V-PROLI/NO, a prodrug of the nitric oxide donor, PROLI/NO

The sensitivity to decomposition of the nitric oxide (NO) donor ion, 1-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (PROLI/NO), complicates direct electrophilic substitution to form useful prodrug derivatives. A modified general synthetic approach involving 1-[2-(hydroxymethyl)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate ion (structure A, above) was used to prepare several PROLI/NO prodrugs including the previously inaccessible O2-vinyl derivative, V-PROLI/NO. Metabolism of V-PROLI/NO by liver microsomes enriched in human cytochrome P450 isoforms was demonstrated.     

Arylation of Sensitive 1-(Pyrrolidin-1-yl)-diazen-1-ium-diolate in Ionic Liquids

The purpose of this research was to investigate the stability and reactivity of 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (PYRRO/NO) in dimethylformamide (DMF, as the reference solvent) and compare them to those obtained using different ionic liquids. The results of our experiments showed that PYRRO/NO is more stable (based on reactivity) in ionic liquid [EMIM][Ms] (with reaction yields up to 52%) than in DMF, that substitution products can be separated directly and quantitatively from the ionic liquid using a single flash-column separation, and that the ionic liquids can also be recovered and reused in a second iteration of the same reaction to achieve similar yields.     

Electrochemical analysis of the kinetics of nitric oxide release from two diazeniumdiolates in buffered aqueous solutions

We have investigated in this work the kinetics of NO-release from two commercially available and commonly used diazeniumdiolates (so-called NONOates), namely diethylammonium (Z)-1-(N,N-diethylamino)-diazen-1-ium-1,2-diolate (DEA-NONOate) and (Z)-1-[N-(2-aminoepropyl)-N-(2-ammoniopropyl)amino]-diazen-1-ium-1,2-diolate (PAPA-NONOate) by electrochemical measurements. This choice was driven by the distinctive half-life of each compound (2–20 min at 37 °C for DEA- and PAPA-NONOate, respectively) that allow covering a relatively wide range of rate of NO-release. The release of NO from NONOate decomposition was followed using a home-made NO-sensitive electrochemical sensor. The electrochemical features of the starting NONOates and of the by-products of the fully decomposed molecules were also examined. Also, the electrochemical experimental results obtained under aerobic atmosphere were numerically fitted to model the production of NO and its degradation through its oxidation by molecular oxygen. All these information gathered together allows in predicting the real amount of NO released under real aerobic conditions.     

Microchip electrophoresis with amperometric detection for the study of the generation of nitric oxide by NONOate salts

Microchip electrophoresis (ME) with electrochemical detection was used to monitor nitric oxide (NO) production from diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA/NO) and 1-(hydroxyl-NNO-azoxy)-L-proline disodium salt (PROLI/NO). NO was generated through acid hydrolysis of these NONOate salts. The products of acid hydrolysis were introduced into a 5-cm separation channel using gated injection. The separation was accomplished using reverse polarity and a background electrolyte consisting of 10 mM boric acid and 2 mM tetradecyltrimethylammonium bromide, pH 11. Electrochemical detection was performed using an isolated potentiostat in an in-channel configuration. Potentials applied to the working electrode, typically higher than +1.0 V vs. Ag/AgCl, allowed the direct detection of nitrite, NO, DEA/NO, and PROLI/NO. Baseline resolution was achieved for the separation of PROLI/NO and NO while resolution between DEA/NO and NO was poor (1.0 ± 0.2). Nitrite was present in all samples tested.     

