Cross-coupling Products Research Articles

Crystallization-Induced Dimerization and Solution-Phase Bond Dissociation of Stable Dibenzoolympicenyl Radicals.

Crystallization of organic materials can lead to different assembly structure with different reactivity, but this phenomenon is rarely observed for delocalized hydrocarbon radicals. This report introduces a crystallization-induced radical-radical coupling reaction, which employs a series of stable nonplanar organic π-radicals as reactants. Six stable radical congeners are synthesized, resulting in radical-radical coupling at the allenyl radical site during crystallization to produce close-shell dimers. This coupling reaction is absent in the solution phase, which highlights the importance of preorganization in the lattice. Remarkably, the attempts of cocrystallization of different congeners yielded homocoupling products instead of cross-coupling products. In specific cases, two distinct polymorphs are observed and their reactivity is different according to the distance of the reaction sites. Theoretical calculations indicate that the transition from a metastable preorganized monomer to a dimer is barrierless and spontaneous. The dimer could regenerate free radicals by heating or photoirradiation in the solution phase. This discovery may lead to controllable molecular switches.

The Cross-selectivity in Pd-catalyzed coupling of simple aryl C-H bonds

Abstract Pd-catalyzed cross-couplings of C-H bonds have been pursued by researchers to produce unsymmetrical C-C bonds directly for over fifty years, which are currently prepared by Suzuki, Kumada, Stille, Neigishi, Heck, or Sonogashira coupling of C-halogen with C-M or C-H bonds. A big challenge is to obtain the high cross-selectivity of cross-coupling products, especially when the substrates have similar chemical C-H bonds, such as simple arenes. Lu and co-workers have studied Pd catalysis in the cross-couplings of aryl C-H bonds since 2003. This account introduces their strategy, understanding and research in cross-selectivity control, C-H activation mode, cross-coupling establishment and application in synthesis. 1 Introduction 2 Cross-selectivity Control 3 Conclusion

Programmable Plasma-Microdroplet Cascade Reactions for Multicomponent Systems.

The concept of programmable cascade reactions in charged microdroplets is introduced using carbon-carbon (C-C) bond formation via uncatalyzed Michael addition in a three-tier study culminating in programmable Hantzsch multicomponent, multistep reactions. In situ generated reactive oxygen species (ROS) from nonthermal plasma discharge are fused with charged water microdroplets (devoid of ROS) in real time for accelerated chemical reactions. This plasma-microdroplet fusion platform utilizing a coaxial spray configuration enabled product selection while avoiding unwanted side reactions. Hydrogen abstraction via ROS facilitated the formation of enolate anions without strong base use. Reaction enhancement factors >103 were calculated for plasma-microdroplet fusion versus microdroplet-only reactions. The platform programmability was showcased through (i) uncatalyzed 1,4-Michael addition of α,β-unsaturated carbonyls, (ii) novel C-C bond formation via the use of pro-electrophilic amine and alcohol substrates─activated through collisions in the microdroplet environment to serve as Michael acceptors, and (iii) selective Hantzsch cascade reaction with cross-coupling products, avoiding side reactions including N-alkylation and self-coupling product formation. Milligram quantity product collection is achieved, showcasing plasma-microdroplet fusion as an effective tool for preparative-scale synthesis. Thus, the controlled generation of ROS via plasma discharge during charged water microdroplet evolution establishes a green synthetic method for uncatalyzed C-C bond formation.

Development of cellulose-supported Pd-nanocatalyst for the heck coupling and michael addition reactions

The development of reusable, bio-resource based nanocatalysts with high turnover numbers (TONs) is essential for increased sustainability in the chemical sector. Herein, cellulose-supported bio-resourced poly(hydroxamic acid) is employed as a ligand in the synthesis of a palladium nanocomposite (PdNc-PHA) that exhibits higher TONs that previously reported similar systems for the Mizoroki-Heck and Michael addition reactions. The PdNc-PHA catalyst was characterised using Fourier transform infrared spectroscopy (FTIR), field-emission scanning electron microscopy (FE-SEM), energy dispersive X-ray spectrometry (EDX), high-resolution transmission electron microscopy (HR-TEM), X-ray photoelectron spectroscopy (XPS), and inductively coupled plasma-atomic emission spectroscopy (ICP-AES) analyses. Results showed that the PdNc-PHA catalyst exhibits excellent durability and high catalytic activity in the Mizoroki-Heck and Michael addition reactions, leading to high yields of the desired corresponding products. The Mizoroki-Heck reaction of aryl/heteroaryl chlorides with olefins resulted in the production of cross-coupled products, while the Michael addition reaction of phenol/thiophenol and aliphatic cyclic/alicyclic amines with a variety of olefins synthesised the corresponding O-, S-, and N-alkylated products. The recycle and reusability of the catalyst were tested using 4-nitrochlorobenzene and butyl acrylate. The results demonstrated that the catalyst maintained its catalytic activity effectively for up to ten cycles without any noticeable loss in performance. This research represents a promising strategy for efficient catalysis based on bio-waste as a wealth material.

