Theoretical design of new ligands to boost reaction rate and selectivity in palladium-catalyzed aromatic fluorination.

The development of palladium-catalyzed fluorination with biaryl monophosphine ligands has faced two important problems that limit its application for bromoarenes: the formation of regioisomers and insufficient catalysis for heteroaryl substrates as bromothiophene derivatives. Overcoming these problems requires more ligand design. In this work, reliable theoretical calculations were used to elucidate important ligand features necessary for achieving more rate acceleration and selectivity. These features include increasing the ligand-substrate repulsion and creating a negative charge in the space around the fluoride ion bonded to the palladium. The investigated L5 ligand presents these features, and the calculations predict that this ligand completely suppresses the regioisomer formation in the difficult case of 4-bromoanisole. In addition, the free energy barriers are decreased by 2-3 kcal mol-1 in comparison with the catalysis involving the AlPhos ligand. Thus, the present study points out a direction for new developments in palladium-catalyzed fluorination.

Carbonyl-Supported Coordination in Imidazolates: A Platform for Designing Porous Nickel-Based ZIFs as Heterogeneous Catalysts.

Zeolitic imidazolate frameworks (ZIFs) are a subclass of metal-organic framework that have attracted considerable attention as potential functional materials due to their high chemical stability and ease of synthesis. ZIFs are usually composed of zinc ions coordinated with imidazole linkers, with some other transition metals, such as Cu(II) and Co(II), also showing potential as ZIF-forming cations. Despite the importance of nickel in catalysis, no Ni-based ZIF with permanent porosity is yet reported. It is found that the presence and arrangement of the carbonyl functional groups on the imidazole linker play a crucial role in completing the preferred octahedral coordination of nickel, revealing a promising platform for the rational design of Ni-based ZIFs for a wide range of catalytic applications. Herein, the synthesis of the first Ni-based ZIFs is reported and their high potential as heterogeneous catalysts for Suzuki-Miyaura cross-coupling C─C bond forming reactions is demonstrated.

Perfect Partners: Biocatalytic Halogenation and Metal Catalysis for Protein Bioconjugation.

Flavin-dependent halogenases (FDHs) are the most extensively researched halogenases and show great potential for biotransformation applications. These enzymes use chloride, bromide, or iodide ions as halogen donors to catalyze the oxygen-dependent halogenation of electron-rich aryl moieties, requiring stochiometric amounts of FADH2 in the process. This makes FDH-catalyzed aryl halogenation a highly selective and environmentally friendly tool for the synthesis of aryl halides. The latter in turn serve as valuable intermediates for transition metal catalyzed cross coupling reactions for C-C bond formation. Previous research made extensive use of this approach to halogenate small molecules as building blocks for late-stage functionalization by transition-metal catalyzed cross-coupling reactions. Based on these results, several groups have managed to expand this research to protein targets over the past two years. Their work indicates an emerging methodology for bioconjugation using late-stage biocatalytic halogenation in conjunction with biorthogonal Suzuki-Miyaura cross-coupling. This strategy could present an attractive alternative to existing approaches due to the stability of the C-C bond bridging the generated biaryl moiety and the ease of late-stage enzymatic modification while maintaining excellent selectivity under mild conditions.

Halo-1,2,3-triazoles: Valuable Compounds to Access Biologically Relevant Molecules.

1,2,3-triazole is an important building block in organic chemistry. It is now well known as a bioisostere for various functions, such as the amide or the ester bond, positioning it as a key pharmacophore in medicinal chemistry and it has found applications in various fields including life sciences. Attention was first focused on the synthesis of 1,4-disubstituted 1,2,3-triazole molecules however 1,4,5-trisubstituted 1,2,3-triazoles have now emerged as valuable molecules due to the possibility to expand the structural modularity. In the last decade, methods mainly derived from the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction have been developed to access halo-triazole compounds and have been applied to nucleosides, carbohydrates, peptides and proteins. In addition, late-stage modification of halo-triazole derivatives by metal-mediated cross-coupling or halo-exchange reactions offer the possibility to access highly functionalized molecules that can be used as tools for chemical biology. This review summarizes the synthesis, the functionalization, and the applications of 1,4,5-trisubstituted halo-1,2,3-triazoles in biologically relevant molecules.

