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.

Electroreductive Synthesis of Nickel(0) Complexes.

Over the last fifty years, the use of nickel catalysts for facilitating organic transformations has skyrocketed. Nickel(0) sources act as useful precatalysts because they can enter a catalytic cycle through ligand exchange, without needing to undergo additional elementary steps. However, most Ni(0) precatalysts are synthesized with stoichiometric aluminum-hydride reductants, pyrophoric reagents that are not atom-economical and must be used at cryogenic temperatures. Here, we demonstrate that Ni(II) salts can be reduced on preparative scale using electrolysis to yield a variety of Ni(0) and Ni(II) complexes that are widely used as precatalysts in organic synthesis, including bis(1,5-cyclooctadiene)nickel(0) [Ni(COD)2 ]. This method overcomes the reproducibility issues of previously reported methods by standardizing the procedure, such that it can be performed anywhere in a robust manner. It can be transitioned to large scale through an electrochemical recirculating flow process and extended to an in situ reduction protocol to generate catalytic amounts of Ni(0) for organic transformations. We anticipate that this work will accelerate adoption of preparative electrochemistry for the synthesis of low-valent organometallic complexes in academia and industry.

Nickel-Electrocatalytic Decarboxylative Arylation to Access Quaternary Centers.

There is a pressing need, particularly in the field of drug discovery, for general methods that will enable direct coupling of tertiary alkyl fragments to (hetero)aryl halides. Herein a uniquely powerful and simple set of conditions for achieving this transformation with unparalleled generality and chemoselectivity is disclosed. This new protocol is placed in context with other recently reported methods, applied to simplify the routes of known bioactive building blocks molecules, and scaled up in both batch and flow. The role of pyridine additive as well as the mechanism of this reaction are interrogated through Cyclic Voltammetry studies, titration experiments, control reactions with Ni(0) and Ni(II)-complexes, and ligand optimization data. Those studies indicate that the formation of a BINAPNi(0) is minimized and the formation of an active pyridine-stabilized Ni(I) species is sustained during the reaction. Our preliminary mechanistic studies ruled out the involvement of Ni(0) species in this electrochemical cross-coupling, which is mediated by Ni(I) species via a Ni(I)-Ni(II)-Ni(III)-Ni(I) catalytic cycle.

Overcoming Limitations in Decarboxylative Arylation via Ag-Ni Electrocatalysis.

A useful protocol for achieving decarboxylative cross-coupling (DCC) of redox-active esters (RAE, isolated or generated in situ) and halo(hetero)arenes is reported. This pragmatically focused study employs a unique Ag-Ni electrocatalytic platform to overcome numerous limitations that have plagued this strategically powerful transformation. In its optimized form, coupling partners can be combined in a surprisingly simple way: open to the air, using technical-grade solvents, an inexpensive ligand and Ni source, and substoichiometric AgNO3, proceeding at room temperature with a simple commercial potentiostat. Most importantly, all of the results are placed into context by benchmarking with state-of-the-art methods. Applications are presented that simplify synthesis and rapidly enable access to challenging chemical space. Finally, adaptation to multiple scale regimes, ranging from parallel milligram-based synthesis to decagram recirculating flow is presented.

Practical and Regioselective Synthesis of C-4-Alkylated Pyridines.

The direct position-selective C-4 alkylation of pyridines has been a long-standing challenge in heterocyclic chemistry, particularly from pyridine itself. Historically this has been addressed using prefunctionalized materials to avoid overalkylation and mixtures of regioisomers. This study reports the invention of a simple maleate-derived blocking group for pyridines that enables exquisite control for Minisci-type decarboxylative alkylation at C-4 that allows for inexpensive access to these valuable building blocks. The method is employed on a variety of different pyridines and carboxylic acid alkyl donors, is operationally simple and scalable, and is applied to access known structures in a rapid and inexpensive fashion. Finally, this work points to an interesting strategic departure for the use of Minisci chemistry at the earliest possible stage (native pyridine) rather than current dogma that almost exclusively employs Minisci chemistry as a late-stage functionalization technique.

Decatungstate-Mediated C(sp3 )-H Heteroarylation via Radical-Polar Crossover in Batch and Flow.

