Palladium-catalyzed Cross-coupling Reactions Research Articles

Toward New Horizons in Verdazyl-Nitroxide High-Spin Systems: Thermally Robust Tetraradical with Quintet Ground State.

High-spin organic tetraradicals with significant intramolecular exchange interactions have high potential for advanced technological applications and fundamental research, but examples reported to date exhibit limited stability and processability. In this work, we designed the first tetraradical based on an oxoverdazyl core and nitronyl nitroxide radicals and successfully synthesized it using a palladium-catalyzed cross-coupling reaction of an oxoverdazyl radical bearing three iodo-phenylene moieties with a gold(I) nitronyl nitroxide-2-ide complex in the presence of a recently developed efficient catalytic system. The molecular and crystal structures of the tetraradical were confirmed by single crystal X-ray diffraction analysis. The tetraradical possesses good thermal stability with decomposition onset at ∼125 °C in an inert atmosphere; in a toluene solution upon prolonged heating at 90 °C in air, no decomposition was observed. The resulting unique verdazyl-nitroxide conjugate was thoroughly studied using a range of experimental and theoretical techniques, such as SQUID magnetometry of polycrystalline powders, EPR spectroscopy in various matrices, cyclic voltammetry, and high-level quantum chemical calculations. All collected data confirm the high thermal stability of the resulting tetraradical and quintet multiplicity of its ground state, which makes the synthesis of this important paramagnet a new milestone in the field of creating high-spin systems.

Sadphos as Adaptive Ligands in Asymmetric Palladium Catalysis.

ConspectusPalladium catalysis, as one of the most important strategies in asymmetric synthesis, has continuously attracted the attention of organic chemists. With the development of chiral ligands, increasingly challenging reactions and substantial progress in asymmetric catalysis are being realized.Since 2014, we have focused on exploiting a series of sulfinamide phosphine ligands called "Sadphos," including Ming-Phos, Xu-Phos, Xiao-Phos, Xiang-Phos, TY-Phos, PC-Phos, GF-Phos, and WJ-Phos. These ligands can be easily prepared in two to four steps using commercial materials. These new types of ligands have shown remarkable performance in transition-metal-catalyzed reactions, especially in Pd-catalyzed transformations. X-ray diffraction analysis, mechanistic studies, and density functional theory calculations have revealed that Sadphos ligands can coordinate with the Pd0 and PdII species in the Pd0/P, Pd0/P,S, or PdII/P,O modes.This Account summarizes our recent efforts toward palladium-catalyzed enantioselective reactions using Sadphos ligands. These ligands were found to be privileged and very crucial to promote the reactions by increasing the reactivity and enantioselectivity. Ming-Phos is an effective ligand in Pd-catalyzed asymmetric coupling and intramolecular Heck reactions, providing highly enantioselective trisubstituted allenes, axially chiral anilides, gem-diarylmethine silanes, and disubstituted dihydroisoquinolinones. Incorporation of an electron-rich cyclohexyl group in the phosphine moiety afforded Xu-Phos, which showed a unique effect in a series of asymmetric transformations, including reductive Heck, dearomative Mizoroki-Heck, tandem Heck/Suzuki coupling, carboiodination, carboamination, and cross-coupling reactions. Using a similar strategy, our group synthesized more electron-rich TY-Phos and Xiang-Phos ligands bearing t-butyl and 1-adamantyl group at P atoms, respectively. Regarding stereoelectronic features, these two characteristic ligands were the best choice to satisfy the requirements of the palladium-catalyzed fluoroarylation of gem-difluoroalkenes, intermolecular α-arylation of aldehydes, carboetherification of alkenyl oximes, and carboheterofunctionalization of 2,3-dihydrofurans. Compared with the aforementioned Sadphos ligands, the attractive features of Xiao-Phos, including high nucleophilicity originating from the CH2PPh2 group and the ortho-substituent effect at the side of the aryl ring, are presumably responsible for its efficiency. The Pd/Xiao-Phos catalyst system shows good performance in a series of cross-coupling reactions of secondary phosphine oxides, affording P-stereogenic products bearing multiple types of molecular skeletons. The modification of the basic Sadphos backbone by introducing a xanthene skeleton motivated us to design and synthesize monophosphines, named PC-Phos and GF-Phos. PC-Phos is effective in various reactions, including arylation of sulfenate anions, denitrogenative cyclization of benzotriazoles, and dearomatization of indoles. The practicability of GF-Phos was validated in the Pd-catalyzed asymmetric three-component coupling of N-tosylhydrazones, aryl halides, and terminal alkynes, as well as in the cross-coupling of N-tosylhydrazones and vinyl iodides with pendent amines. In addition, ferrocene-derived WJ-Phos was employed in the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction, affording axially chiral biaryl monophosphine oxides in excellent enantiomeric excesses.

