Arylboronic Esters Research Articles

Nickel-catalyzed carbonylative domino cyclization of arylboronic acid pinacol esters with 2-alkynyl nitroarenes towardN-aroyl indoles

A nickel-catalyzed carbonylative domino cyclization of arylboronic acid pinacol esters with 2-alkynyl nitroarenes has been developed.

Photochemical and electrochemical C-N borylation of arylhydrazines.

The C-N borylation of arylhydrazine hydrochlorides with bis(pinacolato)diboron was achieved under photochemical and electrochemical conditions, respectively. This novel and scalable transformation provides two efficient and mild transition-metal-free synthetic routes towards aryl boronate esters from easily available arylhydrazines.

NHC induced radical formation via homolytic cleavage of B-B bonds and its role in organic reactions.

New borylation methodologies have been reported recently, wherein diboron(4) compounds apparently participate in free radical couplings via the homolytic cleavage of the B–B bond. We report herein that bis-NHC adducts of the type (NHC)2·B2(OR)4, which are thermally unstable and undergo intramolecular ring expansion reactions (RER), are sources of boryl radicals of the type NHC–BR2˙, exemplified by Me2ImMe·Bneop˙ 1a (Me2ImMe = 1,3,4,5-tetramethyl-imidazolin-2-ylidene, neop = neopentylglycolato), which are formed by homolytic B–B bond cleavage. Attempts to apply the boryl moiety 1a in a metal-free borylation reaction by suppressing the RER failed. However, based on these findings, a protocol was developed using Me2ImMe·B2pin23 for the transition metal- and additive-free boryl transfer to substituted aryl iodides and bromides giving aryl boronate esters in good yields. Analysis of the side products and further studies concerning the reaction mechanism revealed that radicals are likely involved. An aryl radical was trapped by TEMPO, an EPR resonance, which was suggestive of a boron-based radical, was detected in situ, and running the reaction in styrene led to the formation of polystyrene. The isolation of a boronium cation side product, [(Me2ImMe)2·Bpin]+I−7, demonstrated the fate of the second boryl moiety of B2pin2. Interestingly, Me2ImMe NHC reacts with aryl iodides and bromides generating radicals. A mechanism for the boryl radical transfer from Me2ImMe·B2pin23 to aryl iodides and bromides is proposed based on these experimental observations.

Mechanistic study of the bismuth mediated fluorination of arylboronic esters and further rational design.

Density functional theory (DFT) calculations have been performed to gain insight into the catalytic mechanism of the bismuth redox catalyzed fluorination of arylboronic esters to deliver the widely used arylfluoride compounds (Science 2020, 367, 313–317). The study reveals that the whole catalysis can be characterized via three stages: (i) transmetallation generates the Bi(iii) intermediate 5, capitalizing on the use of KF as an activator. (ii) 5 then reacts with the electrophilic fluorination reagent 1-fluoro-2,6-dichloropyridinium 4via oxidative addition to give the Bi(v) intermediate IM4A. (iii) IM4A undergoes a reductive elimination step to yield aryl fluoride compounds and regenerates the bismuth catalyst for the next catalytic cycle. Each stage is kinetically and thermodynamically feasible. The transmetallation step, with a barrier of 25.4 kcal mol−1, is predicted to be the rate-determining step (RDS) during the whole catalytic cycle. Furthermore, based on a mechanistic study, new catalysts with the framework of tethered bis-anionic ligands were designed, which will help to improve current catalytic systems and develop new bismuth mediated fluorination of arylboronic esters.

Enabling Suzuki-Miyaura coupling of Lewis-basic arylboronic esters with a nonprecious metal catalyst.

The high cost and negative environmental impact of precious metal catalysts has led to increased demand for nonprecious alternatives for widely practiced reactions such as the Suzuki-Miyaura coupling (SMC). Ni-catalyzed versions of this reaction have failed to achieve high reactivity with Lewis-basic arylboron nucleophiles, especially pinacolboron esters. We describe the development of (PPh2Me)2NiCl2 as an inexpensive and air-stable precatalyst that addresses this challenge. Under activation by n-BuMgCl, this complex can catalyze the coupling of synthetically important heteroaryl pinacolborons with heteroaryl halides. Mildly basic conditions (aqueous K3PO4) allow the reaction to tolerate sensitive functional groups that were incompatible with other Ni-SMC methods. Experimental and computational studies suggest that catalyst inhibition by substitution of PPh2Me from Ni(ii) intermediates by Lewis basic reactants and products is disfavored relative to more commonly employed ligands in the Ni-SMC, which allows it to operate efficiently in the presence of Lewis bases such as unhindered pyridines.

