Synthesis and Characterization of New Boron Compounds Using Reaction of Diazonium Tetraphenylborate with Enaminoamides

A family of oxazaborines, diazaborinones, triazaborines, and triazaborinones was prepared by reaction of polarized ethylenes, such as β-enaminoamides, with 4-methylbenzenediazonium tetraphenylborates. The reaction conditions (stirring in CH2Cl2 at room temperature (Method A) or stirring with CH3COONa in CH2Cl2 at room temperature (Method B) or refluxing in the CH2Cl2/toluene mixture (Method C)) controlled the formation and relative content of these compounds in the reaction mixtures from one to three products. Substituted oxazaborines gradually rearranged into diazaborinones at 250 °C. The prepared compounds were characterized by 1H NMR, 13C NMR, IR, and UV–Vis spectroscopy, HRMS, or microanalysis. The structure of individual compounds was confirmed by 11B NMR, 15N NMR, 1D NOESY, and X-ray analysis. The mechanism of reaction of enaminoamides with 4-methylbenzenediazonium tetraphenylborate was proposed.

Relationship between the Crystal Structure and Tuberculostatic Activity of Some 2-Amidinothiosemicarbazone Derivatives of Pyridine

Tuberculosis remains one of the most common diseases affecting developing countries due to difficult living conditions, the rapidly increasing resistance of M. tuberculosis strains and the small number of effective anti-tuberculosis drugs. This study concerns the relationship between molecular structure observed in a solid-state by X-ray diffraction and the 15N NMR of a group of pyridine derivatives, from which promising activity against M. tuberculosis was reported earlier. It was found that the compounds exist in two tautomeric forms: neutral and zwitterionic. The latter form forced the molecules to adopt a stable, unique, flat frame due to conjugation and the intramolecular hydrogen bond system. As the compounds exist in a zwitterionic form in the crystal state generally showing higher activity against tuberculosis, it may indicate that this geometry of molecules is the “active” form.

Chiral Aminoalcohols and Squaric Acid Amides as Ligands for Asymmetric Borane Reduction of Ketones: Insight to In Situ Formed Catalytic System by DOSY and Multinuclear NMR Experiments

A series of squaric acid amides (synthesized in 66–99% isolated yields) and a set of chiral aminoalcohols were comparatively studied as ligands in a model reaction of reduction of α-chloroacetophenone with BH3•SMe2. In all cases, the aminoalcohols demonstrated better efficiency (up to 94% ee), while only poor asymmetric induction was achieved with the corresponding squaramides. A mechanistic insight on the in situ formation and stability at room temperature of intermediates generated from ligands and borane as possible precursors of the oxazaborolidine-based catalytic system has been obtained by 1H DOSY and multinuclear 1D and 2D (1H, 10/11B, 13C, 15N) NMR spectroscopy of equimolar mixtures of borane and selected ligands. These results contribute to better understanding the complexity of the processes occurring in the reaction mixture prior to the possible oxazaborolidine formation, which play a crucial role on the degree of enantioselectivity achieved in the borane reduction of α-chloroacetophenone.

