Palladium-Catalyzed Cyanation Research Articles

Palladium-Catalyzed Cyanation of Aryl Sulfonium Salts.

A palladium-catalyzed cyanation of aryl dimethylsulfonium salts using cheap, nontoxic, and bench-stable K4[Fe(CN)6]·3H2O as the cyanating reagent has been developed. The reactions proceeded well under base-free conditions with various sulfonium salts and provided aryl nitrile with yields of up to 92%. Aryl sulfides can be transformed to aryl nitriles directly via a one-pot process, and the protocol is scalable. Density functional theory calculations were performed to investigate the reaction mechanism that involved a catalytic cycle involving oxidative addition, ligand exchange, reductive elimination, and regeneration to yield the product.

Palladium-Catalyzed Cyanation of Nucleobases: Total Synthesis of Toyocamycin, Sangivamycin, and a Mycalisine A Precursor

AbstractInstallation of cyano group functionality onto nucleosides has always been a challenging task for chemists, and catalytic protocols developed for simple aryl substrates have, in most cases, failed to replicate their success when applied to nucleobase or sugar moieties of nucleosides. Given the importance of the cyano and amide functionalities in nucleoside chemistry, we herein disclose an efficient Pd-catalyzed cyanation protocol specifically applied to iodo nucleobases. Furthermore, the developed cyanation method has been explored for the synthesis of naturally occurring and bioactive nucleosides such as toyocamycin, sangivamycin, and a mycalisine A precursor.

Open-Source Chromatographic Data Analysis for Reaction Optimization and Screening.

Automation and digitalization solutions in the field of small molecule synthesis face new challenges for chemical reaction analysis, especially in the field of high-performance liquid chromatography (HPLC). Chromatographic data remains locked in vendors' hardware and software components, limiting their potential in automated workflows and data science applications. In this work, we present an open-source Python project called MOCCA for the analysis of HPLC-DAD (photodiode array detector) raw data. MOCCA provides a comprehensive set of data analysis features, including an automated peak deconvolution routine of known signals, even if overlapped with signals of unexpected impurities or side products. We highlight the broad applicability of MOCCA in four studies: (i) a simulation study to validate MOCCA's data analysis features; (ii) a reaction kinetics study on a Knoevenagel condensation reaction demonstrating MOCCA's peak deconvolution feature; (iii) a closed-loop optimization study for the alkylation of 2-pyridone without human control during data analysis; (iv) a well plate screening of categorical reaction parameters for a novel palladium-catalyzed cyanation of aryl halides employing O-protected cyanohydrins. By publishing MOCCA as a Python package with this work, we envision an open-source community project for chromatographic data analysis with the potential of further advancing its scope and capabilities.

Palladium-Catalyzed Cyanation of Arenediazonium Tetrafluoroborate Derivatives with 2-(Piperidin-1-yl)acetonitrile as the Cyano Source

AbstractThe present study describes the one-pot palladium-catalyzed cyanation of commercially available aryldiazonium tetrafluoroborate derivatives with 2-(piperidin-1-yl)acetonitrile (an organic cyano reagent) under mild conditions. This process utilizes a Pd/(Me3Si)2 system and is applied to a wide scope of aromatic diazonium substrates to give the corresponding nitrile-containing products in moderate to high yields (59–92%). This methodology is employed for the preparation of etravirine, a drug used for the treatment of HIV, and for transformations of 1H-indole-2-carbonitrile into compounds that are used as a NMDA receptor antagonists and that have high potential against mutant HIV strains. The mechanism proposed for this Pd-catalyzed cyanation involves cyanide ions, as confirmed using indicator paper.

Palladium-Catalyzed Cyanation under Mild Conditions: A Case Study to Discover Appropriate Substrates among Halides and Pseudohalides

A case study has been effectively carried out to identify a suitable substrate among halides and pseudohalides for the palladium-catalyzed cyanation reactions under mild conditions. Among the various substrates considered for evaluation, aryl pentafluorobenzenesulfonates and nonaflates were identified to be the best substrates when compared to corresponding halides and pseudohalides. The substoichiometric use of nontoxic, environmentally benign potassium hexacyanoferrate as a cyanide source and exceptionally milder conditions further highlights the significance of the protocol developed. A wide range of electronically biased and sterically challenging substrates provided the corresponding the nitriles in good to excellent yields.

A New CN Source for the Palladium-Catalyzed Cyanation of Aryl Halides

Key words cyanation - palladium catalysis - aryl halides - formamide - cyanuric chloride - benzonitriles

Recent advances and prospects in the palladium-catalyzed cyanation of aryl halides.

