Palladium-catalyzed Cross-coupling Reactions Research Articles

Pd-Catalyzed coupling of benzyl bromides with BMIDA-substituted N-tosylhydrazones: synthesis of trans-alkenyl MIDA boronates.

A palladium-catalyzed stereoselective synthesis of alkenyl boronates from N-methyliminodiacetyl boronate (BMIDA)-substituted N-tosylhydrazone and benzyl bromides is developed. A range of trans-alkenyl MIDA boronates as single stereoisomers were obtained in moderate yields with good functional group compatibility. The resultant boronate products may be transformed to other boron-containing compounds and may also be directly used in cross-coupling reactions.

Palladium-Catalyzed Asymmetric Cross-Coupling Reactions of Cyclobutanols and Unactivated Olefins.

Transition-metal-catalyzed activations of carbon-carbons bonds of small strained rings have widespread applications in synthetic and medicinal chemistry. However, coupling reactions of cyclobutanols involving β-carbon elimination to construct C(sp3)-C(sp3) bonds have scarcely been developed. Here, we demonstrate a highly enantioselective Pd-catalyzed intermolecular C(sp3)-C(sp3) coupling reaction of a broad range of cyclobutanol derivatives and unactivated alkenes, allowing convenient access to a series of chiral benzene-fused cyclic compounds in a highly regio-, chemo-, and enantioselective manner.

Convenient Synthesis of 3-Deazapurine Nucleosides (3-Deazainosine, 3-Deazaadenosine and 3-Deazaguanosine) Using Inosine as a Starting Material.

A convenient synthetic method for preparing 3-deazapurine nucleosides (3-deazainosine, 3-deazaadenosine, and 3-deazaguanosine) from inosine via a 5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide (EICAR) derivative, which is a key intermediate, is described. A large-scale synthesis of an EICAR derivative starting from inosine was achieved in six steps via dinitrophenylation at the N1 position followed by ring opening, iodination of the resulting 5-amino group, and a palladium-catalyzed cross-coupling reaction. The resulting EICAR derivative was then converted into 3-deazainosine, 3-deazaadenosine, and 3-deazaguanosine. This route enabled us to synthesize 3-deazapurine nucleosides conveniently in good yields. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Preparation of 5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide (EICAR) derivative 6 Basic Protocol 2: Preparation of 3-deazapurine nucleosides 8, 11, and 14.

Arylketones as Aryl Donors in Palladium-Catalyzed Suzuki-Miyaura Couplings.

Herein, we report the arylation, alkylation, and alkenylation of aryl ketones via a palladium-catalyzed Suzuki-Miyaura cross-coupling reaction. The use of the pyridine-oxazoline ligand is the key to the cleavage of the unstrained C-C bond. The late-stage arylation of aryl ketones derived from drugs and natural products demonstrated the synthetic utility of this protocol.

Palladium-Catalyzed Carbene Coupling Reactions of Cyclobutanone N-Sulfonylhydrazones.

Described herein are the palladium-catalyzed cross-coupling reactions of cyclobutanone-derived N-sulfonylhydrazones with aryl or benzyl halides, suggesting that the metal carbene process and β-hydride elimination can smoothly occur in strained ring systems. Structurally diversified products including cyclobutenes, methylenecyclobutanes, and conjugated dienes are selectively afforded in good to excellent yields. Preliminary success in asymmetric carbene coupling reactions in strained ring systems has been achieved, providing a promising route for the synthesis of enantioenriched four-membered-ring molecules.

Vinyl Thianthrenium Tetrafluoroborate: A Practical and Versatile Vinylating Reagent Made from Ethylene.

The use of vinyl electrophiles in synthesis has been hampered by the lack of access to a suitable reagent that is practical and of appropriate reactivity. In this work we introduce a vinyl thianthrenium salt as an effective vinylating reagent. The bench-stable, crystalline reagent can be readily prepared from ethylene gas at atmospheric pressure in one step and is broadly useful in the annulation chemistry of (hetero)cycles, N-vinylation of heterocyclic compounds, and palladium-catalyzed cross-coupling reactions. The structural features of the thianthrene core enable a distinct synthesis and reactivity profile, unprecedented for other vinyl sulfonium derivatives.

