Pyridone Ligand Research Articles

Palladium-catalysed methylene C(sp3)–H lactamization and cycloamination enabled by chlorinated pyridine–pyridone ligands

Palladium-catalysed methylene C(sp3)–H lactamization and cycloamination enabled by chlorinated pyridine–pyridone ligands

Palladium-Catalyzed β-C(sp3)-H Bond Arylation of Tertiary Aldehydes Facilitated by 2-Pyridone Ligands.

2-Pyridone ligand-facilitated palladium-catalyzed direct C-H bond functionalization via the transient directing group strategy has become an attractive topic. Here, we report a Pd-catalyzed direct β-C(sp3)-H arylation reaction of tertiary aliphatic aldehydes by using an α-amino acid as a transient directing group in combination with a 2-pyridone ligand.

Palladium-catalyzed disilylation of ortho-halophenylethylenes enabled by 2-pyridone ligand.

A palladium-catalyzed disilylation reaction applicable for a variety of non-, α-, or β-substituted and α,β-disubstituted ortho-halophenylethylenes has been developed. This reaction proceeds with high yields and very low catalyst loadings. The two C-Si bonds of the disilylated products could be well-differentiated chemoselectively in the reaction with various electrophiles.

Native Amide-Directed C(sp3 )-H Amidation Enabled by Electron-Deficient RhIII Catalyst and Electron-Deficient 2-Pyridone Ligand.

Trivalent group-9 metal catalysts with a cyclopentadienyl-type ligand (CpMIII ; M=Co, Rh, Ir, Cp=cyclopentadienyl) have been widely used for directed C-H functionalizations, albeit that their application to challenging C(sp3 )-H functionalizations suffers from the limitations of the available directing groups. In this report, we describe directed C(sp3 )-H amidation reactions of simple amide substrates with a variety of substituents. The combination of an electron-deficient CpE Rh catalyst (CpE =1,3-bis(ethoxycarbonyl)-substituted Cp) and an electron-deficient 2-pyridone ligand is essential for high reactivity.

Synthesis, Structure, and Hydroboration Reactivity of Anionic Nickel(0) Complexes Supported by Bidentate NHC-Pyridone Ligands

A family of anionic, formally nickel(0) complexes supported by bidentate NHC–pyridone ligands is described. The unsymmetric chelating environment and capping [K(18-crown-6)]+ countercation allow isolation of single-component, monometallic complexes in high yield. The steric and electronic properties are assessed through a battery of experimental (NMR, IR, UV–vis, X-ray diffraction) and computational tools. Catalytic activity for highly branched-selective hydroboration of styrene with HBpin is demonstrated. Control experiments implicate an important role of the pyridone in establishing reactivity and regioselectivity, suggesting the potential to leverage secondary coordination sphere effects with these single-component precatalysts for reagent activation and delivery.

Roles of Ligand and Oxidant in Pd(II)-Catalyzed and Ligand-Enabled C(sp3)–H Lactonization in Aliphatic Carboxylic Acid: Mechanistic Studies

The mechanism of Pd(II)-catalyzed, mono-N-protected amino acid (MPAA) ligand and TBHP oxidant-mediated lactonization of β-C(sp3)–H bond in aliphatic carboxylic acid has been studied. We have shown that the combination of TBHP oxidant and MPAA ligand is very critical: the reaction proceeds via MPAA ligand-mediated Pd(II)/Pd(IV) oxidation by TBHP, followed by C–O reductive elimination from the Pd(IV) intermediate. While Pd(II)/Pd(IV) oxidation is a rate-limiting step, C–H bond activation is the regioselectivity-controlling step. MPAA ligand acts not only as an auxiliary ligand to stabilize the catalytic active species but also as a proton acceptor in C–H bond deprotonation and as a proton donor during Pd(II)/Pd(IV) oxidation by TBHP. The use of a peroxide-based oxidant with the hydroxyl group is required: in the rate-limiting Pd(II)/Pd(IV) oxidation transition state, the H-atom of the OH group participates in the 1,2-hydrogen shift to facilitate proton-shuttling between MPAA ligand and peroxide. Thus, lactonization of the C(sp3)–H bond in aliphatic carboxylic acid occurs via the Pd(II)/Pd(IV) catalytic cycle, unlike the previously reported Pd(II)-catalyzed pyridone ligand and O2 oxidant-assisted benzylic C–H lactonization in aromatic o-methyl benzoic acid, which occurs via the Pd(II)/Pd(0) catalytic cycle and an intramolecular SN2 nucleophilic substitution mechanism. A comparison of these findings for C(sp3)–H bond lactonization in aliphatic and aromatic carboxylic acids enabled us to identify the roles of catalyst, substrate, ligand, and oxidant.

