Electron-rich Aromatic Compounds Research Articles

One-step synthesis of [15]paracyclophane and [16]paracyclophane via Pd-catalyzed C(sp2)–C(sp3) coupling and the cyclohexane-encapsulating crystal structure of [16]paracyclophane

Abstract Macrocycles consisting of methylene-bridged aromatic rings had been synthesized by aromatic electrophilic substitution reactions, thus limiting the substrates to electron-rich aromatic compounds. In this work, we developed a novel method for 1-step synthesis of [15]paracyclophane (PCP) and [16]PCP by the self-condensation of 4-bromobenzyl bromide via a Pd-catalyzed desulfinative coupling reaction between C(sp2) and C(sp3) carbon atoms. In the crystal structure, [16]PCP encapsulated cyclohexane and formed a 1D columnar structure

Syntheses of Diarylmethanes Via an Oxidative Benzylic Functionalization of P-Alkyl Phenol Derivatives Under Quaternary Ammonium Hypoiodite Catalysis.

We herein report two strategies for the quaternary ammonium hypoiodite-mediated oxidative benzylic functionalization of p-alkyl phenol derivatives. By using either dibenzoylperoxide or H2O2 in hexafluoroisopropanol in the presence of tetrabutyl ammonium iodide gives access to activated intermediates which can then be coupled with electron-rich aromatic compounds. Overall, this sequential two-step one-pot procedure gives access to diversely decorated diarylmethane derivatives straightforwardly. Furthermore, the suitability of these products to undergo further oxidation reactions was successfully demonstrated.

Alkoxyalkylation of Electron-Rich Aromatic Compounds.

Alkoxyalkylation and hydroxyalkylation methods utilizing oxo-compound derivatives such as aldehydes, acetals or acetylenes and various alcohols or water are widely used tools in preparative organic chemistry to synthesize bioactive compounds, biosensors, supramolecular compounds and petrochemicals. The syntheses of such molecules of broad relevance are facilitated by acid, base or heterogenous catalysis. However, degradation of the N-analogous Mannich bases are reported to yield alkoxyalkyl derivatives via the retro-Mannich reaction. The mutual derivative of all mentioned species are quinone methides, which are reported to form under both alkoxy- and aminoalkylative conditions and via the degradation of the Mannich-products. The aim of this review is to summarize the alkoxyalkylation (most commonly alkoxymethylation) of electron-rich arenes sorted by the methods of alkoxyalkylation (direct or via retro-Mannich reaction) and the substrate arenes, such as phenolic and derived carbocycles, heterocycles and the widely examined indole derivatives.

Metal-free introduction of primary sulfonamide into electron-rich aromatics.

We report herein a direct and practical synthesis of arylsulfonamides from electron-rich aromatic compounds by using in situ generated N-sulfonylamine as the active electrophile. Substrates include derivatives of aniline, indole, pyrrole, furan, styrene and so on. The reaction proceeds under mild conditions and tolerates many sensitive functional groups such as alkyne, acetate, the trifluoromethoxy group or acetoxymethyl ester. Applications of this method for the construction of metal ion sensors and fluorogenic dye have been demonstrated, thus highlighting the potential of this method for probe development.

Increasing the Stability of Flavin-Dependent Halogenases by Disulfide Engineering.

Flavin-dependent halogenases allow halogenation of electron-rich aromatic compounds under mild reaction conditions even at electronically unfavored positions with high regioselectivity. In order to expand the application of halogenases, the enzymes need to be improved in terms of stability and efficiency. A previous study with the tryptophan 6-halogenase Thal demonstrated that thermostable Thal variants tend to form dimers in solution while the wild type is present as a monomer. Based on this a dimeric Thal variant was generated that is covalently linked by disulfide bonds. Introducing two cysteine residues at the dimer interface resulted in the variant Thal CC with significantly increased thermostability (▵T50 =15.7 K) and stability over time at elevated temperature compared to the wild type. By introducing the homologous mutations into the tryptophan 5-halogenase PyrH, we were able to show that the stabilization by covalent dimerization can also be transferred to other halogenases. Moreover, it was possible to further increase the thermostability of PyrH by inserting cysteine mutations at alternative sites of the dimer interface.

