Six-membered N-heterocycles Research Articles

Microwave-Induced Synthesis of Bioactive Nitrogen Heterocycles.

There are many different applications of heterocyclic molecules in the pharmaceutical and materials science fields, which make them an important family of compounds. Among these heterocyclic compounds, nitrogen-containing heterocyclic (N-heterocyclic) compounds have attracted a lot of interest among researchers due to their various applications across a wide variety of fields. Many studies have been performed over the past few years to study the synthesis of N-heterocycles under different reaction conditions, such as solvent-free, catalytic, reactants immobilized on a solid support, one-pot synthesis, and microwave irradiation. It has been demonstrated by our research group that microwaves can be utilized for rapid and efficient synthesis of biologically active compounds. In this review, we provide an overview of the microwave-assisted non-catalytic and catalytic preparation of nitrogen-containing heterocycles, mostly polycyclic N-heterocycles, five-membered N-heterocycles, six-membered N-heterocycles, and fused N-heterocycles. Mostly in this article, we explore the microwave-assisted preparation of biologically important compounds, such as pyrimidines, thiazoles, imines, tetrazoles, steroidal derivatives, quinolines, indolizine, triazoles, beta-lactams, pyrroles and quinoxalines.

Directing group-assisted selective C–H activation of six-membered N-heterocycles and benzo-fused N-heterocycles

Directing group-assisted selective C–H bond activation of six-membered N-heterocycles and benzo-fused N-heterocycles has been reported.

Monofluoromethylation of N-Heterocyclic Compounds.

The review focuses on recent advances in the methodologies for the formation or introduction of the CH2F moiety in N-heterocyclic substrates over the past 5 years. The monofluoromethyl group is one of the most versatile fluorinated groups used to modify the properties of molecules in synthetic medical chemistry. The review summarizes two strategies for the monofluoromethylation of N-containing heterocycles: direct monofluoromethylation with simple XCH2F sources (for example, ICH2F) and the assembly of N-heterocyclic structures from CH2F-containing substrates. The review describes the monofluoromethylation of pharmaceutically important three-, five- and six-membered N-heterocycles: pyrrolidines, pyrroles, indoles, imidazoles, triazoles, benzothiazoles, carbazoles, indazoles, pyrazoles, oxazoles, piperidines, morpholines, pyridines, quinolines and pyridazines. Assembling of 6-fluoromethylphenanthridine, 5-fluoromethyl-2-oxazolines, C5-monofluorinated isoxazoline N-oxides, and α-fluoromethyl-α-trifluoromethylaziridines is also shown. Fluoriodo-, fluorchloro- and fluorbromomethane, FCH2SO2Cl, monofluoromethyl(aryl)sulfoniummethylides, monofluoromethyl sulfides, (fluoromethyl)triphenylphosphonium iodide and 2-fluoroacetic acid are the main fluoromethylating reagents in recent works. The replacement of atoms and entire functional groups with a fluorine atom(s) leads to a change and often improvement in activity, chemical or biostability, and pharmacokinetic properties. The monofluoromethyl group is a bioisoster of -CH3, -CH2OH, -CH2NH2, -CH2CH3, -CH2NO2 and -CH2SH moieties. Bioisosteric replacement with the CH2F group is both an interesting task for organic synthesis and a pathway to modify drugs, agrochemicals and useful intermediates.

Microwave-Assisted Synthesis of Biologically Relevant Six-Membered N-Heterocycles

Abstract: One of the most efficient non-conventional heating methods is microwave irradiation. In organic synthesis, microwave irradiation has become a popular heating technique as it enhances product yields and purities, reduces reaction time from hours to minutes, and decreases unwanted side reactions. Microwave-assisted organic synthesis utilizes dielectric volumetric heating as an alternative activation method, which results in rapid and more selective transformations because of the uniform heat distribution. Heterocyclic compounds have a profound role in the drug discov-ery and development process along with their applications as agrochemicals, fungicides, herbi-cides, etc., making them the most prevalent form of biologically relevant molecules. Hence, enor-mous efforts have been made to flourish green routes for their high-yielding synthesis under mi-crowave irradiation as a sustainable tool. Among the different clinical applications, heterocyclic compounds have received considerable attention as anti-cancer agents. Heterocyclic moieties have always been core parts of the development of anti-cancer drugs, including market-selling drugs, i.e., 5-fluorouracil, doxorubicin, methotrexate, daunorubicin, etc., and natural alkaloids, such as vinblastine and vincristine. In this review, we focus on the developments in the microwave-assisted synthesis of heterocycles and the anti-cancer activities of particular heterocycles.

