Palladium‐Catalyzed ortho ‐C–H Alkylation of Benzamides With α ‐Bromo Ketones Accessing 2‐(2‐Oxo‐2‐phenylethyl)benzamides and Their Anti‐Inflammatory Activity

Background and objective: Hyperlipidemia refers to elevated levels of lipids and cholesterol in the blood, and is also identified as dyslipidemia, to describe the manifestations of different disorders of lipoprotein metabolism. The aim of this study was to investigate the available and commonly distracted natural and synthetic antihyperlipidemic agents in herbal shops, pharmacies and prescribed by physicians in Erbil city, and to determine physicians' response for the use of natural products. Methods: Between November 2013 to February 2014; 20 herbal shops and 40 pharmacies in Erbil city were visited randomly for asking on available and most commonly distracted natural and synthetic antihyperlipidemic agents. Forty doctors at private clinics were asked about the most frequently prescribed natural and synthetic antihyperlipidemic agents in Erbil city. Results: Of eight synthetic drugs available in pharmacies, statins were considered the first line agents as antihyperlipidemic drugs particularly atorvastatin and rosuvastatin. Of 16 natural products available in Erbil herbal shops and pharmacies, garlic and omega 3 give positive response by patients and highly distracted by pharmacist and herbalist. Of 40 physicians, 27 (68%) prescribe both natural and synthetic agents while only 13 (32%) prescribe synthetic drugs as antihyperlipidemic agents for patients. Conclusion: Statins used in first order as antihyperlipidemic drugs and uses of natural products, as lipid lowering agents in Erbil, is getting larger interest by people, herbalists, pharmacists and doctors. Of 40 doctors, 68% prescribe natural products along with synthetic drugs but also there is a need to educate the people on how to use these natural agents and choice suitable products for them.

The 2-Aminonicotinonitrile derivative was reacted with different bi-functional reagents such as formamide, thiourea, acetic anhydride, and phthalic anhydride under optimized conditions to give pyrimidine, thiourea, acetamide, and isoindoline derivatives, respectively, When it was treated with active methylene reagents as malononitrile, phenacyl bromide, and ethyl bromoacetate under varied experimental modulation, it afforded 1, 8-naphthyridine, ethyl, and methylamino nicotinonitrile derivatives, respectively. Also, it was reacted with p-toluene sulfonyl chloride, chloroacetyl chloride, and benzoyl chloride to give sulfonamide, 2-chloro-N-acetamide, and benzamide derivatives, respectively. Likewise, it was reacted with diethyl malonate, ethyl cyanoacetate, and cyano acetic acid to give ethylpropanoate, naphthyridine, and cyano acetamide derivatives, respectively. However, treatment of ethylpropanoate and cyano acetamide derivatives with hydrazine hydrate gave pyrazole and 5-amino-pyrazole nicotinonitrile derivatives, respectively. In addition, it was reacted with p-anisaldehyde, phenyl isocyanate, and triethyl orthoformate to give benzylamino nicotinonitrile, phenyl urea, and N-formamide derivatives, respectively. Furthermore, it was reacted with nitrous acid then coupled with aniline; it was also reacted with isatine and 1,3- dibromo propane to give oxoindoline derivative, and the dimer. Elemental analyses, together with spectroscopic data including IR, 1H-NMR in addition to 13C-NMR and mass spectra submit proofs for the chemical structures for all compounds.

Hip to be square: A strategy for assembling tetrasubstituted cyclobutanes is reported in the context of a short, protecting-group-free synthesis of the proposed structure of pipercyclobutanamide A. The route features sequential CH functionalizations on an unactivated cyclobutane wherein CC bonds to aryl and styryl groups are made one by one in a stereocontrolled fashion. DG=directing group. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

The intermolecular dehydrogenative amidation of various arenes via C—H bond activation assisted by a 2‐pyridyl or 1‐pyrazolyl chelating group using air as the terminal oxidant is achieved using N‐aryl amides, N‐alkyl amides, benzamide derivative, imides, and lactams as coupling partners.