Mechanistic Aspects of the Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling Reaction.

The story of C−C bond formation includes several reactions, and surely Suzuki‐Miyaura is among the most outstanding ones. Herein, a brief historical overview of insights regarding the reaction mechanism is provided. In particular, the formation of the catalytically active species is probably the main concern, thus the preactivation is in competition with, or even assumes the role of the rate determining step (rds) of the overall reaction. Computational chemistry is key in identifying the rds and thus leading to milder conditions on an experimental level by means of predictive catalysis.

Experimental and theoretical investigation of synthesized pregnenolone derivatives via palladium catalyzed cross coupling reactions, their anticancer activity against lung cancer cells

In the current research work synthesis of novel steroids, PGLCROBB, PGLCROMBT, and PGLCROB are being reported employing palladium catalyzed Mizoroki-Heck reaction. Structure elucidation of all the synthesized compounds was done by 1H NMR, 13C NMR, IR, and mass spectrometry. These prodrugs PGL, PGLCRO, PGLCROBB, PGLCROMBT, and PGLCROB were tested on human lung cancer cell line (A549). The results were very promising as PGLCROB has shown significant anticancer activity against lung cancer cells. In order to look into the structural stability and electronic feature analyses, quantum chemical calculations have been performed using the DFT approach. To spot, describe, and estimate competently the weak C-H⋯O H-bonding and H⋯H (conventional) as well as C⋯H (unconventional) non-covalent interactions (NCIs) involved therein, the Bader's QTAIM and NCI-plot have also been executed. The H⋯H bond paths range from 2.021 Å to 2.039 Å however the C⋯H bond paths fall between 2.806 Å and 2.871 Å and such type of interactions demonstrate all the characteristics of a closed-shell interaction. The analyzed chemical reactivity mainly emphasized for PGLCRO, PGLCROB, PGLCROBB and PGLCROMBT systems shows that the PGLCROB (with a very marginal difference with the PGLCROBB) is chemically more reactive (highly sensitive) species among all steroids. This work represents another instance of the utilization and successful application of the concept of bond path and the QTAIM.

Highly Efficient Synthesis of 2-Substituted Benzo[b]furan Derivatives from the Cross-Coupling Reactions of 2-Halobenzo[b]furans with Organoalane Reagents

AbstractA highly efficient and simple route for the synthesis of 2-substituted benzo[b]furans has been developed by palladium-catalyzed cross-coupling reaction of 2-halobenzo[b]furans with aryl, alkynyl, and alkylaluminum reagents. Various 2-aryl-, 2-alkynyl-, and 2-alkyl-substituted benzo[b]furan derivatives can be obtained in 23–97% isolated yields using 2–3 mol% PdCl2/4–6 mol% XantPhos as the catalyst under mild reaction conditions. The aryls bearing electron-donating or electron-withdrawing groups in 2-halobenzo[b]furans gave products in 40–97% isolated yields. In addition, aluminum reagents containing thienyl, furanyl, trimethylsilanyl, and benzyl groups worked efficiently with 2-halobenzo[b]furans as well, and three bioactive molecules with 2-substituted benzo[b]furan skeleton were synthesized. Furthermore, the broad substrates scope and the typical maintenance of vigorous efficiency on gram scale make this protocol a potentially practical method to synthesize 2-substituted benzo[b]furan derivatives. On the basis of the experimental results, a possible catalytic cycle has been proposed.

