Borylation Reactions Research Articles

An Air-Stable, Single-Component Iridium Precatalyst for the Borylation of C-H Bonds on Large to Miniaturized Scales.

The functionalization of C-H bonds enables the modification of complex molecules, often with the intention of forming compound libraries. The borylation of aryl C-H bonds is a widely used class of C-H bond functionalization, and conventional catalyst systems for the borylation of C-H bonds consist of an iridium source and an N,N-ligand, in conjunction with pinacolborane, to form the active iridium(III) tris(boryl) catalyst. These multicomponent catalyst systems complicate borylation reactions at large and small scales, due to the air sensitivity of the most common iridium precursor [Ir(cod)OMe]2, and, particularly on small scale, the challenges associated with dispensing multiple components with differing solubilities or that are air-sensitive. We describe the discovery of an air-stable, single-component iridium precatalyst, [(tmphen)Ir(coe)2Cl], that generates the same active iridium(III) tris(boryl) catalyst and reacts with higher turnovers, comparable selectivity, and similar scope to those of known catalyst systems for the borylation of aryl and heteroaryl C-H bonds. We show how the development of this precatalyst enables reactions to be run on submicromole scale in a high-throughput experimentation format in conjunction with ChemBead technology, and with a second diversification step that illustrates the potential to diversify structures by chemical sequences involving catalytic reactions, including C-H bond functionalizations, on submicromole scales in the same reaction vessel.

Stepwise One‐Shot Borylation Reactions for Intersecting DABNA Substructures Exhibiting Bright Yellow‐Green Electroluminescence with EQE Beyond 40 % and Mild Roll‐Off

AbstractBoron/nitrogen (B/N)‐doped polycyclic aromatic hydrocarbons (PAHs) with the multiple resonance (MR) effect are promising for organic light‐emitting diodes (OLEDs) because of their narrowband emission and thermally activated delayed fluorescence (TADF) characteristics. Nevertheless, exploring the variety of such emitters is challenging because of the tricky and limited synthetic protocols. Herein, we designed a novel B/N‐doped PAH, L–DABNA‐1, whose backbone (L–DABNA) could not be achieved via conventional routes (e.g., one‐pot borylation or one‐shot borylation). We successfully synthesized it through stepwise one‐shot borylations with precisely introducing decorations. The unique MR backbone with intersecting DABNA substructures sharing an aniline group, avoiding any para‐N‐π‐B motif, allows L–DABNA‐1 to maintain narrowband TADF emission while significantly redshifting to the yellow‐green region with a reverse intersystem crossing rate (kRISC) of 1.28×105 s−1. An L–DABNA‐1‐based OLED device achieved a maximum external quantum efficiency (EQE) of over 40 % and maintained a high EQE of 36.3 % at 1000 cd m−2, with a current efficiency reaching ~170 cd A−1. This work not only demonstrated the great potential of stepwise borylations in synthesizing B/N‐doped PAH backbones, expanding their chemical space, but also provided a promising pathway for exploring MR‐TADF emitters at longer wavelengths.

Photocatalytic Borylation of Imines and Alkenes via Decarboxylation of Trimethylamine Carboxyborane: A New Approach for Generating Boryl Radicals.

In this study, we investigated the photocatalytic decarboxylation of trimethylamine carboxyborane under mild conditions, successfully generating boryl radicals for subsequent borylation reactions with imines and various alkenes. This method exhibited broad substrate compatibility, including the functionalization of biologically relevant molecules. Our findings expand the utility of trimethylamine carboxyborane beyond its role as a carbon-monoxide- and drug-releasing agent, highlighting its potential in radical chemistry through decarboxylation. This work establishes a robust foundation for further exploration of the synthetic application of trimethylamine carboxyborane.

Recent Advances in Methodologies for Radical‐Mechanistic Borylation†

Comprehensive SummaryWe reviewed works on radical borylation reactions since 2020 from two aspects. 1. Borylation from alkyl or aryl radicals: This approach involves the generation of alkyl or aryl radicals from various precursors such as halides and carboxylic acids, followed by their reaction with diboron reagents to form boron esters. 2. Borylation from boron‐centered radicals: This approach involves generating boron‐centered radicals, which then react with substrates to achieve borylation. Key Scientists

Stepwise One-Shot Borylation Reactions for Intersecting DABNA Substructures Exhibiting Bright Yellow‒Green Electroluminescence with EQE Beyond 40% and Mild Roll-Off.

