Heterocyclic Synthesis

Imidazole is a five-membered planar ring that is solvable in water and other polar diluents. In the arena of five membered heterocyclic structures, the imidazole nucleus exhibits a range of properties. Favoured structures have been identified and nitrogen-including heterocyclic structures have been connected to a wide range of biological activities. Imidazole is an entity that has been synthesised in many of its derivative forms over the last few years; the entity has piqued the curiosity of numerous medicinal chemists who want to investigate its many pharmacological potentials. The chemistry of imidazole and its synthetic derivatives is reviewed in this article. A review of the literature on several research papers and other publications that give thorough information on the chemistry of imidazole. As a result, the goal of this article is to examine published research on the introduction, chemistry, synthesis, properties, industrial, biological and medicinal applications with efficacy of imidazole derivatives in order to better understand and explore their various properties and pharmacological potentials.

Acylation of nitronates affords α-acyloxyoxime derivatives via an umpolung functionalization of the α-position. This transformation involves generation of hitherto unknown N-acyloxy, N-oxyenamines and their fast [3,3]-sigmatropic rearrangement driven by the cleavage of the weak N-O bond. The reaction has a broad scope, and it is regioselective in the case of nitronates possessing nonsymmetrically substituted α-positions. Application to the formal total synthesis of clausenamide and cis-clausenamide is presented.

Growing environmental concerns have compelled chemists to develop environmentally benign synthetic strategies called Green Chemistry. There are many ways to achieve the goals of Green Chemistry, one of which is Ultra Sound assisted reactions. Azolopyrimidines have attracted the attention of synthetic organic chemists due to their potent biological properties. Herein, we present a review on the synthesis of Azolopyrimidines under the influence of Ultra Sound reported during the last two decades.

3-Aminopyrazoles required for the synthesis of pyrazolo[1,5-a]pyrimidines were obtained by the reaction of enaminonitriles with hydrazine hydrate. The resulting aminopyrazoles are reacted with formylated acetophenones under reflux at 60 • C assisted by KHSO 4 in aqueous media to form regioselectively 3,7-diarylpyrazolo[1,5-a]pyrimidines and 3,6-diarylpyrazolo[1,5-a]pyrimidine-7-amines. X-ray crystallography of selected compounds 5b and 7i further confirmed the regioselective formation of these products.

Acylation of nitronates affords α-acyloxyoxime derivatives via an umpolung functionalization of the α-position. This transformation involves generation of hitherto unknown Nacyloxy,N-oxyenamines and their fast [3,3]-sigmatropic rearrangement driven by the cleavage of the weak N−O bond. The reaction has a broad scope, and it is regioselective in the case of nitronates possessing nonsymmetrically substituted α-positions. Application to the formal total synthesis of clausenamide and cis-clausenamide is presented.

This study examines the synthesis, characterization, computational analysis, and antibacterial activity of chromium (III) complexes with pyrazolone phenylhydrazone ligands. The ligands and their chromium (III) complexes have been synthesized and confirmed using various analytical techniques such as 1 H and 13 C NMR, mass spectrometry, elemental analysis, infrared spectroscopy, and UV-visible spectroscopy. The characterization of chromium (III) complexes involves elemental analysis, thermogravimetric analysis (TGA/DTG), differential scanning calorimetry (DSC), FAB mass spectrometry, and UV-visible spectroscopy, which validated their structures and properties. Additionally, the electronic properties and reactivity of the ligands and complexes have been investigated using DFT with the B3LYP/6-31G(d, p) basis set. The antimicrobial efficacy of the ligands and complexes have been tested against Gram-positive and Gram-negative bacteria, revealing significant antibacterial potential. These findings highlight the importance of pyrazolone phenylhydrazone-based chromium (III) complexes and suggest further exploration of their antimicrobial properties.

