Catalyzed Cross-coupling Reaction Research Articles

Efficient synthesis of conjugated 2-(9H-fluoren-7-yl)-9H-fluorene via Br elimination in 2-bromofluorene using electron beam-irradiation

This study demonstrates the synthesis of conjugated 2-(9H-fluoren-7-yl)-9H-fluorene using electron beam irradiation within 3 min in place of the conventional catalytic cross-coupling reactions. 2-bromofluorene was irradiated at various doses (10, 30, 50, 70, 90, and 100 kGy), resulting in the elimination of Br from the 2-position and the formation of C–C bonds between the Br-eliminated fluorenes. The yield of 2-(9H-fluoren-7-yl)-9H-fluorene increased with higher absorbed doses, reaching 65% at 100 kGy. UV–Vis absorption of synthesized 2-(9H-fluoren-7-yl)-9H-fluorene showed an onset at 357 nm and a maximum absorption peak at 325 nm, and blue emission ranging from 340 to 450 nm in photoluminescence (PL). The results of UV–Vis absorption and PL indicated expanded conjugation of 2-(9H-fluoren-7-yl)-9H-fluorene due to the formation of C–C bonds between 2-bromofluorene through the electron beam-induced coupling reaction. Electron beam irradiation offers the potential to significantly reduce the reaction times for synthesis of conjugated organic compounds.

Bifunctional iron-catalyzed alkyne Z-selective hydroalkylation and tandem Z-E inversion via radical molding and flipping

The challenging synthesis of thermodynamic-unfavored cis-olefins through catalytic cross-coupling reactions requires the synergistic interaction of substrate-activating units and configuration-regulating catalysts. Successfully hitting these two birds with one stone, we herein develop a convenient photoredox access to Z-alkenes from alkynes and light alkanes with a bifunctional iron-catalyzed system possessing both C(sp3)−H activation and configuration-controlling abilities. The protocol exhibits 100% atom utilization, mild conditions, a broad substrate scope, and compatibility with multitudinous functional groups. The detailed reaction mechanism and the origin of geometry regulation are well investigated by experimental and computational studies. Progressively, a catalytic amount of diaryl disulfides is introduced for consecutive photoinduced Z−E isomerization via reversible radical addition and flipping. Big steric hindrance substituents assembled on the disulfide emerge necessity for suppressing double-bond migration. This tandem strategy paves a promising way for stereoselective alkene construction and will bring significant inspiration for the development of transition metal photocatalysis.

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.

Electrochemical Generation of Aryl Radicals from Organoboron Reagents Enabled by Pulsed Electrosynthesis.

Aryl radicals play a pivotal role as reactive intermediates in chemical synthesis, commonly arising from aryl halides and aryl diazo compounds. Expanding the repertoire of sources for aryl radical generation to include abundant and stable organoboron reagents would significantly advance radical chemistry and broaden their reactivity profile. While traditional approaches utilize stoichiometric oxidants or photocatalysis to generate aryl radicals from these reagents, electrochemical conditions have been largely underexplored. Through rigorous mechanistic investigations, we identified fundamental challenges hindering aryl radical generation. In addition to the high oxidation potentials of aromatic organoboron compounds, electrode passivation through radical grafting, homocoupling of aryl radicals, and decomposition issues were identified. We demonstrate that pulsed electrosynthesis enables selective and efficient aryl radical generation by mitigating the fundamental challenges. Our discoveries facilitated the development of the first electrochemical conversion of aryl potassium trifluoroborate salts into aryl C-P bonds. This sustainable and straightforward oxidative electrochemical approach exhibited a broad substrate scope, accommodating various heterocycles and aryl chlorides, typical substrates in transition-metal catalyzed cross-coupling reactions. Furthermore, we extended this methodology to form aryl C-Se, C-Te, and C-S bonds, showcasing its versatility and potential in bond formation processes.

