Synthesis Of Pyrrolidines Research Articles

Application of 1,3-Dipolar Reactions between Azomethine Ylides and Alkenes to the Synthesis of Catalysts and Biologically Active Compounds.

The (3+2) cycloaddition between azomethine ylides and alkenes is an efficient, convergent and stereocontrolled method for the synthesis of unnatural pyrrolidine and proline scaffolds. In this review, the application of this reaction to the synthesis of enantiopure organometallic ligands for asymmetric catalysis is presented first. These new EhuPhos ligands can participate in a second generation of 1,3‐dipolar reactions that generate an offspring of unnatural proline derivatives that behave as efficient organocatalysts. These densely substituted unnatural l‐proline derivatives exhibit distinct features, different to those described for natural l‐proline and its derivatives. Finally, several examples of biologically active proline derivatives obtained by means of (3+2) cycloadditions involving azomethine ylides are presented. These applications show the character of privileged structures of these polysubstituted pyrrolidine rings.

Synthesis of N‐Heterocycles by Dehydrogenative Annulation of N‐Allyl Amides with 1,3‐Dicarbonyl Compounds

AbstractDehydrogenative annulation under oxidizing reagent‐free conditions is an ideal strategy to construct cyclic structures. Reported herein is an unprecedented synthesis of pyrrolidine and tetrahydropyridine derivatives through electrochemical dehydrogenative annulation of N‐allyl amides with 1,3‐dicarbonyl compounds. The electrolytic method employs an organic redox catalyst, which obviates the need for oxidizing reagents and transition‐metal catalysts. In these reactions, the N‐allyl amides serve as a four‐atom donor to react with dimethyl malonate to give pyrrolidines by a (4+1) annulation, or with β‐ketoesters to afford tetrahydropyridine derivatives by a (4+2) annulation.

Synthesis of N-Heterocycles by Dehydrogenative Annulation of N-Allyl Amides with 1,3-Dicarbonyl Compounds.

Dehydrogenative annulation under oxidizing reagent-free conditions is an ideal strategy to construct cyclic structures. Reported herein is an unprecedented synthesis of pyrrolidine and tetrahydropyridine derivatives through electrochemical dehydrogenative annulation of N-allyl amides with 1,3-dicarbonyl compounds. The electrolytic method employs an organic redox catalyst, which obviates the need for oxidizing reagents and transition-metal catalysts. In these reactions, the N-allyl amides serve as a four-atom donor to react with dimethyl malonate to give pyrrolidines by a (4+1) annulation, or with β-ketoesters to afford tetrahydropyridine derivatives by a (4+2) annulation.

Vinyl-aziridines and cyclopropanes in Pd-catalyzed (3+2)-cycloaddition reactions with cyclic N-sulfonyl imines

Efficient palladium-catalyzed (3 + 2)-cycloaddition reactions of cyclic N-sulfonyl imines and vinyl-aziridines (or cyclopropanes) have been achieved. The reactions, with either vinylic substrate, proceed with excellent yields affording highly functionalized imidazolidine and pyrrolidine derivatives. The cycloadditions take place via the reaction of zwitterionic π-allyl palladium intermediates with cyclic N-sulfonyl imines through i) the formation of two NC bonds in the presence of vinylaziridines (synthesis of imidazolidines) and ii) one CC bond and one NC bond in the presence of vinylcyclopropanes (synthesis of pyrrolidines). Following on preliminary works on the diastereoselective synthesis of imidazolidines, herein we wish to give a broader view on the subject by describing derivatization reactions and attempts towards an enantioselective version. Moreover, we describe and discuss the behavior of each vinylic substrate (aziridine or cyclopropane) on the (3 + 2)-cycloaddition reactions. Mechanistic and (intriguing) selectivity outcomes are also going to be discussed.

Enantioselective Synthesis of 2-Aminomethyl and 3-Amino Pyrrolidines and Piperidines through 1,2-Diamination of Aldehydes.

An efficient method for the synthesis of 1,2-diamines from aldehydes through proline-catalyzed asymmetric α-amination followed by reductive amination is reported. The products resemble those obtained through direct asymmetric diamination of terminal alkenes. The methodology is used to synthesize 2-aminomethyl and 3-amino pyrrolidines and piperidines in high yields and with a good enantioselectivity. The usefulness of the method is demonstrated through the synthesis of a 2-aminomethyl iminocyclitol.

