Electrochemical Borylation of C−C and C−Het Bonds
Graphical Abstract
Electrosynthesis enables the cleavage and borylation of C−C, C−N, C−O, and C−S bonds, representing a significant advancement in organic chemistry. This approach offers a metal-free strategy for synthesizing organoboron compounds, which find extensive applications across synthetic chemistry, biomedicine, and materials science.
Abstract
Recently, electrochemical methods have been harnessed as a transition metal-free strategy for borylation reactions in the synthesis of organoboron compounds. This article reviews the electrochemical borylation of C−C and C−Het bonds, offering a systematic discussion of C−C, C−N, C−O, and C−S bond borylation reactions. These transformations are applied to substrates including ammonium salts, aryl azo sulfones, carboxylic acids, arylhydrazines, nitroarenes, alcohols, and thioethers, showcasing broad compatibility. Additionally, the review discusses reaction mechanisms, scalability, and practical applications of these electrochemical strategies. The article concludes by outlining future research directions for electrochemical borylation reactions, aiming at expending their applications in incorporating boron into a wider array of organic compounds, including the challenging unactivated C−Het and C−F bond borylations.
1 Introduction
Organoboron compounds play a crucial role in various areas of chemistry, including synthetic chemistry,1 materials science,2 and medicinal chemistry.3 For example, five FDA-approved boron-containing drugs have been developed and used for various medicinal purposes.2d Besides, boronic acid steboronine, is the first drug approved for boron neutron capture therapy (BNCT) to treat various types of cancer.2d In organic synthesis, organoboron compounds participate in significant transformations such as Brown hydroboration1a and Suzuki-Miyaura cross-coupling reactions,1n which have been widely used in drug discovery and the synthesis of building blocks in functional materials.
In this connection, incorporation of boron into organic compounds has attracted growing research interest, leading to considerable achievements in methodology development of borylation reactions. In comparison to the well-developed carbon-hydrogen (C−H) bond and carbon-halogen (C−X) bond borylation reactions,4 those targeting carbon-carbon (C−C) bond and carbon-heteroatom (C−Het) bond remain less-explored.1i Transition metal catalysis has been crucial in activating these relatively inert C−C and C−Het bond.5 Additionally, photoinduced borylation also provides alternative transition-metal free approaches for organoboron compounds synthesis.6
In recent years, electrochemical borylation has emerged as a promising strategy for synthesizing organoboron compounds.7 The advantages of electrochemical conditions include mild reaction conditions, scalability, tunable redox potentials, and sustainability, making them suitable alternatives to traditional chemical reagents in organic synthesis.8 The application of electrochemical methods to C−C and C−Het bond borylation presents new opportunities for developing efficient and sustainable strategy to directly displace diverse functional groups with boron moieties.
Utilizing electricity as a green, sustainable, and cost-effective energy source to facilitate C−C and C−Het bond borylation, these approaches reduce the dependency on chemical reagents and harsh conditions, thus enhancing functional group compatibility and reduce side reactions. Furthermore, electrochemical methods facilitate precise control over electron transfer processes, enabling both direct and indirect electrosynthesis pathways to generate active intermediates more selectively.8o-8r Compared to traditional transition metal-catalyzed methods, such as decarboxylative borylation which typically requires precious metal catalysts, ligands, and high reaction temperatures,9a-9c electrochemical C−C and C−Het bond borylation offers a more environmentally friendly and milder alternative. The integration of electrochemical techniques not only broadens the scope of accessible organoboron compounds but also aligns with the principles of sustainable chemistry, making it a transformative strategy in the synthesis of valuable boron-containing molecules.
This review article provides a comprehensive overview of electrochemical C−C and C−Het borylation reactions, categorized into C−C, C−N, C−O, and C−S bond borylations (Scheme 1). The mechanisms of these reactions are also discussed. Covering literature up to April 2024, the review aims to highlight recent developments in this field. In Summary and Outlook, future desired advancements in electrochemical organoboron synthesis and borylation reactions will be highlighted.
Electrochemical borylation of C−C and C−Het bonds.
