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

Hayes, Hannah L. D.; Wei, Ran; Assante, Michele; Geogheghan, Katherine J.; Jin, Na; Tomasi, Simone; Noonan, Gary M.; Leach, Andrew G.; Lloyd‐Jones, Guy C.

doi:10.1021/jacs.1c06863

Cited by 44 publications

(55 citation statements)

References 145 publications

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“…In addition, base-sensitive heteroaryl boronic acids ( 2l – 2p ) efficiently provided the desired products ( 3ak – 3ao ) in excellent yield (86–99%). Unfortunately, 2-pyridyl boronic acid pinacol ester ( 2q ), which is highly sensitive to protodeboronation, − did not react under the applied solid-state conditions.…”

Section: Resultsmentioning

confidence: 99%

Palladium-Catalyzed Solid-State Polyfluoroarylation of Aryl Halides Using Mechanochemistry

et al. 2021

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The Suzuki–Miyaura cross-coupling between polyfluorinated arylboron nucleophiles and aryl halides enables the efficient construction of polyfluorinated structural motifs frequently found in organic materials and catalysts. A key challenge associated with this transformation involves the slow transmetalation with weakly nucleophilic polyfluorinated organoboron reagents, which often reduces the yield of the coupling products. Here, we show that solid-state high-temperature ball-milling conditions facilitate a palladium-catalyzed cross-coupling with polyfluorinated arylboronic acids and pinacol esters employing a simple catalytic system in the absence of any stoichiometric additives. This reaction exhibits a broad substrate scope and can be carried out in air, and the use of large amounts of dry and degassed organic solvents is not required. The successful cross-coupling of weakly nucleophilic polyfluorinated organoboron reagents was ascribed to the extremely high concentrations of the substrates and the catalyst under solid-state conditions.

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Section: Resultsmentioning

confidence: 99%

Palladium-Catalyzed Solid-State Polyfluoroarylation of Aryl Halides Using Mechanochemistry

et al. 2021

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“…In addition to being directly catalyzed by water, the protodeboronation of arylboronic acids and arylboronic acid pinacol esters is known to occur under acidic and basic conditions and by reaction with various metal salts. [243][244][245] Polyfluorinated and 2-heteroaryl boronic acids have been revealed to be exceptionally unstable and readily undergo deboronation. [246] The mechanism by which aryl boronic acids undergo base-induced protodeboronation is proposed to commence by the formation of an arylboric acid (Ar-B(OH) 3 -) (Scheme 71).…”

Section: Synthesis Of Biaryls 69 Using Suzuki-miyaura Cross-coupling ...mentioning

confidence: 99%

“…The base-induced protodeboronation of aryl boronic acid pinacol esters is believed to proceed via a similar mechanism. [245] Scheme 71: Proposed mechanism for the base-induced protodeboronation of arylboronic acids. [243,244] The strong electronegative effect exhibitied by the trifluoromethyl group of pinacol ester 83d is presumably sufficient to destabilize the C-B bond, causing deboronation to form 4-(trifluoromethyl)aniline.…”

Section: Synthesis Of Biaryls 69 Using Suzuki-miyaura Cross-coupling ...mentioning

confidence: 99%

Divergent Synthesis of Indolo[3,2- c]quinolines, Neocryptolepines and Related Tetracyclic Ring-Systems Containing Promising Biological Activities

