Suzuki-Miyaura Cross-coupling Reaction Research Articles

Synthesis of benzo[f]quinazoline-1,3(2H,4H)-diones

We report the synthesis of polycyclic uracil derivatives. The method is based on palladium-catalysed Sonogashira–Hagihara and Suzuki–Miyaura cross-coupling reactions followed by Brønsted acid-mediated cycloisomerisation. The developed methodology tolerates various functional groups and leads to moderate up to quantitative yields of the final products. The impact of different functional groups on the optical properties was studied by UV–vis and fluorescence spectroscopy.

NiII, PdII and PtII pincer complexes of 2-(diphenylphosphanyl)-N-(2-(diphenyl-phosphanyl)benzyl)benzamide: synthesis, reactivity and catalytic studies.

In this article, the synthesis of bis(phosphine), o-Ph2PC6H4C(O)N(H)CH2C6H4PPh2-o (1) (hereafter referred to as "PCNHCP" and its anionic form as "PCNCP") and its group 10 metal chemistry and catalytic studies are described. PCNHCP (1) on reaction with NiCl2(DME) and PdCl2(COD) afforded pincer complexes, [MCl{(PCNCP)κ3-P,N,P}] (M = Ni, 2; Pd, 3). A similar reaction of 1 with PtCl2(COD) yielded a chelate complex, [PtCl2{(PCNHCP)κ2-P,P}] (4), which on further treatment with LiHMDS produced the 1,2-azaphospholene-phosphine complex, [PtCl(Ph){(o-P(Ph)C6H4CONCH2C6H4PPh2-o)κ2-P,P}] (5) via P-C/P-N bond metathesis. Passing dry HCl gas through the solution of 5 resulted in benzene elimination to form [PtCl2{(o-P(Ph)C6H4CONCH2C6H4PPh2-o)κ2-P,P}] (6). Treatment of 1 with PtCl2(COD) and Pt(Cl)(Me)(COD) in the presence of a base resulted in pincer complexes [PtX{(PCNCP)κ3-P,N,P}] (X = Cl, 7; Me, 8). Nickel complex 2 catalyzed the Suzuki-Miyaura cross coupling reaction between bromobenzene and phenyl boronic acid to give the corresponding biphenyls in good yield. The platinum complex 5 showed good catalytic activity towards regio- and stereoselective hydroboration of terminal alkynes. Both the catalytic reactions were performed under mild reaction conditions with a very low catalyst loading.

Upcycling of Chitin to Cross-Coupling Catalysts: Tailored Supports and Opportunities in Mechanochemistry.

In this study chitin derived from shrimp shells was used in the design of heterogeneous Pd-based catalysts for Heck and Suzuki-Miyaura cross-coupling reactions. The synthesis of Pd nanoparticles supported on N-doped carbons was performed through different approaches, including a sustainable mechanochemical approach, by using a twin-screw extruder. All catalytic systems were characterized by a multitechnique approach and the effect of nanoparticles size, N-doping on the support, and their synergistic interactions were elucidated. Specifically, Kelvin Probe Atomic Force Microscopy provided valuable insights on charge transfer and metal-support interactions. The catalytic behaviour of the samples was investigated in cross-coupling reactions under batch conditions and under semi-continuous flow solvent-free conditions, respectively obtaining a quantitative yield and a noteworthy productivity of 8.7 mol/(gPdh).

Advancing Base-Metal Catalysis: Developing Nickel Catalysis for the Direct Telescope of Miyaura Borylation and Suzuki–Miyaura Cross-Coupling Reactions

Advancing Base-Metal Catalysis: Developing Nickel Catalysis for the Direct Telescope of Miyaura Borylation and Suzuki–Miyaura Cross-Coupling Reactions

Cyclization by Intramolecular Suzuki-Miyaura Cross-Coupling - A Review.

