Cross-Dehydrogenative Coupling for Carbon-Carbon Bond Formation

Cross-dehydrogenative coupling (CDC) has emerged as a transformative strategy in organic synthesis, enabling the direct formation of carbon–carbon bonds through the oxidative activation of C–H bonds. Unlike traditional cross-coupling methods that require preactivated partners such as halides or organometallic reagents, CDC streamlines synthetic sequences by harnessing unfunctionalised substrates. This approach enhances atom economy and reduces waste, while opening new avenues for constructing complex molecular architectures—ranging from heterocycles and quaternary centres to polycyclic frameworks. The core principle involves simultaneous or sequential removal of hydrogen atoms from two substrates in the presence of an oxidant and, frequently, a catalyst (often a transition metal or an organocatalyst). Advances in catalyst design, mechanistic understanding and the development of mild, selective oxidation systems have broadened the scope of CDC, allowing for enantioselective variants and the incorporation of challenging sp³ centres. Innovations in photochemical and electrochemical activation have further expanded the toolbox, permitting reactions under ambient conditions with minimal environmental footprint. The versatility and sustainability of CDC have driven its adoption in the synthesis of pharmaceuticals, natural products and advanced materials, underlining its global significance and potential industrial applications.

Research from Nature Portfolio

Recent studies have advanced enantioselective CDC protocols to access all-carbon stereocentres directly from saturated ethers and carboxylic acid derivatives. One approach employs a sequential oxidative acetalisation followed by nickel-catalysed asymmetric alkylation, delivering a diverse array of cyclic and acyclic ethers with excellent enantioselectivity and functional-group tolerance. This one-pot method demonstrates broad applicability to medium- and large-ring systems and enables streamlined synthesis of biologically active targets. Another line of work has unveiled metal-free intramolecular CDC of aliphatic and aromatic C–H bonds using simple organic oxidants under mild conditions. These protocols achieve high regioselectivity by leveraging radical initiation strategies, tolerate diverse functional groups and preserve stereochemical information in amino-acid-derived substrates, thereby offering a sustainable complement to metal-catalysed processes.

Cross-Dehydrogenative Coupling for Carbon-Carbon Bond Formation publication trend

The graph below shows the total number of articles in cross-dehydrogenative coupling for carbon-carbon bond formation across all publications each year (not limited to Nature Index journals).

Technical terms

Cross-dehydrogenative coupling: A reaction that forms a new bond between two carbon centres by direct dehydrogenation of C–H bonds without prefunctionalisation.

C–H activation: The process by which a reactive species cleaves a carbon–hydrogen bond to enable subsequent chemical transformation.

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

Quaternary stereocentre: A carbon atom bonded to four distinct substituents, creating a chiral centre with no hydrogen atoms.

Atom economy: A measure of the efficiency of a synthesis, calculated as the proportion of reactant atoms incorporated into the final product.

References

1. Cross-dehydrogenative coupling enables enantioselective access to CF 3 -substituted all-carbon quaternary stereocenters. Chemical Science (2020).
2. Copper-catalyzed diastereoselective aerobic intramolecular dehydrogenative coupling of hydrazones via sp 3 C–H functionalization. Chemical Science (2015).
3. Catalytic enantioselective oxidative coupling of saturated ethers with carboxylic acid derivatives. Nature Communications (2019).
4. New Trends in Enantioselective Cross-Dehydrogenative Coupling. Catalysts (2020).
5. Transition metal-free intramolecular regioselective couplings of aliphatic and aromatic C-H bonds. Scientific Reports (2016).