Aromatic C(sp2 )-H Functionalization by Consecutive Paired Electrolysis: Dibromination of Aryl Amines with Dibromoethane at Room Temperature.

Herein, we disclose a facile and efficient electrochemical method for the dibromination of aryl amines by double functionalization of aromatic C(sp2 )-H (both para and ortho) under metal- and external oxidant-free conditions at room temperature for the first time. The reaction is demonstrated using 1,2-dibromoethane to dibrominate a wide range of N-substituted aryl amines in a simple setup with C(+)/Pt(-) electrodes under mild reaction conditions. This transformation proceeds smoothly with a broad substrate scope affording the valuable and versatile N-substituted 2,4-dibromoanilines in moderate to excellent yields with high regioselectivity. In this paired electrolysis, cathodic reduction of 1,2-DBE followed by anodic oxidation generates bromonium intermediates, which then couple with anilines to furnish the dibrominated products. It represents a distinctive approach to challenging redox-neutral reactions. The versatility of the electrochemical ortho-, para-dibromination was reflected by unique regioselectivities for challenging aryl amines and gram-scale electrosynthesis without the use of a stoichiometric oxidant or an activating agent.

PIDA-promoted metal-free [3 + 2] heteroannulation of ß-ketothioamides with 4-hydroxy coumarins: chemo-/regioselective access to furo[3,2-c]chromen-4-ones at room temperature.

Herein, we report a viable protocol to access furo[3,2-c]chromen-4-ones by engaging easily accessible 4-hydroxy coumarins as a three-atom CCO unit and thioamides as a C2 coupling partner, mediated by phenyliodine(III) diacetate (PIDA) at room temperature in a highly efficient and pot-/step-economical manner. This strategy not only avoids potential toxicity and tiresome workup conditions, but also features operational simplicity, a broad substrate scope, good functional group tolerance, high yields, easy scalability and exclusive selectivity. A mechanistic study has shown that this metal-free reaction is triggered by PIDA via activation of the ß-carbon of 4-hydroxy coumarin, followed by a nucleophilic addition/intramolecular cyclization/dethiohydration cascade. High-resolution mass spectra (HRMS) study confirms the key intermediates involved during the course of the reaction, elucidating the reaction pathways, and demonstrates the excellent regio- and chemoselectivity of this approach.

REverse transcriptase ACTivity (REACT) assay for point-of-care measurement of established and emerging antiretrovirals for HIV treatment and prevention.

Maintaining adequate levels of antiretroviral (ARV) medications is crucial for the efficacy of HIV treatment and prevention regimens. Monitoring ARV levels can predict or prevent adverse health outcomes like treatment failure or drug resistance. However, conventional ARV measurement using liquid chromatography-tandem mass spectrometry (LC-MS/MS) is slow, expensive, and centralized delaying clinical and behavioral interventions. We previously developed a rapid enzymatic assay for measuring nucleotide reverse transcriptase inhibitors (NRTIs) - the backbone of HIV treatment and prevention regimens - based on the drugs' termination of DNA synthesis by HIV reverse transcriptase (RT) enzyme. Here, we expand our work to include non-nucleoside reverse transcriptase inhibitors (NNRTIs) - an ARV class used in established and emerging HIV treatment and prevention regimens. We demonstrate that the REverse Transcriptase ACTivity (REACT) assay can detect NNRTIs including medications used in oral and long-acting/extended-release HIV treatment and prevention. We demonstrate that REACT can measure NNRTIs spiked in either buffer or diluted plasma and that fluorescence can be measured on both a traditional plate reader and an inexpensive portable reader that can be deployed in point-of-care (POC) settings. REACT measured clinically relevant concentrations of five NNRTIs spiked in aqueous buffer. REACT measurements showed excellent agreement between the plate reader and the portable reader, with a high correlation in both aqueous buffer (Pearson's r = 0.9807, P < 0.0001) and diluted plasma (Pearson's r = 0.9681, P < 0.0001). REACT has the potential to provide rapid measurement of NNRTIs in POC settings and may help to improve HIV treatment and prevention outcomes.

