Showing papers in "Journal of Organic Chemistry in 2020"
TL;DR: This Perspective introduces the recently reported bottom-up synthetic methods for graphene nanoribbons and the theoretical and experimental researches on those physical properties and applications and emphasizes how structurally controlled synthesis is important and provides future outlooks in graphenenanoribbon science.
Abstract: Graphene nanoribbons are the class of next-generation carbon materials that are attracting many researchers in various research fields. Their unique properties, such as band gap, conductivity, carr...
89 citations
TL;DR: The manuscript will hopefully dispel a number of misconceptions and provide a framework for thinking about how electrochemistry can be uniquely applied to solving problems in synthesis and to obtaining mechanistic insights.
Abstract: The author describes perspectives gained over many years of engagement in the field of organic electrochemistry. The manuscript will hopefully dispel a number of misconceptions and provide a framew...
76 citations
TL;DR: A case study of anaphylaxis induced by three uronium agents: HATU, HBTU, and HCTU is presented as a cautionary note for researchers who handle peptide coupling agents frequently and recommendations for handling coupling agents more safely in the research laboratory are included.
Abstract: Peptide coupling agents pose a special hazard because they are immune sensitizers. Here, we present a case study of anaphylaxis induced by three uronium coupling agents, HATU, HBTU, and HCTU, as a cautionary note for researchers who handle peptide coupling agents frequently. We also include recommendations for handling coupling agents more safely in the research laboratory.
62 citations
TL;DR: In polar environments, the HOO• radical scavenging of SA is 1.53 times higher than that of ascorbic acid, indicating that SA is a promising antioxidant and antinitrosant agent in polar environments.
Abstract: Syringic acid (SA) is a natural phenolic acid found in vegetables, fruits, and other plant-based foods. A range of biological activities were proposed for this compound including anticancer, antimicrobial, anti-inflammation, and anti-diabetic activities, as well as antioxidant and antinitrosant properties. In this study, the focus is on the latter two. The HO•, HOO•, NO, and NO2 scavenging activities of SA were evaluated in physiological environments by kinetic and thermodynamic calculations. The computed rate constants of the HO• radical scavenging of SA were 4.63 × 109 and 9.77 × 107 M-1 s-1 in polar and nonpolar solvents, respectively. A comparison with the experimentally determined rate constant in aqueous solution yields a kcalculated/kexperimental ratio of 0.3, thus the computed kinetic data are reasonably accurate. SA exhibited excellent HOO• and NO2 scavenging activity in water (koverall(HOO•) = 1.53 × 108 M-1 s-1 and koverall(NO2) = 1.98 × 108 M-1 s-1), whereas it did not show NO scavenging activity in any of the studied environments. In lipid medium, SA exhibited weak activity. Thus, in polar environments, the HOO• radical scavenging of SA is 1.53 times higher than that of ascorbic acid. Consistently, SA is a promising antioxidant and antinitrosant agent in polar environments.
61 citations
TL;DR: The present reaction could be accomplished through the trifluoroalkylation of quinoxalin-2(1H)-ones with unactivated alkenes and Langlois' reagent (CF3SO2Na), which provided a highly attractive approach to access a series of biologically important 3-trifluoalkylated quin oxalin-1H-ones.
Abstract: A K2S2O8-mediated three-component protocol has been developed for the construction of 3-trifluoroalkylated quinoxalin-2(1H)-ones under metal-free conditions. The present reaction could be accomplis...
61 citations
TL;DR: Aluminum dihydride catalyzed both intra- and intermolecular chemoselective hydroboration of nitriles and alkynes over other reducible functionalities for the first time and is expanded to more challenging substrates such as alkene, pyridine, imine, carbodiimide and isocyanides.
