The Versatile and Strategic O-Carbamate Directed Metalation Group in the Synthesis of Aromatic Molecules: An Update.

The aryl O-carbamate (ArOAm) group is among the strongest of the directed metalation groups (DMGs) in directed ortho metalation (DoM) chemistry, especially in the form Ar-OCONEt2. Since the last comprehensive review of metalation chemistry involving ArOAms (published more than 30 years ago), the field has expanded significantly. For example, it now encompasses new substrates, solvent systems, and metalating agents, while conditions have been developed enabling metalation of ArOAm to be conducted in a green and sustainable manner. The ArOAm group has also proven to be effective in the anionic ortho-Fries (AoF) rearrangement, Directed remote metalation (DreM), iterative DoM sequences, and DoM-halogen dance (HalD) synthetic strategies and has been transformed into a diverse range of functionalities and coupled with various groups through a range of cross-coupling (CC) strategies. Of ultimate value, the ArOAm group has demonstrated utility in the synthesis of a diverse range of bioactive and polycyclic aromatic compounds for various applications.

Probing Alzheimer's pathology: Exploring the next generation of FDDNP analogues for amyloid ß detection.

Fluorescent probes are a powerful tool for imaging amyloid ß (Aß) plaques, the hallmark of Alzheimer's disease (AD). Herein, we report the synthesis and comprehensive characterization of 21 novel probes as well as their optical properties and binding affinities to Aß fibrils. One of these dyes, 1Ae, exhibited several improvements over FDDNP, an established biomarker for Aß- and Tau-aggregates. First, 1Ae had large Stokes shifts (138-213 nm) in various solvents, thereby reducing self-absorption. With a high quantum yield ratio (φ(dichloromethane/methanol) = 104), 1Ae also ensures minimal background emission in aqueous environments and high sensitivity. In addition, compound 1Ae exhibited low micromolar binding affinity to Aß fibrils in vitro (Kd = 1.603 µM), while increasing fluorescence emission (106-fold) compared to emission in buffer alone. Importantly, the selective binding of 1Ae to Aß1-42 fibrils was confirmed by an in cellulo assay, supported by ex vivo fluorescence microscopy of 1Ae on postmortem AD brain sections, allowing unequivocal identification of Aß plaques. The intermolecular interactions of fluorophores with Aß were elucidated by docking studies and molecular dynamics simulations. Density functional theory calculations revealed the unique photophysics of these rod-shaped fluorophores, with a twisted intramolecular charge transfer (TICT) excited state. These results provide valuable insights into the future application of such probes as potential diagnostic tools for AD in vitro and ex vivo such as determination of Aß1-42 in cerebrospinal fluid or blood.

Towards structurally versatile mesoionic N-heterocyclic olefin ligands and their coordination to palladium, gold, and boron hydride.

We have developed an efficient and versatile approach for the synthesis of a family of 1,2,3-triazole-based mesoionic N-heterocyclic olefin (mNHO) ligands and investigated their coordination to palladium, gold, and boron hydride experimentally and computationally. We reacted mNHOs obtained through deprotonation of the corresponding methylated and ethylated 1,3,4-triaryl-1,2,3-triazolium salts with [Pd(allyl)Cl]2 to give the corresponding [Pd(η3-allyl)Cl(mNHO)] coordination complexes. 13C NMR data revealed the strong σ-donor character of the mNHO ligands, consistent with the calculated bond orders and atom-condensed charges. Furthermore, we also synthesized [AuCl(mNHO)] and a BH3-mNHO adduct by reacting the triazolium salts with AuCl(SMe2) and BH3·THF, respectively. The BH3-mNHO adduct was tested in the reduction of select aldehydes and ketones to alcohols.

Leveraging Ligand Affinity and Properties: Discovery of Novel Benzamide-Type Cereblon Binders for the Design of PROTACs.

