Pyrrolidine Derivatives Research Articles

Acid-Base Dual-Functional Catalysis by Axially Chiral Guanidine in Enantioselective [3+2] Cycloaddition of Maleate to Schiff Bases as a Precursor of Azomethine Ylides

The enantioselective [3+2] cycloaddition reaction of dimethyl maleate with Schiff bases as the precursor of azomethine ylide was developed using axially chiral guanidine catalysts to provide optically active pyrrolidine derivatives. Acid-base dual-functional catalysis by an axially chiral guanidine through double hydrogen-bonding interaction is proposed to give the cycloaddition products in good yields.

Synthesis of Functionalized N-Vinyl Nitrogen-Containing Heterocycles

Microwave-assisted 1,3-dipolar cycloaddition of the azomethine ylide generated by ring opening of a N-vinylaziridine gave new N-vinyl derivatives of pyrrolidine, 3-pyrroline, octahydropyrrolo[3,4-c]pyrrole and 1,2,4-triazolidine.

Utilization of N−X Bonds in The Synthesis of N-Heterocycles

Nitrogen-containing heterocycles--such as aziridines, pyrrolidines, piperidines, and oxazolines--frequently show up as substructures in natural products. In addition, some of these species show potent biological activities. Therefore, researchers would like to develop practical and convenient methods for constructing these heterocycles. Among the available methods, the transfer of N(1) units to organic molecules, especially olefins, is a versatile method for the synthesis of N-heterocycles. This Account reviews some of our recent work on the synthesis of N-heterocycles using the N-X bond. A nitrogen-halogen bond bearing an electron-withdrawing group on the nitrogen can be converted to a halonium ion. In the presence of C-C double bonds, these species produce three-membered cyclic halonium intermediates, which can be strong electrophiles and can produce stereocontrolled products. N-Halosuccinimides are representative sources of halonium ions, and the nitrogen of succinimide is rarely used in organic synthesis. If the nitrogen could act as a nucleophile, after releasing halonium ions to C-C double bonds, we expect great advances would be possible in the stereoselective functionalization of olefins. We chose N-chloro-N-sodio-p-toluenesulfonamide (chloramine-T, CT), an inexpensive and commercially available reagent, as our desired reactant. In the presence of a catalytic amount of CuCl or I(2) and AgNO(3), we achieved the direct aziridination of olefins with CT. The reaction catalyzed by I(2) could be carried out in water or silica-water as a green process. The reaction of iodoolefins with CT gave pyrrolidine derivatives under extremely mild conditions with complete stereoselectivity. We also extended the utility of the N-chloro-N-metallo reagent, which is often unstable and difficult to work with. Although CT does not react with electron-deficient olefins without a metal catalyst or an additive, we found that N-chloro-N-sodiocarbamates react with electron-deficient olefins in the presence of a phase transfer catalyst to give the corresponding aziridines. We also used this method to synthesize asymmetric aziridines using quaternary cinchona alkaloid catalysts. We also developed a facile synthetic method for preparing N-heterocycles that involves the in situ generation of an N-X bond using tert-butyl hypochlorite or tert-butyl hypoiodite (tert-BuOI). Treatment of alkenylamides containing an active hydrogen on the nitrogen with tert-BuOI led to the production of various N-heterocycles via intramolecular cyclization. Iodination of readily available sulfonamides or carboxamides with tert-BuOI generated reactive N-iodinated amides, which smoothly reacted with olefins to give aziridines or oxazolines. The reaction of fullerene, C(60), with CT also led to aziridination: the resulting aziridinofullerene underwent a unique rearrangement to an azafulleroid. Chlorination of readily available amide derivatives with tert-BuOCl, followed by a reaction with C(60) in the presence of an organic base, afforded aziridinofullerenes with various substituents on the nitrogen. The results in this Account contribute to the development of convenient methods for constructing simple and useful heterocycles.

