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Hydrogen atom abstraction is an important elementary chemical process but is very difficult to carry out enantioselectively. We have developed catalysts, readily derived from the Cinchona alkaloid family of natural products, which can achieve this by virtue of their chiral amine structure. The catalyst, following single-electron oxidation, desymmetrizes meso -diols by selectively abstracting a hydrogen atom from one carbon center, which then regains a hydrogen atom by abstraction from a thiol. This results in an enantioselective epimerization process, forming the chiral diastereomer with high enantiomeric excess. Cyclic and acyclic 1,2-diols are compatible, as are acyclic 1,3-diols. Additionally, we demonstrate the viability of combining our approach with carbon-carbon bond formation in Giese addition. Given the increasing number of synthetic methods involving hydrogen atom transfer steps, we anticipate that this work will have a broad impact in the field of enantioselective radical chemistry.

This work describes highly enantioselective nitrene transfer to hydrocinnamyl alcohols (benzylic C-H amination) and allylic alcohols (aziridination) using ion-paired Rh (II,II) complexes based on anionic variants of Du Bois' esp ligand that are associated with cinchona alkaloid-derived chiral cations. Directed by a substrate hydroxyl group, our previous work with these complexes had not been able to achieve high enantioselectivity on these most useful short-chain compounds, and we overcame this challenge through a combination of catalyst design and modified conditions. A hypothesis that modulation of the linker between the anionic sulfonate group and the central arene spacer might provide a better fit for shorter chain length substrates led to the development of a new biaryl-containing scaffold, which has allowed a broad scope for both substrate classes to be realized for the first time. Furthermore, we describe a systematic structural "knockout" study on the cinchona alkaloid-derived chiral cation to elucidate which features are crucial for high enantioinduction. De novo synthesis of modified scaffolds led to the surprising finding that for high ee the quinoline nitrogen of the alkaloid is crucial, although its location within the heterocycle could be varied, even leading to a superior catalyst. The free hydroxyl is also crucial and should possess the naturally occurring diastereomeric configuration of the alkaloid. These findings underline the privileged nature of the cinchona alkaloid scaffold and provide insight into how these cations might be used in other catalysis contexts.

Palladium-catalyzed asymmetric allylic alkylation is a versatile method for C-C bond formation. Many established classes of chiral ligands can perform allylic alkylation reactions enantioselectively, but identification of new ligand classes remains important for future development of the field. We demonstrate that enantiopure sSPhos, a bifunctional chiral monophosphine ligand, when used as its tetrabutyl ammonium salt, is a highly effective ligand for a benchmark Pd-catalyzed allylic alkylation reaction. We explore the scope and limitations and perform experiments to probe the origin of selectivity. In contrast with reactions previously explored using enantiopure sSPhos, it appears that steric bulk around the sulfonate group is responsible for the high enantioselectivity in this case, rather than attractive noncovalent interactions.

Enantioselective C-H amination at a benzylic methylene is a vital disconnection towards chiral benzylamines. Here we disclose that butyric and valeric acid-derived tertiary amides can undergo highly enantioselective benzylic amination using an achiral anionic Rh complex that is ion-paired with a Cinchona alkaloid-derived chiral cation. A broad scope of compounds can be aminated encompassing numerous arene substitutions, amides, and two different chain lengths. Excellent tolerance of ortho substituents was observed, which has not been achieved before in asymmetric intermolecular C-H amination with Rh. We speculate that the tertiary amide group of the substrate engages in hydrogen bonding interactions directly with the chiral cation, enabling a high level of organisation at the transition state for C-H amination. This is in contrast with our previous work where a substrate bearing a hydrogen bond donor was required. Control experiments led to the discovery that methyl ethers also function as proficient directing groups under the optimised conditions, potentially also acting as hydrogen bond acceptors. This finding has the promise to dramatically expand the applicability of our ion-paired chiral catalysts., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Arylative phenol dearomatization affords complex, cyclohexanone-based scaffolds from simple starting materials, and asymmetric versions allow access to valuable enantioenriched structures. However, bespoke chiral ligands must typically be identified for each new scaffold variation. We have addressed this limitation by applying the concept of electrostatically-directed palladium catalysis whereby the chiral sulfonated ligand sSPhos engages in electrostatic interactions with a phenolate substrate via its associated alkali metal cation. This approach allows access to highly enantioenriched spirocyclohexadienones, a process originally reported by Buchwald and co-workers in a predominantly racemic manner. In addition, sSPhos is proficient at forming two other distinct scaffolds, which had previously required fundamentally different chiral ligands, as well as a novel oxygen-linked scaffold. We envisage that the broad generality displayed by sSPhos will facilitate the expansion of this important reaction type and highlight the potential of this unusual design principle, which harnesses attractive electrostatic interactions.

