Meerwein Arylation Research Articles

Synthesis of α-Bromo Arylethyl Sulfonyl Fluorides and β-Arylethenesulfonyl Fluorides via Copper-Catalyzed Meerwein Arylation.

A practical copper-catalyzed process for the synthesis of the β-arylethenesulfonyl fluorides is described. A series of α-bromo arylethyl sulfonyl fluorides was prepared via Meerwein reaction from arenediazonium tetrafluoroborates and ethenesulfonyl fluoride (ESF) under mild conditions. The following β-arylethenesulfonyl fluorides were further obtained through a β-elimination reaction. This protocol features excellent regio- and stereoselectivity and broad substrate scope.

Catalytic asymmetric cationic shifts of aliphatic hydrocarbons

Asymmetric catalysis is an advanced area of chemical synthesis, but the handling of abundantly available, purely aliphatic hydrocarbons has proven to be challenging. Typically, heteroatoms or aromatic substructures are required in the substrates and reagents to facilitate an efficient interaction with the chiral catalyst. Confined acids have recently been introduced as tools for homogenous asymmetric catalysis, specifically to enable the processing of small unbiased substrates1. However, asymmetric reactions in which both substrate and product are purely aliphatic hydrocarbons have not previously been catalysed by such super strong and confined acids. We describe here an imidodiphosphorimidate-catalysed asymmetric Wagner–Meerwein shift of aliphatic alkenyl cycloalkanes to cycloalkenes with excellent regio- and enantioselectivity. Despite their long history and high relevance for chemical synthesis and biosynthesis, Wagner–Meerwein reactions utilizing purely aliphatic hydrocarbons, such as those originally reported by Wagner and Meerwein, had previously eluded asymmetric catalysis.

Meerwein Arylation of Aryl(alkyl)idenemalononitriles and Diazonium Salts for the Synthesis of 2-(Aryl(alkyl)/arylmethylene)malononitrile Derivatives.

A metal-free Meerwein arylation reaction from aryl(alkyl)idenemalononitriles and diazonium salts for the synthesis of 2-(aryl(alkyl)/arylmethylene)malononitrile derivatives under mild conditions was well developed. Different from the general addition reactions between alkenes and diazonium salts, this study performed the traditional coupling reaction for the formation of C(sp2)-C(sp2) bond arylation products. The radical reaction mechanism was well verified in the control experiments. The other advantages of the approach are broad-scope substrates and good group tolerance. Moreover, the obtained products can be readily converted into high-value asymmetric ketones and hydrogenation reactions.

Recent advances in the application of Meerwein arylation for the synthesis of complex heterocycles at the Ivan Franko National University of Lviv (microreview)

Recent advances in the application of Meerwein arylation for the synthesis of complex heterocycles at the Ivan Franko National University of Lviv (microreview)

From Diazonium Salts to Optically Active 1‐Arylpropan‐2‐ols Through a Sequential Photobiocatalytic Approach

AbstractThe photocatalytic Meerwein arylation between aromatic diazonium salts and isopropenyl acetate under blue LED light irradiation in aqueous medium has been deeply investigated. Optimization of the reaction conditions in terms of substrate concentration, ester equivalents, cosolvent type and amount, reaction time and photocatalyst source, has allowed the access to a variety of 1‐arylpropan‐2‐ones with yields up to 95% using 9‐mesityl‐10‐methylacridinium perchlorate ([Acr‐Mes]ClO4). Next, the design of a one‐pot sequential photobiocatalytic linear approach was accomplished, by the combination of the Meerwein arylation with the bioreduction of the corresponding ketone intermediates. Thus, a total of 19 pairs of 1‐arylpropan‐2‐ol enantiomers were obtained depending on the alcohol dehydrogenase stereopreference. Global yields up to 76% were attained with high to excellent stereoselectivity (90 to >99% ee). Also, it was possible to get access to both 1‐phenylpropan‐2‐ol antipodes (51–53% yield) starting from aniline through a one‐pot three‐step sequential photobiocatalytic protocol.

