Diastereoselective Dearomatizing Cyclizations of 5-Arylpentan-2-ones by Samarium Diiodide - A Computational Analysis.

This study analyzes the samarium diiodide-promoted cyclizations of 5-arylpentan-2-ones to dearomatized bicyclic products utilizing density functional theory. The reaction involves a single electron transfer to the carbonyl group, which occurs synchronously with the rate determining cyclization event, and a second subsequent proton-coupled electron transfer. These redox reactions are accurately computed employing small core pseudo potentials explicitly involving all f-electrons of samarium. Comparison of the energies of the possible final products rules out thermodynamic control of the observed regio- and diastereoselectivities. Kinetic control via appropriate transition states is correctly predicted, but to obtain reasonable energy levels the influence of the co-solvent hexamethylphosphortriamide has to be estimated by using a correction term. The steric effect of the bulky samarium ligands is decisive for the observed stereoselectivity. Carbonyl groups in para-position of the aryl group change the regioselectivity of the cyclization and lead to spiro compounds. The computations suggest again kinetic control of this deviating outcome. However, the standard mechanism has to be modified and the involvement of a complex activated by two SmI2 moieties is proposed in which two electrons are transferred simultaneously to form the new C-C bond. Computation of model intermediates show the feasibility of this alternative+ mechanism.

One-pot nucleophilic substitution-double click reactions of biazides leading to functionalized bis(1,2,3-triazole) derivatives.

The nucleophilic substitution of benzylic bromides with sodium azide was combined with a subsequent copper-catalyzed (3 + 2) cycloaddition with terminal alkynes. This one-pot process was developed with a simple model alkyne, but then applied to more complex alkynes bearing enantiopure 1,2-oxazinyl substituents. Hence, the precursor compounds 1,2-, 1,3- or 1,4-bis(bromomethyl)benzene furnished geometrically differing bis(1,2,3-triazole) derivatives. The use of tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA) as ligand for the click step turned out to be very advantageous. The compounds with 1,2-oxazinyl end groups can potentially serve as precursors of divalent carbohydrate mimetics, but the reductive cleavage of the 1,2-oxazine rings to aminopyran moieties did not proceed cleanly with these compounds.

Spin State in Homoleptic Iron(II) Terpyridine Complexes Influences Mixed Valency and Electrocatalytic CO2 Reduction.

Two homoleptic Fe(II) complexes in different spin states bearing superbasic terpyridine derivatives as ligands are investigated to determine the relationship between spin state and electrochemical/spectroscopic behavior. Antiferromagnetic coupling between a ligand-centered radical and the high-spin metal center leads to an anodic shift of the first reduction potential and results in a species that shows mixed valency with a moderately intense intervalence-charge-transfer band. The differences afforded by the different spin states extend to the electrochemical reactivity of the complexes: while the low-spin species is a precatalyst for electrocatalytic CO2 reduction and leads to the preferential formation of CO with a Faradaic efficiency of 37%, the high-spin species only catalyzes proton reduction at a modest Faradaic efficiency of approximately 20%.

The Boekelheide Rearrangement of Pyrimidine N-oxides as a Case Study of Closed or Open Shell Reactions - Experimental and Computational Evidence for the Participation of Radical Intermediates.

In a case study, the acetic anhydride-promoted reaction of a model pyrimidine N-oxide to the corresponding 4-acetoxymethyl-substituted pyrimidine derivative (Boekelheide rearrangement) was investigated in detail by experiment and quantum chemical calculations. The reaction conditions were varied and several side products formed in low to moderate yields were identified. These experiments indicate that a (pyrimidin-4-yl)methyl radical is one of the key species of the rearrangement. This interpretation was supported by the fact that rearrangements performed in solvents which can easily lose hydrogen atoms, afford considerable quantities of products incorporating the solvent. With TEMPO the key radical could be trapped. Other carboxylic acid anhydrides confirm the conclusion that the Boekelheide rearrangement of the model pyrimidine N-oxide proceeds, at least in part, via radical intermediates. The high level closed and open shell quantum chemical calculations show that concerted [3,3]-sigmatropic rearrangements or stepwise processes, either via ion pairs or via radicals, are energetically feasible.