Immunomodulatory imide drugs (IMiDs) such as thalidomide, pomalidomide, and lenalidomide are the most common cereblon (CRBN) recruiters in proteolysis-targeting chimera (PROTAC) design. However, these CRBN ligands induce the degradation of IMiD neosubstrates and are inherently unstable, degrading hydrolytically under moderate conditions. In this work, we simultaneously optimized physiochemical properties, stability, on-target affinity, and off-target neosubstrate modulation features to develop novel nonphthalimide CRBN binders. These efforts led to the discovery of conformationally locked benzamide-type derivatives that replicate the interactions of the natural CRBN degron, exhibit enhanced chemical stability, and display a favorable selectivity profile in terms of neosubstrate recruitment. The utility of the most potent ligands was demonstrated by their transformation into potent degraders of BRD4 and HDAC6 that outperform previously described reference PROTACs. Together with their significantly decreased neomorphic ligase activity on IKZF1/3 and SALL4, these ligands provide opportunities for the design of highly selective and potent chemically inert proximity-inducing compounds.

Elucidating the reaction mechanism of a palladium-palladium dual catalytic process through kinetic studies of proposed elementary steps.

In the synergistic dual catalytic process, the kinetics of the catalytic cycles must be balanced for the successful outcome of the reaction. Therefore, the analysis of the kinetics of the independent catalytic cycles is essential for such reactions, as it enables their relational optimization as well as their design. Here we describe an analysis of the mechanism of a catalytic synergistic bimetallic reaction through the experimental study of a palladium-catalysed cross-coupling of aryl halides with terminal alkynes, an example of a monometallic dual catalytic process. The proposed mechanism of the investigated reaction was disassembled into two palladium catalytic cycles and further into elementary reactions, and each step was studied independently. The described mechanistic analysis allowed us to identify the rate-determining step of the catalytic process by comparing the rates of the elementary reactions under similar reaction conditions, balanced kinetics of the palladium catalytic cycles, and also in which step which reagent enters the catalytic cycle and how.

Deuterated Drugs and Biomarkers in the COVID-19 Pandemic.

Coronavirus disease 2019 (COVID-19) is a highly contagious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Initially identified in Wuhan (China) in December 2019, COVID-19 rapidly spread globally, resulting in the COVID-19 pandemic. Carriers of the SARS-CoV-2 can experience symptoms ranging from mild to severe (or no symptoms whatsoever). Although vaccination provides extra immunity toward SARS-CoV-2, there has been an urgent need to develop treatments for COVID-19 to alleviate symptoms for carriers of the disease. In seeking a potential treatment, deuterated compounds have played a critical role either as therapeutic agents or as internal MS standards for studying the pharmacological properties of new drugs by quantifying the parent compounds and metabolites. We have identified >70 examples of deuterium-labeled compounds associated with treatment of COVID-19. Of these, we found 9 repurposed drugs and >20 novel drugs studied for potential therapeutic roles along with a total of 38 compounds (drugs, biomarkers, and lipids) explored as internal mass spectrometry standards. This review details the synthetic pathways and modes of action of these compounds (if known), and a brief analysis of each study.

Database Independent Automated Structure Elucidation of Organic Molecules Based on IR, 1H NMR, 13C NMR, and MS Data.

Herein, we report a computational algorithm that follows a spectroscopist-driven elucidation process of the structure of an organic molecule based on IR, 1H and 13C NMR, and MS tabular data. The algorithm is independent from database searching and is based on a bottom-up approach, building the molecular structure from small structural fragments visible in spectra. It employs an analytical combinatorial approach with a graph search technique to determine the connectivity of structural fragments that is based on the analysis of the NMR spectra, to connect the identified structural fragments into a molecular structure. After the process is completed, the interface lists the compound candidates, which are visualized by the WolframAlpha computational knowledge engine within the interface. The candidates are ranked according to the predefined rules for analyzing the spectral data. The developed elucidator has a user-friendly web interface and is publicly available (http://schmarnica.si).

Designing Homogeneous Copper-Free Sonogashira Reaction through a Prism of Pd-Pd Transmetalation.

Simultaneous introduction of two different palladium (pre)catalysts, one tuned to promote oxidative addition to (hetero)aryl bromide and another to activate terminal alkyne substrate, leads to productive Pd-Pd transmetalation, subsequent reductive elimination, and formation of disubstituted alkyne. This conceptually novel rational design of copper-free Sonogashira reaction enabled facile identification of the reaction conditions, suitable for the synthesis of alkyl, aryl, and heteroaryl substituted alkynes at room temperature with as low as 0.125 mol % total Pd loading.

Pyridine Wingtip in [Pd(Py-tzNHC)2]2+ Complex Is a Proton Shuttle in the Catalytic Hydroamination of Alkynes.

