2-substituted Piperidines Research Articles

Preparation and Suzuki—Miyaura Coupling Reactions of Tetrahydropyridine‐2‐boronic Acid Pinacol Esters.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Catalytic Asymmetric Hydrogenation of N‐Iminopyridinium Ylides: Expedient Approach to Enantioenriched Substituted Piperidine Derivatives.

We have developed an efficient catalytic enantioselective hydrogenation of pyridine derivatives. Enhanced reactivity was possible by an optimization of the electronic properties of the catalyst through ligand modification. This methodology shows the particular reactivity of N-iminopyridinium ylides that provides access to substituted piperidines in good enantiomeric excesses.

Preparation and Suzuki−Miyaura Coupling Reactions of Tetrahydropyridine-2-boronic Acid Pinacol Esters

[reaction: see text] A study on the conversion of lactam-derived vinyl triflates and phosphates into the corresponding vinyl boronates was carried out. While delta-valerolactam-derived vinyl triflates were successfully converted into 1,4,5,6-tetrahydropyridine-2-boronic acid pinacol ester derivatives by Pd-catalyzed coupling reaction with both bis(pinacolato)diboron and pinacolborane, pyrrolidinone and epsilon-caprolactam derivatives either did not react or were readily reduced. The delta-valerolactam-derived vinyl boronates are thermally stable compounds that efficiently coupled, under Pd catalysis, with structurally diverse aryl and heteroaryl bromides and triflates, vinyl iodides and bromides, and aromatic acid chlorides, to give the corresponding 2-substituted piperidines in good to excellent yields. The number of electrophiles that can virtually be coupled with these new boronic esters makes them very useful reagents for the synthesis of N-heterocyclic compounds.

Stereoselective synthesis of optically active 2-alkylpiperidines utilizing electrochemical oxidation as a key step

Efficient asymmetric carbon–carbon bond-forming reaction at the 2-position of a piperidine skeleton was achieved through scrutinizing chiral catalysts, copper ions, nucleophiles, and reaction temperatures. The key intermediates in this method were 2-methoxy-3,4-didehydropiperidines, which were easily prepared by electrochemical oxidation of 1-protected piperidines in methanol followed by didehydrogenation of the oxidation products. This method involved a chiral Cu(II) catalyzed coupling reaction between 1-(4-methoxybenzoyl)-3,4-didehydro-2-methoxypiperidine and nucleophiles such as dimethyl malonate and methyl acetoacetate to afford 2-substituted piperidines with up to 82%e.e. (e.e., enantiomeric excess).

A novel class of sodium/calcium exchanger inhibitor: design, synthesis, and structure–activity relationships of 3,4-dihydro-2(1H)-quinazolinone derivatives

Design, synthesis, and structure–activity relationships of 3,4-dihydro-2(1H)-quinazolinone derivatives as inhibitors of the sodium/calcium (Na+/Ca2+) exchanger are discussed. These studies, based on a lead compound 9a, which was identified in our library, involved systematic modification of three regions and revealed that (1) the 3,4-dihydro-2(1H)-quinazolinone having a tertiary amino alkyl side chain at the 3-position is essential for activity, (2) a nonsubstituted phenyl ring is most suitable for high activity, and (3) introduction of a 4-substituted piperidine moiety enhanced the activity, in particular 4-benzylpiperidin-1-yl showed strong inhibitory activity. Based on these SAR studies, a structurally novel and highly potent inhibitor against the Na+/Ca2+ exchanger, 12g (SM-15811), was discovered. In particular, SM-15811 directly inhibited the Na+-dependent Ca2+ influx via the Na+/Ca2+ exchanger in cardiomyocytes with a high potency. The activity was almost two orders more potent than the lead compound 9a and SM-15811 exerted a protective effect against myocardial ischemic reperfusion injury. These Na+/Ca2+ inhibitors could have a therapeutic potential for the treatment of ischemic reperfusion injury.

A Lactam‐Derived Vinyl Boronate as a Stable and Crystalline Reagent for the Synthesis of 2‐Substituted Piperidines by Pd‐Catalyzed Coupling Reactions.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A lactam-derived vinyl boronate as a stable and crystalline reagent for the synthesis of 2-substituted piperidines by Pd-catalyzed coupling reactions

A δ-valerolactam-derived vinyl triflate has been converted into the corresponding vinyl boronate by Pd-catalyzed coupling with bis(pinacolato)diboron, which results in an umpolung. This boronate efficiently couples under Pd catalysis with aryl and heteroaryl bromides to give the corresponding 2-substituted piperidines in excellent yields.

New piperidine scaffolds via nucleophilic reactivity of (-)-phenyloxazolopiperidine.