Hetero-Diels-Alder Reactions of In Situ-Generated Azoalkenes with Thioketones; Experimental and Theoretical Studies.

The hetero-Diels-Alder reactions of in situ-generated azoalkenes with thioketones were shown to offer a straightforward method for an efficient and regioselective synthesis of scarcely known N-substituted 1,3,4-thiadiazine derivatives. The scope of the method was fairly broad, allowing the use of a series of aryl-, ferrocenyl-, and alkyl-substituted thioketones. However, in the case of N-tosyl-substituted cycloadducts derived from 1-thioxo-2,2,4,4-tetramethylcyclobutan-3-one and the structurally analogous 1,3-dithione, a more complicated pathway was observed. By elimination of toluene sulfinic acid, the initially formed cycloadducts afforded 2H-1,3,4-thiadiazines as final products. Advanced DFT calculations revealed that the observed high regioselectivity was due to kinetic reaction control and that the (4 + 2)-cycloadditions of sterically less unhindered thiones occurred via highly unsymmetric transition states with shorter C..S-distances (2.27-2.58 Å) and longer N..C-distances (3.02-3.57 Å). In the extreme case of the sterically very hindered 2,2,4,4-tetramethylcyclobutan-1,3-dione-derived thioketones, a zwitterionic intermediate with a fully formed C‒S bond was detected, which underwent ring closure to the 1,3,4-thiadiazine derivative in a second step. For the hypothetical formation of the regioisomeric 1,2,3-thiadiazine derivatives, the DFT calculations proposed more symmetric transition states with considerably higher energies.

A Homage to Siegfried Hünig and His Research.

Examples from different research areas of Siegfried Hünig are displayed to remind us that organic chemistry owes much more than Hünig's base to this exceptionally versatile and creative chemist. The main research lines dealing with the synthesis and physical characterization of new dyes, multistage redox systems, and organic metals will be presented as well as his contributions to enamine chemistry, the discovery of diimine as a hydrogenation agent, and nucleophilic acylation with trimethylsilyl cyanide, which are less well-known nowadays. In addition, exotic compounds with parallel C=C and N=N bonds were systematically studied in Hünig's group. Reflecting on the development of his research demonstrates both the importance of a systematic approach and how fruitful entirely unexpected results are if they meet a "well-prepared mind". During Hünig's academic career, teaching played an indisputable role. His efforts in modernizing the chemistry institute at Würzburg and his support of young researchers in the academic system in Germany are also highlighted.

Rolf Huisgen (1920-2020).

Rolf Huisgen would have celebrated his 100th birthday this year. Three of his academic progeny look back on Huisgen as a person, teacher, and scientist. They underline his leading role in rebuilding the chemistry department in Munich after the Second World War and the enduring importance of the 1,3-dipolar cycloaddition (Huisgen reaction).

The Huisgen Reaction: Milestones of the 1,3-Dipolar Cycloaddition.

The concept of 1,3-dipolar cycloadditions was presented by Rolf Huisgen 60 years ago. Previously unknown reactive intermediates, for example azomethine ylides, were introduced to organic chemistry and the (3+2) cycloadditions of 1,3-dipoles to multiple-bond systems (Huisgen reaction) developed into one of the most versatile synthetic methods in heterocyclic chemistry. In this Review, we present the history of this research area, highlight important older reports, and describe the evolution and further development of the concept. The most important mechanistic and synthetic results are discussed. Quantum-mechanical calculations support the concerted mechanism always favored by R. Huisgen; however, in extreme cases intermediates may be involved. The impact of 1,3-dipolar cycloadditions on the click chemistry concept of K. B. Sharpless will also be discussed.

The [4+2]-Cycloaddition of α-Nitrosoalkenes with Thiochalcones as a Prototype of Periselective Hetero-Diels-Alder Reactions-Experimental and Computational Studies.

