Jin-Quan Yu

Palladium(II)-Catalyzed C―H Activation/C―C Cross- Coupling Reactions: Versatility and Practicality

In the past decade, palladium-catalyzed C-H activation/C-C bond-forming reactions have emerged as promising new catalytic transformations; however, development in this field is still at an early stage compared to the state of the art in cross-coupling reactions using aryl and alkyl halides. This Review begins with a brief introduction of four extensively investigated modes of catalysis for forming C-C bonds from C-H bonds: Pd(II)/Pd(0), Pd(II)/Pd(IV), Pd(0)/Pd(II)/Pd(IV), and Pd(0)/Pd(II) catalysis. A more detailed discussion is then directed towards the recent development of palladium(II)-catalyzed coupling of C-H bonds with organometallic reagents through a Pd(II)/Pd(0) catalytic cycle. Despite the progress made to date, improving the versatility and practicality of this new reaction remains a tremendous challenge.

Ligand-Enabled Reactivity and Selectivity in a Synthetically Versatile Aryl C–H Olefination

Heck of an Alternative The Mizoroki-Heck reaction is widely used in organic synthesis to link together unsaturated carbon fragments such as olefins and arenes. However, one of its drawbacks is the need to append a reactive group such as a halogen to one of the reagents beforehand. Wang et al. (p. 315, published online 26 November) present an alternative palladium-catalyzed reaction that links olefins directly to aryl acids. Oxygen added to the reaction medium concurrently oxidizes the aryl C-H bond at the linkage site, eliminating the need for prior halogenation. Introducing amino acid–derived ligands tunes the aryl site at which the reaction takes place, and efficient reactivity can be achieved across a diverse range of substrates. A palladium-based catalyst eliminates the need for halogenated compounds for the formation of carbon-carbon bonds. The Mizoroki-Heck reaction, which couples aryl halides with olefins, has been widely used to stitch together the carbogenic cores of numerous complex organic molecules. Given that the position-selective introduction of a halide onto an arene is not always straightforward, direct olefination of aryl carbon-hydrogen (C–H) bonds would obviate the inefficiencies associated with generating halide precursors or their equivalents. However, methods for carrying out such a reaction have suffered from narrow substrate scope and low positional selectivity. We report an operationally simple, atom-economical, carboxylate-directed Pd(II)-catalyzed C–H olefination reaction with phenylacetic acid and 3-phenylpropionic acid substrates, using oxygen at atmospheric pressure as the oxidant. The positional selectivity can be tuned by introducing amino acid derivatives as ligands. We demonstrate the versatility of the method through direct elaboration of commercial drug scaffolds and efficient syntheses of 2-tetralone and naphthoic acid natural product cores.

Activation of remote meta -C–H bonds assisted by an end-on template

Functionalization of unactivated carbon–hydrogen (C–H) single bonds is an efficient strategy for rapid generation of complex molecules from simpler ones. However, it is difficult to achieve selectivity when multiple inequivalent C–H bonds are present in the target molecule. The usual approach is to use σ-chelating directing groups, which lead to ortho-selectivity through the formation of a conformationally rigid six- or seven-membered cyclic pre-transition state. Despite the broad utility of this approach, proximity-driven reactivity prevents the activation of remote C–H bonds. Here we report a class of easily removable nitrile-containing templates that direct the activation of distal meta-C–H bonds (more than ten bonds away) of a tethered arene. We attribute this new mode of C–H activation to a weak ‘end-on’ interaction between the linear nitrile group and the metal centre. The ‘end-on’ coordination geometry relieves the strain of the cyclophane-like pre-transition state of the meta-C–H activation event. In addition, this template overrides the intrinsic electronic and steric biases as well as ortho-directing effects with two broadly useful classes of arene substrates (toluene derivatives and hydrocinnamic acids).

Pd(II)-Catalyzed ortho-Trifluoromethylation of Arenes Using TFA as a Promoter

A Pd(II)-catalyzed C-H activation/trifluoromethylation of arenes with an electrophilic trifluoromethylation reagent using diverse heterocycle directing groups is reported. The presence of trifluoroacetic acid is crucial for this catalytic reaction.

