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Suzuki-Miyaura mediated biphenyl synthesis: a spotlight on the boronate coupling partner
The biaryl motif is found in many natural and synthetic products that display a wide range of biological activities. This explains why biphenyls are widely encountered in medicinal chemistry as a privileged scaffold. The palladium-catalysed Suzuki-Miyaura (SM) coupling is one of the most important and efficient strategies for the synthesis of symmetrical and unsymmetrical biaryl compounds; the arylboronic acid or ester is a key partner in this coupling reaction.
This work presents the synthesis of a library of new molecules containing the biphenyl scaffold; o-, m- and p-(bromomethyl)phenylboronic acid pinacol esters, 2a-c, were selected as coupling partners. Nucleophilic substitution of the bromide was carried out with amine, thiol, alcohol or phenol nucleophiles. Supported reagents and microwave assisted organic synthesis conditions were employed to enhance this chemistry and made it amenable to parallel synthesis. The resulting arylboronates were used in SM coupling reactions in order to obtain a range of biphenyls.
The use of Boc-piperazine as a nucleophile in the SN2 reaction, with 2a-c, and 1-bromo-, 2-, 3- or 4-nitrobenzene or 2-bromo-5-nitropyridine as aryl halides in the SM coupling reaction, allowed two other points of functionalisation to be added to the biaryl motif.
The conditions for the SM coupling of mercaptomethylphenylboronic esters and orthosubstituted methylphenylboronic esters were optimised in order to broaden the scope of the biaryl library.
Phosphines were found to be good nucleophiles in the SN2 reaction with 2a-c. A Wittig reaction was performed with the resulting phosphonium arylboronates in order to synthesise arylboronic esters containing an alkene function prior the reduction of the resulting double bond of the stilbene derivatives and realising a SM coupling to synthesise arylethylbiphenyls.
The stilbene derivatives were also synthesised by using the olefin cross-metathesis reaction of 4-vinylphenylboronic acid pinacol ester.
A solid state crystallographic study was undertaken on a small library of methylbiphenylamides to compare the crystal structures of isomers or biphenyls with different functional groups
Cytotoxicity of the urokinase-plasminogen activator inhibitor carbamimidothioic acid (4-boronophenyl) methyl ester hydrobromide (BC-11) on triple-negative MDA-MB231 breast cancer cells
Abstract: BC-11 is an easily synthesized simple thiouronium-substituted phenylboronic acid, which has been shown to be cytotoxic on triple negative MDA-MB231 breast cancer cells by inducing a perturbation of cell cycle when administered at a concentration equal to its ED50 at 72 h (117 ÎŒM). Exposure of cells to BC-11, either pre-absorbed with a soluble preparation of the N-terminal fragment of urokinase-plasminogen activator (uPa), or in co-treatment with two different EGFR inhibitors, indicated that: (i) BC-11 acts via binding to the N-terminus of the enzyme where uPa- and EGF receptor-recognizing sites are present, thereby abrogating the growth-sustaining effect resulting from receptor binding; and (ii) the co-presence of the EGFR inhibitor PD153035 potentiates BC-11âs cytotoxicity. Exposure of cells to a higher concentration of BC-11 corresponding to its ED75 at 72 h (250 ÎŒM) caused additional impairment of mitochondrial activity, the production of reactive oxygen species and promotion of apoptosis. Therefore, BC-11 treatment appears to show potential for the development of this class of compounds in the prevention and/or therapy of âaggressiveâ breast carcinoma
Microwave Mediated Suzuki-Miyaura Couplings of S- and Ortho-Substituted Methylphenylboronic Acid Esters
Hitherto unsuccessful cross couplings of ortho-substituted or thioether-substituted methylphenylboronates have been achieved, under microwave conditions, enabling the synthesis of a library of novel biaryls. Tetrakis(triphenylphosphine)palladium and various bases e.g. sodium carbonate or cesium fluoride were found to mediate the crucial C-C bond forming cross coupling reaction
Synthesis of a (piperazin-1-ylmethyl)biaryl library via microwave-mediated Suzuki-Miyaura cross-couplings