The [4+2]-cycloadditions of α-nitrosoalkenes with thiochalcones occur with high selectivity at the thioketone moiety of the dienophile providing styryl-substituted 4H-1,5,2-oxathiazines in moderate to good yields. Of the eight conceivable hetero-Diels-Alder adducts only this isomer was observed, thus a prototype of a highly periselective and regioselective cycloaddition has been identified. Analysis of crude product mixtures revealed that the α-nitrosoalkene also adds competitively to the thioketone moiety of the thiochalcone dimer affording bis-heterocyclic [4+2]-cycloadducts. The experiments are supported by high-level DFT calculations that were also extended to related hetero-Diels-Alder reactions of other nitroso compounds and thioketones. These calculations reveal that the title cycloadditions are kinetically controlled processes confirming the role of thioketones as superdienophiles. The computational study was also applied to the experimentally studied thiochalcone dimerization, and showed that the 1,2-dithiin and 2H-thiopyran isomers are in equilibrium with the monomer. Again, the DFT calculations indicate kinetic control of this process.

Adsorption of Mono- and Divalent 4-(Dimethylamino)pyridines on Gold Surfaces: Studies by Surface-Enhanced Raman Scattering and Density Functional Theory.

The adsorption thermodynamics of 4-(dimethylamino)pyridine (DMAP) and its five divalent derivatives di-DMAP- n (2 ≤ n ≤ 6) with gradually increasing methylene-spacer lengths n binding to planar gold surfaces has been studied by surface-enhanced Raman spectroscopy (SERS) and density functional theory (DFT). SERS intensities of the totally symmetrical breathing mode of the pyridine ring at approximately 1007 cm-1 are used to monitor the surface coverage of the DMAP and di-DMAP- n ligands on gold surfaces at different concentrations. The equilibrium constant as a measure of the binding affinity is obtained from these measurements by using a modified Langmuir isotherm. Due to multivalent binding to the gold substrate, a characteristic enhancement of the binding affinity of di-DMAP- n compared to the monovalent DMAP is observed for all divalent species. First principles calculations of the di-DMAP- n ligands on an ideal Au(111) surface model as well as step terrace models have been performed to understand the adsorption structures and the multivalent binding enhancements. Furthermore, Raman spectra of the adsorbed molecules have been studied by first principles calculations to correlate the binding affinities to experimentally determined adsorption constants. The joint experimental and theoretical investigation of an oscillatory behavior of the binding affinity as a function of the methylene-spacer length in mono- and divalent 4-(dimethylamino)pyridines reveals that the molecular architecture plays an important role for the structure-function interplay of multivalently bound adsorbates.

New Dyes Based on Extended Fulvene Motifs: Synthesis through Redox Reactions of Naphthoquinones with Donor-Acceptor Cyclopropanes and Their Spectroelectrochemical Behavior.

Novel dyes based on extended fulvene motifs are reported. The carbon skeleton was generated by a catalyzed addition of donor-acceptor cyclopropanes to naphthoquinone. The hydroxy group at the central ring of the tricyclic fulvene motif was converted into the triflate, which reacted efficiently with a wide range of nucleophiles, resulting in substitution and thereby providing new derivatives. The synthetic versatility allowed us to investigate the absorption, electrochemical, and UV/Vis-NIR spectroelectrochemical properties of these dyes as a function of the substituents. The dyes were shown to participate in reductive electrochemistry, the reversibility of which can be improved by appropriate selection of the substituents. Additionally, first signs of NIR electrochromism are presented, opening new avenues for the future investigations of such dyes.

Stereoselective Cascade Cyclizations with Samarium Diiodide to Tetracyclic Indolines: Precursors of Fluorostrychnines and Brucine.

