A fast and efficient bromination of isoxazoles and pyrazoles by microwave irradiation

A fast and efficient method has been developed for the bromination of isoxazoles and pyrazoles using microwave irradiation. In this method, N-bromosuccinimide was used in different acid solvents according to the reactivity of the substrates to give mono-brominated isoxazoles and pyrazoles in good yields. Trifluoroacetic acid was found to be the best solvent for highly unreactive isoxazoles and pyrazoles.     

The effect of boronic acid acidity on performance of viologen-based boronic acids in a two-component optical glucose-sensing system

A two-component saccharide sensing system using the fluorescent dye, hydroxypyrene trisulfonic acid, combined with a boronic acid functional viologen as a receptor/quencher in pH 7.4 buffer solution has been further investigated. The effect of substituents on the acidity of the boronic acid was measured. The boronic acid pK_a changed in the expected manner when electron donating or withdrawing groups were present. The glucose binding constants were dependent on pK_a, but no simple correlation was observed for the Stern-Volmer quenching constants and the fluorescence signal modulation.     

Synthesis of a paramagnetic boronic acid as a useful synthetic building block and carbohydrate affinity spin probe

A paramagnetic boronic acid was synthesized by lithiation of 1-acetoxy-3-bromo-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole followed by treatment with trimethyl borate. This paramagnetic boronic acid proved to be a useful starting compound in Suzuki cross-coupling reactions and it exhibited affinity toward fructose and inulin.     

A direct copper-catalyzed route to pyrrolo-fused heterocycles from boronic acids

A convenient route to prepare azaindoles and related pyrrolo-fused heterocycles from boronic acids, DBAD (di-tert-butyl-diazodicarboxylate) and enolizable aldehydes and ketones is presented. The reaction proceeds via a one-pot four-step cascade sequence with key steps involving a copper-catalyzed boronic acid coupling to DBAD and a Fischer indolization providing access to a variety of pharmaceutically interesting heterocycles including pyrrolo-pyridines, -pyrimidines, -quinolines, and -isoquinolines from readily available aza–aryl boronic acid precursors.     

“Clickable” affinity ligands for effective separation of glycoproteins

In this paper, we present a new modular approach to immobilize boronic acid ligands that can offer effective separation of glycoproteins. A new “clickable” boronic acid ligand was synthesized by introducing a terminal acetylene group into commercially available 3-aminophenyl boronic acid. The clickable ligand, 3-(prop-2-ynyloxycarbonylamino)phenylboronic acid (2) could be easily coupled to azide-functionalized hydrophilic Sepharose using Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction under mild condition. Compared to other boronic acid affinity gels, the new affinity gel displayed superior effectiveness in separating model glycoproteins (ovalbumin and RNase B) from closely related bovine serum albumin and RNase A in the presence of crude Escherichia coli proteins. Because of the simplicity of the immobilization through “click chemistry”, the new ligand 2 is expected to not only offer improved glycoprotein separation in other formats, but also act as a useful building block to develop new chemical sensors for analysis of other glycan compounds.     

Facile synthesis of alkynyl‐, aryl‐ and ferrocenyl‐substituted pyrazoles via Sonogashira and Suzuki–Miyaura approaches

A concise and efficient synthesis of densely substituted novel pyrazoles with alkynyl, aryl and ferrocenyl functionalities is reported, providing a platform for biological studies. The general strategy involves Sonogashira and Suzuki–Miyaura cross‐coupling reactions of easily obtainable 5‐ferrocenyl/phenyl‐4‐iodo‐1‐phenylpyrazoles with terminal alkynes and boronic acids, respectively. The starting 4‐iodopyrazoles were synthesized by electrophilic cyclization of α,β‐alkynic hydrazones with molecular iodine. Sonogashira reactions have been achieved by employing 5 mol% PdCl₂(PPh₃)₂, 5 mol% CuI, excess Et₃N and 1.2 equiv. of terminal alkyne, relative to 4‐iodopyrazole, in tetrahydrofuran at 65 °C, while Suzuki–Miyaura reactions have been accomplished using 5 mol% PdCl₂(PPh₃)₂ and 1.4 equiv. of both boronic acid/ester and KHCO₃, with respect to 4‐iodopyrazole, in 4:1 dimethylformamide–H₂O solution at 110 °C. Both Sonogashira and Suzuki–Miyaura coupling reactions have proven effective for the synthesis of alkynyl‐, aryl‐ and ferrocenyl‐substituted pyrazoles and demonstrated good tolerance to a diverse range of substituents, including electron‐donating and electron‐withdrawing groups. These coupling approaches could allow for the rapid construction of a library of functionalized pyrazoles of pharmacological interest. Copyright © 2016 John Wiley & Sons, Ltd.     

