Heteroaryl Boronic Acids Research Articles

Heteroaryl Group Containing Trisubstituted Alkenes: Synthesis and Anti-Tumor Activity.

Pancreatobililary cancers are fatal solid tumors that pose a significant threat to human life. It is imperative to investigate novel small molecule active compounds for controlling these cancers. Heterocyclic compounds (e. g. gemcitabine) and multi-substituted alkenes (e. g. resveratrol) are commonly applied in tumor treatment. Researchers have proposed that the synthesis of new trisubstituted alkenes containing heteroaromatic rings by combining these two scaffolds may be a fresh strategy to develop new active molecules. In this study, we utilized alkenyl bromide and heteroaryl boronic acid as substrates, employing Suzuki coupling to generate a series of triarylethylenes featuring nitrogen, oxygen, and sulfur atoms. Through in vitro experiments, the results indicated that some compounds exhibited remarkable anti-tumor efficacy (e. g. IC50[3be, GBC-SD]=0.13 μM and IC50[3be, PANC-1]=0.27 μM). The results further demonstrated that the antitumor efficacy of these compounds was dependent on the heteroatom, π-system, skeleton-bonding site, and substituent type.

Chiral Binaphthol-Catalyzed Enantioselective Conjugate Addition of Alkenyl and Arylboronic Acids to α,β-Unsaturated Cyclic N-Sulfonyl Ketimines.

The chiral binaphthol-catalyzed enantioselective conjugate addition of alkenylboronic acids and heteroarylboronic acids to cyclic N-sulfonyl ketimines is reported, providing the 1,4-addition products in high yields and moderate to excellent enantioselectivities (up to >99% ee). This mild, scalable catalytic system exhibits high efficiency and broad substrate scopes. Additionally, arylboronic acids were viable nucleophiles under more forcing conditions.

Construction and characterization of a magnetic nanoparticle-supported Cu complex: a stable and active nanocatalyst for synthesis of heteroaryl-aryl and di-heteroaryl sulfides.

Diaryl and di-heteroaryl sulfides exist in the structure of many drugs and important biological compounds, also these compounds are well-known in medicinal chemistry due to important biological and pharmaceutical activities. Therefore, the development of novel, ecofriendly and efficient catalytic systems for the preparation of diaryl and di-heteroaryl sulfides is a very attractive and important challenge in organic synthesis. In this attractive methodology, we wish to introduce Fe3O4-supported 3-amino-4-mercaptobenzoic acid copper complex (Fe3O4@AMBA-CuI) nanomaterials as a novel and efficient magnetically recoverable catalyst for the preparation of heteroaryl-aryl and di-heteroaryl sulfides with high yields through reaction of heteroaryl halides with aryl or heteroaryl boronic acids and S8 as the sulfur source under ecofriendly conditions. This catalytic system was very efficient and practical for a diverse range of heteroaryl substrates including benzothiazole, benzoxazole, benzimidazole, oxadiazole, benzofuran, and imidazo[1,2-a]pyridine, because the desired diaryl and di-heteroaryl sulfides were prepared with high yields. The reusability-experiments revealed that the Fe3O4@AMBA-CuI nanocatalyst can be magnetically separated and reused at least six times without a significant decrease in its catalytic activity. VSM and ICP-OES analyses confirmed that despite using the Fe3O4@AMBA-CuI nanocatalyst 6 times, the magnetic properties and stability of the catalyst were still maintained. Although all the obtained heteroaryl-aryl and di-heteroaryl sulfide products are known and previously reported, the synthesis of this number of heteroaryl-aryl and di-heteroaryl sulfides has never been reported by any previouse methods.

Highly efficient deborylative hydroxylation of boronic acids through a metal and base-free process using pectin as a reusable carbocatalyst: The positive effect of hydrogen-bond donating groups

