Suzuki Miyaura Cross-coupling Research Articles

A Rationally Designed Iron(II) Catalyst for C(sp3)-C(sp2) and C(sp3)-C(sp3) Suzuki-Miyaura Cross-Coupling.

Despite the paramount importance of the Suzuki-Miyaura coupling (SMC) in academia and industry, and the great promise of iron to offer sustainable catalysis, iron-catalyzed SMC involving sp3-hybridized partners is still in its infancy. We herein report the development of a versatile, well-defined electron-deficient anilido-aldimine iron(II) catalyst. This catalyst effectively performed C(sp3)-C(sp2) and C(sp3)-C(sp3) SMC of alkyl halide electrophiles and (hetero)aryl boronic ester and alkyl borane nucleophiles respectively, in the presence of a lithium amide base. These couplings operated under mild reaction conditions and displayed wide functional group compatibility including various medicinally relevant N-, O- and S-based heterocycles. They also tolerated primary, secondary and tertiary alkyl halides (Br, Cl, I), electron-neutral, -rich and -poor boronic esters and primary and secondary alkyl boranes. Our methodology could be directly and efficiently applied to synthesize key intermediates relevant to pharmaceuticals and a potential drug candidate. For C(sp3)-C(sp2) couplings, radical probe experiments militated in favor of a carbon-centered radical derived from the electrophile. At the same time, reactions run with a pre-formed activated boron nucleophile coupled to competition experiments supported the involvement of neutral, rather than an anionic, (hetero)aryl boronic ester in the key transmetalation step.

Discovery of a New Class of Lipophilic Pyrimidine-Biphenyl Herbicides Using an Integrated Experimental-Computational Approach

Herbicides are useful tools for managing weeds and promoting food production and sustainable agriculture. In this study, we report on the development of a novel class of lipophilic pyrimidine-biphenyl (PMB) herbicides. Firstly, three PMBs, Ia, IIa, and IIIa, were rationally designed via a scaffold hopping strategy and were determined to inhibit acetohydroxyacid synthase (AHAS). Computational simulation was carried out to investigate the molecular basis for the efficiency of PMBs against AHAS. With a rational binding mode, and the highest in vitro as well as in vivo potency, Ia was identified as a preferable hit. Furthermore, these integrated analyses guided the design of eighteen new PMBs, which were synthesized via a one-step Suzuki–Miyaura cross-coupling reaction. These new PMBs, Iba-ic, were more effective in post-emergence control of grass weeds compared with Ia. Interestingly, six of the PMBs displayed 98–100% inhibition in the control of grass weeds at 750 g ai/ha. Remarkably, Ica exhibited ≥ 80% control against grass weeds at 187.5 g ai/ha. Overall, our comprehensive and systematic investigation revealed that a structurally distinct class of lipophilic PMB herbicides, which pair excellent herbicidal activities with new interactions with AHAS, represent a noteworthy development in the pursuit of sustainable weed control solutions.

Solvent-Switchable Remote C-H Activation via 1,4-Palladium Migration Enables Site-Selective C-P Bond Formation: A Tool for the Synthesis of P-Chiral Phosphinyl Imidazoles.

Solvent-switchable and site-selective phosphorylation of imidazoles at the C2 or C5 position of the imidazole ring was achieved via 1,4-palladium migration. P-Chiral tert-butyl(aryl)phosphine oxides were cross-coupled to 1-(2-bromophenyl)-1H-imidazoles with high enantiospecificity, thereby leading to a novel class of chiral imidazole-based phosphine oxides. As proof of concept, reduction of an analogue yielded the corresponding P-chiral 2-phosphinyl imidazole ligand, which was shown to induce high enantioselectivity in the formation of axially chiral molecules synthesized via Pd-catalyzed Suzuki-Miyaura cross-coupling.

Pd-Catalyzed Miyaura Borylation and Telescopic Borylation/Suzuki-Miyaura Cross-Coupling Processes in Deep-Eutectic Solvents.

