−)‐filiformin. This ring contraction methodology was extended to the more challenging synthesis of highly strained methylene cyclobutane 41, which was obtained in 63 % yield and >99:1 e.r.

Scheme 8

Intramolecular Zweifel olefination with α‐substituted alkenes.

Intramolecular <span class="Chemical">Zweifel olefination with α‐substituted <class="Chemical">span class="Chemical">alkenes.

Since its introduction over 50 years ago, the class="Chemical">Zweifel olefination has become a powerful method to transform <class="Chemical">span class="Chemical">boronic esters into structurally diverse alkenes with excellent control of alkene geometry. Importantly, by proceeding through a stereospecific 1,2‐migration mechanism, the chiral information of the boronic ester substrate is fully translated to the alkene product. This high level of stereocontrol is often unachievable with metal‐catalyzed Suzuki–Miyaura cross‐couplings, which has resulted in the Zweifel olefination being commonly employed in the synthesis of complex natural products and pharmaceutical intermediates.

Sulfur and Selenium‐Based Electrophiles

In 2017, Aggarwal reported a modified class="Chemical">Zweifel‐type <class="Chemical">span class="Chemical">olefination proceeding through a novel syn elimination process (Scheme 9).27 This was achieved by employing PhSeCl as the electrophile for the selenation of alkenyl boronates 43, which led to β‐selenoboronic esters 46 through the stereospecific 1,2‐migration ring‐opening of seleniranium intermediates 45. It was found that m‐CPBA was able to chemoselectively oxidise the selenide to give selenoxide intermediate 47, which underwent syn elimination to provide alkenes 44 in high stereoselectivity. DFT calculations showed that the oxygen atom of selenoxide 47 interacts strongly with the boron atom, therefore resulting in a syn elimination pathway. This selenium‐mediated olefination showed broad substrate scope in terms of both the boronic esters and the alkenyl lithium reagents (di‐ and trisubstituted), leading to synthetically useful alkene products 44 with high selectivity for retention of olefin geometry.

Scheme 9

Selenium‐mediated Zweifel‐type olefination via syn elimination.

class="Chemical">Selenium‐mediated <class="Chemical">span class="Chemical">Zweifel‐type olefination via syn elimination.

In 2018, Denmark reported an alternative chalcogenation‐induced 1,2‐migration of <span class="Chemical">alkenyl boronates (Scheme 10).28 Through the use of a chiral Lewis base catalyst in combination with N‐(phenylthio)saccharin (51) as a source of electrophilic <class="Chemical">span class="Chemical">sulfur, an enantioselective sulfenylation was achieved. This provided access to a broad array of enantioenriched anti β‐sulfenoboronic esters 50 with two contiguous stereogenic centers with complete diastereoselectivity. Chiral sulfenylating reagent 52, formed from the nucleophilic addition of chiral selenophosphoramide catalyst (S)‐L to 51, is a cationic donor‐acceptor species with a highly electrophilic sulfur atom. Reaction of 52 with alkenyl boronate 48 generates the enantioenriched thiiranium ion 49, which undergoes 1,2‐migration to generate anti‐products 50 with high enantioselectivity.

Scheme 10

Lewis base‐catalyzed enantioselective electrophile‐induced 1,2‐migration of alkenyl boronates.

Lewis base‐catalyzed enantioselective electrophile‐induced 1,2‐migration of <span class="Chemical">alkenyl boronates.