Pinacol Cross-Coupling Promoted by an Aluminyl Anion.

A simple sequential addition protocol for the reductive coupling of ketones and aldehydes by a potassium aluminyl grants access to unsymmetrical pinacolate derivatives. Isolation of an aluminium ketyl complex presents evidence for the accessibility of radical species. Product release from the aluminium centre was achieved using an iodosilane, forming the disilylated 1,2-diol and a neutral aluminium iodide, thereby demonstrating the steps required to generate a closed synthetic cycle for pinacol (cross) coupling at an aluminyl anion.

Eight-Membered Palladacycle Intermediate Enabled Synthesis of Cyclic Biarylphosphonates.

Transition-metal-catalyzed coupling reactions that involve the direct functionalization of insert C-H bond represent one of the most efficient strategies for forming carbon-carbon bonds. Herein, a palladium-catalyzed intramolecular C-H bond arylation of triaryl phosphates is reported to access seven-membered cyclic biarylphosphonate targets. The reaction is achieved via a unique eight-membered palladacyclic intermediate and shows good functional group compatibility. Meanwhile, the product can be readily converted into other valuable phosphate compounds.

Redox-Mediated Amination of Pyrogallol-Based Polyphenols.

Flavonoids are known to covalently modify amyloidogenic peptides by amination reactions. The underlying coupling process between polyphenols and N-nucleophiles is assessed by several in vitro and in silico approaches. The coupling reaction involves a sequence of oxidative dearomatization, amination, and reductive amination (ODARA) reaction steps. The C6-regioselectivity of the product is confirmed by crystallographic analysis. Under aqueous conditions, the reaction of baicalein with lysine derivatives yields C-N coupling as well as hydrolysis products of transient imine intermediates. The observed C-N coupling reactions work best for flavonoids combining a pyrogallol substructure with an electron-withdrawing group attached to the C4a-position. Thermodynamic properties such as bond dissociation energies also highlight the key role of pyrogallol units for the antioxidant ability. Combining the computed electronic properties and in vitro antioxidant assays suggests that the studied pyrogallol-containing flavonoids act by various radical-scavenging mechanisms working in synergy. Multivariate analysis indicates that a small number of descriptors for transient intermediates of the ODARA process generates a model with excellent performance (r=0.93) for the prediction of cross-coupling yields. The same model has been employed to predict novel antioxidant flavonoid-based molecules as potential covalent inhibitors, opening a new avenue to the design of therapeutically relevant anti-amyloid compounds.

Suzuki-Miyaura Cross-Coupling Reaction Using Palladium Catalysts Supported on Phosphine Periodic Mesoporous Organosilica.

Phosphine periodic mesoporous organosilicas (R-P-PMO-TMS: R=Ph, tBu), which possess electron-donating alkyl substituents on the phosphorus atom, were synthesized using bifunctional compounds with alkoxysilyl- and phosphino groups, bis[3-(triethoxysilyl)propyl]phenylphosphine borane (1 a) and bis[3-(triethoxysilyl)propyl]-tert-butylphosphine borane (1 b). Immobilization of Pd(0) species was performed to give R-P-Pd-PMO-TMS: R=Ph (2 a), tBu (3 a), respectively. The Pd(0) immobilized 2 a and 3 a were applicable as catalysts for Suzuki-Miyaura cross-coupling reactions of aryl chlorides with phenylboronic acid. It was revealed that 3 a bearing more electron-donating tBu groups exhibited higher catalytic activity. Various functional groups including both electron withdrawing and donating substituents were compatible in the system. The recyclability of 3 a was examined to support its moderate utility for the recycle use.

