Heterocyclic Motifs Research Articles

Cross-Coupling of Chloro(hetero)arenes with Thiolates Employing a Ni(0)-Precatalyst.

A general and efficient Ni-catalyzed coupling of challenging aryl chlorides and in situ generated aliphatic and aromatic thiolates is described. The employed on-cycle, air-stable defined Ni precatalysts allow for transformation of a broad scope of substrates. A variety of functional groups and heterocyclic motifs as well as structurally varied thiols are tolerated at unprecedented moderate catalyst loadings and reaction temperatures. Depending on reaction conditions, aryl thiols can selectively undergo C-S orC-C couplings.

A Review on Current Synthetic Strategies of Oxazines

In the past three decades, the heterocyclic oxazine cores have been intensely concerned. Oxazine derivatives are promising vital heterocyclic motifs. They are eminent for their synthetic potential and extensive biological properties. Oxazines are versatile intermediates for the synthesis of a variety of heterocycles and bifunctional compounds. Researchers have reported several synthetic approaches for the preparation of oxazines. This review emphasises the recent approaches for the synthesis of oxazine derivatives.

An Update of the Use of Thiocarbohydrazides and Thiosemicarbazides in the Preparation of Heterocycles and Their Biological Importance

The inherent reactivity of thiocarbohydrazides and thiosemicarbazides makes them valuable as building blocks for the synthesis of other heterocyclic motifs. This review article discusses the recent applications of classes of compounds in syntheses of five‐membered to seven‐membered heterocycles of biological activities and remarkable number of metal complexes. Many previous reviews dealt with the reactivity of either thiosemicarbazides or thiocarbohydrazides. However, a large number of publications have recently dealt with the reactivity of thiosemicarbazides and thiocarbohydrazides. Consequently, we have found that it is of importance to shed new light on these interesting molecules.

Recent Advances in the Organocatalytic Enantioselective Synthesis of Functionalized β-Lactones.

This Focus Review highlights recent developments in the organocatalytic enantioselective synthesis of β-lactone derivatives. Owing to the importance of β-lactones as a heterocyclic motif that is present in a variety of natural products and biologically active molecules, several catalytic methods have been developed for the synthesis of these compounds in their enantiomerically pure form. Organocatalytic methods that employ N-heterocyclic carbenes (NHCs), cinchona alkaloids, isothioureas, 4-dimethylaminopyridine (DMAP) derivatives, and phosphines have allowed the highly enantioselective synthesis of β-lactones from cheap and readily available starting materials. Moreover, the inherent strain in the four-membered ring of β-lactones has also been utilized in further synthetic transformations, thus making β-lactones a versatile intermediate in organic synthesis.

Simulation results source for the identification of biological active compounds: synthesis, antimicrobial evaluation and SARs of three in one heterocyclic motifs

For comprehensive studies on drugs primarily in the form of biomimetic systems, electronic parameters are becoming essential tools in elucidating the structures of the investigated compounds. In this study we present the synthesis, characterization, and evaluation of biological potency of 4(a–g), 5(a–g), and 7(a–g) by conducting structure–activity relationship (SAR) studies. Further conducting density functional theory (DFT) simulation studies for entitled compounds 4(a–g), 5(a–g), and 7(a–g) allowed us to fully study the effect of the changes of electronic and molecular structures on their biological activity by demonstrating the role of frontier molecular orbitals, in particular LUMO. The electron withdrawing nitro group substituted compounds 5d and 7d have higher activity than all other active compounds. Thus, the results strongly suggest that the SARs are in good agreement with simulation studies.

Recent Advances in the Regioselective Synthesis of Indoles via C–H Activation/Functionalization