Pd(II)-Catalyzed Olefination of Electron-Deficient Arenes Using 2,6-Dialkylpyridine Ligands

Pd(II)-catalyzed meta-olefination of highly electron-deficient arenes is achieved through the use of a rationally designed mutually repulsive ligand. The combination of directed and nondirected C-H functionalization of arenes provides a versatile route for the synthesis of highly sought after 1,2,4-trisubstituted arenes.

Synthesis of β-, γ-, and δ-Lactams via Pd(II)-Catalyzed C−H Activation Reactions

Pd(II)-catalyzed intramolecular amination of sp2 and sp3 C-H bonds are developed using a combination of CuCl2 and AgOAc as the oxidant. The reaction protocol tolerates the presence of a double bond in the substrates. This catalytic reaction provides practical access to a wide range of beta-, gamma-, and delta-lactams.

Pd(II)-Catalyzed Cross-Coupling of sp3 C−H Bonds with sp2 and sp3 Boronic Acids Using Air as the Oxidant

O-Methyl hydroxamic acids, readily available from carboxylic acids, are found to be extremely reactive for beta-C-H activation by Pd(OAc)2. This reactivity is exploited to develop the first example of cross-coupling sp3 C-H bonds with sp3 boronic acids. Air was shown to be a suitable stoichiometric oxidant for the catalytic oxidative coupling reaction. A biologically active natural product is readily converted to its novel analogues through this coupling reaction.

PdII-Catalyzed Enantioselective Activation of C(sp2)H and C(sp3)H Bonds Using Monoprotected Amino Acids as Chiral Ligands†

Enantioselective C H activation has been a longstanding challenge in catalysis and organic chemistry. The insertion of metal-bound carbenes or nitrenes into C H bonds has been employed to develop highly enantioselective carbon–carbon and carbon–nitrogen bond-forming reactions. The enantioselective lithiation of C(sp) H bonds adjacent to the nitrogen atom in N-tert-butyloxycarbonylpyrrolidine using secBuLi/( )sparteine has provided a broadly useful method for the differentiation of prochiral C(sp) H bonds. Investigations into the biomimetic oxidation of C H bonds using chiral metal–porphyrin complexes and other synthetic catalysts continue to provide inspiration for the development of methods for the asymmetric oxidation of C H bonds. Remarkable progress in understanding the fundamental mechanisms of C H activation by means of metal insertion has spurred the development of metal-catalyzed carbon– carbon and carbon–heteroatom bond-forming reactions in organic molecules containing functional groups. Such reactions will impact synthetic and medicinal chemistry in the context of retrosynthetic analysis by providing unprecedented and more efficient strategic disconnections. A major hurdle remaining in Pd-catalyzed C H activation reactions, however, is the need for an external ligand that coordinates to the Pd species and controls the chemo-, regio-, and stereoselectivity of its insertion into C H bonds. With this in mind, we embarked on the development of a Pd-catalyzed enantioselective C H activation/C C coupling reaction, a process previously unknown owing to the difficulty in differentiating prochiral C H bonds through metal insertions. Herein we demonstrate a proof of concept by the design of a Pd/amino acid complex capable of catalyzing asymmetric activation of prochiral C(sp) H and C(sp) H bonds to form chiral products with new C C bonds in excellent enantioselectivity [Eq. (1)].

Pd(II)-catalyzed amination of C-H bonds using single-electron or two-electron oxidants.

Pd(II)-catalyzed intramolecular amination of arenes is developed using either a one- or two-electron oxidant. The reaction protocol tolerates a wide range of deactivating groups including acetyl, cyano, and nitro groups. This catalytic reaction allows expedient syntheses of broadly useful substituted indolines or indoles.

Versatile Pd(OTf)2·2H2O-Catalyzed ortho-Fluorination Using NMP as a Promoter

Pd(OTf)(2) x 2 H(2)O-catalyzed ortho-fluorination of triflamide-protected benzylamines is reported. The use of N-fluoro-2,4,6-trimethylpyridinium triflate as the F(+) source and NMP as a promoter is crucial for this reaction. The conversion of triflamide into a wide range of synthetically useful functional groups makes this fluorination protocol broadly applicable in medicinal chemistry and synthesis.