Abstract: The reaction of LH [L = {(ArNH)(ArN)-C=N-C=(NAr)(NHAr)}; Ar =2,6-Et2-C6H3] with a commercially available alane amine adduct (H3Al·NMe2Et) in toluene resulted in the formation of a conjugated bis-guanidinate (CBG)-supported aluminum dihydride complex, i.e., LAlH2 (1), in good yield. The new complex has been thoroughly characterized by multinuclear magnetic resonance, IR, mass, and elemental analyses, including single-crystal structural studies. Further, we have demonstrated the aluminum-catalyzed hydroboration of a variety of nitriles and alkynes. Moreover, aluminum-catalyzed hydroboration is expanded to more challenging substrates such as alkene, pyridine, imine, carbodiimide, and isocyanides. More importantly, we have shown that the aluminum dihydride catalyzed both intra- and intermolecular chemoselective hydroboration of nitriles and alkynes over other reducible functionalities for the first time.
60 citations
TL;DR: This study reveals a transition metal and external oxidant free electrochemical method for the C3-H sulfonylation of bio-logically diverse 2H-indazoles at room temperature and under ambient air.
Abstract: This study reveals a transition-metal- and external oxidant-free electrochemical method for the C3–H sulfonylation of biologically diverse 2H-indazoles at room temperature and under ambient air. Us...
60 citations
TL;DR: This C-H activation approach enables the most straightforward and convergent synthesis of C6-substituted isoquinolino[1,2-b]quinazolines reported to date, and operates with exquisite N-lactam cyclization selectivity, thus enabling expedient access to new heterocyclic analogues featuring promising cytotoxic properties.
Abstract: We report the synthesis of C6-substituted isoquinolino[1,2-b]quinazolinones via rhodium(III)-catalyzed C-H annulation with sulfoxonium ylides and evaluation of the cytotoxic activity of the scaffold. This C-H activation approach enables the most straightforward and convergent synthesis of C6-substituted isoquinolino[1,2-b]quinazolines reported to date. This operationally simple method is compatible with a wide variety of the sulfoxonium ylide and arene C-H activation coupling partners, permitting access to diverse isoquinolino[1,2-b]quinazolines. This method shows a high atom economy, generating H2O and dimethyl sulfoxide (DMSO) as by-products. This method is scalable and operates with exquisite N-lactam cyclization selectivity, thus enabling expedient access to new heterocyclic analogues featuring promising cytotoxic properties.
55 citations
TL;DR: The high demand for new and efficient routes toward synthesis of nitrogen-containing heterocyclic scaffolds has inspired organic chem-ists to discover several methodologies over recent years, which involves the use of pyri-dotriazoles and related compounds in denitrogenative transformations.
Abstract: The high demand for new and efficient routes toward synthesis of nitrogen-containing heterocyclic scaffolds has inspired organic chemists to discover several methodologies over recent years. This Perspective highlights one standout approach, which involves the use of pyridotriazoles and related compounds in denitrogenative transformations. Readily available pyridotriazoles undergo ring-chain isomerization to produce uniquely reactive α-diazoimines. Such reactivity, enabled by metal catalysts, additives, or visible-light irradiation, can be applied in transannulation, insertion, cyclopropanation, and many other transformations.
53 citations
TL;DR: The present protocol provides an atom-economical and sustainable route for the synthesis of various quinoxaline and quinazoline derivatives by employing an earth-abundant manganese salt and simple phosphine-free NNN-tridentate ligand.
Abstract: Direct synthesis of N-heterocycles via the acceptorless dehydrogenative coupling is very challenging and scarcely reported under 3d transition-metal catalysis. Here, we have developed an efficient Mn(I)-catalyzed sustainable synthesis of various quinoxalines from 1,2-diaminobenzenes and 1,2-diols via the acceptorless dehydrogenative coupling reaction. Further, this strategy was successfully applied for the unprecedented synthesis of quinazolines by the reaction of 2-aminobenzyl alcohol with primary amides. The present protocol provides an atom-economical and sustainable route for the synthesis of various quinoxaline and quinazoline derivatives by employing an earth-abundant manganese salt and simple phosphine-free NNN-tridentate ligand.
