Showing papers on "Piperidine published in 2014"

Catalytic Asymmetric 1,3-Dipolar [3 + 6] Cycloaddition of Azomethine Ylides with 2-Acyl Cycloheptatrienes: Efficient Construction of Bridged Heterocycles Bearing Piperidine Moiety

Abstract: Conjugated cyclic trienes without nonbenzenoid aromatic characteristic were successfully employed as fine-tunable dipolarophiles in the Cu(I)-catalyzed asymmetric azomethine ylide-involved 1,3-dipolar [3 + 6] cycloaddition for the first time, affording a variety of bridged heterocycles bearing piperidine moiety in good yield with exclusive regioselectivity and excellent stereoselectivity. 2-Acyl group is the key factor that determines the annulation preferentially through [3 + 6]-pathway, while 2-ester group modulates the annulation through [3 + 2]-pathway.

Relation between the catalytic efficiency of the synthetic analogues of catechol oxidase with their electrochemical property in the free state and substrate-bound state.

Abstract: A library of 15 dicopper complexes as synthetic analogues of catechol oxidase has been synthesized with the aim to determine the relationship between the electrochemical behavior of the dicopper(II) species in the absence as well as in the presence of 3,5-di-tert-butylcatechol (3,5-DTBC) as model substrate and the catalytic activity, kcat, in DMSO medium. The complexes have been characterized by routine physicochemical techniques as well as by X-ray single-crystal structure analysis in some cases. Fifteen “end-off” compartmental ligands have been designed as 1 + 2 Schiff-base condensation product of 2,6-diformyl-4-R-phenol (R = Me, tBu, and Cl) and five different amines, N-(2-aminoethyl)piperazine, N-(2-aminoethyl)pyrrolidine, N-(2-aminoethyl)morpholine, N-(3-aminopropyl)morpholine, and N-(2-aminoethyl)piperidine. Interestingly, in case of the combination of 2,6-diformyl-4-methylphenol and N-(2-aminoethyl)morpholine/N-(3-aminopropyl)morpholine/N-(2-aminoethyl)piperidine 1 + 1 condensation becomes the real...

A Toggle Nanoswitch Alternately Controlling Two Catalytic Reactions

Abstract: Reversible switching between two states of the triangular nanoswitch [Cu(1)]+ was accomplished by alternate addition of 2-ferrocenyl-1,10-phenanthroline (2) and copper(I) ions. The two switching states regulate the binding and release of two distinct catalysts, piperidine and [Cu(2)]+, in a fully interference-free manner and allow alternating on/off switching of two orthogonal catalytic processes. In switching state I, piperidine is released from the nanoswitch and catalyzes a Knoevenagel addition between 4-nitrobenzaldehyde and diethyl malonate (ON-1 and OFF-2), while in state II the released [Cu(2)]+ catalyzes a click reaction between 4-nitrophenylacetylene and benzylazide (OFF-1 and ON-2). Upon addition of one equivalent of 2 to the (OFF-1 and ON-2)-state, both catalytically active processes are shut down (OFF-1 and OFF-2).

Iodonium ylides for one-step, no-carrier-added radiofluorination of electron rich arenes, exemplified with 4-(([18F]fluorophenoxy)-phenylmethyl)piperidine NET and SERT ligands

Abstract: Iodonium ylide precursors of electron rich arenes, i.e. the NET and SERT ligands 4-((3- and 4-fluorophenoxy)phenylmethyl)piperidine, served as model compounds for the direct substitution with n.c.a. [18F]fluoride. Good radiochemical yields of about 20% were obtained in reaction times of ca. 130 minutes with a molar activity of the labelled ligands of more than 50 GBq μmol−1. Those failed as in vivo probes in first evaluation studies. Several important insights, however, were gained into the reaction of ylides, e.g. an unexpected formation of regioisomers. The results clearly demonstrate that aryliodonium ylides are a promising alternative to the well-known diaryliodonium salts for the direct preparation of complex, electron rich n.c.a. [18F]fluoroarenes.

Efficient modulation of γ-aminobutyric acid type A receptors by piperine derivatives.

