Showing papers on "Piperidine published in 2012"
TL;DR: Large kinetic isotope effects and group 2 element-dependent ΔS(++) values implicated the formation of an amine-assisted rate-determining alkene insertion transition state in which there is a considerable entropic advantage associated with use of the larger strontium center.
Abstract: The heavier group 2 complexes [M{N(SiMe3)2}2]2(1, M = Ca; 2, M = Sr) and [M{CH(SiMe3)2}2(THF)2] (3, M = Ca; 4, M = Sr) are shown to be effective precatalysts for the intermolecular hydroamination of vinyl arenes and dienes under mild conditions. Initial studies revealed that the amide precatalysts, 1 and 2, while compromised in terms of absolute activity by a tendency toward transaminative behavior, offer greater stability toward polymerization/oligomerization side reactions. In every case the strontium species, 2 and 4, were found to outperform their calcium congeners. Reactions of piperidine with para-substituted styrenes are indicative of rate-determining alkene insertion in the catalytic cycle while the ease of addition of secondary cyclic amines was found to be dependent on ring size and reasoned to be a consequence of varying amine nucleophilicity. Hydroamination of conjugated dienes yielded isomeric products via η3-allyl intermediates and their relative distributions were explained through stereoel...
164 citations
TL;DR: In this paper, a simple, straightforward, and highly efficient diastereoselective multicomponent one-pot synthesis of a series of pharmaceutically interesting functionalized piperidine derivatives has been developed based on a low-cost and environmentally benign Bi(NO3)3·5H2O catalyst via tandem reactions of 1,3-dicarbonyl compounds, aromatic aldehydes, and various amines in ethanol at room temperature.
142 citations
TL;DR: Iminium salts generally exhibit higher activity than the corresponding imines in hydrogenation, therefore it is envisioned that the activation of simple pyridines as the corresponding N-benzyl-pyridinium bromides would effectively eliminate coordination ability of the substrate and thus the reactivity could be greatly enhanced.
Abstract: As one of the most straightforward and powerful approaches for the preparation of optically active compounds, asymmetric hydrogenation has been successfully used for different types of aromatic compounds, including quinolines, isoquinolines, quinoxalines, indoles, pyrroles, furans, imidazoles, and aromatic carbocyclic ring, with excellent enantioselectivities. Despite these advances, direct hydrogenation of simple pyridines is still a challenge. The inherent problems are apparent: First, substrates and corresponding products that possess strong coordination ability might cause the deactivation of catalysts. Second, pyridines have a stabilizing aromatic structure that might impede the reduction. Therefore, only limited examples of hydrogenation of specific pyridine derivatives bearing powerful electron-withdrawing substituent at the 2or 3-position have been previously described. In 2000, Studer et al. reported the first homogeneous rhodium-catalyzed asymmetric hydrogenation of pyridines, but only poor enantioselectivity was obtained. Zhang and co-workers described an efficient three-step rhodium-catalyzed asymmetric hydrogenation of nicotinates. Subsequently, the group of Rueping documented the first enantioselective organocatalytic transfer hydrogenation of 3-cyanoor carbonyl-substituted pyridines using Hantzsch esters as hydrogen sources, and our group also employed [{Ir(cod)Cl}2]/(S)-MeO-biphep/I2 catalyst system for asymmetric hydrogenation of specific pyridines with excellent enantioselectivities. Additionally, an elegant asymmetric hydrogenation of activated pyridines, that is, N-iminopyridinium ylides, was developed by Charette et al. As chiral piperidines are important building blocks for the synthesis of biologically active molecules and natural products, the development of an efficient strategy for the highly challenging hydrogenation of the simple pyridines is still of great significance. Iminium salts generally exhibit higher activity than the corresponding imines in hydrogenation, therefore we envisioned that the activation of simple pyridines as the corresponding N-benzyl-pyridinium bromides would effectively eliminate coordination ability of the substrate and thus the reactivity could be greatly enhanced. Moreover, the stoichiometric amount of hydrogen bromide generated in situ would effectively inhibit the coordination ability of the desired product through the formation of its piperidine hydrogen bromide salt (Scheme 1). Also, the benzyl protecting groups could be conveniently removed by hydrogenolysis. Herein, we disclose the iridium-catalyzed asymmetric hydrogenation of 2-substituted pyridinium salts with excellent enantioselectivity.
