Showing papers on "Piperidine published in 2019"
TL;DR: In this article, the authors report the synthesis, characterization, and activity of Pd-doped hydrotalcites (Pd-HTs) for acceptorless dehydrogenation of both primary and secondary amines (cyclic and acyclic).
Abstract: The acceptorless dehydrogenation of acyclic secondary amines is a highly desirable but still elusive catalytic process. Here we report the synthesis, characterization, and activity of Pd-doped hydrotalcites (Pd-HTs) for acceptorless dehydrogenation of both primary and secondary amines (cyclic and acyclic). These multifunctional catalysts comprise Bronsted basic and Lewis acidic surface sites that stabilize Pd in 0, 2+, and 4+ oxidation states. Pd speciation and corresponding catalytic performance is a strong function of metal loading. High activity is observed for the dehydrogenation of secondary aliphatic amines to imines, and N-heterocycles, such as indoline, 1,2,3,4-tetrahydroquinoline, and piperidine, to aromatic compounds. Oxidative transamination of primary amines is achieved using low Pd loading (0.5 mol %), without the need for oxidants. The relative yields of secondary imines afforded are consistent with trends for calculated free energy of reaction, while yields for transamination products corre...
32 citations
TL;DR: The use of HCl·DMPU as both non-nucleophilic base and chloride source constitutes an environmentally benign alternative for piperidine formation and has a broad substrate scope, and the conditions offer good chemical yields with high functional group tolerance and scalability.
Abstract: We report that HCl·DMPU induces the formation of (thiomethyl)methyl carbenium ion from DMSO under mild conditions. Homoallylic amines react with this electrophile to generate 4-chloropiperidines in good yields. The method applies to both aromatic and aliphatic amines. The use of HCl·DMPU as both non-nucleophilic base and chloride source constitutes an environmentally benign alternative for piperidine formation. The reaction has a broad substrate scope, and the conditions offer good chemical yields with high functional group tolerance and scalability.
28 citations
TL;DR: The use of simple 2-pyridones in the synthesis of alkaloids and alkaloids-inspired compounds based on the piperidine or pyridine framework is discussed in this paper.
Abstract: 2-Pyridone is characterized by a very wide range of reactivity of a different nature, ranging from electrophilic aromatic substitution, CH–metal-mediated reactions, and NH/OH functionalization of both possible lactam/lactim tautomers, through cycloaddition, to nucleophilic addition and transformation of the tautomeric C=O/C–OH moiety. The high availability of 2-pyridones and the possibility of their far-reaching functionalization additionally increased their values. Therefore, they are very useful building blocks for the synthesis of structurally diverse piperidine and pyridine compounds, including naturally occurring 2-pyridones. This review reports on the use of simple 2-pyridones in the synthesis of alkaloids and alkaloids-inspired compounds based on the piperidine or pyridine framework. 1 Introduction 2 Structure, Availability, and Reactivity of 2-Pyridones 3 Monocyclic Piperidine Alkaloids from 2-Pyridones 4 Polycyclic Alkaloids, Their Derivatives, and Alkaloid-Inspired Compounds from 2-Pyridones 4.1 New Ring Formation Involving C/N Atoms of the 2-Pyridone Ring 4.1.1 Indolizine-Fused 2-Pyridones: Camptothecins and Related Compounds 4.1.2 Other Indolizines from 2-Pyridones 4.1.3 Compounds Bearing the Quinolizine Ring System 4.2 New Ring Formation Involving C/C Atoms of the 2-Pyridone Ring 4.2.1 C-2/C-3 Ring Fusion 4.2.2 C-3/C-4 Ring Fusion 4.2.3 C-4/C-5 Ring Fusion 4.2.4 C-5/C-6 Ring Fusion 4.2.5 C-2/C-4 Ring Bridge 4.2.6 C-2/C-6 Ring Bridge 4.2.7 C-3/C-5 Ring Bridge 4.2.8 C-3/C-6 Ring Bridge 4.2.9 C-4/C-6 Ring Bridge 5 Conclusion
27 citations
TL;DR: In this paper, the authors presented the synthesis and characterisation of 3-(2-hydroxyethyl)-1-vinyl-1H-imidazol-3-ium chloride [EvimOH][Cl] ionic liquids for cycloaddition reactions of CO2 and epoxides into cyclic carbonates.
