Ligand‐Controlled α‐ and β‐Arylation of Acyclic N‐Boc Amines

The palladium‐catalyzed ligand‐controlled arylation of α‐zincated acyclic amines, obtained by directed α‐lithiation and transmetalation, is described. Whereas PtBu₃ gave rise to α‐arylated Boc‐protected amines, more flexible N‐phenylazole‐based phosphine ligands induced major β‐arylation through migrative cross‐coupling.     

Palladium(II)‐Catalyzed ortho‐CH Arylation/Alkylation of N‐Benzoyl α‐Amino Ester Derivatives

The palladium‐catalyzed arylation/alkylation of ortho‐C?H bonds in N‐benzoyl α‐amino ester derivatives is described. In such a system both the NH‐amido and the CO₂R groups in the α‐amino ester moieties play a role in successful C?H activation/C?C bond formation using iodoaryl coupling partners. A wide variety of functional groups and electron‐rich/deficient iodoarenes are tolerated. The yields obtained range from 20 to 95 %.     

Transition‐Metal‐Free α‐Arylation of Enolizable Aryl Ketones and Mechanistic Evidence for a Radical Process

The α‐arylation of enolizable aryl ketones can be carried out with aryl halides under transition‐metal‐free conditions using KOtBu in DMF. The α‐aryl ketones thus obtained can be used for step‐ and cost‐economic syntheses of fused heterocycles and Tamoxifen. Mechanistic studies demonstrate the synergetic role of base and solvent for the initiation of the radical process.     

A Highly Efficient Gold‐Catalyzed Photoredox α‐C(sp3)H Alkynylation of Tertiary Aliphatic Amines with Sunlight

A new α‐C(sp³)? H alkynylation of unactivated tertiary aliphatic amines with 1‐iodoalkynes as radical alkynylating reagents in the presence of [Au₂(μ‐dppm)₂]²⁺ in sunlight provides propargylic amines. Based on mechanistic studies, a C? C coupling of an α‐aminoalkyl radical and an alkynyl radical is proposed for the C(sp³)? C(sp) bond formation. The mild, convenient, efficient, and highly selective C(sp³)? H alkynylation reaction shows excellent regioselectivity and good functional‐group compatibility. A scale‐up to gram quantities is possible with sunlight used as a clean and sustainable energy source.     

Copper‐Catalyzed Dehydrogenative Cross‐Coupling Reaction between Allylic CH Bonds and α‐CH Bonds of Ketones or Aldehydes

A dehydrogenative cross‐coupling reaction between allylic C?H bonds and the α‐C?H bond of ketones or aldehydes was developed using Cu(OTf)₂ as a catalyst and DDQ as an oxidant. This synthetic approach to γ,δ‐unsaturated ketones and aldehydes has the advantages of broad scope for both ketones and aldehydes as reactants, mild reaction conditions, good yields and atom economy. A plausible mechanism using Cu(OTf)₂ as a Lewis acid catalyst was also proposed (DDQ=2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone; Tf=trifluoromethanesulfonate).     

Palladium(0)/PAr3‐Catalyzed Intermolecular Amination of C(sp3)H Bonds: Synthesis of β‐Amino Acids

An intermolecular C(sp³)? H amination using a Pd⁰/PAr₃ catalyst was developed. The reaction begins with oxidative addition of R₂N? OBz to a Pd⁰/PAr₃ catalyst and subsequent cleavage of a C(sp³)? H bond by the generated Pd? NR₂ intermediate. The catalytic cycle proceeds without the need for external oxidants in a similar manner to the extensively studied palladium(0)‐catalyzed C? H arylation reactions. The electron‐deficient triarylphosphine ligand is crucial for this C(sp³)? H amination reaction to occur.     

