Nickel-Catalyzed Functionalization Reactions Involving C-H Bond Activation via an Amidate-Promoted Strategy and Its Extension to the Activation of C-F, C-O, C-S, and C-CN Bonds.

ConspectusThe development of functionalization reactions involving the activation of C-H bonds has evolved extensively due to the atom and step economy associated with such reactions. Among these reactions, chelation assistance has been shown to provide a powerful solution to the serious issues of reactivity and regioselectivity faced in the activation of C-H bonds. The vast majority of C-H functionalization reactions reported thus far has involved the use of precious metals. Kleiman and Dubeck reported the cyclonickelation of azobenzene and NiCp2 in which an azo group directs a Ni center to activate the ortho C-H bond in close proximity. Although this stoichiometric reaction was discovered earlier than that for other transition-metal complexes, its development as a catalytic reaction was delayed. No general catalytic systems were available for Ni-catalyzed C-H functionalization reactions for a long time. This Account details our group's development of Ni(0)- and Ni(II)-catalyzed chelation-assisted C-H functionalization reactions. It also highlights how the new strategy can be extended to the activation of other unreactive bonds.In the early 2010s, we found that the Ni(0)-catalyzed reaction of aromatic amides that contain a 2-pyridinylmethylamine moiety as a directing group with alkynes results in C-H/N-H oxidative annulation to give isoquinolinones. In addition, the combination of a Ni(II) catalyst and an 8-aminoquinoline directing group was found to be a superior combination for developing a wide variety of C-H functionalization reactions with various electrophiles. The reactions were proposed to include the formation of unstable Ni(IV) and/or Ni(III) species; the generation of such high-valence Ni species was rare at that time, but since then, many papers dealing with DFT and organometallic studies have appeared in the literature in attempts to understand the mechanism. Based on our in-depth considerations of the mechanism with respect to why an N,N-bidentate directing group is required, we realized that the formation of a N-Ni bond by the oxidative addition of a N-H bond to a Ni(0) species or a ligand exchange between a N-H bond and Ni(II) species is the key step. We concluded that the precoordination of the N(sp2) atom in the directing group positions the Ni species to be in close proximity to the N-H bond which permits the formation of a N-Ni bond. Based on this working hypothesis, we carried out the reaction using KOtBu as a base and found that the Ni(0)-catalyzed reaction of aromatic amides that do not contain such a specific directing group with alkynes results in the formation of the desired isoquinolinone, in which an amidate anion acts as the actual directing group. Remarkably, this strategy was found to be applicable to the activation of various other unreactive bonds such as C-F, C-O, C-S, and C-CN.

Carboxylate-Assisted Iridium (III)-Catalyzed C(sp2)-H Amidation of 2-Aroylimidazoles With Dioxazolones.

The Ir(III)-catalyzed ortho C-H amidation of 2-aroylimidazoles with 3-aryldioxazolones as an amidating reagent is reported. The method provides a broad substrate scope with wide functional group compatibility. Mechanistic studies indicate that C-H bond cleavage is reversible and appears not to be the rate-determining step. The presence of an electron-donating group in the 2-aroylimidazoles and an electron-withdrawing group in the 3-aryldioxazoles significantly accelerates the reaction, suggesting that nitrene insertion is the rate-determining step.

Selective Nickel-Catalyzed Hydrodefluorination of Amides Using Sodium Borohydride.

Hydrodefluorination selective to the ortho position to amides is accomplished under mild conditions using sodium borohydride and a nickel catalyst. The facile formation of a nickelacycle intermediate with a specific geometry ensures selectivity without the need for electronic directing groups, and fluorine atoms in other positions remain intact. This method avoids the use of stoichiometric silanes which are typical for most other defluorination reactions, resulting in virtually no organic waste byproducts.

Ir(III)-Catalyzed C(sp2)-H Amidation of 2-Aroylimidazoles with 2,2,2-Trichloroethoxycarbonyl Azide (TrocN3).

The Ir(III)-catalyzed ortho-C-H amidation of 2-aroylimidazole derivatives with 2,2,2-trichloroethyl azide (TrocN3) as an amidating reagent is reported. The reaction proceeds smoothly, even at room temperature, and various important functional groups are tolerated. The results of deuterium-labeling experiments indicate that C-H bond cleavage is irreversible and does not appear to be the rate-determining step. The presence of an electron-donating group on the phenyl ring in the 2-aroylimidazole results in a dramatic acceleration in the reaction.