The introduction of nitrogen atoms into small molecules is of fundamental importance and it is vital that ever more efficient and selective methods for achieving this are developed. With this aim, the potential of nitrene chemistry has long been appreciated but its application has been constrained by the extreme reactivity of these labile species. This liability however can be attenuated by complexation with a transition metal and the resulting metal nitrenoids have unique and highly versatile reactivity which includes the amination of certain types of aliphatic C-H bonds as well as reactions with alkenes to afford aziridines. At least one new chiral centre is typically formed in these processes and the development of catalysts to exert control over enantioselectivity in nitrenoid-mediated amination has become a growing area of research, particularly over the past two decades. Compared with some synthetic methods, metal nitrenoid chemistry is notable in that chemists can draw from a diverse array of metals and catalysts , ranging from metal-ligand complexes, bearing a variety of ligand types, via bio-inspired metalloporphyrins, all the way through to, very recently, engineered enzymes themselves. In the latter category in particular, rapid progress is being made, the rate of which suggests that this approach may be instrumental in addressing some of the outstanding challenges in the field. This review covers key developments and strategies that have shaped the field, in addition to the latest advances, up until September 2023., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Rendering a common ligand scaffold anionic and then pairing it with a chiral cation represents an alternative strategy for developing enantioselective versions of challenging transformations, as has been recently demonstrated in the enantioselective borylation of arenes using a quinine-derived chiral cation. A significant barrier to the further generalization of this approach is the lack of understanding of the specific interactions involved between the cation, ligand, and substrate, given the complexity of the system. We have embarked on a detailed computational study probing the mechanism, the key noncovalent interactions involved, and potential origin of selectivity for the desymmetrizing borylation of two distinct classes of substrate. We describe a deconstructive, stepwise approach to tackling this complex challenge, which involves building up a detailed understanding of the pairwise components of the nominally three component system before combining together into the full 263-atom reactive complex. This approach has revealed substantial differences in the noncovalent interactions occurring at the stereodetermining transition state for C-H oxidative addition to iridium for the two substrate classes. Each substrate engages in a unique mixture of diverse interactions, a testament to the rich and privileged structure of the cinchona alkaloid-derived chiral cations. Throughout the study, experimental support is provided, and this culminates in the discovery that prochiral phosphine oxide substrates, lacking hydrogen bond donor functionality, can also give very encouraging levels of enantioselectivity, potentially through direct interactions with the chiral cation. We envisage that the findings in this study will spur further developments in using chiral cations as controllers in asymmetric transition-metal catalysis., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Direct amination of arene C-H bonds is an attractive disconnection to form aniline-derived building blocks. This transformation presents significant practical challenges; classical methods for ortho -selective amination require strongly acidic or forcing conditions, while contemporary catalytic processes often require bespoke directing groups and/or precious metal catalysis. We report a mild and procedurally straightforward ortho -selective amination of arene carboxylic acids, arising from a facile rearrangement of acyl O -hydroxylamines without requiring precious metal catalysts. A broad scope of benzoic acid substrates are compatible and the reaction can be applied to longer chain arene carboxylic acids. Mechanistic studies probe the specific requirement for trifluoroacetic acid in generating the active aminating agent, and suggest that two separate mechanisms may be operating in parallel in the presence of an iron catalyst: (i) an iron-nitrenoid intermediate and (ii) a radical chain pathway. Regardless of which mechanism is followed, high ortho selectivity is obtained, proposed to arise from the directivity (first) or attractive interactions (second) arising with the carboxylic acid motif., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

