Electron-rich Aryl Research Articles

SNAr hexafluoroisopropoxylation of electron-rich aryl fluoride with a catalytic electrical input

Abstract Anodic oxidation–promoted SNAr reactions of electron-rich aryl fluoride were developed. The anodic oxidation of 4-fluoroanisole in hexafluoroisopropyl alcohol (HFIP) with K2CO3 led to SNAr-type hexafluoroisopropoxylation, and the reaction was completed with a catalytic electrical input. The results of cyclic voltammetry suggest that the radical cation of 4-fluoroanisole, which would react with the alkoxide of HFIP, is generated. Electron transfer between the intermediate and the starting material constructs the catalytic cycle, and the elimination of fluoride from the Meisenheimer complex produces the desired compound.

Ni-Catalyzed Asymmetric Reductive Arylation of α-Substituted Imides.

α-Aryl imides are common structural motifs in bioactive molecules and proteolysis-targeting chimeras designed for targeted protein degradation. An asymmetric Ni-catalyzed reductive cross-coupling of imide electrophiles and (hetero)aryl halides has been developed to synthesize enantioenriched α-arylglutarimides from simple starting materials. Judicious selection of electrophile pairs allows for coupling of both electron-rich and electron-deficient (hetero)aryl halides in good yields and enantioselectivities.

Transition-Metal Free Amination and Hydrodefluorination of Aryl Fluorides Promoted by Solvated Electrons.

Cross-coupling reactions for constructing C-N bonds represent a pivotal advancement in chemical science. Traditional methodologies, including nucleophilic aromatic substitution (SNAr) and transition metal-catalyzed cross-couplings, have limitations concerning aryl scope, reliance on toxic and costly transition-metal catalysts, and issues related to atom economy and waste generation from ligands and additives. In this work, we introduce a novel method for aminating neutral, electron-rich, and electron-deficient aryl halides, eliminating the need for transition metals. Our approach involves the activation of aryl halides using solvated electrons generated from granulated lithium and sonication. This serves as a sustainable source of reducing power, facilitating the efficient formation of C-N bonds under near ambient conditions. Competitive selectivity studies between halide and ester functionalities were explored. Reaction scope and conducted mechanistic studies which supported the proposed radical-nucleophilic substitution (SRN1) mechanism for the reaction. Notably, the developed reaction has a highly competitive reductive dehalogenation pathway during the C-N coupling reaction, and this mechanistic divergency was thoroughly explored. This work not only broadens the scope of C-N coupling reactions which typically employs aryl bromides and iodides and rarely aryl fluorides which is also equally abundant, but also introduces a new way to do C-N coupling reactions using solvated electrons.

Enantioselective Synthesis of α-Aryl Ketones by a Cobalt-Catalyzed Semipinacol Rearrangement.

A highly enantioselective cobalt-catalyzed semipinacol rearrangement of symmetric α,α-diarylallylic alcohols is disclosed. A chiral cobalt-salen catalyst generates a highly electrophilic carbocation surrogate following hydrogen atom transfer and radical-polar crossover steps. This methodology provides access to enantioenriched α-aryl ketones through invertive displacement of a cobalt(IV) complex during 1,2-aryl migration. A combination of readily available reagents, silane and N-fluoropyridinium oxidant, are used to confer this type of reactivity. An exploration into the effect of aryl substitution revealed the reaction tolerates para- and meta-halogenated, mildly electron-rich and electron-poor aromatic rings with excellent enantioselectivities and yields. The yield of the rearrangement diminished with highly electron-rich aryl rings whereas very electron-deficient and ortho-substituted arenes led to poor enantiocontrol. A Hammett analysis demonstrated the migratory preference for electron-rich aromatic rings, which is consistent with the intermediacy of a phenonium cation.

Stable Meisenheimer Complexes as Powerful Photoreductants Readily Obtained from Aza-Hetero Aromatic Compounds.

