Hetero Aryl Research Articles

An Efficient Metal-Free Methodology for the Synthesis of Hydrazo-Linked 5-(4-aryl)-1H-1,2,4-Triazoles

Hydrazo compounds have displayed significant roles in both biological and physical aspects, such as spinamycin as a potent growth inhibitor against fungi and rat sarcoma cells, hydrazo tocopherol as a component of vitamin E, and electron-rich hydrazo-linked triazines as energetic materials. In this study, a metal-free approach was proposed for the synthesis of hydrazo-linked 5-(4- aryl)-1H-1,2,4-triazoles. The methods for the synthesis of 5-(4-aryl)-1H-1,2,4-triazoles initiated by the reaction of aldehyde with semicarbazide. The resulted compound, 5-(4-aryl)-1H-1,2,4-triazol-3- ol, upon reaction with phosphorous oxychloride yielded 3-chloro-5-(4-aryl)-1H-1,2,4-triazoles. These synthesized compounds upon fusión with various aryl and hetero aryl substituted hydrazines provided desired hydrazo moieties. Synthesized hydrazo compounds were characterized by spectroscopic techniques, viz. 1H-NMR, FT-IR and mass spectrometry. In this study, a series of novel hydrazo- linked 5-(4-aryl)-1H-1,2,4-triazoles were synthesized. The methodology proposed in this study eliminates the use of complicated procedures and heavy metals.

Diindolocarbazole-Based Rigid Donor-Acceptor TADF Molecules for Energy and Electron Transfer Photocatalysis.

The design and synthesis of four twisted donor-acceptor (D-A) thermally activated delayed fluorescence (TADF) molecules CBZ-IQ, CBZ-2FIQ, DI-IQ and DI-2FIQ is reported in this work based on diindolocarbazole (DI) and phenyl carbazole as donor and indoloquinoxalines as acceptor. These compounds serve as photocatalysts for organic transformations. Theoretical calculations and experimental data showed reasonable singlet and triplet energy gaps of 0.17-0.26 eV for all compounds. All molecules showed increase in fluorescence quantum yields after degassing the solution and the transient photoluminescence decay showed two components: shorter prompt components (11.4 ns to 31 ns) and longer delayed components (36.4 ns to 1.5 μs) which further indicate the occurrence of TADF process. Cyclic voltammetry studies indicated well-suited excited state redox potentials of all compounds to catalyze organic transformations such as heteroarene arylation. Accordingly, photocatalytic C-H arylation of heteroarenes were performed using these compounds with excellent isolated yields of upto 80 %. Due to their suitable efficient triplet energy levels, all the emitters were also employed as energy transfer photocatalysts in E to Z isomerization of stilbene with the excellent conversion of ~90 %.

α-Diimine-based conjugated microporous polymers as heterogeneous ligands for highly efficient palladium-catalyzed direct C–H arylations

α-Diimine palladium embedded conjugated microporous polymers (DIM-Pd-CMPs) as highly efficient heterogeneous catalysts for direct C–H arylations of heteroarenes with heteroaryl bromides.

A facile tert-butyl nitrite-assisted preparation of deamino graphitic carbon nitride (DA-gCN) as a photocatalyst for the C-H arylation of heteroarenes using anilines as radical source.

In pristine graphitic carbon nitride (g-CN), amino groups often function as structural defects that trap photogenerated charges, resulting in low photocatalytic activity as well as reaction with nitrite, aldehyde, etc., ensuing in poor product yield. Without significantly altering the optical characteristics, the removal of amino groups is necessary to increase the photocatalytic activity and structural stability of pristine g-CN. The deamino graphitic carbon nitride (DA-gCN-5) was prepared by tert-butyl nitrite (TBN)-treatment, characterized and used as a photocatalyst for the radical C-H arylation of heteroarenes using anilines as radical source. Indeed, the photophysical characteristics of DA-gCN-5 and those of pristine g-CN are very comparable, except that DA-gCN-5 has a fewer residual amino groups, higher crystallinity, and compressed structure with a different morphology. Moreover, DA-gCN-5-catalyzed C-H arylation reaction offers greater product yield in a shorter reaction time compared to that of pristine g-CN in the coupling between heteroarenes and the in situ generated aryl diazonium salts from anilines under visible light irradiation. The amino groups in pristine g-CN absorbed the TBN that was added to convert aniline into the appropriate diazonium ions during the reaction. As a result, deamino graphitic carbon nitride produced by chemical treatment has better photophysical properties and catalytic activity than pristine g-CN. Additionally, this is the first method that uses diazotization reaction for the preparation of deamino graphitic carbon nitride, as far as we are aware.