ConspectusThe class of reactions now known as Minisci reactions is broadly defined as the addition of nucleophilic carbon-based radicals to basic heteroarenes with subsequent rearomatization to form a new carbon-carbon bond. Since the pioneering work of Minisci in the 1960s and 1970s, these reactions are now widely used in medicinal chemistry due to the ubiquity of basic heterocycles in druglike molecules. One of the long-standing challenges of Minisci chemistry has been that of regioselectivity due to the mixtures of positional isomers commonly obtained on many substrates if there is a choice between similarly activated sites. At the outset of the work described herein, we hypothesized that it may be possible to tackle this using a catalytic strategy whereby a bifunctional Brønsted acid catalyst simultaneously activates the heteroarene and engages attractive non-covalent interactions with the incoming nucleophile, resulting in a proximal attack. Using chiral BINOL-derived phosphoric acids, we not only were able to achieve this goal of regiocontrol but also discovered that we could control the absolute stereochemistry at the new stereocenter formed when prochiral α-amino radicals were employed. At the time, this discovery was unprecedented in the context of Minisci reactions.This Account details the discovery of this protocol and the further development, expansion, and investigations into the mechanism that we have carried out since then, several in collaboration with other research groups. Collaborative efforts have involved an expansion of the scope to diazines guided by multivariate statistical analysis through the development of a predictive model (collaboration with Sigman). Also, a mechanistic study involving detailed DFT analysis (collaboration with Goodman and Ermanis) unveiled the selectivity-determining step as being the deprotonation of a key cationic radical intermediate by the associated chiral phosphate anion. We have additionally carried out a number of synthetic developments of the protocol such as removing the need to prefunctionalize the radical nucleophile; hydrogen-atom transfer can be used to enable a formal coupling of two C-H bonds to form a C-C bond while retaining high enantio- and regioselectivity. Most recently, we have been able to expand the protocol so that α-hydroxy radicals can be used: until this point, all examples had concerned α-amino radicals. Again, HAT was used to generate the α-hydroxy radicals, and DFT studies carried out in collaboration (Ermanis) provided mechanistic insights.Since our original report, there have appeared a number of exciting developments from other research groups whereby the protocol has been applied to new substrates or using different precursors to generate the requisite α-amino radical. There have also been several examples in which alternative photocatalyst systems have been used to reduce the redox-active esters in the original enantioselective Minisci protocol. While primarily an Account, these contributions from other research groups will be covered briefly for context toward the end of the article.

Alkene aziridination is a highly versatile transformation for the construction of chiral nitrogen-containing compounds. Inspired by the success of analogous substrate-directed epoxidations, we report an enantioselective aziridination of alkenyl alcohols, which enables asymmetric nitrene transfer to alkenes with varied substitution patterns, including those not covered by the current protocols. We believe that our method is effective because it is substrate-directed, exploiting a network of attractive non-covalent interactions between the substrate, an achiral dianionic rhodium(II,II) tetracarboxylate dimer, and its two associated cinchona alkaloid-derived cations. It is these cations that provide a defined chiral pocket in which the aziridination can occur. In addition to a thorough evaluation of compatible alkene classes, we advance a practical mnemonic to predict reaction outcome and disclose a range of post-functionalization protocols that highlight the unique synthetic potential of the enantioenriched aziridine-alcohol products.