Reaction of six-membered cyclic nitronates with disubstituted ketenes affords hitherto unknown saturated oxazolo[3,2-b][1,2]oxazines possessing up to four contiguous stereogenic centers. The process involves a tandem of [3+2]-cycloaddition across the CO bond of ketene, followed by a spontaneous [1,3]-rearrangement of transient vinylidene-substituted bicyclic nitrosoacetals. DFT calculations of the mechanism suggest that the [1,3]-O,C-shift proceeds through a recyclization of a biradical intermediate formed by an unusually mild homolytic cleavage of the N−O bond. The resulting products can be utilized as precursors of other fused 1,2-oxazines derivatives, in particular 1,2-oxazino-1,2,4-triazin-3-ones.

Cyclic boronate esters play important roles in organic synthesis, pharmacology, supramolecular chemistry and materials science owing to their stability in air and versatile reactivity. Most of these compounds contain a B-O-C linkage with an alkoxy-or carboxylate group bound to the boron atom (e.g. boronate-diol esters, MIDA boronates). Boron chelates comprising a B-ON motif (BON heterocycles) are much less explored, although first representatives of this class were prepared in the early 1960s. In recent years, there has been a growing interest in BON heterocycles as new chemotypes for drug design. The exocyclic B-ON linkage, which is readily formed under mild conditions, shows surprising hydrolytic and thermal resistance. This allows the formation of BON heterocycles to be used as click-type reactions for the preparation of bioconjugates and functionally modified polymers. We believe that BON heterocycles are promising yet underrated organoboron derivatives. This review summarizes the scattered information about known types of BON heterocycles, including their synthesis, reactivity and structural data. Available applications of BON heterocycles in materials science and medicinal chemistry, along with their prospects, are also discussed. The bibliography contains 289 references.

The silver(I)-catalyzed reaction of ortho-alkynylbenzaldoximes with propargylic alcohols represents a new strategy for the divergent one-pot synthesis of 2-(isoquinolin-1-yl) prop-2-en-1-ones via tandem 6-endo-cyclization, 1,3-dipolar cycloaddition, and intramolecular dehydrative opening of the 2,3-dihydroisoxazole ring. This synthetic protocol tolerates a wide variety of ortho-alkynylbenzaldoximes and propargylic alcohols and affords the corresponding products in excellent yields.

General experimental details. p. S2 Synthesis of 2-(tosylamino)ethyl tosylate. p. S3 Synthesis of 1-tosylaziridine. p. S3 Synthesis of 1,7-ditosyl-4-benzyl-1,4,7-triazaheptane. p. S4 Synthesis of 2,6-bis(methanesulfonyloxymethyl)pyridine. p. S4 Synthesis of 6-benzyl-3,9-ditosyl-3,6,9,15-tetraaza-bicyclo[9,3,1]pentadeca-1(15),11,13triene 1. p. S5 General procedure for the synthesis of silver complexes 2 a-c. p. S5 General Procedure for the synthesis of 2-alkynylbenzaldehydes 3 a-e. p. S7 Synthesis of 2-(4-hydroxybut-1-ynyl)benzaldehyde 3f. p. S7 General procedure for the synthesis of 1-alkoxyisochromenes 4 a-l. p. S8 Synthesis of 1-(dimethoxymethyl)-2-((4-methoxyphenyl)ethynyl)benzene 5a. p. S13 Reaction of acetal 5a with the catalyst 2a. p. S14 Stability experiments of isochromene 4a: under acidic conditions. p. S14 Stability experiments of isochromene 4a: under alkaline conditions. p. S14 Trapping experiment: synthesis of isochromene 4m. p. S15 PART II 1 H and 13 C NMR spectra of 1,7-ditosyl-4-benzyl-1,4,7-triazaheptane. p. S16 1 H and 13 C NMR spectra of ligand 1 and complex 2a-c. p. S17 Superimposed UV spectra of ligand 1 and Ag complexes 2a and 2b. p. S20 1 H NMR spectra of aldehydes 3a-f. p. S22 1 H NMR spectrum of reaction of 3a in methanol (Table 1 entry 1). p. S25 1 H and 13 C NMR spectra of isochromenes 4 a-l. p. S25 1 H NMR spectrum of isochromene 4m. p. S39 1 H NMR spectra of reaction crudes of stability experiments on isochromene 4a. p. S39 1 H NMR spectra of acetal 5a. p. S40 1 H NMR spectra of the crude of the reaction of acetal 5a with the catalyst 2a. p. S41 References. p. S41