Phenols are important organic compounds with a broad range of application in pharmaceuticals, polymers, and agrochemicals. A metal- and base-free pectin-catalyzed methodology has been introduced for the sustainable ipso-hydroxylation of aryl and heteroaryl boronic acids to phenols using 30% H2O2 as a benign oxidant. Pectin (Pec, galacturonic acid ≥74.0%) was chosen as an inexpensive and available polysaccharide with numerous extraction sources. Control experiments using high methoxy pectin (HM-Pec, 70-75% esterification) confirmed that the abundant carboxylic acid and hydroxyl groups on the Pec surface act as catalytically active sites to improve the oxidation process by adsorbing the substrates via hydrogen bonding. The use of H2O:EtOH (1:1 v/v) as a solvent system instead of H2O enhanced the reaction yield, substrate scope and separation of catalyst by improving the dissolution of less soluble arylboronic acids in water such as 1-naphthylboronic acid and 2-naphthylboronic acid and preventing the gel formation of Pec nanoparticles. The reaction endured a broad substrate scope for aryl and heteroaryl boronic acids with good to excellent yields (75-99%). Pec showed an excellent reusability up to 6 runs with negligible loss of activity which verified by FT-IR, XRD and FESEM of recycled catalyst. More importantly, as a metal- and base-free catalyst system, the present research gave a comparable result to previous homogeneous and heterogeneous catalyst systems in view of reaction time, yield, oxidant loading, and number of reusability cycles.

Arylazopyrazole linked Schiff bases as organocatalysts for the ipso-hydroxylation of arylboronic acids for the synthesis of phenols

A simple metal-free strategy for the synthesis of phenols from aryl and hetero aryl-boronic acids using arylazopyrazole linked o-hydroxyl Schiff base has been illustrated. These sustainable ipso-hydroxylations have very short reaction times, using aqueous H2O2 as the oxidant in aqueous-alcoholic medium. The current protocol has been demonstrated to be effective with a variety of electron-rich and electron-deficient aromatic substrates and provides access to a wide range of phenols. This is the first time that an azoyrazole linked Schiff base has been used to increase the nucleophilicity of H2O2, in oxidative hydroxylation reactions.

Rh(III)-Catalyzed Reaction of 4-Diazoisochroman-3-imines with (2-Formylaryl)boronic Acids To Access a Straightforward Construction of 5H-Isochromeno[3,4-c]isoquinolines.

An Rh(III)-catalyzed one-pot synthesis of 5H-isochromeno[3,4-c]isoquinolines from readily available 4-diazoisochroman-3-imines and (2-formylphenyl)boronic acids is reported. The cascade annulation involves a Rh(III)-catalyzed cross-coupling and an intramolecular nucleophilic addition-elimination process. A series of biologically important 5H-isochromeno[3,4-c]isoquinolines were obtained in good to excellent yields. The method can be extended to synthesize 7H-isochromeno[3,4-b]thieno[3,2-d]pyridines and 7H-isochromeno[3,4-b]thieno[2,3-d]pyridines from the corresponding heteroaryl boronic acids.

Catalytic Enantioselective Synthesis of 3-Piperidines from Arylboronic Acids and Pyridine.

Piperidines are frequently found in natural products and are of importance to the pharmaceutical industry. A generally useful asymmetric route to enantiomerically enriched 3-substituted piperidines remains elusive. Here we report a cross-coupling approach to enantioenriched 3-piperidines from pyridine- and sp2-hybridized boronic acids. The key step involves a Rh-catalyzed asymmetric reductive Heck reaction of aryl, heteroaryl, or vinyl boronic acids and phenyl pyridine-1(2H)-carboxylate to provide 3-substituted tetrahydropyridines in high yield and excellent enantioselectivity with a wide functional group tolerance. A three-step process involving i) partial reduction of pyridine, ii) Rh-catalyzed asymmetric carbometalation, and then iii) another reduction provides access to a wide variety of enantioenriched 3-piperidines, including clinically used materials such as Preclamol and Niraparib.

Synthesis of Thieno[3,2-d]pyrimidine Derivatives through Sequential SN Ar and Suzuki Reactions as Selective h-NTPDase Inhibitors.

In this study various of thieno[3,2-d]pyrimidine derivatives have been synthesized by treating different secondary amines through aromatic nucleophilic substitution reaction (SN Ar) followed by Suzuki reaction with aryl and heteroaryl boronic acids. A bis-Suzuki coupling was also performed to generate bis-aryl thienopyrimidine derivatives. The synthesized compounds were screened for the hydrolytic activity of h-NTPdase1, h-NTPdase2, h-NTPdase3, and h-NTPdase8. The compound N-benzyl-N-methyl-7-phenylthieno[3,2-d]pyrimidin-4-amine 3 j selectively inhibits the activity of h-NTPdase1 with IC50 value of 0.62±0.02 μM whereas, the compound 4 d was the most potent inhibitor of h-NTPdase2 with sub-micromolar IC50 value of 0.33±0.09 μM. Similarly, compounds 4 c and 3 b were found to be selective inhibitors for isozymes h-NTPdase3 (IC50 =0.13±0.06 μM) and h-NTPdase8 (IC50 =0.32±0.10 μM), respectively. The molecular docking study of the compounds with the highest potency and selectivity revealed the interactions with the important amino acid residues.