50 citations
TL;DR: This perspective highlights examples of atom-economical addition and condensation reactions with heterogeneous catalysts under continuous-flow conditions, and their implications for the synthesis of complex organic molecules such as natural products and APIs.
Abstract: While organic synthesis carried out in most laboratories uses batch methods, there is growing interest in modernizing fine chemical synthesis through continuous-flow processes. As a synthetic method, flow processes have several advantages over batch systems in terms of environmental compatibility, efficiency, and safety, and recent advances have allowed for the synthesis of several complex molecules, including active pharmaceutical ingredients (APIs). Nevertheless, due to several reasons related to the difficulties arising from byproduct formation during the flow process, such as lower yields, poor selectivities, clogging of columns due to poor solubility, catalyst poisoning, etc., successful examples of continuous-flow synthesis of complex organic molecules are still limited. In order to solve this bottleneck, the development of selective and atom-economical continuous-flow organic transformations are needed. This perspective highlights examples of atom-economical addition and condensation reactions with heterogeneous catalysts under continuous-flow conditions and their applications for the synthesis of complex organic molecules such as natural products and APIs. In order to realize new continuous-flow methodologies, based on addition and condensation reactions, in place of substitution reactions, the development of novel reactions and heterogeneous catalysts is required.
TL;DR: The combination of experimental results with quantum-chemical calculations provides insights into the structure-property relationship, the elucidation of which will accelerate the development of cyanines with properties tailored for specific applications, such as fluorescent probes and sensors, photouncaging, photodynamic therapy, or singlet-oxygen detection.
Abstract: Heptamethine cyanines (Cy7) are fluorophores essential for modern bioimaging techniques and chemistry. Here, we systematically evaluated the photochemical and photophysical properties of a library of Cy7 derivatives containing diverse substituents in different positions of the heptamethine chain. A single substitution allows modulation of their absorption maxima in the range of 693-805 nm and photophysical properties, such as quantum yields of singlet-oxygen formation, decomposition, and fluorescence or affinity to singlet oxygen, within 2-3 orders of magnitude. The same substituent in different positions of the chain often exhibits distinctly contradictory effects, demonstrating that both the type and position of the substituent are pivotal for the design of Cy7-based applications. The combination of experimental results with quantum-chemical calculations provides insights into the structure-property relationship, the elucidation of which will accelerate the development of cyanines with properties tailored for specific applications, such as fluorescent probes and sensors, photouncaging, photodynamic therapy, or singlet-oxygen detection.
TL;DR: Metal template Schiff base condensations have produced multinuclear metal complexes exhibiting the shape of tetrahedral containers, of double helices, and, supreme wonder, of the Borromean rings.
Abstract: In 1864, Hugo Schiff, aged 30, discovered the reaction of aromatic aldehydes with primary amines to give imine derivatives. A C═N imine bond presents the unique properties of being strong, as expec...
TL;DR: Az-BN-1 and Az-BN -2 exhibit unexpected deboronization upon addition of trifluoroacetic acid, which distinguishes them from other reported BN-heteroaromatics and can be ascribed to the unique property of azulene unit.
Abstract: Azulene, a nonalternant bicyclic aromatic hydrocarbon, has unique chemical and physical properties and is considered to be a promising building block for constructing novel polycyclic aromatic hydrocarbons (PAHs) and heteroaromatics. We present here the first two azulene-based BN-heteroaromatics Az-BN-1 and Az-BN-2. The chemical structures and optical and electrochemical properties of both compounds have been investigated, as well as their sensing behavior in response to fluoride ion. Az-BN-1 and Az-BN-2 show different photophysical properties from other reported BN-embedded PAHs, such as lower band gaps and unusual fluorescence. In addition, Az-BN-1 and Az-BN-2 exhibit unexpected deboronization upon addition of trifluoroacetic acid, which distinguishes them from other reported BN-heteroaromatics and can be ascribed to the unique property of the azulene unit.
