Use of greyscale and Doppler ultrasound in initial evaluation and follow-up of neurovascular malformations in children.

Pediatric intracranial arteriovenous shunts are rare vascular malformations that can be diagnosed prenatally or postnatally, as an incidental finding or due to complications. We propose a review of cerebral vascular malformations in newborns and infants with special emphasis on neurosonography and Doppler ultrasound as the first diagnostic method. Sonography can thus contribute in the planning of further studies that are always necessary, and in post-therapy follow-up.

Fluorescence Amplification of Unsaturated Oxazolones Using Palladium: Photophysical and Computational Studies.

Weakly fluorescent (Z)-4-arylidene-5-(4H)-oxazolones (1), ΦPL < 0.1%, containing a variety of conjugated aromatic fragments and/or charged arylidene moieties, have been orthopalladated by reaction with Pd(OAc)2. The resulting dinuclear complexes (2) have the oxazolone ligands bonded as a C^N-chelate, restricting intramolecular motions involving the oxazolone. From 2, a variety of mononuclear derivatives, such as [Pd(C^N-oxazolone)(O2CCF3)(py)] (3), [Pd(C^N-oxazolone)(py)2](ClO4) (4), [Pd(C^N-oxazolone)(Cl)(py)] (5), and [Pd(C^N-oxazolone)(X)(NHC)] (6, 7), have been prepared and fully characterized. Most of complexes 3-6 are strongly fluorescent in solution in the range of wavelengths from green to yellow, with values of ΦPL up to 28% (4h), which are among the highest values of quantum yield ever reported for organometallic Pd complexes with bidentate ligands. This means that the introduction of the Pd in the oxazolone scaffold produces in some cases an amplification of the fluorescence of several orders of magnitude from the free ligand 1 to complexes 3-6. Systematic variations of the substituents of the oxazolones and the ancillary ligands show that the wavelength of emission is tuned by the nature of the oxazolone, while the quantum yield is deeply influenced by the change of ligands. TD-DFT studies of complexes 3-6 show a direct correlation between the participation of the Pd orbitals in the HOMO and the loss of emission through non-radiative pathways. This model allows the understanding of the amplification of the fluorescence and the future rational design of new organopalladium systems with improved properties.

Synthesis of 1,2-diaminotruxinic δ-cyclobutanes by BF3-controlled [2 + 2]-photocycloaddition of 5(4H)-oxazolones and stereoselective expansion of δ-cyclobutanes to give highly substituted pyrrolidine-2,5-dicarboxylates.

The irradiation of (Z)-4-arylidene-5(4H)-oxazolones 1a-1u with blue light (465 nm) in the presence of the photosensitizer [Ru(bpy)3](BF4)2 (2.5 mol%) and the Lewis acid BF3·OEt2 (2 equiv.) in deoxygenated methanol at room temperature affords the corresponding 1,2-diaminotruxinic cyclobutane bis-amino esters 2a-2u stereoselectively as the δ-isomer. Characterization of cyclobutanes 2 shows that the photocycloaddition takes place by the coupling of two Z-oxazolones in a head-to-head 1,2-anti way. This change in the orientation of the coupling is promoted by O- or/and N-bonding of the BF3 additive. The δ-cyclobutanes 2 undergo a ring expansion when heated in methanol in the presence of NaOMe (1/1 molar ratio) to give densely substituted pyrrolidine-2,5-dicarboxylates 3 in a regio- and stereoselective way. The mechanism of the cyclobutane-to-pyrrolidine ring expansion has been elucidated using DFT methods.

Ultrasound attenuation imaging: a reproducible alternative for the noninvasive quantitative assessment of hepatic steatosis in children.

