Substituted Piperidine Derivatives Research Articles

Yb/Chitosan Catalyzed Synthesis of Highly Substituted Piperidine Derivatives for Potential Nuclease Activity and DNA Binding Study.

Herein, a new chitosan-supported ytterbium nano-catalyst has been prepared and used in a mild, efficient, and expeditious method for the synthesis of substituted piperidine derivatives via threecomponent condensation of substituted anilines, formaldehyde and different cyclic/acyclic active methylene compounds at room temperature. The catalyst was characterized by FTIR, XRD, SEM, EDX, TEM, ICP-AES and the stability of the catalyst was evaluated by TG analysis. The synthesized compound 3,3,11,11-Tetramethyl-15-(phenyl)-15- azadispiro[5.1.5.3]hexadecane-1,5,9,13-tetrone (3a) was explored for pBR322 DNA cleavage activity and genotoxicity. Further, the interaction of 3a with CT-DNA was investigated through UV-vis, fluorescence and viscosity. The preparation of Yb/chitosan nano-catalyst was verified and the catalyst was found effective towards substituted piperidine formations with the catalyst reusability. Compound 3a was successfully tested for DNA cleavage activity. In addition, fluorescence results revealed that compound 3a interacted with DNA with a binding affinity of 4.84 x 104 M-1. Our findings suggest that compounds bearing spiro-piperidine scaffold, synthesized using reusable nano-catalyst, could be effective biological agents.

One-Pot Synthesis and Antioxidant Properties of Highly Substituted Piperidine Derivatives Promoted by Choline Chloride/Urea

The simple pseudo four-component reaction of 2,7-naphthalenediol, tow molecules of aldehydes and ammonum carboxylates to produce a series of N-acylated and non-acylated highly substituted piperidine derivatives has been carried out in the presence of choline chloride/urea at 80 °C. One-pot reaction, high efficiency, appropriate reaction time, and easy purification of products by simple recrystallization are some of the considerable advantages of this procedure. The produced highly substituted piperidine derivatives were screened for their antioxidant property. The results indicated that the highly substituted piperidine derivative 4h had higher antioxidant properties.

Highly Diastereoselective Functionalization of Piperidines by Photoredox-Catalyzed α-Amino C-H Arylation and Epimerization.

We report a photoredox-catalyzed α-amino C-H arylation reaction of highly substituted piperidine derivatives with electron-deficient cyano(hetero)arenes. The scope and limitations of the reaction were explored, with piperidines bearing multiple substitution patterns providing the arylated products in good yields and with high diastereoselectivity. To probe the mechanism of the overall transformation, optical and fluorescent spectroscopic methods were used to investigate the reaction. By employing flash-quench transient absorption spectroscopy, we were able to observe electron transfer processes associated with radical formation beyond the initial excited-state Ir(ppy)3 oxidation. Following the rapid and unselective C-H arylation reaction, a slower epimerization occurs to provide the high diastereomer ratio observed for a majority of the products. Several stereoisomerically pure products were resubjected to the reaction conditions, each of which converged to the experimentally observed diastereomer ratios. The observed distribution of diastereomers corresponds to a thermodynamic ratio of isomers based upon their calculated relative energies using density functional theory (DFT).

Design, synthesis and evaluation of substituted piperidine based KCNQ openers as novel antiepileptic agents

Epilepsy is a kind of disease with complicated pathogenesis. KCNQ (Kv7) is a voltage dependent potassium channel that is mostly associated with epilepsy and thus becomes an important target in the treatment of epilepsy. In this paper, a series of substituted piperidine derivatives targeting KCNQ were designed and synthesized by using scaffold hopping and active substructure hybridization. Compounds were evaluated by fluorescence-based thallium influx assay, Rb+ flow assay and electrophysiological patch-clamp assay. Results showed that some compounds possessed more potent potassium channel opening activity than Retigabine. More significantly, compound 11 was found to have good pharmacokinetic profiles in vivo.

