Nickel-Catalyzed Stereoselective Coupling Reactions of Benzylic and Alkyl Alcohol Derivatives.

ConspectusNickel-catalyzed reactions of alkyl alcohol derivatives leverage the high prevalence of hydroxyl groups in natural products, medicinal agents, and synthetic intermediates to provide access to C(sp3)-rich frameworks. This Account describes our laboratory's development of stereospecific and stereoconvergent C-C bond forming reactions employing C(sp3)-O and C(sp3)-N electrophiles. In the context of development of new transformations, we also define fundamental characteristics of the nickel catalysts.Part I details the nickel-catalyzed cross-coupling reactions developed by our group which hinges on stereospecific formation of stable π-benzyl intermediates. Acyclic and cyclic ethers, esters, carbamates, lactones, and sulfonamides undergo Kumada-, Suzuki-, and Negishi-type coupling reactions to produce enantioenriched products with high fidelity of stereochemical information. We describe extension to include ring-opening reactions of saturated heterocycles to afford acyclic 1,3-fragments in high diastereomeric ratios. We also describe our advances in stereospecific nickel-catalyzed cross-electrophile coupling reactions. Tethered C-O and C-X electrophiles proved fruitful for construction of a variety of carbocyclic frameworks. We report an intramolecular cross-electrophile coupling of benzylic pivalates with aryl bromides for the synthesis of indanes and tetralins. We found that 4-halotetrahydropyrans and 4-halopiperidines readily undergo stereospecific ring contraction to afford substituted cyclopropanes. Mechanistic investigations are consistent with closed-shell intermediates, a Ni(0)/Ni(II) cycle, and an intramolecular SN2-type reaction of a key organonickel intermediate to form the cyclopropane. Building toward more complex cascade reactions, we have demonstrated that 2-alkynyl piperidines incorporate MeMgI in a dicarbofunctionalization of the alkyne to afford highly substituted vinyl cyclopropanes.In Part II we present our development of stereoconvergent reactions of alkyl alcohol derivatives. In order to expand the utility of the intramolecular XEC reaction, we sought to employ unactivated alkyl electrophiles. Specifically, alkyl dimesylates engage in intramolecular XEC reactions to form alkyl cyclopropanes. In contrast to our previous work, these reactions proceed through open-shell intermediates and favor stereoconvergent formation of the trans-cyclopropane. Enantioselective aldol reactions can be employed in syntheses of 1,3-diols which furnish enantioenriched cyclopropanes in high ee. Experimental and computational evidence reveals that MeMgI mediates formation of alkyl iodides in situ. The coupling reaction initiates with halogen atom abstraction at the secondary alkyl iodide. The alkyl Ni(II) complex then proceeds through a stereospecific SN2-type ring closure to form cyclopropane. In an effort to increase functional group compatibility in the synthesis of cyclopropanes from alkyl dimesylates we developed a zinc-mediated reaction of 1,3-dimesylates prepared from medicinal analogues. In challenging nickel-catalyzed intramolecular cross-electrophile coupling we were also able to show that vicinal carbocycles can be prepared under similar conditions, affording vicinal cyclopentyl-cyclopropyl motifs in high yield.In Part III we discuss our recent findings on the role of ligand identity in catalyst selectivity for stereospecific vs stereoablative mechanisms for oxidative addition. We demonstrate multivariable control of mechanism, where the choice of substrate and ligand work together to promote open- or closed-shell intermediates. In divergent reactions of 4-halotetrahydropyrans we observe distinct ligand preference for reactions at the C(sp3)-O center or the C(sp3)-Cl center. These findings are the source of continued investigations in our laboratory.

Cross-selective Deoxygenative Coupling of Aliphatic Alcohols: Installation of Methyl Groups including Isotopic Labels by Nickel Catalysis.

