Nickel Chain-Walking Catalysis: A Journey to Migratory Carboboration of Alkenes.

ConspectusChain-walking offers extensive opportunities for innovating synthetic methods that involve constructing chemical bonds at unconventional sites. This approach provides previously inaccessible retrosynthetic disconnections in organic synthesis. Through chain-walking, transition metal-catalyzed alkene difunctionalization reactions can take place in a 1,n-addition (n ≠ 2) mode. Unlike classical 1,2-regioselective difunctionalization reactions, there remains a scarcity of reports regarding migratory patterns. Moreover, the range of olefins utilized in these studies is quite limited.About five years ago, our research group embarked on a project aimed at developing valuable migratory difunctionalization reactions of alkenes through chain-walking. Our focus was on carboboration of alkenes utilizing nickel catalysis. The reaction commences with the migratory insertion of an olefin into a Ni-Bpin species. Subsequently, a thermodynamically stable alkyl nickel complex is generated through a chain-walking process. This complex then couples with a carbon-based electrophile, leading to the formation of an alkylboron compound. It is worth highlighting that the success of these transformations relies significantly on the utilization of a bisnitrogen-based ligand and LiOMe as a B2pin2 activator. Synthetically, these migratory carboboration reactions establish a robust platform for the rapid and efficient synthesis of a wide range of structurally diverse organoboron compounds, which are not facially accessed by conventional methods. The incorporation of a versatile boron group introduces a wealth of possibilities for subsequent diversifications, significantly enhancing the value of the resulting products and allowing for the creation of a broader range of valuable derivatives and applications.This Account provides a comprehensive overview of our research efforts and advancements in the field of migratory carboboration of unactivated alkenes using nickel catalysis. We begin by outlining the development of a series of 1,1-regioselective carboboration reactions of terminal alkenes. A significant focus is placed on the initial integration of boronate, which not only triggers the formation of thermodynamically stable metal species but also exerts control over remote stereochemistry in reactions involving substituted methylenecyclohexenes. Continuing our exploration, remarkable success is achieved in 1,3-regio- and cis-stereoselectivity when dealing with cyclic alkenes. Remarkably, nickel chain-walking catalysis enables heterocyclic alkenes to be viable coupling partners within our transformations. Moreover, it grants us the ability to achieve regioselectivity for cyclohexenes that was previously unattainable, thus expanding the horizons of regiochemical control in these reactions. Lastly, we present the evolution of ligand-modulated regiodivergent carboboration of allylarenes. By gaining insights into the underlying mechanisms driving regiodivergence, we lay a strong foundation for tackling challenges related to selecting specific sites in chain-walking reactions, especially when dealing with multiple stable factors. We anticipate that our findings, coupled with the mechanistic insights we've gained, will not only advance the realm of nickel chain-walking catalysis but also contribute to the broader understanding of selectivity control in reactions of this nature. This advancement will also catalyze the synthesis of intricate functional molecules, contributing to the creation of complex and valuable compounds in the realm of organic chemistry.

Ligand-modulated nickel-catalyzed regioselective silylalkylation of alkenes.

Organosilicon compounds have shown tremendous potential in drug discovery and their synthesis stimulates wide interest. Multicomponent cross-coupling of alkenes with silicon reagents is used to yield complex silicon-containing compounds from readily accessible feedstock chemicals but the reaction with simple alkenes remains challenging. Here, we report a regioselective silylalkylation of simple alkenes, which is enabled by using a stable Ni(II) salt and an inexpensive trans-1,2-diaminocyclohexane ligand as a catalyst. Remarkably, this reaction can tolerate a broad range of olefins bearing various functional groups, including alcohol, ester, amides and ethers, thus it allows for the efficient and selective assembly of a diverse range of bifunctional organosilicon building blocks from terminal alkenes, alkyl halides and the Suginome reagent. Moreover, an expedient synthetic route toward alpha-Lipoic acid has been developed by this methodology.

Asymmetric anti-Selective Borylalkylation of Terminal Alkynes by Nickel Catalysis.

