Autocatalysis in Eschenmoser Coupling Reactions.

The Eschenmoser coupling reaction (ECR) of thioamides with electrophiles is believed to proceed via thiirane intermediates. However, little is known about converting the intermediates into ECR products. Previous mechanistic studies involved external thiophiles to remove the sulfur atom from the intermediates. In this work, an ECR proceeding without any thiophilic agent or base is studied by electrospray ionization-mass spectrometry. ESI-MS enables the detection of the so-far elusive polysulfide species Sn , with n ranging from 2 to 16 sulfur atoms, proposed to be the key species leading to product formation. Integrating observations from ion mobility spectrometry, ion spectroscopy, and reaction monitoring via flow chemistry coupled with mass spectrometry provides a comprehensive understanding of the reaction mechanism and uncovers the autocatalytic nature of the ECR reaction.

Immobilization of Trifluoromethyl-Substituted Pyridine-Oxazoline Ligand and Its Application in Asymmetric Continuous Flow Synthesis of Benzosultams.

This study presents an improved synthetic route to ligand (S)-4-(tert-butyl)-2-(5-(trifluoromethyl)pyridin-2-yl)-4,5-dihydrooxazole and its application as a highly active and enantioselective catalyst in the addition of arylboronic acids to cyclic N-sulfonylketimines. Immobilization of such a ligand was achieved using a commercially available starting material and a PS-PEG TentaGel S NH2 support, resulting in a stable heterogeneous catalyst. Although the anchored catalyst exhibited a slight reduction in enantioselectivity and a 4-fold decrease in reaction rate, it displayed remarkable stability, enabling 10 consecutive reaction cycles. Furthermore, the successful transition to a continuous flow system demonstrated even higher turnover numbers compared to batch arrangements. These findings provide valuable insights into the development of efficient flow reactors for continuous synthesis of benzosultams, further advancing the field of asymmetric catalysis.

Eschenmoser coupling reactions starting from primary thioamides. When do they work and when not?

Reactions of thiobenzamide or thioacetamide with 4-bromo-1,1-dimethyl-1,4-dihydroisoquinoline-3(2H)-one, 4-bromoisoquinoline-1,3(2H,4H)-dione and two α-bromo(phenyl)acetamides were examined under various conditions (base, solvent, thiophile, temperature) and structure/medium features that influence product distribution (Eschenmoser coupling reaction, Hantzsch thiazole synthesis and elimination to nitriles) were identified. The key factor that enables the successful Eschenmoser coupling reaction involves the optimum balance in acidity of nitrogen and carbon atoms of the intermediary α-thioiminium salts.

The complex photochemistry of coumarin-3-carboxylic acid in acetonitrile and methanol.

Irradiation of coumarin-3-carboxylic acid in acetonitrile and methanol solutions at 355 nm results in complex multistep photochemical transformations, strongly dependent on the solvent properties and oxygen content. A number of reaction intermediates, which themselves undergo further (photo)chemical reactions, were identified by steady-state and transient absorption spectroscopy, mass spectrometry, and NMR and product analyses. The triplet excited compound in acetonitrile undergoes decarboxylation to give a 3-coumarinyl radical that traps molecular oxygen to form 3-hydroxycoumarin as the major but chemically reactive intermediate. This compound is oxygenated by singlet oxygen, produced by coumarin-3-carboxylic acid sensitization, followed by a pyrone ring-opening reaction to give an oxalic acid derivative. The subsequent steps lead to the production of salicylaldehyde, carbon monoxide, and carbon dioxide as the final products. When 3-coumarinyl radical is not trapped by oxygen in degassed acetonitrile, it abstracts hydrogen from the solvent and undergoes triplet-sensitized [2 + 2] cycloaddition. The reaction of 3-coumarinyl radical with oxygen is largely suppressed in aerated methanol as a better H-atom donor, and coumarin is obtained as the primary product in good yields. Because coumarin derivatives are used in many photophysical and photochemical applications, this work provides detailed and sometimes surprising insights into their complex phototransformations.