Porphyrins – Effective Photocatalysts for Red Light-Induced Functionalizations of Biomolecules

Recently, photoredox catalysis has begun to influence molecular biology and medical sciences for its mild conditions for generating highly reactive species (i.e., radicals), enabling novel and selective functionalisations of biomolecules.[1] In line with this, porphyrins, which can transfer energy (photosensitization) or electrons (photoredox catalysis) when exposure to light, seem to be highly advantageous. Given that their electron absorption shows a characteristic Soret band at 420 nm with a high molar extinction coefficient (105 M-1 cm-1),[2] they have been mainly used in blue-light-induced reactions. These molecules, however, absorb red light (four Q-bands at 518, 553, 592 and 648 nm with molar extinction coefficients of 104 M-1 cm), which has the benefit of low energy, lower health risks,[3] and more in-depth penetration of various media.[4] Fig. 1: Porphyrins in red lightinduced transformationsWe established that due to their diverse photophysical properties, porphyrins promote photoinduced electron transfer events under red light irradiation.[5] They act as effective photooxidants (alkylation of carbonyl compounds, thiol-ne reaction and reductive decarboxylation) and photoreductants (in arylation of heteroarenes, selenylation, thiolation and reduction of nitro compounds). These bioinspired photocatalysts exhibit features that outperform other catalysts operating under red light, as they are really non-toxic and can be applied in biological systems. Thus, we believe that free-radical porphyrins are a valuable contribution to the set of red-light photocatalysts, and this study will lead to more practical biosynthetic applications.

Robust Zinc(II)porphyrin Catalyst for Visible Light Induced C-H Arylation of Heteroarenes.

Zinc(II)porphyrin catalyzed light induced C-H arylation of heteroarenes from anilines is discussed. The method is nontoxic and efficient, using only 0.5 mol % of porphyrin catalyst to produce bi(hetero)aryls in good yields. This work demonstrates the potential use of porphyrin photocatalysts as efficient and robust alternatives to organic dyes.

Discovery of Linvencorvir (RG7907), a Hepatitis B Virus Core Protein Allosteric Modulator, for the Treatment of Chronic HBV Infection.

Described herein is the first-time disclosure of Linvencorvir (RG7907), a clinical compound and a hepatitis B virus (HBV) core protein allosteric modulator, for the treatment of chronic HBV infection. Built upon the core structure of hetero aryl dihydropyrimidine, RG7907 was rationally designed by combining all the drug-like features of low CYP3A4 induction, potent anti-HBV activity, high metabolic stability, low hERG liability, and favorable animal pharmacokinetic (PK) profiles. In particular, the chemistry strategy to mitigate CYP3A4 induction through introducing a large, rigid, and polar substituent at the position that has less interaction with the therapeutic biological target (HBV core proteins herein) is of general interest to the medicinal chemistry community. RG7907 demonstrated favorable animal PK, pharmacodynamics, and safety profiles with sufficient safety margins supporting its clinical development in healthy volunteers and HBV-infected patients.

Visible light-induced borylation and arylation of small organic molecules using carbon dots

Efficient synthetic protocols for borylation of haloarenes and arylation of heteroarenes using nonmetal-doped CDots as metal-free photocatalysts under visible-light irradiation at room temperature are reported.

Palladium(ii)/N-heterocyclic carbene (NHC) catalyzed direct C–H arylation of heteroarenes with different aryl bromides and chlorides

The growing interest of industry in the field of bi(hetero)arene compounds motivated us to synthesize these compounds via a homogeneous catalytic route using Pd PEPPSI-type complexes through direct arylation.

