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.

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.

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.

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.

Preparation of enantioenriched helical- and axial-chiral molecules by dynamic asymmetric induction.

Dynamic asymmetric induction (DYASIN) of racemic dynamic chiral heterohelicenes afforded their highly enantioenriched forms (up to 96% ep) in quantitative yields. These heterohelicenes were readily converted into semi-static axial-chiral 1,1'-binaphthyl derivatives in a stereospecific manner.

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.

Fluoride anion-initiated bis-trifluoromethylation of phenyl aromatic carboxylates with (trifluoromethyl)trimethylsilane.

The fluoride anion-initiated reaction of phenyl aromatic carboxylates with (trifluoromethyl)trimethylsilane (Me3SiCF3) that results in the formation of O-silyl-protected 2-aryl-1,1,1,3,3,3-hexafluoroisopropanols is reported. A phenoxide anion, generated during the trifluoromethylation of the phenyl carboxylate, also activates the Me3SiCF3, which permits a catalytic amount of the fluoride anion source to be used. Various functional groups, which can be used for further elaboration, are tolerated in the reaction.

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.

Nickel-catalyzed reductive defunctionalization of esters in the absence of an external reductant: activation of C-O bonds.

The nickel-catalyzed reductive cleavage of esters in the absence of an external reductant, which involves the cleavage of an inert acyl C-O bond in O-alkyl esters is reported. Various groups, such as N-containing heterocycles, esters, amides, and even arene rings can function as a directing group.

The Pd-catalyzed C-H alkylation of ortho-methyl-substituted aromatic amides with maleimide occurs preferentially at the ortho-methyl C-H bond over the ortho-C-H bond.

The reaction of ortho-methyl-substituted aromatic amides with maleimides in the presence of Pd(OAc)2 and AgOAc results in C-H alkylation at the ortho-methyl C-H bond. DFT calculations indicate that the formation of a five-membered palladacycle is a kinetically favorable step, but the insertion of the maleimide into the six-membered palladacycle is energetically favored.

Nickel-catalyzed oxidative C-H/N-H annulation of N-heteroaromatic compounds with alkynes.

The reaction of N-heteroaromatic compounds, such as 2-aryl-pyrrole, benzimidazole, imidazole, indole, and pyrazole derivatives, with alkynes in the presence of a catalytic amount of a nickel complex results in C-H/N-H oxidative annulation. The reaction shows a high functional group compatibility. While both Ni(0) and Ni(ii) complexes show a high catalytic activity, Ni(0) is proposed as a key catalytic species in the main catalytic cycle. In the case of the Ni(ii) system, the presence of a catalytic amount of a strong base, such as KOBu t , is required for the reaction to proceed. In sharp contrast, a base is not required in the case of the Ni(0) system. The proposed mechanism is supported by DFT studies.

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.

Nickel-catalyzed C-H/N-H annulation of aromatic amides with alkynes in the absence of a specific chelation system.

The Ni-catalyzed reaction of aromatic amides with alkynes in the presence of KOBu t involves C-H/N-H oxidative annulation to give 1(2H)-isoquinolinones. A key to the success of the reaction is the use of a catalytic amount of strong base, such as KOBu t . The reaction shows a high functional group compatibility. The reaction with unsymmetrical alkynes, such as 1-arylalkynes, gives the corresponding 1(2H)-isoquinolinones with a high level of regioselectivity. This discovery would lead to the development of Ni-catalyzed chelation-assisted C-H functionalization reactions without the need for a specific chelation system.

Catalytic enantioselective synthesis of planar-chiral cyclic amides based on a Pd-catalyzed asymmetric allylic substitution reaction.

The highly enantioselective synthesis of planar-chiral nine-membered cyclic amides was achieved by the Pd-catalyzed asymmetric allylic cyclization of achiral linear precursors in the presence of a catalytic amount of chiral ligand.

Palladium-catalyzed direct ortho-alkynylation of aromatic carboxylic acid derivatives.

The palladium-catalyzed direct alkynylation of C-H bonds in aromatic carboxylic acid derivatives is described. The use of 8-aminoquinoline as a directing group facilitates the alkynylation of an electronically diverse range of C(sp(2))-H bonds.

Nickel-catalyzed chelation-assisted transformations involving ortho C-H bond activation: regioselective oxidative cycloaddition of aromatic amides to alkynes.

Although the pioneering example of ortho metalation involving cleavage of C-H bonds was achieved using a nickel complex (Kleiman, J. P.; Dubeck, M. J. Am. Chem. Soc. 1963, 85, 1544), no examples of catalysis using nickel complexes have been reported. In this work, the Ni-catalyzed transformation of ortho C-H bonds utilizing chelation assistance, such as oxidative cycloaddition of aromatic amides with alkynes, has been achieved.

Palladium-catalyzed direct ethynylation of C(sp3)-H bonds in aliphatic carboxylic acid derivatives.

The first catalytic alkynylation of unactivated C(sp(3))-H bonds has been accomplished. The method allows for the straightforward introduction of an ethynyl group into aliphatic acid derivatives under palladium catalysis. This new reaction can be applied to the rapid elaboration of complex aliphatic acids, for example, via azide/alkyne cycloaddition.

Palladium-catalyzed direct alkynylation of C-H bonds in benzenes.

Palladium-catalyzed ortho-alkynylation of aromatic C-H bonds in anilides is described. Preliminary mechanistic studies reveal that electrophilic palladation is involved. Synthetic elaborations of alkynylated products are also demonstrated.