Transition Metal‐Catalyzed Conjunctive Cross‐Couplings

It is known that π‐acidic late transition class="Chemical">metal complexes in high oxidation states, such as <class="Chemical">span class="Chemical">PdII and NiII, are highly electrophilic and able to strongly coordinate to π‐bonds. In 2015, Morken reported that such species could interact with the electron‐rich π‐bond of alkenyl boronate complexes, triggering a 1,2‐migration of an alkyl or aryl group on boron (Scheme 11).29 Key to the success of this reaction was the use of aryl triflates rather than aryl halides, which generated a more reactive cationic PdII intermediate, and the use of the Mandyphos ligand L to reduce the propensity for β‐hydride elimination of intermediate alkylpalladium(II) intermediates. Furthermore, using a chiral phosphine ligand gave the conjunctive coupling products in good yield and high enantioselectivity. The choice of diol ligand on boron played an important role in determining the enantioselectivity. Interestingly, the optimum diol ligand was found to be dependent on the triflate electrophile, with neopentyl glycol ligands proving optimal for aryl triflates, whereas pinacol ligands provided significantly improved selectivity in reactions of alkenyl triflates. Mechanistically, it was postulated that oxidative addition of Pd0 species 55 to an aryl/alkenyl triflate generates the electrophilic PdII intermediate 56 (Scheme 12). This complexes with alkenyl boronate 53 to form complex 57, which triggers 1,2‐migration to generate alkyl palladium(II) intermediate 58. This is followed by reductive elimination, giving the boronic ester 59 and regenerating the Pd0 catalyst 55. The large bite‐angle of ligand L limited the undesired β‐hydride elimination of 58.

Scheme 11

Enantioselective conjunctive cross‐coupling enabled by palladium‐induced 1,2‐migration. [a] Using the pinacol‐derived boronate complex. RM=Migrating group.

Scheme 12

Proposed catalytic cycle of the conjunctive cross‐coupling. neo=neopentyl glycolato. RM=Migrating group.

Enantioselective conjunctive cross‐coupling enabled by <span class="Chemical">palladium‐induced 1,2‐migration. [a] Using the <class="Chemical">span class="Chemical">pinacol‐derived boronate complex. RM=Migrating group.

Proposed catalytic cycle of the conjunctive cross‐coupling. <span class="Chemical">neo=<class="Chemical">span class="Chemical">neopentyl glycolato. RM=Migrating group.

class="Chemical">Morken has built on this discovery with a number of important developments (Scheme 13). Firstly, the reaction has been extended to Grignard reagents instead of <class="Chemical">span class="Chemical">organolithiums and to halide electrophiles in place of triflates (Scheme 13 a).30 It was found that the conjunctive cross‐coupling was inhibited by halide ions, which had previously limited the use of aryl halide electrophiles. However, this limitation was overcome by using a combination of NaOTf and DMSO as additives, which allowed the formation of cross‐coupled products 61 with high yields and enantioselectivities. The effect of these additives was two‐fold: (i) the NaOTf resulted in precipitation of the sodium halide salt, thus avoiding the detrimental coordination of halide ions to palladium and creating the more electrophilic PdII complex; and (ii) the combination of NaOTf and DMSO greatly increased the stability of the alkenyl boronate complexes 60 generated from the vinyl Grignard reagent. Conjunctive cross‐couplings between alkenyl boronic esters 62, vinyllithium, and aryl/alkenyl triflate were next explored (Scheme 13 b).31 These reactions proceed through bis‐alkenyl‐boronate complexes 63, with the PdII intermediate showing a preference for reaction with the less substituted alkene, and allow access to chiral allylboronic esters 64. Extension of this approach to boronate complexes derived from α‐substituted alkenyl boronic esters 65 allowed access to highly desirable tertiary boronic esters 66 with good enantioselectivity (Scheme 13 c).32 β‐Substituted alkenyl boronic esters 67 were also successfully employed, but required alterations to the boron ligand design to prevent undesired Suzuki‐Miyura‐type reactivity, which was found to dominate with pinacol and neopentyl glycol boronic ester substrates (Scheme 13 d).33 A more sterically demanding boronic substituent (mac), derived from acenaphthoquinone, was required to minimize Suzuki–Miyaura coupling and direct the approach of the palladium(II) complex to the more congested β‐carbon, thus enabling access to the conjunctive cross‐coupling products 68 with excellent stereoselectivities. Furthermore, this approach was applied to β‐silyl alkenyl boronate complexes 69 for the efficient construction of anti‐1,2‐borosilanes (Scheme 13 d).34 Finally, using propargylic carbonates 72 in place of aryl triflates furnished fully substituted β‐boryl allenes with high enantioselectivity (Scheme 13 e).35 It was found that a methanol additive resulted in formation of a dimethoxyboronate intermediate through boron ligand exchange, which significantly enhanced both the yield and enantioselectivity of the reaction.