113 citations
TL;DR: Ag/Al2O3 catalysts were found to be highly active and selective in the Nalkylation of aniline with a variety of aromatic and linear alcohols as mentioned in this paper.
98 citations
TL;DR: In this paper, an absorption parameter for different types of amine-based solvents is evaluated by performing absorption tests at 298 K and atmospheric pressure with a gas-liquid contactor and deducing apparent kinetic constants.
Abstract: In relation with CO2 capture by chemical absorption into aqueous amine-based solvents, absorption and regeneration parameters by separate absorption and regeneration tests are determined. An absorption parameter for different types of amine-based solvents is evaluated by performing absorption tests at 298 K and atmospheric pressure with a gas-liquid contactor and deducing apparent kinetic constants. The regeneration parameter is obtained from a CO2 concentration temporal profile measured in a regeneration cell at the boiling temperature of each solvent. By combining both parameters it is possible to compare the absorption-regeneration performances of all the solvents studied. Good absorption-regeneration performances of cyclical amines, especially of piperidine (PIP) and piperazine (PZ), are highlighted. The interesting potential of 2-amino-2-methyl-1-propanol (AMP) and methyldiethanolamine (MDEA) activated with PZ and PIP is also considered.
83 citations
TL;DR: Monitoring of the lithiation using in situ IR spectroscopy indicated that the rotation of the tert-butoxycarbonyl (Boc) group is slower in a 2-lithiated pyrrolidine than a 2/2 piperidine; low yields for the lithiated-substitution of N-Boc-2-phenylpyrrolidines at -78 °C can be ascribed to this slow rotation.
Abstract: A general and enantioselective synthesis of 2-substituted 2-phenylpyrrolidines and -piperidines, an important class of pharmaceutically relevant compounds that contain a quaternary stereocenter, has been developed. The approach involves lithiation–substitution of enantioenriched N-Boc-2-phenylpyrrolidine or -piperidine (prepared by asymmetric Negishi arylation or catalytic asymmetric reduction, respectively). The combined use of synthetic experiments and in situ IR spectroscopic monitoring allowed optimum lithiation conditions to be identified: n-BuLi in THF at −50 °C for 5–30 min. Monitoring of the lithiation using in situ IR spectroscopy indicated that the rotation of the tert-butoxycarbonyl (Boc) group is slower in a 2-lithiated pyrrolidine than a 2-lithiated piperidine; low yields for the lithiation–substitution of N-Boc-2-phenylpyrrolidine at −78 °C can be ascribed to this slow rotation. For N-Boc-2-phenylpyrrolidine and -piperidine, the barriers to rotation of the Boc group were determined using den...
82 citations
TL;DR: In this paper, the formation of carbamates of selected series of primary and secondary amines over the temperature range (288 to 318) K has been investigated by equilibrium 1H NMR studies, and the stability constants (K9) for the equilibrium: RNH 2 + HCO 3 - ⇄ K 9 RNHCOO - + H 2 O are reported.
70 citations
TL;DR: The overall suitability of an amine for PCC in terms of kinetics and energy is discussed and a Brønsted correlation relating the protonation constant of the amine to the carbamic acid formation rate and equilibrium constants at 25.0 °C has been established.
