Miyaura Borylation Research Articles

Catalytic Transformations of Sulfonium Salts via C-S Bond Activation.

After the 20-year dormant period since Liebeskind's seminal report, triorganosulfonium salts have now proved to be reliably useful surrogates of or complement to organic halides in a variety of transition-metal-catalyzed transformations. By necessity, my group developed Suzuki-Miyaura ring-opening arylation of sulfonium salts of dibenzothiophenes with tetraarylborates and Pd-catalyzed intramolecular C-H/C-S coupling. Following this starting point and experiencing the decent reactivity of sulfonium salts, in order to maximize the synthetic utility of organosulfur compounds, we successfully applied readily available sulfonium salts to Ni-catalyzed coupling with arylzinc reagents, Pd- or photoredox-catalyzed Mizoroki-Heck reaction, Pd-catalyzed alkoxycarbonylation, Pd-catalyzed Miyaura borylation, Ni-catalyzed reductive carboxylation, and Ni-catalyzed zincation. I sincerely hope this Personal Account will facilitate further development of reactions of triorganosulfonium salts which are difficult to achieve using conventional organic (pseudo)halides.

Improvement in the Palladium-Catalyzed Miyaura Borylation Reaction by Optimization of the Base: Scope and Mechanistic Study.

Aryl boronic acids and esters are important building blocks in API synthesis. The palladium-catalyzed Suzuki-Miyaura borylation is the most common method for their preparation. This paper describes an improvement of the current reaction conditions. By using lipophilic bases such as potassium 2-ethyl hexanoate, the borylation reaction could be achieved at 35 °C in less than 2 h with very low palladium loading (0.5 mol %). A preliminary mechanistic study shows a hitherto unrecognized inhibitory effect by the carboxylate anion on the catalytic cycle, whereas 2-ethyl hexanoate minimizes this inhibitory effect. This improved methodology enables borylation of a wide range of substrates under mild conditions.

Miyaura Borylation Reaction

Key words Miyaura borylation - cross-coupling - palladium catalysis - arylboronic esters

Facile and economical Miyaura borylation and one-pot Suzuki–Miyaura cross-coupling reaction

Facile and economical method for Miyaura borylation reaction between B2pin2 and aryl bromides is reported. The catalytic system containing 2 mol% PdCl2(PPh3)2 and KOAc serves to enable borylations to occur under solvent-free and atmospheric conditions. The developed protocol can be applied to synthesize symmetrical and unsymmetrical biaryls via one-pot two-step Suzuki–Miyaura cross-coupling reaction and also offers the up-scalability.

Significant rate enhancement via potassium pivalate in a Miyaura borylation approach to verinurad

We describe herein the significant rate-enhancing effect of employing potassium pivalate as a base in a Miyaura borylation. The manufacturing route to verinurad currently employs a Suzuki-Miyaura cross-coupling, requiring cryogenic conditions to generate the boronic acid coupling partner. This process has manufacturability challenges including those associated with low temperature operations and thus an alternative Miyaura borylation approach is described. High throughput screening was employed to investigate the effects of various carboxylate bases and their corresponding counterions on reactivity. Our results highlight potassium pivalate as producing exceptional rate acceleration. To the best of our knowledge this base has not previously been reported for use in Miyaura borylations. Diethanolamine transesterification is also reported as a facile and robust boronate isolation protocol. Successful application of this diethanolamine boronate ester in downstream cross-coupling chemistry has demonstrated the potential for this new route in commercial manufacture of verinurad.

Selective C-C Bond Scission of Ketones via Visible-Light-Mediated Cerium Catalysis

Summary Here, we report a general catalytic manifold for the selective C–C bond scission of ketones via the exploitation of the ligand-to-metal charge transfer (LMCT) excitation mode. Through a cooperative utilization of Lewis acid catalysis and LMCT catalysis, the C–C bond of ketones could be selectively and effectively cleaved, enabling the installation of different functionalities at each carbon of the cleaved C–C bond through a sequential and orthogonal manner. This reaction manifold serves as a photocatalytic alternative to the Norrish type I reaction with the combination of visible light and inexpensive cerium salts. Under operationally simple conditions, a wide range of acyclic and cyclic ketones, from simple strained cyclobutanones to complex androsterone with less strained cyclopentanone moiety, could be successfully transformed into versatile chemical building blocks.

