Visible-light-driven synthesis of alkenyl thiocyanates: novel building blocks for assembly of diverse sulfur-containing molecules.

The first visible-light-induced protocol for the general preparation of alkenyl thiocyanates from alkenyl bromides is presented. The reaction is simple, proceeds under very mild conditions and demonstrates broad functional group tolerance. Additionally, a flow protocol was developed to enable efficient scale-up of alkenyl thiocyanate synthesis, further enhancing the practicality and value of the method. Importantly, these alkenyl thiocyanates serve as valuable building blocks for the construction of diverse families of sulfur-containing molecules through trifluoromethylations, cycloadditions, oxidations, and C-S or P-S bond forming reactions.

Advancements in visible-light-induced reactions via alkenyl radical intermediates.

In recent years, visible-light-induced organic transformations have taken a central role driving forward the progress of modern organic synthesis. These processes typically involve the transient generation of highly reactive radical intermediates, facilitating a diverse array of chemical reactions. Despite the abundance of synthetic strategies enabling the access of aryl and alkyl-centered radicals, the exploitation of photochemistry to generate highly reactive alkenyl radicals has remained notably underdeveloped. In this review, we present recent advancements in visible-light-induced transformations that proceed through the generation of alkenyl radicals from alkenyl-containing precursors, predominantly alkenyl halides, showcasing their application in various organic transformations.

Synthesis of substituted benzylboronates by light promoted homologation of boronic acids with N-sulfonylhydrazones.

The synthesis of benzylboronates by photochemical homologation of boronic acids with N-tosylhydrazones under basic conditions is described. The reaction involves the photolysis of the N-tosylhydrazone salt to give a diazoalkane followed by the geminal carboborylation of the diazoalkane. Under the mild reaction conditions, the protodeboronation of the unstable benzylboronic acid is circumvented and the pinacolboronates can be isolated after reaction of the benzylboronic acid with pinacol. The metholodogy has been applied to the reactions of alkylboronic acids with N-tosylhydrazones of aromatic aldehydes and ketones, and to the reactions of arylboronic acids with N-tosylhydrazones of aliphatic ketones. Moreover, the employment of the DBU/DIPEA bases combination allows for homogeneous reactions which have been adapted to photochemical continuous flow conditions. Additionally, the synthetic versatility of boronates enables their further transformation via Csp3-C or Csp3-X bond forming reactions converting this methodology into a novel method for the geminal difunctionalization of carbonyls via N-tosylhydrazones.

Photochemical halogen-bonding assisted carbothiophosphorylation reactions of alkenyl and 1,3-dienyl bromides.

Herein, we present a synthetic procedure for the facile and general preparation of novel S-alkenyl and dienyl phosphoro(di)thioates for the first time. Extensive mechanistic investigations support that the reactions rely on a photochemical excitation of a halogen-bonding complex, formed with a phosphorothioate salt and an alkenyl or dienyl bromide, which light-induced fragmentation leads to the formation of the desired products through a radical-based pathway. The substrate scope is broad and exhibits a wide functional group tolerance in the formation of the final compounds, including molecules derived from natural products, all with unknown and potentially interesting biological properties. Eventually, a very efficient continuous flow protocol was developed for the upscale of these reactions.

Creating a Defined Chirality in Amino Acids and Cyclic Dipeptides by Photochemical Deracemization.

2,5-Diketopiperazines are cyclic dipeptides displaying a wide range of applications. Their enantioselective preparation has now been found possible from the respective racemates by a photochemical deracemization (53 examples, 74 % to quantitative yield, 71-99 % ee). A chiral benzophenone catalyst in concert with irradiation at λ=366 nm enables to establish the configuration at the stereogenic carbon atom C6 at will. If other stereogenic centers are present in the diketopiperazines they remain unaffected and a stereochemical editing is possible at a single position. Consecutive reactions, including the conversion into N-aryl or N-alkyl amino acids or the reduction to piperazines, occur without compromising the newly created stereogenic center. Transient absorption spectroscopy revealed that the benzophenone catalyst processes one enantiomer of the 2,5-diketopiperazines preferentially and enables a reversible hydrogen atom transfer that is responsible for the deracemization process. The remarkably long lifetime of the protonated ketyl radical implies a yet unprecedented mode of action.