Abstract: Carbon dioxide (CO2) mitigation via utilization can be a potential solution to global warming issues such as increasing CO2 concentration. In this study, we present the synthesis and characterisation of 3-(2-hydroxyethyl)-1-vinyl-1H-imidazol-3-ium chloride [EvimOH][Cl] and 3-(2-hydroxyethyl)-1-vinyl-1H-imidazol-3-ium sulphate [EvimOH][HSO4] ionic liquids for cycloaddition reactions of CO2 and epoxides into cyclic carbonates. The synthesized ionic liquids were characterized by FT-IR, 1H- and 13C-NMR spectroscopic methods. Also, we have analysed the physical properties of ionic liquids by using TGA and DTA. Further, the CO2 consumption was done by developing a binary catalytic system with bases such as DBU, TEA, DIPEA, piperidine, pyrrolidine, aniline. The developed binary ([EvimOH][Cl]/base) catalytic system exhibited the excellent catalytic activity of 99.8% conversion and ≥99% selectivity under mild reaction conditions without the aid of solvent and metal co-catalysts. Furthermore, the results show that the improved activity from the binary system is due to synergistic effect among −OH functional group from the cation, reactive acidic C(2)-H in the imidazolium ring and amine containing bases which promote the CO2 absorption. Also, a plausible mechanism of cyclic carbonate formation and kinetic study in the presence of binary catalytic system was demonstrated.
25 citations
TL;DR: To circumvent a current limitation in palladium-catalyzed C-N cross-coupling methodology, high-throughput experimentation was used to identify a catalyst capable of fusing piperidine-based nucleophores as discussed by the authors.
22 citations
TL;DR: Either pyrrolidin-2-ones or 3-iodopyrroles could be obtained selectively from the same substrates, and the selectivity was easily tuned by using a specific oxidant and additive.
Abstract: In this paper, a selective synthesis of pyrrolidin-2-ones and 3-iodopyrroles via the cascade reactions of N-substituted piperidines is presented. Mechanistically, the formation of pyrrolidin-2-ones involves a domino process including the in situ formation of pyrrolidine-2-carbaldehyde followed by carboxylic acid formation, decarboxylation and ipso-oxidation. On the other hand, 3-iodopyrroles are believed to be formed via the initial generation of pyrrolidine-2-carbaldehyde followed by carboxylic acid formation, decarboxylation, dehydrogenation, iodination and aromatization. Interestingly, either pyrrolidin-2-ones or 3-iodopyrroles could be obtained selectively from the same substrates, and the selectivity was easily tuned by using a specific oxidant and additive.
22 citations
TL;DR: A series of 2,2′:6′,2″-terpyridine derivatives with electron donating amino groups (dimethylamine, piperidine, morpholine and diphenylamine) connected to the terpy/dtpy/dppy skeleton via phenylene linkage have been thoroughly investigated in order to get an insight into the impact of amine donors and nitrogen-based π-deficient heterocycles on the thermal, redox, UV-Vis absorption and emission properties as mentioned in this paper.
20 citations
TL;DR: Systematic exploration of the structure-activity relationship of compound A12 led to the discovery of the superior 3,4,6-trisubstituted piperidine derivative E22, which showed increased potency in Akt1 and cancer cell inhibition, remarkably reduced hERG blockage, and significantly improved safety profiles.
Abstract: A series of 3,4-disubstituted piperidine derivatives were obtained based on a conformational restriction strategy and a lead compound, A12, that exhibited potent in vitro and in vivo antitumor efficacies; however, obvious safety issues limited its further development. Thus, systematic exploration of the structure-activity relationship of compound A12, involving the phenyl group, hinge-linkage, and piperidine moiety, led to the discovery of the superior 3,4,6-trisubstituted piperidine derivative E22. E22 showed increased potency in Akt1 and cancer cell inhibition, remarkably reduced human ether-a-go-go-related gene blockage, and significantly improved safety profiles. Compound E22 also exhibited good kinase selectivity, had a good pharmacokinetic profile, and displayed very potent in vivo antitumor efficacy, with over 90% tumor growth inhibition in the SKOV3 xenograft model. Further mechanistic studies were conducted to demonstrate that compound E22 could significantly inhibit the phosphorylation of proteins downstream of Akt kinase in cells and tumor tissue from the xenograft model.
19 citations
TL;DR: In this paper, three β-cyclodextrin compounds derived with piperidine which is flexible, l -proline containing a chiral center, ionic liquid with 3,5-diamino-1,2,4-triazole as the cation were designed and synthesized as chiral selectors for enantiomer separation.
19 citations
TL;DR: The reported method allows the synthesis of a wide range of five‐ and six‐membered N‐alkylated heterocycles in moderate‐to‐excellent yields starting from predominantly proline and a broad range of benzyl alcohols, and primary and secondary aliphatic alcohols.
