Structural and Electronic Factors Controlling the Efficiency and Rate of Intersystem Crossing to the Triplet State in Thiophene Polycyclic Derivatives.

Thiophene polycyclic derivatives are widely used in organic light-emitting diodes, photovoltaics, and medicinal chemistry applications. Understanding the electronic and structural factors controlling their intersystem crossing rates is paramount for these applications to be successful. This study investigates the photophysical, electronic structure, and excited state dynamics of 1,2-benzodiphenylene sulfide, benzo[b]naphtho[1,2-d]thiophene, and benzo[b]naphtho[2,3-d]thiophene in polar aprotic and non-polar solvents. Steady-state absorption and emission spectroscopy, femtosecond transient absorption spectroscopy, and DFT and TD-DFT calculations are employed. Low fluorescence quantum yields of 1.2 to 2.7% are measured in acetonitrile and cyclohexene, evidencing that the primary relaxation pathways in these thiophene derivatives are nonradiative. Linear interpolation of internal coordinates calculations predict that an S-C bond elongation reaction coordinate facilitates the efficient intersystem crossing to the T1 state. Excitation of 1,2-benzodiphenylene sulfide and benzo[b]naphtho[1,2-d]thiophene at 350 nm or benzo[b]naphtho[2,3-d]thiophene at 365 nm, populates the lowest-energy 1ππ* state, which relaxes to the 1ππ* minimum in tens of picoseconds or intersystem crosses to the triplet manifold in ca. 500 ps to 1.1 ns depending on the position at which the benzene rings are added. Excitation at 266 nm does not affect the intersystem crossing rates. Laser photodegradation experiments demonstrate that the thiophene polycyclic derivatives are highly photostable.

Desymmetrization of Cyclic Sulfonimidamides by Asymmetric Allylation.

Herein we report the first transition metal-catalyzed approach to the enantioenriched synthesis of cyclic sulfonimidamides relying on commercially available palladium catalysts and ligands. High-throughput experimentation (HTE) was employed to identify the optimal catalyst system and solvent. The method is applied to a variety of saturated and unsaturated rings and exhibits the highest selectivity for 2-substituted allyl electrophiles. The products are further elaborated to complex, tricyclic scaffolds. DFT experiments presented herein highlight the key ligand substrate interactions leading to the high levels of enantioselectivity.

Sorption of Polycyclic Aromatic Sulfur Heterocycles (PASH) on Nylon Microplastics at Environmentally Relevant Concentrations.

Microplastics have garnered an infamous reputation as a sorbate for many concerning environmental pollutants and as a delivery vehicle for the aquatic food chain through the ingestion of these contaminated small particulates. While sorption mechanisms have been extensively studied for polycyclic aromatic hydrocarbons, polycyclic aromatic sulfur heterocycles (PASHs) have not been investigated, partly due to their low concentrations in aquatic ecosystems. Herein, an analytical methodology is presented for the analysis of dibenzothiophene, benzo[b]naphtho[1,2-b]thiophene, benzo[b]naphtho[2,1-b]thiophene, benzo[b]naphtho[2,3-b]thiophene, chryseno[4,5-bcd]thiophene and dinaphtho[1,2-b:1',2'-d]thiophene at relevant environmental concentrations based on solid phase extraction and high-performance liquid chromatography. The sorption uptake behavior and the sorption kinetics of the three benzo[b]napthothiophene isomers were then investigated on nylon microplastics to provide original information on their environmental fate and avoid human contamination through the food chain. The obtained information might also prove relevant to the development of successful remediation approaches for aquatic ecosystems.

Extended Tetrathiafulvalenes with Fluoreno[3,2-b]fluorene and Diindeno[1,2-b : 1',2'-i]anthracene Cores.

In one-dimensional polycyclic aromatic hydrocarbons (PAHs) containing five- and six-membered rings fused together, one key question is whether the structures possess a quinoidal or aromatic diradical character. Here, we generate such PAHs by reversible oxidation of PAH-extended tetrathiafulvalenes (TTFs). Extended TTFs were thus prepared and studied for their geometrical properties (crystallography), redox properties, and UV/Vis/NIR/EPR characteristics as a function of charge state. The EPR measurements of radical cations showed unique features for each PAH-TTF. The dications, formally composed of fluoreno[3,2-b]fluorene and diindeno[1,2-b:1',2'-i]anthracene cores, were experimentally found to exhibit singlet ground states. For the latter, calculations reveal the closed shell, quinoid singlet state to be isoenergetic with the open shell singlet diradical. Each charge state exhibited unique optical properties with radical cations absorbing strongly in the NIR region with signatures from π-dimers for the large core. The experimental results were paralleled and supported by detailed computations, including spin density distribution calculations, EPR simulations, and nucleus independent chemical shift (NICS) xy scans.

