Miyaura Borylation Research Articles

Advancing Base-Metal Catalysis: Developing Nickel Catalysis for the Direct Telescope of Miyaura Borylation and Suzuki–Miyaura Cross-Coupling Reactions

Advancing Base-Metal Catalysis: Developing Nickel Catalysis for the Direct Telescope of Miyaura Borylation and Suzuki–Miyaura Cross-Coupling Reactions

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.

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.

Catalytic 2-Ethylhexanoic Acid Promotes Mild Miyaura Borylations.

The Miyaura borylation of aryl and heteroaryl chlorides and bromides using a combination of potassium carbonate and 5 mol % 2-ethylhexanoic acid at 25 °C is reported. The in situ generation of a catalytic amount of potassium 2-ethylhexanoate under these conditions avoids the need for special handling of stoichiometric quantities of hygroscopic potassium 2-ethylhexanoate during the reaction setup as well as difficulties in removing the resulting carboxylic acid during product isolation.

Applications of biaryl cyclization in the synthesis of cyclic enkephalin analogs with a highly restricted flexibility

A series of 10 cyclic, biaryl analogs of enkephalin, with Tyr or Phe residues at positions 1 and 4, were synthesized according to the Miyaura borylation and Suzuki coupling methodology. Biaryl bridges formed by side chains of the two aromatic amino acid residues are of the meta–meta, meta–para, para–meta, and para–para configuration. Conformational properties of the peptides were studied by CD and NMR. CD studies allowed only to compare conformations of individual peptides while NMR investigations followed by XPLOR calculations provided detailed information on their conformation. Reliability of the XPLOR calculations was confirmed by quantum chemical ones performed for one of the analogs. No intramolecular hydrogen bonds were found in all the peptides. They are folded and adopt the type IV β-turn conformation. Due to a large steric strain, the aromatic carbon atoms forming the biaryl bond are distinctly pyramidalized. Seven of the peptides were tested in vitro for their affinity for the µ-opioid receptor.

Pd(0)-Catalyzed Diastereoselective and Enantioselective Intermolecular Heck–Miyaura Borylation of Internal Enamides for the β-Aminoboronate Ester Synthesis

Pd(0)-Catalyzed Diastereoselective and Enantioselective Intermolecular Heck–Miyaura Borylation of Internal Enamides for the β-Aminoboronate Ester Synthesis

Synthesis of a Pinacol Boronate Precursor for [18F]Rucaparib Radiosynthesis

AbstractA novel synthetic approach toward pinacol boronate used as a precursor in the recent radiosynthesis of [18F]rucaparib is described in this study. The Heck reaction of an ortho‐iodoaniline derivative bearing a chloride group at the meta‐position with acrylonitrile produced the desired (E)‐2‐aminocinnamonitrile derivative. The subsequent cyanide‐catalyzed imino‐Stetter reaction of aldimine derived from the obtained 2‐aminocinnamonitrile and aldehyde afforded the required trisubstituted indole‐3‐acetonitrile. The reduction of the nitrile group with cobalt boride followed by the construction of an azepinone scaffold generated indoloazepinone bearing a chloride substituent at the C6‐position of the indole scaffold. The Suzuki–Miyaura borylation of the chloride substituent produced pinacol boronate previously used in the synthesis of [18F]rucaparib. Detailed outcomes of different approaches using different 2‐aminocinnamonitriles were discussed as well.

Regioselective Pd-Catalyzed Suzuki–Miyaura Borylation Reaction for the Dimerization Product of 6-Bromoimidazo[1,2-a]pyridine-2-carboxylate: Mechanistic Pathway, Cytotoxic and Tubercular Studies

AbstractIn the pharmaceutical industry, boronic acid and esters play an important role in API-based synthesis. The most efficient way of preparing various active agents is palladium-catalyzed Suzuki–Miyaura borylation reactions. Herein, we report the formation of dimerization product [6,6′-biimidazo[1,2-a]pyridine]-2,2′-dicarboxamide derivatives 7a–j from 6-bromoimidazo[1,2-a]pyridine-2-carboxylate by employing the same conditions. A regioselective borylation of ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate (3) was examined for the formation of ethyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine-2-carboxylate (4a) but it was found to be directed towards the dimerization product 5. The nitrogen-rich system was incorporated into potential anti-cancer and anti-TB agents through acid amine coupling reactions between acid 6 and various amines (dialkyl/cyclic sec./tert.) to form the final adducts 7. Five derived scaffolds were identified as moderately active in TB activity against the H37Rv strain, while two compounds were found to be particularly potent in NCI-60 anti-cancer screening in nine cancer panels.