Photocatalytic hydrogen atom transfer is a very powerful strategy for the regioselective C(sp3 )-H functionalization of organic molecules. Herein, we report on the unprecedented combination of decatungstate hydrogen atom transfer photocatalysis with the oxidative radical-polar crossover concept to access the direct net-oxidative C(sp3 )-H heteroarylation. The present methodology demonstrates a high functional group tolerance (40 examples) and is scalable when using continuous-flow reactor technology. The developed protocol is also amenable to the late-stage functionalization of biologically relevant molecules such as stanozolol, (-)-ambroxide, podophyllotoxin, and dideoxyribose.

Silyl Radical-Mediated Activation of Sulfamoyl Chlorides Enables Direct Access to Aliphatic Sulfonamides from Alkenes.

Single electron reduction is more challenging for sulfamoyl chlorides than sulfonyl chlorides. However, sulfamoyl and sulfonyl chlorides can be easily activated by Cl-atom abstraction by a silyl radical with similar rates. This latter mode of activation was therefore selected to access aliphatic sulfonamides, applying a single-step hydrosulfamoylation using inexpensive olefins, tris(trimethylsilyl)silane, and photocatalyst Eosin Y. This late-stage functionalization protocol generates molecules as complex as sulfonamide-containing cyclobutyl-spirooxindoles for direct use in medicinal chemistry.

The Fundamentals Behind the Use of Flow Reactors in Electrochemistry.

In the past decade, research into continuous-flow chemistry has gained a lot of traction among researchers in both academia and industry. Especially, microreactors have received a plethora of attention due to the increased mass and heat transfer characteristics, the possibility to increase process safety, and the potential to implement automation protocols and process analytical technology. Taking advantage of these aspects, chemists and chemical engineers have capitalized on expanding the chemical space available to synthetic organic chemists using this technology. Electrochemistry has recently witnessed a renaissance in research interests as it provides chemists unique and tunable synthetic opportunities to carry out redox chemistry using electrons as traceless reagents, thus effectively avoiding the use of hazardous and toxic reductants and oxidants. The popularity of electrochemistry stems also from the potential to harvest sustainable electricity, derived from solar and wind energy. Hence, the electrification of the chemical industry offers an opportunity to locally produce commodity chemicals, effectively reducing inefficiencies with regard to transportation and storage of hazardous chemicals. The combination of flow technology and electrochemistry provides practitioners with great control over the reaction conditions, effectively improving the reproducibility of electrochemistry. However, carrying out electrochemical reactions in flow is more complicated than just pumping the chemicals through a narrow-gap electrolytic cell. Understanding the engineering principles behind the observations can help researchers to exploit the full potential of the technology. Thus, the prime objective of this Account is to provide readers with an overview of the underlying engineering aspects which are associated with continuous-flow electrochemistry. This includes a discussion of relevant mass and heat transport phenomena encountered in electrochemical flow reactors. Next, we discuss the possibility to integrate several reaction steps in a single streamlined process and the potential to carry out challenging multiphase electrochemical transformations in flow. Due to the high control over mass and heat transfer, electrochemical reactions can be carried out with great precision and reproducibility which provide opportunities to enhance and tune the reaction selectivity. Finally, we detail on the scale-up potential of flow electrochemistry and the importance of small interelectrode gaps on pilot and industrial-scale electrochemical processes. Each principle has been illustrated with a relevant organic synthetic example. In general, we have aimed to describe the underlying engineering principles in simple words and with a minimum of equations to attract and engage readers from both a synthetic organic chemistry and a chemical engineering background. Hence, we anticipate that this Account will serve as a useful guide through the fascinating world of flow electrochemistry.

Sulfonamide Synthesis through Electrochemical Oxidative Coupling of Amines and Thiols.

Sulfonamides are key motifs in pharmaceuticals and agrochemicals, spurring the continuous development of novel and efficient synthetic methods to access these functional groups. Herein, we report an environmentally benign electrochemical method which enables the oxidative coupling between thiols and amines, two readily available and inexpensive commodity chemicals. The transformation is completely driven by electricity, does not require any sacrificial reagent or additional catalysts and can be carried out in only 5 min. Hydrogen is formed as a benign byproduct at the counter electrode. Owing to the mild reaction conditions, the reaction displays a broad substrate scope and functional group compatibility.

