Synthesis Strategies for Dihydrobenzofuran Derivatives

The dihydrobenzofuran scaffold has attracted sustained interest owing to its prevalence in natural products and pharmacologically active compounds. Synthetic approaches centre on construction of the heterocyclic ring via intramolecular cyclisation, radical-mediated annulation, transition-metal-catalysed C–O bond formation and organocatalytic tandem processes. Key advancements include Brønsted and Lewis acid catalysts to induce ring closure, domino sequences that forge multiple bonds in one operation, and chiral catalysts enabling enantioselective access to complex architectures. Methodologies are often classified according to the bond disconnection exploited—whether aryl–oxygen, carbon–carbon or carbon–heteroatom linkages—and tailored to impart high stereo- and regioselectivity. These strategies underpin the rapid assembly of diverse dihydrobenzofuran libraries for applications in drug discovery, agrochemicals and materials science.

Research from Nature Portfolio

Recent studies have demonstrated a highly efficient route to a tetracyclic indole alkaloid featuring the dihydrobenzofuran unit. A BINOL-derived phosphoric acid catalyst promotes a tandem oxidative cyclisation using a hypervalent iodine oxidant, streamlining the synthesis in fewer steps and with improved overall yield. This organocatalytic approach highlights the power of chiral Brønsted acid promoters to orchestrate sequential bond formations without isolating intermediates, paving the way for concise routes to complex natural products and their analogues.

Synthesis Strategies for Dihydrobenzofuran Derivatives publication trend

The graph below shows the total number of articles in synthesis strategies for dihydrobenzofuran derivatives across all publications each year (not limited to Nature Index journals).

Technical terms

Dihydrobenzofuran: an aromatic heterocycle comprising a benzene ring fused to a saturated furan ring.

Intramolecular cyclisation: formation of a ring by a reaction within a single molecule.

Domino reaction: a sequence of bond-forming steps occurring under the same reaction conditions without isolation of intermediates.

Diastereoselectivity: preference for formation of one diastereomer over another in a chemical reaction.

Tandem oxidative cyclisation: sequential oxidation steps that trigger cyclisation events in a single operational sequence.

References

1. Strategies for the Synthesis of 2,3-Dihydrobenzofurans. Journal of Chemical Research (2011).
2. Synthesis of Functionalized Indolines and Dihydrobenzofurans by Iron and Copper Catalyzed Aryl C–N and C–O Bond Formation. The Journal of Organic Chemistry (2018).
3. K 3 PO 4 -promoted domino reactions: diastereoselective synthesis of trans -2,3-dihydrobenzofurans from salicyl N-tert -butanesulfinyl imines and sulfur ylides. RSC Advances (2019).
4. Total synthesis of (±)-decursivine via BINOL-phosphoric acid catalyzed tandem oxidative cyclization. Scientific Reports (2021).