Boron/nitrogen (B/N)-doped polycyclic aromatic hydrocarbons (PAHs) with the multiple resonance (MR) effect are promising for organic light-emitting diodes (OLEDs) because of their narrowband emission and thermally activated delayed fluorescence (TADF) characteristics. Nevertheless, exploring the variety of such emitters is challenging because of the tricky and limited synthetic protocols. Herein, we designed a novel B/N-doped PAH, L-DABNA-1, whose backbone (L-DABNA) could not be achieved via conventional routes (e.g., one-pot borylation or one-shot borylation). We successfully synthesized it through stepwise one-shot borylations with precisely introducing decorations. The unique MR backbone with intersecting DABNA substructures sharing an aniline group, avoiding any para-N-π-B motif, allows L-DABNA-1 to maintain narrowband TADF emission while significantly redshifting to the yellow-green region with a reverse intersystem crossing rate (kRISC) of 1.28 × 105 s-1. An L-DABNA-1-based OLED device achieved a maximum external quantum efficiency (EQE) of over 40% and maintained a high EQE of 36.3% at 1000 cd m-2, with a current efficiency reaching ~170 cd A-1. This work not only demonstrated the great potential of stepwise borylations in synthesizing B/N-doped PAH backbones, expanding their chemical space, but also provided a promising pathway for exploring MR-TADF emitters at longer wavelengths.

Nickel-catalyzed, silyl-directed, ortho-borylation of arenes via an unusual Ni(II)/Ni(IV) catalytic cycle

Nickel-catalyzed C–H bond functionalization reactions provide an impressive alternative to those with noble metal catalysts due to their unique reactivity and low cost. However, the regioselective C(sp2)–H borylation reaction of arenes accomplished by nickel catalyst remains limited. We herein disclose a silyl-directed ortho C(sp2)–H borylation of substituted arenes with a Ni(cod)2/PMe3/KHMDS catalyst system. Using readily available starting materials, this protocol provides easy access to ortho-borylated benzylic hydrosilanes bearing flexible substitution patterns. These products can serve as versatile building blocks for the synthesis of sila or sila/borine heterocycles under mild conditions. Control experiments and DFT calculations suggest that a catalytic amount of base prompts the formation of Ni(II)-Bpin-ate complex, likely related to the C(sp2)–H bond activation. This borylation reaction might follow an unusual Ni(II)/Ni(IV) catalytic cycle.

Recent Advances in Photoinduced Borylation via N-Heterocyclic Carbene Boryl Radicals

Organoboron compounds, recognized as essential synthetic intermediates in organic chemistry, have found broad applications in pharmaceutical and materials science. In recent years, the development of novel boronating reagents has opened new avenues for the synthesis of organoboron. Among these, NHC–boranes, with their unique advantages, have garnered sustained interest and have evolved into significant precursors for boron-centered radicals, participating in a diverse array of visible light-induced borylation reactions. This article primarily focuses on the visible light-induced radical borylation reactions involving NHC–boranes, summarizing the latest advancements in the field, and offering inspiration for subsequent research.

Pd-Catalyzed Borylation in Water and Its Application to the Synthesis of Active Pharmaceutical Ingredient (API) Intermediates.

An efficient catalytic borylation reaction of aryl bromides in water based on Pd catalysis under micellar conditions is presented. The peculiar combination of the proper Pd precursor with a Sphos ligand and a hindered lipophilic base ensures good yields in the synthesis of a wide range of boronic esters, even for heteroaryl derivatives with a good purity profile. The method is specifically developed for the in situ preparation of boronic esters that are directly converted into examples of relevant active pharmaceutical ingredient intermediates through cross-coupling reactions or via oxidation to phenols.

Stereodivergency in Copper-Catalyzed Borylative Difunctionalizations: The Impact of Boron Coordination.

A reagent-controlled diastereodivergent copper-catalyzed borylative difunctionalization is reported. The formation of Lewis adducts that guide selectivity is commonly invoked in organic reaction mechanisms. Using density functional theory calculations, we identified BpinBdan as a sterically similar and less Lewis acidic alternative to B2pin2. Using a newly developed borylative aldol domino reaction as the proof-of-concept, we demonstrate a change in stereochemical outcome by a simple change of borylating reagent-B2pin2 affords the diastereomer associated with coordination control while BpinBdan overturns this mode of binding. We show that this strategy can be generalized to other scaffolds and, more importantly, that BpinBdan does not alter the diastereomeric outcome of the reaction when coordination is not involved. BpinBdan can be viewed as a mechanistic probe for coordination in future copper-catalyzed borylation reactions.