Elaborating E/Z‐Geometry of Alkenes via Cage‐Confined Arylation Catalysis of Terminal Olefins

AbstractA visible light photosensitizing metal‐organic cage is applied as an artificial supramolecular reactor to control the reaction of aryl radicals with terminal olefins under green light/solvent conditions, which facilitates selective transformation in the confined enzyme‐mimicking environment to give a series of geometrically defined E/Z‐alkenes. The hydrophobic cage displays good host–guest inclusion with aromatic substrates, promoting Meerwein arylation and protecting E‐isomeric products during reaction; while a small amount of benzonitrile can turn on efficient E→Z isomerization. Besides π–π stacking, the hydrogen bonding and halogen bonding interactions also act as control forces for the arylation of aliphatic terminal olefins known as poor acceptors in classic Meerwein arylation. The application of this switchable cage‐confined arylation catalysis has been demonstrated by the syntheses of Tapinarof and a marine natural product from the same substrate via controllable E/Z selectivity.

Elaborating E/Z-Geometry of Alkenes via Cage-Confined Arylation Catalysis of Terminal Olefins.

A visible light photosensitizing metal-organic cage is applied as an artificial supramolecular reactor to control the reaction of aryl radicals with terminal olefins under green light/solvent conditions, which facilitates selective transformation in the confined enzyme-mimicking environment to give a series of geometrically defined E/Z-alkenes. The hydrophobic cage displays good host-guest inclusion with aromatic substrates, promoting Meerwein arylation and protecting E-isomeric products during reaction; while a small amount of benzonitrile can turn on efficient E→Z isomerization. Besides π-π stacking, the hydrogen bonding and halogen bonding interactions also act as control forces for the arylation of aliphatic terminal olefins known as poor acceptors in classic Meerwein arylation. The application of this switchable cage-confined arylation catalysis has been demonstrated by the syntheses of Tapinarof and a marine natural product from the same substrate via controllable E/Z selectivity.

Erratum to: Trifluoroethoxylation of Styrenes via Photoredox-Catalyzed Meerwein Reaction

Erratum to: Trifluoroethoxylation of Styrenes via Photoredox-Catalyzed Meerwein Reaction

Trifluoroethoxylation of Styrenes via Photoredox-Catalyzed Meerwein Reaction

Trifluoroethoxylation of Styrenes via Photoredox-Catalyzed Meerwein Reaction

Thiocyanatoarylation of Methyl Vinyl Ketone under Meerwein Conditions for the Synthesis of 2-Aminothiazole-Based Heterocyclic Systems.

4-Aryl-3-thiocyanatobutan-2-ones were prepared by Meerwein reactions from methyl vinyl ketone and aryldiazonium salts under copper(II) catalysis in 35-75% yields. α-Thiocyanato ketones regioselectively react with 1-methyl-3-aminopyrazole forming N-(3-pyrazolyl)-substituted 2-aminothiazoles in 80-91% yields. An ester group in position 3 of the pyrazole induced a regioselective ring-closure reaction followed by an intramolecular cyclization, which gave first representatives of a new heterocyclic system, pyrazolo[4,3-e]thiazolo[3,2-a]pyrimidine, in 74-93% yields. In addition, the preparations of 5-benzyl-4-methylthiazol-2-ones in 84-93% yields are described.