BACKGROUND: Pediatric hepatic steatosis is a global public health concern, as an increasing number of children are affected by this condition. Liver biopsy is the gold standard diagnostic method; however, this procedure is invasive. Magnetic resonance imaging (MRI)-derived proton density fat fraction has been accepted as an alternative to biopsy. However, this method is limited by cost and availability. Ultrasound (US) attenuation imaging is an upcoming tool for noninvasive quantitative assessment of hepatic steatosis in children. A limited number of publications have focused on US attenuation imaging and the stages of hepatic steatosis in children. OBJECTIVE: To analyze the usefulness of ultrasound attenuation imaging for the diagnosis and quantification of hepatic steatosis in children. MATERIAL AND METHODS: Between July and November 2021, 174 patients were included and divided into two groups: group 1, patients with risk factors for steatosis (n = 147), and group 2, patients without risk factors for steatosis (n = 27). In all cases, age, sex, weight, body mass index (BMI), and BMI percentile were determined. B-mode US (two observers) and US attenuation imaging with attenuation coefficient acquisition (two independent sessions, two different observers) were performed in both groups. Steatosis was classified into four grades (0: absent, 1: mild, 2: moderate and 3: severe) using B-mode US. Attenuation coefficient acquisition was correlated with steatosis score according to Spearman's correlation. Attenuation coefficient acquisition measurements' interobserver agreement was assessed using intraclass correlation coefficients (ICC). RESULTS: All attenuation coefficient acquisition measurements were satisfactory without technical failures. The median values for group 1 for the first session were 0.64 (0.57-0.69) dB/cm/MHz and 0.64 (0.60-0.70) dB/cm/MHz for the second session. The median values for group 2 for the first session were 0.54 (0.51-0.56) dB/cm/MHz and 0.54 (0.51-0.56) dB/cm/MHz for the second. The average attenuation coefficient acquisition was 0.65 (0.59-0.69) dB/cm/MHz for group 1 and 0.54 (0.52-0.56) dB/cm/MHz for group 2. There was excellent interobserver agreement at 0.94 (95% CI 0.92-0.96). There was substantial agreement between both observers (κ = 0.77, with a P < 0.001). There was a positive correlation between ultrasound attenuation imaging and B-mode scores for both observers (r = 0.87, P < 0.001 for observer 1; r = 0.86, P < 0.001 for observer 2). Attenuation coefficient acquisition median values were significantly different for each steatosis grade (P < 0.001). In the assessment of steatosis by B-mode US, the agreement between the two observers was moderate (κ = 0.49 and κ = 0.55, respectively, with a P < 0.001 in both cases). CONCLUSION: US attenuation imaging is a promising tool for the diagnosis and follow-up of pediatric steatosis, which provides a more repeatable form of classification, especially at low levels of steatosis detectable in B-mode US.

Synthesis of Bis(amino acids) Containing the Styryl-cyclobutane Core by Photosensitized [2+2]-Cross-cycloaddition of Allylidene-5(4H)-oxazolones.

The irradiation of 2-aryl-4-(E-3'-aryl-allylidene)-5(4H)-oxazolones 1 with blue light (456 nm) in the presence of [Ru(bpy)3](BF4)2 (bpy = 2,2'-bipyridine, 5% mol) gives the unstable cyclobutane-bis(oxazolones) 2 by [2+2]-photocycloaddition of two oxazolones 1. Each oxazolone contributes to the formation of 2 with a different C=C bond, one of them reacting through the exocyclic C=C bond, while the other does so through the styryl group. Treatment of unstable cyclobutanes 2 with NaOMe/MeOH produces the oxazolone ring opening reaction, affording stable styryl-cyclobutane bis(amino acids) 3. The reaction starts with formation of the T1 excited state of the photosensitizer 3[Ru*(bpy)3]2+, which reacts with S0 of oxazolones 1 through energy transfer to give the oxazolone T1 state 3(oxa*)-1, which is the reactive species and was characterized by transient absorption spectroscopy. Measurement of the half-life of 3(oxa*)-1 for 1a, 1b and 1d shows large values for 1a and 1b (10-12 µs), while that of 1d is shorter (726 ns). Density functional theory (DFT) modeling displays strong structural differences in the T1 states of the three oxazolones. Moreover, study of the spin density of T1 state 3(oxa*)-1 provides clues to understanding the different reactivity of 4-allylidene-oxazolones described here with respect to the previously reported 4-arylidene-oxazolones.