Peptoid Helix Displaying Flavone and Porphyrin: Synthesis and Intramolecular Energy Transfer.

Natural light-harvesting complexes (LHCs) absorb a broad spectrum of sunlight using a collection of photosynthetic pigments whose spatial arrangement is controlled by a protein matrix and exhibit efficient energy transfer. We constructed a novel light-harvesting protein mimic, which absorbs light in the UV to visible region (280-700 nm) by displaying flavone and porphyrin on a peptoid helix. First, an efficient synthesis of 4'-derivatized 7-methoxyflavone (7-MF, 3 and 4) was developed. The flavone-porphyrin-peptoid conjugate (FPPC) was then prepared via Miyaura borylation on a resin-bound peptoid followed by Suzuki coupling between the peptoid and pigment. Circular dichroism spectroscopy indicated that the FPPC underwent helix-to-loop conversion of the peptoid scaffold upon changing the solvent conditions. A distinct intramolecular energy transfer was observed from 7-MF to porphyrin with greater efficiency in the helix than that in the loop conformation of the peptoid, whereas no clear evidence of energy transfer was obtained for unstructured FPPC. We thus demonstrate the value of the helical peptoid, which provided a controlled orientation for 7-MF and porphyrin and modulated the energy transfer efficiency via conformational switching. Our work provides a way to construct a sophisticated LHC mimic with enhanced coverage of the solar spectrum and controllable energy transfer efficiency.

Enantioselective Conjugate Addition of Aryl Halides and Triflates to Electron-Deficient Olefins via Nickel- and Rhodium-Catalyzed Sequential Relay Reactions.

Asymmetric conjugate addition of aryl halides or aryl triflates to electron-deficient olefins was realized by sequential Miyaura borylation and Hayashi-Miyaura conjugate addition in one pot. A nickel-catalyzed borylation of aryl halides or triflates and a rhodium-chiral diene complex catalyzed enantioselective conjugate addition was executed as a pair of relay reactions as a more efficient and greener protocol.

How Solvents Control the Stereospecificity of Ni-Catalyzed Miyaura Borylation of Allylic Pivalates

Solvents act as a powerful control of stereospecificity in Ni-catalyzed Miyaura borylation of allylic pivalates. Low polar solvents lead to stereoretentive borylation, whereas highly polar solvents...

Preparation of the Serotonin Transporter PET Radiotracer 2-({2-[(Dimethylamino)methyl]phenyl}thio)-5-[18F]fluoroaniline (4-[18F]ADAM): Probing Synthetic and Radiosynthetic Methods

Serotonin transporters (SERTs) are involved in regulating the concentration of synaptic serotonin and present a good target for many neurologic and psychiatric disorder drugs. Positron-emission tomography (PET) is a valuable tool in both diagnosis and monitoring treatment therapies, and hence much effort is being given to developing suitable PET agents for imaging SERT. Our interest in applying the fluorine-18 analogue 4-[18F]ADAM for imaging SERT prompted the development of an improved synthetic route to access unlabelled ADAM. This is achieved using Pd-catalysed coupling with thiosalicylic acid and an EDC/HOBt amide coupling in 36% yield over 4 steps. A novel radiolabelling precursor, the pinacol-derived boronic ester, is prepared from the bromide using the Miyaura borylation and is obtained in 27% yield over 6 steps. Pinacolate is then used for the radiolabelling of 4-[18F]ADAM based on Cu-mediated nucleophilic fluorination in which the presence of oxygen is critical for the reaction. A 1:1 substrate to copper ratio is found to be optimal when the reaction is performed in dimethylacetamide at 85 °C. Using these conditions, 4-[18F]ADAM is prepared in 29 ± 10% (n = 6) radiochemical conversion after hydrolysis of the Boc group with HCl. Furthermore, the method is successfully automated to afford 4-[18F]ADAM in 10% radiochemical conversion.

