Synthesis Of Piperidines Research Articles

Synthesis of Piperidine Conjugated Dihydroquinazolin-4(1H)-ones and their Antiproliferative Activity, Molecular Docking Studies and DFT Calculations

Background: Xanthatin, fluoropyrimidine and thienopyrimidine, pyrazolopyrimidine, pyrimidine carboxamides, and SKLB1002 are reported as VEGFR2 tyrosine kinase inhibitors. Recently, many studies related to different heterocycles conjugated with dihydroquinazolinones are known to have very good biological activities. In this study, we are intended to explore the cytotoxic studies of piperidine conjugated dihydroquinazolinones against colorectal/colon cancer cell lines and along with molecular docking studies and DFT calculations. Methods: The colorectal/colon cell lines HCT116 and A549 cell lines were treated with these compounds and cytotoxic activities were evaluated by MTT dye uptake method. We performed molecular modelling for compound 3d using the Auto Dock software. The binding of compound 3d with target proteins was studied with the collection of experimentally determined PDB database. Optimized geometry by DFT calculations was performed with B3LYP/6-31G (d) basis set. Results: Piperidine-conjugated dihydroquinazolinone analogues displayed anticancer activity. Particularly, the compound 3d with electron-withdrawing substituents on a phenyl ring showed significant cytotoxicity against HCT116 and A549 cell lines. Molecular docking studies proved that the compound 3d has good fitting by forming hydrogen bonds with amino acid residues at the active sites of VEGFR2. The HOMO, LUMO, their energies and UV visible spectrum were predicted using DFT calculations. Conclusion: Four piperidine-conjugated dihydroquinazolinones were synthesized and evaluated against colorectal and colon cancer cell lines. Compound 3d significantly inhibited the growth of HCT116 and A549. Molecular docking studies displayed good fitting of compound 3d by forming different H-bonds with the amino acid at the active sites of the VEGFR2 target. Using a theoretical approach, we optimized HOMO and LUMO plots for the compound 3d.

Mild and Efficient Synthesis of Polysubstituted Phthalimides and Piperidines Catalyzed by DABCO

Polysubstituted phthalimide derivatives have been isolated in excellent yield from the addition reaction between acetoacetanilide and dialkyl acetylenedicarboxylates by using DABCO as an efficient basic catalyst in EtOH at room temperature. This procedure led to the formation of new phthalimide derivative in the presence of di-tert-butylacetylendicarboxylate as acetylenic ester. The methodology has also been applied successfully for the synthesis of novel piperidine substitutes via the simple reaction between acetoacetanilide and alkyl propiolates. These reactions have some advantages such as not only the process is eco-friendly but also the yields are good and the work-up is simple.

Multi-component synthesis of piperidines and dihydropyrrol-2-one derivatives catalyzed by a dual-functional ionic liquid

N,N,N’, N’-tetramethyl- N,N’-bis(sulfo)ethane-1,2-diaminium mesylate ([TMBSED][OMs]2) was employed for the synthesis of piperidines and dihydropyrrol-2-ones via one-pot multi-component reactions in simple and green processes. This pseudo five-component reaction of aromatic aldehydes, anilines and alkyl acetoacetates was carried out under reflux conditions in ethanol to afford substituted piperidines. Also, dihydropyrrol-2-one derivatives were synthesized by means of four-component reactions of various amines, dialkyl acetylenedicarboxylates and formaldehyde in ethanol at room temperature. The present approaches have several advantages such as good yields, easy work-ups, short reaction times, and utilize mild and clean reaction conditions.

Cooperative Catalysis for the Asymmetric Synthesis of Piperidines

Key words Diels–Alder reaction - Brønsted acids - Lewis acids - asymmetric catalysis - piperidines

Piperidines decorated by small (cyclo)alkyl substituents (microreview)

The microreview describes recently developed methods for the synthesis of piperidines bearing small (cyclo)alkyl substituent via functionalization of preexisting unsaturated ring system.

