Organoboron chemistry comes to light: recent advances in photoinduced synthetic approaches to organoboron compounds

Abstract

Photoinduced synthetic approaches to organoboron compounds have attracted significant attention in the recent years. Photochemical activation of organic molecules enables generation of reactive intermediates from a variety of precursors, resulting in borylation methods with improved and broader substrate scopes. The review summarizes recent developments in the area of photoinduced reactions of organoboron compounds with an emphasis on borylation of haloarenes, amine derivatives, and redox-active esters of carboxylic acids, as well as photoinduced rearrangements of organoboron compounds and photoinduced synthesis of organoboron compounds from alkenes and alkynes.

Graphical Abstract

1. Introduction

Organoboron compounds are among the most versatile classes of heteroatom-substituted organic molecules. Applications of boronic acids and their derivatives have seen a particularly dramatic surge in the past three decades (Figure 1). In analytical chemistry, the mildly Lewis acidic character of the boron atom is exploited in the context of carbohydrate¹ and fluoride sensing² that is enabled by formation of tetracoordinate borates with fluoride anions and polyols. Boron is more electropositive than carbon, and this fundamental property is exploited to the fullest in organic synthesis that has become one of the most prominent areas of application of organoboron compounds. They serve as key nucleophilic coupling partners for a variety of C−C bond forming reactions, most notably the Suzuki-Miyaura reaction,³ as well as versatile synthetic intermediates derived from hydroboration⁴ and carboboration reactions.⁵ Boronic acids and their derivatives have also been successfully used as catalysts, e.g., for enantioselective reactions⁶ and for the formation of amide bonds.⁷ The recent explosive growth of materials science has led to new applications for boronic acids as building blocks for covalent organic frameworks and hydrogels, as well as neutron capture and phosphorescent materials.⁸ Another recent addition to boronic acids’ repertoire is their emerging role as therapeutic agents and biological probes. In this arena, the first-in-class anticancer drug bortezomib has been joined by the recently approved antifungal tavaborole, and anti-eczema drug crisaborole, while many other boronic acid derivatives have shown promising activities in a large number of clinical and preclinical studies.⁹

Figure 1.

Applications of organoboron compounds.

The most prevalent method of synthesis of boronic acids still relies on the reaction of borate esters with organomagnesium or organolithium reagents, as first described over 100 years ago by Khotinsky and Melamed.¹⁰ In the meantime, new borylation methods have entered the synthetic scene. The most notable of them, the Pd-catalyzed borylation of aryl halides with diboron reagents developed by Miyaura¹¹ obviates the use of organometallic reagents that, in addition to air and moisture sensitivity, can suffer from low functional group tolerance. Miyaura borylation was further extended by Molander and Dreher to allow for a direct synthesis of boronic acids using tetrahydoxydibroron.¹² Other notable borylation approaches include transition metal-catalyzed C–H-borylation,¹³ transition metal-free, base-mediated borylation reactions of iodo- and bromoarenes,¹⁴ as well as electrophilic borylation of electron-rich arenes, alkynes and alkenes,¹⁵ Sandmeyer-type borylation of anilines,¹⁶ and catalytic decarboxylative borylation of N-hydroxyphthalimide esters.¹⁷ Photochemical activation allows for achieving new reactivity patterns and generation of highly reactive intermediates that would not be possible by thermal activation methods.¹⁸ Photoactivation is particularly suitable for homolytic processes, although photoinduced heterolytic pathways are also available. Given the synthetic importance of aryl halides, a number of carbon–carbon and carbon–heteroatom bond-forming reactions, including nucleophilic substitution,¹⁹ arylation,²⁰ alkylation,²¹ and photocyclization²² have been reported that are based on the photoinduced Ar–X bond dissociation. The majority of photoinduced borylation reactions are enabled by radical intermediates that take part in homolytic substitution at one of the boron atoms of diboron reagents (Figure 2). Homolytic substitution is a general type of reaction for organoboron compounds.²³ Although homolytic substitution at diboron reagents would produce boryl radicals that are inherently unstable and electron deficient species (as reflected in the high bond dissociation energies for B−H bonds),²⁴ the reaction could be made more thermodynamically favorable by prior formation of sp²-sp³ adducts of diboron reagents with Lewis bases. Such adducts have been observed and in some cases isolated (e.g., with fluoride, alkoxides, N-heterocyclic carbenes, 4-methylpyridine and phosphines).²⁵ The Lewis base-stabilized boryl radicals that are produced from the sp²-sp³ adducts via homolytic substitution are substantially more stable, and they have previously been observed experimentally.²⁶ Consequently, most of the photoinduced borylation reactions have been rationalized in terms of homolytic substitution at sp²-sp³ adducts of diboron reagents with Lewis bases that are present in the reaction, e.g., solvents, bases, and halide anions.

Figure 2.

Homolytic substitution at boron.

The various new photoinduced synthetic approaches that have appeared in the past decade will be classified by types of reactions. Synthesis of boronic acids and their derivatives by functional group interconversion of halides, carboxylic acids and amine derivatives comprises the largest category of the new methods, and it will be discussed first. Other approaches that make use of alkenes and alkynes will then be covered. Each class of transformations, when possible, will be discussed in the chronological order to highlight current trends in the development of photoinduced borylation and boration methods.

2. C−X Borylation and related reactions

In 2016, Larionov and coworkers reported a photoinduced borylation of haloarenes, including electron-rich fluoroarenes, and quaternary arylammonium salts using tetrahydroxydiboron and other diboron reagents (Figure 3).²⁷ Diverse substituted arylboronic acids bearing functional groups including amide, hydroxy, and ester, as well as heteroarylboronic acids were prepared in good to excellent yields in methanol as a solvent. Aryl iodides and aryl chlorides were also transformed to the corresponding boronic acids, with the iodides giving the boronic acid products in excellent yields within 1 h, compared to 3−24 h in the case of aryl bromides and 24 h with lower yields for aryl chlorides. This reactivity pattern is in line with the increase in the bond dissociation energies (BDE) of Ar-X (C−I 272, C−Br 336, C−Cl 400 kJ·mol⁻¹).²⁸ Interestingly, tavaborole (1), recently approved by the FDA for treatment of onychomycosis was readily prepared in good yield from the corresponding bromoarene following a straightforward workup. The reactions were performed in batch and flow, and also on gram scales.

Figure 3.

Photoinduced borylation of haloarenes.