Excited states of radical anions derived from the photoreduction of stable organic molecules are suggested to serve as potent reductants. However, excited states of these species are too short-lived to allow bimolecular quenching processes. Recently, the singlet excited state of Meisenheimer complexes, which possess a long-lived excited state, was identified as the competent species for the reduction of challenging organic substrates (-2.63 V vs. SCE, saturated calomel electrode). To produce reasonably stable and simply accessible different Meisenheimer complexes, the addition of nBuLi to readily available aromatic heterocycles was investigated, and the photoreactivity of the generated species was studied. In this paper, we present the straightforward preparation of a family of powerful photoreductants (*Eox<-3 V vs. SCE in their excited states, determined by DFT and time-dependent TD-DFT calculations; DFT, density functional theory) that can induce dehalogenation of electron-rich aryl chlorides and to form C-C bond through radical cyclization. Photophysical analyses and computational studies in combination with experimental mechanistic investigations demonstrate the ability of the adduct to act as a strong electron donor under visible light irradiation.

Perfect Partners: Biocatalytic Halogenation and Metal Catalysis for Protein Bioconjugation.

Flavin-dependent halogenases (FDHs) are the most extensively researched halogenases and show great potential for biotransformation applications. These enzymes use chloride, bromide, or iodide ions as halogen donors to catalyze the oxygen-dependent halogenation of electron-rich aryl moieties, requiring stochiometric amounts of FADH2 in the process. This makes FDH-catalyzed aryl halogenation a highly selective and environmentally friendly tool for the synthesis of aryl halides. The latter in turn serve as valuable intermediates for transition metal catalyzed cross coupling reactions for C-C bond formation. Previous research made extensive use of this approach to halogenate small molecules as building blocks for late-stage functionalization by transition-metal catalyzed cross-coupling reactions. Based on these results, several groups have managed to expand this research to protein targets over the past two years. Their work indicates an emerging methodology for bioconjugation using late-stage biocatalytic halogenation in conjunction with biorthogonal Suzuki-Miyaura cross-coupling. This strategy could present an attractive alternative to existing approaches due to the stability of the C-C bond bridging the generated biaryl moiety and the ease of late-stage enzymatic modification while maintaining excellent selectivity under mild conditions.

Electrocatalytic Radical Cation Diels-Alder Reactions Using Enol Ethers As Dienophiles

Single-electron oxidation enables the conversion of electron-rich alkenes such as styrene derivatives to radical cation species. We have been developing various cycloaddition reactions of radical cations produced by single-electron oxidation using electrochemical and TiO2 photochemical methods. Introducing an electron-rich aryl group which we call a redox tag is a critical part of the process to control the reactivity of the radical cations. During carbon-carbon bonds formation the motif functions as both electron donor and electron acceptor. In addition to styrene derivatives, enol ethers can also be readily oxidized by single electron transfer (SET) electrochemically or photochemically to generate the radical cations. For instance, enol ethers tethered redox tag serves efficient radical cation precursors for [2+2] cycloadditions.[1] The cycloadditions are net redox-neutral reactions and are initiated by the formation of a radical cation by single-electron oxidation and completed by reduction after ring formation.Herein, we present [4+2] cycloadditions using enol ethers as dienophiles by electrochemical oxidation in lithium perchlorate (LiClO4)/nitromethane (MeNO2) system. In the case of disubstituted enol ethers prepared from aldehydes, the approach involving redox tag was successful in obtaining the corresponding cycloadducts, while the desired products were not obtained when the substrates without redox tag were subjected.[2] This result suggests that intramolecular electron transfer from the redox tag is crucial for the formation of the cyclohexene ring systems. In contrast, the trisubstituted enol ethers prepared from ketones allowed the cycloaddition reaction to proceed without the involvement of redox tag. It is expected that the methyl group significantly stabilizes the cyclohexene radical cations to have enough lifetime to be reduced by intermolecular SET. Furthermore, since the cycloaddition reaction of enol ether was completed with a catalytic amount of electricity (0.4 F/mol), a radical cation chain mechanism is proposed in which electron acts as a catalyst.

Indole Nucleophile Triggers Mechanistic Divergence in Ni-Photoredox N-Arylation.

