Synthesis Of Piperidines Research Articles

N-acyl-4-arylaminopiperidines: Design and synthesis of a potential antimicrobial scaffold

We report a concise synthesis of N-acylated piperidines through a Knoevenagel-Doebner condensation/amide construction/ amination sequence. The design of the piperidines considered the pharmacophoric features found in previously reported inhibitors of FabI, an enzyme implicated in bacterial fatty acid biosynthesis. After the microbiological evaluation at 50 μM, the analogs displayed moderate activity against some pathogens from the ESKAPE group, reaching up to 42 % of growth inhibition for MRSA, 54 % for K. pneumoniae, and 37 % for P. aeruginosa (multiresistant strains). Docking studies demonstrate that almost all of them docked satisfactorily into the catalytic domain of S. aureus FabI, maintaining a similar pose as other reported inhibitors. The results shown herein propose the N-acyl-4-arylaminopiperidines as the basis for the development of more active candidates.

Regio- and Diastereoselective Synthesis of Polysubstituted Piperidines Enabled by Boronyl Radical-Catalyzed (4+2) Cycloaddition.

Piperidines are widely present in small molecule drugs and natural products. Despite many methods have been developed for their synthesis, new approaches to polysubstituted piperidines are highly desirable. This work presents a radical (4+2) cycloaddition reaction for synthesis of piperidines featuring dense substituents at 3,4,5-positions that are not readily accessible by known methods. Using commercially available diboron(4) compounds and 4-phenylpyridine as the catalyst precursors, the boronyl radical-catalyzed cycloaddition between 3-aroyl azetidines and various alkenes, including previously unreactive 1,2-di-, tri-, and tetrasubstituted alkenes, has delivered the polysubstituted piperidines in generally high yield and diastereoselectivity. The reaction also features high modularity, atom economy, broad substrate scope, metal-free conditions, simple catalysts and operation. The utilization of the products has been demonstrated by selective transformations. A plausible mechanism, with the ring-opening of azetidine as the rate-limiting step, has been proposed based on the experimental and computational results.

Regio‐ and Diastereoselective Synthesis of Polysubstituted Piperidines Enabled by Boronyl Radical‐Catalyzed (4+2) Cycloaddition

AbstractPiperidines are widely present in small molecule drugs and natural products. Despite many methods have been developed for their synthesis, new approaches to polysubstituted piperidines are highly desirable. This work presents a radical (4+2) cycloaddition reaction for synthesis of piperidines featuring dense substituents at 3,4,5‐positions that are not readily accessible by known methods. Using commercially available diboron(4) compounds and 4‐phenylpyridine as the catalyst precursors, the boronyl radical‐catalyzed cycloaddition between 3‐aroyl azetidines and various alkenes, including previously unreactive 1,2‐di‐, tri‐, and tetrasubstituted alkenes, has delivered the polysubstituted piperidines in generally high yield and diastereoselectivity. The reaction also features high modularity, atom economy, broad substrate scope, metal‐free conditions, simple catalysts and operation. The utilization of the products has been demonstrated by selective transformations. A plausible mechanism, with the ring‐opening of azetidine as the rate‐limiting step, has been proposed based on the experimental and computational results.

Catalytic enantioselective intramolecular hydroamination of alkenes using chiral aprotic cyclic urea ligand on manganese (II)

Asymmetric catalysis for enantioselective intramolecular hydroamination of alkenes is a critical method in the construction of enantioenriched nitrogen-containing rings, often prevalent in biologically active compounds and natural products. Herein, we demonstrate a facile enantioselective intramolecular hydroamination of alkenes for the synthesis of chiral pyrrolidine, piperidine, and indoline moieties, using a manganese (II) chiral aprotic cyclic urea catalyst. The cyclic ligand hinders the inversion of the N atom of the urea and effectively discriminate between the enantiomers of substrates. High-resolution mass spectrometry, deuterium labeling experiments, and molecular orbital energy analysis clearly reveal the intermediates and mechanism of the transformation. As a key step, oxygen coordination by chiral aprotic urea presents a robust control over the asymmetric intra-HA reaction through the involvement of a convergent assembly of two vital intermediates (Mn-N and C-Mn-Br), providing access to chiral cyclic amine systems in high yields with excellent enantioselectivity.

