The Pyridyldiisopropylsilyl Group: A Masked Functionality and Directing Group for Monoselective ortho-Acyloxylation and ortho-Halogenation Reactions of Arenes.
TL;DR: A general mechanism involving the formation of a palladacycle via a C-H activation process as the rate-determining step has been proposed, and the silicon-tethered directing group in both acyloxylated and halogenated products can easily be removed or efficiently converted into an array of other valuable functionalities.
Abstract: A novel, easily removable and modifiable silicon-tethered pyridyldiisopropylsilyl directing group for C—H functionalizations of arenes has been developed. The installation of the pyridyldiisopropylsilyl group can efficiently be achieved via two complementary routes using easily available 2-(diisopropylsilyl)pyridine (5). The first strategy features a nucleophilic hydride substitution at the silicon atom in 5 with aryllithium reagents generated in situ from the corresponding aryl bromides or iodides. The second milder route exploits a highly efficient roomtemperature rhodium(I)-catalyzed cross-coupling reaction between 5 and aryl iodides. The latter approach can be applied to the preparation of a wide range of pyridyldiisopropylsilyl-substituted arenes possessing a variety of functional groups, including those incompatible with organometallic reagents. The pyridyldiisopropylsilyl directing group allows for a highly efficient, regioselective palladium(II)-catalyzed mono-ortho-acyloxylation and ortho-halogenation of various aromatic compounds. Most importantly, the silicon-tethered directing group in both acyloxylated and halogenated products can easily be removed or efficiently converted into an array of other valuable functionalities. These transformations include protio-, deuterio-, halo-, boro-, and alkynyl-desilylations, as well as a conversion of the directing group into the hydroxy functionality. In addition, the construction of aryl-aryl bonds via the Hiyama―Denmark cross-coupling reaction is feasible for the acetoxylated products. Moreover, the ortho-halogenated pyridyldiisopropylsilylarenes, bearing both nucleophilic pyridyldiisopropylsilyl and electrophilic aryl halide moieties, represent synthetically attractive 1,2-ambiphiles. A unique reactivity of these ambiphiles has been demonstrated in efficient syntheses of arylenediyne and benzosilole derivatives, as well as in a facile generation of benzyne. In addition, preliminary mechanistic studies of the acyloxylation and halogenation reactions have been performed. A trinuclear palladacycle intermediate has been isolated from a stoichiometric reaction between diisopropyl-(phenyl)pyrid-2-ylsilane (3a) and palladium acetate. Furthermore, both C―H functionalization reactions exhibited equally high values of the intramolecular primary kinetic isotope effect (k H /k D =6.7). Based on these observations, a general mechanism involving the formation of a palladacycle via a C―H activation process as the rate-determining step has been proposed.
Citations
More filters
TL;DR: The present review is devoted to summarizing the recent advances (2015–2017) in the field of metal-catalysed group-directed C–H functionalisation.
Abstract: 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
1,057 citations
TL;DR: In this article, a cross-coupling of organosilicon reagents with organic halides or pseudohalides has been considered to be a useful tool for constructing the carbon frameworks of various target molecules such as pharmaceuticals and π-conjugated functional materials.
Abstract: Organosilicon compounds act as a nucleophile upon activation by an appropriate base and behave in a manner similar to main-group organometallic reagents. In the last decades, structurally divergent organosilicon reagents are available and have become more employed for synthetic transformation with the aid of transition-metal complexes, because organosilicon compounds are in general superior to other organometallic compounds in view of stability, solubility, nontoxicity, and easy-handling. Particularly, cross-coupling of organosilicon reagents with organic halides or pseudohalides has been considered to be a useful tool for constructing the carbon frameworks of various target molecules such as pharmaceuticals and π-conjugated functional materials. Perfluoroalkylsilicon compounds such as CF3SiEt3 have found use as reagents for the metal-catalyzed introduction of perfluoroalkyl groups into many substrates. In addition, functionalized organosilicon reagents are readily accessible by catalytic approach startin...
