Hetero Aryl Research Articles

Direct C–H Functionalization of Heteroarenes via Redox-Neutral Radical Process: A Facile Route to C–C Bonds Formation

Aromatic heterocycles are an important class of compounds found in a wide range of natural products, pharmaceutically active molecules and organic materials. Recently, the direct radical functionalization of heteroaromatic C–H bonds has become an efficient and attractive method to access substituted heteroarenes. Especially, redox-neutral radical reactions have attracted much attention of chemists due to their potential advantages such as mild conditions, free of external oxidants, and good functional group tolerance. So far, a series of redox-neutral radical reactions have been developed. In this review, we mainly focus on the recent advance in direct redox-neutral radical C–H functionalization of heteroarenes. Herein, the direct C–H arylation, C–H alkylation, and C–H fluoroalkylation of heteroarenes are represented respectively, providing practical routes to C–C bond formation.1 Introduction2 C–H Arylation of Heteroarenes with Aryl Radicals3 C–H Alkylation of Heteroarenes with Alkyl Radicals4 C–H Fluoroalkylation of Heteroarenes with Fluorine-Containing Carbon Radicals5 Concluding Remarks

Enantioselective reduction of aryl and hetero aryl methyl ketones using plant cell suspension cultures of Vigna radiata

Vigna radiata was investigated as whole cell catalyst for the bioreduction of aryl and heteroaryl prochiral ketones into optically active alcohols. The study indicates selective bioreduction of different substituted aryl and heteroaryl ketones (1a–12a) to their respective (S) – chiral alcohols (1b–12b) in good to high enantioselectivity (77.7–97.5%) with very good yields (73–82%). The results obtained confirm that the keto reductase has broad substrate specificity and selectivity in catalyzing both six and five-membered heteroaryl methyl ketones. The current methodology substantiates a promising and alternative green approach for the synthesis of secondary chiral alcohols of biological importance in a mild, cheap and environmentally benign process.

Synthesis and biological evaluation of novel quinazoline-sulfonamides as anti-cancer agents

A robust economic approach to N-(quinazoline-4-yl)sulfonamides was developed and synthesized different aryl, hetero aryl, alkyl and cyclopropyl sulfonamides in excellent yields. All the compounds were evaluated for cytotoxic affinity to SKOV3, DU145, THP1, U937, and COLO205 cell lines. Interesting to find that the bulkiness of substituent at C-2 position of quinazoline forces the molecule to flip around in order to bind in the active site, when compared to the binding preference of previously known quinazoline compounds. Among the 21 compounds synthesized 2b, 2d, 2e, 2h, 2i, 3c, 3d, 3f, 3g and 3h found to be active on all the cell lines tested with IC50 values <10µg/mL. Performed docking simulations to understand the binding preference of various C-2 substituted quinazoline sulfonamides.

Copper-Catalyzed Arylation with Diaryliodonium Salts

The unique reactivity of diaryliodonium salts with copper complexes has been applied to a variety of synthetic organic transformations. These hypervalent iodine compounds have been used for diverse copper-catalyzed cross-coupling reactions including C–H functionalizations, enantioselective C–C bond formation, cascade reactions and different heteroatom arylation processes. This review provides a summary of recent developments on this topic and discusses both the synthetic utility and mechanisms of these transformations. 1 Introduction 2 Historical Background 3 Arylation of Carbon Nucleophiles 3.1 Arylation of Organometallic Compounds 3.2 Arylation of Heteroarenes 3.3 Arylation of Arenes 3.4 Arylation of Alkenes 3.5 Arylation of Alkynes 4 Nitrogen Arylation 4.1 Arylation of Acyclic Amine Derivatives 4.2 Arylation of Cyclic Amine Derivatives 4.3 Arylation of Nitriles 4.4 Arylation of Azides 5 Oxygen Arylation 6 Arylation of Other Heteroatoms 6.1 Fluorine Arylation 6.2 Sulfur Arylation 6.3 Phosphorus Arylation 6.4 Iodine Arylation 7 Summary and Conclusions