Abstract: The kinetics of the fast reversible carbamate formation reaction of CO2(aq) with a series of substituted cyclic secondary amines as well as the noncyclic secondary amine diethanolamine (DEA) has been investigated using the stopped-flow spectrophotometric technique at 25.0 °C. The kinetics of the slow parallel reversible reaction between HCO3– and amine has also been determined for a number of the amines by 1H NMR spectroscopy at 25.0 °C. The rate of the reversible reactions and the equilibrium constants for the formation of carbamic acid/carbamate from the reactions of CO2 and HCO3– with the amines are reported. In terms of the forward reaction of CO2(aq) with amine, the order with increasing rate constants is as follows: diethanolamine (DEA) < morpholine (MORP) ∼ thiomorpholine (TMORP) < N-methylpiperazine (N-MPIPZ) < 4-piperidinemethanol (4-PIPDM) ∼ piperidine (PIPD) < pyrrolidine (PYR). Both 2-piperidinemethanol (2-PIPDM) and 2-piperidineethanol (2-PIPDE) do not form carbamates. For the carbamate formi...
68 citations
TL;DR: A novel series of piperidine-linked amino-triazine derivatives were designed, synthesized and evaluated for in vitro anti-HIV activity as non-nucleoside reverse transcriptase inhibitors and preliminary structure-activity relationship and molecular modeling of these new analogs were detailed in this manuscript.
63 citations
TL;DR: Piperidine-4-carboxylic acid (PPCA) functionalized Fe 3O 4 nanoparticles as a novel organic-inorganic hybrid heterogeneous catalyst was fabricated and characterized by XRD, FT-IR, TGA, TEM and VSM as discussed by the authors.
60 citations
TL;DR: A cationic CpRu complex of chiral picolinic acid derivatives catalyzes asymmetric intramolecular dehydrative N-allylation of N-substituted ω-amino- and -aminocarbonyl allylic alcohols to give α-alkenyl pyrrolidine-, piperidine-, and azepane-type N-heterocycles with an enantiomer ratio of up to >99:1.
TL;DR: The γ-butenolide obtained from an organocatalyzed, direct vinylogous aldol reaction of γ -crotonolactone and benzaldehyde serves as the key starting material in the expedient synthesis of a 3-hydroxy-2-phenyl piperidine intermediate which is converted to the target 2,3-disubstituted piperidines.
Abstract: The γ-butenolide obtained from an organocatalyzed, direct vinylogous aldol reaction of γ-crotonolactone and benzaldehyde serves as the key starting material in the expedient synthesis of a 3-hydroxy-2-phenyl piperidine intermediate which is converted to the target 2,3-disubstituted piperidines.
TL;DR: Dichlorobis is a highly efficient alkyne hydrothiolation catalyst and the first generally applicable system that selectively generates cis-configured anti-Markovnikov adducts in excellent yields within only a few minutes at 120 °C in the presence of only 0.05 mol % of the catalyst.
Abstract: Cis all round: Dichlorobis[1-(dicyclohexylphosphanyl)piperidine]palladium, [(P{(NC(5)H(10))(C(6)H(11))(2)})(2)Pd(Cl)(2)], is a highly efficient alkyne hydrothiolation catalyst and the first generally applicable system that selectively generates cis-configured anti-Markovnikov adducts in excellent yields within only a few minutes at 120 °C in the presence of only 0.05 mol % of the catalyst (see scheme).
TL;DR: In this paper, N-Vinyl amides, carbamates, and sulfonamides that contain pendent π-nucleophiles react with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to form piperidine structures with good to excellent levels of efficiency and stereocontrol.
Abstract: N-Vinyl amides, carbamates, and sulfonamides that contain pendent π-nucleophiles react with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to form piperidine structures with good to excellent levels of efficiency and stereocontrol. Reactions proceed nearly instantaneously at room temperature. Transition state models show the preferred configuration around the intermediate acyliminium ion and the orientation of the nucleophile.
TL;DR: Novel series of 1-substituted aminomethyl-3-[1-(4-isobutylphenyl)ethyl]-4-(3-aryl-4-sydnonylidene) amino-1,2,4-triazol-5-thiones showed promising anti-inflammatory and analgesic activity.
TL;DR: Mechanistic investigations demonstrate that palladium nanoparticles were the catalytically active form of compound 1, a highly active and generally applicable C-C cross-coupling catalyst.