Nickel-catalyzed cross-electrophile coupling reactions of two aliphatic alcohol derivatives remain a challenge. Herein, we report a nickel-catalyzed reductive methylation reaction of aliphatic mesylates with methyl tosylate. This reaction provides straightforward access to compounds bearing aliphatic methyl groups from alkyl alcohol derivatives. Isotopically labelled substrates and reagents can be employed in the reaction to provide perdeuterated and 13C-labelled products. This transformation can be achieved by employing stoichiometric Mn reductant or electrochemically. Additionally, mechanistic experiments show that alkyl iodides are key intermediates in the transformation which undergo a stereoablative reaction via radical intermediates.

Halogenation Reactions of Alkyl Alcohols Employing Methyl Grignard Reagents.

Grignard reagents are commonly used as carbanion equivalents. Herein, we report an example of Grignard reagents acting as halide nucleophiles to form alkyl iodides and bromides. We establish that Grignard reagents can convert alkyl mesylates into alkyl halides, as well as be employed in a one-pot halogenation reaction starting from alcohols, which proceed through mesylate intermediates. The halogenation reaction is confirmed to occur by an SN2 pathway with inversion of configuration and is demonstrated to be efficient on multi-gram scale.

Nickel-Catalyzed Kumada Cross-Coupling Reactions of Benzylic Sulfonamides.

Herein, we report a Kumada cross-coupling reaction of benzylic sulfonamides. The scope of the transformation includes acyclic and cyclic sulfonamide precursors that cleanly produce highly substituted acyclic fragments. Preliminary data are consistent with a stereospecific mechanism that allows for a diastereoselective reaction.

Nickel-Catalyzed Alkyl-Alkyl Cross-Electrophile Coupling Reaction of 1,3-Dimesylates for the Synthesis of Alkylcyclopropanes.

Cross-electrophile coupling reactions of two Csp3-X bonds remain challenging. Herein we report an intramolecular nickel-catalyzed cross-electrophile coupling reaction of 1,3-diol derivatives. Notably, this transformation is utilized to synthesize a range of mono- and 1,2-disubstituted alkylcyclopropanes, including those derived from terpenes, steroids, and aldol products. Additionally, enantioenriched cyclopropanes are synthesized from the products of proline-catalyzed and Evans aldol reactions. A procedure for direct transformation of 1,3-diols to cyclopropanes is also described. Calculations and experimental data are consistent with a nickel-catalyzed mechanism that begins with stereoablative oxidative addition at the secondary center.

Identification of the Active Catalyst for Nickel-Catalyzed Stereospecific Kumada Coupling Reactions of Ethers.

A series of nickel complexes in varying oxidation states were evaluated as precatalysts for the stereospecific cross-coupling of benzylic ethers. These results demonstrate rapid redox reactions of precatalysts, such that the oxidative state of the precatalyst does not dictate the oxidation state of the active catalyst in solution. These data provide the first experimental evidence for a Ni0 -NiII catalytic cycle for a stereospecific alkyl-alkyl cross-coupling reaction, including spectroscopic analysis of the catalyst resting state.

Engaging Sulfonamides: Intramolecular Cross-Electrophile Coupling Reaction of Sulfonamides with Alkyl Chlorides.

The application of amine derivatives as coupling partners is rare due to the inherent strength of the C-N bond. Herein, we report the first cross-electrophile coupling reaction of unstrained benzylic sulfonamides. Nickel-catalyzed intramolecular cross-electrophile coupling reactions of acyclic and cyclic benzylic sulfonamides with pendant alkyl chlorides generate cyclopropane products. Mechanistic experiments and DFT calculations are consistent with initiation of the reaction by magnesium iodide accelerated oxidative addition of the benzylic sulfonamide. This work establishes neutral and unstrained amine derivatives as XEC partners, furnishes structural rearrangement of benzylic sulfonamides, and provides valuable information regarding catalyst design for the development of new cross-electrophile coupling reactions of carbon-heteroatom bonds.

Stereospecific Cross-Coupling Reactions Provide Conformationally-Biased Arylalkanes with Anti-Leukemia Activity.

