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.

Electrifying Friedel-Crafts Intramolecular Alkylation toward 1,1-Disubstituted Tetrahydronaphthalenes.

In this work, we successfully employed electrochemical conditions to promote a Hofer-Moest, intramolecular Friedel-Crafts alkylation sequence. The reaction proceeds under mild conditions, employing carboxylic acids as starting materials. Notably, the electrochemical process performed in batch was adapted to a continuous flow electrolysis apparatus to provide a significant improvement.

Aniline Derivatives from Lignin under Mild Conditions Enabled by Electrochemistry.

The development of environmentally friendly methods for the valorization of important phenolic platform chemicals originating directly from lignin-first depolymerization into value-added N-chemicals, such as aniline derivatives, is of high industrial interest. In this work, we tackle this challenging transformation by the judicious combination of electrochemical conversion and chemical functionalization steps. In the first step, lignin-derived para-substituted guaiacols and syringols undergo an atom-efficient, room-temperature anodic oxidation using methanol both as solvent and reagent towards the formation of the corresponding cyclohexadienone derivatives, which are subsequently converted to synthetically challenging ortho-methoxy substituted anilines by reaction with ethyl glycinate hydrochloride under mild conditions.

Metal-Free Electrochemical Reduction of Disulfides in an Undivided Cell under Mass Transfer Control.

Electroorganic synthesis is generally considered to be a green alternative to conventional redox reactions. Electrochemical reductions, however, are less advantageous in terms of sustainability, as sacrificial metal anodes are often employed. Divided cell operation avoids contact of the reduction products with the anode and allows for convenient solvent oxidation, enabling metal free greener electrochemical reductions.

Electrochemical Nickel-Catalyzed C(sp)-C(sp) Cross-Coupling of Alkyl Halides with Alkyl Tosylates.

Formation of new C(sp)-C(sp) bonds is a powerful synthetic tool to increase molecular diversity, which is highly sought after in medicinal chemistry. Traditional generation of carbon nucleophiles and more modern cross-electrophile-coupling methods typically lack sufficient selectivity when cross-coupling of analogous C(sp)-containing reactants is attempted. Herein, we present a nickel-catalyzed, electrochemically driven method for the coupling of alkyl bromides with alkyl tosylates.

Synthesis of active pharmaceutical ingredients using electrochemical methods: keys to improve sustainability.

Organic electrochemistry is receiving renewed attention as a green and cost-efficient synthetic technology. Electrochemical methods promote redox transformations by electron exchange between electrodes and species in solution, thus avoiding the use of stoichiometric amounts of oxidizing or reducing agents. The rapid development of electroorganic synthesis over the past decades has enabled the preparation of molecules of increasing complexity.

Electrochemical α-Arylation of Ketones via Anodic Oxidation of In Situ Generated Silyl Enol Ethers.

An electrochemical procedure for the α-arylation of ketones has been developed. The method is based on the generation and one-pot anodic oxidation of silyl enol ethers in the presence of the arene. This strategy avoids isolation of the silyl enol intermediate and the utilization of external supporting electrolytes.

Electrochemically Enabled One-Pot Multistep Synthesis of C19 Androgen Steroids.

The synthesis of many valuable C19 androgens can be accomplished by removal of the C17 side chain from more abundant corticosteroids, followed by further derivatization of the resulting 17-keto derivative. Conventional chemical reagents pose significant drawbacks for this synthetic strategy, as large amounts of waste are generated, and quenching of the reaction mixture and purification of the 17-ketosteroid intermediate are typically required. Herein, we present mild, safe, and sustainable electrochemical strategies for the preparation of C19 steroids.

Advanced Real-Time Process Analytics for Multistep Synthesis in Continuous Flow*.

In multistep continuous flow chemistry, studying complex reaction mixtures in real time is a significant challenge, but provides an opportunity to enhance reaction understanding and control. We report the integration of four complementary process analytical technology tools (NMR, UV/Vis, IR and UHPLC) in the multistep synthesis of an active pharmaceutical ingredient, mesalazine. This synthetic route exploits flow processing for nitration, high temperature hydrolysis and hydrogenation reactions, as well as three inline separations.

