Pd-catalyzed Coupling Reaction Research Articles

Molecular rotors of naphthalimide and benzodithiophene as effective solvent polarity probes, temperature sensors, and for g-C3 N4 sensitization.

Acceptor-donor-acceptor (A-D-A) molecular rotors have drawn substantial attention for their applications in monitoring temperature variations within cellular microenvironments, biomimetic photocatalysis, and bioimaging. In this study, we have synthesized two novel rotor molecules, NBN1 and NBN2, by incorporating benzodithiophene (BDT) as the donor core and naphthalic anhydride/naphthalimide (NA/NI) moieties as acceptors using Pd-catalyzed Stille coupling reactions. These molecules exhibited distinct charge transfer (CT) behavior in both their absorption and emission spectra and displayed prominent emission solvatochromism. Notably, NBN1 exhibited better CT properties among the two molecules. Moreover, these A-D-A molecular rotors demonstrated remarkable sensitivities of their emission spectra toward solvent polarities and temperatures. Rotors NBN1 and NBN2 showed positive temperature coefficients with internal temperature sensitivities of 0.34% °C-1 and 0.13% °C-1 in chloroform, respectively, and thus hold significant promise for detecting temperature variations in cellular microenvironment. Furthermore, we have modeled these molecules with graphitic carbon nitride (g-C3 N4 ) to form composite systems and performed theoretical calculations to obtain valuable insights into their charge transfer behavior. Theoretical results suggested that these molecules have the potential to efficiently sensitize and modulate the band gap of g-C3 N4 and show potential for diverse photocatalytic applications.

Regioselective Arylation of Amidoaryne Precursors via Ag-Mediated Intramolecular Oxy-Argentation.

An unprecedented silver-mediated intramolecular oxy-argentation of 3-amidoaryne precursors that quickly generates a heteroarylsilver species is developed. AgF acts as both a stoichiometric fluoride source and a reagent for the formation of a benzoxazolylsilver intermediate via aryne generation. Pd-catalyzed coupling reactions of (hetero)aryl iodides with a silver species, generated in situ, allow for the synthesis of various C7-arylated benzoxazoles. As a result, an aryl group is selectively introduced into the meta-position of 3-amidobenzyne precursors. Mechanistic studies have indicated the presence of a benzoxazolylsilver intermediate and revealed that the reaction proceeds via an intramolecular oxy-argentation process, which is initiated by a direct fluoride attack on the silyl group.

Pyrene-Based Deep-Blue Fluorophores with Narrow-Band Emission.

High-efficiency narrow-band luminescent materials have attracted intense interest, resulting in their great colorimetric purity. This has led to a variety of high-tech applications in high-definition displays, spectral analysis, and biomedicine. In this study, a rigid pyrene core was employed as the molecular backbone, and four narrow-band pyrene-based blue emitters were synthesized using various synthetic methods (such as Lewis-acid catalyzed cyclization domino reactions, Pd-catalyzed coupling reactions like Suzuki-Miyaura and Sonogashira). Due to the steric effect of the hydroxy group at the 2-position, the target compounds exhibit deep blue emission (<429 nm, CIEy < 0.08) with full width at half-maximum (FWHM) less than 33 nm both in solution and when solidified. The experimental and theoretical results indicated that the substituents at the 1- and 3-positions afford a large dihedral angle with the pyrene core, and the molecular motion is almost fixed by multiple intra- and intermolecular hydrogen bonding interactions in the crystallized state, leading to a suppression of the vibrational relaxation of the molecular structure. Moreover, we observed that the suppression of the vibrational relaxation in the molecular structures and the construction of rigid conjugated structures can help develop narrow-band organic light-emitting materials.

Kinetically Controlled Stereoselective Synthesis of 2-Oxo-2-aryl-1,3,2-dioxaphosphorinane Derivatives via a Palladium-Catalyzed Reaction.