Polynuclear Iron(II) Pyridonates: Synthesis and Reactivity of Fe4 and Fe5 Clusters.

The combination of pyridonate ligands with transition metal ions enables the synthesis of an especially rich set of diverse coordination compounds involving various κ- and μ-bonding modes and higher nuclearities. With iron(II) ions, this chemical space is rather poorly explored beyond some biomimetic models of the pyridone iron-containing hydrogenase. Here, the topologically new Fe5 and Fe4 clusters, Fe5(LH)6[N(SiMe3)2]4 (1) and Fe4(LMe)6[N(SiMe3)2]2 (2), were synthesized (LH = 2-pyridonate; LMe = 6-methyl-2-pyridonate). Complex 1 contained an unprecedented diamondoid Fe@Fe4 tetrahedron with a central-to-peripheral Fe-Fe distance of ∼3.1 Å. The crystal structure of complex 2 displayed an Fe4O6 butterfly motif containing a planar Fe4 arrangement. Mössbauer spectroscopy confirmed the high-spin ferrous character of all iron ions. SQUID magnetometry reveals that the Fe(II) ions are involved in weak magnetic exchange coupling across the pyridonate bridges that results in antiferromagnetic interactions. The Fe4 cluster exhibits slow relaxation of magnetization under an applied magnetic field with an effective energy barrier of 38.5 K, rarely observed among the very rare examples of Fe(II) cluster-based single-molecule magnets. Studies of protolytic substitution of the amido ligands demonstrated the lability of the diamondoid Fe5 core in 1 and the stability of the Fe4 rhomboid in 2.

PdII-Catalyzed Site-selective β- and γ-C(sp3)-H Arylation of Primary Aldehydes Controlled by Transient Directing Groups.

Pd(II)-catalyzed site-selective β- and γ-C(sp3)-H arylation of primary aldehydes is developed by rational design of L,X-type transient directing groups (TDG). External 2-pyridone ligands are identified to be crucial for the observed reactivity. By minimizing the loading of acid additives, the ligand effect is enhanced to achieve high reactivities of the challenging primary aldehyde substrates. Site selectivity can be switched from the proximate to the relatively remote position by changing the bite angle of TDG to match the desired palladacycle size. Experimental and computational investigations support this rationale for designing TDG to potentially achieve remote site-selective C(sp3)-H functionalizations.

Palladium(II)-Catalyzed Selective Arylation of Tertiary C-H Bonds of Cyclobutylmethyl Ketones Using Transient Directing Groups.

We report the first example of selective PdII -catalyzed tertiary C-H activation of cyclobutylmethyl ketones using a transient directing group. An electron-deficient 2-pyridone ligand was identified as the optimal external ligand to enable tertiary C-H activation. A variety of cyclobutylmethyl ketones bearing quaternary carbon centers was readily accessed without preinstalling internal directing groups in up to 81 % yield and >95 : 5 regioisomeric ratios of tertiary C-H arylation to β-methylene (β-methyl) or γ-C-H arylation.

Ligand Enabled Pd(II)-Catalyzed γ-C(sp3)-H Lactamization of Native Amides.

γ-Lactams form important structural cores of a range of medicinally relevant natural products and clinical drugs, principal examples being the new generation of immunomodulatory imide drugs (IMiDs) and the brivaracetam family. Compared to conventional multistep synthesis, an intramolecular γ-C-H amination of aliphatic amides would allow for the direct construction of valuable γ-lactam motifs from abundant amino acid precursors. Herein we report a novel 2-pyridone ligand enabled Pd(II)-catalyzed γ-C(sp3)-H lactamization of amino acid derived native amides, providing the convenient synthesis of γ-lactams, isoindolinones, and 2-imidazolidinones. C6-Substitution of the 2-pyridone ligand is crucial for the lactam formation. This protocol features the use of N-acyl amino acids, which serve as both the directing group and cyclization partner, practical and environmentally benign tert-butyl hydrogen peroxide (TBHP) as the sole bystanding oxidant, and a broad substrate scope. The utility of this protocol was demonstrated through the two-step syntheses of a lenalidomide analog and brivaracetam from readily available carboxylic acids and amino acids.

Pd(II)-Catalyzed Synthesis of Benzocyclobutenes by β-Methylene-Selective C(sp3)-H Arylation with a Transient Directing Group.

Methylene-selective C-H functionalization is a significant hurdle that remains to be addressed in the field of Pd(II) catalysis. We report a Pd(II)-catalyzed synthesis of benzocyclobutenes by methylene-selective C(sp3)-H arylation of ketones. The reaction utilizes glycine as a transient directing group and a 2-pyridone ligand, which may govern the methylene selectivity by making intimate molecular associations with the substrate during concerted metalation-deprotonation. This reaction is shown to be highly selective for intramolecular methylene C(sp3)-H arylation, thus enabling sequential C(sp3)-H functionalization.

