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.

Theoretical Investigations of Palladium-Catalyzed [3+2] Annulation via Benzylic and meta C-H Bond Activation.

The palladium-catalyzed reaction of aromatic amides with maleimides results in the formation of a double C-H bond activation product, which occurs at both the benzylic and meta positions. Computational chemistry studies suggest that the first C-H bond activation unfolds via a six-membered palladacycle, maleimide insertion, protonation of the Pd-N bond, and then activation of the meta C-H bond. The process concludes with reductive elimination, producing an annulation product. The energy decomposition analysis (EDA) showed that the deformation energy favors the ortho C-H bond activation process. However, this route is non-productive. The interaction energy controls the site where the maleimide is inserted into the Pd-C(sp3 ) bond, which determines its site selectivity. The energetic span model indicates that the meta C-H bond activation step is the one that determines the turnover frequency. Regarding the directing group, it has been concluded that the strong Pd-S bonding and the destabilizing effect of the deformation energy allow the 2-thiomethylphenyl to function effectively as a directing group.

Nickel-catalyzed direct methylation of arylphosphines via carbon-phosphorus bond cleavage using AlMe3.

We report herein on the nickel-catalyzed methylation of arylphosphines using AlMe3via the cleavage of unactivated C(aryl)-P bonds. This reaction allows for the direct, catalytic substitution of an aryl group on a phosphorus center with a methyl group. This catalytic methylation can proceed, when phosphine oxides and sulfides are used as a substrate.

Palladium-Catalyzed 1,1-Alkynyloxygenation of 2-Vinylbenzoates with Alkynyl Bromides.

The palladium-catalyzed reaction of alkyl 2-vinylbenzoates with silyl-protected alkynyl bromides leads to the selective production of 3-alkynylated isochroman-1-ones. The use of an alkyl ester group as an effective oxygen nucleophile is crucial for the efficient 1,1-alkynyloxygenation of alkenes.

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.

Nucleophilic aromatic substitution of non-activated aryl fluorides with aliphatic amides.

Nucleophilic aromatic substitution (SNAr) reactions of non-activated aryl fluorides with amide enolates are reported. The reaction proceeds under relatively mild reaction conditions. Lactams also participate in the reaction to give 2-arylated lactams. DFT calculations suggest that the reaction proceeds through a concerted SNAr pathway.

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.

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.

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.

Palladium-catalyzed synthesis of nitriles from N-phthaloyl hydrazones.

The Pd-catalyzed transformation of N-phthaloyl hydrazones into nitriles involving the cleavage of an N-N bond is reported. The use of N-heterocyclic carbene as a ligand is essential for the success of the reaction. N-Phthaloyl hydrazones prepared from aromatic aldehydes or cyclobutanones are applicable to this transformation, which gives aryl or alkenyl nitriles, respectively.

Rh(I)-catalysed imine-directed C-H functionalization via the oxidative [3 + 2] cycloaddition of benzylamine derivatives with maleimides.

The Rh(I)-catalysed imine-directed oxidative [3 + 2] cycloaddition of benzylamines with maleimides is reported. A wide range of both benzylamines and maleimides is applicable to the reaction. A one-pot three component strategy using benzylamines, 2-pyridinecarboxaldehyde, and maleimides is successfully achieved. Mechanistic studies including deuterium labelling experiments suggest that a zwitterionic intermediate is formed and is a key intermediate through the Rh-catalysed activation of a benzylic C(sp3)-H bond of the imine.

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.

Origin of the Enhanced Reactivity in the ortho C-H Borylation of Benzaldehydes with BBr3.

The metal-free ortho C-H borylation of benzaldehyde derivatives using a transient imine directing group was recently developed by our group, providing an efficient strategy for the synthesis of organoboron reagents. Herein, we report on an extensive investigation of the reaction mechanism using density functional theory (DFT) calculations. Computations for the reaction pathway with various imine substrates, as well as the effect of an added base were examined, and the experimentally observed reactivity enhancement is proposed to originate from the tunability of the destabilizing strain energies that results in a reversible complexation process with BBr3.

Palladium-catalyzed 1,1-alkynylbromination of alkenes with alkynyl bromides.

The palladium-catalyzed 1,1-alkynylbromination of terminal alkenes with a silyl-protected alkynyl bromide is reported. The method tolerates a diverse range of alkenes including vinylarenes, acrylates, and even electronically unbiased alkene derivatives to afford propargylic bromides regioselectively. Mechanistic studies and DFT calculations indicate that the 1,1-alkynylbromination reaction proceeds via the migration of the Pd center followed by the formation of a π-allenyl Pd intermediate, leading to the stereoselective reductive elimination of the C(sp3)-Br bond at the propargylic positon.

Pyrimidine-directed metal-free C-H borylation of 2-pyrimidylanilines: a useful process for tetra-coordinated triarylborane synthesis.

Convenient, easily handled, laboratory friendly, robust approaches to afford synthetically important organoboron compounds are currently of great interest to researchers. Among the various available strategies, a metal-free approach would be overwhelmingly accepted, since the target boron compounds can be prepared in a metal-free state. We herein present a detailed study of the metal-free directed ortho-C-H borylation of 2-pyrimidylaniline derivatives. The approach allowed us to synthesize various boronates, which are synthetically important compounds and various four-coordinated triarylborane derivatives, which could be useful in materials science as well as Lewis-acid catalysts. This metal-free directed C-H borylation reaction proceeds smoothly without any interference by external impurities, such as inorganic salts, reactive functionalities, heterocycles and even transition metal precursors, which further enhance its importance.

Rh(i)- and Rh(ii)-catalyzed C-H alkylation of benzylamines with alkenes and its application in flow chemistry.

The Rh-catalyzed C-H alkylation of benzylamines with alkenes using a picolinamide derivative as a directing group is reported. Both Rh(i) and Rh(ii) complexes can be used as active catalysts for this transformation. In addition, a flow set up was designed to successfully mimic this process under flow conditions. Several examples are presented under flow conditions and it was confirmed that a flow process is advantageous over a batch process. Deuterium labelling experiments were performed to elucidate the mechanism of the reaction, and the results indicated a possible carbene mechanism for this C-H alkylation process.

Rh(II)-Catalyzed C-H Alkylation of Benzylamines with Unactivated Alkenes: The Influence of Acid on Linear and Branch Selectivity.

The Rh-catalyzed C-H alkylation of benzylamine derivatives with unactivated 1-alkenes that proceeds via a picolinamide directing group is reported. The crucial role of an acid additive in this transformation is confirmed. Aromatic acids showed high linear selectivity, and aliphatic acids provided branched alkylation products as the major product. The reaction has a broad scope for benzylamines and alkenes. Deuterium labeling experiments suggest that a Rh-carbene intermediate is involved in the case of linear product formation. A different reaction pathway, however, appears to be involved in the case of branched alkylation products, and this pathway also appeared to be a minor pathway in linear-selective reactions.

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.

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.

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.