Tri(pentaflurophenyl)borane-catalyzed reduction of cyclic imides with hydrosilanes: Synthesis of pyrrolidines

B(C6F5)3-catalyzed hydrosilylation of cyclic imides afforded an efficient synthetic method of pyrrolidines. In the presence of 5 mol% B(C6F5)3, various aromatic, aliphatic and polycyclic imides were smoothly reduced by PhSiH3 to generate the corresponding pyrrolidines in high yields. The reaction profiles monitored by 1H NMR spectroscopy disclosed the reduction process of cyclic imides and the effect of difference structure of the hydrosilanes on the hydrosilylation.

Intramolecular Hydrogen Bond Activation: Thiourea-Organocatalyzed Enantioselective 1,3-Dipolar Cycloaddition of Salicylaldehyde-Derived Azomethine Ylides with Nitroalkenes.

An organocatalytic strategy for the synthesis of tetrasubstituted pyrrolidines with monoactivated azomethine ylides in high enantiomeric excess and excellent exo/endo selectivity is presented. The key to success is the intramolecular activation via hydrogen bonding through an o-hydroxy group, which allows the dipolar cycloaddition to take place in the presence of azomethine ylides bearing only one activating group. The intramolecular hydrogen bond in the azomethine ylide and the intermolecular hydrogen bond with the catalyst have been demonstrated by DFT calculations and mechanistic proofs to be crucial for the reaction to proceed.

Enantioselective Regiodivergent Synthesis of Chiral Pyrrolidines with Two Quaternary Stereocenters via Ligand-Controlled Copper(I)-Catalyzed Asymmetric 1,3-Dipolar Cycloadditions.

An unprecedented ligand-controlled regiodivergent Cu(I)-catalyzed asymmetric intermolecular (3 + 2) cycloaddition reaction of α-substituted iminoesters with β-fluoromethyl β,β-disubstituted enones was developed. This novel strategy provides an efficient method for the enantioselective regiodivergent synthesis of pyrrolidines bearing two adjacent quaternary stereocenters or two discrete quaternary stereocenters, opening up a new era for medicinal chemistry and diversity-oriented synthesis. DFT calculations showed that the P,N-ligand L2 acts as a pseudobidentate ligand. The formation of a O-Cu bond with the carbonyl oxygen atom of the enone and dissociation of the amine nitrogen of L2 from the Cu(I) center occurs during the catalytic cycle; this is the main reason for the tuning the regioselectivity of the cycloaddition reaction caused by switching of the ligand. The salient features of this work include high yields (up to >99%), a general substrate scope, the use of commercially available ligands, and high regio-(up to >20:1 rr), diastereo- (up to >20:1 dr), and enantioselectivity (up to >99% ee).

Metal-Catalyzed Unsaturated Hydrocarbon Functionalization Applied in the Synthesis of Pyrrolidines and Pyrrolines

Metal-Catalyzed Unsaturated Hydrocarbon Functionalization Applied in the Synthesis of Pyrrolidines and Pyrrolines

Synthesis, characterization and antibacterial activity of Pyrrolidine based Mannich base ligand and its metal (II) complexes

Synthesis, characterization and antibacterial activity of Pyrrolidine based Mannich base ligand and its metal (II) complexes

Catalyst-Controlled Diastereoselective Synthesis of Cyclic Amines via C-H Functionalization.

Reliable regio- and stereochemical techniques applicable to nonactivated aliphatic systems remain largely elusive due to the challenges of discriminating between multiple, relatively strong sp3 C-H bonds whose chemical behavior often differ only subtly. Nevertheless, approaches that employ directing groups and/or auxiliaries have emerged, but impose practical restrictions, especially in complex molecule synthesis. This report describes a catalyst-controlled regio- and diastereoselective synthesis of N-unprotected pyrrolidines via dirhodium catalyzed intramolecular nitrene insertion into sp3 C-H bonds. The reaction proceeds at rt without external oxidants, nitrene stabilizing groups, or directing functionality. The insights that emerged from the conformational/stereoselectivity relationships (CSR) between catalysts and substrates provide a framework for rational catalyst design that can accommodate a broader range of aliphatic C-H chemistry.

