Coupling Partners Research Articles

Dichloromethane as C1 Synthon for the Photoredox Catalytic Cyclopropanation of Aromatic Olefins

AbstractDichloromethane, as a readily available and inexpensive C1 synthon is proposed as a powerful building block for cyclopropanation of alkenes under mild conditions. Herein, we report a highly efficient and versatile dual photoredox system, involving a nickel aminopyridine coordination complex and a photocatalyst, for the cyclopropanation of aromatic olefins using dichloromethane, under visible‐light irradiation. The cyclopropanation protocol has been successfully applied at gram scale. Mechanistic studies suggest a Ni(II) pyridyl radical complex as the key intermediate for the homolytic cleavage of the Csp3−Cl bond, generating a chloromethyl radical that is captured by the olefin coupling partner. Our findings also highlight the versatility of this methodology. By directing the radical/polar crossover process, we were able to selectively drive the reaction towards either the formation of cyclopropyl derivatives or the corresponding non‐cyclic alkyl chloride products. The methodology also successfully apply to geminal dichloroalkanes, including the formation of spiro[2,2] compounds. Moreover, our methodology extends to the synthesis of deuterium‐labelled cyclopropanes, demonstrating its utility in isotopic labelling and broadening its applicability in chemical synthesis and drug development.

Rapid Aminations of Functionalized Aryl Fluorosulfates in Water.

Aryl fluorosulfates of varying complexities have been used in amination reactions in water using a new Pd oxidative addition complex (OAC-1) developed specifically to match the needs of the fine chemicals industry, not only in terms of functional group tolerance, but also reflecting time considerations associated with these important C-N couplings. Also especially noteworthy is that they replace both PFAS-related triflates and nonaflates, which are today out of favor due to recent government regulations. The new complex based on the BippyPhos ligand is used at low loadings and under aqueous micellar conditions. Moreover, it is easily prepared and stable to long term storage. DFT calculations on the OAC precatalyst compare well with the X-ray structure of the crystals with π-complexation to the aromatic system of the ligand and also confirm the NMR data showing a mixture of conformers in solution that differ from the X-ray structure in rotation of the phenyl and t-butyl ligand substituents. An extensive variety of coupling partners, including pharmaceutically relevant APIs, readily participate under mild and environmentally responsible reaction conditions.

Directed Arylation of 7‐Oxabicyclo[2.2.1]heptane to Prepare 3D Fragments

AbstractDirected Pd‐catalysed β‐(hetero)arylation of the 7‐oxabicyclo[2.2.1]heptane framework is described. Arylated products were formed in up to 99 % yield, and heteroarylated products in up to 88 % yield with complete diastereoselectivity. Different minor diarylated side products were formed, depending on whether electron deficient aryl or pyridyl iodides were used as the coupling partners. Cleavage of the 8‐aminoquinoline directing group provided small bridged compounds that may be of value in fragment based drug discovery.

Graphitisches Kohlenstoffnitrid als Photokatalysator für die decarboxylative C(sp2)−C(sp3) Kupplung mittels Nickelkatalyse

AbstractDie Entwicklung robuster und zuverlässiger Methoden für den Aufbau von C(sp2)−C(sp3)‐Bindungen ist entscheidend, um eine Vielzahl strukturell diverser Substanzen in der Wirkstoffforschung und ‐entwicklung zugänglich zu machen. Obwohl bedeutende Fortschritte auf diesem Gebiet durch den Einsatz der Metallaphotoredox‐Chemie erzielt wurden, nutzen viele dieser Methoden nach wie vor Photokatalysatoren auf Edelmetallbasis aufgrund ihrer effizienten Redoxprozesse und gut anpassbaren Eigenschaften. Aufgrund der hohen Kosten, Ressourcenknappheit und oftmals erheblichen Toxizität dieser Metalle, ist es von großem Interesse, die Suche nach geeigneten Ersatz voranzutreiben. In dieser Publikation zeigen wir den Einsatz des kommerziell erhältlichen, heterogenen Halbleiters graphitisches Kohlenstoffnitrid (gCN) als Photokatalysator in Kombination mit Nickelkatalyse für die Kreuzkupplung von Arylhalogenid‐ und Carbonsäure‐Derivaten. Wie in vorherigen Berichten gezeigt, kann gCN effektiv an Einelektronenübertragungen (SET) und Energietransfer‐(EnT) Prozessen zur Bildung von C−X‐Bindungen teilnehmen. Dieses Manuskript beinhaltet neue Strategien, um die bislang auf C−O Bindungsknüpfung beschränkten Methoden mittels carbonsäurehaltigen Bausteinen um C−C Bindungsknüpfungen zu erweitern. Es wird gezeigt, dass eine Vielzahl an Arylhalogeniden als auch Carbonsäuren für diese Transformation genutzt werden kann. Im Weiteren wird das Recycling des Photokatalysators demonstriert und der Mechanismus der Reaktion untersucht.