Reaction Path Determination of Rhodium(I)-Catalyzed C-H Alkylation of N-8-Aminoquinolinyl Aromatic Amides with Maleimides.

The rhodium(I)-catalyzed reaction of N-8-aminoquinolinyl aromatic amides with maleimides results in C-H alkylation at the ortho position of the amide. The reaction path and formation of the alkylation product with density functional theory (DFT) calculations were done. The detailed computational study showed that the reaction proceeds in the following steps: (I) deprotonation of the NH amide proton, (II) oxidative addition of the ortho C-H bond, (III) migratory insertion of the maleimide, (IV) reductive elimination with the C-C bond formation, and (V) protonation. The energetic span model showed that the turnover frequency (TOF)-determining transition state (TDTS) is the oxidative addition, while the TOF-determining intermediate (TDI) is the formation of an Rh(I)-complex after N-H deprotonation. It was also found that the change in the oxidation number of the Rh catalyst is a key determinant of the reaction path.

Bidentate Directing Groups: An Efficient Tool in C-H Bond Functionalization Chemistry for the Expedient Construction of C-C Bonds.

During the past decades, synthetic organic chemistry discovered that directing group assisted C-H activation is a key tool for the expedient and siteselective construction of C-C bonds. Among the various directing group strategies, bidentate directing groups are now recognized as one of the most efficient devices for the selective functionalization of certain positions due to fact that its metal center permits fine, tunable, and reversible coordination. The family of bidentate directing groups permit various types of assistance to be achieved, such as N,N-dentate, N,O-dentate, and N,S-dentate auxiliaries, which are categorized based on the coordination site. In this review, we broadly discuss various C-H bond functionalization reactions for the formation of C-C bonds with the aid of bidentate directing groups.

Regioselective Transition-Metal-Free C(sp2 )-H Borylation: A Subject of Practical and Ongoing Interest in Synthetic Organic Chemistry.

Considerable advances have been made in the area of C-H functionalization in the last few decades. A number of approaches including both directed and nondirected strategies have been developed thus far. Among the various C-H functionalizations, C-H borylation is of special interest due to the wide applications of organoboron compounds. In this regard, various transition-metal-catalyzed regioselective strategies have been developed. However, the major concern regarding metal-catalyzed C-H borylation procedures is the requirement of a precious metal as well as the contamination by metal precursors in the desired products, which limit the application of this process in large-scale synthesis. Therefore, recent trends have involved the use of transition-metal-free systems. We summarize recent developments in transition-metal-free regioselective C-H borylation. We believe that this Review will help to increase interest in this field and stimulate further progress.

Transient Imine as a Directing Group for the Metal-Free o-C-H Borylation of Benzaldehydes.

Organoboron reagents are important synthetic intermediates and have wide applications in synthetic organic chemistry. The selective borylation strategies that are currently in use largely rely on the use of transition-metal catalysts. Hence, identifying much milder conditions for transition-metal-free borylation would be highly desirable. We herein present a unified strategy for the selective C-H borylation of electron-deficient benzaldehyde derivatives using a simple metal-free approach, utilizing an imine transient directing group. The strategy covers a wide spectrum of reactions and (i) even highly sterically hindered C-H bonds can be borylated smoothly, (ii) despite the presence of other potential directing groups, the reaction selectively occurs at the o-C-H bond of the benzaldehyde moiety, and (iii) natural products appended to benzaldehyde derivatives can also give the appropriate borylated products. Moreover, the efficacy of the protocol was confirmed by the fact that the reaction proceeds even in the presence of a series of external impurities.

Effect of Sulfonamide and Carboxamide Ligands on the Structural Diversity of Bimetallic RhII-RhII Cores: Exploring the Catalytic Activity of These Newly Synthesized Rh2 Complexes.

A new class of dirhodium(II) complexes with tethered sulfonamide and carboxamide ligands was synthesized and characterized. A new type of coordination mode was found for the quinoline moiety containing a sulfonamide ligand, which afforded the axially coordination-free bimetallic dirhodium complexes. Studies were conducted on the catalytic properties of these complexes for cyclopropanation reactions, and the findings indicate that a free axial coordination site is crucial for achieving a high degree of reactivity.

Palladium-Catalyzed Site-Selective [3+2] Annulation via Benzylic and meta C-H Bond Activation.

