Methyl Arenes Research Articles

Meta‐Dimethylation of Arenes via Catellani Reaction from Aryl Thianthrenium Salts

AbstractHere we report the reaction of aryl thianthrenium salts that allows selective functionalization of the meta position of arenes. The combination of a site‐selective thianthrenation with a Catellani reaction provides access to 3,5‐dimethylated arenes. The developed reaction is complementary to the previously discovered reductive ipso‐alkylation of aryl thianthrenium salts and extends the possibilities for late‐stage methylation of arenes with a single aryl thianthrenium salt.

Meta-Dimethylation of Arenes via Catellani Reaction from Aryl Thianthrenium Salts.

Here we report the reaction of aryl thianthrenium salts that allows selective functionalization of the meta position of arenes. The combination of a site-selective thianthrenation with a Catellani reaction provides access to 3,5-dimethylated arenes. The developed reaction is complementary to the previously discovered reductive ipso-alkylation of aryl thianthrenium salts and extends the possibilities for late-stage methylation of arenes with a single aryl thianthrenium salt.

Direct Benzylic C-H Etherification Enabled by Base-Promoted Halogen Transfer.

We disclose a benzylic C-H oxidative coupling reaction with alcohols that proceeds through a synergistic deprotonation, halogenation and substitution sequence. The combination of tert-butoxide bases with 2-halothiophene halogen oxidants enables the first general protocol for generating and using benzyl halides through a deprotonative pathway. In contrast to existing radical-based methods for C-H functionalization, this process is guided by C-H acidity trends. This gives rise to new synthetic capabilities, including the ability to functionalize diverse methyl(hetero)arenes, tolerance of oxidizable and nucleophilic functional groups, precision site-selectivity for polyalkylarenes and use of a double C-H etherification process to controllably oxidize methylarenes to benzaldehydes.

Direct Benzylic C−H Etherification Enabled by Base‐Promoted Halogen Transfer

AbstractWe disclose a benzylic C−H oxidative coupling reaction with alcohols that proceeds through a synergistic deprotonation, halogenation and substitution sequence. The combination of tert‐butoxide bases with 2‐halothiophene halogen oxidants enables the first general protocol for generating and using benzyl halides through a deprotonative pathway. In contrast to existing radical‐based methods for C−H functionalization, this process is guided by C−H acidity trends. This gives rise to new synthetic capabilities, including the ability to functionalize diverse methyl(hetero)arenes, tolerance of oxidizable and nucleophilic functional groups, precision site‐selectivity for polyalkylarenes and use of a double C−H etherification process to controllably oxidize methylarenes to benzaldehydes.

C-H activation under visible light using DDQ organo-photocatalyst: Practical, tunable and additive free

Here we present a practical, mild, selective, eco-friendly, metal-free, cost-effective, and tunable method for the photoactivation of C-H compounds using an organo photocatalyst without any additives. For this purpose, the organo photocatalyst DDQ was employed as a versatile and highly efficient catalyst for C-H bond functionalization under visible light irradiation in a straightforward reaction setup, free from additives and co-catalysts. Notably, under appropriate solvent conditions, the photooxidation of alkylarenes produced ketones, aldehydes, and carboxylic acids from corresponding starting materials. In CH3CN solvent, carboxylic acids were obtained. Interestingly over oxidation to carboxylic acid is avoided and aldehydes were produced from methyl arenes via acetal formation in CH3CN:MeOH. Furthermore, our results demonstrated that the photooxidation of 4-methoxytoluene was more efficient than that of 4-methoxybenzylalcohol. The proposed mechanism for this reaction involved the formation of a charge transfer complex between the starting material and DDQ, as indicated by UV–Vis and fluorescence spectra. Also, this method exhibited promising scalability, with 30 mmol of 4-methoxytoluene being converted to 4-methoxybenzoic acid with a yield of 92 % (TON: 345).

Catalytic ortho C–H methylation and trideuteromethylation of arylthianthrenium salts via the Catellani strategy

We report a Pd/NBE cooperative catalyzed ortho C–H methylation and trideuteromethylation of arylthianthrenium salts, enabling the efficient synthesis of a wide variety of (trideutero)methylated arenes in moderate to good yields.

Montmorillonite K-10 catalyzed synthesis of Hantzsch dihydropyridine derivatives from methyl arenes via in situ generated ammonia under microwave irradiation in neat conditions.

An expeditious, efficient, and environmentally friendly approach has been established for the synthesis of diverse Hantzsch 1,4-dihydropyridine derivatives utilizing montmorillonite K-10 as a catalyst in solvent-free conditions. The procedure entails the reaction of methyl arynes as a sustainable surrogate of aryl aldehydes, active methylene compounds, and urea hydrogen peroxide (UHP) as an oxidising agent as well as a source of ammonia under microwave irradiation, facilitated by montmorillonite K-10.

Iron-Catalyzed Oxidative Cyclization of 2-Amino Styrenes with Alcohols and Methyl Arenes for the Synthesis of Polysubstituted Quinolines.

