Heck Reaction Research Articles

Mizoroki-Heck Macrocyclization Reactions at 1 M Concentration Catalyzed by Sub-nanometric Palladium Clusters.

The synthesis of cyclized organic compounds with more than ten atoms (macrocycles) is traditionally based on reversible reactions under highly diluted conditions, typically <0.05 M, in order to circumvent the formation of intermolecular products. These reaction conditions severely hamper industrial productivity and the use of solid catalysts. Herein, it is shown that the intramolecular Mizoroki-Heck reaction of ω-iodide cinnamates proceeds at 1 M concentration when catalyzed by few-atom Pd clusters, either in solution or supported on a solid, to give different macrocycles in good yields. This paradigmatic increase in reaction concentration not only opens the door for macrocycle production with high throughputs but also enables the use of solid catalysts for a macrocyclization reaction in flow.

An unusual Microdomain Factor Controls Interaction of Organic Halides with the Palladium Phase and Influences Catalytic Activity in the Mizoroki-Heck Reaction.

In this work, using a combination of scanning and transmission electron microscopy (SEM and TEM), the transformations of palladium-containing species in imidazolium ionic liquids in reaction mixtures of the Mizoroki-Heck reaction and in related organic media are studied to understand a challenging question of the relative reactivity of organic halides as key substrates in modern catalytic technologies. The microscopy technique detects the formation of a stable nanosized palladium phase under the action of an aryl (Ar) halide capable of forming microcompartments in an ionic liquid. For the first time, the correlation between the reactivity of the aryl halide and the microdomain structure is observed: Ar-I (well-developed microdomains) > Ar-Br (microphase present) > Ar-Cl (minor amount of microphase). Previously, it is assumed that molecular level factors, namely, carbon-halogen bond strength and the ease of bond breakage, are the sole factors determining the reactivity of aryl halides in catalytic transformations. The present work reports a new factor connected with the nature of the organic substrates used and their ability to form a microdomain structure and concentrate metallic species, highlighting the importance of considering both the molecular and microscale properties of the reaction mixtures.

Total Synthesis of Illisimonin A and Merrilactone A

AbstractIllicium sesquiterpenes are a large family of biologically active secondary metabolites isolated from Illicium species of plants and are well‐known for their activity of neurite outgrowth in cultured neurons. Herein, we propose a comprehensive biosynthetic pathway for illicium sesquiterpenes and report a synthetic route to illisimonin A and merrilactone A based on it. We think that the carbon scaffolds of most of the illicium sesquiterpenes could be synthesized from a dicarbonyl derivative of allo‐cedrane through retro‐Dieckmann condensation, oxidative cleavage and aldol reaction at suitable oxidation states in Nature. The common intermediate for illisimonin A and merrilactone A similar to the dicarbonyl derivative of allo‐cedrane was assembled with up to 82 % ee by an asymmetric intramolecular desymmetrizing reductive Heck reaction by the use of a new type of chiral phosphine ligand. The syntheses of illisimonin A and merrilactone A supported the key transformations of the proposed biosynthetic pathway.

Total Synthesis of Illisimonin A and Merrilactone A.

Illicium sesquiterpenes are a large family of biologically active secondary metabolites isolated from Illicium species of plants and are well-known for their activity of neurite outgrowth in cultured neurons. Herein, we propose a comprehensive biosynthetic pathway for illicium sesquiterpenes and report a synthetic route to illisimonin A and merrilactone A based on it. We think that the carbon scaffolds of most of the illicium sesquiterpenes could be synthesized from a dicarbonyl derivative of allo-cedrane through retro-Dieckmann condensation, oxidative cleavage and aldol reaction at suitable oxidation states in Nature. The common intermediate for illisimonin A and merrilactone A similar to the dicarbonyl derivative of allo-cedrane was assembled with up to 82 % ee by an asymmetric intramolecular desymmetrizing reductive Heck reaction by the use of a new type of chiral phosphine ligand. The syntheses of illisimonin A and merrilactone A supported the key transformations of the proposed biosynthetic pathway.

Catalytic Enantioselective Synthesis of 3-Piperidines from Arylboronic Acids and Pyridine.