Abstract: A modular and waste-free strategy for constructing N-substituted cyclic amines via decarboxylative N-alkylation of α-amino acids employing ruthenium- and iron-based catalysts is presented. The reported method allows the synthesis of a wide range of five- and six-membered N-alkylated heterocycles in moderate-to-excellent yields starting from predominantly proline and a broad range of benzyl alcohols, and primary and secondary aliphatic alcohols. Examples using pipecolic acid for the construction of piperidine derivatives, as well as the one-pot synthesis of α-amino nitriles, are also shown.
17 citations
TL;DR: The tetraamino-2-pyridyl(N/O)spirocyclotriphosphazenes (3a-3c) were identified by single crystal X-ray crystallography.
Abstract: The Cl exchange reaction of hexachlorocyclotriphosphazene, N3P3Cl6 (1), with one equimolar amount of sodium salt of N/O donor type bidentate ligand containing a 2-pyridyl pendant arm (2) afforded, regioselectively, the partly substituted 2-pyridyl(N/O)spirocyclotriphosphazene (3; with a yield of 65%) in THF. The reactions of 3 with excess pyrrolidine, morpholine and 1,4-dioxa-8-azaspiro[4,5]decane (DASD) led to the formation of the tetraamino-2-pyridyl(N/O)spirocyclotriphosphazenes (3a-3c) in high yields. Compound 3 also gave both tetrapiperidino (3d) and gem-bispiperidino (3e) products with excess piperidine. The structures of all the compounds were determined by elemental analyses, ESI-MS, FTIR, HSQC, HMBC and 1H, 13C, and 31P NMR techniques. The crystal structure of 3c was identified by single crystal X-ray crystallography. Besides, the compound 3e had one stereogenic P atom, and its chirality was verified by 31P NMR spectroscopy in the presence of (S)-(+)-2,2,2-trifluoro-1-(9’-anthryl)-ethanol...
TL;DR: A stereoselective synthesis of functionalized N‐heterocycles was accomplished in two steps, comprising the biocatalytic aldol addition of ethanal and simple aliphatic ketones such as propanone and 3‐pentanone to N‐Cbz‐protected aminoaldehydes.
Abstract: Nitrogen heterocycles are structural motifs found in many bioactive natural products and of utmost importance in pharmaceutical drug development. In this work, a stereoselective synthesis of functionalized N-heterocycles was accomplished in two steps, comprising the biocatalytic aldol addition of ethanal and simple aliphatic ketones such as propanone, butanone, 3-pentanone, cyclobutanone, and cyclopentanone to N-Cbz-protected aminoaldehydes using engineered variants of d-fructose-6-phosphate aldolase from Escherichia coli (FSA) or 2-deoxy-d-ribose-5-phosphate aldolase from Thermotoga maritima (DERA Tma ) as catalysts. FSA catalyzed most of the additions of ketones while DERA Tma was restricted to ethanal and propanone. Subsequent treatment with hydrogen in the presence of palladium over charcoal, yielded low-level oxygenated N-heterocyclic derivatives of piperidine, pyrrolidine and N-bicyclic structures bearing fused cyclobutane and cyclopentane rings, with stereoselectivities of 96-98 ee and 97:3 dr in isolated yields ranging from 35 to 79%.
TL;DR: The synthesis of the piperidine alkaloids (+)-241D, (-)-epimyrtine, and (-)-lasubine II demonstrated the utility of the Mannich condensation methodology.
Abstract: Enantiopure β-amino ketone derivatives were synthesized by decarboxylative Mannich reaction of chiral N- tert-butanesulfinyl imines with β-keto acids and were subsequently transformed into cis-2,6-disubstituted piperidin-4-ones through an organocatalyzed condensation with aldehydes. Both enantiomers were accessible from the same precursors by inverting the order in the reaction sequence of the aldehydes involved in the imine formation and the intramolecular Mannich condensation. The synthesis of the piperidine alkaloids (+)-241D, (-)-epimyrtine, and (-)-lasubine II demonstrated the utility of this methodology.
TL;DR: Structurally unique thiopyranodipyridine alkaloids xylaridines C and D were isolated from the fungus Xylaria longipes by comprehensive spectroscopic analysis combined with single-crystal X-ray diffraction and electron-capture detection calculations.
TL;DR: A practical enantioselective total synthesis of the unnatural (+)-quinine and (–)-9-epi-quinine enantiomers, which are important organocatalysts, is reported.