Nickel-catalyzed switchable arylative/endo-cyclization of 1,6-enynes

Carbo- and heterocycles are frequently used as crucial scaffolds in natural products, fine chemicals, and biologically and pharmaceutically active compounds. Transition-metal-catalyzed cyclization of 1,6-enynes has emerged as a powerful strategy for constructing functionalized carbo- and heterocycles. Despite significant progress, the regioselectivity of alkyne functionalization is entirely substrate-dependent. And only exo-cyclization/cross-coupling products can be obtained, while endo-selective cyclization/cross-coupling remains elusive and still poses a formidable challenge. In this study, we disclose a nickel-catalyzed switchable arylation/cyclization of 1,6-enynes in which the nature of the ligand dictates the regioselectivity of alkyne arylation, while the electrophilic trapping reagents determine the selectivity of the cyclization mode. Specifically, using a commercially available 1,10-phenanthroline as a ligand facilitates trans-arylation/cyclization to obtain seven-membered ring products, while a 2-naphthyl-substituted bisbox ligand promotes cis-arylation/cyclization to access six-membered ring products. Diastereoselective cyclizations have also been developed for the synthesis of enantioenriched piperidines and azepanes, which are core structural elements of pharmaceuticals and natural products possessing important biological activities. Furthermore, experimental and density functional theory studies reveal that the regioselectivity of the alkyne arylation process is entirely controlled by the steric hindrance of the ligand; the reaction mechanism involves exo-cyclization followed by Dowd-Beckwith-type ring expansion to form endo-cyclization products.

Synthesis of piperidines and pyridine from furfural over a surface single-atom alloy Ru1CoNP catalyst

The sustainable production of value-added N-heterocycles from available biomass allows to reduce the reliance on fossil resources and creates possibilities for economically and ecologically improved synthesis of fine and bulk chemicals. Herein, we present a unique Ru1CoNP/HAP surface single-atom alloy (SSAA) catalyst, which enables a new type of transformation from the bio-based platform chemical furfural to give N-heterocyclic piperidine. In the presence of NH3 and H2, the desired product is formed under mild conditions with a yield up to 93%. Kinetic studies show that the formation of piperidine proceeds via a series of reaction steps. Initially, in this cascade process, furfural amination to furfurylamine takes place, followed by hydrogenation to tetrahydrofurfurylamine (THFAM) and then ring rearrangement to piperidine. DFT calculations suggest that the Ru1CoNP SSAA structure facilitates the direct ring opening of THFAM resulting in 5-amino-1-pentanol which is quickly converted to piperidine. The value of the presented catalytic strategy is highlighted by the synthesis of an actual drug, alkylated piperidines, and pyridine.

Catalytic enantioselective reductive alkynylation of amides enables one-pot syntheses of pyrrolidine, piperidine and indolizidine alkaloids

The primary objective in synthetic organic chemistry is to develop highly efficient, selective, and versatile synthetic methodologies, which are essential for discovering new drug candidates and agrochemicals. In this study, we present a unified strategy for a one-pot, catalytic enantioselective synthesis of α-alkyl and α,α′-dialkyl pyrrolidine, piperidine, and indolizidine alkaloids using readily available amides and alkynes. This synthesis is enabled by the identification and development of an Ir/Cu/N-PINAP catalyzed highly enantioselective and chemoselective reductive alkynylation of α-unbranched aliphatic amides, which serves as the key reaction. This reaction is combined with Pd-catalyzed tandem reactions in a one-pot approach, enabling the collective, catalytic enantioselective total syntheses of eight alkaloids and an anticancer antipode with 90–98% ee. The methodology’s enantio-divergence is exemplified by the one-step access to either enantiomer of alkaloid bgugaine.

Chiral Aminoalcohol-Derived δ-Lactams Provide Easy Access to Piperidines and Acyclic Five-Carbon Building Blocks Bearing a Tertiary and a Quaternary Stereocenter.

A procedure for the synthesis of enantiopure piperidines and acyclic building blocks (5-aminopentanols, O-protected 5-hydroxypentanenitriles) containing a tertiary and a quaternary stereocenter has been developed. Starting from a phenylglycinol- or aminoindanol-derived δ-lactam bearing an alkyl substituent at the α-position of the N,O-acetal carbon, easily accessible by a cyclocondensation reaction, the stereoselective dialkylation at the carbonyl α-position generates the quaternary stereocenter and the subsequent two-step reductive removal of the chiral inductor provides enantiopure 3,3,5-trisubstituted piperidines. Alternatively, the simultaneous reductive opening of the oxazolidine and piperidone rings of the dialkylated lactams followed by reductive or oxidative cleavage of the chiral inductor opens access to chiral 2,2,4-trisubstituted 5-amino-1-pentanols or 2,4,4-trisubstituted 5-hydroxypentanenitriles.

