An Automated Electrochemical Flow Platform to Accelerate Library Synthesis and Reaction Optimization.

Automated batch and flow setups are well-established for high throughput experimentation in both thermal chemistry and photochemistry. However, the development of automated electrochemical platforms is hindered by cell miniaturization challenges in batch and difficulties in designing effective single-pass flow systems. In order to address these issues, we have designed and implemented a new, slug-based automated electrochemical flow platform.

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.

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.

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.

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 AgNO, proceeding at room temperature with a simple commercial potentiostat.

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(sp)-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(sp)-H bonds, only few examples have been reported for the direct amination of aliphatic C(sp)-H bonds.

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.

β-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 β-zeolite as catalyst in a flow-through reactor was carried out. Birch, spruce, and walnut shells were compared as lignocellulosic feedstocks. β-Zeolite acted as a bifunctional catalyst, preventing lignin repolymerization due to its size-selective properties and also cleaving β-O-4 lignin intralinkages while stabilizing reactive intermediates.

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

Photocatalytic hydrogen atom transfer is a very powerful strategy for the regioselective C(sp )-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(sp )-H heteroarylation. The present methodology demonstrates a high functional group tolerance (40 examples) and is scalable when using continuous-flow reactor technology.

Optimization of a Decatungstate-Catalyzed C(sp)-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(sp)-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.

C(sp)-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(sp)-H bond cleavage, barring potential applications in synthetic organic chemistry. Here, we report a general and mild strategy to activate C(sp)-H bonds in methane, ethane, propane, and isobutane through hydrogen atom transfer using inexpensive decatungstate as photocatalyst at room temperature.

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.

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.

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.

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.

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

The biocatalytic preparation of -hex-2-enal from -hex-2-enol using a novel aryl alcohol oxidase from (AAOx) is reported. As O-dependent enzyme AAOx-dependent reactions are generally plagued by the poor solubility of O 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) and turnover numbers (more than 300000) pointing towards preparative usefulness of the proposed reaction scheme.

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

A mild and selective C(sp )-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).

Design and application of a modular and scalable electrochemical flow microreactor.

Electrochemistry constitutes a mild, green and versatile activation method of organic molecules. Despite these innate advantages, its widespread use in organic chemistry has been hampered due to technical limitations, such as mass and heat transfer limitations which restraints the scalability of electrochemical methods. Herein, we describe an undivided-cell electrochemical flow reactor with a flexible reactor volume.

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.