Intermolecular Cyclization Reaction Research Articles

Easy Access to Functionalized Indolines and Tetrahydroquinolines via a Photochemical Cascade Cyclization Reaction.

Herein, the development of a light-mediated synthesis of functionalized indolines and tetrahydroquinolines is reported. These structural motifs are considered as highly valuable targets, attributed to their widespread occurrence in pharmaceuticals and natural products. The gold-mediated approach offers a direct route to functionalized indolines in yields of up to 81% under mild photochemical conditions. Thereby, easily accessible Boc-protected N-aryl-allylamine and homoallylamine derivatives were reacted with sp3-hybridized haloalkanes in an intermolecular cascade cyclization reaction. A broad scope of substrates, including a variety of different substituents on the aromatic backbone as well as various haloalkanes, could be utilized. Indoline derivatives, which are functionalized in position 2, are also accessible by applying ortho-allylic anilines. Moreover, the synthetic appeal was demonstrated for a total synthesis of the anti-inflammatory agent AN669 in three reaction steps in an overall yield of 64%.

Iron‐catalyzed intermolecular and intramolecular cyclization reactions of N‐heterocycles

AbstractN‐Heterocyclic compounds have been appealing pharmacophores in their use as drug production substrates. In this review paper, the cyclization of N‐heterocycles, using iron as a catalyst, and their mechanistic pathways have been highlighted and presented comprehensively. This paper will provide researchers with in‐depth knowledge of their approach to synthesis by employing a greener way rather than a conventional one. The present review firmly establishes that iron catalysts by their innate ability and inherent potential to acquire the four oxidation states coupled with their easy accessibility, inexpensive, and environment‐friendly nature have remained the mainstay in chemistry as the evergreen catalyst in the domain of organic synthesis. This review paper extensively explores iron‐catalyzed cyclization of N‐heterocycles, elucidating mechanistic pathways and emphasizing greener synthesis methods. Iron's versatility, accessibility, and eco‐friendliness solidify its position as a cornerstone in organic synthesis.

Synthesis of cyclobutane-fused oxazolidine-2-thione derivatives

An expedient, solvent-free, mild base catalyzed intermolecular cyclization reaction has been developed to enable the one-pot synthesis of fourteen examples of cyclobutane-fused oxazolidine-2-thiones in good to high yields. Bicyclic structures of this type have not previously been described in the literature; they have a cis ring junction with both rings deviating slightly from planarity.

Synthesis, characterization and anticancer activity of Ni(II), Cu(II), Pd(II) and Au(III) complexes derived from novel Mannich base

AbstractNew four complexes of Ni(II), Cu(II), Pd(II), and Au(III) were derived from the tridentate ligand 3‐((3‐(4‐hydroxyphenyl)‐5‐mercapto‐4H‐1,2,4‐triazol‐4‐yl)(3‐oxobutyl)amino)naphtho[2,3‐b]furan‐2(3H)‐one (L), which synthesized using condensation reaction of formaldehyde, acetone, and secondary amine (Mannich reaction). The secondary amine is a heterocyclic compound possesses two rings, naphthafuran and triazole, both rings prepared through intermolecular cyclization reactions. Considering that naphthafuran‐2‐one derived from α‐amino nitrile. The α‐amino nitrile compound contains the other triazole ring which illustrated to the structure through successive steps. The compounds were characterized using elemental analysis (C.H.N.S), FT‐IR, ultraviolet–visble spectroscopy, thermal gravimetric analysis (TGA), flame atomic absorption, molar conductivity, and magnetic susceptibility measurements. Accordingly, the probable geometries of the complexes were suggested as square planner, and they have electrolytic nature. Thus, chemical formula; [NiLCl]Cl·6H2O, [CuLCl]Cl·2H2O, [PdLCl]Cl·2H2O, and [AuLCl]Cl2·3H2O. Cytotoxic effect was studied on brain cancer cell line (AMJM cell line) at different concentrations for L and complexes. The results showed that gold(III) complex has the highest cytotoxicity among all compounds.