Direct C–H Arylation of Heteroarenes with Aryl Chlorides by Using an Abnormal N‐Heterocyclic‐Carbene–Palladium Catalyst

Herein, we report a versatile catalytic system for the direct C–H arylation of heteroarenes with activated aryl chloride substrates. The catalyst works successfully for a variety of heteroarenes and aryl chloride coupling partners under very low catalyst‐loading conditions. We have successfully performed the direct C–H arylations of 1‐methylpyrrole, 1‐methylindole, furan, thiophene, furfural, and N‐benzyl‐1,2,3‐triazole with aryl chloride partners in good yields without the use of any additives. Furthermore, we used this catalytic process to develop a one‐pot synthetic protocol for the muscle relaxant dantrolene on a gram scale. Additionally, the present catalytic system can be used to perform consecutive arylations in one pot.

Anion Induced Dediazotization of In Situ Generated Aniline Diazonium Compounds in Direct C–H Arylation of Heteroarenes: An Experimental and Computational Study

AbstractDirect C–H arylation of heteroarenes with in situ generated diazonium compounds has been accomplished in the presence of hydrogen peroxide as an additive. The scope and limitation of this method were examined for several electron deficient aniline and electron rich heteroarenes. Computational studies revealed an intriguing mechanism for the generation of aryl radical from in situ generated aniline diazonium compounds.

Blue light mediated C–H arylation of heteroarenes using TiO2as an immobilized photocatalyst in a continuous-flow microreactor

Improved contacting of TiO2catalyst, substrate and light results in an impressive boost in reactor performance for blue light mediated C–H arylation of heteroarenes in continuous-flow mode.

A new face of phenalenyl-based radicals in the transition metal-free C-H arylation of heteroarenes at room temperature: trapping the radical initiator via C-C σ-bond formation.

The radical-mediated transition metal-free approach for the direct C-H bond functionalization of arenes is considered as a cost effective alternative to transition metal-based catalysis. An organic ligand-based radical plays a key role by generating an aryl radical which undergoes a subsequent functionalization process. The design principle of the present study takes advantage of a relatively stable odd alternant hydrocarbon-based phenalenyl (PLY) radical. In this study, the first transition metal-free catalyzed direct C-H arylation of a variety of heteroarenes such as azoles, furan, thiophene and pyridine at room temperature has been reported using a phenalenyl-based radical without employing any photoactivation step. This protocol has been successfully applied to the gram scale synthesis of core moieties of bioactive molecules. The phenalenyl-based radical initiator has been characterized crystallographically by trapping it via the formation of a C-C σ-bond between the phenalenyl radical and solvent-based radical species.

Mild and selective base-free C-H arylation of heteroarenes: experiment and computation.

A mild and selective C-H arylation strategy for indoles, benzofurans and benzothiophenes is described. The arylation method engages aryldiazonium salts as arylating reagents in equimolar amounts. The protocol is operationally simple, base free, moisture tolerant and air tolerant. It utilizes low palladium loadings (0.5 to 2.0 mol% Pd), short reaction times, green solvents (EtOAc/2-MeTHF or MeOH) and is carried out at room temperature, providing a broad substrate scope (47 examples) and excellent selectivity (C-2 arylation for indoles and benzofurans, C-3 arylation for benzothiophenes). Mechanistic experiments and DFT calculations support a Heck-Matsuda type coupling mechanism.

Silver-Mediated Sulfenylation of Indoles and Benzimidazoles with Di(hetero)aryl Disulfides

Silver-Mediated Sulfenylation of Indoles and Benzimidazoles with Di(hetero)aryl Disulfides

Ruthenium catalyzed β-C(sp3)-H functionalization on the 'privileged' piperazine nucleus.

β-C(sp3)-H functionalization on the 'privileged' piperazine nucleus has been disclosed using ruthenium catalysis. The ruthenium catalyzed synthesis of a variety of piperazine fused indoles from ortho-piperazinyl (hetero)aryl aldehydes is presented. This transformation takes place via the dehydrogenation of piperazine followed by an intramolecular nucleophilic addition of the transient enamine moiety onto the carbonyl group and aromatization cascade.