The Role of Five-Membered Heterocycles in the Molecular Structure of Antibacterial Drugs Used in Therapy.

Five-membered heterocycles are essential structural components in various antibacterial drugs; the physicochemical properties of a five-membered heterocycle can play a crucial role in determining the biological activity of an antibacterial drug. These properties can affect the drug's activity spectrum, potency, and pharmacokinetic and toxicological properties. Using scientific databases, we identified and discussed the antibacterials used in therapy, containing five-membered heterocycles in their molecular structure. The identified five-membered heterocycles used in antibacterial design contain one to four heteroatoms (nitrogen, oxygen, and sulfur). Antibacterials containing five-membered heterocycles were discussed, highlighting the biological properties imprinted by the targeted heterocycle. In some antibacterials, heterocycles with five atoms are pharmacophores responsible for their specific antibacterial activity. As pharmacophores, these heterocycles help design new medicinal molecules, improving their potency and selectivity and comprehending the structure-activity relationship of antibiotics. Unfortunately, particular heterocycles can also affect the drug's potential toxicity. The review extensively presents the most successful five-atom heterocycles used to design antibacterial essential medicines. Understanding and optimizing the intrinsic characteristics of a five-membered heterocycle can help the development of antibacterial drugs with improved activity, pharmacokinetic profile, and safety.

Progress on the Cu-Catalyzed 1,4-Conjugate Addition to Thiochromones.

Carbon-carbon bond formation is one of the most important tools in synthetic organic chemists' toolbox. It is a fundamental transformation that allows synthetic chemists to synthesize the carbon framework of complex molecules from inexpensive simple starting materials. Among the many synthetic methodologies developed for the construction of carbon-carbon bonds, organocopper reagents are one of the most reliable organometallic reagents for this purpose. The versatility of organocuprate reagents or the reactions catalyzed by organocopper reagents were demonstrated by their applications in a variety of synthetic transformations including the 1,4-conjugate addition reactions. Sulfur-containing heterocyclic compounds are a much less studied area compared to oxygen-containing heterocycles but have gained more and more attention in recent years due to their rich biological activities and widespread applications in pharmaceuticals, agrochemicals, and material science. This paper will provide a brief review on recent progress on the synthesis of an important class of sulfur-heterocycles-2-alkylthiochroman-4-ones and thioflavanones via the conjugate additions of Grignard reagents to thiochromones catalyzed by copper catalysts. Recent progress on the synthesis of 2-substituted thiochroman-4-ones via alkynylation and alkenylation of thiochromones will also be covered in this review.

An Organocatalytic and Stereoselective Vinylogous Domino Process towards Thiochromans.

A highly diastereoselective organocatalyzed domino vinylogous sulfa-Michael-aldol-cyclocondensation (VMAC) reaction has been developed using alkylidene Meldrum's acid as dienes highlighting two vinylogous steps, an unprecedented sulfa-1,6-conjugate addition and a diastereoselective aldol reaction triggering a formal (4+2) cycloaddition. This work opens a new route towards bio-relevant and original tricyclic thiochroman derivatives.

Higher-order [8+2]-cycloadditions of tropothione with levoglucosenone (LGO) and structurally similar exo-cyclic enones derived from cyrene.

Levoglucosenone (LGO) and structurally similar exo-cyclic enones derived from cyrene (dihydrolevoglucosenone) react with tropothione following the higher-order [8 + 2]-cycloaddition pathway. Reactions were performed at room temperature in CH2Cl2 solutions in absence of any activating reagent. Whereas reaction of tropothione with LGO occurred with complete stereoselectivity, leading to a single, sterically favored exo cycloadduct, identified as polycylic thiophene derivative, reactions performed with exo-cyclic enones yielded in some instances mixtures of two isomeric exo and endo cycloadducts, derived from spiro-tetrahydrothiophene as major and minor components, respectively, of the studied reaction mixtures. Exo and endo [8 + 2] cycloadducts differ in absolute configuration at the newly created chiral centers. Structures of exo and endo cycloadducts were confirmed by single crystal X-ray diffraction analysis.