Synthesis of the Kinase Inhibitors Nintedanib, Hesperadin, and Their Analogues Using the Eschenmoser Coupling Reaction.

A novel synthetic approach involving an Eschenmoser coupling reaction of substituted 3-bromooxindoles (H, 6-Cl, 6-COOMe, 5-NO2) with two substituted thiobenzanilides in dimethylformamide or acetonitrile was used for the synthesis of eight kinase inhibitors including Nintedanib and Hesperadin in yields exceeding 76%. Starting compounds for the synthesis are also easily available in good yields. 3-Bromooxindoles were prepared either from corresponding isatins using a three-step synthesis in an average overall yield of 65% or by direct bromination of oxindoles (yield of 65-86%). Starting N-(4-piperidin-1-ylmethyl-phenyl)-thiobenzamide was prepared by thionation of the corresponding benzanilide in an 86% yield and N-methyl-N-(4-thiobenzoylaminophenyl)-2-(4-methylpiperazin-1-yl)acetamide was prepared by thioacylation of the corresponding aniline with methyl dithiobenzoate in an 86% yield.

Synthesis of (Z)-3-[amino(phenyl)methylidene]-1,3-dihydro-2H-indol-2-ones using an Eschenmoser coupling reaction.

A highly modular method for the synthesis of (Z)-3-[amino(phenyl/methyl)methylidene]-1,3-dihydro-2H-indol-2-ones starting from easily available 3-bromooxindoles or (2-oxoindolin-3-yl)triflate and thioacetamides or thiobenzamides is described. A series of 49 compounds, several of which have previously been shown to possess significant tyrosin kinase inhibiting activity, was prepared in yields varying mostly from 70 to 97% and always surpassing those obtained by other published methods. The method includes an Eschenmoser coupling reaction, which is very feasible (even without using a thiophile except tertiary amides) and scalable. The (Z)-configuration of all products was confirmed by NMR techniques.

Recent advances in palladium-catalysed asymmetric 1,4-additions of arylboronic acids to conjugated enones and chromones.

The transition metal (palladium)-catalysed asymmetric 1,4-addition of arylboronic acids to conjugated enones belong to the most important and emerging strategies for the construction of C-C bonds in an asymmetric fashion. This review covers known catalytic systems used for this transformation. For clarity, we are using the type of ligand as a sorting criterion. Finally, we attempted to create a flowchart facilitating the selection of a suitable ligand for a given combination of enone and arylboronic acid.

Structural Modifications of Nile Red Carbon Monoxide Fluorescent Probe: Sensing Mechanism and Applications.

Carbon monoxide (CO) is a cell-signaling molecule (gasotransmitter) produced endogenously by oxidative catabolism of heme, and the understanding of its spatial and temporal sensing at the cellular level is still an open challenge. Synthesis, optical properties, and study of the sensing mechanism of Nile red Pd-based CO chemosensors, structurally modified by core and bridge substituents, in methanol and aqueous solutions are reported in this work. The sensing fluorescence "off-on" response of palladacycle-based sensors possessing low-background fluorescence arises from their reaction with CO to release the corresponding highly fluorescent Nile red derivatives in the final step. Our mechanistic study showed that electron-withdrawing and electron-donating core substituents affect the rate-determining step of the reaction. More importantly, the substituents were found to have a substantial effect on the Nile red sensor fluorescence quantum yields, hereby defining the sensing detection limit. The highest overall fluorescence and sensing rate enhancements were found for a 2-hydroxy palladacycle derivative, which was used in subsequent biological studies on mouse hepatoma cells as it easily crosses the cell membrane and qualitatively traces the localization of CO within the intracellular compartment with the linear quantitative response to increasing CO concentrations.

C-H Functionalizations by Palladium Carboxylates: The Acid Effect.