Shining light on halogen-bonding complexes: a catalyst-free activation mode of carbon-halogen bonds for the generation of carbon-centered radicals.

The discovery of new activation modes for the creation of carbon-centered radicals is a task of great interest in organic chemistry. Classical activation modes for the generation of highly reactive radical carbon-centered intermediates typically relied on thermal activation of radical initiators or irradiation with unsafe energetic UV light of adequate reaction precursors. In recent years, photoredox chemistry has emerged as a leading strategy towards the catalytic generation of C-centered radicals, which enabled their participation in novel synthetic organic transformations which is otherwise very challenging or even impossible to take place. As an alternative to these activation modes for the generation of C-centered radicals, the pursuit of greener, visible-light initiated reactions that do not necessitate a photoredox/metal catalyst has recently caught the attention of chemists. In this review, we covered recent transformations, which rely on photoactivation with low-energy light of a class of EDA complexes, known as halogen-bonding adducts, for the creation of C-centered radicals.

Photochemical halogen-bonding assisted generation of vinyl and sulfur-centered radicals: stereoselective catalyst-free C(sp2)-S bond forming reactions.

The combination of photochemistry and halogen bonding interactions has risen in the last few years as a powerful synthetic tool for the creation of radical intermediates under mild conditions. In the formation of carbon-centered radicals, this reactivity has been to date restricted to the employment of aryl and alkyl halides as precursors. We now envisioned that the halogen-bonding initiated formation of highly reactive vinyl radicals would be a feasible process for the photochemical cross-coupling between thiols and alkenyl halides under basic conditions. The reaction shows indeed a very broad functional group tolerance, is stereoselective, simple and scalable. In-depth mechanistic studies point at the formation of vinyl and sulfur-centered radicals as the intermediates of the reaction and DFT calculations support the pre-formation of a halogen-bonding complex as the initiator of the photochemical transformation. Synthetic applications were developed to extend the utility of this methodology.

Reactivity and selectivity modulation within a molecular assembly: recent examples from photochemistry.

In recent years, photochemical reactions have emerged as powerful transformations which significantly expand the repertoire of organic synthesis. However, a certain lack of selectivity can hamper their application and limit their scope. In this context, a major research effort continues to focus on an improved control over stereo- and chemoselectivity that can be achieved in molecular assemblies between photosubstrates and an appropriate host molecule. In this tutorial review, some recent, representative examples of photochemical reactions have been collected whose unique outcome is dictated by the formation of a molecular assembly driven by non-covalent weak interactions.

Photochemical Deracemization at sp3-Hybridized Carbon Centers via a Reversible Hydrogen Atom Transfer.

A photochemical deracemization of 5-substituted 3-phenylimidazolidine-2,4-diones (hydantoins) is reported (27 examples, 69%-quant., 80-99% ee). The reaction is catalyzed by a chiral diarylketone which displays a two-point hydrogen bonding site. Mechanistic evidence (DFT calculations, radical clock experiments, H/D labeling) suggests the reaction to occur by selective hydrogen atom transfer (HAT). Upon hydrogen binding, one substrate enantiomer displays the hydrogen atom at the stereogenic center to the photoexcited catalyst allowing for a HAT from the substrate and eventually for its conversion into the product enantiomer. The product enantiomer is not processed by the catalyst and is thus enriched in the photostationary state.

Photochemical Deracemization of Primary Allene Amides by Triplet Energy Transfer: A Combined Synthetic and Theoretical Study.