Site-Selective Pd-Catalyzed C(sp3 )-H Arylation of Heteroaromatic Ketones.

A ligand‐controlled site‐selective C(sp3)−H arylation of heteroaromatic ketones has been developed using Pd catalysis. The reaction occurred selectively at the α‐ or β‐position of the ketone side‐chain. The switch from α‐ to β‐arylation was realized by addition of a pyridone ligand. The α‐arylation process showed broad scope and high site‐ and chemoselectivity, whereas the β‐arylation was more limited. Mechanistic investigations suggested that α‐arylation occurs through C−H activation/oxidative addition/reductive elimination whereas β‐arylation involves desaturation and aryl insertion.

Thermal and Emission Properties of a Series of Lanthanides Complexes with N-Biphenyl-Alkylated-4-Pyridone Ligands: Crystal Structure of a Terbium Complex with N-Benzyl-4-Pyridone

This work focuses on the investigation of the liquid crystalline behavior and luminescence properties of the lanthanide complexes of Eu(III), Sm(III) and Tb(III) with N-biphenyl-alkylated-4-pyridone ligands. The organic ligands having a biphenyl group attached via a long flexible spacer with either 9 or 10 carbon atoms were synthesized by the reaction between 4-hydroxypyridine and the corresponding bromide compounds. The chemical structures of the organic and lanthanide complexes were assigned based on elemental analysis, single-crystal X-ray diffraction, 1H, 13C NMR and IR spectroscopies, and thermogravimetric analysis (TGA). The X-ray diffraction analysis of a parent compound shows that the lanthanide ions are surrounded by three monodentate pyridone ligands and three bidentate nitrate ions, giving a 9-coordinate environment. The mesogenic behavior and the type of liquid crystalline phases exhibited by the new complexes were analyzed by differential scanning calorimetry (DSC) and polarizing optical microscopy (POM), and powder X-ray diffraction (XRD) studies. Only the lanthanide complexes with longer spacer (10) display a monotropic SmA phase, typically on a short thermal range (less than 10 °C). The complexes with shorter flexible chains (9) show no liquid crystalline properties with melting temperatures lower than their analogs with longer spacers. The emission spectra recorded in solid state at room temperatures show typical emission bands for each lanthanide ion employed (Eu(III), Tb(III) and Sm(III)).

MIA-Directed 2-Pyridione-Enabled Selective Ortho-C-H Arylation of Phenylalanine: A Mechanistic Study.

The 2-methoxyiminoacyl-mediated arylation of substituted phenylalanines has been examined. Selective monoarylation at the ortho position was achieved using pyridone ligands which decelerate the arylation process. Density functional theory (DFT) study of a continuous C-H arylation process that included the first and second arylation stage was performed. The computational result shows that the introduction of a pyridone ligand obviously disfavors the second arylation stage, which directly contributes to the selectivity between the mono/diarylated products. Furthermore, results of the kinetic isotope effect and a control experiment are agreed with DFT study.

Formation of Nucleophilic Allylboranes from Molecular Hydrogen and Allenes Catalyzed by a Pyridonate Borane that Displays Frustrated Lewis Pair Reactivity.

Here we report the in situ generation of nucleophilic allylboranes from H2 and allenes mediated by a pyridonate borane that displays frustrated‐Lewis‐pair reactivity. Experimental and computational mechanistic investigations reveal that upon H2 activation, the covalently bound pyridonate substituent becomes a datively bound pyridone ligand. Dissociation of the formed pyridone borane complex liberates Piers borane and enables a hydroboration of the allene. The allylboranes generated in this way are reactive towards nitriles. A catalytic protocol for the formation of allylboranes from H2 and allenes and the allylation of nitriles has been devised. This catalytic reaction is a conceptually new way to use molecular H2 in organic synthesis.

Insights into the Role of Transient Chiral Mediators and Pyridone Ligands in Asymmetric Pd-Catalyzed C-H Functionalization.

Mechanistic investigations uncover a novel role for 2-pyridone ligands and interrogate the origin of enantioselectivity in the (+)-norbornene-mediated Pd-catalyzed meta-C(aryl)-H functionalization of diarylmethylamines. Observations from kinetic analysis in concert with in situ 19F NMR monitoring allow us to propose that the pyridone ligand plays a role in enhancing the rate- and enantio-determining insertion of an arylpalladium species into a chiral norbornene derivative. The unprecedented features of 2-pyridone ligands in asymmetric 1,2 migratory insertion, and norbornene as a transient chiral mediator in relay chemistry, provide new insights into this ligand scaffold for future developments in stereoselective transition-metal-catalyzed C-H functionalization.