A focused small library of carbamates and alcohols was prepared employing stereospecific Kumada-ring opening reactions of tetrahydropyrans. The core framework of the library members is acyclic and incorporates 1,3-substituents, to provide a conformational bias in avoiding syn-pentane interactions. A new compound with micromolar activity against MOLT-4, CCRF-CEM, and HL-60(TB) leukemia cell lines was identified from this series.

A Unified Explanation for Chemoselectivity and Stereospecificity of Ni-Catalyzed Kumada and Cross-Electrophile Coupling Reactions of Benzylic Ethers: A Combined Computational and Experimental Study.

Ni-catalyzed C(sp3)-O bond activation provides a useful approach to synthesize enantioenriched products from readily available enantioenriched benzylic alcohol derivatives. The control of stereospecificity is key to the success of these transformations. To elucidate the reversed stereospecificity and chemoselectivity of Ni-catalyzed Kumada and cross-electrophile coupling reactions with benzylic ethers, a combined computational and experimental study is performed to reach a unified mechanistic understanding. Kumada coupling proceeds via a classic cross-coupling mechanism. Initial rate-determining oxidative addition occurs with stereoinversion of the benzylic stereogenic center. Subsequent transmetalation with the Grignard reagent and syn-reductive elimination produce the Kumada coupling product with overall stereoinversion at the benzylic position. The cross-electrophile coupling reaction initiates with the same benzylic C-O bond cleavage and transmetalation to form a common benzylnickel intermediate. However, the presence of the tethered alkyl chloride allows a facile intramolecular SN2 attack by the benzylnickel moiety. This step circumvents the competing Kumada coupling, leading to the excellent chemoselectivity of cross-electrophile coupling. These mechanisms account for the observed stereospecificity of the Kumada and cross-electrophile couplings, providing a rationale for double inversion of the benzylic stereogenic center in cross-electrophile coupling. The improved mechanistic understanding will enable design of stereoselective transformations involving Ni-catalyzed C(sp3)-O bond activation.

Keeping Track of the Electrons.

Mechanistic investigation and new reaction development are intertwined. This interdependence presents challenges and opportunities in development of all transformations, particularly for those that employ base metal catalysts. In comparison to precious metal counterparts, these catalysts yield less easily to mechanistic analysis. However, base metal catalysts can provide new modes of reactivity and opportunities for discovery. In this Commentary, we highlight a developing field: nickel-catalyzed stereoselective alkyl cross-coupling reactions. While key features of the relevant catalytic cycles remain ambiguous, chemical intuition and key mechanistic experiments have provided the stepping stones for discovery of stereoselective transformations.

Outer-Sphere Control for Divergent Multicatalysis with Common Catalytic Moieties.

We herein report two examples of one-pot, simultaneous reactions, mediated by multiple, orthogonal catalysts with the same catalytic motif. First, BINOL-derived chiral phosphoric acids (CPA) and phosphothreonine (pThr)-embedded peptides were found to be matched for two different steps in double reductions of bisquinolines. Next, two π-methylhistidine (Pmh)-containing peptides catalyzed enantio- and chemoselective acylations and phosphorylations of multiple substrates in one pot. The selectivity exhibited by common reactive moieties is adjusted solely by the appended chiral scaffold through outer-sphere interactions.

Mechanism and Origins of Ligand-Controlled Stereoselectivity of Ni-Catalyzed Suzuki-Miyaura Coupling with Benzylic Esters: A Computational Study.