N-N(+) Bond-Forming Intramolecular Cyclization of O-Tosyloxy β-Aminopropioamidoximes and Ion Exchange Reaction for the Synthesis of 2-Aminospiropyrazolilammonium Chlorides and Hexafluorophosphates.

Our research area is related to the spiropyrazolinium-containingcompounds, which are insufficiently studied compared with pyrazoline-containing compounds. Nitrogen-containing azoniaspiromolecules have also been well studied. In drug design and other areas, they are a priori important structures, since rigid spirocyclic scaffolds with the reduced conformational entropy are able to organize a closely spaced area. Azoniaspirostructures are currently of wide practical interest as ionic liquids, current sources (membranes), structure-directing agents in organocatalysis, and in the synthesis of ordered ceramics. Our goal was the synthesis of 2-aminospiropyrazolilammonium chlorides and hexafluorophosphates. Our methodology is based on the tosylation of β-aminopropioamidoximes with six-membered N-heterocycles (piperidine, morpholine, thiomorpholine, and phenylpiperazine) at the β-position. 2-Aminospiropyrazolilammonium chlorides and hexafluorophosphates were obtained by the reaction of double ion substitution in the reaction of toluenesulfonates of 2-aminospiropyrazolinium compounds with an ethereal solution of HCl in ethanol and with ammonium hexafluorophosphate in ethanol in quantitative yields of 55-97%. The physicochemical characteristics of the synthesized compounds and their IR and NMR spectra are presented. The obtained salts were additionally characterized by the single-crystal XRD analysis. The presence of both axial and equatorial conformations of spirocations in solids was confirmed. 2-Aminospiropyrazolilammonium chlorides and hexafluorophosphates have weak in vitro antimicrobial activity on Gram-positive and Gram-negative bacterial lines.

Synthesis of Phosphorus(V)-Substituted Six-Membered N-Heterocycles: Recent Progress and Challenges.

Heterocycles functionalized with pentavalent phosphorus are of great importance since they include a great variety of biologically active compounds and pharmaceuticals, advanced materials, and valuable reactive intermediates for organic synthesis. Significant progress in synthesis of P(O)R2-substituted six-membered heterocycles has been made in the past decade. This review covers the synthetic strategies towards aromatic monocyclic six-membered N-heterocycles, such as pyridines, pyridazines, pyrimidines, and pyrazines bearing phosphonates and phosphine oxides, which were reported from 2012 to 2022.

Reaction Products of β-Aminopropioamidoximes Nitrobenzenesulfochlorination: Linear and Rearranged to Spiropyrazolinium Salts with Antidiabetic Activity.

Nitrobenzenesulfochlorination of β-aminopropioamidoximes leads to a set of products depending on the structure of the initial interacting substances and reaction conditions. Amidoximes, functionalized at the terminal C atom with six-membered N-heterocycles (piperidine, morpholine, thiomorpholine and phenylpiperazine), as a result of the spontaneous intramolecular heterocyclization of the intermediate reaction product of an SN2 substitution of a hydrogen atom in the oxime group of the amidoxime fragment by a nitrobenzenesulfonyl group, produce spiropyrazolinium ortho- or para-nitrobenzenesulfonates. An exception is ortho-nitrobenzenesulfochlorination of β-(thiomorpholin-1-yl)propioamidoxime, which is regioselective at room temperature, producing two spiropyrazolinium salts (ortho-nitrobezenesulfonate and chloride), and regiospecific at the boiling point of the solvent, when only chloride is formed. The para-Nitrobezenesulfochlorination of β-(benzimidazol-1-yl)propioamidoxime, due to the reduced nucleophilicity of the aromatic β-amine nitrogen atom, is regiospecific at both temperatures, and produces the O-para-nitrobenzenesulfochlorination product. The antidiabetic screening of the new nitrobezenesulfochlorination amidoximes found promising samples with in vitro α-glucosidase activity higher than the reference drug acarbose. 1H-NMR spectroscopy and X-ray analysis revealed the slow inversion of six-membered heterocycles, and experimentally confirmed the presence of an unfavorable stereoisomer with an axial N–N bond in the pyrazolinium heterocycle.