Scheme 13

Catalytic conjunctive cross‐coupling reactions enabled by palladium‐induced 1,2‐migration. RM=Migrating group.

Catalytic conjunctive cross‐coupling reactions enabled by <span class="Chemical">palladium‐induced 1,2‐migration. RM=Migra<class="Chemical">span class="Chemical">ting group.

class="Chemical">Morken has since extended this conjunctive cross‐coupling to include <class="Chemical">span class="Chemical">enyne‐derived boronate complexes 74, which give α‐hydroxy allenes 75 after oxidative work‐up (Scheme 14).36 Interestingly, enyne boronates derived from Z‐alkenes provided α‐boryl allenes with high diastereoselectivity, whereas E‐alkene substrates gave low diastereoselectivity. This was rationalized based on the steric interactions between the migrating group and the palladium complex: in the case of the Z‐alkene, complex syn‐76 has these moieties in close proximity so they orientate to minimize steric interactions, making anti‐76 the reactive conformer; whereas in the E substrate, there is little interaction between the migrating group and the palladium complex in either conformers anti‐77 or syn‐77, resulting in poor diastereocontrol. For reactions with alkyl migrating groups, substitution of the pinacol ligand on boron for an acenaphthoquinone‐derived boronic substituent (hac*) was essential for achieving high stereoselectivity, which was attributed to enhanced catalyst‐substrate steric interactions.

Scheme 14

Palladium‐catalyzed enantioselective conjunctive cross‐coupling reactions of enyne boronate complexes. [a] Using B(hac*) instead of Bpin. RM=Migrating group.

class="Chemical">Palladium‐catalyzed enantioselective conjunctive cross‐coupling reactions of <class="Chemical">span class="Chemical">enyne boronate complexes. [a] Using B(hac*) instead of Bpin. RM=Migrating group.

Electrophilic class="Chemical">palladium complexes have also been used to trigger a 1,2‐migration in <class="Chemical">span class="Chemical">indole‐derived boronate complexes. Following Ishikura's studies on palladium‐catalyzed allylation of 2‐indolyboronates derived from trialkylboranes,37 Ready showed that these reactions could be extended to boronic esters and rendered asymmetric using Pd(BINAP) catalysts (Scheme 15).38 The indole‐derived boronate complexes 78 reacted with Pd(π‐allyl) complexes, to form indolin‐2‐yl boronic esters 79 with high levels of diastereo‐, regio‐, and enantioselectivity. The boronic esters products were oxidized with basic hydrogen peroxide to provide the corresponding indoles 80. Alternately, protodeborylation of benzylic boronic ester products (79, R1=aryl) with TBAF trihydrate gave 2,3‐disubsituted indolines 81. Various aryl and alkyl migrating groups could be employed in this asymmetric three‐component coupling, which provided indoline products with three contiguous stereogenic centers. The scope of the reaction was subsequently extended to 3‐alkyl‐substituted indoles by using a Pd/phosphoramidite catalyst system, which enabled the enantioselective formation of indolin‐2‐yl boronic esters 82 with adjacent quaternary stereocenters.39

Scheme 15

Palladium‐catalyzed enantioselective three‐component coupling.

<span class="Chemical">Palladium‐catalyzed enantioselective three‐component coupling.

class="Chemical">Morken has also demonstrated that <class="Chemical">span class="Chemical">nickel(II) complexes interact with alkenyl boronates in a similar manner to palladium(II) complexes.40 When investigating a one‐pot 9‐BBN hydroboration/enantioselective conjunctive cross‐coupling reaction between alkenes and aryl iodides, they found that the Pd/Mandyphos catalyst system that was optimal for pinacol boronate substrates only provided racemic products when applied to the 9‐BBN‐derived boronates 83 (Scheme 16). However, a nickel catalyst in combination with the diamine ligand (S,S)‐L gave the products 84 in high enantioselectivity. Detailed mechanistic studies indicated that the reaction involves initial oxidative addition of the aryl iodide to Ni0 to give a NiII species, which binds the alkene (forming 85) to induce 1,2‐migration with stereospecific anti addition of the migrating group and NiII across the alkene. Morken subsequently extended the scope of these nickel‐catalyzed conjunctive cross‐couplings to other electrophiles, including alkyl halides and acid chlorides.41

Scheme 16

Ni‐catalyzed enantioselective conjunctive cross‐coupling reactions.