Luminescence and Palladium: The Odd Couple.

The synthesis, photophysical properties, and applications of highly fluorescent and phosphorescent palladium complexes are reviewed, covering the period 2018-2022. Despite the fact that the Pd atom appears closely related with an efficient quenching of the fluorescence of different molecules, different synthetic strategies have been recently optimized to achieve the preservation and even the amplification of the luminescent properties of several fluorophores after Pd incorporation. Beyond classical methodologies such as orthopalladation or the use of highly emissive ligands as porphyrins and related systems (for instance, biladiene), new concepts such as AIE (Aggregation Induced Emission) in metallacages or in coordination-driven supramolecular compounds (CDS) by restriction of intramolecular motions (RIM), or complexes showing TADF (Thermally Activated Delayed Fluorescence), are here described and analysed. Without pretending to be comprehensive, selected examples of applications in areas such as the fabrication of lighting devices, biological markers, photodynamic therapy, or oxygen sensing are also here reported.

Stereoselective, Ruthenium-Photocatalyzed Synthesis of 1,2-Diaminotruxinic Bis-amino Acids from 4-Arylidene-5(4H)-oxazolones.

The irradiation of (Z)-2-phenyl-4-aryliden-5(4H)-oxazolones 1 in deoxygenated CH2Cl2 at 25 °C with blue light (465 nm) in the presence of [Ru(bpy)3](BF4)2 (5% mole ratio) as a triplet photocatalyst promotes the [2+2] photocycloaddition of the C═C bonds of the 4-arylidene moiety, thus allowing the completely regio- and stereoselective formation of cyclobutane-bis(oxazolone)s 2 as single stereoisomers. Cyclobutanes 2 have been unambiguously characterized as the µ-isomers and contain two E-oxazolones coupled in an anti-head-to-head form. The use of continuous-flow techniques in microreactors allows the synthesis of cyclobutanes 2 in only 60 min, compared with the 24-48 h required in batch mode. Ring opening of the oxazolone heterocycle in 2 with a base affords the corresponding 1,2-diaminotruxinic bis-amino esters 3, which are also obtained selectively as µ-isomers. The ruthenium complex behaves as a triplet photocatalyst, generating the reactive excited state of the oxazolone via an energy-transfer process. This reactive excited state has been characterized as a triplet diradical 3(E/Z)-1* by laser flash photolysis (transient absorption spectroscopy). This technique also shows that this excited state is the same when starting from either (Z)- or (E)-oxazolones. Density functional theory calculations show that the first step of the [2+2] cycloaddition between 3(E/Z)-1* and (Z)-1 is formation of the C(H)-C(H) bond and that (Z) to (E) isomerization takes place at the 1,4-diradical thus formed.

Forecasting of a complex phenomenon using stochastic data-based techniques under non-conventional schemes: The SARS-CoV-2 virus spread case.

