Catalytic Multicomponent Reactions with Diazo Compounds

Diazo compounds serve as versatile precursors to metal-carbenes and free carbenes, enabling the convergence of three or more reactants in a single operation. Such multicomponent reactions have transformed synthetic strategies by combining high atom economy with the ability to construct complex molecular architectures in few steps. Catalysts based on rhodium, copper and other transition metals orchestrate carbene transfer to varied nucleophiles or insertion partners, while organocatalytic approaches and cooperative catalyst systems expand the scope into asymmetric synthesis. Recent innovations have focused on controlling competing pathways—such as C–H or O–H insertions and undesired rearrangements—through ligand design, dual activation modes, and transient trapping of reactive intermediates. These advances have led to rapid access to chiral amino-functionalised ketones, heterocycles and densely functionalised scaffolds that underpin new leads in medicinal chemistry, agrochemical development and materials science.

Research from Nature Portfolio

Recent studies have unveiled novel asymmetric multicomponent processes leveraging diazo-derived metal carbenoids. One advanced protocol employs α-halo rhodium carbenes to achieve three-component trifunctionalisation under the control of a chiral phosphoric acid catalyst. This methodology delivers chiral α-cyclic ketal β-amino esters in high yields and enantiomeric excess by invoking carbynoid properties of the metal carbene intermediate. In a complementary development, a four-component coupling unites alcohols, diazoesters, enamines or indoles, and aldehydes through sequential trapping of iminium and enolate intermediates. This approach affords over a hundred examples of structurally diverse adducts with high diastereo- and enantioselectivity under mild conditions. Earlier foundational work demonstrated a rhodium-chiral phosphoric acid cooperative framework for three-component aminomethylation of α-diazo ketones with alcohols and 1,3,5-triazines, enabling efficient and highly stereocontrolled access to β-amino-α-hydroxy ketones from simple substrates.

Catalytic Multicomponent Reactions with Diazo Compounds publication trend

The graph below shows the total number of articles in catalytic multicomponent reactions with diazo compounds across all publications each year (not limited to Nature Index journals).

Technical terms

Diazo compound: An organic molecule containing a diazo functional group (–N₂) that can generate a reactive carbene under catalytic conditions.

Carbene: A divalent carbon species bearing two nonbonded electrons, which can insert into bonds or participate in cyclopropanation.

Metal-carbene: A reactive intermediate in which a carbene is coordinated to a transition metal, enabling selective transformations.

Multicomponent reaction: A process in which three or more starting materials combine in a single operation to form a complex product.

Ylide: A neutral species with adjacent positively and negatively charged atoms, often formed by trapping a carbene intermediate.

Cooperative catalysis: The use of two or more catalysts that work in concert to activate different substrates or intermediates for improved selectivity.

References

1. Asymmetric multi-component trifunctionalization reactions with α-Halo Rh-carbenes. Nature Communications (2025).
2. Enantioselective three-component aminomethylation of α-diazo ketones with alcohols and 1,3,5-triazines. Nature Communications (2020).
3. A DFT calculation-inspired Rh( i )-catalyzed reaction via suppression of α-H shift in α-alkyldiazoacetates. Chemical Science (2017).
4. Overcoming O–H Insertion to Para-Selective C–H Functionalization of Free Phenols: Rh(II)/Xantphos Catalyzed Geminal Difunctionalization of Diazo Compounds. ACS Central Science (2022).
5. An enantioselective four-component reaction via assembling two reaction intermediates. Nature Communications (2022).