Fluorobenzene that has a high BDE of the Ar−F bond (526 kJ·mol⁻¹) proved resistant to the borylation. However, fluoroarenes bearing electron-donating substituents are compatible with this transformation. (4-Aminophenyl)boronic acid and (4-hydroxyphenyl)boronic acid were isolated as trifluoroborates in good yields from corresponding unprotected fluoroarenes. For the photoinduced borylation of fluoroarenes, it was suggested that the generation of the triplet aryl cation via the heterolysis of the C−F bond first takes place, which is then followed by the formation of a transient sp²-sp³ B₂(OR)₄−F⁻ species and the subsequent reaction between those two species. The borylation of Ar−N bond was also investigated for arylammonium iodides. Various boronic acids were prepared from corresponding arylammonium iodides in good to excellent yields. Thus, cyclic salt 2 gave boronic acid 3 in good yield.

Besides tetrahydroxydiboron, various diboron esters were employed as effective borylation reagents, producing corresponding phenylboronic esters in acetonitrile as a solvent. A detailed experimental procedure was subsequently reported to facilitate the use of the photoinduced borylation method.²⁹

Mechanistically, initial excitation is followed by intersystem crossing to triplet 4 (Figure 4). Three divergent pathways were proposed for the subsequent borylation. In the first pathway, homolysis of triplet 4 leads to generation of aryl radical 5 that produces boronic acid or ester 6 and radical intermediates 7 or 8 upon homolytic substitution in diboron species 9 or 10. Alternatively, the homolytic substitution can produce anion radical 11. In the second pathway, heterolysis of triplet 4 produces triplet aryl cation 12 that further reacts with in diboron species 9 or 13 to give cation radical 14 and anion radicals 15 or 16. Subsequent single electron transfer (SET) produces boronic acid or ester 6. Given the relatively high photochemical quantum yield (Ф = 0.34), a radical chain pathway was also proposed that involves single electron transfer from anion radical species 7 or 11 to triplet 4 or the ground state haloarene, resulting in aryl radical 5 via the intermediacy of anion radical 17.

Figure 4.

Mechanism of photoinduced borylation of haloarenes.

Following up on the photoinduced monoborylation of haloarenes, Larionov and coworkers further reported an additive-and metal-free photoinduced regioselective 1,2- and 1,3-C−H/C−X diborylation of haloarenes in the same year.³⁰ A notable feature of this method is the strong influence of the solvent on the regioselectivity of the diborylation. While monoborylation is observed in low viscosity solvents (methanol and acetonitrile), a higher viscosity solvent (isopropanol) leads to formation of 1,2-diborylation product 18 and 1,3-diborylation product 19 in 5.3:1 ratio from bromobenzene (Figure 5). This result was explained by the reaction between monoborylation product 20 and the Bpin radical that are formed in the homolytic substitution step. Confinement of intermediate 20 and the Bpin radical in the solvent cage of isopropanol enables addition of the Bpin radical to boronic ester 20 that leads to radical 21. The ortho-selectivity was explained by the stabilization of the radical through conjugation with the boryl group.

Figure 5.

1,2-C−H/C−X diborylation of haloarenes in isopropanol.

On the other hand, in the very polar hexafluoroisopropanol (HFIP) 1,3-C−H/C−X diborylation was observed with a high regioselectivity (19/18/22 ratio 42:5:1) (Figure 6). In this case, it was proposed that the photoinduced heterolytic cleavage generates triplet aryl cation 12 that further undergoes borylation with the sp²-sp³ diboron adduct 23. The resulting cation radical 14 and anion radical 24 further react to give the cationic intermediate 25 that is less destabilized by the electron-withdrawing boryl substituent than cation 26, resulting in meta-product 19. However, the 1,3-substitution pattern induced by weak π-acceptor boryl group can change to 1,2-diborylation if a stronger electron-withdrawing or electron-donating group is present in the para or meta position of the haloarene (Figure 7). High yields were observed for 2- and 4-alkyl-, as well as 2,3-dialkyl- substituted haloarenes in HFIP. In addition, fluoro and chloro groups were tolerated, and the sterically hindered mesitylene also afforded 1,3-diborylation product in good yield. Iodoarenes bearing electron-acceptor groups, e.g., pentafluorosulfanyl, trifluoromethyl, boryl and cyano groups gave the expected single regioisomers of 1,2- or 1,3-diborylation products with the regioselectivity determined by the substituents (Figure 7).

Figure 6.

1,3-C−H/C−X Diborylation of haloarenes in hexafluoroisopropanol.

Figure 7.

Products of 1,2- and 1,3-C−H/C−X diborylation of haloarenes in hexafluoroisopropanol.

The reaction was successfully used to prepare diborylation products on gram scales under batch and continuous flow conditions. HFIP was efficiently recovered by distillation and reused for subsequent diborylation reactions. In addition, UV-transparent plastic vessels were used for batch applications instead of quartz glassware.

In 2016, Li and coworkers reported a photoinduced borylation of haloarenes in the presence of TMDAM (N,N,N′,N′-tetramethyldiaminomethane) (27) in aqueous methanol for boronic acids or a mixture of acetonitrile, acetone and water for boronic esters (Figure 8).³¹ Interestingly, performing the reaction in a continuous-flow setup not only improved the reaction yield but also reduced the amount of B₂pin₂ (1.5 equiv. compared to 2 equiv. in a batch setup) and the reaction time (15 min compared to 4 h in a batch setup). A variety of electron-donating, and electron-withdrawing substituents including hydroxy, amino and carbonyl groups were well-tolerated, giving corresponding boronic acids and esters in good to excellent yields. Aryl iodides afforded borylation products in higher yields than aryl bromides.

Figure 8.

Photoinduced borylation of aryl bromides and iodides in the presence of TMDAM (27).

Mechanistically, the borylation is thought to be initiated by the photoinduced homolytic cleavage of the Ar-X bond (Figure 9). Aryl radical intermediate 5 further reacts with sp³-sp² diboron adduct 28 formed in the reaction between TMDAM (27) with B₂pin₂ in the presence of water, affording borylation product 6. Given the importance of TMDAM (27) for the reaction (e.g., a low yielding borylation is observed with TMDAM in the dark), single electron transfer pathway from both ground state and excited haloarene to give anion radical 17 and cation radical 29 was also proposed. Finally, boron-containing anion radical 30 that is initially produced in the homolytic substitution step is quenched by SET with iodide radical or cation radical 29.

