Cross-electrophile Couplings Research Articles

Palladium-Catalyzed Cross-Electrophile Couplings of Aryl Thianthrenium Salts with Aryl Bromides via C-S Bond Activation.

We report here a step-economic and cost-effective cross-electrophile coupling of aryl thianthrenium salts with widely available aryl bromides, which proceeded effectively via C-S bond activation at ambient temperature in THF in the presence of a palladium catalyst, magnesium turnings, and lithium chloride to enable the facile assembly of a wide array of structurally diverse biaryls in modest to good yields with good functional group compatibility. In addition, the gram-scale reaction could also be realized.

Magnesium-Mediated Cross-Electrophile Couplings of Aryl 2-Pyridyl Esters with Aryl Bromides for Ketone Synthesis through In Situ-Formed Arylmagnesium Intermediates.

Aryl 2-pyridyl esters could efficiently undergo cross-electrophile couplings with aryl bromides with the aid of magnesium as a reducing metal in the absence of a transition-metal catalyst, leading to the unsymmetrical diaryl ketones in modest to good yields with wide functionality compatibility. In addition, the reaction could be easily scaled up and applied in the late-stage modification of biologically active molecules. Preliminary mechanistic study showed that the coupling reaction presumably proceeds through the in situ formation of arylmagnesium reagents as key intermediates.

Cross-Electrophile Couplings of Benzyl Sulfonium Salts with Thiosulfonates via C-S Bond Activation.

A zinc-mediated cross-electrophile coupling of benzyl sulfonium salts with thiosulfonates via C-S bond cleavage was achieved. The reductive thiolation proceeded well under transition metal-free conditions to afford the desired benzyl sulfides in good yields, exhibiting both broad substrate scope and good functionality tolerance. In addition, the reaction could be applied to the use of selenosulfonate as an effective selenylation agent and be subjected to scale-up synthesis.

Nickel-catalyzed cross-electrophile couplings of aryl fluorosulfates with vinyl chlorosilanes

An efficient cross-electrophile couplings of aryl fluorosulfates with vinyl chlorosilanes by using nickel as transition metal catalyst and manganese as reductant has been achieved. The reactions proceeded smoothly at room temperature via C-O bond activation to give a series of structurally varied aryl silanes in moderate to good yields, displaying broad substrate generality and good functional group compatibility. In addition, the reaction could be subjected to scale-up synthesis and be applied to late-stage functionalization of biologically active molecules.

Cross-Electrophile Coupling of Benzyl Halides and Disulfides Catalyzed by Iron.

Cross-electrophile couplings are influential reactions that typically require a terminal reductant or photoredox conditions. We discovered an iron-catalyzed reaction that couples benzyl halides with disulfides to yield thioether products in the absence of a terminal reductant and under photoredox conditions. The disclosed platform proceeds without sulfur-induced catalyst poisoning or the use of an exogenous base, supporting a broad scope and circumventing undesired elimination pathways. We applied the developed chemistry in a new mode of disulfide bioconjugation, drug synthesis, gram-scale synthesis, and product derivatization. Lastly, we performed mechanistic experiments to better understand the stereoablative reaction between two electrophiles. Disulfides and benzylic thioethers are imperative for biological and pharmaceutical applications but remain severely understudied in comparison to their ethereal and amino counterparts. Hence, we expect this platform of iron catalysis and the downstream applications to be of interest to the greater scientific community.

Computational Methods Enable the Prediction of Improved Catalysts for Nickel-Catalyzed Cross-Electrophile Coupling.

Cross-electrophile coupling has emerged as an attractive and efficient method for the synthesis of C(sp2)-C(sp3) bonds. These reactions are most often catalyzed by nickel complexes of nitrogenous ligands, especially 2,2'-bipyridines. Precise prediction, selection, and design of optimal ligands remains challenging, despite significant increases in reaction scope and mechanistic understanding. Molecular parameterization and statistical modeling provide a path to the development of improved bipyridine ligands that will enhance the selectivity of existing reactions and broaden the scope of electrophiles that can be coupled. Herein, we describe the generation of a computational ligand library, correlation of observed reaction outcomes with features of the ligands, and the in silico design of improved bipyridine ligands for Ni-catalyzed cross-electrophile coupling. The new nitrogen-substituted ligands display a 5-fold increase in selectivity for product formation versus homodimerization when compared to the current state of the art. This increase in selectivity and yield was general for several cross-electrophile couplings, including the challenging coupling of an aryl chloride with an N-alkylpyridinium salt.

Electrosynthesis of iminophosphoranes and applications in nickel catalysis.