Abstract: Dichloro[bis{1-(dicyclohexylphosphanyl)piperidine}]palladium [(P{(NC(5)H(10))(C(6)H(11))(2)})(2)PdCl(2)] (1) is a highly active and generally applicable C-C cross-coupling catalyst. Apart from its high catalytic activity in Suzuki, Heck, and Negishi reactions, compound 1 also efficiently converted various electronically activated, nonactivated, and deactivated aryl bromides, which may contain fluoride atoms, trifluoromethane groups, nitriles, acetals, ketones, aldehydes, ethers, esters, amides, as well as heterocyclic aryl bromides, such as pyridines and their derivatives, or thiophenes into their respective aromatic nitriles with K(4)[Fe(CN)(6)] as a cyanating agent within 24 h in NMP at 140 °C in the presence of only 0.05 mol % catalyst. Catalyst-deactivation processes showed that excess cyanide efficiently affected the molecular mechanisms as well as inhibited the catalysis when nanoparticles were involved, owing to the formation of inactive cyanide complexes, such as [Pd(CN)(4)](2-), [(CN)(3)Pd(H)](2-), and [(CN)(3)Pd(Ar)](2-). Thus, the choice of cyanating agent is crucial for the success of the reaction because there is a sharp balance between the rate of cyanide production, efficient product formation, and catalyst poisoning. For example, whereas no product formation was obtained when cyanation reactions were examined with Zn(CN)(2) as the cyanating agent, aromatic nitriles were smoothly formed when hexacyanoferrate(II) was used instead. The reason for this striking difference in reactivity was due to the higher stability of hexacyanoferrate(II), which led to a lower rate of cyanide production, and hence, prevented catalyst-deactivation processes. This pathway was confirmed by the colorimetric detection of cyanides: whereas the conversion of β-solvato-α-cyanocobyrinic acid heptamethyl ester into dicyanocobyrinic acid heptamethyl ester indicated that the cyanide production of Zn(CN)(2) proceeded at 25 °C in NMP, reaction temperatures of >100 °C were required for cyanide production with K(4)[Fe(CN)(6)]. Mechanistic investigations demonstrate that palladium nanoparticles were the catalytically active form of compound 1.
Patent•
13 Mar 2012TL;DR: In this article, morpholine spirocyclic piperidine amide compounds useful as inhibitors of ion channels were described and provided pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.
Abstract: The invention relates to morpholine spirocyclic piperidine amide compounds useful as inhibitors of ion channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.
TL;DR: A range of phenanthrene derivatives were efficiently synthesized by the palladium-catalyzed annulation of 2,2'-diiodobiphenyls with alkynes by the Pictet-Spengler reaction.
Abstract: A range of phenanthrene derivatives were efficiently synthesized by the palladium-catalyzed annulation of 2,2′-diiodobiphenyls with alkynes. The scope, limitations and regioselectivity of the reaction were investigated. The described method was adopted to synthesize 9,10-dialkylphenanthrenes, sterically overcrowded 4,5-disubstituted phenanthrenes and phenanthrene-based alkaloids. Reactions of highly methoxy-substituted biphenyls with 2-(2-propynyl)pyrrolidine and 2-(2-propynyl)piperidine gave 2-(9-phenanthylmethyl)pyrrolidines and 2-(9-phenanthylmethyl)piperidines, respectively. The products were transformed to phenanthroindolizidine and phenanthroquinolizidine alkaloids by the Pictet–Spengler reaction.
TL;DR: In this paper, a three-component one-pot synthesis of highly functionalized piperidine derivatives was carried out by condensing 1,3-dicarbonyl compounds with aromatic aldehydes and aniline using a catalytic amount (10mol%) of LaCl3·7H2O in methanol at room temperature.
Abstract: The three-component one-pot synthesis of highly functionalized piperidine derivatives was carried out by condensing 1,3-dicarbonyl compounds with aromatic aldehydes and aniline using a catalytic amount (10 mol%) of LaCl3·7H2O in methanol at room temperature. The main features of current protocol include easy work up, mild reaction conditions, good yields and high atom economy.