Abstract: Piperine activates TRPV1 (transient receptor potential vanilloid type 1 receptor) receptors and modulates γ-aminobutyric acid type A receptors (GABAAR). We have synthesized a library of 76 piperine analogues and analyzed their effects on GABAAR by means of a two-microelectrode voltage-clamp technique. GABAAR were expressed in Xenopus laevis oocytes. Structure–activity relationships (SARs) were established to identify structural elements essential for efficiency and potency. Efficiency of piperine derivatives was significantly increased by exchanging the piperidine moiety with either N,N-dipropyl, N,N-diisopropyl, N,N-dibutyl, p-methylpiperidine, or N,N-bis(trifluoroethyl) groups. Potency was enhanced by replacing the piperidine moiety by N,N-dibutyl, N,N-diisobutyl, or N,N-bistrifluoroethyl groups. Linker modifications did not substantially enhance the effect on GABAAR. Compound 23 [(2E,4E)-5-(1,3-benzodioxol-5-yl)-N,N-dipropyl-2,4-pentadienamide] induced the strongest modulation of GABAA (maximal GABA-in...

Palladium-catalyzed one-pot three- or four-component coupling of aryl iodides, alkynes, and amines through C-N bond cleavage: efficient synthesis of indole derivatives.

Abstract: An efficient synthesis of N-substituted indole derivatives was realized by combining the Pd-catalyzed one-pot multicomponent coupling approach with cleavage of the C(sp(3))-N bonds. Three or four components of aryl iodides, alkynes, and amines were involved in this coupling process. The cyclopentadiene-phosphine ligand showed high efficiency. A variety of aryl iodides, including cyclic and acyclic tertiary amino aryl iodides, and substituted 1-bromo-2-iodobenzene derivatives could be used. Both symmetric and unsymmetric alkynes substituted with alkyl, aryl, or trimethylsilyl groups could be applied. Cyclic secondary amines such as piperidine, morpholine, 4-methylpiperidine, 1-methylpiperazine, 2-methylpiperidine, and acyclic amines including secondary and primary amines all showed good reactivity. Further application of the resulting indole derivatives was demonstrated by the synthesis of benzosilolo[2,3-b]indole.

Two‐step Synthesis of Multi‐Substituted Amines by Using an N‐Methoxy Group as a Reactivity Control Element

Abstract: The development of a two-step synthesis of multi-substituted N-methoxyamines from N-methoxyamides is reported. Utilization of the N-methoxy group as a reactivity control element was the key to success in this two-step synthesis. The first reaction involves a N-methoxyamide/aldehyde coupling reaction. Whereas ordinary amides cannot condense with aldehydes intermolecularly due to the poor nucleophilicity of the amide nitrogen, the N-methoxy group enhances the nucleophilicity of the nitrogen, enabling the direct coupling reaction. The second reaction in the two-step process was nucleophilic addition to the N-methoxyamides. Incorporation of the N-methoxy group into the amides increased the electrophilicity of the amide carbonyls and promoted the chelation effect. This nucleophilic addition enabled quick diversification of the products derived from the first step. The developed strategy was applicable to a variety of substrates, resulting in the elaboration of multi-substituted piperidines and acyclic amines, as well as a substructure of a complex natural alkaloid.

Electrochemical access to 8-(1-phenyl-ethyl)-1,4-dioxa-8-aza-spiro[4.5]decane-7-carbonitrile. Application to the asymmetric syntheses of (+)-myrtine and alkaloid (+)-241D.

Abstract: The total syntheses of both enantiomers of trans-quinolizidine (+)-myrtine and cis-2,4,6-trisubstituted piperidine alkaloid (+)-241D are reported here. Our approach was based on the N-Boc-directed metalation of enantiopure 4-piperidone (-)-11, which was prepared in four steps from α-amino nitrile 6 through a stereoselective alkylation-reduction decyanation process. α-Amino nitrile 6 was prepared at the anode through electrochemical oxidation of 4-piperidone (+)-5. In our study, α-phenylethylamine (α-PEA) allowed an efficient 1-3 stereoinduction, and an orthogonal cleavage of the N-Boc protecting group in piperidone derivatives was carried out by stirring them in a suspension of SnCl4·(Et2O)2 complex in diethyl ether. When appropriate, the er's were determined by proton and carbon NMR spectroscopy utilizing (+)-tert-butylphenylphosphinothioic acid and (+)-DBTA as chiral solvating agents.