258 citations
TL;DR: A silanol-directed, Pd(II)-catalyzed C-H alkenylation of phenols is reported, which allows for efficient synthesis of diverseAlkenylated phenols, including an estrone derivative.
Abstract: A silanol-directed, Pd(II)-catalyzed C–H alkenylation of phenols is reported. This work features silanol, as a novel traceless directing group, and a directed o-C–H alkenylation of phenols. This new method allows for efficient synthesis of diverse alkenylated phenols, including an estrone derivative.
228 citations
TL;DR: A nitrile-based template that enables meta-selective C-H bond functionalization was developed and uses a silicon atom for attachment, allowing for a facile introduction/deprotection strategy increasing the synthetic practicality of this template.
Abstract: A nitrile-based template that enables meta-selective C–H bond functionalization was developed. The template is applicable to a range of substituted arenes and tolerates a variety of functional groups. The directing group uses a silicon atom for attachment, allowing for a facile introduction/deprotection strategy increasing the synthetic practicality of this template.
192 citations
TL;DR: The present review summarizes primary publications on the cross-dehydrogenative C–O coupling, with special emphasis on the studies published after 2000, and classes the data according to the structures of C-reagents and the type of oxidative systems.
Abstract: The present review summarizes primary publications on the cross-dehydrogenative C-O coupling, with special emphasis on the studies published after 2000. The starting compound, which donates a carbon atom for the formation of a new C-O bond, is called the CH-reagent or the C-reagent, and the compound, an oxygen atom of which is involved in the new bond, is called the OH-reagent or the O-reagent. Alcohols and carboxylic acids are most commonly used as O-reagents; hydroxylamine derivatives, hydroperoxides, and sulfonic acids are employed less often. The cross-dehydrogenative C-O coupling reactions are carried out using different C-reagents, such as compounds containing directing functional groups (amide, heteroaromatic, oxime, and so on) and compounds with activated C-H bonds (aldehydes, alcohols, ketones, ethers, amines, amides, compounds containing the benzyl, allyl, or propargyl moiety). An analysis of the published data showed that the principles at the basis of a particular cross-dehydrogenative C-O coupling reaction are dictated mainly by the nature of the C-reagent. Hence, in the present review the data are classified according to the structures of C-reagents, and, in the second place, according to the type of oxidative systems. Besides the typical cross-dehydrogenative coupling reactions of CH- and OH-reagents, closely related C-H activation processes involving intermolecular C-O bond formation are discussed: acyloxylation reactions with ArI(O2CR)2 reagents and generation of O-reagents in situ from C-reagents (methylarenes, aldehydes, etc.).
150 citations
References
More filters
TL;DR: In this paper, a cross-coupling reaction is proposed for coupling 1 -Alkenylboron Derivatives: Synthesis of Conjugated Dienes 6.
Abstract: B. Other Catalyti; Process by Transition-Metal Complexes IV. Cross-Coupling Reaction A. Coupling of 1 -Alkenylboron Derivatives: Synthesis of Conjugated Dienes 6. Coupling of Arylboron Derivatives: Synthesis of Biaryls C. Coupling of Alkylboron Derivatives D. Coupling with Triflates E. Synthesis of Vinylic Sulfides F. Coupling with lodoalkanes: Alkyl-Alkyl CouDlino G. Coupling with Other Organic Halides and Boron Reagents V. Head-to-Tail Coupling VI. Carbonylative Coupling VII. Alkoxycarbonylation and Dimerization VIII. Conclusion 2457 2458 2458
10,937 citations
TL;DR: This is the first comprehensive review encompassing the large body of work in this field over the past 5 years, and will focus specifically on ligand-directed C–H functionalization reactions catalyzed by palladium.
Abstract: 1.1 Introduction to Pd-catalyzed directed C–H functionalization
The development of methods for the direct conversion of carbon–hydrogen bonds into carbon-oxygen, carbon-halogen, carbon-nitrogen, carbon-sulfur, and carbon-carbon bonds remains a critical challenge in organic chemistry. Mild and selective transformations of this type will undoubtedly find widespread application across the chemical field, including in the synthesis of pharmaceuticals, natural products, agrochemicals, polymers, and feedstock commodity chemicals. Traditional approaches for the formation of such functional groups rely on pre-functionalized starting materials for both reactivity and selectivity. However, the requirement for installing a functional group prior to the desired C–O, C–X, C–N, C–S, or C–C bond adds costly chemical steps to the overall construction of a molecule. As such, circumventing this issue will not only improve atom economy but also increase the overall efficiency of multi-step synthetic sequences.