Peripheral carbazole units-decorated MR emitter containing B−N covalent bond for highly efficient green OLEDs with low roll-off

Boron−nitrogen doped multiple resonance (BN-MR) emitters, characterized by B−N covalent bonds, offer distinctive advantages as pivotal building blocks for facile access to novel MR emitters featuring narrowband spectra and high efficiency. However, there remains a scarcity of exploration concerning synthetic methods and structural derivations to expand the library of novel BN-MR emitters. Herein, we present the synthesis of a BN-MR emitter, tCz[B−N]N, through a one-pot borylation reaction directed by the amine group, achieving an impressive yield of 94%. The emitter is decorated by incorporating two 3,6-di-t-butylcarbazole (tCz) units into a B−N covalent bond doped BN-MR parent molecule via para-C−π−D and para-N−π−D conjugations. This peripheral decoration strategy enhances the reverse intersystem crossing process and shifts the emission band towards the pure green region, peaking at 526 nm with a narrowband full-width at half maximum (FWHM) of 41 nm. Consequently, organic light emitting diodes (OLEDs) employing this emitter achieved a maximum external quantum efficiency (EQEmax) value of 27.7%, with minimal efficiency roll-off. Even at a practical luminance of 1000 cd∙m−2, the device maintains a high EQE value of 24.6%.

Yuki Nagashima.

"My long-term goal is to expand the chemical space of organic compounds for drug discovery, by utilizing underutilized physical chemistry in current organic chemistry… My favorite name reaction is the Miyaura borylation reaction…" Find out more about Yuki Nagashima in his Introducing… Profile.

Photoredox Catalysis by 21-Thiaporphyrins: A Green and Efficient Approach for C-N Borylation and C-H Arylation.

Photoredox catalysis provides a green and sustainable alternative for C-H activation of organic molecules that eludes harsh conditions and use of transition metals. The photocatalytic C-N borylation and C-H arylation mostly depend on the ruthenium and iridium complexes or eosin Y and the use of porphyrin catalysts is still in infancy. A series of novel 21-thiaporphyrins (A2B2 and A3B type) were synthesized having carbazole/phenothiazine moieties at their meso-positions and screened as catalysts for C-N borylation and C-H arylation. This paper demonstrates the 21-thiaporphyrin catalyzed C-N borylation and het-arylation of anilines under visible light. The method utilizes only 0.1 mol % of 21-thiaporphyrin catalyst under blue light for the direct C-N borylation and het-arylation reactions. A variety of substituted anilines were used as source for expensive and unstable aryl diazonium salts in the reactions. The heterobiaryls and aryl boronic esters were obtained in decent yields (up to 88 %). Versatility of the 21-thiaporphyrin catalyst was tested by thiolation and selenylation of anilines under similar conditions. Mechanistic insight was obtained from DFT studies, suggesting that 21-thiaporphyrin undergo an oxidative quenching pathway. The photoredox process catalyzed by 21-thiaporphyrins offers a mild, efficient and metal-free alternative for the formation of C-C, C-S, and C-Se bonds in aryl compounds; it can also be extended to borylation reaction.

Cobalt-Catalyzed Borylative Reduction of Azobenzenes to Hydrazobenzenes via a Diborylated-Hydrazine Intermediate.

Cobalt-catalyzed borylative reduction of azobenzenes using pinacolborane is developed. The simple cobalt chloride catalyst and reaction conditions make this protocol attractive for hydrazobenzene synthesis. This borylative reduction shows good functional group compatibility and can be readily scaled up to the gram scale. Preliminary mechanistic studies clarified the proton source of the hydrazine products. This cobalt-catalyzed azobenzene borylative reaction provides a practical protocol to prepare synthetically useful diborylated hydrazines.

Asymmetric Total Synthesis of Anti-HBV Drug Entecavir: Catalytic Strategies for the Stereospecific Construction of Densely Substituted Cyclopentene Cores.

We have successfully accomplished a catalytic asymmetric total synthesis of entecavir, a first-line antihepatitis B virus medication. The pivotal aspect of our strategy lies in the utilization of a Pd-catalyzed enyne borylative cyclization reaction, enabling the construction of a highly substituted cyclopentene scaffold with exceptional stereoselectivity. Additionally, we efficiently accessed the crucial 1,3-diol enyne system early in our synthetic route through a diarylprolinol organocatalyzed enantioselective cross-aldol reaction and Re-catalyzed allylic alcohol relocation. By strategically integrating these three catalytic protocols, we established a practical pathway for acquiring valuable densely heteroatom-substituted cyclopentene cores.

Pd-Catalyzed Miyaura Borylation and Telescopic Borylation/Suzuki-Miyaura Cross-Coupling Processes in Deep-Eutectic Solvents.

We report an efficient procedure to carry out palladium-catalyzed Miyaura borylation reactions of (hetero)aromatic halides and triflates in choline chloride (ChCl)-based deep eutectic solvents (DESs). The procedure employs bis(pinacolato)diboron as a boron source and a catalyst prepared in situ from readily available Pd2(dba)3 and the phosphine ligand XPhos. Reactions proceed well in different ChCl-based DESs, among which the best results were provided by environmentally friendly and biodegradable mixtures with glycerol and glucose. The reaction tolerates both EDG and EWG substituents on the substrates and can be run on different halides (chloride, bromide, iodide) and pseudohalides (triflate). Furthermore, for several substrates, the catalyst loading can be reduced to 1 mol % Pd (0.5% mol Pd2(dba)3) without compromising the reaction yield. Moreover, we show that the Miyaura borylation protocol in DES can be combined with a subsequent Suzuki-Miyaura cross-coupling reaction in a one-pot procedure, allowing access to various biaryl products and demonstrating its synthetic utility by preparing the precursors of two compounds with reported applications in the photovoltaics sector. Finally, two green metrics (E-factor and EcoScale) of the new one-pot procedure in DES were calculated and compared with literature values to assess the potential advantages in terms of waste reduction, safety, and energy consumption.