An Asymmetric Hydrogenation/N-Alkylation Sequence for a Step-Economical Route to Indolizidines and Quinolizidines.

The direct catalytic asymmetric hydrogenation of pyridines for the synthesis of piperidines remains a challenge. Herein, we report a one-pot asymmetric hydrogenation of pyridines with subsequent N-alkylation using a traceless Brønsted acid activation strategy. Catalyzed by the iridium-BINAP complex, the substrates undergo ketone reduction, cyclization and pyridine hydrogenation in sequence to form indolizidines and quinolizidines. The absolute configuration ofthe chiral center of the alcohol is retained and influences the formation of the second chiral center. The experimental and theoretical mechanistic studies reveal that the chloride anion and certain noncovalent interactions govern the stereoselectivity of the cascade reaction throughout the catalytic process.

An Asymmetric Hydrogenation/N‐Alkylation Sequence for a Step‐Economical Route to Indolizidines and Quinolizidines

AbstractThe direct catalytic asymmetric hydrogenation of pyridines for the synthesis of piperidines remains a challenge. Herein, we report a one‐pot asymmetric hydrogenation of pyridines with subsequent N‐alkylation using a traceless Brønsted acid activation strategy. Catalyzed by an iridium‐BINAP complex, the substrates undergo ketone reduction, cyclization and pyridine hydrogenation in sequence to form indolizidines and quinolizidines. The absolute configuration of the stereocenter of the alcohol is retained and influences the formation of the second stereocenter. Experimental and theoretical mechanistic studies reveal that the chloride anion and certain noncovalent interactions govern the stereoselectivity of the cascade reaction throughout the catalytic process.

A Photoinduced Palladium-Catalyzed Cascade Reaction for the Synthesis of Chiral Piperidines with Chiral Amino Acid Derivatives and 1,3-Dienes

AbstractA photoinduced palladium-catalyzed cascade reaction involving remote C(sp3)–H functionalization and intramolecular Tsuji–Trost annulation is developed. The reaction is proposed to proceed through a sequence involving the amidyl radical generation, 1,5-HAT-mediated alkyl radical formation, and subsequent difunctionalization of 1,3-dienes. Without the use of exogeneous photosensitizers and external oxidants, the reaction provided an efficient approach to multi-substituted chiral piperidines in high yields, employing readily available chiral amino acid derivatives and 1,3-dienes as the substrates. In most cases, the syn/anti ratio of the product could be further improved by treatment with catalytic amount of iron salt.

Total Synthesis of Pyrrolidine and Piperidine Natural Products via TMSOTf-Mediated "5/6-endo-dig" Reductive Hydroamination of Enynyl Amines.

Stereoselective syntheses of pyrrolidines and piperidines bearing hydrophobic chains have been achieved through a metal free, Lewis acid-mediated 5/6-endo-dig reductive hydroamination cascade of enynyl amines. The brevity of the developed strategy allowed for the collective stereoselective total synthesis of various alkaloids, including (±)-pyrrolidine cis-225H, (±)-epi-197B, (±)-epi-225C, the family of (+)-solenopsins and (+)-isosolenopsins, and the formal synthesis of (±)-bgugaine and (+)-azimic acid.

Isolable iminium ions as a platform for N-(hetero)aryl piperidine synthesis

Isolable iminium ions as a platform for N-(hetero)aryl piperidine synthesis

Catalyst-Controlled Enantioselective and Regiodivergent Addition of Aryl Boron Nucleophiles to N-Alkyl Nicotinate Salts.

Dihydropyridines are versatile building blocks for the synthesis of pyridines, tetrahydropyridines, and piperidines. Addition of nucleophiles to activated pyridinium salts allows synthesis of 1,2-, 1,4-, or 1,6-dihydropyridines; however, this process often leads to a mixture of constitutional isomers. Catalyst-controlled regioselective addition of nucleophiles to pyridiniums has the potential to solve this problem. Herein, we report that the regioselective addition of boron-based nucleophiles to pyridinium salts can be accomplished by the choice of a Rh catalyst.