A series of γ-indolylketones with fluorine, cyano or alkoxy substituents at the benzene moiety was prepared and subjected to samarium diiodide-promoted cyclization reactions. The desired dearomatizing ketyl cascade reaction forming two new rings proceeded in all cases with high diastereoselectivity, but with differing product distribution. In most cases, the desired annulated tetracyclic compounds were obtained in moderate to good yields, but as second product tetracyclic spirolactones were isolated in up to 29 % yield. The reaction rate was influenced by the substituents at the benzene moiety of the substrate as expected, with electron-accepting groups accelerating and electron-donating groups decelerating the cyclization process. In case of a difluoro-substituted γ-indolylketone a partial defluorination was observed. The intermediate samarium enolate of the tetracyclic products could be trapped by adding reactive alkylating agents as electrophiles delivering products with quarternary carbons. In the case of a dimethoxy-substituted tetracyclic cyclization product a subsequent reductive amination stereoselectively provided a pentacyclic compound that was subsequently N-protected and subjected to a regioselective elimination. The obtained functionalized pentacyclic product should be convertible into the alkaloid brucine by four well-established steps. Overall, the presented report shows that functionalized tetracyclic compounds with different substituents are rapidly available with the samarium diiodide cascade cyclization as crucial step. Hence, analogues of the landmark alkaloid strychnine, for example, with specific fluorine substitutions, should be easily accessible.

The LANCA three-component reaction to highly substituted ß-ketoenamides - versatile intermediates for the synthesis of functionalized pyridine, pyrimidine, oxazole and quinoxaline derivatives.

The LANCA three-component reaction of lithiated alkoxyallenes LA, nitriles N and carboxylic acids CA leads to ß-ketoenamides KE in good to excellent yields. The scope of this reaction is very broad and almost all types of nitriles and carboxylic acids have successfully been used. The alkoxy group introduced via the allene component is also variable and hence the subsequent transformation of this substituent into a hydroxy group can be performed under different conditions. Enantiopure nitriles or carboxylic acids can also be employed leading to chiral KE with high enantiopurity and dinitriles or dicarboxylic acids also lead to the expected bis-ß-ketoenamides. ß-Ketoenamides incorporate a unique combination of functional groups and hence a manifold of subsequent reactions to highly substituted heterocyclic compounds is possible. An intramolecular aldol-type condensation reaction efficiently furnishes pyridin-4-ols PY that can be further modified by palladium-catalyzed reactions, e.g., to specifically substituted furopyridine derivatives. Condensations of ß-ketoenamides with ammonium salts or with hydroxylamine hydrochloride afford pyrimidines PM or pyrimidine N-oxides PO with a highly flexible substitution pattern in good yields. The functional groups of these heterocycles also allow a variety of subsequent reactions to various pyrimidine derivatives. On the other hand, acid-labile alkoxy substituents such as a 2-(trimethylsilyl)ethoxy group are required for the conversion of ß-ketoenamides into 5-acetyl-substituted oxazoles OX, again compounds with high potential for subsequent functional group transformations. For acid labile ß-ketoenamides bearing bulky substituents the acid treatment leads to acylamido-substituted 1,2-diketones DK that could be converted into quinoxalines QU. All classes of heterocycles accessed through the key ß-ketoenamides show a unique substitution pattern - not easily accomplishable by alternative methods - and therefore many subsequent reactions are possible.

Efficient Syntheses of New Super Lewis Basic Tris(dialkylamino)-Substituted Terpyridines and Comparison of Their Methyl Cation Affinities.

Syntheses of very electron-rich dialkylamino-substituted 2,2':6',2''-terpyridines (TPYs) were adapted to moderate scale preparation without tedious purification of intermediates. The key 4'-bromo-6,6''-dimethyl-2,2':6',2''-terpyridine-4,4''-diyl bisnonaflate is now available in gram quantities. Its nucleophilic aromatic substitution with dimethylamine provided mixtures of 4'-bromo-substituted 4,4''-bis(dimethylamino)-TPY and the tris(dimethylamino)-TPY. The bromo compound was used in a Buchwald-Hartwig amination to provide the tris(dimethylamino)-TPY in excellent yield. The 4'-bromo substituent was reductively removed to furnish the bis(dimethylamino)-TPY. The same sequence of reactions with pyrrolidine as nucleophile leads to the hitherto unknown pyrrolidino-TPYs. Calculations at the MP2(FC)/6-31+G(2d,p)//B98/6-31G(d) level predict very high methyl cation affinities for compounds of this type, with the 4,4',4''-tri(pyrrolidin-1-yl)-TPY being the most Lewis basic TPY synthesized to date. The efficiently prepared electron-rich TPYs should be excellent ligands for many applications.