Graphitic Carbon Nitride as a Photocatalyst for Decarboxylative C(sp2)-C(sp3) Couplings via Nickel Catalysis.

The development of robust and reliable methods for the construction of C(sp2)-C(sp3) bonds is vital for accessing an increased array of structurally diverse scaffolds in drug discovery and development campaigns. While significant advances towards this goal have been achieved using metallaphotoredox chemistry, many of these methods utilise photocatalysts based on precious-metals due to their efficient redox processes and tuneable properties. However, due to the cost, scarcity, and toxicity of these metals, the search for suitable replacements should be a priority. Here, we show the use of commercially available heterogeneous semiconductor graphitic carbon nitride (gCN) as a photocatalyst, combined with nickel catalysis, for the cross-coupling between aryl halide and carboxylic acid coupling partners. gCN has been shown to engage in single-electron-transfer (SET) and energy-transfer (EnT) processes for the formation of C-X bonds, and in this manuscript we overcome previous limitations to furnish C-C over C-O bonds using carboxylic acids. A broad scope of both aryl halides and carboxylic acids is presented, and recycling of the photocatalyst demonstrated. The mechanism of the reaction is also investigated.

Versatile Synthesis of α‐Oxygen Organoboron Compounds via Photo‐Induced Siloxycarbene†

Comprehensive SummaryA novel method for synthesizing α‐oxygen organoboron compounds has been developed through acylsilane‐based carbene insertion reactions into C—B bonds. As coupling partners, readily available organoboron compounds (alkenyl, allyl, and allenyl B(pin)) were employed. Based on the substrates, pure insertion into C—B bonds or insertion followed by a siloxy group rearrangement process (from carbon to boron) would occur, delivering the α‐oxygen organoboron compounds with great diversities. Control experiments demonstrated that the electronic effect of the substituents mainly controlled the rearrangement process. Besides, no matter which isomer of substrate (Z or E) was used, the reaction with β‐aryl‐substituted alkenyl B(pin) affords both isomers of products (Z and E, separable through column chromatography). Trapping experiments indicated the triplet energy transfer process was involved.

Nickel‐Catalyzed Highly Selective Radical C−C Coupling from Carboxylic Acids with Photoredox Catalysis

AbstractControlling the cross‐coupling reaction between two different radicals is a long‐standing challenge due to the process occurring statistically, which would lead to three products, including two homocoupling products and one cross‐coupling product. Generally, the cross‐coupling selectivity is achieved by the persistent radical effect (PRE) that requires the presence of a persistent radical and a transient radical, thus resulting in limited radical precursors. In this paper, a highly selective cross‐coupling of alkyl radicals with acyl radicals to construct C(sp2)−C(sp3) bonds, or with alkyl radicals to construct C(sp3)−C(sp3) bonds have been achieved with the readily available carboxylic acids and their derivatives (NHPI ester) as coupling partners. The success originates from the use of tridentate ligand (2,2′ : 6′,2′′‐terpyridine) to enable radical cross‐coupling process to Ni‐mediated organometallic mechanism. This protocol offers a facile and flexible access to structurally diverse ketones (up to 90 % yield), and also a new solution for the challenging double decarboxylative C(sp3)−C(sp3) coupling. The broad utility and functional group tolerance are further illustrated by the late‐stage functionalization of natural‐occurring carboxylic acids and drugs.

Nickel-Catalyzed Highly Selective Radical C-C Coupling from Carboxylic Acids with Photoredox Catalysis.

