N-substituted Pyrrolidines Research Articles

Synthesis of trans N-Substituted Pyrrolidine Derivatives Bearing 1,2,4- triazole Ring.

1,2,4-triazoles scaffolds display significant biological activities due to hydrogen bonding, solubility, dipole character, and rigidity. The core motif of 1,2,4-triazoles plays a vital role in clinical drugs such as Rizatriptan (antimigraine), Ribavirin (antiviral), anastrozole (anticancer), etizolam (anxiolytic), estazolam (anticonvulsant), alprazolam (anti-hypnotic), letrozole (aromatase inhibitor), loreclezole (anticonvulsant), trazadone (antidepressant) etc. Methods: Epoxide ring opening of tert-butyl 6-oxa-3-azabicyclo [3.1.0] hexane-3-carboxylate followed by methylation under basic conditions and de-protection gave the corresponding trans 1-(4- methoxypyrrolidin-3-yl)-1H-1,2,4-triazole hydrochloride salt as the precursor. This precursor on reaction with substituted benzoyl chlorides and benzyl bromides gave the desired amide and amine products. A library of 14 N-substituted pyrrolidine derivatives i.e. trans3-methoxy-4-(1H-1,2,4-triazol- 1-yl) pyrrolidin-1-yl) (phenyl)methanone and trans 1-benzyl-4-methoxypyrrolidin-3-yl)-1H-1,2,4- triazole were prepared. Eight novel amides (6a-h) and six amines (8a-f) derivatives were synthesized using 1-(4- methoxypyrrolidin-3-yl)-1H-1,2,4-triazole 4 salt with substituted benzoyl chlorides and benzyl bromides.

Microwave-assisted synthesis, molecular docking and anti-HIV activities of some drug-like quinolone derivatives

In targeted therapy of breast cancer, human epidermal growth factor receptor 2 HER2 (PDB ID: 3PP0) is being considered as a promising route to design novel anti-breast cancer drugs. In this work, we report two of novel N-substituted pyrrolidine at C-8 position of quinolone derivatives 18 and 19, their synthesis under microwave technique, spectral methods, molecular docking study and anti-HIV activities. Docking study exhibited hydrogen bonding, polar, and Van der Waals interactions with the active site residues of HER2 target. The binding energy and hydrogen bonding interactions show that synthesized compounds are being considered to have a potential activity against breast cancer. In addition, quinolone derivatives were evaluated in vitro for antiviral activity against the replication of HIV-1 and HIV-2 in MT-4 cells. The results showed that quinolone derivatives 18 and 19 possess a potent activity against HIV-1 replication with IC50 values of ≥15.20 and 14.26 μM, SI ≤ 6 and >7, respectively.

Discovery of novel indolylarylsulfones as potent HIV-1 NNRTIs via structure-guided scaffold morphing

For more in-depth exploration of the chemical space around the entrance channel of HIV-1 reverse transcriptase (RT), a series of novel indolylarylsulfones (IASs) bearing different chiral N-substituted pyrrolidine, azetidine or substituted sulfonamide groups at indole-2-carboxamide were designed and synthesized as potent HIV NNRTIs by structure-guided scaffold morphing approach. All the IASs exhibited moderate to excellent potency against wild-type HIV-1 with EC50 values ranging from 0.0043 μM to 4.42 μM. Notably, compound 27 (EC50 = 4.7 nM, SI = 5183) and 33 (EC50 = 4.3 nM, SI = 7083) were identified as the most potent compounds, which were more active than nevirapine, lamivudine and efavirenz, and also reached the same order of etravirine. Furthermore, some compounds maintained excellent activity against various single HIV-1 mutants (L100I, K103 N, E138K, Y181C) as well as one double mutant (F227L/V106A) with EC50 values in low-micromolar concentration ranges. Notably, 34 displayed outstanding potency against F227L/V106A (EC50 = 0.094 μM), and also showed exceptional activity against E138K (EC50 = 0.014 μM), L100I (EC50 = 0.011 μM) and K103 N (EC50 = 0.025 μM). Additionally, most compounds showed markedly reduced cytotoxicity (CC50) compared to lead compounds, especially 36 (CC50 > 234.91 μM, SI > 18727) and 37 (CC50 > 252.49 μM, SI > 15152). Preliminary SARs and molecular modeling studies were also discussed in detail, which may provide valuable insights for further optimization.

Transient and intermediate carbocations in ruthenium tetroxide oxidation of saturated rings.

The ruthenium tetroxide-mediated oxidation of cyclopentane, tetrahydrofuran, tetrahydrothiophene and N-substituted pyrrolidines has been studied computationally by DFT and topological (analysis of the electron localization function, ELF) methods. In agreement with experimental observations and previous DFT calculations, the rate-limiting step of the reaction takes place through a highly asynchronous (3 + 2) concerted cycloaddition through a single transition structure (one kinetic step). The ELF analysis identifies the reaction as a typical one-step-two-stages process and corroborates the existence of a transient carbocation. In the case of pyrrolidines, the carbocation is completely stabilized as an energy minimum in the form of an iminium ion and the reaction takes place in two steps.

