Synthesis Of Piperidines Research Articles

Synthesis of New Piperidine based N(2)-Alkylated 1,2,3-Triazole Hybrids in Basic Medium

The nucleophilic reaction of 1H-triazole derivatives with piperidines under basic conditions is the essential step in the synthesis of a new series of dibenzyl N(2)-C-linked triazolyl piperidines. The triazole derivative was synthesized via the CuAAc reaction of 1-phenylprop-2-yn-1-ol (1a-b) with azidomethyl pivalate. Compound 3a-b underwent dehydroxylation and deprotection reactions using TFA, triethyl silane and 1 M NaOH respectively, yielding monobenzyl 1H-1,2,3-triazole (4a-b). The N(2)-piperidinyltriazoles (6a-j) were synthesized in significant amounts by nucleophilically reacting 1H-triazole derivatives (4a-b) with 4-mesyl-1-boc-piperidine (5) under basic conditions using sodium hydride, which further on acidic deprotection followed by benzylation reaction furnished dibenzyl N(2)-C-linked triazolyl piperidines (9a-j).

Synthesis of Stereoenriched Piperidines via Chemo-Enzymatic Dearomatization of Activated Pyridines.

The development of efficient and sustainable methods for the synthesis of nitrogen heterocycles is an important goal for the chemical industry. In particular, substituted chiral piperidines are prominent targets due to their prevalence in medicinally relevant compounds and their precursors. A potential biocatalytic approach to the synthesis of this privileged scaffold would be the asymmetric dearomatization of readily assembled activated pyridines. However, nature is yet to yield a suitable biocatalyst specifically for this reaction. Here, by combining chemical synthesis and biocatalysis, we present a general chemo-enzymatic approach for the asymmetric dearomatization of activated pyridines for the preparation of substituted piperidines with precise stereochemistry. The key step involves a stereoselective one-pot amine oxidase/ene imine reductase cascade to convert N-substituted tetrahydropyridines to stereo-defined 3- and 3,4-substituted piperidines. This chemo-enzymatic approach has proved useful for key transformations in the syntheses of antipsychotic drugs Preclamol and OSU-6162, as well as for the preparation of two important intermediates in synthetic routes of the ovarian cancer monotherapeutic Niraparib.

Synthesis of chiral piperidines from pyridinium salts via rhodium-catalysed transfer hydrogenation

Synthesis of chiral piperidines from pyridinium salts via rhodium-catalysed transfer hydrogenation

Diastereoselective Synthesis of α-Chiral Piperidines in Flow

Key words Grignard reagents - cyclization - piperidines - diastereoselectivity - asymmetric synthesis

Synthesis, structural investigation and molecular docking studies of pyridinyl tetrahydroisoquinoline, morpholine and piperidine containing schiff's bases

The present work was conducted to synthesize some Schiff's bases derived from pyridinyl tetrahydroisoquinoline, morpholine and piperidine moieties by the condensation reaction of aminobenzaldehyde with various aromatic amines in good to excellent yield. The structures of synthesized compounds were confirmed by 1H NMR, 13C NMR and mass spectra (ESI-MS) data. These compounds also evaluated for their in silico anti-microbial properties by molecular docking studies. Docking studies were carried out by using Argus Lab 4.0.1 software.

Mechanistic Studies on the Synthesis of Pyrrolidines and Piperidines via Copper-Catalyzed Intramolecular C-H Amination.

We have recently developed a method for the synthesis of pyrrolidines and piperidines via intramolecular C–H amination of N-fluoride amides using [TpxCuL] complexes as precatalysts [Tpx = tris(pyrazolyl)borate ligand and L = THF or CH3CN]. Herein, we report mechanistic studies on this transformation, which includes the isolation and structural characterization of a fluorinated copper(II) complex, [(TpiPr2OH)CuF] [TpiPr = hydrotris(3,5-diisopropylpyrazolyl)borate], pertinent to the mechanistic pathway. The effects of the nature of the Tpx ligand in the copper catalyst as well as of the halide in the N–X amides employed as reactants have been investigated both from experimental and computational perspectives.

Rapid Synthesis of α-Chiral Piperidines via a Highly Diastereoselective Continuous Flow Protocol.

A practical continuous flow protocol has been developed using readily accessible N-(tert-butylsulfinyl)-bromoimine and Grignard reagents, providing various functionalized piperidines (34 examples) in superior results (typically >80% yield and with >90:10 dr) within minutes. The high-performance scale-up is smoothly carried out, and efficient synthesis of the drug precursor further showcases its utility. This flow process offers rapid and scalable access to enantioenriched α-substituted piperidines.

