Recent synthetic strategies for N-arylation of pyrrolidines: a potential template for biologically active molecules.

The chemistry of nitrogen-containing heterocyclic compounds has been a multifaceted area of research for an extended period due to their varied therapeutic and biological significance. N-Aryl pyrrolidine formed by condensation of aryl group with nitrogen atom of pyrrolidine is present in a wide array of compounds. Various significant activities shown by N-arylated pyrrolidine include anti-Alzheimer, antihypoxic, anticancer, plant activator, analgesic effect, and hepatitis C inhibitor. This review summarizes different synthetic approaches, e.g., transition-metal catalyzed and transition-metal-free synthesis, decarboxylation reaction, reductive amination, nucleophilic cyclization, Ullmann-Goldberg amidation, Buchwald-Hartwig reaction, Chan-Evans-Lam coupling, addition to benzyne, multistep reaction, green synthesis, rearrangement reaction, and multicomponent reaction, to afford the derivatives of N-aryl pyrrolidine. It encompasses synthetic strategies documented from 2015 to 2023.

Exploration of N-Arylation of Backbone Amides as a Novel Tool for Conformational Modification in Peptides.

A set of 15 cyclic-hexaalanine and 10 cyclic-pentaalanine peptides containing one or two backbone N-aryl amide bonds were synthesized by following a combination of solution-phase and solid-phase peptide synthesis. NMR-based conformation studies of these N-aryl cyclic-hexaalanine peptides revealed five distinct template conformations with an antiparallel ß-sheet structure; for N-aryl cyclic-pentaalanine peptides three template structures were revealed. All the template structures have distinct peptide-turn features. The conformations in these N-aryl peptides were compared to those in the commonly studied N-methyl peptide analogues. We observed that the N-aryl peptides exhibit a considerable conformational homogeneity, and their conformations differ significantly from those in N-methyl analogues. We anticipate that the N-arylation of backbone amides has the potential for application as a novel tool for conformation and physicochemical modification in peptides.

Synthesis and Anti-Inflammatory Activity of N(2)-Arylindazol-3(2H)-One Derivatives: Copper-Promoted Direct N-Arylation via Chan-Evans-Lam Coupling.

Inflammatory-related diseases are becoming increasingly prevalent, leading to a growing focus on the development of anti-inflammatory agents, with a particular emphasis on creating novel structural compounds. In this study, we present a highly efficient synthetic method for direct N-arylation to produce a variety of N(2)-arylindazol-3(2H)-ones 3, which exhibit anti-inflammatory activity. The Chan-Evans-Lam (CEL) coupling of N(1)-benzyl-indazol-3-(2H)-ones 1 with arylboronic acids 2 in the presence of a copper complex provided the corresponding N(2)-arylindazol-3(2H)-ones 3 in good-to-excellent yields, as identified with NMR, MS, and X-ray crystallography techniques. The cell viability and anti-inflammatory effects of the synthesized compounds (3 and 5) were briefly assessed using the MTT method and Griess assay. Among them, compounds 5 exhibited significant anti-inflammatory effects with negligible cell toxicity.

Aryne-Enabled C-N Arylation of Anilines.

Anilines are potentially high-value arylating agents, but are limited by the low reactivity of the strong C-N bond. We show that the reactive intermediate benzyne can be used to both activate anilines, and set-up an aryl transfer reaction in a single step. The reaction does not require any transition metal catalysts or stoichiometric organometallics, and establishes a metal-free route to valuable biaryl products by functionalizing the aniline C-N bond.

N-Arylation of 3-Formylquinolin-2(1H)-ones Using Copper(II)-Catalyzed Chan-Lam Coupling.

3-formyl-2-quinolones have attracted the scientific community's attention because they are used as versatile building blocks in the synthesis of more complex compounds showing different and attractive biological activities. Using copper-catalyzed Chan-Lam coupling, we synthesized 32 new N-aryl-3-formyl-2-quinolone derivatives at 80 °C, in air and using inexpensive phenylboronic acids as arylating agents. 3-formyl-2-quinolones and substituted 3-formyl-2-quinolones can act as substrates, and among the products, the p-methyl derivative 9a was used as a substrate to obtain different derivatives such as alcohol, amine, nitrile, and chalcone.