Piperidines are frequently found in natural products and are of importance to the pharmaceutical industry. A generally useful asymmetric route to enantiomerically enriched 3-substituted piperidines remains elusive. Here we report a cross-coupling approach to enantioenriched 3-piperidines from pyridine- and sp2-hybridized boronic acids. The key step involves a Rh-catalyzed asymmetric reductive Heck reaction of aryl, heteroaryl, or vinyl boronic acids and phenyl pyridine-1(2H)-carboxylate to provide 3-substituted tetrahydropyridines in high yield and excellent enantioselectivity with a wide functional group tolerance. A three-step process involving i) partial reduction of pyridine, ii) Rh-catalyzed asymmetric carbometalation, and then iii) another reduction provides access to a wide variety of enantioenriched 3-piperidines, including clinically used materials such as Preclamol and Niraparib.

Gold-Catalyzed Heck Reaction with Selective β-Hydride Elimination

Gold-Catalyzed Heck Reaction with Selective β-Hydride Elimination

Ni-Catalyzed Enantioselective Intramolecular Mizoroki-Heck Reaction for the Synthesis of Phenanthridinone Derivatives.

A Ni-catalyzed enantioselective intramolecular Mizoroki-Heck reaction has been developed to transform symmetrical 1,4-cyclohexadienes with attached aryl halides into phenanthridinone analogues containing quaternary stereocenters. Herein, we report important advances in reaction optimization enabling control of unwanted proto-dehalogenation and alkene reduction side products. Moreover, this approach provides direct access to six-membered ring heterocyclic systems bearing all-carbon quaternary stereocenters, which have been much more challenging to form enantioselectively with nickel-catalyzed Heck reactions. A wide range of substrates were demonstrated to work in good to excellent yields. Good enantioselectivity was demonstrated using a new synthesized chiral iQuinox-type bidentate ligand (L27). The sustainability, low price of nickel catalysts, and significantly faster reaction rate (1 h) versus that of a recently reported palladium-catalyzed reaction (20 h) make this process an attractive alternative.

Base-Mediated Transformation of Glycals to Their Corresponding Vinyl Iodides and Their Application in the Synthesis of C-3 Enofuranose and Bicyclic 3,4-Pyran-Fused Furanose.

A simple method for the iodination of unsaturated sugars to form sugar vinyl iodides was developed under oxidant-free conditions using NaH/DMF/iodine as a reagent system at ambient temperature. 2-Iodoglycals bearing ester, ether, silicon, and acetonide protection were synthesized in good to excellent yield. 3-Vinyl iodides derived from 1,2:5,6-diacetonide glucofuranose were transformed to C-3 enofuranose and bicyclic 3,4-pyran-fused furanose via Pd-catalyzed C-3 carbonylation and intramolecular Heck reaction, respectively, as the key step.

Air-tolerant, ligand-free nickel-catalyzed, manganese-assisted reductive Heck reaction of alkyl/aryl halides with electron-deficient olefins

An air-tolerant reductive Heck reaction of alkyl/aryl halides with α, β-unsaturated esters, nitriles and amides catalyzed by simple nickel bromide has been developed by using manganese as reductant in refluxing acetonitrile. Water plays a double-face role in the catalytic process, hydrolysis of the enolate and/or C-tautomer intermediates to afford the conjugate adducts while suppressing the catalysis at high concentration. The scope and limitations of the nickel-catalyzed manganese-mediated process have been demonstrated by more than 40 examples, showing large steric effects and good functional group compatibility except for reduction-sensitive ones.

Theoretical Measurements of Quantitative Effects Caused by Spectator Ligands on Palladium-catalyzed C–H Activation

Ligands can definitely influence C–H activation at the metal center. A ligand not directly participating in the reaction is called a spectator ligand. We attempt to quantitatively characterize the effects of diverse spectator ligands on C-H activation at palladium. We designed a model palladium catalyst and selected an array of spectator ligands, such as methoxyl, amide, methyl, phenyl, cyanide, fluorine, chlorine, and several neutral ligands, and performed density functional theory calculations on the mechanism and energetics of C–H activation reactions of benzene with different catalysts. Univalent ligands have substantially larger effects than neutral ligands, and strongly σ-donating ligands (e.g., methyl and phenyl) severely hinder the C-H activation in progress. A ligand trans to the reaction site influences C–H activation more than that cis to the reaction site, indicating electronic effects to be at work. For example, the existence of a methyl ligand raises the barrier height of C-H activation by 6.4 or 14.4 kcal/mol when it is placed at the position cis or trans to the C–H activation site. The effects of poorly σ-donating ligands are not significant and similar to those of the κ1-acetate ligand. Some σ-donating and π-accepting ligands, such as cyanide and isonitrile, hinder the C–H activation trans to them but appear to facilitate the C–H activation cis to them. On the basis of molecular orbital analyses, a chemical model is proposed to understand the observed ligand effects. Lastly, the conclusions are applied to explain the plausible mechanism of the dehydrogenative Heck coupling.