TfOH-Catalyzed Cascade Reaction: Metal-Free Access to 3,3-Disubstituted Phthalides from o-Alkynylbenzoic Acids.

A facile new method for the synthesis of 3,3-disubstituted phthalides is reported. A successive reaction process begins with the TfOH-catalyzed cyclization of o-alkynylbenzoic acids followed by an ortho-regioselective electrophilic alkylation of various electron-rich aromatic compounds or alkenes, which has been successfully developed. The corresponding regioselective products of 3-substituted phthalide were obtained in good to high yields.

Asymmetric catalysis by flavin-dependent halogenases.

In nature, flavin-dependent halogenases (FDHs) catalyze site-selective chlorination and bromination of aromatic natural products. This ability has led to extensive efforts to engineer FDHs for selective chlorination, bromination, and iodination of electron rich aromatic compounds. On the other hand, FDHs are unique among halogenases and haloperoxidases that exhibit catalyst-controlled site selectivity in that no examples of enantioselective FDH catalysis in natural product biosynthesis have been characterized. Over the past several years, our group has established that FDHs can catalyze enantioselective reactions involving desymmetrization, atroposelective halogenation, and halocyclization. Achieving high activity and selectivity for these reactions has required extensive mutagenesis and mitigation of problems resulting from hypohalous acid generated during FDH catalysis. The single-component flavin reductase/FDH AetF is unique among the wild type enzyme we have studied in that it provides high activity and selectivity toward several asymmetric transformations. These results highlight the ability of FDH active sites to tolerate different substrate topologies and suggest that they could be useful for a broad range of oxidative halogenations.

Transition Metal‐Catalyzed Dearomative Vinylation of Electron Rich Benzenes, Naphthalenes and Indoles with Alkynes

AbstractDearomatization reactions are among the most efficient chemical processes, combining atom economy, stereospecificity and the ability to generate molecular complexity in a single step. Dearomative vinylation reactions provide a synthetic connection between readily available, simple aromatic starting materials and more unsaturated alkynes. The last decade has witnessed a steady increase in the development of transition metal‐catalyzed dearomative vinylation methods of electron rich aromatic compounds with alkynes, providing new synthetic approaches to high‐value building blocks and natural products. This review aims to serve as a comprehensive reference for work in transition metal‐catalyzed dearomative vinylation reactions of electron rich aromatic compounds with alkynes.magnified image

C(3)-Aryl isoindolinones: a PTSA-mediated access and improved synthesis of (±)-nuevamine

We achieved a facile synthesis of some C(3)-aryl isoindolinones with free N(2)H from isoindolinone-3-ols and electron-rich aromatic compounds in a two-step method. In continuation we demonstrated a high yielding synthesis of the tetracyclic alkaloid nuevamine.

Recent advances in aza Friedel–Crafts reaction: strategies for achiral and stereoselective synthesis

The aza-Friedel–Crafts (aza-FC) reaction is a very powerful tool for forming C–C and C–N bonds, based on an acid-catalyzed addition of electron-rich aromatic compounds to imines.

Direct C-H/C-H Coupling of the Azoloannulated Pteridines with Electron Rich (Hetero)Aromatic Compounds.

The methods for modification of azoloannulated pteridines with (hetero)aromatic nucleophiles using a nucleophilic substitution of hydrogen (SNH) methodology have been developed in this work. Stable intermediate σH-adducts, as well as products of an unexpected intramolecular rearrangement of diadducts, have been isolated and characterized. The potential of the proposed approach for obtaining donor-acceptor systems, in which the pteridine fragment of the molecule acts as an acceptor, was demonstrated. The main photophysical properties of the obtained D-A compounds have been studied.

