Arylation Reactions Research Articles

Palladium-catalyzed benzylic C(sp3)–H arylation of o-alkylbenzaldehydes

The palladium-catalyzed benzylic C(sp3)–H arylation of o-alkylbenzaldehyde derivatives was achieved utilizing 2-dimethylaminoethylamine as a novel transient directing group. The γ-C(sp3)–H arylation reaction efficiently afforded a variety of arylated o-alkylbenzaldehydes and polycyclic aromatic hydrocarbons (PAHs) in one pot, exhibiting high functional group tolerance with broad substrate scope. The aliphatic diamine auxiliary represents a simple, inexpensive, readily available, and removable directing group for CH activation. The resultant o-benzylbenzaldehyde products could be diversely transformed into potentially important synthetic intermediates under mild conditions.

Selective B(5,8,9)-Triarylation Reaction of o-Carboranes through Determination of the Order of Introduction of Aryl Groups into B(4)-Acylamino-o-carboranes.

Palladium-catalyzed iterative cage B-H arylation reaction of a wide range of B(4)-acylamino-o-carboranes with aryl iodides has been developed, leading to the formation of B(5,8,9)-triarylated B(4)-acylamino-o-carboranes with excellent regioselectivity. Moreover, B(5,8,9)-triarylated carboranes bearing three different aryl groups were synthesized from B(4)-acylamino-o-carborane and three different aryl iodides. The order of introduction [B(9) > B(8) > B(5)] of aryl groups into the B(5,8,9)-triarylation reaction was determined for the first time through NMR monitoring and X-ray analyses.

Bayesian reaction optimization as a tool for chemical synthesis.

Reaction optimization is fundamental to synthetic chemistry, from optimizing the yield of industrial processes to selecting conditions for the preparation of medicinal candidates1. Likewise, parameter optimization is omnipresent in artificial intelligence, from tuning virtual personal assistants to training social media and product recommendation systems2. Owing to the high cost associated with carrying out experiments, scientists in both areas set numerous (hyper)parameter values by evaluating only a small subset of the possible configurations. Bayesian optimization, an iterative response surface-based global optimization algorithm, has demonstrated exceptional performance in the tuning of machine learning models3. Bayesian optimization has also been recently applied in chemistry4-9; however, its application and assessment for reaction optimization in synthetic chemistry has not been investigated. Here we report the development of a framework for Bayesian reaction optimization and an open-source software tool that allows chemists to easily integrate state-of-the-art optimization algorithms into their everyday laboratory practices. We collect a large benchmark dataset for a palladium-catalysed direct arylation reaction, perform a systematic study of Bayesian optimization compared to human decision-making in reaction optimization, and apply Bayesian optimization to two real-world optimization efforts (Mitsunobu and deoxyfluorination reactions). Benchmarking is accomplished via an online game that links the decisions made by expert chemists and engineers to real experiments run in the laboratory. Our findings demonstrate that Bayesian optimizationoutperforms human decisionmaking in both average optimization efficiency (number of experiments) and consistency (variance of outcome against initially available data). Overall, our studies suggest that adopting Bayesian optimization methods into everyday laboratory practices could facilitate more efficient synthesis of functional chemicals by enabling better-informed, data-driven decisions about which experiments to run.

One‐Pot Synthesis of 3‐ to 15‐Mer π‐Conjugated Discrete Oligomers with Widely Tunable Optical Properties

Main observation and conclusionA series of all‐donor type alternating (D1‐D2) monodisperse oligomers based on cyclopentadithiophene (CPDT) and 1,4‐difluorobenzene (DFB) with gradually increasing chain lengths containing 3 to 15 monomers were successfully synthesized via one‐pot C—H direct arylation reaction. As confirmed by various structural characterizations, all these long‐chain oligomers are monodispersed with defined structures. The length‐dependent optical and electrochemical properties with the evolution from the shortest oligomer (O1) to the longest oligomer (O7) and their parent polymer P1 have been studied in details. By simply tuning the mixing ratio of discrete oligomers, the photoluminescence (PL) in a wide range of color emissions extending to near‐white can be facilely modulated, illustrating the potential of these monodisperse conjugated oligomers for light emission application. The atom‐, step‐ and pot‐economic synthetic strategy here developed will open the door toward efficient and controllable synthesis of π‐conjugated oligomers for accurate structure‐property relationship study and optic & electronic device applications.