Harnessing the Efficacy of 2-Pyridone Ligands for Pd-Catalyzed (β/γ)-C(sp3)-H Activations.

Mechanisms of palladium-aminooxyacetic acid and 2-pyridone-enabled cooperative catalysis for the β- and γ-C(sp3)-H functionalizations of ketones are investigated with density functional theory. 2-Pyridone-assisted dissociation of the trimeric palladium acetate [Pd3(OAc)6] is found to be crucial for these catalytic pathways. The evolution of the [6,6]-membered palladacycles (Int-4) are elucidated and are active complexes in Pd(II/IV) catalytic cycles. Nevertheless, 2-pyridone acts as an external ligand, which accelerates β-C(sp3)-H activation. Computational investigations suggest that the C(sp3)-H bond activation is the rate-limiting step for both the catalytic processes. To overcome the kinetic inertness, an unsubstituted aminooxyacetic acid auxiliary is used for the β-C(sp3)-H activation pathway to favor the formation of the [5,6]-membered palladacycle intermediate, Int-IV. Among the several modeled ligands, 3-nitro-5-((trifluoromethyl)sulfonyl)pyridine-2(1H)-one (L8) is found to be highly valuable for both the (β/γ)-C(sp3)-H functionalization catalytic cycles. A favorable free energy pathway of late-stage functionalization of (R)-muscone paves the path to design other bioactive molecules.

Luminescent lanthanides complexes with mesogenic pyridone ligands: Emission and liquid crystals properties

In this work, a systematic investigation of the influence of N-alkylated 4-pyridone ligands containing one cyanobiphenyl mesogenic group linked via a spacer with variable length (6, 8, 9 or 10 methylene groups) on the liquid crystalline properties and luminescence properties of the resulting lanthanide complexes with Eu(III), Sm(III) and Tb(III). The chemical structures of the new products were determined by 1H and 13C NMR spectroscopy, as well as elemental analysis and IR spectroscopy. The lanthanide ions are 9-coordinate and surrounded by three pyridone ligands and three bidentate nitrate ions. The thermal behavior of the new products was analyzed by differential scanning calorimetry (DSC) and thermogravimetrical analysis (TG). The nature of the liquid crystalline phase was confirmed by polarizing optical microscopy (POM) and powder X-ray diffraction (XRD) studies. All complexes remain in the glassy state at room temperature while at higher temperature these materials display a SmA phase. Higher clearing temperatures were recorded for longer spacers. The emission spectra show characteristic emission bands for each lanthanide ion. The emission of the new complexes measured as a function of temperature decreases noticeably upon the increase of temperature and this process is reversible on cooling.

Pd-Catalyzed γ-C(sp3)-H Fluorination of Free Amines.

The first example of free amine γ-C(sp3)-H fluorination is realized using 2-hydroxynicotinaldehyde as the transient directing group. A wide range of cyclohexyl and linear aliphatic amines could be fluorinated selectively at the γ-methyl and methylene positions. Electron withdrawing 3,5-disubstituted pyridone ligands were identified to facilitate this reaction. Computational studies suggest that the turnover determining step is likely the oxidative addition step for methylene fluorination, while it is likely the C-H activation step for methyl fluorination. The explicit participation of Ag results in a lower energetic span for methylene fluorination and a higher energetic span for methyl fluorination, which is consistent with the experimental observation that the addition of silver salt is desirable for methylene but not for methyl fluorination. Kinetic studies on methyl fluorination suggest that the substrate and PdL are involved in the rate-determining step, indicating that the C-H activation step may be partially rate-determining. Importantly, an energetically preferred pathway has identified an interesting pyridone-assisted bimetallic transition state for the oxidative addition step in methylene fluorination, thus uncovering a potential new role of the pyridone ligand.

PdII‐Catalyzed Enantioselective C(sp3)–H Arylation of Cyclobutyl Ketones Using a Chiral Transient Directing Group

AbstractThe use of chiral transient directing groups (TDGs) is a promising approach for developing PdII‐catalyzed enantioselective C(sp3)−H activation reactions. However, this strategy is challenging because the stereogenic center on the TDG is often far from the C−H bond, and both TDG covalently attached to the substrate and free TDG are capable of coordinating to PdII centers, which can result in a mixture of reactive complexes. We report a PdII‐catalyzed enantioselective β‐C(sp3)−H arylation reaction of aliphatic ketones using a chiral TDG. A chiral trisubstituted cyclobutane was efficiently synthesized from a mono‐substituted cyclobutane through sequential C−H arylation reactions, thus demonstrating the utility of this method for accessing structurally complex products from simple starting materials. The use of an electron‐deficient pyridone ligand is crucial for the observed enantioselectivity. Interestingly, employing different silver salts can reverse the enantioselectivity.