Palladium-catalyzed Reaction Research Articles

Palladium-catalyzed epoxidation of olefins using electrophiles as oxidizing agents

The development of palladium-catalysed olefin epoxidation reactions using electrophilic reagents as oxidants: modular synthesis of oxazolines. The efficient synthesis of esters, alcohols and halogen-containing products was achieved.

Palladium-catalyzed enantioselective umpolung allylation of amido-tethered allylic carbonates with isatin-derived ketimines.

A palladium-catalyzed enantioselective umpolung allylation reaction of amido-tethered allyl carbonates with N-2,2,2-trifluoroethylisatin ketimines has been realized herein. The reaction worked well under mild reaction conditions to give various chiral oxindole derivatives in moderate to excellent yields with high enantioselectivities. Notably, this work represents the first Pd-catalyzed asymmetric umpolung allylation reaction of N-2,2,2-trifluoroethylisatin ketimines.

Construction of quaternary alkyl motifs through palladium-catalyzed oxidative coupling of 1,3-dicarbonyl compounds with alkenes followed by C-C bond cleavage.

A palladium-catalyzed coupling reaction has been developed for the generation of tertiary alkylation products by reacting olefins with diversely functionalized 1,3-dicarbonyls. The reaction involves the tertiary C-H alkylation of 1,3-dicarbonyls with olefins to produce a tertiary alcohol, followed by C-C bond cleavage.

Water-assisted cascade synthesis of trifluoromethylated dipyridodiazepinone analogues: in vitro and in silico antibacterial studies.

A base-promoted palladium-catalyzed cascade reaction is described to access trifluoromethylated dipyridodiazepinone derivatives in an aqueous system (1,4-dioxane-H2O). This methodology uses simple chemicals, has a broad substrate scope, is waste minimized (E-factor = 0.3-0.9) and produces 11-CF3-tethered dipyridiodiazepinone derivatives in good to excellent yields. All the synthesized analogues were preliminarily examined for antibacterial activity against E. coli and S. aureus and compared to the reference drugs. Furthermore, inhibition of the peptide deformylase enzyme and antibiofilm studies were performed and compound 5i exhibited the best inhibitory effect among the other analogues. Furthermore, these analogues were in silico analysed via molecular docking, molecular simulation, drug-likeness, physicochemical and ADMET studies. Results from biological evaluation and computational studies revealed that compound 5i could be used as a lead molecular structure for the development of novel antibacterial agents. In conclusion, the green metrics evaluation of the defined protocol provides advantages in the synthesis of biologically active compounds.

Palladium-catalyzed Suzuki-Miyaura cross-coupling of carboxylic-phosphoric anhydrides via C-O bond cleavage.

A robust palladium-catalyzed Suzuki-Miyaura reaction of carboxylic-phosphoric anhydrides via highly selective C(O)-O bond cleavage under inorganic base-free conditions has been reported. Carboxylic-phosphoric anhydrides, generated through activating carboxylic acids using phosphates by esterification or direct dehydrogenative reaction with phosphites, have been employed as highly reactive electrophiles for Suzuki-Miyaura cross-coupling reactions. Broad substrate scope and excellent functional group tolerance have been demonstrated to be a general and practical approach for the synthesis of highly valuable ketones.

Palladium-catalyzed synthesis of indene-1-acetates via sequential double carbopalladation and aryloxycarbonylation

A novel palladium-catalyzed cascade reaction of o-iodostyrenes, internal alkynes and formates to access various indene-1-acetates was developed. The method enables the construction of three C-C and one C-O bonds through...

Palladium-catalyzed carbonylation of activated alkyl halides via radical intermediates

In this review, we summarize and discuss recent achievements in palladium-catalyzed carbonylative reactions of activated alkyl halides. Aliphatic carboxylic acid derivates were prepared effectively with various nucleophiles.

β-C-H Allylation of Trialkylamines with Allenes Promoted by Synergistic Borane/Palladium Catalysis.