Organocatalytic Enantioselective Oxidative CH Alkenylation and Arylation of N‐Carbamoyl Tetrahydropyridines and Tetrahydro‐β‐carbolines

The first organocatalytic enantioselective C? H alkenylation and arylation reactions of N‐carbamoyl tetrahydropyridines and tetrahydro‐β‐carbolines (THCs) are described. The metal‐free processes represent an efficient and straightforward approach to a variety of structurally and electronically diverse α‐substituted tetrahydropyridines and THCs in good yields with excellent regio‐ and enantioselectivities. Preliminary control experiments provide important insights into the reaction mechanism.     

A Regioselective Synthesis of Benzopinacolones through Aerobic Dehydrogenative α‐Arylation of the Tertiary sp3 CH Bond of 1,1‐Diphenylketones with Aromatic and Heteroaromatic Compounds

A regioselective synthesis of symmetrical and unsymmetrical benzopinacolones through aerobic dehydrogenative α‐arylation at the tertiary sp³ C?H bond of substituted 1,1‐diphenylketones with aromatic and heteroaromatic compounds, in the presence of K₂S₂O₈ in CF₃COOH at room temperature, is described. The reaction is proposed to go via a carbocation intermediate, which could be generated directly from cleavage of the sp³ C?H bond of 1,1‐diphenylketone. Subsequent α‐arylation was achieved at the methene sp³ carbon atom of the substituted ketone. A variety of substituted aromatic and heteroaromatic compounds were compatible with this reaction. In addition, benzopinacolones were converted into sterically hindered, tetrasubstituted alkenes and polycyclic aromatic compounds.     

Nickel‐Catalyzed α‐Arylation of Ketones with Phenol Derivatives

The nickel‐catalyzed α‐arylation of ketones with readily available phenol derivatives (esters and carbamates) provides access to useful α‐arylketones. For this transformation, 3,4‐bis(dicyclohexylphosphino)thiophene (dcypt) was identified as a new, enabling, air‐stable ligand for this transformation. The intermediate of an assumed C? O oxidative addition was isolated and characterized by X‐ray crystal‐structure analysis.     

α‐MsO/TsO/Cl Ketones as Oxidized Alkyne Equivalents: Redox‐Neutral Rhodium(III)‐Catalyzed CH Activation for the Synthesis of N‐Heterocycles

α‐Halo and pseudohalo ketones are used for the first time as C(sp³)‐based electrophiles in transition‐metal‐catalyzed C? H activation and as oxidized alkyne equivalents in Rh^III‐catalyzed redox‐neutral annulations to generate diverse N‐heterocycles. This transformation is efficient and scalable. Due to the mild reaction conditions, a variety of functional groups could be tolerated.     

Palladium‐Catalyzed C(sp3)H Activation: A Facile Method for the Synthesis of 3,4‐Dihydroquinolinone Derivatives

3,4‐Dihydroquinolinones were synthesized by the palladium‐catalyzed, oxidative‐addition‐initiated activation and arylation of inert C(sp³)? H bonds. Pd(OAc)₂ and P(o‐tol)₃ were used as the catalyst and ligand, respectively, to improve the efficiency of the reaction. A further advantage of this reaction is that it could be performed in air. A relatively rare seven‐membered palladacycle was proposed as a key intermediate of the catalytic cycle.     

Sulfonamide‐Promoted Palladium(II)‐Catalyzed Alkylation of Unactivated Methylene C(sp3)H Bonds with Alkyl Iodides

The alkylation of unactivated β‐methylene C(sp³)? H bonds of α‐amino acid substrates with a broad range of alkyl iodides using Pd(OAc)₂ as the catalyst is described. The addition of NaOCN and 4‐Cl‐C₆H₄SO₂NH₂ was found to be crucial for the success of this transformation. The reaction is compatible with a diverse array of functional groups and proceeds with high diastereoselectivity. Furthermore, various β,β‐hetero‐dialkyl‐ and β‐alkyl‐β‐aryl‐α‐amino acids were prepared by sequential C(sp³)? H functionalization of an alanine‐derived substrate, thus providing a versatile strategy for the stereoselective synthesis of unnatural β‐disubstituted α‐amino acids.     