Equimolar Cross-Coupling Using Reactive Coiled Coils for Covalent Protein Assemblies.

Biocompatible cross-coupling reactions enable the efficient covalent attachment of large biomolecules at near-stoichiometric ratios, ensuring the stability and integrity of the resulting products. We present an affinity-based peptide platform utilizing coiled coils containing reactive side chains for proximity-driven protein cross-coupling in the presence of a cross-linking agent. This platform supports both chemical synthesis and recombinant expression, using canonical amino acids to generate reactive affinity tags. Employing the E3/R3 coiled coil pair as a scaffold, we design four complementary coils with cysteine residues as cross-linking sites, achieving >90% conversion to covalent heterodimeric coupling products using 3,4-dibromomaleimide. Equimolar mixtures of proteins with reactive coils at their termini yield near-quantitative heterodimeric cross-coupling products. The strategic selection of complementary coiled coil pairs and cross-linking agents enables orthogonal assembly of macromolecules with diverse architectures. This method offers a versatile approach for creating covalent fusion proteins, enhancing their stability and functionality for applications in chemical biology, biotechnology, and medicine.

Iodine Promoted Desulfurization of Isothiocyanate in Water: Synthesis of 5-Amino-1-Aryl/Alkyl Tetrazoles, Aryl/Alkyl Guanidines and their Conversion

A general and efficient multi-component reaction has been established for the construction of 5-amino tetrazoles and guanidines under mild reaction conditions. All the substrates are readily carried out under optimized reaction conditions to provide their respective target products in good to excellent yields. The regioselectivity of the reaction is also explained in this manuscript. Further, this method is free, uses water as a green solvent, and is practical (at room temperature and under an open atmosphere). In addition, we could not identify any other products during the reaction procedure. Phenyltetrazoleamines are readily converted into their C-N cross-coupled products in good to high yield under mild reaction conditions.

Synthesis of Secondary Boronates via Deaminative Cross-Coupling of Alkyl Nitroso Carbamates and Boronic Acids.

A strategy for transition metal-free cross-coupling of alkyl nitroso-carbamates and boronic acids is reported. The N-nitroso carbamates are easily prepared from the corresponding amine in two simple steps. This method allows for the synthesis of a wide variety of secondary boronates, benzylic boronates and formal Csp3-Csp2 cross-coupling products under operationally simple conditions. Functional group tolerance is also demonstrated and applied in the modification of lysine to make non-canonical amino acids.

Key Blocks for Constructing π-Conjugated Systems Based on Thieno[3,2-b]pyrroles

Cross-coupling products with isobutyl acrylate were obtained by the Heck reaction based on dibromides of methyl esters of 4-methyl- and 4-benzyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acids.

Luminescent Hydride-Free [Cu7(SC5H9)7(PPh3)3] Nanocluster: Facilitating Highly Selective C-C Bond Formation.

Amidst burgeoning interest, atomically precise copper nanoclusters (Cu NCs) have emerged as a remarkable class of nanomaterials distinguished by their unparalleled reactivity. Nonetheless, the synthesis of hydride-free Cu NCs and their role as stable catalysts remain infrequently explored. Here, we introduce a facile synthetic approach to fabricate a hydride-free [Cu7(SC5H9)7(PPh3)3] (Cu7) NC and delineate its photophysical properties intertwined with their structural configuration. Moreover, the utilization of its photophysical properties in a photoinduced C-C coupling reaction demonstrates remarkable specificity toward cross-coupling products with high yields. The combined experimental and theoretical investigation reveals a nonradical mechanistic pathway distinct from its counterparts, offering promising prospects for designing hydride-free Cu NC catalysts in the future and unveiling the selectivity of the hydride-free [Cu7(SC5H9)7(PPh3)3] NC in photoinduced Sonogashira C-C coupling through a polar reaction pathway.