Selective transformation of alkyne triple bonds to double bonds serves as an efficient platform to construct substituted alkenes. While significant advances have been made in its spatiotemporal regulation, achieving a multicomponent enantioselective reaction that requires multifaceted selectivity issues to be overcome is still uncommon. Here, we report an unprecedented asymmetric anti-stereoselective borylcarbofunctionalization of terminal alkynes by nickel catalysis. The utilization of an inexpensive chiral diamine ligand enables the three-component cross-coupling of terminal alkynes, a diboron reagent, and prochiral alkyl electrophiles with high levels of regio-, stereo-, and enantioselectivities. This reaction provides an efficient protocol to access enantioenriched alkenyl esters bearing an α-stereogenic center, is remarkably practical, and has a broad scope and an outstanding functional group compatibility. In addition, the value of this method has been highlighted in a diversity of follow-up stereoretentive derivatizations and the stereoselective concise synthesis of complex drug molecules.

Base-Modulated 1,3-Regio- and Stereoselective Carboboration of Cyclohexenes.

While chain-walking stimulates wide interest in both polymerization and organic synthesis, site- and stereoselective control of chain-walking on rings is still a challenging task in the realm of organometallic catalysis. Inspired by a controllable chain-walking on cyclohexane rings in olefin polymerization, we have developed a set of chain-walking carboborations of cyclohexenes based on nickel catalysis. Different from the 1,4-trans-selectivity disclosed in polymer science, a high level of 1,3-regio- and cis-stereoselectivity is obtained in our reactions. Mechanistically, we discovery that the base affects the reduction ability of B2 pin2 and different bases lead to different catalytic cycles and different regioselective products (1,2- Vs 1,3-addition). This study provides a concise and modular method for the synthesis of 1,3-disubstituted cyclohexylboron compounds. The incorporation of a readily modifiable boronate group greatly enhances the value of this method, the synthetic potential of which was highlighted by the synthesis of a series of high-valued commercial chemicals and pharmaceutically interesting molecules.

Nickel-Catalyzed Regio- and Enantioselective Borylative Coupling of Terminal Alkenes with Alkyl Halides Enabled by an Anionic Bisoxazoline Ligand.

Chiral boronic esters are a class of versatile building blocks. We describe herein an asymmetric nickel-catalyzed borylative coupling of terminal alkenes with nonactivated alkyl halides. The success of this asymmetric reaction is ascribed to the application of a chiral anionic bisoxazoline ligand. This study provides a three-component strategy to access α- and ß-stereogenic boronic esters from easily accessible starting materials. This protocol is characterized by mild reaction conditions, wide substrate scope and high regio- and enantioselectivity. We also showcase the value of this method in simplifying the synthesis of several drug molecules. Mechanistic studies suggest that the generation of enantioenriched boronic esters bearing an α-stereogenic center results from a stereoconvergent process, while the enantioselectivity-controlling step in the generation of boronic esters with a ß-stereocenter is switched to the olefin migratory insertion step due to coordination of an ester group.

Practical Synthesis of Chiral Allylboronates by Asymmetric 1,1-Difunctionalization of Terminal Alkenes.

We report herein a modular catalytic method for the efficient enantioselective synthesis of chiral allylboronates from abundant feedstock chemicals through an asymmetric 1,1-difunctionalization of alkenes. This protocol is distinguished by its use of an inexpensive chiral catalyst, mild and convenient reaction conditions, wide substrate scope, scalability and practicality. The utility of this method is demonstrated by the rapid synthesis of key intermediates of complex drug molecules. Mechanistic studies reveal that ß-H elimination is a highly regioselective step and the reversible homolysis and convergance to the lower energy pre-reductive elimination intermediate is the enantio-determining step.

Modular access to substituted cyclohexanes with kinetic stereocontrol.