Stereospecific sp2–sp3 Coupling of Chiral Boronic Esters with Aromatic Compounds

In 2014, Aggarwal disclosed an efficient and general method for stereospecific <span class="Chemical">sp2–<class="Chemical">span class="Chemical">sp3 couplings of electron‐rich (hetero)aromatics with chiral secondary and tertiary boronic esters (Scheme 17 a).42 The reaction occurs by initial reaction of an aryllithium with boronic ester 18 to form aryl boronate complex 86, followed by treatment with an electrophilic halogenating agent to provide the arylated product 87 in high yield and with complete stereospecificity. This process could be used to introduce various electron‐rich aromatic groups, including 5‐membered ring heteroaromatics and 6‐membered ring aromatics with meta‐electron‐donating groups, and was applicable to a broad range of secondary and tertiary boronic esters with different steric demands. In most cases, NBS was the optimal electrophile, with NIS being employed in cases where further halogenation of the electron‐rich aromatic ring occurred. Mechanistically, the addition of NBS to the aromatic ring of boronate complex 86 generates cation 88. This triggers a stereospecific 1,2‐migration, forming δ‐halo allylic boronic ester intermediate 89, and subsequent elimination/rearomatization leads to the arylated product 87. Subsequent DFT calculations on the reaction between furyl boronate complex 86 a and NBS provided evidence for simultaneous electrophilic bromination and 1,2‐migration steps, without formation of the postulated cationic intermediate 88.43

Scheme 17

Coupling boronic esters with electron‐rich aromatic compounds.

Coupling <span class="Chemical">boronic esters with electron‐rich aromatic compounds.

In later studies, it was found that the coupling of 6‐membered ring aromatics was dramatically affected by solvent choice (Scheme 17 b).43 Solvent exchange from <span class="Chemical">THF to <class="Chemical">span class="Chemical">MeOH led to improved yields of coupled products 87, which was due to a reduction of the amount of undesired SE2 bromination of the C−B bond of 86. Interestingly, switching to less nucleophilic alcohol solvents promoted an alternative arylation pathway to provide Bpin‐incorporated coupling products 93 with complete stereospecificity. Using an PrOH‐MeCN mixed solvent system resulted in an inefficient nucleophile‐promoted Bpin elimination of dearomatized intermediate 91, therefore 91 underwent a 1,2‐Wagner–Meerwein shift44 of the Bpin moiety to form carbocation 92, which relieved steric encumbrance and allowed subsequent rearomatization by deprotonation to afford 93.

Aggarwal has since expanded this concept of electrophilic‐induced arylation of <span class="Chemical">boronic esters to allow coupling of a range of substituted aromatic rings. For example, <class="Chemical">span class="Chemical">phenylacetylene products 95 and 96 could be accessed by coupling between p‐lithiated phenylacetylenes (generated by halogen‐lithium exchange of the corresponding bromide 94) and a range of chiral boronic esters 18 (Scheme 18).45 Treatment of the intermediate TMS‐phenylacetylene‐derived boronate complex with NBS results in bromination of the alkyne motif, which triggered a stereospecific 1,2‐migration leading to dearomatized bromoallene intermediate 97. Using unhindered neopentyl glycol boronic esters and MeOH as solvent, subsequent nucleophile‐promoted elimination and rearomatization of 97 a occurred, resulting in the formation of coupled product 95. In contrast, the use of the more hindered pinacol boronic esters and PrOH as the solvent prevented nucleophile‐promoted elimination, therefore 1,2‐Wagner–Meerwein shift of the Bpin moiety occurred instead. This led to carbocation 98, which, after loss of a proton, furnished the ortho Bpin‐incorporated product 96.

Scheme 18

Coupling boronic esters with phenylacetylenes via alkyne activation.