Epidemics are complex dynamical processes that are difficult to model. As revealed by the SARS-CoV-2 pandemic, the social behavior and policy decisions contribute to the rapidly changing behavior of the virus' spread during outbreaks and recessions. In practice, reliable forecasting estimations are needed, especially during early contagion stages when knowledge and data are insipient. When stochastic models are used to address the problem, it is necessary to consider new modeling strategies. Such strategies should aim to predict the different contagious phases and fast changes between recessions and outbreaks. At the same time, it is desirable to take advantage of existing modeling frameworks, knowledge and tools. In that line, we take Autoregressive models with exogenous variables (ARX) and Vector autoregressive (VAR) techniques as a basis. We then consider analogies with epidemic's differential equations to define the structure of the models. To predict recessions and outbreaks, the possibility of updating the model's parameters and stochastic structures is considered, providing non-stationarity properties and flexibility for accommodating the incoming data to the models. The Generalized-Random-Walk (GRW) and the State-Dependent-Parameter (SDP) techniques shape the parameters' variability. The stochastic structures are identified following the Akaike (AIC) criterion. The models use the daily rates of infected, death, and healed individuals, which are the most common and accurate data retrieved in the early stages. Additionally, different experiments aim to explore the individual and complementary role of these variables. The results show that although both the ARX-based and VAR-based techniques have good statistical accuracy for seven-day ahead predictions, some ARX models can anticipate outbreaks and recessions. We argue that short-time predictions for complex problems could be attained through stochastic models that mimic the fundamentals of dynamic equations, updating their parameters and structures according to incoming data.

Environmental Impact of UV Filters. / Impacto de los filtros ultravioleta en el entorno natural.

UV filters are used daily by millions of people. Not all of these filters, however, are 100% biodegradable, and many wastewater treatments plants are ill-equipped to filter them properly. As a result, UV filters are increasingly reaching the environment. Various types have been detected in soil, continental water, oceans, and numerous organisms, including algae, corals, fish, mammals, and even land birds. In addition, some filters, benzophenone-3 and octocrylene in particular, are toxic to these organisms. Toxic effects include coral bleaching and interference with metabolic, enzymatic, and reproductive activities in practically all organisms. Preliminary data suggest that UV filters may be bioaccumulating in humans, as they have been detected in urine and breast milk. It should be noted, however, that research into the environmental impact of UV filters holds challenges and limitations.

Reactivity of (Z)-4-Aryliden-5(4H)-thiazolones: [2 + 2]-Photocycloaddition, Ring-Opening Reactions, and Influence of the Lewis Acid BF3.

The irradiation of (Z)-2-phenyl-4-aryliden-5(4H)-thiazolones 2 with blue light (465 nm) in CH2Cl2 solution promotes [2 + 2]-photocycloaddition of the exocyclic C═C bonds and the formation of the dispirocyclobutanes 3. This reaction takes place with high stereoselectivity, given that the ε-isomer (1,3 head-to-tail syn coupling) is formed in more than 90% yield in most of the cases. However, irradiation of 5(4H)-thiazolones 2 with blue light (456 nm) in dry MeOH in the presence of BF3·OEt2 leads to the monospirocyclobutanes 4 with full stereoselectivity, also affording the ε-isomer. A ring-opening reaction of only one of the thiazolone rings appears to have taken place in 4 upon methanolysis, leading to the corresponding ester and thioamide groups. The treatment of free 4-aryliden-5(4H)-thiazolones 2 with a base in alcohol (NaOR/ROH) also produces a ring-opening reaction of the heterocycle by methanolysis, although, under these reaction conditions, further intramolecular S-attack at the exocyclic C(H)═C bond and cyclization is observed, forming the dihydrothiazoles 5 or 6 as mixtures of cis (RS/SR)- and trans (RR/SS)-isomers with high diastereomeric excess. trans-(RR/SS)-Dihydrothiazoles 6 can be isolated as pure diastereoisomers by column chromatography. Surprisingly, dihydrothiazoles 5 can also be obtained by the treatment of 4-aryliden-5(4H)-thiazolones 2 with BF3·OEt2 in methanol in the absence of a base.

Pd-Oxazolone complexes conjugated to an engineered enzyme: improving fluorescence and catalytic properties.

