光催化Negishi偶联反应

The merging of photoredox and transition-metal catalysis has become one of the most attractive approaches for carbon-carbon bond formation. Such reactions require the use of two organo-transition-metal species, one of which acts as a photosensitizer and the other one as a cross-coupling catalyst. We report herein an exogenous-photosensitizer-free photocatalytic process for the formation of carbon-carbon bonds by direct acceleration of the well-known nickel-catalyzed Negishi cross-coupling that is based on the use of two naturally abundant metals. This finding will open new avenues in cross-coupling chemistry that involve the direct visible-light absorption of organometallic catalytic complexes.

… Photocatalysis evolved as a significant tool to accelerate transition-metal catalysis associated with various benefits such as mild and environmentally benign characteristics. Wang and …

Abstract Visible-light induced catalysis is of high interest for its mild and environmentally benign properties. Herein, a general Ni catalysis accelerated by visible-light was successfully developed for one-pot Negishi coupling reactions at room temperature in a short reaction time ( C bond formation for important biaryl components. It tolerates various functional groups, and Hammett study illuminates the possiblility of Ni(III)/Ni(I) redox catalytic cycle.

The scale up of light-induced nickel-catalyzed Negishi reactions is reported herein, with output rates reaching multigram quantities per hour. This level of throughput is suitable to support preclinical medicinal chemistry programs in late lead optimization, where tens of grams to hundreds of grams of final product is needed. Adjusting reaction times and concentrations was critical in achieving this robust output. This example demonstrates how visible photochemistry and use of solid metal reagent can be used and how the progress of the reaction can be followed by in-line NMR monitoring.

ConspectusTransition-metal catalyzed cross-coupling reactions are fundamental reactions in organic chemistry, facilitating strategic bond formations for accessing natural products, organic materials, agrochemicals, and pharmaceuticals. Redox chemistry enables access to elusive cross-coupling mechanisms through single-electron processes as an alternative to classical two-electron strategies predominated by palladium catalysis. The seminal reports of Baran, MacMillan, Doyle, Molander, Weix, Lin, Fu, Reisman, and others in merging redox perturbation (photochemical, electrochemical, and purely chemical) with catalysis are pivotal to the current resurgence and mechanistic understanding of first-row transition metal-based catalysis. The hallmark of this redox platform is the systematic modulation of transition-metal oxidation states by a photoredox catalyst or at a heterogeneous electrode surface. Electrocatalysis and photocatalysis enhance transition metal catalysis' capacity for bond formation through electron- or energy-transfer processes that promote otherwise challenging elementary steps or elusive mechanisms. Cross-coupling conditions promoted by electrocatalysis and photocatalysis are mild, and bond formation proceeds with exceptionally high chemoselectivity and wide functional group tolerance. The interfacing of abundant first-row transition-metal catalysis with electrocatalysis and photocatalysis has brought about a paradigm shift in cross-coupling technology as practitioners are quickly applying these tools in synthesizing fine chemicals and pharmaceutically relevant motifs. In particular, the merger of Ni catalysis with electro- and photochemistry ushered in a new era for carbon-carbon and carbon-heteroatom cross-couplings with expanded generality compared to their thermally driven counterparts. Over the past decade, we have developed enabling photo- and electrochemical methods throughout our combined research experience in industry (BMS, AstraZeneca) and academia (Professor Baran, Scripps Research) in cross-disciplinary collaborative environments. In this Account, we will outline recent progress from our past and present laboratories in photo- and electrochemically mediated Ni-catalyzed cross-couplings. By highlighting these cross-coupling methodologies, we will also compare mechanistic features of both electro- and photochemical strategies for forging C(sp2)-C(sp3), C(sp3)-C(sp3), C-O, C-N, and C-S bonds. Through these side-by-side comparisons, we hope to demystify the subtle differences between the two complementary tools to enact redox control over transition metal catalysis. Finally, building off the collective experience of ourselves and the rest of the community, we propose a tactical user guide to photo- and electrochemically driven cross-coupling reactions to aid the practitioner in rapidly applying such tools in their synthetic designs.