Indole is an important heterocyclic motif that occurs ubiquitously in bioactive natural products and pharmaceuticals. Immense efforts have been devoted to the synthesis of indoles starting from the Fisher indole synthesis to the recently developed C–H activation/functionalization-based methods. Herein, we have reviewed the progress made on the regioselective synthesis of functionalized indoles, including 2-substituted, 3-substituted and 2,3-disusbstituted indoles, since the year 2010.1 Introduction2 Metal-Catalyzed Synthesis of 2-Substituted Indoles3 Metal-Catalyzed Synthesis of 3-Substituted Indoles4 Metal-Free Synthesis of 3-Substituted Indoles5 Metal-Catalyzed 2,3-Disubstituted Indole Synthesis5.1 Metal-Catalyzed Intramolecular 2,3-Disubstituted Indole Synthesis5.2 Metal-Catalyzed Intermolecular 2,3-Disubstituted Indole Synthesis6 Metal-Free 2,3-Disubstituted Indole Synthesis6.1 N-Protected 2,3-Disubstituted Indole Synthesis6.2 N-Unprotected 2,3-Disubstituted Indole Synthesis7 Applications8 Summary and Outlook

Alkaloid Synthesis via Gold‐Catalyzed Carbon‐Carbon Bond Formation Using Enamine‐type Nucleophile

AbstractIn this account, various types of cyclizations/cycloisomerizations of alkyne substrates with internal enamine‐type nucleophiles including enamide, enaminone, enaminoester and in situ generated enamine in the presence of electrophilc transition metal catalysts (Pt, Rh, Cu, Au) are firstly introduced. Then, the applications of the gold‐catalyzed reactions in the synthesis of an array of alkaloids are discussed. These natural products feature heterocyclic structural motifs such as pyridine, azaanthraquinone, pyridoacridine, pyrrole, indole, indolenine and carbazole, as well as chiral tetrahydroindolizine, azocine units and six‐membered carbocycles bearing a quaternary carbon center.

New Tacrines as Anti-Alzheimer's Disease Agents. The (Benzo)Chromeno- PyranoTacrines.

Tacrine was the first drug approved by FDA (US) for the treatment of Alzheimer's disease suffering patients. Nowadays, this agent has been withdrawn from the clinics due to secondary effects, which, most importantly, include hepatotoxicity. However, the research on new tacrine analogues devoid of these therapeutically undesirable effects, but benefiting of their high and well known positive cholinergic power, has produced a number of new non-hepatotoxic tacrines. In this context, our laboratory has recently prepared a new set of heterocyclic tacrines by changing the benzene ring present in tacrine by appropriate heterocyclic motifs. Based on this approach, in this review we summarize the results that we have found in the ChromenoPyranoTacrines, one of the families of tacrine analogues. This highlights their pharmacological profile, such as their cholinesterase inhibition power, calcium channel blockade, antioxidant capacity, Aβ-anti-aggregating, and neuroprotective properties. As a result of this work we have identified permeable, neuroprotective MTD tacrines racemic hit-tacrines 11-amino-12-(3,4,5-trimethoxyphenyl)-7,9,10,12-tetrahydro-8H-chromeno[2,3- b]quinolin-3-ol (6g) and 14-(3,4-dimethoxyphenyl)-9,11,12,14-tetrahydro-10H-benzo[5,6] chromeno [2,3-b] quinolin-13-amine (7i),devoid of toxic effects and showing potent anti-cholinesterasic properties, that deserve attention and further development in order to find new, and more efficient drugs, for AD therapy.

Flow Photo-Nazarov Reactions of 2-Furyl Vinyl Ketones: Cyclizing a Class of Traditionally Unreactive Heteroaromatic Enones.

Nazarov reactions of 2-furyl vinyl ketones and related heteroaromatic enones, to produce furan-fused cyclopentanones using a flow photochemical approach, are described. Compounds possessing this connectivity between heterocycle and ketone (2-furyl, 2-benzofuryl, 2-thiophene-yl, and 2-benzothiophene-yl) have traditionally proven difficult or impossible to cyclize with typical Brønsted and Lewis acid mediated methods. Using mild flow photochemistry conditions and acetic acid (AcOH) or hexafluoroisopropanol (HFIP) as solvent, these compounds were found to cyclize in 45-97% yields, with typical UV exposure times of 3.4-6.8 min. In all cases, 2-furyl and 2-thiophene-yl enones cyclized, whereas 2-benzofuryl and 2-benzothiophene-yl enones exhibited divergent properties with reactivity patterns tied to the identity of the vinyl group. This report discloses the first photo-Nazarov reactions of tetrahydropyridine-substituted 2-furyl ketones, providing a direct approach to the corresponding fused heterocyclic motifs built around a central cyclopentanone. These motifs constitute the core structures of biologically active natural products, including the marine alkaloid nakadomarin A.