Stereoselective synthesis of O-tosyl azabicyclic derivatives via aza Prins reaction of endocyclic N-acyliminium ions: application to the total synthesis of (±)-epi-indolizidine 167B and 209D

Abstract: A diastereoselective protocol has been established for the synthesis of 4-O-tosyl piperidine containing hexahydroindolizin-3(2H)-one, hexahydro-1H-quinolizin-4(6H)-one and 1,3,4,10b-tetrahydropyrido[2,1-a]isoindol-6(2H)-one derivatives via the aza-Prins cyclization reaction of cyclic N-acyliminium ions mediated by p-toluene sulphonic acid (p-TSA) under mild conditions. The reaction is highly diastereoselective and gives excellent yields. This method has been applied to an efficient total synthesis of indolizidine alkaloids, (±)-epi-indolizidine 167B and 209D.

Piperidine and Piperazine Immobilized on Iron Oxide Nanoparticles as Magnetically Recyclable Heterogeneous Catalysts for One-Pot Synthesis of β-Phosphonomalonates

Abstract: Piperidine and piperazine immobilized on silica-coated γ-Fe2O3 magnetic nanoparticles were synthesized as new supported bases via the reaction of chloro-functionalized γ-Fe2O3@SiO2 with piperidine and piperazine, respectively. The resulting bases were employed as magnetically recyclable heterogeneous catalysts for the efficient one-pot three-component synthesis of β-phosphonomalonates. The catalysts were easily separated from the reaction mixture by using a magnet and recycled for five times without significant loss of the catalytic activity.

Microwave assisted synthesis of 2-amino-6-methoxy-4H-benzo[h]chromene derivatives

Abstract: A convenient and efficient method using microwave assisted synthesis of 4 H -benzo[ h ]chromenes (7 and 8), by the reaction of 4-methoxy-1-naphthol (1) with a mixture of aromatic aldehydes (2) and malononitrile (3) or ethyl cyanoacetate (5) and also, by the reaction of 4-methoxy-1-naphthol (1) with α -cyanocinnamonitriles (4) or ethyl α -cyanocinnamates (6) in ethanolic piperidine solution was examined. Structures of the newly synthesized compounds were established on the basis of spectral data, IR, 1 H NMR, 13 C NMR, 13 C NMR-DEPT and MS data.

Hydroaminomethylation of Styrene Catalyzed by Rhodium Complexes Containing Chiral Diphosphine Ligands and Mechanistic Studies: Why Is There a Lack of Asymmetric Induction?

Abstract: Various chiral diphosphine ligands (P–P) have been introduced in the coordination sphere of neutral or cationic rhodium complexes, and the generated species catalyze efficiently the hydroaminomethylation reaction of styrene with piperidine. The diphospholane ligand family is particularly adapted to this tandem reaction leading to the branched amine with good chemo- and regioselectivity. We analyzed in detail the main reasons why the reaction proceeds with no enantioselectivity. Catalytic and HP-NMR experiments reveal the presence of the [Rh(H)(CO)2(P–P)] species as the resting state. DFT calculations allow us to elucidate the mechanism of the hydrogenation of the branched (Z) or (E)-enamine. From the [Rh(H)(CO)(P–P)] active species, the coordination of the two enamine isomers, the hydride transfer, the H2 activation, and then the final reductive elimination follow similar energetic pathways, explaining the lack of enantioselectivity for the present substrates. Analysis of the energy-demanding steps highli...

Lycodine-Type Alkaloids from Lycopodiastrum casuarinoides and Their Acetylcholinesterase Inhibitory Activity

Abstract: Four new lycodine-type alkaloids, namely 16-hydroxyhuperzine B (1), N-methyl-11-acetoxyhuperzine B (2), 8,15-dihydrolycoparin A (3) and (7S,12S,13R)-huperzine D-16-O-β-d-glucopyranoside (4), along with ten known analogues 5−14, were isolated from the whole plant of Lycopodiastrum casuarinoides. The structures of the new compounds were elucidated by means of spectroscopic techniques (IR, MS, NMR, and CD) and chemical methods. Compounds 1 and 2 possessed four connected six-membered rings, while compounds 3 and 4 were piperidine ring cleavage products. In particular, compound 4 was a lycopodium alkaloidal glycoside which is reported for the first time. Among the isolated compounds N-demethylhuperzinine (7), huperzine C (8), huperzine B (9) and lycoparin C (13) possessed significant inhibitory activity against acetylcholinesterase, and the new compound 1 showed moderate inhibitory activity. The structure activity relationships were discussed.