Asymmetric Synthesis of Substituted Piperidine Derivatives Based on the Indirect Cation Pool Method

N-Acyliminium ions having a piperidine skeleton were attractive because the functionalized piperidines frequently show interesting biologically properties. The “indirect cation pool method” 1) is useful to prepare a solution of synthetically valuable N-acyliminium ions having a protecting group that is labile under acidic conditions, because organic cations can be generated and accumulated under neutral conditions. In this presentation we demonstrated utilities of highly enantiomerically enriched chiral N-Acyliminium ions bearing a piperidine skeleton, which are generated by the indirect cation pool method. Almost enantiomerically pure chiral precursor 2 was prepared by using the enantioselective lithiation strategy using chiral diamine 1 (Scheme 1).2) N-Acyliminium ion pool 3 was then irreversibly generated from 2 by the treatment of ArS(ArSSAr)+, which was generated by low temperature electrolysis (Scheme 2). The reaction of 3 with allylstannane gave trans isomer in high diastereomer and enantiomer ratios. In contrast, the coupling between 3 and allylmagnesium bromide afforded cis isomer in high stereoselectivity. As a result, we could selectively synthesized two 1) Suga, S.; Matsumoto, K.; Ueoka, K.; Yoshida, J. J. Am. Chem. Soc. 2006, 128, 7710-7711. Matsumoto, K.; Suga, S.; Yoshida, J. Org. Biomol. Chem. 2011, 9, 2586-2596. 2) Coldham, I.; O’Brien, P.; Patel, J. J.; Raimbault, S.; Sanderson, A. J.; Stead, D.; Whittaker, D. T. E. Tetrahedron: Asymmetry 2007, 18, 2113–2119. Figure 1

Efficient, rapid avenue for synthesis of highly substituted piperidines using polystyrene sulfonic acid

A proficient and meticulously designed diasterioselective, multicomponent, one-pot synthesis of densely substituted piperidine derivatives has been elaborated using polystyrene sulfonic acid catalyst via tandem reactions of 1,3-dicarbonyl compounds, aromatic aldehydes and various amines. Shorter reaction times, high yields and a polymer-supported inexpensive catalyst are the noteworthy aspects of the scaffold.

ChemInform Abstract: A Highly Stereo‐Controlled Protocol to Prepare Pipecolic Acids Based on Heck and Cyclohydrocarbonylation Reactions.

A novel synthetic protocol based on an indium-mediated glyoxylate allylation, Heck coupling and Rh-catalysed cyclohydrocarbonylation (CHC) was established to access enantiomerically pure polysubstituted pipecolic acids. The key steps are the Heck reaction, which is performed exclusively using a phenone-oxime derived palladacycle and the domino hydroformylation-cyclisation of a styryl derivative obtained from the Heck coupling. The reaction scheme, proceeding with good stereoselectivity, is also suitable for the preparation of substituted piperidine derivatives.

Regio- and Stereoselective Modification of Chiral α-Amino Ketones by Pd-Catalyzed Allylic Alkylation.

Chiral α-amino ketones are excellent nucleophiles for stereoselective palladium-catalyzed allylic alkylations. Both chiral as well as achiral allylic substrates can be applied, while the stereochemical outcome of the reaction is controlled by the chiral ketone enolate. The substituted amino ketones formed can be reduced stereoselectively, and up to five consecutive stereogenic centers can be obtained. This approach can be used for the synthesis of highly substituted piperidine derivatives.

Synthesis, Spectral Analysis, In Vitro Microbiological Evaluation, and Molecular Docking Studies of Some Novel 1-(1-Aryl-1H-tetrazol-5-yl)-2-(piperidin-1-yl)ethanone Derivatives.