Plant coumarins. 4.* Synthesis of N-containing derivatives of oreoselone

Bromination of peucedanin by various reagents was studied. Conditions for forming 2-(1,3-dibromopropan-2-ylidene)-2H-furo[3,2-g][1]benzopyran-3,7-dione were found. Several 2-aminofuranocoumarins were synthesized by reaction of 2-bromoreoselone with derivatives of pyrrolidine, piperidine, and piperazine. The new compounds were interesting as potential biologically active compounds.

ChemInform Abstract: Facile Synthesis of Monofluoro γ‐Lactones and Pyrrolidine Derivatives via Electrophilic Fluorination of Allenoic Acids and Amides.

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Cu(I)-Catalyzed Intramolecular Hydroamination of Unactivated Alkenes Bearing a Primary or Secondary Amino Group in Alcoholic Solvents

The Cu-Xantphos system [Cu(O-t-Bu)-Xantphos, 10-15 mol %] catalyzes the intramolecular hydroamination of unactivated terminal alkenes bearing an unprotected aminoalkyl substituent in alcoholic solvents, giving pyrrolidine and piperidine derivatives in excellent yields. This system is applicable to both primary and secondary amines and tolerates a variety of functional groups.

Synthesis of polycyclic heterocycles via sequential Au-catalyzed cycloisomerization and Ru-catalyzed metathesis reactions

A sequential and efficient catalytic preparation of polycyclic heterocycles, including tetrahydro furo- or cyclopenta- pyran, hexahydropyrano pyrrolidine, and tetrahydroisochromene derivatives is described based on a gold-catalyzed cycloisomerization reaction followed by a Ru-catalyzed ring-closing metathesis. An isomerization of the alkene moiety leading diastereoselectively to cis tetrahydrocyclopenta[ c]pyran and tetrahydro-1 H-furo[3,4- c]pyran is observed in some cases. The catalytic hydrogenation reactions of these tetrahydropyrans led to the formation of polycyclic-functionalized saturated compounds.

Construction of Carbo- and Heterocycles Using Radical Relay Cyclizations Initiated by Alkoxy Radicals

An efficient method for the rapid construction of carbo- and heterocycles has been developed using radical relay cyclizations initiated by alkoxy radicals. Linear substrates were cyclized to form a wide range of cyclopentane, pyrrolidine, tetrahydropyran, and tetrahydrofuran derivatives in excellent yields. This methodology was utilized as a key step in the synthesis of the tetrahydrofuran fragment in (-)-amphidinolide K.

4-Piperidines and 3-pyrrolidines as dual serotonin and noradrenaline reuptake inhibitors: Design, synthesis and structure–activity relationships

Single enantiomer [(aryloxy)(pyridinyl)methyl]piperidine and pyrrolidine derivatives 5– 9 are inhibitors of monoamine reuptake. Structure–activity relationships established that monoamine reuptake inhibition are functions of amine, pyridine isomer, aryloxy ring substitution and stereochemistry. Consequently, selective NRIs, selective SRIs, dual SNRIs and triple SNDRIs were all identified. Dual SNRIs 5l– a and 9c were evaluated in additional pharmacology and pharmacokinetic studies as representative examples from this series.

Synthesis of Poly(Ethylene Glycol)–Supported (R)-BINOL Derivatives and Their First Application in Enantioselective Mukaiyama Aldol Reactions

The Mukaiyama aldol reaction of 2-styryl-oxazole-4-carbaldehyde (1) as model substrate with S-ketene silyl acetal 2 catalyzed by poly(ethylene glycol)-supported binaphthyl-derived chiral titanium(IV) complexes afforded the corresponding aldol product in good to excellent yields and enantioselectivities up to 94% ee. The chemical yields and/or the enantioselectivities are enhanced by generating the active catalyst from Ti(OiPr)4, polymer-supported ligands (R)-6 or (R)-8, and chiral or achiral promoters. Pyrrolidine derivative (S)-13 and trifluoromethyl-substituted phenol 12 are the most efficient additives found.