Figure 9.

Mechanism of photoinduced borylation of aryl bromides and iodides in the presence of TMDAM (27).

In the same year, Li and coworkers further expanded the scope of their photoinduced borylation method to electron-rich aryl chlorides, fluorides, mesylates and phosphates (Figure 10).³² The reaction was carried out in a continuous flow reactor with 1.5−2 equiv. of B₂pin₂, 0.5 equiv. of TMEDA (N,N,N′,N′-tetramethylethylenediamine) and 0.1 equiv. of TBAF in a mixture of acetonitrile, acetone and water.

Figure 10.

Photoinduced borylation of electron-rich aryl chlorides, fluorides, and pseudohalides.

The reaction mixture was irradiated by a 300 W high pressure mercury lamp with the retention time ranging from 26 min to 1 h. Chloroarenes containing strong electron-donating substituents including O-, S-, and N-derived groups in the ortho- or para-position afforded corresponding boronic esters. Several aryl fluorides, mesylates and phosphates were also successfully converted to corresponding boronic esters. Aryl triflates, on the other hand, were found to be ineffective, due to hydrolysis. Electron-neutral and electron-deficient aryl chlorides were unreactive under the reaction conditions. Based on experimental and computational data, the mechanism is thought to involve formation of a triplet aryl cation, whose energy is 1.4 kcal mol⁻¹ lower than that of the singlet species, via photoinduced heterolytic cleavage of Ar−X bond. Subsequent three-component combination of the triplet aryl cation, chloride anion and B₂pin₂ passes through a singlet transition state via a crossing point between the triplet and singlet potential energy surfaces, resulting in the ground state borylation product.

The photoinduced borylation was recently successfully used by Sarpong and coworkers in the context of total synthesis of monomeric and dimeric stephacidin A (31) congeners from ketopremalbrancheamide (32) (Figure 11).³³ It was found that ketopremalbrancheamide (32) can be readily converted to malbrancheamide C (33) via a remarkable sequence of C3 bromination and C3 to C6 bromine translocation that is followed by regioselective amide reduction. However, the analogous C6 chlorination approach en route to malbrancheamide B (34) could not be accomplished. Thus, malbrancheamide C (33) was subjected to photoinduced borylation to give boronic ester 35 that was successfully chlorinated with copper dichloride.

Figure 11.

Application of photoinduced borylation in Sarpong’s synthesis of (+)-stephacidin A (31).

In addition, the preparation of (+)-stephacidin A (31) called for installation of a hydroxyl group at C6 in ketopremalbrancheamide (32). The C6 hydroxylation was likewise accomplished by photoinduced borylation of iodoindole 36, followed by oxidation to give hydroxyindole 37 in a 55% yield over two steps. The authors mention that the photoinduced borylation reactions developed by P. Li and Larionov were the only borylation methods that produced the desired products among several protocols that were tested.

In 2016, Fu and coworkers reported a visible light-induced photoredox-catalyzed borylation of haloarenes using iridium photocatalyst 38 (Figure 12). The authors also showed that the borylation can be combined with subsequent aerobic oxidation of the boronate products to phenols.³⁴ In the model reaction of p-iodoanisole with bis(pinacolato)diboron, iridium photocatalyst 38 (fac-Ir(ppy)₃) demonstrated optimal performance with tributylamine as a sacrificial reduction agent. Aqueous acetonitrile proved to be the solvent of choice for this reaction. Replacement of tributylamine with other amines (e.g., triethylamine or diisopropylethylamine) resulted in lower yields. The generality of the method was examined with a number of bromo- and iodoarenes (Figure 12). A variety of functional groups were tolerated the reaction including ether, ketone, nitrile, ester and aldehyde groups. In general, iodoarenes were more reactive than bromoarenes. Aryl iodides bearing both electron-donating and electron-withdrawing substituents performed equally well. On the other hand, electron-deficient aryl bromides gave higher yields of borylation products than electron-rich aryl bromides. Boronic acids were also prepared using this method with tetrahydroxydiboron, however, only aryl iodides were found to be suitable substrates, and the yields were lower than for boronic esters. The reaction was also tested with alkyl bromides under standard conditions, − moderate yields were obtained. Finally, one-pot, two-step reaction including borylation of aryl halides and hydroxylation of arylboronic esters to afford phenols was conducted. Moderate to good yields were observed for the isolated phenols, proving that aryl halides can be converted to phenols by using the developed borylation/oxidation protocol.

Figure 12.

Visible light-induced photoredox borylation of aryl bromides and iodides.

Involvement of hydroxide-diboron adduct 39 is postulated to be promoted by the amine in the aqueous acetonitrile solution (Figure 13). A SET oxidation of the amine by the photoexcited iridium catalyst generates Ir^II species that transfers an electron to aryl halide. The transient anion radical 40 produces aryl radical that further reacts with diboron adduct 39 to give anion radical intermediate 41, which can serve as reductive quencher for the photoexcited Ir catalyst. Brief experimental and EPR studies were performed, and the experimental evidence supported the proposed mechanism. However, it should be pointed out that catalyst 38 (E_1/2(Ir^III*/Ir^II) = +0.31 V vs SCE in MeCN)³⁵ may not be able to oxidize the tertiary amine (E_1/2^red = +0.99 V vs SCE in MeCN for triethylamine),³⁶ but it may be a sufficiently strong reductant (E_1/2(Ir^IV/Ir^III*) = −1.73 V vs SCE in MeCN)³⁵ to mediate the SET-induced cleavage of the aryl halides, as previously shown by Stephenson and coworkers.³⁷

Figure 13.

Mechanism of visible light-induced photoredox borylation of aryl bromides and iodides.

Generation of aryl radicals from aryl triflates is challenging, due to the ease of the S−O bond cleavage that outcompetes the C−O bond cleavage³⁸ and the propensity to undergo hydrolysis, as discussed above for P. Li’s photoinduced borylation method. Based on their earlier work,³⁹ C.-J. Li and coworkers developed a metal-free method of generation of aryl radicals from aryl triflates and applied it to synthesis of aryl boronates (Figure 14).⁴⁰ Specifically, the authors observed that photoinduced borylation of aryl triflates takes place in the presence of TMDAM and NaI. The system is close to the one reported earlier by P. Li,³² but it produces aryl boronates in higher yields. Various substituted boronic esters could be obtained with this protocol. The authors propose that the aryl triflate radical anion is first produced by a photoinduced SET from the iodide anion, due to its noticeable reducing ability (path a, Figure 15). The aryl triflate radical anion further produces aryl radical 5 and the triflate anion. Aryl radical 5 can then engage B₂(Pin)₂ in homolytic substitution at boron. This mechanism does not account for the role of TMDAM (27), and, since aryl iodides can also be obtained from aryl triflates, involvement of transient aryl iodides that undergo TMDAM-induced SET reduction (path b, Figure 15) as proposed by P. Li³² cannot be ruled out.

