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The preparation of high-sulfur content organosulfur polymers has generated considerable interest as an emerging area in polymer science that has been driven by advances in the inverse vulcanization polymerization of elemental sulfur with organic comonomers. While numerous new inverse vulcanized polysulfides have been made over the past decade, insights into the mechanism of inverse vulcanization and structural characterization of the high-sulfur-content copolymers remain limited in scope. Furthermore, the exploration of new molecular architectures for organic comonomer synthesis remains an important frontier to enhance the properties of these new polymeric materials. In the current report, the first detailed study on the synthesis and inverse vulcanization of polycyclic rigid comonomers derived from norbornadiene was conducted, affording a quantitative assessment of polymer microstructure for these organopolysulfides and insights into the inverse vulcanization polymerization mechanism for this class of monomers. In particular, a stereoselective synthesis of the endo-exo norbornadiene cyclopentadiene adduct (Stillene) was achieved, which enabled direct comparison with the known exo-exo norbornadiene dimer (NBD2) previously used for inverse vulcanization. Reductive degradation of these sulfur copolymers and detailed structural analysis of the recovered sulfurated organic fragments revealed that remarkable exo-stereospecificity was achieved in the inverse vulcanization of elemental sulfur with both these polycyclic dienyl comonomers, which correlated to the robust thermomechanical properties associated with organopolysulfides made from NBD2 previously. Melt processing and molding of these sulfur copolymers were conducted to fabricate free-standing plastic lenses for long-wave infrared thermal imaging.
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This Perspective is a continuation of our analysis of U.S. FDA-approved small-molecule drugs (1938-2012) containing nitrogen heterocycles. In this study we report drug structure and property analyses of 321 unique new small-molecule drugs approved from January 2013 to December 2023 as well as information about frequency of important heteroatoms such as sulfur and fluorine and key small nitrogen substituents (CN and NO2). The most notable change is an incredible increase in drugs containing at least one nitrogen heterocycleâ82%, compared to 59% from preceding decadesâas well as a significant increase in the number of nitrogen heterocycles per drug. Pyridine has claimed the #1 high-frequency nitrogen heterocycle occurrence spot from piperidine (#2), with pyrimidine (#5), pyrazole (#6), and morpholine (#9) being the big top 10 climbers. Also notable is high number of fused nitrogen heterocycles, apparently driven largely by newly approved cancer drugs.
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Aprobación de Drogas , Compuestos Heterocíclicos , Nitrógeno , United States Food and Drug Administration , Humanos , Compuestos Heterocíclicos/química , Nitrógeno/química , Preparaciones Farmacéuticas/química , Estados Unidos , Pirimidinas/químicaRESUMEN
Dithiophosphoric acids (DTPAs) are an intriguing class of compounds that are sourced from elemental sulfur and white phosphorus and are prepared from the reaction of phosphorus pentasulfide with alcohols. The electrophilic addition of DTPAs to alkenes and unsaturated olefinic substrates is a known reaction, but has not been applied to polymer synthesis and polymer functionalization. We report on the synthesis and application of DTPAs for the functionalization of challenging poly-enes, namely polyisoprene (PI) and polynorbornene (pNB) prepared by ring-opening metathesis polymerization (ROMP). The high heteroatom content within DTPA moieties impart intriguing bulk properties to poly-ene materials after direct electrophilic addition reactions to the polymer backbone introducing DTPAs as side chain groups. The resulting materials possess both enhanced optical and flame retardant properties vs the poly-ene starting materials. Finally, we demonstrate the ability to prepare crosslinked polydiene films with di-functional DTPAs, where the crosslinking density and thermomechanical properties can be directly tuned by DTPA feed ratios.
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We report a stereoselective synthesis of conjugated di- and trienamides from the direct one pot γ-selective union of a dienolate and chiral nonconjugated and conjugated sulfinyl imines, respectively. This class of anionic cascades was uncovered as part of efforts to challenge the steric limitations of an anionic asymmetric amino-Cope rearrangement platform. Reaction scope studies have uncovered the substitution patterns essential for starting chiral tri- and Z-disubstituted conjugated and nonconjugated sulfinyl imines to be matched for the anionic cascade. Mechanistic studies indicate that, following an initial γ-dienolate Mannich attack, an intermediate 5,6-dihydropyridin-2(1H)-one is formed and then ring-opened.