Synthesis of ferrocene boronic acid-based block copolymers via RAFT polymerization and their micellization,redox responsive and glucose sensing properties

Current study is focused on the synthesis of three novel diblock copolymers poly(2-methacryloyloxy)ethyl ferrocene carboxylate-b-polymethyl vinyl amido phenyl boronic acid, poly(2-methacryloyloxy)ethyl ferrocene carboxylate-b-poly vinylamido phenyl boronic acid and poly(2-methacryloyloxy)ethyl ferrocene carboxylate-b-polystyrene boronic acid using S-methoxycarbonylphenylmethyl dithiobenzoate as reversible addition–fragmentation chain transfer polymerization agent. The synthesized block copolymers were characterized by gel permeation chromatography, fourier transform infrared spectroscopy, ¹H nuclear magnetic resonance spectroscopy, dynamic light scattering, scanning electron microscopy and transmission electron microscopy. Detailed micellization behaviour of poly(2-methacryloyloxy)ethyl ferrocene carboxylate-b-polymethyl vinyl amido phenyl boronic acid (in binary organic solvents mixture and aqueous solution) was studied. Comparative studies of micellization showed that the larger aggregates were obtained in binary organic solvents system than during dialysis in aqueous medium. The redox responsive behaviour of poly(2-methacryloyloxy)ethyl ferrocene carboxylate-b-polymethyl vinyl amido phenyl boronic acid was investigated by water soluble oxidizing (Ammonium cerium nitrate) and reducing (Sodium hydrogen sulphite) agents. Glucose binding/sensing properties of poly(2-methacryloyloxy)ethyl ferrocene carboxylate-b-polymethyl vinyl amido phenyl boronic acid were also explored by micellization. It was found that the increase in polarity and swelling of poly(2-methacryloyloxy)ethyl ferrocene carboxylate-b-polymethyl vinyl amidophenyl boronic acid micelles was due to the redox behaviour of ferrocene, while binding of glucose with boronic acids hydroxyls appears as unimers or small aggregates.     

Ethylene polymerization catalyzed by nickel-based complex combined with various modified EBAOs

A series of novel aluminoxanes, ethyl-isobutylalulminoxanes (EBAO) modified with n-butaneboronic acid, phenylboronic acid and 4-fluorobenzeneboronic acid are synthesized. The ethylene polymerization activity of [diacetyl-bis(2,6-diisopropylanil)] NiBr₂(1)/different aluminoxanes were investigated. It is found that boronic acid greatly affects the catalytic activity of modified EBAO. Bulky substituted boronic site of EBAO improved ethylene polymerization activity of nickel complex.     

Boronate derivatives of bioactive amines: potential neutral receptors for anionic oligosaccharides

Oligomeric δ-aminoboronates were synthesized via reductive amination of o-formylbenzene boronic acid with several polymines. The process entails the direct addition of o-formylbenzene boronic acid to the polyamine in methanol at room temperature followed by reduction of the resulting imine with NaBH₄. Di-, tri-, and tetrameric δ-aminoboronates have been prepared in this manner and these are anticipated to have enhanced affinities for certain oligosaccharides. A novel templating method for the synthesis of these compounds is also described.     

Facile microwave assisted decarbonylation of 4-formyl group in 5-alkyl amino substituted pyrazoles

Facile decarbonylation of the 4-formyl group in 5-alkyl amino pyrazoles was seen when reacted with catalytic p-toluene sulfonic acid in methanol under microwave irradiation to provide parent 4-H pyrazoles in good yields.     