The photochemical deracemization of 2,4-disubstituted 2,3-butadienamides (allene amides) was investigated both experimentally and theoretically. The reaction was catalyzed by a thioxanthone which is covalently linked to a chiral 1,5,7-trimethyl-3-azabicyclo[3.3.1]nonan-2-one skeleton providing a U-shaped arrangement of the sensitizing unit relative to a potential hydrogen-bonding site. Upon irradiation at λ = 420 nm in the presence of the sensitizer (2.5 mol %), the amides reached at -10 °C a photostationary state in which one enantiomer prevailed. The enantioenriched allene amides (70-93% ee) were isolated in 74% to quantitative yield (19 examples). Based on luminescence data and DFT calculations, energy transfer from the thioxanthone to the allene amides is thermodynamically feasible, and the achiral triplet allene intermediate was structurally characterized. Hydrogen bonding of the amide enantiomers to the sensitizer was monitored by NMR titration. The experimental association constants (Ka) were similar (59.8 vs 25.7 L·mol-1). DFT calculations, however, revealed a significant difference in the binding properties of the two enantiomers. The major product enantiomer exhibits a noncovalent dispersion interaction of its arylmethyl group to the external benzene ring of the thioxanthone, thus moving away the allene from the carbonyl chromophore. The minor enantiomer displays a CH-π interaction of the hydrogen atom at the terminal allene carbon atom to the same benzene ring, thus forcing the allene into close proximity to the chromophore. The binding behavior explains the observed enantioselectivity which, as corroborated by additional calculations, is due to a rapid triplet energy transfer within the substrate-catalyst complex of the minor enantiomer.

Photochemical Deracemization of Allenes and Subsequent Chirality Transfer.

Trisubstituted allenes with a 3-(1'-alkenylidene)-pyrrolidin-2-one motif were successfully deracemized (13 examples, 86-98 % ee) employing visible light (λ=420 nm) and a chiral triplet sensitizer as the catalyst (2.5 mol %). The photocatalyst likely operates by selective recognition of one allene enantiomer via hydrogen bonds and by a triplet-sensitized racemization process. Even a tetrasubstituted allene (45 % ee) and a seven-membered 3-(1'-alkenylidene)-azepan-2-one (62 % ee) could be enantiomerically enriched under the chosen conditions. It was shown that the axial chirality of the allenes can be converted into point chirality by a Diels-Alder (94-97 % ee) or a bromination reaction (91 % ee). Ring opening of the five-membered pyrrolidin-2-one was achieved without significantly compromising the integrity of the chirality axis (92 % ee).

Domino Synthesis of Benzo-Fused ß,γ-Unsaturated Ketones from Alkenylboronic Acids and N-Tosylhydrazone-Tethered Benzonitriles.

The transition-metal-free domino reaction between alkenylboronic acids and N-tosylhydrazones from o-(2-oxoalkyl)- and o-(3-oxoalkyl)benzonitriles leads to ß,γ-unsaturated indanones and tetralones featuring an α-"all-carbon" quaternary center. The employment of derivatives of α-substituted cyclopentanones and cyclohexanones led to the stereoselective preparation of ß,γ-unsaturated tetrahydrocyclopenta[ a]inden-8(1 H)-ones, hexahydrofluorenones, and hexahydroanthracenones as cis-fused single stereoisomers. A domino sequence involving diazo compound formation/reductive alkenylation/1,3-borotropic rearrangement/intramolecular bora-aza-ene reaction is proposed to justify the formation of the products as well as the stereoselectivity.

Heterocyclization and Spirocyclization Processes Based on Domino Reactions of N-Tosylhydrazones and Boronic Acids Involving Intramolecular Allylborylations of Nitriles.

Polycyclic molecules featuring all-carbon quaternary bridgehead centers were synthesized through domino cyclizations between N-tosylhydrazones and boronic acids. Variations of the general cascade have been applied for the preparation of 3-quinuclidinones and related alkaloid-like scaffolds through transannular heterocyclizations. Moreover, the employment of 3-cyanopropyl and 4-cyanobutylboronic acids and α,ß-unsaturated N-tosylhydrazones led to spirocycles through unprecedented formal [n+1] cyclizations, including the stereoselective spirocyclization of the Hajos-Parrish ketone. The common feature of all the new reactions described is the creation of an all-carbon quaternary center by formation of two Csp3 -C bonds on the hydrazonic carbon atom. DFT-based calculations suggested the occurrence of cascade processes, which involve a diazo compound carboborylation followed by a 1,3-borotropic rearrangement on an intermediate allylboronic acid and a novel bora-aza-ene cyclization.

