Keto Enamine Research Articles

Synthesis and structure of regioisomeric amino enones containing 2-pyridyl and CF3 substituents

Regioisomeric amino enones (Z)-4-amino-1,1,1-trifluoro-4-(2-pyridyl)but-3-en-2-one and (Z)-3-amino-4,4,4-trifluoro-1-(2-pyridyl)but-2-en-1-one were synthesized by the reaction of lithium (Z)-1,1,1-trifluoro-4-oxo-4-(2-pyridyl)but-2-en-2-olate with ammonium acetate in glacial AcOH. A comparative study of physicochemical properties and the crystal structures showed that the molecules of these new compounds are planar (except for two fluorine atoms) with an U-shaped configuration of the keto enamine moiety. A change in the position of the amino group with respect to the CF3 substituent leads to significant changes in the electron density distribution and the C-C bond lengths in the keto enamine moiety and also in the character of intermolecular hydrogen bonds responsible for the crystal packing mode of regioisomeric amino enones.

Crystal structure and Hirshfeld surface analysis of (Z)-6-[(2-hy-droxy-5-nitro-anilino)methyl-idene]-4-methyl-cyclo-hexa-2,4-dien-1-one.

The title compound, C14H12N2O4, is a Schiff base that exists in the keto-enamine tautomeric form and adopts a Z configuration. The mol-ecule is almost planar, the rings making a dihedral angle of 4.99 (7)°. The mol-ecular structure is stabilized by an intra-molecular N-H⋯O hydrogen bond forming an S(6) ring motif. In the crystal, inversion-related mol-ecules are linked by pairs of O-H⋯O hydrogen bonds, forming dimers with an R 2 2(18) ring motif. The dimers are linked by pairs of C-H⋯O contacts with an R 2 2(10) ring motif, forming ribbons extended along the [20] direction. Hirshfeld surface analysis, two-dimensional fingerprint plots and the mol-ecular electrostatic potential surfaces were used to analyse the inter-molecular inter-actions present in the crystal, indicating that the most important contributions for the crystal packing are from H⋯H (33.9%), O⋯H/H⋯O (29.8%) and C⋯H/H⋯C (17.3%) inter-actions.

Coordination properties of a Schiff base probe for Zn2+ ion in aqueous media having no Cu2+ ion interference

The coordination properties and acid–base behavior of 2-[{(1S,2R)-1-hydroxy-1-phenylpropan-2-ylimino}methyl]-4-bromophenol Schiff base probe (L1) were characterized by UV–Vis and fluorescence titrations in water. The dissociation constants for the ligand account for a keto–enamine tautomer at pH 7. Detailed complexation studies were carried out, observing the formation of stable 1:1 complex for Zn2+, where a “turn-on” fluorescence effect is obtained. More importantly, no Cu2+ interference is observed, which is a typical problem for Zn2+ probes, this is awarded to the keto–enamine tautomeric form of the probe L1 according to UV–Vis and X-ray structure data. Also, the Zn2+vs. Cd2+ ion discrimination for L1 is proved. Finally, TD-DFT theoretical calculations were conducted in order to stablish the detection mechanism of the probe.

Targeting Cystalysin, a Virulence Factor of Treponema denticola‐Supported Periodontitis

Cystalysin from Treponema denticola is a pyridoxal 5'-phosphate dependent lyase that catalyzes the formation of pyruvate, ammonia, and sulfide from cysteine. It is a virulence factor in adult periodontitis because its reaction contributes to hemolysis, which sustains the pathogen. Therefore, it was proposed as a potential antimicrobial target. To identify specific inhibitors by structure-based in silico methods, we first validated the crystal structure of cystalysin as a reliable starting point for the design of ligands. By using single-crystal absorption microspectrophotometry, we found that the enzyme in the crystalline state, with respect to that in solution, exhibits: 1) the same absorption spectra for the catalytic intermediates, 2) a close pKa value for the residue controlling the keto enamine ionization, and 3) similar reactivity with glycine, L-serine, L-methionine, and the nonspecific irreversible inhibitor aminoethoxyvinylglycine. Next, we screened in silico a library of 9357 compounds with the Fingerprints for Ligands and Proteins (FLAP) software, by using the three-dimensional structure of cystalysin as a template. From the library, 17 compounds were selected and experimentally evaluated by enzyme assays and spectroscopic methods. Two compounds were found to competitively inhibit recombinant T. denticola cystalysin, with inhibition constant (Ki ) values of 25 and 37 μM. One of them exhibited a minimum inhibitory concentration (MIC) value of 64 μg mL(-1) on Moraxella catarrhalis ATCC 23246, which proves its ability to cross bacterial membranes.