… further achieved the enantioselective cross-coupling of an array of organozinc reagents with … In 2014, Molander’s group reported the photoredox/nickel dual-catalyzed cross-coupling of …

The cross‐coupling of esters of N‐hydroxyphthalimide with fluorinated alkyl zinc reagents resulting in the C(sp 3 )−C(sp 3 ) bond formation is described. The method involves readily accessible perfluorinated and tetrafluorinated alkyl zinc bromides. The reaction is performed under copper and photoredox dual catalysis conditions.

The development of transition metal (TM) catalysis for organic synthesis under visible light without recourse to typical photoredox catalysts has become a rapidly growing area of research and has b...

Abstract A visible‐light‐induced Negishi cross‐coupling is enabled by the activation of a Pd 0 –Zn complex. With this photocatalytic method, the scope of deactivated aryl halides that can be employed in the Negishi coupling was significantly expanded. NMR experiments conducted in the presence and absence of light confirmed that the formation of the palladium–zinc complex is key for accelerating the oxidative addition step.

… Visible light photoredox reactions are the fore front in organic chemistry, commonly using … Wang and co-workers 14 reported a Ni-catalyzed Negishi cross-coupling of ArN 2 BF 4 . The …

In recent years, visible light-induced transition metal catalysis has emerged as a new paradigm in organic photocatalysis, which has led to the discovery of unprecedented transformations as well as the improvement of known reactions. In this subfield of photocatalysis, a transition metal complex serves a double duty by harvesting photon energy and then enabling bond forming/breaking events mostly via a single catalytic cycle, thus contrasting the established dual photocatalysis in which an exogenous photosensitizer is employed. In addition, this approach often synergistically combines catalyst–substrate interaction with photoinduced process, a feature that is uncommon in conventional photoredox chemistry. This Review describes the early development and recent advances of this emerging field.

A new area of visible light-induced Pd-catalysis has been emerging into the field. In contrast to the classical ground-state Pd-catalyzed reactions mostly proceeding via two-electron redox manifold, the mechanisms for these new Pd-photoexcited methods usually operate via a single electron transfer process, thus leading to putative Pd-radical hybrid species, which exhibit both radical and classical Pd-type reactivity. This minireview highlights the recent progress in this rapidly growing area.

ConspectusOver the past decade, photoredox catalysis has blossomed as a powerful methodology because of its wide applicability in sustainable free-radical-mediated processes, in which light is used as a cleaner energy source to alter the redox properties of organic molecules and to drive unique chemical transformations. Numerous examples of highly selective C-C and C-heteroatom bond formation processes have been achieved this way in an efficient and waste-reducing way. Therein, the activation of widely available organic halides via single-electron reduction has been broadly applied for organic synthesis. However, in comparison with alkyl and aryl halides, the analogous utilization of vinyl halides is less developed, most likely as a consequence of the highly unstable vinyl radicals generated as intermediates along with their strong tendency to abstract hydrogen atoms from a suitable source (e.g., the solvent), resulting in a synthetically less useful reduction.Nevertheless, during the last years, a number of photocatalytic processes involving vinyl halides have been developed, featuring the generation of vinyl radicals, diradicals, or radical cations as the key transient species. Moreover, photoredox processes in which a radical reacts with a vinyl halide or with an in situ-generated vinylmetal halide have been developed. Thus, identifying suitable conditions to generate and manipulate these reactive species has resulted in novel synthetic processes in a controllable manner. Moreover, in view of the great versatility of vinyl halides in palladium-catalyzed cross-coupling reactions, their activation by visible light might provide an attractive alternative to such processes, especially when non-noble metals could be used as photoinitiators in the future.In this Account, we discuss the various strategies of photoredox processes involving vinyl halides, classifying the material into four categories: (a) formation of a vinyl radical upon receipt of an electron from the photocatalyst, (b) formation of a radical cation after donation of an electron to the photocatalyst, (c) energy transfer corresponding to diradical formation upon triplet-triplet sensitization, and (d) dual transition metal and photocatalysis employing vinyl halides as precursors. While in the first three approaches the activation of vinyl halides is part of the photochemical step, the fourth one involves the interaction of a photochemically generated radical with a vinylnickel(II) halide obtained in turn by the oxidative addition of nickel(0) to the vinyl halide. Therefore, we highlight these important developments for conceptual comparison to the direct activation of vinyl halides by light, but they are not covered in depth in this Account.

