One-Pot Synthetic Approach to 3-Carboxyl- and 3-Ketopyridines in Aqueous Media.

We describe a one-pot strategy to access 3-carboxyl- and 3-ketopyridines from readily available alkynes and propargylamine via a hydroamination process. This one-pot protocol uses alkynes as starting materials, has a broad substrate scope, and operates in aqueous media and open-air conditions. A series of aryl- and alkyl-substituted pyridines were synthesized. This green methodology can be scaled to laboratory size and was used for the synthesis of the natural product core, 4-aza-fluorenone. Density-functional theory and control mechanistic studies support a domino hydroamination/pericyclic reaction, which includes the formation of the enaminone intermediate and its transformation through an aza-Claisen rearrangement to the desired pyridine product.

Interesting chemical and physical features of the products of the reactions between trivalent lanthanoids and a tetradentate Schiff base derived from cyclohexane-1,2-diamine.

The initial use of a tetradentate Schiff base (LH2) derived from the 2 : 1 condensation between 2-hydroxyacetophenone and cyclohexane-1,2-diamine in 4f-metal chemistry is described. The 1 : 2 reaction of Ln(NO3)3·xH2O (Ln = lanthanoid or yttrium) and LH2 in MeOH/CH2Cl2 has provided access to isostructural complexes [Ln(NO3)3(L'H2)(MeOH)] in moderate to good yields. Surprisingly, the products contain the corresponding Schiff base ligand L'H2 possessing six aliphatic -CH2- groups instead of the -CH-(CH2)4-CH- unit of the cyclohexane ring, i.e. an unusual ring-opening of the latter has occurred. A mechanism for this LnIII-assisted/promoted LH2 → L'H2 transformation has been proposed assuming transient LnII species and a second LH2 molecule as the H2 source for the reduction of the cyclohexane moiety. DFT calculations provide strong evidence for the great thermodynamic stability of the products in comparison with analogous complexes containing the original intact ligand. The structures of the PrIII, SmIII, GdIII, TbIII, and HoIII complexes have been determined by single-crystal X-ray crystallography. The 9-coordinate LnIII centre in the molecules is bound to six oxygen atoms from the three bidentate chelating nitrato groups, two oxygen atoms that belong to the bidentate chelating organic ligand, and one oxygen atom from the coordinated MeOH group. In the overall neutral bis(zwitterionic) L'H2 ligand, the acidic H atoms are clearly located on the imino nitrogen atoms and this results in the formation of an unusual 16-membered chelating ring. The coordination polyhedra defined by the nine donor atoms around the 4f-metal-ion centres can be best described as distorted, spherical capped square antiprisms. The EuIII, TbIII, and DyIII complexes exhibit LnIII-based luminescence in the visible region, with the coordinated L'H2 molecule acting as the antenna. Ac magnetometry experiments show that the DyIII member of the family behaves as an SIM at zero field and under external dc fields of 0.1 and 0.2 T without the enhancement of the peaks' maxima, suggesting that QTM is not the relaxation path. The GdIII complex behaves, rather unexpectedly, as a SIM with two different magnetic relaxation paths occurring at very close temperatures; this behaviour is tentatively attributed to a very small axial zero-field splitting (D ∼ 0.1 cm-1), which cannot be detected by magnetization or susceptibility experiments. The prospects of the present, first results in the lanthanoid(III)-LH2 chemistry are discussed.

Probing the anomeric effect and mechanism of isomerization of oxazinane rings by DFT methods.

Mechanistic studies of the thermal amine-promoted isomerization of oxazinane rings by DFT methods showed that the isomerization proceeds through abstraction of the C-3 hydrogen atom by the amine nitrogen atom followed by its re-recruitment from C-3 that helps the oxazinane ring to avoid breaking, leading to the same or an isomeric conformer. Calculations also provided evidence that steric effects are responsible for the breaking of the O-N bond in the transition state of the thermal amine-promoted transformations of oxazinane rings, leading to the transformation of the 6-membered ring to a 5-membered ring. Extensive computational studies of the origin of the anomeric effect in the di-substituted oxazinane rings, bearing the EtO substituent at C-6 and CO2Et at C-3, and a series of analogous tetrahydro-2H-pyran ring conformers, revealed that the conformational preferences in both series of compounds are tuned by the balance of non-covalent (weak vDW, dipole-dipole, electrostatic forces, hydrogen bonding) steric effects and hyperconjugative interactions.

Site-selectivity control in hetero-Diels-Alder reactions of methylidene derivatives of lawsone through modification of the reactive carbonyl group: an experimental and theoretical study.