Functionalization of the C(sp3 )-H bonds of trialkylamines is challenging, especially for reactions at positions other than the α position. Herein, we report a method for β-C(sp3 )-H allylation of trialkylamines. In these reactions, which involve synergistic borane/palladium catalysis, an enamine intermediate is first generated from the amine via α,β-dehydrogenation promoted by B(C6 F5 )3 and a base, and then the enamine undergoes palladium-catalyzed reaction with an allene to give the allylation product. Because the hydride and the proton resulting from the initial dehydrogenation are ultimately shuttled to the product by B(C6 F5 )3 and the palladium catalyst, respectively, these reactions show excellent atom economy. The establishment of this method paves the way for future studies of C-H functionalization of trialkylamines by means of synergistic borane/transition-metal catalysis.

Synthesis and antituberculosis activity of new 5-alkynyl derivatives of 2-thiouridine: application of new scaffold

We herein describe new potent inhibitors of mycobacteria based on 5-substituted 2-thiouridine derivatives. A series of new 5-alkynyl-substituted 2-thiouridine derivatives were synthesized via palladium-catalysed Sonogashira cross-coupling reaction of 5-iodo-2-thiopyrimidine base with terminal acetylenes with good yields in DMF at room temperature. It was found that sulfur atom in C2 position of pyrimidine ring had no impact on yields of target compounds. All obtained compounds were evaluated for their antimycobacterial activity against Mycobacetrium bovis and Mycobacterium tuberculosis at concentrations of 0.1-100 µg/ml using MABA test. Synthesized nucleosides showed high antimycobacterial activity against Mycobacterium bovis and Mycobacteri um tuberculosis. The obtained MIC50 values of 2-thionucleosides 14, 15 and 16 (0.28-0.75 µg/ml) significantly exceed characteristics of reference drug rifampicin, D-cycloserine and isoniazid, which gives prerequisites for further more detailed studies.

Palladium-Catalyzed Synthesis of Indanone via C-H Annulation Reaction of Aldehydes with Norbornenes.

A novel methodology for the synthesis of indanone derivates has been developed. The palladium-catalyzed annulation reaction of o-bromobenzaldehydes with norbornene derivatives is achieved through extremely concise reaction processes. The indanone skeleton was established directly via C-H activation of the aldehyde group under a mild reaction condition. This method is simple and practical, which simplified the traditional synthesis method for the rapid construction of indanone.

Palladium-Catalyzed Diversified Synthesis of Monofluorinated Alkenes from Allylic gem-Difluorides through Pd-OH Intermediate.

Significant advancements in synthesis of monofluoroalkenes via palladium-catalyzed reactions involving allylic gem-difluorides and diverse nucleophiles have been achieved. This method allows regioselective arylation, alkylation, allylation, alkenylation, and hydrogenation of allylic gem-difluorides, yielding high Z-selectivity and favorable product yields under mild conditions. Tolerating various functional groups, these transformations utilize a common Pd-OH intermediate. Additionally, employing triple Pd-catalyzed cross-coupling yields diverse trisubstituted alkenes efficiently.

Rapid Assembly of Unsymmetrically Linked Bis-heterocycles via Palladium Domino Catalysis.

A palladium-catalyzed domino reaction of alkene-tethered oxime esters is reported. This transformation uses an air-stable palladium precatalyst that initiates a Narasaka-Heck reaction, that is interrupted with a Pd(II)-promoted cyclization. Through this methodology, a novel class of unsymmetrical alkyl-linked bis-heterocycles were synthesized in yields up to 99%. The reaction is scalable up to 1.0 mmol, with simplified purification steps. This transformation expands the scope of accessible bis-heterocycles available through Narasaka-Heck reactions beyond C-H activation and direct anionic capture termination steps.