Photoinduced release of nitroxyl and nitric oxide from diazeniumdiolates

Aqueous photochemistry of diazen-1-ium-1,2,2-triolate (Angeli's anion) and (Z)-1[N-(3-aminopropyl)-N-(3-aminopropyl)amino]diazen-1-ium-1,2-diolate (DPTA NONOate) has been investigated by laser kinetic spectroscopy. In neutral aqueous solutions, 266 nm photolysis of these diazeniumdiolates generates a unique spectrum of primary products including the ground-state triplet (3NO-) and singlet (1HNO) nitroxyl species and nitric oxide (NO*). Formation of these spectrophotometrically invisible products is revealed and quantitatively assayed by analyzing a complex set of their cross-reactions leading to the formation of colored intermediates, the N2O2*- radical and N3O3- anion. The experimental design employed takes advantage of the extremely slow spin-forbidden protic equilibration between 3NO- and 1HNO and the vast difference in their reactivity toward NO*. To account for the kinetic data, a novel combination reaction, 3NO-+1HNO, is introduced, and its rate constant of 6.6x10(9) M-1 s-1 is measured by competition with the reduction of methyl viologen by 3NO-. The latter reaction occurring with 2.1x10(9) M-1 s-1 rate constant and leading to the stable, colored methyl viologen radical cation is useful for detection of 3NO-. The distributions of the primary photolysis products (Angeli's anion: 22% 3NO-, 58% 1HNO, and 20% NO*; DPTA NONOate: 3% 3NO-, 12% 1HNO, and 85% NO*) show that neither diazeniumdiolate is a highly selective photochemical generator of nitroxyl species or nitric oxide, although the selectivity of DPTA NONOate for NO* generation is clearly greater.     

E/Z conformation and the vibrational spectroscopy of Me2NN(O)=NOMe

The simple neutral diazenium diolate, O2-methyl-1-(N, N-dimethylamino)diazen-1-ium-1,2-diolate, [Me2NN(O)=NOMe], was experimentally examined by vibrational spectroscopy and the results compared to the theoretically calculated values in an effort to detect both Z and E conformers which result from the stereochemistry of the N=N multiple bond. Room-temperature Raman and infrared spectra were measured and the results compared with the values calculated theoretically with MP2 and density functional techniques (B3LYP). An analysis of the observed frequencies suggests that, down to a detection limit of about 1/1000, only a small quantity of trans (E) diazeniumdiolate, <0.05%, may be present at room temperature.     

The homologous tert-amino effect: a route to fused 2-benzazepine derivatives

2-Cyano- and 2-carbethoxy-3-[2-(pyrrolidin-1-ylmethyl)phenyl]acrylonitriles were prepared through either amination of appropriate 3-[2-(bromomethyl)phenyl]acrylonitriles with pyrrolidine or condensation of 2-(pyrrolidin-1-ylmethyl)benzaldehyde with malononitrile and ethyl cyanoacetate. These acrylonitrile derivatives were shown to undergo easy mutual interconversion with 1-(pyrrolidin-1-yl)indane-2-carbonitriles driven by solvent polarity. Upon heating at 140-150 °C both acrylonitrile and indane derivatives were found to give 2,3,5,10,11,11a-hexahydro-1H-pyrrolo[1,2-b][2]benzazepine-11-carbonitriles. All transformations observed were rationalized in the terms of reactions related to the tert-amino effect. Furthermore, the corresponding piperidin-1-yl and azepan-1-yl analogs of the above acrylonitriles and indanes were obtained similarly. By analogy their heating afforded 1,2,3,4,6,11,12,12a-octahydropyrido[1,2-b][2]benzazepine-12-carbonitriles and 7,8,9,10,11,11a, 12,13-octahydro-5H-azepino[1,2-b][2]benzazepine-12-carbonitriles.     

Greener synthesis using hydrogen peroxide in ethyl acetate of alicyclic ring-fused benzimidazoles and anti-tumour benzimidazolequinones

Environmentally-friendly and cost effective hydrogen peroxide in ethyl acetate was used to prepare in high yields pyrrolo[1,2-a]benzimidazoles from commercial o-(pyrrolidin-1-yl)anilines without the requirement for organic-aqueous extraction and chromatography. Six, seven and eight membered ring-fused analogues were similarly obtained in high yields with methanesulfonic acid required for the pyrido[1,2-a]benzimidazole. Anti-tumour benzimidazolequinone derivatives were obtained in high yield via the cyclization of 3,6-dimethoxy-2-(cycloamino)anilines.     