Analysis of laboratory-evolved flavin-dependent halogenases affords a computational model for predicting halogenase site selectivity

Flavin-dependent halogenases (FDHs) catalyze selective halogenation of electron-rich aromatic compounds without the need for harsh oxidants required by conventional oxidative halogenation reactions. Predictive models for halogenase site selectivity could greatly improve their utility for chemical synthesis. Toward this end, we analyzed the structures and selectivity of three halogenase variants evolved to halogenate tryptamine with orthogonal selectivity. Crystal structures and reversion mutations revealed key residues involved in altering halogenase selectivity. Density functional theory calculations and molecular dynamics simulations are both consistent with hypohalous acid as the active halogenating species in FDH catalysis. This model was used to accurately predict the site selectivity of halogenase variants toward different synthetic substrates, providing a valuable tool for implementing halogenases in biocatalysis efforts.

Red edge effect and chromoselective photocatalysis with amorphous covalent triazine-based frameworks

Chromoselective photocatalysis offers an intriguing opportunity to enable a specific reaction pathway out of a potentially possible multiplicity for a given substrate by using a sensitizer that converts the energy of incident photon into the redox potential of the corresponding magnitude. Several sensitizers possessing different discrete redox potentials (high/low) upon excitation with photons of specific wavelength (short/long) have been reported. Herein, we report design of molecular structures of two-dimensional amorphous covalent triazine-based frameworks (CTFs) possessing intraband states close to the valence band with strong red edge effect (REE). REE enables generation of a continuum of excited sites characterized by their own redox potentials, with the magnitude proportional to the wavelength of incident photons. Separation of charge carriers in such materials depends strongly on the wavelength of incident light and is the primary parameter that defines efficacy of the materials in photocatalytic bromination of electron rich aromatic compounds. In dual Ni-photocatalysis, excitation of electrons from the intraband states to the conduction band of the CTF with 625 nm photons enables selective formation of C‒N cross-coupling products from arylhalides and pyrrolidine, while an undesirable dehalogenation process is completely suppressed.

Rose Bengal-photocatalyzed perfluorohexylation reactions of organic substrates in water. Applications to late-stage syntheses.

The Rose Bengal-photocatalyzed perfluorohexylation of olefins, alkynes, and electron-rich aromatic compounds in water was achieved employing perfluorohexyl iodide as fluoroalkyl source and TMEDA as sacrificial donor under green LED irradiation. Alkenes and alkynes rendered products derived from the atom transfer radical addition (ATRA) pathway, and in the case of alkynes, exclusively as E-stereoisomers. These are the first examples of photocatalyzed ATRA reactions carried out excursively in water alone. The reactions of aromatic compounds under the current protocol in water present the advantage of employing a perfluoroalkyl iodide (C6F13-I) as source of perfluorohexyl radicals. Examples of photocatalytic late-stage incorporations of fluoroalkyl moieties into two commercial drugs of widespread use are reported.

Diamine Synthesis via the Nitrogen-Directed Azidation of σ- and π-C-C Bonds.

Diamines are essential building blocks for the synthesis of agrochemicals, drugs, and organic materials, yet their synthesis remains challenging, as both nitrogens need to be differentiated and diverse substitution patterns (1,2, 1,3, or 1,4) are required. We report herein a new strategy giving access to 1,2, 1,3, and 1,4 amido azides as orthogonally protected diamines based on the nitrogen-directed diazidation of alkenes, cyclopropanes, and cyclobutanes. Commercially available copper thiophene-2-carboxylate (CuTc, 2 mol %) as catalyst promoted the diazidation of both π and σ C-C bonds within 10 min in the presence of readily available oxidants and trimethylsilyl azide. Selective substitution of the formed α-amino azide by carbon nucleophiles (electron-rich aromatic, malonate, organosilicon, organoboron, organozinc, and organomagnesium compounds) was then achieved in a one-pot fashion, leading to the formation of 1,2-, 1,3-, and 1,4-diamines with the amino groups protected orthogonally as an amide/carbamate and an azide.

Electro-reductive Fragmentation of Oxidized Lignin Models.