α‐Benzylation of Carbonyl Compounds Enabled by Synergistic Copper/Amine Catalyzed Decarboxylation of Arylacetic Acids

AbstractHerein, we report synergistic copper/amine‐catalyzed reactions for directly α‐benzylating carbonyl compounds with arylacetic acids. These reactions represent the first examples of decarboxylative oxidative synergistic transition‐metal/enamine catalysis for α‐functionalizing carbonyl compounds. The process features starting‐material availability, good functional group tolerance, mild reaction conditions, and good‐to‐excellent yields. Dibenzylated products were formed in moderate yields under slightly altered reaction conditions, and some products were transformed into 1,2,3,4‐tetrahydrocyclopenta[b]indole derivatives by acid‐catalyzed intermolecular cyclization reactions with indoles. Moreover, biological studies revealed that some products have anticancer properties and may be useful in drug‐discovery studies.magnified image

Solvent‐Free Synthesis of Quaternary Oxazolidine‐2‐thione β3‐Amino Ester Analogs

AbstractA solvent‐free organocatalyzed intermolecular cyclization reaction starting from β‐substituted γ‐hydroxy‐α,β‐unsaturated esters and aryl isothiocyanates proceeds via an aza‐Michael addition to provide previously unknown quaternary oxazolidine‐2‐thione β3‐amino ester analogs. A panel of diversely‐substituted esters was investigated, including β,γ‐disubstituted examples which provided the target molecules with very high cis diastereoselectivity.

Iron-catalyzed synthesis of N-heterocycles via intermolecular and intramolecular cyclization reactions: A review

Small N -heterocyclic molecules are important scaffolds in the pharmaceutical industry and most FDA-approved drugs are nitrogen-containing heterocycles. Chemists try to employ iron-based catalysts for organic transformations due to their abundance, economic, easily accessible and environment-friendly behaviour. N -heterocycles are synthesized by the cyclization reactions. This review covered the synthesis of N -heterocycles by employing iron-based catalysts via intermolecular or intramolecular cyclizations.

Bifunctional sulfilimines enable synthesis of multiple N-heterocycles from alkenes

Intramolecular cyclization of nitrogen-containing molecules onto pendant alkenes is an efficient strategy for the construction of N-heterocycles, which are of paramount importance in, for example, pharmaceuticals and materials. Similar intermolecular cyclization reactions, however, are scarcer for nitrogen building blocks, including N-centred radicals, and divergent and modular versions are not established. Here we report the use of sulfilimines as bifunctional N-radical precursors for cyclization reactions with alkenes to produce N-unprotected heterocycles in a single step through photoredox catalysis. Structurally diverse sulfilimines can be synthesized in a single step, and subsequently engage with alkenes to afford synthetically valuable five-, six- and seven-membered heterocycles. The broad and diverse scope is achievable by a radical-polar crossover annulation enabled by the bifunctional character of the reagents, which distinguishes itself from all other N-centred-radical-based reactions. The modular synthesis of the sulfilimines allows for larger structural diversity of N-heterocycle products than is currently achievable with other single cyclization methods.

A Selenide Catalyst for the Activation of Alkenes through Se⋅⋅⋅π Bonding.

Chalcogen bonding catalysis with divalent chalcogenides required using heteroatoms as electron donors to give reactivity, while the activation of hydrocarbons such as alkenes by this concept remains an unresolved challenge. Herein, we discovered a powerful selenide catalyst that showed unprecedented capability in the activation of alkenes. The Se⋅⋅⋅π interactions were capable of catalyzing a broad range of transformations, including intermolecular cyclization and coupling reactions. Significantly, the Se⋅⋅⋅π bonding activation mode can be exploited to achieve intermolecular enyne cyclizations and controlled cross-coupling of triple alkenes. The activation of alkenes by divalent selenides opens up a new avenue for supramolecular catalysis.