We report an efficient procedure to carry out palladium-catalyzed Miyaura borylation reactions of (hetero)aromatic halides and triflates in choline chloride (ChCl)-based deep eutectic solvents (DESs). The procedure employs bis(pinacolato)diboron as a boron source and a catalyst prepared in situ from readily available Pd2(dba)3 and the phosphine ligand XPhos. Reactions proceed well in different ChCl-based DESs, among which the best results were provided by environmentally friendly and biodegradable mixtures with glycerol and glucose. The reaction tolerates both EDG and EWG substituents on the substrates and can be run on different halides (chloride, bromide, iodide) and pseudohalides (triflate). Furthermore, for several substrates, the catalyst loading can be reduced to 1 mol % Pd (0.5% mol Pd2(dba)3) without compromising the reaction yield. Moreover, we show that the Miyaura borylation protocol in DES can be combined with a subsequent Suzuki-Miyaura cross-coupling reaction in a one-pot procedure, allowing access to various biaryl products and demonstrating its synthetic utility by preparing the precursors of two compounds with reported applications in the photovoltaics sector. Finally, two green metrics (E-factor and EcoScale) of the new one-pot procedure in DES were calculated and compared with literature values to assess the potential advantages in terms of waste reduction, safety, and energy consumption.

Synthesis of novel 7-substituted pyrido[3,2-b]pyrazin-3(4H)-one derivatives via Suzuki-Miyaura cross-coupling reaction

In this work, 7-substituted Pyrido[3,2-b]pyrazin-3(4H)-one derivatives are reported starting from 4-methyl-3-nitropyridin-2-amine [1], which underwent further transformations followed by Suzuki–Miyaura coupling reaction under microwave conditions. Primarily, 5-bromo-4-methyl-3-nitropyridin-2-amine (Conejo-Garcia et al., 2010) [2] was prepared according to literature, was converted into many other derivative forms that involve different types of reactions like, reduction, cyclization, chlorination, N-alkylation and yielded as 7-bromo-2,8-dimethyl-4-(2-oxo-2-(pyrrolidin-1-yl)ethyl)pyrido[2,3-b]pyrazin-3(4H)-one (Kamble et al., 2016) [6] which was further subjecting with versatile boronic acids via Suzuki–Miyaura coupling to make comparable novel 7-substituted Pyrido[3,2-b]pyrazin-3(4H)-one derivatives (8a-p). The chemical constructions of all yielded compounds were well elucidated by analytical and spectral analyses (TLC, 1H NMR, 13C NMR, and HRMS).

Total synthesis of (-)-ilicicolin H

A concise total synthesis of (-)-ilicicolin H was efficiently achieved in 9 steps from commercially available (S)-(-)-citronellol. Key steps include a strategic convergent method to synthesize the densely substituted pyridone key intermediate by Suzuki-Miyaura cross-coupling reaction, a facile construction of polyene fragment through a regioselective Wittig olefination and construction of the decalin moiety via IMDA. Herein, we describe our efforts towards the synthesis of (-)-ilicicolin H..

Regioselective Propargylic Suzuki-Miyaura Coupling by SciPROP-Iron Catalyst.

The iron-catalyzed Suzuki-Miyaura cross-coupling of secondary propargyl electrophiles with lithium organoborates has been established. A propyl-bridged bulky bisphosphine ligand, SciPROP-TB, cooperated with the bulky TIPS substituent at the alkyne terminal position to achieve the cross-coupling reaction with exclusive propargylic selectivity. The reaction features high functional group compatibility, regioselectivity, and yield with a broad substrate scope. The reaction of an optically active chiral propargyl bromide proceeds with complete racemization, supporting a mechanism involving propargyl radical formation.

Synthesis and properties of 6-alkynyl-5-aryluracils.

The development of a new and straightforward chemoselective method for the synthesis of uracil-based structures by combining Suzuki-Miyaura and Sonogashira-Hagihara cross-coupling is reported. The methodology was applied to synthesize a series of novel compounds. The tolerance of the combination of different functional groups was tested. The influence of different functional groups on the physical properties was studied by ultraviolet-visible (UV-vis) and fluorescence spectroscopy, providing new insights into the potential applications of uracil-based structures.