The present work illustrates the power of compound 2 as a chiral, nonracemic, and stable 2-piperideine (enamine) equivalent in the rapid and efficient construction of 3-substituted piperidines (carbon-carbon and carbon-sulfur bonds) such as 3-spiropiperidines. This methodology offers a new route to such systems that could compete with previously reported strategies.

Synthesis of Alkaloids from Aminol Derivatives by β‐Fragmentation of Primary Alkoxyl Radicals.

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Zirconium‐Mediated Coupling Reactions of Amines and Enol or Allyl Ethers: Synthesis of Allyl‐ and Homoallylamines.

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Efficient Solution‐Phase Parallel Synthesis of 4‐Substituted N‐Protected Piperidines.

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Synthesis of alkaloids from aminol derivatives by β-fragmentation of primary alkoxyl radicals

The fragmentation of primary alkoxyl radicals, often described as low yielding and plagued by side reactions, proceeded in good to excellent yields when aminol derivatives were used as substrates. Remarkably, no side reactions such as hydrogen abstraction or oxidation were observed. The fragmentation can be coupled with an alkylation reaction to give 2-substituted pyrrolidine and piperidine rings such as alkaloid analogues and functionalized, chiral nitrogen heterocycles.

Asymmetric synthesis and applications of beta-amino Weinreb amides: asymmetric synthesis of (S)-coniine.

Conjugate addition of lithium (S)-N-benzyl-N-alpha-methylbenzylamide to a range of alpha, beta-unsaturated Weinreb amides proceeds with high levels of diastereoselectivity (>95% de). The beta-amino Weinreb amide products may be transformed into beta-amino ketones via reactions with Grignard reagents, while treatment with DIBAL-H furnishes beta-amino aldehydes. Trapping of the aldehyde via Wadsworth-Emmons reaction and subsequent manipulation offers an efficient route to homochiral delta-amino acid derivatives and 2-substituted piperidines. The application of this methodology for the synthesis of (S)-coniine is demonstrated.

Zirconium-mediated coupling reactions of amines and enol or allyl ethers: synthesis of allyl- and homoallylamines.

An easy and efficient zirconium-mediated synthesis of allylamines from simple amines and enol ethers is described. This strategy also allows the synthesis of amino alcohol derivatives containing a Z double bond in their structure when 2,3-dihydrofuran is used. Simple conventional modification of these amino alcohols leads to 2-substituted piperidine derivatives. By applying this approach, a formal total synthesis of the alkaloid coniine is easily achieved from a protected butylamine. Finally, the zirconium-mediated reaction of amines and allyl phenyl ether furnishes homoallylamines or amino ethers depending on the structure of the starting amine.

Development of a [3 + 3] Cycloaddition Strategy Toward Functionalized Piperidines.

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A Facile Synthesis of Racemic 2‐Aminomethyl‐4‐oxo‐piperidine Intermediates.

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Development of a [3+3] cycloaddition strategy toward functionalized piperidines.

This paper describes a novel route to functionalized piperidines via a formal [3+3] cycloaddition reaction of activated aziridines and palladium-trimethylenemethane (Pd-TMM) complexes. The cycloaddition reaction generally proceeds enantiospecifically with ring opening at the least hindered site of the aziridine. Therefore, readily available enantiomerically pure 2-substituted aziridines can be utilized to prepare enantiomerically pure 2-substituted piperidines in good to excellent yield. The N-substituent on the aziridine proved to be crucial to the success of this reaction with only 4-toluenesulfonyl (Ts) and 4-methoxybenzenesulfonyl (PMBS) aziridines permitting smooth cycloaddition to take place. Additionally, spirocyclic aziridines have been found to participate in the [3+3] cycloaddition reaction, whereas 2,3-disubstituted aziridines can be applied to provide fused bicyclic piperidines, albeit in low yield.

Synthesis of trans‐(3S)‐Amino‐(4R)‐alkyl‐ and ‐(4S)‐aryl‐piperidines via Ring‐Closing Metathesis Reaction.

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Asymmetric Carbon—Carbon Bond Formations in Conjugate Additions of Lithiated N‐Boc Allylic and Benzylic Amines to Nitroalkenes: Enantioselective Synthesis of Substituted Piperidines, Pyrrolidines, and Pyrimidinones.

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A Facile Synthesis of Racemic 2-Aminomethyl-4-oxo-piperidine Intermediates

Facile access to the 2-substituted piperidine nucleus was achieved by a 3-component hetero Diels-Alder reaction. The use of an appropriately functionalized imine allowed the installation of a protecting group for both the piperidine and 2-position side chain nitrogens in one step. Also, by employing 2-trimethylsiloxy-1,3-butadiene, a reduction step was avoided, thus providing rapid entry into the piperidine core structure. This protocol led to the synthesis of some racemic 2-aminomethyl-4-oxo-piperidines; intermediates that were synthesized in multigram quantities.