Malononitrile dimer as a privileged reactant in design and skeletal diverse synthesis of heterocyclic motifs.

Malononitrile dimer as a precursor reactant has been extensively applied in the diversity-oriented synthesis of various heterocyclic motifs, bis-heterocyclic compounds, fused heterocycle derivatives, bicyclic bridged heterocyclic scaffolds, and highly substituted carbocyclic compounds. These remarkable products were synthesized via various types of reactions, such as cycloaddition, cyclocondensation, cascade/domino/tandem reactions along with multi-component reactions. In addition, the flexibility and high reactivity of malononitrile dimer as a multi-functional reagent and its potential to the preparation of novel beneficial scaffolds as well as biologically active molecules signify it as a suitable building block in total synthesis, medicinal chemistry, and dyes. In the present review, the advances in the chemistry of malononitrile dimer as a potent reagent in organic synthesis have been reported in the past to now.

Enantioselective 1,4-Michael addition reaction of pyrazolin-5-one derivatives with 2-enoylpyridines catalyzed by Cinchona derived squaramides.

The bifunctional nature of the cinchonidine squaramides has been successfully employed to catalyze the enantioselective 1,4-Michael addition reaction of pyrazolin-5-ones with 2-enoylpyridines under mild reaction conditions. Through this methodology, a broad range of optically active heterocyclic derivatives bearing both pyrazole and pyridine motifs have been synthesized in yields up to 88% and enantiomeric excess up to 96%.

A lesson for site-selective C-H functionalization on 2-pyridones: radical, organometallic, directing group and steric controls.

A 2-pyridone ring is a frequently occurring subunit in natural products, biologically active compounds, and pharmaceutical targets. Thus, the selective synthesis of substituted 2-pyridone derivatives through decoration and/or formation of pyridone rings has been one of the important longstanding subjects in organic synthetic chemistry. This minireview focuses on recent advances in site-selective C-H functionalization on 2-pyridone. The reported procedures are categorized according to the site selectivity that is achieved, and the substrate scope, limitations, mechanism, and controlling factors are briefly summarized.

Dendritic Polynitrato Energetic Motifs: Development and Exploration of Physicochemical Behavior through Theoretical and Experimental Approach.

Considering the fundamental and most desirable characteristics of energetic materials, a series of 1,2,3-triazole-based heterocyclic energetic motifs nicely tuned with nitrato (−ONO2) functionality were synthesized by a microwave-assisted environmental friendly synthetic approach with good yields. Thermal stability and the nature of evolved gases on decomposition of structurally characterized energetic motifs were analyzed by thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) analysis and Fourier transform infrared coupled with TGA–DSC. The explosiveness of these motifs was explored by calculation of enthalpy of formation and density employing density functional theory, and the detonation performances (detonation pressure and velocity) were explored using EXPLO5_V6.03. All of these compounds were calculated to have better oxygen balance (−36 to −52%) as compared to that of trinitrotoluene (−74%). Most of the nitrate ester derivatives were found to exhibit low impact sensitivities, high densities, good thermal stabilities, and promising detonation properties, and PN3 was observed to be a superior candidate in terms of its energetic characteristics. Hence, the experimental and theoretical outcomes strongly reflect that the present approach of developing dendritic high energetic materials bearing green explosive characteristics might be a potential pathway for designing and synthesizing green explosives with desired characteristics.

Ionic liquid mediated stereoselective synthesis of alanine linked hybrid quinazoline-4(3H)-one derivatives perturbing the malarial reductase activity in folate pathway

