Synthesis Of Heterocycles Research Articles

Asymmetric electrophilic functionalization of amino-substituted heteroaromatic compounds: a convenient tool for the enantioselective synthesis of nitrogen heterocycles.

The catalytic asymmetric electrophilic functionalization of the less reactive N-heteroaromatic compounds has been reported using the approach of the introduction of an exocyclic amino substituent. This strategy has allowed enantioselective Friedel-Crafts alkylation in pyrazoles, isoxazoles and isothiazoles, as well as in aminoindoles, aminobenzofurans and aminobenzothiophenes. Several stereoselective methods have been used for the 1,4-addition or 1,2-addition of these heteroaromatic compounds to different electrophiles employing organocatalysts or chiral metal complexes. The activating exocyclic amino substituent has also been used as a nucleophile in tandem reactions, including formal cycloadditions ([3+2] and [3+3]), for the synthesis of highly functionalized chiral nitrogen heterocycles.

Pd/Brønsted acid catalysed intramolecular N-allylation of indoles and pyrroles with alkynes for the synthesis of N-fused heterocycles.

We, herein, report a Pd(0) and Brønsted acid-catalyzed redox-neutral intramolecular N-allylation of indoles and pyrroles with alkynes for the synthesis of biologically important imidazolidinone-fused N-heterocycles. The allylation is completely atom-economical and is applicable to a wide range of substrates. The methodology eliminates the use of a leaving group or an oxidizing agent, often employed for the allylation of nucleophiles. To the best of our knowledge, N-allylation of indoles and pyrroles with alkynes has not been reported to date.

Light-Promoted, Nickel-Catalyzed C–N Coupling of (Hetero)aryl Halides with Benzophenone Hydrazone for the Synthesis of Nitrogen-Containing Heterocycles

A highly effective C-N coupling reaction of (hetero)aryl halides with benzophenone hydrazone is reported. Catalyzed by a Ni(II)–aryl halide complex under UV irradiation (390–395 nm) in the presence of a...

Various Synthesis of Imidazo[1,2-a]pyridines Derivatives and Therapeutic Significance: A Review

The synthesis of bicyclic heterocycles, notably nitrogen-containing imidazopyridines, holds immense appeal due to their structural diversity and pivotal role in biological systems. These compounds are ubiquitously found in nature and are prized for their significance in both chemical and biological contexts. Imidazopyridine derivatives, among nitrogen heterocycles, serve as fundamental structures in various applications spanning pharmaceuticals to food additives. Consequently, their synthesis and modification represent a focal point in both natural and synthetic organic chemistry. This review aims to comprehensively explore conventional methodologies alongside innovative synthesis approaches, while also delving into the diverse biological properties exhibited by these versatile heterocycles. Through this examination, we endeavor to provide valuable insights that will contribute to further advancements in the synthesis and utilization of imidazopyridines in various fields.

Synthesis of imidazole-fused nitrogen-bridgehead heterocycles catalysed by lipase and their antifungal and antimicrobial bioactivity

An effective approach for selective C–N bond formation for synthesising imidazo[1,2-a] pyridine-based heterocycles using porcine pancreatic lipase (PPL) as a biocatalyst has been devised.

Cp*Ir(III) complexes catalyzed solvent-free synthesis of quinolines, pyrroles and pyridines via an ADC strategy.

A trio of Ir(III) complexes that are held together by a picolinamidato moiety were created. In our earlier research, we demonstrated the catalytic activity of the complexes for producing alpha-alkylated ketones from a ketone or secondary alcohol with a primary alcohol in the presence of a catalytic amount of a Cp*Ir(III) catalyst and tBuOK in toluene at 110 °C using the hydrogen-borrowing technique. Earlier many research groups had synthesized quinoline, pyrrole, and pyridine derivatives using 2-amino alcohol and ketone or secondary alcohol derivatives as starting materials, but in all those cases the reaction conditions are not suitable in terms of green synthesis like more catalyst loading, base loading, long reaction time, and high temperature. In addition, most of the reactions contain phosphine a hazardous by-product, along with the catalyst. Keeping in mind these shortcomings, we tried to expand the use of our catalysts after achieving an excellent result in our previous work, and we were successful in producing quinoline, pyrrole, and pyridine derivatives through acceptor-less dehydrogenative coupling (ADC) procedures at 90-110 °C under neat/solvent-free conditions and achieved good to exceptional yields of those nitrogen-containing heterocycles. This methodology is attractive because it is environmentally benign and allows for the "green" synthesis of nitrogen-containing heterocycles. All that is required is a modest quantity of catalyst and base, and the by-products are merely H2O and H2.