Amines featuring an adjacent stereocenter are important building blocks, and recent years have seen remarkable growth in methods forming these via prochiral α-amino radical intermediates. However, very few can exert control over the newly formed stereocenter. We disclose a strategy to overcome this in the context of one of the most widely used radical carbon-carbon bond forming reactions, the Giese reaction. Incorporation of a removable basic heteroarene into the substrate enables a network of attractive noncovalent interactions between a phosphoric acid catalyst, the subsequently formed α-amino radical, and the Giese acceptor, allowing the catalyst to exert control during the C-C bond forming step. Deprotection of the products leads to analogues of γ-aminobutyric acid. We anticipate that this strategy will be applicable to other asymmetric radical transformations in which catalyst control is presently challenging.

Electrostatic attraction between two groups of opposite charge, typically known as ion-pairing, offers unique opportunities for the design of systems to enable selectivity control in chemical reactions. Catalysis using noncovalent interactions is an established and vibrant research area, but it is noticeable that hydrogen bonding interactions are still the main interaction of choice in system design. Opposite charges experience the powerful force of Coulombic attraction and have the ability to exert fundamental influence on the outcome of reactions that involve charged reagents, intermediates or catalysts. In this Perspective, we will examine how ion-pairing interactions have been used to control selectivity in C-H bond functionalization processes. This broad class of reactions provides an interesting and thought-provoking lens through which to examine the application of ion-pairing design strategies because it is one that encompasses great mechanistic diversity, poses significant selectivity challenges, and perhaps most importantly is of immense interest to synthetic chemists in both industry and academia. We survey reactions that proceed via radical and ionic mechanisms alongside those that involve transition metal catalysis and will deal with control of site-selectivity and enantioselectivity. We anticipate that as this emerging area develops, it will become an ever-more important design strategy for selectivity control.

Axial chirality features prominently in molecules of biological interest as well as chiral catalyst designs, and atropisomeric 2,2'-biphenols are particularly prevalent. Atroposelective metal-catalyzed cross-coupling is an attractive and modular approach to access enantioenriched biphenols, and yet existing protocols cannot achieve this directly. We address this challenge through the use of enantiopure, sulfonated SPhos ( sSPhos ), an existing ligand that has until now been used only in racemic form and that derives its chirality from an atropisomeric axis that is introduced through sulfonation. We believe that attractive noncovalent interactions involving the ligand sulfonate group are responsible for the high levels of asymmetric induction that we obtain in the 2,2'-biphenol products of Suzuki-Miyaura coupling, and we have developed a highly practical resolution of sSPhos via diastereomeric salt recrystallization.

Ortho-sulfonyl anilines are important building blocks for a range of applications. We report the discovery of an aromatic rearrangement reaction of O-(arenesulfonyl)hydroxylamines which leads directly to ortho-sulfonyl anilines through formation of a new C-N bond with excellent levels of regiocontrol for the ortho position(s) over all others. We establish that the rearrangement is proceeding through an intermolecular mechanism and propose that the regiocontrol observed is the result of attractive non-covalent interactions occurring during the C-N bond-forming step. Importantly, this method is complementary to classical aniline sulfonation in terms of the variously substituted regioisomers that can be obtained and it is also applicable to O-(benzylsulfonyl) hydroxylamines., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Catalytic enantioselective Minisci reactions have recently been developed but all instances so far utilize α-amino radical coupling partners. We report a substantial evolution of the enantioselective Minisci reaction that enables α-hydroxy radicals to be used, providing valuable enantioenriched secondary alcohol products. This is achieved through the direct oxidative coupling of two C-H bonds on simple alcohol and pyridine partners through a hydrogen atom transfer (HAT)-driven approach: a challenging process to achieve due to the numerous side reactions that can occur. Our approach is highly regioselective as well as highly enantioselective. Dicumyl peroxide, upon irradiation with 390 nm light, serves as both HAT reagent and oxidant whilst selectivity is controlled by use of a chiral phosphoric acid catalyst. Computational and experimental evidence provide mechanistic insight as to the origin of selectivity, revealing a stereodetermining deprotonation step distinct from the analogous reaction of amide-containing substrates., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The enantioselective amination of C( sp 3 )-H bonds is a powerful synthetic transformation yet highly challenging to achieve in an intermolecular sense. We have developed a family of anionic variants of the best-in-class catalyst for Rh-catalyzed C-H amination, Rh 2 (esp) 2 , with which we have associated chiral cations derived from quaternized cinchona alkaloids. These ion-paired catalysts enable high levels of enantioselectivity to be achieved in the benzylic C-H amination of substrates bearing pendant hydroxyl groups. Additionally, the quinoline of the chiral cation appears to engage in axial ligation to the rhodium complex, providing improved yields of product versus Rh 2 (esp) 2 and highlighting the dual role that the cation is playing. These results underline the potential of using chiral cations to control enantioselectivity in challenging transition-metal-catalyzed transformations.

