(3+2)-Cycloadditions of Levoglucosenone (LGO) with Fluorinated Nitrile Imines Derived from Trifluoroacetonitrile: An Experimental and Computational Study.

The in situ-generated N-aryl nitrile imines derived from trifluoroacetonitrile smoothly undergo (3+2)-cycloadditions onto the enone fragment of the levoglucosenone molecule, yielding the corresponding, five-membered cycloadducts. In contrast to the 'classic' C(Ph),N(Ph) nitrile imine, reactions with fluorinated C(CF3),N(Ar) analogues lead to stable pyrazolines in a chemo- and stereoselective manner. Based on the result of X-ray single crystal diffraction analysis, their structures were established as exo-cycloadducts with the location of the N-Ar terminus of the 1,3-dipole at the α-position of the enone moiety. The DFT computation demonstrated that the observed reaction pathway results from the strong dominance of kinetic control over thermodynamic control.

Diastereoselective synthesis and structure-affinity relationships of σ1 receptor ligands with spirocyclic scaffold.

Spirocyclic scaffolds play an increasing role in drug discovery as they define a rigid three-dimensional space to increase specific interactions with protein binding sites. Herein, a spirocyclic center was introduced into the lead compound 1 to rigidify its flexible benzylaminoethyl side chain. The key step of the synthesis was the reaction of different α,ß-unsaturated amides 6 and 13-16 with methyl acrylate in the presence of TBDMSOTf. DFT calculations explain the mechanism of this transformation as concerted Diels-Alder reaction (functionals B3LYP and TPSS) or double (aza)-Michael addition (functionals PBE and wB97X-D). After separation of the diastereomeric spirocyclic products 8 and 17-20, LiAlH4 reduction provided the spirocyclic hydroxymethyl piperidines 21a,b-25a,b showing low nanomolar σ1 affinity (Ki < 100 nM). trans-Configured ligands (a-series) showed higher or equal σ1 affinity and higher selectivity over σ2 receptors and GluN2B-NMDA receptors than their cis-configured analogs (b-series). The additional hydroxymethyl moiety brings the log D7.4 value in a promising range. The high σ1 affinity (Ki = 3.6 nM) and the low lipophilicity result in the highest lipophilic ligand efficiency for the dispiro compound 23a (LLE = 6.0). The spirocyclic compounds reported herein and in particular the dispiro compound 23a demonstrate that ligands containing a large number of sp3 C-atoms possess favorable pharmacological (σ1 receptor affinity, receptor selectivity) and physicochemical properties (log D7.4 value) resulting in promising LLE.

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.

Semisynthetic Approach toward Biologically Active Derivatives of Phenylspirodrimanes from S. chartarum.

The phenylspirodrimanes (PSDs) from Stachybotrys chartarum represent a structurally diverse group of meroterpenoids, which, on the one hand, exhibit a structural exclusivity since their occurrence is not known for any other species and, on the other hand, offer access to chemically and biologically active compounds. In this study, phenylspirodrimanes 1-3 were isolated from S. chartarum and their water-mediated Cannizzaro-type transformation was investigated using quantum chemical DFT calculations substantiated by LC-MS and NMR experiments. Considering the inhibitory activity of PSDs against proteolytic enzymes and their modulatory effect on plasminogen, PSDs 1-3 were used as a starting material for the synthesis of their corresponding biologically active lactams. To access the library of the PSD derivatives and screen them against physiologically relevant serine proteases, a microscale semisynthetic approach was developed. This allowed us to generate the library of 35 lactams, some of which showed the inhibitory activity against physiologically relevant serine proteases such as thrombin, FXIIa, FXa, and trypsin. Among them, the agmatine-derived lactam 16 showed the highest inhibitory activity against plasma coagulation factors and demonstrated the anticoagulant activity in two plasma coagulation tests. The semisynthetic lactams were significantly less toxic compared to their parental natural PSDs.

Insights into Ergochromes of the Plant Pathogen Claviceps purpurea.