Palladium-catalyzed carbon-carbon and carbon-heteroatom bond construction are among the most significant and powerful methods in organic synthesis. Numerous investigations are focusing on the appli...

Nickel (Ni)-catalyzed photoredox reactions are revolutionary methods that transform organic synthesis, enabling highly efficient and selective reactions under mild conditions. The synergy between Ni catalysis and photoredox catalysis is efficacious in activating inert bonds, creating potential reaction pathways, and accessing otherwise inaccessible molecular architectures. This review provides a detailed overview of advances in nickel/photoredox dual catalysis, with particular reference to insights into mechanisms and reaction scope. Among the key developments are enantioselective allyl carbamates, β-phenethylamines, and aryl-C-nucleosides, as well as methods for hydroalkylation, aryl alkylation, and C–N/C–O coupling reactions. The single electron transfer (SET) processes and versatile oxidation states of Ni, coupled with organic and metal-based photocatalysts, underpin the dual catalytic cycles. Such innovations render Ni-catalyzed photoredox reactions more sustainable and cost-effective, providing a strong foundation for future advances in this area.

Developing robust catalytic methods for constructing C(sp3)–C(sp3) bonds is critically important for synthesizing a diverse array of drug molecules. However, this type of reaction poses significant challenges from a chemical standpoint due to issues with regioselectivity, functional group tolerance and complex catalyst design. Current metallaphotoredox approaches do not provide a viable solution because they rely on expensive, toxic, and rare iridium-based photocatalysts, severely limiting their widespread application. In this study, we introduce carbon nitride nanosheets as an efficient and sustainable alternative to traditional photocatalysts. When combined with nickel, carbon nitride nanosheets facilitates the cross-coupling of alkyl halides and carboxylic acids. Our results demonstrate a broad substrate scope and highlight the recyclability of the photocatalyst. Density functional theory calculations provide molecular insights into the role of the catalytic system in facilitating photodecarboxylation and subsequent C–C bond formation. This work expands the potential of photoredox chemistry, and offers a novel method for efficient, industrially relevant light-to-chemical conversion processes.

Transition metal catalyzed cross coupling reactions are important in chemical synthesis for the formation of C-C and C-heteroatom bonds. Suitable catalysts are frequently based on palladium or nickel, and lately the cheaper and more abundant first-row transition metal element has been much in focus. The combination of nickel catalysis with photoredox chemistry has opened new synthetic possibilities, and in some cases electronically excited states of nickel complexes play a key role. This is a remarkable finding, because photo-excited metal complexes are underexplored in the context of organic bond-forming reactions, and because the photophysics and the photochemistry of first-row transition metal complexes are underdeveloped in comparison to their precious metal-based congeners. Consequently, there is much potential for innovation at the interface of synthetic-organic and physical-inorganic chemistry. This minireview highlights recent key findings in light-driven nickel catalysis and identifies essential concepts for the exploitation of photoactive nickel complexes in organic synthesis.