Synthesis and Coordination of Bicyclic Phosphorus-Nitrogen Ligands

<p>This thesis describes the synthesis and coordination chemistry of bicyclic phosphorus-nitrogen (PN) ligands containing the rigid and preorganised bicyclo[3.3.1]nonan-9-one framework. The PN ligands were prepared via the Mannich condensation reaction of four different phosphorinanone classes with amines and aldehydes. The phosphorinanone compounds, 2,6-dimethyl-3,5-diphenyl-4-phenyl-4- phosphacyclohexanone (isomers 50 and 51), 3,5-diphenyl-4-phenyl-4- phosphacyclohexanone (44, 45) and 4-phenyl-4-phosphacyclohexanone (42) were prepared by literature methods, whereas the isomers of 4-t-butyl-2,6- di(carbomethoxy) - 3,5 - bis(p - dimethylaminophenyl) - 4 - phosphacyclohexanone (53, 54) were synthesised by the reaction of ButPH2 with 2,4-di(carbomethoxy)- 1,5 - bis(p - dimethylaminophenyl)penta - 1,4 - dien - 3 - one (38). The Mannich reactions of phosphorinanones 50 and 51 were not successful, whereas the reactions of 44, 45 and 42 produced unidentifiable products. The reaction of phosphorinanone 53 with methylamine and formaldehyde produced the bicyclic PN compound 7-t-butyl-1,5-di(carbomethoxy)-6,8-bis(p-dimethylaminophenyl)- 3 - methyl - 3 - aza - 7 - phosphabicyclo[3.3.1]nonan - 9 - one (65). The identical Mannich reaction of phosphorinanone 54 also yielded 65, as well as the PN compound 4-t-butyl-6-carbomethoxy-5-(p-dimethylaminophenyl)- 2-methyl-2-aza-4-phosphacyclohexanone (66) and the E/Z isomers of 3-(p-dimethylaminophenyl)methyl-2-propenoate (67). The bicyclic PN ligand 65 adopts a chair-chair conformation in solution and the solid state as confirmed by X-ray crystallography. The coordination chemistry of this ligand was comprehensively explored with rhodium, palladium and platinum, and a wide range of complexes were synthesised including [ML2(65)] (M = Pd, Pt; L = Cl, Me), [ML(65)] (M = Rh, Pd, Pt; L = C2H4, cod, dba, norb) (cod = cycloocta-1,5-diene, dba = trans,trans- dibenzylideneacetone, norb = norborn-2-ene), [Pd(n3 -C3H5)(65)]X (X = Cl, SbF6) and [PtL(65)]CH(SO2CF3)2 (L = 1-o,4-5-n-C8H13, 1-3-n-C8H13). Cycloplatination at the ortho-position of the 6,8-dimethylaminophenyl sub- stituents was an interesting feature of the coordination chemistry of PN ligand 65. Ortho-metallation at both dimethylaminophenyl groups led to the formation of complex [Pt(C2H4)(65-2H)] (76), whereas metallation of only one aryl group produced the complex [Pt(C8H13)(65-H)] (87). Further reaction of complex 76 yielded the trans- and cis-hydroxo-bridged dimers [Pt2(u-OH)2(65-H)2] (98, 101). The nitrogen donor atom is not coordinated to the platinum metal centres in the cyclometallated PN complexes. Protonation of [Pt(C2H4)(65)] (75) with CH2(SO2CF3)2 produced the hydride complex [PtH{CH(SO2CF3)2}(65)] (92) and the agostic ethyl complex [Pt(C2H5)(65)]CH(SO2CF3)2 (93). Similarly, protonation of [Pt(norb)(65)] (74) with CHPh(SO2CF3)2 gave the norbornyl agostic complex [Pt(C7H11)(65)]CPh(SO2CF3)2 (94) as confirmed by X-ray crystallography. In addition, hydrated analogues of some of the coordination complexes of PN ligand 65 mentioned previously were also observed. In such complexes, the central carbonyl group at position 9 was hydrated to form a geminal diol. The hydrated complexes exhibited similar chemical characteristics to their ketone counterparts. The 15N NMR chemical shifts of the nitrogen donor atom in PN ligand 65 and its various metal complexes were obtained from inversely-detected 1H- 15N HMBC experiments. The NMR data showed no explicit relationship between the coordination mode of the nitrogen group and the 15N chemical shift.</p>