Telemedicine-Related Opioid Use Disorder Services in Underserved Populations: A Qualitative Evaluation of the Waiver Era.

Introduction: This pilot study examined access to telemedicine-related opioid use disorder (OUD) treatment in underserved communities in Houston, Texas before July 30, 2023. Methods: Participants, both patients and providers, were recruited in partnership with local substance use treatment clinics. Both groups shared experiences before and after the waiver era. Rapid qualitative analysis was conducted by the research team. Results: Fourteen qualitative interviews were conducted via Zoom with 5 treatment providers and 9 self-identified Black or Hispanic patient participants. Participants generally approved telemedicine for OUD treatment due to its technological accessibility and flexibility. However, concerns about technology, care quality, relationship building, and privacy were common among both patients and providers. Discussion: Our study highlights the underutilization of telemedicine for OUD treatment in underserved Houston communities. Efforts to address current limitations and leverage recent policy changes can help bridge the utilization gap in underserved areas.

Electronically-controlled diastereoselective synthesis of spirocycles via [4 + 2] cycloaddition of 2-arylidene-1-indenones with benzyne.

A one-pot electronically controlled [4 + 2] cycloaddition reaction of in situ generated benzyne with 2-arylidene-1-indenone is unveiled to construct novel spirocyclic frameworks in a regio- and diastereoselective fashion. This protocol features operational simplicity, good functional group tolerance and avoids the use of metal catalysts and external additives. This methodology has extended the synthetic application of 2-arylidene-1-indenones enabling easy access to valuable 10'H-spiro[indene-2,9'-phenanthren]-1(3H)-ones in good yields.

Regio- and Chemoselective Access to Dihydrothiophenes and Thiophenes via Halogenation/Intramolecular C(sp2)-H Thienation of α-Allyl Dithioesters at Room Temperature.

An operationally simple, practical, and efficient cascade approach employing α-allyl dithioesters and NBS/NIS has been achieved to access a series of dihydrothiophenes and thiophenes containing diverse functional groups of different electronic and steric natures in good to excellent yields at room temperature in open air. The reaction proceeds via the electrophilic addition of a halogen source (NBS/NIS) to an allylic double bond, followed by intramolecular regio- and chemoselective S-cyclization. This protocol avoids potential toxicity and tedious work-up conditions, and features easy synthesis from readily available starting materials under catalyst-free conditions. Furthermore, 4,5-dihydrothiophenes were aromatized to thiophenes by treatment with KOH in DMF at room temperature. A probable mechanism for the formation of dihydrothiophenes and thiophenes from α-allyl dithioesters has been suggested. Notably, a large-scale experiment and the transformations of products indicated the potential utility of this reaction compared to competing processes for the synthesis of 4,5-dihydrothiophenes and thiophenes.

Metal-Free One-Pot Annulative Coupling of 2-Hydroxybenzaldehydes with ß-Ketothioamides: Access to Diverse 2-Arylimino-2H-Chromenes.

A concise and practical one-pot sustainable approach for expedient synthesis of 2-arylimino-2H-chromenes by two-component cascade [4 + 2] annulative coupling of easily available 2-hydroxybenzaldehydes with ß-ketothioamides has been developed in good yields for the first time. Remarkably, metal- and additive-free conditions, use of simple K2CO3 as a mild base, open atmosphere, exclusive regioselectivity, step/atom economy, nonhazardous reagents, and easy purification are added characteristics to the strategy. This annulative protocol will not only provide an efficient method to access diverse chromene scaffolds, but also enrich the research domain of ß-ketothioamides.

Selective C3-Allylation and Formal [3 + 2]-Annulation of Spiro-Aziridine Oxindoles: Synthesis of 5'-Substituted Spiro[pyrrolidine-3,3'-oxindoles] and Coerulescine.