Synthesis of new adamantyl-imine palladium(II) complexes and their application in Mizoroki-Heck and Suzuki-Miyaura C[sbnd]C cross-coupling reactions

Improving carbon–carbon cross-coupling reactions is an ongoing process and finding the most versatile and stable catalyst precursors has been of great interest. Ligand design has been proven to be important since it is responsible for providing electron density and steric saturation around the metal centre, thus contributing towards the stereo-electronic properties. The adamantyl moiety has been used to generate highly bulky and electron-rich ligands for application in palladium-catalysed cross-coupling reactions. Accordingly, we have prepared some Schiff-base adamantyl ligands (L1-L3) and complexed them with [PdCl2(MeCN)2] to afford the (pre)catalysts C1-C3, which were successfully applied in Mizoroki-Heck and Suzuki-Miyaura carbon–carbon cross-coupling reactions. The cross-coupling reaction products were obtained in good yields using 0.5 mol % Pd catalyst loading. C2 and C3 showed remarkable activity in the Mizoroki-Heck coupling reactions involving substrates with substituents on the olefin and aryl halide (including 4-Cl, 4-CH3, -CO2Me and -CO2Et). We also, observed that the Suzuki-Miyaura cross-coupling system was active towards challenging activated and deactivated aryl chlorides, with to up 70% conversions recorded. The mercury poisoning tests conducted revealed that the catalysts act as homogenous molecular active species in the Mizoroki-Heck reactions and act as both homogenous and heterogeneous catalysts in the Suzuki-Miyaura cross-coupling reactions.

Platform for High-Spin Molecules: A Verdazyl-Nitronyl Nitroxide Triradical with Quartet Ground State

Thermally resistant air-stable organic triradicals with a quartet ground state and a large energy gap between spin states are still unique compounds. In this work, we succeeded to design and prepare the first highly stable triradical, consisting of oxoverdazyl and nitronyl nitroxide radical fragments, with a quartet ground state. The triradical and its diradical precursor were synthesized via a palladium-catalyzed cross-coupling reaction of diiodoverdazyl with nitronyl nitroxide-2-ide gold(I) complex. Both paramagnetic compounds were fully characterized by single-crystal X-ray diffraction analysis, superconducting quantum interference device magnetometry, EPR spectroscopy in various matrices, and cyclic voltammetry. In the diradical, the verdazyl and nitronyl nitroxide centers demonstrated full reversibility of redox process, while for the triradical, the electrochemical reduction and oxidation proceed at practically the same redox potentials, but become quasi-reversible. A series of high-level CASSCF/NEVPT2 calculations was performed to predict inter- and intramolecular exchange interactions in crystals of di- and triradicals and to establish their magnetic motifs. Based on the predicted magnetic motifs, the temperature dependences of the magnetic susceptibility were analyzed, and the singlet-triplet (135 ± 10 cm-1) and doublet-quartet (17 ± 2 and 152 ± 19 cm-1) splitting was found to be moderate. Unique high stability of synthesized verdazyl-nitronylnitroxide triradical opens new perspectives for further functionalization and design of high-spin systems with four or more spins.

NSSN-Type Group 4 Metal Complexes in the Ring-Opening Polymerization of l-Lactide.

A new class of zirconium and hafnium complexes coordinated by linear dianonic tetradentate NSSN ligands is reported. The ligands feature two amide functions coupled with two thioether groups linked by a central flexible ethane bridge and two lateral rigid phenylene bridges and differ for the substituents on the aniline nitrogen atoms, i.e., isopropyl, cyclohexyl, or mesityl substituents: NSSN-iPr, NSSN-Cy, or NSSN-Mes. They were prepared by reacting 2-aminothiophenol with dibromoethane to afford the NSSN ligands without substituents on the aniline nitrogen atoms, which were subsequently alkylated through a reductive amination of acetone or cyclohexanone or palladium-catalyzed cross-coupling reaction with mesityl bromide. The corresponding zirconium and hafnium complexes 1-5 were obtained through a transamination reaction between the neutral ligands and Zr(NMe2)4 or Hf(NMe2)4 [(NSSN-iPr)Zr(NMe2)2 (1), (NSSN-Cy)Zr(NMe2)2 (2), (NSSN-Mes)Zr(NMe2)2 (3), (NSSN-iPr)Hf(NMe2)2 (4), and (NSSN-Cy)Hf(NMe2)2 (5)]. They were characterized in solution by NMR spectroscopy and in solid state by X-ray diffraction analysis (except for 3). All complexes present an octahedral coordination geometry with a fac-fac ligand wrapping and a cis relationship between the other two monodentate ligands. The catalytic performances of 1-5 in the ring-opening polymerization of cyclic esters were investigated. Complex 1 was the most active: its polymerization activity was superior to those generally displayed by zirconium complexes featuring OSSO ligands and compared well with those of the most active group 4 complexes operating in a toluene solution.