Triazine-wingtips accelerated NHC-Pd catalysed carbonylative Suzuki cross-coupling reaction

Triazine conjugated N-heterocyclic carbene palladium complexes were synthesized for reducing the Pd amount in the catalysts to the ppm levels. This work reports the carbonylative Suzuki-Miyaura coupling of aryl iodides catalyzed by N-heterocyclic carbenes palladium with triazine wingtips (T-NHC-Pd). More importantly, the palladacycles have been used to generate high turnover numbers (TON's) and turnover frequencies (TOF's).

Carbene-Assisted Arene Ring-Opening.

Despite the significant achievements in dearomatization and C-H functionalization of arenes, the arene ring-opening remains a largely unmet challenge and is underdeveloped due to the high bond dissociation energy and strong resonance stabilization energy inherent in aromatic compounds. Herein, we demonstrate a novel carbene assisted strategy for arene ring-opening. The understanding of the mechanism by our DFT calculations will stimulate wide application of bulk arene chemicals for the synthesis of value-added polyconjugated chain molecules. Various aryl azide derivatives now can be directly converted into valuable polyconjugated enynes, avoiding traditional synthesis including multistep unsaturated precursors, poor selectivity control, and subsequent transition-metal catalyzed cross-coupling reactions. The simple conditions required were demonstrated in the late-stage modification of complex molecules and fused ring compounds. This chemistry expands the horizons of carbene chemistry and provides a novel pathway for arene ring-opening.

Establishing the main determinants of the environmental safety of catalytic fine chemical synthesis with catalytic cross-coupling reactions

Bio-risk assessment was conducted for Sonogashira and Mizoroki–Heck reactions. bio-Strips showed the cytotoxicity of the reaction components. The study suggests the rules of eco-friendly design for future catalytic processes.

Mechanochemical Synthesis of PdO2 Nanoparticles Immobilized over Silica Gel for Catalytic Suzuki-Miyaura Cross-Coupling Reactions Leading to the C-3 Modification of 1H-Indazole with Phenylboronic Acids.

The C-3 modification of 1H-indazole has produced active pharmaceuticals for the treatment of cancer and HIV. But, so far, this transformation has seemed less available, due to the lack of efficient C-C bond formation at the less reactive C-3 position. In this work, a series of silica gel-supported PdO2 nanoparticles of 25-66 nm size were prepared by ball milling silica gel with divalent palladium precursors, and then employed as catalysts for the Suzuki-Miyaura cross-coupling of 1H-indazole derivative with phenylboronic acid. All the synthesized catalysts showed much higher cross-coupling yields than their palladium precursors, and could also be reused three times without losing high activity and selectivity in a toluene/water/ethanol mixed solvent. Although the palladium precursors showed an order of activity of PdCl2(dppf, 1,1'-bis(diphenylphosphino)ferrocene) > PdCl2(dtbpf, 1,1'-bis(di-tert-butylphosphino)ferrocene) > Pd(OAc, acetate)2, the synthesized catalysts showed an order of C1 (from Pd(OAc)2) > C3 (from PdCl2(dtbpf)) > C2 (from PdCl2(dppf)), which conformed to the orders of BET (Brunauer-Emmett-Teller) surface areas and acidities of these catalysts. Notably, the most inexpensive Pd(OAc)2 can be used as a palladium precursor for the synthesis of the best catalyst through simple ball milling. This work provides a highly active and inexpensive series of catalysts for C-3 modification of 1H-indazole, which are significant for the large-scale production of 1H-indazole-based pharmaceuticals.

Atroposelective NiII -Catalyzed Cross-Coupling Reactions Enable a Deeper Understanding of Negishi Couplings: Isolation and Application of Solid Aryl Higher-Order Zincates.

The Negishi cross-coupling reactions involves the application of organozinc reagents and is a highly versatile reaction in synthetic organic chemistry. The transmetallation step plays a pivotal role in the mechanism of these types of cross-coupling reactions. In this study, mechanistic investigations are presented indicating that higher-order zincates are the transmetallating active species in Pd- and Ni-catalyzed Negishi cross-coupling reactions. These findings are supported by halide salt addition experiments and by obtaining a single X-ray crystal structure of the solid monoaryl higher-order zincate [1-NaphthylZnX3 ]2- Mg(THF)2 2+ . The procedure developed in this work was further applied to the synthesis of various monoaryl higher-order zincates, after which their synthetic usefulness in terms of high reactivity towards transmetallation in Negishi cross-couplings, as well as stability, was exemplified in several reactions.