The palladium-catalyzed [3+2] annulation of aromatic amides with maleimides via the activation of ortho benzylic C-H and meta C-H bonds is reported. Carboxamide and anilide type substrates that contain a 2-methylthiophenyl group both participate in this [3+2] annulation, indicating that the presence of a 2-methylthiophenyl directing group is a key for the success of the reaction. The first C-H bond activation at the benzylic C-H bond is followed by a second C-H bond activation at the meta C-H bond to give five-membered cyclic products. The cleavage of these C-H bonds is irreversible.

Nickel-Catalyzed C-F/N-H Annulation of Aromatic Amides with Alkynes: Activation of C-F Bonds under Mild Reaction Conditions.

The Ni-catalyzed reaction of ortho-fluoro-substituted aromatic amides with alkynes results in C-F/N-H annulation to give 1(2H)-isoquinolinones. A key to the success of the reaction is the use of KOtBu or even weak base, such as Cs2CO3. The reaction proceeds in the absence of a ligand and under mild reaction conditions (40-60 °C). DFT calculations suggest that the pathway for this Ni-catalyzed C-F/N-H annulation involves N-H deprotonation, oxidative addition of a C-F bond, migratory insertion of an alkyne, and reductive elimination to form 1(2H)-isoquinolinone derivatives.

RhIII -Catalyzed Double Dehydrogenative Coupling of Free 1-Naphthylamines with α,ß-Unsaturated Esters.

The RhIII -catalyzed, consecutive double C-H oxidative coupling of free 1-naphthylamine and α,ß-unsaturated esters through C-H/C-H and C-H/N-H bonds is reported. The one step reaction leads to the formation of biologically important alkylidene-1,2-dihydrobenzo[cd]indoles scaffolds. This efficient process is much more synthetically convenient and useful than others because the starting materials, such as 1-naphthylamine derivatives are readily available and the free amine serves as a directing group.

Nickel-Catalyzed Decarboxylation of Aryl Carbamates for Converting Phenols into Aromatic Amines.

Herein, we describe a new catalytic approach to accessing aromatic amines from an abundant feedstock, namely phenols. The most reliable catalytic method for converting phenols to aromatic amines uses an activating group, such as a trifluoromethane sulfonyl group. However, this activating group is eliminated as a leaving group during the amination process, resulting in significant waste. Our nickel-catalyzed decarboxylation reaction of aryl carbamates forms aromatic amines with carbon dioxide as the only byproduct. As this amination proceeds in the absence of free amines, a range of functionalities, including a formyl group, are compatible. A bisphosphine ligand immobilized on a polystyrene support (PS-DPPBz) is key to the success of this reaction, generating a catalytic species that is significantly more active than simple nonsupported variants.

Rhodium-Catalyzed Alkylation of C-H Bonds in Aromatic Amides with Non-activated 1-Alkenes: The Possible Generation of Carbene Intermediates from Alkenes.

The alkylation of C-H bonds (hydroarylation) in aromatic amides with non-activated 1-alkenes using a rhodium catalyst and assisted by an 8-aminoquinoline directing group is reported. The addition of a carboxylic acid is crucial for the success of this reaction. The results of deuterium-labeling experiments indicate that one of deuterium atoms in the alkene is missing, suggesting that the reaction does not proceed through the commonly accepted mechanism for C-H alkylation reactions. Instead the reaction is proposed to proceed through a carbene mechanism. The carbene mechanism is also supported by preliminary DFT calculations.

Rhodium-Catalyzed C(sp2 )- or C(sp3 )-H Bond Functionalization Assisted by Removable Directing Groups.

In recent years, transition-metal-catalyzed C-H activation has become a key strategy in the field of organic synthesis. Rhodium complexes are widely used as catalysts in a variety of C-H functionalization reactions because of their high reactivity and selectivity. The availability of a number of rhodium complexes in various oxidation states enables diverse reaction patterns to be obtained. Regioselectivity, an important issue in C-H activation chemistry, can be accomplished by using a directing group to assist the reaction. However, to obtain the target functionalized compounds, it is also necessary to use a directing group that can be easily removed. A wide range of directed C-H functionalization reactions catalyzed by rhodium complexes have been reported to date. In this Review, we discuss Rh-catalyzed C-H functionalization reactions that are aided by the use of a removable directing group such as phenol, amine, aldehyde, ketones, ester, acid, sulfonic acid, and N-heteroaromatic derivatives.

A Synthesis of 3,4-Dihydroisoquinolin-1(2H)-one via the Rhodium-Catalyzed Alkylation of Aromatic Amides with N-Vinylphthalimide.