A Monophosphine Ligand Derived from Anthracene Photodimer: Synthetic Applications for Palladium-Catalyzed Coupling Reactions.

Herein, we present an air-stable dianthracenyl monophosphine ligand (diAnthPhos) which can be prepared in two steps from commercially available anthracene derivatives. The ligand exhibits excellent efficiency for palladium-catalyzed coupling reactions. In particular, Miyaura borylation of heterocycle-containing electrophiles can be facilitated employing the diAnthPhos ligand with a broad substrate scope and low catalyst loading. The valuable synthetic utility of the new ligand is further demonstrated by a one-pot Miyaura borylation/Suzuki coupling protocol for heteroaryl-containing substrates.

Novel Carbazole-Based N-Heterocyclic Carbene Ligands to Access Synthetically Relevant Stilbenes in Pd-Catalyzed Coupling Processes.

A series of new carbazole-based N-heterocyclic carbene (NHC) ligands have been synthesized in a simple and facile synthetic route and subsequently used in a Pd/carbazole-based NHC catalytic system, which was found to be effective in catalyzing Heck reactions to provide substituted stilbene derivatives in good yields. Several bioactive stilbenes, including pterostilbene, pinosylvin, trimethoxy resveratrol, and resveratrol, were synthesized in good yields, and a 10 mmol scale-up was also performed for trimethoxy resveratrol. The synthetic application was also extended by performing a double-tandem chemoselective Heck reaction followed by Miyaura borylation in a one-pot procedure to give single-step access to synthetically useful stilbenyl boronate esters. Similarly, a unique triple-tandem protocol of a chemoselective Heck reaction/Miyaura borylation/Suzuki-Miyaura coupling reaction sequence was performed for the one-pot modification of biologically relevant molecules.

Micelle-Mediated Chemistry in Water for the Synthesis of Drug Candidates

Micellar reaction conditions, in a predominantly aqueous medium, have been developed for transformations commonly used by synthetic chemists working in the pharmaceutical industry to discover and develop drug candidates. The reactions covered in this review are the Suzuki–Miyaura, Miyaura borylation, Sonogashira coupling, transition-metal-catalysed CAr–N coupling, SNAr, amidation, and nitro reduction. Pharmaceutically relevant examples of these applications will be used to show how micellar conditions can offer advantages in yield, operational ease, amount of waste generated, transition-metal catalyst loading, and safety over the use of organic solvents, irrespective of the setting in which they are used.1 Introduction2 Micelles as Solubilising Agents3 Micelles as Nanoreactors4 Designer Surfactants5 A Critical Evaluation of the Case for Chemistry in Micelles6 Scope of Review7 Suzuki–Miyaura Coupling8 Miyaura Borylation9 Sonogashira Coupling10 Transition-Metal-Catalysed CAr–N Couplings11 SNAr12 Amidation13 Nitro Reduction14 Micellar Sequences15 Summary and Outlook

Room temperature Pd(0)/Ad3P-catalyzed coupling reactions of aryl chlorides with bis(pinacolato)diboron

Room temperature Pd(0)/Ad3P-catalyzed cross-coupling reactions of aryl chlorides with bis(pinacolato)diboron are described. The Pd(0)/Ad3P catalyst, generated from Ad3P-coordinated acetanilide-based palladacycle complex, proved to be an efficient catalyst system for the Miyaura borylation reactions of a variety of aryl chlorides with bis(pinacolato)diboron. The mild reaction condition, the easy availability of the catalyst and good coupling yields make these reactions potentially useful in organic synthesis.

Convergent Synthesis of the NS5B Inhibitor GSK8175 Enabled by Transition Metal Catalysis.