TL;DR: The inexpensive nickel based catalytic methodology displays a broad substrate scope for the N-alkylation of aromatic and heteroaromatic amines using a diverse range of primary alcohols with excellent yields up to 97%.
Abstract: A highly sustainable catalytic protocol for the coupling of alcohols and amines for selective monoalkylated amines using Ni(II)-NΛNΛO pincer type complexes through the borrowing hydrogen methodology is described. An array of Ni(II) catalysts (1-3) was synthesized and characterized by various spectral and analytical methods. Furthermore, the distorted square planar geometry of the complexes (1 and 2) was substantiated with single crystal X-ray diffraction study. The inexpensive nickel-based catalytic methodology displays a broad substrate scope for the N-alkylation of aromatic and heteroaromatic amines using a diverse range of primary alcohols with excellent yields up to 97%. The present approach is environmentally benign, which liberates water as the sole byproduct. A short synthesis of drug intermediates such as mepyramine and chloropyramine illustrates the utility of the present protocol.
TL;DR: An efficacious, nickel-catalyzed synthesis of two important heterocycles such as quinoline and quinoxaline is reported, employing an inexpensive catalyst that can rival many other transition-metal systems that have been developed for the fabrication of two putativeheterocycles.
Abstract: Dehydrogenative coupling-based reactions have emerged as an efficient route toward the synthesis of a plethora of heterocyclic rings. Herein, we report an efficacious, nickel-catalyzed synthesis of...
TL;DR: A visible light-mediated flow process for C-N cross-coupling of (hetero)aryl halides with a variety of amine coupling partners through the use of a photoredox/nickel dual catalyst system is reported, enabling a broader substrate scope and significantly reduced reaction times.
Abstract: We report a visible light-mediated flow process for C-N cross-coupling of (hetero)aryl halides with a variety of amine coupling partners through the use of a photoredox/nickel dual catalyst system. Compared to the method in batch, this flow process enables a broader substrate scope, including less-activated (hetero)aryl bromides and electron-deficient (hetero)aryl chlorides, and significantly reduced reaction times (10 to 100 min). Furthermore, scale up of the reaction, demonstrated through the synthesis of tetracaine, is easily achieved, delivering the C-N cross-coupled products in consistently high yield of 84% on up to a 10 mmol scale.
TL;DR: Inexpensive and simple NiBr2/1,10-phenanthroline system catalyzed synthesis of a series of quinoxalines from both 2-nitroanilines and 1,2-diamines is demonstrated.
Abstract: The inexpensive and simple NiBr2/1,10-phenanthroline system-catalyzed synthesis of a series of quinoxalines from both 2-nitroanilines and 1,2-diamines is demonstrated. The reusability test for this system was performed up to the seventh cycle, which afforded good yields of the desired product without losing its reactivity significantly. Notably, during the catalytic reaction, the formation of the heterogeneous Ni-particle was observed, which was characterized by PXRD, XPS, and TEM techniques.
TL;DR: Mcha-nistic experiments indicate that this reaction involves a radical-chain process that is initiated by an EDA complex formed from difluoroalkyl iodide and phosphine, and is highlighted by photocatalyst-free, mild reaction conditions, and broad substrate scope.
Abstract: A visible light-promoted difluoroalkylation reaction of arenes or heterocycles, using triaryl phosphine as the catalyst and difluoroalkyl iodide as the alkylating agent, is presented. The strategy is highlighted by photocatalyst-free, mild reaction conditions and a broad substrate scope. Mechanistic experiments indicate that this reaction involves a radical-chain process that is initiated by an electron donor–acceptor complex formed from difluoroalkyl iodide and phosphine.