Magnetic Pd–Fe nanoparticles for sustainable Suzuki–Miyaura cross-coupling reactions

The development of palladium-catalyzed cross-coupling reactions has been revolutionized by bimetallic co-catalysis and magnetic separation techniques, which address the dual challenges of reducing the reliance on palladium (Pd) and advancing sustainable chemistry practices.

Synthesis of allenynes via Pd-catalyzed coupling of 1,4-diyn-3-yl carbonates with boronic acids

A palladium-catalyzed cross-coupling reaction of 1,4-diyn-3-yl carbonates with organoboronic acids for a series of conjugated allenynes using S-phos or Gorlos-phos as the ligand under mild conditions has been developed.

Stereoselective Palladium-Catalyzed Hiyama Cross-Coupling Reaction of Tetrasubstituted gem-Difluoroalkenes.

We herein describe a diastereoselective Pd(0)-catalyzed Hiyama cross-coupling reaction of gem-difluoroalkenes. The use of organosilicon reagents in this reaction is advantageous over other organometallic reagents by allowing the introduction of a wide range of functional groups, including challenging alkyl groups. Also conveniently, the additive TBAF was not required for (hetero)aryl-substituted difluoroalkenes.

A Nitronyl Nitroxide-Substituted Benzotriazinyl Tetraradical.

High-spin organic tetraradicals with significant intramolecular exchange interactions have high potential for advanced technological applications and fundamental research, but those synthesized to date possess limited stability and processability. In this work, we have designed a tetraradical based on the Blatter's radical and nitronyl nitroxide radical moieties and successfully synthesized it by using the palladium-catalyzed cross-coupling reaction of a triiodo-derivative of the 1,2,4-benzotriazinyl radical with gold(I) nitronyl nitroxide-2-ide complex in the presence of a newly developed efficient catalytic system. The molecular and crystal structure of the tetraradical was confirmed by X-ray diffraction analysis. The tetraradical possesses good thermal stability with decomposition onset at ∼150 °C under an inert atmosphere and exhibits reversible redox waves at -0.54 and 0.45 V versus Ag/AgCl. The magnetic properties of the tetraradical were characterized by SQUID magnetometry of polycrystalline powders and EPR spectroscopy in various matrices. The collected data, analyzed by using high-level quantum chemical calculations, confirmed that the tetraradical has a triplet ground state and a nearby excited quintet state. The unique high stability of the prepared triazinyl-nitronylnitroxide tetraradical is a new milestone in the field of creating high-spin systems.

Syntheses of Substituted α,β-Unsaturated δ-Lactams from N-Boc-2,4-dioxopiperidine.

A method for the syntheses of substituted α,β-unsaturated δ-lactams (2) from the commercially available compound N-Boc-2,4-dioxopiperidine (1) has been developed. The α-substituents were introduced by a reductive Knoevenagel condensation reaction, and the β-substituents were installed by palladium-catalyzed cross coupling reactions. More than 20 diverse examples were prepared in 2-3 steps. The synthesis was operationally simple, user-friendly, and easy to scale up.