A Copper-Catalyzed Interrupted Domino Reaction for the Synthesis of Fused Triazolyl Benzothiadiazine-1-oxides.

Copper(I)-catalyzed domino reactions of 2-azido sulfoximines with 1-iodoalkynes yield fused triazolyl-containing benzothiadiazine-1-oxides. The protocol features the synthesis of two fused heterocyclic rings in one step with good to excellent yields and a broad functional group tolerance. Detailed mechanistic investigations indicate that a copper π-complex initiates a cycloaddition and oxidative C-N coupling reaction sequence. The results suggest an interrupted domino process involving an iodinated triazole as a key intermediate.

Conjugation Extension and Halochromic Behaviors of S-Fused Polycyclic Aromatic Hydrocarbons Bearing Cyclopenta[b]thiopyran Moieties.

Three S-fused polycyclic aromatic hydrocarbons (PAHs) bearing cyclopenta[b]thiopyran moieties have been designed and successfully synthesized. With the conjugation extension, the absorption onset of the longest PAH reaches 1110 nm. All the three S-fused PAHs exhibit significant halochromic properties in both solution and solid states. Upon protonation, the proton is incorporated on the cyclopentadiene ring while the positive charge is localized on the thiopyrylium ring. Moreover, no significant difference can be found for the two shorter PAHs upon the protonation by different organic acids, such as trifluoroacetic acid (TFA) and trifluoromethanesulfonic acid (TfOH), while the longest PAH can be only mono-protonated by TFA but di-protonated by stronger TfOH. Furthermore, after protonation, the non-emissive S-fused PAHs exhibit strong fluorescence and can be regenerated by simply neutralization with triethylamine. The enhanced emission of mono-protonated products stem from S2 →S0 transitions, which disobey the Kasha's rule.

Synthesis of Fluorinated and Fluoroalkylated Heterocycles Containing at Least One Sulfur Atom via Cycloaddition Reactions.

Fluorinated heterocycles constitute an important group of organic compounds with a rapidly growing number of applications in such areas as medicinal chemistry, agrochemicals production, polymer chemistry, as well as chemistry of advanced materials. In the latter case, fluorinated thiophenes are considered as a lead class of compounds with numerous spectacular applications. On the other hand, cycloaddition reactions offer a superior methodology for stereo-chemically controlled synthesis of heterocycles with a diverse ring size and a variable number of heteroatoms. A comprehensive review of methods based on cycloaddition reactions and applied for construction of fluorinated and/or fluoroalkylated S-heterocycles has not yet been published. For this reason, the main goal of the presented review was to fill the existing gap and to summarize the results published over last six decades. In this context, the [3+2]- and [4+2]-cycloadditions (Huisgen reactions, and Diels-Alder reactions, respectively) are of special importance. Some questions related to the discussed mechanisms of cycloaddition processes observed in reactions with electron deficient, fluorinated substrates (dipolarophiles and dienophiles), and electron-rich sulfur containing counter partners, are of fundamental importance for the development of interpretations of organic reaction mechanisms.

New Cycloadditon Reaction of 2-Chloroprop-2-enethioamides with Dialkyl Acetylenedicarboxylates: Synthesis of Dialkyl 2-[4,5-bis(alkoxycarbonyl)-2-(aryl{alkyl}imino)-3(2H)-thienylidene]-1,3-dithiole-4,5-dicarboxylates.

The 1,3-dipolar cycloaddition of 1,2-dithiole-3-thiones with alkynes to form 1,3-dithioles is one of the most studied reactions in this class of polysulfur-containing heterocycles. Nucleophilic substitution of chlorine atoms in dimethyl 2-(1,2-dichloro-2-thioxoethylidene)-1,3-dithiole-4,5-dicarboxylate, which was obtained by addition one molecules of DMAD to 4,5-dichloro-3H-1,2-dithiole-3-thione, led to a series of 2-chloro-2-(1,3-dithiol-2-ylidene)ethanethioamides. Cycloaddition reaction of 2-chloro-2-(1,3-dithiol-2-ylidene)ethanethioamides with activated alkynes led to the unexpected formation of 2-(thiophen-3(2H)-ylidene)-1,3-dithioles via new intermediate, 1-(1,3-dithiol-2-ylidene)-N-phenylethan-1-yliumimidothioate. Structure of dimethyl 2-(4,5-bis(methoxycarbonyl)-2-(phenylimino)thiophen-3(2H)-ylidene)-1,3-dithiole-4,5-dicarboxylate was finally proven by single crystal X-ray diffraction study. Optimized reaction conditions and a mechanistic rationale for the 1,3-dipolar cycloaddition of novel intermediate are presented.