Copper-Promoted Dimerization of Benzyl Thiocyanates to Access Functionalized Bibenzyls

AbstractThe synthesis of bibenzyl derivatives holds significance in organic chemistry due to their diverse pharmacological and synthetic applications. Herein, we report a novel copper-promoted dimerization reaction for the efficient synthesis of functionalized bibenzyls from benzyl thiocyanates. The coupling reaction proceeds under aerobic and mild conditions through a cascade C–S bond cleavage in one pot. Diverse substituents, including electron-withdrawing groups on the aryl ring, are well tolerated to afford the desired products in moderate to good yields. The developed protocol could be utilized to obtain the cross-coupling product from two different electron-deficient benzyl thiocyanates.

Overlooked interaction between redox-mediator and bisphenol-A in permanganate oxidation

Research efforts on permanganate (Mn(VII)) combined with redox-mediator (RM), have received increasing attention due to their significant performance for bisphenol-A (BPA) removal. However, the mechanisms underpinning BPA degradation remain underexplored. Here we show the overlooked interactions between RM and BPA during permanganate oxidation by introducing an RM—N-hydroxyphthalimide (NHPI). We discovered that the concurrent generation of MnO2 and phthalimide-N-oxyl (PINO) radical significantly enhances BPA oxidation within the pH range of 5.0–6.0. The detection of radical cross-coupling products between PINO radicals and BPA or its derivatives corroborates the pivotal role of radical cross-coupling in BPA oxidation. Intriguingly, we observed the formation of an NHPI-BPA complex, which undergoes preferential oxidation by Mn(VII), marked by the emergence of an electron-rich domain in NHPI. These findings unveil the underlying mechanisms in the Mn(VII)/RM system and bridge the knowledge gap concerning BPA transformation via complexation. This research paves the way for further exploration into optimizing complexation sites and RM dosage, significantly enhancing the system's efficiency in water treatment applications.

Electro/Ni Dual-Catalyzed Decarboxylative C(sp3)-C(sp2) Cross-Coupling Reactions of Carboxylates and Aryl Bromide.

Paired redox-neutral electrolysis offers an attractive green platform for organic synthesis by avoiding sacrificial oxidants and reductants. Carboxylates are non-toxic, stable, inexpensive, and widely available, making them ideal nucleophiles for C-C cross-coupling reactions. Here, we report the electro/Ni dual-catalyzed redox-neutral decarboxylative C(sp3)-C(sp2) cross-coupling reactions of pristine carboxylates with aryl bromides. At a cathode, a NiII(Ar)(Br) intermediate is formed through the activation of Ar-Br bond by a NiI-bipyridine catalyst and subsequent reduction. At an anode, the carboxylates, including amino acid, benzyl carboxylic acid, and 2-phenoxy propionic acid, undergo oxidative decarboxylation to form carbon-based free radicals. The combination of NiII(Ar)(Br) intermediate and carbon radical results in the formation of C(sp3)-C(sp2) cross-coupling products. The adaptation of this electrosynthesis method to flow synthesis and valuable molecule synthesis was demonstrated. The reaction mechanism was systematically studied through electrochemical voltammetry and density functional theory (DFT) computational studies. The relationships between the electrochemical properties of carboxylates and the reaction selectivity were revealed. The electro/Ni dual-catalyzed cross-coupling reactions described herein expand the chemical space of paired electrochemical C(sp3)-C(sp2) cross-coupling and represent a promising method for the construction of the C(sp3)-C(sp2) bonds because of the ubiquitous carboxylate nucleophiles and the innate scalability and flexibility of electrochemical flow-synthesis technology.

Nickel-Based Catalysts for the Selective Monoarylation of Dichloropyridines: Ligand Effects and Mechanistic Insights.

