Synthesis Of Piperidines Research Articles

Benzylamines via Iron-Catalyzed Direct Amination of Benzyl Alcohols

Benzylamines play a prominent role in numerous pharmaceutically active compounds. Thus, the development of novel, sustainable catalytic methodologies to provide access to these privileged structural motifs is of central importance. Herein we describe a systematic study for the construction of a large variety of benzylamines using a well-defined homogeneous iron complex. The methodology consists of the direct coupling of readily available benzyl alcohols with simpler amines through the borrowing hydrogen methodology, producing a variety of substituted secondary and tertiary benzylamines in moderate to excellent yields for the first time with an iron catalyst. Notably, we explore the versatility of this methodology in the one-pot synthesis of nonsymmetric tertiary amines, sequential functionalization of diols with distinctly different amines, and the synthesis of N-benzyl piperidines via various synthetic pathways. In addition, direct conversion of the renewable building block 2,5-furan-dimethanol to pharma...

Bis-amino methylation for the synthesis of spiro-fused piperidines using iron(III) trifluroacetate in aqueous micellar medium

An environmentally benign, multicomponent integrated chemical process has been developed for the synthesis of 3,5-dispirosubstituted piperidines by cyclo-condensation reaction of amines, formaldehyde, and dimedone using iron(III) trifluroacetate [Fe(F3CCO2)3] Lewis acid in aqueous micellar medium at ambient temperature (25–30 °C). The heterogeneous solid acid catalyst conveniently promotes this double amino methylation reaction in which six molecules condense in one pot to form six new covalent bonds. The synthesized 3,5-dispirosubstituted piperidines have been screened for their in vitro antibacterial activity using agar well method. Many of these compounds showed satisfactory antibacterial activity as compared to standard drugs against all the bacteria tested.

Gold(I)/(III)-catalyzed synthesis of 2-substituted piperidines; valency-controlled cyclization modes

Strategic use of hard gold(III) and soft gold(I) catalysts provides facile access to two types of 2-substituted piperidines from propargylic alcohols. Thus, heating propargylic alcohols in the presence of AuBr3 results in cyclization to furnish piperidines having an acetylenic moiety, due to activation of the propargylic hydroxyl group by coordination of gold(III). On the other hand, the catalyst [Ph3PAuNTf2]2PhMe induces Meyer–Schuster rearrangement of propargylic alcohols to give α,β-unsaturated ketones, which undergo intramolecular aza-Michael addition to afford piperidines bearing a carbonyl group, due to activation of the triple bond by coordination of gold(I).

Synthesis and pharmacological evaluation of piperidine (piperazine)-substituted benzoxazole derivatives as multi-target antipsychotics.

The present study describes the optimization of a series of novel benzoxazole-piperidine (piperazine) derivatives combining high dopamine D2 and serotonin 5-HT1A, 5-HT2A receptor affinities. Of these derivatives, the pharmacological features of compound 29 exhibited high affinities for the DA D2, 5-HT1A and 5-HT2A receptors, but low affinities for the 5-HT2C and histamine H1 receptors and human ether-a-go-go-related gene (hERG) channels. Furthermore, compound 29 reduced apomorphine-induced climbing and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head twitching without observable catalepsy, even at the highest dose tested. Thus, compound 29 is a promising candidate as a multi-target antipsychotic treatment.

ChemInform Abstract: New Building Blocks for Iminosugars: A Concise Synthesis of Polyhydroxylated N‐Alkoxypiperidines Through an Intramolecular Azepine Ring Contraction.

Polyhydroxylated piperidines are a functionally rich class of biologically active molecules that have broad therapeutic potential. Recently developed aza-[4 + 3] cycloadditions of putative aza-oxyallylic cations provide heterocyclic scaffolds that enabled a concise synthesis of polyhydoxylated piperidines. Chemoselective amide reduction and reductive hemiaminal ring opening was achieved in one pot by the action of aluminium hydride generated in situ via aluminium chloride and lithium aluminium hydride. Aziridinium ion mediated ring contraction and chloride displacement was triggered by silver acetate, followed by simple acetate hydrolysis using potassium carbonate to give four tetrahydropyridine diols. Olefin oxidation by osmium tetroxide installed the final hydroxyl groups, which yielded four novel polyhydroxylated N-alkoxypiperidines in good overall yield and high diastereoselectivity.

ChemInform Abstract: Zn‐Catalyzed Enantio‐ and Diastereoselective Formal [4 + 2] Cycloaddition Involving Two Electron‐Deficient Partners: Asymmetric Synthesis of Piperidines from 1‐Azadienes and Nitro‐Alkenes.