Lignin provides a potential sustainable source for production of electron-rich aromatic compounds. Recently, electrochemical lignin degradation via an oxidation/reduction sequence under mild conditions has garnered much attention within the lignin community, as electrochemistry simplifies redox reactions and offers an electron source/sink for synthesis without using stoichiometric oxidants or reductants. This paper describes a fundamental approach for the electrochemical fragmentation of the primary connection in native lignin, β-O-4. Potential-controlled electrolysis enables selective reduction and provides fragmentation products and/or coupling products in isolated yields of 59-92%.

Solvent‐free Reactions for the Synthesis of Indolenine‐based Squaraines and Croconaines: Comparison of Thermal Heating, Mechanochemical Milling, and IR Irradiation

Squaraines and croconaines are organic dyes characterized by intense absorption in the visible or near-infrared spectral regions with applications ranging from biology to material sciences. They are commonly synthesized by condensation reactions of oxocarbonic acids (squaric or croconic acid, respectively) with electron-rich aromatic compounds in high-boiling organic solvents. Here, a simple, cost-effective, and environmentally benign process was developed for the synthesis of indolenine-based squaraines and croconaines under solvent-free conditions. Protocols based on conventional thermal heating, mechanochemical milling, and IR-light activation were compared.

Visible‐Light Cercosporin Catalyzed Sulfenylation of Electron‐Rich Compounds with Thiols under Transition‐Metal‐Free Conditions

AbstractIn the present study, an efficient visible‐light and cercosporin catalyzed direct sulfenylation of electron rich aromatic compounds such as indoles, active methylenes, and phenols with thiols through a photoredox catalyzed process has been reported through the cleavage of a C−H/S−H bond at room temperature under transition‐metal‐free conditions. The reported methodology gives a direct way in the formation of C−S bonds with broad functional group compatibility, which produces 3‐sulfenylated indoles, α‐sulfenylated carbonyl compounds and diaryl sulfides in moderate to good yields. The advantage of the reaction is that it meets the criteria of green and sustainable synthetic chemistry and can be used widely in the fields of organic synthesis and pharmaceutical chemistry.

In situ quantitative determination of the intermolecular attraction between amines and a graphene surface using atomic force microscopy

The adsorption of pollutants on carbonaceous environmental media has been widely studied via batch sorption experiments and spectroscopic characterization. However, the molecular interactions between pollutants and interfacial sites on carbonaceous materials have only been indirectly investigated. To comprehend the adsorption mechanisms in situ, we applied atomic force microscopy force spectroscopy (AFM-FS) to quantitatively determine the molecular interactions between typical amines (methylamines and N-methylaniline) and the surface of highly oriented pyrolytic graphite (HOPG), which was supported by the single molecule interaction derived from density functional theory and batch adsorption experiments. This method achieved direct and in situ characterization of the molecular interactions in the adsorption process. The molecular interactions between the amines and the adsorption sites on the graphite surface were affected by pH and peaked at pH 7 due to strong cation-π interactions. When the pH was 11, the attractions were weak due to a lack of cation-π interaction, whereas, when the pH was 3, the competitive occupation of hydronium ions on the surface reduced the attraction between the amines and HOPG. Based on AFM-FS, the single molecule force of methylamine and N-methylaniline on the graphite surface was estimated to be 0.224 nN and 0.153 nN, respectively, which was consistent with density functional theory (DFT) calculations. This study broadens our comprehension of cation-π interactions between amines and electron-rich aromatic compounds at the micro/nanoscale.

Bispidine-based bis-azoles as a new family of supramolecular receptors: the theoretical approach

Two new bis-azoles derived from 1,5-dimethylbispidin-9-one were synthesized and structurally characterized. In both cases the bispidine backbone adopts the double chair conformation, which is also confirmed by calculations. In both structures, the azole rings are spatially pre-reorganized for the supramolecular interactions with the proper substrates like electron-rich aromatic compounds; the origin and nature of tiny intramolecular interactions are discussed in view of conformation stability.