Aromatic Substitution Process Research Articles

Robust Catalytic SEAr H/D Exchange of Arenes with D2O: Metal‐Free Deuteration of Natural Complexes and Drugs

AbstractA catalytic metal‐free approach for the H/D exchange in aromatic compounds using D2O as the terminal deuterating reagent has been developed. This metal‐free protocol employs a triaryl carbenium as the mediator and showcases a wide applicability in the late‐stage deuteration of various natural products and small‐molecule drugs. Gram‐scale deuteration was successfully demonstrated with β‐Estradiol, highlighting the method‘s practicability. Detailed mechanistic insights, supported by DFT calculations, unveiled the essential role of in situ generated acidic species in this electrophilic aromatic substitution process. This newly developed method offers a sustainable and versatile alternative to traditional metal‐catalyzed H/D exchange techniques, addressing challenges such as the use of expensive metals, impurity formation, and the necessity for residual metal removal from the final products.

Robust Catalytic SEAr H/D Exchange of Arenes with D2O: Metal-Free Deuteration of Natural Complexes and Drugs.

A catalytic metal-free approach for the H/D exchange in aromatic compounds using D2O as the terminal deuterating reagent has been developed. This metal-free protocol employs a triaryl carbenium as the mediator and showcases a wide applicability in the late-stage deuteration of various natural products and small-molecule drugs. Gram-scale deuteration was successfully demonstrated with β-Estradiol, highlighting the method's practicability. Detailed mechanistic insights, supported by DFT calculations, unveiled the essential role of in situ generated acidic species in this electrophilic aromatic substitution process. This newly developed method offers a sustainable and versatile alternative to traditional metal-catalyzed H/D exchange techniques, addressing challenges such as the use of expensive metals, impurity formation, and the necessity for residual metal removal from the final products.

Photoinduced α-Aminoalkylation of Sulfonylarenes with Alkylamines.

α-Aminoalkylation of sulfonylarenes with alkylamines was found to be induced by photoirradiation. Here various types of alkylamines, such as trialkylamines, dialkylamines, N,N-dialkylanilines and N-alkylanilines as well as sulfonylarenes containing an azole, azine, heterole or benzene ring are available. The reaction proceeds through a homolytic aromatic substitution (HAS) process consisting of addition of an α-aminoalkyl radical to a sulfonylarene and elimination of the sulfonyl radical to give the α-arylalkylamine, where photoirradiation is considered to induce homolysis of sulfonylarenes leading to the generation of α-aminoalkyl radicals that make a radical chain operative.

Palladium-catalyzed C8–H arylation and annulation of 1-naphthalene carboxylic acid derivatives with aryl iodides

Disclosed herein is palladium-catalyzed C8–H arylation and annulation of 1-naphthoic acid derivatives with aryl iodides in a low reactant molar ratio via an electrophilic aromatic substitution (SEAr) process.

Gold(I)-Catalyzed Aromatization: Expeditious Synthesis of Polyfunctionalized Naphthalenes.

SummaryA gold-catalyzed 6-endo-dig carbocyclization of alkyne with the pendent diazo group is reported. It provides an expeditious approach for the synthesis of multi-functionalized naphthalene derivatives under mild conditions. Mechanistic studies suggest that a vinyl gold carbene is generated as the key intermediate in this cascade transformation that smoothly delivers naphthalene products through an unprecedented stepwise aromatization or an intermolecular aromatic substitution process. The unique endocyclic vinyl species is inaccessible with other precursors; thus, novel carbene cascade transformations could be envisioned with the current catalytic model. Functional groups, such as alkenyl, hydroxyl, amino, and carboxyl groups, remain untouched under these conditions. In addition, the utility of these generated 2-carboxyl naphthalenes is illustrated by the synthesis of chiral 1,2′-binaphthalene ligands and π-conjugated polycyclic hydrocarbons (CPHs).

Cooperative Au/Ag Dual-Catalyzed Cross-Dehydrogenative Biaryl Coupling: Reaction Development and Mechanistic Insight.

An operationally simple and highly selective Au/Ag bimetallic-catalyzed cross-dehydrogenative biaryl coupling between pyrazoles and fluoroarenes has been developed. With this reaction, a wide range of biheteroaryl products can be obtained in moderate to good yields with excellent functional group compatibility. The exact role of silver salts, previously overlooked in most gold-catalyzed transformations, has been carefully investigated in this biaryl coupling. Insightful experimental and theoretical studies indicate that silver acetate is the actual catalyst for C-H activation of electron-poor arenes, rather than the previously reported gold(I)-catalyzed process. An unprecedented Au/Ag dual catalysis is proposed, in which silver(I) is responsible for the activation of electron-poor fluoroarenes via a concerted metalation-deprotonation pathway, and gold(III) is responsible for the activation of electron-rich pyrazoles via an electrophilic aromatic substitution process. Kinetic studies reveal that ArFnAu(III)-mediated C-H activation of pyrazoles is most likely the rate-limiting step.