A convergent eight-stage synthesis of the boron-containing NS5B inhibitor GSK8175 is described. The previous route involves 13 steps in a completely linear sequence, with an overall 10% yield. Key issues include a multiday SNAr arylation of a secondary sulfonamide using HMPA as solvent, multiple functional group interconversions after all of the carbon atoms are installed (including a Sandmeyer halogenation), use of carcinogenic chloromethyl methyl ether to install a protecting group late in the synthesis, and an unreliable Pd-catalyzed Miyaura borylation as the penultimate step. We have devised an orthogonal approach using a Chan-Lam coupling between a halogenated aryl pinacol boronate ester and an aryl methanesulfonamide. This reaction is performed using a cationic Cu(I) precatalyst, which can be easily generated in situ using KPF6 as a halide abstractor. High-throughput screening revealed a new Pd catalyst system to effect the penultimate borylation chemistry using simple monodentate phosphine ligands, with PCyPh2 identified as optimal. Reaction progress analysis of this borylation indicated likely mass-transfer rate limitations under standard conditions using KOAc as the base. We have devised a K2CO3/pivalic acid system as an alternative, which dramatically outperforms the standard conditions. This new synthesis proceeds in eight stages with a 20% overall yield.

Photoinduced Miyaura Borylation by a Rare-Earth-Metal Photoreductant: The Hexachlorocerate(III) Anion.

The first photoinduced carbon(sp2 )-heteroatom bond forming reaction by a rare-earth-metal photoreductant, a Miyaura borylation, has been achieved. This simple, scalable, and novel borylation method that makes use of the hexachlorocerate(III) anion ([CeIII Cl6 ]3- , derived from CeCl3 ) has a broad substrate scope and functional-group tolerance and can be conducted at room temperature. Combined with Suzuki-Miyaura cross-coupling, the method is applicable to the synthesis of various biaryl products, including through the use of aryl chloride substrates.

Photoinduced Miyaura Borylation by a Rare‐Earth‐Metal Photoreductant: The Hexachlorocerate(III) Anion

AbstractThe first photoinduced carbon(sp2)–heteroatom bond forming reaction by a rare‐earth‐metal photoreductant, a Miyaura borylation, has been achieved. This simple, scalable, and novel borylation method that makes use of the hexachlorocerate(III) anion ([CeIIICl6]3−, derived from CeCl3) has a broad substrate scope and functional‐group tolerance and can be conducted at room temperature. Combined with Suzuki–Miyaura cross‐coupling, the method is applicable to the synthesis of various biaryl products, including through the use of aryl chloride substrates.

3-Boryl-2,1-borazaronaphthalene: Umpolung Reagents for Diversifying Naphthalene Isosteres.

A Pd-catalyzed Miyaura borylation of 3-bromo-2,1-borazaronaphthalenes is reported. This method allows the formation of umpolung reagents for subsequent Pd-mediated cross-coupling. Coupling of this nucleophilic partner with a variety of commercially available aryl- and heteroaryl halides allows facile and rapid diversification of these cores.

Iridium-Catalyzed Regioselective Borylation of Substituted Biaryls

Biarylboronic esters are generally prepared by directed ortho­-metalation or by Miyaura borylation and hence rely on the presence of a directing group or pre-functionalization. In this paper, the preparation of biarylboronic esters by direct C–H borylation of biaryl substrates is reported. Sterically governed regioselectivities were observed in the borylation of appropriately substituted biaryls by using [Ir(OMe)(COD)]2 precatalyst and di-tert-butylbipyridyl ligand. The resulting biarylboronic esters were isolated in 38–98% yields. The synthesized biarylboronic esters were further successfully employed in C–O, C–Br, and C–C coupling reactions.

Catalytic asymmetric synthesis of α-methyl-p-boronophenylalanine

p-Boronophenylalanine (l-BPA) is applied in clinical settings as a boron carrier for boron neutron capture therapy (BNCT) to cure malignant melanomas. Structural modification or derivatization of l-BPA, however, to improve its uptake efficiency into tumor cells has scarcely been investigated. We successfully synthesized (S)-2-amino-3-(4-boronophenyl)-2-methylpropanoic acid in enantioenriched form as a novel candidate molecule for BNCT. Key steps to enhance the efficiency of this synthesis were enantioselective alkylation of N-protected alanine tert-butyl ester with a Maruoka catalyst and Miyaura borylation reaction to install the boron functionality.