Decarboxylative Iodination and Suzuki-Miyaura Coupling Reactions to Access Chiral 3,3'-Diaryl-1,1'-bi-2-naphthols.

An efficient synthesis of the enantiomerically pure 3,3'-bis-arylated BINOLs is accomplished through decarboxylative iodination of the dimethyl ether derivative of BINOL-3,3'-dicarboxylic acid followed by Suzuki-Miyaura coupling using a one-pot protocol. The decarboxylative iodination is effected with the dimethyl ether derivative of BINOL-3,3'-dicarboxylic acid using iodine as a terminal oxidant and the cheaply available K3PO4 as a base under neat conditions. This protocol facilitated the introduction of the aryl group at the 3,3'-position on the binaphthyl system using aryl boronic acid through a palladium-catalyzed Suzuki-Miyaura coupling reaction.

A first example of a palladium-catalyzed allylic substitution reaction at a perfluoroalkylene-attached asymmetric carbon center with carbon, nitrogen, and oxygen nucleophiles

Palladium-catalyzed allylic substitution reaction of ethyl tetrafluorocyclopentenyl carbonate or tetrafluorocyclopentenyl methanesulfonate with carbon, nitrogen, and oxygen nucleophiles was systematically investigated. As a result, malonate-derived enolates as a carbon nucleophile, primary and secondary amines as a nitrogen nucleophile, and phenoxide derivatives as an oxygen nucleophile participated all in the reaction very well to furnish the corresponding allylated malonates, allylic amines, and allyl aryl ethers in high yields, respectively. DFT calculations of the reaction mechanism indicate that the direction of nucleophile's attack in the case of carbon nucleophiles, unlike other nucleophiles, is considerably off from the ideal direction, and thus the distance of the newly formed carbon-carbon bond is also considerably longer than the commonly accepted one. It was found then that the activation energies for reactions with carbon nucleophiles were considerably larger than those for reactions with nitrogen or oxygen nucleophiles, and hence the reaction with carbon nucleophiles is less likely proceed.

Mechanistic study on the side arm effect in a palladium/Xu-Phos-catalyzed enantioselective alkoxyalkenylation of γ-hydroxyalkenes

Recently, the asymmetric bifunctionalization of alkenes has received much attention. However, the development of enantioselective alkoxyalkenylation has posed a considerable challenge and has lagged largely behind. Herein, we report a new palladium-catalyzed enantioselective alkoxyalkenylation reaction, using a range of primary, secondary, and tertiary γ-hydroxy-alkenes with alkenyl halides. By employing newly identified Xu-Phos (Xu8 and Xu9) with a suitable side-arm adjacent to the PCy2 motif, a series of allyl-substituted tetrahydrofurans were obtained in good yields with up to 95% ee. Besides (E)-alkenyl halides, (Z)-alkenyl halide was also examined and provided the corresponding (Z)-product as a single diastereomer, supporting a stereospecific oxidative addition and reductive elimination step. Moreover, deuterium labeling and VCD experiments were employed to determine a cis-oxypalladation mechanism. DFT calculations helped us gain deeper insight into the side-arm effect on the chiral ligand. Finally, the practicability of this method is further demonstrated through a gram-scale synthesis and versatile transformations of the products.

Palladium-Catalyzed Tandem Cyclization of Bromoalkynes, Anilines and CO: Access to 1,3-Substituted Maleimides.

A novel palladium-catalyzed three-component carbonylation reaction for the assembly of various 1,3-substituted maleimide derivatives from haloalkynes and simple anilines. The nucleophilic addition reaction of haloalkynes, anilines and CO, and insertion of carbonyl have been achieved sequentially in this reaction. The high chemo- and regioselectivities, as well as no need of expensive ligands or additives further illustrate the synthetic value of this approach.