Pyrimidine-morpholine hybrids as potent druggable therapeutics for Alzheimer’s disease: Synthesis, biochemical and in silico analyses

The identification of effective and druggable cholinesterase inhibitors to treat progressive neurodegenerative Alzheimer’s disorder remains a continuous drug discovery hunt. In this perspective, the present study investigates the design and discovery of pyrimidine-morpholine hybrids (5a-l) as potent cholinesterase inhibitors. Palladium-catalyzed Suzuki-Miyaura cross-coupling reaction was employed to introduce the structural diversity on the pyrimidine heterocyclic core. A range of commercially available boronic acids was successfully coupled showing a high functional group tolerance. In vitro cholinesterase inhibitory potential using Ellman’s method revealed significantly strong potency. Compound 5h bearing a meta-tolyl substituent at 2-position of pyrimidine ring emerged as a lead candidate against AChE with an inhibitory potency of 0.43 ± 0.42 µM, ∼38-fold stronger value than neostigmine (IC50 = 16.3 ± 1.12 µM). Compound 5h also showed the lead inhibition against BuChE with an IC50 value of 2.5 ± 0.04 µM. The kinetics analysis of 5h revealed the non-competitive mode of inhibition against AChE whereas computational modelling results of potent leads depicted diverse contacts with the binding site amino acid residues. Molecular dynamics simulations revealed the stability of biomolecular system, while, ADME analysis demonstrated druglikeness behaviour of potent compounds. Overall, the investigated pyrimidine-morpholine scaffold presented a remarkable potential to be developed as efficacious anti-Alzheimer’s drugs.

Modular Synthesis of Phosphino Hydrazones and Their Use as Ligands in a Palladium-Catalysed Cu-Free Sonogashira Cross-Coupling Reaction.

Invited for this month's cover is the group of Evamarie Hey-Hawkins at Leipzig University. The cover picture shows the three different bonding modes (mono-, bi- and tridentate) of the modular ligand towards palladium(II) or platinum(II), illustrated with Winston who kindly served as the model. The cat has three binding sites (mouth, front paws and hind paws = P, N and pyridine) to bind the metal dichloride fragment. When all three are used in a tridentate bonding mode, one chlorido ligand is cleaved off. Cover design by Dr. Christoph Selg. More information can be found in the Research Article by Evamarie Hey-Hawkins and co-workers.

Synthesis of phenylethanoid glycosides from acrylic esters of glucose and aryldiazonium salts via palladium-catalyzed cross-coupling reactions and evaluation of their anti-Alzheimer activity

Cinnamic acid-containing sugar compounds such as phenylethanoid glycosides are widely present in nature and display various biological activities. In this work, the synthesis of trans-cinnamic acid containing phenylethanoid glycosides was achieved via palladium-catalyzed cross-coupling reactions between glycosyl acrylic esters and aryldiazonium salts. A wide range of functionalized aryldiazonium salts were successfully coupled with 6-O- and 4-O-acrylic esters of glucose under optimized conditions. The reactions proceeded at room temperature in the absence of additives and base. The desired products were obtained in good to excellent yields. Selected compounds from the library were screened for anti-Alzheimer activity, while compound 16 displayed significant inhibitory activities against butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) enzymes.

Palladium-catalyzed direct C[sbnd]H allylation of indoles derivatives with allyltrimethylsilanes

A palladium-catalyzed cross-coupling reaction between 2-susbtituted indole and allyltrimethylsilanes in the absence of fluoride anion source was studied. The optimal conditions for the reaction were identified after various reaction conditions examined, using Pd(OAc)2 as the catalyst, Cu(OTf)2 as oxidant, and DMSO as solvent, leading to the synthesis of a series of benzindoles bearing allyl group in good to high yields.

Palladium-Catalyzed Arylation of Endocyclic 1-Azaallyl Anions: Concise Synthesis of Unprotected Enantioenriched cis-2,3-Diarylpiperidines.

Unprotected cis-2,3-diarylpiperidines are synthesized through an unprecedented palladium-catalyzed cross-coupling reaction between aryl halides and elusive endocyclic 1-azaallyl anions. These intermediates are generated in situ by the deprotonation of 2-aryl-1-piperideines, precursors that are readily prepared in two operations from simple piperidines. An asymmetric version of this reaction with (2R, 3R)-iPr-BI-DIME as the ligand provides products in moderate to good yields and enantioselectivities. This study significantly expands the synthetic utility of endocyclic 1-azaallyl anions.