P(v) iminophosphorane compounds are accessed via electrochemical oxidation of commercially available P(iii) phosphines, including mono-, di- and tri-dentate phosphines, as well as chiral phosphines. The reaction uses inexpensive bis(trimethylsilyl)carbodiimide as an efficient and safe aminating reagent. DFT calculations, cyclic voltammetry, and NMR studies provide insight into the reaction mechanism. The proposed mechanism reveals a special case of sequential paired electrolysis. DFT calculations of the frontier orbitals of an iminophosphorane are compared with those of the analogous phosphines and phosphine oxides. X-ray crystallographic studies of the ligands as well as a Ni-coordination complex provide structural insight for these ligands. The utility of these iminophosphoranes as ligands is demonstrated in nickel-catalyzed cross-electrophile couplings including C(sp2)-C(sp3) and C(sp2)-C(sp2) couplings, an electrochemically driven C-N cross-coupling, and a photochemical arylative C(sp3)-H functionalization. In some cases, these new ligands provide improved performance over commonly used sp2-N-based ligands (e.g. 4,4'-di-tert-butyl-2,2'-bipyridine).

Tetrabutylammonium Borohydride: A Sacrificial Reductant in Organic Electrosynthesis

In this work, tetrabutylammonium borohydride (TBAB) is investigated as a terminal reductant in reductive organic electrosynthesis as replacement for sacrificial anodes. Sacrificial anodes are typically based on easily oxidized metals, such as Mg, Zn, or Al, and are consumed during the reaction, resulting in stoichiometric metal waste. In contrast, oxidation of TBAB enables the use of inert anodes and results in anodic H2 formation, effectively serving as the inverse of cathodic proton reduction. Our results indicate that TBAB oxidation at carbon-based electrodes can replace the use of sacrificial anodes in several organic electrosynthetic reactions, including Birch reduction, hydrodesulfurization of thioethers, hydrodeoxygenation of alcohols1, and cross-electrophile couplings.References Villo, P.; Lill, M.; Alsaman, Z.; Soto Kronberg, A.; Chu, V.; Ahumada, G.; Agarwala, H.; Ahlquist, M.; Lundberg, H. Electroreductive Deoxygenative C–H and C–C Bond Formation from Non-Derivatized Alcohols Fueled by Borohydride Oxidation. ChemElectroChem. 2023, accepted for publication (a previous version can be found in ChemRxiv, DOI: 10.26434/chemrxiv-2023-tw9l1-v2.) Figure 1

Nickel-Catalyzed Radical Mechanisms: Informing Cross-Coupling for Synthesizing Non-Canonical Biomolecules.

Nickel excels at facilitating selective radical chemistry, playing a pivotal role in metalloenzyme catalysis and modern cross-coupling reactions. Radicals, being nonpolar and neutral, exhibit orthogonal reactivity to nucleophilic and basic functional groups commonly present in biomolecules. Harnessing this compatibility, we delve into the application of nickel-catalyzed radical pathways in the synthesis of noncanonical peptides and carbohydrates, critical for chemical biology studies and drug discovery.We previously characterized a sequential reduction mechanism that accounts for chemoselectivity in cross-electrophile coupling reactions. This catalytic cycle begins with nickel(I)-mediated radical generation from alkyl halides, followed by carbon radical capture by nickel(II) complexes, and concludes with reductive elimination. These steps resonate with mechanistic proposals in nickel-catalyzed cross-coupling, photoredox, and electrocatalytic reactions. Herein, we present our insights into each step involving radicals, including initiation, propagation, termination, and the nuances of kinetics, origins of selectivity, and ligand effects.Radical generation from C(sp3) electrophiles via one-electron oxidative addition with low-valent nickel radical intermediates provides the basis for stereoconvergent and cross-electrophile couplings. Our electroanalytical studies elucidate a concerted halogen atom abstraction mechanism, where electron transfer is coupled with halide dissociation. Using this pathway, we have developed a nickel-catalyzed stereoselective radical addition to dehydroalanine, facilitating the synthesis of noncanonical peptides. In this application, chiral ligands modulate the stereochemical outcome through the asymmetric protonation of a nickel-enolate intermediate.The capture of the alkyl radical by nickel(II) expands the scope of cross-coupling, promotes reductive elimination through the formation of high-valent nickel(III) species, and governs chemo- and stereoselectivity. We discovered that nickel(II)-aryl efficiently traps radicals with a barrier ranging from 7 to 9 kcal/mol, followed by fast reductive elimination. In contrast, nickel(II)-alkyl captures radicals to form a nickel(III) species, which was characterized by EPR spectroscopy. However, the subsequent slow reductive elimination resulted in minimal product formation. The observed high diastereoselectivity of radical capture inspired investigations into C-aryl and C-acyl glycosylation reactions. We developed a redox auxiliary that readily couples with natural carbohydrates and produces glycosyl radicals upon photoredox activation. Nickel-catalyzed cross-coupling of the glycosyl radical with bromoarenes and carboxylic acids leads to diverse non-natural glycosides that can facilitate drug discovery.Stoichiometric studies on well-defined d8-nickel complexes have showcased means to promote reductive elimination, including ligand association, oxidation, and oxidative addition.In the final section, we address the influence of auxiliary ligands on the electronic structure and redox activity of organonickel intermediates. Synthesis of a series of low-valent nickel radical complexes and characterization of their electronic structures led us to a postulate that ligand redox activity correlates with coordination geometry. Our data reveal that a change in ligand redox activity can shift the redox potentials of reaction intermediates, potentially altering the mechanism of catalytic reactions. Moreover, coordinating additives and solvents may stabilize nickel radicals during catalysis by adjusting ligand redox activity, which is consistent with known catalytic conditions.

