Fluorinated Alcohol Solvent Drives Catalyst-Free Pyran Synthesis in Minutes

Chemists have long chased a deceptively simple goal: build complicated drug-like molecules quickly, cleanly, and without the heavy metal catalysts that often make industrial chemistry expensive and wasteful. A new study published in Results in Chemistry brings that goal a step closer. A team of researchers at the University of Mazandaran, led by Behrooz Maleki, reports that a single fluorinated alcohol, 1,1,1,3,3,3-hexafluoro-2-propanol, better known to chemists as HFIP, can act as both the reaction medium and the driving force for assembling tetrahydrobenzo[b]pyran derivatives in a one-pot, three-component reaction. No Lewis acid, no Brønsted acid, no metal salt, and no organocatalyst were added. The products emerged in yields as high as 95 percent within minutes at a modest 55 degrees Celsius.

The compounds at the center of the work, tetrahydrobenzo[b]pyrans and related 2-amino-3-cyano-4H-pyrans, belong to a family of oxygen-containing ring systems with an impressive portfolio of biological activities. Published studies have linked members of this class to anticancer, antimicrobial, antioxidant, anti-inflammatory, antiviral, anticoagulant, antidiabetic, analgesic, and spasmolytic effects. Beyond pharmacology, these fused pyran frameworks serve as versatile intermediates for constructing more elaborate heterocyclic architectures and functional organic materials. That combination of therapeutic relevance and synthetic utility explains why finding faster, greener ways to make them has become one of the busiest corners of modern heterocyclic chemistry.

The reaction the team exploited is a classic of multicomponent chemistry. An aromatic aldehyde, malononitrile, and a cyclic 1,3-dicarbonyl compound such as dimedone, or alternatively ethyl acetoacetate, are combined in a single flask. The domino sequence that follows proceeds through a Knoevenagel condensation, in which the aldehyde and malononitrile form an activated alkene, followed by a Michael addition of the enolized dicarbonyl compound, and finally an intramolecular cyclization that closes the pyran ring. Because three or more starting materials merge in one operation, multicomponent reactions of this type offer excellent atom economy, operational simplicity, high bond-forming efficiency, short reaction times, low energy consumption, and minimal waste, all hallmarks of green chemistry.

What has historically held this transformation back is the catalyst. Most reported protocols rely on Brønsted acids, Lewis acids, transition-metal complexes, ionic liquids, deep eutectic solvents, metal-organic frameworks, carbon-based materials, or recyclable magnetic nanocatalysts. Many of these systems deliver good yields, but they often demand laborious, multistep catalyst preparation, carry high costs, resist large-scale recycling, or require elevated temperatures, long reaction times, and environmentally undesirable organic solvents. The Iranian team’s answer was to strip the catalyst out entirely and let the solvent do the work.

HFIP is an unusual liquid. It is highly polar, weakly nucleophilic, and possesses an exceptional capacity to donate hydrogen bonds, along with very high ionizing power. Those properties allow it to stabilize cationic intermediates and polar transition states, activate carbonyl compounds, and facilitate proton transfers, all without being consumed or incorporated into the product. In recent years HFIP has attracted growing attention as a medium for cyclizations, electrophilic additions, carbon-hydrogen functionalization, oxidative transformations, and multicomponent processes, and mounting evidence suggests it can reduce or even eliminate the need for conventional acid catalysts. What had been missing, the authors note, was a demonstration of HFIP acting alone as the promoter for this particular pyran synthesis.

The optimization experiments tell a striking story. Using benzaldehyde, malononitrile, and dimedone as the model reaction, the researchers varied the amount of HFIP and the temperature. At room temperature with 0.30 milliliters of HFIP, the isolated yield reached 87 percent in just ten minutes. Raising the temperature to 55 degrees Celsius cut the time to five minutes and pushed the yield to 92 percent. Adding more HFIP brought no further benefit. Most tellingly, when HFIP was removed altogether, only a trace of product appeared after thirty minutes under otherwise identical conditions. Because the yield and rate climb with HFIP concentration, the authors interpret the effect as promotional rather than catalytic, and they are careful not to claim a catalytic turnover cycle without dedicated kinetic evidence.