This study presents a Ni-photoredox method for indole N-arylation, broadening the range of substrates to include indoles with unprotected C3-positions and base-sensitive groups. Through detailed mechanistic inquiries, a Ni(I/III) mechanism was uncovered, distinct from those commonly proposed for Ni-catalyzed amine, thiol, and alcohol arylation, as well as from the Ni(0/II/III) cycle identified for amide arylation under almost identical conditions. The key finding is the formation of a Ni(I) intermediate bearing the indole nucleophile as a ligand prior to oxidative addition, which is rare for Ni-photoredox carbon-heteroatom coupling and has a profound impact on the reaction kinetics and scope. The pre-coordination of indole renders a more electron-rich Ni(I) intermediate, which broadens the scope by enabling fast reactivity even with challenging electron-rich aryl bromide substrates. Thus, this work highlights the often-overlooked influence of X-type ligands on Ni oxidative addition rates and illustrates yet another mechanistic divergence in Ni-photoredox C-heteroatom couplings.

Earth-Abundant Metal-Catalyzed Cross-Coupling Reactions of 1-Bromocyclobut-1-enes with Grignard Reagents

AbstractCross-coupling reactions have been developed between C2-substituted 1-bromocyclobut-1-enes and Grignard reagents using two effective catalysts, e.g., Fe(acac)3 and Ni(acac)2. The iron catalyst works in THF but requires NMP as the co-solvent, with the advantage of achieving cross-coupling reactions with alkyl Grignard reagents. The nickel catalyst was able to promote the reactions in THF without any additive and showed high reactivity with electron-rich aryl Grignard reagents. These catalysts gave various types of substituted cyclobutenes in good yields.

C–heteroatom coupling with electron-rich aryls enabled by nickel catalysis and light

Nickel photoredox catalysis has resulted in a rich development of transition-metal-catalysed transformations for carbon–heteroatom bond formation. By harnessing light energy, the transition metal can attain oxidation states that are difficult to achieve through thermal chemistry in a catalytic manifold. For example, nickel photoredox reactions have been reported for both the synthesis of anilines and aryl ethers from aryl(pseudo)halides. However, oxidative addition to simple nickel systems is often sluggish in the absence of special, electron-rich ligands, leading to catalyst decomposition. Electron-rich aryl electrophiles therefore currently fall outside the scope of many transformations in the field. Here we provide a conceptual solution to this problem and demonstrate nickel-catalysed C–heteroatom bond-forming reactions of arylthianthrenium salts, including amination, oxygenation, sulfuration and halogenation. Because the redox properties of arylthianthrenium salts are primarily dictated by the thianthrenium, oxidative addition of highly electron-rich aryl donors can be unlocked using simple NiCl2 under light irradiation to form the desired C‒heteroatom bonds.

Catalytic 1,1-diazidation of alkenes.

Compared to well-developed catalytic 1,2-diazidation of alkenes to produce vicinal diazides, the corresponding catalytic 1,1-diazidation of alkenes to yield geminal diazides has not been realized. Here we report an efficient approach for catalytic 1,1-diazidation of alkenes by redox-active selenium catalysis. Under mild conditions, electron-rich aryl alkenes with Z or E or Z/E mixed configuration can undergo migratory 1,1-diazidation to give a series of functionalized monoalkyl or dialkyl geminal diazides that are difficult to access by other methods. The method is also effective for the construction of polydiazides. The formed diazides are relatively safe by TGA-DSC analysis and impact sensitivity tests, and can be easily converted into various valuable molecules. In addition, interesting reactivity that geminal diazides give valuable molecules via the geminal diazidomethyl moiety as a formal leaving group in the presence of Lewis acid is disclosed. Mechanistic studies revealed that a selenenylation-deselenenylation followed by 1,2-aryl migration process is involved in the reactions, which provides a basis for the design of new reactions.

Dissymmetrical Chiral Peropyrenes: Synthesis via Iridium-Catalyzed C-H Activation/Alkyne Benzannulation and Study of Their Properties.

Dissymmetrical chiral peropyrenes with electron-rich and electron-deficient aryl substituents in the bay regions were synthesized via iridium-catalyzed C-H activation and alkyne benzannulation. The electronic properties were studied using cyclic and differential pulse voltammetry. The enantiomers were separated and exhibited high glum and gabs values in circularly polarized luminescence (CPL) and circular dichroism (CD), respectively. Variable-temperature NMR experiments were conducted on symmetrical and dissymmetrical chiral peropyrenes to compare the barrier to rotation of the aryl groups in the bay region.

Tuning Active Site Electron Density for Enhanced Molecular Recognition and Catalysis.

