A Biginelli-reakció és reprodukálhatóságának vizsgálata = The Biginelli reaction and its reproducibility study

Milen, Mátyás and Pollák, Patrik (2026) A Biginelli-reakció és reprodukálhatóságának vizsgálata = The Biginelli reaction and its reproducibility study. MAGYAR KÉMIAI FOLYÓIRAT, 132 (1-2). pp. 48-51. ISSN 1418-9933 (nyomtatott); 1418-8600 (online)

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Abstract

A Biginelli-reakció az egyik legrégebben ismert és legfontosabb multikomponensű reakciók közé tartozik. Multikomponensű reakciónak nevezzük azt a reakciót, amelyben három vagy több kiindulási anyag vesz részt egyszerre és a reaktánsok atomjainak többsége beépül a termékbe. Néhány esetben csak egyetlen termék keletkezik, de gyakran előfordul, hogy a főterméket valamilyen kis molekulatömegű vegyület, rendszerint víz, alkohol, ammónia, kén-hidrogén kíséri. A multikomponensű reakciók a kétkomponensű és a polimerizációs reakciók között foglalnak helyet, általában gyűrűs vegyületek előállítására használhatók és gyakran a felfedező nevét viselik. Ilyen a következőkben tárgyalt Biginelli-reakció is. | Multicomponent reactions are transformations where three or more components react to afford a single product. The Biginelli reaction is a well-known multicomponent reaction involving the condensation of urea, ethyl acetoacetate, and aldehydes to form 3,4-dihydropyrimidin-2(1H)-ones. This reaction is significant due to producing a variety of biologically active compounds and its application in the synthesis of polymers, dyes, and natural products.Pietro Biginelli (1860−1937) discovered the three-component re-action of various aldehydes (aliphatic aldehydes, furfural, α,β-un-saturated aldehydes), ethyl acetoacetate and urea, which is cata-lyzed by the addition of hydrochloric acid. Later, the role of the acid was also confirmed by the investigation of the reaction mech-anism, which was carried out by Kappe using 1H and 13C NMR spectroscopy. From the measurement results, he concluded that the addition reaction of urea and benzaldehyde takes place first. The N-(1-hydroxybenzyl)urea formed in this way loses water un-der the influence of hydrochloric acid, leading to the short-lived, reactive N-acyliminium ion. In the next step, the N-acyliminium ion reacts with the enol form of ethyl acetoacetate, and then the product is formed by ring closure from the addition open-chain intermediate via a hexahydropyrimidine derivative with intramo-lecular water elimination.Atwal and co-workers extended the scope of the Biginelli reaction. The reaction was modified by first forming an α,β-unsaturated oxo compound from an aldehyde and a β-ketoester. The isolated α,β-unsaturated oxo compound was then reacted with 2-methyl-isourea in the presence of a weak base, e.g., sodium bicarbonate. The 2-methoxydihydropyrimidine derivative is readily hydrolyzed with hydrochloric acid or trifluoroacetic acid, as it is typical of enol ethers, to form the Biginelli product. Although Atwal’s meth-od consists of two steps, its great advantage is that it is also well applicable to aliphatic and ortho-substituted aromatic aldehydes, and the methoxy group of the intermediate can be easily replaced by ammonia and primary amines.Currently, there are hundreds of experimental conditions de-scribed in the literature for the Biginelli reaction. Various Brønsted and Lewis acids, zeolites, ion exchange resins, ionic liquids, organocatalysts and enzymes can be used as catalysts. In the presence of some catalysts, the Biginelli reaction proceeds in excellent yields in a very short time even at room temperature, but typically heating of the reaction mixture is required. Microwave irradiation is often used for heating, and ethanol, methanol, less often tetrahydrofuran or acetonitrile are used as solvents, but the reaction is also often carried out without any solvent.In the natural sciences, including chemistry, the reliability of the described experiments has high importance. Since the Biginelli reaction has been performed under a wide range of conditions and the results have been published, a few examples can easily be selected for testing reproducibility. In our research group, seven simple experiments were repeated, using benzaldehyde, urea and ethyl acetoacetate as starting materials.Our study examined the reproducibility of the Biginelli reaction under various conditions using different catalysts. Seven experi-ments were conducted using benzaldehyde, urea, and ethyl ace-toacetate with different catalysts such as HCl, ZnBr2, NH4Cl, LiBr, InCl3, CaF2, and CuI. The results showed that reactions with HCl, ZnBr2, and NH4Cl were reproducible, while those with LiBr, InCl3, CaF2, and CuI showed significant deviations from literature values. The reproducibility of the reaction can be affected by the choice of catalyst and reaction conditions. Some catalysts, such as CaF2 and CuI, were found to be ineffective under the tested conditions.Of course, it cannot be ruled out that other research groups would obtain results different from those given by us in the mentioned experiments. Although, it is worth drawing attention in organic chemistry as well to the fact that the reproducibility of the ex-periments described in the literature is indeed not always easy or perhaps not even possible.

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