Reduced Graphene Oxide Supported Copper Oxide Nanocomposites from a Renewable Copper Mineral Precursor: A Green Approach for Decarboxylative C(sp3)–H Activation of Proline Amino Acid To Afford Value-Added Synthons

A green approach for decarboxylative C(sp3)–H activation of proline amino acid was accomplished by coupling with aldehydes and alkynes to afford α-alkynylated N-substituted pyrrolidines as value-added synthons using reduced graphene oxide supported copper oxide (RGO@CuO) nanocatalysts. The RGO@CuO nanocomposites were obtained by the impregnation of micrometer-sized malachite spheres, as a renewable and sustainable copper mineral precursor, on the graphene oxide (GO) sheets followed by calcination at 300–450 °C for 5 h. The characterization of as-synthesized composites revealed the generation of monodispersed and uniformly embedded copper oxide (CuO) nanoparticles with sizes ranging from 10 to 15 nm on RGO thin sheets via GO as a support as well as indirect template for dissembling and decomposition of micrometer-sized malachite spheres. The RGO@CuO composites were found to be efficient and robust nanocatalysts compared with CuO nanoparticles (NPs) alone. The present method offers several advantages, such ...

N-Substituted pyrrolidines and tetrahydrofurans as novel AMPAR positive modulators

A series of novel AMPA receptor positive modulators displaying CNS penetration have been discovered with sub-micromolar activity and good selectivity over the cardiac channel receptor, hERG. We describe here the synthesis of these compounds which are biaryl pyrrolidine and tetrahydrofuran sulfonamides and disclose their activities against the human GluA2 flip isoform homotetrameric receptor.

Study of minimum energy conformers of N-substituted derivatives of piperidine and pyrrolidine. Evidence of weak H-bonding by theoretical correlation with experimental NMR data

Four N-substituted piperidines and four N-substituted pyrrolidines were synthesized and characterized by common spectroscopic techniques. In order to investigate the dynamic behavior of these important heterocyclic building blocks, a conformational study was carried out, using suitable tools of computational chemistry. The comparison of computed and experimental NMR chemical shifts is now accepted as a valuable aid in the elucidation of structures and that was the strategy followed in the present study. After a conformational search by statistical methods, the lowest three minimum-energy conformers of each piperidine/pyrrolidine derivative were analyzed (24 conformers in total). The relative proportion of each conformer was estimated by thermodynamic calculations, involving the Boltzmann weighting factor; P i. Using DFT methods, the geometry of each conformer was fully optimized and their chemical shifts ( 1H, 13C) were calculated. A very good coincidence between calculated and experimental data of both, 1H and 13C shifts was found, indicating that the theoretical geometries obtained were reliable enough for the study of structure-properties relationships. For all the conformers, specific weak unusual hydrogen bonding involving H–C instead of H–X (where X=electronegative atom) was observed. The nitrogen atom and the carbonyl oxygen participate in these interactions and could play an important role in the activity of these compounds and, therefore, they should be considered in the modeling of bioactive compounds. Furthermore, the good quality of theoretical/experimental data validates the theoretical methods used. The solvent effect (CDCl 3 in this case) was found of small significance on the observed H-bonding.

Simple and Efficient Synthesis of Substituted 2‐Pyrrolidinones, 2‐Pyrrolones, and Pyrrolidines from Enaminones of Baylis—Hillman Derivatives of 3‐Isoxazolecarbaldehydes.

The enaminones, generated from derivatives of appropriately substituted Baylis-Hillman adducts of 3-isoxazolecarbaldehydes, undergo intramolecular ring-closure reactions to afford substituted 2-pyrrolidinones, 1,5-dihydro-2-pyrrolones, and N-substituted pyrrolidines in good yields.

Simple and Efficient Synthesis of Substituted 2-Pyrrolidinones, 2-Pyrrolones, and Pyrrolidines from Enaminones of Baylis−Hillman Derivatives of 3-Isoxazolecarbaldehydes,

The enaminones, generated from derivatives of appropriately substituted Baylis-Hillman adducts of 3-isoxazolecarbaldehydes, undergo intramolecular ring-closure reactions to afford substituted 2-pyrrolidinones, 1,5-dihydro-2-pyrrolones, and N-substituted pyrrolidines in good yields.

Ring-closing double reductive amination route to aza-heteroannulated sugars

1,4-Dicarbonyl derivatives of glycosides are produced by ozonolysis or Wacker oxidation. A stable ozonide is isolated and a carbonyl group reduced whilst maintaining the ozonide functionality. The 1,4-dicarbonyl compounds are converted to various N-substituted pyrrolidines by diastereoselective double reductive amination The resulting aza-heteroannulated sugars no significant inhibition of any glycosidase, with the exception of compound 12g , which is a weak inhibitor of β-galactosidase.

Pyrrolidinic and piperidinic ring fission by conjugate elimination

Treating N-substituted pyrrolidines and piperidines bearing an allylic chain α to the nitrogen with strong bases leads to the opening of the heterocycle and provides 1,3-dienes disubstituted with an alkoxy and an aminoalkyl chain. The effects of the base and the solvent have been studied, as well as the influence of the ring size and the nitrogen substituent. The results obtained suggest a possible pre-chelation of the base cation before the deprotonation.