Grimmel’s method was optimized as well as modified leading to the cyclization and incorporation of alanine linked sulphonamide in 4-quinazolin-(3H)-ones. Further, the generation of heterocyclic motif at position-3 of 4-quinazolinones was explored by synthesis of imines, which unfortunately led to an isomeric mixture of stereoisomers. The hurdle of diastereomers encountered on the path was eminently rectified by development of new rapid and reproducible methodology involving the use of imidazolium based ionic liquid as solvents as well as catalyst for cyclization as well as synthesis of imines in situ at position-3 leading to procurement of single E-isomer as the target hybrid heterocyclic molecules. The purity and presence of single isomer was also confirmed by HPLC and spectroscopic techniques. Further, the synthesized sulphonamide linked 4-quinazolin-(3H)-ones hybrids were screened for their antimalarial potency rendering potent entities (4b, 4c, 4 l, 4 t and 4u). The active hybrids were progressively screened for enzyme inhibitory efficacy against presumed receptor Pf-DHFR and h-DHFR computationally as well as in vitro, proving their potency as dihydrofolate reductase inhibitors. The ADME properties of these active molecules were also predicted to enhance the knowhow of the oral bioavailability, indicating good bioavailability of the active entities.

Intermolecular Regio- and Stereoselective Sulfenoamination of Alkenes with Thioimidazoles.

An intermolecular sulfenoamination reaction utilizing a stable sulfur precursor with a broad range of alkene structures is described. More importantly, these reactions proceed in a highly regio- and stereoselective manner to afford interesting heterocyclic motifs ready for biological studies. In addition, a highly regiodivergent approach to access the opposite regioisomers for styrene derivatives was also developed.

CuBr2-catalyzed alkylation of furans with benzyl alcohols and benzaldehydes. Domino reactions including this alkylation as a key step

A CuBr2-catalyzed alkylation of furans with a broad scope of benzyl alcohols and benzaldehydes is reported. Reaction proceeds efficiently under mild reaction conditions requiring no inert atmosphere or other precautions. Moreover, it is shown that CuBr2 catalyzes domino reactions of furans with benzyl alcohols or benzaldehydes bearing a nucleophilic moiety in the ortho-position. These protocols offer a practical approach to densely substituted heterocyclic motifs from easily available furans.

The palladium‐catalyzed C‐N cross‐coupling reaction of diheteroaryl disulfides with heterocyclic amines

The Pd‐catalyzed cross‐coupling reaction of 1, 2‐di(pyrimidin‐2‐yl) disulfides with heterocyclic amines including 2‐amino pyrimidines and 1,3,4‐thiadiazol‐2‐amines to deliver symmetrical C‐N coupling products in moderate to good yields is reported. This method provides an opportunity for synthesis of bioactive molecules and pharmaceutically interesting compounds containing heterocycle motifs. The reported protocol shows good functional group compatibility, and provides a new strategy for preparation of C2‐amination pyrimidine derivatives from heterocyclic disulfides.

Rhodium(III)‐Catalyzed C−H Activation of O‐Acetyl Ketoximes/N‐Methoxybenzamides toward the Synthesis of Isoquinoline/Isoquinolone‐Fused Bicycles

AbstractAn efficient rhodium(III)‐catalyzed C−H activation approach for the construction of fused heterocyclic motifs with urea‐derived bicyclic olefins has been demonstrated. A rhodium‐catalyzed reaction of O‐acetyl ketoximes with these bicyclic motifs furnished isoquinoline derivatives, whereas isoquinolone‐fused bicyclic olefins were obtained with the reaction of N‐methoxybenzamides.

Palladium-Catalyzed Copper-Free Sonogashira Coupling of 2-Bromoarylcarbonyls: Synthesis of Isobenzofurans via One-Pot Reductive Cyclization

Palladium-catalyzed copper-free Sonogashira coupling of 2-bromocarbonyls is presented. This method afforded the 2-alkynylaryl carbonyls, useful synthons for the accomplishment of many carbocyclic and heterocyclic motifs. Significantly, the strategy was extended to the one-pot synthesis of isobenzofurans via reduction followed by intramolecular 5-exo-dig cyclization.

Ruthenium/Iridium-Catalyzed C-2 Activation of Indoles with Bicyclic Olefins: An Easy Access to Functionalized Heterocyclic Motifs

Selective C-2 functionalization of N-protected and free indoles is reported. The ruthenium-catalyzed C-2 activation of indoles provided an easy access to cyclopentenylated indoles. Hydroheteroarylated bicyclic motifs were synthesized via iridium-catalyzed C-2 activation of NH indoles. The methodology was extended to different bicyclic adducts such as diaza- or urea-derived bicyclic olefins.