Enzymes have an extraordinary ability to utilize aromatic interactions for molecular recognition and catalysis. We here report molecularly imprinted nanoparticle receptors. The aromatic "wall" material in the imprinted binding site is used to enhance the molecular recognition of aromatic guests that have similar charges, shapes, and sizes but differ in π-electron density. Additionally, aromatic interactions are employed to activate an electron-rich aryl leaving group on a glycoside, mimicking the nucleoside hydrolase of the parasite Trypanosoma vivax.

Excited-State Nickel-Catalyzed Amination of Aryl Bromides: Synthesis of Diphenylamines and Primary Anilines.

Excited-state nickel-catalyzed C-N cross-coupling of aryl bromides with sodium azide enables the synthesis of diarylamines and primary anilines under mild reaction conditions. The oxidative addition of electron-rich aryl bromides with low-valent Ni under the photochemical conditions is endothermic. Herein, we demonstrate a light-mediated nickel-catalyzed reaction of electronically rich aryl bromides that yields diarylamines, while the reaction with electron-deficient aryl bromides gives access to anilines at room temperature.

Pd-Catalysed Direct Arylation of Distyrylbenzene: Strong Dual-state Fluorescence and Electrochromism.

Distyrylbenzenes (DSBs) are well-known for their strong multicolour fluorescence. Fluorescence tuning of DSB via further functionalization/arylation, on the other hand, is uncommon. This paper reports a Pd-catalysed direct arylation approach for introducing different aryl groups onto fluorobenzene-containing DSB moiety (7) in high yields (67-72 %). The versatile methodology allows the substitution of neutral [tolyl (1)], electron-deficient [p-formyl benzene (2), p-acetyl benzene (3), p-nitrobenzene (4)] and electron-rich [carbazole (5), triphenylamine (6)] aryl groups. The electron-deficient aryls render mono-substitution, while the electron-rich counterparts promote di-substitution. The compounds (1-6) show blue, green, and yellow fluorescence in both the solution and solid states; the fluorescence quantum yields reach >98 % and the peak maxima span from 425 to 560 nm. The mono-carbazole DSB (5) exhibit white light emission (WLM) in polar solvents (acetone, DMF, CH3CN, DMSO and NMP) with very high fluorescence quantum yields (φf) of 60-80 %. For WLM, such high efficiency (φf) is somewhat uncommon. Moreover, visible-to-NIR reversible electrochromism is demonstrated by the TPA-integrated DSB (6). The colour of 6 changes from pristine light yellow to orange, and the absorption maxima shifts from 372 to 1500 nm when a positive potential of 1.0 V vs Ag/Ag+ is applied. Moreover, the system shows high colouration efficiency in the NIR region with fast switching speeds for colouration and decolouration as fast as 0.98 s and 1.05 s.

Intermolecular Enamine Mizoroki-Heck Reactions on a Bio-Derived Scaffold.

The intramolecular enamine-Mizoroki-Heck reaction allows for the construction of nitrogen-containing heterocycles, although the related intermolecular version is less known. The reactions of enamines derived from Cyrene were investigated under Mizoroki-Heck conditions. An optimization study was used to identify that 1.5 mol % Pd(dba)2 with PCy3 in xylene at reflux temperature gave the highest yield with electron-rich aryl iodides. Arylation occurred predominantly at the C-N center of the enamine, while the diastereoselectivity was dependent on the nitrogen substitution in the enamine.

Palladium(II) complexes bearing thioether-NHC ligand: Synthesis, characterization, and their application in Suzuki-Miyaura coupling

A series of palladium(II) complexes bearing thioether-functionalized N-heterocyclic carbene ligands, namely [Pd(N-(R1,2,3)-N'-(2-(phenylthio)ethyl)-5,6-dimethylbenzimidazol-2-ylidene)Cl2(py)] (R1: 1-bromohexane, R2: 1-bromododecane, R3: 1-bromooctadecane, R’: 2-chloroethyl phenyl sulfide, py: pyridine), have been synthesized and characterized. The synthesized ligands (2a-c) and complexes (3a-c) were characterized by NMR, FT-IR, and elemental analysis. The crystal structure of Pd(II) complex 3a was determined by single-crystal X-ray diffraction. X-ray diffraction analysis revealed that the palladium ion has a slightly distorted square-planar geometry. The catalytic activity of all complexes (3a-c) for the Suzuki-Miyaura cross-coupling reaction was examined. Under the optimized conditions, aryl bromides were successfully converted into corresponding coupled products. Yields ranged high for electron-rich aryl bromides, moderate for electron-neutral bromides, and low for electron-poor bromides.