Substituted six-membered cyclic hydrocarbons are common constituents of biologically active compounds. Although methods for the synthesis of thermodynamically favored, disubstituted cyclohexanes are well established, a reliable and modular protocol for the synthesis of their stereoisomers is still elusive. Herein, we report a general strategy for the modular synthesis of disubstituted cyclohexanes with excellent kinetic stereocontrol from readily accessible substituted methylenecyclohexanes by the implementation of chain-walking catalysis. Mechanistically, the initial introduction of a sterically demanding boron ester group adjacent to the cyclohexane is key to guiding the stereochemical outcome. The synthetic potential of this methodology has been highlighted in late-stage modification of complex bioactive molecules and in comparison with current cross-coupling techniques.

Nickel/Brønsted acid dual-catalyzed regio- and enantioselective hydrophosphinylation of 1,3-dienes: access to chiral allylic phosphine oxides.

While chiral allylic organophosphorus compounds are widely utilized in asymmetric catalysis and for accessing bioactive molecules, their synthetic methods are still very limited. We report the development of asymmetric nickel/Brønsted acid dual-catalyzed hydrophosphinylation of 1,3-dienes with phosphine oxides. This reaction is characterized by an inexpensive chiral catalyst, broad substrate scope, and high regio- and enantioselectivity. This study allows the construction of chiral allylic phosphine oxides in a highly economic and efficient manner. Preliminary mechanistic investigations suggest that the 1,3-diene insertion into the chiral Ni-H species is a highly regioselective process and the formation of the chiral C-P bond is an irreversible step.

Regio- and Stereoselective Alkylboration of Endocyclic Olefins Enabled by Nickel Catalysis.

Whereas there is a significant interest in the rapid construction of diversely substituted saturated heterocycles, direct and modular access is currently limited to the mono-, 2,3-, or 3,4-substitution pattern. This Communication describes the straightforward and modular construction of 2,4-substituted saturated heterocycles from readily available materials in a highly stereo- and regioselective manner, which sets the stage for numerous readily accessible drug motifs. The strategy relies on chain walking catalysis.

Synergistic Ni/Cu catalyzed migratory arylsilylation of terminal olefins.

Synthesis of organosilanes from alkenes is a very important topic owing to their wide applications. A Ni/Cu dual metal-catalyzed arylsilylation of terminal alkenes, featuring migratory selectivity, has been developed. A wide diversity of aliphatic silanes have been prepared from terminal alkenes, aryl halides and Suginome's reagent. This protocol is highlighted by excellent regioselectivity, mild reaction conditions and good functional group tolerance. In addition to benzylic positions, carbon-carbon bonds can also be constructed at allylic positions. Preliminary mechanistic studies suggest that the copper cocatalyst promotes the transmetalation of Suginome's reagent, and the addition of a PyrOx ligand inhibits the formation of side-products from the carbon-Heck pathway. Moreover, studies toward the nature of the PyrOx ligand revealed that the steric hindrance of the oxazoline moiety greatly affects the chain-walking process, but not the arylation step.

Reaction scope and mechanistic insights of nickel-catalyzed migratory Suzuki-Miyaura cross-coupling.

Cross-coupling reactions have developed into powerful approaches for carbon-carbon bond formation. In this work, a Ni-catalyzed migratory Suzuki-Miyaura cross-coupling featuring high benzylic or allylic selectivity has been developed. With this method, unactivated alkyl electrophiles and aryl or vinyl boronic acids can be efficiently transferred to diarylalkane or allylbenzene derivatives under mild conditions. Importantly, unactivated alkyl chlorides can also be successfully used as the coupling partners. To demonstrate the applicability of this method, we showcase that this strategy can serve as a platform for the synthesis of terminal, partially deuterium-labeled molecules from readily accessible starting materials. Experimental studies suggest that migratory cross-coupling products are generated from Ni(0/II) catalytic cycle. Theoretical calculations indicate that the chain-walking occurs at a neutral nickel complex rather than a cationic one. In addition, the original-site cross-coupling products can be obtained by alternating the ligand, wherein the formation of the products has been rationalized by a radical chain process.

Nickel-catalyzed migratory alkyl-alkyl cross-coupling reaction.

