Innovative metal-free protocols for constructing valuable pharmaceutical scaffolds
In the intricate world of medicinal chemistry, certain molecular architectures repeatedly emerge as unsung heroes in our ongoing battle against disease. Among these, the 2,3-dihydrobenzofuran scaffold—a simple structure consisting of a benzene ring fused with a saturated furan ring—stands out for its remarkable presence in numerous bioactive compounds and natural products 1 .
From antimalarial agents to antidepressants, this versatile framework forms the structural backbone of treatments for a surprising range of conditions.
For decades, creating these valuable structures typically required expensive transition metal catalysts like palladium, rhodium, or iridium, often under energy-intensive conditions that generated substantial waste 3 . Recently, however, a quiet revolution has been unfolding in laboratories worldwide—the development of innovative metal-free synthetic protocols that offer more sustainable, efficient pathways to these vital molecular architectures 1 .
This article explores these groundbreaking advances that are making pharmaceutical chemistry cleaner and greener.
At its simplest, a 2,3-dihydrobenzofuran consists of two connected rings: a benzene ring (the same hexagonal structure found in benzene) fused to a dihydrofuran ring (a five-membered ring containing oxygen and two saturated carbon atoms) 1 .
The "dihydro" designation indicates that the furan ring is saturated, meaning it contains single bonds rather than the double bonds found in simple benzofurans, making it more flexible and stable 1 .
This unique architecture provides structural stability while allowing sufficient molecular flexibility for effective biological interactions, making it an ideal scaffold for drug design 5 .
Visualization of the 2,3-dihydrobenzofuran molecular structure showing the benzene ring fused to a saturated furan ring.
The true significance of the dihydrobenzofuran scaffold becomes apparent when we examine its prevalence in nature. Numerous biologically potent natural products contain this structural motif in their architecture 1 .
| Natural Product | Biological Source | Biological Activities |
|---|---|---|
| (+)-Lithospermic acid | Lithospermum plants | Anti-HIV, antioxidant |
| (-)-Linderol A | Lindera plants | Inhibition of melanin biosynthesis |
| Bisabosqual A | Fungal source | Antifungal, squalene synthase inhibitor |
| (+)-Decursivine | Rhaphidophora decursiva | Antimalarial |
| (+)-Conocarpan | Piper species | Antifungal, anti-trypanosomal, insecticidal |
These natural products demonstrate the structural versatility and medicinal value of the dihydrobenzofuran scaffold, explaining why synthetic chemists have been so interested in developing efficient methods to create them and their analogs in the laboratory 1 5 .
Traditional synthetic routes to dihydrobenzofurans often relied on transition metal catalysts, which, while effective, present several challenges including potential toxicity, high cost, and the need to remove metal residues from pharmaceutical products 1 . In response to these limitations and growing environmental concerns, researchers have developed innovative metal-free approaches that circumvent these issues while maintaining high efficiency and selectivity.
Bronsted acids—proton donors that can activate electrophilic centers—have emerged as powerful catalysts for forming the carbon-carbon and carbon-oxygen bonds necessary to build dihydrobenzofuran rings 1 .
In 2021, Yang and colleagues demonstrated that polyphosphoric acid (PPA) could efficiently convert ortho-allyl phenols into 2,3-dihydrobenzofuran derivatives in moderate to excellent yields (52%-90%) 1 .
Photochemical reactions harness the energy of light to drive chemical transformations, offering an environmentally benign alternative to conventional thermal processes.
A particularly elegant example, reported in 2025, described a visible light-mediated synthesis of 2,3-dihydrobenzofuran chalcogenides using an I2/SnCl2 promoter system under blue LED irradiation 5 .
Beyond acid catalysis, other organocatalytic approaches have emerged for dihydrobenzofuran synthesis.