The cationic palladium(II) complex 1 of pyridyl-mesoionic carbene ligand catalyzes Markovnikov-selective intermolecular hydroamination between anilines and terminal alkynes into the corresponding imines. The reaction proceeds at room temperature, in the absence of additives, with exquisite selectivity and diverse functional group tolerance. The key intrinsic feature of the catalyst is the pyridine wingtip confined to the proximity of the alkynophilic metal active site, which mimics the function of enzyme-like architectures by assisting entropically favored proton transfers.

Preparation of Quinoline-2,4-dione Functionalized 1,2,3-Triazol-4-ylmethanols, 1,2,3-Triazole-4-carbaldehydes and 1,2,3-Triazole-4-carboxylic Acids.

(1-(2,4-Dioxo-1,2,3,4-tetrahydroquinolin-3-yl)-1H-1,2,3-triazol-4-yl)methyl acetates substituted on nitrogen atom of quinolinedione moiety with propargyl group or (1-substituted 1H-1,2,3-triazol-4-yl)methyl group, which are available from the appropriate 3-(4-hydroxymethyl-1H-1,2,3-triazol-1-yl)quinoline-2,4(1H,3H)-diones unsubstituted on quinolone nitrogen atom by the previously described procedures, were deacetylated by acidic ethanolysis. Thus obtained primary alcohols, as well as those aforenamed unsubstituted on quinolone nitrogen atom, were oxidized to aldehydes on the one hand with pyridinium chlorochromate (PCC), on the other hand with manganese dioxide, and to carboxylic acids using Jones reagent in acetone. The structures of all prepared compounds were confirmed by 1H, 13C and 15N NMR spectroscopy. The corresponding resonances were assigned on the basis of the standard 1D and gradient selected 2D NMR experiments (1H-1H gs-COSY, 1H-13C gs-HSQC, 1H-13C gs-HMBC) with 1H-15N gs-HMBC as a practical tool to determine 15N NMR chemical shifts at the natural abundance level of 15N isotope.

Scalable Synthesis of Salt-free Quaternary Ammonium Carboxylate Catanionic Surfactants.

Surfactants in commercial products commonly contain catanionic mixtures thus many studies of aqueous surfactant mixtures have been carried out. However, hardly any studies have been dedicated to pure catanionic surfactants often termed salt-free catanionic surfactants. One of the difficulties is in acquirement of samples with required purity due to difficult separation of these compounds from inorganic salts. In this work we present an alternative method of synthesis using dimethyl carbonate as the alkylating agent in order to obtain alkyl trimethylammonium alkanecarboxylates with medium alkyl chain lengths (6-10).

Arylation of Click Triazoles with Diaryliodonium Salts.

A robust, selective, and highly efficient method for the preparation of 1,3,4-triaryl 1,2,3-triazolium salts has been developed. It features arylation of a click triazole with a diaryliodonium salt in the presence of a copper catalyst under neat conditions. The presence of pyridine functionality is tolerated, enabling the first access to key precursors of pyridyl-mesoionic carbene ligands. The method has been integrated into a one-pot protocol with terminal alkyne, sodium azide, and diaryliodonium salt as starting compounds.

1 H-15 N HMBC NMR as a tool for rapid identification of isomeric azaindoles: The case of 5F-MDMB-P7AICA.

The high frequency of the synthetic cannabinoid receptor agonists (SCRAs) emergence renders this group of new psychoactive compounds particularly demanding in terms of detection, identification, and responding. Without the available reference material, one of the specific problems is differentiation and structure elucidation of constitutional isomers. Herein, we report a simple and efficient flow chart diagram applicable for a rapid nuclear magnetic resonance (NMR) identification and differentiation between azaindoles, 4-, 5-, 6-, and 7-azaindole, which is a common structural motif of synthetic cannabinoids. The flow chart diagram is based on 1 H NMR and 1 H-15 N NMR spectra, and to prove the concept, it has been tested on 5F-MDMB-P7AICA (1). Spectral and analytical data including standard 1D and 2D NMR spectra, gas chromatography-mass spectrometry (GC-MS), Fourier transform infrared-attenuated total reflectant (FTIR-ATR), Raman, melting point, and combustion analysis are provided for compound 1.