Nickel catalysts have shown unique ligand control of stereoselectivity in the Suzuki-Miyaura cross-coupling of boronates with benzylic pivalates and derivatives involving C(sp3)-O cleavage. The SIMes ligand (1,3-dimesityl-4,5-dihydroimidazol-2-ylidene) produces the stereochemically inverted C-C coupling product, while the tricyclohexylphosphine (PCy3) ligand delivers the retained stereochemistry. We have explored the mechanism and origins of the ligand-controlled stereoselectivity with density functional theory (DFT) calculations. The oxidative addition determines the stereoselectivity with two competing transition states, an SN2 back-side attack type transition state that inverts the benzylic stereogenic center and a concerted oxidative addition through a cyclic transition state, which provides stereoretention. The key difference between the two transition states is the substrate-nickel-ligand angle distortion; the ligand controls the selectivity by differentiating the ease of this angle distortion. For the PCy3 ligand, the nickel-ligand interaction involves mainly σ-donation, which does not require a significant energy penalty for the angle distortion. The facile angle distortion with PCy3 ligand allows the favorable cyclic oxidative addition transition state, leading to the stereoretention. For the SIMes ligand, the extra d-p back-donation from nickel to the coordinating carbene increases the rigidity of the nickel-ligand bond, and the corresponding angle distortion is more difficult. This makes the concerted cyclic oxidative addition unfavorable with SIMes ligand, and the back-side SN2-type oxidative addition delivers the stereoinversion.

Nickel-Catalyzed Cross-Electrophile Coupling of Alkyl Fluorides: Stereospecific Synthesis of Vinylcyclopropanes.

The stereospecific reductive cross-electrophile coupling reaction of 2-vinyl-4-halotetrahydropyrans for vinylcyclopropane synthesis is reported. The nickel-catalyzed reaction occurs with both alkyl fluorides and alkyl chlorides. To the best of our knowledge, this is the first reported cross-electrophile coupling reaction of an alkyl fluoride. Ring contraction proceeds with high stereospecificity, providing selective synthesis of either diastereomer of di- and trisubstituted cyclopropanes. The utility of this methodology is demonstrated by several synthetic applications including the synthesis of the natural product dictyopterene A. 2-Vinyl-4-fluorotetrahydrofurans also undergo stereospecific ring contractions, providing access to synthetically useful hydroxymethyl cyclopropanes.

Stereospecific nickel-catalyzed cross-coupling reactions of benzylic ethers and esters.

This Account presents the development of a suite of stereospecific alkyl-alkyl cross-coupling reactions employing nickel catalysts. Our reactions complement related nickel-catalyzed stereoconvergent cross-coupling reactions from a stereochemical and mechanistic perspective. Most reactions of alkyl electrophiles with low-valent nickel complexes proceed through alkyl radicals and thus are stereoablative; the correct enantioselective catalyst can favor the formation of one enantiomer. Our reactions, in contrast, are stereospecific. Enantioenriched ethers and esters are cleanly converted to cross-coupled products with high stereochemical fidelity. While mechanistic details are still to be refined, our results are consistent with a polar, two-electron oxidative addition that avoids the formation of radical intermediates. This reactivity is unusual for a first-row transition metal. The cross-coupling reactions engage a range of benzylic ethers and esters, including methyl ethers, tetrahydropyrans, tetrahydrofurans, esters, and lactones. Coordination of the arene substituent to the nickel catalyst accelerates the reactions. Arenes with low aromatic stabilization energies, such as naphthalene, benzothiophene, and furan, serve as the best ligands and provide the highest reactivity. Traceless directing groups that accelerate reactions of sluggish substrates are described, providing partial compensation for arene coordination. Kumada, Negishi, and Suzuki reactions provide incorporation of a broad range of transmetalating agents. In Kumada coupling reactions, a full complement of Grigard reagents, including methyl, n-alkyl, and aryl Grignard reagents, are employed. In reactions employing methylmagnesium iodide, ligation of the nickel catalyst by rac-BINAP or DPEphos provides the highest yield and stereospecificity. For all other Grignard reagents, Ni(dppe)Cl2 has emerged as the best catalyst. Negishi cross-coupling reactions employing dimethylzinc are reported as a strategy to increase the functional group tolerance of the reaction. We also describe Suzuki reactions using arylboronic esters. These reactions provided the first example in the series of a switch in stereochemical outcome. The reactions maintain stereospecificity, but reactions employing different achiral ligands provide opposite enantiomers of the product. Use of an N-heterocyclic carbene ligand, SIMes, provides inversion, consistent with our prior work in Kumada and Negishi coupling reactions. Use of the electron-rich phosphine PCy3, however, provides retention with stereospecificity, signaling a change in the mechanistic details. Potential applications of the reported cross-coupling reactions include the synthesis of medicinal agents containing the 2-arylalkane and 1,1-diarylalkane moieties, which are pharmacophores in medicinal chemistry. These moieties are found in compounds with activity against a broad range of indications, including cancer, heart disease, diabetes, osteoporosis, smallpox, tuberculosis, and insomnia. We highlight representative examples of bioactive compounds that we have prepared with high enantioselectivity employing our methods, as well as the discovery of a new anti-cancer agent.