A new series of novel heterocyclic compounds containing both tetrazoles and piperidine nuclei together, namely, 1-(1-aryl-1H-tetrazol-5-yl)-2-(piperidin-1-yl)ethanone (22–28), were synthesized by the treatment of the respective 2-chloro-1-(1-aryl-1H-tetrazol-5-yl)ethanone (15–21) with piperidine in acetonitrile for 6 h. A series of novel tetrazole substituted piperidine derivatives were synthesized and evaluated for their antimicrobial activity using serial dilution method. The structures of the synthesized compounds were characterized by IR, 1H NMR, 13C NMR, mass spectral data, and elemental analysis. Evaluation of antimicrobial activity shows that several compounds exhibit good activity when compared with the reference drug candidates and thus could be promising new lead molecules.

Highly efficient one-pot synthesis of tetrahydropyridines

Abstract The combination of aromatic aldehydes, and 1,3-dicarbonyl compounds in the presence of a catalytic amount of poly(N,N′-dibromo-N-ethyl-benzene-1,3-disulfonamide) [PBBS] and N,N,N′,N′-tetrabromobenzene-1,3-disulfonamide [TBBDA] leads to the formation of highly substituted tetrahydropyridines. In this way, a series of pharmacologically interesting substituted piperidine derivatives were obtained in moderate to high yields at room temperature.

Proton donor acidity controls selectivity in nonaromatic nitrogen heterocycle synthesis.

Piperidines are prevalent in natural products and pharmaceutical agents and are important synthetic targets for drug discovery and development. We report on a methodology that provides highly substituted piperidine derivatives with regiochemistry selectively tunable by varying the strength of acid used in the reaction. Readily available starting materials are first converted to dihydropyridines via a cascade reaction initiated by rhodium-catalyzed carbon-hydrogen bond activation. Subsequent divergent regio- and diastereoselective protonation of the dihydropyridines under either kinetic or thermodynamic control provides two distinct iminium ion intermediates that then undergo highly diastereoselective nucleophilic additions. X-ray structural characterization of both the kinetically and thermodynamically favored iminium ions along with density functional theory calculations provide a theoretical underpinning for the high selectivities achieved for the reaction sequences.

Novel 1,4 substituted piperidine derivatives. Synthesis and correlation of antioxidant activity with structure and lipophilicity.

A series of novel piperidine derivatives was prepared and their lipophilicity was determined (as RM values). These compounds as well as two intermediate alpha-keto-esters were tested for antioxidant activity. It was found that the cysteamine derivatives were efficient antioxidants, i.e. they could inhibit lipid peroxidation, act as hydroxyl radical scavengers and interact with 2,2-diphenyl-1-picrylhydrazyl radicals. This interaction could be attributed to the free SH group and this activity seemed to be favoured by increased lipophilicity. Replacement of SH by NH2 or OH resulted in a decreased antioxidant activity of the compounds. However, the described activities seem not to be connected with any O2-.scavenging ability, at least under the experimental conditions applied. Furthermore, cysteamine derivatives seem to induce O2-.generation, a phenomenon often observed with thiol compounds. The antioxidant activity of the intermediate alpha-keto-esters varied and is probably mediated by different mechanisms.

Cerium Ammonium Nitrate-Catalyzed Multicomponent Reaction for Efficient Synthesis of Functionalized Tetrahydropyridines

A highly atom-economic one-pot synthesis of functionalized tetrahydropyridines by a multicomponent condensation reaction of β-keto ester, two equivalents of aromatic aldehyde, and two equivalents of amine in the presence of a catalytic amount of cerium ammonium nitrate (CAN) is reported. In this way, a series of pharmacologically interesting substituted piperidine derivatives were obtained in moderate to good yields at room temperature.

Inverse-Electron-Demand Diels-Alder Reactions of N-(Heteroarylsulfonyl)-1-aza-1,3-dienes Catalyzed by Chiral Lewis Acids

The feasibility of using chiral Lewis acids as catalysts to promote the inverse-electron-demand Diels-Alder reactions of 1-azadienes with vinyl ethers has been demonstrated. Two catalyst systems were identified for this reaction, both relying on the presence of a coordinating 2-pyridylsulfonyl or 8-quinolylsulfonyl group at the imine nitrogen of the 1-azadiene. The combination of a 8-quinolylsulfonyl moiety and nickel(II)/DBFOX-Ph proved to be highly efficient, allowing the synthesis of substituted piperidine derivatives in good yields, excellent endo selectivity, and enantio­selectivities typically in the range of 77 to 92% ee.

