Al(H2PO4)3 as an efficient and reusable catalyst for the multi-component synthesis of highly functionalized piperidines and dihydro-2-oxypyrroles

Extremely facile and efficient procedures have been developed for the synthesis of highly functionalized piperidines and dihydro-2-oxypyrroles via one-pot multi-component reactions in the presence of Al(H₂PO₄)₃ as a heterogeneous and eco-friendly catalyst under mild conditions. The multi-component reaction of aromatic aldehydes, aromatic amines, and β-keto esters catalyzed by Al(H₂PO₄)₃ in EtOH at room temperature provides highly functionalized piperidines in good to excellent yields. The structure as well as the relative stereochemistry of these functionalized piperidines was confirmed by single X-ray crystallographic analysis. The same catalyst was found useful for the synthesis of polyfuntionalized dihydro-2-oxypyrroles using a four-component reaction of amines, dialkyl acetylenedicarboxylates and formaldehyde in MeOH at ambient temperature. It is found that the catalyst is recyclable and can be used up to five times without significant loss of its activity.     

Intramolecular Metalloamination of N,N‐Dimethylhydrazinoalkenes: A Versatile Method to Access Functionalized Piperidines and Pyrrolidines

Highly diastereoselective metalloamination/cyclization reactions of zinc(II) hydrazides obtained through reaction of diethylzinc with N,N‐dimethylhydrazinoalkenes are described. The resulting organozinc intermediates undergo facile allylation and acylation, in situ, to provide the corresponding functionalized piperidines and pyrrolidines.     

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.     

Organocatalytically Enantioselective Approach to Polysubstituted Tetrahydropyridines and Piperidines

A convenient and highly enantioselective method for assembly of functionalized 1,2,3,4,5‐pentasubstituted tetrahydropyridines and piperidines was developed. This method relies on preparing the required enantiopure cyclic semi‐acetals via an organocatalyzed Michael addition/cyclization cascade reaction of aldehydes and α‐keto‐α,β‐unsaturated esters, and subsequent reductive amination/condensation with primary amines.     

A three-component reaction for diversity-oriented synthesis of polysubstituted piperidines: solution and solid-phase optimization of the first tandem aza[4+2]/allylboration

This article describes the design and optimization of a simple three-component aza[4+2]/allylboration reaction to access polysubstituted alpha-hydroxyalkyl piperidines in a highly diastereocontrolled fashion from maleimides, 4-boronohydrazonodienes, and aldehydes. The aldehyde component does not interfere with the first aza[4+2] step, and it was found that this tandem reaction provides better yields of piperidine products 5 when carried out in one-pot. The required 4-borono-hydrazonodienes 1 are synthesized efficiently from the condensation of 3-boronoacrolein pinacol ester (4) with hydrazines. Overall, the three-component process using N-substituted maleimides as dienophiles produces four stereogenic centers and is quite general. It tolerates the use of a wide variety of aldehydes and hydrazine precursors with different electronic and steric characteristics. By allowing such a wide substrate scope and up to four elements of diversity, this reaction process is particularly well adapted towards applications in diversity-oriented synthesis of polysubstituted piperidine derivatives. The suitability of the aza[4+2]/allylboration reaction for use in solid-phase chemistry was also demonstrated using a N-arylmaleidobenzoic acid functionalized resin. This novel multicomponent reaction thus offers a high level of stereocontrol and versatility in the preparation of densely functionalized nitrogen heterocycles.     

Multicomponent reaction for the synthesis of highly functionalized piperidine scaffolds catalyzed by TMSI

Research on Chemical Intermediates - An efficient method for the synthesis of highly functionalized piperidines via one-pot domino reaction of β-ketoesters, aromatic aldehydes, and aromatic...     

Iodine catalyzed one-pot five-component reactions for direct synthesis of densely functionalized piperidines

A simple and convenient one-pot multicomponent reaction (MCR) has been developed for the synthesis of highly functionalized piperidines catalyzed by molecular iodine. This strategy demonstrated five-component reactions of 1,3-dicarbonyl compounds, amines and aromatic aldehydes in methanol using 10 mol % of iodine at room temperature. This methodology provides an alternative approach for easy access of highly and fully substituted piperidines in moderate to good yields using three readily available starting materials. Notably, this method is mild, cheap, straight forward, applicable to broad range of substrates and environmentally friendly as compared to the existing methods. Synthetic and mechanistic studies are presented here.     

NMR evidence of the kinetic and thermodynamic products in the NIS promoted cyclization of 1-phenyl-4-pentenylamines. Synthesis and reactivity of trans-2-phenyl-5-iodopiperidines

The intramolecular reaction of secondary amines with tethered alkenes using NIS was studied, which gave insight into the kinetic vs. thermodynamic control of the iodoaminocyclization and the regioselectivity of the aziridinium ring-opening reactions, and led to functionalized piperidines.     

One-pot five-component synthesis of highly functionalized piperidines using oxalic acid dihydrate as a homogenous catalyst

An efficient green protocol is described for the preparation of highly functionalized piperidines via a one-pot five-component reaction between aromatic aldehydes,anilines andβ-ketoesters in the presence of oxalic acid dihydrate as catalyst in ethanol at ambient temperature.The structure as well as the relative stereochemistry of these compounds was confirmed by single X-ray crystallographic analysis.     

Cerium(IV) triflate-catalyzed domino annulation approaches to the synthesis of highly substituted piperidines

A simple, diastereoselective, inexpensive, and efficient route for the synthesis of highly functionalized piperidines by the condensation of β-keto-esters, aromatic aldehydes and anilines using cerium(IV) triflate as a catalyst is described. In most cases, the piperidine precipitates out of the solution.     

