Discovery of N-X anomeric amides as electrophilic halogenation reagents.

Electrophilic halogenation is a widely used tool employed by medicinal chemists to either pre-functionalize molecules for further diversity or incorporate a halogen atom into drugs or drug-like compounds to solve metabolic problems or modulate off-target effects. Current methods to increase the power of halogenation rely on either the invention of new reagents or activating commercially available reagents with various additives such as Lewis or Brønsted acids, Lewis bases and hydrogen-bonding activators. There is a high demand for new reagents that can halogenate otherwise unreactive compounds under mild conditions. Here we report the invention of a class of halogenating reagents based on anomeric amides, taking advantage of the energy stored in the pyramidalized nitrogen of N-X anomeric amides as a driving force. These robust halogenating methods are compatible with a variety of functional groups and heterocycles, as exemplified on over 50 compounds (including 13 gram-scale examples and 1 flow chemistry scale-up).

Carbon quaternization of redox active esters and olefins by decarboxylative coupling.

The synthesis of quaternary carbons often requires numerous steps and complex conditions or harsh reagents that act on heavily engineered substrates. This is largely a consequence of conventional polar-bond retrosynthetic disconnections that in turn require multiple functional group interconversions, redox manipulations, and protecting group chemistry. Here, we report a simple catalyst and reductant combination that converts two types of feedstock chemicals, carboxylic acids and olefins, into tetrasubstituted carbons through quaternization of radical intermediates. An iron porphyrin catalyst activates each substrate by electron transfer or hydrogen atom transfer, and then combines the fragments using a bimolecular homolytic substitution (SH2) reaction. This cross-coupling reduces the synthetic burden to procure numerous quaternary carbon---containing products from simple chemical feedstocks.

Simplified Modular Access to Enantiopure 1,2-Aminoalcohols via Ni-Electrocatalytic Decarboxylative Arylation.

Chiral aminoalcohols are omnipresent in bioactive compounds. Conventional strategies to access this motif involve multiple-step reactions to install the requisite functionalities stereoselectively using conventional polar bond analysis. This study reveals that a simple chiral oxazolidine-based carboxylic acid can be readily transformed to substituted chiral aminoalcohols with high stereochemical control by Ni-electrocatalytic decarboxylative arylation. This general, robust, and scalable coupling can be used to synthesize a variety of medicinally important compounds, avoiding protecting and functional group manipulations, thereby dramatically simplifying their preparation.

Simplifying Access to Targeted Protein Degraders via Nickel Electrocatalytic Cross-Coupling.

C-C linked glutarimide-containing structures with direct utility in the preparation of cereblon-based degraders (PROTACs, CELMoDs) can be assessed in a single step from inexpensive, commercial α-bromoglutarimide through a unique Brønsted-acid assisted Ni-electrocatalytic approach. The reaction tolerates a broad array of functional groups that are historically problematic and can be applied to the simplified synthesis of dozens of known compounds that have only been procured through laborious, wasteful, multi-step sequences. The reaction is scalable in both batch and flow and features a trivial procedure wherein the most time-consuming aspect of reaction setup is weighing out the starting materials.

Complex molecule synthesis by electrocatalytic decarboxylative cross-coupling.

Modern retrosynthetic analysis in organic chemistry is based on the principle of polar relationships between functional groups to guide the design of synthetic routes1. This method, termed polar retrosynthetic analysis, assigns partial positive (electrophilic) or negative (nucleophilic) charges to constituent functional groups in complex molecules followed by disconnecting bonds between opposing charges2-4. Although this approach forms the basis of undergraduate curriculum in organic chemistry5 and strategic applications of most synthetic methods6, the implementation often requires a long list of ancillary considerations to mitigate chemoselectivity and oxidation state issues involving protecting groups and precise reaction choreography3,4,7. Here we report a radical-based Ni/Ag-electrocatalytic cross-coupling of substituted carboxylic acids, thereby enabling an intuitive and modular approach to accessing complex molecular architectures. This new method relies on a key silver additive that forms an active Ag nanoparticle-coated electrode surface8,9 in situ along with carefully chosen ligands that modulate the reactivity of Ni. Through judicious choice of conditions and ligands, the cross-couplings can be rendered highly diastereoselective. To demonstrate the simplifying power of these reactions, concise syntheses of 14 natural products and two medicinally relevant molecules were completed.

Scalable Electrochemical Decarboxylative Olefination Driven by Alternating Polarity.

A mild, scalable (kg) metal-free electrochemical decarboxylation of alkyl carboxylic acids to olefins is disclosed. Numerous applications are presented wherein this transformation can simplify alkene synthesis and provide alternative synthetic access to valuable olefins from simple carboxylic acid feedstocks. This robust method relies on alternating polarity to maintain the quality of the electrode surface and local pH, providing a deeper understanding of the Hofer-Moest process with unprecedented chemoselectivity.