Palladium-catalyzed facile synthesis of imidazo[1,2-a]pyridine-flavone hybrids and evaluation of their antiplasmodial activity

An efficient cross-coupling reaction between imidazo[1,2-a]pyridine derivatives and 6-bromoflavones has been well established. This reaction proceeds through a Palladium-catalyzed cross-coupling reaction to provide imidazo[1,2-a]pyridine-flavone hybrids in good to excellent yield. Short reaction time, high yield, and wide substrate scope are the major advantages of this method. Using SYBR Green I assay, these hybrid molecules were examined for anti-plasmodial activity against Chloroquine-sensitive 3D7 and Chloroquine-resistant K1 strains of Plasmodium falciparum. The compounds 9o {IC50s (µM) 1.983D7, 1.98K1} and 9p {IC50s (µM) 1.923D7, 5.45K1} were found to be the most potent anti-plasmodial compounds in the series. Also, all these compounds were found to be non-cytotoxic towards Vero cells with their CC50s > 100 µM. We have conducted microscopic examination experiments on compounds 9o and 9p, which resulted in a drastic impact on parasite growth of the malaria parasite. The interaction of these two potent hybrids was also examined in the binding site of wild-type Pf-DHFR-TS (Plasmodium falciparum dihydrofolate reductase-thymidylate synthase) using molecular docking studies. The computational ADME studies of the hybrid compounds confirmed their significant physicochemical, pharmacokinetic, and drug-likeness properties confirming these hybrids as a new oral antimalarial agent. As a result, these new hybrid compounds could be valuable in the creation of future antimalarial drugs.

Perylenemonoimide-subphthalocyanine derivatives: Synthesis, characterization and photovoltaic performance as non-fullerene acceptors in bulk heterojunction solar cells

Imide-based Subphthalocyanines (SubPcs) is gaining momentum as non-fullerene acceptors in organic solar cells (OSCs). Herein we report the synthesis, characterization, and photovoltaic performance of Perylenemonoimide (PMI)-SubPc conjugates in which the PMI is linked to the SubPc core by either alkynes or direct C-C bond. These derivatives are prepared via palladium-catalyzed cross-coupling reactions. The introduction of PMI units results in a red-shifted absorption, which can be described as the combination of the absorption properties of both SubPc and PMIs fragments. The absorption spectra are thus mainly composed of two transitions, one derived from the SubPc Q-band and the other from transitions within the PMI moieties. These PMI-SubPc systems exhibit moderate acceptor properties and therefore their use as non-fullerene acceptors in bulk-heterojunction organic solar cells is briefly explored.

Synthesis of ortho-Methylated Benzamides via Palladium-Catalyzed Denitrogenative Cross-Coupling Reaction of [1,2,3]-Benzotriazin-4(3H)-ones with DABAL-Me3.

We herein developed a palladium-catalyzed reaction of [1,2,3]-benzotriazin-4(3H)-ones with DABAL-Me3 [bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane adduct], a cheap, stable, and solid organoaluminum reagent. In the presence of Pd(OAc)2/XantPhos as a commercially available catalyst, [1,2,3]-benzotriazin-4(3H)-ones underwent denitrogenative coupling with DABAL-Me3 to afford a wide array of N-aryl amides derived from ortho-methylated carboxylic acids. Under the same catalytic conditions, ortho-ethylation of [1,2,3]-benzotriazin-4(3H)-ones could also be achieved by using triethylaluminum.

Synthesis and Palladium-Catalyzed Cross-Coupling of an Alkyl-Substituted Alkenylboronic Acid Pinacol Ester with Aryl Bromides