3-Aryl-2-azidopropanoic acids in cycloaddition reactions

3-Aryl-2-azidopropanoic acids and their derivatives were studied in the [3+2] and [2+2] cycloaddition reactions. New heterocyclic scaffolds of 3-aryl-2-(1 H -1,2,3-triazol-1-yl)propanoic acids, [1,2,3]triazolo[1,5-a]pyrazin-6(7 H )-one and [1,2,3]triazolo[1,5-a]pyrazine-4,6(5 H ,7 H )-dione were obtained. α-Azidoacids and their derivatives are convenient precursors in the synthesis of drug-like compounds. The azido group can be used as a protected amino group or a precursor of the 1,2,3-triazole ring as a bioisostere to amide moiety. α-Azidoacids are synthetically available and can be easily obtained in diazotransfer reactions from the corresponding α-aminoacids or during the anionic Meerwein arylation of acrylates. In view of this, we decided to investigate them in 1,3-dipolar cycloaddition reactions in order to obtain new compounds for the study of their biological properties. 3-Aryl-2-azidopropanoic acids were investigated in 1,3-dipolar cycloaddition reactions to alkynes. The interaction of acids 1a,b with diethyl ester acetylenedicarboxylic acid 2 under Huisgen cycloaddition (metal free) resulted in the formation of 3-aryl-2-triazolylpropanoic acids 3a,b with good yields. The presence of compounds 3 of carboxyl and ester groups makes them convenient precursors for further heterocyclizations. On the example of 3-aryl-2-triazolylpropanoic acid 3b we have shown the possibility of obtaining [1,2,3]triazolo[1,5- a ] pyrazine rings. The acid 3b was converted by the action of oxalyl chloride to the corresponding acid chloride 4b , the latter in the reaction with isobutylamine under heating led to the formation of a bicyclic derivative 5b . Another synthetic approach to obtaining [1,2,3]triazolo[1,5- a ]pyrazines is the intramolecular cyclization of propargylamides of 2-azidoacids. To implement this approach, we obtained from 3-aryl-2-azidopropanoic acids 1c-f the corresponding propargyl amides 7c-f through intermediate chlorides 6c-f . Reflux of amides 7d,e in toluene for 24 h allowed to obtain the target [1,2,3]triazolo[1,5- a ]pyrazines 8d,e with low yields. We investigated 3-aryl-2-azidopropanoic acid chlorides 6c,f under the conditions of the [2+2]cycloaddition reaction with Schiff bases. However, in contrast to unsubstituted azidoacetic acid chloride, the interaction of acid chlorides 6c , f with Schiff bases 9a,b in the presence of triethylamine as a base at –20 o C did not lead to the formation of azetidinones 10 . The main reaction products were amides 11a,b . Thus, 3-aryl-2-azidopropanoic acids and their derivatives in cycloaddition reactions were investigated. A number of new functionalized 1,2,3-triazole and [1,2,3]triazolo[1,5- a ]pyrazine derivatives were synthesized. The obtained substances can be used for further modifications, and are of considerable interest for medical and pharmaceutical chemistry. Keywords: 3-aryl-2-azidopropanoic acids, alkynes, 1,3-dipolar cycloaddition, 1,2,3-triazoles, [1,2,3]triazolo[1,5- a ]pyrazines.

Bromoarylation of Methyl 2-Chloroacrylate under Meerwein Conditions for the Synthesis of Substituted 3-Hydroxythiophenes

AbstractMethyl 3-aryl-2-bromo-2-chloropropanoates can be prepared by Meerwein reaction from methyl 2-chloroacrylate and various arenediazonium salts under copper(II) bromide catalysis. The resulting readily available compounds were used as starting materials in reactions with substituted methanethiols for the construction of substituted 3-hydroxythiophenes which have not yet been accessible by other routes. Structural variety of the obtained 2-substituted 5-aryl-3-hydroxythiophenes has been achieved due to a wide range of available starting materials, including both anilines and thiols.

Application of the Meerwein reaction of 1,4-benzoquinone to a metal-free synthesis of benzofuropyridine analogues.

Several new heterocyclic systems based on a hydroxybenzofuro[2,3-b]pyridine building block were prepared. This benzofuropyridine is easily available from the Meerwein reaction of benzoquinone and a heterocyclic diazonium salt, followed by reduction and cyclization. Electrophilic substitution and further condensations give polycyclic systems, including oxazolo- and chromeno-fused analogues.

Antimicrobial and antimycotic activity of some derivatives of 3-arylpyridin-2-one and 3-arylpyran-2-one

2-Pyridones and 2-pyrones are a well-known heterocyclic compounds having significant biological and medical application. The molecular structures and various activities of 2-pyridone derivatives as well as their syntheses and natural occurrence are analyzed and discussed. Previously, we developed an effective method for the synthesis of 3-aryl-substituted derivatives of 2-pyranone. This method consists in the interaction of commercially available starting reagents with comercially available arenediazonium salts via the Meerwein reaction conditions. In this paper, we report on an effective method for the synthesis of 3-arylpyridin-2-ones starting from 3-arylpyranones. Reaction of methyl or ethyl esters of 4,6-dimethyl-3-aryl-2-oxo-2 H -5-pyrancarboxylic acids with ammonium acetate in acetic acid gave methyl or ethyl esters of 2,4-dimethyl-6-oxo-5-aryl-1,6-dihydropyridine-3-carboxylic acids in high yields. For some compounds (ethyl 4,6-dimethyl-3-(2-nitrophenyl)-2-oxo-2 H -pyran-5-carboxylate ( 1c ), ethyl 2,4-dimethyl-5-(4-nitrophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylate ( 2c ), 6-methyl-3-(3-nitrophenyl)-2-oxo-2 H -pyran-5-carboxylic acid ( 5 ), 4-methyl-6-(2-methylprop-1-en-1-yl)-3-(4-nitrophenyl)-2 H -pyran-2-one ( 6 ), methyl 4,6-dimethyl-3-(2-nitrophenyl)-2-oxo-2 H -pyran-5-carboxylate ( 7 )) we investigated antifungal and antimicrobial activity. The antimicrobial activity of the obtained compounds ( 1c , 2c , 5 , 6 , 7 ) was studied by a micromethod using disposable 96-well sterile polystyrene tablets and Takachi microtiters. The test strains of bacteria were grown for 18–20 h on beveled meat-peptone agar (MPA) at a temperature of +37 ºС. The highest activity, especially of compound 6 , was found against "true" fungi ‑ strain № 7 (S. cerevisiae 61). Compounds 5 and 6 act on strain B. subtilis ATCC6633 at a concentration of 31.3 μg/ml. Keywords: pyran-2-one, pyridin-2-one, recyclization, antimicrobial activity, antifungal activity.