Copper-Catalyzed Trifluoromethylation of (Hetero)aryl Boronic Acid Pinacol Esters with YlideFluor.

A copper-catalyzed trifluoromethylation of (hetero)arylboronic acid pinacol esters with YlideFluor for the preparation of trifluoromethylated (hetero)arenes was described. The reaction conditions are mild and compatible with a broad range of functional groups. Heteroaryl boronic acid pinacol esters could also be trifluoromethylated in high yields. Application of this protocol for trifluoromethylation of drug and OLED molecules was demonstrated.

Synthesis and Antimicrobial Activity of the Pathogenic E. coli Strains of p-Quinols: Additive Effects of Copper-Catalyzed Addition of Aryl Boronic Acid to Benzoquinones.

A mild and efficient protocol for the synthesis of p-quinols under aqueous conditions was developed. The pivotal role of additives in the copper-catalyzed addition of aryl boronic and heteroaryl boronic acids to benzoquinones was observed. It was found that polyvinylpyrrolidone (PVP) was the most efficient additive used for the studied reaction. The noteworthy advantages of this procedure include its broad substrate scope, high yields up to 91%, atom economy, and usage of readily available starting materials. Another benefit of this method is the reusability of the catalytic system up to four times. Further, the obtained p-quinols were characterized on the basis of their antimicrobial activities against E. coli. Antimicrobial activity was further compared with the corresponding 4-benzoquinones and 4-hydroquinones. Among tested compounds, seven derivatives showed an antimicrobial activity profile similar to that observed for commonly used antibiotics such as ciprofloxacin, bleomycin, and cloxacillin. In addition, the obtained p-quinols constitute a suitable platform for further modifications, allowing for a convenient change in their biological activity profile.

Microwave Irradiated, Sodium Aluminate Supported and Zinc Catalyzed Suzuki-Miyaura Cross-Coupling Reaction on Fused Tricyclic Oxa-Aza-Quinolone: A Green Protocol

Alternative synthesis methods are need of the hour to provide easy protocol for synthesizing biologically active heterocyclic compounds. In this connection, this paper describes the development of a concise, convergent protocol for diversely substituted Suzuki–Miyaura cross-coupling reactions of heteroaryl bromides and boronic acids under microwave irradiation using Sodium aluminate (NaAlO2) as a solid support as well as base. According to my knowledge, this is the first report of the strategy that involves the use of zinc as a catalyst on fused tricyclic di-halo quinolones in a solvent-free condition using simple microwave irradiation. Earlier research from the same laboratory established a solid support assisted Suzuki–Miyaura cross-coupling reaction for forming C–C bonds under the influence of microwave irradiation. Therefore, sodium aluminate (NaAlO2) was attempted as a base and solid support instead of traditional mineral bases. Moreover, zinc was used as a catalyst replacing palladium. The new method is unique and effective due to its energy economy, procedural simplicity, and general applicability. Moreover, the use of Sodium aluminate (NaAlO2) is expected to extend this green-protocol and atom-friendly chemistry for the synthesis of varied heterocyclic compounds of interest.

Palladium complex supported on the surface of magnetic Fe3O4 nanoparticles: an ecofriendly catalyst for carbonylative Suzuki-coupling reactions.