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The synthesis of deuterated, sulfurated, proton-free, glassy polymers offers a route to optical polymers for infrared (IR) optics, specifically for midwave IR (MWIR) photonic devices. Deuterated polymers have been utilized to enhance neutron cross-sectional contrast with proteo polymers for morphological neutron scattering measurements but have found limited utility for other applications. We report the synthesis of perdeuterated d14-(1,3-diisopropenylbenzene) with over 99% levels of deuteration and the preparation of proton-free, perdeuterated poly(sulfur-random-d14-(1,3-diisopropenylbenzene)) (poly(S-r-d14-DIB)) via inverse vulcanization with elemental sulfur. Detailed structural analysis and quantum computational calculations of these reactions demonstrate significant kinetic isotope effects, which alter mechanistic pathways to form different copolymer microstructures for deutero vs proteo poly(S-r-DIB). This design also allows for molecular engineering of MWIR transparency by shifting C-H bond vibrations around 3.3 µm/3000 cm-1 observed in proteo poly(S-r-DIB) to 4.2 µm/2200 cm-1. Furthermore, the fabrication of thin-film MWIR optical gratings made from molding of deuterated-sulfurated, proton-free poly(S-r-d14-DIB) is demonstrated; operation of these gratings at 3.39 µm is achieved successfully, while the proteo poly(S-r-DIB) gratings are opaque at these wavelengths, highlighting the promise of MWIR sensors and compact spectrometers from these materials.
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Organosulfur polymers, such as those derived from elemental sulfur, are an important new class of macromolecules that have recently emerged via the inverse vulcanization process. Since the launching of this new field in 2013, the development of new monomers and organopolysulfide materials based on the inverse vulcanization process is now an active area in polymer chemistry. While numerous advances have been made over the last decade concerning this polymerization process, insights into the mechanism of inverse vulcanization and structural characterization of the high-sulfur-content copolymers that are produced remain challenging due to the increasing insolubility of the materials with a higher sulfur content. Furthermore, the high temperatures used in this process can result in side reactions and complex microstructures of the copolymer backbone, complicating detailed characterization. The most widely studied case of inverse vulcanization to date remains the reaction between S8 and 1,3-diisopropenylbenzene (DIB) to form poly(sulfur-random-1,3-diisopropenylbenzene)(poly(S-r-DIB)). Here, to determine the correct microstructure of poly(S-r-DIB), we performed comprehensive structural characterizations of poly(S-r-DIB) using nuclear magnetic resonance spectroscopy (solid state and solution) and analysis of sulfurated DIB units using designer S-S cleavage polymer degradation approaches, along with complementary de novo synthesis of the sulfurated DIB fragments. These studies reveal that the previously proposed repeating units for poly(S-r-DIB) were incorrect and that the polymerization mechanism of this process is significantly more complex than initially proposed. Density functional theory calculations were also conducted to provide mechanistic insights into the formation of the derived nonintuitive microstructure of poly(S-r-DIB).
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We report a detailed study on the synthesis and aldehyde vinylogation applications of chiral N-sulfinyl imine phosphonate reagents. Two complementary scalable reagent routes, from trialkyl phosphites and methyl phosphonates, respectively, are presented. This reagent class enables significant streamlining in synthesis of conjugated Ellman imines from aldehydes, which can now be accomplished in a single step compared to a more classic 4-step redox-based approach. Aldehyde vinylogation optimizations have revealed significant counterion effects and unexpected competing reaction challenges that needed to be addressed to achieve high yields.
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A polymerization methodology is reported using sulfur monochloride (S2Cl2) as an alternative feedstock for polymeric materials. S2Cl2 is an inexpensive petrochemical derived from elemental sulfur (S8) but has numerous advantages as a reactive monomer for polymerization vs S8. This new process, termed sulfenyl chloride inverse vulcanization, exploits the high reactivity and miscibility of S2Cl2 with a broad range of allylic monomers to prepare soluble, high molar-mass linear polymers, segmented block copolymers, and crosslinked thermosets with greater synthetic precision than achieved using classical inverse vulcanization. This step-growth addition polymerization also allows for preparation of a new class of thiol-free, inexpensive, highly optically transparent thermosets (α = 0.045 cm-1 at 1310 nm), which exhibit among the best optical transparency and low birefringence relative to commodity optical polymers, while possessing a higher refractive index (n > 1.6) in the visible and near-infrared spectra. The fabrication of large-sized optical components is also demonstrated.