The Craven reaction with 2-aryl-1,4-benzoquinones

It is known that the interaction of 1,4-quinones with 1,3-dicarbonyl compounds mainly results in the formation of benzo[ b ]furan derivatives, which attract special attention because many compounds of this class are biologically active and are used as drugs. However, in some cases, this interaction is ambiguous, and along with the main reaction products – substituted benzofurans, significant amounts of benzodifurans are formed. Cyanoacetic acid derivatives are particularly prone to react with 1,4-quinones to form benzodifurans. In particular, the addition of compounds with an active methylene group to quinones takes place with the formation of colored intermediates and is known in the literature as the Craven reaction. On the other hand, benzodifurans are widely used in the bioorganic and medical fields, as building blocks for optoelectronic devices, organic dyes for solar panels, components in the manufacture of organic LEDs, as well as polymeric materials with a rigid structure such as Kevlar. Possibility of preparation of linear heterocyclic systems arylfuro[2’,3’:4,5]benzo[ b ]-furanes based on 2-aryl-1,4-benzoquinones was investigated. The 2-aryl-1,4-benzoquinones 1 а – і (аryl = 4-MeC 6 H 4 ( a ), 2-C 10 H 7 ( b ), 3-CF 3 C 6 H 4 ( c ), 4-COMeC 6 H 4 ( d ), 4-NHCOMeC 6 H 4 ( e ), 3-NO 2 C 6 H 4 ( f ), 3,4-Me 2 C 6 H 3 ( g ), 3-Cl-4-MeC 6 H 3 ( h ), 3,4-Cl 2 C 6 H 3 ( i )) were obtained by the reaction between arenediazonium salts and 1,4-benzoquinone under Meerwein reactions conditions. The interaction of 2-aryl-1,4-benzoquinones 1a – i with some bifunctional C-nucleophiles under the conditions of the Craven reaction was studied. It was found that esters of cyanoacetic acid (ethyl-, propyl-, allylcyanoacetates) and malononitrile react selectively with arylquinones – substituted furobenzo[ b ]furanеs 2a – с , 3a – с , 4 , 5a – e were obtained in a medium yields. The structures of the synthesized compounds were confirmed by the 1 H NMR spectroscopy and element analysis data. Keywords: 2-aryl-1,4-benzoquinones, cyanoacetic esters, malononitrile, Craven reaction, arylfuro[2’,3’:4,5]benzo[ b ]furanes.

A Three-Step Synthesis of 1,7-Diazaperylene and Derivatives

Abstract1,7-Diazaperylene and various derivatives were synthesised in an upscaleable route from 1,5-diaminoanthraquinone and its Meerwein­ reaction with acrylonitrile and subsequent cyclisation with ammonia. The application of tert-butyl alcohol as the solvent led to a significant improvement in the Meerwein reaction.

Efficient Processing of Reactions Involving Diazonium Salts: Meerwein Arylation in an Impinging-Jet Reactor

This work reports a novel approach for performing high-throughput synthesis of Meerwein arylation in an impinging-jet reactor. The multistep reaction was performed in a single reactor via in situ diazonium salt generation followed by Meerwein arylation. The work involves many iterations between experiments and simulations (where we integrate simulating the flow, heat transfer, and reaction simultaneously) for optimization of conditions in an inverted impinging-jet reactor. The effect of design variables viz. catalyst concentration, inlet temperature, and monomer mole ratio on the yield of the desired product was studied in detail, and the simulation results were used to plan the continuous experiments. An infrared camera was used to monitor the transient reactor temperature for steady-state analysis. The lab-scale inverted impinging-jet reactor with over 93% isolated yield can offer a space-time yield of 277.78 tons/m3/day. The numbering-up of an inverted impinging-jet reactor can be an effective way for cleaner production of products through typical Meerwein arylation.