Figure 14.

Synthesis of aryl boronates from aryl triflates as radical precursors.

Figure 15.

Mechanism of photoinduced borylation of aryl triflates in the presence of iodide.

Cerium complexes have recently attracted attention as photocatalysts, due to the relative abundance of cerium and their favorable photophysical properties.⁴¹ Continuing their work on the photocatalysis with cerium complexes,^41b–d Schelter and coworkers developed a photoinduced borylation of aryl halides catalyzed by hexachlorocerate ([Ce^IIICl₆]^3-) anion (Figure 16).⁴² The team, in collaboration with Anna and coworkers, had previously discovered that [Ce^IIICl₆]^3-, which can be generated in situ from CeCl₃ and NEt₄Cl in acetonitrile is a potent photoreductant, which can mediate single electron transfer reductions of aryl bromides and chlorides.^41d Combining hexachlorocerate(III) photocatalysis with radical borylation mediated by diboron reagents, they obtained a variety of aromatic boronic esters (Figure 16).

Figure 16.

Photoinduced, hexachlorocerate(III)-catalyzed borylation of aryl chlorides and bromides.

Chloroarenes and bromoarenes bearing electron-donating and electron-withdrawing groups in the para, meta, and ortho positions, were converted into the corresponding borylation products, although lower yields were observed for ortho-substituted and heteroaryl products, in the latter case possibly due to coordination of the substrates to the cerium cation. The high quantum yield (Ф = 6.1) points to a radical chain process. The reaction is thought to be initiated by a single electron transfer from the photoexcited hexachlorocerate(III) anion to haloarene (Figure 17). The resulting aryl radical further reacts with diboron reagent and chloride anion to give the borylation product and radical anion 42. Radical anion 42 can further propagate the chain by reacting with haloarene to give radical anion 43 and product 41. A reaction of radical anion 43 with B₂pin₂ regenerates radical anion 42. The photogenerated hexachlorocerate(IV) is reduced via photoinduced ligand to metal charge transfer (LMCT) that produces radical anion 43 upon ligand exchange with chloride anion from Et₄NCl. Reaction of radical anions 42 and 43 is thought to terminate the radical chain process.

Figure 17.

Mechanism of photoinduced, hexachlorocerate(III)-catalyzed borylation of aryl chlorides and bromides.

Following up on their earlier-reported metal-free 1,2-carboboration reaction (see Section 5),⁴³ Studer and coworkers developed a blue LED light-induced borylation of alkyl and aryl iodides with bis(catecholato)diboron, B₂cat₂, (44) in DMF (N,N-dimethylformamide) as a solvent (Figure 18).⁴⁴ The intermediate catecholatoboronic esters were converted to Bpin esters in a reaction with pinacol and trimethylamine to facilitate isolation.

Figure 18.

Blue LED light-induced borylation of alkyl and aryl iodides.

The reaction has a broad scope with respect to alkyl iodides. Thus, primary, secondary and tertiary alkyl iodides were efficiently converted to the corresponding boronic esters in good to excellent yields. Aryl iodides also proved to be suitable substrates, including the ortho-substituted 2-iodotoluene. 1-Cyclohexenyl iodide also produced the corresponding boronic-ester, albeit in a lower yield. Radical clock kinetic measurements were carried out to determine the rate constants for the reaction of the intermediate radical with B₂cat₂. Interestingly, the results of the study suggest that primary alkyl radicals react at a rate that is comparable to that of the reduction with Bu₃SnH. Aryl radicals, on the other hand, react one order of magnitude slower, likely due to the rate-dampening steric interactions.

A detailed computational study was also performed that expanded on the previously suggested mechanism for the blue LED-induced 1,2-carboboration. The borylation is thought to be initiated by photoinduced homolysis of the C−I bond (Figure 19). The produced radical 45 reacts with B₂cat₂ (44) to give intermediate 46 that cannot undergo direct homolytic cleavage of the B−B bond, due to the high thermodynamic and kinetic costs of the process. Instead, an intermediate 47 is formed in a reaction with a molecule of DMF. The homolytic splitting of intermediate 47 into borylation product 48 and a radical intermediate represented by resonance structures 49 and 49ʹ is thermodynamically and kinetically favored. Computational studies indicate that the spin density in 49/49ʹ is much higher at the C atom in the O−C−N fragment than at the boron atom. Thus, subsequent reaction of intermediate 49/49ʹ produces iodide 50, regenerating radical 45 via a kinetically-favored iodine atom abstraction.

Figure 19.

Mechanism of the borylation of alkyl and aryl iodides with B₂cat₂ (44) in DMF.

The area of photoinduced Ar−X borylation has experienced a rapid growth in the past two years. While the catalyst-free methods are operationally simple and readily scalable, photoredox-catalyzed approaches can offer complementary substrate scopes and the practicality of the visible light-induced methodology. While only two of the methods have so far been evaluated in the context of complex target-oriented synthesis, the area will continue to expand, and new practical photoinduced Ar−X borylation methods will no doubt enter the synthetic scene in the near future.

3. Decarboxylative borylation

Glorius and coworkers devised a decarboxylation-based method for conversion of N-hydroxyphthalimide (NHPI) esters of abundant aromatic carboxylic acids 51 to aromatic boronic esters (Figure 20).⁴⁵ The decarboxylative borylation reaction of NHPI esters 51 tolerated a broad range of substrates. Carboxylic acids bearing electron-donating or electron-withdrawing substituents in para- or meta-positions performed well in the reaction and afforded aryl boronic esters in good yields.

Figure 20.

Visible light-induced borylation of NHPI esters of aromatic carboxylic acids.