Chiral phosphonate esters have been widely applied in the fields of organic chemistry, medicine, and photoelectric materials. However, it requires the challenging enantioselective synthesis of cyclic phosphonate esters with the desired chiral configuration. The two epimers of 2-oxo-2H-1,3,2-dioxaphosphorinane derivatives should have different reactivities in Pd-catalyzed coupling reactions, which could lead to an effective methodology for the asymmetric synthesis of 2-oxo-2-aryl-1,3,2-dioxaphosphorinane derivatives. A thorough investigation of the coupling reactions both computationally and experimentally led to the stereoselective synthesis of chiral cyclic phosphonate esters. The axial isomer of products can be obtained with both high diastereoselectivity and good chemical yields from the mixture of 2-oxo-2H-1,3,2-dioxaphosphorinane derivatives under kinetically controlled conditions.

Total Synthesis of the Racemate of Laurolitsine

The total synthesis of laurolitsine was achieved for the first time. This reaction was accomplished in 14 steps with a 2.3% yield (this was calculated using 3-hydroxy-4-methoxybenzaldehyde as the starting material) starting from two simple materials, 3-hydroxy-4-methoxybenzaldehyde and 2-(3-hydroxy-4-methoxyphenyl)acetic acid, and the longest linear sequence consisted of 11 steps. The key steps included an electrophilic addition reaction in which a nitro group was reduced to an amino group using lithium tetrahydroaluminum and a Pd-catalyzed direct biaryl coupling reaction. In this paper, many of the experimental steps were optimized, and an innovative postprocessing method in which 2-(3-(benzyloxy)-4-methoxyphenyl)ethanamine is salted with oxalic acid was proposed.

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.

Tuning emission of luminescent 2-7 disubstituted sila-and germafluorenes with –(trifluoromethyl)phenyl, -(malononitrile)phenyl, and -nitrobenzene substituents

2,7-Disubstitution and DFT-guided design have been used to tune emission wavelengths for three new fluorescent 2,7-alkynyl(aryl)-3,6-dimethoxy-9,9-diphenyl-sila- and germafluorenes. Two germafluorenes with trifluoromethyl phenyl and nitrobenzene substituents were prepared using a Pd-catalyzed Sonogashira coupling reaction to incorporate alkynyl(aryl) groups at the 2,7-positions of the ring. Another new silafluorene was prepared by modifying a benzaldehyde-substituted silafluorene to incorporate a malononitrile group. These compounds were characterized utilizing multinuclear NMR, UV–Vis, and fluorescence spectroscopic techniques. The germafluorene with the trifluoromethyl phenyl substituent was also characterized via elemental analysis and X-ray crystallography. These metallafluorenes (MFs), which are yellow or red-orange crystals in the solid state, showed a wide range of quantum yields and spectroscopic features, with the malononitrile-containing MF exhibiting significantly red-shifted emission relative to other MFs. These data demonstrate the value in applying DFT to MF design and the dramatic impact the 2,7-substituent has on the optical properties of this class of compounds.

Origin of Ligand and Acid Effects on the Pd-Catalyzed Regiodivergent Coupling Reaction of Indazoles and Isoprene: A DFT Study.

Comprehensive computational studies were carried out to explore the mechanisms and origin of regioselectivity in the Pd-catalyzed regiodivergent coupling reaction of indazoles and isoprene. Three different insertion models were investigated for regioselectivity 1,2- or 4,3-insertion with respect to the electrophilic sites on isoprene under two different ligands (L1 and L2) and acids ((PhO)2PO2H, (nBuO)2PO2H) via PdII-H species, allyl-π-PdII-O, and indazoles-acid-assisted PdII-π-allyl. The calculated results show that the PdII-π-allyl coordinated mechanism is the most preferred one. The noncovalent interactions between the less bulky ligand L1, substrates, and (PhO)2PO2- are found to be key factors for 1,2-insertion. The 4,3-insertion selectivity is primarily controlled by the steric repulsion of the t-Bu group of bulky ligand L2 and substrate, as well as the geometry distortion. Therefore, the regioselectivity difference of the 1,2- and 4,3-insertion on electrophilic sites is controlled by the synergistic effect of ligands and acids instead of the size of the ligand. Similarly, nucleophilic site selectivity at N1 or N2 of indazoles is governed by cooperative acid BF3 and solvent iPrOH rather than BF3 alone. Overall, our findings might open a new avenue for designing more efficient regioselective 1,2- or 4,3-addition or N1-/N2-selective nucleophilic reactions.