Metal nitride clusterfullerenes (NCFs) have significant applications in molecular electronics, biomedical imaging, and nonlinear optical devices due to their unique structures. However, their wide applications are limited by the production quantity. In this work, the yields of metal nitride clusterfullerenes M3N@C80 (M=Y, Sc, Gd) were greatly enhanced by utilizing zirconium nitride (ZrN) as an efficient nitrogen source for the arc-discharge method. Compared with the traditional synthetic route using N2 gas as nitrogen source, the ZrN inside graphite tube can be vaporized simultaneously with metal and graphite, and then afford the high concentration of nitrogen atoms in the arc region, which will promote the formation of metal nitride clusterfullerenes finally. The ZrN can promote the yields of Y3N@C80, Sc3N@C80 and Gd3N@C80, revealing the universal applicability of ZrN as a highly efficient nitrogen source. Specifically, the yield of Sc3N@C80 was greatly improved when adding ZrN, and it shows over double yield compared to traditional synthetic route using N2 gas. In addition, ZrN can also enhance the yields of paramagnetic azametallofullerene M2@C79N due to the high concentration of nitrogen atoms in the arc region. This new method enhances the production quantity of metal nitride clusterfullerenes and azametallofullerenes, and it will greatly promote the research and application of these molecular carbon materials.

The efficiency, selectivity, and sustainability benefits offered by enzymes are enticing chemists to consider biocatalytic transformations to complement or even supplant more traditional synthetic routes. Increasing demands for efficient and versatile synthetic methods combined with powerful new discovery and engineering tools have prompted innovations in biocatalysis, especially the development of new enzymes for precise transformations. The past decade has witnessed impressive expansion of the catalytic repertoire of enzymes to include new and useful transformations not known (or relevant) in the biological world. The continuing discovery and improvement of these new enzyme activities is opening a floodgate that connects the chemistry of the biological world to that invented by humans over the last 100 years. This thesis describes a new set of enzymes, derived from a cytochrome P450 monooxygenase and a cytochrome c electron-transfer protein, which are able to function as carbene transferases to construct diverse molecular structures, including strained carbocycles and lactone derivatives. Chapter 1 illustrates different approaches researchers have utilized to explore and develop new catalytic machineries of diverse enzymes. These efforts have identified new genetically-encoded biocatalysts that can be tuned and diversified through directed evolution. Chapter 2 presents the discovery of P450 variants that catalyze the formation of highly strained carbocycles, bicyclobutanes and cyclopropenes, via carbene addition to carbon‒carbon triple bonds. The intrinsic strain energies of these small rigid carbocycles allow them to have broad applications in different fields, but also create challenges for their construction. Using a diazo substrate as the carbene precursor, the enzyme variants optimized by directed evolution could act on structurally diverse alkynes (aromatic or aliphatic, terminal or internal) with high efficiency and selectivity, providing an effective route to an array of chiral strained structures. The carbene transferase activity is then extended to the assembly of various lactone structures, a fundamental class of organic moieties with applications in fields varying from synthetic chemistry, to materials science, to medicinal chemistry. Chapter 3 details a strategy using lactone-based carbenes, for the transfer to different functionalities, enabling rapid access to a broad range of α-substituted and spiro-lactones with unprecedented efficiencies and selectivities. A different approach based on intramolecular carbene C–H insertion is outlined in Chapter 4, which allows for the synthesis of lactones in a higher order of structural diversity. Directed evolution of a P450 variant identified a lineage of potent variants, capable of assembling lactones in different sizes (5- to 7-membered) and also with sophisticated three-dimensional structures based on fused, spiro and bridged rings. Computational tools were employed to understand the reaction mechanisms and to explain some mutational effect. In sum, the thesis work lays out how protein engineering integrated with chemical rationalization enables the expansion of the chemical space accessible to native hemeproteins, especially in building diverse molecular structures.