Reductive One Batch Synthesis of N-Substituted Pyrrolidines from Primary Amines and 2,5-Dimethoxytetrahydrofuran

Reductive One Batch Synthesis of N-Substituted Pyrrolidines from Primary Amines and 2,5-Dimethoxytetrahydrofuran

A Convenient Synthesis of Hindered N-Aryl Substituted Cyclic Amines

An efficient and high yielding synthesis of N-substituted pyrrolidines and piperidines is described.

The Nucleophilic Substitution Reaction of p-Chloronitrobenzene with N-Substituted Cyclic Amines under High Pressure

Abstract An aromatic nucleophilic substitution (SNAr) reaction of p-chloronitrobenzene with N-substituted pyrrolidines under high pressure gave p-pyrrolidinonitrobenzene and ring-opening products through quaternary ammonium salt. The selectivity of dealkylation and ring-opening depends on the electronic and steric factors of N-substituents. The reactions with N-methylaziridine and N-methylazetidine gave ring-opening products without affording any demethylation product.

Further chemical reactions of 1-pyrroline fatty ester: N-substituted pyrrolinium and pyrrolidine derivatives

The reactive CN bond of the 1-pyrroline fatty acid ester, methyl 8-(5-hexyl-2-pyrroline-1-yl)octanoate synthesized from methyl iso-ricinoleate (methyl 9-hydroxy-12- cis-octadecenoate) readily undergoes N-protonation, N-bromination, N-iodination N-nitration, N-nitrosation and N-oxymercuration to give the N-substituted 1-pyrrolinium derivatives by electrophilic addition reactions. Sodium borohydride reduction of the pyrrolinium derivatives yields the corresponding cis and trans N-substituted pyrrolidines. Addition of a nucleophile (CN −) to CN + bond of an N-methyl 1-pyrrolinium derivative forms trans-2,5,5-trisubstituted N-methyl ester derivative exclusively. The structures of these derivatives were characterized by infrared, 1H and 13C nuclear magnetic resonance spectroscopy.

Photocatalysed addition of pyrrolidines to butenolides: a concise synthesis of the pyrrolizidine alkaloid ring system

The regiospecific and stereoselective photocatalysed addition of N-substituted pyrrolidines to 5(S)-substituted furan-2-(5H)-ones (butenolides), and subsequent conversion of the adduct from N-(trimethylsilyl)pyrrolidine into the 1-azabicyclo[3.3.0]octane ring system of the pyrrolizidine alkaloids are described.

1,3-Dipolar cyctoadditions of 4,5-dihydroimidazolium ylides: new protocols for the synthesis of pyrrolidines and pyrrolo[1,2-a]pyrazines

1,3-Dipolar cycloadditions of 4,5-dihydroimidazolium ylides formed from 1-benzyl-4,5-dihydroimidazole proceed via a convenient one-step, one-pot protocol to give hexahydropyrrolo[1,2-a]imidazole esters, reduction of which leads to either hexahydropyrrolo[1,2-a]pyrazines or N-substituted pyrrolidines depending on the nature of the ester.

A simple asymmetric synthesis of 2-substituted pyrrolidines and 5-substituted pyrrolidinones

An efficient procedure for the preparation of the title compounds in high enantiomeric purity has been realized starting from 3-acylpropionic acids. Stereoselective reduction of chiral bicyclic lactams 2a-h, prepared from the corresponding γ-keto acid and (R)-phenylglycinol, using alane or triethylsilane with titanium tetrachloride provided the N-substituted pyrrolidines and pyrrolidinones, respectively. Subsequent cleavage of the phenylglycinol returned the desired amines and lactams. The enantiomeric purity of these compounds was determined to be >98% by chiral stationary-phase HPLC

Reaction of quinazoline-2,4(1H,3H)-dione with N-substituted cyclic amines in combination with phosphoryl trichloride

The reaction of quinazoline-2,4(1H,3H)-dione with N-allyl, N-benzyl and N-methyl cyclic amines in combination with phosphoryl trichloride in the presence of tripropylamine in 1,4-dioxane afforded 4-chloro-2-(cycloalkylamino)quinazolines. In the case of N-substituted pyrrolidines, 4-chloro-2-(N-substituted 4-chlorobutylamino) quinazolines were also obtained.

Borane-Methyl Sulfide Reductive Cyclization of ω-Ester Alkylamides: A Convenient Synthesis ofN-Substituted Cyclic Amines

Borane-methyl sulfide (BMS) reduction of variously N-substituted succinamic and glutaramic esters affords the corresponding N-substituted pyrrolidines and piperidines in high yields. The limitations, mainly caused by steric hinderance around the amine nitrogen, and putative intermediates involved in this conversion, as detected by incomplete reaction and/or synthesis followed by BMS reduction, indicate that cyclization and amide reduction successfully compete with ester reduction to afford the N-substituted cyclized amines.