Asymmetric three-component Tsuji-Trost allylation reaction enabled by chiral aldehyde/palladium combined catalysis.

Despite the long-standing exploration of the catalytic asymmetric Tsuji-Trost allylation reaction since the mid-20th century, most reported instances have adhered to a two-component approach. Here, we present a remarkably efficient three-component asymmetric allylation reaction enabled by the collaborative action of chiral aldehyde and palladium. A diverse array of NH2-unprotected amino acid esters, aryl or alkenyl iodides, and allyl alcohol esters exhibit robust participation in this reaction, resulting in the synthesis of structurally diverse non-proteinogenic α-amino acid esters with favorable experimental outcomes. Mechanistic investigations reveal the dominance of the allylation/Heck coupling cascade in reactions involving electron-rich aryl iodides, while the Heck coupling/allylation cascade emerges as the dominant pathway in reactions involving electron-deficient aryl iodides. This chiral aldehyde/palladium combining catalytic system precisely governs the chemoselectivity of C-allylation and N-allylation, the regioselectivity of linear and branched allylation, and the enantioselectivity of C-allylation products.

Electrochemistry and Organic Synthesis: New Adventures with Olefin Coupling Reactions and Electrode Surfaces

Electrochemistry has long offered opportunities to explore new modes of reactivity, new approaches for introducing selectivity into synthetic reactions, and new strategies for the synthesis of everything from complex molecules to complex, addressable molecular surfaces. In the talk to be given, two aspects of our efforts along these lines will be detailed. In the first, we will take a look at recent efforts to use anodically-generated reactive intermediates to convert readily available small molecules into functionalized synthetic building blocks and natural product derivatives. Key to these efforts are oxidation reactions that generate reactive radical cation and radical intermediates. In one application, newly available chiral lactols synthesized using methodology developed by the Lin (Cornell) and Miller (Yale) groups are being transformed into C-glycoside and aza-C-glycoside derivatives. The reactions take advantage of oxidation reactions of either enol ether or vinylsulfide groups. The cyclization reactions and the subsequent deprotection strategy needed for converting the cyclization products into a useful synthetic building block will be highlighted. In a second application of an anodic cyclization, the role of thioamides in reactions targeting the chrysosoporazine family of natural products will be discussed. The reactions seek to provide an efficient method for converting lignin derived building blocks into molecules that reduce the efflux of anticancer drugs from cells. Initial cyclization attempts utilizing amide based N-radicals and anodic olefin coupling reactions were not successful. Those reactions consistently led to over-oxidation of the products that contain a highly electron-rich aryl ring. The use of thio-amide derived radicals provides a method to circumvent this problem.In the second topic to be discussed, the question of how one might begin to induce asymmetry into such electrochemical cyclizations will be highlighted. The chemistry focuses on efforts to influence the course of both electrochemical oxidation and reduction reaction and non-redox based transition metal catalyzed reactions with the surface of an electrode.

Cobalt-Catalyzed Asymmetric Reductive Alkenylation and Arylation of Heterobiaryl Tosylates: Kinetic Resolution or Dynamic Kinetic Resolution?

Herein, we report a cobalt-catalyzed atroposelective reductive cross-coupling of racemic heterobiaryl tosylates with a C(sp2)-X type electrophile. Both aryl and alkenyl halides are competent precursors for this reaction, providing a variety of heterobiaryls as the products in a highly enantioselective manner with high functionality tolerance. The related asymmetric arylation and alkenylation are discovered to proceed with divergent mechanisms. The reaction pathway changes from kinetic resolution (KR) when alkenyl bromides and aryl iodides bearing strong electron-withdrawing substitution on the para-position are employed as the starting materials to an enantioconvergent transformation via dynamic KR of configurationally labile cobaltacycles when relatively electron-rich aryl iodides are used. The change of the reaction mechanisms turns out to arise from the relative rates of two competing elementary steps, which are the epimerization of the cyclic Co(I) intermediates and their trapping by the coupling electrophiles of the C(sp2)-type via oxidative addition.