Mechanochemical Simmons–Smith cyclopropanation via ball-milling-enabled activation of zinc(0)

The bulk solvent-free synthesis of cyclopropanes via a ball-milling-enabled Simmons–Smith reaction is herein described

Evolution of Solid Processing Methods in Continuous Flow Technology: Reactive Extrusion

The frustrations of precipitation, fouling and blockages of liquid-based flow reactors is familiar to all researchers that have worked with continuous flow equipment. There have been many innovative solutions to try and circumvent this issue. This short review will highlight the emerging technique of mechanochemistry and reactive extrusion as a continuous process that can directly work on solid (and liquid) materials and elicit chemical transformations

Regioselective Transition-Metal-Catalyzed C–H Functionalization of Anilines

Anilines are a vital synthetic core of pharmaceuticals, agrochemicals, natural products and building blocks. Metal-catalyzed C–H functionalization has emerged as a powerful tool to derivatize biologically relevant molecules. To this end, the derivation of anilines via catalytic C–H functionalization has been the subject of important new synthetic methodology. This review focuses on the tactics used to allow regioselective C–H functionalization of anilines.1 Introduction2 ortho-Selective C–H Functionalization2.1 Palladium2.2 Rhodium2.3 Ruthenium2.4 Nickel3 meta-Selective C–H Functionalization4 para-Selective C–H Functionalization5 Conclusion</jats:p

Beyond C2 and C3: Transition-Metal-Catalyzed C–H Functionalization of Indole

The indole scaffold will continue to play a vital part in the future of drug discovery and agrochemical development. Because of this, the necessity for elegant techniques to enable selective C–H functionalization is vast. Early developments have led to primarily C2 and C3 functionalization because of the inherent reactivity of the pyrrole ring. Despite this, elegant methods have been developed to enable selective C–H functionalization on the benzenoid moiety at C4, C5, C6, and C7. This review focuses on the contributions made in benzenoid C–H functionalization of indoles and other related heteroaromatics such as carbazoles

Temperature-Controlled Mechanochemistry for the Nickel-Catalyzed Suzuki-Miyaura-Type Coupling of Aryl Sulfamates via Ball Milling and Twin-Screw Extrusion

The use of temperature-controlled mechanochemistry to enable the mechanochemical nickel-catalyzed Suzuki-Miyaura coupling is herein described. Transitioning from a capricious room-temperature protocol, through to a heated, PID-controlled programmable jar heater manifold was required to deliver an efficient method for the coupling of aryl sulfamates (derived from ubiquitous phenols) and aryl boronic acid species. Furthermore, this process is conducted using a base-metal nickel catalyst, in the absence of bulk solvent, and in the absence of air/moisture sensitive reaction set-ups. This methodology is showcased through translation to large-scale twin-screw extrusion methodology enabling 200-fold scale increase, producing decagram quantities of C-C coupled material

Continuous flow mechanochemistry: reactive extrusion as an enabling technology in organic synthesis

Rapid and wide-ranging developments have established mechanochemistry as a powerful avenue in sustainable organic synthesis. This is primarily due to unique opportunities which have been offered in solvent-free - or highly solvent-minimised - reaction systems. Nevertheless, despite elegant advances in ball-milling technology, limitations in scale-up still remain. This tutorial review covers the first reports into the translation from "batch-mode" ball-milling to "flow-mode" reactive extrusion, using twin-screw extrusion

Dual catalytic enantioselective desymmetrization of allene-tethered cyclohexanones

The construction of enantioenriched azabicyclo[3.3.1]nonan-6-one heterocycles via an enantioselective desymmetrization of allene-linked cyclohexanones, enabled through a dual catalytic system, that provides synchronous activation of the cyclohexanone with a chiral prolinamide and the allene with a copper(I) co-catalyst to deliver the stereodefined bicyclic core, is described. Successful application to oxygen analogues was also achieved, thereby providing a new enantioselective synthetic entry to architecturally complex bicyclic ethereal frameworks. The mechanistic pathway and the origin of enantio- and diastereoselectivities has been uncovered using density functional theory (DFT) calculations

Ruthenium catalyzed remote C4-selective C–H functionalisation of carbazoles via σ-activation

We report the C4-selective C–H alkylation of carbazole derivatives furnished with a pyrimidine directing group at N9. This was realized using ruthenium catalyzed r-activation methodology, whereby C–H activation at C1 enables the interaction of this ruthenacycle, at the para position to the metal center, with tertiary alkyl radical

Use of Microwave Dielectric Spectroscopy for the In Actu Assessment of Frustrated Lewis Pair Encounter Complexes

Frustrated Lewis pairs (FLPs) offer an important and promising paradigm for main group catalysis. Reported here is the use of microwave dielectric spectroscopy for the in actu detection of FLP encounter complexes. This technique focuses on the room-temperature measurement of the loss component of microwave permittivity (ε2) over the bandwidth from 0.5 to 6.8 GHz. The microwave loss measured for a Lewis pair in a toluene host solution is compared with the losses of the individual components when measured separately, and the difference in loss Δε2 is used to characterize the electrostatic interaction between the pair. The Δε2 value shows a direct correlation with an ability for the FLP encounter complex to split hydrogen gas and abstract hydrogen from γ-terpinene and has led to the identification of a novel FLP encounter complex, tris-pentafluorophenyl borane-eucalyptol pairing

A ball-milling-enabled cross-electrophile coupling

The nickel-catalyzed cross-electrophile coupling of aryl halides and alkyl halides enabled by ball-milling is herein described. Under a mechanochemical manifold, the reductive C–C bond formation was achieved in the absence of bulk solvent and air/moisture sensitive setups, in reaction times of 2 h. The mechanical action provided by ball milling permits the use of a range of zinc sources to turnover the nickel catalytic cycle, enabling the synthesis of 28 cross-electrophile coupled products