Synthesis of piperidine and pyrrolidine derivatives by electroreductive cyclization of imine with terminal dihaloalkanes in a flow microreactor.

We have successfully synthesized piperidine and pyrrolidine derivatives by electroreductive cyclization using readily available imine and terminal dihaloalkanes in a flow microreactor. Reduction of the substrate imine on the cathode proceeded efficiently due to the large specific surface area of the microreactor. This method provided target compounds in good yields compared to a conventional batch-type reaction. Furthermore, piperidine and pyrrolidine derivatives could be obtained on preparative scale by continuous electrolysis for approximately 1 hour.

Blue light enhanced Heck arylation at room temperature applied to allenes

A blue light enhanced synthesis of 2-vinyl pirrolidines and piperidines through a domino Heck arylation–cyclisation applied to allenyl amines is described. Essential is the role of the light in the aryl migration in the carbo-palladation step.

Nickel-Mediated Enantioselective Piperidine Synthesis

Nickel-Mediated Enantioselective Piperidine Synthesis

Cyclisations and Strategies for Stereoselective Synthesis of Piperidine Iminosugars.

This personal account focuses on synthesis of polyhydroxylated piperidines, a subset of compounds within the iminosugar family. Cyclisations to form the piperidine ring include reductive amination, substitution via amines, iminium ions and cyclic nitrones, transamidification (N-acyl transfer), addition to alkenes, ring contraction and expansion, photoinduced electron transfer, multicomponent Ugi reaction and ring closing metathesis. Enantiomerically pure piperidines are obtained from chiral pool precursors (e. g. sugars, amino acids, Garner's aldehyde) or asymmetric reactions (e. g. epoxidation, dihydroxylation, aminohydroxylation, aldol, biotransformation). Our laboratory have contributed cascades based on reductive amination from glycosyl azide precursors as well as Huisgen azide-alkene cycloaddition. The latter's combination with allylic azide rearrangement has given substituted piperidines, including those with quaternary centres adjacent to nitrogen.

Synthesis of α-trifluoromethyl piperidine derivatives from tetrahydropyridines via nucleophilic trifluoromethylation of pyridinium cations

The synthesis of α-trifluoromethyl piperidines from tetrahydropyridine derivatives in three steps (the oxidation into the corresponding pyridinium, the nucleophilic trifluoromethylation and then, the hydrogenation) is described. The trifluoromethylation step occurs at the less hindered side of the pyridinium intermediate, with moderate-to-high regioselectivity. The method was also successfully applied to the direct trifluoromethylation of one piperidine derivative.

Memory of Chirality in the Asymmetric Synthesis of Piperidines with Vicinal Stereocenters by Intramolecular Sn2′ Reaction

Intramolecular Sn2' cyclization of α-amino ester enolates provided piperidine derivatives with vicinal quaternary-tertiary stereocenters with excellent diastereo- and enantioselectivity via memory of chirality and the Thorpe-Ingold effect. DFT calculations provided a mechanistic rationale for the increase in chirality preservation via the Thorpe-Ingold effect. This new method has the potential to be integrated into concise asymmetric synthesis of bioactive molecules containing multisubstituted piperidine moieties.

N-heterocyclic carbene-catalyzed intramolecular aza-Michael addition of alkyl amines to α,β-unsaturated carboxylic acid: Synthesis of pyrrolidines and piperidines

N-heterocyclic carbene-catalyzed intramolecular aza-Michael addition of alkyl amines to α,β-unsaturated carboxylic acid has been realized. The corresponding pyrrolidine and piperidine derivatives can be obtained in good to excellent yields. Reaction using chiral NHC catalyst showed promising enantioselectivities up to 55% ee. Further chemical transformations of the products provided carboxylic acids, alcohols, and unprotected amines.

Copper-Catalyzed Regio- and Diastereoselective Additions of Boron-Stabilized Carbanions to Heteroarenium Salts: Synthesis of Azaheterocycles Containing Contiguous Stereocenters

Nucleophilic addition of diborylalkyl reagents to N-alkyl or N-acylpyridinium and related heteroarenium salts has been developed as a key step for the synthesis of nonaromatic nitrogen heterocycles that contain contiguous stereogenic centers. Derivatization of the dihydropyridine products for the synthesis of tetrahydropyridines and piperidines have also been described.