The selective cross-coupling of activated electrophiles with unactivated ones has been regarded as a challenging task in cross-electrophile couplings. Herein we describe a migratory cross-coupling strategy, which can overcome this obstacle to access the desired cross-coupling products. Accordingly, a selective migratory cross-coupling of two alkyl electrophiles has been accomplished by nickel catalysis. Remarkably, this alkyl-alkyl cross-coupling reaction provides a platform to prepare 2°-2° carbon-carbon bonds from 1° and 2° carbon coupling partners. Preliminary mechanistic studies suggest that chain-walking occurs at both alkyl halides in this reaction, thus a catalytic cycle with the key step involving two alkylnickel(ii) species is proposed for this transformation.

Difunctionalization of Alkenes Involving Metal Migration.

The direct difunctionalization of alkenes, a cheap and abundant feedstock, represents one of the most attractive strategies for increasing molecular complexity in synthetic organic chemistry. In contrast with the 1,2-difunctionalization of alkenes, recent advances showcase alkene 1,n-difunctionalizations (n≠2) involving metal migration is an emerging and rapidly growing area of research. This promising strategy not only opens a novel avenue for future development of alkene transformations, but also significantly expands upon the bond disconnections available in modern organic synthesis. This Minireview summarizes recent progress in the migratory difunctionalization of alkenes, with an emphasis on the driving force for metal migration.

Nickel/Brønsted Acid-Catalyzed Chemo- and Enantioselective Intermolecular Hydroamination of Conjugated Dienes.

A novel nickel/Brønsted acid-catalyzed asymmetric hydroamination of acyclic 1,3-dienes has been established. A wide array of primary and secondary amines can be transformed into allylic amines with high yields and high enantioselectivities under very mild conditions. Moreover, our method is compatible with various functional groups and heterocycles, allowing for late-stage functionalization of biologically active complex molecules. Remarkably, this protocol exhibits good chemoselectivity with respect to amines bearing two different nucleophilic sites. Mechanistic studies reveal that the enantioselective carbon-nitrogen bond-forming step is reversible.

Nickel-Catalyzed 1,1-Alkylboration of Electronically Unbiased Terminal Alkenes.

An unprecedented nickel-catalyzed 1,1-alkylboration of electronically unbiased alkenes has been developed, providing straightforward access to secondary aliphatic boronic esters from readily available materials under very mild reaction conditions. The regioselectivity of this reaction is governed by a unique pyridyl carboxamide ligated catalyst, rather than the substrates. Moreover, this transformation shows excellent chemo- and regio-selectivity and remarkably good functional-group tolerance. We also demonstrate that under balloon pressure, ethylene can also be utilized as a substrate. Additionally, competence experiments indicate that selective bond formation is favored at the α-position of boron and preliminary mechanistic studies indicate that the key step in this three-component reaction involves a 1,2-nickel migration.

Nickel-Catalyzed 1,2-Arylboration of Vinylarenes.

A novel nickel-catalyzed 1,2-arylboration of vinylarenes is reported. A variety of 2-boryl-1,1-diarylalkanes, which constitute a class of significant pharmacophores, are efficiently prepared from readily available olefins and aryl halides in the presence of bis(pinacolato)diboron under mild reaction conditions. The success of this three-component cascade is mainly attributed to the redox-active nitrogen-based ligand. Moreover, this method exhibits good functional group tolerance and excellent chemo- and stereoselectivity.

Migratory Arylboration of Unactivated Alkenes Enabled by Nickel Catalysis.

An unprecedented arylboration of unactivated terminal alkenes, featuring 1,n-regioselectivity, has been achieved by nickel catalysis. The nitrogen-based ligand plays an essential role in the success of this three-component reaction. This transformation displays good regioselectivity and excellent functional-group tolerance. In addition, the incorporation of a boron group into the products provides substantial opportunities for further transformations. Also demonstrated is that the products can be readily transformed into pharmaceutically relevant molecules. Unexpectedly, preliminary mechanistic studies indicate that although the metal migration favors the α-position of boron, selective and decisive bond formation is favored at the benzylic position.

Site-Selective C-S Bond Formation at C-Br over C-OTf and C-Cl Enabled by an Air-Stable, Easily Recoverable, and Recyclable Palladium(I) Catalyst.