TL;DR: The Jocic-Reeve and Corey-Link type reaction of dichloromethyllithium with suitably protected 5-keto-hexofuranoses followed by treatment with sodium azide and sodium borohydride reduction gave 5-azido-5-hydroxylmethyl substituted hex ofuranoses 7a-c with required geminal dihydroxymethyl group.
Abstract: The Jocic–Reeve and Corey–Link type reaction of dichloromethyllithium with suitably protected 5-keto-hexofuranoses followed by treatment with sodium azide and sodium borohydride reduction gave 5-azido-5-hydroxylmethyl substituted hexofuranoses 7a–c with required geminal dihydroxymethyl group. Removal of protecting groups and converting the C-1 anomeric carbon into free hemiacetal followed by intramolecular reductive aminocyclization with in situ generated C5-amino functionality afforded corresponding 5C-dihydroxymethyl piperidine iminosugars 2a–c. Alternatively, removal of protecting groups in 7b and 7c and chopping of C1-anomeric carbon gave C2-aldehyde that on intramolecular reductive aminocyclization with C5-amino gave 4C-dihydroxymethyl pyrrolidine iminosugars 1b and 1c, respectively. On the basis of the 1H NMR studies, the conformations of 2a/2b were assigned as 4C1 and that of 2c as 1C4. The glycosidase inhibitory activities of all five iminosugars were studied with various glycosidase enzymes and c...
Patent•
09 Mar 2012
TL;DR: In this article, methods of treating, preventing and/or managing cancers, which comprise administering to a patient 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3- yl)-piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, are presented.
Abstract: Provided herein are methods of treating, preventing and/or managing cancers, which comprise administering to a patient 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3- yl)-piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.
TL;DR: In this paper, a three-component process for the synthesis of highly functionalized 2,3-dihydrofurans from 1,3dicarbonyl compounds, aromatic aldehydes, and N-phenacylpyridinium bromides has been developed.
TL;DR: A series of novel phenylmethylene bis-isoxazolo[4,5-b]azepine derivatives have been synthesized from 3-methyl-4-nitro-5-styrylisoxazoles from which the title compounds 10a-j exhibited good anticancer activity as that of standard drug Cisplatin.
TL;DR: Expedient routes to three classes of novel spiro-fused pyrrolidine, piperidine, and indoline heterocycle scaffolds are described, which allow for good to excellent levels of diastereoselectivity.
TL;DR: The conjugated double bond and carbonyl group of p Piperine are proved to be an essential feature for piperine and related alkylamides to exhibit MAO-inhibitory activity.
TL;DR: An efficient protocol for the aza-Diels-Alder reaction of electron-deficient 1,3-dienes with unactivated imines in the presence of a cationic cobalt(III) porphyrin complex was developed and proceeded smoothly to afford the desired piperidine scaffold within 2 h at ambient temperature.
TL;DR: Only in the cases of N-acylated cysteine, methionine, and tryptophan, attempts to carry out the Hofer-Moest reaction in the applied conditions failed, probably because of the susceptibility of these α-amino acids to an electrochemical oxidation on the side chain.
Abstract: N-Acyl-α-amino acids were efficiently transformed in a two-step procedure into 1-N-(acylamino)alkyltriphenylphosphonium salts, new powerful α-amidoalkylating agents. The effect of the α-amino acid structure, the base used [MeONa or a silica gel-supported piperidine (SiO2–Pip)], and the main electrolysis parameters (current density, charge consumption) on the yield and selectivity of the electrochemical decarboxylative α-methoxylation of N-acyl-α-amino acids (Hofer–Moest reaction) was investigated. For most proteinogenic and all studied unproteinogenic α-amino acids, very good results were obtained using a substoichiometric amount of SiO2–Pip as the base. Only in the cases of N-acylated cysteine, methionine, and tryptophan, attempts to carry out the Hofer–Moest reaction in the applied conditions failed, probably because of the susceptibility of these α-amino acids to an electrochemical oxidation on the side chain. The methoxy group of N-(1-methoxyalkyl)amides was effectively displaced with the triphenylpho...
