Chemoselective Synthesis of Amides and Their Derivatives

Amides represent one of the most abundant and versatile functional groups in organic chemistry, featuring prominently in pharmaceuticals, agrochemicals and advanced materials. Their inherent stability, however, poses a challenge to selective functionalisation. Chemoselective strategies have therefore been devised to activate or transform the amide carbonyl under mild conditions, avoiding competing reactions at other sites. Recent advances encompass catalytic reduction, electrophilic activation, polarity inversion (umpolung) and multicomponent coupling, enabling the direct construction of C–C, C–N and C–heteroatom bonds. These methodologies grant access to α-functionalised amides, enamides, heterocyclic scaffolds and complex alkaloid frameworks. The ability to engage amides in synthetically valuable transformations underpins innovations in drug discovery, sustainable synthesis and the rapid assembly of three-dimensional molecular architectures.

Research from Nature Portfolio

Recent studies have unveiled a highly enantioselective, one-pot reductive alkynylation of aliphatic amides and alkynes that furnishes α-alkyl and α,α′-dialkyl nitrogen heterocycles. The reaction employs sequential Ir/Cu/N-PINAP catalysis to convert simple amides into propargylic amines and, in tandem with palladium-catalysed cyclisations, delivers pyrrolidine, piperidine and indolizidine alkaloids with excellent enantiomeric excess. This unified protocol underscores the power of chemoselective reductive activation to streamline total syntheses of complex natural products. In parallel, an iridium-catalysed reductive route to C,N,N-cyclic azomethine imines has been developed. Using a readily available hydrazide precursor and a silane reductant, stabilised azomethine imine dimers are generated and, upon dissociation, undergo [3+2] cycloaddition with a broad range of dipolarophiles to yield nitrogen-rich, sp3-hybridised polycyclic pyrazolines with high yields and good diastereoselectivities. Computational analyses elucidate the origin of this selectivity and highlight the method’s potential for rapid exploration of three-dimensional chemical space.

Chemoselective Synthesis of Amides and Their Derivatives publication trend

The graph below shows the total number of articles in chemoselective synthesis of amides and their derivatives across all publications each year (not limited to Nature Index journals).

Technical terms

Chemoselectivity: The preferential reaction of one functional group in the presence of other potentially reactive sites.

Umpolung: Reversal of the normal polarity of a functional group, enabling unconventional bond formations.

Reductive Alkynylation: A process combining catalytic reduction of an amide and subsequent addition of an alkyne to form a new C–C bond.

Enantioselectivity: The preferential formation of one enantiomer over another in a chiral reaction.

Azomethine Imine: A 1,3-dipolar species featuring a C=N–N motif, used in [3+2] cycloaddition to construct nitrogen-rich heterocycles.

References

1. Amide activation: an emerging tool for chemoselective synthesis. Chemical Society Reviews (2018).
2. Catalytic enantioselective reductive alkynylation of amides enables one-pot syntheses of pyrrolidine, piperidine and indolizidine alkaloids. Nature Communications (2023).
3. Iridium-catalysed synthesis of C,N,N-cyclic azomethine imines enables entry to unexplored nitrogen-rich 3D chemical space. Nature Synthesis (2024).
4. New Strategies for the Functionalization of Carbonyl Derivatives via α‑Umpolung: From Enolates to Enolonium Ions. Accounts of Chemical Research (2023).
5. Free Amino Group Transfer via α‐Amination of Native Carbonyls. Angewandte Chemie International Edition (2023).
6. Direct enantioselective α-amination of amides guided by DFT prediction of E/Z selectivity in a sulfonium intermediate. Chem (2023).