Facile access to 1,3-bis(boryl) dienes to build molecular complexity through cycloadditions

An operationally simple method to access 1,3-bis(boryl) dienes from parent 1,3-diones via bis-triflation and a Pd0-catalyzed double Miyaura borylation is described. The prepared 1,3-bis(boryl) dienes are bench-stable and competent in [4+2] cycloadditions with common dienophiles affording diastereoselective access to borylated bicyclo[2.2.2]octenes. The addition of LaCl3·2 LiCl, as a mild Lewis acid helps improve the outcome. A detailed computational investigation of multiborylated dienes further identifies reactivity and stability trends of these linchpin reagents with comparison to more typical dienes.

Computer vision for non-contact monitoring of catalyst degradation and product formation kinetics.

We report a computer vision strategy for the extraction and colorimetric analysis of catalyst degradation and product-formation kinetics from video footage. The degradation of palladium(ii) pre-catalyst systems to form 'Pd black' is investigated as a widely relevant case study for catalysis and materials chemistries. Beyond the study of catalysts in isolation, investigation of Pd-catalyzed Miyaura borylation reactions revealed informative correlations between colour parameters (most notably ΔE, a colour-agnostic measure of contrast change) and the concentration of product measured by off-line analysis (NMR and LC-MS). The breakdown of such correlations helped inform conditions under which reaction vessels were compromised by air ingress. These findings present opportunities to expand the toolbox of non-invasive analytical techniques, operationally cheaper and simpler to implement than common spectroscopic methods. The approach introduces the capability of analyzing the macroscopic 'bulk' for the study of reaction kinetics in complex mixtures, in complement to the more common study of microscopic and molecular specifics.

Coupling-Condensation Strategy for the Convergent Synthesis of an Imidazole-Fused 2-Aminoquinoline NLRP3 Agonist

The development of a convergent route to the NLRP3 (nucleotide-binding domain and leucine-rich repeat-containing protein 3) agonist BMS-986299 is reported. The synthesis relies on a key Miyaura borylation and a tandem Suzuki-Miyaura coupling between an iodoimidazole and an o-aminochloroarene, followed by acid-mediated cyclization to afford the aminoquinoline core. The subsequent Boc cleavage and regioselective acylation afford the target compound. Two routes to the iodoimidazole intermediate are presented, along with the synthesis of the o-aminochloroarene via Negishi coupling. The convergent six-step route leads to an 80% reduction in process mass intensity compared to the linear enabling synthesis.