Development of a Chromane-Forming Heck Reaction: Bisphosphine Mono-Oxide Mediated Regioselectivity Perturbed by Solvent-Based Peroxide Formation

Development of a Chromane-Forming Heck Reaction: Bisphosphine Mono-Oxide Mediated Regioselectivity Perturbed by Solvent-Based Peroxide Formation

Regioselective and Geometrically Controlled Heck 1,1-Diarylation of Unactivated Aliphatic Alkenes.

Pd-catalyzed double Heck reaction allows regioselective 1,1-diarylation of unactivated aliphatic alkenes. When two different aryl bromides are used, the second aryl rings are added trans to aliphatic chains in the main olefinic isomers, consistent with a mechanism of two consecutive Heck arylations at the terminal carbons.

Enantioselective Synthesis of Isoindolones via Palladium – Catalyzed Intramolecular Heck‐Mizoroki Reactions of Endocyclic Enamides Using N,N‐Ligands

AbstractThe enantioselective synthesis of isoindolones via Heck‐Mizoroki reactions of endocyclic enamides using a palladium‐bis(oxazoline) catalyst system is described. The N,N‐ligands, which are under‐represented in palladium‐catalyzed reactions involving aryl halides, proved to be an effective and low‐cost alternative to their phosphine‐based chiral ligand counterparts. The intramolecular Heck reaction of aryl iodides and endocyclic enamides enabled the construction of tricyclic isoindolones containing tertiary and quaternary chiral centers under mild conditions in yields up to 73 % and enantiomeric ratios up to 97 : 3. Vibrational circular dichroism (VCD) was instrumental in determining the absolute configuration of the enantioenriched isoindolones.

Organic–Inorganic Polyimides with POSS Cages in the Main Chains: An Impact of POSS R Groups on Morphologies and Properties

Two well-defined POSS diamines were synthesized with phenyl (Ph) and iso-butyl (i-Bu) POSS trisilanols as the starting compounds. This approach involves the protection and deprotection of silanol hydroxyl groups with phenylboronic acid and pinacol, followed by the silylation of silanol hydroxyl groups with mono- and dichlorosilanes. With this route of synthesis, two well-defined divinyl POSS macromers were obtained, as evidenced by 1H, 29Si NMR, and mass spectroscopy. These two divinyl POSS macromers were further functionalized into well-defined POSS diamines via the Heck reaction with p-bromoaniline. The successful synthesis of POSS diamines enabled the synthesis of organic–inorganic polyimides with the POSS cages in the main chains. More importantly, the syntheses of these two POSS diamines allowed the examination of the effect of POSS R groups (i.e., Ph and i-Bu) on the morphologies and thermomechanical and dielectric properties of organic–inorganic polyimides. Notably, the types of POSS R groups exerted a profound impact on the morphologies and properties of the organic–inorganic polyimides.

Probing of DNA Photochemistry with C-Nucleosides of Xanthones and Triphenylene as Photosensitizers To Study the Formation of Cyclobutane Pyrimidine Dimers.

The direct and sequence-dependent investigation of photochemical processes in DNA on the way to cyclobutane pyrimidine dimers (CPDs) as DNA damage requires the probing by photochemically different photosensitizers. The C-nucleosides of xanthone, thioxanthone, 3-methoxyxanthone, and triphenylene as photosensitizers were synthesized by Heck couplings and incorporated into ternary photoactive DNA architectures. This structural approach allows the site-selective excitation of the DNA by UV light. Together with a single defined site for T-T dimerization, not only the direct CPD formation but also the distance-dependent CPD formation in DNA as well as the possibility for energy transport processes could be investigated. Direct CPD formation was observed with xanthone, 3-methoxyxanthone, and triphenylene as sensitizers but not with thioxanthone. Only xanthone was able to induce CPDs remotely by a triplet energy transfer over up to six intervening A-T base pairs. Taken together, more precise information on the sequence dependence of the DNA triplet photochemistry was obtained.