Brønsted acid- and/or Lewis acid-catalyzed selective C3-allylation and formal [3 + 2]-annulation of spiro-aziridine oxindoles with allylsilanes have been demonstrated to deliver direct access to 3-allyl-3-aminomethyl oxindoles and 5-silyl methyl spiro[pyrrolidine-3,3'-oxindoles], respectively. The acid-catalyzed methods do not provide any stereoselectivity when chiral spiroaziridines are used. However, the reaction of nonracemic sprioaziridines with allyl-Grignard reagent under catalyst-free conditions afforded 3-allyl-3-aminomethyl oxindoles with good stereoselectivity (ee up to 80%). The allylation protocol is utilized for the short synthesis of coerulescine and various 5'-substituted spiro[pyrrolidine-3,3'-oxindoles].

Magnesium catalyzed [3 + 3] heteroannulation of α-enolic dithioesters with MBH acetate: access to functionalized 3,4-dihydro-2H-thiopyrans.

Magnesium catalysis proved to be efficient towards [3 + 3] chemo- and diastereoselective heteroannulation employing racemic Morita-Baylis-Hillman (MBH) acetate as the C3 unit and α-enolic dithioester as the C2S1 unit, leading to highly substituted 3,4-dihydro-2H-thiopyrans in excellent yields. The compatibility with a wide range of functional groups makes this domino formation of C-C and C-S bonds interesting. DFT analyses for the regioselective formation of the intermediate was performed.

Unusual Behavior of Ketoximes: Reagentless Photochemical Pathway to Alkynyl Sulfides.

The unique properties of ketoximes are used prominently for the synthesis of heterocycles. In contrast, their potential to absorb light and photoelectron transfer processes remains challenging. Widespread interest in controlling direct excitation of ketoxime tacticity unlocks unconventional reaction pathways, enabling photochemical intramolecular skeletal modification to constitute alkynyl sulfides that cannot be realized via traditional activation. Despite decades of advancements, the alkynyl sulfides, particularly those composed of polar functionalities and derived from renewable sources, remain unknown. These findings demonstrate the importance of decelerated ketoxime from ß-oxodithioester for the identification of reaction conditions. The method uses mild reaction conditions to generate excited-state photoreductant for the functionalization of an array of alkynyl sulfides. Additionally, a fundamental understanding of elementary steps using electrochemical and spectroscopic techniques/experiments revealed a PCET pathway to this transformation, while the involved substrates and their properties with improved economical tools indicated the translational potential of this method.

Electrochemical Synthesis of 1,2,3-Thiadiazoles from α-Phenylhydrazones.

We have developed an electrochemical approach for the synthesis of fully substituted 1,2,3-thiadiazoles from α-phenylhydrazones at room temperature, which is very challenging and complementary to the conventional thermal reactions. The key step involves anodic oxidation of phenylhydrazone derivatives at a constant current followed by N,S-heterocyclization. The protocol is remarkable in that it is free of a base and free of an external oxidant and can be converted to a gram scale for postsynthetic drug development with functional thiadiazoles. Most importantly, the electrochemical transformation reflected efficient electro-oxidation with an operationally friendly easy procedure with ample functional molecules. Cyclic voltammograms support the mechanism of this electro-oxidative cyclization process.

Visible-Light-Driven Photocatalyst- and Additive-Free Cross-Coupling of ß-Ketothioamides with α-Diazo 1,3-Diketones: Access to Highly Functionalized Thiazolines.

A photocatalyst- and additive-free, visible-light-mediated chemoselective domino protocol was devised to access fully substituted thiazoline derivatives from ß-ketothioamides and α-diazo 1,3-diketones at moderate temperature in open air. The reaction proceeds through in situ generation of electrophilic carbenes from α-diazo 1,3-diketones by a low-energy blue LED (448 nm), which undergoes selective coupling with nucleophilic ß-ketothioamides to give thiazolines by successive formation of C-S and C-N bonds in one stretch. Notably, the benign and clean conditions, operational simplicity, sustainability, 100 % carbon economy, high yields, and wide functional-group tolerance are further attributes of the strategy. A mechanistic rationale for this cascade reaction sequence is well supported by control experiments.