Decarboxylative Alkyl-Alkyl Cross-Coupling Reactions.

Alkyl with alkyl: A significant development in alkyl-alkyl cross-coupling reactions, namely the nickel-catalyzed decarboxylative Negishi coupling of N-hydroxyphthalimide esters, was recently reported by Baran and co-workers. This method enables the synthesis of various highly functionalized compounds, including natural product derivatives.

Intra- and Intermolecular Nickel-Catalyzed Reductive Cross-Electrophile Coupling Reactions of Benzylic Esters with Aryl Halides.

Nickel-catalyzed cross-electrophile coupling reactions of benzylic esters and aryl halides have been developed. Both inter- and intramolecular variants proceed under mild reaction conditions. A range of heterocycles and functional groups are tolerated under the reaction conditions. Additionally, the first example of a stereospecific cross-electrophile coupling of a secondary benzylic ester is described.

Stereospecific Intramolecular Reductive Cross-Electrophile Coupling Reactions for Cyclopropane Synthesis.

The stereospecific reductive cross-electrophile coupling reaction of 2-aryl-4-chlorotetrahydropyrans to afford disubstituted cyclopropanes is reported. This ring contraction presents surprises with respect to the stereochemical outcome of reaction of the alkyl halide moiety. While cross-coupling and reductive cross-electrophile coupling reactions of alkyl halides are typically stereoablative, using a chiral catalyst to set the stereocenter, this transformation proceeds with high stereochemical fidelity at the alkyl halide and ether bearing stereogenic centers. This approach provides straightforward access to highly substituted cyclopropanes in two steps from commercially available aldehydes.

Selective synthesis of either enantiomer of an anti-breast cancer agent via a common enantioenriched intermediate.

A stereoselective synthesis of a bioactive triarylmethane is described. Key to the synthesis is a nickel-catalyzed Suzuki-Miyaura coupling which proceeds with retention at the benzylic center. This method is complementary to our previously reported nickel-catalyzed Kumada coupling which proceeds with inversion. Together, the two methods allow for efficient access to either enantiomer of biologically relevant triarylmethanes from a common enantioenriched intermediate.

Selective Cross-Electrophile Coupling by Dual Catalysis.

Palladium and nickel: This Highlight summarizes recent developments in the area of dual-catalytic Ullman-type coupling reactions of aryl bromides and triflates: Weix and co-workers took advantage of the different selectivities and stabilities of palladium and nickel catalysts to favor the desired cross-coupling and suppress homocoupling.

Enantiospecific intramolecular Heck reactions of secondary benzylic ethers.

Enantioenriched methylenecyclopentanes are synthesized by stereospecific, nickel-catalyzed Heck cyclizations of secondary benzylic ethers. The reaction proceeds in high yield and enantiospecificity for benzylic ethers of both π-extended and simple arenes. Ethers with pendant 1,2-disubstituted olefins form trisubstituted olefins with control of both absolute configuration and alkene geometry. Diastereoselective synthesis of a polycyclic furan is demonstrated.