A new perspective on the reactivity of hydroxyquinones was revealed as an acetal derivative of lawsone was synthesized, isolated, and used in tandem Knoevenagel/hetero-Diels-Alder reactions catalyzed by S-proline. The intermediate alkylidene-1,3-diones that were formed in situ reacted with electron rich alkenes to predominantly afford pyrano-1,2-naphthoquinone (ß-lapachone) derivatives along with the isomeric pyrano-1,4-naphthoquinone (α-lapachone) derivatives in high to excellent total yields. Interestingly, the highly reactive arylidene-1,3-dione derivatives were found to be stable and isolable. DFT calculations suggest that these hetero-Diels-Alder reactions have a high polar character, taking place through a two-stage one-step mechanism. An analysis of the conceptual DFT indices allows explaining the remarkable site-selectivity observed.

Cycloaddition Reactions of Indanedioneketene with Electron-Rich Dienophiles: An Experimental and a Theoretical Study.

Thermal decomposition of the phenyliodonium ylide of lawsone gives rise to a highly reactive cyclic α,α'-dioxoketene, indanedioneketene, which reacts with electron-rich dienophiles such as enol ethers to afford [4 + 2] cycloadducts. The initially formed 2,3-dihydro-2-alkoxy-indeno[1,2-b]pyrano-4,5-diones are labile compounds since through an opening of the pyranone ring upon heating they easily tautomerize to alkoxyallylidene-indenedione derivatives and under acid-catalysis they are additionally transformed to 2-(1,3-dihydroxyallylidene)-1H-indene-1,3(2H)-dione or by loss of alcohol to indeno[1,2-b]pyran-4,5-diones. A DFT study explains the polar nature of the cycloaddition reaction, the observed reactivity and suggests a possible mechanism operating in these reactions.

Dimerization of indanedioneketene to spiro-oxetanone: a theoretical study.

Indanedioneketene, a compound resulting from the thermal degradation of the phenyliodonium ylide of lawsone, dimerizes quantitatively to a spiro-oxetanone derivative, a key compound for further transformations. A theoretical electronic structure study of this unusual for alpha-oxoketenes [2 + 2] cyclization reaction both in the gas phase (DFT, MP2) and in dichloromethane solution (DFT), provides support for (a) a single-step, transition-state (involving a four-membered cyclic ring) charge-controlled, concerted mechanism and (b) a [4 + 2] cyclization reaction, not observed but studied theoretically in this study. A parallel study of an open-chain alpha,alpha'-dioxoketene dimerization explains the difference in the stability and reactivity observed experimentally between the cyclic and open-chain products.

Theoretical insights, in the liquid phase, into the antioxidant mechanism-related parameters in the 2-monosubstituted phenols.

The paper describes a DFT/B3LYP study, in the liquid phase, [using the PCM continuum model] on the O-H bond dissociation enthalpy (BDE) and ionization energy (IE) parameter values of the 2-monosubstituted phenols (2-X-ArOH), related to the H-atom transfer (HAT) and single-electron transfer (SET) mechanisms. The solvent and substituent effects on the conformers, the BDEs, and the IEs were studied using four electron-donating (EDG) and five electron-withdrawing (EWG) groups, in seven different solvents. In both the EDG- and/or EWG-substituted species of the parent compounds, radicals, and/or cation radicals, the most stable conformer is varied, depending on the medium and the substitution. The EWG-substituents increase IEs, resulting in a weaker antioxidant activity than the EDG ones; the effect appears stronger on the IEs than on BDEs. However, although the liquid-phase IEs, which are related to solution-phase oxidation potentials, decrease with the polarity and/or the hydrogen-bonding ability of the solvent, the opposite holds true for the BDEs, exhibiting a weaker effect. The gas-phase-calculated IE for benzene is among the most accurate ones in the field, compared to the experiment, that for phenol being the most accurate. In addition, calculated IEs for the 2-X-ArOH are in close agreement with the very few existing experimental ones. It is shown that the oxidation potentials are (a) highly correlated with the gas-phase ones, and (b) strongly solvent dependent. The stabilization/destabilization of the cation radical (SPC) contribution, in all media, is the decisive factor in the DeltaIE calculation. The reasonable correlations found between the DeltaBDE and DeltaIE could account well for the assumption of the simultaneous action of both mechanisms in the 2-X-ArOH, in both the gas and the liquid phase. It seems, however, that the presence of a particular solvent by itself is not sufficient enough for the HAT to SET transition. The involvement of specific ED and/or EW groups in the 2-X-ArOH seems also necessary. It appears that our theoretical approach is not only generally applicable to the set of substituents important to antioxidant activity but also useful in (a) the rational design of phenolic antioxidants and (b) affording accurate BDE and IE parameter values related to both possible antioxidant mechanisms.