Multicomponent Synthesis of Unsymmetrical 4,5-Disubstituted Imidazolium Salts as N-Heterocyclic Carbene Precursors: Applications in Palladium-Catalyzed Cross-Coupling Reactions.

Various novel (a)chiral 4,5-disubstituted 1-aryl-3-alkyl-imidazolium salts were synthesized via the multicomponent reaction of diketone derivatives, sterically congested arylamines, and alkylamines. Moreover, two novel unsymmetrical bulky cycloalkyl-based NHC-Pd complexes proved highly active as catalysts for Suzuki-Miyaura and Negishi cross-coupling reactions.

Site-Selective Late-Stage C–H Functionalization via Thianthrenium Salts

AbstractThe high abundance of C–H bonds in organic molecules makes C–H functionalization a powerful approach to quickly increase the complexity of an organic molecule. However, the high abundance of C–H bonds also provides a challenge to C–H functionalization reactions: selectivity. While most C–H functionalization reactions produce mixtures of different products for most substrates, we have developed a highly selective method for aromatic C–H functionalization via sulfonium salts. The reaction does not require a certain directing group to be selective. The introduced functional group is a sulfonium group, which participates in various follow-up reactions such as palladium-catalyzed cross-coupling reactions and photoredox catalysis. Here we discuss our pathway to develop the reaction as well as its scope and utility.1 Introduction2 Site-Selective Synthesis of Sulfonium Salts3 Sulfonium Salts in Palladium-Catalyzed Cross-Coupling4 Sulfonium Salts in Photoredox Catalysis5 Sulfur(IV) Reductive Elimination6 Cine Substitution7 Conclusion

Regioirregular and catalytic Mizoroki–Heck reactions

The palladium-catalysed cross-coupling reaction between alkenes and aryl halides (the Mizoroki–Heck reaction) is a powerful methodology to construct new carbon–carbon bonds. However, the success of this reaction is in part hampered by an extremely marked regioselectivity on the double bond, which dictates that electron-poor alkenes react exclusively on the β-carbon. Here, we show that ligand-free, few-atom palladium clusters in solution catalyse the α-selective intramolecular Mizoroki–Heck coupling of iodoaryl cinnamates, and mechanistic studies support the formation of a sterically encumbered cinnamate–palladium cluster intermediate. Following this rationale, the α-selective intermolecular coupling of aryl iodides with styrenes is also achieved with palladium clusters encapsulated within fine-tuned and sterically restricted zeolite cavities to produce 1,1-bisarylethylenes, which are further engaged with aryl halides by a metal-free photoredox-catalysed coupling. These ligand-free methodologies significantly expand the chemical space of the Mizoroki–Heck coupling. The standard Mizoroki–Heck reaction of aryl halides usually makes electron-poor alkenes react exclusively on the β-carbon. Now, α-selective intramolecular and intermolecular versions of this reaction with electron-deficient alkenes are reported, giving access to otherwise difficult-to-synthesize products.

Chemical Biology Studies Using Vitamin A Analogs

"Retinoid" is the general term for vitamin A derivatives and chemical compounds that act like vitamin A. Vitamin A are composed of four isoprene units and are named according to their terminal functional group, such as retinol (OH, 1), retinal (CHO, 2), and retinoic acid (CO2H, 3). Vitamin A usually refers to retinol. In the past few decades, major advances in research on vitamin A have improved our understanding of its fundamental roles and physiological significance in living cells. In this review, three types of chemical biology studies using vitamin A analogs are described: (1) conformational studies of the chromophore in retinal proteins (rhodopsin, phoborhodopsin, and retinochrome), especially the conformation around the cyclohexene ring; (2) structure-activity relationship studies of retinoic acid analogs to create new signaling molecules for activating nuclear receptors; and (3) development of a new channelrhodopsin with an absorption maximum at longer wavelength to overcome the various demerits of channelrhodopsins used in optogenetics, as well as the stereoselective synthesis of retinoid isomers and their analogs using a diene-tricarbonyliron complex or a palladium-catalyzed cross-coupling reaction between vinyl triflates and stannyl olefins.