Nickel (II) imidazol-2-ylidine Complexes Supported Through Internally Functionalized Amido Linkage Synthesis and Catalytic Studies for Suzuki Miyaura Cross Coupling

Nickel (II) imidazol-2-ylidine Complexes Supported Through Internally Functionalized Amido Linkage Synthesis and Catalytic Studies for Suzuki Miyaura Cross Coupling

Exploring the energetics of Suzuki cross-coupling reaction: A computational study of palladium and nickel catalysts

The present study employed density-functional theory (DFT) calculations to investigate the Suzuki-Miyaura Cross-Coupling reaction using single atom catalysis (SAC) via palladium or nickel. The reaction barriers for chloride bond cleavage in phenyl chloride were found to be 34.68 kJ/mol and 24.24 kJ/mol for palladium and nickel catalysts, respectively. During the transmetalation process, the energy barrier for boronic acid release from phenyl trihydroxyboronate using SAC via palladium and SAC via nickel was calculated to be 74.17 kJ/mol and 65.22 kJ/mol, respectively. The results indicated that in the oxidative addition and transmetalation reactions, the SAC via nickel outperforms the SAC via palladium, while the SAC via palladium excels in the reductive elimination reaction. These findings suggest the effectiveness of a SAC via nickel as a substitute for SAC via palladium in the synthesis of biphenyls in the Suzuki-Miyaura cross-coupling reaction.

Droplet-Based Microfluidics Reveals Insights into Cross-Coupling Mechanisms over Single-Atom Heterogeneous Catalysts.

Single-atom heterogeneous catalysts (SACs) hold promise as sustainable alternatives to metal complexes in organic transformations. However, their working structure and dynamics remain poorly understood, hindering advances in their design. Exploiting the unique features of droplet-based microfluidics, we present the first in-situ assessment of a palladium SAC based on exfoliated carbon nitride in Suzuki-Miyaura cross-coupling using X-ray absorption spectroscopy. Our results confirm a surface-catalyzed mechanism, revealing the distinct electronic structure of active Pd centers compared to homogeneous systems, and providing insights into the stabilizing role of ligands and bases. This study establishes a valuable framework for advancing mechanistic understanding of organic syntheses catalyzed by SACs.

Novel diarylated tacrine derivatives: Synthesis, characterization, anticancer, antiepileptic, antibacterial, and antifungal activities.

In this study, our goal was to synthesize novel aryl tacrine derivatives and assess their potential as anticancer, antibacterial agents, and enzyme inhibitors. We adopted a two-step approach, initiating with the synthesis of dibromotacrine derivatives 3 and 4 through the Friedlander reaction. These intermediates underwent further transformation into diarylated tacrine derivatives 3a-e and 4a-e using a Suzuki-Miyaura cross-coupling reaction. Thorough characterization of these novel diarylated tacrines was achieved using various spectroscopic techniques. Our findings highlighted the potent anticancer effects of these innovative compounds across a range of cancer cell lines, including lung, gynecologic, bone, colon, and breast cancers, while demonstrating low cytotoxicity against normal cells. Notably, these compounds surpassed the control drug, 5-Fluorouracil, in terms of antiproliferative activity in numerous cancer cell lines. Moreover, our investigation included an analysis of the inhibitory properties of these novel compounds against various microorganisms and cytosolic carbonic anhydrase enzymes. The results suggest their potential for further exploration as cancer-specific, enzyme inhibitory, and antibacterial therapeutic agents. Notably, four compounds, namely, 5,7-bis(4-(methylthio)phenyl)tacrine (3d), 5,7-bis(4-(trifluoromethoxy)phenyl)tacrine (3e), 2,4-bis(4-(trifluoromethoxy)phenyl)-7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-amine (4e), and 6,8-dibromotacrine (3), emerged as the most promising candidates for preclinical studies.

Donor-donor-acceptor (D-D-A) luminogens containing a central carbazole core: Aggregation-induced emission (AIE), full-color solid-state emission and diverse mechanofluorochromic characteristics

The construction of multi-functionalized luminophores with full-color emission based on the same core skeleton is an appealing yet significantly challenging task. In this work, we rationally designed and facilely constructed a series of donor-donor-acceptor (D-D-A) based luminogens by representative Suzuki-Miyaura cross-coupling reaction. Using electron-donating carbazole with hexyl chain as basic core structure, a series of donor-donor-acceptor (D-D-A) typed luminogens with different donor and acceptor units were designed and synthesized. Some compounds showed AIEE or aggregate fluorescence change behaviors due to TICT and RIM. Among them, these compounds displayed diverse mechanofluorochromic characteristics, including reversible or irreversible, red-shifted or blue-shifted mechanofluorochromisms. This provided new ideas for the development of multifunctional organic light-emitting molecules.