Controlling the cross-coupling reaction between two different radicals is a long-standing challenge due to the process occurring statistically, which would lead to three products, including two homocoupling products and one cross-coupling product. Generally, the cross-coupling selectivity is achieved by the persistent radical effect (PRE) that requires the presence of a persistent radical and a transient radical, thus resulting in limited radical precursors. In this paper, a highly selective cross-coupling of alkyl radicals with acyl radicals to construct C(sp2)-C(sp3) bonds, or with alkyl radicals to construct C(sp3)-C(sp3) bonds have been achieved with the readily available carboxylic acids and their derivatives (NHPI ester) as coupling partners. The success originates from the use of tridentate ligand (2,2' : 6',2''-terpyridine) to enable radical cross-coupling process to Ni-mediated organometallic mechanism. This protocol offers a facile and flexible access to structurally diverse ketones (up to 90 % yield), and also a new solution for the challenging double decarboxylative C(sp3)-C(sp3) coupling. The broad utility and functional group tolerance are further illustrated by the late-stage functionalization of natural-occurring carboxylic acids and drugs.

Transition‐Metal Catalyzed Synthesis of N‐Heterocycles using Solvent‐Carbon (C1) Synthons

AbstractNitrogen‐containing heterocycles represent fundamental components found in a myriad of natural compounds, pharmaceuticals, tailored bioactive substances, and agrochemicals. In recent decades, the field of synthetic chemistry has prioritized these compounds, directing considerable research endeavour toward developing efficient and concise methodologies for their synthesis. Consequently, there is a growing interest in pioneering novel synthetic approaches to fabricate these immensely coveted structural motifs. Transition metal‐catalyzed reactions leveraging solvents as carbon (C1) synthons offer notable advantages, including streamlined processes, enhanced atom economy, and environmental sustainability. This review sheds light on the recent advancements in the utilization of collective solvents such as methanol (alongside other alcohols), N,N‐dimethylethanolamine (DMEA), and triethylamine (TEA) (in conjunction with other amines), tetrahydrofuran (THF), toluene, dichloromethane (DCM), dimethyl sulfoxide (DMSO), and dimethylformamide (DMF) as C1 synthons, serving as foundational units for the synthesis of N‐heterocycles, including quinazolinone, quinazoline, quinoxaline, pyridine, and pyrimidine, among others. Various reaction conditions employing diverse transition metals, coupling partners, and solvents as carbon synthons or reagents, as reported in the literature, have been explored.

Regio- and Diastereoselective Synthesis of Trisubstituted Alkenes Through Hydroalkylation of Alkynyl Boronamides.

Hydroalkylation of alkynes is a powerful method for alkene synthesis. However, regioselectivity has been difficult to achieve in transformations of internal alkynes hindering applications in the synthesis of trisubstituted alkenes. To overcome these limitations, we explored using boryl groups as versatile directing groups that can control the regioselectivity of the hydroalkylation and subsequently be replaced in a cross-coupling reaction. The result of our exploration is a nickel-catalyzed hydroalkylation of alkynyl boronamides that provides access to a wide range of trisubstituted alkenes with high regio- and diastereoselectivity. The reaction can be accomplished with a variety of coupling partners, including primary and secondary alkyl iodides, α-bromo esters, α-chloro phthalimides, and α-chloro boronic esters. Preliminary studies of the reaction mechanism provide evidence for the hydrometalation mechanism and the formation of alkyl radical intermediates.

Regio‐ and Diastereoselective Synthesis of Trisubstituted Alkenes Through Hydroalkylation of Alkynyl Boronamides

Hydroalkylation of alkynes is a powerful method for alkene synthesis. However, regioselectivity has been difficult to achieve in transformations of internal alkynes hindering applications in the synthesis of trisubstituted alkenes. To overcome these limitations, we explored using boryl groups as versatile directing groups that can control the regioselectivity of the hydroalkylation and subsequently be replaced in a cross‐coupling reaction. The result of our exploration is a nickel‐catalyzed hydroalkylation of alkynyl boronamides that provides access to a wide range of trisubstituted alkenes with high regio‐ and diastereoselectivity. The reaction can be accomplished with a variety of coupling partners, including primary and secondary alkyl iodides, α‐bromo esters, α‐chloro phthalimides, and α‐chloro boronic esters. Preliminary studies of the reaction mechanism provide evidence for the hydrometalation mechanism and the formation of alkyl radical intermediates.

Boryl radical-mediated halogen-atom transfer enables arylation of alkyl halides with electrophilic and nucleophilic coupling partners

Boryl radical-mediated halogen-atom transfer enables arylation of alkyl halides with electrophilic and nucleophilic coupling partners

Protecting-Group-Free Synthesis of ADP-Ribose and Dinucleoside Di-/Triphosphate Derivatives via P(V)-P(V) Coupling Reaction.