Regio‐ and Diastereoselective and Enantiospecific Metal‐Free C(sp3)H Arylation: Facile Access to Optically Active 5‐Aryl 2,5‐Disubstituted Pyrrolidines

Optically active 5‐aryl 2,5‐disubstituted pyrrolidines are the principal structural moiety of many bioactive compounds including natural products and catalysts for asymmetric synthesis. A highly regio‐ and diastereoselective and enantiospecific method for direct C?H arylation of aliphatic amine has been developed. Structurally diverse enantiopure arylated pyrrolidines were synthesized from commercially available starting materials, through a single‐step three‐component reaction under metal‐ and oxidant‐free conditions. Furthermore, the complex analogous structure of CCK antagonist RP 66803 and angiotensin‐converting enzyme inhibitors was easily constructed using the synthesized arylated pyrrolidine derivative. Detailed theoretical calculations (M06‐2X/TZVPP/SMD//M06‐2X/6‐31+G(d,p) level) were also carried to investigate the mechanism and high level of stereocontrol involved in this direct sp³ C?H arylation reaction. Preference for a given regio‐ and stereoselectivity in the arylated product can be explained through elucidation of the mechanism for dehydration, generating azomethine ylide, and for the final re‐aromatization step. The calculated energies reveals that the re‐aromatization step is essentially rate determining, accompanying an activation barrier of Δ^≠${G{{{\rm S}\hfill \atop {\rm L}\hfill}}}$ =25.6 kcal mol^?1.     

Rhodium(III)‐ and Iridium(III)‐Catalyzed C7 Alkylation of Indolines with Diazo Compounds

A Rh^III‐catalyzed procedure for the C7‐selective C?H alkylation of various indolines with α‐diazo compounds at room temperature is reported. The advantages of this process are: 1) simple, mild, and pH‐neutral reaction conditions, 2) broad substrate scope, 3) complete regioselectivity, 4) no need for an external oxidant, and 5) N₂ as the sole byproduct. Furthermore, alkylation and bis‐alkylation of carbazoles at the C1 and C8 positions have also been developed. More significantly, for the first time, a successful Ir^III‐catalyzed intermolecular insertion of arene C?H bonds into α‐diazo compounds is reported.     

Dimethylzinc‐Initiated Radical Coupling of β‐Bromostyrenes with Ethers and Amines

A new coupling reaction has been developed in which β‐bromostyrenes react with ethers and tertiary amines to introduce the styryl group in the α‐position. The transformation is mediated by Me₂Zn/O₂ with 10 % MnCl₂ and is believed to proceed by a radical addition–elimination mechanism. The ether and the amine are employed as solvent and the coupling takes place through the most stable α radical for unsymmetrical substrates. The products are obtained in moderate to good yields as the pure E isomers. The coupling can be achieved with a range of smaller cyclic and acyclic ethers/amines as well as various substituted β‐bromostyrenes.     

Palladium‐Catalyzed Arylation of Unactivated γ‐Methylene C(sp3)H and δ‐CH Bonds with an Oxazoline‐Carboxylate Auxiliary

A palladium‐catalyzed arylation of unactivated γ‐methylene C(sp³)?H and remote δ‐C?H bonds by using an oxazoline‐carboxylate directing group has been developed. Arylation occurs with a broad substrate scope and high tolerance of functional groups (i.e., halogen, nitro, cyano, ether, trifluoromethyl, amine, and ester). The oxazoline‐type auxiliary can be removed under acidic conditions.     