… 2007 describing a light mediated Sonogashira cross-coupling between aryl bromides 1 and … -coupling reaction between aryl bromides 19 and a large variety of organozinc Reformatsky-…

Photoredox catalysis has experienced a revitalized interest from the synthesis community during the past decade. For example, photoredox/Ni dual catalysis protocols have been developed to overcome several inherent limitations of palladium-catalyzed cross-couplings by invoking a single-electron transmetalation pathway. This Perspective highlights advances made by our laboratory since the inception of the photoredox/Ni cross-coupling of benzyltrifluoroborates with aryl bromides. In addition to broadening the scope of trifluoroborate coupling partners, research using readily oxidized hypervalent silicates as radical precursors that demonstrate functional group compatibility is highlighted. The pursuit of electrophilic coupling partners beyond (hetero)aryl bromides has also led to the incorporation of several new classes of C(sp2)-hybridized substrates into light-mediated cross-coupling. Advances to expand the radical toolbox by utilizing feedstock chemicals (e.g., aldehydes) to access radicals that were previously inaccessible from trifluoroborates and silicates are also emphasized. Additionally, several organic photocatalysts have been investigated as replacements for their expensive iridium- and ruthenium-based counterparts. Lastly, the net C–H functionalization of the radical partner in an effort to improve atom economy is presented. An underlying theme in all of these studies is the value of generating radicals in a catalytic manner, rather than stoichiometrically.

1,2-Dicarbofunctionalization of unactivated olefin has been reported under photoredox/nickel dual catalysis. The mildness of the visible-light-mediated reaction allows the use of various alkyl and aryl electrophiles with several sensitive functional groups. The protocol was equally applied for late-stage diversification of drugs and biologically active molecules. Investigations elucidated the importance of photoredox/nickel dual catalysis and α-amino-radical-mediated halogen atom transfer and provided us with the nickel complexes involved in the reaction.

Conspectus The use of photocatalysis in organic chemistry has encountered a surge of novel transformations since the start of the 21st century. The majority of these transformations are driven by the generation and subsequent reaction of radicals, owing to the intrinsic property of common photocatalysts to transfer single electrons from their excited state. While this is a powerful and elegant method to develop novel transformations, several research groups recently sought to further extend the toolbox of photocatalysis into the realm of polar ionic reactivity by the formation of cationic as well as anionic key reaction intermediates to furnish a desired product. Our group became especially interested in the photocatalytic formation of anionic carbon nucleophiles, as the overall transformation resembles classical organometallic reactions like Grignard, Barbier, and Reformatsky reactions, which are ubiquitous in organic synthesis with broad applications especially in the formation of valuable C–C bonds. Although these classical reactions are frequently applied, their use still bears certain disadvantages; one is the necessity of an (over)stoichiometric amount of a reducing metal. The reducing, low-valent, metal is solely applied to activate the starting material to form the organometallic carbanion synthon, while the final reaction product does generally not contain a metal species. Hence, a stoichiometric amount of metal salt is bound to be generated at the end of each reaction, diminishing the atom economy. The use of visible light as mild and traceless activation agent to drive chemical reactions can be a means to arrive at a more atom economic transformation, as a reducing metal source is avoided. Beyond this, the vast pool of photocatalytic activation methods offers the potential to employ easily available starting materials, as simple as unfunctionalized alkanes, to open novel and more facile retrosynthetic pathways. However, as mentioned above, photocatalysis is dominated by open-shell radical reactivity. With neutral radicals showing an intrinsically different reactivity than ionic species, novel strategies to form intermediates expressing a polar behavior need to be developed in order to achieve this goal. In the last couple of years, several methods toward this aim have been reported by our group and others. This Account aims to give an overview of the different existing strategies to photocatalytically form carbon centered anions or equivalents of those in order to form C–C bonds. As the main concept is to omit a stoichiometric reductant source (like a low-valent metal in classical organometallic reactions), only redox-neutral and reductant-free transformations were taken into closer consideration. We present selected examples of important strategies and try to illustrate the intentions and concepts behind the methods developed by our group and others.