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Cloruros , Polímeros , Azufre , Luz , PolimerizacionRESUMEN
We report a new anionic cascade for assembling 2,4-substituted benzoate esters in one pot from racemic ß-fluoro-substituted conjugated tert-butylsulfinyl imines and 3-substituted methyl 2-butenoates. Dienolate formation triggers a Mannich addition followed by an amino-Cope like rearrangement, which results in immediate elimination of fluoride by a lithiated enamine. The newly formed 1,4-diene intermediate contains a highly acidic proton which is spontaneously deprotonated, leading to a facile intramolecular cyclization followed by sulfinamide group elimination and aromatization.
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Benzoatos , Ésteres , Estereoisomerismo , Ciclización , Iminas , AnionesRESUMEN
Phenols and phenolic ethers are significant scaffolds recurring both in nature and among approved small-molecule pharmaceuticals. This compendium presents the first comprehensive compilation and analysis of the structures of U.S. FDA-approved molecules containing phenol or phenolic ether fragments. This dataset comprises 371 structures, which are strongly represented by natural products. A total of 55 of the compounds described here are on the World Health Organization's list of essential medicines. Structural analysis reveals significant differences in the physicochemical properties imparted by phenols versus phenol ethers, each having benefits and drawbacks for drug developability. Despite trends over the past decade to increase the fraction of sp3 centers in drug leads, thereby "escaping flatland", phenols and phenolic ethers are represented in 62% of small-molecule drugs approved in 2020, suggesting that this aromatic moiety holds a special place in drugs and natural products.
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Productos Biológicos , Fenoles , Éteres , Preparaciones Farmacéuticas , Fenol , Fenoles/químicaRESUMEN
The production of elemental sulfur from petroleum refining has created a technological opportunity to increase the valorization of elemental sulfur by the synthesis of high-performance sulfur-based plastics with improved optical, electrochemical, and mechanical properties aimed at applications in thermal imaging, energy storage, self-healable materials, and separation science. In this Perspective, we discuss efforts in the past decade that have revived this area of organosulfur and polymer chemistry to afford a new class of high-sulfur-content polymers prepared from the polymerization of liquid sulfur with unsaturated monomers, termed inverse vulcanization.
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A new intramolecular oxidative amino-hydroxylation of o-allenyl anilines is reported. Treatment of carbamate-protected anilines with lead(IV) carboxylates in dichloromethane at room temperature results in facile tandem C-N (allene cyclization) and C-O bond formation (carboxylate trapping) to form indole products. Detailed reaction scope, mechanistic and kinetic studies suggest a reaction pathway involving an initial Wessely dearomatization step followed by cyclization and rearomatization.
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Compuestos de Anilina , Indoles , Catálisis , Ciclización , Cinética , Estrés OxidativoRESUMEN
The efficient assembly of complex aromatic structures from simple acyclic building blocks is reported. An anion-cascade union of an enoate and a conjugated imine affords cyclohexenone products, which are readily aromatized to phenols. By engaging the intermediate cyclohexenones with Grignard reagents, a facile addition/elimination proceeds yielding chiral cyclohexadienes, which are then aromatized. In a complementary approach, the cyclohexenone products are converted into enol triflates, which provides a gateway to diverse aromatic architectures following cross-couplings and aromatization steps.
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Ciclohexenos , Iminas , FenolesRESUMEN
We report mild new annulation approaches to trisubstituted trifluoromethylthiolated (SCF3) aziridines and cyclopropanes via Darzens inspired protocols. The products of these anionic annulations, rarely studied previously, possess attractive features rendering them valuable building blocks for synthesis platforms. In this study, trisubstituted acetophenone nucleophiles bearing SCF3 and bromine substituents in their α position were shown to undergo [2 + 1] annulations with vinyl ketones and tosyl-protected imines under mild reaction conditions.