The palladium-catalyzed cross-coupling reaction of alkyl-substituted alkenylboron reagents with aryl halides is a versatile method to introduce a hydrophobic hydrocarbon chain onto organic compounds of interest. The application of the cross-coupling reaction is enabled by synthetic methods for the preparation of alkenylboron reagents. The geometrically pure, alkyl-substituted alkenylboron reagent, (E)-octenylboronic acid pinacol ester, was prepared by 9-BBN-catalyzed hydroboration reaction of 1-octene with pinacolborane in refluxing 1 M THF solution. This reagent was then evaluated in palladium-catalyzed cross-coupling reactions with aryl bromides. The highest yield of the (E)-1-phenyloctene was obtained when SPhos was used as the ligand, K2CO3 was used as the base, and DMF was used as the reaction solvent. Other electron-rich, electron-poor, sterically hindered, and heteroaromatic substrates produced the corresponding (E)-1-phenyloctene derivatives in moderate to good yield. KEYWORDS: Organic synthesis; Aryl alkene synthesis; Palladium-catalyzed cross-coupling; Suzuki-Miyaura reaction; Stereocontrolled alkene preparation; Hydroboration; 9-Borobicyclo[3.3.1]nonane; Reaction optimization

Modular Synthesis of Phosphino Hydrazones and Their Use as Ligands in a Palladium-Catalysed Cu-Free Sonogashira Cross-Coupling Reaction.

Phosphino hydrazones represent a versatile class of nitrogen-containing phosphine ligands. Herein, we report a modular synthesis of phosphino hydrazone ligands by hydrazone condensation reaction of three different aryl hydrazines with 3-(diphenylphosphino)propanal (PCHO). Complexation reactions of these phosphino hydrazone ligands with palladium(II) and platinum(II) were investigated and the catalytic activity of the palladium(II) complexes was explored in a Cu-free Sonogashira cross-coupling reaction achieving yields up to 96 %. Additionally it was shown that the catalytically active species is homogeneous.

Porous Supramolecular Assemblies for Efficient Suzuki Coupling of Aryl Chlorides.

The development of catalytic systems that can activate aryl chlorides for palladium-catalyzed cross-coupling reactions is at the forefront of ongoing efforts to synthesize fine chemicals. In this study, a facile ligand-template approach is adopted to achieve active-site encapsulation by forming supramolecular assemblies; this bestowed the pristine inert counterparts with reactivity, which is further increased upon the construction of a porous framework. Experimental results indicated that the isolation of ligands by the surrounding template units is key to the formation of catalytically active monoligated palladium complexes. Additionally, the construction of porous frameworks using the resulting supramolecular assemblies prevented the decomposition of the Pd complexes into nanoparticles, which drastically increased the catalyst lifetime. These findings, along with the simplicity and generality of the synthesis scheme, suggest that the strategy can be leveraged to achieve unique reactivity and potentially enable fine-chemical synthesis.

Palladium-catalyzed synthesis and acetylcholinesterase inhibitory activity evaluation of 1-arylhuperzine A derivatives

A series of arylated huperzine A (HPA) derivatives (1–24) were efficiently synthesized in good yields (45–88% yields) through the late-stage modification of structurally complex natural anti-Alzheimer’s disease (AD) drug huperzine A (HPA), using the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction. The acetylcholinesterase (AChE) inhibitory activity of all synthesized compounds was evaluated to screen the potential anti-AD bioactive molecules. The results showed that introducing the aryl groups to C-1 position of HPA resulted in the unsatisfactory AChE inhibitory activity. The present study demonstrably verifies pyridone carbonyl group could be the necessary and unchangeable pharmacophore for maintaining HPA's anti-AChE potency, and provides the helpful information on the further research for developing anti-AD HPA analogues.

Photoinduced Palladium-Catalyzed 1,2-Difunctionalization of Electron-Rich Olefins via a Reductive Radical-Polar Crossover Reaction

Palladium-catalyzed cross-coupling reactions belong to the most important transformations for the construction of C–C or C-heteroatom bonds. More recently, the photochemical activation of palladium complexes emerged as a key strategy to leverage palladium catalysis at room temperature beyond the scope of conventional cross-coupling chemistry. Herein, we report on the photoinduced palladium-catalyzed 1,2-difunctionalization reaction of electron-rich olefins. Mechanistic experiments and computational studies reveal that this reaction proceeds via the addition of an alkyl radical, followed by the oxidation of a radical intermediate to access carbocation intermediates, which are inaccessible via classic thermal reaction conditions. The carbocation can then be applied to a variety of secondary C–C or C–N bond-forming reactions. This strategy now allows a general approach toward densely functionalized unsymmetric 1,1-bis(heterocyclyl)alkanes.