Biomolecules containing adenosine di- or triphosphate (ADP or ATP) are crucial for diverse biological processes. Synthesis of these biomolecules and development of their chemical probes are important to elucidate their functions. Enabling reproducible and high-yielding access to these ADP- and ATP-containing molecules via conventional P(III)-P(V) and P(V)-P(V) coupling reactions is challenging owing to water content in highly polar phosphate-containing substrates. Herein, we report an efficient and reliable method for protecting-group-free P(V)-P(V) coupling reaction through in situ activation of phosphates using hydrolysis-stable 2-[N-(2-methylimidazoyl)]-1,3-dimethylimidazolinium chloride (2-MeImIm-Cl), providing the corresponding electrophilic P(V) intermediates for subsequent nucleophilic attack using their coupling partners. This P(V)-P(V) coupling reaction proceeded even in a wet reaction medium and showed a broad substrate scope, accommodating protecting-group-free synthesis of ADP-ribose and nicotinamide adenine diphosphate analogs, ATP-containing biomolecules, and ADP-ribosyl peptides.

Gold-Catalyzed C-N Cross-Coupling Reactions of Aryl Iodides with Alkyl Nitriles or Silver Cyanate.

We have gold-catalyzed C-N cross-couplings of aryl iodides with aliphatic nitriles. Although nitriles are usually challenging nitrogen cross-coupling partners, they could be activated by base-mediated deprotonation and isomerization. The method utilizes widely available substrates in moderate to good yields to provide various N-aryl compounds. In addition, a similar strategy could be extended to the cross-couplings of aryl iodides with silver cyanate. The protocol features high humidity/air tolerance and works inter- and intramolecularly.

Beyond the Zincke reaction: Modern advancements in the synthesis and applications of N-aryl pyridinium salts

In this review, we highlight recent advances in the synthesis of N-aryl pyridinium salts, which have moved beyond the classical Zincke SNAr reaction to focus on strategies reliant on C–N bond formation using an ever expanding array of reaction manifolds. This expansion to include C–N bond forming approaches, as well as enabling an unprecedented breadth of both arene and N-heterocyclic coupling partners, has led to a shift in perception of N-aryl pyrdinium salts to now serving as a platform for aryl amine synthesis. As a result, new synthetic applications of these salts have begun to emerge, both utilizing classic (nucleophilic additions, radical reactions, cycloadditions, etc) and emergent transformations such as deaminative transformations, isotopic labeling, and molecular editing. This review provides a timely synopsis of novel N-aryl pyridinium salt syntheses from the last 10 years (2013 to present). These strategies are separated into the two main classes, radical cation and non-radical cation methods. Highlights of recent transformations and applications of the resultant N-aryl pyridinium salts are also discussed to demonstrate the untapped synthetic potential of these scaffolds and highlight areas of continued interest.

Organophotoredox-Catalyzed C-H Functionalizations of Benzophospholes.

An organophotoredox-catalyzed oxidative C-H functionalization of benzophospholes has been developed. The C-H alkoxycarbonylation with methyl carbazate occurs in the presence of Rose bengal, whereas Eosin Y enables the dehydrogenative coupling with secondary phosphine oxides and ethers, delivering the C-H phosphinylated and alkylated products. The scope of coupling partners is complementary to that of conventional metal-promoted C-H activation, thus successfully expanding the chemical space of substituted phospholes accessed by C-H functionalization protocols.

Site‐Selective Ortho/Ipso C−H Difunctionalizations of Arenes using Thianthrene as a Leaving Group