Stereoselective Domino Carbocyclizations of γ- and δ-Cyano-N-tosylhydrazones with Alkenylboronic Acids with Formation of Two Different C(sp(3))-C(sp(2)) Bonds on a Quaternary Stereocenter.

A novel strategy for the synthesis of functionalized carbocycles is defined, through the cascade carbocyclization of alkenylboronic acids with δ- or γ-cyano-N-tosylhydrazones. In the reaction, two C(sp(3))-C(sp(2)) bonds are formed on the former hydrazonic carbon generating an all-carbon quaternary stereocenter, and leading to cyclic ketones featuring an alkenyl side chain with complete diastereoselectivity. The processes are conducted under very simple experimental conditions, only in the presence of K2CO3, in 1,4-dioxane as solvent and under microwave irradiation, and have been applied for the synthesis of a wide structural variety of fused cyclopentanones and cyclohexanones. Moreover, the versatility of this methodology has been demonstrated in the structural modification of androsterone.

Assessment of Layer Thickness and Interface Quality in CoP Electrodeposited Multilayers.

The magnetic properties of CoP electrodeposited alloys can be easily controlled by layering the alloys and modulating the P content of the different layers by using pulse plating in the electrodeposition process. However, because of its amorphous nature, the study of the interface quality, which is a limitation for the optimization of the soft magnetic properties of these alloys, becomes a complex task. In this work, we use Rutherford backscattering spectroscopy (RBS) to determine that electrodeposited Co0.74P0.26/Co0.83P0.17 amorphous multilayers with layers down to 20 nm-thick are composed by well-defined layers with interfacial roughness below 3 nm. We have also determined, using magnetostriction measurements, that 4 nm is the lower limitation for the layer thickness. Below this thickness, the layers are mixed and the magnetic behavior of the multilayered films is similar to that shown by single layers, thus going from in-plane to out-of-plane magnetic anisotropy. Therefore, these results establish the range in which the magnetic properties of these alloys can be controlled by layering.

Structure of the Photo-catalytically Active Surface of SrTiO3.

A major goal of energy research is to use visible light to cleave water directly, without an applied voltage, into hydrogen and oxygen. Although SrTiO3 requires ultraviolet light, after four decades, it is still the "gold standard" for the photo-catalytic splitting of water. It is chemically robust and can carry out both hydrogen and oxygen evolution reactions without an applied bias. While ultrahigh vacuum surface science techniques have provided useful insights, we still know relatively little about the structure of these electrodes in contact with electrolytes under operating conditions. Here, we report the surface structure evolution of a n-SrTiO3 electrode during water splitting, before and after "training" with an applied positive bias. Operando high-energy X-ray reflectivity measurements demonstrate that training the electrode irreversibly reorders the surface. Scanning electrochemical microscopy at open circuit correlates this training with a 3-fold increase of the activity toward the photo-induced water splitting. A novel first-principles joint density functional theory simulation, constrained to the X-ray data via a generalized penalty function, identifies an anatase-like structure as the more active, trained surface.

Stereoselective Csp(3) -Csp(2) Bond-Forming Reactions by Transition-Metal-Free Reductive Coupling of Cyclic Tosylhydrazones with Boronic Acids.

The reactions between alkenylboronic acids and tosylhydrazones derived from substituted cyclohexanones lead to the construction of disubstituted cyclohexanes with total regio- and stereoselectivity. In these transition-metal-free processes, a Csp(3) -Csp(2) and Csp(3) -H bond are formed on the same carbon atom. The stereoselective reaction is general for 2-, 3-, and 4-substituted cyclohexanone tosylhydrazones, as well as for 2-substituted cyclopentanones. However, no stereoselectivity is observed for acyclic derivatives. DFT computational modeling suggests that the stereoselectivity of the reaction is determined by the approach of the boronic acid to the diazocyclohexane on its most stable chair conformation through an equatorial trajectory.