Palladium‐Catalyzed Direct C2‐Arylation of an N‐Heterocyclic Carbene: An Atom‐Economic Route to Mesoionic Carbene Ligands

Blocking the C2 position of an imidazole‐derived classical N‐heterocyclic carbene (NHC) with an aryl group is an essential strategy to establish a route to mesoionic carbenes (MICs), which coordinate to the metal via the C4 (or C5) carbon atom. An efficient catalytic route to MIC precursors by direct arylation of an NHC is reported. Treatment of 1,3‐bis(2,6‐diisopropylphenyl)imidazol‐2‐ylidene (IPr) with an aryl iodide (RC₆H₄I) in the presence of 0.5 mol % of [Pd₂(dba)₃] (dba=dibenzylideneacetone) precatalyst affords the C2‐arylated imidazolium salts {IPr(C₆H₄R)}I (R=H, 4‐Me, 2‐Me, 4‐OMe, 4‐COOMe) in excellent (up to 92 %) yields. Treatment of {IPr(C₆H₅)}I with CuI and KN(SiMe₃)₂ exclusively affords the MIC–copper complex [(IPrPh)CuI].     

C(sp3)H Activation without a Directing Group: Regioselective Synthesis of N‐Ylide or N‐Heterocyclic Carbene Complexes Controlled by the Choice of Metal and Ligand

N‐Ylide complexes of Ir have been generated by C(sp³)?H activation of α‐pyridinium or α‐imidazolium esters in reactions with [Cp*IrCl₂]₂ and NaOAc. These reactions are rare examples of C(sp³)?H activation without a covalent directing group, which—even more unusually—occur α to a carbonyl group. For the reaction of the α‐imidazolium ester [ 3 H]Cl, the site selectivity of C?H activation could be controlled by the choice of metal and ligand: with [Cp*IrCl₂]₂ and NaOAc, C(sp³)?H activation gave the N‐ylide complex 4 ; in contrast, with Ag₂O followed by [Cp*IrCl₂]₂, C(sp²)?H activation gave the N‐heterocyclic carbene complex 5 . DFT calculations revealed that the N‐ylide complex 4 was the kinetic product of an ambiphilic C?H activation. Examination of the computed transition state for the reaction to give 4 indicated that unlike in related reactions, the acetate ligand appears to play the dominant role in C?H bond cleavage.     

Practical Synthesis of anti‐β‐Hydroxy‐α‐Amino Acids by PdII‐Catalyzed Sequential C(sp3)H Functionalization

An improved and practical procedure for the stereoselective synthesis of anti‐β‐hydroxy‐α‐amino acids (anti‐βhAAs), by palladium‐catalyzed sequential C(sp³)?H functionalization directed by 8‐aminoquinoline auxiliary, is described. followed by a previously established monoarylation and/or alkylation of the β‐methyl C(sp³)?H of alanine derivative, β‐acetoxylation of both alkylic and benzylic methylene C(sp³)?H bonds affords various anti‐β‐hydroxy‐α‐amino acid derivatives. As an example, the synthesis of β‐mercapto‐α‐amino acids, which are highly important to the extension of native chemical ligation chemistry beyond cysteine, is described. The synthetic potential of this protocol is further demonstrated by the synthesis of diverse β‐branched α‐amino acids. The observed diastereoselectivities are strongly influenced by electronic effects of aromatic AAs and steric effects of the linear side‐chain AAs, which could be explained by the competition of intramolecular C?OAc bond reductive elimination from Pd^IV intermediates vs. intermolecular attack by an external nucleophile (AcO^?) in an S_N2‐type process.     

Highly Efficient CH Hydroxylation of Carbonyl Compounds with Oxygen under Mild Conditions

A transition‐metal‐free Cs₂CO₃‐catalyzed α‐hydroxylation of carbonyl compounds with O₂ as the oxygen source is described. This reaction provides an efficient approach to tertiary α‐hydroxycarbonyl compounds, which are highly valued chemicals and widely used in the chemical and pharmaceutical industry. The simple conditions and the use of molecular oxygen as both the oxidant and the oxygen source make this protocol very environmentally friendly and practical. This transformation is highly efficient and highly selective for tertiary C(sp³)? H bond cleavage.