However, the more electron deficient tetrachlorinated N-hydroxyphthalimide was required for the borylation of electron-deficient carboxylic acids. Borylation of ortho-substituented acids was challenging, and the products were isolated in low yields. Acids containing naphthalenes or heteroaromatic cores, e.g., quinoline, indole, pyridine, and thiophene were successfully borylated in moderate to good yields. Cinnamic acid was converted to a vinyl boronic ester in 80% yield but with 1:2 Z/E ratio. The reaction performed well with aryl halides, affording borylated aryl halides that can undergo two sequential coupling reactions to form difunctionalized arenes. Furthermore, the decarboxylative borylation was utilized to modify two active pharmaceutical ingredients, − probenecid and adapalene, as well as a derivative of herbicide diflufenican.

Functional group tolerance was additionally investigated by a robustness screen⁴⁶ that showed that reaction performed well with alkynes, ketones, aldehydes, alcohols, but it was shut down by anilines and furans. Additionally, the transformation can be carried out with carboxylic acids as starting materials in one-pot procedure without purification of NHPI esters.

Mechanistically, it is proposed that the reaction is initiated by photoexcitation of N-hydroxyphthalimide ester 51 (Figure 21). The excitation is followed by intersystem crossing to generate triplet excited intermediate 52. B₂pin₂ forms sp²-sp³ diboron complex 53 with pyridine, as previously described by Jiao.¹⁴ⁱ A single electron transfer then takes place between triplet intermediate 52 and diboron complex 53 yielding radical anion 54 and radical cation 55. This conclusion results from the analysis of fluorescence quenching of photoexcited ester 51 by the combination of B₂pin₂ and pyridine. The radical anion 54 subsequently fragments into CO₂, phthalimide anion and an aryl radical that undergoes borylation by boron transfer from anion radical 55. Indeed, formation of HO-Bpin that was confirmed by ¹¹B NMR spectroscopy and the failure of radical traps to intercept the transient aryl radical suggest that the in-solvent-cage borylation takes place after the rapid decarboxylation process.

Figure 21.

Plausible mechanism of visible light-induced borylation of NHPI esters 51.

In 2017, Li and coworkers described a photoredox-catalyzed borylation of N-hydroxyphthalimide esters of readily available aliphatic acids 56 (Figure 22).⁴⁷

Figure 22.

Borylation of aliphatic NHPI esters 56.

The decarboxylative borylation proceeded well in DMF with iridium complex 57 as a photoredox catalyst, producing boronic acids that were converted to easily-isolated potassium alkyltrifluoroborates with aqueous KHF₂ in moderate to good yields. On the other hand, the use of a ternary solvent mixture facilitated the conversion of primary alkyl carboxylic acids into boronic esters derivatives. Primary and secondary carboxylic esters were found to be suitable substrates, tertiary carboxylic esters, on the other hand, only led to alkanes, likely due to competing decarboxylation and hydrogen atom abstraction.

Carboxylic acid bearing esters, ketones, carbamates, ethers, alkenes, terminal alkynes, and halides performed well. Four to six-membered carbocyclic and heterocyclic borylation products were readily prepared using this method. However, the borylation of NHPI esters of aromatic acids 51 was inefficient, e.g., only 10% yield of the corresponding boronic ester was achieved for the NHPI ester of m-toluic acid. It is proposed that upon irradiation the photoexcited Ir catalyst reduces NHPI ester 56, generating anion radical 58 and the oxidizing Ir^IV species (Figure 23). Homolytic cleavage that is followed by decarboxylation of intermediate 58 affords CO₂, phthalimide anion, and alkyl radical 45.

Figure 23.

Mechanism of photoredox-catalyzed borylation of NHPI esters 56.

Nucleophilic sp³-sp² diboron adduct 9 can be generated by a reaction of diboron reagent B₂(OR)₄ with phthalimide anion or hydroxide anion – the product of protonation of phthalimide anion in the presence of water. Diboron reagent 9 then reacts with alkyl radical 45. Radical anion 15 that is produced in this reaction reduces Ir^IV species, regenerating the photoredox catalyst.

In 2017, Aggarwal and coworkers reported a blue LED light-induced borylation of NHPI esters of alkyl carboxylic acids 56 with bis(catecholato)diboron (44) in dimethylacetamide as a solvent and in the absence of photoredox catalysts (Figure 24).⁴⁸ The intermediate catechol boronic esters product were converted to pinacol boronic esters by treating the reaction mixture with pinacol and triethylamine. The scope of the decarboxylative borylation encompasses NHPI esters of primary, secondary and tertiary carboxylic acids with benzylic, heterocyclic and carbocyclic substituents. The reaction tolerates a variety of functional groups, including alkenyl, alkynyl, bromo, keto and unprotected hydroxyl groups. The decarboxylative borylation was also successfully accomplished with a variety of derivatives of natural product and active pharmaceutical ingredients.

Figure 24.

Blue LED light-induced borylation of NHPI esters of alkyl carboxylic acids 56 with B₂cat₂ (44).

Experimental data suggest that the transformation involves a radical chain process that is more efficiently initiated photochemically than under thermal conditions (Figure 25). In the photochemical process, a reaction of N-hydroxyphthalimide ester 56, DMAc (N,N-dimethylacetamide) and B₂cat₂ (44) leads to the formation of transient complex 59 that, upon photoexcitation, undergoes the B-B bond cleavage, producing DMAc-stabilized boryl radical 60 and NHPI ester-derived radical 61. The N-O bond cleavage and decarboxylation of radical 61 produces alkyl radical 45 that is borylated with DMAc-ligated B₂cat₂ complex 62, generating boronic ester 48 and radical intermediate 60. As with intermediate 49/49ʹ in Studer’s borylation mechanism, intermediate 60 further serves as a radical chain carrier, producing NHPI ester-derived radical 61. Under the thermal conditions, the reaction is initiated by formation of DMAc-stabilized boryl radical 60 by thermal homolysis of DMAc-ligated B₂cat₂ complex 62.

Figure 25.

Proposed mechanism for blue LED light-induced borylation of NHPI esters of alkyl carboxylic acids 56 with B₂cat₂ (44).

4. C−N Borylation

Arenediazonium salts have served for a long time as a well-established source of aryl radicals.⁴⁹ In 2012, Yan and coworkers developed a visible light-induced borylation of arenediazonium salts catalyzed by the inexpensive organic dye eosin Y (Figure 26).⁵⁰ The reaction is compatible with substrates bearing electron-donating and electron-withdrawing groups. Somewhat lower yields were observed for ortho-substituted substrates. In addition, since excess diazonium salt is used, the method may be less advantageous with more valuable aniline precursors of diazonium salts.