Ring systems of all sizes are frequent core or substructures in natural products and they are important elements of many drug molecules, as they often confer high binding affinity to and selectivity for disease-relevant biological targets. A uniform key transformation in the synthesis of such structures is the cyclization step. Among the various approaches that have been developed for ring closure, the intramolecular Suzuki-Miyaura reaction has emerged as a powerful option for the construction of normal- and medium-sized rings as well as macrocycles, due to its stereospecificity, the mild reaction conditions, and the non-toxic nature of the boron by-products. In this review, we summarize the state-of-the-art of the application of intramolecular Suzuki-Miyaura cross-coupling reactions in the construction of (macro)cyclic frameworks of natural products and bioactive molecules of synthetic origin, covering (mostly) examples that have been reported since 2015. Target molecules prepared via intramolecular Suzuki-Miyaura cross-coupling as a key step range from natural products / natural product analogs to synthetic drug candidates, featuring ring sizes from 4 to >>12. We highlight the utility, scope, and limitations of the reaction for different ring sizes and arrays of functional groups. Where possible, comparisons with other methods of cyclization are provided.

Organoboron catalysis for direct amide/peptide bond formation.

Amides and peptides are ubiquitous functional groups found in several natural and artificial materials, and they are essential for the advancement of life and material sciences. In particular, their relevance in clinical medicine and drug discovery has increased in recent years. Dehydrative condensation of readily available carboxylic acids with amines is the most "direct" method for amide synthesis; however, this methodology generally requires a stoichiometric amount of condensation agent (coupling reagent). Catalytic direct dehydrative amidation has become an "ideal" methodology for synthesizing amides from the perspective of green chemistry, with water as the only byproduct in principle, high atom efficiency, environmentally friendly, energy saving, and safety. Conversely, organoboron compounds, such as boronic acids, which are widely used in various industries as coupling reagents for Suzuki-Miyaura cross-coupling reactions or pharmaceutical structures, are environmentally friendly molecules that have low toxicity and are easy to handle. Based on the chemical properties of organoboron compounds, they have potential Lewis acidity and the ability to form reversible covalent bonds with dehydration, making them attractive as catalysts. This review explores studies on the development of direct dehydrative amide/peptide bond formation reactions from carboxylic acids using organoboron catalysis, classifying them based on chemical bonding and catalysis over approximately 25 years, from the early developmental days to 2023.

A convenient bottom up route to covalently anchor Pd(II)-PEPPSI on layered zirconium(IV) phosphonate: Efficient catalyst for Suzuki-Miyaura cross coupling of aryl chlorides

A rational and bottom-up route for assembling layered Zr(IV) phosphonate framework decorated with covalently anchored N-heterocyclic carbene NHC-Pd(II) fragment has been developed. Reaction of phosphonic acid functionalized Pd(II)-NHC precursor complex with ZrOCl2·8H2O provides easy access to a layered material with covalently anchored catalytically active Pd(II)-NHC sites. The Pd(II)-NHC functionalized Zr(IV) phosphonate showed enhanced catalytic activity in Suzuki-Miyaura cross coupling reaction of both aryl bromides and chlorides with aryl boronic acid, as compared to their homogeneous counterparts. The Zr(IV) phosphonate framework imparts remarkable robustness to the Pd(II)-NHC catalyst and allowed recycling of the catalyst up to nine catalytic cycles without any major loss of catalytic activity.

Base-free aqueous Suzuki-Miyaura coupling reaction using recoverable bi-functional Pd supported nanocatalyst

A solid base catalyst comprising pyridine-palladium polyorganosiloxane framework was synthesized via a grafting method. The resulting organic–inorganic hybrid palladium nanomaterial was characterized by 13C CP-MAS NMR, 29Si CP-MAS NMR, XRD, EDX, TEM, TGA, and the BET measurements. The hybrid palladium nanomaterial exhibited high catalytic activity for the Suzuki–Miyaura cross-coupling reaction between aryl chlorides and phenylboronic acid under base-free and aerobic conditions. A maximum turnover number (TON) of 3150, with a 0.2 mol% Pd loading and a reaction temperature of 80 °C in aqueous solution. The catalyst demonstrated remarkable stability, maintaining its activity even after six cycles of reuse without significant loss of activity. TEM images showed that the catalyst retained its structure and high-order mesostructure after several uses. ICP-AES also confirmed the absence of palladium contamination in the final products. Leaching test studies further confirmed the true heterogeneous nature of the developed catalytic system.