Stereocontrolled Radical Thiophosphorylation.

The first practical, fully stereoselective P(V)-radical hydrophosphorylation is presented herein by using simple, limonene-derived reagent systems. A set of reagents have been developed that upon radical initiation react smoothly with olefins and other radical acceptors to generate P-chiral products, which can be further diversified (with conventional 2e- chemistry) to a range of underexplored bioisosteric building blocks. The reactions have a wide scope with excellent chemoselectivity, and the unexpected stereochemical outcome has been supported computationally and experimentally. Initial ADME studies are suggestive of the promising properties of this rarely explored chemical space.

An electroaffinity labelling platform for chemoproteomic-based target identification.

Target identification involves deconvoluting the protein target of a pharmacologically active, small-molecule ligand, a process that is critical for early drug discovery yet technically challenging. Photoaffinity labelling strategies have become the benchmark for small-molecule target deconvolution, but covalent protein capture requires the use of high-energy ultraviolet light, which can complicate downstream target identification. Thus, there is a strong demand for alternative technologies that allow for controlled activation of chemical probes to covalently label their protein target. Here we introduce an electroaffinity labelling platform that leverages the use of a small, redox-active diazetidinone functional group to enable chemoproteomic-based target identification of pharmacophores within live cell environments. The underlying discovery to enable this platform is that the diazetidinone can be electrochemically oxidized to reveal a reactive intermediate useful for covalent modification of proteins. This work demonstrates the electrochemical platform to be a functional tool for drug-target identification.

Overcoming the limitations of Kolbe coupling with waveform-controlled electrosynthesis.

The Kolbe reaction forms carbon-carbon bonds through electrochemical decarboxylative coupling. Despite more than a century of study, the reaction has seen limited applications owing to extremely poor chemoselectivity and reliance on precious metal electrodes. In this work, we present a simple solution to this long-standing challenge: Switching the potential waveform from classical direct current to rapid alternating polarity renders various functional groups compatible and enables the reaction on sustainable carbon-based electrodes (amorphous carbon). This breakthrough enabled access to valuable molecules that range from useful unnatural amino acids to promising polymer building blocks from readily available carboxylic acids, including biomass-derived acids. Preliminary mechanistic studies implicate the role of waveform in modulating the local pH around the electrodes and the crucial role of acetone as an unconventional reaction solvent for Kolbe reaction.

Small Change, Big Impact: Reversal of Diastereoselection in Cuprate Conjugate Additions to α,ß-Unsaturated Lactams and Identification of a Competing Mechanism.

A seemingly minor change to a reactant is shown to cause a change in reaction mechanisms. Conjugate addition of organocopper reagents to bicyclic α,ß-unsaturated lactams derived from pyroglutaminol is determined by the nature of the aminal group. Aminals derived from aldehydes give anti addition; those from ketones give syn addition. Divergence in diastereoselection occurs because the substrates react by different mechanisms, ultimately due to a small but significant difference in pyramidalization of the aminal nitrogen.

Scalable, Chemoselective Nickel Electrocatalytic Sulfinylation of Aryl Halides with SO2.

Simple access to aryl sulfinates from aryl iodides and bromides is reported using an inexpensive Ni-electrocatalytic protocol. The reaction exhibits a broad scope, uses stock solution of simple SO2 as sulfur source, and can be scaled up in batch and recycle flow settings. The limitations of this reaction are clearly shown and put into context by benchmarking with state-of-the-art Pd-based methods.

Ni-electrocatalytic Csp3-Csp3 doubly decarboxylative coupling.

Cross-coupling between two similar or identical functional groups to form a new C-C bond is a powerful tool to rapidly assemble complex molecules from readily available building units, as seen with olefin cross-metathesis or various types of cross-electrophile coupling1,2. The Kolbe electrolysis involves the oxidative electrochemical decarboxylation of alkyl carboxylic acids to their corresponding radical species followed by recombination to generate a new C-C bond3-12. As one of the oldest known Csp3-Csp3 bond-forming reactions, it holds incredible promise for organic synthesis, yet its use has been almost non-existent. From the perspective of synthesis design, this transformation could allow one to agnostically execute syntheses without regard to polarity or neighbouring functionality just by coupling ubiquitous carboxylates13. In practice, this promise is undermined by the strongly oxidative electrolytic protocol used traditionally since the nineteenth century5, thereby severely limiting its scope. Here, we show how a mildly reductive Ni-electrocatalytic system can couple two different carboxylates by means of in situ generated redox-active esters, termed doubly decarboxylative cross-coupling. This operationally simple method can be used to heterocouple primary, secondary and even certain tertiary redox-active esters, thereby opening up a powerful new approach for synthesis. The reaction, which cannot be mimicked using stoichiometric metal reductants or photochemical conditions, tolerates a range of functional groups, is scalable and is used for the synthesis of 32 known compounds, reducing overall step counts by 73%.