ChemInform Abstract: Synthesis of Aryl Trimethylstannanes from Aryl Halides: An Efficient Photochemical Method.

An efficient transition-metal-free photochemical method featuring excellent functional group tolerance, mild reaction conditions and short reaction times has been discovered and developed for the synthesis of (hetero)aryl trimethylstannanes from (hetero)aryl halides. A photo-initiated radical chain mechanism was proposed based on preliminary mechanistic studies.

Palladium-Catalyzed Direct α-Arylation of p-Methoxybenzyl-Protected S,S-Dimethylsulfoximine

Sulfoximines have recently gained considerable recognition as an important structural motif in the life sciences. This is especially true for (hetero)aryl-substituted S,S-dimethylsulfoximine derivatives, such as the marketed insecticide sulfoxaflor, as well as the clinical candidates­ PTEFb inhibitor BAY 1143572 and ATR inhibitor AZD 6738 for the treatment of cancer. Herein, the first palladium-catalyzed direct α-arylation of p-methoxybenzyl-protected S,S-dimethylsulfoximine using readily available (hetero)aryl bromides is reported. This new method provides a safe, short, and efficient approach to (hetero)aryl-substituted­ S,S-dimethylsulfoximine derivatives, an important class of bioactive compounds, demonstrated by application of this methodology to an improved synthesis of PTEFb inhibitor BAY 1143572.

Palladium(II) Complex of 4-Pyridylselenolate Ligand: An Efficient Catalyst for Aminocarbonylation of Aryl and Hetero Aryl Iodides with Primary Amines

The present work describes the synthesis of palladium(II) complex with non-chelating 4-pyridylselenolate ligand as [PdCl(4-SeC5H4N)(PPh3)2]. The catalyst was found to be active for aminocarbonylation reaction of aryl and hetero aryl iodides with primary amines using carbon monoxide a simple and efficient C1 source. The catalytic system was optimized with respect to various reaction parameters to give excellent yield of desired products. The milder reaction conditions and wild functional groups tolerance enhance its practical applicability.

ChemInform Abstract: CuI/Oxalamide Catalyzed Couplings of (Hetero)aryl Chlorides and Phenols for Diaryl Ether Formation.

Couplings between (hetero)aryl chlorides and phenols can be effectively promoted by CuI in combination with an N-aryl-N′-alkyl-substituted oxalamide ligand to proceed smoothly at 120 °C. For this process, N-aryl-N′-alkyl-substituted oxalamides are more effective ligands than bis(N-aryl)-substituted oxalamides. A wide range of electron-rich and electron-poor aryl and heteroaryl chlorides gave the corresponding coupling products in good yields. Satisfactory conversions were achieved with electron-rich phenols as well as a limited range of electron-poor phenols. Catalyst and ligand loadings as low as 1.5 mol % are sufficient for the scaled-up variants of some of these reactions.

Direct C–H Arylation of Heteroarenes with Copper Impregnated on Magnetite as a Reusable Catalyst: Evidence for CuO Nanoparticle Catalysis in Solution

A reusable copper-based catalyst system was employed for the direct arylation of electron-rich heteroarenes. Under mild and operationally simple reaction conditions good yields and selectivities were obtained using diaryliodonium salts as coupling partners. A combination of experimental methods including kinetic studies, filtration tests, and a series of analytical tools (TXRF, ICP-MS, SEM, XPS, TEM, EFTEM) provide evidence for catalytically active soluble nanoparticles formed from an amorphous heterogeneous precursor. Mechanistic studies hint at a redox-neutral process which promotes counterion dissociation from the diaryliodonium salt by a copper(II) oxide species.

Visible Light Mediated Photoredox Catalytic Arylation Reactions.