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We report a dramatic effect on product outcomes of the lithium ion enabled amino-Cope-like anionic asymmetric cascade when different γ-dienolate heteroatom substituents are employed. For dienolates with azide, thiomethyl, and trifluoromethylthiol substituents, a Mannich/amino-Cope/cyclization cascade ensues to form chiral cyclohexenone products with two new stereocenters in an anti-relationship. For fluoride-substituted nucleophiles, a Mannich/amino-Cope cascade proceeds to afford chiral acyclic products with two new stereocenters in a syn-relationship. Bromide- and chloride-substituted nucleophiles appear to proceed via the same pathway as the fluoride albeit with the added twist of a 3-exo-trig cyclization to yield chiral cyclopropane products with three stereocenters. When this same class of nucleophiles is substituted with a γ-nitro group, the Mannich-initiated cascade is now diverted to a ß-lactam product instead of the amino-Cope pathway. These anionic asymmetric cascades are solvent- and counterion-dependent, with a lithium counterion being essential in combination with etheral solvents such as MTBE and CPME. By altering the geometry of the imine double bond from E to Z, the configurations at the R1 and X stereocenters are flipped. Mechanistic, computational, substituent, and counterion studies suggest that these cascades proceed via a common Mannich-product intermediate, which then proceeds via either a chair (X = N3, SMe, or SCF3) or boat-like (X = F, Cl, or Br) transition state to afford amino-Cope-like products or ß-lactam in the case of X = NO2.
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The FDA Green Book is a list of all drug products that have been approved by the FDA for use in veterinary medicine. The Green Book, as published, lacks structural information corresponding to approved drugs. To address this gap, we have compiled the structural data for all FDA Green Book drugs approved through the end of 2019. Herein we discuss the relevance of this data set to human drugs in the context of structural classes and physicochemical properties. Analysis reveals that physicochemical properties are highly optimized and consistent with a high probability of favorable drug metabolism and pharmacokinetic properties, including good oral bioavailability for most compounds. We provide a detailed analysis of this data set organized on the basis of structure and function. Slightly over half (51%) of vet drugs are also approved in human medicine. Combination drugs are biologics are also discussed.
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Aprobación de Drogas , Drogas Veterinarias/química , Anestésicos/química , Anestésicos/metabolismo , Anestésicos/uso terapéutico , Animales , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/uso terapéutico , Antiinflamatorios/química , Antiinflamatorios/metabolismo , Antiinflamatorios/uso terapéutico , Antifúngicos/química , Antifúngicos/metabolismo , Antifúngicos/uso terapéutico , Antiparasitarios/química , Antiparasitarios/metabolismo , Antiparasitarios/uso terapéutico , Sistema Enzimático del Citocromo P-450/metabolismo , Humanos , Insecticidas/química , Insecticidas/metabolismo , Insecticidas/uso terapéutico , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Estados Unidos , United States Food and Drug Administration , Drogas Veterinarias/metabolismo , Drogas Veterinarias/uso terapéuticoRESUMEN
Vinylogous Darzens and aza-Darzens reactions employing a benzothiophene 1,1-dioxide nucleophile are reported. These new [2 + 1] annulation reactions, which proceed under mild reaction conditions, are γ-selective, affording trans-epoxides selectively and favoring trans-aziridines. The reactions are base-dependent, with KOtBu and Cs2CO3 being optimal for aldehyde and imine annulations, respectively. Comparison of the benzothiophene nucleophile to its acyclic counterpart reveals superior performance in the case of aldehydes, while the outcome varies depending on the sulfonamide imine used.
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Combination drugs are an important class of US FDA approved pharmaceuticals. These drugs have been on a continuous growth trajectory since the first combination drugs were approved in the 1940s. In this Perspective, we report the first comprehensive compilation and analysis of US FDA approved combination drugs, from the first approval in 1943 through 2018. Our database contains 419 combination drugs, which are represented by 328 unique small molecule structures. Breakdown of these drugs according to disease category, structure, combination composition, and year of approval is presented as well as the top 24 most commonly used small molecule combination drug components. For frequently used small molecule components, we present "relationship diagrams" to aid in the visualization of the many drug combinations these structures are part of. The main body contains 10 disease-focused sections wherein every small molecule component utilized as part of a combination for each disease category is displayed.
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Combinación de Medicamentos , Compuestos Orgánicos/química , Aprobación de Drogas/estadística & datos numéricos , Humanos , Estructura Molecular , Compuestos Orgánicos/uso terapéutico , Estereoisomerismo , Estados Unidos , United States Food and Drug AdministrationRESUMEN
A new asymmetric approach to assemble cis-vinyl aziridines is reported. A reaction of strategically substituted dienolates, decorated with a γ-leaving group, with chiral sulfinimines afforded chiral vinyl aziridine products in good to excellent yields. This is the first systematic study toward the realization of a useful asymmetric vinylogous aza-Darzens reaction. The reaction is initiated by a syn-selective addition, affording cis-vinyl aziridine products after displacement of bromide. The low syn-diastereoselectivity is attributed to competing retro-Mannich pathways.