Chemoselective (Hetero)Arene Electroreduction Enabled by Rapid Alternating Polarity.

Conventional chemical and even electrochemical Birch-type reductions suffer from a lack of chemoselectivity due to a reliance on alkali metals or harshly reducing conditions. This study reveals that a simpler avenue is available for such reductions by simply altering the waveform of current delivery, namely rapid alternating polarity (rAP). The developed method solves these issues, proceeding in a protic solvent, and can be easily scaled up without any metal additives or stringently anhydrous conditions.

Chemoselective Electrosynthesis Using Rapid Alternating Polarity.

Challenges in the selective manipulation of functional groups (chemoselectivity) in organic synthesis have historically been overcome either by using reagents/catalysts that tunably interact with a substrate or through modification to shield undesired sites of reactivity (protecting groups). Although electrochemistry offers precise redox control to achieve unique chemoselectivity, this approach often becomes challenging in the presence of multiple redox-active functionalities. Historically, electrosynthesis has been performed almost solely by using direct current (DC). In contrast, applying alternating current (AC) has been known to change reaction outcomes considerably on an analytical scale but has rarely been strategically exploited for use in complex preparative organic synthesis. Here we show how a square waveform employed to deliver electric current-rapid alternating polarity (rAP)-enables control over reaction outcomes in the chemoselective reduction of carbonyl compounds, one of the most widely used reaction manifolds. The reactivity observed cannot be recapitulated using DC electrolysis or chemical reagents. The synthetic value brought by this new method for controlling chemoselectivity is vividly demonstrated in the context of classical reactivity problems such as chiral auxiliary removal and cutting-edge medicinal chemistry topics such as the synthesis of PROTACs.

Chemoselective, Scalable Nickel-Electrocatalytic O-Arylation of Alcohols.

The formation of aryl-alkyl ether bonds through cross coupling of alcohols with aryl halides represents a useful strategic departure from classical SN 2 methods. Numerous tactics relying on Pd-, Cu-, and Ni-based catalytic systems have emerged over the past several years. Herein we disclose a Ni-catalyzed electrochemically driven protocol to achieve this useful transformation with a broad substrate scope in an operationally simple way. This electrochemical method does not require strong base, exogenous expensive transition metal catalysts (e.g., Ir, Ru), and can easily be scaled up in either a batch or flow setting. Interestingly, e-etherification exhibits an enhanced substrate scope over the mechanistically related photochemical variant as it tolerates tertiary amine functional groups in the alcohol nucleophile.

N-Ammonium Ylide Mediators for Electrochemical C-H Oxidation.

The site-specific oxidation of strong C(sp3)-H bonds is of uncontested utility in organic synthesis. From simplifying access to metabolites and late-stage diversification of lead compounds to truncating retrosynthetic plans, there is a growing need for new reagents and methods for achieving such a transformation in both academic and industrial circles. One main drawback of current chemical reagents is the lack of diversity with regard to structure and reactivity that prevents a combinatorial approach for rapid screening to be employed. In that regard, directed evolution still holds the greatest promise for achieving complex C-H oxidations in a variety of complex settings. Herein we present a rationally designed platform that provides a step toward this challenge using N-ammonium ylides as electrochemically driven oxidants for site-specific, chemoselective C(sp3)-H oxidation. By taking a first-principles approach guided by computation, these new mediators were identified and rapidly expanded into a library using ubiquitous building blocks and trivial synthesis techniques. The ylide-based approach to C-H oxidation exhibits tunable selectivity that is often exclusive to this class of oxidants and can be applied to real-world problems in the agricultural and pharmaceutical sectors.

A Survival Guide for the "Electro-curious".

