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.

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.

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.

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.

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.

Recent Developments in Arylation of N-Nucleophiles via Chan-Lam Reaction: Updates from 2012 Onwards.

''Chan-Evans-Lam'' (CEL) reaction is the copper-mediated cross-coupling of N-nucleophiles with boronic acids that was independently reported in 1998 by Chan, Evans, and Lam for the first time. This reaction is accomplished at room temperature with a remarkably wide range of nucleophiles. In the recent decade, it has been particularly attractive as a convenient method for constructing the various C- N bonds in organic synthesis. Therefore, a comprehensive survey through all reported process was crucial. In this review, we summarized research progress about N-Arylation, based on the type of N-nucleophile involved in this reaction and catalysts from 2012 onwards.

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.

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.

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.

Recent Advances in Transition-Metal-Free Late-Stage C-H and N-H Arylation of Heteroarenes Using Diaryliodonium Salts.

Transition-metal-free direct arylation of C-H or N-H bonds is one of the key emerging methodologies that is currently attracting tremendous attention. Diaryliodonium salts serve as a stepping stone on the way to alternative environmentally friendly and straightforward pathways for the construction of C-C and C-heteroatom bonds. In this review, we emphasize the recent synthetic advances of late-stage C(sp2)-N and C(sp2)-C(sp2) bond-forming reactions under metal-free conditions using diaryliodonium salts as arylating reagent and its applications to the synthesis of new arylated bioactive heterocyclic compounds.

Novel magnetic lignosulfonate-supported Pd complex as an efficient nanocatalyst for N-arylation of 4-methylbenzenesulfonamide.

This study presents a novel, economical, and environmentally technique for synthesizing magnetic palladium complex conjugated to activated calcium lignosulfonate with triethylenetetramine (Fe3O4@lignosulfonate@triethylenetetramine@Pd complex (FLT-Pd complex)) as a practical and air-stable catalyst. FLT-Pd complex is used as a catalyst for the fabrication of 4-methyl-N-phenyl-benzenesulfonamide derivatives via N-arylation of 4-methylbenzenesulfonamide in good yields. Furthermore, because of the complex magnetic reparability and high stability, it could be removed easily from the reaction media using a magnet and reused 5 cycles without a remarkable loss of catalytic prowess.

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.

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.

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.

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.

Development of Porous Cobalt-/Copper-Doped Carbon Nanohybrids Derived from Functionalized MOFs as Efficient Catalysts for the Ullmann Cross-Coupling Reaction: Insights into the Active Centers.

Newly emerging poly-functional metal-organic frameworks (MOFs) have been proved to be a promising alternative method for the hard/soft template to generate different carbon-based heterostructures. Herein, we have synthesized a sulfonyl-amide-based MOF (TMU-81) with an exceptionally high concentration of functional groups, which can interact strongly with metal ions and utilized it as a double-template platform to fabricate versatile catalysts by remaining structural regularity. The preloaded copper ions resided in pores of TMU-81 not only play a significant role in pore-forming by in situ renovating into Cu nanoparticles via the pyrolysis process but also trigger the morphological transformations of the resultant metal/carbon hybrids. The morphology of the TMU-81 was tuned from truncated octahedron to cubic in cobalt-/copper-doped carbon nanohybrids (MC-81), and also the Brunauer-Emmett-Teller surface area increased significantly up to 1450 cm2/g. Benchmarks have been established for the performance of TMU-81, pyrolyzed TMU-81 (P-TMU-81), and MC-81s, as efficient and robust catalysts for the C-N cross-coupling reaction with aryl-halides and amines. The obtained MC-81 showed superior performance compared with pristine TMU-81 and pyrolyzed P-TMU-81. The catalysis performance is found to be closely dependent on the amount of preloaded Cu2+ ions in the MOFs. After 5 cycles, the catalysts were reusable without any significant loss of activity. Benefiting from the structural and compositional advantages, the present approach offers an intelligent way to synthesis and design of structurally complex MOF hybrid and derived functionalized systems.

Efficient Arylation of 2,7-Naphthyridin-1(2H)-one with Diaryliodonium Salts and Discovery of a New Selective MET/AXL Kinase Inhibitor.

New 8-chloro-2-phenyl-2,7-naphthyridin-1(2H)-one building blocks bearing diverse substitutes on the 2-phenyl group were synthesized via an efficient diaryliodonium salt-based N-arylation strategy with the advantage of mild conditions, short reaction times, and high yields. A small combinatorial library of 8-amino substituted 2-phenyl-2,7-naphthyridin-1(2H)-one was further conveniently constructed based on the above chlorinated naphthyridinones and substituted aniline. Preliminary biochemical screening resulted in the discovery of the new 2,7-naphthyridone-based MET/AXL kinase inhibitors. More importantly, 17c (IC50,MET of 13.8 nM) or 17e (IC50,AXl of 17.2 nM) and 17i (IC50,AXl of 31.8 nM) can efficient selectively inhibit MET or AXL kinase, respectively, while commercial cabozantinib showed no selectivity. The further exploration of the 8-substituted 2-phenyl-2,7-naphthyridin-1(2H)-one combinatorial library would significantly accelerate the discovery of more potent and selective inhibitors against diverse kinases.

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.