Palladium-catalyzed Research Articles

Defluorinative Multicomponent Cascade Reaction of Trifluoromethylarenes via Photoexcited Palladium Catalysis

Defluorinative Multicomponent Cascade Reaction of Trifluoromethylarenes via Photoexcited Palladium Catalysis

C‐H alkylation of heterocycles via light‐mediated palladium catalysis

Methods enabling direct C‐H alkylation of heterocycles are of fundamental importance in the late‐stage modification of natural products, bioactive molecules, and medicinally relevant compounds. However, there is a scarcity of a general strategy for the direct C‐H alkylation of a variety of heterocycles using commercially available alkyl surrogates. We report an operationally simple palladium‐catalyzed direct C‐H alkylation of heterocycles using alkyl halides under the visible light irradiation with good scalability and functional group tolerance. Our studies suggest that the photoinduced alkylation proceeds through cascade of events comprising, site‐selective alkyl radical addition, base‐assisted deprotonation, and oxidation. A combination of experiments and computations was employed for the generalization of this strategy, which was successfully translated towards the modification of natural products and pharmaceuticals.

C-H alkylation of heterocycles via light-mediated palladium catalysis.

Methods enabling direct C-H alkylation of heterocycles are of fundamental importance in the late-stage modification of natural products, bioactive molecules, and medicinally relevant compounds. However, there is a scarcity of a general strategy for the direct C-H alkylation of a variety of heterocycles using commercially available alkyl surrogates. We report an operationally simple palladium-catalyzed direct C-H alkylation of heterocycles using alkyl halides under the visible light irradiation with good scalability and functional group tolerance. Our studies suggest that the photoinduced alkylation proceeds through cascade of events comprising, site-selective alkyl radical addition, base-assisted deprotonation, and oxidation. A combination of experiments and computations was employed for the generalization of this strategy, which was successfully translated towards the modification of natural products and pharmaceuticals.

Nickel-Catalyzed Asymmetric (3 + 2) Annulations of Propargylic Carbonates and Vinylogous Donors via an Alkenylation Pathway.

The transition-metal-catalyzed alkenylation strategy of propargylic alcohol derivatives provides an efficient protocol to access multifunctional products in a double-nucleophilic attack pattern. While limited relevant asymmetric examples have been reported via palladium catalysis, here we first demonstrate that a nonprecious Ni(0)-based chiral complex can efficiently promote the tandem substitution process between propargylic carbonates and N-trifluoroethyl ketimines via consecutive aza-vinylogous activations, finally accomplishing a (3 + 2) annulation reaction to afford products embedding a 4-methylene-3,4-dihydro-2H-pyrrole framework with high regio-, diastereo-, and enantiocontrol. Their assemblies with a few all-carbon-based vinylogous precursors are also successful, and enantioenriched adducts containing a 3-methylenecyclopentene scaffold are furnished effectively. The substitution patterns for both types of substrates are substantial, and an array of synthetic elaborations is conducted to deliver more versatile architectures with high application potential. In addition, density functional theory calculations and control experiments have been conducted to rationalize the catalytic pathways and regio- and enantioselectivity control.

Visible-light-induced palladium-catalyzed C-H acylation of Azobenzenes at room temperature

An efficient C-H acylation of azobenzenes has been achieved through the synergistic use of palladium catalysis and visible-light photoredox catalysis at room temperature. This metallaphotocatalytic system is effective for reaction systems composed of TBHP and benzaldehyde, as well as those involving oxygen and benzoyl formic acid. The strategy exhibits good tolerance to various sensitive functional groups, producing a series of azo-substituted aryl ketones in moderate to good yields. The method is cost-effective, highly efficient, and environmentally friendly, providing a basis for the future development of novel metallaphotocatalytic reactions.