An approach to the synthesis of 3-substituted piperidines bearing partially fluorinated alkyl groups

An approach to the synthesis of 3-substituted piperidines bearing partially fluorinated alkyl groups was proposed. The method was based on the DAST-mediated nucleophilic fluorination of easily available 2-bromopyridin-3-yl alcohols and ketones affording 2-bromo-3-(1-fluoroalkyl)pyridines and 2-bromo-3-(1,1-difluoroalkyl)pyridines, respectively, followed by catalytic hydrogenation. The hydrogenation step was studied with common heterogeneous Pd-, Pt-, and Rh-based catalyst. It was found that in the case of fluoroalkyl derivatives, the pyridine core reduction was accompanied by hydrodefluorination, which became a limitation of the strategy. Nevertheless, the method worked well with 1,1-difluoroalkyl derivatives

Tandem N, N-Dialkylation Reaction of N-Trimethylsilyl α-Iminoesters Utilizing an Umpolung Reaction and Characteristics of the Silyl Substituent: Synthesis of Pyrrolidine, Piperidine, and Iminodiacetate.

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. Efficient syntheses of pyrrolidines, piperidines, and iminodiacetate derivatives were also developed via tandem N,N- or N, C-dialkylation reactions utilizing characteristics of the silyl substituent. Furthermore, under the influence of silica gel, the addition of an enolate to the imino nitrogen proceeded to give an iminodiacetate derivative.

Synthesis of Polyfunctionalised 2-Piperidinones Catalysed by Fe(acac)3

Herein is reported the synthesis of polyfunctionalised piperidines and 2-piperidinones, through hydrogen atom transfer (HAT) chemistry catalysed by Fe(acac)3. The nature and substitution around the Michael acceptor, as well as the allylic amine, allowed access to all positions of the piperidine ring. The chemistry tolerates a range of different functionalities, allowing the investigation of new and diverse scaffolds.

Enantioselective Aza-Heck Cyclizations of N-(Tosyloxy)carbamates: Synthesis of Pyrrolidines and Piperidines.

Pd(0)-systems modified with SPINOL-derived phosphoramidate ligands promote highly enantioselective aza-Heck cyclizations of alkenyl N-(tosyloxy)carbamates. The method provides versatile access to challenging N-heterocycles and represents the broadest scope enantioselective aza-Heck protocol developed to date.

Iodine-mediated aminosulfonylation of alkenyl sulfonamides with sulfonyl hydrazides: synthesis of sulfonylmethyl piperidines, pyrrolidines and pyrazolines.

An aminosulfonylation of alkenyl sulfonamides was reported. Using iodine as the catalyst, TBHP as the oxidant, and sulfonyl hydrazides as the sulfonyl radical sources, a variety of sulfonylmethyl piperidines, pyrrolidines and pyrazolines were obtained in moderate to excellent yields.

Pyrrolidines and piperidines bearing chiral tertiary alcohols by nickel-catalyzed enantioselective reductive cyclization of N-alkynones

Pyrrolidines and piperidines are important building blocks in organic synthesis. Numerous methods exist for constructing substituted pyrrolidines and piperidines. However, efficient syntheses of pyrrolidines and piperidines bearing chiral tertiary alcohols are limited. Here we report an efficient enantioselective nickel-catalyzed intramolecular reductive cyclization of N-alkynones. A P-chiral bisphosphorus ligand DI-BIDIME is designed and applied in the synthesis of tertiary allylic siloxanes bearing pyrrolidine and piperidine rings in high yields and excellent enantioselectivities, with triethylsilane as reducing reagent. The highest turn over number achieved is 1000 (0.1 mol% catalyst loading) with > 99:1 er. This reaction provides a practical way to synthesize pyrrolidine and piperidine derivatives with chiral tertiary alcohols from easily accessible starting materials under mild conditions. The products can be scaled up and transformed to various useful chiral intermediates. The P-chiral bisphosphorus ligand developed in this study represents one of the few ligands for highly enantioselective cyclization of alkynones.