Alkoxyallene-based syntheses of preussin and its analogs and their cytotoxicity.

Short syntheses of oxa-preussin, racemic preussin and (-)-preussin are reported. Starting from a racemic 3-nonyl-substituted methoxyallene derivative, its lithiation and addition to phenylethanal provided the corresponding allenyl alcohol that was converted into two diastereomeric dihydrofuran derivatives by silver nitrate-catalyzed 5-endo-trig cyclization. The acid hydrolysis of the enol ether moiety gave heterocyclic ketones and subsequent highly stereoselective reductions with l-selectride furnished 2-benzyl-5-nonylfuran-3-ol derivatives in good overall yield. The major all-cis-diastereomer has the skeleton and relative configuration of preussin and is hence called oxa-preussin. An analogous sequence with the same allene, but an N-sulfonyl imine as the electrophile, finally led to racemic preussin. The stereoselectivities of the individual steps are discussed in detail. With an enantiopure 2-benzyl-5-nonylpyrrolidin-3-one intermediate the preparation of (-)-preussin with an enantiomeric ratio of >95 : 5 could be accomplished in a few steps. The sign of the optical rotation of this product finally proved the absolute configurations of its precursors and demonstrated that our chiral auxiliary-based route led to the antipode of the natural product. The cytotoxicity of several of the prepared heterocycles against MCF-7 tumor cells was investigated and five compounds, including racemic and enantiopure (-)-preussin, were identified as highly cytotoxic with IC50 values in the range of 3-6 µM.

To Anion-π or not to Anion-π: The Case of Anion-Binding to Divalent Fluorinated Pyridines in the Gas Phase.

A series of mono- and divalent fluorinated pyridine derivatives is investigated by electrospray ionization (tandem) mass spectrometry and quantum chemical calculations with respect to their capability to bind anions in the gas phase. The pyridine derivatives differ not only in valency, but also with regard to the degree of fluorination of the pyridine rings, the positions of the fluorine atoms, the rigidity of the spacers connecting the two pyridines in the divalent compounds, and the relative configuration. While the monovalent compounds did not form anion complexes, the divalent analogues exhibit anion binding even to weakly coordinating anions such as tetrafluoroborate. Three different tandem mass spectrometric experiments were applied to rank the gas-phase binding energies: (i) collision-induced dissociation (CID) experiments in a Fourier transform ion-cyclotron-resonance (FTICR) mass spectrometer on two different, simultaneously mass-selected complexes with different receptors, (ii) determination of the collision energy required to fragment 50 % of the mass-selected complexes in an ESI-QToF mass spectrometer, and (iii) CID of heterodimers formed from two different, competing pyridine receptors and indigo carmine, a dianion with two identical binding sites. All three experiments result in consistent binding energy ranking. This ranking reveals surprising features, which are not in agreement with binding through anion-π interactions. Density functional theory (DFT) calculations comparing different potential binding modes provide evidence that the ranking can instead nicely be explained, when C-H⋅⋅⋅anion interactions with the spacers are invoked. These results are supported by gas-phase IR spectroscopy and ion mobility-mass spectrometry (IM-MS) on a selected set of chloride pyridine complexes.

A computational study of samarium diiodide-induced cyclizations of N-oxoalkyl-substituted methyl indole-3-carboxylates-A rationale of the diastereoselectivity.

A detailed model for the reaction mechanism of the samarium diiodide (SmI2 ) mediated reductive coupling of N-oxoalkyl-substituted methyl indole-3-carboxylates is developed in this study by determining the Gibbs energies for the intermediates of possible reaction pathways. The Gibbs energies at ambient temperature are calculated with dispersion corrected density functional theory in combination with implicit (D-COSMO-RS) and explicit solvent description. Temperature dependent ro-vibrational contributions are considered with the help of statistical thermodynamics. In contrast to previous proposals for the reaction mechanism, the high diastereoselectivity in the cyclization is found to be due to the formation of an energetically highly favorable chelate complex in which the final relative configuration is already preformed. After cyclization and a second electron transfer, alkylation of the resulting anion takes place under kinetic control from the more "open" face whereas protonation is under thermodynamic control. The calculations are in good agreement with these experimental findings. © 2017 Wiley Periodicals, Inc.