Aromatic compounds interact with organozinc reagents under photoredox conditions leading to the substitution products. The reaction is performed under blue light irradiation via in situ generated organozinc reagents (Barbier conditions), which are oxidized by the photocatalyst followed by radical attack at the aromatic substrate. The method works with polyfluorinated arenes, 2‐chlorobenzoxazoles, and 2‐sulfonyl‐substituted benzothiazole.

Fluorinated organic compounds are frequently used across the chemical and life sciences. Although a large, structurally diverse pool of alkyl fluorides is nowadays available, synthetic applications trail behind the widely accepted utility of other halides. We envisioned that C(sp2)-C(sp3) cross-coupling reactions of alkyl fluorides with fluorophilic organozinc compounds should be possible through a heterolytic mechanism that involves short-lived ion pairs and uses the stability of the Zn-F bond as the thermodynamic driving force. This would be mechanistically different from previously reported radical reactions and overcome long-standing limitations of organometallic cross-coupling methodology, including competing β-hydride elimination, homodimerization and hydrodefluorination. Here, we show a practical Csp3-F bond functionalization method that expands the currently restricted synthetic space of unactivated primary, secondary and tertiary C(sp3)-F bonds but also uses benzylic, propargylic and acyl fluorides. Many functional groups and sterically demanding substrates are tolerated, which allows practical carbon-carbon bond formation and late-stage functionalization. Many alkyl fluorides are readily available, but the synthetic applications trail behind the widely accepted utility of other halides. Here, the authors report a practical Csp3-F bond functionalization method that expands the currently restricted synthetic space of unactivated C(sp3)-F bonds, but also uses benzylic, propargylic and acyl fluorides.

… coupling reaction of NHPI esters with organozinc and organomagnesium compounds. This … to construct carbon–carbon bonds. In 1993, the Okada group developed a photocatalytic …

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Conspectus The important role of transition metal-catalyzed cross-coupling in expanding the frontiers of accessible chemical territory is unquestionable. Despite empowering chemists with Herculean capabilities in complex molecule construction, contemporary protocols are not without their Achilles’ heel: Csp3–Csp2/sp3 coupling. The underlying challenge in sp3 cross-couplings is 2-fold: (i) methods employing conventional, bench-stable precursors are universally reliant on extreme reaction conditions because of the high activation barrier of transmetalation; (ii) circumvention of this barrier invariably relies on use of more reactive precursors, thereby sacrificing functional group tolerance, operational simplicity, and broad applicability. Despite the ubiquity of this problem, the nature of the transmetalation step has remained unchanged from the seminal reports of Negishi, Suzuki, Kumada, and Stille, thus suggesting that the challenges in Csp3–Csp2/sp3 coupling result from inherent mechanistic constraints in the traditional cross-coupling paradigm. Rather than submitting to the limitations of this conventional approach, we envisioned that a process rooted in single-electron reactivity could furnish the same key metalated intermediate posited in two-electron transmetalation, while demonstrating entirely complementary reactivity patterns. Inspired by literature reports on the susceptibility of organoboron reagents toward photochemical, single-electron oxidative fragmentation, realization of a conceptually novel open shell transmetalation framework was achieved in the facile coupling of benzylic trifluoroborates with aryl halides via cooperative visible-light activated photoredox and Ni cross-coupling catalysis. Following this seminal study, we disclosed a suite of protocols for the cross-coupling of secondary alkyl, α-alkoxy, α-amino, and α-trifluoromethylbenzyltrifluoroborates. Furthermore, the selective cross-coupling of Csp3 organoboron moieties in the presence of Csp2 organoboron motifs was also demonstrated, highlighting the nuances of this approach to transmetalation. Computational modeling of the reaction mechanism uncovered useful details about the intermediates and transition-state structures involved in the nickel catalytic cycle. Most notably, a unique dynamic kinetic resolution process, characterized by radical homolysis/recombination equilibrium of a NiIII intermediate, was discovered. This process was ultimately found to be responsible for stereoselectivity in an enantioselective variant of these cross-couplings. Prompted by the intrinsic limitations of organotrifluoroborates, we sought other radical feedstocks and quickly identified alkylbis(catecholato)silicates as viable radical precursors for Ni/photoredox dual catalysis. These hypervalent silicate species have several notable benefits, including more favorable redox potentials that allow extension to primary alkyl systems incorporating unprotected amines as well as compatibility with less expensive Ru-based photocatalysts. Additionally, these reagents exhibit an amenability to alkenyl halide cross-coupling while simultaneously expanding the aryl halide scope. In the process of exploring these reagents, we serendipitously discovered a method to effect thioetherification of aryl halides via a H atom transfer mechanism. This latter discovery emphasizes that this robust cross-coupling paradigm is “blind” to the origins of the radical, opening opportunities for a wealth of new discoveries. Taken together, our studies in the area of photoredox/nickel dual catalysis have validated single-electron transmetalation as a powerful platform for enabling conventionally challenging Csp3–Csp2 cross-couplings. More broadly, these findings represent the power of rational design in catalysis and the strategic use of mechanistic knowledge and manipulation for the development of new synthetic methods.