Flow Technology for Telescoped Generation, Lithiation and Electrophilic (C ) Functionalization of Highly Strained 1-Azabicyclo[1.1.0]butanes.

Strained compounds are privileged moieties in modern synthesis. In this context, 1-azabicyclo[1.1.

Organomagnesium Based Flash Chemistry: Continuous Flow Generation and Utilization of Halomethylmagnesium Intermediates.

The generation of highly unstable chloromethylmagnesium chloride in a continuous flow reactor and its reaction with aldehydes and ketones is reported. With this strategy, chlorohydrins and epoxides were synthesized within a total residence time of only 2.6 s.

Electrochemical -Demethylation of 14-Hydroxy Morphinans: Sustainable Access to Opioid Antagonists.

The most challenging step in the preparation of many opioid antagonists is the selective -demethylation of a 14-hydroxymorphinan precursor. This process is carried out on a large scale using stoichiometric amounts of hazardous chemicals like cyanogen bromide or chloroformates. We have developed a mild reagent- and catalyst-free procedure for the -demethylation step based on the anodic oxidation of the tertiary amine.

Organophotocatalytic N-Demethylation of Oxycodone Using Molecular Oxygen.

N-Demethylation of oxycodone is one of the key steps in the synthesis of important opioid antagonists like naloxone or analgesics like nalbuphine. The reaction is typically carried out using stoichiometric amounts of toxic and corrosive reagents. Herein, we present a green and scalable organophotocatalytic procedure that accomplishes the N-demethylation step using molecular oxygen as the terminal oxidant and an organic dye (rose bengal) as an effective photocatalyst.

Continuous Flow Synthesis of Terminal Epoxides from Ketones Using in Situ Generated Bromomethyl Lithium.

A scalable procedure for the direct preparation of epoxides from ketones has been developed. The method is based on the carefully controlled generation of (bromomethyl)lithium (LiCHBr) from inexpensive CHBr and MeLi in a continuous flow reactor. The reaction has shown excellent selectivity for a variety of substrates, including α-chloroketones, which typically fail under classic Corey-Chaykovsky conditions.

Cathodic C-H Trifluoromethylation of Arenes and Heteroarenes Enabled by an in Situ-Generated Triflyltriethylammonium Complex.

While several trifluoromethylation reactions involving the electrochemical generation of CF radicals via anodic oxidation have been reported, the alternative cathodic, reductive radical generation has remained elusive. Herein, the first cathodic trifluoromethylation of arenes and heteroarenes is reported. The method is based on the electrochemical reduction of an unstable triflyltriethylammonium complex generated in situ from inexpensive triflyl chloride and triethylamine, which produces CF radicals that are trapped by the arenes on the cathode surface.

Visible Light-Promoted Beckmann Rearrangements: Separating Sequential Photochemical and Thermal Phenomena in a Continuous Flow Reactor.

The Beckmann rearrangement of oximes to amides typically requires strong acids or highly reactive, hazardous electrophiles and/or elevated temperatures to proceed. A very attractive alternative is the in situ generation of Vilsmeier-Haack reagents, by means of photoredox catalysis, as promoters for the thermal Beckmann rearrangement. Investigation of the reaction parameters for this light-induced method using a one-pot strategy has shown that the reaction is limited by the different temperatures required for each of the two sequential steps.

On the reactivity of anodically generated trifluoromethyl radicals toward aryl alkynes in organic/aqueous media.

An in-depth study of the reaction of electrochemically generated trifluoromethyl radicals with aryl alkynes in the presence of water is presented. The radicals are readily generated by anodic oxidation of sodium triflinate, an inexpensive and readily available CF3 source, with concomitant reduction of water. Two competitive pathways, i.

Continuous-flow protocol for the synthesis of enantiomerically pure intermediates of anti epilepsy and anti tuberculosis active pharmaceutical ingredients.