2 Electrochemical Borylation
2.1 Electrochemical C−C Bond Borylation
Electrochemical borylation of C−C bond restricts on the decarboxylative borylation reaction. The abundant chemical building block, carboxylic acids, can be converted to N-hydroxyphthalimide (NHPI) ester intermediate, facilitating efficient cross-coupling reactions. This strategy has been widely used in transition metal catalyzed and photoinduced decarboxylative borylation.9
In 2021, Baran, Blackmond and colleagues demonstrated an electrochemical method to convert alkyl carboxylic acids into borylated derivatives via NHPI esters intermediates. The reaction utilized bis(catecholato)diboron (B2cat2) as borylation reagent and was conducted in an undivided cell with low-cost carbon electrodes (Scheme 2a).10 This scalable technique is versatile enough to accommodate various substrates and can be applied as key steps in the synthesis of complex natural product jawsamycin.
Electrochemical decarboxylative borylation of carboxylic acids.
The mechanism of this decarboxylative borylation relies on a radical pathway initiated by electrochemical reduction. The alkyl N-hydroxyphthalimide ester here serves as a redox-active ester (RAE). Initially, dimethylformamide (DMF) reacts with one equivalent of B2cat2 to form complex 1. Then, 1 coordinates with the alkyl N-hydroxyphthalimide ester to form a ternary complex. The rate-determining step occurs at the cathode, where this complex undergoes a single-electron reduction, forming intermediate 2. Intermediate 2 rapidly decomposes, releasing CO2, borate ester 3, and an alkyl radical 4. This radical then reacts with complex 6, yielding the desired alkyl boronic ester 5 and a boron-centered radical 6. Although the boron-centered radical is typically neutralized, a minor pathway involves it initiating a radical chain reaction by attacking another RAE, forming intermediate 7. Finally, 7 undergoes fragmentation to regenerate alkyl radical 4 and complete the catalytic cycle.
In the same year, Xu, Dai and coworkers reported an electrochemical pathway for C(sp3)−B bond formation via a similar decarboxylic borylation.11 The work demostrated that electrochemically driven reductive decarboxylation could facilitate the borylation of alkyl N-hydroxyphthalimide esters using B2cat2 (Scheme 2b). This method can be used for synthesizing diverse alkyl boronic esters, showcasing a broad substrate scope and compatibility with various functional groups, as well as transformations of natural products, for example, transforming γ-amino acids, gabapentin and pregabalin to borylated compounds. Also, gemfibrozil, a lipid-lowring drug can be converted with this method in a moderate yield.
2.2 Electrochemical C−N Bond Borylation
In 2021, Xu and co-workers reported a direct electrocatalytic C−N borylation of aryl and benzyl trimethylammonium salts with B2pin2 under room temperature (Scheme 3).12 This reaction tolerates a range of functional groups, including halides, which are typically incompatible with previously reported nickel and photoredox catalysis.13 Importantly, this metal-free approach can be carried out on gram scale without using external reducing agents or sacrificial anodes. The electroreductive approach affords aryl and benzyl radicals that when intercepted by borylating agents such as bis(pinacolato)diboron (B2pin2) can produce organoboron compounds. This protocol enables a useful C−N bond activation reaction that features mild conditions, operational simplicity, efficiency, and a broad substrate scope.
Electrochemical borylation of aryl and benzyl ammonium salts.
The mechanism proposed is that the aryl or benzyl radical 8 is generated by the cathodic reduction of ammonium triflate. This radical then reacts with borate 9, which is formed form the B2pin2 in and methoxide (MeO−), to give the desired product and radical anion 11 via intermediates 10, while simultaneously oxidizing the solvent and trimethylamine at the anode. Subsequently, radical anion 11 is neutralized via a solvent single-electron-transfer radical mechanism to give 12. It is noted that the formation of desired product through boron-centered radicals cannot be excluded.
In 2021, Yi, Jiang and coworkers demonstrated that the bench-stable arylazo sulfones could serve as radical precursors to generate aryl radicals through electrochemical C−N bond cleavage, which were then utilized in borylation reaction (Scheme 4).14 With B2pin2 as borylation reagent, this method allows the synthesis of aryl boronates with a variety of functional groups in excellent yields. Moreover, this method can be applied in gram-scale borylation in 73 % yield. Based on the plausible mechanism of the C−S bond formation from their work,14 the electrochemical borylation involves a similar pathway for generating an aryl radical intermediate. 1-(methylsulfonyl)-2-phenyldiazene 13 is reduced at the cathode to give the phenyl radical 14. The radical is trapped by the borate 15 formed from B2pin2 and the base, generating product 16 and an radical anion [ROBpin]⋅−. The radical anion is oxidized through a single electron transfer process on the anode, yielding an alkyl borate and making the whole reaction redox neutral.