Aryl nitriles are compounds with wide significance. They have made their own space in various sectors including pharmaceuticals, industries, natural product chemistry, and so on. Furthermore, they are also key intermediates in various transformations in organic chemistry. Transition metal-catalyzed cyanation reactions have proved to be a better replacement for the existing traditional synthetic strategies for aryl nitriles. Palladium is one of the most studied transition metals other than copper and nickel owing to its wide functional group compatibility and catalytic efficacy. There have been drastic developments in the field of palladium-catalyzed cyanation since its discovery in the 1973. This review summarizes the recent developments in the palladium-catalyzed cyanation of aryl halides and covers literature from 2012–2020.

Pd Nanocatalyst Adorning Coral Reef Nanocomposite for the Synthesis of Nitriles: Utility of Cucurbita pepo Leaf Extract as a Stabilizing and Reducing Agent.

A simple procedure for the palladium-catalyzed cyanation of aryl halides is described via a nucleophilic non-toxic cyanide source, K4[Fe(CN)6] in the presence of Pd/coral reef nanocomposite as a heterogeneous catalyst; the protocol provides a useful and easy method for the synthesis of aryl nitriles that are generated from the corresponding variant aryl halides, with sodium carbonate as a base. The nanocatalyst was prepared by a biological process using aqueous extract of leaves of Cucurbita pepo as a stabilizing and reducing agent and coral reef as a natural support, without deploying any hazardous chemicals. The catalyst, that is easily separable from the reaction mixture and reused multiple times, was characterized by FT-IR (Fourier-Transform Infrared Spectroscopy), ICP-AES (Inductively Coupled Plasma Atomic Emission Spectroscopy), XRD (X-ray Diffraction), TEM (Transmission Electron Microscopy), FE-SEM (Field Emission Scanning Electron Microscopy), EDS (Energy Dispersive X-ray Spectroscopy) and elemental mapping.

Pd-Catalyzed Cyanation of (Hetero)Aryl Halides by Using Biphosphine Ligands.

Tetraadamantylbiphosphine (TABP; L1), which showed superior activity in the palladium-catalyzed cyanation of 4-chloroanisole compared to standard phosphines, was synthesized as a new ligand. The generality of the new catalytic system was shown by the cyanation reaction of approximately 30 (hetero)aryl halides including hindered, electron-rich, and electron-poor aryl chlorides. These reactions constitute the first examples of using biphosphine ligands in Pd-catalyzed coupling reactions.

Palladium-Catalyzed Safe Cyanation of Aryl Iodides with Hexamethylenetetramine.

A palladium-catalyzed cyanation of aryl halides with hexamethylenetetramine as a safe cyanide source is achieved, providing aromatic nitriles in moderate to good yields. This approach shows good functional group compatibilities and avoids the use of toxic cyanide source.

Improving Robustness: In Situ Generation of a Pd(0) Catalyst for the Cyanation of Aryl Bromides.

Conditions have been developed for the palladium-catalyzed cyanation of aryl bromides utilizing the air-stable XantPhos-PdCl2 precatalyst. By employing a trialkylamine as a reducing agent, the active Pd(0) species is generated in situ, alleviating the need to employ the air-sensitive Pd2(dba)3. Twenty-two substituted benzonitriles have been synthesized using this method.

ChemInform Abstract: A Homogeneous Method for the Conveniently Scalable Palladium‐ and Nickel‐Catalyzed Cyanation of Aryl Halides.

Homogeneous conditions for the palladium-catalyzed cyanation of aryl halides were developed. This new system features a broad scope of aryl chlorides and bromides, uses 2-propanol or 1-butanol as solvent, and is readily scalable. The same conditions can also provide simple benzonitriles using the recently developed (TMEDA)NiCl(o-tolyl) precatalyst in conjunction with 1,1′-bis(diphenylphosphino)ferrocene (dppf) as a ligand.

A Homogeneous Method for the Conveniently Scalable Palladium- and Nickel-Catalyzed Cyanation of Aryl Halides

Homogeneous conditions for the palladium-catalyzed cyanation of aryl halides were developed. This new system features a broad scope of aryl chlorides and bromides, uses 2-propanol or 1-butanol as solvent, and is readily scalable. The same conditions can also provide simple benzonitriles using the recently developed (TMEDA)NiCl(o-tolyl) precatalyst in conjunction with 1,1′-bis(diphenylphosphino)ferrocene (dppf) as a ligand.

Flexible Total Synthesis of (±)-Aureothin, a Potent Antiproliferative Agent.

Amenable to late-stage preparation of analogues, a flexible and convergent total synthesis of (±)-aureothin is presented. The strategy was based on a desymmetrization of α,α'-dimethoxy-γ-pyrone by a process combining 1,4-addition and alkylation of vinylogous enolate to stereoselectively reach the backbone of the target. Palladium-catalyzed cyanation of an elaborated and isomerizable E,Z dienyl motif followed by Pinner cyclization enabled the construction of the tetrahydrofuran motif while a first approach based on a late-stage oxidation was unsuccessful.