Herein, we present the iron-catalyzed oxidative cyclization of alcohol/methyl arene with 2-amino styrene to synthesize polysubstituted quinoline. Low-oxidation level substrates such as alcohols and methyl arenes are converted to aldehydes in the presence of an iron catalyst and di-t-butyl peroxide. Then, the quinoline scaffold is synthesized through imine condensation/radical cyclization/oxidative aromatization. Our protocol showed a broad substrate scope, and various functionalization and fluorescence applications of quinoline products demonstrated its synthetic ability.

Nickel-Catalyzed Exhaustive Hydrodefluorination of Perfluoroalkyl Arenes

Perfluoroalkyl compounds are persistent environmental pollutants due to their strong C(sp3)-F bonds. Hydrodefluorination has emerged as a potential alternative disposal method for perfluoroalkyl compounds. Although the transformation of trifluoromethyl arenes into the corresponding methyl arenes has been studied by several research groups, hydrodefluorination reactions of longer perfluoroalkyl chains remain rare. Herein, we report exhaustive hydrodefluorination reactions of pentafluoroethyl arenes and longer-chain analogues using molecular nickel catalysis. Despite the cleavage of multiple C(sp3)-F bonds, the reaction already proceeds upon gentle heating (60 °C). A mechanistic investigation indicated that the reaction proceeds via benzylic hydrodefluorination reactions followed by homobenzylic ones. We reveal the multiple roles of the Ni catalyst, which include C-F bond cleavage, promotion of HF elimination, and hydrosilylation.

Thianthrenation-Enabled Pyrrolidin-2-yl and Tetrahydrofuran-2-yl Methylation of (Hetero)Arenes.

The mild and efficient palladium-catalyzed pyrrolidin-2-yl and tetrahydrofuran-2-yl methylation of (hetero)arenes has been developed. A wide range of (hetero)arenes underwent the regioselective thianthrenation to generate the arylthianthrenium triflate, and the developed Pd-catalyzed alkene carboamination and carboalkoxylation reactions afforded the corresponding biologically important pyrrolidine and tetrahydrofuran derivatives. Mechanistic studies indicated that this reaction proceeds through a syn-heteropalladation mechanistic pathway. The demonstrated late-stage functionalization and enantioselective reaction will help to promote the potential application of the established method in organic synthesis and related fields.

Catalytically Generated Meerwein's Salt-Type Oxonium Ions for Friedel-Crafts C(sp2)-H Methylation with Methanol.

A catalytic protocol for a Friedel-Crafts-type direct C(sp2)-H methylation of various arenes with methanol is disclosed. The reaction is initiated by counteranion-stabilized silylium or arenium ions, which form Meerwein's salt-like oxonium ions with methanol as the active methylating agents. The silylated methyloxonium ions are stronger electrophiles than their protonated congeners, allowing the Friedel-Crafts alkylation to proceed more efficiently and at a lower reaction temperature. The regeneration of these superelectrophiles within the catalytic cycle is accomplished by the addition of a tetraorganosilane additive, i.e., trimethyl(phenyl)silane or tetraethylsilane, that releases a silylium ion through protodesilylation by the Brønsted acidic Wheland intermediate, thereby acting as a productive "proton-into-silylium ion" generator. By this method, even the C-H methylation of electronically deactivated aryl halides with methanol is achieved. The protocol is also applicable to nonactivated primary as well as π-activated benzylic alcohols. Dialkyl ethers are also competent alkylating agents in the presence of the quaternary phenylsilane additive.

Solvent-free and ball mill-free catalytic C–H methylation

The selective and efficient catalytic C–H methylation of (hetero)arenes is demonstrated without involving solvents or ball milling.

Electrochemical C-F bond activation of trifluoromethylarenes using silylium ions.

We report a mild, electrochemical trihydrodefluorination (e-THDF) for breaking highly stable C-F bonds in trifluoromethyl arenes to form the corresponding methyl arene products. Uniquely, this "green" approach relies on the in situ generation of Lewis acidic silyl cations that mediate fluoride abstraction. Overall, e-THDF has significantly improved functional group tolerance over current methods and should inspire the continued development of defluorinative processes.

Ruthenium-Catalyzed Monoselective C-H Methylation and d 3-Methylation of Arenes.

Site-selective installation of C-Me bonds remains a powerful and sought-after tool to alter the chemical and pharmacological properties of a molecule. Direct C-H functionalization provides an attractive means of achieving this transformation. Such protocols, however, typically utilize harsh conditions and hazardous methylating agents with poor applicability toward late-stage functionalization. Furthermore, highly monoselective methylation protocols remain scarce. Herein, we report an efficient monoselective, directed ortho-methylation of arenes using N,N,N-trimethylanilinium salts as noncarcinogenic, bench-stable methylating agents. We extend this protocol to d 3-methylation in addition to the late-stage functionalization of pharmaceutically active compounds. Detailed kinetic studies indicate the rate-limiting in situ formation of MeI is integral to the observed reactivity.