Triethylamine‐Promoted Stereoselective Synthesis of Dialkyl 2‐Thiofumarates by the Reaction of Thiols and Dialkyl Acetylenedicarboxylates

AbstractA mild, efficient and stereoselective synthesis of dialkyl 2‐thiofumarates is described based on the addition reaction of aryl(benzyl) thiols and dialkyl acetylenedicarboxylates in the presence of triethylamine as a mild base. The reactions were stereoselectively performed in CH2Cl2 at room temperature toward synthesis of Z‐stereoimers as the major isomer in good yields.

Regiodivergent C-H Arylation of Triphenylene Derivatives Controlled by Electronic Effects of Diaryliodonium Salts.

A regiodivergent C-H arylation of triphenylene derivatives with diaryliodonium salts was developed. The regiodivergence was controlled by electronic effects of diaryliodonium salts. When the aryl(mesityl)iodonium salts bearing strong electron-donating groups at the para-position of aryl groups were used, the arylation reactions occurred ortho to amide groups. However, if the aryl(mesityl)iodonium salts bearing electron-withdrawing groups or weak electron-donating groups at the para-position of aryl groups were utilized, the arylation reactions occurred meta to amide groups.

Sequential N‐Arylation and Intramolecular Imine Addition Reaction of Indoloazomethine Ylides with Arynes for the Synthesis of Thiadiazepine Derivatives

AbstractMetal‐free reaction of indoloazomethine ylides with 2‐(trimethylsilyl)aryl triflates in the presence of TMAF and MeOH provided 1,4‐thiadiazepines through sequential N‐arylation and intramolecular imine addition reaction, which is fully oxidized with p‐chloranil. These compounds are smoothly isomerized to indoloindolizines in quantitative yield. Moreover, formation of indoloindolizine was accessed from indoloazomethine ylide and 2‐(trimethylsilyl)aryl triflate in semi‐one‐pot.magnified image

Regiospecific and site-selective C–H allylation of phenols with vinyldiazo compounds catalyzed by In(iii)

An In(OTf)3-catalyzed regiospecific, site-selective, and C–H chemoselective insertion reaction of phenols with vinyldiazoacetates was developed. The reactions of aryl or alkyl substituted vinyldiazoacetates exhibited different selective manners.

Understanding the reaction mechanism of the regioselective piperidinolysis of aryl 1-(2,4-dinitronaphthyl) ethers in DMSO: Kinetic and DFT studies

Reactions of aryl 1-(2,4-dinitronaphthyl) ethers with piperidine in dimethyl sulfoxide at 25oC resulted in substitution of the aryloxy group at the ipso carbon atom. The reaction was measured spectrophotochemically and the kinetic studies suggested that the titled reaction is accurately third order. The mechanism is began by fast nucleophilic attack of piperidine on C1 to form zwitterion intermediate (I) followed by deprotonation of zwitterion intermediate (I) to the Meisenheimer ion (II) in a slow step, that is, SB catalysis. The regular variation of activation parameters suggested that the reaction proceeded through a common mechanism. The Hammett equation using reaction constant σo values and Brønsted coefficient value showed that the reaction is poorly dependent on aryloxy substituent and the reaction was significantly associative and Meisenheimer intermediate-like. The mechanism of piperidinolysis has been theoretically investigated using density functional theory method using B3LYP/6-311G(d,p) computational level. The combination between experimental and computational studies predicts what mechanism is followed either through uncatalyzed or catalyzed reaction pathways, that is, SB and SB-GA. The global parameters of the reactants, the proposed activated complexes, and the local Fukui function analysis explained that C1 carbon atom is the most electrophilic center of ether. Also, kinetics and theoretical calculation of activation energies indicated that the mechanism of the piperidinolysis passed through a two-step mechanism and the proton transfer process was the rate determining step.

Magnetically recoverable nickel-palladium alloy nanocatalysts for direct C-H arylation reactions.