New Tricyclic Aryl Quinazoline Derivatives by Suzuki-Miyaura Cross-Coupling.

A number of new deoxyvasicinone (2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one) and mackinazolinone (6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazolin-11-one) derivatives with aryl substituents at C7/C8 and at C5 are reported. These compounds are rare representatives of their kind and were prepared in high yields by Suzuki-Miyaura cross-coupling reactions between 7-bromo-2,3-dihydro[2,1-b]quinazoline-9-(1H)-one, 5,7-dibromo-2,3-dihydro[2,1-b]quinazoline-9-(1H)-one or 8-bromomackinazolinone and respective arylboronic acids with palladium acetate as the catalyst. The products were characterized spectroscopically and, in addition, by X-ray crystal structure analyses in six cases.

Chemical Graph-Based Transformer Models for Yield Prediction of High-Throughput Cross-Coupling Reaction Datasets.

The chemical reaction yield is an important factor to determine the reaction conditions. Recently, many data-driven models for yield prediction using high-throughput experimentation datasets have been reported. In this study, we propose a neural network architecture based on the chemical graphs of the reaction components to predict the reaction yield. The proposed model is the sequential combination of a message-passing neural network and a transformer encoder (MPNN-Transformer). The reaction components are converted to molecular matrices by the first network, followed by the interplay of the reaction components in the second network after adding the embeddings of the compound roles in the chemical reaction. The predictive ability of the proposed models was compared with state-of-the-art yield prediction models using two high-throughput experimental datasets: the Buchwald-Hartwig cross-coupling (BHC) and Suzuki-Miyaura cross-coupling (SMC) reaction datasets. Overall, the MPNN-Transformer models showed high prediction accuracy for the BHC reaction datasets and some of the extrapolation-oriented SMC reaction datasets. These models also performed well when the training dataset size was relatively large. Furthermore, analyzing the poorly predicted reactions for the BHC reaction dataset revealed a limitation of the data-driven yield prediction approach based on the chemical structural similarity.

Revealing the Hidden Complexity and Reactivity of Palladacyclic Precatalysts: The P(o-tolyl)3 Ligand Enables a Cocktail of Active Species Utilizing the Pd(II)/Pd(IV) and Pd(0)/Pd(II) Pathways for Efficient Catalysis.