Visible-Light Photocatalysis of Eosin Y: HAT and Complementing MS-CPET Strategy to Trifluoromethylation of ß-Ketodithioesters with Langlois' Reagent.

A metal- and oxidant-free photoinduced strategy for thioxo sulfur-selective trifluoromethylation of ß-ketodithioesters at room temperature is reported. Excellent Z/E-stereoselectivity has been achieved with cheap and viable Langlois' reagent (CF3SO2Na, sodium triflinate) in the presence of eosin Y, which acts as a hydrogen atom transfer (HAT) catalyst. The reaction proceeds via disulfide intermediate disulfanediylbis(3-(alkylthio)-1-phenylprop-2-en-1-one) (a dimer of ß-ketodithioester) followed by complementing proton-coupled electron transfer-mediated reverse HAT cycle of eosin Y. This operationally simple and efficient protocol allows direct access to triflinated α-oxoketene dithioacetals in good to excellent yields bearing diverse synthetically useful functional groups of different electronic and steric nature.

Rhodium(II)-Catalyzed Annulative Coupling of ß-Ketothioamides with α-Diazo Compounds: Access to Highly Functionalized Thiazolidin-4-ones and Thiazolines.

An operationally simple and efficient one-pot protocol for the synthesis of highly functionalized thiazolidin-4-ones and thiazolines has been devised via Rh(OAc)2-catalyzed annulative coupling of ß-ketothioamides with diazo compounds under mild reaction conditions for the first time. This double functionalization of diazo compounds proceeds via selective S-alkylation followed by intramolecular N-cyclization enabling the formation of C-S and C-N bonds at moderate temperature. Notably, the products possess Z-stereochemistry with regard to the exocyclic C═C double bond at the 2-position of the ring. Further, the synthetic utility of the strategy has been revealed to access 2,3-dihydrobenzo[d]thiazoles. Remarkably, atom economy and tolerance of a wide range of functional groups are added characteristics to this strategy.

Organocatalytic Domino Reaction of Spiroaziridine Oxindoles and Malononitrile for the Enantiopure Synthesis of Spiro[dihydropyrrole-3,3'-oxindoles].

The first organocatalytic regio- and stereoselective domino reactions of spiroaziridine oxindoles and malononitrile have been developed using DBU as a catalyst without any metal/Lewis acid activation for the enantiopure synthesis of spiro[dihydropyrrole-3,3'-oxindoles] (ee up to >99%). The protocol is also equally effective for the phenyl aziridine with excellent regio- and stereoselectivity.

Visible-Light-Mediated Synthesis of 1,2,4-Dithiazolidines from ß-Ketothioamides through a Hydrogen-Atom-Transfer Photocatalytic Approach of Eosin Y.

An efficient protocol for visible-light-mediated synthesis of a specific class of 1,2,4-dithiazolidines from ß-ketothioamides is devised employing eosin Y as a photoinitiator at ambient temperature in an open pot. The reaction proceeds via an in situ-generated thiyl radical followed by dimerization/deaminative cyclization cascade, enabling the creation of a dithiazolidine ring through successive formation of S-S and N-C bonds under metal- and additive-free conditions. Remarkably, the benign conditions, sustainability, and quantifying forbearance of wide horizons of functional groups are added characteristics to the strategy. The developed hydrogen-atom-transfer methodology will be helpful in postsynthetic modification via added synthetic handles.

Phosphonium ylide catalysis: a divergent diastereoselective approach to synthesize cyclic ketene acetals [thia(zolidines/zinanes)] from ß-ketothioamides and dihaloalkanes.