Finding optimal reaction conditions is usually complex, requires many experiments, and is therefore demanding in terms of human, financial, and environmental resources. This work provides a simple workflow for easier design of popular palladium-catalyzed C-H functionalization reactions, where the active palladium catalysts contain carboxylate ligands. The key factor for optimizing reaction conditions is to find a balance between two opposing effects of the carboxylic acid in the reaction mixture: generation of more reactive palladium catalyst versus deactivation of a substrate by its protonation.

[3 + 2]-Cycloaddition reaction of sydnones with alkynes.

This review covers all known examples of [3 + 2]-cycloaddition between sydnones and both terminal as well as internal alkynes/cycloalkynes taken from literature since its discovery by Huisgen in 1962 up to the current date. Except enumeration of synthetic applications it also covers mechanistic studies, catalysis, effects of substituents and reaction conditions influencing reaction rate and regioselectivity.

Inverse neighboring group participation: explanation of an unusual S→N alkyl migration of isothiuronium salts containing a lactone group.

A detailed experimental and DFT study of the S to N alkyl migration of substituted S-(1(3H)-isobenzofuranon-3-yl)isothiuronium bromide to N,N'-dimethyl-N-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)thiourea provided evidence for the existence of an unusual double displacement mechanism involving two consecutive back-side S(N)2 reactions where a carboxylate anion has a crucial role both as a leaving group as well as an internal nucleophile. The thiazetidine zwitterionic species that is involved in this mechanism as an intermediate was characterized by infrared multiphoton dissociation spectroscopy and was trapped with methyl iodide. It was found that the intermediate has a structure of a free ion pair. The double-displacement mechanism can be considered as a new type of inverse lactone neighboring group participation.

Direct Cyclopalladation of Fluorinated Benzyl Amines by Pd3(OAc)6: The Coexistence of Multinuclear Pdn Reaction Pathways Highlights the Importance of Pd Speciation in C-H Bond Activation.

Palladacycles are key intermediates in catalytic C-H bond functionalization reactions and important precatalysts for cross-couplings. It is commonly believed that palladacycle formation occurs through the reaction of a substrate bearing a C-H bond ortho to a suitable metal-directing group for interaction with, typically, mononuclear "Pd(OAc)2" species, with cyclopalladation liberating acetic acid as the side product. In this study, we show that N,N-dimethyl-fluoro-benzyl amines, which can be cyclopalladated either ortho or para to fluorine affording two regioisomeric products, can occur by a direct reaction of Pd3(OAc)6, proceeding via higher-order cyclopalladated intermediates. Regioselectivity is altered subtly depending on the ratio of substrate:Pd3(OAc)6 and the solvent used. Our findings are important when considering mechanisms of Pd-mediated reactions involving the intermediacy of palladacycles, of particular relevance in catalytic C-H bond functionalization chemistry.

Switchable cyclopalladation of substrates containing two directing groups: on the way to non-symmetrical [2.2]-dipalladaparacyclophanes.

Simple switching of the site-selectivity of C-H activation reactions of substrates containing multiple directing groups is particularly important for the so-called late stage functionalization synthetic approach. In this work, we verified the possibility of achieving this by adding acids of different strengths. Using a substrate containing two differently strong (and basic) directing groups, the influence of the addition of acids on the regioselectivity of the C-H activation step of the reaction with palladium acetate was thoroughly studied. The addition of no or weak acids results in cyclopalladation being controlled by a stronger directing group. However, the addition of a strong acid causes protonation of this group and the reaction is then controlled by a weaker directing group. Finally, this approach enables double C-H activation leading to a unique class of compounds: "non-symmetrical" [2.2]-dipalladaparacyclophanes.

A phylogeny of the northern temperate leafy liverwort genus Scapania (Scapaniaceae, Jungermanniales).

Scapania is a northern temperate genus with a few disjunctions in the south. Despite receiving considerable attention, the supraspecific classification of this genus remains unsatisfactorily solved. We use three molecular markers (nrITS, cpDNA trnL-F region, atpB-rbcL spacer) and 175 accessions belonging to 50 species (plus eight outgroup taxa) to estimate the phylogeny and to test current classification systems. Our data support the classification of Scapania into six rather than three subgenera, rearrangements within numerous sections, and inclusion of Macrodiplophyllum microdontum. Scapania species with a plicate perianth form three early diverging lineages; the most speciose subgenus, Scapania s.str., represents a derived clade. Most morphological species concepts are supported by the molecular topologies but classification of sect. Curtae requires further study. Southern lineages are nested in northern hemispheric clades. Palearctic-Nearctic distribution ranges are supported for several species.