Claviceps purpurea is an ergot fungus known for its neurotropic alkaloids, which have been identified as the main cause of ergotism, a livestock and human disease triggered by ergot consumption. Tetrahydroxanthone dimers, the so-called ergopigments, presumably also contribute to this toxic effect. Overexpression of the cluster-specific transcription factor responsible for the formation of these pigments in C. purpurea led to the isolation of three new metabolites (8-10). The new pigments were characterized utilizing HRMS, NMR techniques, and CD spectroscopy and shown to be xanthone dimers. Secalonic acid A and its 2,4'- and 4,4'-linked isomers were also isolated, and their absolute configuration was investigated. The contribution of secalonic acid A, its isomers, and new metabolites to the toxicity of C. purpurea was investigated in HepG2 and CCF-STTG1 cells. Along with cytotoxic properties, secalonic acid A was found to inhibit topoisomerase I and II activity.

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.

Synthesis of Alkyl Silanes via Reaction of Unactivated Alkyl Chlorides and Triflates with Silyl Lithium Reagents.

The reaction of unactivated secondary and primary alkyl chlorides as well as primary alkyl triflates with silyl lithium reagents to access tetraorganosilanes is reported. These nucleophilic substitutions proceed in the absence of any transition metal catalyst under mild conditions in moderate to very good yields. The silyl lithium reagents are readily generated from the corresponding commercially available chlorosilanes. Enantioenriched secondary alkyl chlorides react with high stereospecificity under inversion of configuration.

New Reactivity Patterns in 3H-Phosphaallene Chemistry [Aryl-P=C=C(H)-tBu]: Hydroboration of the C=C Bond, Deprotonation and Trimerisation.

3H-Phosphaallenes, R-P=C=C(H)C-R' (3), are accessible in a multigram scale on a new and facile route and show a fascinating chemical reactivity. BH3 (SMe2 ) and 3 a (R=Mes*, R'=tBu) afforded by hydroboration of the C=C bonds of two phosphaallene molecules an unprecedented borane (7) with the B atom bound to two P=C double bonds. This compound represents a new FLP based on a B and two P atoms. The increased Lewis acidity of the B atom led to a different reaction course upon treatment of 3 a with H2 B-C6 F5 (SMe2 ). Hydroboration of a C=C bond of a first phosphaallene is followed in a typical FLP reaction by the coordination of a second phosphaallene molecule via B-C and P-B bond formation to yield a BP2 C2 heterocycle (8). Its B-P bond is short and the B-bound P atom has a planar surrounding. Treatment of 3 a with tBuLi resulted in deprotonation of the ß-C atom of the phosphaallene (9). The Li atom is bound to the P atom as demonstrated by crystal structure determination, quantum chemical calculations and reactions with HCl, Cl-SiMe3 or Cl-PtBu2 . The thermally unstable phosphaallene Ph-P=C=C(H)-tBu gave a unique trimeric secondary product by P-P, P-C and C-C bond formation. It contains a P2 C4 heterocycle and was isolated as a W(CO)4 complex with two P atoms coordinated to W (15).

Tridentate Ligand with Three Carbanions as Donor Atoms: Formation of Dinuclear, Heptacyclic Complexes of Boron, Aluminum, or Gallium with B-C-B, Al-C-Al, or Ga-C-Ga Three-Center-Two-Electron Bonds.

The trilithium compound 1,3-[PhMe2Si-C(Li)═C(H)]2C6H3Li (2b) reacted with BCl3, AlCl3, or GaCl3 by salt elimination to yield dinuclear heptacyclic compounds (4). Two tridentate tricarbanionic ligands coordinate two B, Al, or Ga atoms and adopt a helical arrangement of the ligands around a central E2 unit. The unusual structures comprise E2C2 heterocycles with two 3c-2e (three-center-two-electron) E-C-E bonds and two C atoms of aromatic rings in the bridging positions. While such a bonding situation is well-documented in Al chemistry, it is rare for B and Ga compounds. Insight into the bonding situation of the molecules is provided by DFT calculations.

Aspects of Phosphaallene Chemistry: Heat-Induced Formation of 1,2-Dihydrophosphetes by Intramolecular Nucleophilic Aromatic Substitution and Photochemical Generation of Tricyclic Phosphiranes.