Palladium(I)-Iodide-Catalyzed Deoxygenative Heck Reaction of Vinyl Triflates: A Formate-Mediated Cross-Electrophile Reductive Coupling with cine-Substitution.

The first deoxygenative Heck reactions are described, as illustrated by formate-mediated cine-substitutions of vinyl triflates with aryl iodides. The collective data corroborate a mechanism in which Pd(OAc)2 and Bu4NI form the dianionic iodide-bridged dimer [Pd2I6][NBu4]2, which, under reducing conditions, serves as a precursor to the palladium(I) complex [Pd2I4][NBu4]2. Dinculear oxidative addition of aryl iodide forms [Pd2I5(Ar)][NBu4]2, which dissociates to the monometallic complex [PdI2(Ar)][NBu4]. Vinyl triflate migratory insertion-sulfonate elimination delivers a palladium(IV) carbene, which upon β-hydride elimination/C-H reductive elimination gives the product of cine-substitution. These processes are the first efficient formate-mediated cross-electrophile reductive couplings beyond carbonyl addition.

Cross-Electrophile C-PIII Coupling of Chlorophosphines with Organic Halides: Photoinduced PIII and Aminoalkyl Radical Generation Enabled by Pnictogen Bonding.

Pnictogen bonding (PnB) has gained recognition as an appealing strategy for constructing novel architectures and unlocking new properties. Within the synthetic community, the development of a straightforward and much simpler protocol for cross-electrophile C-PIII coupling remains an ongoing challenge with organic halides. In this study, we present a simple strategy for photoinduced PnB-enabled cross-electrophile C-PIII couplings using readily available chlorophosphines and organic halides via merging single electron transfer (SET) and halogen atom transfer (XAT) processes. In this photomediated transformation, the PnB formed between chlorophosphines and alkyl amines facilitates the photogeneration of PIII radicals and α-aminoalkyl radicals through SET. Subsequently, the resulting α-aminoalkyl radicals activate C-X bonds via XAT, leading to the formation of carbon radicals. This methodology offers operational simplicity and compatibility with both aliphatic and aromatic chlorophosphines and organic halides.

Cobalt-Catalyzed Enantioselective Cross-Electrophile Couplings: Stereoselective Syntheses of 5-7-Membered Azacycles.

Cobalt complexes of chiral pyrox ligands catalyzed enantioselective reductive couplings of nonconjugated iododienes with aryl iodides or alkenyl bromides. The reaction enabled stereoselective syntheses of 5-7-membered azacycles carrying quaternary stereocenters. Mechanistically, cross-electrophile selectivity originated from selective coupling of alkylcobalt(I) complexes generated after cyclization with aryl iodides.

Ni-Catalyzed Electro-Reductive Cross-Electrophile Couplings of Alkyl Amine-Derived Radical Precursors with Aryl Iodides.

In recent years, the "Escape-from-Flatland" trend has prompted the synthetic community to develop a set of cross-coupling strategies to introduce sp3-carbon-based fragments in organic compounds. This study presents a novel nickel-catalyzed electrochemical methodology for reductive cross-electrophile coupling. The method enables C(sp2)-C(sp3) linkages using inexpensive amine-derived radical precursors and aryl iodides. The use of electrochemistry as a power source reduces waste and avoids chemical reductants, making this approach a more sustainable alternative to traditional cross-coupling methods.

Primary vs. secondary alkylpyridinium salts: a comparison under electrochemical and chemical reduction conditions.