Synthesis and Scale-up of Imino–Enamido Hafnium and Zirconium Olefin Polymerization Catalysts

New imino–enamido hafnium and zirconium trimethyl complexes were prepared in high yield by reacting a mixture of an imino–enamine ligand and hafnium or zirconium tetrachloride with four equivalents of methylmagnesium bromide in toluene. A significantly improved imine formation reaction in the final step of the ligand synthesis was developed that involves the reaction between the keto–enamine and a reagent formed in situ by mixing 0.55 equivalents of titanium tetrachloride and 5.5 equivalents of n-butylamine. Ethylene/1-octene polymerization evaluations at 120 °C revealed that polymerization characteristics of the imino–enamido hafnium and zirconium trimethyl derivatives were very similar to those of the tribenzyl analogues. A scale-up of the hafnium trimethyl derivative, performed on a 255 g scale, was accomplished in an overall yield of 57% in four steps starting with commercially available cyclohexa-1,2-dione. Hafnium and zirconium complexes derived from two isomeric imino–enamine ligands each resulted in very high molecular weight ethylene/1-octene copolymers, which differ significantly, however, in the level of incorporated octene. These features make these new catalysts good candidates for the preparation of olefin block copolymers via chain-shuttling polymerization.

(Z)-4-[(Ethylamino)(furan-2-yl)methylidene]-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one

In the crystal of the title compound, C17H17N3O2, the mol­ecules exist in the keto–enamine form. The pyrazole ring is oriented at 10.59 (4) and 57.98 (5)° to the phenyl and furyl rings, respectively, and the dihedral angle between phenyl and furyl rings is 73.30 (11)°. An intra­molecular N—H⋯O hydrogen bond occurs between imino and carbonyl groups. In the crystal, weak C—H⋯O hydrogen bonds link the mol­ecules into supra­molecular chains along the b axis.

Methyl 2-{[(3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-4-ylidene)(4-nitrophenyl)methyl]amino}-3-phenylpropanoate

The mol­ecule of the title compound, C27H24N4O5, exists in the keto–enamine tautomeric form, stabilized by an intra­molecular N—H⋯O hydrogen bond. An intra­molecular C—H⋯·O hydrogen bond also occurs. In the crystal, C—H⋯O hydrogen bonds link the mol­ecules into chains.

Synthesis of 7-Oxo-dihydrospiro[indazole-5,4′-piperidine] Acetyl-CoA Carboxylase Inhibitors

Synthesis of oxo-dihydrospiroindazole-based acetyl-CoA carboxylase (ACC) inhibitors is reported. The dihydrospiroindazoles were assembled in a regioselective manner in six steps from substituted hydrazines and protected 4-formylpiperidine. Enhanced regioselectivity in the condensation between a keto enamine and substituted hydrazines was observed when using toluene as the solvent, leading to selective formation of 1-substituted spiroindazoles. The 2-substituted spiroindazoles were formed selectively from alkyl hydrazones by ring closure with Vilsmeier reagent. The key step in the elaboration to the final products is the conversion of an intermediate olefin to the desired ketone through elimination of HBr from an O-methyl bromohydrin. This methodology enabled the synthesis of each desired regioisomer on 50-75 g scale with minimal purification. Acylation of the resultant spirocyclic amines provided potent ACC inhibitors.

E/Z(C=C)-Isomerization of enamines of 3-formyl-4-hydroxycoumarin induced by organic solvents

According to 1? and 13? NMR data, enamines of 3-formyl-4-hydroxycoumarin exist in the keto enamine tautomeric form and undergo Z/E-isomerization around the C=C bond in CDCl3, DMSO-d6, and CD3OD at room temperature. The activation energies of ?/Z-isomerization were measured experimentally and calculated by the B3LYP/6-311++G(d,p) method. An X-ray diffraction study showed that 3-(benzyliminomethyl)chromane-2,4-dione in the crystalline state exists as a mixture of two keto enamine isomers.

4-[(Z)-Allylamino(phenyl)methylene]-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one

The title compound, C20H19N3O, exists in a keto–enamine tautomeric form. The pyrazolone ring makes dihedral angles of 20.52 (10) and 77.73 (5)° with the two phenyl rings and an intra­molecular N—H⋯O hydrogen bond occurs. A weak inter­molecular C—H⋯O hydrogen bond is observed in the crystal structure. The allyl group is disordered over two positions, with site-occupancy factors of 0.533 (5) and 0.467 (5).

4-{(Z)-(sec-Butylamino)(phenyl)methylene}-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one

In the title compound, C21H23N3O, the dihedral angles formed by the pyrazolone ring with two phenyl rings are 10.38 (8) and 76.94 (6)°. The sec-butyl­amino group is disordered over two positions, with refined site-occupancy factors of 0.730 (4) and 0.270 (4). The compound could potentially be ligand stabilized in the solid state in a keto–enamine tautomeric form. The amine functionality is involved in an intra­molecular N—H⋯O hydrogen bond, while weak inter­molecular C—H⋯O and C—H⋯N hydrogen bonds participate in the formation of the crystal structure.

