Palladium-catalyzed Cross-coupling Reactions Research Articles

Synthesis of Cy5-Labelled C5-Alkynyl-modified cytidine triphosphates via Sonogashira coupling for DNA labelling

New applications of palladium-catalyzed Sonogashira-type cross-coupling reaction between C5-halogenated 2′-deoxycytidine-5′-monophosphate and novel cyanine dyes with a terminal alkyne group have been developed. The present methodology allows to synthesize of fluorescently labeled C5-nucleoside triphosphates with different acetylene linkers between the fluorophore and pyrimidine base in good to excellent yields under mild reaction conditions. Modified 2′-deoxycytidine-5′-triphosphates were shown to be good substrates for DNA polymerases and were incorporated into the DNA by polymerase chain reaction.

Cross-Coupling of Cyclobutenone N-Tosylhydrazones with Organohalides: Access to Conjugated Enynes and Enallenes via a Strained Allylpalladium Intermediate

A palladium-catalyzed cross-coupling reaction of cyclobutenone N-tosylhadrazones with organohalides is disclosed. The protocol involves the generation of a strained allylpalladium intermediate from readily available starting materials through palladium carbene migratory insertion, which undergoes electrocyclic ring opening and β-hydride elimination for the production of conjugated enynes and enallenes. The broad substrate scope, good to excellent yields, and tunable product diversity make the protocol potentially useful in organic synthesis.

Shining Visible Light on Reductive Elimination: Acridine-Pd-Catalyzed Cross-Coupling of Aryl Halides with Carboxylic Acids.

Despite the recent tremendous progress on transition-metal/photoredox dual catalysis in organic synthesis, single transition-metal catalysis under visible-light irradiation, which can utilize light energy more efficiently, is still underdeveloped. Herein, we report the design of photosensitizing phosphinoacridine bidentate ligands for visible-light-induced transition-metal catalysis, expecting that the electron-accepting acridine moiety would create a highly reactive electron-deficient metal center toward reductive elimination via metal-to-ligand charge transfer (MLCT). Using these ligands, we have achieved a palladium-catalyzed cross-coupling reaction of aryl halides with carboxylic acids under visible-light irradiation. Electronic tuning of the phosphinoacridine ligands not only enabled the use of a variety of aryl halides as the coupling partner, including less reactive aryl chlorides, under blue light irradiation, but also realized the employment of lower-energy green and red light for the cross-coupling. Experimental mechanistic studies have proved that the reductive elimination of aryl esters is induced by photoirradiation of phosphinoacridine-ligated arylpalladium(II) carboxylate complexes. The theoretical calculation suggests that the reductive elimination in the excited state is promoted by decreasing the electron density of the Pd center through photoinduced intramolecular electron transfer, i.e., MLCT, in the transition state owing to the electron-deficient acridine scaffold. This is a very rare example of photoinduced reductive elimination on palladium(II) complexes.

Porphycenes as broad-spectrum antimicrobial photosensitizers. Potentiation with potassium iodide

Two novel meso-tetrasubstituted porphycenes (Pc-Cbz and Pc-NEt2) have been synthesized by palladium-catalyzed Suzuki cross-coupling reactions over 9,10,19,20-tetrakis(4-iodophenyl)porphycene. Pc-Cbz contains four carbazole groups on the periphery of the tetrapyrrolic macrocycle. Instead, Pc-NEt2 presents four basic tertiary amine substituents, which can be protonated at physiological pH, acquiring four positive charges. Both photosensitizers (PSs) were designed to evaluate the effect of different substitution patterns on the photodynamic inactivation of microorganisms. Their absorption and fluorescence properties were almost unmodified regardless of the substituent groups on the periphery. The characteristic red emission makes them promising fluorescent probes for cell imaging. Moreover, both macrocycles were able to generate reactive oxygen species by both photodynamic mechanisms under aerobic light irradiation. The photokilling action of these PSs was assessed in vitro against Candida albicans (yeast), Staphylococcus aureus (Gram-positive bacterium), and Escherichia coli (Gram-negative bacterium). Our results demonstrate that the peripheral substitution significantly affected the photoinactivation performance. Thus, Pc-NEt2 was more effective than Pc-Cbz in killing microorganisms using lower concentrations and shorter irradiation periods, evidencing that external substitution is a main structural feature. Also, the photoinactivation efficiency mediated by these porphycenes was potentiated by adding KI. Under these conditions, a complete eradication of all pathogenic microorganisms was obtained by combining Pc-NEt2 and KI. Therefore, Pc-NEt2 can be used as an effective broad-spectrum antimicrobial PS. Accordingly, this work stands out as a promising starting point for the design of new porphycene-based PSs for photodynamic inactivation (PDI) of microorganisms. Our outcomes also disclose that the combination of these PSs with KI is an important factor in order to improve the PDI treatments and the current antimicrobial therapies.