The formation of arene C-N bonds directly from C-H bonds is of great importance and there has been rapid recent development of methods for achieving this through radical mechanisms, often involving reactive N -centered radicals. A major challenge associated with these advances is that of regiocontrol, with mixtures of regioisomeric products obtained in most protocols, limiting broader utility. We have designed a system that utilizes attractive noncovalent interactions between an anionic substrate and an incoming radical cation in order to guide the latter to the arene ortho position. The anionic substrate takes the form of a sulfamate-protected aniline and telescoped cleavage of the sulfamate group after amination leads directly to ortho -phenylenediamines, key building blocks for a range of medicinally relevant diazoles. Our method can deliver both free amines and monoalkyl amines allowing access to unsymmetrical, selectively monoalkylated benzimidazoles and benzotriazoles. As well as providing concise access to valuable ortho -phenylenediamines, this work demonstrates the potential for utilizing noncovalent interactions to control positional selectivity in radical reactions.

Minisci-type reactions constitute one of the most powerful methods for building up complexity around basic heteroarenes. The most desirable variants involve formal oxidative coupling of a C-H bond on each partner, leading back to the simplest possible starting materials. We herein disclose a method that enables such a coupling of linear amides and heteroarenes with full control of enantioselectivity at the newly formed stereocenter as well as site selectivity on both the heteroarene and the amide. This is achieved by the use of a chiral phosphoric acid catalyst in conjunction with diacetyl as a combined hydrogen atom transfer reagent and oxidant. Diacetyl is directly photoexcitable, and thus, no extraneous photocatalyst is required: an added feature that contributes to the simplicity and practicality of the protocol.

Use of attractive noncovalent interactions between ligand and substrate is an emerging strategy for controlling positional selectivity. A key question relates to whether fine control on molecules with multiple, closely spaced reactive positions is achievable using typically less directional electrostatic interactions. Herein, we apply a 10-piece "toolkit" comprising of two closely related sulfonated phosphine ligands and five bases, each possessing varying cation size, to the challenge of site-selective cross-coupling of multiply chlorinated arenes. The fine tuning provided by these ligand/base combinations is effective for Suzuki-Miyaura coupling and Buchwald-Hartwig coupling on a range of isomeric dichlorinated and trichlorinated arenes, substrates that would produce intractable mixtures when typical ligands are used. This study develops a practical solution for site-selective cross-coupling to generate complex, highly substituted arenes.

The Minisci reaction is one of the most valuable methods for directly functionalizing basic heteroarenes to form carbon-carbon bonds. Use of prochiral, heteroatom-substituted radicals results in stereocenters being formed adjacent to the heteroaromatic system, generating motifs which are valuable in medicinal chemistry and chiral ligand design. Recently a highly enantioselective and regioselective protocol for the Minisci reaction was developed, using chiral phosphoric acid catalysis. However, the precise mechanism by which this process operated and the origin of selectivity remained unclear, making it challenging to develop the reaction more generally. Herein we report further experimental mechanistic studies which feed into detailed DFT calculations that probe the precise nature of the stereochemistry-determining step. Computational and experimental evidence together support Curtin-Hammett control in this reaction, with initial radical addition being quick and reversible, and enantioselectivity being achieved in the subsequent slower, irreversible deprotonation. A detailed survey via DFT calculations assessed a number of different possibilities for selectivity-determining deprotonation of the radical cation intermediate. Computations point to a clear preference for an initially unexpected mode of internal deprotonation enacted by the amide group, which is a crucial structural feature of the radical precursor, with the assistance of the associated chiral phosphate. This unconventional stereodetermining step underpins the high enantioselectivities and regioselectivities observed. The mechanistic model was further validated by applying it to a test set of substrates possessing varied structural features.