Milling Medium-Free Suzuki Coupling by Direct Mechanocatalysis: From Mixer Mills to Resonant Acoustic Mixers.

Here we describe the development of a sustainable and cost-effective approach for catalytic cross-coupling reactions in mechanochemistry. It is found that the substrate's impact with the vessel wall alone is sufficient to initiate the reaction, thus indicating that milling balls function primarily as a mixing agent for direct mechanocatalytic Suzuki coupling. The absence of milling balls can be offset by adjusting the rheology using liquid-assisted grinding (LAG). The LAG sweet spot of 0.25 μL mg-1 is confirmed for both resonance acoustic mixers (RAMs) and ball-free mixer mills, and is higher than in the presence of milling balls. RAMs exhibit excellent performance in the Suzuki reaction, achieving yields of 90 % after 60 min and complete conversion after 90 min. The longevity of the milling vessel is significantly improved in a RAM, allowing for at least 20 reactions without deterioration.

ChemCNet: An Explainable Integrated Model for Intelligent Analyzing Chemistry Synthesis Reactions

Palladium (Pd)-catalyzed cross coupling reactions are of great significance in organic synthesis. However, the reaction route is more complex, time-consuming and costly. For addressing the above problems, a model-related feature selection strategy is introduced, focusing on iterative optimization of feature description and prediction to guide and strengthen each other. Then, we combine the lightweight convolution neural network (CNN) driven by attention mechanism with CatBoost to build an intelligent chemical synthesis reaction analysis model-ChemCNet. Moreover, we conduct the interpretability analysis based on ChemCNet model. The results show that ChemCNet model has achieved relatively high prediction accuracy and generalization, and it is helpful to provide reliable decision-making information for the experimenter or institution.

A Paradigm Shift in Catalysis: Electro- and Photomediated Nickel-Catalyzed Cross-Coupling Reactions.

ConspectusTransition-metal catalyzed cross-coupling reactions are fundamental reactions in organic chemistry, facilitating strategic bond formations for accessing natural products, organic materials, agrochemicals, and pharmaceuticals. Redox chemistry enables access to elusive cross-coupling mechanisms through single-electron processes as an alternative to classical two-electron strategies predominated by palladium catalysis. The seminal reports of Baran, MacMillan, Doyle, Molander, Weix, Lin, Fu, Reisman, and others in merging redox perturbation (photochemical, electrochemical, and purely chemical) with catalysis are pivotal to the current resurgence and mechanistic understanding of first-row transition metal-based catalysis. The hallmark of this redox platform is the systematic modulation of transition-metal oxidation states by a photoredox catalyst or at a heterogeneous electrode surface. Electrocatalysis and photocatalysis enhance transition metal catalysis' capacity for bond formation through electron- or energy-transfer processes that promote otherwise challenging elementary steps or elusive mechanisms. Cross-coupling conditions promoted by electrocatalysis and photocatalysis are mild, and bond formation proceeds with exceptionally high chemoselectivity and wide functional group tolerance. The interfacing of abundant first-row transition-metal catalysis with electrocatalysis and photocatalysis has brought about a paradigm shift in cross-coupling technology as practitioners are quickly applying these tools in synthesizing fine chemicals and pharmaceutically relevant motifs. In particular, the merger of Ni catalysis with electro- and photochemistry ushered in a new era for carbon-carbon and carbon-heteroatom cross-couplings with expanded generality compared to their thermally driven counterparts. Over the past decade, we have developed enabling photo- and electrochemical methods throughout our combined research experience in industry (BMS, AstraZeneca) and academia (Professor Baran, Scripps Research) in cross-disciplinary collaborative environments. In this Account, we will outline recent progress from our past and present laboratories in photo- and electrochemically mediated Ni-catalyzed cross-couplings. By highlighting these cross-coupling methodologies, we will also compare mechanistic features of both electro- and photochemical strategies for forging C(sp2)-C(sp3), C(sp3)-C(sp3), C-O, C-N, and C-S bonds. Through these side-by-side comparisons, we hope to demystify the subtle differences between the two complementary tools to enact redox control over transition metal catalysis. Finally, building off the collective experience of ourselves and the rest of the community, we propose a tactical user guide to photo- and electrochemically driven cross-coupling reactions to aid the practitioner in rapidly applying such tools in their synthetic designs.