Different Pd-complexes containing orthometallated push-pull oxazolones were inserted by supramolecular Pd-amino acid coordination on two genetically engineered modified variants of the thermoalkalophilic Geobacillus thermocatenolatus lipase (GTL). Pd-lipase conjugation was performed on the solid phase in the previously immobilized form of GTL under mild conditions, and soluble conjugated Pd-GTL complexes were obtained by simply desorbing by washing with an acetonitrile aqueous solution. Three different Pd complexes were incorporated into two different genetically modified enzyme variants, one containing all the natural cysteine residues changed to serine residues, and another variant including an additional Cys mutation directly in the catalytic serine (Ser114Cys). The new Pd-enzyme conjugates were fluorescent even at ppm concentrations, while under the same conditions free Pd complexes did not show fluorescence at all. The Pd conjugation with the enzyme extremely increases the catalytic profile of the corresponding Pd complex from 200 to almost 1000-fold in the hydrogenation of arenes in aqueous media, achieving in the case of GTL conjugated with orthopalladated 4a an outstanding TOF value of 27 428 min-1. Also the applicability of GTL-C114 conjugated with orthopalladated 4b in a site-selective C-H activation reaction under mild conditions has been demonstrated. Therefore, the Pd incorporation into the enzyme produces a highly stable conjugate, and improves remarkably the catalytic activity and selectivity, as well as the fluorescence intensity, of the Pd complexes.

Fluorescent Orthopalladated Complexes of 4-Aryliden-5(4H)-oxazolones from the Kaede Protein: Synthesis and Characterization.

The goal of the work reported here was to amplify the fluorescent properties of 4-aryliden-5(4H)-oxazolones by suppression of the hula-twist non-radiative deactivation pathway. This aim was achieved by simultaneous bonding of a Pd center to the N atom of the heterocycle and the ortho carbon of the arylidene ring. Two different 4-((Z)-arylidene)-2-((E)-styryl)-5(4H)-oxazolones, the structures of which are closely related to the chromophore of the Kaede protein and substituted at the 2- and 4-positions of the arylidene ring (1a OMe; 1b F), were used as starting materials. Oxazolones 1a and 1b were reacted with Pd(OAc)2 to give the corresponding dinuclear orthometalated palladium derivates 2a and 2b by regioselective C-H activation of the ortho-position of the arylidene ring. Reaction of 2a (2b) with LiCl promoted the metathesis of the bridging carboxylate by chloride ligands to afford dinuclear 3a (3b). Mononuclear complexes containing the orthopalladated oxazolone and a variety of ancillary ligands (acetylacetonate (4a, 4b), hydroxyquinolinate (5a), aminoquinoline (6a), bipyridine (7a), phenanthroline (8a)) were prepared from 3a or 3b through metathesis of anionic ligands or substitution of neutral weakly bonded ligands. All species were fully characterized and the X-ray determination of the molecular structure of 7a was carried out. This structure has strongly distorted ligands due to intramolecular interactions. Fluorescence measurements showed an increase in the quantum yield (QY) by up to one order of magnitude on comparing the free oxazolone (QY < 1%) with the palladated oxazolone (QY = 12% for 6a). This fact shows that the coordination of the oxazolone to the palladium efficiently suppresses the hula-twist deactivation pathway.

Bidimensional shear-wave elastography for assessing liver fibrosis in children: a proposal of reference values that correlate with the histopathological Knodell-Ishak score.