A series of novel Azetidinone derivatives have been synthesized from the intermediate schiff bases. Schiff bases are prepared from sulfamethoxazole moiety by reacting the hydrazide of the parent compound with different aromatic aldehydes. Cyclocondensation of schiff's bases with acetylchloride resulted in the formation of azetidinone derivatives. The products, characterized on the basis of satisfactory spectral data (IR, NMR, Mass spectroscopy), have shown moderate to good antimicrobial activity against some bacteria and fungi.

Iminosugars have been shown to be very potent inhibitors of glycosidases and glycolsyltransferases. Due to their ability to resemble the transition states of the sugars involved in these processes, a variety of monocyclic and bicyclic iminosugars have been synthesized or isolated from natural sources over the years. As part of our ongoing work on the preparation of glycosidase inhibitors, we developed stereoselective methods for synthesizing iminosugars from 2,3-epoxyamides obtained from monosaccharides. Now, we are interested in the syntheses of novel bicyclic triazoles 1, by intramolecular cycloaddition, due to the possibility of combining azido group and unsaturated esters in the same molecule. The triazole system is broadly considered in syntheses of bioactive products and the option of fused iminosugar with triazole has been evaluated. Firstly, we started with a less complex azido derivative 2a to continue with azido compounds 2b obtained from our 2,3-epoxyamides 3, by regiosel...

Novel peptidomimetics containing a pyrrolone fragment were synthesized by a tandem combination of Doebner and Ugi-type multicomponent reactions with controlled diastereoselectivity. This approach represents a convenient synthesis in the temperature range from 25 °C to 45 °C. In most cases, the new method allowed each diastereomer to be isolated separately.

Dichloro-6-phenyl-2(H)-1,4-oxazin-2-one 3, 5-chloro-3,6-dimethyl-2(H)-1,4-oxazin-2-one 4, 5-chloro-6-methyl-3phenyl-2(H)-1,4-oxazin-2-one 5 and 5-chloro-3,6-diphenyl-2(H)-1,4-oxazin-2-one 7, are ambident azadienes reacting efficiently and selectively with both electron rich and electron poor dienophiles.

An e cient and mild condensation reaction of 6-aminouracil derivatives with various aromatic aldehydes and ethyl or methyl acetoacetate was performed in the presence of catalytic amounts of H 14 [NaP 5 W 30 O 110 ]/SiO 2 as a recyclable, eco-friendly, and green nano-catalyst to a ord the desired pyrido[2,3-d]pyrimidine derivatives in good to excellent yields.

Alkynoic acids have been widely employed as alkyne and alkene sources in decarboxylative reactions. Alkynoic acid coupling leads to the formation of direct coupling products and cyclized products through sequential reactions. Moreover, homocoupling and multicomponent reactions have been developed. The decarboxylative addition of alkynoic acids generates the corresponding alkene products. A number of synthetic methods are utilized for the preparation of arylpropynoic acids including the Sonogashira coupling and the carboxylation of terminal alkynes. Recently, the use of decarboxylative halogenations has also been reported. This review covers decarboxylative reactions of alkynoic acids reported between 2013 and 2019; further, it is divided into several sections according to the type of reaction.1 Introduction2 Direct Coupling3 Sequential Reactions4 Homocoupling5 Multicomponent Reactions6 Addition7 Halogenations8 Synthesis of Alkynoic Acids9 Conclusion

The first enamine mediated anti-selective and highly enantioselective Mannich reaction of aldehydes and unactivated imines is reported. The key for success is the combined use of a Brønsted acid with an a,a-dialkylprolinol ether catalyst that leads to adducts with good yields (typically 70-75%), anti : syn ratios greater than 90 : 10, and ee values usually above 95%. The method works particularly well with propargylic imines and, unlike previous catalytic routes to optically active propargylamines, provides adducts featuring two contiguous stereocenters and a functionalized side chain amenable for ulterior synthetic applications.