Leveraging Language Model Multitasking To Predict C-H Borylation Selectivity.

C-H borylation is a high-value transformation in the synthesis of lead candidates for the pharmaceutical industry because a wide array of downstream coupling reactions is available. However, predicting its regioselectivity, especially in drug-like molecules that may contain multiple heterocycles, is not a trivial task. Using a data set of borylation reactions from Reaxys, we explored how a language model originally trained on USPTO_500_MT, a broad-scope set of patent data, can be used to predict the C-H borylation reaction product in different modes: product generation and site reactivity classification. Our fine-tuned T5Chem multitask language model can generate the correct product in 79% of cases. It can also classify the reactive aromatic C-H bonds with 95% accuracy and 88% positive predictive value, exceeding purpose-developed graph-based neural networks.

Cellulose supported TiO2/Cu2O for highly asymmetric conjugate addition of α,β-unsaturated compounds in aqueous phase

A series of new kind green cellulose-supported bimetallic TiO2/Cu2O (Cell@TiO2/Cu2O) catalytic materials were obtained by in-situ reduction method employing cellulose as the carrier. The effects of metal percentage composition on the morphology and construction of the catalytic materials were systematically investigated. The Cell@TiO2/Cu2O were characterized by FT-IR, TG, XPS, SEM, TEM, EDS, and the element content was obtained by elemental analysis. Then, the achieved catalytic materials were applied to the chiral borylation reaction of α,β-unsaturated compounds, including nitrile compounds, esters, and α,β-unsaturated ketones. Remarkably, this approach provides an efficient strategy to gain an important class of chiral organic boron compounds with target chiral products in high yields as well as enantioselectivities. Besides, the Cell@TiO2/Cu2O could be easily recycled and effectively reused. This work constructed bimetallic TiO2/Cu2O on cellulose as a newly catalyst to obtain chiral boron compounds in aqueous phase.

Photoinduced Site-Selective Aryl C-H Borylation with Electron-Donor-Acceptor Complex Derived from B2Pin2 and Isoquinoline.

Due to boron's metalloid properties, aromatic boron reagents are prevalent synthetic intermediates. The direct borylation of aryl C-H bonds for producing aromatic boron compounds offers an appealing, one-step solution. Despite significant advances in this field, achieving regioselective aryl C-H bond borylation using simple and readily available starting materials still remains a challenge. In this work, we attempted to enhance the reactivity of the electron-donor-acceptor (EDA) complex by selecting different bases to replace the organic base (NEt3) used in our previous research. To our delight, when using NH4HCO3 as the base, we have achieved a mild visible-light-mediated aromatic C-H bond borylation reaction with exceptional regioselectivity (rr > 40:1 to single isomers). Compared with our previous borylation methodologies, this protocol provides a more efficient and broader scope for aryl C-H bond borylation through the use of N-Bromosuccinimide. The protocol's good functional-group tolerance and excellent regioselectivity enable the functionalization of a variety of biologically relevant compounds and novel cascade transformations. Mechanistic experiments and theoretical calculations conducted in this study have indicated that, for certain arenes, the aryl C-H bond borylation might proceed through a new reaction mechanism, which involves the formation of a novel transient EDA complex.

Towards Catalytic C–H Activation Using Main Group Elements

AbstractCatalytic C–H activation reactions are now established as a means to directly transform organic molecules and are commonly associated with metals such as palladium, rhodium, ruthenium and iridium. This Account will describe a short number of reports demonstrating that structures containing main group elements can facilitate C–H activation processes. In particular, boron-based catalysts can promote catalytic arene C–H borylation reactions, and an emerging approach using phosphenium ions can also cleave sp2 C–H bonds. These processes use a Lewis acidic main group atom combined with a pendant base to cleave C–H bonds, which compares with metal-catalyzed reactions that proceed via concerted metalation deprotonation mechanisms.1 Introduction2 Metal-Catalyzed C–H Activation via CMD/AMLA Mechanisms3 C–H Borylation via Boron-Based Catalysts4 C–H Activation Using Phosphenium Ions5 Conclusions

Highly Productive Flow Synthesis for Lithiation, Borylation, and/or Suzuki Coupling Reaction

Highly Productive Flow Synthesis for Lithiation, Borylation, and/or Suzuki Coupling Reaction