Synthesis and Coordination of Bicyclic Phosphorus-Nitrogen Ligands

<p>This thesis describes the synthesis and coordination chemistry of bicyclic phosphorus-nitrogen (PN) ligands containing the rigid and preorganised bicyclo[3.3.1]nonan-9-one framework. The PN ligands were prepared via the Mannich condensation reaction of four different phosphorinanone classes with amines and aldehydes. The phosphorinanone compounds, 2,6-dimethyl-3,5-diphenyl-4-phenyl-4- phosphacyclohexanone (isomers 50 and 51), 3,5-diphenyl-4-phenyl-4- phosphacyclohexanone (44, 45) and 4-phenyl-4-phosphacyclohexanone (42) were prepared by literature methods, whereas the isomers of 4-t-butyl-2,6- di(carbomethoxy) - 3,5 - bis(p - dimethylaminophenyl) - 4 - phosphacyclohexanone (53, 54) were synthesised by the reaction of ButPH2 with 2,4-di(carbomethoxy)- 1,5 - bis(p - dimethylaminophenyl)penta - 1,4 - dien - 3 - one (38). The Mannich reactions of phosphorinanones 50 and 51 were not successful, whereas the reactions of 44, 45 and 42 produced unidentifiable products. The reaction of phosphorinanone 53 with methylamine and formaldehyde produced the bicyclic PN compound 7-t-butyl-1,5-di(carbomethoxy)-6,8-bis(p-dimethylaminophenyl)- 3 - methyl - 3 - aza - 7 - phosphabicyclo[3.3.1]nonan - 9 - one (65). The identical Mannich reaction of phosphorinanone 54 also yielded 65, as well as the PN compound 4-t-butyl-6-carbomethoxy-5-(p-dimethylaminophenyl)- 2-methyl-2-aza-4-phosphacyclohexanone (66) and the E/Z isomers of 3-(p-dimethylaminophenyl)methyl-2-propenoate (67). The bicyclic PN ligand 65 adopts a chair-chair conformation in solution and the solid state as confirmed by X-ray crystallography. The coordination chemistry of this ligand was comprehensively explored with rhodium, palladium and platinum, and a wide range of complexes were synthesised including [ML2(65)] (M = Pd, Pt; L = Cl, Me), [ML(65)] (M = Rh, Pd, Pt; L = C2H4, cod, dba, norb) (cod = cycloocta-1,5-diene, dba = trans,trans- dibenzylideneacetone, norb = norborn-2-ene), [Pd(n3 -C3H5)(65)]X (X = Cl, SbF6) and [PtL(65)]CH(SO2CF3)2 (L = 1-o,4-5-n-C8H13, 1-3-n-C8H13). Cycloplatination at the ortho-position of the 6,8-dimethylaminophenyl sub- stituents was an interesting feature of the coordination chemistry of PN ligand 65. Ortho-metallation at both dimethylaminophenyl groups led to the formation of complex [Pt(C2H4)(65-2H)] (76), whereas metallation of only one aryl group produced the complex [Pt(C8H13)(65-H)] (87). Further reaction of complex 76 yielded the trans- and cis-hydroxo-bridged dimers [Pt2(u-OH)2(65-H)2] (98, 101). The nitrogen donor atom is not coordinated to the platinum metal centres in the cyclometallated PN complexes. Protonation of [Pt(C2H4)(65)] (75) with CH2(SO2CF3)2 produced the hydride complex [PtH{CH(SO2CF3)2}(65)] (92) and the agostic ethyl complex [Pt(C2H5)(65)]CH(SO2CF3)2 (93). Similarly, protonation of [Pt(norb)(65)] (74) with CHPh(SO2CF3)2 gave the norbornyl agostic complex [Pt(C7H11)(65)]CPh(SO2CF3)2 (94) as confirmed by X-ray crystallography. In addition, hydrated analogues of some of the coordination complexes of PN ligand 65 mentioned previously were also observed. In such complexes, the central carbonyl group at position 9 was hydrated to form a geminal diol. The hydrated complexes exhibited similar chemical characteristics to their ketone counterparts. The 15N NMR chemical shifts of the nitrogen donor atom in PN ligand 65 and its various metal complexes were obtained from inversely-detected 1H- 15N HMBC experiments. The NMR data showed no explicit relationship between the coordination mode of the nitrogen group and the 15N chemical shift.</p>