Novel magnetically recoverable nanocatalyst comprising nickel-palladium (NiPd) alloy nanoparticles (NPs) supported on reduced graphene oxide (rGO) modified with cobalt ferrite (CoFe2O4) NPs was fabricated for the direct C-H arylation of imidazopyridine, imidazole, indolizine and furan with aryl halides. To prepare the presented catalyst, rGO nanosheets were first modified with as-synthesized CoFe2O4 NPs and then the obtained CoFe2O4-rGO nanocomposites served as a support material for the synthesis of bimetallic NiPd alloy NPs at various compositions. The obtained CoFe2O4-rGO/NiPd nanocatalysts were characterized by many advanced analytical techniques including TEM, STEM-EDS, XRD, XPS, and ICP-MS. Next, to optimize the reaction conditions, CoFe2O4-rGO/NiPd nanocatalysts with different alloy compositions and their monometallic counterparts (CoFe2O4-rGO/Ni and CoFe2O4-rGO/Pd) were initially tested in the direct C-H arylation of imidazopyridine with bromobenzene. Among all tested nanocatalysts under the optimum reaction conditions, CoFe2O4-rGO/Ni20Pd80 showed the best catalytic activity in terms of the isolated product yields. The C-H arylation reactions were studied over a broad substrate scope (35 examples from 36 substrates) and gave the related biaryl products in good to excellent yields. Besides a broad substrate scope, the late-stage C-H arylation of zolimidine, a gastroprotective drug, was realized under the optimized reaction conditions. Moreover, the CoFe2O4-rGO/Ni20Pd80 nanocatalysts were recovered from the reaction medium using a simple magnet and reused in the C-H arylation reactions up to five consecutive runs without a significant drop in the product yield. This study shows that magnetically recoverable Pd nanoalloys are promising heterogeneous catalysts to be used in sustainable C-H functionalization reactions.

Palladium catalyzed 8-aminoimidazo[1,2-a]pyridine (AIP) directed selective β-C(sp2)-H arylation.

Palladium catalyzed arylation of the inert β-C(sp2)-H bond of carboxylic acid derivatives is reported herein for the first time utilizing 8-aminoimidazo[1,2-a]pyridine (AIP) as an efficacious and new inbuilt 6,5-fused bicyclic removable directing group. This protocol is scalable, exhibits high levels of β-site selectivity and tolerates a broad spectrum of functional groups.

Theoretical Study of the Reactivity of Phenyl Radicals Toward Enol Acetates

Arylation reactions are an important class of reactions and allow the synthesis of natural and synthetic products. Despite the efficient, but high cost and toxic methodologies involving transition metals, radical arylations have gained importance after the advent of photoredox catalysis. Arylation of enol acetates is an important tool for obtaining aryl ketones but the scope of the reaction is limited to the pattern of substitution at phenyl radical and α-carbon of the enol. Theoretical calculations ((U)BHandHLYP/6-311G**) show that the polar effect is the key factor in this reaction. A good correlation of calculated rate constants with field effect explained why phenyl radicals with electron-withdrawing groups react faster toward enol acetate. The presence of alkyl groups at α carbon at the enol showed some influence of enthalpic effect but strong influence of steric effect, evidenced by great correlations with Taft and Charton parameters. Finally, substitution at β carbon showed no significant effect at reaction rates.

Polyfluoroalkylated antipyrines in Pd-catalyzed transformations.

In the direct C–H arylation with arylhalogenides in the presence of Pd(OAc)2, trifluoromethyl-containing antipyrine reacts very slowly and incompletely owing to the low nucleophilicity of its C4 center. However, it was effective in modifying polyfluoroalkyl-substituted 4-bromo- and 4-iodo antipyrines by the Suzuki and Sonogashira reactions. It was established that using Pd2(dba)3 as catalyst and XPhos as phosphine ligand was the optimal catalytic system for the synthesis of 4-aryl- and 4-phenylethynyl-3-polyfluoroalkyl-antipyrines. Moreover, iodo-derivatives as the initial reagents were found to be more advantageous compared to bromo-containing analogs. It was found that 4-phenylethynyl-5-CF3-antipyrine has a moderate activity against the influenza virus A/Puerto Rico/8/34 (H1N1) and 4-iodo-5-CF3-antipyrine reveals a weak activity against the vaccine virus (strain Copenhagen) and bovine diarrhea virus (strain VC-1).