TL;DR: 2,3-Dichloropyridine N-oxide, a novel oxygen transfer reagent, allows the conductance of the gold(I)-catalyzed oxidation of alkynes to 1,2-dicarbonyls in the absence of any acid additives and under mild conditions to furnish the target species including those derivatized by highly acid-sensitive groups.
Abstract: 2,3-Dichloropyridine N-oxide, a novel oxygen transfer reagent, allows the conductance of the gold(I)-catalyzed oxidation of alkynes to 1,2-dicarbonyls in the absence of any acid additives and under mild conditions to furnish the target species, including those derivatized by highly acid-sensitive groups. The developed strategy is effective for a wide range of alkyne substrates such as terminal- and internal alkynes, ynamides, alkynyl ethers/thioethers, and even unsubstituted acetylene (40 examples; yields up to 99%). The oxidation was successfully integrated into the trapping of reactive dicarbonyls by one-pot heterocyclization and into the synthesis of six-membered azaheterocycles. This synthetic acid-free route was also successfully applied for the total synthesis of a natural 1,2-diketone.
TL;DR: This study exhibited unique potential of anionic metal-ligand bifunctional iridium catalysts for transfer hydrogenation with methanol as a hydrogen source.
Abstract: An anionic iridium complex [Cp*Ir(2,2′-bpyO)(OH)][Na] was found to be a general and highly efficient catalyst for transfer hydrogenation of ketones and imines with methanol under base-free conditio...
TL;DR: The role of photoisomerization in the heptamethine cyanine scaffold is clarified and the dramatic effect of restraint on the temperature sensitivity of these dyes is demonstrated and the fluorescence lifetime is significantly extended at moderately elevated temperatures relative to the parent cyanine.
Abstract: Appending conformationally restraining ring systems to the cyanine chromophore creates exceptionally bright fluorophores in the visible range. Here, we report the application of this strategy in the near-infrared range through the preparation of the first restrained heptamethine indocyanine. Time-resolved absorption spectroscopy and fluorescence correlation spectroscopy verify that, unlike the corresponding parent unrestrained variant, the restrained molecule is not subject to photoisomerization. Notably, however, the room-temperature emission efficiency and the fluorescence lifetime of the restrained cyanine are not extended relative to the parent cyanine, even in viscous solvents. Thus, in contrast to prior reports, the photoisomerization of heptamethine cyanines does not contribute significantly to the excited-state chemistry of these molecules. We also find that the fluorescence lifetime of the restrained heptamethine cyanine is temperature-insensitive and significantly extended at moderately elevated temperatures relative to the parent cyanine. Finally, computational studies have been used to evaluate the impact of the conformational restraint on atomic and orbital structure across the cyanine series. These studies clarify the role of photoisomerization in the heptamethine cyanine scaffold and demonstrate the dramatic effect of restraint on the temperature sensitivity of these dyes.
TL;DR: This research exhibited the potential of transition metal-catalyzed the activation of methanol as a C1 source for the construction of C-N bond in aqueous solution.
Abstract: The N-methylation of amines with methanol in aqueous solution was proposed and accomplished by using a water-soluble metal-ligand bifunctional dinuclear iridium catalyst. In the presence of [(Cp*IrCl)2(thbpym)][Cl]2 (1 mol %), a range of desirable products were obtained in high yields under environmentally benign conditions. Notably, this research exhibited the potential of transition metal-catalyzed activation of methanol as a C1 source for the construction of the C-N bond in aqueous solution.
TL;DR: An electrochemical method for the C(sp2)-H thioetherification of quinoxalin-2(1H)-ones with primary, secondary, and tertiary thiols is reported.
Abstract: An electrochemical method for the C(sp2)–H thioetherification of quinoxalin-2(1H)-ones with primary, secondary, and tertiary thiols has been reported. Various quinoxalin-2(1H)-ones underwent this t...
TL;DR: Recent advancements in the field of helicene functionalization are discussed with emphasis on different types of transformations, their versatility and regioselectivity.