Synthesis of Spirocyclic Piperidines by Radical Hydroarylation.

Reported here are conditions for the construction of spirocyclic piperidines from linear aryl halide precursors. These conditions employ a strongly reducing organic photoredox catalyst in combination with a trialkylamine reductant to achieve formation of aryl radical species. Regioselective cyclization followed by hydrogen-atom transfer affords a range of complex spiropiperidines. This system operates efficiently under mild conditions without the need for toxic reagents or precious metals.

Probing sulfatide-tissue lectin recognition with functionalized glycodendrimersomes.

SummaryThe small 3-O-sulfated galactose head group of sulfatides, an abundant glycosphingolipid class, poses the (sphinx-like) riddle on involvement of glycan bridging by tissue lectins (sugar code). First, synthesis of head group derivatives for functionalization of amphiphilic dendrimers is performed. Aggregation of resulting (biomimetic) vesicles, alone or in combination with lactose, demonstrates bridging by a tissue lectin (galectin-4). Physiologically, this can stabilize glycolipid-rich microdomains (rafts) and associate sulfatide-rich regions with specific glycoproteins. Further testing documents importance of heterobivalency and linker length. Structurally, sulfatide recognition by galectin-8 is shown to involve sphingosine's OH group as substitute for the 3′-hydroxyl of glucose of lactose. These discoveries underscore functionality of this small determinant on biomembranes intracellularly and on the cell surface. Moreover, they provide a role model to examine counterreceptor capacity of more complex glycans of glycosphingolipids and to start their bottom-up glycotope surface programming.

Autocombustion‐Promoted Synthesis of Lanthanum Iron Oxide: Application as Heterogeneous Catalyst for Synthesis of Piperidines, Substituted Amines and Light‐Assisted Degradations

AbstractAn autocombustion technique was adopted to synthesize the Perovskite structured Lanthanum iron oxide nanoparticles (LaFeO3, abbreviated as LFO NPs). This technique offered lots of benefits such as short reaction time along with quick heating rate. LFO NPs were fabricated at different calcination temperatures (300‐800 °C) through the aid of sucrose as chelating agent. The prepared LFO NPs were well characterized by various techniques like X‐ray diffraction (XRD), Fourier transform infrared spectroscopy (FT‐IR), Vibrating sample magnetometer (VSM), Ultraviolet‐Visible spectroscopy (UV‐Vis), Brunauer–Emmett–Teller (BET), X‐ray Photo‐Electron Spectroscopy (XPS) and Transmission electron microscopy (TEM) which affirmed that highly crystalline LFO NPs were obtained at 700 °C. Subsequently, the catalytic activity of the LFO NPs was surveyed for three independent approaches: (i) for the synthesis of functionalized piperidines through activation of carbonyl groups in the reacting partners (ii) for the sunlight‐assisted mineralization of health hazardous food colorant, Allura Red AC (iii) for the hydrogenation of nitro aromatic compounds (NACs) using NaBH4 (sodium borohydride) as source of hydrogen in aqueous medium at room temperature.

Synthesis and pharmacological evaluation of piperidine (piperazine)-amide substituted derivatives as multi-target antipsychotics

We report the optimisation of a series of novel amide-piperidine (piperazine) derivatives using the multiple ligand approach with dopamine and serotonin receptors. Of the derivatives, compound 11 exhibited high affinity for the D2, 5-HT1A, and 5-HT2A receptors, but low affinity for the 5-HT2C and histamine H1 receptors and human ether-a-go-go-related gene (hERG) channels. In vivo, compound 11 reduced apomorphine-induced climbing, MK-801-induced hyperactivity and DOI-induced head twitching without observable catalepsy, even at the highest dose tested. In addition, it exhibited suppression in a CAR test. Furthermore, in a novel object recognition task, it displayed procognition properties. Therefore, compound 11 is a promising candidate multi-target antipsychotic.

The endo-aza-Michael addition in the synthesis of piperidines and pyrrolidines

Intramolecular endo-aza-Michael additions are categorised in various ways. Firstly whether they are single or double reactions, secondly whether they are endo- or exo-activated (or both), thirdly whether the Michael acceptor is an alkene or an alkyne, and finally whether the product is a six or a five membered ring. Reactions in the various categories are illustrated by syntheses of piperidines and pyrrolidines, including a range of natural products. The question of the stereochemical outcome and whether it is understood is discussed.