Boc-protected (piperazin-1-ylmethyl)biaryls have been synthesised from (Boc-piperazin-1-ylmethyl) phenylboronic acid pinacol esters via a microwave-mediated SuzukiâMiyaura coupling with aryl bromides viz. 1-bromo-, 2-, 3- or 4-nitrobenzene or 2-bromo-5-nitropyridine. Judicial removal of the protecting group on the piperazine, or facile reduction of the nitro group on the biaryl system enabled the manipulation of two points of functionality in order to diversify the scope of the resulting biaryl library
Thermal analysis of novel biphenylamide derivative
The physicochemical properties of a small library of 4-methyl-biphenylamide derivatives have been investigated by means of differential scanning calorimetry, thermogravimetric analysis and hot-stage microscopy. The obtained results show that positional isomerism has a significant influence on the thermal behaviour of the 4-methyl-biphenylamide derivatives; however, no clear relationship between functional group isomerism and thermal properties could be established. Ortho-substituted derivatives revealed two polymorphic forms, whilst the para-substituted derivatives exhibit three polymorphic forms. The ortho-substituted biphenylamides were more likely to generate metastable forms when cooled from the melt. Furthermore, the self-heating properties were revealed by the para-substituted 4-methyl-biphenylamide derivatives, in which the highly energetic crystallization processes raised the sample temperature by as much as 4 °C during cooling. Such a high-energy exothermic crystallization process suggests crystallization to be highly favourable, from a thermodynamic standpoint. Hence, the para-substituted derivatives are unlikely to generate amorphous forms. Pharmaceutical application of these compounds will depend on the solubility of their crystalline forms, but their manufacture may possess some challenges due to the number of monotropic polymorphic forms that may coexist
Synthesis of a biphenyl library for studies of hydrogen bonding in the solid state
A biphenyl library incorporating amide and sulfonamide groups has been synthesised via microwave-mediated Suzuki-Miyaura couplings. Many derivatives were crystallised from dichloromethane/methanol and analysed by single crystal X-ray diffraction. An interesting structure was obtained for N-(4'-methylbiphenyl-4-yl)acetamide with Z'=6 and hydrogen-bonding networks of the type N-H ··· O in the unit cell
Olefin cross-metathesis/SuzukiâMiyaura reactions on vinylphenylboronic acid pinacol esters
A series of alkenyl phenylboronic acid pinacol esters has been synthesized via an olefin cross-metathesis reaction of vinylphenylboronic acid pinacol ester derivatives. After catalytic hydrogenation, the resulting boronates were coupled via a microwave-mediated SuzukiâMiyaura reaction to afford a library of biarylethyl aryl and biarylethyl cycloalkyl derivatives. A complementary reaction sequence involved an initial SuzukiâMiyaura coupling
VĂœzkum sedimentĆŻ pĆehradâ nĂĄdrĆŸĂ a jezer - zhodnocenĂ rizik a nĂĄvrhy opatĆenĂ:Ć lichovĂĄ charakteristika okolĂ nĂĄdrĆŸe Vrchlice
PĆĂprava podkladĆŻ a regionĂĄlnĂ zhodnocenĂ geochemickĂœch (ĆĄlichovĂœch) dat v oblasti VN Vrchlice. Svazek obsahuje jeĆĄtÄ tyto zprĂĄvy: ShrnutĂ hlavnĂch principĆŻ vytvĂĄĆenĂ eroznĂch a transportnĂch procesĆŻ z povodĂ nĂĄdrĆŸĂ (Aplikace v povodĂ VN Vrchlice). NĂĄdrĆŸnĂ sedimenty a jejich role v procesech eutrofizace
Data from: A synthetic, catalytic and theoretical investigation of an unsymmetrical SCN pincer palladacycle
The SCN ligand 2-{3-[(methylsulfanyl)methyl]phenyl}pyridine, 1, has been synthesized starting from an initial SuzukiâMiyaura (SM) coupling between 3-((hydroxymethyl)phenyl)boronic acid and 2-bromopyridine. The CâH activation of 1 with in situ formed Pd(MeCN)4(BF4)2 has been studied and leads to a mixture of palladacycles, which were characterized by X-ray crystallography. The monomeric palladacycle LPdCl 6, where L-Hâ=â1, has been synthesized, and tested in SM couplings of aryl bromides, where it showed moderate activity. Density functional theory and the atoms in molecules (AIM) method have been used to investigate the formation and bonding of 6, revealing a difference in the nature of the PdâS and PdâN bonds. It was found that S-coordination to the metal in the rate determining CâH bond activation step leads to better stabilization of the Pd(II) centre (by 13â28â
kJâ
molâ1) than with N-coordination. This is attributed to the electron donating ability of the donor atoms determined by Bader charges. The AIM analysis also revealed that the PdâN bonds are stronger than the PdâS bonds influencing the stability of key intermediates in the palladacycle formation reaction pathway