Mass spectrometric studies on the formation of chiral N-sulphonylated oxazaborolidinones

The formation of N-tosyl-2-phenyl-1,3,2-oxazaborolidin-5-one 1 as a result of a condensation reaction between N-tosyl valine 2 and phenyl boronic acid was studied as a model of the formation of chiral oxazaborolidines used as Lewis acidic catalysts for various enantioselective syntheses. Intermediates of the formation of 1 along with those arising from further reactions (of 1) were investigated by electrospray ionization mass spectrometry (ESI-MS). Results of the study indicate that one phenyl boronic acid may react with one or two molecules of 2 and/or with one or two molecules of phenyl boronic acid. In addition, side-products implying dephenylation of 1 and self-condensation of phenyl boronic acid (formation of triphenylboroxine) were found.     

Amperometric biosensor based on immobilization of acetylcholinesterase via specific binding on biocompatible boronic acid-functionalized Fe@Au magnetic nanoparticles

A new method based on specific binding between glycoprotein acetylcholinesterase and boronic acid-functionalized Fe@Au magnetic nanoparticles was presented for the development of acetylcholinesterase biosensor. Alginate–graphene composite-modified electrode was firstly prepared as the substrate. Then, biocompatible boronic acid-functionalized Fe@Au magnetic nanoparticles were anchored by the covalence between the cis-diol of alginate and the boronic acid group on Fe@Au nanoparticles. Acetylcholinesterase was subsequently immobilized via the bonding between the glycosyl of acetylcholinesterase and the boronic acid group. The immobilized enzyme retained relatively high bioactivity and the fabricated biosensor exhibited high sensitivity and fast response to acetylthiocholine chloride. Based on enzyme inhibition, carbamate pesticide was detected using Furadan as a model compound. Two linear ranges of 0.05–15 and 15–400?ppb were obtained with a detection limit of 0.01?ppb. The biosensor also showed acceptable reproducibility and relatively good storage stability. Moreover, satisfactory results were obtained in the real sample analysis.     

Room temperature spontaneous surface condensation of boronic acids observed by scanning tunneling microscopy

Herein, we discovered that the surface-confined condensation of boronic acid can happen spontaneously at room temperature, by comparing the kinetics of condensation of boronic acids with and without the negative sample bias, we found that the negative sample bias indeed accelerates the self-condensation reaction of boronic acid. Combining with in-situ STM images and ultraviolet photoemission spectrum (UPS) analysis, a reversible adsorption mechanism model was proposed and reasonably explains the reversible electric-field-induced phase transformation.     

Unusual reactivity of ortho-carbonylphenylboronic acids with diethanolamine

The reaction of carbonyl-substituted phenylboronic acids with diethanolamine has been investigated. For compounds containing carbonyl groups at the meta or para positions the reaction occurs exclusively at the boronic acid. Different reactivities were observed for ortho-substituted acetyl- and formylphenylboronic acids where the reaction occurred at both the boronic acid and at the carbonyl group. X-ray studies revealed the presence of a polycyclic structure with tetravalent boron and nitrogen atoms.     

meta-Selective C–H functionalisation of aryl boronic acids directed by a MIDA-derived boronate ester

N-Methyliminodiacetic acid (MIDA) boronates are boronic acid derivatives which are stable to reduction, oxidation and transmetalation. This has led to their widespread use as boronic acid protecting groups (PGs) and in iterative cross-couplings. We describe herein the development of a novel MIDA derivative that acts in a dual manner, as a protecting group and a directing group (DG) for meta C(sp²)–H functionalisation of arylboronic acids. Palladium catalysed C–H alkenylations, acetoxylations and arylations are possible, at room temperature and under aerobic conditions. Deprotection to reveal the functionalised boronic acids is rapid and allows for full recovery of the DG. The technique allows the facile diversification of aryl boronic acids and their subsequent use in a range of reactions or in iterative processes.

An N-methyliminodiacetic acid derivative allows the meta-C–H functionalisation of boronic acids, acting simultaneously as a directing and protecting group.     