Bis-benzofulvenes: Synthesis and Studies on Their Optoelectronic Properties.

We report the synthesis of bis-benzofulvenes and the studies on their optical and redox properties. Bis-benzofulvenes were achieved through the Pd-catalyzed intramolecular Heck coupling followed by Ni0-mediated C(sp2)-Br dimerization. Low optical and electrochemical energy gaps of 2.05 and 1.68 eV were achieved by tuning the substituent on the exomethylene unit and the aromatic ring. The observed trends in the energy gaps were compared, and the frontier molecular orbitals were visualized using the density functional theory.

π -Extended BTD derivatives: synthesis, photophysical properties, and applications in biological systemsimagingfor discriminating living and dead cells.

Benzothiadiazole (BTD) is one of the popular compounds for organic electronic devices, organic synthesis, and fluorescent probes. Here, benzothiadiazole derivatives were successfully synthesized by heck coupling reaction, which exhibited the the advantages of simplicity and efficiency, wild substrate csope, easily available substrates and high yield. The fluorescent probe BTDAr-PEG targeting lipid droplets was successfully prepared by the nucleophilic substitution reaction between the heck coupling reaction product 3h and Amino polyethylene glycol monomethyl ether (Mn=2000). BTDAr-PEG exhibited the advantages of high selectivity, good stability and pH resistance. The use of PEG as a substrate gave BTDAr-PEG good biocompatibility. It was worth mentioning that BTDAr-PEG could not only track LDs in cells under different physiological conditions, but also distinguish between living and dead cells in biological systems.

Collective Syntheses of 8-Oxoprotoberberines via Sequential In(OTf)3-Catalyzed Cyclization and Pd(OAc)2-Catalyzed Heck Coupling.

Six 8-oxoprotoberberines were synthesized collectively in four steps with acceptable yields (14-19%), of which the products 8-oxopalmatine, 8-oxopseudopalmatine, 8-oxoberberine, and 8-oxopseudoberberine come from nature. The synthetic route was featured with the In(OTf)3-catalyzed cyclization and Heck coupling. Moreover, the syntheses of the natural products berberine, canadine, and iambertine were achieved via various reductions from 8-oxoberberine, which provided a concise approach to the syntheses of this kind of alkaloids.

Photoinduced Nitrogen-to-Alkyl Radical Relay Heck Reaction of o-Alkylbenzamides with Vinyl Arenes by Palladium Catalysis.

Here, a palladium-catalyzed photoinduced N-to-alkyl radical relay Heck reaction of o-alkylbenzamides at benzylic sites with vinyl arenes is described. The reaction employs neither exogeneous photosensitizers nor external oxidants. It is proposed to proceed via a N-to-alkyl hybrid palladium-radical mechanism which occurs under mild conditions that are compatible with a wide range of functional groups. The products are easily transformed to azepinone derivatives, which are prevalent in pharmaceuticals and natural products.

‘Homeopathic’ palladium catalysis? The observation of distinct kinetic regimes in a ligandless Heck reaction at (ultra-)low catalyst loadings

The catalytic behaviour of ‘ligandless’ palladium(II) acetate in the Heck arylation reaction of iodobenzene with methyl acrylate is examined at (ultra-)low catalyst loadings using in situ spectroscopy. The study reveals two distinctive kinetic regimes with distinct Pd orders. A simplified microkinetic model revealed the presence of at least two kinetically competent catalysts, represented by a monomeric (Pd1) and dimeric (Pd2) species. The relative catalytic activity and deactivation rates for both species can also be estimated from the experimental results. This work provides direct kinetic evidence that a higher-order Pd species can be more active than a monomeric species, and the key role played by catalyst deactivation, particularly at higher catalyst loadings. This implies that lowering the catalyst loading may be an effective strategy to combat catalyst deactivation without necessarily incurring significant deterioration in reaction rate.