The past decade has seen unprecedented growth in the development of new chemical methods that proceed by mechanisms involving radical intermediates. This new attention has served to highlight a long-standing challenge in the field of radical chemistry - that of controlling absolute stereochemistry. This Review will examine developments using a strategy that offers enormous potential, in which attractive non-covalent interactions between a chiral catalyst and the substrate are leveraged to exert enantiocontrol. In a simplistic sense, such an approach mimics the modes of activation and control in enzyme catalysis and the realization that this can be achieved in the context of small-molecule catalysts has had sizable impact on the field of asymmetric catalysis in recent years. This strategy is now starting to quickly gather pace as a powerful approach for control of enantioselectivity in radical reactions and we hope that this focused survey of progress so far will inspire future developments in the area.

Enantioselective transition metal catalysis is an area very much at the forefront of contemporary synthetic research. The development of processes that enable the efficient synthesis of enantiopure compounds is of unquestionable importance to chemists working within the many diverse fields of the central science. Traditional approaches to solving this challenge have typically relied on leveraging repulsive steric interactions between chiral ligands and substrates in order to raise the energy of one of the diastereomeric transition states over the other. By contrast, this Review examines an alternative tactic in which a set of attractive noncovalent interactions operating between transition metal ligands and substrates are used to control enantioselectivity. Examples where this creative approach has been successfully applied to render fundamental synthetic processes enantioselective are presented and discussed. In many of the cases examined, the ligand scaffold has been carefully designed to accommodate these attractive interactions, while in others, the importance of the critical interactions was only elucidated in subsequent computational and mechanistic studies. Through an exploration and discussion of recent reports encompassing a wide range of reaction classes, we hope to inspire synthetic chemists to continue to develop asymmetric transformations based on this powerful concept., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Chiral cations have been used extensively as organocatalysts, but their application to rendering transition metal-catalyzed processes enantioselective remains rare. This is despite the success of the analogous charge-inverted strategy in which cationic metal complexes are paired with chiral anions. We report here a strategy to render a common bipyridine ligand anionic and pair its iridium complexes with a chiral cation derived from quinine. We have applied these ion-paired complexes to long-range asymmetric induction in the desymmetrization of the geminal diaryl motif, located on a carbon or phosphorus center, by enantioselective C-H borylation. In principle, numerous common classes of ligand could likewise be amenable to this approach., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Systems incorporating catalyst-substrate non-covalent interactions are emerging as a versatile approach to address site-selectivity challenges in remote functionalization reactions. Given the achievements that have been made in this regard using metals such as iridium, manganese and rhodium, it is surprising that non-covalent catalyst direction has not been utilized in reactions incorporating palladium-catalyzed C-H activation steps, despite palladium being arguably the most versatile metal for C-H activation. Herein, we demonstrate that electrostatically directed, site-selective C-Cl oxidative addition is compatible with a subsequent C-H activation step, proceeding via a concerted metalation deprotonation-type mechanism. This results in site-selective cross-coupling of dichloroarenes with fluoroarenes and fluoroheteroarenes, with selectivity controlled by catalyst structure. This study demonstrates that Pd-catalyzed C-H activation can be used productively in combination with a non-covalently-directed mode of catalysis, with important implications in both fields., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The Minisci reaction is one of the most direct and versatile methods for forging new carbon-carbon bonds onto basic heteroarenes: a broad subset of compounds ubiquitous in medicinal chemistry. While many Minisci-type reactions result in new stereocenters, control of the absolute stereochemistry has proved challenging. An asymmetric variant was recently realized using chiral phosphoric acid catalysis, although in that study the substrates were limited to quinolines and pyridines. Mechanistic uncertainties and nonobvious enantioselectivity trends made the task of extending the reaction to important new substrate classes challenging and time-intensive. Herein, we describe an approach to address this problem through rigorous analysis of the reaction landscape guided by a carefully designed reaction data set and facilitated through multivariate linear regression (MLR) analysis. These techniques permitted the development of mechanistically informative correlations providing the basis to transfer enantioselectivity outcomes to new reaction components, ultimately predicting pyrimidines to be particularly amenable to the protocol. The predictions of enantioselectivity outcomes for these valuable, pharmaceutically relevant motifs were remarkably accurate in most cases and resulted in a comprehensive exploration of scope, significantly expanding the utility and versatility of this methodology. This successful outcome is a powerful demonstration of the benefits of utilizing MLR analysis as a predictive platform for effective and efficient reaction scope exploration across substrate classes.