The Value of In Vitro Binding as Predictor of In Vivo Results: A Case for [18F]FDDNP PET.

PURPOSE: Caution is warranted when in vitro results of biomarkers labeled with tritium were perfunctorily used to criticize in vivo data and conclusions derived with the same tracers labeled with positron emitters and positron emission tomography (PET). This concept is illustrated herein with the PET utilization of [18F]FDDNP, a biomarker used for in vivo visualization of ß-amyloid and tau protein neuroaggregates in humans, later contradicted by in vitro data reported with [3H]FDDNP. In this investigation, we analyze the multiple factors involved in the experimental design of the [3H]FDDNP in vitro study that led to the erroneous interpretation of results. PROCEDURE: The present work describes full details on the synthesis, characterization, purity, and kinetics of radiolytic stability of [3H]FDDNP. The optimal in vitro conditions for detecting tau and ß-amyloid protein aggregates using macroscopic and microscopic autoradiography with both [18F]FDDNP and [3H]FDDNP are also presented. Macroscopic autoradiography determinations were performed with [3H]FDDNP of verified purity using established methods described previously in the literature. RESULTS: The autoradiographic results using phosphate buffered saline (PBS) with less than 1 % EtOH and pure, freshly prepared [3H]FDDNP compared with the earlier reported data using [3H]FDDNP of undetermined purity and PBS in 10 % EtOH demonstrate the critical importance of rigorous experimental design for meaningful in vitro determinations. [18F]FDDNP binding to both amyloid plaques and neurofibrillary tangles was confirmed by amyloid and tau immunohistochemical stains of adjacent tissues. CONCLUSIONS: This work illustrates the sensitivity of in vitro techniques to various experimental conditions and underscores that conclusions obtained from translational in vitro to in vivo determinations must always be performed with extreme care to avoid wrong interpretations that can be perpetuated and assumed without further analysis.

Mechanism of copper-free Sonogashira reaction operates through palladium-palladium transmetallation.

The seminal contributions by Sonogashira, Cassar and Heck in mid 1970s on Pd/Cu- and Pd-catalysed (copper-free) coupling of acetylenes with aryl or vinyl halides have evolved in myriad applications. Despite the enormous success both in academia and in industry, however, critical mechanistic questions of this cross-coupling process remain unresolved. In this study, experimental evidence and computational support is provided for the mechanism of copper-free Sonogashira cross-coupling reaction. In contrast to the consensus monometallic mechanism, the revealed pathway proceeds through a tandem Pd/Pd cycle linked via a multistep transmetallation process. This cycle is virtually identical to the Pd/Cu tandem mechanism of copper co-catalysed Sonogashira cross-couplings, but the role of CuI is played by a set of PdII species. Phosphine dissociation from the square-planar reactants to form transient three-coordinate Pd species initiates transmetallation and represents the rate-determining step of the process.

Synthesis of Bis(1,2,3-Triazole) Functionalized Quinoline-2,4-Diones.

Derivatives of 3-(1H-1,2,3-triazol-1-yl)quinoline-2,4(1H,3H)-dione unsubstituted on quinolone nitrogen atom, which are available by the previously described four step synthesis starting from aniline, were exploited as intermediates in obtaining the title compounds. The procedure involves the introduction of propargyl group onto the quinolone nitrogen atom of mentioned intermediates by the reaction of them with propargyl bromide in N,N-dimethylformamide (DMF) in presence of a potassium carbonate and the subsequent formation of a second triazole ring by copper catalyzed cyclisation reaction with azido compounds. The products were characterized by ¹H, 13C and 15N NMR spectroscopy. The corresponding resonances were assigned on the basis of the standard 1D and gradient selected 2D NMR experiments (¹H⁻¹H gs-COSY, ¹H⁻13C gs-HSQC, ¹H⁻13C gs-HMBC) with ¹H⁻15N gs-HMBC as a practical tool to determine 15N NMR chemical shifts at the natural abundance level of 15N isotope.

Versatile Coordination of Azocarboxamides: Redox-Triggered Change of the Chelating Binding Pocket in Ruthenium Complexes.