Catalytic Asymmetric Hydrogenation of N‐Iminopyridinium Ylides: Expedient Approach to Enantioenriched Substituted Piperidine Derivatives.

We have developed an efficient catalytic enantioselective hydrogenation of pyridine derivatives. Enhanced reactivity was possible by an optimization of the electronic properties of the catalyst through ligand modification. This methodology shows the particular reactivity of N-iminopyridinium ylides that provides access to substituted piperidines in good enantiomeric excesses.

Synthesis and Affinity for Serotonin and Dopamine Transporters of Some Benzophenone Oxime Ether Derivatives.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis and affinity for serotonin and dopamine transporters of some benzophenone oxime ether derivatives

In a previous study, we reported the synthesis of several 3-(methylenaminoxymethyl)-substituted piperidine derivatives and their ability to interfere with the transmission mediated by biogenic amines. The present study describes the preparation of some new oxime derivatives and their capacity to inhibit serotonin (SERT) and dopamine (DAT) transporters expressed at the level of the rabbit cortex and the striatal membranes, respectively. All the compounds showed K i values in the micromolar range on both transporters.

Renin inhibition by substituted piperidines: A novel paradigm for the inhibition of monomeric aspartic proteinases?

The aspartic proteinase renin catalyses the first and rate-limiting step in the conversion of angiotensinogen to the hormone angiotensin II, and therefore plays an important physiological role in the regulation of blood pressure. Numerous potent peptidomimetic inhibitors of this important drug target have been developed, but none of these compounds have progressed past clinical phase II trials. Limited oral bioavailability or excessive production costs have prevented these inhibitors from becoming new antihypertensive drugs. We were interested in developing new nonpeptidomimetic renin inhibitors. High-throughput screening of the Roche compound library identified a simple 3, 4-disubstituted piperidine lead compound. We determined the crystal structures of recombinant human renin complexed with two representatives of this new class. Binding of these substituted piperidine derivatives is accompanied by major induced-fit adaptations around the enzyme's active site. The efficient optimisation of the piperidine inhibitors was facilitated by structural analysis of the renin active site in two renin-inhibitor complexes (some of the piperidine derivatives have picomolar affinities for renin). These structural changes provide the basis for a novel paradigm for inhibition of monomeric aspartic proteinases.

Synthesis of homochiral piperidine derivatives from S-glutamic acid. Stereoselective 1,4-addition of organocuprates to a Δ3-piperidine-2-one. A paroxetine analogue

Abstract Enantiomerically pure S-5-hydroxy-2-piperidinone 4, readily available from S-glutamic acid, serves as a key intermediate for the synthesis of 3,4-trans substituted piperidine derivatives. The substituents in the 4-position are introduced via 1,4 conjugate organocuprate addition to 7 with excellent trans selectivity. This reaction is employed for the synthesis of a paroxetine analogue 21g. All attempts to transform 16 to (+)-meroquinene 17 failed.

Application of NMR Spectroscopy to the Study of Substituted Piperidine Derivatives. Part II: Use of 15N NMR in Drug Formulations

The evaluation of piperidine derivatives is important to the understanding of the pharmacological activity of the fentanyl class of analgesics. Typically, these compounds are administered in the salt form, and the drug formulation step is made easier since the salt forms readily dissolve in water. It is essential to know of any structural changes that occur during the preparation of formulations. It is possible that some of these compounds form cis and trans isomers, which can not be easily separated. An elucidation of any structural changes by spectroscopic means will assist in pharmacological testing and, also, enable development of a better understanding of structure-activity relationships.