Self-reproduction of chirality on α-aminophosphonates: asymmetric synthesis of α-alkylated diethyl pyrrolidin-2-yl-phosphonate

A simple method for the asymmetric synthesis of α-substituted diethyl pyrrolidin-2-yl-phosphonate is described. The chiral oxazolopyrrolidine phosphonate was alkylated diastereospecifically with an alkyl halide. The key intermediate is an α-phosphonate-stabilized carbanion that can be alkylated without loss of optical activity and a single enantiomer of product was formed exclusively in 10-80% yield. The configurational assignment of the products relied on ¹H-¹H NOESY analysis of the alkylated oxazolopyrrolidine phosphonates. This represents an unprecedented case of self-regeneration of stereocenters (SRS) of cyclic aminophosphonates. The enantiomerically pure α-aminophosphonate diethyl-(2S)-(2-methylpyrrolidin-2-yl)-phosphonate, a surrogate of 2-methyl proline, was obtained upon hydrogenolysis of the chiral auxiliary in 83% yield.     

Ultrasound- and microwave-assisted synthesis of (E)-1-aryl-3-[2-(piperidin-1-yl)quinolin-3-yl]prop-2-en-1-ones and (E)-1-aryl-3-[2-(pyrrolidin-1-yl)quinolin-3-yl]prop-2-en-1-ones,and their antimicrobial activity

Series of new (E)-1-aryl-3-[2-(piperidin-1-yl)quinolin-3-yl]prop-2-en-1-ones and (E)-1-aryl-3-[2-(pyrrolidin-1-yl)quinolin-3-yl]prop-2-en-1-ones have been efficiently prepared via the Claisen-Schmidt condensation of 2-(piperidin-1-yl)quinoline-3-carbaldehyde and 2-(pyrrolidin-1-yl)quinoline-3-carbaldehyde, respectively, with aryl methyl ketones under conditions of ultrasound and microwave irradiation. Structures of the products have been confirmed by IR, ¹H NMR, ¹³C NMR, and mass spectroscopy, as well as by elemental analysis. Evaluation of the in vitro antibacterial activity against bacterial (Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli) and fungal (Aspergillus niger and Candida metapsilosis) strains has revealed good antimicrobial activity of some of the tested compounds.     

An efficient stereoselective synthesis of (3S,4R)-4-(hydroxymethyl)pyrrolidin-3-ol from (S)-diethylmalate

A concise stereoselective synthesis of an imino sugar, (3S,4R)-4-(hydroxymethyl)pyrrolidin-3-ol from (S)-diethylmalate has been developed in five steps and in overall yield of 28%.     

Cyclohexadienone diazeniumdiolates from nitric oxide addition to phenolates

Sterically hindered phenols react with nitric oxide under basic condititons to give either cyclohexadienone diazeniumdiolates or oximates. Phenols with 2,6-di-tert-butyl and 4-methyl (butylated hydroxy toluene, BHT), 4-ethyl, or 4-methoxy methylene substituents yield the corresponding 2,6-di-tert-butyl-2, 5-cyclohexadienone-4-alkyl-4-diazeniumdiolate salts (4-methyl 1a, 4-ethyl 3a, 4-methoxymethylene 5a). Phenols with 2,6-di-tert-butyl and 4-methylene (2,6-di-tert-butylphenol) substituents yield 4-methoxymethylenediazeniumdiolate (5a) together with 2, 6-di-tert-butyl benzoquinone oximate (6a), while phenols with 2, 6-di-tert-butyl and 4-methylenedimethylamino or hydrogen substituents yield exclusively 2,6-di-tert-butyl benzoquinone oximate (6a). Alkylation of the silver salts of 1a, or treating the O(2)-protonated diazeniumdiolate with diazomethane, both yield mixtures of O(1)- and O(2)-methylated isomers. All the compounds exhibit exothermic thermal decomposition except the quinuclidinium (1e, 3e, 5e) and triethylenediammonium (1f) salts which decompose endothermically. Three of the compounds namely "O(2)-protonated" (Z)-1-[4-(2, 6-di-tert-butyl-4-methyl-cyclohexadienonyl)]diazen-1-ium+ ++-1, 2-diolinic acid (1b), O(2)-methyl (Z)-1-[4-(2, 6-di-tert-butyl-4-methyl-cyclohexadienonyl)]diazen-1-ium+ ++-1,2-diolate (1c), and "O(2)-protonated" (Z)-1-[4-(2, 6-di-tert-butyl-4-methoxymethylenecyclohexadienonyl)]diazen- 1-ium-1, 2-diolinic acid (5b) were characterized by single-crystal X-ray diffraction studies. The diazeniumdiolate framework in all the structures is coplanar with considerable pi-bonding delocalized over the O-N-N-O framework.     