A Selenide Catalyst for the Activation of Alkenes through Se⋅⋅⋅π Bonding

AbstractChalcogen bonding catalysis with divalent chalcogenides required using heteroatoms as electron donors to give reactivity, while the activation of hydrocarbons such as alkenes by this concept remains an unresolved challenge. Herein, we discovered a powerful selenide catalyst that showed unprecedented capability in the activation of alkenes. The Se⋅⋅⋅π interactions were capable of catalyzing a broad range of transformations, including intermolecular cyclization and coupling reactions. Significantly, the Se⋅⋅⋅π bonding activation mode can be exploited to achieve intermolecular enyne cyclizations and controlled cross‐coupling of triple alkenes. The activation of alkenes by divalent selenides opens up a new avenue for supramolecular catalysis.

1,10‐Phenanthroline Copper(I) Complexes with A3 Coupling to Access Allenes for Cycloaddition Reactions

AbstractPropargylamines are significant building blocks for the generation of polyfunctional amino analogues, natural products, and pharmacologically active drugs. Herein we report the most straightforward approach is to use 1,10‐phenanthroline copper(I) complexes as a catalyst to promote the (Alkyne‐Alkyne‐Amine) A3 coupling reaction between cyclic secondary amines and two terminal alkynes that generates a ketimine intermediate in situ through hydroamination, which subsequently interacts with the alkenyl copper complex to produce tetrasubstituted propargylamine. In the addition of zinc halide, the propargylamines converted into trisubstituted allenes with up to 90% yield. When Sc(OTf)3 is used to perform the [4+2] cycloaddition reaction with enophile (alkene), the cyclized product obtained in up to 72% yield. On the other hand, the allene was subjected to a metal‐free intermolecular cyclization reaction to produce the highly substituted pyridine derivative, although this provides only up to 30% yield.

Two U(VI)-Containing Silicotungstates with Sandwich Structures: Lewis Acid-Base Synergistic Catalyzed Synthesis of Benzodiazepines and Pyrazoles.

Two new U(VI)-containing silicotungstates with similar sandwiched polyanions but different space structures, two-dimensional Na10.5H3.5(H2O)36[Na(UO2)(α-SiW9O34)]2·2.5H2O (1) and three-dimensional Na14(H2O)36[Na(UO2)(α-SiW9O34)]2·4H2O (2), have been synthesized by the reactions of UO2(OAc)2 and Na10[α-SiW9O34]·18H2O in aqueous solution at different pH values. Structure analyses demonstrated that different reaction conditions may provide different self-assembly conditions and result in the different coordination environments of Na(I)-H2O clusters with different disorders, which are the keys to the differences between 1 and 2. Compound 2 was demonstrated to show excellent catalytic activity for the synthesis of 3H-benzo[b][1,4]diazepines and pyrazoles via the intermolecular cyclization reactions, and the yields of the desired products reached 99%. This work illustrates the catalytic properties for U(VI)-containing POMs.

Synthesis of novel 2,5-bis(substituted thio)-1,3,4-thiadiazoles by acid catalyzed intermolecular cyclization reactions of substituted dithiocarbazates as a possible 2019-nCoV main protease inhibitor

A convenient and facile synthesis of a privileged pharmaceutical scaffolds, 2,5-bis(substituted thio)-1,3,4-thiadiazoles is accomplished. The reaction of hydrazine hydrate with carbon disulfide and substituted alkyl/aryl chloride in basic medium yielded S-substituted alkyl/aryl dithiocarbazates in high yield. These dithiocarbazates on reaction with tetrafluoro acetic acid underwent a unique acid catalyzed intermolecular cyclization reaction to afford a novel 2,5-bis(substituted thio)-1,3,4-thiadiazoles. A simple procedure and high yields are the characteristic features of these reactions. These compounds are characterized on the basis of physico-chemical and spectral (FT-IR, ESI Mass, 1H, 13C and DEPT 135° 13C {1H} NMR) studies. Compound 2b crystallizes in orthorhombic system with point group P bca. Using the DFT/B3LYP/6–311 G (d,p) level of theory, HOMO-LUMO energy gap and molecular electrostatic potential (MEP) analyses were carried out. The HOMO-LUMO energy gap allowed the calculation of chemical hardness, chemical inertness, electronegativity and the electrophilicity index of the molecule, which depicted their potential kinetic stability and reactivity. The molecular docking studies of 2b-2e with 2019-nCoV main protease(7BRO) revealed binding free energies of (ΔGb) = -6.22, -5.38, -4.43 and -4.25 kcal mol−1 respectively. Docking study revealed that the aromatic congeners exhibit appreciable therapeutic efficiency to be used as 2019-nCoV main protease inhibitors.