TL;DR: In this paper, a simple and highly practical method for the synthesis of 2-N-substituted benzothiazoles has been developed by using nanocopper oxide as a recyclable catalyst.
TL;DR: The first approach to these alkaloids is described, culminating in a convergent total synthesis of racemic alstilobanine A (3), which lacks the bridging oxepane ring found in 1 and 2, in the same plant.
Abstract: The monoterpene indole alkaloids, which are usually comprised of a tryptamine moiety appended to a single C9- or C10-terpenoid unit, constitute one of the largest known classes of natural products.[1] In 2004, Kam and Choo isolated a new type of monoterpenoid indole alkaloid, angustilodine (1), which contains a unique rearranged skeleton, from the leaves of the Malayan plant Alstonia angustiloba (Figure 1).[2] The structure of angustilodine was determined by detailed spectroscopic analysis to include an indole appended to a cis-fused 2-azadecalin ring system bearing a 7-membered ring ether bridge. An interesting conformational feature of this molecule established by 2D NMR studies is the observation that the piperidine ring exists as a boat. More recently, Morita and coworkers discovered the N-demethyl congener alstilobanine E (2), along with alstilobanine A (3), which lacks the bridging oxepane ring found in 1 and 2, in the same plant.[3] Unlike alkaloids 1 and 2, it was proposed that alstilobanine A has the piperidine ring in a chair conformation as shown in Figure 1. Alstilobanines A and E were found to possess modest relaxant activity against phenylephrine-induced contractions of thoracic rat aortic rings with endothelium. In this communication we describe the first approach to these alkaloids, culminating in a convergent total synthesis of racemic alstilobanine A (3).
TL;DR: The palladium-based dichlorobis[1-(dicyclohexylphosphanyl)piperidine] complex is readily prepared in quantitative yield from the reaction of [Pd(cod)(Cl)2] (cod=cycloocta-1,5-diene) with two equivalents of 1-(dicyclehexyl-phosphany) piperidine in toluene under N2 within only a few minutes at room temperature as discussed by the authors.
Abstract: The palladium-based dichlorobis[1-(dicyclohexylphosphanyl)piperidine] complex – [(P{(NC5H10)(C6H11)2})2Pd(Cl)2] is readily prepared in quantitative yield from the reaction of [Pd(cod)(Cl)2] (cod=cycloocta-1,5-diene) with two equivalents of 1-(dicyclohexylphosphanyl)piperidine in toluene under N2 within only a few minutes at room temperature. This complex is a highly active Heck catalyst with excellent functional group tolerance, which reliably operates at low catalyst loadings. Various activated, non-activated, deactivated, functionalized, sterically hindered, and heterocyclic aryl bromides, which may contain nitro, chloro or trifluoromethane groups, nitriles, acetales, ketones, aldehydes, ethers, esters, lactones, amides, anilines, phenols, alcohols, carboxylic acids, and heterocyclic aryl bromides, such as pyridines and derivatives, as well as thiophenes and aryl bromides containing methylsulfanyl groups have been successfully coupled with various (also functionalized) alkenes in excellent yields and selectivities (the E-isomers are typically exclusively formed) at 140 °C in the presence of 0.05 mol % of the catalyst in DMF. Even though lower catalyst loadings could be used for many electronically activated, non-activated and some electronically deactivated aryl bromides without noticeable loss of activity, the great advantage of the reaction protocol presented here lies in its reliability and general applicability, which allows its direct adoption to other aryl bromides without the neccessity of its modification. Experimental observations indicated that palladium nanoparticles are the catalytically active form. Consequently, whereas comparable levels of activity were observed for dichloro-bis(aminophosphine) complexes of palladium, a dramatic drop in activity was found for their phosphine-based analogue [(P(C6H11)3)2Pd(Cl)2].