Development of an ATP-independent bioluminescent probe for detection of extracellular hydrogen peroxide.

This work reports a new ATP-independent bioluminescent probe (bor-DTZ) for detecting hydrogen peroxide that is compatible with the Nanoluciferase enzyme. The probe is designed with an arylboronate ester protecting group appended to a diphenylterazine core via a self-immolative phenolate linker. Reaction with hydrogen peroxide reveals diphenylterazine, which can then react with Nanoluciferase to produce a detectable bioluminescent signal. Bor-DTZ shows a dose-dependent response to hydrogen peroxide and selectivity over other biologically relevant reactive oxygen species and can be applied to detect either intra- or extracellular species. We further demonstrate the ability of this platform to monitor fluxes in extracellular hydrogen peroxide in a breast cancer cell line in response to the anticancer treatment, cisplatin.

Unreactive C-N Bond Activation of Anilines via Photoinduced Aerobic Borylation.

Unreactive C-N bond activation of anilines was achieved by photoinduced aerobic borylation. A diverse range of tertiary and secondary anilines were converted to aryl boronate esters in moderate to good yields with wide functional group tolerance under simple and ambient photochemical conditions. This transformation achieved the direct and facile C-N bond activation of unreactive anilines, providing a convenient and practical route transforming widely available anilines into useful aryl boronate esters.

Copper‐Catalyzed Preparation of Alkenylboronates and Arylboronates

AbstractOrganoboron compounds, especially alkenylboronates and arylboronates are highly useful reagents and versatile building blocks in the modern synthetic chemistry toolbox. This review focuses on copper‐catalyzed routes to access alkenyl‐ and arylboronate esters. Various copper salts and ligands have been employed to access them in excellent regio‐ and stereoselectivity as well as high yields. Both addition and substitution reactions to alkenylboronates have been highlighted based on various methodologies including hydroboration, carboboration, borylative opening of propargyl three‐ and four‐membered rings, dehalogenative borylation of alkenyl bromides and iodides, defluoroborylation of fluoroalkenes and direct C(sp2)−H bond activation of alkenes. Preparation of arylboronates involving borylation of aryl halides, C(sp2)−H borylation of arenes and cascade 1,3‐halogen migration/borylation of 2‐halostyrenes have been reviewed. Mechanistic aspects of those borylation reactions are discussed briefly.

Palladium-catalyzed borylation of aryl bromides and chlorides using phosphatrioxa-adamantane ligands

Catalysts based on the combination of Pd(OAc)2 and the electron-deficient phosphatrioxa-adamantane ligands are described for borylation of aryl bromides and chlorides. Catalytic evaluation of a small library of phosphatrioxa-adamantane ligands provided some insights on the preferred ligand steric profile for borylation reactions. The corresponding aryl boronate esters were accessed under mild conditions (25–70 °C) and isolated in high yields (up to 96%).

Palladium-Catalyzed Decarbonylative Borylation of Aryl Anhydrides.

A palladium-catalyzed base-free decarbonylative borylation of aryl anhydrides has been developed. Catalyst system consisting of Pd(OAc)2/dppb enables readily available aryl anhydrides to be employed as electrophiles for the synthesis of versatile arylboronate esters via O-C(O) bond activation and decarbonylation. This method is characterized by an excellent functional group tolerance and broad substrate scope, using bench stable aryl anhydrides as aryl electrophiles in C-B bond formation. Mechanistic studies and functionalization of late-stage pharmaceutical molecules are disclosed.

Chiral Benzothiophene Synthesis via Enantiospecific Coupling of Benzothiophene S‐Oxides with Boronic Esters

AbstractBenzothiophenes are valuable heterocycles that are widely used in medicines, agrochemicals, and materials science. Herein, we report a general method for the synthesis of enantioenriched 2,3‐disubstituted benzothiophenes via a transition‐metal‐free C2‐alkylation of benzothiophenes with boronic esters. The reactions utilize benzothiophene S‐oxides in lithiation‐borylations to generate intermediate arylboronate complexes, and subsequent Tf2O‐promoted S−O bond cleavage to trigger a Pummerer‐type 1,2‐metalate shift, which gives the coupled products with complete enantiospecificity. Primary, secondary and tertiary alkyl boronic esters and aryl boronic esters are successfully coupled with a range of C3‐substituted benzothiophenes. Importantly, this transformation does not require the use of C3 directing groups, therefore it overcomes a major limitation of previously developed transition‐metal‐mediated C2 alkylations of benzothiophenes.