A series of substituted pyrazoline (9a-j) analogues were synthesized via 1,3-dipolar cycloaddition of substituted 2-benzylidene-1phenylhydrazine (8a-d) with 5-(3-phenylacryloyl)2-hydroxybenzoic acid (5a-f) and the synthesized compounds were characterized by Infrared (IR), Proton Nuclear Magnetic Resonance (1 H-NMR), Carbon-13 Nuclear Magnetic Resonance (13 C-NMR) and mass spectral techniques. The antimicrobial activity of all the synthesized compounds were screened for both Gram-positive and Gram-negative bacteria along with a fungal strain and the Minimum Inhibitory Concentration (MIC) was calculated. The toxicity of the compounds on human cells were determined by haemolytic activity. The mechanism of action of antimicrobial activity of the synthesized compounds was evaluated by membrane permeabilization assay and confirmed by scanning electron microscopy. Among the synthesized compounds, compounds 9b, 9f and 9g showed strong plasma membrane-permeabilizing activity, further the membrane disruption was confirmed by large dents as observed in E. coli cells under scanning electron microscopy.

The solubilization of 4,10-dihydrothieno[3¢,2¢:5,6]pyrimido[2,1-a]isoindol-4-ones by b-cyclodextrin by two routes-solvatofluorochromic and extraction methods was studied. The solvatofluorochromic investigations showed that the changes occurred in the medium's polarity do not influence onto the fluorescent characteristics of these compounds. However, using extraction method their solubilization by b-cyclodextrin was observed.

Aziridines are known to undergo hydrolysis in the presence of cyclodextrins, whereas the latter are largely investigated as potential vectors of biologically active compounds. Despite this easy cyclodextrininduced cleavage of aziridines in aqueous medium, it was of interest to find out a model aziridine derivative that would be sufficiently water-stable and form a stable complex with -cyclodextrin in aqueous medium, so that it could be used as a reference in future formulations or vectorization work. Among compounds we have investigated, we found out that only (S)-2-isopropyl-1-(o-nitrophenyl)sulfonyl)aziridine complied with the above-mentioned solubility and stability requirements. NMR studies of the inclusion complex of this derivative with -cyclodextrin provided useful parameters related to the stoichiometry of the complex and the association constant Ka. The geometry of the complex was assessed by 2D-ROESY experiments, suggesting a deep insertion of the aziridine into the cavity of -cyclodextrin.

An exclusive regioselective formation of 2-thiomethyl ether substituted isomer of the privileged nucleus of 1,5-benzodiazepines was achieved from the reaction of p-nitro-o-phenylenediamine with a variety of α-oxoketene dithioacetals derived from several active methylene compounds, by exploiting the strategy based on the variation of electrophilicity of the two electrophilic centers of α-oxoketene dithioacetals and the hard and soft nucleophilic profiles of the p-nitro substituted o-phenylenediamines.

The cascade hetorocyclizations involving α-aminoazoles and carbonyl compounds is a simple and efficient way for the construction of different five-and six-membered heterocycles. Among them, there are aza-Diels-Alder, 1-4 Biginelli, 4,5 Doebner, Povarov reactions, 6,7 etc. 4 The most well-studied amines in such heterocyclizations are different 3(5)-aminopyrazoles, 2-aminobenzimidazoles, 3-amino-1,2,4-triazoles, and 5-aminotetrazoles. 8-13 However, the α-aminoazoles based on isoxazole moiety had not been well studied in such reactions before our research: 14-18 there are significantly fewer publications devoted to the treatments of 5-amino-3-methylisoxazole 1,19-27 and 3-amino-5-methylisoxazole 6,28-33 in one-pot reactions. Concerning 5-amino-3-methylisoxazole, it was shown that its two-and multicomponent heterocyclizations in the most cases led to isoxazolopyridines (Fig. 1). It was found by our group that 5-amino-3-methylisoxazole was not stable in two-and multicomponent reactions with pyruvic acid and its arylidene derivatives while two-component condensations with ethyl 4-aryl-2-oxobut-3-enoate in the presence of Sc(OTf) 3 gave not only isoxazolo[5,4-b]pyridines I, but also both di-and tetrahydropyridines II and III. 18 Thus, 5-amino-3-methylisoxazole usually reacts as 1,3-binucleophile involving exocyclic amino group and position C-4 in the isoxazole moiety as reaction centers. It is also