Electrochemical borylation of arylazo sulfones.
In addition to arylazo sulfones, arylhydrazines, versatile and readily accessible building blocks, are also used as aryl radical precursors under electrochemical conditions. In 2022, Zhang and co-workers introduced a scalable electrochemical C−N borylation using B2pin2 to synthesize aryl boronic esters from easily obtainable arylhydrazines (Scheme 5).15 This research also underscores the feasibility of electrochemical approaches in achieving C−N borylation, and broad functional group tolerance, including reactive groups −Cl, −Br, and −CF3. In the proposed mechanism of C−N borylation, 17 first reacts with triethylamine to form phenylhydrazine 18, which is then oxidized with the assistance of nBu4NI at the anode, generating the phenyl radical 19. The phenyl radical 19 reacts with an adduct 20 formed from B2pin2 and the base, resulting in the generation of product 21 and the radical anion. This radical anion undergoes single electron oxidation to yield a borate ester. Meanwhile, hydrogen gas is produced from the reduction of protons at the cathode.
Electrochemical borylation of arylhydrazines.
Nitroarenes, commonly found in pharmaceuticals and agrochemicals, offer versatile options for functionalization.16 However, methods for C−N bond transformation of nitroarene are limited.17 In 2023, Zhang, Cai and co-workers developed a electrochemical method to convert readily available nitroarenes into aryl boronic esters through a denitrative borylation (Scheme 6).18 This reaction exhibits good functional group compatibility, leading to the facile preparation of aryl boronic esters that contain halogens, esters, nitriles, alkenyl groups, and (hetero)aromatics. The proposed mechanism involves the oxidation of H2O at the anode and the reduction of nitrobenzene 22 at the cathode, leading to the formation of nitrosobenzene 23. Nitrosobenzene 23 then reacts with B2pin2 and H2O to produce aniline 24 and (Bpin)2O. Aniline 24 undergoes diazotization with tBuONO to form a phenyldiazonium salt 25, which yields a tert-butyl oxide anion and a phenyl radical 26 through a single electron transfer (SET) process. The phenyl radical 26 subsequently reacts with B2pin2 and tert-butyloxide to generate the desired boronic ester 27 and a radical anion intermediate. The radical anion intermediate then undergoes further SET to form the alkyl borate by-product.
Electrochemical borylation of nitroarenes.
2.3 Electrochemical C−O Bond Borylation
With an abundance of C−O bond containing feedstock in nature,19 developing new methods for their activation and functionalization is crucial for synthesis and derivatization of natural products and pharmaceuticals. Recently, Lin and coworkers reported a unified method to transform benzylic and allylic alcohols, aldehydes, and ketones into boronic esters under electroreductive conditions (Scheme 7).20 This approach utilized pinacolborane (HBpin) as both activator and an electrophile, yielding the deoxygenative C−O borylation product. The versatility of this method allows its application to a broad scope of substrates and makes it suitable for the late-stage functionalization of complex natural products. This strategy effectively addresses the challenges of activating strong C−O bonds by employing a radical-polar crossover mechanism.
Electrochemical borylation of alcohols and carbonyls.
The proposed mechanism involves activating alcohol or ketone in situ to form a redox-active trialkyl borate intermediate 28, which has a reduction potential similar to that of alkyl halides. The intermediate 28 is then reduced via an electron transfer-chemical reaction-electron transfer (ECE) pathway to generate alkyl radical 29. Stabilized by aryl or vinyl group, radical 29 undergoes further reduction to form carbanion 30, which can be captured by another equivalent of electrophile (HBpin) to obtain the desired boronic esters 31. This process eliminates the need for preactivation steps with additional reagents.
2.4 Electrochemical C−S Bond Borylation
Recently, Lungberg and coworkers presented an electrochemical C−S bond borylation method for converting benzyl thioethers into benzyl boronic esters using HBpin and graphite electrodes (Scheme 8).21 The electrochemical reaction operated under mild conditions, accommodating a broad substrate scope and tolerating various functional groups, including halides, esters, and heteroaromatics. The versatility of this electrochemical desulfuration has been demonstrated through applications in modification of pharmaceutical and natural product, such as roflumilast. Moreover, it is scalable, allowing the production of gram-scale quantities of the desired product. This work has provided a metal-free protocol for direct electrolytic desulfurative C−S bond borylation, thereby enabling the synthesis of benzyl boronic acids from thioethers.