Copper-Promoted N-Arylation of the Imidazole Side Chain of Protected Histidine by Using Triarylbismuth Reagents.

The N-arylation of the side chain of histidine by using triarylbismuthines is reported. The reaction is promoted by copper(II) acetate in dichloromethane at 40 °C under oxygen in the presence of diisopropylethylamine and 1,10-phenanthroline and allows the transfer of aryl groups with substituents at any position of the aromatic ring. The reaction shows excellent functional group tolerance and is applicable to dipeptides where the histidine is located at the N terminus. A histidine-guided backbone N-H arylation was observed in dipeptides where the histidine occupies the C terminus.

Stereoretentive N-Arylation of Amino Acid Esters with Cyclohexanones Utilizing a Continuous-Flow System.

The N-arylation of chiral amino acid esters with minimal racemization is a challenging transformation because of the sensitivity of the α-stereocenter. A versatile synthetic method was developed to prepare N-arylated amino acid esters using cyclohexanones as aryl sources under continuous-flow conditions. The designed flow system, which consists of a coil reactor and a packed-bed reactor containing a Pd(OH)2 /C catalyst, efficiently afforded the desired N-arylated amino acids without significant racemization, accompanied by only small amounts of easily removable co-products (i. e., H2 O and alkanes). The efficiency and robustness of this method allowed for the continuous synthesis of the desired product in very high yield and enantiopurity with high space-time yield (74.1 g L-1 h-1 ) and turnover frequency (5.9 h-1 ) for at least 3 days.

Transition Metal Exchanged Hydroxyapatite/Fluorapatite Catalysts for C-C and C-N Bond Forming Reactions.

Transition metal (Cu, Zn, Rh, Pd) exchanged hydroxyapatite (HAP)/fluorapatite (FAP) materials have been synthesized by ion-exchange method resulting in incorporation of the metal ions in the HAP/FAP structure. C-C and C-N bond forming reactions are important in synthetic organic chemistry as these organic transformations are very critical. Transition metal exchanged FAP provides an efficient catalytic system for N-arylation of haloarenes and Suzuki and Heck coupling of haloarenes. By designing such catalytic materials, our group has developed synthetic methods which allow higher product yields and easy separation with the use of a small amount of catalyst in a shorter reaction time. This account addresses the work carried out in last two decades in the area of C-C and C-N bond forming reactions using transition metal exchanged fluorapatite.

Deprotometalation-Iodolysis and Direct Iodination of 1-Arylated 7-Azaindoles: Reactivity Studies and Molecule Properties.

Five protocols were first compared for the copper-catalyzed C-N bond formation between 7-azaindole and aryl/heteroaryl iodides/bromides. The 1-arylated 7-azaindoles thus obtained were subjected to deprotometalation-iodolysis sequences using lithium 2,2,6,6-tetramethylpiperidide as the base and the corresponding zinc diamide as an in situ trap. The reactivity of the substrate was discussed in light of the calculated atomic charges and the pKa values. The behavior of the 1-arylated 7-azaindoles in direct iodination was then studied, and the results explained by considering the HOMO orbital coefficients and the atomic charges. Finally, some of the iodides generated, generally original, were involved in the N-arylation of indole. While crystallographic data were collected for fifteen of the synthesized compounds, biological properties (antimicrobial, antifungal and antioxidant activity) were evaluated for others.

Recent Progress Concerning the N-Arylation of Indoles.

This review summarizes the current state-of-the-art procedures in terms of the preparation of N-arylindoles. After a short introduction, the transition-metal-free procedures available for the N-arylation of indoles are briefly discussed. Then, the nickel-catalyzed and palladium-catalyzed N-arylation of indoles are both discussed. In the next section, copper-catalyzed procedures for the N-arylation of indoles are described. The final section focuses on recent findings in the field of biologically active N-arylindoles.

N-Arylation of Protected and Unprotected 5-Bromo-2-aminobenzimidazole as Organic Material: Non-Linear Optical (NLO) Properties and Structural Feature Determination through Computational Approach.