Diaryl ketone derivatives include well-known compounds with important physiological and biological properties. In order to prepare diaryl ketone derivatives, we constructed a pallidum (0) complex immobilized on Fe3O4 nanoparticles modified with aminobenzoic acid and phenanthroline [Fe3O4@ABA/Phen-DCA-Pd(0)], and evaluated its catalytic performance for carbonylative Suzuki-coupling reactions of aryl iodides with aryl boronic acid in the presence of Mo(CO)6 as the CO source under mild conditions. FT-IR, SEM, TEM, EDX, VSM, TGA, XRD, ICP-OES and Elemental mapping techniques were employed to identify the structure of the Fe3O4@ABA/Phen-DCA-Pd(0) nanocatalyst. Different derivatives of aryl iodides and aryl boronic acids containing withdrawing and donating functional groups were studied for the preparation of diaryl ketones. Also, various derivatives of heteroaryl iodides and boronic acids were used and the desired products were prepared with high yields. The Fe3O4@ABA/Phen-DCA-Pd(0) nanocatalyst was separated magnetically and reused 7 consecutive times without reducing its catalytic activity. VSM, TEM and ICP-OES spectroscopic techniques confirmed that the synthesized Fe3O4@ABA/Phen-DCA-Pd(0) catalyst was still stable and maintained its structure despite repeated reuse.

Scale-Up of a Rh-Catalyzed Asymmetric sp3-sp2 Suzuki-Miyaura-Type Reaction.

Csp2-Csp2 Suzuki-Miyaura couplings (SMCs) are ubiquitous in the synthesis of small molecules, but analogous Csp2-Csp3 bond-forming SMCs are rare, especially asymmetric variants. Recently, we developed a series of Rh-catalyzed couplings between racemic sp3-hybridized allyl chlorides and heteroaryl boronic acids. Here, we demonstrate that these catalytic asymmetric reactions can be scaled-up to give over 100 g of a product. The reaction we chose to test couples a heteroaromatic boronic acid derivative and a racemic bicyclic electrophile to give a product with three contiguous stereogenic centers. The SMC product was obtained as a single diastereomer in 90% yield and 98% ee. Kinetic analysis of the reaction reveals two exothermic steps in the reaction setup and revealed the means by which to prevent the generation of heat spikes detrimental to the stability of the catalyst.

Enantioselective Conjugate Addition of Boronic Acids to α,β-Unsaturated 2-Acyl Imidazoles Catalyzed by Chiral Diols.

Herein, we report the enantioselective conjugate addition of organic boronic acids to α,β-unsaturated 2-acyl imidazoles using (R)-3,3'-I2-BINOL as the catalyst. The catalytic system shows high efficiency and tolerance to alkenylboronic acids and heteroarylboronic acids. The corresponding Michael addition products were obtained in moderate to excellent yields and with moderate to excellent enantioselectivities (up to 97% ee). A gram-scale reaction was also conducted, and the desired product was obtained in high yield with no erosion in enantioselectivity. Finally, the synthetic utility of the methodology was demonstrated by transforming the 2-acyl imidazole moiety to the corresponding aldehyde, carboxylic acid, ester, and amide derivatives.

Redox-Neutral Organometallic Elementary Steps at Bismuth: Catalytic Synthesis of Aryl Sulfonyl Fluorides.

A Bi-catalyzed synthesis of sulfonyl fluorides from the corresponding (hetero)aryl boronic acids is presented. We demonstrate that the organobismuth(III) catalysts bearing a bis-aryl sulfone ligand backbone revolve through different canonical organometallic steps within the catalytic cycle without modifying the oxidation state. All steps have been validated, including the catalytic insertion of SO2 into Bi–C bonds, leading to a structurally unique O-bound bismuth sulfinate complex. The catalytic protocol affords excellent yields for a wide range of aryl and heteroaryl boronic acids, displaying a wide functional group tolerance.

Diversification and Design of Novel Aniline‐Pyrimidines via Sonogashira/Suzuki Cross Coupling Reactions Catalyzed by Novel CLPN‐Pd

AbstractAniline‐pyrimidines derivatives, especially Mepanipyrim are used as fungicides and obliging to control several diseases, particularly grey mould (Botrytis cinerea) of vegetables and vines. A series of novel Aniline‐pyrimidines derivatives like Mepanipyrim have been synthesized by using novel strategy via Sonogashira/Suzuki cross‐coupling reaction. High competence, novel and recyclable CLPN−Pd (cross‐linked ploy(ionic liquid)s Nano gels) is used as a catalyst in this synthetic method which we recycled three times. Various characterization like XPS, DLS, XPA, X‐rays, HNMR and CNMR have been done for confirmation of CLPN−Pd. For these two combined reactions we used a lower amount of catalyst, has advantages of wide substrate range, compatibility with multiple functional groups, and higher yields. In this novel technique of diversification two hetero aryl chlorides, 4‐chloro‐6‐methyl‐N‐phenylpyrimidin‐2‐amine and ‐chloro‐6‐methyl‐N‐(p‐tolyl) pyrimidin‐2‐amine with hetero phenyl acetylene and hetero aryl boronic acid delivered the subsequent compounds with reasonable to excellent 50 %–93 % yields. All the diversified compounds have been verified by various spectroscopic analysis such as 1HNMR, 13CNMR, and HR‐MS spectral study. The analysis and preliminary conclusion provided some reference value for further development of this kind of research and applications in the future.

