Volume 2 Issue 11, November 2023

Catalytic multi-component transformations often require a delicate balance between the reactivities of the starting materials and catalyst. Now, chromium catalysis enables consecutive C–O and C–H functionalization to form tertiary alkane centres.

Cyclic iminium salts are used as versatile intermediates in the synthesis of diverse N-(hetero)aryl piperidines. This method facilitates the C2 and/or C3 functionalization of the piperidine backbone with motifs relevant to medicinal chemistry, enabling the exploration of previously inaccessible chemical space for the discovery of medicines.

A mild and efficient electrochemical strategy has been developed for the multicomponent 1,4-arylalkylation, unsymmetrical dialkylation and hydro(deutero)alkylation of 1,3-enynes with aryl and alkyl bromides as cross-coupling partners. This protocol can be used to synthesize diverse allenes bearing various functionalities, including allenes found in natural products and drugs.

The most popular reactions used by medicinal chemists are often incompatible with nanoscale ultrahigh-throughput experimentation (ultraHTE). Now, a set of ultraHTE-amenable reaction conditions is reported for four of the most important transformations in drug discovery, and their generality and scalability tested on a range of complex natural products and drug candidates.

Catalytic enantioselective synthesis of all-carbon quaternary stereocentres is a long-term challenge in organic synthesis because of substantial steric repulsion and dissimilarities between the substituents around the stereocentre. This Review presents how the desymmetrization strategy plays an important role in constructing these types of motifs.

meta-Selective acylation of arenes typically requires directing groups or steric hindrance. Now, a combined N-heterocyclic carbene and organic photoredox catalysed of electron-rich arenes, using acyl imidazoles as acylating agents, is reported. Mechanistic studies reveal the process proceeds through single-electron oxidation and radical–radical coupling steps.

Multiple-component cross-coupling reactions can often be unselective and inefficient, making them difficult to develop. Now a chemoselective chromium-catalysed process is reported, forming tertiary alkane centres from benzylic ethers, a Grignard reagent and a silyl chloride, alkyl tosylate or trifluoromethyl-substituted alkene.

Piperidine heterocycles are widely prevalent in drug molecules; however, their synthesis remains challenging. Now, a general approach for N-(hetero)aryl piperidine synthesis using isolable iminium salts is reported. A variety of substituents are installed at the C2 and C3 positions, giving access to densely functionalized piperidines that are challenging to obtain using other methods.

The synthesis of allenes through 1,4-difunctionalization of 1,3-enynes typically requires preformed organometallic species, high temperature or specific alkyl radical precursors. Now an electrochemical multicomponent protocol for the chemo- and regioselective 1,4-difunctionalization of 1,3-enynes is reported, which uses alkyl bromides with aryl bromides, alkyl bromides or H₂O/D₂O as reagents for 1,4-difunctionalization.

The most popular reactions used by medicinal chemists are often incompatible with nanoscale ultrahigh-throughput experimentation (ultraHTE). Now, ultraHTE-amenable reaction conditions are developed through miniaturization of four of the most important drug discovery transformations, and their generality and scalability are tested on a range of natural products and drug candidates.

Visible-light-driven dual photoredox catalysis often uses expensive metals, such as iridium. Now, a photocatalytic approach using a Ni single-atom carbon nitride catalyst is reported for the C–O cross-coupling of carboxylic acids and alkyl halides, demonstrating broad functional group tolerance, short reaction times, facile recovery and excellent stability.

Atomically precise graphene fragments are synthesized by using a radical-mediated coupling approach. One open-shell doublet graphene fragment forms a persistent bilayer assembly with highly delocalized 32-centre-2-electron pancake bonding.

The combination of nickel-catalysis and sensitized electron transfer is underdeveloped. Now, a nickel-catalysed sensitized electron transfer method for the synthesis of methyl thioesters from carboxylic acids is reported. Mechanistic investigations reveal that the merger of photocatalytic electron transfer, energy transfer and nickel catalysis plays an essential role in this thioesterification reaction.