The interest in the NLO response of organic compounds is growing rapidly, due to the ease of synthesis, availability, and low loss. Here, in this study, Cu(II)-catalyzed selective N-arylation of 2-aminobenzimidazoles derivatives were achieved in the presence of different bases Et3N/TMEDA, solvents DCM/MeOH/H2O, and various aryl boronic acids under open atmospheric conditions. Two different copper-catalyzed pathways were selected for N-arylation in the presence of active nucleophilic sites, providing a unique tool for the preparation of NLO materials, C-NH (aryl) derivatives of 2-aminobenzimidazoles with protection and without protection of NH2 group. In addition to NMR analysis, all synthesized derivatives (1a-1f and 2a-2f) of 5-bromo-2-aminobenzimidazole (1) were computed for their non-linear optical (NLO) properties and reactivity descriptor parameters. Frontier molecular orbital (FMO) analysis was performed to get information about the electronic properties and reactivity of synthesized compounds.

Mild Copper-Catalyzed, l-Proline-Promoted Cross-Coupling of Methyl 3-Amino-1-benzothiophene-2-carboxylate.

Cu-catalyzed N-arylation is a useful tool for the chemical modification of aromatic heterocycles. Herein, an efficient carbon-nitrogen cross-coupling of methyl 3-amino-1-benzothiophene-2-carboxylate with a range of (hetero)aryl iodides using CuI, l-proline and Cs2CO3 in dioxane at moderate temperature is described. The procedure is an extremely general, relatively cheap, and experimentally simple way to afford the N-substituted products in moderate to high yields. The structures of the new heterocyclic compounds were confirmed by NMR spectroscopy and HRMS investigation.

New Synthetic Approaches to N-Aryl and π-Expanded Diketopyrrolopyrroles as New Building Blocks for Organic Optoelectronic Materials.

Diketopyrrolopyrrole (DPP) as a building block has been intensively investigated for organic semiconductors and light emitting materials. The synthesis of N-aryl DPPs remains challenging. Herein, we firstly report a new easily handled synthetic method toward N-aryl DPPs through H-DPP with diaryliodonium salt in the presence of CuI, which shows broad reaction scope. Sixteen N-aryl DPPs, including phenyl, furan and thiophene as flanking aromatic groups, were synthesized with yields up to 78 %. These N-aryl DPPs are fluorescent in both solutions and solid states, with quantum yields up to 96 % and 40 %, respectively. Moreover, we show that the reaction between H-DPP and diaryliodonium salt can lead to π-expanded DPPs by using Pd(OAc)2 as catalyst. Nine π-expanded DPPs were obtained in 27-61 % yields. These π-expanded DPPs exhibit good semiconducting properties with hole mobility of 0.71 cm2 V-1 s-1 , demonstrating that they are useful building blocks for high performance organic semiconductors.

Efficient N-arylation of 4-chloroquinazolines en route to novel 4-anilinoquinazolines as potential anticancer agents.

Microwave-mediated N-arylation of 4-chloroquinazolines in THF/H2O rapidly and efficiently afforded a library of novel 6-halo-2-phenyl-substituted 4-anilinoquinazolines. The methodology was compatible with numerous ortho-, meta-, and para-substituted N-methylanilines as well as substituted anilines and furnished the corresponding 4-anilinoquinazolines in good yields. Preliminary screening of the synthesized compounds against tumor cells (HCT-116 and T98G) showed promising antiproliferative properties.

Functionalization of 9-thioxanthone at the 1-position: From arylamino derivatives to [1]benzo(thio)pyrano[4,3,2-de]benzothieno[2,3-b]quinolines of biological interest.

Original 1-amino substituted thioxanthone derivatives were easily prepared from the bare heterocycle by a deprotometalation-iodolysis-copper-catalyzed CN bond formation sequence. This last reaction delivered mono- or/and diarylated products depending on the aniline involved. 1-Amino-9-thioxanthone was also prepared and reacted with 2-iodoheterocycles. Interestingly, while 1-(arylamino)-9-thioxanthones could be isolated, their subsequent cyclization was found to deliver original hexacyclic derivatives of helicoidal nature. Evaluation of their photophysical properties revealed high fluorescence in polar media, indicating potential applications for biological imaging. These compounds being able to inhibit PIM1 kinase, their putative binding mode was examined through molecular modeling experiments. Altogether, these results tend to suggest the discovery of a new family of fluorescent PIM inhibitors and pave the way for their future rational optimization.