Metal-Catalyzed and Metal-Free Nucleophilic Substitution of 7-I-B18H21.

In this work, two pathways of reactivity are investigated to generate site-specific substitutions at the B7 vertex of the luminescent boron cluster, anti-B18H22. First, a palladium-catalyzed cross-coupling reaction utilizing the precursor 7-I-B18H21 and a series of model nucleophiles was developed, ultimately producing several B-N- and B-O-substituted species. Interestingly, the B-I bond in this cluster can also be substituted in an uncatalyzed fashion, leading to the formation of various B-N, B-O, and B-S products. This work highlights intricate differences corresponding to these two reaction pathways and analyzes the role of solvents and additives on product distributions. As a result of our synthetic studies, seven new B18-based clusters were synthesized, isolated, and characterized by mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. The photoluminescence properties of two structurally similar ether and thioether products were further investigated, with both exhibiting blue fluorescence in solution at 298 K and long-lived green or yellow phosphorescence at 77 K. Overall, this work shows, for the first time, the ability to perform substitution of a boron-halogen bond with nucleophiles in a B18-based cluster, resulting in the formation of photoluminescent molecules.

Covalent Modification of Nucleobases using Water-Soluble Palladium Catalysts.

Nucleosides represent one of the key building blocks of biochemistry. There is significant interest in the synthesis of nucleoside-derived materials for applications as probes, biochemical models, and pharmaceuticals. Palladium-catalyzed cross-coupling reactions are effective methods for making covalent modification of carbon and nitrogen sites on nucleobases under mild conditions. Water-soluble catalysts derived from palladium and hydrophilic ligands, such as tris(3-sulfonatophenyl)phosphine trisodium (TPPTS), are efficient catalysts for a range of coupling reactions of unprotected halonucleosides. Over the past two decades, these methods have been extended to direct functionalization of halonucleotides, as well as RNA and DNA oligonucleotides (ONs) containing halogenated bases. These methods can be run under biocompatible conditions, including examples of Suzuki coupling of modified DNA in whole cells and tissue samples. In this account, development of this methodology by our group and others is highlighted along with the extension of these catalyst systems to modification of nucleotides and ONs.

Palladium-Catalyzed Cross-Coupling Reactions of Borylated Alkenes for the Stereoselective Synthesis of Tetrasubstituted Double Bond

The stereoselective formation of tetrasubstituted alkenes remains one of the key goals of modern organic synthesis. In addition to other methods, the stereoselective synthesis of tetrasubstituted alkenes can be achieved by means of cross-coupling reactions of electrophilic and nucleophilic alkene templates. The use of electrophilic templates for the stereoselective synthesis of tetrasubstituted alkenes has previously been described. Therefore, the present review summarizes the procedures available for the stereoselective preparation of tetrasubstituted alkenes using stable and isolable nucleophilic templates.

Synthesis and structural analysis of push-pull imidazole-triazole based fluorescent bifunctional chemosensor for Cu2+ and Fe2+ detection

Fluorescent imidazole-triazole based ligands L1 and L2 have been designed as chemical push-pull chemosensors for divalent metal ions and synthesized through palladium-catalyzed cross-coupling reactions using indium organometallics and click chemistry. The novel ligands exhibit intense absorption in the ultraviolet region with high molar extinction coefficients, and strong fluorescence emission with large Stokes displacements. On the basis of UV–Vis absorption spectroscopy and fluorescence emission data in acetonitrile, L1 is shown as a bifuncional chemosensor with differential response for Fe2+ and Cu2+ over a range of selected 3d divalent and other metal ions. The binding site of the ligand was established by single-crystal X-ray diffraction and 1H NMR spectroscopy studies. The association constants, determined by spectrofluorimetric titrations, show a steady binding affinity of L1 for Cu2+ and Fe2+ in comparison with other previously reported fluorescent bidentate chemosensors, offering the lowest limit of detection (LOD) with Cu2+. DFT calculations provide a rationale properly understanding and interpreting the experimentally observed results. Indeed, a mechanism of the different optical responses of L1 towards 3d divalent metal ions is proposed.

Pd-Catalyzed Cross-Couplings: On the Importance of the Catalyst Quantity Descriptors, mol % and ppm.