AbstractSite‐selective ortho/ipso C−H difunctionalizations of aromatic compounds were designed to afford polyfunctionalized arenes including challenging 1,2,3,4‐tetrasubstituted ones (62 examples, up to 97 % yields). To ensure the excellent regioselectivity of the process while keeping high efficiency, an original strategy based on a “C−H thianthenation/Catellani‐type reaction” sequence was developed starting from simple arenes. Non‐prefunctionalized arenes were first regioselectively converted into the corresponding thianthrenium salts. Then, a palladium‐catalyzed, norbornene (NBE)‐mediated process allowed the synthesis of ipso‐olefinated/ortho‐alkylated polyfunctionalized arenes using a thianthrene as a leaving group (revisited Catellani reaction). Pleasingly, using a commercially available norbornene (NBE) and a unique catalytic system, synthetic challenges known for the Catellani reaction with aryl iodides were smoothly and successfully tackled with the “thianthrenium” approach. The protocol was robust (gram‐scale reaction) and was widely applied to the two‐fold functionalization of various arenes including bio‐active compounds. Moreover, a panel of olefins and alkyl halides as coupling partners was suitable. Pleasingly, the “thianthrenium” strategy was successfully further applied to the incorporation of other groups at the ipso (CN/alkyl/H, aryl) and ortho (alkyl, aryl, amine, thiol) positions, showcasing the generality of the process.

Site-Selective Ortho/Ipso C-H Difunctionalizations of Arenes using Thianthrene as a Leaving Group.

Site-selective ortho/ipso C-H difunctionalizations of aromatic compounds were designed to afford polyfunctionalized arenes including challenging 1,2,3,4-tetrasubstituted ones (62 examples, up to 97 % yields). To ensure the excellent regioselectivity of the process while keeping high efficiency, an original strategy based on a "C-H thianthenation/Catellani-type reaction" sequence was developed starting from simple arenes. Non-prefunctionalized arenes were first regioselectively converted into the corresponding thianthrenium salts. Then, a palladium-catalyzed, norbornene (NBE)-mediated process allowed the synthesis of ipso-olefinated/ortho-alkylated polyfunctionalized arenes using a thianthrene as a leaving group (revisited Catellani reaction). Pleasingly, using a commercially available norbornene (NBE) and a unique catalytic system, synthetic challenges known for the Catellani reaction with aryl iodides were smoothly and successfully tackled with the "thianthrenium" approach. The protocol was robust (gram-scale reaction) and was widely applied to the two-fold functionalization of various arenes including bio-active compounds. Moreover, a panel of olefins and alkyl halides as coupling partners was suitable. Pleasingly, the "thianthrenium" strategy was successfully further applied to the incorporation of other groups at the ipso (CN/alkyl/H, aryl) and ortho (alkyl, aryl, amine, thiol) positions, showcasing the generality of the process.

Electroreductive alkylations of (hetero)arenes with carboxylic acids

Carboxylic acids are widely available and generally inexpensive from abundant biomass feedstocks, and they are suitable and generic coupling partners in synthetic chemistry. Reported herein is an electroreductive coupling of stable and versatile carboxylic acids with (hetero)arenes using protons as the hydrogen source. The application of an earth-abundant titanium catalyst has significantly improved the deoxygenative reduction process. Preliminary mechanistic studies provide insights into the deoxygenative reduction of in-situ generated ketone pathway, and the intermediacy generation of ketyl radical and alkylidene titanocene. Without the necessity of pressurized hydrogen or stoichiometric hydride as reductants, this protocol enables highly selective and straightforward synthesis of various functionalized and structurally diverse alkylbenzenes under mild conditions. The utility of this reaction is further demonstrated through practical and valuable isotope incorporation from readily available deuterium source.

Dichloromethane as C1 Synthon for the Photoredox Catalytic Cyclopropanation of Aromatic Olefins.

Dichloromethane, as a readily available and inexpensive C1 synthon is proposed as a powerful building block for cyclopropanation of alkenes under mild conditions. Herein, we report a highly efficient and versatile dual photoredox system, involving a nickel aminopyridine coordination complex and a photocatalyst, for the cyclopropanation of aromatic olefins using dichloromethane, under visible-light irradiation. The cyclopropanation protocol has been successfully applied at gram scale. Mechanistic studies suggest a Ni(II) pyridyl radical complex as the key intermediate for the homolytic cleavage of the Csp3-Cl bond, generating a chloromethyl radical that is captured by the olefin coupling partner. Our findings also highlight the versatility of this methodology. By directing the radical/polar crossover process, we were able to selectively drive the reaction towards either the formation of cyclopropyl derivatives or the corresponding non-cyclic alkyl chloride products. The methodology also successfully apply to geminal dichloroalkanes, including the formation of spiro[2,2] compounds. Moreover, our methodology extends to the synthesis of deuterium-labelled cyclopropanes, demonstrating its utility in isotopic labelling and broadening its applicability in chemical synthesis and drug development.