Synergistic effect of hydrogen bonding and C–H…π interactions to modulate the supramolecular assemblies of isobenzofuranones: X-ray crystallography, DFT analysis and antihyperglycemic potential

This manuscript reports the synthesis, X-ray characterization and antihyperglycemic potential of two isobenzofuranone derivatives. The Suzuki-Miyaura cross-coupling of 5-bromoisobenzofuran-1(3H)-one with phenylboronic acid and p-tolylboronic acid under the action of palladium catalysis afforded the desired compounds in good yields. The structures were fully established using FTIR and NMR spectroscopy and X-ray crystallography. The study further delves into the synergistic effects of hydrogen bonding and C–H…π interactions on the supramolecular assemblies of isobenzofuranones, leveraging a holistic approach that combines X-ray crystallography, Density Functional Theory (DFT) analysis, and evaluation of antihyperglycemic activity. Focusing on two isobenzofuranone derivatives, we meticulously elucidate their structural features and how noncovalent interactions shape their crystal packing. Our exploration extends to assessing the antihyperglycemic potential of these compounds, underpinned by α-glucosidase inhibitory assays and augmented by molecular docking analysis. Compound 3b showed the best potency with an IC50 value of 13 ± 0.01 µM which is 67-folds strong inhibition than acarbose (IC50 = 870.2 ± 1.54 µM). Furthermore, the admetSAR and ProTox-II demonstrated that compound 3b follows the druggable criteria with a safe toxicity profile. Overall, these findings highlight the pivotal role of noncovalent interactions in modulating the supramolecular architectures of isobenzofuranones, thereby offering insights into their therapeutic potential against diabetes mellitus.

Palladium‐Catalyzed Remote C−H Functionalization: Non‐Covalent Interactions and Reversibly Bound Templates

AbstractPd‐catalysis has stood as a pivotal force in synthetic transformations for decades, maintaining its status as a paramount tool in the realm of C−H bond activation. While functionalization at proximal positions has become commonplace, achieving selective and sustainable access to distal positions continues to captivate scientific endeavors. Recently, a noteworthy trend has emerged, focusing on the utilization of non‐covalent interactions to address the challenges associated with remote functionalization. The integration of these non‐covalent interactions into palladium catalysis stands as a justified response to the demands of achieving selective transformations at distal positions. This review delves into the latest advancements and trends surrounding the incorporation of non‐covalent interactions within the field of palladium catalysis. Furthermore, it is noteworthy to emphasize that multifunctional templates, particularly those harnessing hydrogen bonding, present an elegant and sophisticated approach to activate C−H bonds in a highly directed fashion. These templates showcase versatility and demonstrate potential applications across diverse contexts within the area of remote functionalization.

Palladium-Catalyzed Remote C-H Functionalization: Non-Covalent Interactions and Reversibly Bound Templates.

Pd-catalysis has stood as a pivotal force in synthetic transformations for decades, maintaining its status as a paramount tool in the realm of C-H bond activation. While functionalization at proximal positions has become commonplace, achieving selective and sustainable access to distal positions continues to captivate scientific endeavors. Recently, a noteworthy trend has emerged, focusing on the utilization of non-covalent interactions to address the challenges associated with remote functionalization. The integration of these non-covalent interactions into palladium catalysis stands as a justified response to the demands of achieving selective transformations at distal positions. This review delves into the latest advancements and trends surrounding the incorporation of non-covalent interactions within the field of palladium catalysis. Furthermore, it is noteworthy to emphasize that multifunctional templates, particularly those harnessing hydrogen bonding, present an elegant and sophisticated approach to activate C-H bonds in a highly directed fashion. These templates showcase versatility and demonstrate potential applications across diverse contexts within the area of remote functionalization.

Visible-Light-Driven Synthesis of N-Alkyl α-Amino Acid Derivatives from Unactivated Alkyl Bromides and In Situ Generated Imines.

One-pot, multicomponent reactions are known for their green and efficient nature. We report a novel three-component reaction of alkyl amines, alkyl glyoxylates, and unactivated alkyl bromides under visible-light-induced palladium catalysis, yielding N-alkyl unnatural α-amino acid derivatives. This method offers mild conditions, broad substrate scope, and excellent functional group tolerance without requiring stoichiometric organometallic reagents. The approach has promising applications in protein engineering and drug discovery.