Quantum-chemical calculation of NMR chemical shifts of organic molecules: III. Intramolecular coordination effects on the 31P NMR chemical shifts of phosphorylated N-vinylazoles

Theoretical and experimental studies on magnetic shielding of the phosphorus nucleus in trichloro-[2-(1H-pyrazol-1-yl)ethenyl]phosphonium hexachlorophosphate(V) and 1,1,1,1-tetrachloro-1H-1λ⁶-pyrazolo-[1,2-a][1,2,3]diazaphosphol-8-ium-1-ide showed that intramolecular coordination of the phosphorus atom in the chlorophosphonium group to the nitrogen atom in the pyrazole ring leads to upfield shift of the phosphorus signal (to δ_P 170 ppm) and that the contribution of the spin-orbital contribution to the ³¹P chemical shift reaches 15%. Relativistic effects and effects of the medium are determining in the theoretical calculation of ³¹P NMR chemical shifts.     

Molecular and crystal structure of (pyrazin-1-ium-1-yl)(perfluoropyridin-4-yl) and (4,4′-bipyridin-1-ium-1-yl)(perfluoropyridin-4-yl)amides

The single crystal X-ray diffraction study of (pyrazin-1-ium-1-yl)(perfluoropyridin-4-yl) and (4,4??-bipyridin)-1-ium-1-yl(perfluoropyridin-4-yl)amides is performed. In all cases, the N⁺-N^? bond length is less than that of the single N_planar.-N_planar. bond, but considerably more than that of the double N=N bond, which indicates a weak involvement of the N^? lone pair of the C₅NF₄N^? group in conjugation with pyrazine or bipyridine moieties. Quantum chemical calculations by DFT/(PBE/L1), B3LYP/L1, and RI-MP2/L1 methods provide the geometry of amides similar to the experimental one. Crystals of (pyrazin-1-ium-1-yl)(perfluoropyridin-4-yl)amide form stacks mainly through F-?? interactions. The stacks are joined in 3D architecture by weak C-H??N and C-H??F hydrogen bonds. In the case of (4,4??-bipyridin)-1-ium-1-yl(perfluoropyridin-4-yl)amide crystals, an essential role is played by the ?? stacking interactions of heteroaromatic rings.     

Total synthesis of lycogarubin C utilizing the Kornfeld-Boger ring contraction

An efficient synthesis of lycogarubin C (3) was completed in seven steps from the known 1-(phenylsulfonyl)indole-3-carbaldehyde in 30% overall yield, via a Diels-Alder reaction between (Z)-1,2-di(1H-indol-3-yl)ethene 9b and dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (7), followed by a Kornfeld-Boger ring contraction to form the pyrrole ring.     

An improved synthesis of 3-[3-(trifluoromethyl)-3H-1,2-diazirin-3-yl]aniline: A key intermediate in the synthesis of photoaffinity probes

An improved synthesis of 3-[3-(trifluoromethyl)-3H-1,2-diazirin-3-yl]aniline, achieving an overall yield of 38% over seven steps is reported. Only three chromatographic separations were needed and the preparation of ～0.7 g of the target compound was demonstrated. The stability of the diazirine in solution at room temperature while exposed to ambient light was studied. No significant degradation of the compound was observed over the course of five weeks in a 130 mM sample and only minor degradation was observed in weaker samples (10, 5, and 2.5 mM), as demonstrated by ¹H and ¹⁹F NMR.     

