Robert J. Phipps

A meta-selective copper-catalyzed C-H bond arylation.

For over a century, chemical transformations of benzene derivatives have been guided by the high selectivity for electrophilic attack at the ortho/para positions in electron-rich substrates and at the meta position in electron-deficient molecules. We have developed a copper-catalyzed arylation reaction that, in contrast, selectively substitutes phenyl electrophiles at the aromatic carbon–hydrogen sites meta to an amido substituent. This previously elusive class of transformation is applicable to a broad range of aromatic compounds.

Cu(II)-Catalyzed Direct and Site-Selective Arylation of Indoles Under Mild Conditions

We have developed a new site-selective Cu(II)-catalyzed C-H bond functionalization process that can selectively arylate indoles at either the C3 or C2 position under mild conditions. The scope of the arylation process is broad and tolerates broad functionality on both the indole and aryl unit, which makes it amenable to further elaboration. The mechanism of the arylation reaction is proposed to proceed via a Cu(III)-aryl species that undergoes initial electrophilic addition at the C3 position of the indole motif. We speculate that site of indole arylation arises through a migration of the Cu(III)-aryl group from C3 to C2, and this can be controlled by the nature of the group on the nitrogen atom; free (NH)- and N-alkylindoles deliver the C3-arylated product, whereas N-acetylindoles afford the C2 isomer, both with excellent yield and selectivity.

Advances in Catalytic Enantioselective Fluorination, Mono-, Di-, and Trifluoromethylation, and Trifluoromethylthiolation Reactions

Despite being largely absent from natural products and biological processes, fluorine plays a conspicuous and increasingly important role within pharmaceuticals and agrochemicals, as well as in materials science.1a−1c Indeed, as many as 35% of agrochemicals and 20% of pharmaceuticals on the market contain fluorine.1d Fluorine is the most electronegative element in the periodic table, and the introduction of one or more fluorine atoms into a molecule can result in greatly perturbed properties. Fluorine substituents can potentially impact a number of variables, such as the acidity or basicity of neighboring groups, dipole moment, and properties such as lipophilicity, metabolic stability, and bioavailability. The multitude of effects that can arise from the introduction of fluorine in small molecules in the context of medicinal chemistry has been extensively discussed elsewhere.2 For these reasons, methods to introduce fluorine into small organic molecules have been actively investigated for many years by specialists in the field of fluorine chemistry. However, particularly in the past decade, a combination of the increasing importance of fluorine-containing molecules and the successful development of bench stable, commercially available fluorine sources has brought the expansion of fluorine chemistry into the mainstream organic synthesis community. This has resulted in an acceleration in the development of new fluorination methods and consequently in methods for the asymmetric introduction of fluorine.3 Catalytic asymmetric fluorination methods have inevitably lagged somewhat behind their nonasymmetric counterparts as understanding of the modes of reactivity of new fluorinating reagents must generally be developed and understood before they can be extended to enantioselective catalysis.3b Indeed, the last special issue of Chemical Reviews dedicated to fluorine chemistry, in 1996, contained no articles addressing asymmetric fluorine chemistry, and the editor of the issue noted that “although fluorine chemistry is much less abstruse now than when I entered the field a generation ago, it remains a specialized topic and most chemists are unfamiliar, or at least uncomfortable, with the synthesis and behavior of organofluorine compounds.”4 The field has undoubtedly undergone great change within the last two decades. As with the incorporation of the fluorine atom, the introduction of the trifluoromethyl (CF3) group into organic molecules can substantially alter their properties. As with fluorine, the prevalence of CF3 groups in pharmaceuticals and agrochemicals coupled with the development of new trifluoromethylating reagents also has led to a recent surge in the development of asymmetric trifluoromethylation and perfluoroalkylation. Although the fluorine and trifluoromethyl moieties are often found on the aromatic rings of many pharmaceutical and agrochemicals rather than in aliphatic regions, this may be a result of the lack of efficient methods for the asymmetric introduction of C–F and C–CF3 bonds into molecules; it could be the case that lack of chemical methods is restricting useful exploration of such molecules. However, there are still encouraging examples of drug candidates containing chiral fluorine and trifluoromethyl-bearing carbons (Figure ​(Figure11). Figure 1 Molecules of medicinal interest bearing C–F and C–CF3 stereocenters.

The progression of chiral anions from concepts to applications in asymmetric catalysis

Despite the tremendous advances of the past four decades, chemists are far from being able to use chiral catalysts to control the stereoselectivity of any desired reaction. New concepts for the construction and mode of operation of chiral catalysts have the potential to open up previously inaccessible reaction space. The recognition and categorization of distinct approaches seems to play a role in triggering rapid exploration of new territory. This Review both reflects on the origins as well as details a selection of the latest examples of an area that has advanced considerably within the past five years or so: the use of chiral anions in asymmetric catalysis. Defining reactions as involving chiral anions is a difficult task owing to uncertainties over the exact catalytic mechanisms. Nevertheless, we attempt to provide an overview of the breadth of reactions that could reasonably fall under this umbrella.