Sulfonyl Fluoride Synthesis through Electrochemical Oxidative Coupling of Thiols and Potassium Fluoride.

Sulfonyl fluorides are valuable synthetic motifs for a variety of applications, among which sulfur(VI) fluoride exchange-based "click chemistry" is currently the most prominent. Consequently, the development of novel and efficient synthetic methods to access these functional groups is of great interest. Herein, we report a mild and environmentally benign electrochemical approach to prepare sulfonyl fluorides using thiols or disulfides, as widely available starting materials, in combination with KF, as an inexpensive, abundant and safe fluoride source. No additional oxidants nor additional catalysts are required and, due to mild reaction conditions, the reaction displays a broad substrate scope, including a variety of alkyl, benzyl, aryl and heteroaryl thiols or disulfides.

Selective C(sp3 )-H Aerobic Oxidation Enabled by Decatungstate Photocatalysis in Flow.

A mild and selective C(sp3 )-H aerobic oxidation enabled by decatungstate photocatalysis has been developed. The reaction can be significantly improved in a microflow reactor enabling the safe use of oxygen and enhanced irradiation of the reaction mixture. Our method allows for the oxidation of both activated and unactivated C-H bonds (30 examples). The ability to selectively oxidize natural scaffolds, such as (-)-ambroxide, pregnenolone acetate, (+)-sclareolide, and artemisinin, exemplifies the utility of this new method.

Biocatalytic synthesis of the Green Note trans-2-hexenal in a continuous-flow microreactor.

The biocatalytic preparation of trans-hex-2-enal from trans-hex-2-enol using a novel aryl alcohol oxidase from Pleurotus eryngii (PeAAOx) is reported. As O2-dependent enzyme PeAAOx-dependent reactions are generally plagued by the poor solubility of O2 in aqueous media and mass transfer limitations resulting in poor reaction rates. These limitations were efficiently overcome by conducting the reaction in a flow-reactor setup reaching unpreceded catalytic activities for the enzyme in terms of turnover frequency (up to 38 s-1) and turnover numbers (more than 300000) pointing towards preparative usefulness of the proposed reaction scheme.

Flow Synthesis of Diaryliodonium Triflates.

A safe and scalable synthesis of diaryliodonium triflates was achieved using a practical continuous-flow design. A wide array of electron-rich to electron-deficient arenes could readily be transformed to their respective diaryliodonium salts on a gram scale, with residence times varying from 2 to 60 s (44 examples).

A Modular Flow Design for the meta-Selective C-H Arylation of Anilines.

Described herein is an effective and practical modular flow design for the meta-selective C-H arylation of anilines. The design consists of four continuous-flow modules (i.e., diaryliodonium salt synthesis, meta-selective C-H arylation, inline copper extraction, and aniline deprotection) which can be operated either individually or consecutively to provide direct access to meta-arylated anilines. With a total residence time of 1 hour, the desired product could be obtained in high yield and excellent purity without the need for column chromatography, and the residual copper content meets the standards for parenterally administered pharmaceutical substances.

Synthesis of Unnatural Amino Acids via Ni/Ag Electrocatalytic Cross-Coupling.

A simple protocol is outlined herein for rapid access to enantiopure unnatural amino acids (UAAs) from trivial glutamate and aspartate precursors. The method relies on Ag/Ni-electrocatalytic decarboxylative coupling and can be rapidly conducted in parallel (24 reactions at a time) to ascertain coupling viability followed by scale-up for the generation of useful quantities of UAAs for exploratory studies.

Decarboxylative Cross-Coupling: A Radical Tool in Medicinal Chemistry.

Carboxylic acids, the most versatile and ubiquitous diversity input used in medicinal chemistry for canonical polar bond constructions such as amide synthesis, can now be employed in a fundamentally different category of reaction to make C-C bonds by harnessing the power of radicals. This outlook serves as a user-guide to aid practitioners in both the design of syntheses that leverage the simplifying power of this disconnection and the precise tactics that can be employed to enable them. Taken together, this emerging area holds the potential to rapidly accelerate access to chemical space of value to modern medicinal chemistry.

