Electron-rich Aromatic Compounds Research Articles

Catalytic Friedel–Crafts Alkylation of Electron Rich Aromatic Derivatives with α-Aryl Diazoacetates Mediated by Brønsted Acids

The catalytic protonation of aryl diazoacetates by strong Brønsted acids, followed by a Friedel-Crafts alkylation reaction with electron rich aromatic compounds, is reported. The reaction provided in a direct fashion 24 geminal diarylacetates in yields of ≤92%.

1,4-Addition of o-naphthoquinone methides induced by silver-catalyzed cyclization of enynones: an approach to unsymmetrical triarylmethanes and benzo[f]chromenes

The 1,4-addition reaction of ortho-naphthoquinone methide (o-NQM) intermediates induced by silver-catalyzed ring formation with electron-rich aromatic compounds and α-methylene ketones has been developed.

Solvent-Free C-3 Coupling of Azaindoles with Cyclic Imines.

By direct coupling 7-azaindole and cyclic imines, such as 3,4-dihydroisoquinoline, 6,7-dihydrothieno[3,2-c]pyridine, 3,4-dihydro-β-carboline, and 4,5-dihydro-3H-benz[c]azepine, new 3-substituted 7-azaindole derivatives have been synthesized. The reaction was extended to 4-azaindoles and 6-azaindoles, as electron-rich aromatic compounds. The lowest reactivity was observed in the case of C-3 substitution of 5-azaindole. In this case, the aza-Friedel-Crafts reaction took place by using 10 mol % of p-toluenesulfonic acid (p-TSA) as the catalyst. The role of the acid catalyst can be explained by the different pKa values of the azaindoles. All reactions were performed in solvent-free conditions by using both classical heating and microwave irradiation. In all cases, microwave heating proved to be more convenient to synthesize new C-3-substituted azaindole derivatives.

Thiocyanation of Aromatic and Heteroaromatic Compounds with 1-Chloro-1,2-benziodoxol-3-(1H)-one and (Trimethylsilyl)isothiocyanate.

Thiocyanation of aromatic compounds has been investigated using the combination of 1-chloro-1,2-benziodoxol-3-(1H)-one (1) and (trimethylsilyl)isothiocyanate (TMSNCS). The reaction with electron rich aromatic compounds proceeded smoothly to provide the thiocyanated products in high yield, while electron deficient heteroaromatic compounds were not suitable for this reaction. In these reactions, the regioselectivity was generally high. Transformations of the products were also investigated to demonstrate the utility of the reaction. Based on NMR experiments, we propose that thiocyanogen chloride is generated in situ as an active species.

Photocatalytic Alkylation of Pyrroles and Indoles with α-Diazo Esters.

This article describes the photoalkylation of electron-rich aromatic compounds with diazo esters. C-2-alkylated indoles and pyrroles are obtained with good yields even though the photocatalyst loading is as low as 0.075 mol %. For EWG-substituted substrates, the addition of a catalytic amount of N,N-dimethyl-4-methoxyaniline is required. Both EWG-EWG- and EWG-EDG-substituted diazo esters are suitable as alkylating agents. The reaction selectivity and mechanistic experiments suggest that carbenes/carbenoid intermediates are not involved in the reaction pathway.

Improved synthesis of 4-[18 F]fluoro-m-hydroxyphenethylguanidine using an iodonium ylide precursor.

Fluorine-18 labeled hydroxyphenethylguanidines were recently developed in our laboratory as a new class of PET radiopharmaceuticals for quantifying regional cardiac sympathetic nerve density in heart disease patients. Studies of 4-[18 F]fluoro-m-hydroxyphenethylguanidine ([18 F]4F-MHPG) and 3-[18 F]fluoro-p-hydroxyphenethylguanidine ([18 F]3F-PHPG) in human subjects have shown that these radiotracers can be used to generate high-resolution maps of regional sympathetic nerve density using the Patlak graphical method. Previously, these compounds were synthesized using iodonium salt precursors, which provided sufficient radiochemical yields for on-site clinical PET studies. However, we were interested in exploring new methods that could offer significantly higher radiochemical yields. Spirocyclic iodonium ylide precursors have recently been established as an attractive new approach to radiofluorination of electron-rich aromatic compounds, offering several advantages over iodonium salt precursors. The goal of this study was to prepare a spirocyclic iodonium ylide precursor for synthesizing [18 F]4F-MHPG and evaluate its efficacy in production of this radiopharmaceutical. Under optimized automated reaction conditions, the iodonium ylide precursor provided radiochemical yields averaging 7.8% ± 1.4% (n = 8, EOS, not decay corrected), around threefold higher than those achieved previously using an iodonium salt precursor. With further optimization and scale-up, this approach could potentially support commercial distribution of [18 F]4F-MHPG to PET centers without on-site radiochemistry facilities.