Photochemistry of 3H-furo[3,4-c]pyrazoles and 3H-thieno[3,4-c]pyrazoles

The first examples of 3H-furo[3,4-c]pyrazoles and 3H-thieno[3,4-c]pyrazoles were prepared in an attempt to isolate examples of cyclopropane-fused thiophenes and furans. Adducts of acetylenic ketones and 2-diazopropane were reacted with 10-camphorsulfonic acid or phosphorus pentasulfide to produce the title compounds. Photolysis of these compounds did not give the cyclopropane-fused products rather an unreported photochemical fragmentation was observed.     

A simple, modular method for the synthesis of 3,4,5-trisubstituted pyrazoles

A modular approach for the regiocontrolled preparation of pyrazoles bearing substituents on all three carbon atoms is described. Central to this method is the use of a switchable metal-directing group (MDG) to enable sequential direct lithiation of the 3- and 5-positions of the pyrazole ring. Pyrazole boronic esters obtained from these lithiated intermediates can undergo efficient Suzuki cross-coupling under the developed nonaqueous conditions, which minimize undesirable protolytic deboronation. Halogenation of the 4-position provides the means for substitution at the remaining carbon atom.     

Binary and ternary phenylboronic acid complexes with saccharides and Lewis bases

Cumulative formation constants for the association of three boronic acids (phenylboronic acid and its ortho-anilinomethyl and ortho-benzylaminomethyl derivatives) with four saccharides (fructose, glucose, mannitol, and sorbitol) were determined by potentiometric titration. Similarly, the constants for the formation binary complexes of the three boronic acids with (hydrogen) phosphate, (hydrogen) citrate, or imidazole were determined. Finally, the formation of ternary complexes of the boronic acids, phosphate, citrate or imidazole, and the saccharides were determined based on the determined values of the binary complexes. The previously unrecognized ternary complexes are significant in all systems investigated, and under some solution compositions, they can be the dominant species in solution over a wide pH range. A value of 15-25 kJ mol⁻¹ was determined for the energy of the B-N interaction in the benzylmethyl derivative based on the relative stabilities of the ternary phosphate complexes of the three boronic acids. The data are used to rationalize the medium dependence of stepwise formation constants and the apparent acidity constants of previous literature reports.     

Diastereoselective Michael addition of (S)-mandelic acid enolate to 2-arylidene-1,3-diketones: enantioselective diversity-oriented synthesis of densely substituted pyrazoles

A diversity-oriented approach to enantiomerically pure densely substituted pyrazoles, α-aryl-α-pyrazolylatrolactic acid and α-aryl-α-pyrazolylacetophenones has been developed. The approach utilises the conjugated addition of the lithium enolate of the (2S,5S)-cis-1,3-dioxolan-4-one derived from optically active (S)-mandelic acid and pivalaldehyde to several 2-arylidene-1,3-diketones, which proceeds readily to give the corresponding Michael adducts in good yields and diastereoselectivities. The cyclocondensation of the 1,3-diketone moieties present in Michael adducts with several hydrazines leads to enantiomerically pure densely substituted pyrazoles. Subsequent basic hydrolysis of the dioxolanone moiety present in these products leads to enantiomerically pure α-aryl-α-pyrazolylatrolactic acids. Finally, oxidative decarboxylation of these using oxygen, pivalaldehyde and the Co(III)-Me₂opba complex as catalyst gives α-aryl-α-pyrazolylacetophenones. In this approach four points of diversity are introduced, one of them is the configuration of the (S)-mandelic acid, which acts as an umpoled chiral equivalent of the benzoyl anion.     

Asymmetric synthesis of 1-acyl-3,4-disubstituted pyrrolidine-2-boronic acid derivatives

An analogue of N-acetylkainic acid having a cyano group and a boronic acid group in place of the two carboxyl groups has been synthesized with high stereocontrol via a series of chain extensions of pinanediol [(trityloxy)methyl]boronate with (dihalomethyl)lithium followed by appropriate nucleophilic substitution of the resulting chloro or bromo boronic ester. Substituents were introduced in the order isopropenyl, cyanomethyl, and bis(trimethylsilyl)amino. The last of these was converted to acetamido, the hydroxyl function was unmasked and mesylated, and the pyrrolidine ring was closed. Attempts to carry out further chain extension on the boronic ester resulted in low yields, evidently the highly polar amido substituent interferes with the (dichloromethyl)lithium insertion process.