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Functionalization of the [beta]-C-H bonds of aliphatic acids is emerging as a valuable synthetic disconnection that complements a wide range of conjugate addition reactions.sup.1-5. Despite efforts for [beta]-C-H functionalization in carbon-carbon and carbon-heteroatom bond-forming reactions, these have numerous crucial limitations, especially for industrial-scale applications, including lack of mono-selectivity, use of expensive oxidants and limited scope.sup.6-13. Notably, the majority of these reactions are incompatible with free aliphatic acids without exogenous directing groups. Considering the challenge of developing C-H activation reactions, it is not surprising that achieving different transformations requires independent catalyst design and directing group optimizations in each case. Here we report a Pd-catalysed [beta]-C(sp.sup.3)-H lactonization of aliphatic acids enabled by a mono-N-protected [beta]-amino acid ligand. The highly strained and reactive [beta]-lactone products are versatile linchpins for the mono-selective installation of diverse alkyl, alkenyl, aryl, alkynyl, fluoro, hydroxyl and amino groups at the [beta] position of the parent acid, thus providing a route to many carboxylic acids. The use of inexpensive tert-butyl hydrogen peroxide as the oxidant to promote the desired selective reductive elimination from the Pd(iv) centre, as well as the ease of product purification without column chromatography, render this reaction amenable to tonne-scale manufacturing. Pd-catalysed [beta]-C(sp.sup.3)-H lactonization of aliphatic acids enabled by a mono-N-protected [beta]-amino acid and tert-butyl hydrogen peroxide is reported, achieving high [beta]-position selectivity without the use of a directing group., Author(s): Zhe Zhuang [sup.1] , Jin-Quan Yu [sup.1] Author Affiliations: (1) Department of Chemistry, The Scripps Research Institute, La Jolla, USA Main Alkyl carboxylic acids are ubiquitous and inexpensive reagents [...]

Enantioselective carbon-hydrogen (C-H) activation reactions by asymmetric metallation could provide new routes for the construction of chiral molecules.sup.1,2. However, current methods are typically limited to the formation of five- or six-membered metallacycles, thereby preventing the asymmetric functionalization of C-H bonds at positions remote to existing functional groups. Here we report enantioselective remote C-H activation using a catalytic amount of a chiral norbornene as a transient mediator, which relays initial ortho-C-H activation to the meta position. This was used in the enantioselective meta-C-H arylation of benzylamines, as well as the arylation and alkylation of homobenzylamines. The enantioselectivities obtained using the chiral transient mediator are comparable across different classes of substrates containing either neutral [sigma]-donor or anionic coordinating groups. This relay strategy could provide an alternative means to remote chiral induction, one of the most challenging problems in asymmetric catalysis.sup.3,4. Remote, enantioselective C-H activation reactions can be achieved by relaying ortho-C-H activation to the meta position, using a chiral norbornene as the mediator., Author(s): Hang Shi [sup.1] , Alastair N. Herron [sup.1] , Ying Shao [sup.1] , Qian Shao [sup.1] , Jin-Quan Yu [sup.1] Author Affiliations: (1) Department of Chemistry, The Scripps Research [...]

Author(s): Peng Wang [1]; Pritha Verma [1]; Guoqin Xia [1]; Jun Shi [2]; Jennifer X. Qiao [3]; Shiwei Tao [2]; Peter T. W. Cheng [2]; Michael A. Poss [3]; Marcus [...]

Achieving site selectivity in C-H functionalization reactions is a significant challenge, especially when the target C-H bond is distant from existing functional groups (1-5). Coordination of a functional group to a metal is often a key driving force and control element in many important reactions including asymmetric hydrogenation (6), epoxidation (7, 8) and lithiation (9). Exploitation of this effect has led to the development of a broad range of directed C-H activation reactions (10-14). However, these C-H activation methods are limited to proximal C-H bonds, which are spatially and geometrically accessible from the directing functional group. The development of meta-selective C-H functionalizations remains a significant challenge (1-5, 15-17). We recently developed a U-shaped template that can be used to overcome this constraint and have shown that it can be used to selectively activate remote meta-C-H bonds (1, 2). Although this approach has proved to be applicable to various substrates and catalytic transformations (3-5), the need for a covalently attached, complex template is a substantial drawback for synthetic applications. Here we report an alternative approach employing norbornene as a transient mediator to achieve meta-selective C-H activation with a simple and common orthodirecting group. The use of a newly developed pyridine-based ligand is crucial for relaying the palladium catalyst to the metaposition by norbornene after initial ortho-C-H activation. This catalytic reaction demonstrates the feasibility of switching ortho-selectivity to metaselectivity in C-H activation of the same substrate by catalyst control., Despite the recent reports of U-shaped templates to direct meta-C-H activation (Fig. 1a) (1-5), the development of more general and efficient approaches to achieve meta-C-H activation remains a significant task. [...]

Achieving site selectivity in carbon-hydrogen (C-H) functionalization reactions is a long-standing challenge in organic chemistry. The small differences in intrinsic reactivity of C-H bonds in any given organic molecule can [...]

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 (1-14). 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 (15) 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)., The development of new transformations in which inert C-H bonds react as dormant functional groups holds great promise for expediting organic synthesis by providing unprecedented retrosynthetic disconnections. In this endeavour, [...]

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 setectivity 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. 10.1126/science.1182512

Author(s): Zhipeng Zhang [1]; Keita Tanaka [1]; Jin-Quan Yu (corresponding author) [1] In chemical syntheses, the activation of carbonhydrogen (CH) bonds converts them directly into carboncarbon or carbonheteroatom bonds without [...]

Author(s): Yue-Jin Liu [1]; Hui Xu [1]; Wei-Jun Kong [1]; Ming Shang [1]; Hui-Xiong Dai (corresponding author) [1]; Jin-Quan Yu (corresponding author) [1, 2] In directed C-H activation reactions, any [...]

The selectivity, simplicity and practicality of the new oxidation methodology for the conversion of an enone subunit, to the corresponding 1,4-enedione are described. The methodology encourages and facilitates the wider use of highly reactive 1,4-enediones as intermediates for the construction of more complex molecules.