Unusual Zig-Zag Effect in the Electrochemical Oxidation of Phenyl End-Capped α-Oligothiophenes

A series of phenyl end-capped α-oligothiophenes containing four to seven thiophene subunits (4T–7T) was synthesized utilizing palladium-catalyzed cross-coupling reactions. UV/Vis spectroscopic analysis revealed one broad absorption band that shifts bathochromically with increasing number of thiophene units. Structured emission spectra are observed with Stokes shift ν~4000 cm−1 and quantum yields of up to 53%. End-capping of the oligothiophene molecules by phenyl units does not only extend the effective conjugation but also prevents from α–α-homocoupling upon electrochemical oxidation. Accordingly, reversible redox waves are observed in cyclic voltammetry with up to four reversible one-electron processes for the two longer congeners. Analyses of the first two oxidation processes in the framework of multiredox systems provide insight into the stabilization or destabilization of polaronic and bipolaronic states. An unusual zig-zag trend for the first (and to a lesser extend second) oxidation process could be explained by the sterical encumbrance of solubilizing hexyl chains in 5T and 7T molecules which counteract the formation of a fully planar quinoidal oligothiophene backbone.

Synthesis of Unsymmetrically Substituted Tetraphenylenes through Palladium-Catalyzed C(sp2)–H Activation

AbstractAn efficient protocol for the palladium-catalyzed cross-coupling reaction of 2-iodobiphenyls with biphenylene has been developed through C–H activation. The reaction provides a simple and efficient method for the synthesis of unsymmetrically substituted tetra­phenylenes.

High-Throughput Peptide Derivatization toward Supramolecular Diversification in Microtiter Plates.

The evolution of life on earth eventually leads to the emergence of species with increased complexity and diversity. Similarly, evolutionary chemical space exploration in the laboratory is a key step to pursue the structural and functional diversity of supramolecular systems. Here, we present a powerful tool that enables rapid peptide diversification and employ it to expand the chemical space for supramolecular functions. Central to this strategy is the exploitation of palladium-catalyzed Suzuki–Miyaura cross-coupling reactions to direct combinatorial synthesis of peptide arrays in microtiter plates under an open atmosphere. Taking advantage of this in situ library design, our results unambiguously deliver a fertile platform for creating a set of intriguing peptide functions including green fluorescent protein-like peptide emitters with chemically encoded emission colors, hierarchical self-assembly into nano-objects, and macroscopic hydrogels. This work also offers opportunities for quickly surveying the diversified peptide arrays and thereby identifying the structural factors that modulate peptide properties.

Unexpected Substituent Effects in Aryl-Aryl Negishi Cross-Coupling Reactions Rationalized by Density Functional Theory and Natural Charges

While numerous studies consider substitution effects at the aromatic system in the arylzinc reactant during the transmetalation step in palladium-catalyzed Negishi cross-coupling reactions, the effects caused by varying substituents at the arylpalladium complex have not been the center of attention so far. Herein, we present results from competition experiments providing the counterintuitive observation that electron-withdrawing (donating) groups in the para position to the palladium center inhibit (accelerate) the transmetalation step in aryl-aryl Negishi cross-coupling reactions. Quantum-chemical calculations based on density functional theory provide mechanistic insights and show that an associative transmetalation mechanism is favored over a dissociative one. Foster–Boys localized orbitals and Mayer bond orders aid in rationalizing molecular and electronic structural features. Natural population analysis reveals that charge accumulation at the palladium center causes a destabilization of the transition state, which clearly correlates with the electronic properties of the substituents represented by their Hammett parameters.