This report widens the repertoire of emerging PdI catalysis to carbon-heteroatom, that is, C-S bond formation. While Pd0 -catalyzed protocols may suffer from the formation of poisonous sulfide-bound off-cycle intermediates and lack of selectivity, the mechanistically diverse PdI catalysis concept circumvents these challenges and allows for C-S bond formation (S-aryl and S-alkyl) of a wide range of aryl halides. Site-selective thiolations of C-Br sites in the presence of C-Cl and C-OTf were achieved in a general and a priori predictable fashion. Computational, spectroscopic, X-ray, and reactivity data support dinuclear PdI catalysis to be operative. Contrary to air-sensitive Pd0 , the active PdI species was easily recovered in the open atmosphere and subjected to multiple rounds of recycling.

Photochemical Nickel-Catalyzed Reductive Migratory Cross-Coupling of Alkyl Bromides with Aryl Bromides.

A novel method to access 1,1-diarylalkanes from readily available, nonactivated alkyl bromides and aryl bromides via visible-light-driven nickel and iridium dual catalysis, wherein diisopropylamine ( iPr2NH) is used as the terminal stoichiometric reductant, is reported. Both primary and secondary alkyl bromides can be successfully transformed into the migratory benzylic arylation products with good selectivity. Additionally, this method showcases tolerance toward a wide array of functional groups and the presence of bases.

Palladium(II)-Catalyzed Oxidative Difunctionalization of Alkenes: Bond Forming at a High-Valent Palladium Center.

Difunctionalization of alkenes to incorporate two functional groups across a double bond has emerged as a powerful transformation to greatly increase molecular complexity in organic synthesis with improved efficiency. Historically, palladium-catalyzed difunctionalization of alkenes has suffered from difficulties with introducing a second functional group through reductive elimination of a Pd(II) intermediate and competing ß-hydride elimination reactions. To overcome these challenges, one strategy involves utilizing a steric bulky ligand to promote the reductive elimination steps from the Pd(II) center and impeding the ß-hydride elimination reactions, which are beyond the scope of this Account. Alternatively, strong oxidants have been utilized to generate high-valent palladium species, which are prone to undergo reductive elimination to form a second C-X bond. This new strategy has been extensively applied to explore the difunctionalization of alkenes with enriched functional group diversity over the past decade. In this Account, we discuss our exploration and application of a "high-valent palladium strategy" for the synthesis of fluorine-containing organic molecules that are typically inaccessible from other methods. These studies were focused on the difunctionalization of alkenes that was initiated by nucleopalladation to form the alkyl C-Pd(II) species in high exo/endo regioselectivity. In the presence of nucleophilic fluorine-containing reagents (e.g., AgF, TMSCF3, and AgOCF3) and strong oxidants (hypervalent iodine and electrophilic fluorinating reagents), the in situ generated fluorine-containing high-valent Pd(IV) intermediates undergo reductive elimination to provide the corresponding alkyl C-F, C-CF3, and C-OCF3 bonds. Using these methods, we synthesized a variety of heterocycles containing fluorine, trifluoromethyl, and trifluoromethoxyl moieties from alkene substrates under mild reaction conditions. Besides hypervalent iodine reagents and electrophilic fluorinating reagents, our group has demonstrated that hydrogen peroxide, which is an environmentally friendly oxidant, can oxidize alkyl C-Pd(II) species to form high-valent alkyl C-Pd intermediates, and based on this observation, several catalytic difunctionalizations of alkenes, such as aminochlorination, aminoacetoxylation, and aminohydroxylation reactions, have been successfully developed. In addition, water was the only waste derived from the oxidant. All of these studies provide attractive methods for the stereoselective introduction of C-N and C-O bonds across double bonds via high-valent palladium intermediates. To gain a deeper understanding of this "high-valent palladium strategy", systematic mechanistic studies were performed to illustrate the stereochemistry of aminopalladation and reductive elimination. These results are summarized in the final section and serve as a guide for further exploration of novel alkene transformation as well as in other areas, such as Pd-catalyzed C-H bond functionalization reactions.