Direct C–H bond functionalization reactions are limited by two fundamental challenges: (i) the inert nature of most carbon-hydrogen bonds and (ii) the requirement to control site selectivity in molecules that contain diverse C–H groups. A multitude of studies have addressed the first challenge by demonstrating that transition metals can react with C–H bonds to produce C–M bonds in a process known as “C–H activation”.1 The resulting C–M bonds are far more reactive than their C–H counterparts, and in many cases they can be converted to new functional groups under mild conditions.
The second major challenge is achieving selective functionalization of a single C–H bond within a complex molecule. While several different strategies have been employed to address this issue, the most common (and the subject of the current review) involves the use of substrates that contain coordinating ligands. These ligands (often termed “directing groups”) bind to the metal center and selectively deliver the catalyst to a proximal C–H bond. Many different transition metals, including Ru, Rh, Pt, and Pd, undergo stoichiometric ligand-directed C–H activation reactions (also known as cyclometalation).2,3 Furthermore, over the past 15 years, a variety of catalytic carbon-carbon bond-forming processes have been developed that involve cyclometalation as a key step.1b–d,4
The current review will focus specifically on ligand-directed C–H functionalization reactions catalyzed by palladium. Palladium complexes are particularly attractive catalysts for such transformations for several reasons. First, ligand-directed C–H functionalization at Pd centers can be used to install many different types of bonds, including carbon-oxygen, carbon-halogen, carbon-nitrogen, carbon-sulfur, and carbon-carbon linkages. Few other catalysts allow such diverse bond constructions,5,6,7 and this versatility is predominantly the result of two key features: (i) the compatibility of many PdII catalysts with oxidants and (ii) the ability to selectively functionalize cyclopalladated intermediates. Second, palladium participates in cyclometalation with a wide variety of directing groups, and, unlike many other transition metals, promotes C–H activation at both sp2 and sp3 C–H sites. Finally, the vast majority of Pd-catalyzed directed C–H functionalization reactions can be performed in the presence of ambient air and moisture, making them exceptionally practical for applications in organic synthesis.
While several accounts have described recent advances, this is the first comprehensive review encompassing the large body of work in this field over the past 5 years (2004–2009). Both synthetic applications and mechanistic aspects of these transformations are discussed where appropriate, and the review is organized on the basis of the type of bond being formed.
5,179 citations
TL;DR: A review of palladium-catalyzed coupling of CH bonds with organometallic reagents through a PdII/Pd0 catalytic cycle can be found in this paper.
Abstract: Pick your Pd partners: A number of catalytic systems have been developed for palladium-catalyzed CH activation/CC bond formation. Recent studies concerning the palladium(II)-catalyzed coupling of CH bonds with organometallic reagents through a PdII/Pd0 catalytic cycle are discussed (see scheme), and the versatility and practicality of this new mode of catalysis are presented. Unaddressed questions and the potential for development in the field are also addressed.
In the past decade, palladium-catalyzed CH activation/CC 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 CC bonds from CH bonds: PdII/Pd0, PdII/PdIV, Pd0/PdII/PdIV, and Pd0/PdII catalysis. A more detailed discussion is then directed towards the recent development of palladium(II)-catalyzed coupling of CH bonds with organometallic reagents through a PdII/Pd0 catalytic cycle. Despite the progress made to date, improving the versatility and practicality of this new reaction remains a tremendous challenge.
3,533 citations
TL;DR: This review focuses on Rh-catalyzed methods for C-H bond functionalization, which have seen widespread success over the course of the last decade and are discussed in detail in the accompanying articles in this special issue of Chemical Reviews.