Regio‐ and Stereoselective Synthesis of Functionalized Dihydropyridines,Pyridines, and 2H‐Pyrans: Heck Coupling of Monocyclopropanated Heterocycles

A palladium‐catalyzed coupling between aryl halides and monocyclopropanated pyrroles or furans has been developed, leading to valuable six‐membered N‐ and O‐heterocycles. As the key step, a selective cleavage of the non‐activated endocyclic C?C bond of the 2‐heterobicyclo‐[3.1.0]hexane framework is achieved. The developed method offers access to highly functionalized piperidines, pyridines, and pyrans that are challenging to access by traditional methods.     

Diastereoselective synthesis of trisubstituted piperidines: a versatile synthon for elaboration of uncommon poly(aza)heterocyclic structures

Hetero Michael addition on chiral β′-amino-α,β-unsaturated ketone furnished, after some structural modifications, β,β′-diaminoketals. Mannich type reaction of these diamines with an aldehyde led, with a high diastereoselectivity, to trisubstituted piperidines. Starting from a functionalized aldehyde and after subsequent deprotection of the amino group, an intramolecular Michael addition provided octahydro-2H-pyrrolo-[3,4-b]-pyridine, an uncommon framework found in compounds exhibiting biological activity.     

Asymmetric synthesis of functionalized trans-2,6-disubstituted piperidines with N-sulfinyl delta-amino beta-ketoesters. Synthesis of (-)-lasubine I

[reaction: see text] The hydroxy-directed reduction of 1,2-dehydropiperidines with the "ate" complex of DIBAL-H and n-BuLi affords functionalized trans-2,6-disubstituted piperidines. This methodology was employed in the asymmetric synthesis of the quinolizidine alkaloid (-)-lasubine I.     

Reductive Hydroxymethylation of 4-Heteroarylpyridines

The activation of pyridinium salts with electron-withdrawing heterocycles enables an iridium-catalyzed reductive hydroxymethylation reaction to proceed smoothly, facilitating the preparation of useful 3D heteroaryl-substituted functionalized piperidines. The methodology is used to prepare 3-hydroxymethylated analogues of pharmaceutical agents. Mechanistically, formaldehyde acts as both a hydride donor and the electrophile, leading to the formation of two new carbon–hydrogen bonds and one new carbon–carbon bond under relatively mild conditions.     

Aminals as substrates for sulfur ylides: a synthesis of functionalized aziridines and N-heterocycles

Sulfur ylides stabilized by Ar, vinyl, or amide groups react with five-membered-ring tert-butylsulfinyl aminals to give functionalized chiral, nonracemic aziridines in high yield and with good selectivities (up to 15:1 trans:cis, up to >95:5 trans dr, always >95:5 cis dr). The intermediate aziridines can be converted into pyrrolidines or piperidines depending on the reaction conditions.     

Synthesis of functionalized 3-hydroxypiperidines

The synthetic versatility of three chemoenzymatically prepared hydroxypiperidine building blocks has been explored, resulting in a library of enantiopure functionalized piperidines. Key steps involved N-acyliminium ion-mediated CC-bond formation and cross-metathesis reactions, after which full deprotection led to the set of free 3-hydroxypiperidines.     

Efficient one-pot synthesis of functionalized piperidine scaffolds via ZrOCl2·8H2O catalyzed tandem reactions of aromatic aldehydes with amines and acetoacetic esters

A highly efficient diastereoselective one-pot synthesis of functionalized piperidines has been developed based on an aqua-compatible ZrOCl₂·8H₂O catalyst via tandem reactions of aromatic aldehydes, amines, and acetoacetic esters.     

A heterocycle-forming double michael reaction. [5 + 1] annulation route to highly substituted and functionalized piperidines

[reaction: see text]. Nitrogen-containing tethered diacids, easily prepared by reductive alkylation of diethyl aminomalonate or ethyl cyanoglycinate, undergo double Michael reactions with 3-butyn-2-one to give highly functionalized and substituted piperidines (pipecolic acid derivatives) with surprisingly high stereoselectivity. The heterocyclic double Michael adducts can be induced to undergo further cyclizations to give a variety of azabicyclic and diazabicyclic compounds.     

Diastereoselective synthesis of 4-hydroxypiperidin-2-ones via Cu(I)-catalyzed reductive aldol cyclization

[chemical reaction: see text]. 4-Hydroxypiperidin-2-ones may be prepared in highly diastereoselective fashion using a Cu(I)-catalyzed reductive aldol cyclization of alpha,beta-unsaturated amides with ketones. Used in combination with proline-catalyzed asymmetric Mannich reactions, this methodology enables the enantioselective synthesis of more highly functionalized piperidin-2-ones and hydroxylated piperidines.     

Effects of substituents in the beta-position of 1,3-dicarbonyl compounds in bromodimethylsulfonium bromide-catalyzed multicomponent reactions: a facile access to functionalized piperidines

1,3-Dicarbonyl compounds can be converted to Mannich-type products A or highly functionalized piperidines B in the presence of a catalytic amount of bromodimethylsulfonium bromide (BDMS). The combination of aromatic aldehyde, amine, and 1,3-dicarbonyl compounds in the presence of a catalytic amount of BDMS leads to the formation of Mannich-type product A when R is a non-enolizable carbon or an alkoxy group, whereas in cases when R = CH3, the same combination yielded highly functionalized piperidines B. A synthetic study and mechanistic proposal are presented.