Electrochemical borylation of benzyl thioethers.
The proposed desulfurative borylation mechanism features paired electrolysis, starting with a single electron reduction of benzyl phenyl thioether 32 at the graphite cathode, triggeringmesolytic C−S bond cleavage and generating a phenylthiolate and a benzylic radical intermediate 33. The intermediate 33 rapidly undergoes a radical-polar crossover via a second SET, forming a carbanion 34, which is then captured by HBpin. The resulting borohydride intermediate 35 is oxidized at the graphite anode, producing the desired product 36 and H2. Concurrently, at the anode, the oxidation of the supporting electrolyte nBu4NBH4 and the phenylthiolate by-product provides extra electrons toward the electrochemical cell for charge balance.
3 Summary and Outlook
The review provides an in-depth demonstration of recent advancements in electrochemical methods for C−C and C−Het borylation reactions as a metal-free alternative to traditional synthesis methods. Through the electrochemical cleavage of C−C, C−N, C−O, and C−S bonds, these methods successfully achieve the direct borylations of diverse substrates, including ammonium salts, aryl azo sulfones, nitroarenes, alcohols, ketones, and thioethers, offering excellent functional group compatibility and sustainability, especially the tolerance of halide functional groups increases the further functionalization versatility of the borylated compounds. The review underscores the potential of the electrochemical strategy in boron incorporation reactions, while also calling for further research to optimize and broaden its applications. Despite growing research interest, the field of electrochemical C−C and C−Het borylation is still in its early stages of development. As outlined in this review, except for the recently reported C−O and C−S borylation, all reactions proceed via a radical pathway in which a carbon radical intermediate is generated and reacts with B2pin2 or B2cat2. The formation of a carbanion intermediate in electrochemical borylation remains limited. Additionally, most of these transformations require substrates that either inherently possess a leaving group or have a leaving group introduced in situ to serve as the carbon radical precursor. Direct decarboxylative borylation of carboxylic acids, rather than NHPI esters, and the activation of less reactive C−Het bonds such as those in amines (C−N bond) and ethers (C−O bond), continue to be significant challenges. Moreover, the scope of C−C and C−Het substrates is expected to broaden in the future. Particularly in C−Het borylation, currently, examples are still limited and primarily focus on the borylation of aryl, allyl, and benzyl C−Het substrates. Electrochemical borylation of unactivated alkyl C−Het bond remains underdeveloped. Furthermore, direct C−F bond borylation via electrochemical methods has not been disclosed, despite being well-documented under transition metal catalysis conditions.22 Meanwhile, we also anticipate that a broader range of boron reagents beyond B2pin2, B2cat2 and HBpin will be employed in future electrochemical borylation reactions.
Acknowledgments
This work was supported by research start-up fund (Project No. 4933621) from the Chinese University of Hong Kong.
Conflict of Interests
The authors declare no conflict of interest.
Open Research
Data Availability Statement
Data sharing is not applicable to this article as no new data were created or analyzed in this study.
Biographical Information
Tsoh Lam Cheung was born in 1998. In 2021, he obtained his bachelor's degree from Hong Kong Polytechnic University. Then, he embarked on a Ph.D. program under the guidance of Prof. Hairong Lyu at The Chinese University of Hong Kong. His current research interests mainly focus on the development of electrocatalysis with boron-based-reagents.
Biographical Information
Hairong Lyu obtained her bachelor's degree from Nankai University in 2014. She received her Ph.D. degree under the supervision of Prof. Zuowei Xie at The Chinese University of Hong Kong in 2018. Following that, she continued her research as a postdoc at the University of Chicago under the supervision of Prof. Guangbin Dong. In 2022, she joined The Chinese University of Hong Kong as an assistant professor as part of the Vice-Chancellor Early Career Professorship Scheme and commenced her independent research. The current research focus in her team is the development of new reagents, catalytic systems and synthetic methodologies involving transition metal catalysis and photo-/electro-catalysis.