Recent approaches for the synthesis of heterocycles from amidines via a metal catalyzed C-H functionalization reaction.

Transition metal catalyzed C-H bond activation has become one of the most important tools for constructing new chemical bonds. Introducing directing groups to the substrates is the key to a successful reaction, these directing groups can also be further transformed in the reaction. Amidines with their unique structure and reactivity are ideal substrates for transition metal-catalyzed C-H transformations. This review describes the major advances and mechanistic investigations of the C-H activation/annulation tandem reactions of amidines until early 2024, focusing on metal-catalyzed C-H activation of amidines with unsaturated compounds, such as alkynes, ketone, vinylene carbonate, cyclopropanols and their derivatives. Meanwhile this manuscript also explores the reaction of amidines with different carbene precursors, for example diazo compounds, azide, triazoles, pyriodotriazoles, and sulfoxonium ylides as well as their own C-H bond activation/cyclization reactions. A bright outlook is provided at the end of the manuscript.

Green advancements towards the electrochemical synthesis of heterocycles

Green advancements towards the electrochemical synthesis of heterocycles

Decarboxylative [3 + 2] cycloaddition of propargyl cyclic carbonates with C,O-bis(nucleophile)s to access dihydrofuro[3,2-c]coumarins and dihydronaphtho[1,2-b]furans with quaternary center.

The development of efficient and straightforward strategies for obtaining chiral complex molecules from readily available starting materials is of great value in drug discovery. The stereodivergent synthesis of heterocycles bearing quaternary centers remains a challenge due to inherent steric issues. Herein, we report an enantioselective copper-catalyzed decarboxylative [3 + 2] cycloaddition of propargyl cyclic carbonates/carbamates with 4-hydroxycoumarins to afford a wide range of dihydrofuro[3,2-c]coumarins in excellent yields and enantioselectivity. The strategy has been successfully applied to other C,O-bisnucleophiles, such as α-naphthols, to obtain dihydronaphtho[1,2-b]furans with good yields.

Trifluoromethylnitrone: a versatile building block for synthesizing trifluoromethyl-containing heterocyclic compounds.

This review explores the significance of trifluoromethylnitrones in synthesizing fluorine-containing compounds, with a particular focus on trifluoromethylated heterocycles. It explores the versatility of trifluoromethylnitrones, especially in [3 + 2] cycloaddition reactions, highlighting their unique reactivity with various dienophile substrates. Trifluoromethylnitrones are valuable precursors for the rapid synthesis of medicinally important trifluoromethylated heterocycles, including isoxazolidines, dihydroisoxazoles, oxathiazolidines, β-lactams, and aziridines. These heterocycles, in turn, serve as synthons for synthesizing trifluoromethylated lactams and aminoalcohols. Additionally, nitrone chemistry extends to synthesizing trifluoromethylated nucleosides and trifluorinated organoborane heterocycles, demonstrating their versatility. While sharing similarities with trifluorodiazoethane reactivity, trifluoromethylnitrones offer distinct advantages by enabling the synthesis of heterocycles typically inaccessible with trifluorodiazoethane.

BF3·OEt2-catalyzed/mediated alkyne cyclization: a comprehensive review of heterocycle synthesis with mechanistic insights.

The quest for efficient and versatile methods for heterocycle synthesis continues to drive innovation in organic chemistry. In this context, the cyclization of alkynes catalyzed or mediated by boron trifluoride diethyl etherate (BF3·OEt2) has emerged as a powerful and widely applicable strategy. This review provides a comprehensive and authoritative overview of BF3·OEt2-catalyzed/mediated alkyne cyclization reactions, covering the scope, mechanisms, and applications of these processes. We discuss the synthesis of a diverse range of heterocyclic compounds, including dihydropyrans, quinolines, dehydropiperidines, oxindoles and others, and highlight the unique advantages of BF3·OEt2 as a catalyst/mediator. Recent advances, challenges, and future directions in this rapidly evolving field are also addressed. This review aims to serve as a valuable resource for synthetic chemists, inspiring further research and applications in this exciting area.

Metallaelectro-catalyzed alkyne annulations via C-H activations for sustainable heterocycle syntheses.

Alkyne annulation represents a versatile and powerful strategy for the assembly of structurally complex compounds. Recent advances successfully enabled electrocatalytic alkyne annulations, significantly expanding the potential applications of this promising technique towards sustainable synthesis. The metallaelectro-catalyzed C-H activation/annulation stands out as a highly efficient approach that leverages electricity, combining the benefits of electrosynthesis with the power of transition-metal catalyzed C-H activation. Particularly attractive is the pairing of the electro-oxidative C-H activation with the valuable hydrogen evolution reaction (HER), thereby addressing the growing demand for green energy solutions. Herein, we provide an overview of the evolution of electrochemical C-H annulations with alkynes for the construction of heterocycles, with a topical focus on the underlying mechanism manifolds.