Preparation and analytical characterization of 1-(1-phenylcyclohexyl)piperidine (PCP) and 1-(1-phenylcyclohexyl)pyrrolidine (PCPy) analogues

Abstract: Classic examples of psychoactive arylcycloalkylamines include ketamine and 1-(1-phenylcyclohexyl)piperidine (PCP) and many others serve as important structural templates for neuropharmacological research. The recent emergence of PCP analogues that can be obtained from internet retailers requires the implementation of appropriate monitoring strategies for harm reduction purposes. Access to analytical data plays a key part when encountering these substances, especially if reference material is not available. The present study describes the synthesis of three substituted 1-(1-phenylcyclohexyl)piperidines, (3-MeO-, 4-MeO- and 3-Me-PCP) and three substituted 1-(1-phenylcyclohexyl)pyrrolidine analogues (3-MeO-, 4-MeO- and 3-Me-PCPy). Analytical characterizations of all six arylcyclohexylamines and their primary 1-phenylcyclohexanamine intermediates included gas chromatography ion trap electron- and chemical ionization and high resolution mass spectrometry, liquid chromatography electrospray hybrid triple-quadrupole linear ion trap tandem mass spectrometry, infrared, diode array detection and 1H and 13C nuclear magnetic resonance (NMR) spectroscopy. Solvent (CDCl3 vs. d6-DMSO) and protonation effects (free bases vs hydrochloride salts) were studied in order to investigate the impact on shifts and splitting patterns, for example, when attempting to assign separate axial and equatorial proton chemical shifts of NMR spectra. Differentiation between the isomeric 3-MeO-/4-MeO-PCP and PCPy analogues was feasible under mass spectral conditions. Gas chromatography analysis appeared to induce notable degradation of the 4-MeO-substituted analytes, especially when dealing with the HCl salts which led to the detection of the substituted 1-phenylcyclohex-1-ene nucleus. This phenomenon was observed to be less pronounced with the 3-MeO isomers, possibly due to the resonance properties of the para-methoxy group followed by more facile elimination of the amine. Copyright © 2013 John Wiley & Sons, Ltd.

Fully Diastereoselective Synthesis of Polysubstituted, Functionalized Piperidines and Decahydroquinolines Based on Multicomponent Reactions Catalyzed by Cerium(IV) Ammonium Nitrate

Abstract: The cerium(IV) ammonium nitrate (CAN)-catalyzed, three-component reaction between primary amines, β-dicarbonyl compounds, and α,β-unsaturated aldehydes in ethanol heated to reflux, constitutes a general, one-pot synthesis of 1,4-dihydropyridines. Their reduction with sodium triacetoxyborohydride furnished piperidine derivatives bearing up to five substituents with full diastereoselectivity in a hitherto inaccessible stereochemical arrangement. The reaction proceeded with no significant loss of enantiomeric purity under mild reduction conditions that are compatible with several functional groups that are normally sensitive to reduction. Octahydroquinolin-5-one derivatives, which were prepared by a modified version of the initial multicomponent reaction, were not suitable substrates for the sodium triacetoxyborohydride mediated reduction, but they were transformed into the corresponding decahydroquinolines, including a precursor of the amphibian alkaloid pumiliotoxin C, by catalytic hydrogenation under a variety of conditions.

Asymmetric organocatalytic synthesis of 4,6-bis(1H-indole-3-yl)-piperidine-2 carboxylates

Abstract: We developed an asymmetric organocatalytic synthesis of 4,6-bis(1H-indole-3-yl)-piperidine-2-carboxylates using 10 mol% of a chiral phosphoric acid. The products, which are novel bisindole-piperidine-amino acid hybrids, can be obtained in one step from 3-vinyl indoles with imino esters in dichloromethane at room temperature after 1 h of reaction time. A variety of these compounds could be synthesized in up to 70% yield and 99% ee, and they were experimentally and computationally analyzed regarding their relative and absolute stereochemistry.

Organocatalytic [4 + 2] cyclocondensation of α,β-unsaturated acyl chlorides with imines: highly enantioselective synthesis of dihydropyridinone and piperidine derivatives

Abstract: The cinchona alkaloid-catalyzed [4 + 2] cyclocondensation of α,β-unsaturated acyl chlorides with imines is developed to give the corresponding substituted dihydropyridinones in good yields with high to excellent enantioselectivities. Reduction of the dihydropyridinones gave highly optically active substituted tetrahydropyridinone and piperidine derivatives.

Synthesis and DNA cleavage activity of Bis-3-chloropiperidines as alkylating agents.