The ligand, P(o-tolyl)3, is ubiquitous in applied synthetic chemistry and catalysis, particularly in Pd-catalyzed processes, which typically include Pd(OAc)2 (most commonly used as Pd3(OAc)6) as a precatalyst. The Herrmann-Beller palladacycle [Pd(C^P)(μ2-OAc)]2 (where C^P = monocyclopalladated P(o-tolyl)3) is easily formed from reaction of Pd(OAc)2 with P(o-tolyl)3. The mechanisms by which this precatalyst system operates are inherently complex, with studies previously implicating Pd nanoparticles (PdNPs) as reservoirs for active Pd(0) species in arylative cross-coupling reactions. In this study, we reveal the fascinating, complex, and nontrivial behavior of the palladacyclic group. First, in the presence of hydroxide base, [Pd(C^P)(μ2-OAc)]2 is readily converted into an activated form, [Pd(C^P)(μ2-OH)]2, which serves as a conduit for activation to catalytically relevant species. Second, palladacyclization imparts unique stability for catalytic species under reaction conditions, bringing into play a Pd(II)/Pd(IV) cross-coupling mechanism. For a benchmark Suzuki-Miyaura cross-coupling (SMCC) reaction, there is a shift from a mononuclear Pd catalytic pathway to a PdNP-controlled catalytic pathway during the reaction. The activation pathway of [Pd(C^P)(μ2-OH)]2 has been studied using an arylphosphine-stabilized boronic acid and low-temperature NMR spectroscopic analysis, which sheds light on the preactivation step, with water and/or acid being critical for the formation of active Pd(0) and Pd(II) species. In situ reaction monitoring has demonstrated that there is a sensitivity to the structure of the arylboron species in the presence of pinacol. This work, taken together, highlights the mechanistic complexity accompanying the use of palladacyclic precatalyst systems. It builds on recent findings involving related Pd(OAc)2/PPh3 precatalyst systems which readily form higher order Pdn clusters and PdNPs under cross-coupling reaction conditions. Thus, generally, one needs to be cautious with the assumption that Pd(OAc)2/tertiary phosphine mixtures cleanly deliver mononuclear "Pd(0)Ln" species and that any assessment of individual phosphine ligands may need to be taken on a case-by-case basis.

Thiocarbohydrazide-cross-linked pectin: A promising support material for palladium nanoparticles in the water-mediated Suzuki-Miyaura cross-coupling reaction and the catalytic reduction of 4-nitrophenol

Suzuki-Miyaura reaction is a classic palladium-catalyzed reaction for forming Csp2-Csp2 bonds. However, the leaching of Pd species and using organic solvents are two important problems that adversely affect their performance, reusability, and greenness. Considering the abundant resources, cheapness, and availability of pectin (Pec), a Pec-based catalyst for the Suzuki reaction in pure water as a non-toxic reaction medium was developed for the first time. In this regard, Pec was chosen as a benign support and cross-linked by thiocarbohydrazide (TCH) to prepare Pec-TCH. The Pec-TCH acted as an efficient reducing and stabilizing agent for in-situ fabrication of Pd(0) nanoparticles. The heterogeneous and air-stable Pec-TCH-Pd(0) nanoparticles were thoroughly characterized. The results exhibited a significant catalytic activity (up to 99%) and reusability (at least 7 times) for in-water Suzuki-Miyaura cross-coupling reaction. The use of TBAB as a phase-transfer catalyst improved the yield of Suzuki reaction since it prevented the problems related to the immiscibility of water and aryl halides as well as the gelation of catalyst. The catalyst was also utilized for water-mediated 4-nitrophenol reduction to 4-aminophenol with NaBH4 which showed excellent activity (k = 9.2 × 10−3 s−1). A very good compatibility with iodobenzene, bromobenzene, and chlorobenzene was observed for the Suzuki reaction. Because of various binding sites such as amino, hydroxyl, carbonyl and thiocarbonyl groups, negligible leach of Pd nanoparticles was observed, as shown by ICP-MS after runing 7th of reusability studies. Moreover, the leaching, mercury poisoning, and large-scale tests showed its potential for industrial applications.

Morphology-dependent support effect of PdCu/alpha-Fe2O3 catalysts on Suzuki-Miyaura cross-coupling reaction

The palladium-catalyzed Suzuki-Miyaura cross-coupling (SMC) reaction has received worldwide attention as a powerful and convenient synthetic tool for the formation of biaryl compounds. However, these reactions are highly dependent on the activity and stable of catalysts. Herein, the support morphology-dependent catalytic performance of SMC reactions was investigated. The truncated hexagonal bipyramid (α-Fe2O3-O) and rod-shaped morphologies of alpha-Fe2O3 (α-Fe2O3-R) were used as support to prepare PdCu nanoparticles (NPs) catalysts by NaBH4 reduction method. For PdCu/α-Fe2O3-R catalysts, the smaller size of PdCu NPs and more low coordination Pd sites leading to its superior catalytic performance for SMC reactions. Furthermore, it can be easily recycled through centrifugation and reused several times without obvious loss on its catalytic performance. Identical location transmission electron microscopy method was used to investigate the structural evolution of PdCu/α-Fe2O3-R catalysts. The results found that its structure almost unchanged during the catalytic reaction.