Abstract: A practical enantioselective total synthesis of the unnatural (+)-quinine and (−)-9-epi-quinine enantiomers, which are important organocatalysts, is reported. The key transformation is a successive organocatalytic formal aza [3 + 3] cycloaddition/Strecker-type cyanation reaction to form an optically active tetrasubstituted piperidine derivative. This organocatalytic reaction proceeded in high yield and gave excellent enantiomeric excess with only 0.5 mol% catalyst loading. In addition, an imidate group, derived from a cyano group, was incorporated in the strategy for site-selective modification of the C4-alkyl chiral piperidine ring of quinine. Furthermore, an efficient coupling between the quinuclidine precursor and dihydroquinoline unit was achieved on a gram scale. The 15-step (LLS) synthetic protocol provided both (+)-quinine and (−)-9-epi-quinine, each with 16% overall yield.
TL;DR: Although the Michael products were generated as a mixture of syn- and anti-isomers, they can be transformed to single isomers of other useful compounds, such as lactone, lactam, piperidine, dihydropyran containing trifluoromethyl groups, or fluoro substituents.
TL;DR: In this paper, a new series of pyrimidinothienocinnoline derivatives are synthesized for their anti-inflammatory activity, which are tested for their antiseptic activity.
Abstract: Synthesis of a new series of pyrimidinothienocinnoline derivatives involves the reaction of 9-aminodibenzo[f, h]pyrimido[4′,5′:4,5]thieno[2,3-c]cinnoline-8-carbonitrile with formamide that gives 8-amino-dibenzo[f, h]-pyrimido[4′,5′:4,5]thieno[2,3-c]cinnoline. Reactions of the latter with morpholine, piperidine, malononitrile, phenylbromide, aromatic aldehydes, and ethyl cyanoacetate have been studied. Some synthesized compounds have been subjected to further transformations. The synthesized pyrimidinothienocinnoline derivatives are tested for their anti-inflammatory activity.
TL;DR: Umpolung reactions of N-trimethylsilyl α-iminoester with organometallics gave directly N-alkylaminoesters in high yields without the need for removing a protecting group at the nitrogen atom.
TL;DR: This is the first synthetic effort to access the core skeleton of (-)-quinagolide and an interesting reductive cleavage of the C-N bond in the electron-deficient isoquinuclidine skeleton under the Birch reduction conditions has been observed.
TL;DR: A total synthesis has been developed that builds off prior work on (+)-fastigiatine and features a transannular Mannich reaction and cyclization to complete the quinolizidine segment.
Abstract: (-)-Himeradine A is a complex lycopodium alkaloid with seven rings and ten stereogenic centers that shows anticancer activity against lymphoma L1210 cells. A total synthesis has been developed that builds off prior work on (+)-fastigiatine. A 2,4,6-trisubstitited piperidine ring forms the core of the quinolizidine segment, and was prepared by diastereoselective reduction of a pyridine and classic resolution of an intermediate. The remaining secondary amine was introduced with a catalyst-controlled Overman rearrangement. The piperidine segment was coupled in a B-alkyl Suzuki reaction with a bicyclic bromoenone, which was a key intermediate for the synthesis of (+)-fastigiatine. The final transformation featured a transannular Mannich reaction and cyclization to complete the quinolizidine. Five bonds and four new rings were generated in this one-pot procedure. (-)-Himeradine A was prepared in 17 steps in the longest linear sequence.
TL;DR: A library of highly functional 2-amino-4,6-diarylpyridine derivatives was easily constructed using the cascade reaction described in this study, suitable for the efficient parallel synthesis of pyridines.
Abstract: A general and concise method was developed for the synthesis of 2-amino-4,6-diarylpyridine derivatives 4–6 through the cascade reaction, which includes Michael addition, intramolecular cyclization, aromatization, and/or loss of HNO2, of different types of α,β-unsaturated ketones 1 and 1,1-enediamines 2 and 3 in 1,4-dioxane promoted by the base Cs2CO3 or piperidine. This method is suitable for the efficient parallel synthesis of pyridines. A library of highly functional 2-amino-4,6-diarylpyridine derivatives was easily constructed using the cascade reaction described in this study.
TL;DR: The reaction of 4-(adamantan-1-yl)-3-thiosemicarbazide 3 with various aromatic aldehydes yielded the corresponding thiazolidin-4-one and its 5-arylidene derivatives 11a,b were obtained via microwave-assisted synthesis.