This report describes a detailed study of Ni phosphine catalysts for the Suzuki-Miyaura coupling of dichloropyridines with halogen-containing (hetero)aryl boronic acids. With most phosphine ligands these transformations afford mixtures of mono- and diarylated cross-coupling products as well as competing oligomerization of the boronic acid. However, a ligand screen revealed that PPh2Me and PPh3 afford high yield and selectivity for monoarylation over diarylation as well as minimal competing oligomerization of the boronic acid. Several key observations were made regarding the selectivity of these reactions, including: (1) phosphine ligands that afford high selectivity for monoarylation fall within a narrow range of Tolman cone angles (between 136° and 157°); (2) more electron-rich trialkylphosphines afford predominantly diarylated products, while less-electron rich di- and triarylphosphines favor monoarylation; (3) diarylation proceeds via intramolecular oxidative addition; and (4) the solvent (MeCN) plays a crucial role in achieving high monoarylation selectivity. Experimental and DFT studies suggest that all these data can be explained based on the reactivity of a key intermediate: a Ni0-π complex of the monoarylated product. With larger, more electron-rich trialkylphosphine ligands, this π complex undergoes intramolecular oxidative addition faster than ligand substitution by the MeCN solvent, leading to selective diarylation. In contrast, with relatively small di- and triarylphosphine ligands, associative ligand substitution by MeCN is competitive with oxidative addition, resulting in selective formation of monoarylated products. The generality of this method is demonstrated with a variety of dichloropyridines and chloro-substituted aryl boronic acids. Furthermore, the optimal ligand (PPh2Me) and solvent (MeCN) are leveraged to achieve the Ni-catalyzed monoarylation of a broader set of dichloroarene substrates.

Effect of small-molecule phenolic compounds on the removal of triclosan (TCS) by heat/persulfate process: Formation of cross-coupling products and implications for wastewater treatment

In this study, the effect of three small molecule phenolic compounds (SMPCs) (Phenol (PHOH), p-hydroxybenzoic acid (PHBA) and 3,5-dihydroxytoluene (DHT)) on the transformation of triclosan (TCS) in heat activated persulfate (heat/PS) process was investigated. TCS in single and mixed solutions were almost completely removed after 120 min of heat/PS treatment. Compared with single TCS system, the generation of cross-coupling products in the mixed system was beneficial for the removal of total organic carbon (TOC). Overall cytotoxicity and genotoxicity tests on mammalian cells showed that the reaction products in mixed phenol system was less toxic than those in the single TCS system, which confirmed the low toxicity of cross-coupling products. Product analysis was combined with theoretical calculations to propose a mechanism for the cross-coupling of coexisting phenolic pollutants that hydrogen on the phenolic hydroxyl groups of different pollutants was extracted by SO4•- to form phenoxy radicals, which coupled with each other to form cross-coupling products. Lowering the pH of the reaction solution can promote the occurrence of cross-coupling reaction, favoring the removal of TOC and the reduction of toxicity. These results will provide insights into the transformation of phenolic pollutants in water treatment for further control of environmental risks.

An efficient palladium catalyzed mizoroki-heck cross-coupling in water: synthesis, characterization and catalytic activities

A series of new palladium complexes known as PEPPSI-type complexes 3 were successfully synthesized by reacting benzimidazolium salts 2a-e, potassium carbonate (K2CO3), and palladium chloride (PdCl2) in pyridine for 16 h at 80 °C. Both the benzimidazolium salts 2a-e and the resulting complexes 3 were characterized through spectroscopic data and elemental analysis. The Mizoroki-Heck coupling reaction, catalyzed by the homogeneous Pd, was effectively carried out in water without the need for any additional substances under aerobic conditions. The optimization of various key reaction parameters was performed to enhance the yield of the desired cross coupling product. The catalytic performance of these complexes in a catalytic system containing palladium complexes 3a, Et3N, and H2O was evaluated in the Mizoroki-Heck coupling reaction. The PEPPSI-type palladium complex 3a /Et3N/H2O/98 °C catalyst system exhibited high activity, with a turnover frequency (TOF) ranging from 12 to 14 /hour towards achieving the excellent yield of the Mizoroki-Heck coupling products for a wide range of electron withdrawing as well as electron donating aryl bromide and chlorides in shortest reaction time.

Development and synthesis of a novel salen-type ligand based on phenylalanine for Mizoroki-Heck, and S-arylation cross-coupling reactions

In this article, we introduced a novel salen-type ligand precursor and applied it in the Pd-catalyzed Mizoroki–Heck and Cu-catalyzed S-arylation cross-coupling reactions. For the preparation of this structure, (DL)-phenyl alanine was employed as a starting material. These ligand precursor and related catalytic system can be readily synthesised. Various aryl halides (-I, -Br) and alkenes were applied successfully in this protocol to give the corresponding Mizoroki-Heck cross-coupling and S-arylated products in high to excellent yields.