Structure-DPPH* scavenging activity relationships: parallel study of catechol and guaiacol acid derivatives.

The scavenging behavior of a series of catechol and guaiacol acid derivatives toward DPPH(*) was examined having as a starting point the order of activity derived on the basis of theoretically calculated BDE values. The studied compounds were protocatechuic, homoprotocatechuic, dihydrocaffeic, and caffeic acids and also vanillic, homovanillic, dihydroferulic, and ferulic acids. Catechol and guaiacol were used as reference compounds. Observations from the parallel study were made with regard to structural features (number and position of hydroxyl groups and the side-carbon chain characteristics) that regulated the behavior of the compounds experimentally. The exceptional DPPH(*) scavenging behavior observed for homoprotocatechuic acid in ethanol and for caffeic acid in acetonitrile could not be supported by the respective BDE values. Ferulic was the most active among guaiacolic acids, whereas dihydroferulic exhibited the highest stoichiometry. Ionizable carboxylic groups seem to affect considerably the relative order of activity as was also evidenced using the ORAC assay. Questions raised about the validity of widely accepted views on criteria for SARs are discussed with regard to literature findings.

A DFT study on the thermal aryl migration in aryliodonium ylides. Support for a concerted mechanism.

A DFT study on the intramolecular thermal phenyl migration in iodonium ylides supports a concerted mechanism. In contrast to the two, different than each other, suggested mechanisms, involving only intermediates, this study indicates a single-step, transition-state one--involving a five-membered cyclic ring--with no intermediates. The frontier-orbital-controlled migration also confirms the different thermal behavior of two different ylides.

PCM study of the solvent and substituent effects on the conformers, intramolecular hydrogen bonds and bond dissociation enthalpies of 2-substituted phenols.

A PCM continuum model, at the DFT/B3LYP level, is used to study the solvent and substituent effects on the conformers, intramolecular hydrogen bond (HB) enthalpies, (Delta H(intra)s), and O-H bond dissociation enthalpies, (BDEs), in 2-substituted phenols, 2-X-ArOH, in the liquid phase. Two electron-donating (edg) and three electron-withdrawing (ewg) substituents are chosen, involved in a variety of biochemical transformations. Seven solvents, differing in their H-bonding ability and polarity, are selected to model different environmental situations. Very good correlations are found between the computed R(O-H) and nu(O-H) values in solution for all non-HB 2-X-ArOH, showing that the former can be used as an universal molecular descriptor for the latter and vice-versa. In all 2-X-ArOH, the HB parent conformer is the most stable in all media, closely matching frequency experimental data in CCl4. However, for all 2-X-ArO*, the most stable conformer either forms a "reverse"-HB or a HB is not formed, due to the long distance or steric effects. Changes in the stability, in solution, are observed for some of the 2-X-ArO* conformers. The intramolecular HB-strength in solution, Delta H(S,intra), varies significantly with the size of the HB ring formed and the nature of the substituents. Reasonable correlations, derived between the two energetic parameters (BDE(aw,sol) and Delta H(S,intra)) and the solvent ( and a), and/or molecular, [R(O-H) and nu(O-H)] ones, allow for an approximate estimation of the two former from the four latter. 2-X(edg) decrease BDEs (hence, increase the antioxidant efficiency of the solute, too) in all media; 2-X(ewg) present an opposite result. Moreover, an isodesmic reactions study affords total stabilization effect (TSE) values (identical to the Delta[BDE(aw)]s), which are mainly governed by the stabilization of the phenolic radical (SPR) than that of the parent molecule (SPP). Quantitative correlations between the two effects in the TSE in both the gas and the liquid phases are also given. Unlike in the protic solvents, the better stabilization of the radical than the parent species, derived for the 2-X(edg)-ArOH in the aprotic, apolar, and/or low polar solvents, could account well for their smaller BDE(sol)s. An effective antioxidant in solution should involve either one of the two edg in any one of the two latter solvents.

The gem-Diol Form of (py)2 CO as a Ligand in Cobalt(II) Carboxylate Clusters: A Cubane Complex and a Novel Nonanuclear Species with a Vertex-Sharing Double Square Pyramidal Structure.

A vertex-sharing double square pyramid of cobalt(II) ions (see picture) is present in the nonanuclear complex 1, obtained by treating cobalt acetate with 0.5 equivalents of (py2 )CO. The corresponding 1:1 reaction gave 2, which has a central core with a cubane structure. py=pyridine.