Amination of Aromatic Halides and Exploration of the Reactivity Sequence of Aromatic Halides.

A base-promoted amination of aromatic halides has been developed using a limited amount of dimethylformamide (DMF) or amine as an amino source. Various aryl halides, including F, Cl, Br, and I, have been successfully aminated in good to excellent yields. Although the amination of aromatic halides with amines or DMF is usually considered as an aromatic nucleophilic substitution (SNAr) process, and the reactivity of an aromatic halide is F > Cl > Br > I, the reactivity of aromatic halides in this system was found to be I > Br ≈ F > Cl. This protocol also showed a good regioselectivity for multihalogenated aromatics. This protocol is valuable for industrial application due to the simplicity of operation, the unrestricted availability of amino sources and aromatic halides, transition metal-free conditions, no requirement for solvent, and scalability.

Selective Synthesis of Diaryl Sulfoxides and m-Arylthio Sulfones from Arylsulfinic Acids and Arenes via BF3-Promoted C-S Bond Formation.

A novel and efficient method for selective synthesis of diaryl sulfoxides and m-arylthio sulfones has been achieved from readily available arylsulfinic acids and arenes via an unusual sulfinyl cation, providing a range of structurally diverse products in good to excellent yields under mild conditions. Notably, mechanistic investigations suggested m-arylthio sulfones were generated from diaryl sulfoxides and sulfinyl cation by a sequence of redox reaction and electrophilic aromatic substitution process.

Transition‐Metal‐Free Catalytic Hydrodefluorination of Polyfluoroarenes by Concerted Nucleophilic Aromatic Substitution with a Hydrosilicate

AbstractA transition‐metal‐free catalytic hydrodefluorination (HDF) reaction of polyfluoroarenes is described. The reaction involves direct hydride transfer from a hydrosilicate as the key intermediate, which is generated from a hydrosilane and a fluoride salt. The eliminated fluoride regenerates the hydrosilicate to complete the catalytic cycle. Dispersion‐corrected DFT calculations indicated that the HDF reaction proceeds through a concerted nucleophilic aromatic substitution (CSNAr) process.

Transition-Metal-Free Catalytic Hydrodefluorination of Polyfluoroarenes by Concerted Nucleophilic Aromatic Substitution with a Hydrosilicate.

A transition-metal-free catalytic hydrodefluorination (HDF) reaction of polyfluoroarenes is described. The reaction involves direct hydride transfer from a hydrosilicate as the key intermediate, which is generated from a hydrosilane and a fluoride salt. The eliminated fluoride regenerates the hydrosilicate to complete the catalytic cycle. Dispersion-corrected DFT calculations indicated that the HDF reaction proceeds through a concerted nucleophilic aromatic substitution (CSN Ar) process.

Polysubstituted and ring-fused pyridazine systems from tetrafluoropyridazine

Tetrafluoropyridazine 1 reacts with a range of oxygen-, nitrogen-, sulfur- and carbon-centred nucleophiles to give, in general, products 2 arising from substitution of fluorine para to ring nitrogen. Subsequent reaction of the trifluoropyridazine derivatives 2 gave a range of 4,5-di- and tri-substituted products 3 and 6. Related reactions of tetrafluoropyridazine 1 with difunctional nucleophiles gave [6,6]-, [5,6]- and [6,5,6]-polycyclic ring fused pyridazine scaffolds 4 and 9. Further functionalisation of scaffolds 4 by nucleophlic aromatic substitution processes involving displacement of fluorine atoms at activated sites ortho to ring nitrogen provide an indication of the synthetic possibilities offered using tetrafluoropyridazine as a starting material for the preparation of polysubstituted pyridazine and novel polyfunctional ring fused pyridazine systems with potential applications in the drug discovery arena.

ChemInform Abstract: Carbon‐Hydrogen to Carbon‐Phosphorus Transformations

AbstractReview: literature published between 2008 and 2013; 97 refs.

Synthesis of substituted imidazopyridines from perfluorinated pyridine derivatives

4-Phenylsulfonyl tetrafluoropyridine was reacted with various N-aryl amidines to give the corresponding imidazopyridine systems via an intramolecular nucleophilic aromatic substitution process whilst pentafluoropyridine gave N′-(perfluoropyridin-4-yl)-N-phenylbenzimidamide and 2,3,5,6-tetrafluoro-N-phenylpyridin-4-amine by a competing elimination reaction.

Direct synthesis of anilines and nitrosobenzenes from phenols.

A one-pot synthesis of anilines and nitrosobenzenes from phenols has been developed using an ipso-oxidative aromatic substitution ((i)SOAr) process. The products are obtained in good yields under mild and metal-free conditions. The leaving group effect on reactions that proceed through mixed quionone monoketals has also been investigated and a predictive model has been established.