Glucose-6-phosphatedehydrogenase is also increased in erythrocytes from adolescents with Down syndrome.

For some time it has been claimed that trisomic cells are more sensitive to oxidative stress since there is an imbalance in hydrogen peroxide metabolism due to an increase in superoxide dismutase (SOD) catalytic activity. We designed the present study to assess activity levels of antioxidant enzymes [superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) and glucose-6-phosphate-dehydrogenase (G6PDH)] in erythrocytes in 31 male adolescents with Down syndrome (mean age 16.3 +/- 1.1). An increase of 35.2%, 15.3% and 14.9% in the catalytic activity of SOD, GPx and G6PDH respectively was observed in male adolescents with Down syndrome compared to age-matched controls. For CAT, a slight increase of 6.0% was also found. It is concluded that our data are consistent with previous evidence of the existence of oxidative stress in individuals with Down syndrome as revealed by significantly enhanced activities of SOD and GPx. The most striking feature was that G6PDH, in contrast to CAT, presented a similar behaviour. Further studies are required to identify other antioxidant enzymes in red blood cells as well as in white blood cells in order to increase the range of potential bioindicators of oxidative stress.

Medidas antropométricas como predictores del comportamiento lipídico sérico en adolescentes con síndrome de Down / Anthropometrical measurements as predictor of serum lipid profile in adolescents with Down syndrome

Current findings suggest that more attention needs to be given to the increase in body mass being achieved by disabled populations in general and individuals with mental retardation in particular, to minimize long-term negative health consequences. Given that physical activity programs have been reported as one of the most effective ways of improving the health of individuals with Down syndrome, it would be of interest facilitate different tools to contribute to their clinical follow-up. Consequently, this study was designed to assess the correlation between anthropometrical parameters and lipid profile in adolescents with Down syndrome. Anthropometric variables such as body mass index, waist circumference and waist-to-hip ratio as well as serum lipids (total cholesterol, high-density-lipoprotein cholesterol, total-choles-terol/high-density-lipoprotein cholesterol and triglycerides) were measured in 21 male adolescents (16.3 ± 1.1 years) with Down syndrome. Anthropometric parameters presented a positive association with serum lipids except for high-density-lipoprotein cholesterol that was negative. It should be emphasized the strongest association of waist-to-hip ratio to total cholesterol/high-density-lipoprotein cholesterol ratio (r = 0.48; p < 0.05). It is concluded waist circumference and waist-to-hip ratio may be highly recommended in clinical practice as appropriate anthropometric predictors of lipid profile in adolescents with Down syndrome. Further studies are required to assess their behavior during physical activity programs as well as to determine more correlations in these individuals.

Si la obesidad como epidemia está alcanzando cotas preocupantes en la población general, la situación es aún más alarmante entre poblaciones con retraso mental en general y síndrome de Down en particular. Afortunadamente, recientes estudios sugieren que los programas de actividad física parecen una buena estrategia para combatirla, especialmente a edades tempranas. Para facilitar el seguimiento clínico de los mismos, diseñamos este trabajo para determinar las correlaciones más significativas entre parámetros antropométricos (índice masa corporal; índice cintura cadera; perímetro cadera) y el perfil lipídico sérico (colesterol total; colesterol-HDL; ratio colesterol total/HDL; triglicéridos) de 21 jóvenes adolescentes (16.3 ± 1.1) con trisomía 21. El coeficiente de correlación de Pearson demostró que las variables antropométricas ensayadas mostraron una correlación positiva con los distintos parámetros lipidicos excepto para colesterol-HDL que fue negativa. En líneas generales el perímetro de la cintura mostró el mejor comportamiento, mientras el índice cintura cadera mostró la mayor fuerza de asociación con la ratio colesterol-total/colesterol-HDL (r = 0.48; p < 0.05). Futuros estudios en los que se confirme la utilidad de estos hallazgos durante la aplicación de programas de actividad física y en los que se evalúen nuevas asociaciones son necesarios para contribuir a un mejor seguimiento y manejo de estos pacientes.