3H-Phosphaallenes are accessible on a new and facile route and show a fascinating chemical behavior. The thermally induced rearrangement of Mes*P═C═C(H)R' (R' = tBu, Ad) afforded by C-H activation, isobutene elimination, and C-C and P-H bond formation bicyclic 1-benzo-dihydrophosphetes (2) with PC3 heterocycles. DFT calculations suggest a mechanism with intramolecular nucleophilic aromatic substitution and replacement of an alkyl group by the nucleophilic α-C atom of the phosphaallene. These bicycles formed W(CO)5 complexes (3) or afforded 1,2-dihydrophosphetes with P-bound alkenyl groups by catalyst-free hydrophosphination of alkynes (4 and 5). The resulting bulky phosphines formed complexes with IrCp*Cl2, RuCl2, AuCl, or CuO3SCF3. The Ru atom is coordinated by the P atom and a phenyl group. Irradiation of TripP═C═C(H)tBu led by the insertion of the central C atom of the P═C═C group into the α-C-H bond of an iPr substituent and by C-C and P-C bond formation to a new isomer of phosphaallenes, 10, which features a strained PC2 heterocycle. It formed adducts with M(CO)5 (M = Cr, Mo, W) and AuCl and reacted with SO2Cl2 by cleavage of one of the phosphirane P-C bonds to yield PC4 or PC5 heterocycles. Hydrolysis yielded a PC5 compound with a P(O)Cl group.

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.

Al/P- and Ga/P-Based Frustrated Lewis Pairs and Electronically Unsaturated Substrates: Ring Cleavage and Ring Closure, C-C and C-N Bond Formation.

Al/P- and Ga/P-based frustrated Lewis pairs (FLPs) reacted with an azirine under mild conditions under cleavage of the heterocycle on two different positions. Opening of the C-C bond yielded an unusual nitrile-ylide adduct in which a C-N moiety coordinated to the FLP backbone. Cleavage of a C-N bond afforded the thermodynamically favored enamine adduct with the N atom bound to P and Al or Ga atoms. Ring closure was observed upon treatment of an Al/P FLP with electronically unsaturated substrates (4-(1-cyclohexenyl)-1-aza-but-1-en-3-ynes) and yielded by C-N bond formation hexahydroquinoline derivatives, which coordinated to the FLP through P-C and Al-C bonds. Diphenylcyclopropenone showed a diverse reactivity, which depending on steric shielding and the polarizing effect of Al or Ga atoms afforded different products. An AltBu2 /P FLP yielded an adduct with the C=O group coordinated to P and Al. The dineopentyl derivative gave an equilibrium mixture consisting of a similar product and a simple adduct with O bound to Al and a three-coordinate P atom. Both compounds co-crystallize. The Ga/P FLP only formed the simple adduct with the same substrate. Rearrangement resulted in all cases in C3 -ring cleavage and migration of a mesityl group from P to a former ring C atom by C-C bond formation. Diphenylthiocyclopropenone (evidence for the presence of P=C bonds) and an imine derivative afforded similar products.

Silyldefluorination of Fluoroarenes by Concerted Nucleophilic Aromatic Substitution.

The reaction of readily generated silyl lithium reagents with various aryl fluorides to provide the corresponding aryl silanes is reported. DFT calculations reveal that the nucleophilic aromatic substitution of the fluoride anion by the silyl lithium reagent proceeds through concerted ipso substitution. In contrast to the classical nucleophilic aromatic substitution, this concerted ionic silyldefluorination also occurs on more electron-rich aryl fluorides.

A P-H functionalized Al/P-based frustrated Lewis pair - hydrophosphination of nitriles, ring opening with cyclopropenones and evidence of P[double bond, length as m-dash]C double bond formation.