Front Cover Picture: Asymmetric Synthesis of Trisubstituted Piperidines via Biocatalytic Transamination and Diastereoselective Enamine or Imine Reduction (Adv. Synth. Catal. 13/2023)

The front cover picture shows the assembly of a trisubstituted piperidine derivative through the controlled formation of C−N and C−H bonds. Different stereoselective synthetic tools – namely transaminase and IRED enzymes, and platinum(0)-catalysed flow hydrogenation – are combined to obtain the target N-heterocycles from achiral, open-chain precursors with excellent enantio- and diastereocontrol. The cover design is by Verena Resch and used with her permission. Details can be found in the Research Article by Joerg Schrittwieser and co-workers (P. Petermeier, C. Kohlfuerst, A. Torvisco, R. C. Fischer, A. Mata, D. Dallinger, C. O. Kappe, J. H. Schrittwieser, W. Kroutil, Adv. Synth. Catal. 2023, 365, XXXX–XXXX; DOI: 10.1002/adsc.202300050)

Enantio-Complementary Synthesis of 2-Substituted Pyrrolidines and Piperidines via Transaminase-Triggered Cyclizations.

Chiral N-heterocycles are a common motif in many active pharmaceutical ingredients; however, their synthesis often relies on the use of heavy metals. In recent years, several biocatalytic approaches have emerged to reach enantiopurity. Here, we describe the asymmetric synthesis of 2-substituted pyrrolidines and piperidines, starting from commercially available ω-chloroketones by using transaminases, which has not yet been comprehensively studied. Analytical yields of up to 90% and enantiomeric excesses of up to >99.5% for each enantiomer were achieved, which has not previously been shown for bulky substituents. This biocatalytic approach was applied to synthesize (R)-2-(p-chlorophenyl)pyrrolidine on a 300 mg scale, affording 84% isolated yield, with >99.5% ee.

Asymmetric Synthesis of Trisubstituted Piperidines via Biocatalytic Transamination and Diastereoselective Enamine or Imine Reduction

AbstractSubstituted piperidine rings are a common motif in natural products and pharmaceutical drugs. The asymmetric synthesis of piperidines bearing multiple stereocentres remains a challenge, and current approaches often rely on lengthy reaction sequences and ‘chiral pool’ strategies. Herein, we report multi‐enzymatic and chemo‐enzymatic methods that allow the preparation of piperidines with three chirality centres in only two steps from achiral diketoester precursors. Stereocontrol is achieved by a highly enantioselective transamination leading to optically pure (ee >99%) enamine or imine intermediates, followed by diastereoselective reduction of these unsaturated N‐heterocycles using either platinum(0)‐catalysed flow hydrogenation or enzymatic imine reduction. In the latter case, coupling of the two biocatalytic reactions in a concurrent one‐pot process is possible, thus reducing the synthetic sequence to a single biotransformation. In total, nine trisubstituted piperidines were prepared in high stereoisomeric purities (dr ≥98:2) and isolated yields of up to 73%. Lead‐likeness analysis of five representative products using an open‐source webtool suggests that these compounds possess considerable application potential as building blocks in drug discovery.

Asymmetric Reductive Transamination for the Synthesis of Chiral Piperidines

Key words transfer hydrogenation - asymmetric synthesis - piperidines - amination

Tunable [3+2] and [4+2] annulations for pyrrolidine and piperidine synthesis.

N-heterocycles are privileged pharmaceutical scaffolds in drug discovery and development. We disclose here divergent intermolecular coupling strategies that can access diverse N-heterocycles directly from olefins. The radical-to-polar mechanistic switching is key for the divergent cyclization processes. These distinctive annulations result in the coupling of alkenes with simple bifunctional reagents for divergent N-heterocycle syntheses.

Photocatalytic synthesis of azaheterocycle-fused piperidines and pyrrolidines via tandem difunctionalization of unactivated alkenes.

A variety of azaheterocycle-fused piperidines and pyrrolidines bearing CF3 and CHF2 functionalities were obtained using CF3SO2Na and CHF2SO2Na by visible light photocatalysis. This protocol involves a radical cascade cyclization via tandem tri- and difluoromethylation-arylation of pendent unactivated alkenes. Benzimidazole, imidazole, theophylline, purine, and indole serve as applicable anchors, thereby enriching the structural diversity of piperidine and pyrrolidine derivatives. This method features mild, additive-free and transition metal-free conditions.