Pd-catalyzed α-selective C(sp3)–H acetoxylation of amides through an unusual cyclopalladation mechanism (original) (raw)
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Ligand-enabled cross-coupling of C(sp3)–H bonds with arylboron reagents via Pd(II)/Pd(0) catalysis
Nature Chemistry, 2014
There have been numerous developments in C-H activation reactions in the past decade. Attracted by the ability to directly functionalize molecules at ostensibly unreactive C-H bonds, chemists have discovered reaction conditions that enable reaction of C(sp 2)-H and C(sp 3)-H bonds with a variety of coupling partners. Despite these advances, the development of suitable ligands that enable catalytic C(sp 3)-H bond functionalization remains a significant challenge. Here, we report the discovery of a mono-N-protected amino acid (MPAA) ligand that enables Pd(II)-catalyzed coupling of γ-C(sp 3)-H bonds in triflyl-protected amines (R-NHTf) with arylboron reagents. Remarkably, no background reaction was observed in the absence of ligand. A variety of amine substrates and arylboron reagents were cross-coupled using this method. Arylation of optically active amino acid-derived substrates also provides a potential route for preparing nonprotenogenic amino acids.
Overcoming the limitations of directed C–H functionalizations of heterocycles
Nature, 2014
In directed C-H activation reactions, nitrogen and sulfur atoms present in heterocyclic substrates coordinate strongly with metal catalysts. This coordination, which can lead to catalyst poisoning or C-H functionalization at an undesired position, limits the application of C-H activation reactions in heterocycle-based drug discovery. 1-5 Herein, we report a robust and synthetically useful reaction that overcomes the complications associated with performing C-H functionalization reactions on heterocycles. Our approach employs a simple N-methoxy amide group, which serves as both a directing group and an anionic ligand to promote the in situ generation of the reactive PdX 2 (X = ArCONOMe) species from a Pd(0) source using air as the sole oxidant. In this way, the PdX 2 species is inherently anchored in close proximity with the target C-H bond adjacent to CONHOMe group, thus avoiding the interference from various heterocycles. Remarkably, this reaction overrides the conventional positional selectivity patterns observed with substrates containing strongly coordinating heteroatoms, including nitrogen, sulfur, and phosphorus. Thus, this operationally simple aerobic reaction demonstrates the feasibility of bypassing a fundamental limitation that has long plagued applications of directed C-H activation in medicinal chemistry. Heterocycles are commonly found in drug candidates owing to their ability to improve solubility and reduce the lipophilicity of a drug molecule. 1-2 The potential application of C-H activation technologies in the rapid synthesis and diversification of novel heterocycles has attracted widespread attention from the pharmaceutical industry. 3-5 One of the most significant challenges in the application of C-H functionalization reactions is achieving robust control of positional selectivity. Directed C-H metalation has recently emerged as a reliable approach for achieving a diverse collection of selective C-H functionalization Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Advances in Development of C–H Activation/Functionalization Using a Catalytic Directing Group
The transition metal catalyzed direct site‐selective carbon –hydrogen functionalization is ubiquitous in organic synthesis and has reached an impressive level of sophistication and efficiency emerging as a powerful synthetic strategy for C–C bond and C–X bond formation to access various useful arylated organic molecules. For the past two decades, directing group strategy has been used for selective activation and functionalization of certain inert C–H bonds. Despite the enormous development in this field, still, the majority of systems require two redundant steps, i. e. installation and removal of DGs. To overcome these limitations, recently, traceless and multitasking groups were invented as a partial solution to DG release however installation still remains unsolved. Ideally, use of the catalytic directing group, which can be reversibly linked to the substrate and can serve as an efficient directing role would circumvent this problem and is considered as one of the most efficient and powerful strategies for the non‐activated C–H functionalization (C(sp2)–H or C(sp3)–H). In this review, we describe the enormous advances in this field for direct selective C–H functionalization without involving additional steps, i. e. installation and removal of directing groups and also discuss less explored but significant non‐covalent interactions such as hydrogen bonding or ion pairing, which helps to control the selectivity of a substrate in a catalytic organic reaction.
