N-substituted Piperidines Research Articles

On the Reaction Mechanism of the Selective C(sp3)–H Functionalization of N-Benzylpiperidines Mediated by TEMPO Oxoammonium Cation

AbstractThe selective and dual C(sp3)–H oxidation of N-heterocycles to their corresponding 3-alkoxyamino lactams mediated by TEMPO oxoammonium cation (TEMPO+) is turning into a convenient nonmetallic strategy for the rapid functionalization of piperidines and pyrrolidines to bioactive alkaloids. Mechanistic proposal suggests that TEMPO+ prefers to oxidize the endocyclic C–Hα bond of either N-substituted piperidines or pyrrolidines to their corresponding endocyclic iminium intermediates, which are transformed into enamine intermediates, and then trapped by oxoammonium cation. Although the product formation seems to be in concordance with this mechanistic rationale, neither experimental evidence nor theoretical calculations have been reported. Accordingly, the current investigation provides computational findings explaining that the origin of the selective C–Hα oxidation can be attributed to an unprecedented C–H···π interaction between two hydrogen atoms of TEMPO+ with the aromatic ring of the piperidine benzyl group. To prove the existence of the enamine intermediate, we developed an unprecedented transition-metal-free tetra C–H oxidation of two N-benzyl-4-methylenepiperidines. Accordingly, the existence of the elusive enamine intermediate was attained by generating a transitory dienamine intermediate, which was trapped by TEMPO+ and NaClO2­ to give the corresponding 4-(aminooxymethyl)-3,4-epoxy-2-piperidone.

Visible-light-induced C(sp3)-H functionalizations of piperidines to 3,3-dichloro-2-hydroxy-piperidines with N-chlorosuccinimide.

A visible-light-induced synthesis of 3,3-dichloro-2-hydroxy-piperidines via site-selective functionalizations of C(sp3)-H in N-substituted piperidines using easily available N-chlorosuccinimide as chlorine source was developed. Mechanistic investigations suggest that chlorine radical is involved in this transformation.

Selective synthesis of pyrrolidin-2-ones and 3-iodopyrroles via the ring contraction and deformylative functionalization of piperidine derivatives.

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.

ANTIOXIDANT POTENTIAL OF PIPERIDINE CONTAINING COMPOUNDS-A SHORT REVIEW

Piperidine is a saturated heterocyclic ring, considered as a privileged scaffold in view of its role in wide range of biological activities. Piperidine is good candidate molecule for obtaining potent antioxidant agents. The planar nature of this heterocyclic nucleus allows the introduction of substituent groups at different positions on the ring. In the present review, the antioxidant profile of piperidine containing compounds has been focused. The compounds were classified into naturally occurring piperidines, unsaturated piperidines, N-substituted piperidines, piperamides, piperanols, piperidine oximes, and hydrazides.

N-substituted akyl- and nonalkylpiperidines: Equatorial, axial or intermediate conformations?

Detailed quantum chemical calculations for a series alkyl- and nonalkyl-derivatives were performed continuing a systematic study of N-substituted piperidines. Three groups have been proposed to sort out the compounds distinguishing from each other by preference of the substituent’s position: (a) adopting exclusively equatorial position (alkylpiperidines); (b) with no exceptional priority of any of the conformers; (c) a peculiar group for which the terms ‘equatorial and axial’ are not applicable – the nitrogen bond configuration is planar or nearly planar (formyl, carbonyl, etc.). Geometry, pathways and barriers for nitrogen and ring inversions were calculated. Most of the MP2 calculations predict higher axial form contribution as compared with those by DFT-B3LYP.

ChemInform Abstract: Metal—Organic Frameworks as Solid Catalysts for the Synthesis of Nitrogen‐Containing Heterocycles

AbstractReview: 90 refs.

Solid-phase synthesis of N-substituted pyrrolidinone-tethered N-substituted piperidines via Ugi reaction.