Detecting Organic Nitrogen with 1H-15N HMBC Spectra

NMR spectroscopy has been the most important tool for organic chemistry research, providing detailed structure information. While 1H and 13C NMR spectra were frequently measured, 15N NMR spectra were relatively rare, even though nitrogen is commonly observed in organic molecules. This is due to the low gyromagnetic ratio and nature abundance. Usually 15N NMR spectra are observed when the sample is in very high concentration or the nitrogen is enriched with 15N isotope. HMBC is one of the 2D NMR techniques, measuring the through-bond correlations inside a molecule. 1H-15N HMBC actually collects a series of measurements of 1H NMR spectra with 15N information. Therefore, HMBC could get stronger signals than 15N signals and provide the opportunity for the indirect measurement of 15N signals.

Membrane Interactions of Latarcins: Antimicrobial Peptides from Spider Venom

A group of seven peptides from spider venom with diverse sequences constitute the latarcin family. They have been described as membrane-active antibiotics, but their lipid interactions have not yet been addressed. Using circular dichroism and solid-state 15N-NMR, we systematically characterized and compared the conformation and helix alignment of all seven peptides in their membrane-bound state. These structural results could be correlated with activity assays (antimicrobial, hemolysis, fluorescence vesicle leakage). Functional synergy was not observed amongst any of the latarcins. In the presence of lipids, all peptides fold into amphiphilic α-helices as expected, the helices being either surface-bound or tilted in the bilayer. The most tilted peptide, Ltc2a, possesses a novel kind of amphiphilic profile with a coiled-coil-like hydrophobic strip and is the most aggressive of all. It indiscriminately permeabilizes natural membranes (antimicrobial, hemolysis) as well as artificial lipid bilayers through the segregation of anionic lipids and possibly enhanced motional averaging. Ltc1, Ltc3a, Ltc4a, and Ltc5a are efficient and selective in killing bacteria but without causing significant bilayer disturbance. They act rather slowly or may even translocate towards intracellular targets, suggesting more subtle lipid interactions. Ltc6a and Ltc7, finally, do not show much antimicrobial action but can nonetheless perturb model bilayers.

Convenient Synthesis of Pyrazolo[4′,3′:5,6]pyrano[4,3-c][1,2]oxazoles via Intramolecular Nitrile Oxide Cycloaddition

A simple and efficient synthetic route to the novel 3a,4-dihydro-3H,7H- and 4H,7H-pyrazolo[4′,3′:5,6]pyrano[4,3-c][1,2]oxazole ring systems from 3-(prop-2-en-1-yloxy)- or 3-(prop-2-yn-1-yloxy)-1H-pyrazole-4-carbaldehyde oximes has been developed by employing the intramolecular nitrile oxide cycloaddition (INOC) reaction as the key step. The configuration of intermediate aldoximes was unambiguously determined using NOESY experimental data and comparison of the magnitudes of 1JCH coupling constants of the iminyl moiety, which were greater by approximately 13 Hz for the predominant syn isomer. The structures of the obtained heterocyclic products were confirmed by detailed 1H, 13C and 15N NMR spectroscopic experiments and HRMS measurements.

(±)-2-{[4-(4-Bromophenyl)-5-phenyl-4H-1,2,4-triazol-3-yl]sulfanyl}-1-phenyl-1-ethanol

The novel racemic secondary alcohol (±)-2-{[4-(4-bromophenyl)-5-phenyl-4H-1,2,4-triazol-3-yl]sulfanyl}-1-phenyl-1-ethanol (12) has been successfully synthesized through S-alkylation of 4-(4-bromophenyl)-5-phenyl-4H-1,2,4-triazole-3-thiol (10) in alkaline medium with 2-bromo-1-phenylethanone followed by reduction of the corresponding ketone 11. All the synthesized compounds were characterized by IR, 1D (1H, 13C, DEPT135) and 2D (1H-1H, 1H-13C and 1H-15N) NMR spectroscopy, elemental analysis and HRMS spectrometry.