Novel Alkoxy-Substituted Dipyrrins and Near-IR BODIPY Dyes-Preparation and Photophysical Properties.

Starting from 3-alkoxy-2-aryl-substituted pyrroles and aromatic aldehydes, a collection of new dipyrrins was prepared. Under the standard conditions of Treibs, these were converted into the corresponding boron dipyrrins (BODIPYs). Compounds of this type with alkoxy groups at C-3 position of both pyrrole subunits are new and hence the photophysical properties of this collection of novel dipyrrins and BODIPY dyes were investigated. The dipyrrins show absorption maxima up to 596 nm and emissions of up to 677 nm. For the BODIPY series a remarkable effect of the alkoxy groups was identified, resulting in red shifts for absorptions and emissions. The compound substituted with two 2-thien-2-yl groups and a meso-C6 F5 substituent shows an absorption maximum at 725 nm and emits at 754 nm and thus is a new representative of a near-IR BODIPY dye related to certain aza-BODIPYs. Our results demonstrate the influence of the alkoxy groups on the spectroscopic data and reveal the potential of 3-alkoxy-2-aryl-substituted pyrroles for the design of new fluorophores.

Ruthenium Complexes with Strongly Electron-Donating Terpyridine Ligands: Effect of the Working Electrode on Electrochemical and Spectroelectrochemical Properties.

The combination of 2,2':6',2''-terpyridines (tpy) and RuII is known to deliver molecular and supramolecular assemblies with remarkable properties. Here new RuII complexes, with modified tpy ligands substituted with varying numbers of dimethlyamino groups, are presented. Electrochemistry shows that the incorporation of the strongly electron-donating groups on the tpy ligands leads to a negative shift of the RuII oxidation potential by close to 1 V. The reductive electrochemical responses are strongly dependent on the nature of the working electrode, with glassy carbon and gold working electrodes showing the best results. These observations led to the development of a modified Optically Transparent Thin Layer Electrochemical (OTTLE) cell, based on a gold working electrode. The use of UV/Vis/NIR spectroelectrochemical methods with that OTTLE cell, together with simulations of the cyclic voltammograms, allowed the characterization of four reduction steps in these complexes, the final two of which lead to bond activations at the ruthenium center. This observation is to the best of our knowledge unprecedented in coordinatively saturated complexes of type [Ru(tpy)2 ]2+ . The various redox states of the complexes were characterized by EPR spectroelectrochemistry and through DFT calculations. The results presented here establish these substituted tpy ligands as highly attractive ligands in coordination chemistry, and display the utility of a gold-based OTTLE cell for spectroelectrochemical measurements.

Alkoxyallene-Based Stereodivergent Syntheses of (-)-Hyacinthacine B4 and of Putative Hyacinthacine C5 Epimers: Proposal of Hyacinthacine C5 Structure.

Hyacinthacines are members of the class of polyhydroxylated pyrrolizidines exhibiting outstanding biological activity as glycosidases inhibitors. Their structural complexity is embodied in the densely functionalized core, possessing a series of contiguous stereogenic centers. In this synthetic study we report a route to the more complex congeners of this class of alkaloids exploiting the diastereoselective addition of an axially chiral lithiated alkoxyallene to an enantiopure cyclic nitrone. Our stereodivergent approach enabled the installation of the targeted configuration at the ring A by minimal synthetic manipulations and at ring B by using stage dependent selective functionalizations. The versatility and robustness of this methodology were demonstrated by the syntheses of (-)-hyacinthacine B4 and of two epimers of (+)-hyacinthacine C5, allowing a suggestion of the likely structure of the isolated natural product.