Abstract: The reaction of 4-(adamantan-1-yl)-3-thiosemicarbazide 3 with various aromatic aldehydes yielded the corresponding thiosemicarbazones 4a–g. 1-Adamantyl isothiocyanate 2 was reacted with 1-methylpiperazine or piperidine to yield the corresponding N-(adamantan-1-yl)carbothioamides 5 and 6, respectively. The latter was reacted with benzyl or substituted benzyl bromides to yield the S-arylmethyl derivatives 7a–c. Attempted cyclization of 1,3-bis(adamantan-1-yl)thiourea 8 with chloroacetic acid via prolonged heating to the corresponding thiazolidin-4-one 9 resulted in desulfurization of 8 to yield its urea analogue 10. The thiazolidin-4-one 9 and its 5-arylidene derivatives 11a,b were obtained via microwave-assisted synthesis. The in vitro antimicrobial activity of the synthesized compounds was evaluated against a panel of Gram-positive and Gram-negative bacteria and yeast-like pathogenic fungus Candida albicans. Compounds 7a–c displayed marked broad spectrum antibacterial activities (minimal inhibitory concentration (MIC), 0.5–32 μg/mL) and compounds 4a and 4g showed good activity against Candida albicans. Nine representative compounds were evaluated for anti-proliferative activity towards three human tumor cell lines. Compounds 7a–c displayed significant generalized anti-proliferative activity against all the tested cell lines with IC50 < 10 μM.
TL;DR: In the present study, several spectroscopic techniques were employed to characterize rat serum albumin and, aided by computational techniques, the protein modeling was proposed and the Gibbs free energy, an important thermodynamic parameter, was determined, indicating that the interaction was spontaneous.
Abstract: The bioactive piperine (1-piperoyl piperidine) compound found in some pepper species (Piper nigrum linn and Piper sarmentosum Roxb) has been shown to have therapeutic properties and to be useful for well-being. The tests used to validate these properties were performed in vitro or with small rats. However, in all these assays, the molecular approach was absent. Although the first therapeutic trials relied on the use of rats, no proposal was mentioned either experimentally or computationally at the molecular level regarding the interaction between piperine and rat serum albumin (RSA). In the present study, several spectroscopic techniques were employed to characterize rat serum albumin and, aided by computational techniques, the protein modeling was proposed. From the spectroscopic results, it was possible to estimate the binding constant (3.9 × 104 M-1 at 288 K) using the Stern-Volmer model and the number of ligands (three) associated with the protein applying interaction density function model. The Gibbs free energy, an important thermodynamic parameter, was determined (-25 kJ/mol), indicating that the interaction was spontaneous. This important set of experimental results served to parameterize the computational simulations. The results of molecular docking and molecular dynamics matched appropriately made it possible to have detailed microenvironments of RSA accessed by piperine.
TL;DR: In this paper, an efficient synthetic approach for the construction of fluorine-containing piperidine γ-amino acid derivatives has been developed, based on the oxidative ring opening of an unsaturated bicyclic γ lactam (Vince-lactam) through its ring C=C bond.
TL;DR: In vitro AChE activities of all compounds were evaluated in cerebral cortex and hippocampus of rats and in general, the results in cortex were more promising than hippocampus, and 5Bd suggest preliminary safety, showing no cytotoxicity at 100 µM.
Abstract: A series of nineteen benzothiazin-4-ones from N-(3-aminopropyl) piperidine, 4-(2-aminoethyl)morpholine or 1-(2-aminoethyl)piperidine, aliphatic or aromatic aldehyde and thiosalicylic acid, ...
TL;DR: This protocol provides a facile route towards the synthesis of diverse 3,4-disubstituted chroman, tetrahydroquinoline, piperidine and thiochroman derivatives in high yields with good to excellent diastereo- and enantioselectivities.
TL;DR: The new application of a translate metal chelating ligand α-benzoin oxime for improving Cu-catalyzed C-N coupling reactions could catalyse coupling reactions of (hetero)aryl halides with a wide of nucleophiles in moderate to excellent yields.
Abstract: We first reported the new application of a translate metal chelating ligand α-benzoin oxime for improving Cu-catalyzed C-N coupling reactions. The system could catalyse coupling reactions of (hetero)aryl halides with a wide of nucleophiles (e.g., azoles, piperidine, pyrrolidine and amino acids) in moderate to excellent yields. The protocol allows rapid access to the most common scaffolds found in FDA-approved pharmaceuticals.
TL;DR: The compound with a butyl chain as a spacer between the two pharmacophores and piperidine as the secondary amine component on the isoindoline ring was the most potent and non-cytotoxic among the synthesized compounds.
Abstract: A series of secondary amine-substituted isoindoline-1,3-dione-4-aminoquinolines were prepared via microwave heating and assayed for their anti-mycobacterial activities. The compound with a butyl chain as a spacer between the two pharmacophores and piperidine as the secondary amine component on the isoindoline ring was the most potent and non-cytotoxic among the synthesized compounds, exhibiting a minimum inhibitory concentration (MIC99) of 6.25 μg mL−1 against Mycobacterium tuberculosis.