The alkylation of C-H bonds with N-vinylphthalimide by a rhodium-catalyzed reaction of aromatic amides containing an 8-aminoquinoline moiety as the directing group is reported. N-Vinylphthalimide functions as a 2-aminoethylating reagent. The resulting alkylated products can be converted into 3,4-dihydroisoquinolin-1(2H)-one derivatives in a one-pot transformation. Deuterium-labeling experiments suggest that the reaction proceeds through a carbene mechanism.

Nickel-Mediated Decarbonylation of Simple Unstrained Ketones through the Cleavage of Carbon-Carbon Bonds.

Despite advances in methods for the decarbonylation of aldehydes, the decarbonylation of ketones has been met with limited success because this process requires the activation of two inert carbon-carbon bonds. All of the decarbonylation reactions of simple unstrained ketones reported to date require the addition of a stoichiometric rhodium complex. We report herein the nickel/N-heterocyclic carbene-mediated decarbonylation of simple diaryl ketones. This reaction shows unique acceleration effects based on the presence of both electron-donating and electron-withdrawing groups.

Combined Theoretical and Experimental Studies of Nickel-Catalyzed Cross-Coupling of Methoxyarenes with Arylboronic Esters via C-O Bond Cleavage.

Nickel(0)-catalyzed cross-coupling of methoxyarenes through C-O bond activation has been the subject of considerable research because of their favorable features compared with those of the cross-coupling of aryl halides, such as atom economy and efficiency. In 2008, we have reported nickel/PCy3-catalyzed cross-coupling of methoxyarenes with arylboronic esters in which the addition of a stoichiometric base such as CsF is essential for the reaction to proceed. Recently, we have also found that the scope of the substrate in the Suzuki-Miyaura-type cross-coupling of methoxyarenes can be greatly expanded by using 1,3-dicyclohexylimidazol-2-ylidene (ICy) as the ligand. Interestingly, a stoichiometric amount of external base is not required for the nickel/ICy-catalyzed cross-coupling. For the mechanism and origin of the effect of the external base to be elucidated, density functional theory calculations are conducted. In the nickel/PCy3-catalyzed reactions, the activation energy for the oxidative addition of the C(aryl)-OMe bond is too high to occur under the catalytic conditions. However, the oxidative addition process becomes energetically feasible when CsF and an arylboronic ester interact with a Ni(PCy3)2/methoxyarene fragment to form a quaternary complex. In the nickel/ICy-catalyzed reactions, the oxidative addition of the C(aryl)-OMe bond can proceed more easily without the aid of CsF because the nickel-ligand bonds are stronger and therefore stabilize the transition state. The subsequent transmetalation from an Ar-Ni-OMe intermediate is determined to proceed through a pathway with lower energies than those required for ß-hydrogen elimination. The overall driving force of the reaction is the reductive elimination to form the carbon-carbon bond.

Ir4(CO)12-Catalyzed Benzylic C(sp3)-H Silylation of 2-Alkylpyridines with Hydrosilanes Leading to 2-(1-Silylalkyl)pyridines.

The iridium-catalyzed C(sp3)-H silylation of 2-alkylpyridines with hydrosilanes at the benzylic position to afford 2-(1-silylalkyl)pyridines is described. The low product yield was markedly improved by adding 3,5-dimethylpyridine. Norbornene is also an essential additive for the reaction to proceed as a hydrogen scavenger. Carbon monoxide plays an important role in the catalytic cycle as a ligand. Other transition-metal carbonyls such as Rh4(CO)12 and Ru3(CO)12 can also be used as catalysts for this C-H silylation.

Catalytic Double Carbon-Boron Bond Formation for the Synthesis of Cyclic Diarylborinic Acids as Versatile Building Blocks for π-Extended Heteroarenes.

The first catalytic synthesis of cyclic diarylborinic acids is developed using a dihydroaminoborane reagent as the boron source. Unlike previously reported methods that use organolithium reagents, this method allows the easy synthesis of cyclic diarylborinic acids bearing a range of functionalities including CN, CO2 Et, CONEt2 and NMeCO2t Bu. Furthermore, these cyclic diarylborinic acids provide rapid access to skeletal diversity, in particular they enable the synthesis of six- to nine-membered π-extended heteroarenes through simple cross-coupling reactions, which are important synthetic targets in both advanced materials and pharmaceuticals.