Diazadioxadecalin and salen podands and macrocycles within dynamic combinatorial virtual libraries: structure, prototropy, complexation and enantioselective catalysis

The reactions of l-1,4-diaminobutanediol ( 3) and d-2,3-diaminobutanediol ( 4) with salicyl aldehyde provide the tautomeric manifolds of l-1,4-bis(salicylideneamino)-2,3-butanediol ( 5) and d-2,3-bis(salicylideneamino)-1,4-butanediol ( 6), respectively. O-alkylation of the salicyl moiety stabilizes the closed dioxadiazadecalin (DODAD) and diazadioxadecalin (DADOD) isomers ( 7″, 8″) and accordingly, the dialdehyde 1,2-bis( o-formylphenoxy)-ethane ( 9) led to the respective macrocyclic manifolds ( 10– 10″ and 11– 11″). These tautomeric manifolds are typical target-driven dynamic combinatorial virtual libraries, which can be biased by complex formation with metal ions of different ionic radius. A rare instance of simultaneous occurrence of keto–enamine and phenol–imine tautomers in the solid state of 6 was unravelled (X-ray at two temperatures) and the strength of the intramolecular hydrogen bonding (and hence, the extent of ring closure) in 6 is temperature dependent. Compounds 6, 11 and 12– 14 constitute a new class of salens, which form heavy and transition metal complexes. Some such Mn(III) complexes are good chirality inducing catalysts, as found in asymmetric indene epoxidation reactions.

Photocyclization of N,N ′-diphenyl-1-hydroxy-9,10-anthraquinone diimines via excited-state intramolecular proton transfer (ESIPT)

Photolysis of 1,5-dihydroxy- and 1-hydroxy-substituted N,N′-diphenyl-9,10-anthraquinone diimines (1a and 1b) produces acridine-condensed ring systems due to oxidative cyclization. In contrast, anthraquinone diimines which bear no hydroxy group on the C1-position show no photoreactivity, providing chemical evidence for participation of excited-state intramolecular proton transfer (ESIPT) in the photocyclization. The ground-state of 1a includes only a small fraction (ca. 4%) of the keto enamine form in fast equilibrium with the enol imine form, as proved by temperature dependent 1H and 13C NMR spectroscopy. An X-ray crystal analysis of 1a reveals that the molecule exists in the crystalline state as the enol imine form with a butterfly conformation of the anthraquinone ring. The involvement of ESIPT in photoexcited 1a has been revealed by means of sub-microsecond time-resolved IR spectroscopy. Upon irradiation of 1a an increase of the ground-state keto form (B) is detected and its lifetime is deduced to be 1.3 ms. Another transient species (A) with a lifetime of 80 µs is also observed, which is assumed to be the intramolecular cycloadduct as a precursor of the photoproduct.

Solid-state electronic absorption, fluorescence and13C CPMAS NMR spectroscopic study of thermo- and photo-chromic aromatic Schiff bases

Solid-state electronic absorption, fluorescence emission and 13C CPMAS spectroscopies have been applied to a series of aromatic Schiff bases displaying both ground and excited state intramolecular proton transfer phenomena. All the results can be explained on the basis of a thermal equilibrium between enolimine and keto–enamine tautomeric forms in the crystalline state. Most of the studied compounds are thermochromic. However, a few are photochromic. The carbon-13 NMR data in the solid state show, in general, residual (13C, 14N) dipolar coupling effects. In certain cases, however, where fast proton transfer occurs in the ground state, these effects are shown to be self-decoupled.

ChemInform Abstract: Reactivity of Secondary, Cross‐Conjugated Keto Enamines Towards Electrophilic Diazenes.

AbstractThe keto enamine (I) reacts with the diazenes (II) to give the products (III) which undergo an acid‐catalyzed rearrangement to provide the isomers (IV).

Benzenoid-quinoid tautomerism of azomethines and their structural analogs. 43. Phenylmercury derivatives of 3-hydroxy-2-acetyl(benzoyl)benzo[b]thiophene and 3-hydroxy-1-methylindole-2-carbaldehyde imines

Phenylmercury derivatives of 3-hydroxy-2-acetyl(benzoyl)benzo[b]thiophene and 3-hydroxy-1-methyl-2-carbaldehyde N-aryl- and N-alkylimines, to which a keto enamine structure with strong intramolecular coordination of the mercury atom and the carbonyl oxygen atom was assigned on the basis of the electronic and vibrational spectra, were synthesized. Compounds of the indole series fluoresce intensely with the usual values of the Stokesian shifts.

Volatility studies of metal chelates. III. Thermal and gas chromatographic properties of the volatile copper(II) and nickel(II) chelates of the isomeric tetradentate β-keto enamines formed in the reaction of 1,1,1-Trifluoro-5,5-dimethylhexane-2,4-dione with Ethane-1,2-diamine

The Schiff base, 6,6,6,6',6',6'-hexafluoro-2,2,2',2'-tetramethyl-5,5'-(ethane-1,2-diyldiimino)bis(hex-4-en-3-one), as normally prepared by the condensation of 1,1,1-trifluoro-5,5-dimethylhexane-2,4-dioneand ethane-1,2-diamine is only one of two isomeric forms which give distinct isomers with copper(II)and nickel(II), readily separated on columns of silica gel. The isomeric chelates have large volatility differences and display greater volatility than other tetradentate β- keto enamine complexes. The excellent gas chromatographic behaviour of the chelates leads to detection limits of about 2 picograms metal with the electron-capture detector.