Cyclopropane Synthesis in Organic Chemistry

Cyclopropanes are three-membered carbocycles whose inherent ring strain endows them with unique chemical and biological properties. Their rigid framework modulates molecular conformation, enhances metabolic stability and fine-tunes pharmacokinetic profiles, making them indispensable motifs in drug discovery, agrochemicals and material science. Classical strategies for cyclopropane formation rely on the generation of highly reactive carbenes or carbenoid species that undergo concerted addition to alkenes, with the Simmons–Smith reaction standing as a prototypical example. Transition-metal-catalysed carbenoid transfer methods, typically employing copper, rhodium or cobalt complexes, have expanded substrate scope and stereochemical control. Recent advances have embraced more sustainable paradigms, including solvent-free mechanochemical activation, flow technologies for safe scale-up and photoredox or electron-transfer approaches that circumvent stoichiometric metal consumption. Biomimetic and cationic cyclopropanations further mirror enzymatic pathways to access densely functionalised scaffolds under mild conditions. Together, these developments underscore a vibrant field in which the interplay of strain, catalysis and innovative activation modes continues to drive the synthesis of complex cyclopropane architectures with global significance in medicinal and synthetic chemistry.

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Cyclopropane Synthesis in Organic Chemistry publication trend

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

Technical terms

Carbene: A neutral species containing a divalent carbon atom with two nonbonded electrons, capable of inserting into C=C bonds to form cyclopropanes.

Carbenoid: A metal-stabilised species that behaves like a carbene in cyclopropanation reactions, often generated from dihalomethane and metal reagents.

Simmons–Smith reaction: A classical cyclopropanation protocol in which diiodomethane and zinc or an organozinc reagent generate a methylene carbenoid for addition to alkenes.

Mechanochemistry: The use of mechanical force, such as grinding or milling, to activate reagents and drive chemical transformations without bulk solvents.

Photocatalysis: The acceleration of a chemical reaction by light in the presence of a catalyst that absorbs photons and mediates electron or energy transfer.

Hydrogen-borrowing catalysis: A method in which an alcohol or ketone is oxidised to form an intermediate that undergoes further transformation before the catalyst returns hydrogen to regenerate a saturated product.

References

1. Mechanochemical Simmons–Smith cyclopropanation via ball-milling-enabled activation of zinc(0). Green Chemistry (2023).
2. Rapid and Safe Continuous‐Flow Simmons‐Smith Cyclopropanation using a Zn/Cu Couple Column. Advanced Synthesis & Catalysis (2023).
3. Cyclopropanation Using Electrons Derived from Hydrogen: Reaction of Alkenes and Hydrogen without Hydrogenation. JACS Au (2024).
4. Reductive Cyclopropanation through Bismuth Photocatalysis. Journal of the American Chemical Society (2024).
5. Synthesis of Cyclopropanes via Hydrogen-Borrowing Catalysis. Organic Letters (2023).
6. Biomimetic Cationic Cyclopropanation Enables an Efficient Chemoenzymatic Synthesis of 6,8-Cycloeudesmanes. Journal of the American Chemical Society (2023).
7. Regioselective Simmons–Smith-type cyclopropanations of polyalkenes enabled by transition metal catalysis. Chemical Science (2018).