AbstractThe novel bisoxazoline diphenylamine ligand (OXA) provides high reactivity and enantioselectivity in the title process, which is proposed to proceed in a stepwise manner via Michael‐type addition of the imine to the nitroalkane followed by cyclization.

ChemInform Abstract: Generation and Regioselective Trapping of a 3,4‐Piperidyne for the Synthesis of Functionalized Heterocycles.

We report the generation of the first 3,4-piperidyne and its use as a building block for the synthesis of annulated piperidines. Experimental and computational studies of this intermediate are disclosed, along with comparisons to the well-known 3,4-pyridyne. The distortion/interaction model is used to explain the observed regioselectivities.

Catalytic Enantioselective Piperidine Synthesis by [4+2] Cyclization

Catalytic Enantioselective Piperidine Synthesis by [4+2] Cyclization

Zn-catalyzed enantio- and diastereoselective formal [4 + 2] cycloaddition involving two electron-deficient partners: asymmetric synthesis of piperidines from 1-azadienes and nitro-alkenes.

We report a catalytic asymmetric synthesis of piperidines through [4 + 2] cycloaddition of 1-azadienes and nitro-alkenes. The reaction uses earth abundant Zn as catalyst and is highly diastereo- and regioselective. A novel BOPA ligand (F-BOPA) confers high reactivity and enantioselectivity in the process. The presence of ortho substitution on the arenes adjacent to the bis(oxazolines) was found to be particularly impactful, due to limiting the undesired coordination of 1-azadiene to the Lewis acid and thus allowing the reaction to be carried out at lower temperature. A series of secondary kinetic isotope effect studies using a range of ligands implicates a stepwise mechanism for the transformation, involving an initial Michael-type addition of the imine to the nitro-alkene followed by a cyclization event. The stepwise mechanism obviates the electronic requirement inherent to a concerted mechanism, explaining the successful cycloaddition between two electron-deficient partners.

Synthesis of Polyhydroxylated Piperidine and Pyrrolidine Peptidomimetics via One-Pot Sequential Lactam Reduction/Joullié–Ugi Reaction

A direct approach to the synthesis of polyhydroxylated piperidine and pyrrolidine peptidomimetics is described. The presented strategy is based on one-pot reduction of sugar-derived lactams with Schwartz's reagent followed by a multicomponent Ugi-Joullié reaction.

Generation and regioselective trapping of a 3,4-piperidyne for the synthesis of functionalized heterocycles.

We report the generation of the first 3,4-piperidyne and its use as a building block for the synthesis of annulated piperidines. Experimental and computational studies of this intermediate are disclosed, along with comparisons to the well-known 3,4-pyridyne. The distortion/interaction model is used to explain the observed regioselectivities.

Proline catalyzed, one-pot three component Mannich reaction and sequential cyclization toward the synthesis of 2-substituted piperidine and pyrrolidine alkaloids

A very effective one-pot three component reaction of 4-bromobutanal or 5-bromopentanal, acetone, and p-anisidine catalyzed by proline is reported. A three component Mannich reaction followed by cyclization leading to the synthesis of 2-substituted pyrrolidine and piperidine derivatives through simultaneous formation of two C–N and one C–C bond is reported. The usefulness of the reaction is demonstrated by the synthesis of (±)coniine, (±)pelletrine, (±)sedridine, and (±)allosedridine.

ChemInform Abstract: Enantioselective Synthesis of Piperidines Through the Formation of Chiral Mixed Phosphoric Acid Acetals: Experimental and Theoretical Studies.

AbstractA highly enantioselective intramolecular cyclization of unsaturated acetals (I) and (III) is utilized for the synthesis of chiral piperidines (II) and (IV), respectively.

Synthesis and biological evaluation of spirocyclic antagonists of CCR2 (chemokine CC receptor subtype 2)

