Pietro

Electrochemical dehydration of carboxamides to nitriles is achieved using thiocyanate-mediated activation, avoiding stoichiometric reagents. In an undivided cell at ambient conditions, 18 aromatic and aliphatic substrates give good-to-excellent yields (up to 84%) with functional-group tolerance. Cyclic voltammetry supports an EC-type-mediated oxidation. The method is scalable with minimal loss in efficiency, offering a mild and sustainable route to nitriles.

An efficient electrochemical strategy for the dehydration of carboxamides to their corresponding nitriles is reported. This method replaces conventional dehydrating reagents with a thiocyanate-mediated electrochemical activation, providing a safer, milder, and more sustainable alternative. Under optimized conditions in an undivided cell, 18 examples of aromatic and aliphatic carboxamides were smoothly converted to the corresponding nitriles at ambient temperature in good-to-excellent yields (up to 84%). Hexafluoroisopropanol proved to be essential for reaction efficiency, while tetrabutylammonium thiocyanate acted as a redox mediator, as confirmed by cyclic voltammetry studies, which revealed an EC-type-mediated oxidation process. The method demonstrates broad functional-group tolerance, including halogenated, methoxylated, and sterically hindered substrates, as well as complex molecules derived from pharmaceuticals and natural products. Importantly, the protocol was successfully scaled up eightfold with minimal loss in yield, illustrating its robustness and practical applicability. Mechanistically, anodic oxidation of thiocyanate generates highly reactive species that activate the amide functionality, leading to nitrile formation via an oxidative dehydration pathway, while hydrogen evolution occurs at the cathode. This work expands the synthetic utility of electrochemical dehydration reactions and offers a valuable, environmentally responsible route to nitrile-containing compounds of broad relevance for pharmaceuticals, agrochemicals, and materials science.

A sustainable synthesis of bempedoic acid is achieved using electrochemical hydroxylative decarboxylation as the key step. Starting from Meldrum's acid, mild metal-free alkylation, hydrolysis, and decarboxylation provide the key precursor, which is electrochemically converted to the alcohol intermediate and then hydrolyzed to the final product, avoiding hazardous reagents and disadvantageous conditions used in previous routes.

Bempedoic acid is a clinically approved lipid-lowering drug that inhibits adenosine triphosphate-citrate lyase, offering an alternative to statins for patients with statin intolerance or inadequate low-density lipoprotein cholesterol reduction. However, existing synthetic routes rely on hazardous reagents and complex multistep procedures. Here, we report a sustainable and efficient synthesis of bempedoic acid based on electrochemical hydroxylative decarboxylation as the key transformation. Starting from Meldrum's acid, an optimized sequence of alkylation, hydrolysis, and decarboxylation affords the carboxylic acid precursor under mild conditions and in the absence of metal-containing reagents. Subsequent electrochemical oxidation in dimethylformamide/hexafluoroisopropanol, using graphite and stainless-steel electrodes, enables direct conversion of the acid to the corresponding alcohol intermediate in up to 60% yield, followed by base-promoted hydrolysis to yield bempedoic acid. Compared with previously reported TosMIC- and malonate-based routes, this approach eliminates the use of toxic and pyrophoric reagents such as NaH and Pd/C, while improving atom economy and scalability. The method described herewith represents a robust and practical synthetic strategy for the synthesis of bempedoic acid and highlights the potential of electrochemical methodologies for sustainable pharmaceutical manufacturing.

We report a safe and scalable flow-based strategy for the on-demand generation of NCF₂R anions using a packed-bed microreactor containing CsF. This protocol enables the late-stage installation of the CF₂ group under mild conditions leveraging three points of diversification, allowing efficient access to a broad range of NCF₂R scaffolds.

Abstract

The α,α-difluoromethylene amine (NCF₂R) motif represents a useful functionality in medicinal chemistry, yet practical and modular methods to access this class of compounds are lacking. Here, we report a safe and scalable flow-based strategy for the on-demand generation of NCF₂R anions using a packed-bed microreactor containing caesium fluoride. This protocol enables the late-stage installation of the CF₂ group under mild conditions, avoiding the use of hazardous fluorinating agents and minimizing fluorinated waste. This fully modular strategy features three points of diversification (carboxylic acid, sulfonamide, and electrophile), allowing efficient access to a broad range of α,α-difluoromethylene amines. The method tolerates a variety of functional groups, supports late-stage functionalization of pharmaceutically relevant scaffolds, and is compatible with downstream cross-coupling reactions, demonstrating the robustness of the reaction protocol. This work provides a versatile platform for the streamlined incorporation of NCF₂ motifs, expanding the range of synthetic strategies available in medicinal and fluorine chemistry.

Electrochemical dehydration reactions are a fascinating and underexplored field of research in the domain of electrosynthesis. They offer a sustainable alternative to hazardous and harsh dehydration reagents. In this review, the recent progress that has been made in this emerging research topic is surveyed.

Electrochemical dehydration reaction is a fascinating and underexplored field of research, which has started to attract significant attention in recent years. Dehydration reactions are characterized by the formal removal of water in the course of the transformation, and they are among the most fundamental types of reactions found throughout chemistry. Examples are esterification reactions, amidation reactions, and the synthesis of carbon-heteroatom multiple bonds. In general, dehydration reactions are not considered to be redox reactions, because no oxidation states change in the substrate from which water is eliminated or in the dehydration reagent that is utilized. At first glance, there does not seem to be a link between dehydration reactions and redox chemistry. In recent years, however, it has been demonstrated that dehydration reactions can be carried out by electrolysis. Given the enormous importance of dehydration reactions from academic to technical scale, electrochemical dehydration reactions offer a more sustainable approach to such transformations. In this review, the recent progress is surveyed and the opportunities of this new and evolving field are highlighted. Electrochemical dehydration reactions are an interesting new discipline in the emerging domain of electroorganic chemistry, which is currently experiencing a remarkable renaissance to establish itself as a 21st-century technique.