Diversity in Heterocycle Synthesis Using α-Iminocarboxylic Acids: Decarboxylation Dichotomy.

Despite the structural similarity with imines, α-iminocarboxylic acids have seldom been used in heterocycles synthesis. The reactions of ortho-substituted anilines and arylglyoxylic acids in DMSO at 40 °C gave various benzo-fused five- to six-membered N-heterocycles in good to excellent yields. The reaction proceeds via intramolecular Michael addition of α-iminocarboxylic acids, generated in situ, with an ortho-substituted nucleophile, yielding an isolable unprecedented tetrahedral carboxylic acids, which upon decarboxylation without any aid of additional reagents forms the N-heterocycles. DMSO is crucial in this reaction, perhaps because of improved solubility and the ease of decarboxylation of these tetrahedral carboxylic acids. However, a copper-catalyzed reaction of ortho-substituted anilines and 2-bromoarylglyoxylic acids gave a dibenzo-fused seven-membered N-heterocycle under a basic reaction condition. Unlike intramolecular cyclization with α-iminocarboxylic acids in the first case, α-iminocarboxylic acid undergoes a competitive decarboxylation under the copper-catalyzed conditions, which upon subsequent heteroarylation form the heterocycles. Taken together, the study described herein represents two different modes of decarboxylation observed with α-iminocarboxylic acids, leading to the synthesis of divergent heterocycles and pharmaceuticals, which remained unexplored previously.

Recent Developments in the Synthesis of Five- and Six-membered N-heterocycles from Dicarbonyl Compounds

Various diketones such as 1,2-diketones, 1,3-diketones, 1,4-diketones, β - diketones and dicarbonyl compounds are used in the synthesis of core heterocyclic compounds such as pyrazoles, isoxazoles, triazoles and quinolones. They play an important role in synthetic organic chemistry. The diketones and dicarbonyl compounds also act as chelating ligands for the lanthanides and a large number of transition metals in material chemistry. 50% of drugs contain nitrogen heterocyclic compounds, so organic chemists have made efforts for the synthesis of nitrogen-containing heterocyclic compounds. This review article has compiled different methodologies for the synthesis of five- and six-membered nitrogencontaining heterocyclic compounds.

Addition of malonic esters to azoalkenes generated in situ from α-bromo- and α-chlorohydrazones

Michael addition of malonic esters to azoalkenes generated in situ from α-bromo- and α-chlorohydrazones was accomplished. Both aliphatic and aromatic substrates bearing different functional groups are tolerated. The use of a strong base (sodium hydride) for generation of azoalkenes and deprotonation of malonate was found to be essential for a successful coupling. Synthetic potential of the obtained β-hydrazonoalkylmalonates was demonstrated by their smooth conversion into five- and six-membered N-heterocycles, functionalized hydrazides, 2-(2-oxo-2-arylethyl)malonates and 2-arylethylmalonates.

Green Synthesis of Five- and Six-membered N-heterocycles by Ultrasonic Irradiation in Aqueous Media

Five- and six-membered N-heterocyclic compounds play an important role in medicinal chemistry and the development of new drugs. There is a constant demand for the development of novel biologically potent compounds, and there is also an increasing pressure to develop alternative and more sustainable synthetic methodologies following the Green Chemistry principles. Thus, the present review aims to compile the latest progress in the use of ultrasound irradiation in water conditions to mediate the synthesis of five- and six-membered N-heterocyclic compounds in an environmentally benign manner.

Metal-free multicomponent reactions: a benign access to monocyclic six-membered N-heterocycles.