Azocarboxamides occupy a special place among azo ligands owing to their versatility for metal coordination. Herein ruthenium complexes with two different azocarboxamide ligands that differ in the presence (or not) of a coordinating pyridyl heterocycle are presented. By making full use of the O,N(amide), N(azo), and N(pyridyl) coordinating sites, the first diruthenium complex that is bridged by an azo ligand containing two different binding pockets was obtained. Moreover, it was conclusively proven that, in the mononuclear complexes, oxidation at the ruthenium center leads to a complete change of coordination at the chelating binding pocket. The complexes were characterized by NMR spectroscopy, mass spectrometry, and single-crystal X-ray diffraction. Additionally, the mechanism of the aforementioned redox-triggered change in the chelating binding pocket and the electronic structures of all the complexes were investigated by a combination of electrochemistry, UV/Vis/NIR/EPR spectroelectrochemistry, and DFT calculations. This is first instance in which a redox-driven change in the complete chelating binding pocket has been observed in a ruthenium complex as well as with azo-based ligands. These results thus show the potential of these versatile azocarboxamide ligands to act as redox-driven switches with possible relevance to electrocatalysis.

Seasonal and spatial variations in the occurrence, mass loadings and removal of compounds of emerging concern in the Slovene aqueous environment and environmental risk assessment.

This study reports the development of a multi-residue method for determining 48 compounds of emerging concern (CEC) including three diclofenac transformation products (TP) in Slovenian wastewater (WW) and surface water (SW). For solid-phase extraction (SPE), Oasis™ Prime cartridges were favoured over Oasis HLB™. The validated method was then applied to 43 SW and 52 WW samples collected at nine locations. Ten bisphenols in WW and 14 bisphenols in SW were traced in Europe for the first time. Among all of the 48 targeted CEC, 21 were >LOQ in the influents and 20 in the effluents. One diclofenac TP was also quantified in WWs (3.04-78.1 ng L-1) for the first time. As expected, based on mass loads in the wastewater treatment plant influents, caffeine is consumed in high amounts (105,000 mg day-1 1000 inhab.-1) in Slovenia, while active pharmaceutical ingredients (APIs) are consumed in lower amounts compared to other European countries. Removal was lower in winter in the case of four bisphenols (17-78%), one preservative (36%) and four APIs (-14-91%), but remained constant for caffeine, one API, two UV-filters and three preservatives (all >85.5%). Overall, a constructed wetland showed the lowest (0-80%) and most inconsistent removal efficiencies (SD > 40% for some CECs) of CECs including caffeine, two UV-filters, two preservatives and two APIs compared to other treatment technologies. The method was also able to quantify Bisphenol S in SW (<36.2 ng L-1). Environmental risk was assessed via risk quotients (RQs) based on WW and SW data. Two UV-filters (oxybenzone and dioxybenzone), estrone and triclosan, despite their low abundance posed a medium to high environmental risk with RQs between 0.282 (for HM-BP) and 15.5 (for E1).

Systematic Evaluation of 2-Arylazocarboxylates and 2-Arylazocarboxamides as Mitsunobu Reagents.

2-Arylazocarboxylate and 2-arylazocarboxamide derivatives can serve as replacements of typical Mitsunobu reagents such as diethyl azodicarboxylate. A systematic investigation of the reactivity and physical properties of those azo compounds has revealed that they have an excellent ability as Mitsunobu reagents. These reagents show similar or superior reactivity as compared to the known azo reagents and are applicable to the broad scope of substrates. p Ka and steric effects of substrates have been investigated, and the limitation of the Mitsunobu reaction can be overcome by choosing suitable reagents from the library of 2-arylazocarboxylate and 2-aryl azocarboxamide derivatives. Convenient recovery of azo reagents is available by one-pot iron-catalyzed aerobic oxidation, for example. SC-DSC analysis of representative 2-arylazocarboxylate and 2-arylazocarboxamide derivatives has shown high thermal stability, indicating that these azo reagents possess lower chemical hazard compared with typical azo reagents.

En Route to 2-(Cyclobuten-1-yl)-3-(trifluoromethyl)-1H-indole.

A six-step synthetic route from 4-chloro-2-methylaniline to 5-chloro-2-(cyclobut-1-en-1-yl)-3-(trifluoromethyl)-1H-indole (1) has been reported. Compound 1a is a key impurity of reverse transcriptase inhibitor efavirenz, an important anti-HIV/AIDS drug. Synthetic challenges, dead ends, and detours are discussed.