Synthesis of Novel Key Chromophoric Intermediates via C-C Coupling Reactions

The fundamentals of Pd-catalyzed Csp2−Csp2 Miyaura borylation, Suzuki cross-coupling, and Stille cross-coupling reactions for a variety of borylated precursors based on phenothiazine (PTZ), phenoxazine (POZ), carbazole (Cz), and quinoxaline (QX) units have been explored. Three palladium-based catalysts were chosen for this study: Pd(PPh3)4, Pd(PPh3)2Cl2, and Pd(dppf)Cl2, applying different reaction conditions. Around 16 desired chromophores were successfully designed and synthesized using C-C cross-coupling reactions in moderate to excellent yields, including PTZ, POZ, and Cz units coupled with QX, indolinium iodide, thienyl, phenyl, or triphenylamine moieties. Additionally, PTZ, POZ, and Cz have been employed in synthesizing various pinacol boronate ester derivatives in good to moderate yields. Interestingly, Pd(dppf)Cl2 was found to be the best catalyst for borylation, and C-C cross-coupling reactions occurred in as little as 30 min, with an excellent yield exceeding 98%. Pd(PPh3)4 and Pd(PPh3)2Cl2 catalyzed the reaction to obtain the desired products in moderate to good yields after a long time (20–24 h). On the other hand, the Suzuki-Miyaura cross-coupling between N-(2-methyl)hexyl carbazole pinacol boronate ester derivative 10c and three halogenated quinoxaline derivatives—4-(3-(5-bromothiophen-2-yl)quinoxalin-2-yl)benzaldehyde (27), 4-(5-(3-(5-bromothiophen-2-yl)quinoxalin-2-yl)thiophen-2-yl)benzaldehyde (30), and 4-(3-chloroquinoxalin-2-yl)benzaldehyde (25) catalyzed by Pd(PPh3)4—afforded three carbazole-quinoxaline chromophores (28, 30, and 31, respectively) in 2–3 h, with good to excellent yields reaching 86%. The electron-deficient QX couplers proved to be coupled efficiently using the Stille coupling reaction, which involves the coupling between electron-rich orgaostannane and electron-deficient halide. The synthesized precursors and desired chromophores were characterized by FTIR, 1H-NMR, 13C-NMR, and HRMS.

Protoboration of Alkynes and Miyaura Borylation Catalyzed by Low Loadings of Palladium.

The versions of Miyaura borylation and protoboration of alkynes catalyzed by low loadings of palladium (400 mol ppm = 0.04 mol %) have been developed. These transformations have a broad substrate scope, good functional-group compatibility, and gram-scale synthetic ability.

PdNP@Cyclodextrin on Cu/Al LDH-containing nanocomposites: Cage effect, crystallite size tuning and composite topology towards cross-couplings

A series of Cu/Al layered double hydroxides and Pd(0/II) composites containing native and modified cyclodextrins were prepared under different conditions of solvent (water or N,N-dimethylformamide), Pd precursors (Na2PdCl4 or Pd2dba3) and cyclodextrin/Pd ratios for the catalytic evaluation in Pd/Cu catalyzed cross-couplings aiming for the preparation of aryl thiophenes and N-arylamines. According to XPS measurements, the nanocomposites prepared in water presented a higher Pd(II)/Pd(0) ratio and subtle evidence of [PdCl4]2− intercalation by analyses of X-ray diffractograms. On the other hand, those prepared in N,N-dimethylformamide showed a higher content of Pd(0), probably dispersed on layered double hydroxides surface. SEM-FEG analyses combined with particle size distribution revealed that cyclodextrins were able to tune the size distribution, especially the β-form (15 nm in the presence of cyclodextrins). Powder X-rays diffraction data refinement using Rietveld method revealed that controlled palladium crystallite sizes of 11.53 nm and 10.22 nm were obtained in the presence of hydroxypropylated cyclodextrins (β and γ forms). Notably, the Rietveld refinement of the Pd nanocomposites revealed the presence of malachite, gibbsite, and sperniite phases in 23.05%, 23.05%, 15.23% contents. It suggests that Pd introduces a distortion in the initial LDH lattice. The catalytic activities of these nanocomposites were evaluated in Suzuki-Miyaura reaction in water/ethanol mixture, under low Pd loadings and room-temperature. Noteworthy, the nanocomposite prepared in N,N-dimethylformamide with native β-cyclodextrin showed higher catalytic activity (turnover number up to 7379) in Suzuki-Miyaura and Buchwald-Hartwig reactions for the synthesis of 2-aryl thiophenes, a component of several classes of functional organic electronic materials, and N-(4-nitrophenyl)-1,2-ethanediamine, respectively. This same nanocomposite was recycled up to three runs without loss in catalytic activity. A tentative test envisaging a one-pot borylation-Suzuki-Miyaura strategy indicated that the Miyaura borylation was conceivably affected by the coexisting malachite and spertiniite phases in the nanocomposite. However, control experiments in the presence of Cu(OH)2, Al(OH)3 and malachite indicate a lack of catalytic activity for these phases in Suzuki-Miyaura reactions. Thus, the catalytic activity is mostly attributed to the nanocomposite Cu–Al LDHs containing CDs. The enhancement in catalytic activity is suggested to occur as a result of deprotonation/adsorption of phenylboronic acid, transmetallation facilitated by a relatively high surface hydroxyl sites, improved substrate complexation by β-CDs and potential soluble Cu(II) active species from the layered matrix.