Disulfide-Catalyzed Iodination of Electron-Rich Aromatic Compounds.

Herein, a disulfide-catalyzed electrophilic iodination of aromatic compounds using 1,3-diiodo-5,5-dimethylhydantoin (DIH) has been developed. The disulfide activates DIH as a Lewis base to promote the iodination reaction in acetonitrile under mild conditions. This system is applicable to a wide range of electron-rich aromatic compounds, including acetanilide, anisole, imidazole, and pyrazole derivatives.

Halogenation of aromatic hydrocarbons by halide anion oxidation with poly(heptazine imide) photocatalyst

Halocarbons have tremendous significance for the chemical industry. Arylchlorides and arylbromides are typically prepared via Friedel-Crafts reaction, using oxidative halogenation or employing halogen transfer agents, such as N-chloro- and N-bromosuccineimide. Herein, we show that K-PHI, a photocatalyst of the carbon nitride family, can easily photooxidize halide anions (Cl−, Br−) in aqueous media to promote oxidative halogenation of electron rich aromatic compounds. The technique is convenient, safe and gives the haloaromatic products with excellent yields from non-harmful starting reagents in the most sustainable fashion. We show that a solution of NaCl, mimicking seawater, can be used as a reagent for photochlorination.

Tris(dimethylamino)silylium ion: structure and reactivity of a dimeric silaguanidinium.

Although several strategies for the stabilization of silylium ions have been established, "π-stabilization" with directly attached π-donor heteroatoms at silicon has not been developed yet. Hydride abstraction from (Me2N)3SiH generates dicationic [(Me2N)3Si+]2 in solution and in the solid state - constituting the dimer of an elusive silaguanidinium ion. This compound can be synthesized on a gram scale and is compatible with common organic solvents. However, it readily undergoes spontaneous electrophilic silylation of electron-rich aromatic compounds or initiates a catalytic hydro-defluorination reaction.

Synthesis of Azo Dyes from Mesoionic Carbenes and Nitrous Oxide

Covalent adducts of imidazole-based mesoionic carbenes and nitrous oxide (N2 O, "laughing gas") can be converted into azo dyes by reaction with arenes in the presence of AlCl3 or HCl. The azo coupling can be achieved with electron-rich aromatic compounds such as mesitylene, trimethoxybenzene, azulene, or dibenzo-18-crown-6. The latter coupling reaction allows for the easy preparation of a colorimetric sensor for potassium or sodium ions. As a putative intermediate of the reaction with acid, we were able to isolate and structurally characterize a rare diazohydroxide. Using imidazolium compounds with two N2 O groups, it was possible to prepare amine-substituted azo dyes or dyes with two azoarene groups attached to the heterocycle. A triazole-based mesoionic carbene was also found to form a stable covalent adduct with N2 O. The adduct could be used to prepare novel azo triazolium dyes in good yields.

Metal- and Oxidant-Free Formal Vinylic C-H/Aromatic C-H Cross Coupling Based on the Stabilized Cation Pool Method