Pd(0)/Xantphos-Catalyzed Benzylic C(sp3)-O Arylation of Benzyl Heteroaryl Ethers: Reduction of Pd(II) to Pd(0) by Xantphos.

Herein, we report the synthesis of 1,1-diarylmethanes via palladium-catalyzed benzylic C(sp3)-O arylation of benzyl alcohol derivatives. An efficient, straightforward approach to synthesizing Pd(0)(xantphos)2 was developed through in situ reduction of Pd(II) to Pd(0) with the bidentate tertiary phosphine xantphos, which proved to be a highly active precatalyst in the Suzuki-Miyaura cross-coupling reaction of benzyl heteroaryl ethers.

Expeditious assembly of N-heteroaryl substituted quercetin derivatives as potent anticancer agents

The synthesis of a small library of N-heteroaryl substituted quercetin derivatives (28 compounds) at the C8 position applying Suzuki-Miyaura cross-coupling reaction between 8-iodoquercetin methyl ether and various pyridylboronic acids or quinolylboronic acids is reported. The obtained quercetin derivatives 2a-2n and 3a-3n were well characterized by the 1H NMR, 13C NMR and HRMS data. Preliminary biological evaluations showed that some of the synthesized 8-heteroarylated quercetin derivatives possessed very high anti-cancer cell proliferation activity in HCC827 cancer cell line (IC50< 5.0 µmol/L) in vitro. Among these synthesized compounds, quinolin-7-yl substituted compound 2m exhibited best activity in HCC827 (IC50 = 3.20 µmol/L), while quinolin-3-yl substituted compound 2i showed best activity in MGC-803 cells (IC50 = 14.92 µmol/L). The 3-pyridyl compound 3c with ortho-fluorine showed best activity in OVCAR-3 cells (IC50 = 10.67 µmol/L). The disclosed structure-activity relationship provides hints that large steric hindrance at the C8 position of quercetin alter the anticancer activities and also offers new examples for new application of electronic and steric modifications as versatile tools in drug discovery.

Ag-Cu2O Supported Biomass-Derived rGO for Catalyzing Suzuki-Miyaura Cross-Coupling.

The search for cost-effective, efficient, and ecofriendly heterogeneous catalysts for the Suzuki-Miyaura reaction is crucial due to challenges with expensive, toxic homogeneous catalysts. This study centrally aims at crafting a pioneering green catalyst by adorning reduced graphene oxide (rGO), sourced from basil seeds (Ocimum basilicum L.), with an Ag-Cu2O composite structure. Comprehensive characterization of the Ag-Cu2O/rGO nanocomposite was conducted through FTIR, SEM, hHR-TEM, EDS, XPS, XRD, TGA, and N2 adsorption/desorption analyses. Results showed that nanosized Ag-Cu2O particles were partially integrated into rGO sheets derived from basil seeds, acting as active species for oxidative addition with aryl halides in the SMR. The catalytic efficacy of this robust nanocatalyst was assessed in Suzuki-Miyaura cross-coupling reactions, targeting the synthesis of biaryls employing various aryl halides and aryl boronic acids. The findings underscore that the Ag-Cu2O/rGO nanocatalyst manifests rapid reaction kinetics (15 min) alongside commendable yields (99%). The Ag-Cu2O/rGO demonstrates impressive recyclability, maintaining catalytic efficiency over four cycles. Utilizing it as a green substrate for metal loading highlights its potential, offering well-defined coordination sites. This approach facilitates stable heterogeneous catalyst fabrication, crucial for significant bond formations. Notable features include broad applicability, exceptional functional tolerance, scalability, and practicality. Moreover, it holds promise for automating safe processes and enabling efficient late-stage functionalization of complex molecules with moderate to high efficiency, presenting promising prospects for various applications in chemical synthesis.