Figure 26.

Visible light-induced, eosin Y-catalyzed borylation of arenediazonium salts.

A plausible mechanism for the borylation of arenediazonium salts is shown in Figure 27. Visible light irradiation generates the excited state of eosin Y. Subsequent single electron transfer to arenediazonium cation 63 produces aryl radical 5. Radical 5 then reacts with sp²-sp³ diboron adduct 64 that is formed from B₂Pin₂ and tetrafluoroborate anion to give radical anion 65 that is oxidized by the eosin Y-derived radical cation, thus regenerating the photocatalyst.

Figure 27.

Mechanism of eosin Y-photocatalyzed borylation of arenediazonium salts.

In 2017, Glorius and coworkers reported a visible light-induced photoredox-catalyzed conversion of N-acylbenzotriazoles 66 to aromatic boronic esters, sulfides, and alkylarenes bearing ortho-N-acylamino group (Figure 28).⁵¹ Mechanistically, upon illumination, photocatalyst Ir^III is promoted to exited state *Ir^III that donates one electron to benzotriazole 66 providing reactive intermediate 67 and the oxidazing Ir^IV species (Figure 29). A single electron transfer takes place between the Ir^IV species and reductive quencher amine 68, forming a radical cation 69 and regenerating the Ir^III photocatalyst. Radical anionic intermediate 67 then undergoes nitrogen extrusion to give radical 70 that subsequently engages B₂pin₂ in the homolytic borylation process. The large measured quantum yield for the borylation (Ф = 64.7) indicates that a radical chain reaction pathway is operative.

Figure 28.

General approach to borylation, thiolation and alkylation of N-acylbenzotriazoles.

Figure 29.

Mechanism of photoredox-catalyzed borylation of N-acylbenzotriazoles 66.

The borylation tolerated both electron-donating and electron-withdrawing groups in the benzotriazole core, and electron-donating groups in the benzoyl fragments (Figure 30). However, introduction of the electron-deficient p-CF₃ substituent in the benzoyl group led to a lower yield. An additive-based robustness screen⁴⁶ was conducted to prove high functional-group tolerance of this borylation and its usefulness for the synthesis of ortho-borylated aniline derivatives. Indeed, the borylation reaction performed well in the presence of nitriles, aryl halides, alkenes, alkynes, esters, amides, furans, thiophenes, pyridines, and N-protected pyrroles. On the other hand, alcohols, alkyl chlorides and alkyl amines did not inhibit the formation of products but were partially consumed under the reaction conditions. While 2-chloroquinoline, N-methylimidazole, and indole slightly lowered the yield, they remained intact. In contrast, aniline completely shut down the reaction and was to a substantial extent consumed. By changing photocatalyst and solvents, Glorius and coworkers were also able to extend the method to synthesis of o-alkyl- and o-alkylthio-N-arylbenzamides in moderate to good yields.

Figure 30.

Representative products of borylation of N-acylbenzotriazoles 66.

In 2018, a photoinduced deaminative borylation, in which N-alkylpyridinium salts 71 were converted to alkylboronic esters, was reported by Aggarwal group (Figure 31).⁵²

Figure 31.

Blue LED light-induced borylation of N-alkylpyridinium salts 71 with B₂cat₂ (44).

The use of B₂cat₂ (44) was essential, as no products were observed with other diboron reagents, such as B₂pin₂ or B₂(OH)₄. As with other similar photoinduced borylation reactions discussed in this review, use of an amide solvent, DMAc in this case, was crucial for achieving high yields.

Salts 71 derived from a variety of secondary amines, including those bearing free alcohols and protected amines were successfully converted to Bpin esters in good yields, after treatment of boronic esters 48 with pinacol and triethylamine. Primary alkylboronic esters were also produced in good to excellent yields from the corresponding primary alkylamines. Many functional groups, e.g., carboxylic acids, esters, ethers, amides, alkynes, alkenes and with aromatic heterocycles were tolerated. Natural product-derived substrates, e.g., leelamine and lysine gave corresponding boronic esters in good yields. Steroids hecogenin and tigogenin proved compatible with this transformation, giving corresponding borylation products with good yields and high diastereoselectivity. Amines bearing tertiary alkyl groups did not form the pyridinium salts 71, thus no tertiary alkylboronic esters were prepared.

It is hypothesized that in the initiation phase, electron donor−acceptor (EDA) complex 72 between N-alkylpyridinium salt 71, B₂cat₂·(44), and DMAc is formed (Figure 32). A photoinduced SET process within complex 72 triggers a radical chain process, generating N-alkylpyridinium-derived radical 73 and DMAc-stabilized B₂cat₂-derived radical 74. Radical 73 further fragments to give alkyl radical 45 and 2,4,6-triphenylpyridine (75). On the other hand, radical 74 reacts with DMAc to give boryl-derived radical 60 and boryl product 76. The chain propagation then proceeds with the reaction between alkyl radical 45 and B₂cat₂ to give radical intermediate 46 that subsequently forms adduct 77 with DMAc. The fragmentation of adduct 77 affords alkylboronic ester 48 and regenerates boryl radical 60, Radical 60 further reacts with N-alkylpyridinium salt 71, propagating the radical chain. The mechanism was supported by experimental studies that confirm formation of an EDA complex and a high photochemical quantum yield (Ф = 7).

Figure 32.

Mechanism of blue LED light-induced borylation of N-alkylpyridinium salts 71 with B₂cat₂ (44).

5. Other photoinduced reactions of organoboron compounds

In 2015, Ogawa and coworkers developed a metal-free photoinduced diborylation of terminal alkynes (Figure 33).⁵³ The transformation was applied to different alkynes to prepare different diborylated alkenes with the variation of E/Z ratio from 24:76 to 34:66. The reaction performed well with terminal alkynes bearing ester, chloro, cyano and phenyl groups. Phenylacetylene failed to form the product due to the competing polymerization occurring under the reaction conditions.

Figure 33.

Photoinduced, disulfide-catalyzed diboration of alkynes.