Starting with resin-bound glutamic acid, an efficient synthesis of N-substituted pyrrolidinones is described, using the Ugi four-component reaction (U-4CR). The same methodology is employed to produce N-substituted pyrrolidinone tethered N-substituted piperidines.

Study of minimum energy conformers of N-substituted derivatives of piperidine and pyrrolidine. Evidence of weak H-bonding by theoretical correlation with experimental NMR data

Four N-substituted piperidines and four N-substituted pyrrolidines were synthesized and characterized by common spectroscopic techniques. In order to investigate the dynamic behavior of these important heterocyclic building blocks, a conformational study was carried out, using suitable tools of computational chemistry. The comparison of computed and experimental NMR chemical shifts is now accepted as a valuable aid in the elucidation of structures and that was the strategy followed in the present study. After a conformational search by statistical methods, the lowest three minimum-energy conformers of each piperidine/pyrrolidine derivative were analyzed (24 conformers in total). The relative proportion of each conformer was estimated by thermodynamic calculations, involving the Boltzmann weighting factor; P i. Using DFT methods, the geometry of each conformer was fully optimized and their chemical shifts ( 1H, 13C) were calculated. A very good coincidence between calculated and experimental data of both, 1H and 13C shifts was found, indicating that the theoretical geometries obtained were reliable enough for the study of structure-properties relationships. For all the conformers, specific weak unusual hydrogen bonding involving H–C instead of H–X (where X=electronegative atom) was observed. The nitrogen atom and the carbonyl oxygen participate in these interactions and could play an important role in the activity of these compounds and, therefore, they should be considered in the modeling of bioactive compounds. Furthermore, the good quality of theoretical/experimental data validates the theoretical methods used. The solvent effect (CDCl 3 in this case) was found of small significance on the observed H-bonding.

Cation-pi interactions: an energy decomposition analysis and its implication in delta-opioid receptor-ligand binding.

The nature and strength of the cation-pi interaction in protein-ligand binding are modeled by considering a series of nonbonded complexes involving N-substituted piperidines and substituted monocylic aromatics that mimic the delta-opioid receptor-ligand binding. High-level ab initio quantum mechanical calculations confirm the importance of such cation-pi interactions, whose intermolecular interaction energy ranges from -6 to -12 kcal/mol. A better understanding of the electrostatics, polarization, and other intermolecular interactions is obtained by appropriately decomposing the total interaction energy into their individual components. The energy decomposition analysis is also useful for parametrizing existing molecular mechanics force fields that could then account for energetic contributions arising out of cation-pi interactions in biomolecules. The present results further provide a framework for interpreting experimental results from point mutation reported for the delta-opioid receptor.

A Convenient Synthesis of Hindered N-Aryl Substituted Cyclic Amines

An efficient and high yielding synthesis of N-substituted pyrrolidines and piperidines is described.

The chemistry of benzotriazole. A novel and versatile synthesis of 1-alkyl-, 1-aryl-, 1-(alkylamino)-, or 1-amido-substituted and of 1,2,6-trisubstituted piperidines from glutaraldehyde and primary amines or monosubstituted hydrazines

Various primary amines and 1-mono- and 1,1-disubstituted hydrazines were converted into the corresponding N-substituted piperidines in good to excellent yields via the products of double condensations with benzotriazole and glutaraldehyde. Reduction of the 2,6-bis(benzotriazolyl) N-substituted piperidines 4 and 7 with sodium borohydride in tetrahydrofuran afforded N-substituted piperidines. The benzotriazole moieties were also replaced by alkyl groups by reaction with Grignard reagents to produce 1,2,6-trisubstituted piperidines

Ruthenium complex catalyzed N-heterocyclization. Syntheses of N-substituted piperidines, morpholines, and piperazines from amines and 1,5-diols

Ruthenium complex catalyzed N-heterocyclization. Syntheses of N-substituted piperidines, morpholines, and piperazines from amines and 1,5-diols

Mass spectra and peculiarities of the fragmentation of some substituted piperidines

N-Substituted piperidines with R = CH2OCH3, (CH2)4COCH2, CH3COOC2H5, (CH2)2N(CH3)2, (CH2)2N(C2H5)2, N=0, CH3, H, COOC2H5, and OH were investigated by mass spectrometry. The ratios of the intensities of the peaks and the behavior of the amine fragments with exocyclic double bonds attached to the quaternary nitrogen atom that are formed from the molecular ion by detachment of a radical from the C2 atom and from the substituent attached to the nitrogen atom were studied. It is shown that the ratios of the intensities of the peaks of the amine fragments are determined both by the type of substituent and the energy of the ionizing electrons.