Recent Advances in Design and Synthesis of 1,3-Thiaselenolane and 1,3-Thiaselenole Derivatives

Recent advances in the design and synthesis of five-membered heterocycles containing both sulfur and selenium atoms—1,3-thiaselenolane and 1,3-thiaselenole derivatives—are discussed in this review. These heterocyclic systems are of interest as intermediates for organic synthesis and compounds that can exhibit various useful properties, including biological activity and electrical conductivity. The main focus of the review is on the works of the last 20 years that make use of catalytic reactions. Synthetic methods for the preparation of structurally related 1,4,5,8-diselenadithiafulvalenes based on catalytic cross-coupling reactions are also presented. To date, the design and synthesis of 1,3-thiaselenolane and 1,3-thiaselenole derivatives have not been discussed in a separate review.

1,2-Diborylsilanes: Catalytic Enantioselective Synthesis and Site-Selective Cross-Coupling.

A Pt-catalyzed enantioselective hydrosilylation of (Z)-1,2-diborylethylene provides a 1,2-diboryl-1-silylalkane that can be used in catalytic cross-coupling reactions. Depending on the catalyst employed and the cross-coupling reaction conditions, the coupling can occur at either α or β relative to the silane center.

Regioselective C-F Bond Transformations of Silyl Difluoroenolates.

Herein, we report the development of a nickel-catalyzed cross-coupling reaction of silyl difluoroenolates with aryl zinc reagents via C-F bond cleavage. Treatment of a stoichiometric amount of Ni(0)/N-heterocyclic carbene (NHC) with silyl difluoroenolates in the presence of a lithium salt resulted in C-F bond cleavage to selectively afford the corresponding (Z)-alkenyl Ni complexes. On the basis of the observations, we developed a catalytic cross-coupling reaction that selectively delivers a single geometric isomer of a fluoroenolate.

Synthesis of 2-Formyl Carbazoles via Tandem Reaction of Indolyl Nitrones with 2-Methylidene Cyclic Carbonate.

The synthesis of functionalized carbazoles as privileged nitrogen heterocycles has emerged as a central topic in drug discovery and material science. We herein disclose the rhodium(III)-catalyzed cross-coupling reaction between indolyl nitrones and 2-methylidene cyclic carbonate as an allylating surrogate, resulting in the formation of C2-formylated carbazoles via tandem C-H allylation, [3 + 2] cycloaddition, aromatization, and benzylic oxidation. The synthetic utility of this protocol is highlighted by a variety of post-transformations of C2-formylated carbazoles.

Enantioselective Radical-Type 1,2-Alkoxy-Phosphinoylation to Styrenes Catalyzed by Chiral Vanadyl Complexes.

A series of vanadyl complexes bearing 3-t-butyl-5-bromo, 3-aryl-5-bromo, 3,5-dihalo-, and benzo-fused N-salicylidene-tert-leucinates was examined as catalysts for 1,2-alkoxy-phosphinoylation of 4-, 3-, 3,4-, and 3,5-substituted styrene derivatives (including Me/t-Bu, Ph, OR, Cl/Br, OAc, NO2 , C(O)Me, CO2 Me, CN, and benzo-fused) with HP(O)Ph2 in the presence of t-BuOOH (TBHP) in a given alcohol or cosolvent with MeOH. The best scenario involved the use of 5 mol % 3-(2,5-dimethylphenyl)-5-Br (i.e., 3-DMP-5-Br) catalyst at 0 °C in MeOH. The desired catalytic cross coupling reactions proceeded smoothly with enantioselectivities of up to 95 % ee of (R)-configuration as confirmed by X-ray crystallographic analysis of several recrystallized products. The origin of enantiocontrol and homolytic substitution of the benzylic intermediates by vanadyl-bound methoxide and radical type catalytic mechanism were proposed.

