Divinylanthracene-Containing Tetracationic Organic Cyclophane with Near-Infrared Photoluminescence.

Near-infrared (NIR) light is known to have outstanding optical penetration in biological tissues and to be non-invasive to cells compared with visible light. These characteristics make NIR-specific light optimal for numerous biological applications, such as the sensing of biomolecules or in theranostics. Over the years, significant progress has been achieved in the synthesis of fluorescent cyclophanes for sensing, bioimaging, and making optoelectronic materials. The preparation of NIR-emissive porphyrin-free cyclophanes is, however, still challenging. In an attempt for fluorescence emissions to reach into the NIR spectral region, employing organic tetracationic cyclophanes, we have inserted two 9,10-divinylanthracene units between two of the pyridinium units in cyclobis(paraquat-p-phenylene). Steady-state absorption, fluorescence, and transient-absorption spectroscopies reveal the deep-red and NIR photoluminescence of this cyclophane. This tetracationic cyclophane is highly soluble in water and has been employed successfully as a probe for live-cell imaging in a breast cancer cell line (MCF-7).

Synthesis of Benzo[b]thiophenes via Electrophilic Sulfur Mediated Cyclization of Alkynylthioanisoles.

A stable dimethyl(thiodimethyl)sulfonium tetrafluoroborate salt was employed for the electrophilic cyclization reaction of o-alkynyl thioanisoles for the synthesis of 2,3-disubstituted benzo[b]thiophenes. The reaction described herein works well with various substituted alkynes in excellent yields, and a valuable thiomethyl group was introduced with ease. The reaction utilizes moderate reaction conditions and ambient temperature while tolerating various functionalities. To elucidate the mechanism, electrophilic addition reactions using the dimethyl(thiodimethyl)sulfonium tetrafluoroborate salt with diphenylacetylene was demonstrated.

A one-pot successive cyclization-alkylation strategy for the synthesis of 2,3-disubstituted benzo[b]thiophenes.

In this study, a new environmentally benign iodine-mediated one-pot iodocyclization/alkylation strategy for the synthesis of benzo[b]thiophene derivatives starting from 2-alkynylthioanisoles was developed. The synthesis of a diverse population of 2,3-disubstituted benzo[b]thiophenes was achieved in high yields by employing moderate reaction conditions using 1,3-dicarbonyl substrates as the nucleophile and various substituted propargyl alcohols as both the cyclization precursor and the alkylating agent. This method resulted in the formation of a series of complex structures obtained in a single step. Additionally, a strategy was devised for the one pot iodocyclization/oxidation of propargyl alcohols into carbonyl functionalized benzo[b]thiophene structures. These green one-pot reaction processes were designed to reduce wastes and byproducts while generating a complex substitution pattern on the benzo[b]thiophene structure. The reported methodologies may be used to synthesize more functionalized benzo[b]thiophene structures that can be used in both biomedical and organic electronic applications.

Sodium halides as the source of electrophilic halogens in green synthesis of 3-halo- and 3,n-dihalobenzo[b]thiophenes.

A convenient methodology for the synthesis of mono- and di-halogenated benzo[b]thiophenes is described herein, which utilizes copper(II) sulfate pentahydrate and various sodium halides in the presence of substituted 2-alkynylthioanisoles. The proposed method is facile, uses ethanol as a green solvent, and results in uniquely substituted benzo[b]thiophene structures with isolated yields up to 96%. The most useful component of this methodology is the selective introduction of bromine atoms at every available position (2-7) around the benzo[b]thiophene ring, while keeping position 3 occupied by a specific halogen atom such as Cl, Br or I. Aromatic halogens are useful reactive handles; therefore, the selective introduction of halogens at specific positions would be valuable in the targeted synthesis of bioactive molecules and complex organic materials via metal-catalyzed cross coupling reactions. This work is a novel approach towards the synthesis of dihalo substituted benzo[b]thiophene core structures, which provides a superior alternative to the current methods discussed herein.

Green Synthesis of Halogenated Thiophenes, Selenophenes and Benzo[b]selenophenes Using Sodium Halides as a Source of Electrophilic Halogens.

Herein, we report the first synthesis of chlorinated benzo[b]selenophenes via environmentally friendly electrophilic chlorocyclization reaction using "table salt" as a source of "electrophilic chlorine" and ethanol as a solvent. In addition, the synthesis of diverse halogenated heterocycles, including 3-chloro, 3-bromo and 3-iodo thiophenes, selenophenes, and benzo[b]selenophenes was successfully accomplished under the same environmentally benign reaction conditions. This methodology has several advantages over other previously reported reactions as it employs simple starting compounds, an environmentally friendly solvent, ethanol, and non-toxic inorganic reagents under mild reaction conditions, resulting in the high product yields.

A study on the cellular and cytotoxic effects of S and Se heterocycles on the myeloid leukemia cell line PLB-985.

This paper describes the synthesis of several halogenated S and Se heterocycles and tests their biological activity by measuring the effects on the myeloid leukemia cell line, PLB-985 cells. We report that select compounds exhibit significant increases in mitochondria membrane potential and increased oxidative stress in PLB-985 cells. Our results contribute to the foundational knowledge of different S and Se containing compounds and their possible impacts on human cells.