Newly designed pyridine and piperidine based Ionic Liquids: Aggregation behavior in ESI-MS and catalytic activity in C[sbnd]C bond formation reactions

Material preparation using Ionic Liquids (ILs) as a catalyst was frequently related to the supramolecular aggregation behavior. Hence, understanding the aggregation behavior of ILs is very significant from basic and applied aspects. The present work suggested an efficient and green protocol for the synthesis of pyridine and piperidine based ILs with different phenoxide as anions. Furthermore, the supramolecular polymeric aggregation due to non-covalent interactions between cations and anions of these ILs were investigated through Electrospray Ionization Mass Spectrometry (ESI-MS). Moreover, assessment of the suitability of these ILs as catalyst has been done in the presence of potassium carbonate for base-catalysed carboncarbon bond formation reactions i.e. case of Knoevenagel and Claisen–Schmidt Condensation. The obtained products were characterized by spectroscopic methods such as 1H NMR, 13C NMR, ESI-MS and UV. The results revealed that the desire products were obtained in excellent yield (up to 98%). Selective ILs which contain electron with drawing group in anions such as m-nitro phenoxide ion, exhibited remarkable catalytic activity in Condensation reaction. In addition to this, ESI-MS of ILs showed that peak distributions prominently exhibited for each aggregate, a decrease in ion abundance occurred.

Stereoselective one-pot synthesis of polycyanosubstituted piperidines

An effective and facile multicomponent method for the synthesis of polysubstituted piperidines is described. The Michael–Mannich type cascade of benzylidenemalononitriles with aromatic aldehydes and ammonium acetate or aqueous ammonia provides convenient access to the stereoselective synthesis of 3,3,5,5-tetracyano-2,4,6-triarylpiperidines in good to excellent yields in one-pot manner. Ammonium acetate or aqueous ammonia plays a role both as a catalyst and as a nitrogen source. It is established that the reaction proceeds via sequence of equilibriums and a competitive mechanisms are implemented.

Synthesis and Kinetics of Highly Substituted Piperidines in the Presence of Tartaric Acid as a Catalyst.

The synthesis of highly substituted piperidine from the one-pot reaction between aromatic aldehydes, anilines and β-ketoesters in the presence of tartaric acid as a catalyst has been investigated in both methanol and ethanol media at ambient temperature. Different conditions of temperature and solvent were employed for calculating the thermodynamic parameters and obtaining an experimental approach to the kinetics and mechanism. Experiments were carried out under different temperature and solvent conditions. Products were characterized by comparison of physical data with authentic samples and spectroscopic data (IR and NMR). Rate constants are presented as an average of several kinetic runs (at least 6-10) and are reproducible within ± 3%. The overall rate of reaction is followed by monitoring the absorbance changes of the products versus time on a Varian (Model Cary Bio- 300) UV-vis spectrophotometer with a 10 mm light-path cell. The best result was achieved in the presence of 0.075 g (0.1 M) of catalyst and 5 mL methanol at ambient temperature. When the reaction was carried out under solvent-free conditions, the product was obtained in a moderate yield (25%). Methanol was optimized as a desirable solvent in the synthesis of piperidine, nevertheless, ethanol in a kinetic investigation had none effect on the enhancement of the reaction rate than methanol. Based on the spectral data, the overall order of the reaction followed the second order kinetics. The results showed that the first step of the reaction mechanism is a rate determining step. The use of tartaric acid has many advantages such as mild reaction conditions, simple and readily available precursors and inexpensive catalyst. The proposed mechanism was confirmed by experimental results and a steady state approximation.

Four-component stereoselective synthesis of tetracyano-substituted piperidines

A novel four-component stereoselective synthesis of polysubstituted piperidines is reported. The Knoevenagel–Michael–Mannich cascade of two equivalents of aromatic aldehydes, formaldehyde, two equivalents of malononitrile and ammonium acetate provides convenient access to the 2,6-diaryl-3,3,5,5-tetracyanopiperidines in good to excellent yields. Ammonium acetate plays a role both as a catalyst and as a nitrogen source. The formation of products is highly stereoselective. Structures of the synthesized compounds were confirmed by 1H NMR, 13C NMR, IR, elemental analysis and mass spectral studies. 2,6-diphenylpiperidine-3,3,5,5-tetracarbonitrile was characterized by X-ray diffraction.