Introducing aryl- and heteroaryl moieties into molecular scaffolds are often key steps in the syntheses of natural products, drugs, or functional materials. A variety of cross-coupling methods have been well established, mainly using transition metal mediated reactions between prefunctionalized substrates and arenes or C-H arylations with functionalization in only one coupling partner. Although highly developed, one drawback of the established sp2-sp2 arylations is the required transition metal catalyst, often in combination with specific ligands and additives. Therefore, photoredox mediated arylation methods have been developed as alternative over the past decade. We begin our survey with visible light photo-Meerwein arylation reactions, which allow C-H arylation of heteroarenes, enones, alkenes, and alkynes with organic dyes, such as eosin Y, as the photocatalyst. A good number of examples from different groups illustrate the broad application of the reaction in synthetic transformations. While initially only photo-Meerwein arylation-elimination processes were reported, the reaction was later extended to photo-Meerwein arylation-addition reactions giving access to the photoinduced three component synthesis of amides and esters from alkenes, aryl diazonium salts, nitriles or formamides, respectively. Other substrates with redox-active leaving groups have been explored in photocatalyzed arylation reactions, such as diaryliodonium and triarylsulfonium salts, and arylsulfonyl chlorides. We discus some examples with their scope and limitations. The scope of arylation reagents for photoredox reactions was extended to aryl halides. The challenge here is the extremely negative reduction potential of aryl halides in the initial electron transfer step compared to, e.g., aryl diazonium or diaryliodonium salts. In order to reach reduction potentials over -2.0 V vs SCE two consecutive photoinduced electron transfer steps were used. The intermediary formed colored radical anion of the organic dye perylenediimide is excited by a second photon allowing the one electron reduction of acceptor substituted aryl chlorides. The radical anion of the aryl halide fragments under the loss of a halide ion and the aryl radical undergoes C-H arylation with biologically important pyrrole derivatives or adds to a double bond. Rhodamine 6G as an organic photocatalyst allows an even higher degree of control of the reaction. The dye is photoreduced in the presence of an amine donor under irradiation with green light (e.g., 530 nm), yielding its radical anion, which is a mild reducing reagent. The hypsochromic shift of the absorption of the rhodamine 6G radical anion toward blue region of the visible light spectrum allows its selective excitation using blue light (e.g., 455 nm). The excited radical anion is highly reducing and able to activate even bromoanisole for C-H arylation reactions, although only in moderate yield. Photoredox catalytic C-H arylation reactions are valuable alternatives to metal catalyzed reactions. They have an excellent functional group tolerance, could potentially avoid metal containing catalysts, and use visible light as a traceless reagent for the activation of arylating reagents.

Room-Temperature Gold-Catalysed Arylation of Heteroarenes: Complementarity to Palladium Catalysis.

Tailoring of the pre-catalyst, the oxidant and the arylsilane enables the first room-temperature, gold-catalysed, innate C-H arylation of heteroarenes. Regioselectivity is consistently high and, in some cases, distinct from that reported with palladium catalysis. Tolerance to halides and boronic esters, in both the heteroarene and silane partners, provides orthogonality to Suzuki-Miyaura coupling.

Practical Method for the Preparation of 2,2-Dimethyl-5-{aryl[(hetero)aryl]methyl}-1,3-dioxane-4,6-diones: Synthesis and Mechanistic Study

An efficient practical synthetic procedure has been developed for the synthesis of 2,2-dimethyl-5-{aryl[(hetero)aryl]methyl}-1,3-dioxane-4,6-diones through Friedel–Crafts alkylation. The scope and limitation of the reaction of 2,2-dimethyl-5-arylidene-1,3-dioxane-4,6-diones with π-excess aromatic systems have been delineated.

β‐Lactam Preparation via Staudinger Reaction with Activated Dimethylsulfoxide

An efficient synthesis of β‐lactams has been expediently accomplished. These β‐lactams were synthesized by the Staudinger reaction of several substituted imines with various carboxylic acids using activated DMSO at ambient temperature. The imines and substituted acetic acids contain alkyl, aryl, hetero aryl, polycyclic, and 3‐electron‐withdrawing group underwent [2 + 2] ketene‐imine cycloaddition reaction smoothly to obtain the desired β‐lactams in good to excellent yields. This method is cheap, simple, convenient, and efficient, and the products are easily isolated.