Abstract: Nitrogen mustards are an important class of bifunctional alkylating agents routinely used in chemotherapy. They react with DNA as electrophiles through the formation of highly reactive aziridinium ion intermediates. The antibiotic 593A, with potential antitumor activity, can be considered a naturally occurring piperidine mustard containing a unique 3-chloropiperidine ring. However, the total synthesis of this antibiotic proved to be rather challenging. With the aim of designing simplified analogues of this natural product, we developed an efficient bidirectional synthetic route to bis-3-chloropiperidines joined by flexible, conformationally restricted, or rigid diamine linkers. The key step involves an iodide-catalyzed double cyclization of unsaturated bis-N-chloroamines to simultaneously generate both piperidine rings. Herein we describe the synthesis and subsequent evaluation of a series of novel nitrogen-bridged bis-3-chloropiperidines, enabling the study of the impact of the linker structure on DNA alkylation properties. Our studies reveal that the synthesized compounds possess DNA alkylating abilities and induce strand cleavage, with a strong preference for guanine residues.

Two [1,2,4-(Me3C)3C5H2]2CeH molecules are involved in hydrogenation of pyridine to piperidine as shown by experiments and computations.

Abstract: Hydrogenation of pyridine to piperidine catalyzed by [1,2,4-(Me3C)3C5H2]2CeH, abbreviated as Cp′2CeH or [Ce]′-H, is reported. The reaction proceeds from Cp′2Ce(2-pyridyl), isolated from the reaction of pyridine with Cp′2CeH, to Cp′2Ce(4,5,6-trihydropyridyl), and then to Cp′2Ce(piperidyl). The cycle is completed by the addition of pyridine, which generates Cp′2Ce(2-pyridyl) and piperidine. The net reaction depends on the partial pressure of H2 and temperature. The dependence of the rate on the H2 pressure is associated with the formation of Cp′2CeH, which increases the rate of the first and/or second additions of H2 but does not influence the rate of the third addition. Density functional theory calculations of several possible pathways are consistent with three steps, each of which are composed of two elementary reactions, (i) heterolytic activation of H2 with a reasonably high energy, ΔG⧧ = 20.5 kcal mol–1, on Cp′2Ce(2-pyridyl), leading to Cp′2CeH(6-hydropyridyl), followed by an intramolecular hydride tr...

An Efficient Approach to the Synthesis of Coumarin-Bearing 2,3-Dihydro-4(1H)-Quinazolinone Derivatives Using a Piperidine and Molecular Iodine Dual-Catalyst System

Abstract: An efficient dual-catalyst system of piperidine and molecular iodine has been developed for the synthesis of 2-alkyl-2-(2-oxo-2H-chromen-3-yl)-2,3-dihydro-4(1H)quinazolinone derivatives by a four-component reaction of salicylaldehydes, β-keto esters, ammonium acetate, and isatoic anhydride. Good yields, mild reaction conditions, and easy purification are attractive features of the present method.

Assessment of the N -nitrosopiperidine formation risk from piperine and piperidine contained in spices used as meat product additives

Abstract: The N-nitrosopiperidine (NPIP) formation in blends of spices and nitrite curing salt was investigated in relation with the piperine and piperidine contents in spices. Firstly, two analytical methods were developed. Piperine was extracted with dichloromethane by means of accelerated solvent extraction (ASE) and determined by high-performance liquid chromatography (HPLC)-diode array detector (λ = 343 nm). A selective hydroextraction of piperidine using ASE and its quantification by HPLC- ELSD was applied. Both methods were sufficiently sensi - tive and accurate (limit of detection, limit of quantification, and recovery: 0.28, 0.84 μg, and 98.9 ± 2.6 % for piper- ine, and 5.76, 17.45 μg, and 95.9 ± 2.9 % for piperidine, respectively). Secondly, both compounds were quantified in commercial samples (black and white pepper, paprika, chili pepper, allspice, and nutmeg). The maximum amount of piperine (21.12 mg g − 1 ) was found in pepper, while the other spices contained only traces. Piperidine was

Pyridine and piperidine derivatives and use thereof

Abstract: The invention provides compounds that are useful as sodium channel blockers. In one aspect, the invention provides compounds of Formula I: or pharmaceutically acceptable salts, solvates, hydrates, or diastereomers thereof, wherein R 1 , R 4 , X, G, n, p, W 1 , W 2 , W 3 , W 4 , and the E ring are defined in the disclosure. In certain embodiments, the invention provides compounds of Formulae II-XIII as set forth supra. The invention also provides the use of compounds of any of the above discussed formulae to treat a disorder responsive to blockade of sodium channels. In one embodiment, Compounds of the Invention are useful for treating pain.