ChemInform Abstract: FACILE SYNTHESIS OF N‐SUBSTITUTED PIPERIDINES FROM GLUTARALDEHYDE USING CARBONYLHYDRIDOFERRATE AS A REDUCING AGENT

Chemischer InformationsdienstVolume 7, Issue 7 Heterocyclic Compounds ChemInform Abstract: FACILE SYNTHESIS OF N-SUBSTITUTED PIPERIDINES FROM GLUTARALDEHYDE USING CARBONYLHYDRIDOFERRATE AS A REDUCING AGENT Y. WATANABE, Y. WATANABESearch for more papers by this authorS. C. SHIM, S. C. SHIMSearch for more papers by this authorT. MITSUDO, T. MITSUDOSearch for more papers by this authorM. YAMASHITA, M. YAMASHITASearch for more papers by this authorY. TAKEGAMI, Y. TAKEGAMISearch for more papers by this author Y. WATANABE, Y. WATANABESearch for more papers by this authorS. C. SHIM, S. C. SHIMSearch for more papers by this authorT. MITSUDO, T. MITSUDOSearch for more papers by this authorM. YAMASHITA, M. YAMASHITASearch for more papers by this authorY. TAKEGAMI, Y. TAKEGAMISearch for more papers by this author First published: February 17, 1976 https://doi.org/10.1002/chin.197607222Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume7, Issue7February 17, 1976 RelatedInformation

THE FACILE SYNTHESIS OF N-SUBSTITUTED PIPERIDINES FROM GLUTARALDEHYDE USING CARBONYLHYDRIDOFERRATE AS A REDUCING AGENT

Abstract Glutaraldehyde reacts with primary amines in the presence of tetracarbonylhydridoferrate to give the corresponding N-substituted piperidines.

Conformational equilibria in N-chloropiperidines

Nitrogen inversion equilibria in the anancomeric piperidines 3–6, 8 and 9 have been studied by variable temperature 1H NMR in order to determine free energy differences ΔG e→a 0 for one class of N-substituted piperidines by an unequivocal method, i.e. direct integration of separate NMR signals for conformers whose interconversion is slow on the NMR timescale at an easily accessible temperature. Using 6 as a model ΔG e→a 0 (N-chloropiperidine) has been found to be 5·3±0·1 kJ mol -1 at 193 K; similarly a study of 10 leads to ΔG e→a 0 (N-chloromorpholine) = 4·2±0·1 kJ mol -1 at 203 K.

Quinuclidine Chemistry

This chapter focuses on general chemical properties and peculiarities of quinuclidine derivatives. Quinuclidine (l-azabicyclo[2.2.2]octane) is a heterocyclic system that is part of the structure of a number of natural physiologically active compounds and synthetic drugs. Quinuclidine is a saturated bicyclic system with a bridgehead nitrogen atom. It has, in contrast to tertiary aliphatic amines and N-substituted piperidines, a rigid structure. The chapter discusses the features of quinuclidine derivatives. For the syntheses of quinuclidine and its derivatives, methods of building up quinuclidine systems and methods of introducing substituents into the quinuclidine ring are elaborated. The chapter also discusses the biological properties of quinuclidine derivatives. The increase in heart muscle excitability induced by some natural quinuclidine derivatives (quinidine, ajmaline), suggesting pharmacological activity of some synthetic quinuclidine compounds and the possibility of using quinuclidines as catalysts for production of polymers, stimulated further interest in the ring system.