Reaction of bromine and chlorine with phenolic compounds and natural organic matter extracts – Electrophilic aromatic substitution and oxidation

Phenolic compounds are known structural moieties of natural organic matter (NOM), and their reactivity is a key parameter for understanding the reactivity of NOM and the disinfection by-product formation during oxidative water treatment. In this study, species-specific and/or apparent second order rate constants and mechanisms for the reactions of bromine and chlorine have been determined for various phenolic compounds (phenol, resorcinol, catechol, hydroquinone, phloroglucinol, bisphenol A, p-hydroxybenzoic acid, gallic acid, hesperetin and tannic acid) and flavone. The reactivity of bromine with phenolic compounds is very high, with apparent second order rate constants at pH 7 in the range of 104 to 107 M−1 s−1. The highest value was recorded for the reaction between HOBr and the fully deprotonated resorcinol (k = 2.1 × 109 M−1 s−1). The reactivity of phenolic compounds is enhanced by the activating character of the phenolic substituents, e.g. further hydroxyl groups. With the data set from this study, the ratio between the species-specific rate constants for the reactions of chlorine versus bromine with phenolic compounds was confirmed to be about 3000.Phenolic compounds react with bromine or chlorine either by oxidation (electron transfer, ET) or electrophilic aromatic substitution (EAS) processes. The dominant process mainly depends on the relative position of the hydroxyl substituents and the possibility of quinone formation. While phenol, p-hydroxybenzoic acid and bisphenol A undergo EAS, hydroquinone, catechol, gallic acid and tannic acid, with hydroxyl substituents in ortho or para positions, react with bromine by ET leading to quantitative formation of the corresponding quinones. Some compounds (e.g. phloroglucinol) show both partial oxidation and partial electrophilic aromatic substitution and the ratio observed for the pathways depends on the pH. For the reaction of six NOM extracts with bromine, electrophilic aromatic substitution accounted for only 20% of the reaction, and for one NOM extract (Pony Lake fulvic acid) it accounted for <10%. This shows that for natural organic matter samples, oxidation (ET) is far more important than bromine incorporation (EAS).

ChemInform Abstract: Pyrido[3,2‐b][1,4]oxazine and Pyrido[2,3‐b][1,4]benzoxazine Systems from Tetrafluoropyridine Derivatives.

Pyrido[3,2-b][1,4]oxazine and pyrido[2,3-b][1,4]benzoxazine systems were synthesised by annelation reactions involving highly fluorinated pyridine derivatives and nitrogen and oxygen centred difunctional nucleophiles by sequential regioselective nucleophilic aromatic substitution processes.

ChemInform Abstract: Silver‐Catalyzed 2‐Isocyanobiaryls Insertion/Cyclization with Phosphine Oxides: Synthesis of 6‐Phosphorylated Phenanthridines.

Abstract A silver-catalyzed 2-isocyanobiaryls insertion/cyclization with phosphine oxides was described for the construction of the 6-phosphorylated phenanthridines through radical addition of in situ formed P-centered radical to 2-isocyanobiphenyls and homolytic aromatic substitution process. The reactions could proceed smoothly to give the desired 6-phosphorylated phenanthridines promoted by AgOAc (20 mol %) with PhI(OAc)2 (3.0 equiv).

ChemInform Abstract: An Approach to 6‐Trifluoromethyl‐phenanthridines Through Visible‐Light‐Mediated Intramolecular Radical Cyclization of Trifluoroacetimidoyl Chlorides.

A mild and efficient visible light-mediated intramolecular radical cyclization of trifluoroacetimidoyl chlorides is developed for the synthesis of 6-(trifluoromethyl)phenanthridine derivatives. The reaction involves the generation of radical intermediates from C(sp2)–Cl bonds and a homolytic radical aromatic substitution (HAS) process.

Silver-catalyzed 2-isocyanobiaryls insertion/cyclization with phosphine oxides: synthesis of 6-phosphorylated phenanthridines

A silver-catalyzed 2-isocyanobiaryls insertion/cyclization with phosphine oxides was described for the construction of the 6-phosphorylated phenanthridines through radical addition of in situ formed P-centered radical to 2-isocyanobiphenyls and homolytic aromatic substitution process. The reactions could proceed smoothly to give the desired 6-phosphorylated phenanthridines promoted by AgOAc (20 mol %) with PhI(OAc)2 (3.0 equiv).

Pyrido[3,2-b][1,4]oxazine and pyrido[2,3-b][1,4]benzoxazine systems from tetrafluoropyridine derivatives

Pyrido[3,2-b][1,4]oxazine and pyrido[2,3-b][1,4]benzoxazine systems were synthesised by annelation reactions involving highly fluorinated pyridine derivatives and nitrogen and oxygen centred difunctional nucleophiles by sequential regioselective nucleophilic aromatic substitution processes.