Chiral Benzothiophene Synthesis via Enantiospecific Coupling of Benzothiophene S‐Oxides with Boronic Esters

Benzothiophenes are valuable heterocycles that are widely used in medicines, agrochemicals, and materials science. Herein, we report a general method for the synthesis of enantioenriched 2,3-disubstituted benzothiophenes via a transition-metal-free C2-alkylation of benzothiophenes with boronic esters. The reactions utilize benzothiophene S-oxides in lithiation-borylations to generate intermediate arylboronate complexes, and subsequent Tf2 O-promoted S-O bond cleavage to trigger a Pummerer-type 1,2-metalate shift, which gives the coupled products with complete enantiospecificity. Primary, secondary and tertiary alkyl boronic esters and aryl boronic esters are successfully coupled with a range of C3-substituted benzothiophenes. Importantly, this transformation does not require the use of C3 directing groups, therefore it overcomes a major limitation of previously developed transition-metal-mediated C2 alkylations of benzothiophenes.

Visualization of Receptor-Interacting Protein Kinase 1 (RIPK1) by Brain Imaging with Positron Emission Tomography.

We report the development of the first positron emission tomography (PET) radiotracer, [18F]CNY-07, based on a highly specific and potent RIPK1 inhibitor, Nec-1s, for RIPK1/necroptosis brain imaging in rodents. [18F]CNY-07 was synthesized through copper-mediated 18F-radiolabeling from an aryl boronic ester precursor and studied in vivo PET imaging in rodents. PET imaging results showed that [18F]CNY-07 can penetrate the blood-brain barrier with a maximum percent injected dose per unit volume of 3 at 10 min postinjection in the brain in vivo. Self-blocking studies of [18F]CNY-07 by pretreating with unlabeled molecules in rodents showed reduced radioactivity in animal brains (30% radioactivity decreased), indicating the binding specificity of our radiotracer. Our studies demonstrate that [18F]CNY-07 has provided a useful PET radioligand enabling brain RIPK1 imaging, which could be a valuable research tool in studying RIPK1-related neurological disorders in animals and potentially humans.

Air-Stable Iron-Based Precatalysts for Suzuki-Miyaura Cross-Coupling Reactions between Alkyl Halides and Aryl Boronic Esters.

The development of an air-stable iron(III)-based precatalyst for the Suzuki-Miyaura cross-coupling reaction of alkyl halides and unactivated aryl boronic esters is reported. Despite benefits to cost and toxicity, the proclivity of iron(II)-based complexes to undergo deactivation via oxidation or hydrolysis is a limiting factor for their widespread use in cross-coupling reactions compared to palladium-based or nickel-based complexes. The new octahedral iron(III) complex demonstrates long-term stability on the benchtop as assessed by a combination of 1H NMR spectroscopy, Mössbauer spectroscopy, and its sustained catalytic activity after exposure to air. The improved stability of the iron-based catalyst facilitates an improved protocol in which Suzuki-Miyaura cross-coupling reactions of valuable substrates can be assembled without the use of a glovebox and access a diverse scope of products similar to reactions assembled in the glovebox with iron(II)-based catalysts.

Protodeboronation of (Hetero)Arylboronic Esters: Direct versus Prehydrolytic Pathways and Self-/Auto-Catalysis.

The kinetics and mechanism of the base-catalyzed hydrolysis (ArB(OR)2 → ArB(OH)2) and protodeboronation (ArB(OR)2 → ArH) of a series of boronic esters, encompassing eight different polyols and 10 polyfluoroaryl and heteroaryl moieties, have been investigated by in situ and stopped-flow NMR spectroscopy (19F, 1H, and 11B), pH-rate dependence, isotope entrainment, 2H KIEs, and KS-DFT computations. The study reveals the phenomenological stability of boronic esters under basic aqueous-organic conditions to be highly nuanced. In contrast to common assumption, esterification does not necessarily impart greater stability compared to the corresponding boronic acid. Moreover, hydrolysis of the ester to the boronic acid can be a dominant component of the overall protodeboronation process, augmented by self-, auto-, and oxidative (phenolic) catalysis when the pH is close to the pKa of the boronic acid/ester.