ConspectusIn recent years, nickel-catalyzed asymmetric coupling reactions have emerged as efficient methods for constructing chiral C(sp3) carbon centers. Numerous novel approaches have been reported to rapidly construct chiral carbon-carbon bonds through nickel-catalyzed asymmetric couplings between electrophiles and nucleophiles or asymmetric reductive cross-couplings of two different electrophiles. Building upon these advances, our group has been devoted to interrogating dual nickel- and photoredox-catalyzed asymmetric reductive cross-coupling reactions.In our endeavors over the past few years, we have successfully developed several dual Ni-/photoredox-catalyzed asymmetric reductive cross-coupling reactions involving organohalides. While some probably think that this system is just a change of the reduction system from traditional metal reductants to a photocatalysis system, a question that we also pondered at the beginning of our studies, both the achievable reaction types and mechanisms suggest a different conclusion: that this dual catalysis system has its own advantages in the chiral carbon-carbon bond formation. Even in certain asymmetric reactions where the photocatalysis regime functions only as a reducing system, the robust reducing capability of photocatalysts can effectively accelerate the regeneration of low-valent nickel species, thus expanding the selectable scope of chiral ligands. More importantly, in many transformations, besides reducing nickel catalysts, the photocatalysis system can also undertake the responsibility of alkyl radical formation, thereby establishing two coordinated, yet independent catalytic cycles. This catalytic mode has been proven to play a crucial role in achieving diverse asymmetric coupling reactions with great challenges.In this Account, we elucidate our understanding of this system based on our experience and findings. In the Introduction, we provide an overview of the main distinctions between this system and traditional Ni-catalyzed asymmetric reductive cross-couplings with metal reductants and the potential opportunities arising from these differences. Subsequently, we outline various chiral carbon-carbon bond-forming types obtained by this dual Ni/photoredox catalysis system and their mechanisms. In terms of chiral C(sp3)-C(sp2) bond formation, extensive discussion focuses on the asymmetric arylations of α-chloroboronates, α-trifluoromethyl alkyl bromides, α-bromophosphonates, and so on. In the realm of chiral C(sp3)-C(sp) bond formation, asymmetric alkynylations of α-bromophosphonates and α-trifluoromethyl alkyl bromides have been presented herein. Regarding C(sp3)-C(sp3) bond formation, we take the asymmetric alkylation of α-chloroboronates as a compelling example to illustrate the great efficiency of this dual catalysis system. This summary would enable a better grasp of the advantages of this dual catalysis system and clarify how the photocatalysis regime facilitates enantioselective transformations. We anticipate that this Account will offer valuable insights and contribute to the development of new methodologies in this field.