In 2025, Yuan and colleagues developed a DBU-catalyzed formal [4+1] annulation between 2-(2-nitrovinyl)phenols and α-bromoacetophenones that afforded 2,3-dihydrobenzofuran derivatives with excellent diastereoselectivity (>20:1 dr) 7 .
| Method | Key Conditions | Yield Range | Key Advantages |
|---|---|---|---|
| Bronsted Acid Catalysis | Polyphosphoric acid, DMF, elevated temperature | 52%-90% | Simple setup, good functional group tolerance |
| Asymmetric [3+2] Annulation | Chiral phosphoric acid, DCE, room temperature | 62%-99% | Excellent enantioselectivity (up to 99% ee) |
| Visible Light-Mediated | I2/SnCl2, blue LED, ethyl acetate, room temperature | Up to 96% | Mild conditions, uses green solvent, no photoredox catalyst needed |
| DBU-Catalyzed Annulation | DBU, DCM, room temperature | Moderate to excellent | High diastereoselectivity, scalable |
The visible light-mediated synthesis of 2,3-dihydrobenzofuran chalcogenides represents a particularly innovative approach that aligns perfectly with green chemistry principles 5 . The experimental procedure is elegantly straightforward:
In a glass tube, 2-allylphenol (0.25 mmol) is combined with a diaryl diselenide (1.0 equivalent), SnCl2·2H2O (2.0 equivalents), and I2 (1.0 equivalent) in 3.0 mL of ethyl acetate.
The reaction mixture is irradiated with a 50 W blue LED lamp at room temperature for 4 hours under air atmosphere.
The progress is tracked by thin-layer chromatography (TLC) to confirm consumption of the starting material.
After completion, the mixture is extracted with ethyl acetate and water, followed by purification via column chromatography using a hexane/ethyl acetate gradient (9:1) as eluent 5 .
This photochemical approach delivers exceptional results across a range of substrates. The reaction tolerates various functional groups on the diselenide component, including electron-withdrawing substituents like chlorine and fluorine, which proceed in high yields (95%-96%) 5 .
The method demonstrates remarkable regioselectivity, exclusively forming the 2,3-dihydrobenzofuran derivatives without competing side products.
The synthetic utility of this protocol is further enhanced by its operational simplicity and avoidance of specialized equipment. By using a simple blue LED light source and eliminating the need for a separate photoredox catalyst, the method offers a more accessible and sustainable alternative to previous photochemical approaches 5 .
| Product | Substituent on Diselenide | Yield | Physical Characteristics |
|---|---|---|---|
| 3a | Phenyl | 95% | White solid, mp 58-60°C |
| 3b | 4-Chlorophenyl | 95% | Yellow oil |
| 3c | 4-Fluorophenyl | 96% | White solid, mp 57-60°C |
Modern metal-free synthetic methodologies employ a diverse array of reagents and catalysts to facilitate the construction of dihydrobenzofuran scaffolds:
(PPA, Phosphoric Acids) - Act as proton donors to activate electrophilic centers, facilitating cyclization through oxygen activation and carbocation formation 1 .
(DBU) - Nitrogen-based organic catalysts that facilitate formal [4+1] annulation reactions through base-mediated enolate formation and subsequent cyclization 7 .
(I2/SnCl2) - Function as promoters in visible light-mediated reactions, likely generating reactive chalcogen species upon irradiation that initiate the cyclization cascade 5 .
(Ethyl Acetate) - Biodegradable, low-toxicity alternatives to traditional organic solvents that maintain reaction efficiency while reducing environmental impact 5 .
(Blue LEDs) - Provide energy to drive photochemical reactions through direct substrate activation or through interaction with promoter systems, eliminating the need for specialized photoredox catalysts 5 .
(TLC, NMR, HPLC) - Essential for monitoring reaction progress, determining yields, and confirming structural identity of synthesized dihydrobenzofuran derivatives.
The development of novel transition metal-free protocols for constructing 2,3-dihydrobenzofurans represents more than just technical innovation—it signifies a fundamental shift toward sustainable medicinal chemistry. These methodologies address critical challenges in pharmaceutical production, including metal contamination concerns, environmental impact, and process cost-effectiveness 1 5 .
As research in this field continues to advance, we can anticipate further refinement of these metal-free strategies, including the development of:
The integration of computational methods and artificial intelligence in reaction optimization promises to accelerate the discovery of even more efficient sustainable protocols 2 .
These scientific advances in green synthesis methodologies ensure that the valuable dihydrobenzofuran-based therapeutics of tomorrow will be created through processes that are not only effective but also environmentally responsible—a crucial convergence as we work toward a more sustainable future for pharmaceutical manufacturing and chemical synthesis as a whole.