3D-QSAR study of pyrrolidine derivatives as matrix metalloproteinase-2 inhibitors

In order to develop potent inhibitors of matrix metalloproteinase-2(MMP-2) as anticancer agents, a three-dimensional quantitative structure–activity relationship (3D-QSAR) model was established by using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. This study correlates the MMP-2 inhibitory activities of 67 pyrrolidine derivatives to steric, electrostatic, hydrophobic, and hydrogen-bond donor and acceptor fields. After using two different molecular alignments, both CoMFA and CoMSIA models resulted in good statistical predictions, a case in point being their high q 2 values of between 0.757 and 0.843. The CoMFA and CoMSIA models established herein will be helpful in understanding the structure–activity relationship of pyrrolidine derivatives as well as in the design of novel derivatives with enhanced MMP-2 inhibitory activity.

Synthesis of 2,3-Dioxo-5-(substituted)arylpyrroles and Their 2-Oxo-5-aryl-3-hydrazone Pyrrolidine Derivatives

Some novel 2,3-dioxo-5-(substituted)arylpyrroles have been synthesized. Among these, pyrrolidine compound 1b was converted to 2,3-dioxo-5-aryl pyrrolidine 2b. Finally a set of hydrazone derivatives was obtained from the reaction of 2b with various hydrazine salts. The structures of all the new synthesized compounds were confirmed by elemental analyses, IR and 1H-NMR spectra.

Metal Nitride Cluster Fullerene M3N@C80 (M=Y, Sc) Based Dyads: Synthesis, and Electrochemical, Theoretical and Photophysical Studies

The first pyrrolidine and cyclopropane derivatives of the trimetallic nitride templated (TNT) endohedral metallofullerenes I(h)-Sc(3)N@C(80) and I(h)-Y(3)N@C(80) connected to an electron-donor unit (i.e., tetrathiafulvalene, phthalocyanine or ferrocene) were successfully prepared by 1,3-dipolar cycloaddition reactions of azomethine ylides and Bingel-Hirsch-type reactions. Electrochemical studies confirmed the formation of the [6,6] regioisomers for the Y(3)N@C(80)-based dyads and the [5,6] regioisomers in the case of Sc(3)N@C(80)-based dyads. Similar to other TNT endohedral metallofullerene systems previously synthesized, irreversible reductive behavior was observed for the [6,6]-Y(3)N@C(80)-based dyads, whereas the [5,6]-Sc(3)N@C(80)-based dyads exhibited reversible reductive electrochemistry. Density functional calculations were also carried out on these dyads confirming the importance of these structures as electron transfer model systems. Furthermore, photophysical investigations on a ferrocenyl-Sc(3)N@C(80)-fulleropyrrolidine dyad demonstrated the existence of a photoinduced electron-transfer process that yields a radical ion pair with a lifetime three times longer than that obtained for the analogous C(60) dyad.

Facile Synthesis of Monofluoro γ ‐Lactones and Pyrrolidine Derivatives via Electrophilic Fluorination of Allenoic Acids and Amides

AbstractA convenient method to synthesize a series of monofluoro γ‐lactones and pyrrolidine derivatives in moderate to good yields via the electrophilic fluorination of γ‐allenoic acids and tosylamides using Selectfluor was developed.

Catalytic Asymmetric Intramolecular Allylation of Aldehyde

The intramolecular asymmetric allylation of aldehydes was catalyzed by a combination of pyrrolidine derivatives and Pd(0) to give 5-exo-cyclized aldehyde with fair ee in good yield.

TiO2-Mediated, One-Pot, Four-Component 1,3-Dipolar Cycloaddition Reaction: A Facile Synthesis of Dispiro-pyrrolidine Ring Systems

An expedient regioselective synthesis of dispiroindenoquinoxaline pyrrolidine derivatives mediated by TiO2 in a one-pot, four-component 1,3-dipolar cycloaddition reaction is described.