Abstract: Once considered the 'holy grail' of organometallic chemistry, synthetically useful reactions employing C-H bond activation have increasingly been developed and applied to natural product and drug synthesis over the past decade. The ubiquity and relative low cost of hydrocarbons makes C-H bond functionalization an attractive alternative to classical C-C bond forming reactions such as cross-coupling, which require organohalides and organometallic reagents. In addition to providing an atom economical alternative to standard cross - coupling strategies, C-H bond functionalization also reduces the production of toxic by-products, thereby contributing to the growing field of reactions with decreased environmental impact. In the area of C-C bond forming reactions that proceed via a C-H activation mechanism, rhodium catalysts stand out for their functional group tolerance and wide range of synthetic utility. Over the course of the last decade, many Rh-catalyzed methods for heteroatom-directed C-H bond functionalization have been reported and will be the focus of this review. Material appearing in the literature prior to 2001 has been reviewed previously and will only be introduced as background when necessary. The synthesis of complex molecules from relatively simple precursors has long been a goal for many organic chemists. The ability to selectively functionalize a molecule with minimal pre-activation can streamline syntheses and expand the opportunities to explore the utility of complex molecules in areas ranging from the pharmaceutical industry to materials science. Indeed, the issue of selectivity is paramount in the development of all C-H bond functionalization methods. Several groups have developed elegant approaches towards achieving selectivity in molecules that possess many sterically and electronically similar C-H bonds. Many of these approaches are discussed in detail in the accompanying articles in this special issue of Chemical Reviews. One approach that has seen widespread success involves the use of a proximal heteroatom that serves as a directing group for the selective functionalization of a specific C-H bond. In a survey of examples of heteroatom-directed Rh catalysis, two mechanistically distinct reaction pathways are revealed. In one case, the heteroatom acts as a chelator to bind the Rh catalyst, facilitating reactivity at a proximal site. In this case, the formation of a five-membered metallacycle provides a favorable driving force in inducing reactivity at the desired location. In the other case, the heteroatom initially coordinates the Rh catalyst and then acts to stabilize the formation of a metal-carbon bond at a proximal site. A true test of the utility of a synthetic method is in its application to the synthesis of natural products or complex molecules. Several groups have demonstrated the applicability of C-H bond functionalization reactions towards complex molecule synthesis. Target-oriented synthesis provides a platform to test the effectiveness of a method in unique chemical and steric environments. In this respect, Rh-catalyzed methods for C-H bond functionalization stand out, with several syntheses being described in the literature that utilize C-H bond functionalization in a key step. These syntheses are highlighted following the discussion of the method they employ.
3,210 citations
TL;DR: A number of improvements have developed the former process into an industrially very useful and attractive method for the construction of aryl -aryl bonds, but the need still exists for more efficient routes whereby the same outcome is accomplished, but with reduced waste and in fewer steps.
Abstract: The biaryl structural motif is a predominant feature in many pharmaceutically relevant and biologically active compounds. As a result, for over a century 1 organic chemists have sought to develop new and more efficient aryl -aryl bond-forming methods. Although there exist a variety of routes for the construction of aryl -aryl bonds, arguably the most common method is through the use of transition-metalmediated reactions. 2-4 While earlier reports focused on the use of stoichiometric quantities of a transition metal to carry out the desired transformation, modern methods of transitionmetal-catalyzed aryl -aryl coupling have focused on the development of high-yielding reactions achieved with excellent selectivity and high functional group tolerance under mild reaction conditions. Typically, these reactions involve either the coupling of an aryl halide or pseudohalide with an organometallic reagent (Scheme 1), or the homocoupling of two aryl halides or two organometallic reagents. Although a number of improvements have developed the former process into an industrially very useful and attractive method for the construction of aryl -aryl bonds, the need still exists for more efficient routes whereby the same outcome is accomplished, but with reduced waste and in fewer steps. In particular, the obligation to use coupling partners that are both activated is wasteful since it necessitates the installation and then subsequent disposal of stoichiometric activating agents. Furthermore, preparation of preactivated aryl substrates often requires several steps, which in itself can be a time-consuming and economically inefficient process.
3,204 citations