Enrico

A novel, electrochemical 3-component reaction for the synthesis of alkyl alkenesulfonates from cinnamic acids, SO2 and alkyl alcohols is reported. This metal-free process employs inexpensive and readily available graphite electrodes in combination with easy-to-use stock solutions of SO2 and enables a straightforward construction of the styrene sulfonate scaffold via a decarboxylative transformation. Mechanistic studies indicate a pseudo-Kolbe type reaction. This novel reaction pathway enables a regioselective synthesis alkenesulfonates from substituted cinnamic acids without double bond translocation. Gram-scale and anolyte reusability experiments demonstrate the applicability of this process for the construction of alkenesulfonates from cinnamic acids as potential biogenic feedstock.

A sustainable, general and scalable electrochemical protocol for the direct access to 3-(acylamidoalkyl)-2,1-benzisoxazoles by cathodic reduction of widely accessible nitro arenes is established. The method is characterised by a simple undivided set-up under constant current conditions, inexpensive and reusable carbon-based electrodes, and environmentally benign reaction conditions. The versatility of the developed protocol is demonstrated on 38 highly diverse examples with up to 81% yield. A 50-fold scale-up electrolysis highlights its relevance for preparative applications.

Nature Chemistry, Published online: 11 October 2024; doi:10.1038/s41557-024-01653-3

Ozonolysis reactions convert alkenes into carbon–oxygen compounds via C=C bond cleavage. Now the cleavage of alkenes to form carbon–nitrogen bonds—the aza version of ozonolysis, termed triazenolysis—has been developed. The reaction produces diamines from cyclic alkenes, while acyclic C=C bonds are broken to generate two separate amine units.

The ability to selectively edit organic molecules at the atomic level has the potential to streamline lead discovery and optimization in the pharmaceutical and agrochemical industry. While numerous atom insertion and deletion reactions have recently been reported, examples of single atom swaps remain scarce due to the challenge of orchestrating the selective cleavage and formation of multiple chemical bonds around the same atom. We herein report a method for the carbon-to-nitrogen atom swap in N-alkyl indoles, allowing for the direct conversion of indoles to the corresponding benzimidazoles. The reaction leverages the innate reactivity of the indole scaffold to engage in an initial oxidative cleavage step, followed by oxidative amination, Hofmann-type rearrangement and cyclization. This complex sequence of steps is mediated by the simple combination of commercially available PIDA and ammonium carbamate as nitrogen atom source. The reaction tolerates a wide range of functional groups which is demonstrated by the interconversion of 15 drug-like molecules implying its immediate applicability across a wide range of discovery programs. Furthermore, it shows how leveraging the innate reactivity of a common heterocycle can unlock otherwise challenging skeletal editing reactions.

(Z)-Enamides are important motifs, due to their prevalence in bio-active molecules. However, few strategies are known to obtain them stereoselectively. Herein we report a nickel catalyst which, combined with simultaneous photoredox and energy transfer catalysis, enables the selective formation of (Z)-enamides. Di- and tri- functionalized functionalized olefin products can be obtained in high yields and stereoselectivity, respectively, from a redox-modulated nickel intermediate. Selective and challenging nickel-catalyzed β-H abstraction is attainable through kinetic control facilitated by an external additive.

Nature, Published online: 27 September 2024; doi:10.1038/d41586-024-03174-y

Andrew Robinson reviews five of the best science picks.

An automated electrochemical flow platform for operator-free data generation is presented, leveraging slug-based reaction mixtures for low material consumption. This platform was employed in the context of library synthesis of 44 medicinal chemistry-relevant compounds. The platform was also used to optimize one previously unsuccessful target via DoE, leading to a 6-fold yield increment.

Abstract

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. This platform was successfully demonstrated for electrochemical C−N cross-couplings of E3 ligase binders with diverse amines (44 examples), which were subsequently transferred to a continuous-flow mode for confirmation and isolation, showing its applicability for medicinal chemistry purposes. To further validate the versatility of the platform, Design of Experiments (DoE) optimization was performed for an unsuccessful library target. This optimization process, fully automated by the platform, resulted in a remarkable 6-fold increase in reaction yield.

Nature, Published online: 26 September 2024; doi:10.1038/d41586-024-03138-2

The fundamental discovery deepens scientists’ understanding of chemical bonding.

More than 100 years after Staudinger's seminal reports on the reaction of iminophosphoranes with aldehydes, an alternative path, the so-called “Azide-Wittig Reaction” has been uncovered. We describe the reaction of bulky azides with PMe₃ in the presence of aromatic aldehydes to give triazabutadienes (TBDs). This azide-Wittig reaction is a versatile route towards TBDs, tolerating various aldehydes and organic azides as coupling partners.

Abstract

The introduction of heteroatoms into conjugated organic molecules is an important strategy to tune their reactivity and physical properties. In this realm triazabutadienes (TBDs) of the general from R₂C=N−N=NR’ are an interesting class of compounds, however, general synthetic protocols for their generation are limited. Based on the serendipitous finding that the sterically encumbered azide Mes*N₃ (Mes*=2,4,6-tBu₃C₆H₂) reacted with PMe₃ in the presence of an aromatic aldehyde to form a TBD, we now report on the “Azide-Wittig” reaction. This azide-Wittig reaction is shown to be a versatile tool for the synthesis of a variety of TBDs, tolerating a wide range of aldehydes and organic azides as coupling partners. The preference for azide-Wittig, rather than aza-Wittig reactivity was rationalized using computational methods. This study shows how kinetic control can significantly alter the reaction pathway, thereby switching from an aza-Wittig to an azide-Wittig regime.

Abstract

Aza-S(VI) fluorides are crucial compounds in the synthesis of various S(VI) derivatives, which find broad applications in drug discovery. However, the synthesis of sulfonimidoyl and sulfondiimidoyl fluorides have been relatively underexplored, often requiring lengthy reaction sequences and/or the use of hazardous gaseous reagents. In this study, we present a rapid one-pot method for producing sulfonimidoyl fluorides from sulfinylamines via a nucleophilic addition/electrophilic fluorination sequence. Similarly, sulfondiimidoyl fluorides can be synthesized using the same sequence, preceded by the formation of unsymmetrical sulfurdiimides readily generated in situ from sulfinylamines. Whereas isolation of sulfondiimidoyl fluorides was not feasible, they could be efficiently converted into primary sulfonimidamides by base hydrolysis in a one-pot process. Furthermore, we explored the reactivity of aza-S(VI) fluorides with various nucleophiles, demonstrating a versatile synthetic platform for the synthesis of aza-S(VI) compounds.

Heterogeneous electrocatalysis has significant potential for the organic transformations of a wide range of molecules. The affordable and high efficiency of the process makes it an excellent platform in electro-organic synthesis. This concept provides a thorough description of the importance and emergence of this innovative approach.

Abstract

Electro-organic synthesis, a method that uses electrical current to drive various organic transformations, has garnered significant attention, and so has heterogeneous electrosynthesis, a process that produces chemicals through electrochemical reactions at the interface between the electrode and an electrolyte. This concept highlights the synergistic potential of heterogeneous electrocatalysts, particularly in their use in cross-coupling reactions. After thoroughly analyzing existing literature, key examples have been highlighted in this paper where heterogeneous electrocatalysts have facilitated the transformation of simple starting materials into useful products. This process lowers energy consumption and reduces waste. We hope this short review sparks the interest among those involved in organic electrosynthesis to explore and use heterogeneous electrocatalysis for cross-coupling reactions.