Update on thiopyran-fused heterocycle synthesis (2013-2024).

Thiopyrans and their fused derivatives have significant synthetic relevance owing to their biological importance and occurrence in natural products. The current article provides an overview of synthetic strategies employed for the construction of thiopyran-fused heterocycles. In particular, this article discusses synthetic methods for the fusion of thiopyran with heterocycles such as indole, quinoline, pyrimidine, pyridine, thiophene, chromene, oxazole, pyrazole, pyran and furan and covers the literature from 2013 to 2024. The most common precursors for thiopyrano[2,3-b]indoles, thiopyranoquinolines and thiopyranothiazoles are indoline-2-thione, 2-mercaptoquinoline-3-carbaldehyde and thiazolidinone, respectively, and various reactions involving these are described in detail here. Asymmetric syntheses of thiopyranoindoles achieved using chiral catalysts based on thiourea, proline and metal complexes are also included. The biological activity associated with some compounds is also discussed.

The introduction of nitrogen-containing heterocyclic compounds (NHC) and Cu2+ in Co-MOF further improves the removal of dibenzothiophene from model fuels

NHC/Co-MOF-Cu2+ composite adsorbent materials were prepared through the in-situ synthesis of nitrogenous heterocyclic compounds (NHC) on Co-containing metal–organic framework (Co-MOF) using terephthalaldehyde (C8H6O2) and p-Phenylenediamine (C6H8N2) at room temperature. Subsequently, further modification with Cu2+ was carried out. These materials were then utilized for the removal of dibenzothiophene (DBT) from simulated gasoline. The samples were analyzed using scanning electron microscopy (SEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FT-IR) and other methods. The results indicated the uniform attachment of NHC and Cu2+ metal particles onto Co-MOF, confirming the successful synthesis of NHC/Co-MOF-Cu2+ adsorption materials. The introduction of Cu2+ enhanced the π-complexation between NHC/Co-MOF-Cu2+ and DBT. The introduction of NHC brought heteroatoms and ring structures to the composite, increasing the electron cloud density of the NHC/Co-MOF-Cu2+ composite and thereby amplifying the π-complexation with DBT. The adsorption capacity of NHC/Co-MOF-Cu2+ for DBT (150.4 mg/g) is significantly larger than that of Co-MOF (102.5 mg/g). The adsorption process of NHC/Co-MOF-Cu2+ for DBT followed the pseudo-second-order kinetic model and Langmuir model. Additionally, the adsorption process was found to be spontaneous and exothermic. Over five consecutive adsorption–desorption cycles, the efficiency of NHC/Co-MOF-Cu2+ decreased by only 10 %, indicating its excellent regeneration performance.

Synthesis of N-substituted heterocycles in a sealed Monowave 50 reactor

The paper examines the process of aromatic nucleophilic substitution in 2-chloronitrobenzene and 2,4-dichloro-1,5-dinitrobenzene in a Monowave 50 synthesis reactor. The authors identify accelerated reactions of substrates with azaheterocyclic compounds (pyridine or indole) in hermetically sealed vessels.

SO3H‐Functionalized Carbon Materials: A Versatile and sustainable heterogeneous Catalyst for Diverse Organic Transformations

AbstractDue to their fascinating biological features, heterocyclic compounds and their derivatives have long been recognized as promising molecules with potential pharmaceutical applications. The significance of heterocyclic compounds in drug discovery and development is evident from the fact that a majority of drugs in the pharmaceutical market incorporate heterocyclic compounds as active substances or ingredients. Various synthetic methods and advancements have been devised to prepare these heterocyclic compounds using diverse catalysts under mild reaction conditions. SO3H functionalized carbon material (C‐SO3H) is heterogeneous green solid catalyst that has been employed to catalyze diverse organic reactions including construction of three‐, four‐, five‐, six‐member and fused heterocycles as well as other open chain organic transformations. The C‐SO3H catalyst works under relatively mild reaction conditions and recovered from the reaction mixtures for reuse. Various cheap carbon sources covering natural organic carbon matter and industrial waste already being used to synthesize SO3H‐functionalized acidic carbon catalyst for replacement of various homogeneous acid catalysts. The present review aims to highlight the organic reactions especially those connecting for heterocyclic synthesis catalyzed by sulfonated carbons (C‐SO3H) from 2010 to till date.