Synthesis of highly water-soluble trisulfonated phthalocyanine with single carboxylic acid via palladium-catalyzed cyanation reaction

Unsymmetrical trisulfonated zinc phthalocyanine with single carboxylic acid (trisulfo-Pc-COOH) was newly prepared via the hydrolysis of cyanotrisulfo-Pc which was obtained from the palladium catalyzed cyanation of iodotrisulfo-Pc. The product exhibited good water solubility along with excellent absorption and emission characteristics in an aqueous condition, proving its feasibility for use in bio-imaging applications.

The application of NCTS (N-cyano-N-phenyl-p-toluenesulfonamide) in palladium-catalyzed cyanation of arenediazonium tetrafluoroborates and aryl halides

Using NCTS (N-cyano-N-phenyl-p-toluenesulfonamide) as an electrophilic cyanation reagent, palladium-catalyzed cyanation of arenediazonium tetrafluoroborates and aryl halides was achieved under mild conditions. The method allowed the effective synthesis of various aryl nitriles in suitable yields via a coupling reaction.

ChemInform Abstract: Microwave‐Assisted Cyanation of 3‐Bromo‐3‐(1‐hydroxyalkyl)benzo[b]selenophene Derivatives.

Microwave-assisted palladium-catalyzed cyanation of 3-bromo-2-(1-hydroxyalkyl)benzo[b]selenophene affords 3-cyano derivatives. Raising the temperature promotes formation of 2-(1-alkenyl)-3-carbamoyl isomers through intramolecular transfer of water.

Phosphinoferrocene Ureas: Synthesis, Structural Characterization, and Catalytic Use in Palladium-Catalyzed Cyanation of Aryl Bromides

Phosphinoferrocene ureas Ph2PfcCH2NHCONR2, where NR2 = NH2 (1a), NHMe (1b), NMe2 (1c), NHCy (1d), and NHPh (1e); the analogous thiourea Ph2PfcCH2NHCSNHPh (1f); and the acetamido derivative Ph2PfcCH2NHCOMe (1g) (Cy = cyclohexyl, fc = ferrocene-1,1′-diyl) were prepared via three different approaches starting from Ph2PfcCH2NH2·HCl (3·HCl) or Ph2PfcCHO (4). The reactions of the representative ligand 1e with [PdCl2(cod)] (cod = cycloocta-1,5-diene) afforded [PdCl(μ-Cl)(1e-κP)2]2 or [PdCl2(1e-κP)2]2 depending on the metal-to-ligand stoichiometry, whereas those with [PdCl(η3-C3H5)]2 and [PdCl(LNC)]2 produced the respective bridge cleavage products, [PdCl(η3-C3H5)(1e-κP)] and [PdCl(LNC)(1e-κP)] (LNC = [(2-dimethylamino-κN)methyl]phenyl-κC1). Attempts to involve the polar pendant in coordination to the Pd(II) center were unsuccessful, indicating that the phosphinoferrocene ureas 1 bind Pd(II) preferentially as modified phosphines rather than bifunctional donors. When combined with palladium(II) acetate, the ligand...

ChemInform Abstract: Cyanation of Unactivated Aryl Chlorides and Aryl Mesylates Catalyzed by Palladium and Hemilabile MOP‐Type Ligands.

Palladium-catalyzed cyanation of aryl halides and pseudo halides with potassium hexacyanoferrate is described employing the hemilabile, bulky, and electron-rich MOP-type ligands. When the mixture of t-BuOH and H2O was used as the solvent and K2CO3 as the base, the MOP-type ligands showed high efficiency for the palladium-catalyzed cyanation. The effect of ligand structure was studied in detail, and 2-di-tert-butylphosphino-2′-isopropoxy-1,1′-binaphthyl was the more effective for the cyanation. The catalyst system allows the cyanation of unactivated aryl chlorides, and even aryl mesylates to occur in good yields. Furthermore, the reactivity of different arylated reagents in the catalytic system was found to be: ArBr > ArCl >> ArOMs > ArOSO2Im > ArOSO2NMe2.

Microwave-assisted cyanation of 3-bromo-3-(1-hydroxyalkyl)benzo[b]selenophene derivatives

Microwave-assisted palladium-catalyzed cyanation of 3-bromo-2-(1-hydroxyalkyl)benzo[b]selenophene affords 3-cyano derivatives. Raising the temperature promotes formation of 2-(1-alkenyl)-3-carbamoyl isomers through intramolecular transfer of water.