Hydroalumination of R-P(H)-C[triple bond, length as m-dash]C-tBu with bulky H-Al[CH(SiMe3)2]2 afforded the new P-H functionalized Al/P-based frustrated Lewis pair R-P(H)-C[[double bond, length as m-dash]C(H)-tBu]-AlR2 [R = CH(SiMe3)2; FLP 7]. A weak adduct of 7 with benzonitrile (8) was detected by NMR spectroscopy, but could not be isolated. tert-Butyl isocyanide afforded a similar, but isolable adduct (9), in which the isocyanide C atom was coordinated to aluminium. The unique reactivity of 7 became evident from its reactions with the heteroatom substituted nitriles PhO-C[triple bond, length as m-dash]N, PhCH2S-C[triple bond, length as m-dash]N and H8C4N-C[triple bond, length as m-dash]N. Hydrophosphination of the C[triple bond, length as m-dash]N triple bonds afforded imines at room temperature which were coordinated to the FLP by Al-N and P-C bonds to yield AlCPCN heterocycles (10 to 12). These processes depend on substrate activation by the FLP. Diphenylcyclopropenone and its sulphur derivative reacted with 7 by addition of the P-H bond to a C-C bond of the strained C3 ring and ring opening to afford the fragment (Z)-Ph-C(H)[double bond, length as m-dash]C(Ph)-C-X-Al (X = O, S). The C-O or C-S groups were coordinated to the FLP to yield AlCPCX heterocycles (13 and 14). The thiocarbonyl derived compound 14 contains an internally stabilized phosphenium cation with a localized P[double bond, length as m-dash]C bond, a trigonal planar coordinated P atom and a short P[double bond, length as m-dash]C distance (168.9 pm). Insight into formation mechanisms, the structural and energetic properties of FLP 7 and compounds 13 and 14 was gained by quantum chemical DFT calculations.

Reactions of an Aluminium/Phosphorus Frustrated Lewis Pair (FLP) with α,ß-Unsaturated Carbonyl Compounds: FLPs as Efficient Two-Electron Reductants with the Formation of Enolates, a cis-Enediolate, and an Allene.

The Al/P-based frustrated Lewis pair (FLP) Mes2 P-C(AltBu)2 =C(H)Ph (1; Mes=mesityl) reacted as an efficient two-electron reductant with benzil to afford a cis-enediolate that was coordinated to the FLP through P-O and Al-O bonds and the formation of a seven-membered heterocycle (2). The phosphorus atom is oxidised from +III to +V. Similar heterocycles (3 a to 3 f) were formed if 1 was treated with various enones (acrolein, acrylate, acrylamide). The resulting enolates are bound to the FLP through P-C and Al-O bonds. Cyclopropenone gave an adduct (4) with the C=O bond coordinated by P and Al. Ynones gave a fascinating variety of different structures. 1,3-Diphenylprop-2-yn-1-one afforded a remarkable allene-type moiety with two cumulated C=C bonds (5); 3-hexyn-2-one yielded a ligand with two conjugated C=C bonds by C-H bond activation at the carbonyl methyl group (7); and 4-(trimethylsilyl)-3-butyn-2-one reacted by C-H bond cleavage, formation of an enolate group with a terminal C=C bond, and shift of the proton to the P atom (8). The C≡C bond was not affected. Allene compound 5 rearranged at elevated temperature and in daylight through the formation of a tricyclic compound by C-H bond activation and C-C bond formation. DFT calculations on this unusual rearrangement suggest insertion of the central allene C atom into the C-H bond of a methyl group and the intermediate formation of a C3 ring.

Transition-Metal-Free Ring-Opening Silylation of Indoles and Benzofurans with (Diphenyl-tert-butylsilyl)lithium.

A practical method is presented for ring opening various indoles and benzofurans with concomitant stereoselective silylation using readily generated (diphenyl-tert-butylsilyl)lithium to afford ortho-ß-silylvinylanilines or -phenols. Dearomatization of the heteroarene core proceeds in the absence of any transition-metal catalyst through addition of a silyl anion and a subsequent stereoselective ß-elimination. DFT calculations provide insight into the mechanism. Functionalizing C-X bond cleavage of heteroarenes is rare and generally requires transition-metal catalysts.

Radical Hydrodehalogenation of Aryl Bromides and Chlorides with Sodium Hydride and 1,4-Dioxane.

A practical method for radical chain reduction of various aryl bromides and chlorides is introduced. The thermal process uses NaH and 1,4-dioxane as reagents and 1,10-phenanthroline as an initiator. Hydrodehalogenation can be combined with typical cyclization reactions, proving the nature of the radical mechanism. These chain reactions proceed by electron catalysis. DFT calculations and mechanistic studies support the suggested mechanism.

Cooperative Activation of Isocyanates by Al-N-Based Active Lewis Pairs and the Generation of a C5 Chain by Simultaneous Formation of Two C-C Bonds.