Two dimeric boron complexes of potentially tetradentate and trianionic β-diketiminate ligands bearing phenol substituents were prepared and characterized. The synthetic routes employed were designed to circumvent the undesirable formation of β-ketimines and 2-methylbenzoxazoles observed when traditional synthetic routes toward the target β-diketiminate ligands were attempted. The title complexes were isolated via demethylation of β-diketimine ligands and boron difluoride complexes bearing 2-anisole N-aryl substituents using boron tribromide. The resulting complexes were found to contain a unique hydrogen-bond-supported boron-oxygen-boron bridge, as confirmed by X-ray crystallography. The stability of the resulting dimeric structures relative to the corresponding monomeric, tetradentate boron complexes was studied computationally, and theory confirmed that the dimeric structures were strongly favored. The absorption spectra of the dimers were red-shifted relative to the parent β-diketimine ligands. The complexes were irreversibly oxidized and reduced electrochemically and were weakly emissive at low concentrations (Stokes shifts between 23 and 31 nm), showing little solvent dependence.

GaAs is one of the most important semiconductors. However, colloidal GaAs nanocrystals remain largely unexplored because of the difficulties with their synthesis. Traditional synthetic routes either fail to produce pure GaAs phase or result in materials whose optical properties are very different from the behavior expected for quantum dots of direct-gap semiconductors. In this work, we demonstrate a variety of synthetic routes toward crystalline GaAs NCs. By using a combination of Raman, EXAFS, transient absorption, and EPR spectroscopies, we conclude that unusual optical properties of colloidal GaAs NCs can be related to the presence of Ga vacancies and lattice disorder. These defects do not manifest themselves in TEM images and powder X-ray diffraction patterns but are responsible for the lack of absorption features even in apparently crystalline GaAs nanoparticles. We introduce a novel molten salt based annealing approach to alleviate these structural defects and show the emergence of size-dependent excitonic transitions in colloidal GaAs quantum dots.

The implementation of next‐generation batteries requires the development of safe, compatible electrolytes that are stable and do not cause safety problems. The difluoro(oxalato)borate ([DFOB]−) anion has been used as an electrolyte additive to aid with stability, but such an approach has most commonly been carried out using flammable solvent electrolytes. As an alternative approach, utilisation of the [DFOB]− anion to make ionic liquids (ILs) or Organic Ionic Plastic Crystals (OIPCs) allows the advantageous properties of ILs or OIPCs, such as higher thermal stability and non‐volatility, combined with the benefits of the [DFOB]− anion. Here, we report the synthesis of new [DFOB]−‐based ILs paired with triethylmethylphosphonium [P1222]+, and diethylisobutylmethylphosphonium [P122i4]+. We also report the first OIPCs containing the [DFOB]− anion, formed by combination with the 1‐ethyl‐1‐methylpyrrolidinium [C2mpyr]+ cation, and the triethylmethylammonium [N1222]+ cation. The traditional synthetic route using halide starting materials has been successfully replaced by a halide‐free tosylate‐based synthetic route that is advantageous for a purer, halide free product. The synthesised [DFOB]−‐based salts exhibit good thermal stability, while the ILs display relatively high ionic conductivity. Thus, the new [DFOB]−‐based electrolytes show promise for further investigation as battery electrolytes both in liquid and solid‐state form.

The application of N-heterocyclic carbene (NHC) catalysis under highly diluted oxidative condition to the polycondensation of dialdehydes and diols is herein presented as an alternative, atomeconomical synthetic route to macrocyclic oligoesters (MCOs). The disclosed protocol paves the way to the straightforward access to MCOs, starting from commercial dialdehydes, avoiding the use of toxic diacyl chlorides, commonly employed in traditional MCOs synthetic processes. The method is totally metal-free, takes place in the green Me-THF solvent and requires the use of a fully recyclable quinone oxidant. The protocol versatility is confirmed by the employment of fossil-based and bio-based monomers such as 2,5diformylfuran (DFF), 2,5-bis(hydroxymethyl)furan (BHMF), and isomannide, synthesizing a series of novel and known synthetically relevant macrocyclic oligoesters, fully characterized by NMR and MALDI-TOF MS analysis, with product yields (51-86%) comparable to those obtained by traditional synthetic routes. Finally, to emphasize the synthetic relevance of the target macrocycles, an entropicallydriven ring opening polymerization (ED-ROP) key study has been performed, optimizing the organocatalyzed synthesis of poly(2,5furan-dimethylene 2,5 furandicarboxylate) (PBHMF) with numberaverage molecular weight up to 8200 g mol-1 and 66% isolated yield.