This Review examines parts per million (ppm) palladium concentrations in catalytic cross-coupling reactions and their relationship with mole percentage (mol %). Most studies in catalytic cross-coupling chemistry have historically focused on the concentration ratio between (pre)catalyst and the limiting reagent (substrate), expressed as mol %. Several recent papers have outlined the use of “ppm level” palladium as an alternative means of describing catalytic cross-coupling reaction systems. This led us to delve deeper into the literature to assess whether “ppm level” palladium is a practically useful descriptor of catalyst quantities in palladium-catalyzed cross-coupling reactions. Indeed, we conjectured that many reactions could, unknowingly, have employed low “ppm levels” of palladium (pre)catalyst, and generally, what would the spread of ppm palladium look like across a selection of studies reported across the vast array of the cross-coupling chemistry literature. In a few selected examples, we have examined other metal catalyst systems for comparison with palladium.

Palladium-Catalyzed Organic Reactions Involving Hypervalent Iodine Reagents.

The chemistry of polyvalent iodine compounds has piqued the interest of researchers due to their role as important and flexible reagents in synthetic organic chemistry, resulting in a broad variety of useful organic molecules. These chemicals have potential uses in various functionalization procedures due to their non-toxic and environmentally friendly properties. As they are also strong electrophiles and potent oxidizing agents, the use of hypervalent iodine reagents in palladium-catalyzed transformations has received a lot of attention in recent years. Extensive research has been conducted on the subject of C—H bond functionalization by Pd catalysis with hypervalent iodine reagents as oxidants. Furthermore, the iodine(III) reagent is now often used as an arylating agent in Pd-catalyzed C—H arylation or Heck-type cross-coupling processes. In this article, the recent advances in palladium-catalyzed oxidative cross-coupling reactions employing hypervalent iodine reagents are reviewed in detail.

Palladium-Catalyzed Cross-Coupling Reaction of Diarylmethanol Derivatives with Diborylmethane.

A palladium-catalyzed cross-coupling reaction of diarylmethanol derivatives with diborylmethane has been developed. The reaction proceeds chemoselectively to deliver the corresponding homobenzylic boronates in good yields.

Palladium-Catalyzed One-Step Synthesis of Stereodefined Difunctionalized Glycals

Palladium-Catalyzed One-Step Synthesis of Stereodefined Difunctionalized Glycals

Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling of Oxygen-Substituted Allylboronates with Aryl/Vinyl (Pseudo)Halides.

An efficient palladium-catalyzed Suzuki-Miyaura cross-coupling reaction of oxygen atom-substituted allylboronates with aryl/vinyl bromides, iodides, and triflates has been developed. The present coupling reactions proceeded smoothly to provide a variety of allylic siloxanes with high efficiency and excellent regioselectivity. This protocol features broad substrate scope, excellent functional group tolerance, and easy gram-scale preparation, and offers an alternative approach for the synthesis of allylic alcohols and their derivatives.

Synthesis of Pyrethroids and Jasmonoids through Palladium-Catalyzed Cross-Coupling Reactions

AbstractThe synthesis of jasmone and related jasmonoids and pyrethroids is described. These compounds play a defensive role in plants and share a common cyclopentenone core with variations in the side chains. Jasmone, cinerone, allylrethrone, and derivatives were synthesized through π-allyl palladium cross-coupling of stannane derivatives. With selective hydrogenation, dihydrojasmone, and dihydrocinerone were also synthesized.

Dearomative Synthesis of Chiral Dienes Enables Improved Late-Stage Ligand Diversification.

An efficient synthesis of chiral nonracemic diene ligands is facilitated by an enantioselective dearomative intermolecular arene cyclopropanation of anisole. The functionality of the resulting cycloheptatriene engenders distinct chemical environments in a downstream tricyclic bis(enol) triflate that permits selective late-stage functionalization. The synthesis of diverse C1- and pseudo-C2-symmetric dienes is therefore viable by iterative palladium-catalyzed cross-coupling reactions. The ligands provide moderate to high selectivities in known Rh(I)-mediated asymmetric transformations.

Photoassisted Cross-Coupling Reaction of α-Chlorocarbonyl Compounds with Arylboronic Acids.

A Suzuki-Miyaura cross-coupling reaction of α-chloroacetates or α-chloroacetamides with arylboronic acids is made possible by visible-light irradiation. This reaction provides a useful method for the synthesis of α-arylacetates and α-arylacetamides from chlorides under mild reaction conditions. An indole-3-acetic acid derivative that is the key intermediate of the plant hormone auxin can be synthesized from 1-Boc-indole in two steps by combining an iridium-catalyzed C-H borylation and a palladium-catalyzed cross-coupling reaction.