Activation of Aryl Carboxylic Acids by Diboron Reagents towards Nickel-Catalyzed Direct Decarbonylative Borylation.

The Ni-catalyzed decarbonylative borylation of (hetero)aryl carboxylic acids with B2 cat2 has been achieved without recourse to any additives. This Ni-catalyzed method exhibits a broad substrate scope covering poorly reactive non-ortho-substituted (hetero)aryl carboxylic acids, and tolerates diverse functional groups including some of the groups active to Ni0 catalysts. The key to achieve this decarbonylative borylation reaction is the choice of B2 cat2 as a coupling partner that not only acts as a borylating reagent, but also chemoselectively activates aryl carboxylic acids towards oxidative addition of their C(acyl)-O bond to Ni0 catalyst via the formation of acyloxyboron compounds. A combination of experimental and computational studies reveals a detailed plausible mechanism for this reaction system, which involves a hitherto unknown concerted decarbonylation and reductive elimination step that generates the aryl boronic ester product. This mode of boron-promoted carboxylic acid activation is also applicable to other types of reactions.

Activation of Aryl Carboxylic Acids by Diboron Reagents towards Nickel‐Catalyzed Direct Decarbonylative Borylation

AbstractThe Ni‐catalyzed decarbonylative borylation of (hetero)aryl carboxylic acids with B2cat2 has been achieved without recourse to any additives. This Ni‐catalyzed method exhibits a broad substrate scope covering poorly reactive non‐ortho‐substituted (hetero)aryl carboxylic acids, and tolerates diverse functional groups including some of the groups active to Ni0 catalysts. The key to achieve this decarbonylative borylation reaction is the choice of B2cat2 as a coupling partner that not only acts as a borylating reagent, but also chemoselectively activates aryl carboxylic acids towards oxidative addition of their C(acyl)−O bond to Ni0 catalyst via the formation of acyloxyboron compounds. A combination of experimental and computational studies reveals a detailed plausible mechanism for this reaction system, which involves a hitherto unknown concerted decarbonylation and reductive elimination step that generates the aryl boronic ester product. This mode of boron‐promoted carboxylic acid activation is also applicable to other types of reactions.

Enantioconvergent Arylation of Racemic Secondary Alcohols to Chiral Tertiary Alcohols Enabled by Nickel/N-Heterocyclic Carbene Catalysis.

The direct upgrading reaction of simple and readily available achiral alcohols via C-H functionalization is an ideal strategy to prepare value-added chiral higher alcohols. Herein, we disclose the first enantioconvergent upgrading reaction of simple racemic secondary alcohols to enantioenriched tertiary alcohols. An N-heterocyclic carbene (NHC)-nickel catalyst was leveraged to enable this highly efficient formal asymmetric alcohol α-C-H arylation via a dehydrogenation using phenyl triflate as a mild oxidant followed by asymmetric addition of arylboronic esters to the transient ketones. Mechanistic studies and control experiments were conducted to reveal the possible reasons for the exceptional control over chemo- and enantioselectivity.

Metal-Stabilized Boronate Ester Cages.

Molecular cages with arylboronate ester caps at the vertices are described. The cages were obtained by metal-templated polycondensation reactions of a tris(2-formylpyridine oxime) ligand with arylboronic acids. Suited templates are triflate or triflimide salts of ZnII, FeII, CoII, or MnII. In the products, the metal ions are coordinated internally to the pyridyl and oximato N atoms adjacent to the boronate ester, resulting in an improved hydrolytic stability of the latter. It is possible to decorate the cages with cyano or aldehyde groups using functionalized arylboronic acids. The aldehyde groups allow for a postsynthetic modification of the cages via an imine bond formation.

Nickel‐Catalyzed Regioselective Alkenylarylation of γ,δ‐Alkenyl Ketones via Carbonyl Coordination

AbstractWe disclose a nickel‐catalyzed reaction, which enabled us to difunctionalize unactivated γ,δ‐alkenes in ketones with alkenyl triflates and arylboronic esters. The reaction was made feasible by the use of 5‐chloro‐8‐hydroxyquinoline as a ligand along with NiBr2⋅DME as a catalyst and LiOtBu as base. The reaction proceeded with a wide range of cyclic, acyclic, endocyclic and exocyclic alkenyl ketones, and electron‐rich and electron‐deficient arylboronate esters. The reaction also worked with both cyclic and acyclic alkenyl triflates. Control experiments indicate that carbonyl coordination is required for the reaction to proceed.