Total Synthesis of the Pyrrole Alkaloids Strychnuxinal and Strychnuxin

AbstractThe first asymmetric total syntheses of the fused-pyrrole alkaloids strychnuxinal and strychnuxin have been achieved in 6 and 7 steps, respectively, starting from commercially available (±)-4-chlorostyrene oxide. Key steps in the synthetic route include a regioselective epoxide opening, a reductive etherification sequence to form the central 1,4-oxazine ring, and a late-stage phenol synthesis using a mild palladium-catalyzed coupling reaction. Notably, the optimized synthetic sequence presented avoids the use of traditional protecting groups. Total synthesis of these two structurally related natural products confirmed both their constitution (via NMR and X-ray crystallography) and their absolute configuration (via optical rotation).

Efficient Iodine Uptake of Ultra Thermally Stable Conjugated Copolymers Bearing Biaceanthrylenyl Moieties and Contorted Aromatic Units Using a [3 + 2] Palladium-Catalyzed Cyclopolymerization Reaction.

A novel series of copolymers made from alternating aromatic surrogates with contorted and spiro compounds, denoted as BCP1-3, was successfully synthesized employing a palladium-catalyzed one-pot [3 + 2] cyclopentannulation reaction. The resulting copolymers BCP1-3, which were isolated in high yields, exhibited weight-average molecular weights (Mw) ranging from 11.0 to 61.5 kg mol-1 (kDa) and polydispersity index (Mw/Mn) values in the range of 1.7 and 2.0, which suggest a narrow molecular weight distribution, thus indicating the formation of uniform copolymer chains. Investigation of the thermal properties of BCP1-3 by thermogravimetric analysis disclosed outstanding stability with 10% weight loss temperature values reaching 800 °C. Iodine adsorption tests revealed remarkable results, particularly for BCP2, which demonstrated a strong affinity toward iodine reaching an uptake of 2900 mg g-1. Additionally, recyclability tests showcased the effective regeneration of BCP2 after several successive iodine adsorption-desorption cycles.

Palladium-catalyzed synthesis of carboxylic acid anhydrides from alkenes

Hydrocarbonylation of alkenes with nucleophiles – water, alcohols and amines, is widely studied and implemented in synthesis of fine chemicals and natural products. Here, an efficient and additive-free palladium-catalyzed hydrocarbonylation reaction of alkenes is described using carboxylic acids as the nucleophile, by which acid anhydrides are obtained in moderate to excellent yields. The relative concentrations of substrate and reagents play an important role in driving the reaction forward, which reaches an equilibrium at equimolar concentrations under a given CO pressure. A ligand-screening study revealed the use of electron-poor phosphine ligands to be crucial for obtaining higher rates of the catalytic reaction. Several substrates including unactivated alkenes were successfully converted to the corresponding symmetric as well as mixed anhydrides. An additional advantage of our synthetic procedure is that the obtained anhydrides can be converted to (primary) amides, thioesters or esters in situ via a simple one-pot derivatization reaction, since acid anhydrides are prone to degradation on isolation.

Computational Determination of the Mechanism of the Palladium-Catalyzed Domino Reaction of ortho-Iodostyrene, Oxanorbornadiene, and Phenylboronic Acid.

The palladium-catalyzed three-component domino reaction of ortho-iodostyrene, 2,3-dicarbomethoxy-7-oxanorbornadiene (ONBD), and phenylboronic acid discovered by the Lautens group provides a convenient method to synthesize indenes derivatives. Herein, density functional theory (DFT) calculations were employed to explore the detailed mechanism of this domino reaction. The computational results suggest that the alkene-insertion-first and the transmetalation-first mechanisms are competitive, and the former mechanism is slightly more favorable because of the difficult intramolecular alkene insertion of the alkyl-PdII-aryl than alkyl-PdII-I complex. Further analysis on substituents of ONBD unveils the impacts of noncovalent interactions and electronic effect on the rate-determining retro-Diels-Alder process. The understanding of this domino reaction has important implications for developing a novel palladium-catalyzed domino reaction with a retro-Diels-Alder strategy.