Synthesis of pyrrolidine and tetrahydroazonine derivatives from <Emphasis Type="Italic">N</Emphasis>-[bis(ethoxycarbonyl)methyl]tetrahydropyridinium bromide and methyl acetylenedicarboxylate

The reaction of N-methyl-N-(diethoxycarbonyl)methyltetrahydropyridinium bromide with dimethyl acetylenedicarboxylate in the presence of triethylamine at room temperature afforded 1,2-dimethyl 1-ethyl 2-[(3-vinyl-1-methyl-3-phenyl-2-ethoxycarbonyl)pyrrolidin-2-yl]-ethene-1,1,2-tricarboxylate in 25% yield. Its structure was proved by XRD analysis. At cooling to −20°C the pyrrolidine yield signifi cantly decreased and 3,4-dimethyl 2,2-diethyl 1-methyl-7-phenyl-1,5,8,9-tetrahydro-2H-azonine-2,2,3,4-tetratcarboxylate was obtained in 31% yield.     

Synthesis of 1-(pyrrolidin-2-ylmethyl)-1H-azoles and their piperidine-derived homologues

A convenient preparation of 1-(pyrrolidin-2-yl)-1H-pyrazoles, -imidazoles, and -1H-1,2,4-triazoles, 1-(piperidin-2-yl)-1H-pyrazoles and -1H-1,2,4-triazoles, and 1-(piperidin-3-yl)-1H-1,2,4-triazoles by alkylation of azoles (viz. pyrazoles, imidazoles, and triazoles) with N-Cbz-prolinol mesylate or its analogues and subsequent deprotection is reported. The two-step method allows for synthesis of the title compounds in 16–65% yields. The utility of the procedure has been demonstrated by multigram preparation of a 15-member building block mini-library for the lead-oriented synthesis of compound libraries. These building blocks perfectly fit the definition of low-molecular-weight hydrophilic three-dimensional templates, which leave much room for the lead-oriented synthesis of the compound libraries.      

Substituent-induced regioselective synthesis of 1,2-teraryls and pyrano[3,4-c]pyran-4,5-diones from 2H-pyran-2-ones

Substituent-controlled regioselective synthesis of highly functionalized 1,2-teraryls 3a-k has been achieved through ring transformation of 6-aryl-4-(pyrrolidin-1-yl/piperidin-1-yl)-2H-pyran-2-one-3-carbonitriles 1a-g by aryl acetones 2a-c in the presence of powdered KOH in DMF in very good yield. Under similar reaction conditions, 6-aryl-4-methylsulfanyl-2H-pyran-2-ones 5a-f afforded 1,7-diaryl-2-methyl-4H,5H-pyrano[3,4-c]pyran-4,5-diones 6a-j as major products and 3,4-diaryl-2-methyl-6-methylsulfanylbenzonitriles as minor constituents 7a-j.     

Photochemistry of 1-(N,N-diethylamino)diazen-1-ium-1,2-diolate: an experimental and computational investigation

The aqueous photochemistry of the sodium salt of 1-(N,N-diethylamino)-diazen-1-ium-1,2-diolate (3) has been investigated by both experimental and computational methods. Photolysis results in the formation of the N-nitrosodiethylamine radical anion (5) and nitric oxide (NO) via a triplet excited state. The nitrosamine radical anion either undergoes electron transfer with NO before cage escape to form triplet NO(-) and nitrosamine (minor process) or rapidly dissociates to form an additional molecule of NO and ultimately amine (major process). The production of nitrosamine radical anion 5 upon photolysis of diazeniumdiolate 3 is confirmed by low-temperature EPR spectroscopy. The calculated energetics for the ground and excited states of the parent diazeniumdiolate ion at the CIS and B3LYP levels of theory as well as B3LYP calculations on the fragmentation processes were very effective in rationalizing the observed photodissociation processes.