Pd-Catalyzed Suzuki-Miyaura Cross-Coupling Reaction in Glycerol Using KOH as Base and Glycerol-Triethanolamine Deep Eutectic Solvent under Inorganic Base‑Free Conditions

Glycerol and glycerol-triethanolamine deep eutectic solvent are both environmentally benign, cost-effective, and practical solvents for the Pd-catalyzed Suzuki-Miyaura cross-coupling of aryl halides with arylboronic acids. Utilizing KOH as base, the reaction in glycerol proceeded smoothly with low catalyst loadings (up to 0.5 mol% of PdCl2(PPh3)2) providing excellent yields (up to 99%) of the cross-coupling products, which can be readily extracted with hexane. However, the recyclability of the glycerol medium containing the catalyst is limited to a few cycles. Furthermore, it was explored the use of chlorodiphenylphosphine as a pre-ligand. Although glycerol phosphinite was not generated in situ, PPh2Cl proved to be an excellent pre-ligand, yielding the coupling product with a 98% yield. Compared to glycerol, glycerol-triethanolamine deep eutectic solvent (TEOA:G DES) proves to be a superior solvent for the cross-coupling reaction. In addition, the presence of amine group in the solvent allowed to obtain an inorganic base-free cross-coupling protocol. Aryl bromides and aryl boronic acids containing both electron releasing and attracting functional groups can be coupled without requiring the addition of any further base, affording the biphenyl products in moderate to good yields. The cross-coupling products can be easily isolated by extraction with hexane. Moreover, we observed the formation of triethanolamine phenylboronate during the reaction. The triethanolamine boronate was subsequently synthesized through the condensation of phenylboronic acid with triethanolamine and fully characterized. 11B nuclear magnetic resonance (NMR) spectroscopy confirmed the coordination of the nitrogen to the boron atom of the triethanolamine boronate.

Recent advances in cross-coupling of alcohols via borrowing hydrogen catalysis.

Application of the borrowing hydrogen strategy facilitates utilization of abundantly available alcohols for linear or branched long-chain alcohols. Selective synthesis of such alcohols is highly challenging and involves the utilization of transition metal catalysts towards the desired cross-coupled product. Herein, we have highlighted recent advances (from 2015 to 2023) towards the synthesis of higher alcohols. Major focus has been given to the development of ligands, including transition metal catalysts. Judicious catalyst design plays a key role in the alkylation process and is summarised in this review.

A Pd-catalyzed route to carborane-fused boron heterocycles.

Due to the expanding applications of icosahedral carboranes in medicinal and materials chemistry research, their functionalizations have become one of the central themes in boron-rich cluster chemistry. Although several strategies for incorporating nitrogen-containing nucleophiles on a single boron vertex of the icosahedral carboranes (C2B10H12) have been developed, methods for preparing clusters with vicinal B-N moieties are still lacking. The steric bulk of icosahedral carboranes and disparate electronic and steric nature of the N-containing groups have rendered the vicinal diamination challenging. In this article, we show how a developed Pd-catalyzed process is used to incorporate an array of NH-heterocycles, anilines, and heteroanilines with various electronic and steric profiles onto the vicinal boron vertices of a meta-carborane cluster via sequential or one-pot fashion. Importantly, oxidative cyclizations of the cross-coupling products with indoles and pyrroles appended to boron vertices generate a previously unknown class of all-boron-vertex bound carborane-fused six- and seven-membered ring heterocycles. Photophysical studies of the meta-carborane-fused heterocycles show that these structures can exhibit luminescence with high quantum yields and are amenable to further manipulations.

Application of 1,4-pentanediol as a renewable solvent for copper-catalyzed Ullmann-type coupling reactions

It was demonstrated that 1,4-pentanediol as a biomass-originated polar protic solvent could be utilized as an alternative reaction medium for copper-catalyzed Ullmann-type coupling reactions of aryl iodides and various amines under mild conditions. The effect of the copper source, the base, the water, and the γ-valerolactone content of the reaction mixture on the reaction performance was investigated. Eighteen cross-coupling products were isolated with yields of 11–69 %, and high purity (>98 %). Two O-arylated products, 4-phenoxypentan-1-ol and 5-phenoxypentan-2-ol were characterized. The recycling of the solvents after product isolation was also demonstrated. These results represent an example that proves that biomass-derived safer solvents can be utilized in common, industrially important transformations.