Håheim¹

2022

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Malaria is a devastating tropical disease, claiming approximately 627 000 lives in 2020. Due to the appearance of resistance towards artemisinin-based therapies, the discovery of novel treatments are of paramount importance. The indoloquinoline natural products cryptolepine, neocryptolepine and isocryptolepine, first discovered in the extracts of the African bush plant Cryptolepis sanguinolenta, have been found to exhibit potent antimalarial properties. More- over, several functionalized derivatives of these compounds have shown great promise as an- tiplasmodial agents. The indoloquinoline alkaloids have also been found to possess significant antiproliferative and antimicrobial properties, making them ideal targets for the development into novel drug candidates. The first project in this work details the application of a synthetic approach first devel- oped by Helgeland and Sydnes to assemble various tetracyclic ring systems. The key synthetic strategies being a Suzuki-Miyaura cross-coupling reaction followed by a palladium-catalyzed intramolecular cyclization. Though the approach was unsuitable to construct all the intended target molecules, it furnished the unexpected pyridophenanthridine scaffold. By further inves- tigating alternative protocols for the construction of indoloquinolines, a regiodivergent inter- mediate was discovered, which allowed for the synthesis of both novel pyridophenanthridine and pyridocarbazole scaffolds by utilizing two different reaction protocols. By subjecting this common intermediate to a diazotization-azidation-nitrene insertion approach, the novel pyrido- carbazoles could be furnished in excellent yields. The unexpected formation of a biquinoline bridged by an aniline during a Suzuki-Miyaura cross-coupling reaction, was deemed interesting for development into a transition metal com- plex for catalysis. Through a collaborative effort with Dr. Eugene Khaskin’s group at Oki- nawa Institute of Science and Technology, five quinoline/pyridine N,N,N ligands were designed and synthesized. The key synthetic tools utilized in their construction was either a sequential Suzuki-Miyaura cross-coupling reaction and Buchwald-Hartwig amination or reductive amina- tion. A novel two-step approach for the synthesis of the natural product neocryptolepine from commercially available bromoquinolines was developed. The key transformations being re- gioselective N-alkylations followed by a cascade Suzuki-Miyaura cross-coupling reaction and intramolecular nucleophilic C-N bond formation. The scope and limitations for the novel pro- tocol was evaluated through the preparation of 24 neocryptolepine derivatives, bearing a diverse range of functional groups, where electron-withdrawing group substitutions were generally su- perior. It became apparent that it would also be possible to prepare a library of indolo[3,2-c]quino- lines from the same starting material as the newly devised strategy to produce neocryptolepines. By utilizing a reaction sequence consisting of a Suzuki-Miyaura cross-coupling reaction, in- stallation of an azido moiety and finally photochemical cyclization, this goal was realized, producing a total of 19 indoloquinolines. This protocol was less robost towards substrate func- tionalizations than the neocryptolepine approach, with no apparent trend concerning electron- withdrawing and electron-donating groups being apparent. The photochemical cyclization was hypothesized to proceed via the formation of a reactive singlet nitrene intermediate. Finally, a selection of the prepared tetracyclic compounds assembled during this work was evaluated for their antiplasmodial, antiproliferative and antimicrobial activities by the help of various external collaborators. The most successful compound was revealed to be the novel pyridophenanthridines, displaying more potent antiproliferative activities than doxoru- bicin against human prostate cancer (IC50 = 24 nM). The novel pyridocarbazoles moreover showed excellent inhibition of biofilm formation, with the potential to be developed into a dual anticancer-antimicrobial agent. Of all the tested compounds, only N-methylated pyridocar- bazole was found to contain any significant activity against the evaluated Plasmodium falci- parum strain. The antimicrobial assays revealed the importance of the inclusion of a methyl group for activity, but not strictly in the form of an N-methyl unit, which is the general con- census in the literature thus far. Further, chlorinated indoloquinolines were revealed to contain excellent antimicrobial activity against both Gram-positive and Gram-negative bacterial cell lines.

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“…Recently, Lloyd-Jones et al investigated the kinetics and mechanism of the base-catalyzed hydrolysis and protodeboronation of a series of fluorinated boronic compounds. They found that pinacol boronic esters display a unique stability at a high pH compared to other commonly employed esters [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

Merging Electron Deficient Boronic Centers with Electron-Withdrawing Fluorine Substituents Results in Unique Properties of Fluorinated Phenylboronic Compounds

Adamczyk‐Woźniak

Sporzyński

2022

Molecules

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Fluorinated boron species are a very important group of organoboron compounds used first of all as receptors of important bioanalytes, as well as biologically active substances, including Tavaborole as an antifungal drug. The presence of substituents containing fluorine atoms increases the acidity of boronic compounds, which is crucial from the point of view of their interactions with analytes or certain pathogen’s enzymes. The review discusses the electron acceptor properties of fluorinated boronic species using both the acidity constant (pKa) and acceptor number (AN) in connection with their structural parameters. The NMR spectroscopic data are also presented, with particular emphasis on 19F resonance due to the wide range of information that can be obtained from this technique. Equilibria in solutions, such as the dehydration of boronic acid to form boroxines and their esterification or cyclization with the formation of 3-hydroxyl benzoxaboroles, are discussed. The results of the latest research on the biological activity of boronic compounds by experimental in vitro methods and theoretical calculations using docking studies are also discussed.

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

Cited by 44 publications

References 145 publications

Palladium-Catalyzed Solid-State Polyfluoroarylation of Aryl Halides Using Mechanochemistry

Palladium-Catalyzed Solid-State Polyfluoroarylation of Aryl Halides Using Mechanochemistry

Divergent Synthesis of Indolo[3,2- c]quinolines, Neocryptolepines and Related Tetracyclic Ring-Systems Containing Promising Biological Activities

Merging Electron Deficient Boronic Centers with Electron-Withdrawing Fluorine Substituents Results in Unique Properties of Fluorinated Phenylboronic Compounds

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