Synthesis and photophysical properties of quinoxaline-based blue aggregation-induced emission molecules

A series of quinoxaline-based compounds 1–4 have been synthesized by a palladium-catalyzed cross-coupling reaction and their photophysical properties have been extensively studied. Compounds 1–4 show deep blue light emission both in solution (λem ≤ 425 nm, Commission Internationale de L’Eclairage y (CIEy) ≤ 0.03) and in the solid state. Moreover, compounds 1–3 show a non-typical aggregation-induced enhanced emission (AIEE), which would be effective deep blue light-emitting materials. The DFT calculation indicated that the HOMO energy levels of compounds 1–3 are distributed throughout the molecule, and the LUMO energy levels are mainly concentrated on the quinoxaline group. However, the HOMO of compound 4 is mainly on the benzene ring at 2,3 position, and the LUMO is distributed both of the quinoxaline and the benzaldehyde group at the 6,7 position.

Coumarin Derivatives Exert Anti-Lung Cancer Activity by Inhibition of Epithelial-Mesenchymal Transition and Migration in A549 Cells.

A series of coumarin derivatives and isosteres were synthesized from the reaction of triflic intermediates with phenylboronic acids, terminal alkynes, and organozinc compounds through palladium-catalyzed cross-coupling reactions. The in vitro cytotoxic effect of the compounds was evaluated against two non-small cell lung carcinoma (NSCLC) cell lines (A-549 and H2170) and a normal cell line (NIH-3T3) using cisplatin as a reference drug. Additionally, the effects of the most promising coumarin derivative (9f) in reversing the epithelial-to-mesenchymal transition (EMT) in IL-1β-stimulated A549 cells and in inhibiting the EMT-associated migratory ability in A549 cells were also evaluated. 9f had the greatest cytotoxic effect (CC50 = 7.1 ± 0.8 and 3.3 ± 0.5 μM, respectively against A549 and H2170 cells) and CC50 value of 25.8 µM for NIH-3T3 cells. 9f inhibited the IL-1β-induced EMT in epithelial cells by inhibiting the F-actin reorganization, attenuating changes in the actin cytoskeleton reorganization, and downregulating vimentin in A549 cells stimulated by IL-1β. Treatment of A549 cells with 9f at 7 µM for 24 h significantly reduced the migration of IL-1β-stimulated cells, which is a phenomenon confirmed by qualitative assessment of the wound closure. Taken together, our findings suggest that coumarin derivatives, especially compound 9f, may become a promising candidate for lung cancer therapy, especially in lung cancer promoted by NSCLC cell lines.

Pd-catalyzed C-C and C-N cross-coupling reactions in 2-aminothieno[3,2-d]pyrimidin-4(3H)-one series for antiplasmodial pharmacomodulation.

In 2015, we identified gamhepathiopine (M1), a 2-tert-butylaminothieno[3,2-d]pyrimidin-4(3H)-one antiplasmodial hit targeting all development stages of the human malarial parasite P. falciparum. However, this hit compound suffers from sensitivity to hepatic oxidative metabolism. Herein, we describe the synthesis of 33 new compounds in the 2-aminothieno[3,2-d]pyrimidin-4(3H)-one series modulated at position 6 of this scaffold. The modulations were performed using three palladium-catalyzed cross coupling reactions, namely Suzuki–Miyaura, Sonogashira, and Buchwald–Hartwig. For the latter, we developed the reaction conditions. Then, we evaluated the synthesized compounds for their antiplasmodial activity on the K1P. falciparum strain and their cytotoxicity on the human HepG2 cell line. Although we did not obtain a compound better than M1 in terms of the antiplasmodial activity, we identified compound 1g bearing a piperidine at position 6 of the thieno[3,2-d]pyrimidin-4(3H)-one ring with an improved cytotoxicity and metabolic stability. 1g is an interesting new starting point for further pharmacomodulation studies. This study also provides valuable antiplasmodial SAR data regarding the nature of the ring at position 6, the possible substituent on this ring, and the introduction of a spacer between this ring and the thienopyrimidinone moiety.

Transition metal complexes with functionalized indenyl phosphine ligands: structures and catalytic properties

Transition-metal indenyl complexes usually exhibit different reactivities compared with their cyclopentadienyl analogues. Up to now, at least 10 metal-indenyl bonding modes have been reported. Because of the "indenyl effect", transition-metal indenyl complexes usually show enhanced reactivity in substitution and related reactions. This review provides an overview on the use and impact of indenyl phosphines in organometallic chemistry and transition-metal-catalysed reactions in the recent two decades. Some cationic and zwitterionic metal complexes supported by P,N-substituted indene or indenide ligands are described. They have been reported to induce the cleavage of E-H (E = H, Si and B) bonds and can be used as catalysts for addition of E-H bonds to unsaturated substrates. 2-Aryl indenyl phosphine ligands L3-L11 have been proven to be a class of versatile ligands for palladium-catalysed C-C and C-N cross-coupling reactions. Moreover, optically active tethered indenyl phosphine ligands can have better stereoselective control over the chirality arising at the metal center in the oxidative addition of their rhodium complexes with alkyl halides.