ChemInform, 2014
Palladium-Catalyzed C-H Acetoxylation of 2-Methoxyimino-2-aryl-acetates and Acetamides.-The direct C-H acetoxylation of the title compounds affords the oxidative coupling products in moderate to good yields. A number of alkyl and alkoxy substituents can be incorporated into the benzene ring at ortho-, meta-, and para positions without significant loss in reaction efficiency. Accordingly, the structural variation of the ester and amide moieties in the acetoxylation reaction is carried out, cf. (VIII). Interestingly, changing the solvent to tBu-COOH results in a pivaloyloxylation product. Furthermore, the resulting α-imino esters can be easily converted into naturally unprecedented α-amino acids in almost quantitative yields.-(WANG, L.;
Current Organic Chemistry, 2011
Heterocyclic compounds are of paramount importance in essentially all fields of chemistry and in our daily life. Therefore, the synthesis and modification of such compounds is an ever expanding field in synthetic chemistry. In recent years, all synthetic efforts were guided increasingly by the search for more atom efficient and economical methods. Transition metal catalyzed C-H activation reactions have proved to provide both: i) an increased atom efficiency since the number of functional groups required to form a desired bond can be reduced due to substitution of at least one functional group usually required in cross-coupling reactions by a C-H bond, and ii) shorter overall reaction times and a reduced number of synthetic steps which ultimately leads to more economical processes. Additionally, the C-H activation approach can be considered as an effort towards a greener chemistry, since the reduction in the number of synthetic steps in the majority of cases leads to a decrease in the amount of waste produced (silica gel, solvents, etc.) and energy consumed. The focus of this review is on the direct functionalization of both saturated and unsaturated heterocycles. Methods for the formation of CC and carbon-heteroatom bonds will be discussed. In the case of saturated heterocycles, another focus will be put on the stereospecific functionalization of such building blocks. Dedicated to Emeritus Prof. Fritz Sauter on the occasion of his 80 th birthday.
Illustrated herein is a Pd(II) catalyzed one-pot direct difunc-tionalization of two distinct C(sp3)-H bonds [gem-ʹ-di-Me groups bearing aliphatic carboxylic acid] with bifunctional reagent (BFR) 2-iodo benzoic acid. The methyl 2-pyridyl sul-foximine (MPyS) bidentate directing group (DG), 2-chloro-5-trifluoromethyl ligand, and NaBrO3 co-oxidant combination helps the concerted metalation deprotonation (CMD) of inert C(sp3)-H bond as well reductive elimination steps; density functional theory (DFT) studies validate such insights. This process makes two [CC and CO] bonds of gem-ʹ-di-Me groups of DG-enabled aliphatic carboxylic acids in a single operation offering access to unusual benzo-fused peripheral substituted ω-membered lactones. This concept is uncovered for the first time. The transformation tolerates labile functional groups featuring broad scope with the construction of wide range of novel molecules of structural diversity. Ki-netic and control experiments study reveal...
Synthesis of Amides and Esters by Palladium(0)‐Catalyzed Carbonylative C(sp 3 )−H Activation
Angewandte Chemie, 2020
The 1,4-palladium shift strategy allows the functionalization of remote C À H bonds that are difficult to reach directly. Reported here is a domino reaction proceeding by C(sp 3)ÀH activation, 1,4-palladium shift, and amino-or alkoxycarbonylation, which generates a variety of amides and esters bearing a quaternary b-carbon atom. Mechanistic studies showed that the aminocarbonylation of the s-alkylpalladium intermediate arising from the palladium shift is fast using PPh 3 as the ligand, and leads to the amide rather than the previously reported indanone product.
Chem. Soc. Rev., 2018
The present review is devoted to summarizing the recent advances (2015-2017) in the field of metal-catalysed group-directed C-H functionalisation. In order to clearly showcase the molecular diversity that can now be accessed by means of directed C-H functionalisation, the whole is organized following the directing groups installed on a substrate. Its aim is to be a comprehensive reference work, where a specific directing group can be easily found, together with the transformations which have been carried out with it. Hence, the primary format of this review is schemes accompanied with a concise explanatory text, in which the directing groups are ordered in sections according to their chemical structure. The schemes feature typical substrates used, the products obtained as well as the required reaction conditions. Importantly, each example is commented on with respect to the most important positive features and drawbacks, on aspects such as selectivity, substrate scope, reaction conditions, directing group removal, and greenness. The targeted readership are both experts in the field of C-H functionalisation chemistry (to provide a comprehensive overview of the progress made in the last years) and, even more so, all organic chemists who want to introduce the C-H functionalisation way of thinking for a design of straightforward, efficient and step-economic synthetic routes towards molecules of interest to them. Accordingly, this review should be of particular interest also for scientists from industrial R&D sector. Hence, the overall goal of this review is to promote the application of C-H functionalisation reactions outside the research groups dedicated to method development and establishing it as a valuable reaction archetype in contemporary R&D, comparable to the role cross-coupling reactions play to date.