Cardiovascular Effects of Polychlorinated Biphenyls and Their Major Metabolites.

Background:Xenobiotic metabolism is complex, and accounting for bioactivation and detoxification processes of chemicals remains among the most challenging aspects for decision making with in vitro new approach methods data.Objectives:Considering the physiological relevance of human organotypic culture models and their utility for high-throughput screening, we hypothesized that multidimensional chemical-biological profiling of chemicals and their major metabolites is a sensible alternative for the toxicological characterization of parent molecules vs. metabolites in vitro.Methods:In this study, we tested 25 polychlorinated biphenyls (PCBs) [PCB 3, 11, 52, 126, 136, and 153 and their relevant metabolites (hydroxylated, methoxylated, sulfated, and quinone)] in concentration–response () for effects in human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) and endothelial cells (ECs) (iPSC-derived and HUVECs). Functional phenotypic end points included effects on beating parameters and intracellular flux in CMs and inhibition of tubulogenesis in ECs. High-content imaging was used to evaluate cytotoxicity, mitochondrial integrity, and oxidative stress.Results:Data integration of a total of 19 physicochemical descriptors and 36 in vitro phenotypes revealed that chlorination status and metabolite class are strong predictors of the in vitro cardiovascular effects of PCBs. Oxidation of PCBs, especially to di-hydroxylated and quinone metabolites, was associated with the most pronounced effects, whereas sulfation and methoxylation of PCBs resulted in diminished bioactivity.Discussion:Risk characterization analysis showed that although in vitro derived effective concentrations exceeded the levels measured in the general population, risks cannot be ruled out due to the potential for population variability in susceptibility and the need to fill data gaps using read-across approaches. This study demonstrated a strategy for how in vitro data can be used to characterize human health risks from PCBs and their metabolites. https://doi.org/10.1289/EHP7030

Synthesis of 2-Arylpyridines and 2-Arylbipyridines via Photoredox-Induced Meerwein Arylation with in Situ Diazotization of Anilines.

We report herein a sustainable method for the preparation of 2-arylpyridines through C-H arylation of pyridines using in situ formed diazonium salts (from commercially available aromatic amines) in the presence of a photoredox catalyst under blue light-emitting diode (LED) irradiation. The reaction is tolerant to a wide range of functional groups (e.g., halogen, nitrile, formyl, acetyl, ester). Applications to the C-H bond arylation of bipyridine ligands is also presented.

Preparation and properties of a novel fluorinated epoxy resin/DGEBA blend for application in electronic materials

A novel epoxy monomer 4-trifluoromethyl phenylhydroquinone epoxy resin (4-TFMEP) was synthesized via a multistep procedure including the Meerwein arylation reaction and followed by nucleophilic reaction. The chemical structure of 4-TFMEP was confirmed by proton nuclear magnetic resonance and Fourier-transform infrared spectrum. Then a mixed system (DGEBA/4-TFMEP x%) composed of diglycidyl ether of bisphenol A (DGEBA) and 4-TFMEP was prepared by a melting method without any solvent. After curing, the properties of this series of mixed epoxy resins were measured and compared with the neat DGEBA. As a result, the blend resins exhibited good thermal stability, excellent hydrophobic and low dielectric properties with 4-TFMEP content increasing. Furthermore, the material of DGEBA/4-TFMEP 40% achieves higher glass transition temperature of 104°C and char yield 33% than DGEBA (char yield = 22%) possessed. In the contact angle testing, DGEBA/4-TFMEP 40% shows 127.2° satisfied the standard of hydrophobic material. In addition, by the test of dielectric properties, DGEBA/4-TFMEP x% materials show lower than DGEBA/boron trifluoride ethylamine (BF3MEA) material, because of the introduced side group of fluorine content into the material improves the electronegativity of epoxy material and reduced the polarizability of molecules efficient. Herein, we believe the novel mixed epoxy system (DGEBA/4-TFMEP x%) has a potential application in electronic industries.