The Synthesis of Nitrogen- and Oxygen-Containing Heterocyclic Scaffolds Assisted by Ionic Liquids: A 2022 Literature Survey

AbstractHeterocycles have gained recognition as vital components in approved drugs, drawing substantial attention from the scientific community. Ionic liquids (ILs) have been utilized for their transformative roles in heterocycle synthesis, showcasing distinctive properties that are pivotal in diverse chemical transformations, while also acting as effective catalysts and offering safer alternatives to volatile organic solvents. This account delves into the synthesis of nitrogen- and oxygen-containing heterocyclic structures, employing various ILs such as ammonium, cholinium, DABCO-based, DBU-based, guanidinium-based, imidazolium, phosphonium, pyridinium, and other miscellaneous examples. They have proven indispensable in facilitating reactions like the Fischer indole synthesis, the Biginelli reaction, Knoevenagel condensations and many more. Notably, the recyclability of ILs serves as a valuable asset, aiding in the completion of intricate synthetic pathways, multicomponent reactions, and one-pot syntheses, ultimately enhancing yields. This account, covering the literature published in 2022, seeks to guide researchers in selecting suitable ILs for specific chemical reactions that enable the synthesis of aza- and/or oxa-heterocycles. The described advancements represent promising prospects for drug development and other applications within the domain of heterocyclic chemistry.

Iron(III) promoted oxidative annulation of benzylic C-H bonds in (α-amino)arylacetic acids for synthesis of 4-aryl pyrrolo[1,2-a]quinoxalines

Using amino acids for synthesis of heterocycles is a synthetically promising field. However, developing the practical methods for transformations of amino acids into heterocycles is still challenging. Given that alpha amino acids are abundant or easily prepared, herein we report a method for annulation of benzylic C-H bonds in derivatives of 2-phenylglycine with 1-(2-nitroaryl)pyrroles. The reactions proceeded well in the presence of iron(III) acetylacetonate catalyst and potassium carbonate base. Scope of pyrrolo[1,2-a]quinoxalines was studied. Regardless of electronic properties of substituents, the pyrrolo[1,2-a]quinoxaline de-rivatives were successfully isolated, as yields varied from 42% to 52%. Pyrrolo[1,2-a]quinoxalines substituted with heterocycles at C4 positions as pyridine and thiophene were competent substrates. Reaction mechanism was proposed to start with a decar-boxylative/deaminative sequence of 2-phenylglycine to afford benzaldehyde. The iron catalyst was presumed to facilitate the re-duction of 1-(2-nitroaryl)pyrroles to furnish the corresponding aniline. Imine condensation followed by cyclisation and oxidation would yield the pyrrolo[1,2-a]quinoxaline. Our method would offer a convenient tactic to transform abundant alpha amino acids into synthetically useful heterocycles.

Visible-Light-Mediated Divergent and Regioselective Vicinal Difunctionalization of Styrenes with Arylazo Sulfones.

Activated by visible light, arylazo sulfones can serve as multifaceted reactants and are employed in diazenylation, sulfonylation, and arylation reactions under (photo)catalyst-free conditions. Such versatile reactivity enabled us to develop an operationally simple, regioselective, and tunable difunctionalization of styrenes with arylazo sulfones to produce α-sulfonyl arylhydrazones and 1,2-alkoxyarylated products in moderate to excellent yields. Furthermore, such difunctionalized products have been exploited as key building blocks for the synthesis of various heterocycles.

Photocatalytic Generation of Trifluoromethyl Nitrene for Alkene Aziridination.

N-Trifluoromethylated organics may be applied in drug design, agrochemical synthesis, and materials science, among other areas. Yet, despite recent advances in the synthesis of aliphatic, cyclic and heterocyclic N-trifluoromethyl compounds, no strategy based on trifluoromethyl nitrene has hitherto been explored. Here we describe the formation of triplet trifluoromethyl nitrene from azidotrifluoromethane, a stable and safe-to-use precursor, by visible light photocatalysis. The addition of CF3 N to alkenes via biradical intermediates afforded previously unknown aziridines substituted with trifluoromethyl group on the nitrogen atom. The obtained aziridines were converted into either N-trifluoromethylimidazolines, via formal [3+2] cycloaddition with nitriles, mediated by a Lewis acid, or into N-trifluoromethylaldimines, via ring opening and aryl group migration mediated by a strong Brønsted acid. Our findings open new opportunities for the development of novel classes of N-CF3 compounds with possible applications in the life sciences.