Accelerated and Scalable C(sp3)-H Amination via Decatungstate Photocatalysis Using a Flow Photoreactor Equipped with High-Intensity LEDs.

Carbon-nitrogen bonds are ubiquitous in biologically active compounds, prompting synthetic chemists to design various methodologies for their preparation. Arguably, the ideal synthetic approach is to be able to directly convert omnipresent C-H bonds in organic molecules, enabling even late-stage functionalization of complex organic scaffolds. While this approach has been thoroughly investigated for C(sp2)-H bonds, only few examples have been reported for the direct amination of aliphatic C(sp3)-H bonds. Herein, we report the use of a newly developed flow photoreactor equipped with high intensity chip-on-board LED technology (144 W optical power) to trigger the regioselective and scalable C(sp3)-H amination via decatungstate photocatalysis. This high-intensity reactor platform enables simultaneously fast results gathering and scalability in a single device, thus bridging the gap between academic discovery (mmol scale) and industrial production (>2 kg/day productivity). The photocatalytic transformation is amenable to the conversion of both activated and nonactivated hydrocarbons, leading to protected hydrazine products by reaction with azodicarboxylates. We further validated the robustness of our manifold by designing telescoped flow approaches for the synthesis of pyrazoles, phthalazinones and free amines.

ß-Zeolite-Assisted Lignin-First Fractionation in a Flow-Through Reactor*.

In the present work, a hydrogen-free one-step catalytic fractionation of woody biomass using commercial ß-zeolite as catalyst in a flow-through reactor was carried out. Birch, spruce, and walnut shells were compared as lignocellulosic feedstocks. ß-Zeolite acted as a bifunctional catalyst, preventing lignin repolymerization due to its size-selective properties and also cleaving ß-O-4 lignin intralinkages while stabilizing reactive intermediates. A rate-limiting step analysis using different reactor configurations revealed a mixed regime where the rates of both solvolytic delignification and zeolite-catalyzed depolymerization and dehydration affected the net rate of aromatic monomer production. Oxalic acid co-feeding was found to enhance monomer production at moderate concentrations by improving solvolysis, while it caused structural changes to the zeolite and led to lower monomer yields at higher concentrations. Zeolite stability was assessed through catalyst recycling and characterization. Main catalyst deactivation mechanisms were found to be coking and leaching, leading to widening of the pores and decrease of zeolite acidity, respectively.

Optimization of a Decatungstate-Catalyzed C(sp3)-H Alkylation Using a Continuous Oscillatory Millistructured Photoreactor.

Tetrabutylammonium decatungstate (TBADT) has emerged as an efficient and versatile photocatalyst for hydrogen atom transfer (HAT) processes that enables the cleavage of both activated and unactivated aliphatic C-H bonds. Using a recently developed oscillatory millistructured continuous-flow photoreactor, investigations of a decatungstate-catalyzed C(sp3)-H alkylation protocol were carried out, and the results are presented here. The performance of the reactor was evaluated in correlation to several chemical and process parameters, including residence time, light intensity, catalyst loading, and substrate/reagent concentration. In comparison with previously reported batch and flow protocols, conditions were found that led to considerably higher productivity, achieving a throughput up to 36.7 mmol/h with a residence time of only 7.5 min.

C(sp3)-H functionalizations of light hydrocarbons using decatungstate photocatalysis in flow.

Direct activation of gaseous hydrocarbons remains a major challenge for the chemistry community. Because of the intrinsic inertness of these compounds, harsh reaction conditions are typically required to enable C(sp3)-H bond cleavage, barring potential applications in synthetic organic chemistry. Here, we report a general and mild strategy to activate C(sp3)-H bonds in methane, ethane, propane, and isobutane through hydrogen atom transfer using inexpensive decatungstate as photocatalyst at room temperature. The corresponding carbon-centered radicals can be effectively trapped by a variety of Michael acceptors, leading to the corresponding hydroalkylated adducts in good isolated yields and high selectivity (38 examples).