Mechanistic investigation indicated that the reaction proceeded through a radical pathway (Figure 34). Indeed, the use of radical initiator 2,2ʹ-azobis(isobutyronitrile) (AIBN) promoted diboration in the dark, albeit sluggishly, with 7% yield. An EPR study confirmed the presence of radical species in the reaction mixture with g = 2.0035, which was proposed to be a boryl-centered radical, since the g value did not correspond to a sulfide-centered radical.⁵⁴ It was suggested that the sulfide facilitates the cleavage of the B−B bond, giving rise to boryl radical 78, which may result from the coordination of sulfur to boron atom or energy transfer. Boryl radical 78 combines with the alkyne in a chain process yielding product and regenerating the disulfide catalyst.

Figure 34.

Plausible mechanism of disulfide-catalyzed diboration of alkynes.

One year later, Owaga and coworkers reported an improved alkyne diboration method that gave a higher trans-selectivity with phosphines as photocatalysts (Figure 35).⁵⁵ Addition of B₂pin₂ to alkynes proceeded well in the presence of relatively bulky phosphines, electron donating substituted aryl phosphines or diarylalkylphosphines. However, the reaction was completely shut down, when electron-deficient phosphines, trialkylphosphines and phosphine oxides were employed. Two reaction conditions were used for diborylation reactions (Figure 35). While the use of xenon lamp with catalytic quantities of PPh₃ (condition A) gave higher trans-selectivity, the use of high-pressure Hg lamp with near-stoichiometric quantities of PPh₃ (condition B) gave higher yields.

Figure 35.

Photoinduced phosphine-catalyzed diboration of alkynes.

Aliphatic alkynes bearing cyano, chloro, ester, ether and hydroxy groups were successfully converted to diborylated alkenes in moderate yields. As with the diphenyl disulfidecatalyzed diborylation reaction, phenylacetylene was a challenging substrate due to polymerization. The similar EPR g value as in their first report53 and the lack of pronounced solvent effects on the product yield indicate that the reaction proceeds by a boryl radical pathway.

As shown in Figure 36, it was suggested that PPh₃ coordinates to B₂pin₂ affording intermediate 79 that undergoes homolytic cleavage to generate radicals 80 and 81. Between these two species, 80 is more reactive, and it attacks the alkyne substrate to form vinyl radical 82. The ensuing homolytic substitution reaction between vinyl radical 82 and B₂pin₂ produces diboration product 83 and regenerates boryl radical 80 that proceeds to combine with radical 81, giving rise to adduct 79. The trans-selectivity was explained by the steric interactions between B₂pin₂ and vinyl radical 82, as well as the photoisomerization mediated by PPh₃.

Figure 36.

Plausible mechanism of photoinduced phosphinecatalyzed diboration of alkynes.

In 2017, Larionov and coworkers developed a method for conversion of readily accessible unsaturated six-membered ring precursors to less abundant five-membered carbocycles and heterocycles using photochemical activation that they termed carboborative ring contraction (Figure 37).⁵⁶ Optimization experiments showed that the reaction proceeded faster and with higher yields in more polar solvents, for example ethanol, dioxane or THF and in the presence of p-xylene as a photosensitizer under UV irradiation (254 nm).

Figure 37.

Photoinduced carboborative ring contraction.

A variety of trialkylboranes were readily prepared and reacted with unsaturated six-membered carbocycles and heterocycles to obtain desired products in moderate to good yields. Remarkably, 9-methoxy-9-borabicyclo[3.3.1]-nonane (9-BBN-OMe) was also a suitable reagent, giving the diol 84 in 63% yield after oxidation, whereas tetrahydrofuran 85 was isolated as a single diastereomer, the diastereomeric ratio was 10:1 for pyrrolidine 86. Terpenoids and their derivatives including terpinolene (87), (R,R)-carveol (88, 89) and its tertiary alcohol derivative 90 afforded corresponding products in good yields and high stereoselectivity, also on gram scales. Likewise, a number of B-ring norsteroids were also prepared in good yields and with high regio- and stereoselectivity (Figure 38) from cholesterol, diosgenin, pregnenolone derivatives, dehydroepiandrosterone and azasteroids with various trialkylboranes (91–96).

Figure 38.

Photoinduced carboborative ring contraction of steroid substrates.

Photoinduced carboborative ring contraction also enabled a concise total synthesis of artalbic acid (97) that commenced with the photoinduced carboborative ring contraction of (S,S)-carveol-derived TBS ether 98 with triethylborane, followed by a sequence of oxidations with trimethylamine N-oxide and Dess−Martin periodinane to give ketone 99 (Figure 39). Subsequent desaturation of the side chain via α-selenylation and hydrogen peroxide-induced selenoxide elimination afforded vinyl ketone 100 that was subjected to the phosphine-catalyzed Rauhut−Currier reaction with acrylonitrile to give nitrile 101. Given the sensitive nature of nitrile 101, the synthesis was completed by hydrolysis of nitrile 101 using two mild protocols. In the first protocol, desilylation of nitrile 101 afforded alcohol 102 that was hydrolyzed biocatalytically with nitrilase at pH 7.2. In the second protocol, hydration of nitrile 101 using Parkins catalyst 103 produced primary amide 104 that was then activated by double N-carbamidation with Boc₂O, and basic hydrolysis at room temperature.

Figure 39.

Total synthesis of artalbic acid (97).

The reaction is thought to proceed by photosensitized isomerization to strained and highly reactive E-isomer of cyclohexene 105, followed by addition of organoborane to the equatorial position on C2 to give zwitterionic intermediate 106. Subsequent 1,2-migration of the C3 atom to C1, accompanied by a shift of one alkyl group R from boron to C2 position produces cyclopentanes with two new stereocenters (Figure 40) either by inversion or retention pathway. The migration of the alkyl group, according to experimental data, favors the inversion pathway, forming the major product 107 rather than the retention pathway, which results in the minor product 108.

Figure 40.

Mechanism of photoinduced carboborative ring contraction.

In 2018, Li, Wang and coworkers discovered a photoinitiated reaction that converts chiral chelated organoboron precursors 109 into air-stable, chiral, N,B,X-containing heterocycles 110 (Figure 41). This transformation expands synthetic access to borinines, in particular 1,2-thiaborinines and 1,2-oxaborinines.⁵⁷ The transformation performed well with sulfur-containing heterocycles bearing various chelating substructures. Quantitative conversions were observed for 2-benzothienyl and 2-(5-phenyl)thienyl substituents (110a-e). It should be noted that the boriranes were also detected in the reaction together with borinine products 110 but were consumed gradually over the reaction time. Replacing pyridine core by benzimidazole and a NHC-type substituent also produced the expected products (110d and 110e, respectively).