Synthesis and Properties of Fluorenone-Containing Cycloparaphenylenes and Their Late-Stage Transformation.

Cycloparaphenylenes (CPPs) are the smallest possible armchair carbon nanotubes, the properties of which strongly depend on their ring size. They can be further tuned by either peripheral functionalization or by replacing phenylene rings for other aromatic units. Here we show how four novel donor-acceptor chromophores were obtained by incorporating fluorenone or 2-(9H-fluoren-9-ylidene)malononitrile into the loops of two differently sized CPPs. Synthetically, we managed to perform late-stage functionalization of the fluorenone-based rings by high-yielding Knoevenagel condensations. The structures were confirmed by X-ray crystallographic analyses, which revealed that replacing a phenylene for a fused-ring-system acceptor introduces additional strain. The donor-acceptor characters of the CPPs were supported by absorption and fluorescence spectroscopic studies, electrochemical studies (displaying the CPPs as multi-redox systems undergoing reversible or quasi-reversible redox events), as well as by computations. The oligophenylene parts were found to comprise the electron donor units of the macrocycles and the fluorenone parts the acceptor units.

Multielectron Redox Afforded by a Pincer Ligand Promoting Kumada Cross-Coupling Reactions.

The redox-active nature of a pincer has been exploited to conduct C-C cross-coupling reactions under mild conditions. A nickel complex with a NNN pincer was dimeric in the solid state, and the structure displayed a Ni2 N2 diamond core. In the dimeric structure, both ligand backbones house an electron, in the iminosemiquinonate form, to keep the metal's oxidation state at +2. In the presence of an aryl Grignard reagent, only 3 mol % loading the nickel complex generates a Kumada cross-coupled product in good yield from a wide variety of aryl-X (X= I, Br, Cl) substrates. That the ligand-based radical remains responsible for promoting such a coupling reaction following a radical pathway is suggested by TEMPO quenching. Furthermore, a radical-clock experiment along with tracing product distribution unambiguously supported the radical's involvement through the catalytic cycle. A series of thorough mechanistic probation, including computational DFT analysis, disclosed the cooperative action of both redox-active pincer ligand and the metal centre to drive the reaction.

Introduction of Molecular Complexity via the Cross-Coupling of Lithium 1,4-Dioxene with Aryl Bromides.

The synthetic potential of substituted 1,4-dioxenes is well recognised, although the chemistry of 2-aryl-1,4-dioxenes is relatively unexplored. Their transition metal-catalysed synthesis has been limited to Stille-type cross-coupling chemistry, typically showing long reaction times, or proceeding at high reaction temperatures. Here we present a facile and general methodology for the cross-coupling of aryl bromides with lithium 1,4-dioxene, affording a range of 2-aryl-1,4-dioxenes in generally good yields. We highlight the synthetic applicability of this transformation at multigram scale, and demonstrate the versatility of the products by conversion of the dioxene units to various carbonyl-based functionalities. Additionally, we present a concise two-step synthesis of an arylated analogue to a known 1,4-dioxene-based antifungal agent.

Ethynyl-B(dan) in [3+2] Cycloaddition and Larock Indole Synthesis: Synthesis of Stable Boron-Containing Heteroaromatic Compounds.

The cycloaddition of nitrile oxides with ethynyl-B(dan) (dan=naphthalene-1,8-diaminato) allowed the facile preparation of diverse isoxazolyl-B(dan) compounds, all of which displayed excellent protodeborylation-resistant properties. The dan-installation on the boron center proves vital to the high stability of the products as well as the perfect regioselectivity arising from hydrogen bond-directed orientation in the cycloaddition. The diminished boron-Lewis acidity of ethynyl-B(dan) also renders it amenable to azide-alkyne cycloaddition, Larock indole synthesis and related heteroannulations. The obtained boron-containing triazole, indoles, benzofuran and indenone exhibit sufficient resistance toward protodeborylation. Despite the commonly accepted transmetalation-inactive property derived from the diminished Lewis acidity, the synthesized heteroaryl-B(dan) compound was still found to be convertible to the oligoarene via sequential Suzuki-Miyaura coupling.