Coupling class="Chemical">boronic esters with <class="Chemical">span class="Chemical">phenylacetylenes via alkyne activation.

Ortho‐ and para‐substituted class="Chemical">phenols provide a different opportunity for triggering 1,2‐migration of <class="Chemical">span class="Chemical">aryl boronate complexes (Scheme 19).46 In the coupling of para‐lithiated phenolates 99 with boronic esters, following formation of boronate complex 100, 1,2‐migration occurred upon the activation of the phenolate with Martin's sulfurane (Ph2S[OC(CF3)2Ph]) or triphenylbismuth difluoride (Ph3BiF2), forming boronate complexes 102 and 103, respectively (Scheme 19 a). Elimination of Bpin from cyclohexandienone 104 then provides the coupled products 101. This method was less effective for ortho‐substituted phenols due to increased steric hindrance, which prevented effective phenolate activation. Interestingly, this limitation was overcome by performing the coupling with lithiated N‐phenoxy benzotriazole 105, where the pre‐incorporated benzotriazole acts as a leaving group (see intermediate 106) so circumvents the challenging ortho‐phenolate activation (Scheme 19 b). 1,2‐Migration successfully occurred at ambient temperature to allow access to ortho‐substituted phenol products 107 with complete stereospecificity.

Scheme 19

Coupling boronic esters with ortho‐ and para‐phenols.

Coupling <span class="Chemical">boronic esters with ortho‐ and para‐<class="Chemical">span class="Chemical">phenols.

A similar strategy was used by Aggarwal to access class="Chemical">aniline products 110 through N‐acylation of <class="Chemical">span class="Chemical">boronate complexes generated from lithiated para‐ and ortho‐phenyl hydrazines 108 (Scheme 20 a).47 Acylation of the para‐hydrazinyl boronate complex with trifluoroacetic anhydride (TFAA) formed acyl ammonium 109, with subsequent concurrent 1,2‐migration and N−N bond cleavage. After Bpin elimation/rearomatization and further reaction of the resulting amino group with TFAA, the trifluoroacetamide products 110 were isolated in good yield and with complete stereospecificity. For the corresponding ortho‐hydrazinyl boronate complexes, changing the N‐activator from TFAA to the less reactive 2,2,2‐trichloro‐1,1‐dimethylethyl chloroformate (Me2Troc‐Cl) was required to obtain the ortho‐aniline products in good yield.

Scheme 20

Coupling boronic esters with lithiated arylhydrazines and ortho‐lithiated benzylamines. TFA=trifluoroacetyl. DMT=2,2,2‐trichloro‐1,1‐dimethylethoxycarbonyl.

Coupling class="Chemical">boronic esters with lithiated <class="Chemical">span class="Chemical">arylhydrazines and ortho‐lithiated benzylamines. TFA=trifluoroacetyl. DMT=2,2,2‐trichloro‐1,1‐dimethylethoxycarbonyl.

By taking advantage of this N‐acylation approach, Aggarwal showed that class="Chemical">boronate complexes 111 derived from ortho‐<class="Chemical">span class="Chemical">benzylamines can also undergo electrophile induced 1,2‐migration (Scheme 20 b).48 Treatment of boronate complex 111 with Me2Troc‐Cl generated N‐acylated intermediate 112, which triggers a 1,2‐migration/anti‐SN2′ reaction to form dearomatized intermediate 113. This step is surprisingly fast and complete within 5 minutes at −78 °C. A subsequent suprafacial Lewis acid mediated 1,3‐borotropic shift of 113 gave enantioenriched ortho‐substituted benzylic boronic esters 114 in high yields and stereospecificities. Furthermore, through the use of enantioenriched secondary benzylic amine substrates, it was shown that the anti‐SN2′ and 1,3‐borotropic shift processes also proceeded with high stereospecificity, which allowed doubly stereospecific reactions to occur when enantioenriched boronic esters were also employed (see product 114 c). Further work highlighted the synthetic utility of the intermediate enantioenriched dearomatized tertiary boronic esters 113, which were utilized in rearomatizing allylic Suzuki–Miyaura cross‐coupling reactions to provide complex enantioenriched 1,1‐diarylmethane products 116 with three readily addressable points of diversification (Scheme 20 c).49