The comprehensive review contains the analysis of literature data concerning reactions of heterocyclization of aminoazoles and demonstrates the application of these types of transformations in diversity-oriented synthesis. The review is oriented to wide range of chemists working in the field of organic synthesis and both experimental and theoretical studies of nitrogen-containing heterocycles.

Heterocyclic ring systems are gaining attention due to their pivotal role in drug design and medicinal chemistry. Quinazolines are nitrogen-containing heterocyclic pharmacophoric units found in abundance in natural and pharmaceutical products. Imidazoquinazolines and benzimidazoquinazolines are fused tricyclic and tetracyclic heterocyclic moieties, respectively. Different isomeric forms of imidazoquinazolines and benzimidazoquinazolines exhibited a plethora of biological applications such as antitumor, antimicrobial, antioxidant, anti-inflammatory, antitubercular, anticancer, antihypertensive, anticonvulsant, antiviral, antimalarial, antiapoptotic, anti-proliferative activities, etc. This chapter addressed the recent synthetic strategies for medicinally privileged scaffolds; imidazoquinazolines and benzimidazoquinazolines. The synthetic routes of various isomeric forms of above-mentioned heterocycles have also been discussed.

Derivatives of ninhydrin are extensively used in the field of forensic sciences as important latent fingerprint reagents. Many works have been performed upon their synthesis and reactivity, but there are many spaces to work on the compounds of quinoline‐2,3,4(1H)‐triones—analogues of ninhydrin, in both dimensions: synthesis and reactivity, and according to the best of our knowledge, not a single detailed or short compiled article has been published for these compounds. This review briefly summarizes the chemistry of quinoline‐2,3,4(1H)‐triones.

According to 1 Н and 13 С NMR data, enamines of 3 formyl 4 hydroxycoumarin exist in the keto enamine tautomeric form and undergo Z/E isomerization around the C=C bond in CDCl 3 , DMSO d 6 , and CD 3 OD at room temperature. The activation energies of Е/Z isomer ization were measured experimentally and calculated by the B3LYP/6 311++G(d,p) method. An X ray diffraction study showed that 3 (benzyliminomethyl)chromane 2,4 dione in the crystalline state exists as a mixture of two keto enamine isomers.

Synthesis of functionalized spirooxindoles have been reviewed and it has been proposed that the unique core ring system that is common to this family of compounds arises by a biological Knoevengal-Michael-Domino cyclization along with the attachment of hydrophobic alkyl chain linkage. These newly synthesized compounds have been also tested for their in vitro antibacterial activities against some bacterial strains viz. Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli and Pseudomonas aeruginosa.

The rate of an ene reaction between cycloheptatriene and trans-diethylazodicarboxylate in 1,2dichloroethane was studied at various pressures and temperatures. The results obtained were compared with kinetic parameters of some other reactions.