A Highly Para‐Selective Copper(II)‐Catalyzed Direct Arylation of Aniline and Phenol Derivatives

The ubiquity of the biaryl motif in natural products, medicines, and novel materials ensures a constant demand for their efficient and selective synthesis. The most widespread biaryl-forming processes are cross-coupling reactions in which two prefunctionalized arene partners are connected by a transition-metal catalyst. Although selectivity in these cross-coupling reactions is not an issue, a compromise is made on efficiency; prior chemical transformations are required to obtain the coupling partners as the prefunctionalization events must be carried out regioselectively, and in some cases this can prove a significant challenge. Much recent attention has been devoted to the development of new concepts to utilize a C H bond in place of one or both of the cross-coupling partners. The benefits of this strategy are considerable, but the crucial issue of selectivity is now relocated to the biaryl bond-forming step. Cyclometalation-based approaches constitute the most common strategy towards the arylation of C H bonds, which results in functionalization ortho to a directing group. Considering the wealth of electrophilic aromatic substitution reactions employed in synthesis, it is surprising that few para-selective direct arylation reactions are known. Several research groups have reported methods to achieve direct metal-catalyzed arylation of electron-rich benzenes, but only moderate selectivity has been observed; in most cases, all three possible isomers were obtained. Higher selectivity was reported by Buchwald and co-workers in a specific case during an oxidative coupling of anisole with anilides, wherein 1:2:12 o/m/p selectivity was achieved. Kita et al. have reported a metal-free thiophenylation of some electron-rich arenes and heteroarenes with high selectivity. Recently, we reported a C3-selective copper-catalyzed direct arylation of indoles with diaryliodonium salts; this selectivity would be expected from an electrophilic substitution-type (SEAr) mechanism (Figure 1). [7a] Intriguingly, we

Copper-catalyzed alkene arylation with diaryliodonium salts.

Alkenes and arenes represent two classes of feedstock compounds whose union has fundamental importance to synthetic organic chemistry. We report a new approach to alkene arylation using diaryliodonium salts and Cu catalysis. Using a range of simple alkenes, we have shown that the product outcomes differ significantly from those commonly obtained by the Heck reaction. We have used these insights to develop a number of new tandem and cascade reactions that transform readily available alkenes into complex arylated products that may have broad applications in chemical synthesis.

Asymmetric Fluorination of Enamides: Access to α-Fluoroimines Using an Anionic Chiral Phase-Transfer Catalyst

The use of a BINOL-derived phosphate as a chiral anionic phase-transfer catalyst in a nonpolar solvent allows the enantioselective fluorination of enamides using Selectfluor as the fluorinating reagent. We demonstrate that a wide range of stable and synthetically versatile α-(fluoro)benzoylimines can be readily accessed with high enantioselectivity. These compounds have the potential to be readily elaborated into a range of highly stereodefined β-fluoroamines, compounds that constitute highly valuable building blocks of particular importance in the synthesis of pharmaceuticals.

Chiral Anion Phase-Transfer Catalysis Applied to the Direct Enantioselective Fluorinative Dearomatization of Phenols

Chiral anion phase-transfer catalysis has enabled the direct and highly enantioselective fluorinative dearomatization of phenols catalyzed by a BINOL-derived phosphate. The process efficiently transforms simple, readily available phenols into fluorinated chiral small molecules bearing reactive functionality under ambient reaction conditions with high enantioselectivity. The close relationship of the products with well-studied o-quinols provides numerous avenues for synthetic elaboration and exciting opportunities for bioisosteric replacement of hydroxyl with fluorine in natural products.

A Doubly Axially Chiral Phosphoric Acid Catalyst for the Asymmetric Tandem Oxyfluorination of Enamides

The selective construction of carbon–fluorine bonds is of great interest to medicinal chemists because the replacement of a carbon–hydrogen bond with a carbon–fluorine bond continues to be an effective approach to the development of biologically active molecules with improved physical and metabolic profiles and biological activities. To this end, a number of impressive examples of catalytic enantioselective fluorination have been reported over the last decade. Our laboratory has recently introduced a novel strategy for asymmetric fluorination based on phase-transfer catalysis using chiral anionic catalysts based on BINOL-derived phosphates [Eq. (1)]. Motivated by the importance of the

A combination of directing groups and chiral anion phase-transfer catalysis for enantioselective fluorination of alkenes

We report a catalytic enantioselective electrophilic fluorination of alkenes to form tertiary and quaternary C(sp3)-F bonds and generate β-amino- and β-aryl-allylic fluorides. The reaction takes advantage of the ability of chiral phosphate anions to serve as solid–liquid phase transfer catalysts and hydrogen bond with directing groups on the substrate. A variety of heterocyclic, carbocyclic, and acyclic alkenes react with good to excellent yields and high enantioselectivities. Further, we demonstrate a one-pot, tandem dihalogenation–cyclization reaction, using the same catalytic system twice in series, with an analogous electrophilic brominating reagent in the second step.