Carboxamide substituted tetramethylcyclopentadiene - synthesis, characterisation and its iridium(III) complex catalysed reduction of imines.

The novel dimeric iodo-iridium(III) complex, [Ir(Cp*CONMe2)I2]2, (Cp*CONMe2 = η5-N,N-2,3,4,5-hexamethylcyclopenta-2,4-diene carboxamide) bearing an amide moiety within the tetramethylcyclopentadiene ring, has been synthesised and characterised. The ligand Cp*CONMe2 is synthesised as two regioisomers, however the 2-substituted isomer exists as two distinguishable conformers due to restricted rotation about the amide carbonyl carbon and the ring carbon. The relative acidities of Cp*CONMe2 and Cp* are compared by their relative rates of H/D exchange. The iridium complex of N,N-2,3,4,5-hexamethylcyclopenta-2-4-diene carboxamide [IrCp*CONMe2] and (R,R)-1,2-diphenyl-N'-tosylethane-1,2-diamine ((R,R)-TsDPEN) has been evaluated in the transfer hydrogenation of imines under acidic conditions - a 5 : 2 molar ratio of formic acid : triethylamine as the hydride source for the transfer hydrogenation of 1-methyl-3,4-dihydroisoquinoline (DHIQ) and its 6,7-dimethoxy derivative in acetonitrile. A decreasing enantiomeric excess with reaction progress is attributed to different kinetic orders for formation of the two product amine enantiomers. The pseudo zero-order formation of the R-amine may be due to a pre-steady-state formation of the less stable form of the diastereomeric catalyst. By contrast, both enantiomeric amines from 1-fluorinated methyl DHIQs as substrates for reduction are formed by pseudo first-order processes.

Plasmon-assisted click chemistry at low temperature: an inverse temperature effect on the reaction rate.

Plasmon assistance promotes a range of chemical transformations by decreasing their activation energies. In a common case, thermal and plasmon assistance work synergistically: higher temperature results in higher plasmon-enhanced catalysis efficiency. Herein, we report an unexpected tenfold increase in the reaction efficiency of surface plasmon-assisted Huisgen dipolar azide-alkyne cycloaddition (AAC) when the reaction mixture is cooled from room temperature to -35 °C. We attribute the observed increase in the reaction efficiency to complete plasmon-induced annihilation of the reaction barrier, prolongation of plasmon lifetime, and decreased relaxation of plasmon-excited-states under cooling. Furthermore, control quenching experiments supported by theoretical calculations indicate that plasmon-mediated substrate excitation to an electronic triplet state may play the key role in plasmon-assisted chemical transformation. Last but not least, we demonstrated the possible applicability of plasmon assistance to biological systems by AAC coupling of biotin to gold nanoparticles performed at -35 °C.

A phylogeny of Adelanthaceae (Jungermanniales, Marchantiophyta) based on nuclear and chloroplast DNA markers, with comments on classification, cryptic speciation and biogeography.