The appeal and promise of synthetic organic electrochemistry have been appreciated over the past century. In terms of redox chemistry, which is frequently encountered when forging new bonds, it is difficult to conceive of a more economical way to add or remove electrons than electrochemistry. Indeed, many of the largest industrial synthetic chemical processes are achieved in a practical way using electrons as a reagent. Why then, after so many years of the documented benefits of electrochemistry, is it not more widely embraced by mainstream practitioners? Erroneous perceptions that electrochemistry is a "black box" combined with a lack of intuitive and inexpensive standardized equipment likely contributed to this stagnation in interest within the synthetic organic community. This barrier to entry is magnified by the fact that many redox processes can already be accomplished using simple chemical reagents even if they are less atom-economic. Time has proven that sustainability and economics are not strong enough driving forces for the adoption of electrochemical techniques within the broader community. Indeed, like many synthetic organic chemists that have dabbled in this age-old technique, our first foray into this area was not by choice but rather through sheer necessity. The unique reactivity benefits of this old redox-modulating technique must therefore be highlighted and leveraged in order to draw organic chemists into the field. Enabling new bonds to be forged with higher levels of chemo- and regioselectivity will likely accomplish this goal. In doing so, it is envisioned that widespread adoption of electrochemistry will go beyond supplanting unsustainable reagents in mundane redox reactions to the development of exciting reactivity paradigms that enable heretofore unimagined retrosynthetic pathways. Whereas the rigorous physical organic chemical principles of electroorganic synthesis have been reviewed elsewhere, it is often the case that such summaries leave out the pragmatic aspects of designing, optimizing, and scaling up preparative electrochemical reactions. Taken together, the task of setting up an electrochemical reaction, much less inventing a new one, can be vexing for even seasoned organic chemists. This Account therefore features a unique format that focuses on addressing this exact issue within the context of our own studies. The graphically rich presentation style pinpoints basic concepts, typical challenges, and key insights for those "electro-curious" chemists who seek to rapidly explore the power of electrochemistry in their research.

Hindered dialkyl ether synthesis with electrogenerated carbocations.

Hindered ethers are of high value for various applications; however, they remain an underexplored area of chemical space because they are difficult to synthesize via conventional reactions1,2. Such motifs are highly coveted in medicinal chemistry, because extensive substitution about the ether bond prevents unwanted metabolic processes that can lead to rapid degradation in vivo. Here we report a simple route towards the synthesis of hindered ethers, in which electrochemical oxidation is used to liberate high-energy carbocations from simple carboxylic acids. These reactive carbocation intermediates, which are generated with low electrochemical potentials, capture an alcohol donor under non-acidic conditions; this enables the formation of a range of ethers (more than 80 have been prepared here) that would otherwise be difficult to access. The carbocations can also be intercepted by simple nucleophiles, leading to the formation of hindered alcohols and even alkyl fluorides. This method was evaluated for its ability to circumvent the synthetic bottlenecks encountered in the preparation of 12 chemical scaffolds, leading to higher yields of the required products, in addition to substantial reductions in the number of steps and the amount of labour required to prepare them. The use of molecular probes and the results of kinetic studies support the proposed mechanism and the role of additives under the conditions examined. The reaction manifold that we report here demonstrates the power of electrochemistry to access highly reactive intermediates under mild conditions and, in turn, the substantial improvements in efficiency that can be achieved with these otherwise-inaccessible intermediates.

Electrochemically Driven, Ni-Catalyzed Aryl Amination: Scope, Mechanism, and Applications.

C-N cross-coupling is one of the most valuable and widespread transformations in organic synthesis. Largely dominated by Pd- and Cu-based catalytic systems, it has proven to be a staple transformation for those in both academia and industry. The current study presents the development and mechanistic understanding of an electrochemically driven, Ni-catalyzed method for achieving this reaction of high strategic importance. Through a series of electrochemical, computational, kinetic, and empirical experiments, the key mechanistic features of this reaction have been unraveled, leading to a second generation set of conditions that is applicable to a broad range of aryl halides and amine nucleophiles including complex examples on oligopeptides, medicinally relevant heterocycles, natural products, and sugars. Full disclosure of the current limitations and procedures for both batch and flow scale-ups (100 g) are also described.

Scalable and safe synthetic organic electroreduction inspired by Li-ion battery chemistry.

Reductive electrosynthesis has faced long-standing challenges in applications to complex organic substrates at scale. Here, we show how decades of research in lithium-ion battery materials, electrolytes, and additives can serve as an inspiration for achieving practically scalable reductive electrosynthetic conditions for the Birch reduction. Specifically, we demonstrate that using a sacrificial anode material (magnesium or aluminum), combined with a cheap, nontoxic, and water-soluble proton source (dimethylurea), and an overcharge protectant inspired by battery technology [tris(pyrrolidino)phosphoramide] can allow for multigram-scale synthesis of pharmaceutically relevant building blocks. We show how these conditions have a very high level of functional-group tolerance relative to classical electrochemical and chemical dissolving-metal reductions. Finally, we demonstrate that the same electrochemical conditions can be applied to other dissolving metal-type reductive transformations, including McMurry couplings, reductive ketone deoxygenations, and epoxide openings.