The cation pool method serves as a powerful tool for electroorganic synthesis.1 In the cation pool method organic cations are electrochemically generated and accumulated in solution at low temperatures. Reactions with subsequently added nucleophiles give the desired products. However, the cation pool method cannot be applied to highly unstable cations that decompose during the course of the electrolysis. To expand the scope of the cation pool method, we have developed the stabilized cation pool method, in which electrochemically generated organic cations are stabilized by suitable stabilizing agents and are accumulated in solution. The reactions of the stabilized organic cations with subsequently added nucleophiles give the desired products. We have already reported that the method is successfully applied to benzylic C−H/ aromatic C−H cross-coupling.2 In this paper we show that vinyl C−H/ aromatic C−H cross-coupling can be achieved. I-O-S+R2 generated by oxidation of I2 in the presence of O=SR2 3 adds to ArCH=CH2 to generate and accumulate the corresponding α-(iodomethyl)beznylaminosulfonium ions as stabilized benzyl cations. In the next step, the (α-iodomethyl)beznylaminosulfonium ions are reacted with subsequently added electron-rich aromatic compounds (Ar’H) as nucleophiles. The elimination of HI with a base gives ArAr’C=CH2 to achieve metal- and oxidant-free formal vinylic C-H/aromatic C-H cross coupling. Yoshida, J.; Ashikari, Y.; Matsumoto, K.; Nokami, T. J. Synth. Org. Chem., Jpn. 2013, 1136.Hayashi, R.; Shimizu, A.; Yoshida, J. J. Am. Chem. Soc. 2016, 138, 8400.Ashikari, Y.; Shimizu, A.; Nokami, T.; Yoshida, J. J. Am. Chem. Soc. 2013, 135, 16070.

B(C6F5)3-Catalyzed Regioselective Deuteration of Electron-Rich Aromatic and Heteroaromatic Compounds.

Deuterium labeled compounds find widespread application in life science. Herein, the deuteration of electron-rich (hetero)aromatic compounds employing B(C6F5)3 as the catalyst and D2O as the deuterium source is reported. This protocol is highly efficient, simply manipulated, and successfully applied in the deuteration of 23 substrates including natural neurotransmitter-like melatonin. It is assumed that the weakening of the O-D bond ultimately results in the formation of electrophilic D+.

Metal- and Oxidant-Free Benzylic C-H/Aromatic C-H Cross Coupling Based on the Stabilized Cation Pool Method

The cation pool method serves as a nice tool in electroorganic synthesis. Organic cations are electrochemically generated and accumulated in solution at low temperatures. Reactions with subsequently added nucleophiles give the desired products. However, the cation pool method cannot be applied to highly unstable cations that decompose during the course of the electrolysis. To expand the scope of the cation pool method, we have developed the stabilized cation pool method, in which organic cations stabilized by suitable stabilizing agents are electrochemically generated and accumulated in solution. The reactions of the stabilized organic cations with subsequently added nucleophiles give the desired products. In this paper we show that C−H/aromatic C−H cross-coupling can be achieved by the electrochemical generation and accumulation of stabilized benzyl cations followed by their reactions with subsequently added aromatic nucleophiles. Beznylaminosulfonium ions as stabilized benzyl cations are generated and accumulated in the electrochemical oxidation of toluene derivatives. In the next step, the reactions with subsequently added electron-rich aromatic compounds as nucleophiles give the corresponding cross-coupled product. The method has been successfully applied to the synthesis of TP27, an inhibitor of PTPase. The reactions of benzylaminosulfonium ions with other carbon nucleophiles such as acetylacetone, ketene silyl acetals, allyltrimethylsilane, and trimethylsilylacetylene will also be discussed in the presentation.

Catalytic Friedel-Crafts C-H Borylation of Electron-Rich Arenes: Dramatic Rate Acceleration by Added Alkenes.

In the electrophilic C-H borylation of electron-rich aromatic compounds with catecholborane, the catalytic generation of the boron electrophile is initiated by heterolysis of the B-H bond by various Lewis and Brønsted acids, with a boronium ion formed exclusively. After ligand dissociation, the corresponding borenium ion undergoes regioselective electrophilic aromatic substitution on aniline derivatives as well as nitrogen-containing heterocycles. The catalysis is optimized using B(C6 F5 )3 as the initiator and proceeds without the addition of an external base or dihydrogen acceptor. Temperatures above 80 °C are generally required to secure efficient turnover in these Friedel-Crafts-type reactions. Mechanistic experiments reveal that regeneration of the boronium/borenium ion with dihydrogen release is rate-determining. This finding finally led to the discovery that, with added alkenes, catalytic C-H borylations can, for the first time, be carried out at room temperature.