BACKGROUND: A limited number of publications correlate bidimensional shear-wave elastography (2-D SWE) and stages of liver fibrosis in children. OBJECTIVE: To correlate liver elastography values using 2-D SWE and liver biopsy classified by Knodell-Ishak score to evaluate fibrosis in pediatric patients with liver disease, and to propose values of 2-D SWE (kPa) correlating with Knodell-Ishak score, which have not been defined in the literature. MATERIALS AND METHODS: We conducted a prospective cross-sectional observational study on the performance of diagnostic tests. Between June 2016 and June 2018, elastography was performed in 213 children and young adults who had undergone liver biopsy. B mode, Doppler and 2-D SWE were performed using an Aixplorer (SuperSonic Imagine, Aix-en-Provence, France). Histology samples were classified using the Knodell-Ishak score. We evaluated performance by assessing sensitivity, specificity, positive predictive value and negative predictive value. To determine cut-off points for the continuous variables, we used receiver operating characteristic (ROC) curves. All the cutoff values we established apply only to the SuperSonic Aixplorer system. RESULTS: Measurement with 2-D SWE was successful, with a good correlation with fibrosis stage. The area under the curve (AUC) to differentiate between early (Stages 1-2) and moderate (Stages 3-4) fibrosis was 0.91 (95% confidence interval [CI]: 0.87-0.96), with a sensitivity of 92% and specificity of 86%, with a cutoff value 12 kPa (2 m/s). The AUC of severe fibrosis (early stages of cirrhosis; Stage 5) was 0.95 (95% CI: 0.92-0.97), with a sensitivity of 94% and specificity of 90%, with a cutoff value 18.5 kPa (2.48 m/s). In two patients with hematopoietic stem cell transplantation and suspicion of graft versus host disease we found high 2-D SWE values in correlation with the fibrosis stages (Stage 0 with a median of 13 kPa [2.08 m/s] with hemosiderosis Grade 2 in one child and Stage 2 with a median of 46 kPa [3.91 m/s] and hemosiderosis Grade 4 in the other). CONCLUSION: Our study shows the usefulness and accuracy of 2-D SWE for detecting liver fibrosis in pediatric patients. We propose reference values for Knodell-Ishak Stages 1 and 5. We found hemosiderosis as a possible confounding factor that hasn't been described with 2-D SWE.

Synthesis of esters of diaminotruxillic bis-amino acids by Pd-mediated photocycloaddition of analogs of the Kaede protein chromophore.

The stereoselective synthesis of truxillic bis-amino esters from polyfunctional oxazolones is reported. The reaction of 4-((Z)-arylidene)-2-(E)-styryl-5(4H)-oxazolones 2 with Pd(OAc)2 resulted in ortho-palladation and the formation of a dinuclear open-book complexes 3 with carboxylate bridges, where the Pd atom is C^N bonded to the oxazolone. In 3 the two exocyclic C=C bonds of the oxazolone are in a face-to-face arrangement, which is optimal for their [2 + 2] photocycloaddition. Irradiation of dimers 3 in CH2Cl2 solution with blue light (465 nm) promoted the chemo- and stereoselective [2 + 2] photocycloaddition of the exocyclic C=C bonds and the formation of cyclobutane-containing ortho-palladated complexes 4. Treatment of 4 with CO in a MeOH/NCMe mixture promoted the methoxycarbonylation of the palladated carbon and the release of the corresponding ortho-functionalized 1,3-diaminotruxillic bis-amino esters 5 as single isomers.

Ru(ii)-Catalysed synthesis of (1H)-isothiochromenes by oxidative coupling of benzylthioethers with internal alkynes.

The synthesis of 1H-isothiochromenes by oxidative coupling of benzyl(tert-butyl)thioethers with internal alkynes, catalysed by Ru(ii), has been achieved. The reaction occurs by S-directed C-H activation at the ortho position of the aryl ring, promoted by ruthenium, migratory insertion of the alkyne, 1,2-thio-Wittig rearrangement of the tert-butyl group and reductive elimination by C-S coupling between the resulting anionic sulfide and the vinylic carbon.

Supramolecular-Enhanced Charge Transfer within Entangled Polyamide Chains as the Origin of the Universal Blue Fluorescence of Polymer Carbon Dots.