Control of positional selectivity in C-H activation reactions remains a challenge for synthetic chemists. Noncovalent catalysis has the potential to be a powerful strategy to address this challenge. As a part of our ongoing investigations into the use of ion-pairing interactions in site-selective catalysis, we demonstrate that several classes of aromatic phosphonium salts undergo iridium-catalyzed C-H borylation with a high selectivity for the arene meta position. This is achieved using a bifunctional bipyridine ligand bearing a pendant sulfonate group, which had previously been successful for borylation of aromatic ammonium salts. In this case, the phosphonium salts give a higher meta selectivity than the corresponding ammonium salts. We propose that the high selectivity occurs due to an attractive electrostatic interaction between the substrate and the ligand in the transition state for borylation.

The selective functionalization of C-H bonds at the arene para position is highly challenging using transition metal catalysis. Iridium-catalyzed borylation has emerged as a leading technique for arene functionalization, but there are only a handful of strategies for para -selective borylation, which operate on specific substrate classes and use bespoke ligands or catalysts. We describe a remarkably general protocol which results in para -selectivity on some of the most common arene building blocks (anilines, benzylamines, phenols, benzyl alcohols) and uses standard borylation ligands. Our strategy hinges upon the facile conversion of the substrates into sulfate or sulfamate salts, wherein the anionic arene component is paired with a tetrabutylammonium cation. We hypothesize that the bulk of this cation disfavors meta -C-H borylation, thereby promoting the challenging para -selective reaction.

Reactions that involve the addition of carbon-centered radicals to basic heteroarenes, followed by formal hydrogen atom loss, have become widely known as Minisci-type reactions. First developed into a useful synthetic tool in the late 1960s by Minisci, this reaction type has been in constant use over the last half century by chemists seeking to functionalize heterocycles in a rapid and direct manner, avoiding the need for de novo heterocycle synthesis. Whilst the originally developed protocols for radical generation remain in active use today, they have been joined in recent years by a new array of radical generation strategies that allow use of a wider variety of radical precursors that often operate under milder and more benign conditions. The recent surge of interest in new transformations based on free radical reactivity has meant that numerous choices are now available to a synthetic chemist looking to utilize a Minisci-type reaction. Radical-generation methods based on photoredox catalysis and electrochemistry have joined approaches which utilize thermal cleavage or the in situ generation of reactive radical precursors. This review will cover the remarkably large body of literature that has appeared on this topic over the last decade in an attempt to provide guidance to the synthetic chemist, as well as a perspective on both the challenges that have been overcome and those that still remain. As well as the logical classification of advances based on the nature of the radical precursor, with which most advances have been concerned, recent advances in control of various selectivity aspects associated with Minisci-type reactions will also be discussed., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Control of site-selectivity in chemical reactions that occur remote from existing functionality remains a major challenge in synthetic chemistry. We describe a strategy that enables three of the most commonly used cross-coupling processes to occur with high site-selectivity on dichloroarenes that bear acidic functional groups. We have achieved this by repurposing an established sulfonylated phosphine ligand to exploit its inherent bifunctionality. Mechanistic studies suggest that the sulfonate group engages in attractive electrostatic interactions with the cation associated with the deprotonated substrate, guiding cross-coupling to the chloride at the arene meta position. This counterintuitive combination of anionic ligand and anionic substrate demonstrates an alternative design principle when considering the application of noncovalent interactions to direct catalysis.