Adelanthaceae (including Jamesoniellaceae) represent a major lineage of jungermannialean liverworts that is characterized by ventral-intercalary, often flagelliform branches, succubous leaves, ovoid to cylindrical, plicate perianths with a contracted mouth, often connate bracts and bracteoles, and 4-7 stratose capsule walls. Here we present the first comprehensive molecular phylogeny of Adelanthaceae using five markers (rbcL, psbA, trnL-trnF region, atpB-rbcL spacer, nrITS1-5.8S-ITS2) and 108 accessions from throughout the geographic range of the family. The molecular data support the separation of subfamilies Adelanthoideae and Jamesonielloideae. The Adelanthoideae include the genera Adelanthus, Pseudomarsupidium and Wettsteinia. The Jamesonielloideae include representatives of the genera Anomacaulis, Cryptochila, Cuspidatula, Jamesoniella, and Syzygiella in five main clades. The monophyly of taxa in current morphological classification schemes of Jamesonielloideae is not supported by the molecular data. Based on the outcome of the molecular phylogenetic analyses we propose to include Anomacaulis and Jamesoniella kirkii in Cuspidatula, and to place Cryptochila, Roivainenia, and Jamesoniella in the synonymy of Syzygiella. Molecular data support intercontinental ranges for several species and a range formation of Adelanthaceae by frequent short-distance dispersal, rare long-distance dispersal, extinction, and diversification. Disjunct distribution patterns within the Adelanthaceae cannot be explained by Gondwanan vicariance.

Kinetic evidence for the coexistence of zwitterionic (T+/-), neutral (T0) and anionic (T-) intermediates during rearrangement of S-(2-oxotetrahydrofuran-3-yl)-N-(4-methoxyphenyl)isothiuronium bromide to 5-(2-hydroxyethyl)-2-(4-methoxyphenylimino)-1,3-thiazolidin-4-one.

The kinetics and mechanism of rearrangement of S-(2-oxotetrahydrofuran-3-yl)-N-(4-methoxyphenyl)isothiuronium bromide (1) into 5-(2-hydroxyethyl)-2-[(4-methoxyphenyl)imino]-1,3-thiazolidin-4-one have been studied under pseudo-first-order reaction conditions in aqueous buffer solutions and in diluted HCl at 25 degrees C. Multiple breaks in the pH profile establish the formation of three different kinetically detectable intermediates T(+/-), T(0), and T(-). Treatment of 1 (pK(a) = 6.7) with base produces reactive isothiourea, which undergoes cyclization to give T(+/-) (rate limiting step at pH < 0.5). Intermediate T(+/-) then undergoes either general acid-catalyzed, concerted (alpha = -0.47) breakdown to 2 (rls at pH 2-3) or a water-mediated proton switch to T(0) which is followed by its general acid-catalyzed breakdown (pH 3-6). The last reaction pathway involves the formation of T(-) either from T(+/-) or from T(0) (pH > 6). The first possibility seems to be more likely because it is in accordance with kinetics observed in basic amine buffers, where the nonlinear increase of the k(obs) with the c(Buffer) changes to a linear increase as a general base-catalyzed pathway is introduced. Coexistence of all three kinetically detectable intermediates is very rare and is possibly due to relatively enhanced stability of these intermediates necessitating participation of an acid for progression to products.

Photochemistry of a 9-Dithianyl-Pyronin Derivative: A Cornucopia of Reaction Intermediates Lead to Common Photoproducts.

Leaving groups attached to the meso-methyl position of many common dyes, such as xanthene, BODIPY, or pyronin derivatives, can be liberated upon irradiation with visible light. However, the course of phototransformations of such photoactivatable systems can be quite complex and the identification of reaction intermediates or even products is often neglected. This paper exemplifies the photochemistry of a 9-dithianyl-pyronin derivative, which undergoes an oxidative transformation at the meso-position to give a 3,6-diamino-9H-xanthen-9-one derivative, formic acid, and carbon monoxide as the main photoproducts. The course of this multi-photon multi-step reaction was studied under various conditions by steady-state and time-resolved optical spectroscopy, mass spectrometry and NMR spectroscopy to understand the effects of solvents and molecular oxygen on individual steps. Our analyses have revealed the existence of many intermediates and their interrelationships to provide a complete picture of the transformation, which can bring new inputs to a rational design of new photoactivatable pyronin or xanthene derivatives.

Bi and trinuclear complexes in palladium carboxylate-assisted C-H activation reactions.

The role of polynuclear species in C-H activations assisted by palladium carboxylates has not been clear so far. The summary of the key findings covering this issue shows its important role under certain conditions. However, much more effort is necessary for a deeper understanding of the whole issue.