Synthesis and optical properties of novel key electron donors-based pinacol boronate ester derived from phenothiazine, phenoxazine and carbazole

Pinacol boronate esters D1-D3 derived from phenothiazine (PTZ), phenoxazine (POZ), and carbazole (CZ), having a tolyl moiety as an auxiliary donor and 2-ethylhexyl as a branched alkyl chain to prevent the molecular aggregation have been synthesized and characterized. Thus, the N-alkylation of PTZ, POZ, and CZ followed by bromination afforded the corresponding products in good yield. These compounds were CC coupled via the Suzuki coupling reaction with tolylboronic acid and then underwent the Miyaura borylation reaction to get the key electron donors D1-D3. The chemical structures of all compounds were confirmed by spectral data (IR, 1H NMR, 13C NMR, 11B-NMR, and HRMS). The UV–vis absorption and fluorescence characteristics of D1-D3 compared with their cores PTZ, POZ and CZ in THF solution have been investigated. The results indicated a red-shift in both absorption and fluorescence of D1-D3, indicating that the tolyl moiety increased the conjugation of the donor cores. A huge Stokes shift ranging from 15,000 to 17,000 cm−1 was observed for D1-D3 intermediates. The newly synthesized boronate key electron donors have the potential to construct optoelectronic materials.

Palladium-Catalyzed Miyaura Borylation of Overly Crowded Aryl Chlorides Enabled by a Complementary Localized/Remote Steric Bulk of Ligand Chassis

Palladium-Catalyzed Miyaura Borylation of Overly Crowded Aryl Chlorides Enabled by a Complementary Localized/Remote Steric Bulk of Ligand Chassis

Economical and Readily Accessible Preparation of o,o-Disubstituted Arylboronates through Palladium-Catalyzed Borylation of Haloarenes.

Miyaura borylation, that is, palladium-catalyzed cross-coupling between bromoarenes and diboron, offers a versatile method for preparing arylboronates; however, a costly and inaccessible catalyst has been required for synthesizing highly congested arylboronates with the method. Here the Pd(OAc)2-tri(4-methoxyphenyl)phosphine catalyst was found to work as an efficient catalyst for the sterically demanding borylation. A broad range of o,o-disubstituted bromoarenes were converted into the corresponding arylboronates in high yields by using the palladium catalyst with Cs2CO3 in EtOAc at 80 °C.

Synthesis of 4,7′-Bibenzo[b]thiophenes Bearing Several Different Substituents at 2-, 2′-, 4′-, and 7-Positions; Structurally Featured Molecular Scaffolds for Selective Substitution

AbstractFour isomers of 4,7′-bibenzothiophene scaffolds bearing two different halogen (Br, Cl) and triisopropylsilyl substituents have been synthesized from the two multihalobenzo[b]thiophenes via iodoselective Miyaura borylation reaction using potassium benzoate as a base. Further investigation into the reactivity of 4,7′-bibenzothiophenes in substitution reaction, Suzuki–Miyaura cross-coupling reaction, and C–H direct arylation reaction revealed that tetrasubstituted 4,7′-bibenzothiophenes can be synthesized site- (chemo-) selectively, which are promising novel components for molecular architecture.

Hydrogen Evolution from Telescoped Miyaura Borylation and Suzuki Couplings Utilizing Diboron Reagents: Process Safety and Hazard Considerations

Hydrogen Evolution from Telescoped Miyaura Borylation and Suzuki Couplings Utilizing Diboron Reagents: Process Safety and Hazard Considerations

Construction of Axially Chiral Arylborons via Atroposelective Miyaura Borylation.

Compared with the well-developed centrally chiral boron chemistry, C-B axially chiral chemistry remains elusive and challenging. Herein we report the first atroposelective Miyaura borylation of bromoarenes with unsymmetrical diboron reagents for the direct catalytic synthesis of optically active atropisomeric arylborons. This reaction features broad substrate scope and produces axially chiral arylborons with high yields and good enantioselectivities.