Basic heteroarenes are a ubiquitous feature of pharmaceuticals and bioactive molecules, and Minisci-type additions of radical nucleophiles are a leading method for their elaboration. Despite many Minisci-type protocols that result in the formation of stereocenters, exerting control over the absolute stereochemistry at these centers remains an unmet challenge. We report a process for addition of prochiral radicals, generated from amino acid derivatives, to pyridines and quinolines. Our method offers excellent control of both enantioselectivity and regioselectivity. An enantiopure chiral Brønsted acid catalyst serves both to activate the substrate and induce asymmetry, while an iridium photocatalyst mediates the required electron transfer processes. We anticipate that this method will expedite access to enantioenriched small-molecule building blocks bearing versatile basic heterocycles., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

The elaboration of simple arenes in order to access more complex substitution patterns is a crucial endeavor for synthetic chemists, given the central role that aromatic rings play in all manner of important molecules. Classical methods are now routinely used alongside stoichiometric organometallic approaches and, most recently, transition metal catalysis in the range of methodologies that are available to elaborate arene C-H bonds. Regioselectivity is an important consideration when selecting a method and, of all those available, it is arguably those that target the meta position that are fewest in number. The rapid development of transition metal-catalysed C-H bond functionalisation over the last few decades has opened new possibilities for meta-selective C-H functionalisation through the diverse reactivity of transition metals and their compatibility with a wide range of directing groups. The pace of discovery of such processes has grown rapidly in the last five years in particular and it is the purpose of this review to examine these but in doing so to place the focus on metals other than palladium, the specific contributions of which have been very recently reviewed elsewhere. It is hoped this will serve to highlight to the reader the breadth of current strategies and mechanisms that have been used to tackle this challenge, which may inspire further progress in the field.

Selective functionalization at the meta position of arenes remains a significant challenge. In this work, we demonstrate that a single anionic bipyridine ligand bearing a remote sulfonate group enables selective iridium-catalyzed borylation of a range of common amine-containing aromatic molecules at the arene meta position. We propose that this selectivity is the result of a key hydrogen bonding interaction between the substrate and catalyst. The scope of this meta-selective borylation is demonstrated on amides derived from benzylamines, phenethylamines and phenylpropylamines; amine-containing building blocks of great utility in many applications., (© 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Asymmetric catalysis has been revolutionised by the realisation that attractive non-covalent interactions such as hydrogen bonds and ion pairs can act as powerful controllers of enantioselectivity when incorporated into appropriate small molecule chiral scaffolds. Given these tremendous advances it is surprising that there are still a relatively limited number of examples of non-covalent interactions being harnessed for control of regioselectivity or site-selectivity in catalysis, two other fundamental selectivity aspects facing the synthetic chemist. This perspective examines the progress that has been made in this area thus far using non-covalent interactions in conjunction with transition metal catalysis as well as in the context of purely organic catalysts. We hope this will highlight the great potential in this approach for designing selective catalytic reactions.

Catalytic synthesis of nonracemic P-chiral phosphine derivatives remains a significant challenge. Here we report Cu-catalyzed enantioselective arylation of secondary phosphine oxides with diaryliodonium salts for the synthesis of tertiary phosphine oxides with high enantiomeric excess. The new process is demonstrated on a wide range of substrates and leads to products that are well-established P-chiral catalysts and ligands.