Lewis Acid Catalyzed Friedel–Crafts Alkylation of Indoles and Other­ Electron-Rich Aromatic Compounds with Ethyl 2-(Diethoxyphosphoryl)acrylate and Tetraethyl Ethene-1,1-diylbis(phosphonate)

Friedel–Crafts alkylation of indoles and other electron-rich aromatic compounds with ethyl 2-(diethoxyphosphoryl)acrylate and tetraethyl ethene-1,1-diylbis(phosphonate) was carried out in the presence of 5 mol% Cu(ClO4)2·6H2O/2,2′-Bipy complex as a catalyst in acetonitrile at room temperature to afford a broad series of heteroaryl- and aryl-substituted 2-(diethoxyphosphoryl)propionates and ethyl-1,1-diylbis(phosphonates) in 58–96% yield.

ChemInform Abstract: 1,6‐Addition Arylation of para‐Quinone Methides: An Approach to Unsymmetrical Triarylmethanes.

A 1,6-addition arylation reaction of para-quinone methides with α-isocyanoacetamides and electron-rich aromatic compounds under metal-free conditions has been developed. BF3·Et2O plays two roles in the reaction: catalyzing the cyclization of α-isocyanoacetamides to give oxazoles, and activating the para-quinone methides to achieve the 1,6-addition arylation process. The reaction shows good functional group tolerance, scalability, and regioselectivity. It is a consice protocol for the synthesis of diverse unsymmetrical triarylmethanes. Further transformation of the resulting triarylmethanes provides an efficient route to some functionalized molecules.

ChemInform Abstract: Lewis Acid and Fluoroalcohol Mediated Nucleophilic Addition to the C2 Position of Indoles.

AbstractThe formation of indolium is described allowing for the 2‐selective inter‐ as well as intramolecular highly regioselective nucleophilic addition of electron rich aromatic compounds.

Furan-iminium cation cyclization (FIC) in a total synthesis of manzamine alkaloids.

Furans are highly electron-rich aromatic compounds and this structure is often found in natural products and medicines. Furans are also useful as a four-carbon unit with oxygen functionalities, and are used in organic syntheses as a building block.1, 2 In 2003, we reported the first total synthesis of nakadomarin A (1),3 a manzamine alkaloid containing a furan ring. In this synthesis, we first reported that a new type of furan-iminium cation cyclization (FIC)4, 5 through intermediate [A] was highly effective for constructing the central core of nakadomarin A (Figure 1). In the structure of intermediate [A], the 3-position of the furan ring was directly bound to a spiro-ring system, and cyclization occurred at the 2-position of the furan ring to give the tetracyclic core of nakadomarin A.

ChemInform Abstract: Copper(II) Bromide‐Catalyzed C—C/C—N Bond‐Forming Reactions: Synthesis of Pyrrole‐Incorporated Triarylmethanes.

AbstractWe have achieved a facile copper(II) bromide–catalyzed synthesis of 2,3,4-trisubtitued pyrrole incorporated into unsymmetrical triarylmethanes through direct replacement of hydroxyl group in the pyrrolyl phenyl methanol with electron-rich aromatic and heteroaromatic compounds. The newly developed method has been applied to a facile synthesis of a C2 symmetric bis-triarylmethane in which the two triarylmethanes were bridged through piperzine. The copper(II) bromide catalysis led to C-C bond formation at the C(5) position when the reacting partner was imidazole. In contrast, C-N bond formation took place with benzimdazole or 2-methylbenzimidazole.

Photocatalytic Selective Bromination of Electron-Rich Aromatic Compounds Using Microporous Organic Polymers with Visible Light

Pure organic, heterogeneous, metal-free, and visible light-active photocatalysts offer a more sustainable and environmentally friendly alternative to traditional metal-based catalysts. Here we report a series of microporous organic polymers containing photoactive conjugated organic semiconductor units as heterogeneous photocatalysts for a visible-light-promoted, highly selective bromination reaction of electron-rich aromatic compounds using HBr as a bromine source and molecular oxygen as a clean oxidant. Via a simple Friedel–Crafts alkylation reaction, the microporous organic polymers were obtained by cross-linking of organic semiconductor compounds with defined valence and conduction band positions. The utilization of the simply prepared porous polymer-based photocatalytic systems opens new opportunities toward a sustainable and efficient material design for catalysis.