The active Al/N Lewis pair, (Me3 C)2 Al-C(SiMe3 )=C(H)-N(CHMe-CH2 )2 CH2 (2), reacted with isocyanates to afford a fascinating variety of products. One equivalent of Ph-N=C=O yielded by the release of H-C≡C-SiMe3 an urea-type ligand which coordinated the Al atom in a chelating manner (4). Dipp-N=C=O gave a similar product, but the bulky substituent hindered the approach of the N-aryl group to Al. A situation similar to that of frustrated Lewis pairs resulted in the coordination of the alkyne to the Al and N atoms (6) by C-H bond activation. Dual insertion was observed upon treatment of 2 with two equivalents of isocyanates (8 to 11). The preferred formation of cyclic oligomers is prevented by the specific cooperative properties of the Lewis pair. A metal-free dimeric isocyanate (13) was formed by hydrolysis. Replacement of the CMe3 groups in 2 by less bulky isobutyl groups (7) afforded the insertion of two isocyanate molecules into the Al-vinyl bonds without alkyne elimination. The resulting highly functionalised compound had a chain formed by two isocyanates and the organic backbone of the Lewis pair. Me3 C-N=C=O and 2 afforded a unique compound (14) in which an isocyanate ligand connects two molecules of 2 by the release of dimethylpiperidine. The combination of a C1 building block and two C2 groups gave an unsaturated branched C5 moiety by the simultaneous formation of two C-C bonds. The molecular structure showed an interaction between an Al atom and a C-C π-bond.

Why Are Vinyl Cations Sluggish Electrophiles?

The kinetics of the reactions of the vinyl cations 2 [Ph2C═C+-(4-MeO-C6H4)] and 3 [Me2C═C+-(4-MeO-C6H4)] (generated by laser flash photolysis) with diverse nucleophiles (e.g., pyrroles, halide ions, and solvents containing variable amounts of water or alcohol) have been determined photometrically. It was found that the reactivity order of the nucleophiles toward these vinyl cations is the same as that toward diarylcarbenium ions (benzhydrylium ions). However, the reaction rates of vinyl cations are affected only half as much by variation of the nucleophiles as those of the benzhydrylium ions. For that reason, the relative reactivities of vinyl cations and benzhydrylium ions depend strongly on the nature of the nucleophiles. It is shown that vinyl cations 2 and 3 react, respectively, 227 and 14 times more slowly with trifluoroethanol than the parent benzhydrylium ion (Ph)2CH+, even though in solvolysis reactions (80% aqueous ethanol at 25 °C) the vinyl bromides leading to 2 and 3 ionize much more slowly (half-lives 1.15 yrs and 33 days) than (Ph)2CH-Br (half-life 23 s). The origin of this counterintuitive phenomenon was investigated by high-level MO calculations. We report that vinyl cations are not exceptionally high energy intermediates, and that high intrinsic barriers for the sp2 ⇌ sp rehybridizations account for the general phenomenon that vinyl cations are formed slowly by solvolytic cleavage of vinyl derivatives, and are also consumed slowly by reactions with nucleophiles.

1,3,5-Triazapentadienes by Nucleophilic Addition to 1,3- and 1,4-Dinitriles-Sterically Constrained Examples by Incorporation into Cyclic Peripheries: Synthesis, Aggregation, and Photophysical Properties.

1,3,5-Triazapentadienes usually show U- or twisted S-shaped conformations along the N-C-N-C-N skeleton due to dominating n/π* interactions. If, however, the 1,3,5-triazapentadiene unit is part of a ring, its W conformation might be restricted to the plane. Here, we describe the synthesis of 13 new 1,3,5-triazapentadienes 10-12, which are sterically restrained by incorporation into six- or seven-membered ring systems, by addition of a lithiated primary amine or hydrazine 5 to a dinitrile 7, 8, or 9 with the two cyano groups in 1,3 or 1,4 distance. These novel compounds show very strong tendency for aggregation due to hydrogen bonding, especially to form homodimers as seen from X-ray data in the solid state. Additional hydrogen bonding generates also linear chains in the crystal. Several of the new compounds show fluorescence in solution. Quantum chemical DFT calculations were used for evaluation of the dimerization energies and for interpretation of the photophysical properties.