CBr4-Mediated Intermolecular Cyclization Reaction: Efficient Synthesis of Substituted N-Acylpyrazoles

CBr₄-Mediated Intermolecular Cyclization Reaction: Efficient Synthesis of Substituted <i>N</i>-Acylpyrazoles

I2‐Catalyzed Intermolecular Cyclization to Synthesis of 3‐Acylated Indolizines

AbstractIndolizine is one of the important nitrogen containing heterocycles due to their wide range of bioactivities. A convenient and efficient intermolecular cyclization reaction catalyzed by I2 was developed, affording 3‐acylated indolizines in good to excellent yields. 2‐Pyridylacetonitrile, 2‐pyridylacetone and 2‐pyridylacetamides were all compatible, and water was considered as the source of the carbonyl oxygen in the products. Furthermore, the conjugated enynenitriles were afforded from 2‐pyridylacetonitrile with ynals in high yields.

An Indirect Strategy for Trifluoromethylation via an Iridium Catalyst: Approach to Generate Isocoumarin Skeletons in Bioactive Molecules.

3-Bromo-1,1,1-trifluoroacetone was first disclosed as an effective indirect trifluoromethylation reagent to construct the important 3-trifluoromethyl isocoumarin skeleton. The reaction proceeds through a ligand-promoted, iridium-catalyzed ortho-selective C-H alkylation of benzoic acid and an intermolecular cyclization reaction promoted by silver acetate. A wide range of 3-trifluoromethyl isocoumarins can be easily obtained in moderate to good yields. Importantly, the isocoumarin skeleton can be easily formed in bioactive compounds, highlighting the importance of this reaction.

One-step 18F-fluorination of smart positron emission tomography tracer for sensing furin activity in tumors

IntroductionPeptide analogues have attracted considerable attention in the field of developing novel positron emission tomography (PET) imaging agents due to their unique properties. Nevertheless, the complicated radiolabeling process and fast metabolism usually pose challenges to the clinical applications of peptide-based molecular probes. Herein a novel PET tracer containing a specific peptide sequence Arg-Val-Arg-Arg (RVRR), Acetyl-Arg-Val-Arg-Arg-Cys(StBu)-Gly(AMB[18F]F3)-CBT ([18F]1), was designed and radiosynthesized using a simple and convenient one-step 18F-fluorination procedure. The smart tracer can be activated by the protease furin and then undergoes an intermolecular cyclization reaction in tumor cells, leading to improved PET imaging efficiency of tumor. MethodsThe radiosynthesis of the target tracer [18F]1 and the control tracer [18F]1-ctrl was performed under facile conditions in pyridazine-HCl buffer (pH~2.5) at 80 °C within 30 min. The enzyme-controlled condensation was studied for non-radioactive compound 1 in the human breast cancer cell lysates (MDA-MB-468). The cellular uptake of [18F]1 and [18F]1-ctrl was studied and compared by measuring the activity in MDA-MB-468 cells using a γ-counter after incubation with 37 kBq of [18F]1 or [18F]1-ctrl, respectively. In vivo behavior of [18F]1 was examined through PET imaging of MDA-MB-468 tumor-bearing mice and compared with that of [18F]1-ctrl as well as that of [18F]1 co-injected with non-radioactive compound 1. ResultsThe tracer [18F]1 was obtained with a high radiochemical yield (RCY) of 42.5 ± 1.47% and an excellent radiochemical purity (RCP > 99%). Under the activation of furin and GSH, the tracer suffered a condensation reaction to form dimers and then self-assembled into nanoparticles to produce enduring signal. The cellular uptake of [18F]1 and [18F]1-ctrl was determined to be 10.2 ± 0.37 and 1.19 ± 0.25%ID at 120 min, respectively. For in vivo PET imaging, [18F]1 exhibited the optimum tumor uptake of 2.39 ± 0.31%ID/g and the tumor-to-muscle uptake ratio of 2.93 ± 0.92 at 10 min post injection. Co-injection of [18F]1 and non-radioactive compound 1 produced a high tumor uptake ranging from 2.83 ± 0.23%ID/g to 3.40 ± 0.18%ID/g at 10 min and 60 min post injection, respectively. ConclusionsThe one-step labeling method of tracer [18F]1 showed advantage in simplifying the radiolabeling process with high RCY, which could enable a real kit process for the synthesis of 18F-radiopharmaceuticals and was significant for the large-scale production of tracers for clinical applications. PET imaging results suggested that the tracer [18F]1 had good tumor uptake and the co-injection strategy of [18F]1 with 1 could enhance the imaging signal in tumor.