In an alternative N‐acylation‐induced 1,2‐migration of <span class="Chemical">aryl boronate complexes, Aggarwal developed a general protocol for the stereoclass="Chemical">specific coupling of chiral secondary and <class="Chemical">span class="Chemical">tertiary boronic esters with electron‐deficient N‐heteroaromatics (Scheme 21 a).50 After formation of chiral boronate complexes 119 from lithiated 6‐membered ring N‐heterocycles 117 (including pyridines, quinolines and isoquinolines), 1,2‐migration was triggered by N‐acylation with 2,2,2‐trichloroethyl chloroformate (Troc‐Cl), leading to dearomatized tertiary boronic ester 121 via the intermediate N‐acyl pyridinium 120. A one‐pot oxidation/hydrolysis/elimination sequence finally furnished the coupled heteroaromatic products 118 with complete stereospecificity. A modified approach was reported by Ready, in which the pyridyl boronate complexes 119 were generated by adding organometallic reagents to 4‐pyridyl boronic ester 18 e (Scheme 21 b).51 It was shown that, in addition to organolithium reagents, organozinc and Grignard reagents could also be employed in this heteroarylation reaction.

Scheme 21

Coupling boronic esters with electron‐deficient N‐heteroaromatics.

Coupling <span class="Chemical">boronic esters with electron‐deficient N‐heteroaromatics.

Electrophile‐Induced 1,2‐Migration of Strained Boronates

It is shown above that electrophilic class="Chemical">metal complexes, including <class="Chemical">span class="Chemical">PdII and NiII, can coordinate with the π‐bonds of alkenyl boronate complexes to trigger 1,2‐migration and achieve carbometallation of alkenes (Scheme 11). Although such metal species readily react with C−C π‐bonds, they generally do not react with C−C σ‐bonds. However, Aggarwal has recently reported that cationic palladium(II) complexes can activate σ‐bonds of highly strained boronate complexes to promote 1,2‐migration and achieve σ‐bond carbopalladations (Scheme 22).52 To achieve such a process, bicyclo[1.1.0]butyl boronate complexes 124 were prepared from sulfoxide 122 by sulfoxide‐lithium exchange and in situ borylation of the resulting bicyclo[1.1.0]butyllithium (123). The high ring strain of the bicyclo[1.1.0]butane (≈66 kcal mol−1) weakens the central σ‐bond, and the release of this strain provides significant driving force to allow efficient reaction of 124 with a PdII catalyst. This enabled a distal cross‐coupling of boronic esters and aryl triflates to provide 1,1,3‐trisubstituted cyclobutanes 125 in high yields and with complete stereospecificity and diastereocontrol. The proposed mechanism involves initial oxidative addition of the aryl triflate to the Pd0 catalyst 126 to form the cationic PdII complex 127. Reaction of 127 with boronate complex 124 occurs at the more nucleophilic β‐carbon to provide the cyclobutyl palladium intermediate 128. As 1,2‐migration requires an anti‐periplanar alignment of the migrating group (RM) and the breaking C−C bond, this makes the endo face of the reactive conformer more sterically hindered, thus the bulky metal complex approaches from the more exposed exo face. This forms intermediate 129 with complete diastereocontrol for syn‐carbopalladation, which, after stereospecific reductive elimination provides 125 in excellent diastereoselectivity. This interesting strain release‐driven 1,2‐migation of bicyclo[1.1.0]butyl boronate complexes opens up new directions for stereospecific transformations involving 1,2‐migration to sp3‐hybridized carbons.

Scheme 22

Pd‐catalyzed strain‐release‐driven diastereoselective distal cross‐coupling reaction. RM=Migrating group.

<span class="Chemical">Pd‐catalyzed strain‐release‐driven diastereoselective distal cross‐coupling reaction. RM=Migra<class="Chemical">span class="Chemical">ting group.