Facile and Green Synthesis of Saturated Cyclic Amines

Single-nitrogen containing saturated cyclic amines are an important part of both natural and synthetic bioactive compounds. A number of methodologies have been developed for the synthesis of aziridines, azetidines, pyrrolidines, piperidines, azepanes and azocanes. This review highlights some facile and green synthetic routes for the synthesis of unsubstituted, multisubstituted and highly functionalized saturated cyclic amines including one-pot, microwave assisted, metal-free, solvent-free and in aqueous media.

Synthesis of Spirocyclic Pyrrolidines: Advanced Building Blocks for Drug Discovery.

In the context of drug discovery, novel spirocyclic pyrrolidines have been synthesized in two steps from common three- to seven-membered-ring (hetero)alicyclic ketones. The key transformation is a reaction between an electron-deficient exocyclic alkene and an in situ generated N-benzyl azomethine ylide. The developed method has been used to synthesize the central diamine core of the known antibacterial agents Sitafloxacin and Olamufloxacin.

Direct and Stereospecific [3+2] Synthesis of Pyrrolidines from Simple Unactivated Alkenes.

Pyrrolidines are important heterocyclic compounds with endless applications in organic synthesis, metal catalysis, and organocatalysis. Their potential as ligands for first-row transition-metal catalysts inspired a new method to access complex poly-heterocyclic pyrrolidines in one step from available materials. This fundamental step forward is based on the discovery of an essential organoaluminum promoter that engages unactivated and electron-rich olefins in intermolecular [3+2] cycloadditions.

Direct and Stereospecific [3+2] Synthesis of Pyrrolidines from Simple Unactivated Alkenes

AbstractPyrrolidines are important heterocyclic compounds with endless applications in organic synthesis, metal catalysis, and organocatalysis. Their potential as ligands for first‐row transition‐metal catalysts inspired a new method to access complex poly‐heterocyclic pyrrolidines in one step from available materials. This fundamental step forward is based on the discovery of an essential organoaluminum promoter that engages unactivated and electron‐rich olefins in intermolecular [3+2] cycloadditions.

Radical Redox-Relay Catalysis: Formal [3+2] Cycloaddition of N-Acylaziridines and Alkenes.

We report Ti-catalyzed radical formal [3+2] cycloadditions of N-acylaziridines and alkenes. This method provides an efficient approach to the synthesis of pyrrolidines, structural units prevalent in bioactive compounds and organocatalysts, from readily available starting materials. The overall redox-neutral reaction was achieved via a redox-relay mechanism, which harnesses radical intermediates for selective C-N bond cleavage and formation.

CuCl/Et3N-Catalyzed Synthesis of Indanone-Fused 2-Methylene Pyrrolidines from Enynals and Propargylamines

An efficient CuCl/Et3N-catalyzed tandem reaction for the synthesis of indanone-fused pyrrolidine was developed. In this process, two rings and four bonds are generated in one pot with high atom-economy and step-efficiency. The addition of Et3N was found as the key factor for the success of the tandem reaction.

Synthesis of 2-Unsubstituted Pyrrolidines and Piperidines from Donor-Acceptor Cyclopropanes and Cyclobutanes: 1,3,5-Triazinanes as Surrogates for Formylimines.

A synthetic procedure to access 2-unsubstituted pyrrolidines and piperidines is presented. In the presence of MgI2 as Lewis acid, donor-acceptor cyclopropanes or corresponding cyclobutanes were treated with 1,3,5-triazinanes, leading to the five- or six-membered ring systems under mild conditions in yields up to 93%. This protocol tolerates a great variety of functional groups and thus provides an efficient entry to this class of pyrrolidines and piperidines.

Organocatalytic Asymmetric Mannich/Aza-Michael Cascade Reaction of δ-Formyl-α,β-unsaturated Ketones with Cyclic N-Sulfimines: Enantioselective Synthesis of Benzosulfamidate-Fused Pyrrolidines.

A catalytic highly enantioselective Mannich/aza-Michael cascade reaction of δ-formyl-α,β-unsaturated ketones with cyclic N-sulfimines, promoted by diphenylprolinol TMS ether as an organocatalyst, has been developed for the synthesis of chiral benzosulfamidate-fused pyrrolidines, which generated in good yields and with high diastero- and enantioselectivities. Further chemical transformations have been performed with chiral benzosulfamidate-fused pyrrolidines.

Enantioselective Synthesis of Pyrrolidines with Vicinal Stereocenters

Enantioselective Synthesis of Pyrrolidines with Vicinal Stereocenters