Two efficient synthetic routes to (S,S)-ethambutol, a first line drug used for tuberculosis treatment, based on the chiral pool approach viewing L-methionine as a starting material are reported. Several advantages over the traditional synthetic routes were observed: simple, safe, inexpensive reagents, and minimum byproduct formation. The key intermediate (S)-(+)-2-amino-1-butanol was obtained in its enantiomerically pure form from the corresponding aminobutyric acid. Keywords: Drugs, L-methionine, 1, 2-diamine, (S)-(+)-2-amino-1-butanol, (S, S)-ethambutol, tuberculosis.

Mechanochemistry, a solvent-free approach that harnesses mechanical energy, is emerging as a transformative technique in modern chemistry. It has emerged from a niche technique to a versatile tool with broad applications. By inducing physical and chemical transformations, it enables the synthesis of complex molecules and nanostructured materials. Recent advancements have extended its applications beyond simple physical transformations to encompass catalytic processes, unlocking new possibilities for selective synthesis and product design. This account delves into the fundamentals of mechanochemistry and its applications in organic synthesis, also beyond traditional synthetic routes. Mechanochemistry offers new avenues for molecular and materials discovery, expanding the scope of accessible chemical space.1 Introduction2 Organic Synthesis in Ball Mills3 Combination with Different Energy Sources4 Advantages of Mechanochemistry5 Future of Mechanochemistry6 Conclusion

Dienols are important structural motifs in organic molecules, but most of the traditional synthetic methods required multistep prefunctionalization of substrates, leading to stoichiometric waste an...

Introduction: Use of natural products for management of diseases has increased widely due to the belief that natural products are less toxic than conventional medicines. Natural products have been utilised for management of chronic diseases such as diabetes and cancers. Respiratory infections have also been managed using natural products. Allium sativum is one of the natural products that has been utilised in the management of SARS-CoV infections, diabetes and cancer. Methods: This study was aimed at screening bioactive agents in Allium sativum using computational analysis. The targets of the bioactive agents were predicted using SwissTargetPrediction tools. Molecular docking followed, where the docking energies of the bioactive agents to the targets were generated. The bioactive agents were analysed for pharmacokinetics properties using SwissADME as well as toxicity profiles using the ProTox II webserver. The docking scores, toxicities and pharmacokinetics profiles of the bioactive agents in Allium sativum were compared with those of reference compounds. Results: All the bioactives showed lower docking scores than the reference compounds. The bioactives, however, showed some activity on specific receptors such as carbonic anhydrases, cyclooxygenase and ghrelin. All the bioactives showed high gastrointestinal tract absorption and none violated Lipinski’s rule of five. Diallyl trisulphide was predicted to be most lethal, with an LD50 of 100mg/kg, while Alliin was the safest, with 8000mg/kg. Conclusions: In conclusion, bioactives showed lower docking scores than the reference compounds, therefore overall pharmacological activity could be attributed to synergy between the bioactives for a particular receptor.

The efficiency, selectivity and sustainability benefits offered by enzymes are enticing chemists to consider biocatalytic transformations to complement or even supplant more traditional synthetic routes. Increasing demands for efficient and versatile synthetic methods, combined with powerful new discovery and engineering tools, has prompted innovations in biocatalysis, especially the development of new enzymes for precise transformations or ‘molecular editing’. As a result, the past decade has witnessed an impressive expansion of the catalytic repertoire of enzymes to include new and useful transformations not known (or relevant) in the biological world. In this Review we illustrate various ways in which researchers have approached using the catalytic machineries of enzymes for new-to-nature transformations. These efforts have identified genetically encoded catalysts that can be tuned and diversified by engineering the protein sequence, particularly by directed evolution. Discovery and improvement of these new enzyme activities is opening a floodgate that connects the chemistry of the biological world to that invented by humans over the past 100 years. Advances in enzyme performance and capabilities are making them increasingly attractive to synthetic chemists. In this Review Chen and Arnold outline the ways that enzymes have been engineered to achieve reactivities well beyond their original functions.