Phosphonium ylides are being reported here as a catalyst for the formation of thiazolidines and 1,3-thiazinanes from ß-ketothioamides (which act as a three atom N, C, and S synthon) with dihaloalkanes via [3 + 2] and [3 + 3] annulations under metal-free conditions. An N,C,S-centred chemoselective dihaloalkane-controlled cascade process has been identified for the preparation of cyclic N,S-heterocycles (thiazolidines and 1,3-thiazinanes) from identical ß-ketothioamides. The reaction proceeds via consecutive sulfur and nitrogen nucleophilic attack of the thioamide on dihaloalkanes enabling the formation of S-C and N-C bonds. The ring size of the skeletally distinct N,S-heterocycles has been efficiently tuned by switching the use of 1,2- and 1,3-dihaloalkanes as α,ß- and α,γ-dielectrophiles. It is noteworthy that the products possess Z-stereochemistry with regard to the exocyclic C[double bond, length as m-dash]C double bond at the 2-position of the ring, revealing exclusive diastereoselectivity. Since phosphorus ylides have found limited use as catalysts, control experiments revealed their behaviour as a catalyst, which not only increase the catalyst tool box, but also would contribute to the field of ylide chemistry.

Metal-Free One-Pot Four-Component Cascade Annulation in Ionic Liquids at Room Temperature: Convergent Access to Thiazoloquinolinone Derivatives.

An efficient, eco-friendly, and highly convergent one-pot route to privileged thiazoloquinolinone derivatives has been developed via four-component cascade coupling (4CCC) of α-enolic dithioesters, cysteamine/2-aminothiophenols, aldehydes, and cyclic 1,3-diketones in recyclable [EMIM][EtSO4] ionic liquid at room temperature for the first time. The reaction proceeds via a N,S-acetal formation, Knoevenagel condensation, aza-ene reaction, imine-enamine/keto-enol tautomerization, and intramolecular N-cyclization cascade sequence. The merit of the protocol is highlighted by its efficacy of forming consecutive five new bonds (two C-C, two C-N, and one C-S) and two rings with all reactants being efficiently utilized. The operational simplicity, sustainability, mild conditions, excellent yields, tolerance of wide functional groups, and avoidance of expensive/toxic reagents are additional attributes to this domino four-component protocol. Notably, the products were easily separated from the ionic liquid, and thus the ionic liquid obtained was reused four times without considerable loss of any activity.

Copper-Catalyzed One-Pot Cross-Dehydrogenative Thienannulation: Chemoselective Access to Naphtho[2,1-b]thiophene-4,5-diones and Subsequent Transformation to Benzo[a]thieno[3,2-c]phenazines.

A facile, cost-effective, and highly efficient copper-catalyzed, TEMPO-mediated straightforward synthesis of 2,3-disubstituted naphtho[2,1-b]thiophene-4,5-diones has been achieved via cross-dehydrogenative thienannulation. The reaction proceeded via in situ generated naphthalene-1,2-diones by dearomatization of ß-naphthols, followed by oxidative heteroannulation with α-enolic dithioesters chemoselectively in an open flask. Further, the naphtho[2,1-b]thiophene-4,5-diones undergo l-proline-catalyzed cross-dehydrative coupling with ortho-phenylenediamine enabling pentacyclic benzo[a]thieno[3,2-c]phenazines in good yields under solvent-free conditions. A mechanistic rationale for this cascade reaction sequence is well supported by the control experiments.

Access to Fully Substituted Thiazoles and 2,3-Dihydrothiazoles via Copper-Catalyzed [4 + 1] Heterocyclization of α-(N-Hydroxy/aryl)imino-ß-oxodithioesters with α-Diazocarbonyls.

An efficient chemoselective practical route to fully substituted thiazoles and 2,3-dihydrothiazoles has been devised by [4 + 1] heterocyclization of α-(N-hydroxy/aryl)imino-ß-oxodithioesters with in situ generated Cu-carbenoids of diazocarbonyls. The α-(N-hydroxy/aryl)imino-ß-oxodithioesters are readily accessible by the reaction of ß-oxodithioesters with nitrous acid/nitrosoarenes. The overall transformation involves sequential N-O/C-N bonds cleavage followed by cascade C-N/C-S bonds formation in one-pot. This new strategy allows full control over the introduction of various sensitive functional groups at different positions of the thiazole ring, broadening the arsenal of synthetic methods to obtain such scaffolds.