The structure of bis(N,N,N¢,N¢-tetramethylthiophosphoramidoyl)-methylamine 1 has been determined by single-crystal X-ray diffraction. The compound 1 crystallizes in the monoclinic system, with a space group P2 1 /c, a = 11.836(2) Å , b = 11.659(2) Å , c = 12.796(5) Å and b = 95.28(3)°, V = 1758.3(5) Å 3 and Z = 4. The X-ray crystallographic data have been assessed by semi-empirical and ab-initio density functional theory and by Hartree-Fock molecular orbital methods. A comparative study of the results of the different methods is given. Keywords bis(N,N,N¢,N¢-tetramethylthiophosphoramidoyl)methylamine Á X-ray structure determination Á Ab-initio calculations Á B3LYP Á Hartree-Fock Á MNDO Á AM1 and PM3 semi-empirical methods Scheme 1

Herein, we report series of isatin-based oxo-spiro chromene Schiff's bases, synthesized by condensing 2,7-diamino-2'-oxospiro[chromene-4,3'-indoline]-3-carbonitrile with aromatic aldehydes using efficient acid catalyst, silica sulfuric acid (SSA). Spectroscopic techniques have corroborated the formation of desired products. Derivatives were screened in vitro for antibacterial and anticancer activities. Molecular docking was also performed to predict the possible mode of action of these derivatives.

The current review covers explosive development of various synthetic approaches for piperidine scaffold and its analogues in the last few decades. The piperidine ring system is a key motif in many natural alkaloids and synthetic organic compounds. Further, piperidine moiety has gained significant consideration in drug discovery due to its wide range of therapeutic applications.

A protocol for the synthesis of some 4-Aryl-1,3,4,6,7,8-hexahydroquinazolin-2,5(1H,6H)-diones (HHQs) was developed by means of a three-component condensation reaction of an aromatic aldehyde, 1,3-cylohexadione and urea in the presence of K 3 AlF 6 (Al 2 O 3 /KF) as catalyst. This reaction is carried out under different conditions including 1) solvent free; 2) reflux in acetonitrile; 3) reflux in ethanol; 4) reflux in chloroform; and 5) reflux in water. In all conditions, the desired products are obtained in high yields after relatively short reaction times. Nevertheless, the reactions proceed faster and in higher yields when they were carried out in acetonitrile. This adopted protocol for some Biginelli-type products has offered the advantages of reusability of the catalyst, high yields and ease of separation of pure products. Furthermore, the catalyst is easily prepared, stabilized and efficiently used under reaction conditions.

h i g h l i g h t s " 2H-indazol [2,1-b]phthalazine-triones synthesized using nano-alumina sulforic acid. " The protocol extended for 1H-pyrazolo[1,2-b]phthalazine-diones synthesis. " The nature of each step of suggested mechanism investigated. " Theoretical spectra and structural analysis performed for synthesized compounds.

A series of new (N'-substituted)-hydrazo-4-aryl-1,4-dihydropyridines was successfully synthesized via a facile one-pot catalytic pathway utilizing azines and propiolate esters as starting materials and a 1D copper benzotriazole-based coordination polymer as catalyst. In the absence of catalyst, the corresponding 5substituted 4,5-dihydropyrazoles were formed in moderate to high yields. Fine-tuning of the catalysts allowed us to gain more insights regarding the plausible reaction mechanism.

In the reactions of 2,3-pyrazinedicarboxylic anhydride with amines and anilines, pyrazine carboxamides are formed in good to excellent yields. A mechanism is proposed involving ring opening of the anhydride and decarboxylation of the heterocyclic ring. Based on other similar heterocyclic decarboxylations, this suggests the involvement of an N-heterocyclic carbene intermediate leading to the product.

A novel nanomagnetic catalyst with Cl[DABCO-NOR 2 R]C(NOR 2 R)R 3 R tags was designed, synthesized and fully characterized by several identical techniques such as Fourier transform spectroscopy infrared (FT-IR), Energy-dispersive X-ray spectroscopy (EDX), elemental mapping analysis, thermal gravimetry analysis (TG), derivative thermal gravimetric (DTG), powder X-ray diffraction patterns (XRD), Field scanning electron microscopy (FESEM), high resolution transmission electron microscopy (HRTEM), physical adsorption and physisorption of NR 2 R isotherms (BET) and vibrating sample magnetometer (VSM). The mentioned nano-magnetic