The importance of sulfur-containing motifs in drug design and discovery.

INTRODUCTION: Sulfur-containing functional groups are privileged motifs that occur in various pharmacologically effective substances and several natural products. Various functionalities are found with a sulfur atom at diverse oxidation states, as illustrated by thioether, sulfoxide, sulfone, sulfonamide, sulfamate, and sulfamide functions. They are valuable scaffolds in the field of medicinal chemistry and are part of a large array of approved drugs and clinical candidates. AREA COVERED: Herein, the authors review the current research on the development of organosulfur-based drug discovery. This article also covers details of their roles in the new lead compounds reported in the literature over the past five years 2017-2021. EXPERT OPINION: Given its prominent role in medicinal chemistry and its importance in drug discovery, sulfur has attracted continuing interest and has been used in the design of various valuable compounds that demonstrate a variety of biological and pharmacological feature activities. Overall, sulfur's role in medicinal chemistry continues to grow. However, many sulfur functionalities remain underused in small-molecule drug discovery and deserve special attention in the armamentarium for treating diverse diseases. Research efforts are also still required for the development of a synthetic methodology for direct access to these functions and late-stage functionalization.

(Dimesityl)boron Benzodithiophenes: Synthesis, Electrochemical, Photophysical and Theoretical Characterization.

Triarylboranes containing linear or angular benzodithiophene moieties and bearing one or two dimesitylboron units were synthesized. The electrochemical and optical features of these compounds were investigated by cyclic voltammetry, UV/Vis and fluorescence spectroscopy while DFT calculations were run to analyze the energetic landscape of these systems. For both linear and angular benzodithiophenes, symmetrical disubstitution leads to the highest photoluminescence yields. The linear benzodithiophene disubstituted with two dimesitylboron units proved to be the most interesting and promising molecule as an electron-transport material for organic electronics owing to its LUMO energy level of -2.84 eV which is close to those of commonly used electron transport materials like bathocuproine or bathophenantroline.

Expedition of sulfur-containing heterocyclic derivatives as cytotoxic agents in medicinal chemistry: A decade update.

This review article proposes a comprehensive report of the design strategies engaged in the development of various sulfur-bearing cytotoxic agents. The outcomes of various studies depict that the sulfur heterocyclic framework is a fundamental structure in diverse synthetic analogs representing a myriad scope of therapeutic activities. A number of five-, six- and seven-membered sulfur-containing heterocyclic scaffolds, such as thiazoles, thiadiazoles, thiazolidinediones, thiophenes, thiopyrans, benzothiazoles, benzothiophenes, thienopyrimidines, simple and modified phenothiazines, and thiazepines have been discussed. The subsequent studies of the derivatives unveiled their cytotoxic effects through multiple mechanisms (viz. inhibition of tyrosine kinases, topoisomerase I and II, tubulin, COX, DNA synthesis, and PI3K/Akt and Raf/MEK/ERK signaling pathways), and several others. Thus, our concise illustration explains the design strategy and anticancer potential of these five- and six-membered sulfur-containing heterocyclic molecules along with a brief outline on seven-membered sulfur heterocycles. The thorough assessment of antiproliferative activities with the reference drug allows a proficient assessment of the structure-activity relationships (SARs) of the diversely synthesized molecules of the series.

Thermoneutral N-H Bond Activation of Ammonia by a Geometrically Constrained Phosphine.

A geometrically constrained phosphine bearing a tridentate NNS pincer ligand is reported. The effect of the geometric constraint on the electronic structure was probed by theoretical calculations and derivatization reactions. Reactions with N-H bonds result in formation of cooperative addition products. The thermochemistry of these transformations is strongly dependent on the substrate, with ammonia activation being thermoneutral. This represents the first example of a molecular compound that reversibly activates ammonia via N-H bond scission in solution upon mild heating.

Chiral Benzothiophene Synthesis via Enantiospecific Coupling of Benzothiophene S-Oxides with Boronic Esters.