Figure 41.

Photoinduced isomerization of organoboron compounds 109 to borinines 110.

The photoisomerization performed well with substrates bearing 2-furyl (110f) and 2-benzofuryl (110g) substituents, providing 2-oxaborinines. However, in these cases the products also undergo a sequential conrotatory electrocyclization and a [1,5]-hydride shift, yielding 4a,12b-dihydrotriphenylene isomers 110fʹ and 110gʹ. Chiral organoboron compounds bearing N-heterocyclic substituents such as pyrrolyl or 2-indolyl showed the lowest photoreactivity, and the corresponding products were formed in low yields. Based on results of computational studies, it is suggested that chiral organoboron compound 109 upon photoexcitation produces biradical intermediate 111 with high spin density on the thienyl and pyridyl substituents (Figure 42). Intermediate 111 undergoes two distinct transformations that yield the kinetic product, borirane 112 and the thermodynamic product, borinine 110, respectively. In the first pathway, formation of borirane 112 is photochemically reversible under the reaction conditions. Thus borirane 112 is converted to borinine 110 via the intermediacy of biradical 111 through the second pathway, wherein biradical 111 undergoes the thiophene ring-opening to give intermediate 113. The ensuing B–S bond-forming ring closure produces borinine 110.

Figure 42.

Plausible mechanism of photoinduced isomerization of organoboron compounds 109 to borinines 110.

The quantitative conversions to products 110 were explained by the low energy barriers for dissociation of C−S bond, as well as the photoequilibrium between borirane 112 and biradical intermediate 111.

In 2018, Aggarwal and coworkers reported a visible light-induced decarboxylative radical addition to vinyl boronic esters to yield alkyl boronic esters (Figure 43).⁵⁸ This method can be valuable to medicinal chemists, because it provides rapid access to structurally diverse and hitherto medicinally unexplored γ-aminoboronic acids. The reaction was carried out with blue LED light in the presence of Ir(ppy)₂(dtbbpy)PF₆ (57) and Ir[dF(Me)ppy]₂(dtbbpy)PF₆ (114) as photoredox catalysts in the presence of cesium carbonate as a base and in dimethylformamide or dimethylacetamide as solvents.

Figure 43.

Photoredox-catalyzed decarboxylative alkylation of vinylboronic esters.

The reaction has a broad scope with respect to various structurally diverse carboxylic acids. Boc-protected α-amino acids that do not have a hydrogen on the α-nitrogen atom reacted well, when catalyst 57 was used (e.g., products 115–117). A stronger reducing photocatalyst 114 was required for a-amino acids with a hydrogen on the α-nitrogen atom and for all other carboxylic acids (e.g., products 118–122). Substituted vinylboronic esters were also suitable substrates (e.g., products 116 and 117). In addition, several boronate products derived from natural products (e.g., boronates 121, 122 and active pharmaceutical ingredients (e.g., products 119, 120) were readily prepared using the developed protocol.

The authors propose that the reactive carboxylate anion 123 is first formed from the carboxylic acid in the reaction with cesium carbonate (Figure 44). Subsequent one-electron oxidation with the photoexcited *Ir^III catalyst leads to decarboxylation and formation of radical 124 that adds to the vinylboronic 125 ester to give α-boryl alkyl radical 126 that is stabilized through π-donation to the boryl group. Radical 126 further undergoes reduction with the reduced Ir^II catalyst species to give anion 127 that is further protonated. The thermodynamic feasibility of the reduction of radical 126 by the Ir^II catalyst was confirmed by DFT calculations. In addition, partial deuteration was observed in the α-position of the alkylboronate moiety, supporting involvement of anion 127.

Figure 44.

Mechanism of photoredox-catalyzed decarboxylative alkylation of vinylboronic esters.

Vicinal difunctionalization is one of the most powerful and valuable transformations in organic synthesis. The 1,2-difunctionalization of alkenes that can construct two distinct chemical bonds in a single operation is an efficient tool for increasing molecular complexity. In recent years, transition metal-catalyzed carboboration has attracted significant attention. However, only few reports on transition metal-free 1,2-carboboration of alkenes have been reported.⁵⁹ In 2018, Studer and coworkers disclosed a photoinduced transition metal-free 1,2-carboboration of unactivated alkenes with B₂cat₂ (44) as the boron source combined with perfluoroalkyl iodides as the alkyl component (Figure 45).⁴³

Figure 45.

Photoinduced metal-free 1,2-carboboration of unactivated alkenes.

The reaction is particularly suitable for carboboration of monosubstituted alkenes (128–131), although reactive disubstituted alkenes can also be used (132 and 133). In the case of a 1,5-diene substrate, the carboboration occurred regioselectivity at the terminal double bond (131). Although perfluorobutyl iodide was used for most examples, other perfluoroalkyl iodides and sources of stabilized electrophilic radicals were used as well (134 and 135). The reaction is initiated by a perfluoroalkyl radical that is generated by a visible light-mediated C‒I bond homolysis. The radical adds to the double bond to give a new radical 136 (Figure 46). Computational studies showed that a homolytic substitution reaction between the newly-formed alkyl radical 136 and bis(catecholato)diboron (44) is disfavored. Instead, the homolytic substitution takes place at the sp²-sp³ adduct of diboron and DMF via intermediate 137. Subsequent scission of the weakened B-B bond gives rise to product 138 and Lewis base-stabilized boryl radical 139 that further reduces alkyl iodide in a SET process. This mechanism is corroborated by the early-phase solvent screen study that showed that DMF was a particularly suitable solvent, indicating that it is a crucial component of the reaction system. Given the computational results obtained in Studer’s subsequent study on C−X borylation (see Figure 19), the reaction likely produces iodide 50 instead of isomer 140.

Figure 46.

Proposed mechanism of photoinduced 1,2-carboboration of alkenes.

6. Conclusion

Synthetic photochemistry of organoboron compounds has seen a tremendous growth in the past several years. While earlier approaches relied on reactive diazonium reagents, new photoinduced methods enable construction of C-B bonds from a variety of functional groups. The mildness and functional group tolerance of the new methods allow for late-stage borylation of complex functionalized molecules. In addition to borylation reactions, methods that engage alkenes and alkynes have also been developed, further expanding the outreach of organoboron chemistry. The fast pace of development is expected to continue, as new applications for organoboron compounds emerge in drug discovery, organic synthesis and materials science.