A Rational Design of Electrochemically and Photophysically Tunable Triarylamine Luminophores by Consecutive (Pseudo-)Four-Component Syntheses.

The concatenation of Suzuki coupling and two-fold Buchwald-Hartwig amination in sequentially palladium-catalyzed consecutive multicomponent syntheses paves a concise, convergent route to diversely functionalized para-biaryl-substituted triarylamines (p-bTAAs) from simple, readily available starting materials. An extensive library of p-bTAAs permits comprehensive investigations of their electronic properties by absorption and emission spectroscopy, cyclic voltammetry, and quantum chemical calculations, which contribute to a deep understanding of their electronic structure. The synthesized p-bTAAs exhibit tunable fluorescence from blue to yellow upon photonic excitation with quantum yields up to 98 % in solution and 92 % in the solid state. Furthermore, a pronounced bathochromic shift of the emission maxima by increasing solvent polarity indicates positive emission solvatochromism. Aggregation-induced enhanced emission (AIEE) in dimethyl sulfoxide (DMSO)/water mixtures causes the formation of intensely blue fluorescent aggregates. Cyclic voltammetry shows reversible first and second oxidations of p-bTAAs at low potentials, which are tunable by variation of the introduced para substituents. 3D Hammett plots resulting from the correlation of oxidation potentials and emission maxima with electronic substituent parameters emphasize the rational design of tailored p-bTAAs with predictable electrochemical and photophysical properties.

Manganese-catalyzed Efficient Synthesis of N-heterocycles and Aminoketones Using Glycerol as a C3 Synthon.

Glycerol is one of the important biomass-derived feedstocks and the high-value utilizations of glycerol have attracted much attentions in recent years. Herein, we report a manganese catalyzed dehydrogenative coupling of glycerol with amines for the synthesis of substituted 2-methylquinoxalines, 2-ethylbenzimidazoles, and α-aminoketones without any external oxidant. In these reactions, NHC-based pincer manganese complex featuring a pyridine backbone displayed high catalytic activity and selectivity, in which hydrogen and water were produced as the only by-products using glycerol as a C3 synthon.

Interrogating Explicit Solvent Effects on the Mechanism and Site-Selectivity of Aryl Halide Oxidative Addition to L2Pd(0).

We report a study of solvent effects on the rate, selectivity, and mechanism of (hetero)aryl (pseudo)halide oxidative addition to Pd(PCy3)2 as an exemplar of L2Pd(0) species. First, 2-chloro-3-aminopyridine is observed to undergo faster oxidative addition in toluene compared to more polar solvents, which is not consistent with the trend we observe with many other 2-halopyridines. We attribute this to solvent basicity hydrogen-bonding (pKHB) between solvent and substrate. Greater hydrogen-bond donation from the substrate leads to a more electron-rich aromatic system, and therefore slower oxidative addition. We demonstrate how this affects rate and site-selectivity for hydrogen-bond donating substrates. Second, electron-deficient multihalogenated pyridines exhibit improved site-selectivity in polar solvents, which we attribute to different C-X sites undergoing oxidative addition by two different mechanisms. The C-X site that favours the more polar nucleophilic displacement transition state is preferred over the site that favours a less-polar 3-centered transition state. Finally, (hetero)aryl triflates consistently undergo faster oxidative addition in more polar solvents, which we attribute to highly polar nucleophilic displacement transition states. This leads to improved site-selectivity for C-OTf oxidative addition, even in the presence of highly reactive 2-pyridylhalides.