Twisted organic TADF triads based on a diindolocarbazole donor for efficient photoisomerization of stilbene and photo-arylation of heteroarenes

Twisted D–A TADF triads DI-PF and DI-PI based on a diindolocarbazole donor and dibenzo[a,c]phenazine (PF) and phenanthro[9,10-d]imidazole (PI) acceptors were utilized for E–Z photoisomerization of stilbene and C–H arylation of heteroarenes.

Exploration of anti-tumor activity of erlotinib derivatives enabled by a Pd-catalyzed late-stage Sonogashira reaction

Fifty-eight erlotinib derivatives were designed and synthesized efficiently by the late-stage functionalization (LSF) strategy, directly installing the aryl, hetero aryl, and vinyl groups into the alkynyl group of the anticancer drug erlotinib. A new Palladium-NiXantphos catalyzed system of Sonogashira reaction was developed to accomplish the LSF of erlotinib. Both sp-sp2 coupling and sp-sp3 coupling could be achieved by the catalyst system. The reaction features mild, clean, high chemo-selectivity, and good functional group tolerance. Five compounds (3d, 3l, 5i, 5p, and 7c) showed potent cytotoxicity against A549 cancer cell lines. Compound 3l displayed excellent activity with IC50 11.4 μM, better than that of erlotinib (IC50 35.5 μM).

Copper-Catalyzed Halodecarboxylation of (Hetero)aryl Carboxylic Acids

Copper-Catalyzed Halodecarboxylation of (Hetero)aryl Carboxylic Acids

Synthesis and biological evaluation of amide derivatives of benzoxazole linked Imidazo[2,1-b][1,3,4]thiadiazole as antiproliferative agents

A new series of various substituted aryl and hetero aryl amide derivatives of benzoxazole linked imidazo[2,1- b ][1,3,4]thiadiazole ( 11a-j ) were synthesized and their structures confirmed by spectral data. These newly synthesized compounds ( 11a-j ) were evaluated for their anticancer profile towards human prostate cancer (PC3 and DU-145), lung cancer (A549) and breast cancer (MCF-7) cell lines by used of MTT assay and etoposide was chosen as positive control. Most of the derivatives displayed good to moderate antiproliferative activities with respective cell lines. Among the evaluated compounds, four compounds ( 11a, 11b, 11c and 11d ) demonstrated more potent anticancer activity. Particularly, compound 11a showed strongest activity as etoposide.

Palladium hetero‐di(N‐heterocyclic carbene) complexes and their catalytic activities in direct C–H arylation of heteroarenes

A library of neutral and cationic palladium complexes of cis‐chelating hetero‐dicarbene ligands have been prepared. These ligands contain two different NHC donors allowing for a wider degree of variation, and the impact of the distinct NHC units has been compared using various spectroscopic means. In addition, the catalytic activities of these complexes in the direct C‐H arylation of thiophenes with aryl halides were studied leading to the finding that the neutral dibromido complexes of the type [PdBr2(diNHC)] generally outperformed their cationic [Pd (NCMe)2(diNHC)](OTf)2 counterparts. More importantly, complexes containing more distinct NHC units give rise to superior catalysts due to an amplified “stereoelectronic asymmetry” within the complex. A preliminary photophysical study of some selected thiophene reaction products has been conducted as well. The ability to individually change each NHC donor in such dicarbene ligands allows for a better fine‐tuning of complex properties in search for superior catalysts.

Quinolinecarbonitrile: Solvent‐free one‐pot synthesis, in vitro studies against leukemia cell lines, molecular docking, and potential Mcl‐1 inhibitors