Regio- and chemoselective synthesis of polyaryl flavones by combination of C-O/C-H activation and Suzuki-Miyaura cross coupling reactions

The first regioselective ruthenium-catalyzed arylation of flavone-derived compounds is reported. Exploring the molecular structure-reactivity different 5-,5,8-, 5,7-, 5,6- and 5,7,8-aryl substituted flavones were prepared through Ru-, Ni- and Pd-catalyzed coupling reactions with aryl boronic species under regio- and chemoselective approach in moderate to excellent yields. The obtained derivatives were thoroughly characterized by spectroscopic techniques, such as 1H NMR, 13C NMR and HRMS data. The convenient availability of starting natural product chrysin confers facility to the employed reactions which products may find application in pharmaceutical and material science areas.

A Hierarchy of Ligands Controls Formation and Reaction of Aryl Radicals in Pd-Catalyzed Ground-State Base-Promoted Coupling Reactions.

Palladium salts and complexes were tested separately and in the presence of added ligands as potential sources of aryl radicals in ground-state coupling reactions of aryl halide with arenes under basic conditions (KOtBu). Our recently developed assay for aryl radicals was employed to test for aryl radicals. In this assay, aryl radicals derived from the test substrate, 1-iodo-2,6-dimethylbenzene 7, undergo base-promoted homolytic aromatic substitution (BHAS) with benzene to produce 2,6-dimethylbiphenyl 8 and biphenyl 9 in an approximately 1:4 ratio as well as m-xylene 10. The biphenyl arises from a diagnostic radical transfer reaction with the solvent benzene. Using substrate 7 with a range of Pd sources as potential initiators led to formation of 8, 9, and 10 in varying amounts. However, when any one of a range of diphosphinoferrocenes (e.g., dppf or dippf) or BINAP or the monophosphine, diphenylphosphinoferrocene, was added as a ligand to Pd(OAc)2, the ratio of [2,6-dimethylbiphenyl 8: biphenyl 9] moved decisively to that expected from the BHAS (radical) pathway. Further studies were conducted with dppf. When dppf was added to each of the other Pd sources, the ratio of coupled products was also diverted to that expected for radical BHAS chemistry. Deuterium isotope studies and radical trap experiments provide strong additional support for the involvement of aryl radicals. Accordingly, under these ground-state conditions, palladium sources, in the presence of defined ligands, convert aryl iodides to aryl radicals. A rationale is proposed for these observations.

Synthesis and Characterization of New Pyrano[2,3-c]pyrazole Derivatives as 3-Hydroxyflavone Analogues.

In this paper, an efficient synthetic route from pyrazole-chalcones to novel 6-aryl-5-hydroxy-2-phenylpyrano[2,3-c]pyrazol-4(2H)-ones as 3-hydroxyflavone analogues is described. The methylation of 5-hydroxy-2,6-phenylpyrano[2,3-c]pyrazol-4(2H)-one with methyl iodide in the presence of a base yielded a compound containing a 5-methoxy group, while the analogous reaction of 5-hydroxy-2-phenyl-6-(pyridin-4-yl)pyrano[2,3-c]pyrazol-4(2H)-one led to the zwitterionic 6-(N-methylpyridinium)pyrano[2,3-c]pyrazol derivative. The treatment of 5-hydroxy-2,6-phenylpyrano[2,3-c]pyrazol-4(2H)-one with triflic anhydride afforded a 5-trifloylsubstituted compound, which was further used in carbon-carbon bond forming Pd-catalyzed coupling reactions to yield 5-(hetero)aryl- and 5-carbo-functionalized pyrano[2,3-c]pyrazoles. The excited-state intramolecular proton transfer (ESIPT) reaction of 5-hydroxypyrano[2,3-c]pyrazoles from the 5-hydroxy moiety to the carbonyl group in polar protic, polar aprotic, and nonpolar solvents was observed, resulting in well-resolved two-band fluorescence. The structures of the novel heterocyclic compounds were confirmed by 1H-, 13C-, 15N-, and 19F-NMR spectroscopy, HRMS, and single-crystal X-ray diffraction data.