Summary and Outlook

class="Chemical">Organoboron compounds are indiclass="Chemical">spensable in synthetic chemistry, providing a powerful platform for myriad transformations. The stereoclass="Chemical">specific 1,2‐migration of <class="Chemical">span class="Chemical">boronate complexes is one of the most important processes in this area. This can be triggered by a suitable α‐leaving group, oxidation of α‐boryl radicals, or electrophilic activation. As described above, electrophilic activation of boronate complexes can take many different forms and provide access to a diverse array of products from readily available chiral boronic ester. In the case of the Zweifel olefination, reaction of alkenyl boronate complexes with iodine transforms boronic esters into alkenes with high selectivity for inversion of alkene geometry, providing a valuable methodology that has been exploited extensively in total synthesis. This concept has more recently been extended chalcogenation of alkenyl boronate complexes, including selenation, which provides a unique opportunity to switch the stereoselectivity of the Zweifel olefination from inversion to retention. Furthermore, the principles behind the Zweifel olefination have inspired the development of a broad range of arylation and heteroarylation reactions. An important advance in alkenyl boronate complex reactivity has been the development of enantioselective metal‐catalyzed conjunctive cross‐couplings, which have greatly expanded the range of electrophiles that can be employed in electrophile‐induced 1,2‐migration chemistry. This new area in boron chemistry and has since been extended to boronate complexes containing highly strained σ‐bonds in place of π‐bonds, providing further unique opportunities for reaction development.

Future developments could see the application of class="Chemical">boronic esters in stereoclass="Chemical">specific 1,2‐migrations of <class="Chemical">span class="Chemical">alkynyl boronate complexes, which have so far been unsuccessful due to their instability. In addition, the development of new electrophilic triggers for various boronate complexes will extend the scope of the chemistry, leading to new opportunities in asymmetric synthesis. While the field of electrophile‐induced 1,2‐migration of boronate complexes is over 50 years old, it remains an exciting area that is continually expanding. It is remarkable that the seminal olefination work by Zweifel in 1967 has inspired so many new methodologies with broad‐ranging applications in synthetic chemistry.

Conflict of interest

The authors declare no conflict of interest.

Biographical Information

Hui Wang was born in Anhui, China. He received his B.Sc. (2011) and M.Sc. (2014) degrees in organic chemistry from Zhengzhou University under the supervision of Prof. Xiuling Cui and Prof. Yangjie Wu. After that he joined the group of Prof. Lutz Ackermann, Georg‐August‐University Göt<span class="Chemical">tingen (Germany) and fi<class="Chemical">span class="Chemical">nished his PhD in 2019. In the same year, he moved to the University of Bristol (UK) as a postdoctoral fellow to work with Prof. Varinder K. Aggarwal on asymmetric synthesis based on boronate complexes.

Changcheng Jing obtained his B.A. from the College of Chemistry, Chemical Engineering and Materials Science at Shandong Normal University in 2009. He then conducted his Ph.D. studies under the supervision of Prof. Wenhao Hu in the School of Chemistry and Molecular Engineering of East China Normal University and Prof. Michael P. In 2017 he moved to the group of Prof. Varinder K. Aggarwal at the University of Bristol as a postdoctoral research associate, where his current research interests focus on total synthesis of natural products.

Adam Noble graduated from the University of Not<span class="Chemical">tingham with an M.Sci. degree in Chemistry in 2008. He subsequently gained his Ph.D. (2012) from University College London, working with Prof. Jim Anderson. He then carried out postdoctoral research with Prof. Davis W. C. MacMillan at Princeton University (2012–2014) and with Prof. Varinder K. Aggarwal at the University of Bristol (2014–2017). In 2017, he started his current position as Research Officer in the Aggarwal group at the University of Bristol.

Varinder K. Aggarwal studied chemistry at Cambridge University and received his Ph.D. in 1986 under the guidance of Dr. Stuart Warren. After postdoctoral studies (1986–1988) under Prof. Gilbert Stork, Columbia University, he returned to the UK as a Lecturer at University of Bath. In 1991 he moved to University of Sheffield, where he was promoted to Professor in 1997. In 2000 he moved to the University of Bristol where he holds the Chair in Synthetic Chemistry. He was elected Fellow of the Royal Society in 2012.