Continuous-flow production of chiral intermediates plays an important role in the development of building blocks for Active Pharmaceutical Ingredients (APIs), being α-amino acids and their derivatives widely applied as building blocks. In this work we developed two different strategies for the synthesis of intermediates used on the synthesis of levetiracetam/brivaracetam and ethambutol. The results obtained show that methionine methyl ester can be continuously converted to the desired ethambutol intermediate by RANEY® Nickel dessulfurization/reduction strategy whereas levetiracetam/brivaracetam intermediates could be synthesized by both RANEY® Nickel (without H2) and Pd/C-H2 approach or by photochemical desulfurization.

Catalyst-Free Oxytrifluoromethylation of Alkenes through Paired Electrolysis in Organic-Aqueous Media.

A mild, catalyst-free electrochemical oxytrifluoromethylation of alkenes has been developed. The procedure is based on the paired electrolysis of sodium triflinate and water in an undivided cell. Anodic oxidation of the triflinate anion generates trifluoromethyl radicals that react with the alkene.

Continuous multistep synthesis of 2-(azidomethyl)oxazoles.

An efficient three-step protocol was developed to produce 2-(azidomethyl)oxazoles from vinyl azides in a continuous-flow process. The general synthetic strategy involves a thermolysis of vinyl azides to generate azirines, which react with bromoacetyl bromide to provide 2-(bromomethyl)oxazoles. The latter compounds are versatile building blocks for nucleophilic displacement reactions as demonstrated by their subsequent treatment with NaN in aqueous medium to give azido oxazoles in good selectivity.

Safe generation and use of bromine azide under continuous flow conditions--selective 1,2-bromoazidation of olefins.

Bromine azide (BrN3), a useful but extremely toxic and explosive reagent for the preparation of vicinal 1,2-bromine azide compounds, was safely generated and reacted in situ with alkenes in a continuous flow photoreactor. BrN3 was generated by a novel procedure from NaBr and NaN3 in water, and efficiently extracted into an organic phase containing the alkene thus avoiding decomposition. The resulting addition products have been used for the preparation of several useful building blocks.

Diazo Strategy for the Synthesis of Pyridazines: Pivotal Impact of the Configuration of the Diazo Precursor on the Process.

Phosphazenes of vinyldiazocarbonyl compounds having cis stereochemistry of the functional groups on the vinyl bond readily produce pyridazines by a diaza-Wittig process, whereas their counterparts with trans configuration remain intact under similar reaction conditions. Upon UV irradiation trans-phosphazenes furnish pyridazines through a tandem trans-to-cis isomerization followed by intramolecular cyclization. At elevated temperatures trans-(triphenyl)phosphazenes dissociate to give the initial vinyldiazo compounds, which produce pyrazoles in high yields.

Light-Induced C-H Arylation of (Hetero)arenes by In Situ Generated Diazo Anhydrides.

Diazo anhydrides (Ar-N=N-O-N=N-Ar) have been known since 1896 but have rarely been used in synthesis. This communication describes the development of a photochemical catalyst-free C-H arylation methodology for the preparation of bi(hetero)aryls by the one-pot reaction of anilines with tert-butyl nitrite and (hetero)arenes under neutral conditions. The key step in this procedure is the in situ formation and subsequent photochemical (>300 nm) homolytic cleavage of a transient diazo anhydride intermediate.

Continuous-flow technology—a tool for the safe manufacturing of active pharmaceutical ingredients.

In the past few years, continuous-flow reactors with channel dimensions in the micro- or millimeter region have found widespread application in organic synthesis. The characteristic properties of these reactors are their exceptionally fast heat and mass transfer. In microstructured devices of this type, virtually instantaneous mixing can be achieved for all but the fastest reactions.

Covalent adduct formation between the plasmalogen-derived modification product 2-chlorohexadecanal and phloretin.

Hypochlorous acid added as reagent or generated by the myeloperoxidase (MPO)-H2O2-Cl(-) system oxidatively modifies brain ether-phospholipids (plasmalogens). This reaction generates a sn2-acyl-lysophospholipid and chlorinated fatty aldehydes. 2-Chlorohexadecanal (2-ClHDA), a prototypic member of chlorinated long-chain fatty aldehydes, has potent neurotoxic potential by inflicting blood-brain barrier (BBB) damage.