Synthesis and Evaluation of 3-Halobenzo[b]thiophenes as Potential Antibacterial and Antifungal Agents.

The global health concern of antimicrobial resistance has harnessed research interest to find new classes of antibiotics to combat disease-causing pathogens. In our studies, 3-halobenzo[b]thiophene derivatives were synthesized and tested for their antimicrobial activities using the broth microdilution susceptibility method. The 3-halo substituted benzo[b]thiophenes were synthesized starting from 2-alkynyl thioanisoles using a convenient electrophilic cyclization methodology that utilizes sodium halides as the source of electrophilic halogens when reacted along with copper(II) sulfate. This environmentally benign methodology is facile, uses ethanol as the solvent, and results in 3-halo substituted benzo[b]thiophene structures in very high yields. The cyclohexanol-substituted 3-chloro and 3-bromobenzo[b]thiophenes resulted in a low MIC of 16 µg/mL against Gram-positive bacteria and yeast. Additionally, in silico absorption, distribution, metabolism, and excretion (ADME) properties of the compounds were determined. The compounds with the lowest MIC values showed excellent drug-like properties with no violations to Lipinski, Veber, and Muegge filters. The time-kill curve was obtained for cyclohexanol-substituted 3-chlorobenzo[b]thiophenes against Staphylococcus aureus, which showed fast bactericidal activity at MIC.

Copper-Catalyzed Electrophilic Chlorocyclization Reaction Using Sodium Chloride as the Source of Electrophilic Chlorine.

The synthesis of 2,3-disubstituted benzo[b]thiophenes with selective placement of a chlorine moiety at the 3 position while maintaining diversity at the 2 position has only been accomplished by a handful of conditions in the past. The development of a greener, less expensive, and simpler method is paramount for the exploration of innovative compounds for application in medicinal and materials chemistry. Herein, the first reported copper-catalyzed electrophilic chlorocyclization method was developed and employed across diverse substrates to generate highly functionalized 2,3-disubstituted benzo[b]thiophenes and 2,3,5-trisubstituted thiophenes in very high yields. This method was optimized in both ethanol and acetonitrile in a comparative solvent study. The utility of this method was further expanded beyond chlorocyclization by changing the sodium halide to generate bromo- and iodocyclization products in excellent yields.

Iodocyclization in Aqueous Media and Supramolecular Reaction Control Using Water-Soluble Hosts.

Iodocyclization of 2-alkynylanisoles is an efficient route for synthesizing substituted benzofurans. Reaction efficiency with copper(II) sulfate and sodium iodide in an aqueous slurry under mild conditions is a manifold higher than in organic solvents. Water-soluble hosts of the cyclodextrin family solubilize the compounds in aqueous media and affect the reaction efficiency through conformation control and steric interactions. Computational chemistry and spectral titration provide information on the host-guest complex structure and insight into the mechanistic basis of the observed effects.

Discovery of Clinical Candidate (1R,4r)-4-((R)-2-((S)-6-Fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexan-1-ol (Navoximod), a Potent and Selective Inhibitor of Indoleamine 2,3-Dioxygenase 1.

A novel class of 5-substituted 5H-imidazo[5,1-a]isoindoles are described as potent inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1). A structure-based drug design approach was used to elaborate the 5H-imidazo[5,1-a]isoindole core and to improve potency and pharmacological properties. Suitably placed hydrophobic and polar functional groups in the lead molecule allowed improvement of IDO1 inhibitory activity while minimizing off-target liabilities. Structure-activity relationship studies focused on optimizing IDO1 inhibition potency and a pharmacokinetic profile amenable to oral dosing while controlling CYP450 and hERG inhibitory properties.

Studies in acyl C-H activation via aryl and alkyl to acyl "through space" migration of palladium.

Examples of the 1,4-migration of a palladium moiety in aryl- and alkylpalladium intermediates to the acyl position of an aldehyde or formamide have been observed. The resulting acylpalladium intermediate can undergo ester or carbamate formation by reaction with an alcohol; decarbonylation, followed by beta hydride elimination to an alkene; reaction with an organomercurial to form an ester; or alkene insertion. Deuterium-labeling studies have been used to confirm the palladium migration mechanism.

Synthesis of 3,4-disubstituted 2H-benzopyrans through C-C bond formation via electrophilic cyclization.

The electrophilic cyclization of substituted propargylic aryl ethers by I2, ICl, and PhSeBr produces 3,4-disubstituted 2H-benzopyrans in excellent yields. This methodology results in vinylic halides or selenides under mild reaction conditions and tolerates a variety of functional groups, including methoxy, alcohol, aldehyde, and nitro groups.

Synthesis of 2,3-disubstituted benzo[b]selenophenes via electrophilic cyclization.

2,3-Disubstituted benzo[b]selenophenes have been prepared by the electrophilic cyclization of various 1-(1-alkynyl)-2-(methylseleno)arenes by Br2, NBS, I2, ICl, PhSeCl, PhSeBr, and Hg(OAc)2. This method tolerates a wide variety of functional groups, including alcohol, ester, nitrile, nitro, and silyl groups, and proceeds under exceptionally mild reaction conditions.