Benzothiophenes are valuable heterocycles that are widely used in medicines, agrochemicals, and materials science. Herein, we report a general method for the synthesis of enantioenriched 2,3-disubstituted benzothiophenes via a transition-metal-free C2-alkylation of benzothiophenes with boronic esters. The reactions utilize benzothiophene S-oxides in lithiation-borylations to generate intermediate arylboronate complexes, and subsequent Tf2 O-promoted S-O bond cleavage to trigger a Pummerer-type 1,2-metalate shift, which gives the coupled products with complete enantiospecificity. Primary, secondary and tertiary alkyl boronic esters and aryl boronic esters are successfully coupled with a range of C3-substituted benzothiophenes. Importantly, this transformation does not require the use of C3 directing groups, therefore it overcomes a major limitation of previously developed transition-metal-mediated C2 alkylations of benzothiophenes.

Discovery of emerging sulfur-containing PAHs in PM2.5: Contamination profiles and potential health risks.

We reported the discovery and identification of emerging sulfur-containing polycyclic aromatic hydrocarbons, namely polycyclic aromatic sulfur heterocycles (PASHs), in PM2.5 collected from two typical regions of China, Taiyuan and Guangzhou. Until now, there is no research on contamination status, sources and potential health risks of this unexpected group of organic contaminants in PM2.5. High atmospheric concentrations (ngm-3) and significant time-dependent variations were determined in PM2.5 of Taiyuan from 2017 to 2018. Coal combustion/secondary formation and traffic emission/secondary formation were apportioned as possible pollution sources for the PM2.5-bound PASHs in Taiyuan and Guangzhou, respectively. Dithiothreitol and cell viability assays were applied for evaluations of PASH-induced reactive oxygen species (ROS) production and cell toxicity based on the determined real exposure levels for adults. The results illustrated that PASHs in PM2.5 possibly caused oxidative stress and inhibition of human bronchial epithelial cells in seriously polluted regions such as Taiyuan, suggesting that the pollutant-induced health concerns may need more investigations. This study provides new insights into PM2.5 pollution, and is beneficial for the development of effective contamination control strategies and reduction of risks on public health.

Hetero-Diels-Alder Reactions of In Situ-Generated Azoalkenes with Thioketones; Experimental and Theoretical Studies.

The hetero-Diels-Alder reactions of in situ-generated azoalkenes with thioketones were shown to offer a straightforward method for an efficient and regioselective synthesis of scarcely known N-substituted 1,3,4-thiadiazine derivatives. The scope of the method was fairly broad, allowing the use of a series of aryl-, ferrocenyl-, and alkyl-substituted thioketones. However, in the case of N-tosyl-substituted cycloadducts derived from 1-thioxo-2,2,4,4-tetramethylcyclobutan-3-one and the structurally analogous 1,3-dithione, a more complicated pathway was observed. By elimination of toluene sulfinic acid, the initially formed cycloadducts afforded 2H-1,3,4-thiadiazines as final products. Advanced DFT calculations revealed that the observed high regioselectivity was due to kinetic reaction control and that the (4 + 2)-cycloadditions of sterically less unhindered thiones occurred via highly unsymmetric transition states with shorter C..S-distances (2.27-2.58 Å) and longer N..C-distances (3.02-3.57 Å). In the extreme case of the sterically very hindered 2,2,4,4-tetramethylcyclobutan-1,3-dione-derived thioketones, a zwitterionic intermediate with a fully formed C‒S bond was detected, which underwent ring closure to the 1,3,4-thiadiazine derivative in a second step. For the hypothetical formation of the regioisomeric 1,2,3-thiadiazine derivatives, the DFT calculations proposed more symmetric transition states with considerably higher energies.

Strategies for the Synthesis of Mono- and Bis-Thionaphthoquinones.

The subclass of compounds that have the nucleus 1, 4-naphthoquinone is the most diverse class of quinones, which have a large number of substances and have useful applications ranging from medicinal chemistry to application in materials with special properties. The introduction of one or two substituents with the sulfur heteroatom in the naphthoquinone nucleus generates products containing alkyl and aryl groups that amplify certain biological properties against bacteria, viruses, and fungi. There are several methods of preparing these compounds, mainly from low molecular weight naphthoquinones with two electrophilic sites capable of reacting with sulfides generating diversity and new classes of compounds, including new sulfur heterocycles and sulfur heterocycles fused with naphthoquinones. These compounds have been shown to be bioactive against several biological targets. This review will describe the methods of their synthesis and, when applicable, their biological activities.