Amino- and Alkoxybenziodoxoles: Facile Preparation and Use as Arynophiles.

We report here on the facile synthesis of amino- and alkoxy-λ3-iodanes supported by a benziodoxole (BX) template and their use as arynophiles. The amino- and alkoxy-BX derivatives can be readily synthesized by reacting the respective amines or alcohols with chlorobenziodoxole in the presence of a suitable base. Unlike previously known nitrogen- and oxygen-bound iodane compounds, which have primarily been employed as electrophilic group transfer agents or oxidants, the present amino- and alkoxy-BX reagents manifest themselves as nucleophilic amino and alkoxy transfer agents toward arynes. This reactivity leads to the aryne insertion into the N-I(III) or O-I(III) bond to afford ortho-amino- and ortho-alkoxy-arylbenziodoxoles, iodane compounds nontrivial to procure by existing methods. The BX group in these insertion products exhibits excellent leaving group ability, enabling diverse downstream transformations.

Phosphine-Catalyzed 1,2-cis-Diboration of 1,3-Butadiynes.

Trialkyl phosphines PMe3 and PEt3 catalyze the 1,2-cis-diboration of 1,3-butadiynes to give 1,2-diboryl enynes. The products were utilized to synthesize 1,1,2,4-tetraaryl enynes using a Suzuki-Miyaura protocol and can readily undergo proto-deborylation.

Bottom-Up Construction of Ni(II)-Incorporated Covalent Organic Framework for Metallaphotoredox Catalysis.

The construction of an all-in-one catalyst, in which the photosensitizer and the transition metal site are close to each other, is important for improving the efficiency of metallaphotoredox catalysis. However, the development of convenient synthetic strategies for the precise construction of an all-in-one catalyst remains a challenging task due to the requirement of precise installation of the catalytic sites. Herein, we have successfully established a facile bottom-up strategy for the direct synthesis of Ni(II)-incorporated covalent organic framework (COF), named LZU-713@Ni, as a versatile all-in-one metallaphotoredox catalyst. LZU-713@Ni showed excellent activity and recyclability in the photoredox/nickel-catalyzed C-O, C-S, and C-P cross-coupling reactions. Notably, this catalyst displayed a better catalytic activity than its homogeneous analogues, physically mixed dual catalyst system, and, especially, LZU-713/Ni which was prepared through post-synthetic modification. The improved catalytic efficiency of LZU-713@Ni should be attributed to the implementation of bottom-up strategy, which incorporated the fixed, ordered, and abundant catalytic sites into its framework. This work sheds new light on the exploration of concise and effective strategies for the construction of multifunctional COF-based photocatalysts.

Photoinduced Redox Cascade Reaction of Isatins and Aliphatic Carboxylic Acids to Access 6-Hydroxyindoloquinazolinones.

A visible-light-induced cascade reaction is described for the one-pot synthesis of 6-hydroxyindoloquinazolinones using isatins (or isatins and isatoic anhydrides) and aliphatic carboxylic acids. The method provides 36 desired products in 33-96 % yield, exhibiting broad substrate scope and good functional group tolerance. This approach utilizes inexpensive and commercially available starting materials, enabling the direct construction of high-value complex structures under mild conditions without the need for photocatalyst, showcasing significant applicability and environmental friendliness.

Electrochemical Decarboxylative Cross-Coupling with Nucleophiles.

Decarboxylative cross-coupling reactions are powerful tools for carbon-heteroatom bonds formation, but typically require pre-activated carboxylic acids as substrates or heteroelectrophiles as functional groups. Herein, we present an electrochemical decarboxylative cross-coupling of carboxylic acids with structurally diverse fluorine, alcohol, H2O, acid, and amine as nucleophiles. This strategy takes advantage of the ready availability of these building blocks from commercial libraries, as well as the mild and oxidant-free conditions provided by electrochemical system. This reaction demonstrates good functional-group tolerance and its utility in late-stage functionalization.