Synthesis of α‐Aryl Ketones by Harnessing the Non‐Innocence of Toluene and its Derivatives: Enhancing the Acidity of Methyl Arenes by a Brønsted Base and their Mechanistic Aspects

AbstractKetones are the key functional group that recurs in chemistry and biology, and accessing them through simple and economic ways is highly desirable. Herein, we report the synthesis of unsymmetrical ketones from abundant toluene and alkyl esters, where volatile alcohols are the sole byproduct. This protocol applies to a repertoire of substrates bearing electron‐donating, electron‐withdrawing, and neutral substituents. Most importantly, the organometallic ferrocenyl ester underwent aroylation with ease. This method is the first example to furnish diketones from methyl arenes and diesters. Furthermore, cyclic imide was synthesized by this protocol utilizing KN(SiMe3)2 as a ′nitrogen′ source. Density functional theory studies provide insight into deprotonation of toluene by K+‐π interaction by increasing its acidity, and this being the rate‐determining step.

Recent Trends in Upgrading of CO2 as a C1 Reactant in N‐ and C‐Methylation Reactions

AbstractCarbon dioxide (CO2) capture and conversion from renewable resources have recently emerged as a viable alternative to the synthesis of core chemicals. Despite the fact that CO2 fixation is limited due to its thermodynamic stability and kinetic inertness, researchers are becoming increasingly interested in developing novel routes with the use of CO2 in synthetic organic chemistry, and the pace of advancements in this field is accelerating. In particular, the development of benign N‐ and C‐methylation reactions employing CO2 as a C1 synthon instead of conventional methylation reagents would enable the release of lower amounts of waste leading to more sustainable chemical industry. This review presents recent new strategies for the chemical transformation of CO2 and its incorporation into N‐ or C‐based nucleophiles to provide access to the respective methylamines and methylated (hetero)arenes. Finally, existing limitations in N−H, and C−H bond activation techniques and future prospects are also discussed. We believe these methodologies will provide a handy reference to the chemists for synthesizing a vast range of methylated molecules in shorter steps by utilizing CO2 as an advantageous single‐carbon source.

C−H Methylation Using Sustainable Approaches

C−H methylation of sp2 and sp3 carbon centers is significant in many biological processes. Methylated drug candidates show unique properties due to the change in solubility, conformation and metabolic activities. Several photo-catalyzed, electrochemical, mechanochemical and metal-free techniques that are widely utilized strategies in medicinal chemistry for methylation of arenes and heteroarenes have been covered in this review.

Progress of Methylation of C6-8~Arene with Methanol: Mechanism, Catalysts, Kinetic/Thermodynamics and Perspectives

High-efficiency production of xylene/trimethylbenzene from benzene/toluene with methanol is a potential way to promote the implementation on the coupled cycle development strategy of petrochemical and coal chemical industry and optimize the resource structure. At the same time, relying on the innovation of catalytic new materials, physical chemistry, intelligent capture technology, process engineering, and other principles and methods, p-xylene (PX) and trimethylbenzene (TMB) with higher added value were prepared by C6-8~arene methylation, which could elevate the level of methylation field and improve the competitiveness of the industry. This paper focuses on the one-step methylation reaction of benzene with methanol or toluene with methanol to obtain high-purity p-xylene (BM-PX/TM-PX), and the one-step methylation reaction of xylene with methanol to obtain mesitylene (XM-TMB). The methylation reaction mechanism and the preparation strategy of a high-performance catalyst were reviewed. The high selectivity of PX obtained by precisely controlling the pore size and acid site distribution of zeolites was emphasized. Meanwhile, the current research progress of TMB, the kinetic/thermodynamics of the BM-PX/TM-PX, and XM-TMB methylation reaction were described. Based on a literature research and the conclusion of our research group, the mechanism of methylation reaction process was expounded. Finally, the new research direction of catalysts used and reaction process in methylation reaction were prospected in order to guide the rapid development of this field.

Cu(I)‐Catalyzed Microwave‐Assisted Multicomponent Reaction Towards Synthesis of Diverse Fluorescent Quinazolino[4,3‐b]quinazolin‐8‐ones and Their Photophysical Study

AbstractA novel, base‐ and ligand‐free one pot protocol for the synthesis of fused‐quinazolinone under microwave irradiation using environmentally friendly PEG‐400 as a solvent has been developed. Besides benzaldehyde, various benzyl alcohols and methyl arenes were used in this protocol, which extend its synthetic applicability. Photophysical study of this highly fluorescent framework was studied by fluorescent study. DFT and ESI/MS studies were carried out to justify the proposed mechanism.

Pd(II)‐Catalyzed Chelation‐Induced C(sp2)‐H Acylation of (Hetero)Arenes Using Toluenes as Aroyl Surrogate

AbstractIn the last few years, transition‐metal‐catalyzed chelation‐controlled ortho‐acylation utilizing methyl arene as the acyl partner has emerged as a powerful technique to achieve diverse complexity with diaryl ketone skeleton contrast to the traditional cross‐coupling/Friedel‐Craft reaction. Diaryl ketones are a significant building block that exists in pharmaceuticals, agrochemicals, natural products, functional materials, and many other useful compounds. In this context, the up‐to‐date developments in Pd(II)‐catalyzed ortho‐acylations of arenes and heteroarenes with toluenes as acyl surrogate are studied with advantages, limitations, mechanistic pathways, and prospective.