Synthesis and serotonin antagonist and antianexity activities of pyrrolidine derivatives from 4-hydrazinyl-1-p-substituted phenyl-2,5-dihydro-1H-pyrrole-3-carbonitriles

AbstractN-(p-substituted phenyl)-4-cyanopyrrolidin-3-ones and their corresponding hydrazines were prepared and used as starting materials to synthesize heterocyclic candidates as serotonin antagonist and antianexity agents. Condensation of hydrazines with selected aromatic aldehydes afforded the corresponding Schiff bases. The hydrazines were treated with phenyl isothiocyanate to afford the corresponding thiosemicarbazides, which were cyclized with ethyl bromoacetate to N-phenylthiazolidinones. The hydrazine was reacted with 1,2,4,5-tetrachlorophthalic anhydride to give the tetrachloroimide derivative. It was reacted with benzoyl acetonitrile, 2-(bismethylsulfanyl-methylene)malononitrile, 2-ethoxymethylenemalononitrile, or 2-cyano-3-ethoxyacrylic acid ethyl ester to afford the corresponding pyrazoline derivatives. Schiff bases were obtained by simple condensation of the hydrazine with different carbonyl compounds. All the compounds were screened for their serotonin antagonistic and antianexity activities, and they showed high activities compared to buspirone and diazepam as controls.Graphical abstract[IMAGE]

Development of Catalytic Asymmetric 1,4-Addition and [3 + 2] Cycloaddition Reactions Using Chiral Calcium Complexes

Catalytic asymmetric 1,4-addition and [3 + 2] cycloaddition reactions using chiral calcium species prepared from calcium isopropoxide and chiral bisoxazoline ligands have been developed. Glycine Schiff bases reacted with acrylic esters to afford 1,4-addition products, glutamic acid derivatives, in high yields with high enantioselectivities. During the investigation of the 1,4-addition reactions, we unexpectedly found that a [3 + 2] cycloaddition occurred in the reactions with crotonate derivatives, affording substituted pyrrolidine derivatives in high yields with high enantioselectivities. On the basis of this finding, we investigated asymmetric [3 + 2] cycloadditions, and it was revealed that several kinds of optically active substituted pyrrolidine derivatives containing contiguous stereogenic tertiary and quaternary carbon centers were obtained with high diastereo- and enantioselectivities. In addition, optically active pyrrolidine cores of hepatitis C virus RNA-dependent polymerase inhibitors and potential effective antiviral agents have been synthesized using this [3 + 2] cycloaddition reaction. NMR spectroscopic analysis and observation of nonamplification of enantioselectivity in nonlinear effect experiments suggested that a monomeric calcium species with an anionic ligand was formed as an active catalyst. A stepwise mechanism of the [3 + 2] cycloaddition, consisting of 1,4-addition and successive intramolecular Mannich-type reaction was suggested. Furthermore, modification of the Schiff base structure resulted in a modification of the reaction course from a [3 + 2] cycloaddition to a 1,4-addition, affording 3-substituted glutamic acid derivatives with high diasterero- and enantioselectivities.

Synthesis and properties of N-methyl[60]fullereno[c]pyrrolidines containing cyclopentadienyl(carbonyl)metal fragments

In new N-methyl[60]fullereno[c]pyrrolidine derivatives, the organometallic substituents in position 2 of the pyrrolidine ring are tricarbonyl(cyclopentadienyl)rhenium, α-bicymantrenyl, and β-bicymantrenyl (also the optically active (+)-enantiomer of the latter). The electrochemical and spectroscopic (NMR) properties of the compounds obtained were studied.

New Efficient RCM-Mediated Synthesis of Pyrrolidine Derivatives

Fast and effective ring-closing olefin metathesis (RCM) of diallyamine derivatives of coumarin, quinolone, pyridine, and substituted benzene, using first-generation RCM ruthenium-based catalyst, leads to corresponding pyrrolidine derivatives in 70–95% yields under very mild conditions.