Transamidation Techniques in Organic Synthesis

Transamidation has emerged as a versatile approach to construct amide bonds under milder and more sustainable conditions than classical coupling methods. This process entails the direct exchange of nitrogen substituents between two amide partners or between an amide and an amine, thereby circumventing the need for stoichiometric activating agents or preformed acid derivatives. Recent strategies have focused on overcoming the intrinsic stability of the amide bond by employing metal catalysts, organocatalysts, ionic liquids and deep eutectic solvents to increase electrophilicity at the carbonyl centre. A range of activated and unactivated amides can now undergo efficient transamidation with high selectivity, aided by reversible equilibrium control, tailored catalyst design and benign reaction media. These developments have expanded the scope of sustainable amide synthesis, with applications spanning pharmaceuticals, polymers and fine chemicals production, while minimising waste and energy consumption.

Research from Nature Portfolio

Recent studies have introduced a reusable deep eutectic solvent system that promotes additive-free N-formylation and N-acetylation of anilines, extending to the synthesis of unsymmetrical urea derivatives in excellent yields. The eutectic mixture serves dual functions as both solvent and catalyst, maintaining performance over multiple cycles without significant loss of activity. A complementary approach utilises MoS2 nanosheets as a robust catalyst for transamidation of a broad array of primary, secondary and heterocyclic amines with various amide donors. This protocol operates under mild conditions without external additives and can also achieve N-acylation of amines, demonstrating the versatility of layered materials in sustainable amide bond interchanges.

Transamidation Techniques in Organic Synthesis publication trend

The graph below shows the total number of articles in transamidation techniques in organic synthesis across all publications each year (not limited to Nature Index journals).

Technical terms

Amide bond: A functional group featuring a carbonyl linked to a nitrogen atom, prevalent in biomolecules and synthetic materials.

Transamidation: The catalytic exchange of nitrogen substituents between amide and amine partners to form new amide bonds.

Catalyst: A substance that increases the rate of a chemical reaction without being consumed, often by lowering activation energy.

Deep eutectic solvent (DES): A low-melting mixture of hydrogen-bond donors and acceptors that can function as both solvent and catalyst.

Activated amide: An amide rendered more electrophilic through structural modification or coordination, facilitating nucleophilic attack.

Unactivated amide: A standard amide lacking additional activating functionalities, typically resistant to direct substitution without catalysis.

References

1. Direct additive-free N-formylation and N-acylation of anilines and synthesis of urea derivatives using green, efficient, and reusable deep eutectic solvent ([ChCl][ZnCl2]2). Scientific Reports (2024).
2. MoS2-Catalyzed transamidation reaction. Scientific Reports (2019).
3. Recent advances in transamidation of unactivated amides. Chemical Papers (2023).
4. Selective Utilization of N-acetyl Groups in Chitin for Transamidation of Amines. Frontiers in Chemical Engineering (2021).