AbstractIn our study, we present an environmentally benign procedure for green synthesis of 4‐aryl/hetero aryl benzo[h]quinolin‐2‐one‐3‐carbonitrile. The synthesis protocol of quinolone carbonitrile derivatives, including the reaction of tetralone 1 and ethyl cyano acetate with hetero aryl and ammonium acetate under solvent‐free conditions, compounds 4a–i, 5, and 6, were obtained and its chemical structure was proved by different spectroscopic methods. The present synthetic approach could effectively produce different quinolone carbonitrile derivatives with high yields in the absence of solvent and in short reaction time, making it a green and sustainable process. All new compounds were screened for cytotoxicity on two kinds of acute lymphoblastic leukemia (ALL) cells, CRL‐2898, and MOLT‐4, and compared with normal human primary peripheral blood mononuclear cells PCS‐800‐011 using MTT assay. Compound 4g showed potent cytotoxicity with IC50 value 9.81, 9.81 μM against CRL‐2898 and MOLT‐4, respectively, without effect on normal cell. The most cytotoxic compounds 4g, 5, and 6 were docked into the active site of myeloid cell leukemia‐1(Mcl‐1). Compounds 4g and 6 showed strong hydrogen bond interaction with Arg263 through their carbonyl groups, achieving a binding mode similar to that of the native ligand.

Photoredox catalysis powered by triplet fusion upconversion: arylation of heteroarenes

In this work, the feasibility of triplet fusion upconversion (TFU, also named triplet–triplet annihilation upconversion) technology for the functionalization (arylation) of furans and thiophenes has been successfully proven. Activation of aryl halides by TFU leads to generation of aryl radical intermediates; trapping of the latter by the corresponding heteroarenes, which act as nucleophiles, affords the final coupling products. Advantages of this photoredox catalytic method include the use of very mild conditions (visible light, standard conditions), employment of commercially available reactants and low-loading metal-free photocatalysts, absence of any sacrificial agent (additive) in the medium and short irradiation times. The involvement of the high energetic delayed fluorescence in the reaction mechanism has been evidenced by quenching studies, whereas the two-photon nature of this photoredox arylation of furans and thiophenes has been manifested by the dependence on the energy source power. Finally, the scaling-up conditions have been gratifyingly afforded by a continuous-flow device.Graphical abstract

Nickel-Catalyzed Reductive Cross-Coupling of (Hetero)Aryl Bromides with Vinyl Acetate

Nickel-Catalyzed Reductive Cross-Coupling of (Hetero)Aryl Bromides with Vinyl Acetate

Generation of Thiyl Radicals from Air-Stable, Odorless Thiophenol Surrogates: Application to Visible-Light-Promoted C–S Cross-Coupling

AbstractThe synthetic versatility of thiophenols is offset by their air-sensitivity and foul odor. It is demonstrated that S-aryl isothiouronium salts can be used as precursors to thiyl radicals, extending the practical benefits of these air-stable, odorless salts from ionic to single electron manifolds. The isothiouronium salts are accessed via Ni-catalyzed cross-coupling of (hetero)aryl iodides and thiourea and are isolated as free-flowing solids following anion exchange. Judicious choice of a redox-innocent counteranion enables use of these convenient thiophenol surrogates in radical processes, as is exemplified by the synthesis of non-symmetrical diaryl thioethers via light-promoted S-arylation.

Palladium-Catalysed Intermolecular Direct C–H Bond Arylation of Heteroarenes with Reagents Alternative to Aryl Halides: Current State of the Art

Abstract: This unprecedented review with 322 references provides a critical up-to-date picture of the Pd-catalysed intermolecular direct C–H bond arylation of heteroarenes with arylating reagents alternative to aryl halides that include aryl sulfonates (aryl triflates, tosylates, mesylates, and imidazole-1-sulfonates), diaryliodonium salts, [(diacetoxy)iodo]arenes, arenediazonium salts, 1-aryltriazenes, arylhydrazines and N’-arylhydrazides, arenesulfonyl chlorides, sodium arenesulfinates, arenesulfinic acids, and arenesulfonohydrazides. Particular attention has been paid to summarise the preparation of the various arylating reagents and to highlight the practicality, versatility, and limitations of the various developed arylation protocols, also comparing their results with those achieved in analogous Pd-catalysed arylation reactions involving the use of aryl halides as electrophiles. Mechanistic proposals have also been briefly summarised and discussed. However, data concerning Pd-catalysed direct C–H bond arylations involving the C–H bonds of aryl substituents of the examined heteroarene derivatives have not been taken into account.

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.