This report details a systematic comparison of the scope of aryl bromides in nickel-catalyzed, reductive cross-electrophile couplings of primary vs. secondary alkylpyridinium salts using both electrochemical and chemical reductants. Facilitated by the use of high-throughput experimentation (HTE) techniques, 37 aryl bromides, including 13 complex, drug-like examples, were investigated. By using primary and secondary substrates differing only by one methylene, we observed that the trends in ArBr scope are similar between the primary and secondary alkylpyridinium salts, although distinctions were observed in isolated cases. In addition, the electrochemical conditions compared favorably to those using chemical reductants, especially among the more complex, drug-like aryl halides.

Catalytic Multicomponent Synthesis of C-Acyl Glycosides by Consecutive Cross-Electrophile Couplings.

C-Acyl glycosides are versatile intermediates to natural products and medicinally relevant entities. Conventional cross-coupling strategies to secure these molecules often relied on two-component manifolds in which a glycosyl precursor is coupled with an acyl donor (pre-synthesized or generated in situ) under transition metal or dual catalysis to forge a C-C bond. Here, we disclose a three-component Ni-catalyzed reductive regime that facilitates the chemoselective union of glycosyl halides, organoiodides and commercially available isobutyl chloroformate as a CO surrogate. The method tolerates multiple functionalities and the resulting products are obtained in high diastereoselectivities. Theoretical calculations provide a mechanistic rationale for the unexpectedly high chemoselectivity of sequential cross-electrophile couplings. This approach enables the expeditious assembly of difficult-to-synthesize C-acyl glycosides, as well as late-stage keto-glycosylation of oligopeptides.

An asymmetric sp3-sp3 cross-electrophile coupling using 'ene'-reductases.

The catalytic asymmetric construction of Csp3-Csp3 bonds remains one of the foremost challenges in organic synthesis1. Metal-catalysed cross-electrophile couplings (XECs) have emerged as a powerful tool for C-C bond formation2-5. However, coupling two distinct Csp3 electrophiles with high cross-selectivity and stereoselectivity continues as an unmet challenge. Here we report a highly chemoselective and enantioselective Csp3-Csp3 XEC between alkyl halides and nitroalkanes catalysed by flavin-dependent 'ene'-reductases (EREDs). Photoexcitation of the enzyme-templated charge-transfer complex between an alkyl halide and a flavin cofactor enables the chemoselective reduction of alkyl halide over the thermodynamically favoured nitroalkane partner. The key C-C bond-forming step occurs by means of the reaction of an alkyl radical with an in situ-generated nitronate to form a nitro radical anion that collapses to form nitrite and an alkyl radical. An enzyme-controlled hydrogen atom transfer (HAT) affords high levels of enantioselectivity. This reactivity is unknown in small-molecule catalysis and highlights the potential for enzymes to use new mechanisms to address long-standing synthetic challenges.

Electrochemistry dials up buzz with new coupling reactions

Chemists are amped up about two new reactions that use electricity to form different types of carbon-carbon bonds. One transformation builds sp 3 -sp 3 C–C bonds, and the other creates sp 2 -sp 3 C–C bonds. Adding these transformations to the synthetic chemist’s toolbox should spark interest in electrochemistry, an increasingly popular molecule-building tool, experts say. Electrochemical transformations use electricity rather than chemical reagents to perform reactions. Both of the new reactions are cross-electrophile couplings, which wed two different electrophiles. Although there are ways to do cross-electrophile couplings using chemical reagents, these alternatives are often plagued by homocouplings, in which one electrophile forms a bond with another electrophile of the same kind instead of with a different type of electrophile. Shannon Stahl , an expert in organic synthesis at the University of Wisconsin–Madison who was not involved in the research, says in an email that “both of these studies

Nickel-Catalyzed Reductive Cross-Couplings: New Opportunities for Carbon–Carbon Bond Formations through Photochemistry and Electrochemistry

Metal-catalyzed cross-electrophile couplings have become a valuable tool for carbon–carbon bond formation. This minireview provides a comprehensive overview of the recent developments in the topica...

Visible-light photoredox-catalyzed selective carboxylation of C(sp3)−F bonds with CO2

Visible-light photoredox-catalyzed selective carboxylation of C(sp3)−F bonds with CO2

Dual Photoredox-/Palladium-Catalyzed Cross-Electrophile Couplings of Polyfluoroarenes with Aryl Halides and Triflates

A visible-light photoredox-/Pd-catalyzed cross-electrophile arylation of polyfluoroarenes with aryl halides and triflates in the presence of dialkylamines is reported for the first time. This syner...