TiO2 supported pallidum-bipyridyl complex as an efficient catalyst for Suzuki–Miyaura reaction in aqueous-ethanol

Owing to their improved catalytic stability and ability to undergo repeated cycles, solid-supported catalysts show great potential for various catalytic reactions. In this study, we synthesized a catalyst comprising a palladium-2,2-bipyridine complex supported on TiO2 nanoparticles (TiO2@BDP-PdCl2) fully characterised and investigated its efficacy in Suzuki–Miyaura cross coupling reactions involving phenyl boronic acid with various aryl halides under mild reaction conditions. The 2,2′- bipyridine (bp) has shown excellent complexation properties for Pd (II) and it could be easily anchored onto functionalized TiO2 support by the bridging carboxylate ions. The composition and structure of the as-prepared catalyst was characterized by powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), Transmission Electron Microscope (TEM), X-ray photoelectron spectroscopy (XPS), and UV–Vis spectroscopy. The catalyst easily demonstrated separability, enhancing its practicality in catalytic processes. Subsequent utilization showed a consistent activity level, suggesting the stabilization of the aggregated catalyst species. This research sheds light on the importance of catalyst stability and maintenance during consecutive reaction cycles.

Rational molecular design converting fascaplysin derivatives to potent broad-spectrum inhibitors against bacterial pathogens via targeting FtsZ

The filamentous temperature-sensitive mutant Z protein (FtsZ), a key player in bacterial cell division machinery, emerges as an attractive target to tackle the plight posed by the ever growing antibiotic resistance over the world. Therefore in this regard, agents with scaffold diversities and broad-spectrum antibacterial activity against Gram-positive and Gram-negative pathogens are highly needed. In this study, a new class of marine-derived fascaplysin derivatives has been designed and synthesized by Suzuki-Miyaura cross-coupling. Some compounds exhibited potent bactericidal activities against a panel of Gram-positive (MIC = 0.024–6.25 μg/mL) and Gram-negative (MIC = 1.56–12.5 μg/mL) bacteria including methicillin-resistant S. aureus (MRSA). They exerted their effects by dual action mechanism via disrupting the integrity of the bacterial cell membrane and targeting FtsZ protein. These compounds stimulated polymerization of FtsZ monomers and bundling of the polymers, and stabilized the resulting polymer network, thus leading to the dysfunction of FtsZ in cell division. In addition, these agents showed negligible hemolytic activity and low cytotoxicity to mammalian cells. The studies on docking and molecular dynamics simulations suggest that these inhibitors bind to the hydrophilic inter-domain cleft of FtsZ protein and the insights obtained in this study would facilitate the development of potential drugs with broad-spectrum bioactivities.

Evaluation of hemilabile Pd(II) NNS and NNSe non-symmetric pincers in Suzuki–Miyaura cross-coupling: Unexpected selective nitrile hydration of 4-bromonitrobenzene in mild conditions

In this work, four non-symmetric NNS and NNSe Pd(II) pincer complexes (1–4) supported by tridentate iminophosphorane ligands bearing both the indole heterocycle and a varying chalcogenoether pending arm [XR = SPh (1), SePh (2), SMe (3), SeMe (4)], were tested in the Suzuki–Miyaura cross coupling reaction between phenyl boronic acid and aryl bromides. The modest catalytic activity of complex 3 under conventional heating (110 °C), was boosted under microwave irradiation, leading to excellent yields of coupling under remarkably mild conditions: 5 min of reaction time at 70 °C under aerobic conditions. The complexes supported by NNS ligands proved to be more robust and superior catalysts than those supported by NNSe ligands, which tended to decompose under catalytic conditions. Among the four complexes, pincer 3 also demonstrated the best catalytic performance and was tested in the coupling of a variety of p-substituted bromobenzenes. Notably, the catalytic performance of complex 3 was unaffected by the mercury drop test, and with most substrates in the series, the percentage of conversion reflected the aryl bromides’ Hammett parameter. However, little to no coupling occurred with p-bromobenzonitrile and the reaction with p-nitrobenzene resulted in only limited conversion yields. In fact, when activated using microwave irradiation, complex 3 unexpectedly catalyzed the nitrile hydration of p-bromobenzonitrile, yielding p-bromobenzamide under remarkably mild Suzuki–Miyaura coupling conditions.