Cu–N‐heterocyclic carbene‐catalysed synthesis of 2‐aryl‐3‐(arylethynyl)quinoxalines from one‐pot tandem coupling ofo‐phenylenediamines and terminal alkynes

A series of new benzimidazolium chlorides bearingN,N′‐benzyl, 2,4,6‐trimethylbenzyl and 2,4,6‐triisopropylbenzyl substituents have been designed and synthesized from variouso‐phenylenediamines. Subsequently, corresponding Cu‐basedN‐heterocyclic carbenes (NHCs) were generatedin situin the reaction medium which represents a new application of NHCs exploiting distinct catalytic property towards intermolecular cyclization reaction cascade for the synthesis of 2‐aryl‐3‐(arylethynyl)quinoxalines fromo‐phenylenediamines and terminal alkynes. The outcome of the cyclization reaction product depends upon theN,N′‐substituents present on the benzimidazolium chlorides.

Trans-Diastereoselective Syntheses of γ-Lactones by Visible Light-Iodine-Mediated Carboesterification of Alkenes.

This study aims to develop an intermolecular lactonization reaction of alkenes with carbonyls mediated by visible light and molecular iodine. The one-step reaction involved the carboesterification of alkenes to produce the corresponding lactones in moderate to good yield. It was also revealed that it is possible to control the diastereoselectivity of the reaction by altering the base used and the reaction conditions. When water was added as a solvent, the reaction resulted in the formation of lactones with trans-selectivity. A mechanistic investigation was undertaken and it was found that the reaction requires the generation of an iodine radical from molecular iodine, driven by visible light irradiation, and proceeds via the formation of an iodine radical alkene adduct. The proposed reaction is an example of a rare-metal free intermolecular addition cyclization reaction, which is an environment-friendly chemical process that only uses molecular iodine. In addition, since diastereoselectivity was observed without the use of any specific reagents, the developed methodology is an example of a novel stereoselective transformation using only cost-effective reagents.

Isocoumarins: General Aspects and Recent Advances in their Synthesis

AbstractBeing an important constituent of naturally occurring lactones with diverse biological activities and as a pivotal intermediate in heterocycle synthesis, the isocoumarin motif has claimed vast interest in synthetic and medicinal research. The methodologies for the synthesis of isocoumarins involve particularly metal‐catalyzed reactions as well as various intramolecular and intermolecular cyclization reactions. The transition metal complexes of palladium, copper, rhodium, ruthenium, iridium, nickel, zinc and silver are frequently used for the construction of this scaffold. Electrophilic cyclization, oxyboration, and iodocyclization reactions are also known to afford isocoumarins. This review article attempts to highlight the recent advances in their synthesis along with general aspects such as natural occurrence, biological activities, etc. of this particular heterocyclic scaffold.magnified image