Synthesis of 2-Cyanomethyl Indane Derivatives via Pd-Catalyzed Alkene Difunctionalization Reactions of Alkyl Nitriles.

The synthesis of indanes bearing substituted cyanomethyl groups at C2 is achieved through Pd-catalyzed coupling reactions between 2-allylphenyl triflate derivatives and alkyl nitriles. Related partially saturated analogues were generated from analogous transformations of alkenyl triflates. The use of a preformed BrettPhosPd(allyl)(Cl) complex as a precatalyst was essential for the success of these reactions.

Construction of Chiral Cyclobutanone-Fused 4-Aminoquinolines via Sequential Chiral Phosphoric Acid and Palladium Catalysis.

A one-pot catalytic asymmetric route to novel chiral quaternary-carbon-containing cyclobutanone-fused 4-aminoquinoline derivatives in good to high yields and enantioselectivities is described. This process consists of a chiral phosphoric acid-catalyzed desymmetric carbonyl-amine condensation of prochiral cyclobutane-1,3-diones with 2-halogenated anilines and a Pd-catalyzed coupling reaction of the chiral enaminone intermediates with isocyanides.

Pd-catalyzed cascade coupling reaction of cyclopropanols with N-allenyl-2-iodoanilines to construct 3-substituted indole derivatives

We report herein a concise and useful method for the construction of 3-substituted indole derivatives via a palladium-catalyzed ring-opening coupling reaction of cyclopropanols with N-allenyl-2-iodoanilines.

Synthesis of fused bis-indazoles/indazoles via a one-pot sequential strategy.

We report here an efficient synthesis of fused bis-indazoles/indazoles via a one-pot sequential strategy starting from o-azido aldehydes and amines. This novel method involves the sequential formation of 2H-indazole followed by a Pd-catalyzed intramolecular cross-dehydrogenative coupling reaction. Overall, this one-pot sequential reaction involved the formation of new five bonds, resulting in the formation of three heterocyclic rings.

Mono-silylated 2,1,3-benzothiadiazole-based precursors. Molecular scaffolds for obtaining fluorescent organic-inorganic hybrid materials with tailored photophysical properties

The present work describes the synthesis of three classes of mono-silylated benzothiadiazole and their application in obtaining organic-inorganic fluorescent hybrid materials. The mono-silylated compounds were obtained through a Pd-catalyzed Sonogashira coupling reaction with silicon-functionalized alkynes (25–61% yield). One of the silylated products was chosen as a model compound and six additional BTD-containing products were obtained using Suzuki-Miyaura (53–91% yield) and Sonogashira (53–89% yield) coupling reactions. All the compounds presented absorption in the UV-A region (360–390 nm) attributed to fully spin- and symmetry-allowed π-π* electronic transitions. The fluorescence emission was located in the green-blue region with moderated Stokes shift and quantum yields. The mono-silylated BTDs were precursors in the synthesis of new organic-inorganic hybrid materials via sol-gel reaction. The materials were obtained over 10 days at 60 °C with low BTD content and presented fluorescence emission in the green-blue region.

Access to Polysubstituted Halophosphorylated Dihydrofurans via Halotrimethylsilane-Promoted Cascade Cyclization of γ-Hydroxyl Ynones with Diphenylphosphine Oxides.

A halotrimethylsilane (TMSX) accelerated cascade halophosphorylation and cycloisomerization of γ-hydroxyl ynones with diphenylphosphine oxides is presented. This methodology allows the one-step synthesis of practical polysubstituted halophosphorylated dihydrofuran derivatives. It is noteworthy that halotrimethylsilane functions as a halogenation reagent as well as a promoter to initiate this transformation. In addition, the reaction system can also be scaled up to gram quantities, and the produced halogenated compounds can undergo further derivatizations by Pd-catalyzed coupling reactions.

Insights into the Active Catalyst Formation from Dinuclear Palladium Acetate in Pd-Catalyzed Coupling Reactions: A DFT Study.