Stereospecific Palladium-Catalyzed Cross-Coupling of Alkylboron Compounds: A Short Account

AbstractStereospecific approaches allow the introduction of a stereogenic center into complex organic molecules using optically active reagents. Among these, the Pd-catalyzed stereospecific cross-coupling of chiral alkylboron compounds stands out as a highly effective tool for organic synthesis. In parallel with advances in the development of borylation technology, the strategy has recently witnessed a growth in its applicability. This account aims to review the progress on Pd-catalyzed stereospecific B-alkyl Suzuki–Miyaura cross-coupling, tracing its evolution from early breakthroughs to the most recent advances.1 Introduction2 Cross-Coupling of 1° Alkylboron Compounds3 Cross-Coupling of Benzylboron Compounds4 Cross-Coupling of Allyl- and Propargylboron Compounds5 Cross-Coupling of Other Types of Activated 2° Alkylboron Compounds6 Cross-Coupling of Unactivated 2° Alkylboron Compounds7 Conclusion and Outlook

Rapid, Homogenous, B-Alkyl Suzuki-Miyaura Cross-Coupling of Boronic Esters.

A rapid, anhydrous Suzuki-Miyaura cross-coupling of alkylboronic esters with aryl halides is described. Parallel experimentation revealed that the combination of AntPhos, an oxaphosphole ligand, neopentyldiol alkylboronic esters, and potassium trimethylsilanolate (TMSOK) enables successful cross-coupling. In general, reactions proceed in under 1 h with good yields and high linear/branched (l/b) selectivities. Crucially, two literature examples which previously took >20 h to reach completion were accomplished in a fraction of the time with the method described herein. Mechanistic studies revealed that the reaction proceeds through a stereoretentive pathway and identified the boronic ester skeleton as a predominant pathway for deleterious protodehalogenation.

Effects of Ring Size and Steric Encumbrance on Boron-to-Palladium Transmetalation from Arylboronic Esters.

The structure of the diol from which an arylboronic ester is derived dramatically influences the rate of transmetalation in the Suzuki-Miyaura cross-coupling reaction. Some esters undergo transmetalation more than 20 times faster than the parent arylboronic acid. Herein, investigations into the influence of arylboronic ester ring size and steric properties on the mechanism of transmetalation in the Suzuki-Miyaura reaction are described. Both factors impact the propensity of an arylboronic ester to bind to a dimeric palladium hydroxide complex. The reaction of hindered arylboronic esters derived from 1,2-diols (1,3,2-dioxaborolanes) with palladium hydroxide dimers to form a complex incorporating a Pd-O-B linkage is thermodynamically favorable, but the barrier to coordination is often higher than the barrier to arene transfer. In contrast, the analogous reaction between arylboronic esters derived from 1,3-diols (1,3,2-dioxaborinanes) and palladium hydroxide dimers is thermodynamically unfavorable, as 1,3,2-dioxaborinanes exhibit decreased electrophilicity compared to esters derived from 1,2- or 1,4-diols. These factors also influence the barrier of the arene transfer step, and in many cases, arylboronic esters that do not easily form Pd-O-B linked complexes undergo transmetalation faster than those that do because of hyperconjugative stabilization of the arene transfer transition state.

Single-Molecule Catalysis in the Palladium Cross-Coupling Reaction Cycle.

Single-molecule (SM) methods are applied to study various types of catalytic processes in chemical and biochemical reactions. In this study, the Suzuki-Miyaura cross-coupling reaction forming a fluorescent product is investigated within the SM approximation. Stochastic analysis of emission intermittency in selected nanoscopic spots allows us to determine the single-molecule turnover frequency (SM-TOF) of the Pd catalyst in a specific probe reaction. We generate and analyze simulated intermittency time traces of a single catalyst surrounded by reactant molecules to assess the reliability of the method applied to real intermittency time trace data from hundreds of nanoscopic fluorescence spots. The results demonstrate that the proposed method can be used to evaluate the average SM-TOF of Pd in a cross-coupling reaction.