Activation of chemokine CC receptors subtype 2 (CCR2) plays an important role in chronic inflammatory processes such as atherosclerosis, multiple sclerosis and rheumatoid arthritis. A diverse set of spirocyclic butanamides 4 (N-benzyl-4-(3,4-dihydrospiro[[2]benzopyran-1,4′-piperidin]-1′-yl)butanamides) was prepared by different combination of spirocyclic piperidines 8 (3,4-dihydrospiro[[2]benzopyran-1,4′-piperidines]) and γ-halobutanamides 11. A key step in the synthesis of spirocyclic piperidines 8 was an Oxa-Pictet–Spengler reaction of β-phenylethanols 5 with piperidone acetal 6. The substituted γ-hydroxybutanamides 11c–e were prepared by hydroxyethylation of methyl acetates 13 with ethylene sulfate giving the γ-lactones 14c and 14e. Aminolysis of the γ-lactones 14c and 14e with benzylamines provided the γ-hydroxybutanamides 15c–e, which were converted into the bromides 11c–e by an Appel reaction using polymer-bound PPh3. In radioligand binding assays the spirocyclic butanamides 4 did not displace the iodinated radioligand 125I-CCL2 from the human CCR2. However, in the Ca2+-flux assay using human CCR2 strong antagonistic activity of butanamides 4 was detected. Analysis of the IC50-values led to clear relationships between the structure and the inhibition of the Ca2+-flux. 4g (4-(3,4-dihydrospiro[[2]benzopyran-1,4′-piperidin]-1′-yl)-N-[3,5-bis(trifluoromethylbenzyl)]-2-(4-fluorophenyl)butanamide) and 4o (N-[3,5-bis(trifluoromethyl)benzyl]-2-cyclopropyl-4-(3,4-dihydrospiro[[2]benzopyran-1,4′-piperidin]-1′-yl)butanamide) represent the most potent CCR2 antagonists with IC50-values of 89 and 17nM, respectively. Micromolar activities were found in the β-arrestin recruitment assay with murine CCR2, but the structure–activity-relationships detected in the Ca2+-flux assay were confirmed.

ChemInform Abstract: Selective Synthesis of Functionalized Trifluoromethylated Pyrrolidines, Piperidines, and Azepanes Starting from 1‐Tosyl‐2‐(trifluoromethyl)aziridine.

AbstractA convenient synthesis of 2‐(ω‐chloroalkyl)‐1‐tosyl‐2‐(trifluoromethyl)aziridines (III) is developed and their reaction with a variety of nucleophiles is presented to yield trifluoromethylated pyrrolidines and piperidines.

Divergent synthesis of various iminocyclitols from D-ribose.

A very efficient route to the diastereoselective synthesis of polyhydroxy pyrrolidines, piperidines and azepanes from an aldehyde derivative of ribose is reported. Asymmetric α-amination of aldehydes using proline catalysed hydrazination is the key step in the synthesis. The method utilizes the stereocenters present in ribose and the extra carbon atoms present in the target molecules are incorporated using Wittig reactions. The incorporation of the amino group is carried out asymmetrically to account for additional stereocenters. This synthetic route to iminocyclitols has the potential to be extended for the synthesis of a large class of such compounds starting from other sugar derived aldehydes.

ChemInform Abstract: Fully Diastereoselective Synthesis of Polysubstituted, Functionalized Piperidines and Decahydroquinolines Based on Multicomponent Reactions Catalyzed by Cerium(IV) Ammonium Nitrate.

AbstractThe CAN‐catalyzed three‐component reaction between acrolein derivatives, β‐dicarbonyl compounds and primary amines offers a general access to 1,4‐dihydropyridines which can be diastereoselectively hydrogenated to provide piperidines with hitherto inaccessible stereochemical arrangement.

Fluorinated hydroxypiperidines as selective β-glucosidase inhibitors.

A new series of fluoroallylamines derived from hydroxypiperidines was prepared and evaluated against various glycosidases. The short synthesis of target molecules involved the modified Julia reaction between aldehydes and functionalized fluoroaminosulfones. Biological studies revealed good and selective β-glucosidase inhibition in the micromolar range for two compounds, while the non-fluorinated analogue of the most active compound was selective towards α-glucosidase.

Asymmetric hydrogenation of pyridinium salts with an iridium phosphole catalyst.

Iridium-catalyzed asymmetric hydrogenation of N-alkyl-2-alkylpyridinium salts provided 2-aryl-substituted piperidines with high levels of enantioselectivity. Simple benzyl and other alkyl groups successfully activated the challenging pyridine substrates toward hydrogenation. The use of the unusual chiral-phosphole-based MP(2) -SEGPHOS was the key to the success of this approach which provides a versatile and practical procedure for the synthesis of chiral piperidines.

Asymmetric Hydrogenation of Pyridinium Salts with an Iridium Phosphole Catalyst

Iridium-catalyzed asymmetric hydrogenation of N-alkyl-2-alkylpyridinium salts provided 2-aryl-substituted piperidines with high levels of enantioselectivity. Simple benzyl and other alkyl groups successfully activated the challenging pyridine substrates toward hydrogenation. The use of the unusual chiral-phosphole-based MP2-SEGPHOS was the key to the success of this approach which provides a versatile and practical procedure for the synthesis of chiral piperidines.