We studied the steps in the formation of active palladium catalyst species from palladium acetate dimer employing density functional theory calculations. We explored the possible pathways with an automated reaction search and studied the kinetics with stochastic simulation analysis. The dimeric form of palladium acetate is considered a resting state of the catalyst. Our reaction search starting from the dimeric form by sequential ligand addition resulted in experimentally observed monomeric species. We analyzed the bonding in the palladium acetate dimer and the role of Pd in the stability of the dimeric species. We implemented the Gillespie stochastic simulation algorithm to gain more insights into multichannel reaction paths and applied it to the degradation pathways. The analysis of the thermodynamic and kinetic data for these degradation pathways suggests that the dimeric form of the catalyst can be a potential catalytic precursor in the palladium acetate-catalyzed coupling reactions under the experimental reaction conditions.

5]-Helistatins: Tubulin-Binding Helicenes with Antimitotic Activity.

Helicenes are high interest synthetic targets with unique conjugated helical structures that have found important technological applications. Despite this interest, helicenes have had limited impact in chemical biology. Herein, we disclose a first-in-class antimitotic helicene, helistatin 1 (HA-1), where the helicene scaffold acts as a structural mimic of colchicine, a known antimitotic drug. The synthesis proceeds via sequential Pd-catalyzed coupling reactions and a π-Lewis acid cycloisomerization mediated by PtCl2. HA-1 was found to block microtubule polymerization in both cell-free and live cell assays. Not only does this demonstrate the feasibility of using helicenes as bioactive scaffolds against protein targets, but also suggests wider potential for the use of helicenes as isosteres of biaryls or cis-stilbenes-themselves common drug and natural product scaffolds. Overall, this study further supports future opportunities for helicenes for a range of chemical biological applications.

Enantioselective construction of axially chiral cyclohexylidene scaffolds via Pd-catalyzed asymmetric coupling reaction

Axially chiral cyclohexylidenes exhibit unique chirality because of the restricted rotation of the C=C bond. Compared with other axially chiral compounds, they are much less explored, and their efficient construction remains a synthetic challenge. Herein, we report the first palladium-catalyzed asymmetric coupling reaction of aryl iodides with 4-substituted cyclohexanol-derived α-diazocarbonyl compounds to give tetrasubstituted cyclohexylidenes in good yields (up to 92%) with excellent enantioselectivities (up to 96% ee ) under mild conditions. This protocol provides a general access to axially chiral cyclohexylidenes. The utility of this unique scaffold was demonstrated by the carboxylic acid serving as a useful chiral ligand in transition-metal-catalyzed C–H bond activation, which showed great promise as a new type of olefin ligand. • Pd-catalyzed asymmetric cross-coupling reaction • Facile access to enantioenriched axially chiral tetrasubstituted alkenes • Broad scope, good yields, and excellent enantioselectivities • Develop skeleton applications Tetrasubstituted alkenes are important building blocks in many natural products, drugs, and functional materials. Their efficient regio- and stereoselective synthesis poses a significant challenge to synthetic organic chemists due to the crowded nature of the double bonds. The reported palladium/Xu-Phos-catalyzed asymmetric coupling reaction of this method allows the use of readily available simple aryl iodides and 4-substituted cyclohexanol-derived α-diazocarbonyl compounds under mild conditions, furnishing a variety of tetrasubstituted cyclohexylidenes in good yields with excellent enantioselectivities. The utility of this unique scaffold was demonstrated by the carboxylic acid serving as a useful chiral ligand in transition-metal-catalyzed C–H bond activation, which showed great promise as a new type of olefin ligand. The first Pd/Xu-Phos-catalyzed asymmetric coupling reaction of aryl iodides with β -hydroxy α -diazocarbonyl compounds has been established to construct axially chiral cyclohexylidene skeletons (up to 92% yield, up to 96% ee ). This protocol provides easy access to axially chiral cyclohexylidenes, one rarely explored class of the atropisomeric family. The carboxylic acid derivatives could serve as a useful chiral ligand in transition-metal-catalyzed C–H bond activation. The proposed mechanism involves palladium carbene asymmetric migration insertion, β -hydroxyl elimination, and reduction of Pd(II) to Pd(0).