Recent Advances in Asymmetric Functionalization of Olefins Induced by Chiral Hypervalent Iodine Reagents

The functionalization of olefins induced by chiral hypervalent iodine reagents is a basic method for obtaining enantiomerically enriched chiral molecules and biologically active natural products. It is one of the new and promising fields in asymmetric synthesis. Throughout the past 20 years development in this area, on the one hand, stereoselective functionalizations of alkenes such as disulfonyloxylation, diacetoxylation, dihalogenation, diamination, hydroxylation-sulfonyloxylation and halogenation-alkylation and carbonylation have been successfully achieved with chiral hypervalent iodine reagents through intermolecular reactions, in which various functionalized products were enantioselectively obtained. On the other hand, many of hetero-cyclic compounds such as γ-butyrolactones, chromans, isochromans, oxazolidinones, piperidines, pyrrolidines and aziridines can be synthesized by intramolecular oxidative lactonization, etherification, amidation, arylation and other reactions, in which hypervalent iodine reagents can provide efficient methods for the synthesis of chiral heterocyclic compounds. In addition, various functionalization reactions of olefins mediated by chiral hypervalent iodine reagents can afford target compounds with excellent yield and enantioselectivity. Thus, this methodology has also been used in the total synthesis of natural products. The functionalization of olefins induced by chiral hypervalent iodine reagents and their applications in the total synthesis of natural products are reviewed.

Photoredox-mediated hydroalkylation and hydroarylation of functionalized olefins for DNA-encoded library synthesis.

DNA-encoded library (DEL) technology features a time- and cost-effective interrogation format for the discovery of therapeutic candidates in the pharmaceutical industry. To develop DEL platforms, the implementation of water-compatible transformations that facilitate the incorporation of multifunctional building blocks (BBs) with high C(sp3) carbon counts is integral for success. In this report, a decarboxylative-based hydroalkylation of DNA-conjugated trifluoromethyl-substituted alkenes enabled by single-electron transfer (SET) and subsequent hydrogen atom termination through electron donor–acceptor (EDA) complex activation is detailed. In a further photoredox-catalyzed hydroarylation protocol, the coupling of functionalized, electronically unbiased olefins is achieved under air and within minutes of blue light irradiation through the intermediacy of reactive (hetero)aryl radical species with full retention of the DNA tag integrity. Notably, these processes operate under mild reaction conditions, furnishing complex structural scaffolds with a high density of pendant functional groups.

Cobalt-catalyzed cross-coupling reactions of aryl- and alkylaluminum derivatives with (hetero)aryl and alkyl bromides.

A simple cobalt complex, such as Co(phen)Cl2, turned out to be a highly efficient and cheap precatalyst for a host of cross-coupling reactions involving aromatic and aliphatic organoaluminum reagents with aryl, heteroaryl and alkyl bromides. New C(sp2)-C(sp2) and C(sp2)-C(sp3) bonds were formed in good to excellent yields and with high chemoselectivity, under mild reaction conditions.

Organocatalytic cycloaddition-elimination cascade for atroposelective construction of heterobiaryls.

The first chiral phosphoric acid (CPA) catalyzed cycloaddition–elimination cascade reaction of 2-naphthol- and phenol-derived enecarbamates with azonaphthalenes has been established, providing a highly atroposelective route to an array of axially chiral aryl-C3-benzoindoles in excellent yields with excellent enantioselectivities. The success of this strategy derives from the stepwise process involving CPA-catalyzed asymmetric formal [3 + 2] cycloaddition and subsequent central-to-axial chirality conversion by elimination of a carbamate. In addition, the practicality of this reaction had been verified by varieties of transformations towards functionalized atropisomers.

Photolytic amino etherification reactions of aryl diazoacetates with N-heterocycles and a stoichiometric amount of dioxane/tetrahydropyran in aqueous medium: synthesis of 1,4-dioxepane/1,4,7-dioxazonan-6-one systems

Herein we have reported a blue LED mediated reaction of aryl diazoacetate with a stoichiometric amount of 1,4-dioxane/tetrahydropyran and various heterocycles like indoles, pyrrole, phthalimide, succinimide, thiazolidinedione and hydantoin in water.

8-Aminoimidazo[1,2-a]pyridine (AIP) directed Pd(II) catalysis: site-selective ortho-C(sp2)-H arylation in aqueous medium.

We demonstrate herein the first example of a palladium(ii) catalyzed regioselective ortho-C(sp2)-H arylation in aqueous medium (a sustainable solvent) utilizing 8-AIP (8-aminoimidazo[1,2-a]pyridine) as a promising and removable bidentate directing group/auxilliary. This newly developed protocol features a broad substrate scope with excellent functional group tolerance and enables an expeditious route to a library of unsymmetrical amides in good to excellent yields with exclusive site-selectivity.

Recent Progress in Radical Arylation Reaction with Diaryliodonium Salts under Photocatalysis

Recent Progress in Radical Arylation Reaction with Diaryliodonium Salts under Photocatalysis