Enantioselective Carboamination via Palladium Catalysis

Enantioselective Carboamination via Palladium Catalysis

Pd/Cu Dual Metal-Catalyzed Regioselective [2 + 2 + 2] Cycloaddition of Malononitriles with Alkynes to Densely Substituted Pyridines.

Transition metal-catalyzed [2 + 2 + 2] cycloaddition of nitriles and two alkynes is an efficient method for assembling pyridines. However, examples employing palladium catalysis have rarely been disclosed, and the processes of reactivity and selectivity remain unclear. We report here a palladium/copper dual metal-catalyzed [2 + 2 + 2] cycloaddition of diynyl-tethered malononitriles and terminal alkynes to synthesize densely substituted pyridines. This method features a good substrate scope, synthetically useful yields, and perfect regioselectivity. The derivatization of the pyridine products demonstrates the potential application of this method in synthesizing heterocycles and as ligands in photocatalysis. Preliminary mechanistic studies suggest that the reaction undergoes aza-oxidative cycloaddition of Pd(0) with nitrile and alkyne, followed by alkyne insertion and reductive elimination. The presence of copper is crucial to its reactivity and regioselectivity.

N, N’-bidentate ligand anchored palladium catalysts on MOFs for efficient Heck reaction

Metal-organic frameworks (MOFs), recognized as advanced catalyst carriers due to their adjustable porous, diverse structure and highly exposed active sites, have earned increasing attention for their potential to address the longevity of catalytic centers. In this manuscript, we have devised and synthesized a multifunctional amino-pyridine benzoic acid (APBA) ligand to replace the modulator ligand of the MOF-808 and disperse the palladium catalytic centers atomically on the MOF-APBA. The resulting single-site catalytic system, Pd@MOF-APBA, demonstrates preeminent efficiency and stability, as evidenced by a high average turnover number (95000) and a low metal residue (4.8 ppm) in the Heck reaction. This catalyst has exhibited recyclability for multiple runs without significant loss of reactivity for gram-scale reactions. The catalyst’s high activity and efficiency can be attributed to the suitable electrical properties and structures of the N, N’-bidentate ligand for the catalytic palladium ions, postponing their deactivations, including leaching and agglomeration.

Synthesis of Chromone‐3‐phosphonates via Arbuzov‐Type C−P Cross Coupling from o‐Hydroxyphenyl Enaminones and Phosphites

AbstractWith an in situ C−H iodination tactic, a method for the synthesis of chromone‐3‐phosphonates was developed with trialkyl/triaryl phosphites as the reaction partners of o‐hydroxyphenyl enaminones by palladium catalysis. The product formation consists of cascade C−H iodination, chromone annulation, and Arbuzov‐type C−P cross coupling as major transformations. In addition to providing an enaminone‐based synthetic method to chromone‐3‐phosphonates, the work shows the advantage of step economy by skipping the separate operation for preparing the iodo‐functionalized chromone intermediate.

Formate-Mediated Reductive Cross-Coupling of Vinyl Halides and Aryl Iodides: cine-Substitution via Palladium(I) Catalysis.

Formate-mediated reductive cross-couplings of vinyl halides with aryl iodides via palladium(I) catalysis occur with highly uncommon cine-substitution. The active dianionic palladium(I) catalyst, [Pd2I4][NBu4]2, is generated in situ from Pd(OAc)2, Bu4NI, and formate. Oxidative addition of aryl iodide followed by dissociation of the dimer provides the monomeric anionic T-shaped arylpalladium(II) species, [Pd(Ar)(I)2(NBu4)], which, upon vinyl halide carbopalladation, forms products of cine-substitution by way of palladium(IV) carbenes, as corroborated by deuterium-labeling experiments.

Enantioselective Arylation of Sulfenamides to Access Sulfilimines Enabled by Palladium Catalysis.