Abstract: Helicenes, chiral members of the family of polyaromatic hydrocarbons, have been increasingly used in a variety of applications in recent years. Despite their intriguing properties, wider utilization is hindered by difficult functionalization of its skeleton, which would provide access to finely tuned derivatives of desired properties. Herein, the recent advancements in the field of helicene functionalization are discussed with an emphasis on different types of transformations, their versatility, and regioselectivity.
TL;DR: Imidoyl sulfoxonium ylides are presented for the first time as potential precursors to generate α-imino metal-carbene intermediates and applied in direct C-H functionalization reactions catalyzed by [Ir(cod)Cl]2 to provide 2-substituted indoles in just one step.
Abstract: Imidoyl sulfoxonium ylides are presented for the first time as potential precursors to generate α-imino metal-carbene intermediates and applied in direct C-H functionalization reactions catalyzed by [Ir(cod)Cl]2 (4 mol %) to provide 2-substituted indoles (up to 70% yield) in just one step. This class of sulfur ylide is successfully obtained from imidoyl chloride and dimethylsulfoxonium methylide (23 new examples in 45-85% yield) or by imino group formation from the corresponding β-keto sulfoxonium ylides and anilines in the presence of TiCl4 as a Lewis acid (9 examples in 33-94% yield).
TL;DR: An efficient method for visible light-initiated, nickel-catalyzed Sonogashira C(sp)-C(sp2) coupling has been developed via an energy transfer mode.
Abstract: An efficient method for visible-light-initiated, nickel-catalyzed Sonogashira C(sp)–C(sp2) coupling has been developed via an energy-transfer mode. Thioxanthen-9-one as a photosensitizer could sign...
TL;DR: A photoredox-mediated decarboxylative radical conjugate addition to dehydroalanine derivatives is disclosed, which was identified and applied to the diastereoselective synthesis of unnatural amino acids and the late-stage derivatization of a tripeptide.
Abstract: Unnatural amino acids are key building blocks in therapeutically relevant peptides. Thus, the development of novel methods to increase the structural diversity of the unnatural amino acid pool is needed. Herein, a photoredox-mediated decarboxylative radical conjugate addition to dehydroalanine derivatives is disclosed. Mild, robust, and general conditions were identified and applied to the diastereoselective synthesis of unnatural amino acids and the late-stage derivatization of a tripeptide.
TL;DR: Photostability studies, cell culture cytotoxicity, and cell uptake specificity profiles were all studied for indolizine donor-based cyanine and squaraine dyes with water solubilizing sulfonate groups, demonstrating exceptional biological imaging suitability.
Abstract: Organic dyes that absorb and emit in the near-infrared (NIR) region are potentially noninvasive, high-resolution, and rapid biological imaging materials. Indolizine donor-based cyanine and squaraine dyes with water-solubilizing sulfonate groups were targeted in this study due to strong absorptions and emissions in the NIR region. As previously observed for nonwater-soluble derivatives, the indolizine group with water-solubilizing groups retains a substantial shift toward longer wavelengths for both absorption and emission with squaraines and cyanines relative to classically researched indoline donor analogues. Very high quantum yields (as much as 58%) have been observed with absorption and emission >700 nm in fetal bovine serum. Photostability studies, cell culture cytotoxicity, and cell uptake specificity profiles were all studied for these dyes, demonstrating exceptional biological imaging suitability.
TL;DR: There has been a surge in the development of new synthetic methodology for radioiodination, and this synopsis describes the key transformations developed recently.
Abstract: Organic compounds bearing radioisotopes of iodine are widely used for biological research, diagnostic imaging, and radiotherapy. Early reported synthetic methods for the incorporation of radioiodine have generally involved high temperature reactions or strongly oxidizing conditions. To overcome these limitations and to cope with the demand for novel radioiodinated probes, there has been a surge in the development of new synthetic methodology for radioiodination. This synopsis describes the key transformations developed recently.