The emission of a bright blue fluorescence is a unique feature common to the vast variety of polymer carbon dots (CDs) prepared from carboxylic acid and amine precursors. However, the difficulty to assign a precise chemical structure to this class of CDs yet hampers the comprehension of their underlying luminescence principle. In this work, we show that highly blue fluorescent model types of CDs can be prepared from citric acid and ethylenediamine through low temperature synthesis routes. Facilitating controlled polycondensation processes, the CDs reveal sizes of 1-1.5 nm formed by a compact network of short polyamide chains of about 10 monomer units. Density functional theory calculations of these model CDs uncover the existence of a spatially separated highest occupied molecular orbital and a lowest unoccupied molecular orbital located at the amide and carboxylic groups, respectively. Photoinduced charge transfer between these groups thus constitutes the origin of the strong blue fluorescence emission. Hydrogen-bond-mediated supramolecular interactions between the polyamide chains enabling a rigid network structure further contribute to the enhancement of the radiative process. Moreover, the photoinduced charge transfer processes in the polyamide network structure easily explain the performance of CDs in applications as revealed in studies on metal ion sensing. These findings thus are of general importance to the further development of polymer CDs with tailored properties as well as for the design of technological applications.

Selective Synthesis of Tetrasubstituted Olefins by Copper-Mediated Acetoxythiolation of Internal Alkynes: Scope and Mechanistic Studies.

The Cu-mediated synthesis of tetrasubstituted olefins by the addition of an acetate group and a thiolate to an unactivated internal alkyne is described. The reaction is fully stereoselective, because only the E alkene is obtained. If the alkyne is asymmetric, the reaction also shows a very high degree of regioselectivity. The mechanism of the reaction is elucidated by DFT methods, which show that it takes place through Cu-stabilized radical species. Calculations highlight the crucial role of the dimeric copper(II) diacetate in the process, as it generates the active species in which the sulfur center has an incipient thiyl radical character and accepting, through a series of changes in the oxidation states of the two copper centers, the two electrons released in the addition of two nucleophiles to the alkyne.

Stereoselective Synthesis of 1,3-Diaminotruxillic Acid Derivatives: An Advantageous Combination of C-H-ortho-Palladation and On-Flow [2+2]-Photocycloaddition in Microreactors.

The stereoselective synthesis of ε-isomers of dimethyl esters of 1,3-diaminotruxillic acid in three steps is reported. The first step is the ortho-palladation of (Z)-2-aryl-4-aryliden-5(4H)-oxazolones 1 to give dinuclear complexes 2 with bridging carboxylates. The reaction occurs through regioselective activation of the ortho-CH bond of the 4-arylidene ring in carboxylic acids. The second step is the [2+2]-photocycloaddition of the CC exocyclic bonds of the oxazolone skeleton in 2 to afford the corresponding dinuclear ortho-palladated cyclobutanes 3. This key step was performed very efficiently by using LED light sources with different wavelengths (465, 525 or 625 nm) in flow microreactors. The final step involved the depalladation of 3 by hydrogenation in methanol to afford the ε-1,3-diaminotruxillic acid derivatives as single isomers.

Ruthenium-Catalyzed Oxidative Coupling of Primary Amines with Internal Alkynes through C-H Bond Activation: Scope and Mechanistic Studies.

The oxidative coupling of primary amines with internal alkynes catalyzed by Ru complexes is presented as a general atom-economy methodology with a broad scope of applications in the synthesis of N-heterocycles. Reactions proceed through regioselective C-H bond activation in 15 minutes under microwave irradiation or in 24 hours with conventional heating. The synthesis of 2,3,5-substituted pyridines, benzo[h]isoquinolines, benzo[g]isoquinolines, 8,9-dihydro-benzo[de]quinoline, 5,6,7,8-tetrahydroisoquinolines, pyrido[3,4g]isoquinolines, and pyrido[4,3g]isoquinolines is achievable depending on the starting primary amine used. DFT calculations on a benzylamine substrate support a reaction mechanism that consists of acetate-assisted C-H bond activation, migratory-insertion, and C-N bond formation steps that involve 28-30 kcal mol(-1) . The computational study is extended to additional substrates, namely, 1-naphthylmethyl-, 2-methylallyl-, and 2-thiophenemethylamines.