Organocatalyzed Enantioselective Conjugate Addition of Boronic Acids to β,γ-Unsaturated α-Ketoesters.

We report herein the (R)-3,3'-Br2-BINOL-catalyzed enantioselective conjugate addition of organic boronic acids to β,γ-unsaturated α-ketoesters to generate the corresponding Michael addition products in moderate to high yields and with moderate to excellent enantioselectivities (up to 99% ee). This catalytic system features characteristics of mild reaction conditions, high efficiency, and tolerance to alkenylboronic acids and heteroarylboronic acids.

Transition-Metal-Free Alkylation and Acylation of Benzoxazinones with 1,4-Dihydropyridines.

The direct functionalization of N-heterocycles is a vital transformation for the development of pharmaceuticals, functional materials, and other chemical entities. Herein, the transition-metal-free alkylation and acylation of C(sp2)-H bonds in biologically relevant 2-benzoxazinones with 1,4-dihydropyridines as readily accessible radical surrogates is described. Excellent functional group compatibility and a broad substrate scope were attained. Gram-scale reaction and transformations of the synthesized adducts via Suzuki coupling with heteroaryl boronic acids demonstrated the synthetic potential of the developed protocol.

Facile synthesis of 4-aryl-N-(5-methyl-1H-pyrazol-3-yl)benzamides via Suzuki Miyaura reaction: Antibacterial activity against clinically isolated NDM-1-positive bacteria and their Docking Studies

The production of new pyrazole amide derivatives ( 6a-h) and their potential against New Delhi metallo-β-lactamase-1 (NDM-1) producing bacteria was described in the present manuscript. The 4-bromo- N -(5-methyl-1 H -pyrazol-3-yl)benzamide (5 ) was synthesized via direct amidation of protected 5-methyl-1 H -pyrazol-3-amine (3) . The target pyrazole amide derivatives (6a-h) were synthesized in moderate to excellent yield via Palladium catalyzed Suzuki cross-coupling of intermediate molecule (5) with different aryl and heteroaryl boronic acids. NMR and Mass Spectrometry were used to characterize the derivatives. The in vitro antibacterial effect against NDM-1-positive Acinetobacter baumannii and Klebsiella pneumoniae of newly synthesized analogues (6a-h) were determined by Agar well diffusion method. Moreover, MIC and MBC values were also evaluated against the tested bacteria. In addition, the Molecular Docking study of pyrazole amide derivatives (6a-h) against the NDM producing A. baumannii was performed to investigate the intermolecular interaction. The binding affinity and their values were compared with L-captopril. The 6b had greatest potential value and was appeared as a promising antibacterial agent.

Practical iridium-catalyzed direct \u03b1-arylation of N-heteroarenes with (hetero)arylboronic acids by H2O-mediated H2 evolution

Despite the widespread applications of 2-(hetero)aryl N-heteroarenes in numerous fields of science and technology, universal access to such compounds is hampered due to the lack of a general method for their synthesis. Herein, by a H2O-mediated H2-evolution cross-coupling strategy, we report an iridium(III)-catalyzed facile method to direct α-arylation of N-heteroarenes with both aryl and heteroaryl boronic acids, proceeding with broad substrate scope and excellent functional compatibility, oxidant and reductant-free conditions, operational simplicity, easy scalability, and no need for prefunctionalization of N-heteroarenes. This method is applicable for structural modification of biomedical molecules, and offers a practical route for direct access to 2-(hetero)aryl N-heteroarenes, a class of potential cyclometalated C^N ligands and N^N bidentate ligands that are difficult to prepare with the existing α-C-H arylation methods, thus filling an important gap in the capabilities of synthetic organic chemistry.