Sulfur-containing functional groups have garnered considerable attention due to their common occurrence in ligands, pharmaceuticals, and insecticides. Nevertheless, enantioselective synthesis of sulfilimines, particularly diaryl sulfilimines remains a challenging and persistent goal. Herein we report a highly enantio- and chemoselective cross-coupling of sulfenamides with aryl diazonium salt to construct diverse S(IV) stereocenters by Pd catalysis. Bisphosphine ligands bearing sulfinamide groups play a crucial role in achieving high reactivity and selectivity. This approach provides a general, modular and divergent framework for quickly synthesizing chiral sulfilimines and sulfoximines that are otherwise challenging to access. In addition, the origins of the high chemoselectivity and enantioselectivity were extensively investigated using density functional theory calculations.

Enantioselective Arylation of Sulfenamides to Access Sulfilimines Enabled by Palladium Catalysis

AbstractSulfur‐containing functional groups have garnered considerable attention due to their common occurrence in ligands, pharmaceuticals, and insecticides. Nevertheless, enantioselective synthesis of sulfilimines, particularly diaryl sulfilimines remains a challenging and persistent goal. Herein we report a highly enantio‐ and chemoselective cross–coupling of sulfenamides with aryl diazonium salt to construct diverse S(IV) stereocenters by Pd catalysis. Bisphosphine ligands bearing sulfinamide groups play a crucial role in achieving high reactivity and selectivity. This approach provides a general, modular and divergent framework for quickly synthesizing chiral sulfilimines and sulfoximines that are otherwise challenging to access. In addition, the origins of the high chemoselectivity and enantioselectivity were extensively investigated using density functional theory calculations.

Palladium-Catalyzed Regio- and Stereoselective Glycosylation of Azole Heterocycles Enables Access to Diverse Heterocyclic N-Glycosides.

An efficient and practical glycosylation platform for synthesizing N-glycosides by leveraging palladium catalysis is disclosed. This approach enables facile access to diverse heterocyclic N-glycosides with excellent regio- and stereoselectivities and high site selectivity of multiple N atoms. The reaction exhibits a broad substrate scope (65 examples), high functional group tolerance, and easy scalability. Its synthetic utility is demonstrated through late-stage functionalization of pharmaceutically relevant molecules and various diastereoselective transformations of the glycoside products. Overall, our method provides a handy tool for efficient and stereocontrolled synthesis of valuable N-glycosylated heterocycles.

2,3-Arylacylation of allenes through synergetic catalysis of palladium and N-heterocyclic carbene

An unprecedented 2,3-arylacylation reaction of allenes with aryl iodides and aldehydes was developed by resorting to Pd/NHC synergetic catalysis. It's the first time that allene was introduced into transition metal and NHC synergetic catalysis, which demonstrated a versatile three-component reaction pattern, thus enabling two C-C bonds forged regioselectively in the reaction. The important reaction intermediates were successfully captured and characterized by HRMS analysis, and the migrative insertion of allene to the Ph-Pd species was identified as the reaction rate-limiting step by kinetic experiments.

Chemoselective C(sp2)–C(sp2) doubly decarbonylative cross-electrophile coupling enabled by palladium catalysis: Reaction development and mechanism studies

Transition metal-catalyzed cross-electrophile coupling of two electrophiles has proved to be a powerful and step-economic strategy for the construction of C–C bonds in organic synthesis. Despite the considerable advances, cross-electrophile coupling of sp2-hybridized carboxylic acid derivatives via a decarbonylative fashion remains a formidable challenge. Herein, we disclose a chemoselective C(sp2)–C(sp2) doubly decarbonylative cross-electrophile coupling of aroyl fluorides with a wide range of aryl and alkenyl thioesters by palladium catalysis. The catalytic protocol provides an alternative route for the efficient synthesis of biaryls and stilbene derivatives owing to wide accessibility, natural abundance and stability of carboxylic acid and relevant derivatives. The combination of a series of experiments and theoretical calculations reveals that conversion of aroyl fluorides into the corresponding thioesters, chloride anion in catalyst PdCl2 and in situ generated Zn(II) reagents play the crucial roles in the current cross-coupling reactions.

Divergent Synthesis of Dihydrofurans and Tetrahydrofurans Enabled by Palladium Catalysis

Divergent Synthesis of Dihydrofurans and Tetrahydrofurans Enabled by Palladium Catalysis