Accelerating fragment-based library generation by coupling high-performance photoreactors with benchtop analysis.

Herein we report a workflow coupling photoredox-nickel dual-catalyzed N-arylation reactions to benchtop analysis for the efficient generation of fragment-based libraries. Technological advances in photoreactor design facilitated reliable and reproducible experimentation. Knowledge on the reactivity under previously reported reaction conditions of spirocyclic and strained heterocyclic building blocks, viewed as chemistry informers, could thus be rapidly accessed, identifying privileged or challenging scaffolds and paving the way for further exploration.

Synthetic applications and methodology development of Chan-Lam coupling: a review.

Chan-Lam coupling is one of the most popular and easy methods to perform arylation of amines (N-arylations). This cross-coupling is generally performed by reacting aryl boronate derivatives with a variety of substrates involving nitrogen containing functional groups such as amines, amides, ureas, hydrazine, carbamates. This article summarizes the synthetic applications of this reaction and the efforts of scientists to develop novel and efficient methodologies for this reaction.

Base-Promoted SNAr Reactions of Fluoro- and Chloroarenes as a Route to N-Aryl Indoles and Carbazoles.

KOH/DMSO-promoted C-N bond formation via nucleophilic aromatic substitution (SNAr) between chloroarenes or fluoroarenes with indoles and carbazole under transition metal-free conditions affording the corresponding N-arylated indoles and carbazoles has been developed.

Transition-Metal-Free N-Arylation of Amines by Triarylsulfonium Triflates.

A simple and efficient method for transition-metal-free N-arylation of various amines by triarylsulfonium triflates is described. Both aliphatic and aromatic amines were smoothly converted at 80 °C in the presence of tBuOK or KOH to give the corresponding mono N-arylated products in good to high yields. The molar ratios of the reactants and the choice of bases had a big effect on the reaction. When a large excess of [Ph3 S][OTf] and tBuOK were employed for primary amines under the standard conditions, the bis(N-phenyl) products were predominantly formed. This method was also applicable to the synthesis of bioactive N-phenyl amino acid derivatives. The control experiments, the deuterium labelling study, and the presence of regioisomers of N-arylated products when using 4-substituted triarylsulfonium triflates suggested that the reaction might proceed through an aryne intermediate. The present protocol demonstrated that triarylsulfonium salts are versatile arylation reagents in the construction of CAr -N bonds.

Visible-Light-Mediated Photoredox-Catalyzed N-Arylation of NH-Sulfoximines with Electron-Rich Arenes.

The direct C-H/N-H dehydrogenative cross-coupling of NH-sulfoximines with electron-rich arenes was realized by oxidative visible-light photoredox catalysis, applying 9-mesityl-10-methylacridinium perchlorate as an organic photocatalyst. Sulfoximines display diverse desirable properties for medicinal chemistry and the pharmaceutical industry. However, their preparation is still challenging. Our reaction proceeds without sacrificial oxidant, at room temperature and is highly selective for the C-N bond forming reaction. The scope of the reaction includes mono- and multi-alkylated and halogenated arenes, which are reacted with aromatic and aliphatic electron-rich and electron-poor NH-sulfoximines, giving moderate to excellent yields of the N-arylated sulfoximines. In addition, we successfully conducted the developed reaction on a gram scale (1.5 g). Mechanistic investigations show that both arene and NH-sulfoximine interact with the excited-state of the photocatalyst. We propose a radical-based mechanism, where both the arene and the NH-sulfoximine are photo-oxidized to their respective radical intermediates. Radical-radical cross-coupling subsequently leads to the N-arylated sulfoximine. Two electrons and two protons are released during the reaction and are subsequently converted into H2 by a proton-reducing cobalt-catalyst.