Synthesis of Piperidines via Intramolecular Hydride Transfer from α‐Amino sp3 Carbon Atoms to Ethenetricarboxylate‐Derived Fragments and Further Cyclization

AbstractThe cyclization of amides derived from ethenetricarboxylic acid bearing tert‐amino groups has been examined. The amides were efficiently converted to piperidine derivatives (2‐piperidones) upon heating in a polar solvent (e. g., DMSO or DMF) via intramolecular hydride transfer and subsequent ring closure. The reaction was less efficient in the presence of a Lewis acid. The reactivity varies depending on the alkyl substituents of tert‐amino groups, probably due to steric effects. The hydride transfer/cyclization mechanism was investigated by DFT calculations. The reaction of the carboxylic acid and relatively bulky diamines such as diisopropyl‐substituted diamine in the presence of amide condensation reagents at 60 °C gave the piperidine derivatives in a one‐pot reaction. The reaction of the diisopropylamine substituted piperidine product with primary amines gave secondary amine‐substituted piperidines.

Regio‐, Diastereo‐ and Enantioselective Synthesis of Piperidines with Three Stereogenic Centers from Isoxazolinones by Palladium/Iridium Relay Catalysis

Piperidines are currently the most frequently used heterocycles in the development of new pharmaceuticals. A straightforward efficient stereo‐ and regioselective asymmetric access to chiral polysubstituted piperidines creating multiple stereogenic centers is often still a challenge. Herein we report a rapid approach towards trisubstituted piperidines, which is notable for the use of a readily accessible isoxazolinone starting material and for creating three stereocenters in a single step. 3,4‐Dihydropyridines, which are probably formed by a Pd‐catalyzed cycle via a decarboxylative oxidative addition of the substrates, appear to be useful intermediates in this relay catalysis, in which Ir acts as enantioselective hydrogenation catalyst to form the valuable chiral heterocycles under mild conditions.

Asymmetric Cu-Catalyzed 1,4-Dearomatization of Pyridines and Pyridazines without Preactivation of the Heterocycle or Nucleophile.

We show that a chiral copper hydride (CuH) complex catalyzes C-C bond-forming dearomatization of pyridines and pyridazines at room temperature. The catalytic reaction operates directly on free heterocycles and generates the nucleophiles in situ, eliminating the need for stoichiometric preactivation of either reaction partner; further, it is one of very few methods available for the enantioselective 1,4-dearomatization of heteroarenes. Combining the dearomatization with facile derivatization steps enables one-pot syntheses of enantioenriched pyridines and piperidines.

Vapor-phase synthesis of piperidine over SiO2 catalysts

Vapor phase dehydration of 5-amino-1-pentanol to produce piperidine was investigated over various oxide catalysts such as ZrO2, TiO2, Al2O3 and SiO2. Among the tested catalysts, SiO2 selectively produced piperidine at 300 °C. A high 5-amino-1-pentanol conversion of 99.9% with a piperidine selectivity of 94.8% was achieved over weak acidic SiO2. In an experiment using isotope such as deuterated water, surface hydroxy groups of SiO2 are concluded to be the active centers.

Enantioselective Synthesis of α-(Hetero)aryl Piperidines through Asymmetric Hydrogenation of Pyridinium Salts and Its Mechanistic Insights.

Enantioselective synthesis of α-aryl and α-heteroaryl piperidines is reported. The key step is an iridium-catalyzed asymmetric hydrogenation of substituted N-benzylpyridinium salts. High levels of enantioselectivity up to 99.3:0.7 er were obtained for a range of α-heteroaryl piperidines. DFT calculations support an outersphere dissociative mechanism for the pyridinium reduction. Notably, initial protonation of the final enamine intermediate determines the stereochemical outcome of the transformation rather than hydride reduction of the resultant iminium intermediate.