Fe-ppm-Pd on charcoal: Palladium nanoparticles catalyzed Suzuki−Miyaura cross-coupling reactions of aryl boronic acids (aryl neopentyl-1,3-diol boronic ester) with aryl halides

A facile and readily available Fe-ppm-Pd/C catalyst has been developed for catalyzing Suzuki-Miyaura cross-coupling reactions. When combined with dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl) phosphine (SPhos), this catalyst, with low levels of palladium (as low as 180 ppm), efficiently facilitates cross-coupling reactions between aryl boronic acids (or aryl neopentyl-1,3-diol boronic ester) and a wide range of aryl halides, including inactivated aryl chlorides. Additionally, the recovered Fe-ppm-Pd/C catalyst has demonstrated sustained catalytic activity over four runs, indicating minimal decline in performance. This suggests the catalyst's potential for long-term use and its practicality in industrial applications.

Development of a chiral TPr# ligand and application for asymmetric palladium and copper catalysis

We report the design and synthesis of chiral triazolylidene-metal complexes with bulky substituents at the triazole ring. The palladium complex could be applied to the asymmetric Suzuki-Miyaura cross coupling reaction of 1-naphthaleneboronic acid and 1-bromo-2-methoxynaphthalene to afford the coupling product with good enantioselectivity. The reaction was found to proceed even at 10 mol ppm catalyst loading, leading to high turnover numbers of up to 2300. The chiral triazolylidene-copper complex was employed as an asymmetric catalyst for the borylation of methyl cinnamate to provide the borylated product with good enantioselectivity.

Palladium(II) and Platinum(II) Complexes Bearing ONS-Type Pincer Ligands: Synthesis, Characterization and Catalytic Investigations.

This work describes the synthesis of eight new Pd(II) and Pt(II) complexes with the general formula [M(TSC)Cl], where TSC represents the 4N-monosubstituted thiosemicarbazone derived from 2-acetylpyridine N-oxide with the substituents CH3 (H4MLO), C2H5 (H4ELO), phenyl (H4PLO) and (CH3)2 (H4DMLO). These complexes have been characterized by elemental analysis, molar conductivity, IR spectroscopy, 1H, 13C, 195Pt and ESI-MS. The complexes exhibit a square planar geometry around the metallic center coordinated by a thiosemicarbazone molecule acting as a donor ONS-type pincer ligand and by a chloride, as confirmed by the molecular structures of the complexes, [Pd(4ELO)Cl] (3) and [Pd(4PLO)Cl] (5), determined by single-crystal X-ray diffraction. The 195Pt NMR spectra of the complexes of formulae [Pt(4PLO)Cl] (6) and [Pt(4DMLO)Cl] (8) in DMSO show a single signal at -2420.4 ppm, confirming the absence of solvolysis products. Complexes 3 and 5 have been tested as catalysts in the Suzuki-Miyaura cross-coupling reactions of aryl bromides with phenylboronic acid, with yields of between 50 and 90.

Introduction of Electron Donor Groups into the Azulene Structure: The Appearance of Intense Absorption and Emission in the Visible Region.

In this work, through the Suzuki-Miyaura cross-coupling reaction with high yields, new π-conjugated azulene compounds containing diphenylaniline groups at positions 2 and 6 of azulene were synthesized. The obtained diphenylaniline-azulenes have intensely visible-light absorbing and emitting (in the wavelength range from 400 to 600 nm) properties. It has been shown that such unique optical properties, in particular fluorescent emission in the region of blue and green photoluminescence (λem at 495 and 525 nm), which were absent in the original azulene, are the result of the electron donor effect of diphenylaniline groups, which significantly changes the electronic structure of azulene and leads to the allowed HOMO → LUMO electron transition.