The advent of multicomponent reactions in the synthesis of heterocycles and their ever burgeoning applications in drug development, materials chemistry, and catalysis, have attracted a great deal of current scientific interest. In particular, the metal-free multicomponent synthesis of six membered N-heterocycles has undergone intensive research over the last two decades offering an environmentally benevolent means contrary to traditional metal catalysed reactions. To the best of our knowledge, there exists no exclusive review on the metal-free multicomponent synthesis of six membered N-heterocyles, and hence the present report highlights the progress on metal-free multicomponent reactions with their advantages and mechanistic insights to access monocyclic six-membered N-heterocycles including pyridine, pyrimidine, pyrazine, triazine and their hydrogenated derivatives. The literature is covered since 2000, and the contents offer not only striking methods for divergent synthesis of six-membered N-heterocycles but also put forward some new insights into the exploration of metal-free multicomponent chemistry.

Nickel-Catalyzed Dehydrogenation of N-Heterocycles Using Molecular Oxygen.

Herein, an efficient and selective nickel-catalyzed dehydrogenation of five- and six-membered N-heterocycles is presented. The transformation occurs in the presence of alkyl, alkoxy, chloro, free hydroxyl and primary amine, internal and terminal olefin, trifluoromethyl, and ester functional groups. Synthesis of an important ligand and the antimalarial drug quinine is demonstrated. Mechanistic studies revealed that the cyclic imine serves as the key intermediate for this stepwise transformation.

Synthesis of Six-Membered N-Heterocycles Using Ruthenium Catalysts

A wide variety of biological activities are possessed by nitrogen, oxygen, and sulfur containing heterocycles and many methods are explored for the preparation of these heterocyclic compounds. Metal catalysts worked with high activity in organic reactions. The synthesis of heterocycles with the help of metal catalysts became very important in organic synthesis. New protocols have been investigated for the synthesis of heterocycles in the last decades. This article mainly focused on the synthesis of six-membered N-heterocylces in the presence of ruthenium catalyst.

Ultrasound-Assisted Synthesis of Six-Membered N-Heterocycles

Ultrasound-Assisted Synthesis of Six-Membered N-Heterocycles

Samarium(II) Iodide Mediated Synthesis of Five- and Six-Membered N-Heterocycles

Key words pyrrolidines - piperidines - radical cyclization - samarium iodide

A nitrogen-ligated nickel-catalyst enables selective intermolecular cyclisation of β- and γ-amino alcohols with ketones: access to five and six-membered N-heterocycles

Nickel-catalysed conversion of β- and γ-amino alcohols with ketones enables selective construction of pyrroles, pyridines and quinolines by liberation of hydrogen gas and water as sole by-products.

Photochemical Reactions: Synthesis of Six-membered N-heterocycles

Photochemical Reactions: Synthesis of Six-membered N-heterocycles

Hybrid Catalysis Enabling Room-Temperature Hydrogen Gas Release from N-Heterocycles and Tetrahydronaphthalenes.

Hybrid catalyst systems to achieve acceptorless dehydrogenation of N-heterocycles and tetrahydronaphthalenes-model substrates for liquid organic hydrogen carriers-were developed. A binary hybrid catalysis comprising an acridinium photoredox catalyst and a Pd metal catalyst was effective for the dehydrogenation of N-heterocycles, whereas a ternary hybrid catalysis comprising an acridinium photoredox catalyst, a Pd metal catalyst, and a thiophosphoric imide organocatalyst achieved dehydrogenation of tetrahydronaphthalenes. These hybrid catalyst systems allowed for 2 molar equiv of H2 gas release from six-membered N-heterocycles and tetrahydronaphthalenes under mild conditions, i.e., visible light irradiation at rt. The combined use of two or three different catalyst types was essential for the catalytic activity.

Dearomatization of electron poor six-membered N-heterocycles through [3 + 2] annulation with aminocyclopropanes.

Many abundant and highly bioactive natural alkaloids contain an indolizidine skeleton. A simple, high yielding method to synthesize this scaffold from N-heterocycles was developed. A wide range of pyridines, quinolines and isoquinolines reacted with donor-acceptor (DA)-aminocyclopropanes via an ytterbium(iii) catalyzed [3 + 2] annulation reaction to give tetrahydroindolizine derivatives. The products were obtained with high diastereoselectivities (dr > 20 : 1) as anti-isomers. Additionally, the formed aminals could be easily converted into secondary and tertiary amines through iminium formation followed by reduction or nucleophile addition. This transformation constitutes the first example of dearomatization of electron-poor six-membered heterocycles via [3 + 2] annulation with DA cyclopropanes.