The mechanistic picture the team offers, explicitly framed as a plausible hypothesis rather than experimentally confirmed proof, rests on hydrogen bonding. HFIP can hydrogen-bond to the carbonyl oxygen of the aldehyde, increasing the electrophilicity of the carbonyl carbon and thereby accelerating the initial Knoevenagel condensation with malononitrile. The same hydrogen-bonding network is thought to stabilize the charged intermediates that appear during the subsequent Michael addition and the intramolecular cyclization, allowing the entire domino sequence to run quickly and cleanly at relatively low temperature. The authors acknowledge that no specific kinetic experiments or comparative studies with alternative hydrogen-bond-donating solvents were performed, so the separate contribution of hydrogen bonding cannot yet be distinguished from other solvent effects.

With the optimized conditions in hand, the researchers surveyed a representative set of aromatic aldehydes bearing both electron-donating and electron-withdrawing substituents. Methoxy, chloro, and nitro groups were all tolerated. When dimedone served as the dicarbonyl component, the tetrahydrobenzo[b]pyran products were isolated in 91 to 95 percent yields over reaction times of roughly 90 to 100 minutes. Swapping dimedone for ethyl acetoacetate delivered the corresponding 2-amino-3-cyano-4H-pyran derivatives in 83 to 94 percent yields. The authors are candid about the limits: heteroaromatic aldehydes, sterically hindered substrates, and more electronically extreme cases were not systematically examined, so the results demonstrate reliable compatibility within the tested set rather than a universally broad substrate scope.

How does the HFIP protocol stack up against the competition? The team compared its results with representative literature procedures, including magnetic nanocatalysts operating under microwave irradiation or grinding, ammonium hydroxide in water, and urea in aqueous ethanol. For the benchmark products 4a through 4c, the HFIP method delivered 92 to 95 percent isolated yields at 55 degrees Celsius with reaction times similar to or shorter than most of the reference procedures, some of which required reflux, extended stirring, or elaborate catalyst synthesis. The comparison rests on reaction time and isolated yield alone, since parameters such as catalyst loading, solvent quantity, and recycling efficiency are not uniformly reported across studies. The clear advantage of the new protocol is its formulation: a homogeneous medium, a one-pot operation, mild temperature, and no added metal or acid catalyst, with products isolated by simple crystallization from ethanol rather than chromatography.

The authors also weigh the environmental ledger honestly. HFIP is a fluorinated solvent, and although it is readily distilled and was recovered by distillation for reuse in subsequent runs in the laboratory, the study did not experimentally evaluate recovery efficiency, energy costs, or solvent losses at scale. The environmental burden of fluorinated compounds, occupational hazards, and the energy required for solvent recovery all must be counted against the benefits of catalyst elimination, fast reactions, and high atom economy. The team concludes that the method is a valuable addition to the synthetic toolbox for the substrates tested, but that future work should expand the substrate scope, probe the mechanism with kinetic and comparative solvent studies, and rigorously assess HFIP recovery. For now, the message is clear and likely to resonate across medicinal chemistry and green synthesis alike: sometimes the most powerful catalyst in the flask is the solvent itself.

Subject of Research: HFIP-promoted catalyst-free one-pot multicomponent synthesis of tetrahydrobenzo[b]pyran and 2-amino-3-cyano-4H-pyran derivatives

Article Title: HFIP-promoted Lewis acid-free one-pot synthesis of pyran derivatives under mild conditions

Article References: Nouri, F. Z., Maleki, B., Baharfar, R., Alinezhad, H., & Ashrafi, S. S. (2026). HFIP-promoted Lewis acid-free one-pot synthesis of pyran derivatives under mild conditions. Results in Chemistry, 31, Article 103961. https://doi.org/10.1016/j.rechem.2026.103961

Image Credits: AI Generated

DOI: 10.1016/j.rechem.2026.103961

Keywords: HFIP, multicomponent reaction, pyran synthesis, green chemistry, hydrogen bonding, Knoevenagel condensation, Michael addition, heterocyclic chemistry, fluorinated solvents, catalyst-free synthesis, tetrahydrobenzo[b]pyrans, organic synthesis