Enantioselective Radical‐Type 1,2‐Alkoxy‐Phosphinoylation to Styrenes Catalyzed by Chiral Vanadyl Complexes

AbstractA series of vanadyl complexes bearing 3‐t‐butyl‐5‐bromo, 3‐aryl‐5‐bromo, 3,5‐dihalo‐, and benzo‐fused N‐salicylidene‐tert‐leucinates was examined as catalysts for 1,2‐alkoxy‐phosphinoylation of 4‐, 3‐, 3,4‐, and 3,5‐substituted styrene derivatives (including Me/t‐Bu, Ph, OR, Cl/Br, OAc, NO2, C(O)Me, CO2Me, CN, and benzo‐fused) with HP(O)Ph2 in the presence of t‐BuOOH (TBHP) in a given alcohol or cosolvent with MeOH. The best scenario involved the use of 5 mol % 3‐(2,5‐dimethylphenyl)‐5‐Br (i.e., 3‐DMP‐5‐Br) catalyst at 0 °C in MeOH. The desired catalytic cross coupling reactions proceeded smoothly with enantioselectivities of up to 95 % ee of (R)‐configuration as confirmed by X‐ray crystallographic analysis of several recrystallized products. The origin of enantiocontrol and homolytic substitution of the benzylic intermediates by vanadyl‐bound methoxide and radical type catalytic mechanism were proposed.

Catalytic Asymmetric Imine Cross-Coupling Reaction

Catalytic asymmetric cross-coupling of imines constitutes a particularly desirable method for the synthesis of chiral vicinal diamines directly from readily available achiral precursors. The potential of this method lies in the possibility of utilizing a variety of imines as reacting partners. However, the realization of highly stereoselective cross-coupling of two different imines proved to be a formidable challenge. Herein we report an unprecedented catalytic asymmetric cross-coupling reaction that tolerates a variety of ketimines and aldimines as nucleophiles and electrophiles, respectively. The realization of this reaction resulted from the development of a new chiral ammonium catalyst, which was guided by insights from studies of catalyst-substrate interactions. With a 0.5 mol % loading of an organocatalyst, this reaction proceeded in a highly diastereo- and enantioselective manner to afford a diverse range of chiral vicinal diamines as nearly single stereoisomers. This catalytic reaction establishes a new approach for the asymmetric synthesis of chiral vicinal diamines.

Induction heating enables efficient heterogeneous catalytic reactions over superparamagnetic nanocatalysts

Most catalytic processes are achieved by heating the whole reaction systems including the entire reactor, substrate and solvent, which leads to energy loss and obvious heat transfer limits. In this study, induction heating was employed to boost the catalytic Suzuki-Miyaura cross-coupling reactions by using conductive superparamagnetic microspheres with loaded Pd nanoparticles as heterogeneous catalysts. It was found that, at the same apparent reaction temperatures, the reactions by adopting the induction heating all exhibit better catalytic performance with higher conversion and yield, as compared to the reactions using conventional joule heating. The improvement is mainly attributed to the localized heating effect endowed by high efficiency of the heat transfer from the heat source to catalytic sites, which dissipates the electromagnetic energy through Néel relaxation mechanism. Moreover, it has be found that the reactions have been largely accelerated, resulting in much shorter reaction time required to approach a given value of reactant conversion. These results indicate that the unique heating method based on the superparamagnetic nanomaterials as both the inductive component and catalyst support holds a promising application for fast and efficient heterogeneous catalytic process, and exhibits potential for improving energy transfer efficiency and reducing the side reactions attributed to the uneven temperature profile.